Katzung's Basic and Clinical Pharmacology [16 ed.] 1260463311, 9781260463316

Table of contents :
Cover
Contents
Preface
Section I - Basic Principles
1 - Introduction: The Nature of Drugs & Drug Development & Regulation
2 - Drug Receptors & Pharmacodynamics
3 - Pharmacokinetics & Pharmacodynamics: Rational Dosing & the Time Course of Drug Action
4 - Drug Biotransformation
5 - Pharmacogenomics
Section II - Autonomic Drugs
6 - Introduction to Autonomic Pharmacology
7 - Cholinoceptor-Activating & Cholinesterase-Inhibiting Drugs
8 - Cholinoceptor-Blocking Drugs
9 - Adrenoceptor Agonists & Sympathomimetic Drugs
10 - Adrenoceptor Antagonist Drugs
Section III - Cardiovascular-Renal Drugs
11 - Antihypertensive Agents
12 - Vasodilators & the Treatment of Angina Pectoris & Coronary Syndromes
13 - Drugs Used in Heart Failure
14 - Agents Used in Cardiac Arrhythmias
15 - Diuretic Agents
Section IV - Drugs with Important Actions on Smooth Muscle
16 - Histamine, Serotonin, Anti-Obesity Drugs, & the Ergot Alkaloids
17 - Vasoactive Peptides
18 - The Eicosanoids: Prostaglandins, Thromboxanes, Leukotrienes, & Related Compounds
19 - Nitric Oxide
20 - Drugs Used in Asthma & Chronic Obstructive Pulmonary Disease
Section V - Drugs that Act in the Central Nervous System
21 - Introduction to the Pharmacology of CNS Drugs
22 - Sedative-Hypnotic Drugs
23 - The Alcohols
24 - Antiseizure Medications
25 - General Anesthetics
26 - Local Anesthetics
27 - Skeletal Muscle Relaxants
28 - Pharmacologic Management of Parkinsonism & Other Movement Disorders
29 - Antipsychotic Agents & Lithium
30 - Antidepressant Agents
31 - Opioid Agonists & Antagonists
32 - Drugs of Abuse
Section VI - Drugs Used to Treat Diseases on the Blood, Inflammation and Gout
33 - Agents Used in Cytopenias; Hematopoietic Growth Factors
34 - Drugs Used in Disorders of Coagulation
35 - Agents Used in Dyslipidemia
36 - Nonsteroidal Anti-Inflammatory Drugs, Disease-Modifying Antirheumatic Drugs, Nonopioid Analgesics, & Drugs Used in Gout
Section VII - Endocrine Drugs
37 - Hypothalamic & Pituitary Hormones
38 - Thyroid & Antithyroid Drugs
39 - Adrenocorticosteroids & Adrenocortical Antagonists
40 - The Gonadal Hormones & Inhibitors
41 - Pancreatic Hormones & Glucose-Lowering Drugs
42 - Agents That Affect Bone Mineral Homeostasis
Section VIII - Chemotherapeutic Drugs
43 - Beta-Lactam & Other Cell Wall- & Membrane-Active Antibiotics
44 - Tetracyclines, Macrolides, Clindamycin, Chloramphenicol, Streptogramins, Oxazolidinones, & Pleuromutilins
45 - Aminoglycosides & Spectinomycin
46 - Sulfonamides, Trimethoprim, & Quinolones
47 - Antimycobacterial Drugs
48 - Antifungal Agents
49 - Antiviral Agents
50 - Miscellaneous Antimicrobial Agents; Disinfectants, Antiseptics, & Sterilants
51 - Clinical Use of Antimicrobial Agents
52 - Antiprotozoal Drugs
53 - Pharmacology of the Antihelminthic Drugs
54 - Cancer Chemotherapy
55 - Immunopharmacology
Section IX - Toxicology
56 - Introduction to Toxicology: Occupational & Environmental
57 - Heavy Metal Intoxication & Chelators
58 - Management of the Poisoned Patient
Section X - Special Topics
59 - Special Aspects of Perinatal & Pediatric Pharmacology
60 - Special Aspects of Geriatric Pharmacology
61 - Dermatologic Pharmacology
62 - Drugs Used in the Treatment of Gastrointestinal Diseases
63 - Cannabinoid Drugs
64 - Therapeutic & Toxic Potential of Over-the-Counter Agents
65 - Dietary Supplements & Herbal Medications
66 - Rational Prescribing & Prescription Writing
67 - Important Drug Interactions & Their Mechanisms
Appendix 1 - Vaccines, Immune Globulins and other Complex Biologic Products
Appendix 2 - Additional Pharmacology Competencies According to Competency-Based Undergraduate Curriculum
Appendix 3 - Pharmacology Competencies According to CBME Guidelines
Index

Citation preview

a LANGE medical book

Katzung’s Basic & Clinical Pharmacology Sixteenth Edition

Edited by

Todd W. Vanderah, PhD

Regents Professor and Chair Department of Pharmacology University of Arizona College of Medicine, Tucson

New York Chicago San Francisco Athens London Madrid Mexico City Milan New Delhi Singapore Sydney Toronto

Copyright © 2024 by McGraw Hill LLC. All rights reserved. Except as permitted under the Copyright Act of 1976, no part of this publication may be reproduced or distributed in any form or by any means, or stored in a database or retrieval system, without the prior written permission of publisher. ISBN: 978-1-26-046331-6 MHID: 1-26-046331-1 The material in this eBook also appears in the print version of this title: ISBN: 978-1-26-046330-9, MHID: 1-26-046330-3. eBook conversion by codeMantra Version 1.0 All trademarks are trademarks of their respective owners. Rather than put a trademark symbol after every occurrence of a trademarked name, we use names in an editorial fashion only, and to the benefit of the trademark owner, with no intention of infringement of the trademark. Where such designations appear in this book, they have been printed with initial caps. McGraw Hill eBooks are available at special quantity discounts to use as premiums and sales promotions or for use in corporate training programs. To contact a representative, please visit the Contact Us page at www.mhprofessional.com. Notice Medicine is an ever-changing science. As new research and clinical experience broaden our knowledge, changes in treatment and drug therapy are required. The authors and the publisher of this work have checked with sources believed to be reliable in their efforts to provide information that is complete and generally in accord with the standards accepted at the time of publication. However, in view of the possibility of human error or changes in medical sciences, neither the authors nor the publisher nor any other party who has been involved in the preparation or publication of this work warrants that the information contained herein is in every respect accurate or complete, and they disclaim all responsibility for any errors or omissions or for the results obtained from use of the information contained in this work. Readers are encouraged to confirm the information contained herein with other sources. For example and in particular, readers are advised to check the product information sheet included in the package of each drug they plan to administer to be certain that the information contained in this work is accurate and that changes have not been made in the recommended dose or in the contraindications for administration. This recommendation is of particular importance in connection with new or infrequently used drugs. TERMS OF USE This is a copyrighted work and McGraw Hill (“McGraw Hill”) and its licensors reserve all rights in and to the work. Use of this work is subject to these terms. Except as permitted under the Copyright Act of 1976 and the right to store and retrieve one copy of the work, you may not decompile, disassemble, reverse engineer, reproduce, modify, create derivative works based upon, transmit, distribute, disseminate, sell, publish or sublicense the work or any part of it without McGraw Hill’s prior consent. You may use the work for your own noncommercial and personal use; any other use of the work is strictly prohibited. Your right to use the work may be terminated if you fail to comply with these terms. THE WORK IS PROVIDED “AS IS.” McGRAW HILL AND ITS LICENSORS MAKE NO GUARANTEES OR WARRANTIES AS TO THE ACCURACY, ADEQUACY OR COMPLETENESS OF OR RESULTS TO BE OBTAINED FROM USING THE WORK, INCLUDING ANY INFORMATION THAT CAN BE ACCESSED THROUGH THE WORK VIA HYPERLINK OR OTHERWISE, AND EXPRESSLY DISCLAIM ANY WARRANTY, EXPRESS OR IMPLIED, INCLUDING BUT NOT LIMITED TO IMPLIED WARRANTIES OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE. McGraw Hill and its licensors do not warrant or guarantee that the functions contained in the work will meet your requirements or that its operation will be uninterrupted or error free. Neither McGraw Hill nor its licensors shall be liable to you or anyone else for any inaccuracy, error or omission, regardless of cause, in the work or for any damages resulting therefrom. McGraw Hill has no responsibility for the content of any information accessed through the work. Under no circumstances shall McGraw Hill and/or its licensors be liable for any indirect, incidental, special, punitive, consequential or similar damages that result from the use of or inability to use the work, even if any of them has been advised of the possibility of such damages. This limitation of liability shall apply to any claim or cause whatsoever whether such claim or cause arises in contract, tort or otherwise.

Contents Preface  ix Authors xi

S E C T I O N

I

BASIC PRINCIPLES  1   1.  Introduction: The Nature of Drugs & Drug Development & Regulation Todd W. Vanderah, PhD, & Bertram G. Katzung, MD, PhD  1

  2.  Drug Receptors & Pharmacodynamics Mark von Zastrow, MD, PhD  21

  3.  Pharmacokinetics & Pharmacodynamics: Rational Dosing & the Time Course of Drug Action

Nicholas H. G. Holford, MB, ChB, FRACP  42

  4.  Drug Biotransformation

Maria Almira Correia, PhD  57

  5.  Pharmacogenomics

Jennifer E. Hibma, PharmD, & Kathleen M. Giacomini, PhD  77

S E C T I O N

II

AUTONOMIC DRUGS  93   6.  Introduction to Autonomic Pharmacology Todd W. Vanderah, PhD, & Bertram G. Katzung, MD, PhD  93

  7.  Cholinoceptor-Activating & Cholinesterase-Inhibiting Drugs Todd W. Vanderah, PhD  111

  8.  Cholinoceptor-Blocking Drugs Todd W. Vanderah, PhD  129

  9.  Adrenoceptor Agonists & Sympathomimetic Drugs

Italo Biaggioni, MD, & Vsevolod V. Gurevich, PhD  142

10.  Adrenoceptor Antagonist Drugs Italo Biaggioni, MD  161

S E C T I O N

III

CARDIOVASCULAR-RENAL DRUGS 177 11.  Antihypertensive Agents

Neal L. Benowitz, MD  177

12.  Vasodilators & the Treatment of Angina Pectoris & Coronary Syndromes Bertram G. Katzung, MD, PhD  200

13.  Drugs Used in Heart Failure

Bertram G. Katzung, MD, PhD  219

14.  Agents Used in Cardiac Arrhythmias Robert D. Harvey, PhD, & Augustus O. Grant, MD, PhD  235

15.  Diuretic Agents

Ramin Sam, MD, & David Pearce, MD  261

S E C T I O N

IV

DRUGS WITH IMPORTANT ACTIONS ON SMOOTH MUSCLE  287 16.  Histamine, Serotonin, Anti-Obesity Drugs, & the Ergot Alkaloids Bertram G. Katzung, MD, PhD  287

17.  Vasoactive Peptides

Ian A. Reid, PhD  311

18.  The Eicosanoids: Prostaglandins, Thromboxanes, Leukotrienes, & Related Compounds John Hwa, MD, PhD, & Kathleen Martin, PhD  338

v

vi    CONTENTS

19.  Nitric Oxide

Samie R. Jaffrey, MD, PhD  356

20.  Drugs Used in Asthma & Chronic Obstructive Pulmonary Disease Nirav R. Bhakta, MD, PhD, & Eugene Choo, MD  363

S E C T I O N

V

DRUGS THAT ACT IN THE CENTRAL NERVOUS SYSTEM  385

32.  Drugs of Abuse

Christian Lüscher, MD  606

S E C T I O N

VI

DRUGS USED TO TREAT DISEASES OF THE BLOOD, INFLAMMATION, & GOUT  623 33.  Agents Used in Cytopenias; Hematopoietic Growth Factors James L. Zehnder, MD, & Lacrisha J. Go, DNP, FNP-C  623

21.  Introduction to the Pharmacology of CNS Drugs

34.  Drugs Used in Disorders of Coagulation

22.  Sedative-Hypnotic Drugs

35.  Agents Used in Dyslipidemia

John A. Gray, MD, PhD  385

Todd W. Vanderah, PhD  399

23.  The Alcohols

Todd W. Vanderah, PhD, & Anthony J. Trevor, PhD  415

24.  Antiseizure Medications

Michael A. Rogawski, MD, PhD  428

25.  General Anesthetics

Helge Eilers, MD, & Spencer Yost, MD  464

26.  Local Anesthetics

Mohab M. Ibrahim, MD, PhD, & Tally M. Largent-Milnes, PhD  484

27.  Skeletal Muscle Relaxants

Marieke Kruidering-Hall, PhD, & Lundy J. Campbell, MD  499

28.  Pharmacologic Management of Parkinsonism & Other Movement Disorders Michael J. Aminoff, MD, DSc, FRCP  517

29.  Antipsychotic Agents & Lithium Charles DeBattista, MD  537

30.  Antidepressant Agents

Charles DeBattista, MD  558

31.  Opioid Agonists & Antagonists Mark A. Schumacher, MD, PhD, Allan I. Basbaum, PhD, & Ramana K. Naidu, MD  582

James L. Zehnder, MD  640

Mary J. Malloy, MD, & John P. Kane, MD, PhD  659

36.  Nonsteroidal Anti-Inflammatory Drugs, Disease-Modifying Antirheumatic Drugs, Nonopioid Analgesics, & Drugs Used in Gout T. Kevin Kafaja, BA, Sana Anwar, MD, & Daniel E. Furst, MD  674

S E C T I O N

VII

ENDOCRINE DRUGS  703 37.  Hypothalamic & Pituitary Hormones Roger K. Long, MD, & Hakan Cakmak, MD  703

38.  Thyroid & Antithyroid Drugs

Betty J. Dong, PharmD, FASHP, FCSHP, FCCP, FAPHA  723

39.  Adrenocorticosteroids & Adrenocortical Antagonists George P. Chrousos, MD  740

40.  The Gonadal Hormones & Inhibitors George P. Chrousos, MD  757

41.  Pancreatic Hormones & Glucose-Lowering Drugs

Umesh Masharani, MBBS, MRCP (UK), & Lisa Kroon, PharmD, CDCES  785

CONTENTS    vii

42.  Agents That Affect Bone Mineral Homeostasis Daniel D. Bikle, MD, PhD  811

S E C T I O N

VIII

52.  Antiprotozoal Drugs

Philip J. Rosenthal, MD  969

53.  Pharmacology of the Antihelminthic Drugs Philip J. Rosenthal, MD  990

CHEMOTHERAPEUTIC DRUGS  833

54.  Cancer Chemotherapy

43.  Beta-Lactam & Other Cell Wall- & Membrane-Active Antibiotics

55.  Immunopharmacology

Camille E. Beauduy, PharmD, & Lisa G. Winston, MD  834

44.  Tetracyclines, Macrolides, Clindamycin, Chloramphenicol, Streptogramins, Oxazolidinones, & Pleuromutilins Camille E. Beauduy, PharmD, & Lisa G. Winston, MD  855

45.  Aminoglycosides & Spectinomycin Camille E. Beauduy, PharmD, & Lisa G. Winston, MD  868

Edward Chu, MD  1000

Douglas F. Lake, PhD, & Adrienne D. Briggs, MD  1031

S E C T I O N

IX

TOXICOLOGY 1061 56.  Introduction to Toxicology: Occupational & Environmental Alison K. Bauer, PhD  1061

57.  Heavy Metal Intoxication & Chelators Michael J. Kosnett, MD, MPH  1081

46.  Sulfonamides, Trimethoprim, & Quinolones

58.  Management of the Poisoned Patient

47.  Antimycobacterial Drugs

S E C T I O N

Camille E. Beauduy, PharmD, & Lisa G. Winston, MD  877 Camille E. Beauduy, PharmD, & Lisa G. Winston, MD  886

48.  Antifungal Agents

Theora Canonica, PharmD, Jennifer S. Mulliken, MD, Harry W. Lampiris, MD, & Daniel S. Maddix, PharmD  898

49.  Antiviral Agents

Sharon Safrin, MD  910

50.  Miscellaneous Antimicrobial Agents; Disinfectants, Antiseptics, & Sterilants Camille E. Beauduy, PharmD, & Lisa G. Winston, MD  944

51.  Clinical Use of Antimicrobial Agents

Saman Nematollahi, MD, Harry W. Lampiris, MD, & Daniel S. Maddix, PharmD 954

Craig Smollin, MD, & Stephen Petrou, MD  1097

X

SPECIAL TOPICS  1109 59.  Special Aspects of Perinatal & Pediatric Pharmacology

Sean P. Elliott, MD, FAAP, FPIDS, & Gideon Koren, MD, FRCPC, FACMT  1109

60.  Special Aspects of Geriatric Pharmacology Bertram G. Katzung, MD, PhD  1120

61.  Dermatologic Pharmacology

Dirk B. Robertson, MD, Howard I. Maibach, MD, & Rebecca M. Law, PharmD  1131

62.  Drugs Used in the Treatment of Gastrointestinal Diseases George T. Fantry, MD  1153

63.  Cannabinoid Drugs

Todd W. Vanderah, PhD, & Tally M. Largent-Milnes, PhD  1187

viii    CONTENTS

64.  Therapeutic & Toxic Potential of Over-the-Counter Agents

Appendix 1: Vaccines, Immune Globulins, & Other Complex Biologic Products

65.  Dietary Supplements & Herbal Medications

Appendix 2: Additional Pharmacology Competencies According to Competency-Based Undergraduate Curriculum

Valerie B. Clinard, PharmD, & Robin L. Corelli, PharmD  1192

Cathi E. Dennehy, PharmD, & Candy Tsourounis, PharmD  1203

66.  Rational Prescribing & Prescription Writing Paul W. Lofholm, PharmD, & Bertram G. Katzung, MD, PhD  1220

67.  Important Drug Interactions & Their Mechanisms John R. Horn, PharmD, FCCP  1232

Harry W. Lampiris, MD, & Daniel S. Maddix, PharmD  1255

Sangeeta Bhanwra, MD  1263

Appendix 3: Pharmacology Competencies According to CBME Guidelines Sangeeta Bhanwra, MD  1283 Index  1287

Preface The 16th edition of Basic & Clinical Pharmacology will recognize Dr. Bertram Katzung’s legacy of contribution to this book by retitling the book as Katzung’s Basic & Clinical Pharmacology and his mentorship of Dr. Todd W. Vanderah as editor for this edition. This edition continues the extensive use of full-color illustrations and expanded coverage of transporters, pharmacogenomics, and new drugs of all types emphasized in prior editions. The 16th edition also reflects the major expansion of large-molecule drugs in the pharmacopeia, with numerous new monoclonal antibodies and other biologic agents. Case studies accompany most chapters, and answers to questions posed in the case studies appear at the end of each chapter. The book is designed to provide a comprehensive, authoritative, and readable pharmacology textbook for students in the health sciences. This edition continues the sequence used in many pharmacology courses and in integrated curricula: basic principles of drug discovery, pharmacodynamics, pharmacokinetics, and pharmacogenomics; autonomic drugs; cardiovascular-renal drugs; drugs with important actions on smooth muscle; central nervous system drugs; drugs used to treat inflammation, gout, and diseases of the blood; endocrine drugs; chemotherapeutic drugs; toxicology; and special topics. This sequence builds new information on a foundation of information already assimilated. For example, early presentation of autonomic nervous system pharmacology allows students to integrate the physiology and neuroscience they have learned elsewhere with the pharmacology they are learning and prepares them to understand the autonomic effects of other drugs. This is especially important for the cardiovascular and central nervous system drug groups. However, chapters can be used equally well in courses and curricula that present these topics in a different sequence. Within each chapter, emphasis is placed on discussion of drug groups and prototypes rather than offering repetitive detail about individual drugs. Selection of the subject matter and the order of its presentation are based on the accumulated experience of teaching this material to thousands of medical, pharmacy, dental, podiatry, nursing, and other health science students. Health science curricula now place more emphasis on the clinical applications of therapeutic measures. Major features that make this book particularly useful in such curricula include sections that specifically address the clinical choice and use of drugs in patients and the monitoring of their effects—in other words, clinical pharmacology is an integral part of this text. Lists of the trade and generic names of commercial preparations available are provided at the end of each chapter for easy reference by the house officer or practitioner evaluating a patient’s drug list or writing a prescription. The 16th edition includes the novel medications that were quickly designed to prevent and overcome COVID-19 with emphasis on the importance of vaccines and antiviral drugs in pharmacology and clinical medicine.

Significant revisions in this edition include: • Major revisions of the chapters on immunopharmacology; antiseizure, antipsychotic, antidepressant, antidiabetic, antiinflammatory, and antiviral drugs; prostaglandins; and central nervous system neurotransmitters. Major additions on the treatment of COVID have been added in Chapter 49. • Continued expansion of the coverage of general concepts relating to newly discovered receptors, receptor mechanisms, and drug transporters. • Descriptions of important new drugs, especially biologicals, released through January 2022. • Revised illustrations in full color that provide significantly more information about drug mechanisms and effects and help to clarify important concepts. An important related educational resource is Katzung’s Pharmacology: Examination & Board Review, 14th edition (Marieke Kruidering-Hall, Rupa L. Tuan, Todd W. Vanderah, Bertram G. Katzung, eds, McGraw Hill, 2024). This book provides a succinct review of pharmacology with almost 1000 sample examination questions and answers. It is especially helpful to students preparing for board-type examinations. A more highly condensed source of information suitable for review purposes is USMLE Road Map: Pharmacology, 2nd edition (Katzung BG, Trevor AJ: McGraw  Hill, 2006). An extremely useful manual of toxicity due to drugs and other products is Poisoning & Drug Overdose, by Olson KR, ed; 8th edition, McGraw Hill, 2022. The 16th edition marks the 42nd year of publication of Basic & Clinical Pharmacology. The widespread adoption of the first fifteen editions indicates that this book fills an important need. We believe that the 16th edition will satisfy this need even more successfully. Chinese, Croatian, Czech, French, Georgian, Indonesian, Italian, Japanese, Korean, Lithuanian, Portuguese, Spanish, Turkish, and Ukrainian translations of various editions are available. The publisher may be contacted for further information. I wish to acknowledge the prior and continuing efforts of my contributing authors and the major contributions of the staff at Lange Medical Publications, Appleton & Lange, and McGraw Hill, and of our copy editor for this edition, Greg Feldman. I also wish to thank Tasneem Kauser for her contributions. Suggestions and comments about Katzung’s Basic & Clinical Pharmacology are always welcome. They may be sent to me in care of the publisher. Todd W. Vanderah, PhD Tucson, Arizona July 2023 ix

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Authors Michael J. Aminoff, MD, DSc, FRCP Professor, Department of Neurology, University of California, San Francisco Allan I. Basbaum, PhD Professor and Chair, Department of Anatomy and W.M. Keck Foundation Center for Integrative Neuroscience, University of California, San Francisco Camille E. Beauduy, PharmD Assistant Clinical Professor, School of Pharmacy, University of California, San Francisco Neal L. Benowitz, MD Professor of Medicine and Bioengineering & Therapeutic Science, University of California, San Francisco Nirav Bhakta, MD, PhD Associate Professor of Clinical Medicine, University of California, San Francisco Sangeeta Bhanwra, MD Professor, Department of Pharmacology, Government Medical College and Hospital, Chandigarh, India Italo Biaggioni, MD Professor of Pharmacology, Vanderbilt University School of Medicine, Nashville Daniel D. Bikle, MD, PhD Professor of Medicine, Department of Medicine, and Co-Director, Special Diagnostic and Treatment Unit, University of California, San Francisco, and Veterans Affairs Medical Center, San Francisco Adrienne D. Briggs, MD Clinical Director, Bone Marrow Transplant Program, Banner Good Samaritan Hospital, Phoenix Hakan Cakmak, MD Department of Medicine, University of California, San Francisco Lundy Campbell, MD Professor, Department of Anesthesiology and Perioperative Medicine, University of California San Francisco, School of Medicine, San Francisco Theora Canonica, PharmD University of California, San Francisco

Eugene Choo, MD Assistant Clinical Professor, Department of Medicine, University of California San Francisco, School of Medicine, San Francisco George P. Chrousos, MD Professor & Chair, First Department of Pediatrics, Athens University Medical School, Athens, Greece Edward Chu, MD Professor of Medicine and Pharmacology & Chemical Biology; Chief, Division of Hematology-Oncology, Director, University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh Valerie B. Clinard, PharmD Associate Professor, Department of Clinical Pharmacy, School of Pharmacy, University of California, San Francisco Robin L. Corelli, PharmD Clinical Professor, Department of Clinical Pharmacy, School of Pharmacy, University of California, San Francisco Maria Almira Correia, PhD Professor of Pharmacology, Pharmaceutical Chemistry and Biopharmaceutical Sciences, Department of Cellular & Molecular Pharmacology, University of California, San Francisco Charles DeBattista, MD Professor of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford Cathi E. Dennehy, PharmD Professor, Department of Clinical Pharmacy, University of California, San Francisco School of Pharmacy, San Francisco Betty J. Dong, PharmD, FASHP, FCCP, FAPHA Professor of Clinical Pharmacy and Clinical Professor of Family and Community Medicine, Department of Clinical Pharmacy and Department of Family and Community Medicine, Schools of Pharmacy and Medicine, University of California, San Francisco Helge Eilers, MD Professor of Anesthesia and Perioperative Care, University of California, San Francisco Sean P. Elliott, MD Global MD Program, University of Arizona Health Sciences Pediatrics, Tucson Medical Center xi

xii    AUTHORS

George T. Fantry, MD Assistant Vice President, UA/UWA Global MD Program Associate Professor of Medicine, University of Arizona College of Medicine, Tucson Daniel E. Furst, MD Carl M. Pearson Professor of Rheumatology, Director, Rheumatology Clinical Research Center, Department of Rheumatology, University of California, Los Angeles Kathleen M. Giacomini, PhD Professor of Bioengineering and Therapeutic Sciences, Schools of Pharmacy and Medicine, University of California, San Francisco Lacrisha J. Go, DNP, FNP-C Nurse Practitioner, Stanford University Augustus O. Grant, MD, PhD Professor of Medicine, Cardiovascular Division, Duke University Medical Center, Durham John A. Gray, MD, PhD Associate Professor, Department of Neurology, Center for Neuroscience, University of California, Davis Vsevolod V. Gurevich, PhD Cornelius Vanderbilt endowed Chair, Professor of Pharmacology, Vanderbilt University Robert D. Harvey, PhD Professor of Pharmacology and Physiology, University of Nevada School of Medicine, Reno Jennifer E. Hibma, PharmD Department of Bioengineering and Therapeutic Sciences, Schools of Pharmacy and Medicine, University of California, San Francisco Nicholas H. G. Holford, MB, ChB, FRACP Professor, Department of Pharmacology and Clinical Pharmacology, University of Auckland Medical School, Auckland John R. Horn, PharmD, FCCP Professor of Pharmacy, School of Pharmacy, University of Washington; Associate Director of Pharmacy Services, Department of Medicine, University of Washington Medicine, Seattle John Hwa, MD, PhD Professor of Medicine and Pharmacology, Yale University School of Medicine, New Haven Mohab M. Ibrahim, MD, PhD Professor, Department of Anesthesiology, College of Medicine-Tucson Samie R. Jaffrey, MD, PhD Greenberg-Starr Professor of Pharmacology, Department of Pharmacology, Cornell University Weill Medical College, New York City

John P. Kane, MD, PhD Professor of Medicine, Department of Medicine; Professor of Biochemistry and Biophysics; Associate Director, Cardiovascular Research Institute, University of California, San Francisco Bertram G. Katzung, MD, PhD Professor Emeritus, Department of Cellular & Molecular Pharmacology, University of California, San Francisco Michael J. Kosnett, MD, MPH Associate Clinical Professor of Medicine, Division of Clinical Pharmacology and Toxicology, University of Colorado Health Sciences Center, Denver Lisa Kroon, PharmD Professor and Chair, Department of Clinical Pharmacy, School of Pharmacy, University of California San Francisco Marieke Kruidering-Hall, PhD Academy Chair in Pharmacology Education; Professor, Department of Cellular and Molecular Pharmacology, University of California, San Francisco Douglas F. Lake, PhD Professor, The Biodesign Institute, Arizona State University, Tempe Harry W. Lampiris, MD Professor of Clinical Medicine, UCSF, Interim Chief, ID Section, Medical Service, San Francisco VA Medical Center, San Francisco Tally M. Largent-Milnes, PhD Associate Professor, Department of Pharmacology, College of Medicine-Tucson Rebecca M. Law, PharmD School of Pharmacy, Memorial University of Newfoundland Paul W. Lofholm, PharmD Clinical Professor of Pharmacy, School of Pharmacy, University of California, San Francisco Roger K. Long, MD Professor of Pediatrics, Department of Pediatrics, University of California, San Francisco Christian Lüscher, MD Departments of Basic and Clinical Neurosciences, Medical Faculty, University Hospital of Geneva, Geneva, Switzerland Daniel S. Maddix, PharmD1 Associate Clinical Professor of Pharmacy, University of California, San Francisco 1

Deceased

AUTHORS    xiii

Howard I. Maibach, MD Professor of Dermatology, Department of Dermatology, University of California, San Francisco Mary J. Malloy, MD Clinical Professor of Pediatrics and Medicine, Departments of Pediatrics and Medicine, Cardiovascular Research Institute, University of California, San Francisco

Sharon Safrin, MD Associate Clinical Professor, Department of Medicine, University of California, San Francisco; President, Safrin Clinical Research, Hillsborough Ramin Sam, MD Associate Professor, Department of Medicine, University of California, San Francisco

Kathleen Martin, PhD Professor, Yale Cardiovascular Center, Yale University, New Haven

Mark A. Schumacher, PhD, MD Professor, Department of Anesthesia and Perioperative Care, University of California, San Francisco

Umesh Masharani, MBBS, MRCP (UK) Professor of Medicine, Department of Medicine, University of California, San Francisco

Craig Smollin, MD Professor of Emergency Medicine, University of California, San Francisco

Jennifer S. Mulliken, MD Assistant Clinical Professor of Medicine, University of California, San Francisco

Daniel T. Teitelbaum, MD Adjunct Professor of Occupational and Environmental Health, Colorado School of Public Health, Denver; and Adjunct Professor, Civil and Environmental Engineering, Colorado School of Mines, Golden

Ramana K. Naidu, MD Attending Physician, Marin General Hospital, Greenbrae, California Ahmed A. Negm, MD Department of Medicine, University of California, Los Angeles Saman Nematollahi, MD Assistant Professor, Department of Medicine, University of Arizona/Banner, Tucson Martha S. Nolte Kennedy, MD Clinical Professor, Department of Medicine, University of California, San Francisco David Pearce, MD Professor of Medicine, University of California, San Francisco Andrea I. Cesarez Ramirez Research Associate, Division of Rheumatology, UCLA David Geffen School of Medicine, Los Angeles Ian A. Reid, PhD Professor Emeritus, Department of Physiology, University of California, San Francisco Dirk B. Robertson, MD Professor of Clinical Dermatology, Department of Dermatology, Emory University School of Medicine, Atlanta Michael A. Rogawski, MD, PhD Professor of Neurology, Department of Neurology, University of California, Davis Philip J. Rosenthal, MD Professor of Medicine, San Francisco General Hospital, University of California, San Francisco

Anthony J. Trevor, PhD Professor Emeritus, Department of Cellular & Molecular Pharmacology, University of California, San Francisco Candy Tsourounis, PharmD Professor of Clinical Pharmacy, Medication Outcomes Center, University of California, San Francisco School of Pharmacy, San Francisco Todd W. Vanderah, PhD Professor and Chair, Department of Pharmacology, University of Arizona, Tucson Mark von Zastrow, MD, PhD Professor, Departments of Psychiatry and Cellular & Molecular Pharmacology, University of California, San Francisco Lisa G. Winston, MD Clinical Professor, Department of Medicine, Division of Infectious Diseases, University of California, San Francisco; Hospital Epidemiologist, San Francisco General Hospital, San Francisco Spencer Yost, MD Professor, Department of Anesthesia and Perioperative Care, University of California, San Francisco; Medical Director, UCSF-Mt. Zion ICU, Chief of Anesthesia, UCSF-Mt. Zion Hospital, San Francisco James L. Zehnder, MD Professor of Pathology and Medicine, Pathology Department, Stanford University School of Medicine, Stanford

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SECTION I  BASIC PRINCIPLES

C

Introduction: The Nature of Drugs & Drug Development & Regulation

H

1 A

P

T

E

R

Todd W. Vanderah, PhD, & Bertram G. Katzung, MD, PhD

C ASE STUDY A 78-year-old woman is brought to the hospital because of suspected aspirin overdose. She has taken aspirin for joint pain for many years without incident, but during the past year, she has exhibited signs of cognitive decline. Her caregiver finds her confused, hyperventilating, and vomiting. The caregiver finds an empty bottle of aspirin tablets and calls 9-1-1. In the

Pharmacology can be defined as the study of substances that interact with living systems through chemical processes. These interactions usually occur by binding of the substance to regulatory molecules and activating or inhibiting normal body processes. These substances may be chemicals administered to achieve a beneficial therapeutic effect on some process within the patient or for their toxic effects on regulatory processes in parasites infecting the patient. Such deliberate therapeutic applications may be

emergency department, samples of venous and arterial blood are obtained while the airway, breathing, and circulation are evaluated. An intravenous (IV) drip is started, and gastrointestinal decontamination is started. After blood gas results are reported, sodium bicarbonate is administered via the IV. What is the purpose of the sodium bicarbonate?

considered the proper role of medical pharmacology, which is often defined as the science of substances used to prevent, diagnose, and treat disease. Toxicology is the branch of pharmacology that deals with the undesirable effects of chemicals on living systems, from individual cells to humans to complex ecosystems (Figure 1–1). The nature of drugs—their physical properties and their interactions with biological systems—is discussed in part I of this chapter.

1

2    SECTION I  Basic Principles

Pharmacodynamics

Pharmacokinetics

Chemical

Patient

Intended target tissues

Environment

Unintended targets

Other organisms

Food chain Therapeutic effects

Toxic effects Medical pharmacology and toxicology

More organisms Environmental toxicology

FIGURE 1–1  Major areas of study in pharmacology. The actions of chemicals can be divided into two large domains. The first (left side) is that of medical pharmacology and toxicology, which is aimed at understanding the actions of drugs as chemicals on individual organisms, especially humans and domestic animals. Both beneficial and toxic effects are included. Pharmacokinetics deals with the absorption, distribution, and elimination of drugs. Pharmacodynamics concerns the actions of the chemical on the organism. The second domain (right side) is that of environmental toxicology, which is concerned with the effects of chemicals on all organisms and their survival in groups and as species. New drugs are added every year; they are needed for several reasons including: (1) increasing resistance by bacteria and other parasites; (2) discovery of new target processes in diseases that have not been adequately treated; and (3) recognition of new diseases. Furthermore, a dramatic increase has occurred in the number of large molecule drugs (especially antibodies) approved during the last two decades. The development of new drugs and their regulation by government agencies are discussed in part II.

THE HISTORY OF PHARMACOLOGY Prehistoric people undoubtedly recognized the beneficial or toxic effects of many plant and animal materials. Early written records list remedies of many types, including a few that are still recognized as useful drugs today. Most, however, were worthless or actually harmful. Beginning about 1500 years ago, sporadic attempts were made to introduce rational methods into medicine, but none was successful owing to the dominance of systems of thought (“schools”) that purported to explain all of biology and disease without the need for experimentation and observation. These schools promulgated bizarre notions such as the idea that disease was caused by excesses

of bile or blood in the body, that wounds could be healed by applying a salve to the weapon that caused the wound, and so on. Around the end of the 17th century, concepts based on observation and experimentation began to replace theorizing in physiology and clinical medicine. As the value of these methods in the study of disease became clear, physicians in Great Britain and on the Continent began to apply them systematically to the effects of traditional drugs used in their own practices. Thus, materia medica—the science of drug preparation and the medical uses of drugs—began to develop as the precursor to pharmacology. However, any real understanding of the mechanisms of action of drugs was prevented by the absence of methods for purifying active agents from the crude materials that were available and—even more—by the lack of methods for testing hypotheses about the nature of drug actions. In the late 18th and early 19th centuries, François Magendie and his student Claude Bernard began to develop the methods of experimental physiology and pharmacology. Advances in chemistry and the further development of physiology in the 18th, 19th, and early 20th centuries laid the foundation needed for understanding how drugs work at the organ and cellular levels. Paradoxically, real advances in basic pharmacology during this time were accompanied by an outburst of unscientific claims by manufacturers and marketers of worthless “patent medicines.” Not until the concepts of rational therapeutics, especially that of the controlled clinical trial, were reintroduced into medicine—only about 60 years ago—did it become possible to adequately evaluate therapeutic claims. Around the 1940s and 1950s, a major expansion of research efforts in all areas of biology began. As new concepts and new techniques were introduced, information accumulated about drug action and the biologic substrate of that action, the drug receptor. During the last 60 years, many fundamentally new drug groups and new members of old groups have been introduced. The last three decades have seen an even more rapid growth of information and understanding of the molecular basis for drug action. The molecular mechanisms of action of many drugs have now been identified, and numerous receptors have been isolated, structurally characterized, and cloned. In fact, the use of receptor identification methods (described in Chapter 2) has led to the discovery of many orphan receptors—receptors for which no ligand has been discovered and whose function can only be guessed. Studies of the local molecular environment of receptors have shown that receptors and effectors do not function in isolation; they are strongly influenced by other receptors and by companion regulatory proteins. Most recently, it has become clear that gravitational change, radiation, and other aspects of space outside the Earth’s environment require the development of space medicine. This has opened another important area for the future of pharmacology. One result of these discoveries is the confirmation that pharmacology represents an area where anatomy, biochemistry, genetics, physiology, pathology, clinical medicine, and the environment meet. Many problems that the health practitioner confronts can now be corrected or mitigated using pharmacologic tools. Pharmacogenomics—the relation of the individual’s genetic makeup to his or her response to specific drugs—is becoming an important part of therapeutics (see Chapter 5). Decoding of the genomes of many species—from bacteria to humans—has led to

CHAPTER 1  Introduction: The Nature of Drugs & Drug Development & Regulation     3

the recognition of unsuspected relationships between receptor families and the ways that receptor proteins have evolved. Furthermore, discovery of regulatory functions exerted by the neighbors of chromosomes and the noncoding regions of DNA on the expression of exons has opened a new area of possible manipulation of the genes—epigenetics—that control pharmacologic responses. The discovery that small segments of RNA can interfere with protein synthesis with extreme selectivity has led to investigation of small interfering RNAs (siRNAs) and micro-RNAs (miRNAs) as therapeutic agents. Similarly, short nucleotide chains called antisense oligonucleotides (ANOs), synthesized to be complementary to natural RNA or DNA, can interfere with the readout of genes and the transcription of RNA. Recently, the development of mRNA vaccines has led to new medications by activating one’s own immune system to recognize and fight off viruses. New, efficient methods of DNA editing have made possible the modification of genes that encode proteins that are critical to biological function, representing a transformative means of generating medicines. Finally, development in the production of selective monoclonal antibodies to target selective proteins has led to a dramatic increase in large molecule therapeutics in the last 20 years (Table 1–1). Unfortunately, the medication-consuming public is still exposed to vast amounts of inaccurate or unscientific information regarding the pharmacologic effects of chemicals. This results in the irrational use of innumerable expensive, ineffective, and sometimes harmful remedies and the growth of a huge “alternative health care” industry. Furthermore, manipulation of the legislative process in the United States has allowed many substances promoted for health—but not promoted specifically as “drugs”—to avoid meeting the Food and Drug Administration (FDA) standards described in the second part of this chapter. Conversely, lack of understanding of basic scientific principles in biology and statistics and the absence of critical thinking about public health issues have led to rejection of medical science, including vaccines, by a segment of the public and a tendency to assume that all adverse drug effects are the result of malpractice. General principles that the student should remember are (1) that all substances can under certain circumstances be toxic; (2) that the chemicals in botanicals (herbs and plant extracts,

TABLE 1–1  Development of large molecule

therapeutic agents as a percentage of all new drug approvals, 2000–2020.

Year

Total New Drug Approvals

2000

63

3 (5%)

1 (2%)

2008

34

5 (15%)

1 (3%)

2010

49

8 (16%)

4 (8%)

2015

69

13 (19%)

9 (13%)

2017

63

10 (16%)

9 (14%)

2020

61

? (16%)

10 (16%)

MABs, monoclonal antibodies.

New Protein Drugs (~% of new drug approvals)

New MABs (~% of new drug approvals)

“nutraceuticals”) are no different from chemicals in manufactured drugs except for the much greater proportion of impurities in botanicals; and (3) that all dietary supplements and all therapies promoted as health-enhancing should meet the same standards of efficacy and safety as conventional drugs and medical therapies. That is, there should be no artificial separation between scientific medicine and “alternative” or “complementary” medicine. Ideally, all nutritional and botanical substances should be tested by the same types of randomized controlled trials (RCTs) as synthetic compounds.

■■ GENERAL PRINCIPLES OF PHARMACOLOGY THE NATURE OF DRUGS In the most general sense, a drug may be defined as any substance that brings about a change in biologic function through its chemical actions. In most cases, the drug molecule interacts as an agonist (activator) or antagonist (inhibitor) with a specific target molecule that plays a regulatory role in the biologic system. This target molecule is called a receptor. Some of the new large molecule drugs (biologicals) act like receptors themselves and bind endogenous molecules. The nature of receptors is discussed more fully in Chapter 2. In a very small number of cases, drugs known as chemical antagonists may interact directly with other drugs, whereas a few drugs (osmotic agents) interact almost exclusively with water molecules. Drugs may be synthesized within the body (eg, hormones) or may be chemicals not synthesized in the patient’s body (ie, xenobiotics). Poisons are drugs that have almost exclusively harmful effects. However, Paracelsus (1493–1541) famously stated that “the dose makes the poison,” meaning that any substance can be harmful if taken in the wrong dosage. Toxins are usually defined as poisons of biologic origin, ie, synthesized by plants or animals, in contrast to inorganic poisons such as lead and arsenic.

The Physical Nature of Drugs To interact chemically with its receptor, a drug molecule must have the appropriate size, electrical charge, shape, and atomic composition. Furthermore, a drug is often administered at a location distant from its intended site of action, eg, a pill taken orally to relieve a headache. Therefore, a useful drug must have the necessary properties to be transported from its site of administration to its site of action. Finally, a practical drug should be inactivated or excreted from the body at a reasonable rate so that its actions will be of appropriate duration. Drugs may be solid at room temperature (eg, aspirin, atropine), liquid (eg, nicotine, ethanol), or gaseous (eg, nitrous oxide, isoflurane, xenon). These factors often determine the best route of administration. The most common routes of administration are described in Chapter 3, Table 3–3. The various classes of organic compounds—carbohydrates, proteins, lipids, and smaller molecules—are all represented in pharmacology. As noted above,

4    SECTION I  Basic Principles

many proteins and some new mRNA vaccines have been approved while some oligonucleotides have also received approval for use depending on the country’s regulation agencies. A number of inorganic elements, eg, fluoride, lithium, iron, and heavy metals, are both useful and dangerous drugs. Many organic drugs are weak acids or bases. This fact has important implications for the way they are handled by the body, because pH differences in the various compartments of the body may alter the degree of ionization of weak acids and bases (see text that follows).

Drug Size The molecular size of drugs varies from very small (lithium ion, molecular weight [MW] 7) to very large (eg, alteplase [t-PA], a protein of MW 59,050). Many antibodies are even larger; eg, erenumab, an antibody used in the management of migraine, has a MW of more than 145,000. However, most drugs have molecular weights between 100 and 1000. The lower limit of this narrow range is probably set by the requirements for specificity of action. To have a good “fit” to only one type of receptor, a drug molecule must be sufficiently unique in shape, charge, and other properties to prevent its binding to other receptors. To achieve such selective binding, it appears that a molecule should in most cases be at least 100 MW units in size. The upper limit in molecular weight is determined primarily by the requirement that most drugs must be able to move within the body (eg, from the site of administration to the site of action and then to the site of elimination). Drugs much larger than MW 1000 do not diffuse readily between compartments of the body (discussed under Permeation, in following text). Therefore, very large drugs (usually proteins) must often be administered directly into the compartment where they have their effect. In the case of alteplase, a clot-dissolving enzyme, it is administered directly into the vascular compartment by intravenous or intra-arterial infusion.

Drug Reactivity & Drug-Receptor Bonds Drugs interact with receptors by means of chemical forces or bonds. These are of three major types: covalent, electrostatic, and hydrophobic. Covalent bonds are very strong and in many cases not reversible under biologic conditions. Thus, the covalent bond formed between the acetyl group of acetylsalicylic acid (aspirin) and cyclooxygenase, its enzyme target in platelets, is not readily broken. The platelet aggregation–blocking effect of aspirin lasts long (days) after free acetylsalicylic acid has disappeared from the bloodstream (about 15 minutes) and is reversed only by the synthesis of new enzyme in new platelets, a process that takes several days. Other examples of highly reactive, covalent bond-forming drugs include the DNA-alkylating agents used in cancer chemotherapy to disrupt cell division in the tumor. Electrostatic bonding is much more common than covalent bonding in drug-receptor interactions. Electrostatic bonds vary from relatively strong linkages between permanently charged ionic molecules to weaker hydrogen bonds and very weak induced dipole interactions such as van der Waals forces and similar phenomena. Electrostatic bonds are weaker than covalent bonds.

Hydrophobic bonds are usually quite weak and are probably important in the interactions of highly lipid-soluble drugs with the lipids of cell membranes and perhaps in the interaction of drugs with the internal walls of receptor “pockets.” The specific nature of a particular drug-receptor bond is of less practical importance than the fact that drugs that bind through weak bonds to their receptors are generally more selective than drugs that bind by means of very strong bonds. This is because weak bonds require a very precise fit of the drug to its receptor if an interaction is to occur. Only a few receptor types are likely to provide such a precise fit for a particular drug structure. Thus, if we wished to design a highly selective drug for a particular receptor, we would avoid highly reactive molecules that form covalent bonds and instead choose a molecule that forms weaker bonds. A few substances that are almost completely inert in the chemical sense nevertheless have significant pharmacologic effects. For example, xenon, an “inert” gas, has anesthetic effects at elevated pressures.

Drug Shape The shape of a drug molecule must be such as to permit binding to its target site via the bonds just described. Optimally, the drug’s shape is complementary to that of the target site (usually a receptor) in the same way that a key is complementary to a lock. Furthermore, the phenomenon of chirality (stereoisomerism) is so common in biology that more than half of all useful drugs are chiral molecules; that is, they can exist as enantiomeric pairs. Drugs with two asymmetric centers have four diastereomers, eg, ephedrine, a sympathomimetic drug. In most cases, one of these enantiomers is much more potent than its mirror image enantiomer, reflecting a better fit to the receptor molecule. If one imagines the receptor site to be like a glove into which the drug molecule must fit to bring about its effect, it is clear why a “left-oriented” drug is more effective in binding to a lefthand receptor than its “right-oriented” enantiomer. The more active enantiomer at one type of receptor site may not be more active at another receptor type, eg, a type that may be responsible for some other effect. For example, carvedilol, a drug that interacts with adrenoceptors, has a single chiral center and thus two enantiomers (Table 1–2). One of these enantiomers, the (S)(–) isomer, is a potent β-receptor blocker. The (R)(+) isomer is 100-fold weaker at the β receptor. However, the isomers are approximately equipotent as α-receptor blockers. Ketamine, a chiral molecule with two isomers, was introduced as an anesthetic. When administered as

TABLE 1–2  Dissociation constants (Kd) of the

enantiomers and racemate of carvedilol.

Form of Carvedilol

α Receptors (Kd, nmol/L1)

β Receptors (Kd, nmol/L)

(R)(+) enantiomer

14

45

(S)(−) enantiomer

16

0.4

(R,S)(±) enantiomers

11

0.9

1

The Kd is the concentration for 50% saturation of the receptors and is inversely proportionate to the affinity of the drug for the receptors. Data from Ruffolo RR Jr, Gellai M, Hieble JP, et al: The Pharmacology of carvedilol. Eur J Clin Pharmacol 1990;38S2:S82-88.

CHAPTER 1  Introduction: The Nature of Drugs & Drug Development & Regulation     5

an anesthetic, the racemic mixture is administered intravenously. In contrast, the (S) enantiomer has recently been approved for use in nasal spray form as a rapid-acting antidepressant. Finally, because enzymes are usually stereoselective, one drug enantiomer is often more susceptible than the other to drugmetabolizing enzymes. As a result, the duration of action of one enantiomer may be quite different from that of the other. Similarly, drug transporters may be stereoselective. Unfortunately, most studies of clinical efficacy and drug elimination in humans have been carried out with racemic mixtures of drugs rather than with the separate enantiomers. At present, less than half of the chiral drugs used clinically are marketed as the active isomer—the rest are available only as racemic mixtures. As a result, a majority of patients receive drug doses of which 50% is less active or inactive. A few drugs are currently available in both the racemic and the pure, active isomer forms. However, proof that administration of the pure, active enantiomer decreases adverse effects relative to those produced by racemic formulations has not been established.

Rational Drug Design Rational design of drugs implies the ability to predict the appropriate molecular structure of a drug on the basis of information about its biologic receptor. Until recently, no receptor was known in sufficient detail to permit such drug design. Instead, drugs were developed through random testing of chemicals or modification of drugs already known to have some effect. However, the characterization of many receptors during the past three decades has changed this picture. A few drugs now in use were developed through molecular design based on knowledge of the three-dimensional structure of the receptor site. Computer programs are now available that can iteratively optimize drug structures to fit known receptors. As more becomes known about receptor structure, rational drug design will become more common.

Receptor Nomenclature The spectacular success of newer, more efficient ways to identify and characterize receptors (see Chapter 2) has resulted in a variety of differing, and sometimes confusing, systems for naming them. This in turn has led to a number of suggestions regarding more rational methods of naming receptors. The interested reader is referred for details to the efforts of the International Union of Pharmacology (IUPHAR) Committee on Receptor Nomenclature and Drug Classification (reported in various issues of Pharmacological Reviews and elsewhere) and to Alexander SP et al: The Concise guide to pharmacology 2017/18: Overview. Br J Pharmacol 2017;174:S1. The chapters in this book mainly use these sources for naming receptors.

DRUG-BODY INTERACTIONS The interactions between a drug and the body are conveniently divided into two classes. The actions of the drug on the body are termed pharmacodynamic processes (see Figure 1–1); the principles of pharmacodynamics are presented in greater detail in Chapter 2.

These properties determine the group in which the drug is classified, and they play the major role in deciding whether that group is appropriate therapy for a particular symptom or disease. The actions of the body on the drug are called pharmacokinetic processes and are described in Chapters 3 and 4. Pharmacokinetic processes govern the absorption, distribution, and elimination of drugs and are of great practical importance in the choice and administration of a particular drug for a particular patient, eg, a patient with heart failure who also has impaired renal function. The following paragraphs provide a brief introduction to pharmacodynamics and pharmacokinetics.

Pharmacodynamic Principles Most drugs must bind to a receptor to bring about an effect. However, at the cellular level, drug binding is only the first in a sequence of possible steps: •  Drug (D) + receptor-effector (R) → drug-receptor-effector complex → effect •  D + R → drug-receptor complex → effector molecule → effect •  D + R → D-R complex → activation of coupling molecule → effector molecule → effect •  Inhibition of metabolism of endogenous activator → increased activator action on an effector molecule → increased effect Note that the final change in function is accomplished by an effector mechanism. The effector may be part of the receptor molecule or may be a separate molecule. A very large number of receptors communicate with their effectors through coupling molecules, as described in Chapter 2. A.  Types of Drug-Receptor Interactions Agonist drugs bind to and activate the receptor in some fashion, which directly or indirectly brings about the effect (Figure 1–2A). Receptor activation involves a change in conformation in the cases that have been studied at the molecular structure level. Some receptors incorporate effector machinery in the same molecule, so that drug binding brings about the effect directly, eg, opening of an ion channel or activation of enzyme activity. Other receptors are linked through one or more intervening coupling molecules to a separate effector molecule. The major types of drug-receptor-effector coupling systems are discussed in Chapter 2. Pharmacologic antagonist drugs, by binding to a receptor, compete with and prevent binding by other molecules. For example, acetylcholine receptor blockers such as atropine are antagonists because they prevent access of acetylcholine and similar agonist drugs to the acetylcholine receptor site and they stabilize the receptor in its inactive state (or some state other than the acetylcholine-activated state). These agents reduce the effects of acetylcholine and similar molecules in the body (Figure 1–2B), but their action can be overcome by increasing the dosage of agonist. Some antagonists bind very tightly to the receptor site in an irreversible or pseudoirreversible fashion and cannot be displaced by increasing the agonist concentration. Drugs that bind to the same receptor molecule but do not prevent binding of the agonist are said to act allosterically and may enhance (Figure 1–2C) or inhibit (Figure 1–2D) the action of

6    SECTION I  Basic Principles

Drug

Receptor

Effects

A

+

– B

Response

Agonist

A+C

A alone

A+B A+D

Competitive inhibitor

Log Dose

C

Allosteric activator

D

Allosteric inhibitor

FIGURE 1–2  Drugs may interact with receptors in several ways. The effects resulting from these interactions are diagrammed in the doseresponse curves at the right. Drugs that alter the agonist (A) response may activate the agonist binding site, compete with the agonist (competitive inhibitors, B), or act at separate (allosteric) sites, increasing (C) or decreasing (D) the response to the agonist. Allosteric activators (C) may increase the efficacy of the agonist or its binding affinity. The curve shown reflects an increase in efficacy; an increase in affinity would result in a leftward shift of the curve. the agonist molecule. Allosteric inhibition is not usually overcome by increasing the dose of agonist. B.  Agonists That Inhibit Their Binding Molecules Some drugs mimic agonist drugs by inhibiting the molecules responsible for terminating the action of an endogenous agonist. For example, acetylcholinesterase inhibitors, by slowing the destruction of endogenous acetylcholine, cause cholinomimetic effects that closely resemble the actions of cholinoceptor agonist molecules even though cholinesterase inhibitors do not bind or only incidentally bind to cholinoceptors (see Chapter 7). Because they amplify the effects of physiologically released endogenous agonist ligands, their effects are sometimes more selective and less toxic than those of exogenous agonists. C.  Agonists, Partial Agonists, and Inverse Agonists Figure 1–3 describes a useful model of drug-receptor interactions. As indicated, the receptor is postulated to exist partially in the inactive, nonfunctional form (Ri) and partially in the activated

form (Ra). Thermodynamic considerations indicate that even in the absence of any agonist, some of the receptor pool must exist in the Ra form some of the time and may produce the same physiologic effect as agonist-induced activity. This effect, occurring in the absence of agonist, is termed constitutive or basal activity. Agonists have a much higher affinity for the Ra configuration and stabilize it, so that a large percentage of the total pool resides in the Ra–D fraction and a large effect is produced. The recognition of constitutive activity may depend on the receptor density, the concentration of coupling molecules (if a coupled system), and the number of effectors in the system. Many agonist drugs, when administered at concentrations sufficient to saturate the receptor pool, can activate their receptoreffector systems to the maximum extent of which the system is capable; that is, they cause a shift of almost all of the receptor pool to the Ra–D pool. Such drugs are termed full agonists. Other drugs, called partial agonists, bind to the same receptors and activate them in the same way but do not evoke as great a response, no matter how high the concentration. In the model in

CHAPTER 1  Introduction: The Nature of Drugs & Drug Development & Regulation     7

Effect

Ra

Ri D

Ri – D

D

Ra – D Effect

Ra + Da

Response

Full agonist

Ra + Dpa Partial agonist

Ra + Ri Constitutive activity

Ra + Dant + Ri + Dant Antagonist Ri + Di

Inverse agonist

Log Dose

FIGURE 1–3  A model of drug-receptor interaction. The hypothetical receptor is able to assume two conformations. In the Ri conformation, it is inactive and produces no effect, even when combined with a drug molecule. In the Ra conformation, the receptor can activate downstream mechanisms that produce a small observable effect, even in the absence of drug (constitutive activity). In the absence of drugs, the two isoforms are in equilibrium, and the Ri form is favored. Conventional full agonist drugs have a much higher affinity for the Ra conformation, and mass action thus favors the formation of the Ra–D complex with a much larger observed effect. Partial agonists have an intermediate affinity for both Ri and Ra forms. Conventional antagonists, according to this hypothesis, have equal affinity for both receptor forms and maintain the same level of constitutive activity. Inverse agonists, on the other hand, have a much higher affinity for the Ri form, reduce constitutive activity, and may produce a contrasting physiologic result. Figure 1–3, partial agonists do not stabilize the Ra configuration as fully as full agonists, so that a significant fraction of receptors exists in the Ri–D pool. Such drugs are said to have low intrinsic efficacy. Because they occupy the same receptor site, partial agonists can also prevent access by full agonists. Thus, pindolol, a β-adrenoceptor partial agonist, may act either as an agonist (if no full agonist is present) or as an antagonist (if a full agonist such as epinephrine is present). (See Chapter 2.) Intrinsic efficacy is independent of affinity (as usually measured) for the receptor. In the same model, conventional antagonist action can be explained as fixing the fractions of drug-bound Ri and Ra in the same relative amounts as in the absence of any drug. In this situation, no change in activity will be observed, so the drug will appear

to be without effect. However, the presence of the antagonist at the receptor site will block access of agonists to the receptor and prevent the usual agonist effect. Such blocking action can be termed neutral antagonism. What will happen if a drug has a much stronger affinity for the Ri than for the Ra state and stabilizes a large fraction in the Ri–D pool? In this scenario the drug will reduce any constitutive activity, thus resulting in effects that are the opposite of the effects produced by conventional agonists at that receptor. Such drugs are termed inverse agonists (see Figure 1–3). One of the best documented examples of such a system is the γ-aminobutyric acid (GABAA) receptor-effector (a chloride channel) in the nervous system. This receptor is activated by the endogenous transmitter GABA and causes inhibition of postsynaptic cells. Conventional exogenous agonists such as benzodiazepines also facilitate the receptor-effector system and enhance GABA-like chloride entry into cells with sedation as the therapeutic result. This sedation can be reversed by conventional neutral antagonists such as flumazenil. Inverse agonists of this receptor system cause anxiety and agitation, the inverse of sedation (see Chapter 22). Similar inverse agonists have been found for β adrenoceptors, histamine H1 and H2 receptors, and several other receptor systems. D.  Duration of Drug Action Termination of drug action can result from several processes. In some cases, the effect lasts only as long as the drug occupies the receptor, and dissociation of drug from the receptor automatically terminates the effect. In many cases, however, the action may persist after the drug has dissociated because, for example, some coupling molecule is still present in activated form. In the case of drugs that bind covalently to the receptor site, the effect may persist until the drug-receptor complex is destroyed and new receptors or enzymes are synthesized, as described previously for aspirin. In addition, many receptor-effector systems incorporate desensitization mechanisms for preventing excessive activation when agonist molecules continue to be present for long periods. (See Chapter 2 for additional details.) E.  Receptors and Inert Binding Sites To function as a receptor, an endogenous molecule must first be selective in choosing ligands (drug molecules) to bind; and second, it must change its function upon binding in such a way that the function of the biologic system (cell, tissue, etc) is altered. The selectivity characteristic is required to avoid constant activation of the receptor by promiscuous binding of many different ligands. The ability to change function is clearly necessary if the ligand is to cause a pharmacologic effect. In some cases the function of the ligand may be to inhibit the endogenous actions of the receptor (antagonist and inverse agonist). The body contains a vast array of molecules that are capable of binding drugs, however, and not all of these endogenous molecules are regulatory molecules. Binding of a drug to a nonregulatory molecule such as plasma albumin will result in no detectable change in the function of the biologic system, so this endogenous molecule can be called an inert binding site. Such binding is not completely without significance, however, because it affects the

8    SECTION I  Basic Principles

Lumen

Interstitium

A

B

C

D

FIGURE 1–4  Mechanisms of drug permeation. Drugs may diffuse passively through aqueous channels in the intercellular junctions (eg, tight junctions, A), or through lipid cell membranes (B). Drugs with the appropriate characteristics may be transported by carriers into or out of cells (C). Very impermeant drugs may also bind to cell surface receptors (dark binding sites), be engulfed by the cell membrane (endocytosis), and then be released inside the cell or expelled via the membrane-limited vesicles out of the cell into the extracellular space (exocytosis, D). distribution of drug within the body and determines the amount of free drug in the circulation. Both of these factors are of pharmacokinetic importance (see also Chapter 3).

Pharmacokinetic Principles In practical therapeutics, a drug should be able to reach its intended site of action after administration by some convenient route. In many cases, the active drug molecule is sufficiently lipid-soluble and stable to be given as such. In some cases, however, an inactive precursor chemical that is readily absorbed and distributed must be administered and then converted to the active drug by biologic processes—inside the body. Such a precursor chemical is called a prodrug. In only a few situations is it possible to apply a drug directly to its target tissue, eg, by topical application of an anti-inflammatory agent to inflamed skin or mucous membrane. Most often, a drug is administered into one body compartment, eg, the gut, and must move to its site of action in another compartment, eg, the brain in the case of an antiseizure medication. This requires that the drug be absorbed into the blood from its site of administration and distributed to its site of action, permeating through the various barriers that separate these compartments. For a drug given orally to produce an effect in the central nervous system, these barriers include the tissues that make up the wall of the intestine, the walls of the capillaries that perfuse the gut, and the blood-brain barrier, the walls of the capillaries that perfuse the brain. Finally, after bringing about its effect, a drug should be eliminated at a reasonable rate by metabolic inactivation, by excretion from the body, or by a combination of these processes. A. Permeation Drug permeation proceeds by several mechanisms. Passive diffusion in an aqueous or lipid medium is common, but active processes play a role in the movement of many drugs, especially those whose molecules are too large to diffuse readily (Figure 1–4). Drug vehicles can be very important in facilitating transport and permeation, eg, by encapsulating the active agent in liposomes and in regulating release, as in slow release preparations. Newer methods of facilitating transport of drugs by coupling them to nanoparticles are under investigation.

1. Aqueous diffusion—Aqueous diffusion occurs within the larger aqueous compartments of the body (interstitial space, cytosol, etc) and across epithelial membrane tight junctions and the endothelial lining of blood vessels through aqueous pores that—in some tissues—permit the passage of molecules as large as MW 20,000–30,000.* See Figure 1–4A. Aqueous diffusion of drug molecules is usually driven by the concentration gradient of the permeating drug, a downhill movement described by Fick’s law (see below). Drug molecules that are bound to large plasma proteins (eg, albumin) do not permeate most vascular aqueous pores. If the drug is charged, its flux is also influenced by electrical fields (eg, the membrane potential and— in parts of the nephron—the transtubular potential). 2. Lipid diffusion—Lipid diffusion is the most important limiting factor for drug permeation because of the large number of lipid barriers that separate the compartments of the body. Because these lipid barriers separate aqueous compartments, the lipid:aqueous partition coefficient of a drug determines how readily the molecule moves between aqueous and lipid media. In the case of weak acids and weak bases (which gain or lose electrical charge-bearing protons, depending on the pH), the ability to move from aqueous to lipid or vice versa varies with the pH of the medium, because charged molecules attract water molecules. The ratio of lipid-soluble form to water-soluble form for a weak acid or weak base is expressed by the Henderson-Hasselbalch equation (described in the following text). See Figure 1–4B. 3. Special carriers—Special carrier molecules exist for many substances that are important for cell function and are too large or too insoluble in lipid to diffuse passively through membranes, eg, peptides, amino acids, and glucose. These carriers bring about movement by active transport or facilitated diffusion and, unlike passive diffusion, are selective, saturable, and inhibitable. Because * The capillaries of the brain, the testes, and some other tissues are characterized by the absence of pores that permit aqueous diffusion. They may also contain high concentrations of drug export pumps (MDR pump molecules; see text). These tissues are therefore protected or “sanctuary” sites from many circulating drugs.

CHAPTER 1  Introduction: The Nature of Drugs & Drug Development & Regulation     9

many drugs are or resemble such naturally occurring peptides, amino acids, or sugars, they can use these carriers to cross membranes. See Figure 1–4C. Many cells also contain less selective membrane carriers that are specialized for expelling foreign molecules. One large family of such transporters binds adenosine triphosphate (ATP) and is called the ABC (ATP-binding cassette) family. This family includes the P-glycoprotein or multidrug resistance type 1 (MDR1) transporter found in the brain, testes, and other tissues and in some drug-resistant neoplastic cells (Table 1–3). Similar transport molecules from the ABC family, the multidrug resistance-associated protein (MRP) transporters, play important roles in the excretion of some drugs or their metabolites into urine and bile and in the resistance of some tumors to chemotherapeutic drugs. Genomic variation in the expression of these transporters has a profound effect on sensitivity to these drugs (see Chapter 5). Several other transporter families have been identified that do not bind ATP but use ion gradients to drive transport. Some of these (the solute carrier [SLC] family) are particularly important in the uptake of neurotransmitters across nerve-ending membranes. The latter carriers are discussed in more detail in Chapter 6.

TABLE 1–3  Some transport molecules important in pharmacology.

Physiologic Function

Pharmacologic Significance

NET

Norepinephrine reuptake from synapse

Target of cocaine and some tricyclic antidepressants

SERT

Serotonin reuptake from synapse

Target of selective serotonin reuptake inhibitors and some tricyclic antidepressants

VMAT

Transport of dopamine and norepinephrine into adrenergic vesicles in nerve endings

Target of reserpine and tetrabenazine

MDR1

Transport of many xenobiotics out of cells

Increased expression confers resistance to certain anticancer drugs; inhibition increases blood levels of digoxin

MRP1

Leukotriene secretion

Confers resistance to certain anticancer and antifungal drugs

OCT

Organic cationic compound uptake

Target for uptake of organic cationic compounds (acetylcholine, dopamine, norepinephrine, metformin, etc) into many tissues including the brain, liver, heart, kidney

OATP

Organic anionic and neutral compound uptake

Target for uptake of organic anionic compounds (prostaglandins, hormones, bile salts, statins, etc) into many tissues including the brain, liver, kidney, intestine

Transporter

MDR1, multidrug resistance protein-1; MRP1, multidrug resistance-associated protein-1; NET, norepinephrine transporter; OATP, organic anionic transporter polypeptide; OCT, organic cationic transporter; SERT, serotonin reuptake transporter; VMAT, vesicular monoamine transporter.

4. Endocytosis and exocytosis—A few substances are so large or impermeant that they can enter cells only by endocytosis, the process by which the substance is bound at a cell-surface receptor, engulfed by the cell membrane, and carried into the cell by pinching off of the newly formed vesicle inside the membrane. The substance can then be released into the cytosol by breakdown of the vesicle membrane (see Figure 1–4D). This process is responsible for the transport of vitamin B12, complexed with a binding protein (intrinsic factor) across the wall of the gut into the blood. Similarly, iron is transported into hemoglobinsynthesizing red blood cell precursors in association with the protein transferrin. Specific receptors for the binding proteins must be present for this process to work. The reverse process (exocytosis) is responsible for the secretion of many substances from cells. For example, many neurotransmitter substances are stored in membrane-bound vesicles in nerve endings to protect them from metabolic destruction in the cytoplasm. Appropriate activation of the nerve ending causes fusion of the storage vesicle with the cell membrane and expulsion of its contents into the extracellular space (see Chapter 6). B.  Fick’s Law of Diffusion The passive flux of molecules down a concentration gradient is given by Fick’s law: Flux (moles per unit time) =

where C1 is the higher concentration, C2 is the lower concentration, area is the cross-sectional area of the diffusion path, permeability coefficient is a measure of the mobility of the drug molecules in the medium of the diffusion path, and thickness is the length of the diffusion path. In the case of lipid diffusion, the lipid:aqueous partition coefficient is a major determinant of mobility of the drug because it determines how readily the drug enters the lipid membrane from the aqueous medium. C. Ionization of Weak Acids and Weak Bases; the Henderson-Hasselbalch Equation The electrostatic charge of an ionized molecule attracts water dipoles and results in a polar, relatively water-soluble and lipidinsoluble complex. Because lipid diffusion depends on relatively high lipid solubility, ionization of drugs may markedly reduce their ability to permeate membranes. A very large percentage of the drugs in use are weak acids or weak bases; Table 1–4 lists some examples. For drugs, a weak acid is best defined as a neutral molecule that can reversibly dissociate into an anion (a negatively charged molecule) and a proton (a hydrogen ion). For example, aspirin dissociates as follows:

A weak base can be defined as a neutral molecule that can form a cation (a positively charged molecule) by combining with a

10    SECTION I  Basic Principles

TABLE 1–4  Ionization constants of some common drugs. Drug

pKa1

Drug

pKa1

Drug

pKa1

Weak acids

 

Weak bases

 

Weak bases (cont’d)

 

 Acetaminophen

9.5

  Albuterol (salbutamol)

9.3

 Isoproterenol

8.6

 Acetazolamide

7.2

 Allopurinol

9.4, 12.32

 Lidocaine

7.9

 Ampicillin

2.5

 Alprenolol

9.6

 Metaraminol

8.6

 Aspirin

3.5

 Amiloride

8.7

 Methadone

8.4

 Atorvastatin

4.3

 Amiodarone

6.6

 Methamphetamine

10.0

 Chlorothiazide

6.8, 9.42

 Amphetamine

9.8

 Methyldopa

10.6

 Chlorpropamide

5.0

 Atropine

9.7

 Metoprolol

9.8

 Ciprofloxacin

6.1, 8.7

 Bupivacaine

8.1

 Morphine

7.9

 Cromolyn

2.0

 Chlordiazepoxide

4.6

 Nicotine

7.9, 3.12

  Ethacrynic acid

2.5

 Chloroquine

10.8, 8.4

 Norepinephrine

8.6

 Furosemide

3.9

 Chlorpheniramine

9.2

 Pentazocine

7.9

 Ibuprofen

4.4, 5.22

 Chlorpromazine

9.3

 Phenylephrine

9.8

 Levodopa

2.3

 Clonidine

8.3

 Physostigmine

7.9, 1.8

 Methotrexate

4.8

 Cocaine

8.5

 Pilocarpine

6.9, 1.42

 Methyldopa

2.2, 9.22

 Codeine

8.2

 Pindolol

8.6

 Penicillamine

1.8

 Cyclizine

8.2

 Procainamide

9.2

 Pentobarbital

8.1

 Desipramine

10.2

 Procaine

9.0

 Phenobarbital

7.4

 Diazepam

3.0

 Promethazine

9.1

 Phenytoin

8.3

 Diphenhydramine

8.8

 Propranolol

9.4

 Propylthiouracil

8.3

 Diphenoxylate

7.1

 Pseudoephedrine

9.8

  Salicylic acid

3.0

 Ephedrine

9.6

 Pyrimethamine

7.0–7.33

 Sulfadiazine

6.5

 Epinephrine

8.7

 Quinidine

8.5, 4.42

 Sulfapyridine

8.4

 Ergotamine

6.3

 Scopolamine

8.1

 Theophylline

8.8

 Fluphenazine

8.0, 3.92

 Strychnine

8.0, 2.32

 Tolbutamide

5.3

 Hydralazine

7.1

 Terbutaline

10.1

 Warfarin

 5.0

 Imipramine

9.5

 Thioridazine

9.5

2

2

1

The pKa is that pH at which the concentrations of the ionized and nonionized forms are equal.

2

More than one ionizable group.

3

Isoelectric point.

proton. For example, pyrimethamine, an antimalarial drug, undergoes the following association-dissociation process:

Note that the protonated form of a weak acid is the neutral, more lipid-soluble form, whereas the unprotonated form of a weak base is the neutral form. The law of mass action requires that these reactions move to the left in an acid environment (low pH, excess protons available) and to the right in an alkaline environment. The Henderson-Hasselbalch equation relates the ratio of protonated to unprotonated weak acid or weak base to the molecule’s pKa and the pH of the medium as follows:

This equation applies to both acidic and basic drugs. Inspection confirms that the lower the pH relative to the pKa, the greater will be the fraction of drug in the protonated form. Because the uncharged form is the more lipid-soluble, more of a weak acid will be in the lipid-soluble form at acid pH, whereas more of a basic drug will be in the lipid-soluble form at alkaline pH. Application of this principle is made in the manipulation of drug excretion by the kidney (see Case Study). Almost all drugs are filtered at the glomerulus. If a drug is in a lipid-soluble form during its passage down the renal tubule, a significant fraction will be reabsorbed back into the tissue by simple passive diffusion. If the goal is to accelerate excretion of the drug (eg, in a case of drug overdose), it is important to prevent its reabsorption from the tubule. This can often be accomplished by adjusting urine pH to make certain that most of the drug is in the ionized state, as shown in Figure 1–5. As a result of this partitioning effect, the drug is “trapped” in the urine. Thus, weak acids are usually excreted faster in alkaline urine; weak bases are

CHAPTER 1  Introduction: The Nature of Drugs & Drug Development & Regulation     11

Cells of the nephron

Interstitium pH 7.4

Lipid diffusion

H R

0.001 mg

N

H

Urine pH 6.0 H R

N

H

H+

H+

H 0.398 mg

0.001 mg

R

N

H +

H

H 0.399 mg total

R

N

+

H

10 mg

H 10 mg total

FIGURE 1–5  Trapping of a weak base (methamphetamine) in the urine when the urine is more acidic than the blood. In the hypothetical case illustrated, the diffusible uncharged form of the drug has equilibrated across the membrane, but the total concentration (charged plus uncharged) in the urine (more than 10 mg) is 25 times higher than in the blood (0.4 mg). usually excreted faster in acidic urine. Other body fluids in which pH differences from blood pH may cause trapping or reabsorption are the contents of the stomach (normal pH 1.9–3) and small intestine (pH 7.5–8), breast milk (pH 6.4–7.6), aqueous humor (pH 6.4–7.5), and vaginal and prostatic secretions (pH 3.5–7). As indicated by Table 1–4, a large number of drugs are weak bases. Most of these bases are amine-containing molecules. The nitrogen of a neutral amine has three atoms associated with it plus a pair of unshared electrons (see the display that follows). The three atoms may consist of one carbon or a chain of carbon atoms (designated “R”) and two hydrogens (a primary amine), two carbons and one hydrogen (a secondary amine), or three carbon atoms (a tertiary amine). Each of these three forms may reversibly bind a proton with the unshared electrons. Some drugs have a fourth carbon-nitrogen bond; these are quaternary amines. However, the quaternary amine is permanently charged and has no unshared electrons with which to reversibly bind a proton. Therefore, primary, secondary, and tertiary amines may undergo reversible protonation and vary their lipid solubility with pH, but quaternary amines are always in the poorly lipid-soluble charged form.

DRUG GROUPS To learn each pertinent fact about each of the many hundreds of drugs mentioned in this book would be an impractical goal and, fortunately, is unnecessary. Almost all the several thousand drugs

currently available can be arranged into about 70 groups. Many of the drugs within each group are very similar in pharmacodynamic actions and in their pharmacokinetic properties as well. For most groups, one or two prototype drugs can be identified that typify the most important characteristics of the group. This permits classification of other important drugs in the group as variants of the prototype, so that only the prototype must be learned in detail and, for the remaining drugs, only the differences from the prototype.

■■ DRUG DEVELOPMENT & REGULATION A truly new drug (one that does not simply mimic the structure and action of previously available drugs) requires the discovery of a new drug target, ie, the pathophysiologic process or substrate of a disease. Such discoveries are usually made in public sector institutions (universities and research institutes), and molecules that have beneficial effects on such targets are often discovered in the same laboratories. However, the development of new drugs usually takes place in industrial laboratories because optimization of a class of new drugs requires painstaking and expensive chemical, pharmacologic, and toxicologic research. In fact, much of the recent progress in the application of drugs to disease problems can be ascribed to the pharmaceutical industry including “big pharma,” the multibillion-dollar corporations that specialize in drug development and marketing. These companies are uniquely skilled in translating basic findings into successful therapeutic breakthroughs and profit-making “blockbusters” (see https://clincalc.com/DrugStats/Top200Drugs.aspx). Such breakthroughs come at a price, however, and the escalating cost of drugs has become a significant contributor to the increase in the cost of health care. Development of new drugs is enormously

12    SECTION I  Basic Principles

expensive, but considerable controversy surrounds drug pricing. Drug prices in the United States have increased many-fold faster than overall price inflation. Critics claim that the costs of development and marketing drugs are grossly inflated by marketing activities, advertising, and other promotional efforts, which may consume as much as 25% or more of a company’s budget. Furthermore, profit margins for big pharma are relatively high. Recent drug-pricing scandals have been reported in which the rights to an older, established drug that requires no costly development have been purchased by a smaller company and the price increased by several hundred or several thousand percent. This “price gouging” has caused public outrage and attracted regulatory attention that may result in more legitimate and rational pricing mechanisms. Finally, pricing schedules for many drugs vary dramatically from country to country and even within countries, where large organizations can negotiate favorable prices and small ones cannot. Some countries have already addressed these inequities, and it seems likely that all countries will have to do so during the next few decades.

drug metabolism, pharmacokinetic profiles, and relative safety of the drug are recommended to be characterized in vivo in animals before human drug trials can be started but not necessary if studies can be carried out in cells or alternative approaches. With regulatory approval, human testing may then go forward (usually in three phases) before the drug is considered for approval for general use. A fourth phase of data gathering and safety monitoring is becoming increasingly important and follows after approval for marketing. Once approved, the great majority of drugs become available for use by any appropriately licensed practitioner. Highly toxic drugs that are nevertheless considered valuable in lethal diseases may be approved for restricted use by practitioners who have undergone special training in their use and who maintain detailed records.

DRUG DISCOVERY Most new drugs or drug products are discovered or developed through the following approaches: (1) screening for biologic activity of large numbers of natural products, banks of previously discovered chemical entities, or large libraries of peptides, nucleic acids, and other organic molecules; (2) chemical modification of a known active molecule, resulting in a “me-too” analog; (3) identification or elucidation of a new drug target, which suggests molecules that will hit that target; and (4) rational design of a new molecule based on an understanding of biologic mechanisms and drug receptor structure. Steps (3) and (4) are often carried out in academic research laboratories and are more likely to lead to breakthrough drugs, but the costs of steps (1) and (2) usually ensure that industry carries them out. Once a new drug target or promising molecule has been identified, the process of moving from the basic science laboratory to the clinic begins. This translational research involves the preclinical and clinical

NEW DRUG DEVELOPMENT The development of a new drug usually begins with the discovery or synthesis of a potential new drug compound or the elucidation of a new drug target. After a new drug molecule is synthesized or extracted from a natural source, subsequent steps seek an understanding of the drug’s interactions with its biologic targets. Repeated application of this approach leads to synthesis of related compounds with increased efficacy, potency, and selectivity (Figure 1–6). In the United States, the safety and efficacy of drugs must be established before marketing can be legally carried out. In addition to in vitro studies, relevant biologic effects, In vitro studies

Clinical testing

Animal testing Phase 1

Biologic products

20–100 subjects

(Is it safe, pharmacokinetics?)

Phase 2 Lead compound

Chemical synthesis, optimization

0

100–200 patients

Efficacy, selectivity, mechanism

2 Years (average)

Marketing Generics become available

(Does it work in patients?)

Phase 3 (Does it work, double blind?) 1000–6000 patients

Phase 4 (Postmarketing surveillance)

Drug metabolism, safety assessment

4 IND (Investigational New Drug)

8–9 NDA (New Drug Application)

20 (Patent expires 20 years after filing of application)

FIGURE 1–6  The development and testing process required to bring a drug to market in the USA. Some of the requirements may be different for drugs used in life-threatening diseases (see text).

CHAPTER 1  Introduction: The Nature of Drugs & Drug Development & Regulation     13

steps described next. While clinical trials in humans are required only for drugs to be used in humans, all of the other steps described apply to veterinary drugs as well as drugs for human diseases.

Drug Screening Drug screening involves a variety of assays at the molecular, cellular, organ system, and whole animal levels to define the pharmacologic profile, ie, the activity and selectivity of the drug. The type and number of initial screening tests depend on the pharmacologic and therapeutic goal. For example, anti-infective drugs are tested against a variety of infectious organisms, some of which are resistant to standard agents; hypoglycemic drugs are tested for their ability to lower blood sugar, etc. The candidate molecule is also studied for a broad array of other actions to determine the mechanism of action and selectivity of the drug. This can reveal both expected and unexpected toxic effects. Occasionally, an unexpected therapeutic action is serendipitously discovered by a careful observer; for example, the era of modern diuretics was initiated by the observation that certain antimicrobial sulfonamides caused metabolic acidosis in patients. The selection of compounds for development is most efficiently conducted in animal models of human disease. Where good predictive preclinical models exist (eg, infection, hypertension, or thrombotic disease), we generally have good or excellent drugs. Good drugs or breakthrough improvements are conspicuously lacking and slow for diseases for which preclinical models are poor or not yet available, eg, autism and Alzheimer disease. At the molecular level, the candidate compound would be screened for activity on the target, for example, receptor binding affinity to cell membranes containing the homologous animal receptors (or if possible, on the cloned human receptors). Early studies would be done to predict effects that might later cause undesired drug metabolism or toxicologic complications. For example, studies on liver cytochrome P450 enzymes would be performed to determine whether the molecule of interest is likely to be a substrate or inhibitor of these enzymes or to alter the metabolism of other drugs. Effects on cell function determine whether the drug is an agonist, partial agonist, inverse agonist, or antagonist at relevant receptors. Isolated tissues would be used to characterize the pharmacologic activity and selectivity of the new compound in comparison with reference compounds. Comparison with other drugs would also be undertaken in a variety of in vivo studies. At each step in this process, the compound would have to meet specific performance and selectivity criteria to be carried further. Whole animal studies are generally necessary to determine the effect of the drug on organ systems and disease models. Cardiovascular and renal function studies of new drugs are generally first performed in normal animals. Studies on disease models, if available, are then performed. For a candidate antihypertensive drug, animals with hypertension would be treated to see whether blood pressure was lowered in a dose-related manner and to characterize other effects of the compound. Evidence would be collected on duration of action and efficacy after oral and parenteral administration. If the agent possessed useful activity, it would be further

studied for possible adverse effects on other organs, including the respiratory, gastrointestinal, renal, endocrine, and central nervous systems. These studies might suggest the need for further chemical modification (compound optimization) to achieve more desirable pharmacokinetic or pharmacodynamic properties. For example, oral administration studies might show that the drug was poorly absorbed or rapidly metabolized in the liver; modification to improve bioavailability might be indicated. If the drug is to be administered long term, an assessment of tolerance development would be made. For drugs related to or having mechanisms of action similar to those known to cause physical or psychological dependence in humans, ability to cause dependence in animals would also be studied. Drug interactions would be examined. The desired result of this screening procedure (which may have to be repeated several times with congeners of the original molecule) is a lead compound, ie, a leading candidate for a successful new drug. A patent application would be filed for a novel compound (a composition of matter patent) that is efficacious, or for a new and nonobvious therapeutic use (a use patent) for a previously known chemical entity.

PRECLINICAL SAFETY & TOXICITY TESTING All chemicals are toxic in some individuals at some dose. Candidate drugs that survive the initial screening procedures must be carefully evaluated for potential risks before and during clinical testing. Depending on the proposed use of the drug, preclinical toxicity testing includes most or all of the procedures shown in Table 1–5. Although no chemical can be certified as completely “safe” (free of risk), the objective is to estimate the risk associated with exposure to the drug candidate and to consider this in the context of therapeutic needs and likely duration of drug use. The goals of preclinical toxicity studies include identifying potential human toxicities, designing tests to further define the toxic mechanisms, and predicting the most relevant toxicities to be monitored in clinical trials. In addition to the studies shown in Table 1–5, several quantitative estimates are desirable. These include the no-effect dose—the maximum dose at which a specified toxic effect is not seen; the minimum lethal dose— the smallest dose that is observed to kill any experimental animal; and, if necessary, the median lethal dose (LD50)—the dose that kills approximately 50% of the animals in a test group. Presently, the LD50 is estimated from the smallest number of animals possible. These doses are used to calculate the initial dose to be tried in humans, usually taken as one hundredth to one tenth of the no-effect dose in animals. It is important to recognize the limitations of preclinical testing. These include the following: 1. Toxicity testing is time-consuming and expensive. Two to 6 years may be required to collect and analyze data on toxicity before the drug can be considered ready for testing in humans.

14    SECTION I  Basic Principles

TABLE 1–5  Safety tests. Type of Test

Approach and Goals

Acute toxicity

Usually two species, two routes. Determine the no-effect dose and the maximum tolerated dose. In some cases, determine the acute dose that is lethal in approximately 50% of animals.

Subacute or subchronic toxicity

Three doses, two species. Two weeks to 3 months of testing may be required before clinical trials. The longer the duration of expected clinical use, the longer the subacute test. Determine biochemical, physiologic effects.

Chronic toxicity

Rodent and at least one nonrodent species for ≥6 months. Required when drug is intended to be used in humans for prolonged periods. Usually run concurrently with clinical trials. Determine same end points as subacute toxicity tests.

Effect on reproductive performance

Two species, usually one rodent and rabbits. Test effects on animal mating behavior, reproduction, parturition, progeny, birth defects, postnatal development.

Carcinogenic potential

Two years, two species. Required when drug is intended to be used in humans for prolonged periods. Determine gross and histologic pathology.

Mutagenic potential

Test effects on genetic stability and mutations in bacteria (Ames test) or mammalian cells in culture; dominant lethal test and clastogenicity in mice.

2. Large numbers of animals may be needed to obtain valid preclinical data. Scientists are properly concerned about this situation, and progress has been made toward reducing the numbers required while still obtaining valid data. Cell and tissue culture in vitro methods and computer modeling are increasingly being used, but their predictive value is still limited. Nevertheless, some segments of the public attempt to halt all animal testing in the unfounded belief that it has become unnecessary. 3. Extrapolations of toxicity data from animals to humans are reasonably predictive for many but not for all toxicities. 4. For statistical reasons, rare adverse effects are unlikely to be detected in preclinical testing.

EVALUATION IN HUMANS A very small fraction of lead compounds reach clinical trials, and less than one-third of the drugs studied in humans survive clinical trials and reach the marketplace. Federal law in the USA and ethical considerations require that the study of new drugs in humans be conducted in accordance with stringent guidelines. Scientifically valid results are not guaranteed simply by conforming to government regulations, however, and the design and execution of a good clinical trial require interdisciplinary personnel including basic scientists, clinical pharmacologists, clinician specialists, statisticians, and others. The current standard for clinical trials is known as the randomized controlled trial (RCT) and is described below. The need for careful design and execution is based on three major confounding factors inherent in the study of any drug in humans.

Confounding Factors in Clinical Trials A.  The Variable Natural History of Most Diseases Many diseases tend to wax and wane in severity; some disappear spontaneously, even, on occasion, cancer. A good experimental design takes into account the natural history of the disease by evaluating a large enough population of subjects over a sufficient period of time. Further protection against errors of interpretation caused by disease fluctuations is sometimes provided by using a crossover design, which consists of alternating periods of administration of test drug, placebo preparation (the control), and the previous standard treatment (positive control), if any, in each subject. These sequences are systematically varied so that different subsets of patients receive each of the possible sequences of treatment. B.  The Presence of Other Diseases and Risk Factors Known and unknown diseases and risk factors (including lifestyles of subjects) may influence the results of a clinical study. For example, some diseases alter the pharmacokinetics of drugs (see Chapters 3 through 5). Other drugs and some foods alter the pharmacokinetics of many drugs. Concentrations of blood or tissue components being monitored as a measure of the effect of the new agent may be influenced by other diseases or other drugs. Attempts to avoid this hazard usually involve the crossover technique (when feasible) and proper selection and assignment of patients to each of the study groups. This requires obtaining accurate diagnostic tests and medical and pharmacologic histories (including use of recreational drugs, over-the-counter drugs, and “supplements”) and the use of statistically valid methods of randomization in assigning subjects to particular study groups. There is growing interest in analyzing genetic variations as part of the trial that may influence whether a person responds to a particular drug. It has been shown that age, gender, and pregnancy influence the pharmacokinetics of some drugs, but these factors have not been adequately studied because of legal restrictions and reluctance to expose these populations to unknown risks. C.  Subject and Observer Bias and Other Factors Most patients tend to respond in a positive way to any therapeutic intervention by interested, caring, and enthusiastic medical personnel. The manifestation of this phenomenon in the subject is the placebo response (Latin, “I shall please”) and may involve objective physiologic and biochemical changes as well as changes in subjective complaints associated with the disease. The placebo response is usually quantitated by administration of an inert material with exactly the same physical appearance, odor, consistency, etc, as the active dosage form. The magnitude of the response varies considerably from patient to patient and may also be influenced by the duration of the study. In some conditions, a positive response may be noted in as many as 30–40% of subjects given placebo. Placebo adverse effects and “toxicity” also occur but usually involve subjective effects: stomach upset, insomnia, sedation, and so on. Subject bias effects can be quantitated—and minimized relative to the response measured during active therapy—by the single-blind design. This involves use of a placebo as described above, administered to the same subjects in a crossover design, if possible, or to a separate control group of well-matched subjects.

CHAPTER 1  Introduction: The Nature of Drugs & Drug Development & Regulation     15

Observer bias can be taken into account by disguising the identity of the medication being used—placebo or active form—from both the subjects and the personnel evaluating the subjects’ responses (double-blind design). In this design, a third party holds the code identifying each medication packet, and the code is not broken until all the clinical data have been collected. Drug effects seen in clinical trials are obviously affected by the patient taking the drugs at the dose and frequency

prescribed. In a recent phase 2 study, one-third of the patients who said they were taking the drug were found by blood analysis to have not taken the drug. Confirmation of compliance with protocols (also known as adherence) is a necessary element to consider. The various types of studies and the conclusions that may be drawn from them are described in the accompanying text box. (See Box: Drug Studies—The Types of Evidence.)

Drug Studies—The Types of Evidence* As described in this chapter, drugs are studied in a variety of ways, from 30-minute test tube experiments with isolated enzymes and receptors to decades-long observations of populations of patients. The conclusions that can be drawn from such different types of studies can be summarized as follows. Basic research is designed to answer specific, usually single, questions under tightly controlled laboratory conditions, eg, does drug x inhibit enzyme y? The basic question may then be extended, eg, if drug x inhibits enzyme y, what is the concentration-response relationship? Such experiments are usually reproducible and often lead to reliable insights into the mechanism of the drug’s action. First-in-human studies include phase 1–3 trials. Once a drug receives FDA approval for use in humans, case reports and case series consist of observations by clinicians of the effects of drug (or other) treatments in one or more patients. These results often reveal unpredictable benefits and toxicities but do not generally test a prespecified hypothesis and cannot prove cause and effect. Analytic epidemiologic studies consist of observations designed to test a specified hypothesis, eg, that thiazolidinedione antidiabetic drugs are associated with adverse cardiovascular events. Cohort epidemiologic studies utilize populations of patients that have (exposed group) and have not (control group) been exposed to the agents under study and ask whether the exposed groups show a higher or lower incidence of the effect. Casecontrol epidemiologic studies utilize populations of patients that have displayed the end point under study and ask whether they

have been exposed or not exposed to the drugs in question. Such epidemiologic studies add weight to conjectures but cannot control all confounding variables and therefore cannot conclusively prove cause and effect. Meta-analyses utilize rigorous evaluation and grouping of similar studies to increase the number of subjects studied and hence the statistical power of results obtained in multiple published studies. While the numbers may be dramatically increased by meta-analysis, the individual studies still suffer from their varying methods and end points, and a meta-analysis cannot prove cause and effect. Large randomized controlled trials (RCTs) are designed to answer specific questions about the effects of medications on clinical end points or important surrogate end points, using large enough samples of patients and allocating them to control and experimental treatments using rigorous randomization methods. Randomization is the best method for distributing all foreseen confounding factors, as well as unknown confounders, equally between the experimental and control groups. When properly carried out, such studies are rarely invalidated and are considered the gold standard in evaluating drugs. A critical factor in evaluating the data regarding a new drug is access to all the data. Unfortunately, many large studies are never published because the results are negative, ie, the new drug is not better than the standard therapy. This missing data phenomenon falsely exaggerates the benefits of new drugs because negative results are hidden.

*

We thank Ralph Gonzales, MD, for helpful comments.

The Food & Drug Administration The FDA is the administrative body that oversees the drug evaluation process in the USA and grants approval for marketing of new drug products. To receive FDA approval for marketing, the originating institution or company (almost always the latter) must submit evidence of safety and effectiveness. Outside the USA, the regulatory and drug approval process is generally similar to that in the USA. As its name suggests, the FDA is also responsible for certain aspects of food safety, a role it shares with the US Department of Agriculture (USDA). Shared responsibility results in complications when questions arise regarding the use of drugs, eg, antibiotics, in

food animals. A different type of problem arises when so-called food supplements are found to contain active drugs, eg, sildenafil analogs in “energy food” supplements. The FDA’s authority to regulate drugs derives from specific legislation (Table 1–6). If a drug has not been shown through adequately controlled testing to be “safe and effective” for a specific use, it cannot be marketed in interstate commerce for this use.* *

Although the FDA does not directly control drug commerce within states, a variety of state and federal laws control interstate production and marketing of drugs.

16    SECTION I  Basic Principles

TABLE 1–6  Some major legislation pertaining to drugs in the USA. Law

Purpose and Effect

Pure Food and Drug Act of 1906

Prohibited mislabeling and adulteration of drugs.

Opium Exclusion Act of 1909

Prohibited importation of opium.

Amendment (1912) to the Pure Food and Drug Act

Prohibited false or fraudulent advertising claims.

Harrison Narcotic Act of 1914

Established regulations for use of opium, opiates, and cocaine (marijuana added in 1937).

Food, Drug, and Cosmetic Act of 1938

Required that new drugs be safe as well as pure (but did not require proof of efficacy). Enforcement by the FDA.

Durham-Humphrey Act of 1952

Vested in the FDA the power to determine which products could be sold without prescription.

Kefauver-Harris Amendments (1962) to the Food, Drug, and Cosmetic Act

Required proof of efficacy as well as safety for new drugs and for drugs released since 1938; established guidelines for reporting of information about adverse reactions, clinical testing, and advertising of new drugs.

Comprehensive Drug Abuse Prevention and Control Act (1970)

Outlined strict controls in the manufacture, distribution, and prescribing of habit-forming drugs; established drug schedules and programs to prevent and treat drug addiction.

Orphan Drug Amendment of 1983

Provided incentives for development of drugs that treat diseases with fewer than 200,000 patients in the USA.

Drug Price Competition and Patent Restoration Act of 1984

Abbreviated new drug applications for generic drugs. Required bioequivalence data. Patent life extended by amount of time drug delayed by FDA review process. Cannot exceed 5 extra years or extend to more than 14 years post-NDA approval.

Prescription Drug User Fee Act (1992, reauthorized 2007, 2012)

Manufacturers pay user fees for certain new drug applications. “Breakthrough” products may receive special category approval after expanded phase 1 trials (2012).

Dietary Supplement Health and Education Act (1994)

Established standards with respect to dietary supplements but prohibited full FDA review of supplements and botanicals as drugs. Required the establishment of specific ingredient and nutrition information labeling that defines dietary supplements and classifies them as part of the food supply but allows unregulated advertising.

Bioterrorism Act of 2002

Enhanced controls on dangerous biologic agents and toxins. Seeks to protect safety of food, water, and drug supply.

Food and Drug Administration Amendments Act of 2007

Granted the FDA greater authority over drug marketing, labeling, and direct-to-consumer advertising; required post-approval studies, established active surveillance systems, made clinical trial operations and results more visible to the public.

Biologics Price Competition and Innovation Act of 2009

Authorized the FDA to establish a program of abbreviated pathways for approval of “biosimilar” biologics (generic versions of monoclonal antibodies, etc).

FDA Safety and Innovation Act of 2012

Renewed FDA authorization for accelerated approval of urgently needed drugs; established new accelerated process, “breakthrough therapy,” in addition to “priority review,” “accelerated approval,” and “fast-track” procedures.

Drug Quality and Security Act of 2013

Granted the FDA more authority to regulate and monitor the manufacturing of compounded drugs.

Unfortunately, “safe” can mean different things to the patient, the physician, and society. Complete absence of risk is impossible to demonstrate, but this fact may not be understood by members of the public, who frequently assume that any medication sold with the approval of the FDA should be free of serious “side effects.” This confusion is a major factor in litigation and dissatisfaction with aspects of drugs and medical care. The history of drug regulation in the USA (see Table 1–6) reflects several health events that precipitated major shifts in public opinion. For example, the Federal Food, Drug, and Cosmetic Act of 1938 was largely a reaction to deaths associated with the use of a preparation of sulfanilamide marketed before it and its vehicle were adequately tested. Similarly, the Kefauver-Harris Amendments of 1962 were, in part, the result of a teratogenic drug disaster involving thalidomide. This agent was introduced in Europe in 1957–1958 and was marketed as a “nontoxic” hypnotic and promoted as being especially useful as a sleep aid during pregnancy. In 1961, reports

were published suggesting that thalidomide was responsible for a dramatic increase in the incidence of a rare birth defect called phocomelia, a condition involving shortening or complete absence of the arms and legs. Epidemiologic studies provided strong evidence for the association of this defect with thalidomide use by women during the first trimester of pregnancy, and the drug was withdrawn from sale worldwide. An estimated 10,000 children were born with birth defects because of maternal exposure to this one agent. The tragedy led to the requirement for more extensive testing of new drugs for teratogenic effects and stimulated passage of the KefauverHarris Amendments of 1962, even though the drug was not then approved for use in the USA. Despite its disastrous fetal toxicity and effects in pregnancy, thalidomide is a relatively safe drug for humans other than the fetus. Even the most serious risk of toxicities may be avoided or managed if understood, and despite its toxicity, thalidomide is now approved by the FDA for limited use as a potent immunoregulatory agent and to treat certain forms of leprosy.

CHAPTER 1  Introduction: The Nature of Drugs & Drug Development & Regulation     17

Clinical Trials: The IND & NDA Once a new drug is judged ready to be studied in humans, a Notice of Claimed Investigational Exemption for a New Drug (IND) must be filed with the FDA (see Figure 1–6). The IND includes (1) information on the composition and source of the drug, (2) chemical and manufacturing information, (3) all data from animal studies, (4) proposed plans for clinical trials, (5) the names and credentials of physicians who will conduct the clinical trials, and (6) a compilation of the key preclinical data relevant to study of the drug in humans that have been made available to investigators and their institutional review boards. It often requires 4–6 years of clinical testing to accumulate and analyze all required data. Testing in humans is begun only after sufficient acute and subacute animal toxicity studies have been completed. Chronic safety testing in animals, including carcinogenicity studies, is usually done concurrently with clinical trials. In each phase of the clinical trials, volunteers or patients must be informed of the investigational status of the drug as well as the possible risks and must be allowed to decline or to consent to participate and receive the drug. In addition to the approval of the sponsoring organization and the FDA, an interdisciplinary institutional review board (IRB) at each facility where the clinical drug trial will be conducted must review and approve the scientific and ethical plans for testing in humans. In phase 1, the effects of the drug as a function of dosage are established in a small number (20–100) of healthy volunteers. If the drug is expected to have significant toxicity, as may be the case in cancer and AIDS therapy, volunteer patients with the disease participate in phase 1 rather than normal volunteers. Phase 1 trials are done to determine the probable limits of the safe clinical dosage range. These trials may be nonblind or “open”; that is, both the investigators and the subjects know what is being given. Alternatively, they may be “blinded” and placebo controlled. Many predictable toxicities are detected in this phase. Pharmacokinetic measurements of absorption, half-life, and metabolism are often done. Phase 1 studies are usually performed in research centers by specially trained clinical pharmacologists. In phase 2, the drug is studied in patients with the target disease to determine its efficacy (“proof of concept” studies), and the doses to be used in any follow-on trials. A modest number of patients (100–200) are studied in detail. A single-blind design may be used, with an inert placebo medication and an established active drug (positive control) in addition to the investigational agent. Phase 2 trials are usually done in special clinical centers (eg, university hospitals). A broader range of toxicities may be detected in this phase. Phase 2 trials have the highest rate of drug failures, and only 25% of innovative drugs move on to phase 3. In phase 3, the drug is evaluated in much larger numbers— usually thousands—of patients with the target disease to further establish and confirm safety and efficacy. Using information gathered in phases 1 and 2, phase 3 trials are designed to minimize errors caused by placebo effects, variable course of the disease, etc. Therefore, double-blind and crossover techniques are often used. Phase 3 trials are usually performed in settings similar to those anticipated for the ultimate use of the drug. Phase 3 studies can be difficult to

design and execute and are usually expensive because of the large numbers of patients involved and the masses of data that must be collected and analyzed. The drug is formulated as intended for the market. The investigators are usually specialists in the disease being treated. Certain toxic effects, especially those caused by immunologic processes, may first become apparent in phase 3. If phase 3 results meet expectations, application is made for permission to market the new agent. Marketing approval requires submission of a New Drug Application (NDA)—or for biologicals, a Biological License Application (BLA)—to the FDA. The application contains, often in hundreds of volumes, full reports of all preclinical and clinical data pertaining to the drug under review. The number of subjects studied in support of new drug applications has been increasing and currently averages more than 5000 patients for new drugs of novel structure (new molecular entities). The duration of the FDA review leading to approval (or denial) of the new drug application may vary from months to years. If problems arise, eg, unexpected but possibly serious toxicities, additional studies may be required and the review process may extend to several additional years. Many phase 2 and phase 3 studies attempt to measure a new drug’s “noninferiority” to the placebo or a standard treatment. Interpretation of the results may be difficult because of unexpected confounding variables, loss of subjects from some groups, or realization that results differ markedly between certain subgroups within the active treatment (new drug) group. Older statistical methods for evaluating drug trials often fail to provide definitive answers when these problems arise. Therefore, new “adaptive” statistical methods are under development that allow changes in the study design when interim data evaluation indicates the need. Preliminary results with such methods suggest that they may allow decisions regarding superiority as well as noninferiority, shortening of trial duration, discovery of new therapeutic benefits, and more reliable conclusions regarding the results (see Bhatt & Mehta, 2016). In cases of urgent need (eg, cancer chemotherapy), the process of preclinical and clinical testing and FDA review may be accelerated. For serious diseases, the FDA may permit extensive but controlled marketing of a new drug before phase 3 studies are completed; for life-threatening diseases, it may permit controlled marketing even before phase 2 studies have been completed. “Fast track,” “priority approval,” and “accelerated approval” are FDA programs that are intended to speed entry of new drugs into the marketplace. In 2012, an additional special category of “breakthrough” products (eg, for cystic fibrosis) was approved for restricted marketing after expanded phase 1 trials (see Table 1–6). Roughly 50% of drugs in phase 3 trials enter early, controlled marketing. Such accelerated approval is usually granted with the requirement that careful monitoring of the effectiveness and toxicity of the drug be carried out and reported to the FDA. Unfortunately, FDA enforcement of this requirement has not always been adequate. Once approval to market a drug has been obtained, phase 4 begins. This constitutes monitoring the safety of the new drug under actual conditions of use in large numbers of patients. The importance of careful and complete reporting of toxicity by physicians after marketing begins can be appreciated by noting that

18    SECTION I  Basic Principles

many important drug-induced effects have an incidence of 1 in 10,000 or less and that some adverse effects may become apparent only after chronic dosing. The sample size required to disclose drug-induced events or toxicities is very large for such rare events. For example, several hundred thousand patients may have to be exposed before the first case is observed of a toxicity that occurs with an average incidence of 1 in 10,000. Therefore, low-incidence drug effects are not generally detected before phase 4 no matter how carefully phase 1, 2, and 3 studies are executed. Phase 4 has no fixed duration. As with monitoring of drugs granted accelerated approval, phase 4 monitoring has often been lax. The time from the filing of a patent application (which usually precedes clinical trials) to approval for marketing of a new drug may be 5 years or considerably longer. Since the lifetime of a patent is 20 years in the USA, the owner of the patent (usually a pharmaceutical company) has exclusive rights for marketing the product for only a limited time after approval of the new drug application. Because the FDA review process itself can be lengthy (300–500 days for evaluation of an NDA), the time consumed by the review is sometimes added to the patent life. However, the extension (up to 5 years) cannot increase the total life of the patent to more than 14 years after approval of a new drug application. The Patient Protection and Affordable Care Act of 2010 provides for 12 years of patent protection for new drugs. After expiration of the patent, any company may produce the drug, file an abbreviated new drug application (ANDA), demonstrate required equivalence, and, with FDA approval, market the drug as a generic product without paying license fees to the original patent owner. Currently, more than half of prescriptions in the USA are for generic drugs. Even biotechnology-based drugs such as antibodies and other proteins are now qualifying for generic (“biosimilar”) designation, and this has fueled regulatory concerns. More information on drug patents is available at the FDA website at http://www.fda.gov/ Drugs/DevelopmentApprovalProcess/ucm079031.htm. A trademark is a drug’s proprietary trade name and is usually registered; this registered name may be legally protected as long as it is used. A generically equivalent product, unless specially licensed, cannot be sold under the trademark name and is often designated by the official generic name. Generic prescribing is described in Chapter 66.

Conflicts of Interest Several factors in the development and marketing of drugs result in conflicts of interest. Use of pharmaceutical industry funding to support FDA approval processes raises the possibility of conflicts of interest within the FDA. Supporters of this practice point out that chronic FDA underfunding by the government allows for few alternatives. Another important source of conflicts of interest is the dependence of the FDA on outside panels of experts who are recruited from the scientific and clinical community to advise the government agency on questions regarding drug approval or withdrawal. Such experts are often recipients of grants from the companies producing the drugs in question. The need for favorable data in the new drug application leads to phase 2 and 3 trials in which the new agent is compared only to placebo, not to older, effective

drugs. As a result, data regarding the efficacy and toxicity of the new drug relative to a known effective agent may not be available when the new drug is first marketed. Manufacturers promoting a new agent may pay physicians to use it in preference to older drugs with which they are more familiar. Manufacturers sponsor small and often poorly designed clinical studies after marketing approval and aid in the publication of favorable results but may retard publication of unfavorable results. The need for physicians to meet continuing medical education (CME) requirements in order to maintain their licenses encourages manufacturers to sponsor conferences and courses, often in highly attractive vacation sites, and new drugs are often featured in such courses. The common practice of distributing free samples of new drugs to practicing physicians has both positive and negative effects. The samples allow physicians to try out new drugs without incurring any cost to the patient. On the other hand, new drugs are usually much more expensive than older agents, and when the free samples run out, the patient (or insurance carrier) may be forced to pay much more for treatment than if the older, cheaper, and possibly equally effective drug were used. Finally, when the patent for a drug is nearing expiration, the patent-holding manufacturer may try to extend its exclusive marketing status by paying generic manufacturers to not introduce a generic version (“pay to delay”).

Adverse Drug Reactions An adverse drug event (ADE) or reaction to a drug (ADR) is a harmful or unintended response. Adverse drug reactions are claimed to be the fourth leading cause of death, higher than pulmonary disease, AIDS, accidents, and automobile deaths. The FDA has further estimated that 300,000 preventable adverse events occur annually in hospitals, many as a result of confusing medical information or lack of information (eg, regarding drug incompatibilities). Adverse reactions occurring only in certain susceptible patients include intolerance, idiosyncrasy (frequently genetic in origin), and allergy (usually immunologically mediated). During IND studies and clinical trials before FDA approval, all adverse events (serious, life-threatening, disabling, reasonably drug related, or unexpected) must be reported. After FDA approval to market a drug, surveillance, evaluation, and reporting must continue for any adverse events that are related to use of the drug, including overdose, accident, failure of expected action, events occurring from drug withdrawal, and unexpected events not listed in labeling. Events that are both serious and unexpected must be reported to the FDA within 15 days. The ability to predict and avoid adverse drug reactions and optimize a drug’s therapeutic index is an increasing focus of pharmacogenetic and personalized (also called “precision”) medicine. It has been suggested that greater use of electronic health records will reduce some of these risks (see Chapter 66). This hope has not yet been realized.

Orphan Drugs & Treatment of Rare Diseases Drugs for rare diseases—so-called orphan drugs—can be difficult to research, develop, and market. Proof of drug safety and efficacy

CHAPTER 1  Introduction: The Nature of Drugs & Drug Development & Regulation     19

in small populations must be established, but doing so is a complex process. Furthermore, because basic research in the pathophysiology and mechanisms of rare diseases receives relatively little attention or funding in both academic and industrial settings, recognized rational targets for drug action may be few. In addition, the cost of developing a drug can greatly influence priorities when the target population is relatively small. Funding for development of drugs for rare diseases or ignored diseases that do not receive priority attention from the traditional industry has received increasing support via philanthropy or similar funding from notfor-profit foundations such as the Cystic Fibrosis Foundation, the Michael J. Fox Foundation for Parkinson’s Research, the Huntington’s Disease Society of America, and the Gates Foundation. The Orphan Drug Amendment of 1983 provides incentives for the development of drugs for treatment of a rare disease or condition defined as “any disease or condition which (a) affects less than 200,000 persons in the USA or (b) affects more than 200,000 persons in the USA but for which there is no reasonable expectation that the cost of developing and making available in the USA a drug for such disease or condition will be recovered from sales in the USA of such drug.” Since 1983, the FDA has approved for marketing more than 300 orphan drugs to treat more than 82 rare diseases.

physicians. The package insert consists of a brief description of the pharmacology of the product. This brochure contains much practical information, but also lists every toxic effect ever reported, no matter how rare, thus shifting responsibility for adverse drug reactions from the manufacturer to the prescriber. A black box warning, if included, is of medicolegal importance, because it indicates a potentially lethal adverse effect. UpToDate.com is a large subscription website containing detailed descriptions of current standards of care, including drug therapy, for a wide variety of clinical conditions. Micromedex and Lexi-Comp are extensive subscription websites. They provide downloads for personal digital assistant devices, online drug dosage and interaction information, and toxicologic information. A useful and objective quarterly handbook that presents information on drug toxicity and interactions is Drug Interactions: Analysis and Management. Finally, the FDA maintains an Internet website that carries news regarding recent drug approvals, withdrawals, warnings, etc. It can be accessed at http://www.fda.gov. The MedWatch drug safety program is a free e-mail notification service that provides news of FDA drug warnings and withdrawals. Subscriptions may be obtained at https://www.fda .gov/safety/medwatch-fda-safety-information-and-adverse-eventreporting-program.

■■ SOURCES OF INFORMATION

Alexander SPH et al: The Concise Guide to PHARMACOLOGY 2017/18: Overview. Br J Pharmacol 2017;174:S1. Avorn J: Debate about funding comparative effectiveness research. N Engl J Med 2009;360:1927. Avorn J: Powerful Medicines: The Benefits and Risks and Costs of Prescription Drugs. Alfred A. Knopf, 2004. Bauchner H, Fontanarosa PB: Restoring confidence in the pharmaceutical industry. JAMA 2013;309:607. Bhatt DL, Mehta C: Clinical trials series: Adaptive designs for clinical trials. N Engl J Med 2016;375:65. Boutron I et al: Reporting and interpretation of randomized controlled trials with statistically nonsignificant results for primary outcomes. JAMA 2010; 303:2058. Brown WA: The placebo effect. Sci Am 1998;1:91. Cochrane Collaboration website. www.thecochranelibrary.com. Darrow JJ, Avorn J, Kesselheim AS: FDA approval and regulation of pharmaceuticals, 1983-2018. JAMA. 2020;323:164. Downing NS et al: Regulatory review of novel therapeutics—Comparison of three regulatory agencies. N Engl J Med 2012;366:2284. Drug Interactions: Analysis and Management (quarterly). Wolters Kluwer Publications. Emanuel EJ, Menikoff J: Reforming the regulations governing research with human subjects. N Engl J Med 2011;365:1145. FDA accelerated approval website. https://www.fda.gov/patients/fast-trackbreakthrough-therapy-accelerated-approval-priority-review/acceleratedapproval. FDA website. http://www.fda.gov. Goldacre B: Bad Pharma. Faber & Faber, 2012. Hennekens CMH, DeMets D: Statistical association and causation. Contributions of different types of evidence. JAMA 2011;305:1134. Huang S-M, Temple R: Is this the drug or dose for you? Impact and consideration of ethnic factors in global drug development, regulatory review, and clinical practice. Clin Pharmacol Ther 2008;84:287. Katzung BG et al: Katzung & Trevor’s Pharmacology: Examination & Board Review, 13th ed. McGraw Hill, 2021. Kesselheim AS et al: Whistle-blowers’ experiences in fraud litigation against pharmaceutical companies. N Engl J Med 2010;362:1832. Koslowski S et al: Developing the nation’s biosimilar program. N Engl J Med 2011;365:385.

REFERENCES

Students who wish to review the field of pharmacology in preparation for an examination are referred to Pharmacology: Examination and Board Review, by Katzung, Kruidering-Hall, Lalchandani Tuan, Vanderah, and Trevor (McGraw Hill, 2021). This book provides approximately 1000 questions and explanations in USMLE format. A short study guide is USMLE Road Map: Pharmacology, by Katzung and Trevor (McGraw Hill, 2006). Road Map contains numerous tables, figures, mnemonics, and USMLE-type clinical vignettes. The references at the end of each chapter in this book were selected to provide reviews or classic publications of information specific to those chapters. More detailed questions relating to basic or clinical research are best answered by referring to the journals covering general pharmacology and clinical specialties. For the student and the physician, three periodicals can be recommended as especially useful sources of current information about drugs: The New England Journal of Medicine, which publishes much original drug-related clinical research as well as frequent reviews of topics in pharmacology; The Medical Letter on Drugs and Therapeutics, which publishes brief critical reviews of new and old therapies; and Prescriber’s Letter, a monthly comparison of new and older drug therapies with much useful advice. On the Internet/World Wide Web, two sources can be particularly recommended: the Cochrane Collaboration and the FDA site (see reference list below). Other sources of information pertinent to the United States should be mentioned as well. The “package insert” is a summary of information that the manufacturer is required to place in the prescription sales package; Physicians’ Desk Reference (PDR) is a compendium of package inserts published annually with supplements twice a year. It is sold in bookstores and distributed to licensed

20    SECTION I  Basic Principles Landry Y, Gies J-P: Drugs and their molecular targets: An updated overview. Fund & Clin Pharmacol 2008;22:1. The Medical Letter on Drugs and Therapeutics. The Medical Letter, Inc. Ng R: Drugs from Discovery to Approval. Wiley-Blackwell, 2008. Pharmaceutical Research and Manufacturers of America website. http://www .phrma.org. Pharmacology: Examination & Board Review, 12th ed. McGraw Hill Education, 2019. Prescriber’s Letter. Stockton, California: prescribersletter.com. Rockey SJ, Collins FS: Managing financial conflict of interest in biomedical research. JAMA 2010;303:2400. Scheindlin S: Demystifying the new drug application. Mol Interventions 2004;4:188.

Sistare FD, DeGeorge JJ: Preclinical predictors of clinical safety: Opportunities for improvement. Clin Pharmacol Ther 2007;82(2):210. Stevens AJ et al: The role of public sector research in the discovery of drugs and vaccines. N Engl J Med 2011;364:535. Top 200 Drugs of 2019. https://clincalc.com/DrugStats/Top200Drugs.aspx USMLE Road Map: Pharmacology. McGraw Hill Education, 2006. World Medical Association: World Medical Association Declaration of Helsinki. Ethical principles for medical research involving human subjects. JAMA 2013;310:2191. Zarin DA et al: Characteristics of clinical trials registered in ClinicalTrials.gov, 2007-2010. JAMA 2012;307:1838.

C ASE STUDY ANSWER Aspirin overdose commonly causes a mixed respiratory alkalosis and metabolic acidosis. Because aspirin is a weak acid, serum acidosis favors entry of the drug into tissues (increasing toxicity), and urinary acidosis favors reabsorption of excreted drug back into the blood (prolonging the effects of the

overdose). Sodium bicarbonate, a weak base, is an important component of the management of aspirin overdose. It causes alkalosis, reducing entry into tissues, and increases the pH of the urine, enhancing renal clearance of the drug. See the discussion of the ionization of weak acids and weak bases in the text.

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Drug Receptors & Pharmacodynamics

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Mark von Zastrow, MD, PhD

C ASE STUDY A 51-year-old man presents to the emergency department due to acute difficulty breathing. The patient is afebrile and normotensive but anxious, tachycardic, and markedly tachypneic. Auscultation of the chest reveals diffuse wheezes. The clinician provisionally makes the diagnosis of bronchial asthma and administers epinephrine by intramuscular injection, improving the patient’s breathing over several minutes. A normal chest x-ray and electrocardiogram are subsequently obtained, and

Therapeutic and toxic effects of drugs result from their interactions with molecules in the patient. Most drugs act by associating with specific macromolecules in ways that alter the macromolecules’ biochemical or biophysical activities. This idea, more than a century old, is embodied in the term receptor: the component of a cell or organism that interacts with a drug and initiates the chain of events leading to the drug’s observed effects. Receptors have become the central focus of investigation of drug effects and their mechanisms of action (pharmacodynamics). The receptor concept, extended to endocrinology, immunology, and molecular biology, has proved essential for explaining many aspects of biologic regulation. Many drug receptors have been isolated and characterized in detail, thus opening the way to precise understanding of the molecular basis of drug action. The receptor concept has important practical consequences for the development of drugs and for arriving at therapeutic decisions in clinical practice. These consequences form the basis for understanding the actions and clinical uses of drugs described in almost every chapter of this book. They may be briefly summarized as follows: 1. Receptors largely determine the quantitative relations between dose or concentration of drug and pharmacologic effects.

the medical history is remarkable only for mild hypertension that is being treated with propranolol. The clinician instructs the patient to discontinue use of propranolol and changes the patient’s antihypertensive medication to verapamil. Why is the clinician correct to discontinue propranolol? Why is verapamil likely to be a more suitable choice for managing hypertension in this patient? Are there alternative pharmacotherapies that the clinician should also consider?

The receptor’s affinity for binding a drug determines the concentration of drug required to form a significant number of drug-receptor complexes, and the total number of receptors may limit the maximal effect a drug may produce. 2. Receptors are responsible for selectivity of drug action. The molecular size, shape, and electrical charge of a drug determine whether—and with what affinity—it will bind to a particular receptor among the vast array of chemically different binding sites available in a cell, tissue, or patient. Accordingly, changes in the chemical structure of a drug can dramatically increase or decrease a new drug’s affinities for different classes of receptors, with resulting alterations in therapeutic and toxic effects. 3. Receptors mediate the actions of pharmacologic agonists and antagonists. Some drugs and many natural ligands, such as hormones and neurotransmitters, regulate the function of receptor macromolecules as agonists; this means that they activate the receptor to signal as a direct result of binding to it. Some agonists activate a single kind of receptor to produce all their biologic functions, whereas others selectively promote one receptor function more than another. 21

22    SECTION I  Basic Principles

Other drugs act as pharmacologic antagonists; that is, they bind to receptors but do not activate generation of a signal; consequently, they interfere with the ability of an agonist to activate the receptor. Some of the most useful drugs in clinical medicine are pharmacologic antagonists. Still other drugs bind to a different site on the receptor than that bound by endogenous ligands; such drugs can produce useful and quite different clinical effects by acting as so-called allosteric modulators of the receptor.

MACROMOLECULAR NATURE OF DRUG RECEPTORS Most receptors for clinically relevant drugs, and nearly all of those discussed in this chapter, are proteins. Traditionally, drug binding was used to identify or purify receptor proteins from tissue extracts; consequently, receptors were discovered after the drugs that bind to them. Advances in molecular biology and genome sequencing made it possible to identify receptors by predicted structural homology to other (previously known) receptors. This effort revealed that many known drugs bind to a larger diversity of receptors than previously anticipated and motivated efforts to develop increasingly selective drugs. It also identified orphan receptors, so-called because their natural ligands are presently unknown; these may prove to be useful targets for future drug development. The best-characterized drug receptors are regulatory proteins that mediate the actions of endogenous chemical signals such as neurotransmitters, autacoids, and hormones. This class of receptors mediates the effects of many of the most useful therapeutic agents. The molecular structures and biochemical mechanisms of these regulatory receptors are described in a later section entitled Signaling Mechanisms & Drug Action. Other classes of proteins have been clearly identified as drug receptors. Enzymes may be inhibited (or, less commonly, activated) by binding a drug. Examples include dihydrofolate reductase, the receptor for the antineoplastic drug methotrexate; 3-hydroxy-3-methylglutaryl–coenzyme A (HMG-CoA) reductase, the receptor for statins; and various protein and lipid kinases. Transport proteins can be useful drug targets. Examples include Na+/K+-ATPase, the membrane receptor for cardioactive digitalis

RELATION BETWEEN DRUG CONCENTRATION & RESPONSE The relation between dose of a drug and the clinically observed response may be complex. In carefully controlled in vitro systems, however, the relation between concentration of a drug and its effect is often simple and can be described with mathematical precision. It is important to understand this idealized relation in some detail because it underlies the more complex relations between dose and effect that occur when drugs are given to patients.

Concentration-Effect Curves & Receptor Binding of Agonists Even in intact animals or patients, responses to low doses of a drug usually increase in direct proportion to dose. As doses increase, however, the response increment diminishes; finally, doses may be reached at which no further increase in response can be achieved. This relation between drug concentration and effect is traditionally described by a hyperbolic curve (Figure 2–1A) according to the following equation:

B 1.0 Emax

0.5

EC50

Drug concentration (C)

Receptor-bound drug (B)

Drug effect (E)

A 1.0

glycosides; norepinephrine and serotonin transporter proteins that are membrane receptors for antidepressant drugs; and dopamine transporters that are membrane receptors for cocaine and a number of other psychostimulants. Structural proteins are also important drug targets, such as tubulin, the receptor for the antiinflammatory agent colchicine. This chapter deals with three aspects of drug receptor function, presented in increasing order of complexity: (1) receptors as determinants of the quantitative relation between the concentration of a drug and the pharmacologic response, (2) receptors as regulatory proteins and components of chemical signaling mechanisms that provide targets for important drugs, and (3) receptors as key determinants of the therapeutic and toxic effects of drugs in patients.

Bmax 0.5

Kd Drug concentration (C)

FIGURE 2–1  Relations between drug concentration and drug effect (A) or receptor-bound drug (B). The drug concentrations at which effect or receptor occupancy is half-maximal are denoted by EC50 and Kd, respectively.

CHAPTER 2  Drug Receptors & Pharmacodynamics    23

A

Agonist effect

where E is the effect observed at concentration C, Emax is the maximal response that can be produced by the drug, and EC50 is the concentration of drug that produces 50% of maximal effect. This hyperbolic relation resembles the mass action law that describes the association between two molecules of a given affinity. This resemblance suggests that drug agonists act by binding to (“occupying”) a distinct class of biologic molecules with a characteristic affinity for the drug. Radioactive receptor ligands have been used to confirm this occupancy assumption in many drugreceptor systems. In these systems, drug bound to receptors (B) relates to the concentration of free (unbound) drug (C) as depicted in Figure 2–1B and as described by an analogous equation:

Receptor-Effector Coupling & Spare Receptors When an agonist occupies a receptor, conformational changes occur in the receptor protein that represent the fundamental basis of receptor activation and the first of often many steps required to produce a pharmacologic response. The overall transduction process that links drug occupancy of receptors and pharmacologic response is called coupling. The relative efficiency of occupancyresponse coupling is determined, in part, at the receptor itself; full agonists tend to shift the conformational equilibrium of receptors more strongly than partial agonists (described in the text that follows). Coupling is also determined by “downstream” biochemical events that transduce receptor occupancy into cellular response. For some receptors, such as ligand-gated ion channels, the relationship between drug occupancy and response can be simple because the ion current produced by a drug is often directly proportional to the number of receptors (ion channels) bound. For other receptors, such as those linked to enzymatic signal transduction cascades, the occupancy-response relationship is often more complex because the biologic response reaches a maximum before full receptor occupancy is achieved.

C D

0.5

E

EC50 (A)

in which Bmax indicates the total concentration of receptor sites (ie, sites bound to the drug at infinitely high concentrations of free drug) and Kd (the equilibrium dissociation constant) represents the concentration of free drug at which half-maximal binding is observed. This constant characterizes the receptor’s affinity for binding the drug in a reciprocal fashion: If the Kd is low, binding affinity is high, and vice versa. The EC50 and Kd may be identical but need not be, as discussed below. Dose-response data are often presented as a plot of the drug effect (ordinate) against the logarithm of the dose or concentration (abscissa), transforming the hyperbolic curve of Figure 2–1 into a sigmoid curve with a linear midportion (eg, Figure 2–2). This transformation is convenient because it expands the scale of the concentration axis at low concentrations (where the effect is changing rapidly) and compresses it at high concentrations (where the effect is changing slowly), but otherwise has no biologic or pharmacologic significance.

B

EC50 (B)

EC50 (C) EC50 (D,E)

Kd

Agonist concentration (C) (log scale)

FIGURE 2–2  Logarithmic transformation of the dose axis and experimental demonstration of spare receptors, using different concentrations of an irreversible antagonist. Curve A shows agonist response in the absence of antagonist. After treatment with a low concentration of antagonist (curve B), the curve is shifted to the right. Maximal responsiveness is preserved, however, because the remaining available receptors are still in excess of the number required. In curve C, produced after treatment with a larger concentration of antagonist, the available receptors are no longer “spare”; instead, they are just sufficient to mediate an undiminished maximal response. Still higher concentrations of antagonist (curves D and E) reduce the number of available receptors to the point that maximal response is diminished. The apparent EC50 of the agonist in curves D and E may approximate the Kd that characterizes the binding affinity of the agonist for the receptor. Many factors can contribute to nonlinear occupancy-response coupling, and often these factors are only partially understood. A useful concept for thinking about this is that of receptor reserve or spare receptors. Receptors are said to be “spare” for a given pharmacologic response if it is possible to elicit a maximal biologic response at a concentration of agonist that does not result in occupancy of all the available receptors. Experimentally, spare receptors may be demonstrated by using irreversible antagonists to prevent binding of agonist to a proportion of available receptors and showing that high concentrations of agonist can still produce an undiminished maximal response (see Figure 2–2). For example, the same maximal inotropic response of heart muscle to catecholamines can be elicited even when 90% of β adrenoceptors to which they bind are occupied by a quasi-irreversible antagonist. Accordingly, myocardial cells are said to contain a large proportion of spare β adrenoceptors. What accounts for the phenomenon of spare receptors? In some cases, receptors may be simply spare in number relative to the total number of downstream signaling mediators present in the cell, so that a maximal response occurs without occupancy of all receptors. In other cases, “spareness” of receptors appears to be temporal. For example, β-adrenoceptor activation by an agonist promotes binding of guanosine triphosphate (GTP) to a trimeric

24    SECTION I  Basic Principles

G protein, producing an activated signaling intermediate whose lifetime may greatly outlast the agonist-receptor interaction (see also the section G Proteins & Second Messengers). Here, maximal response is elicited by activation of relatively few receptors because the response initiated by an individual ligand-receptor-binding event persists longer than the binding event itself. Irrespective of the biochemical basis of receptor reserve, the sensitivity of a cell or tissue to a particular concentration of agonist depends not only on the affinity of the receptor for binding the agonist (characterized by the Kd) but also on the degree of spareness—the total number of receptors present compared with the number actually necessary to elicit a maximal biologic response. The concept of spare receptors is very useful clinically because it allows one to think precisely about the effects of drug dosage without having to consider (or even fully understand) biochemical details of the signaling response. The Kd of the agonist-receptor interaction determines what fraction (B/Bmax) of total receptors will be occupied at a given free concentration (C) of agonist regardless of the receptor concentration:

Imagine a responding cell with 100 receptors and 100 effectors. Here the number of effectors does not limit the maximal response, and the receptors are not spare in number. Consequently, an agonist that is present at a concentration equal to the Kd will occupy 50% of the receptors, and half of the effectors will be activated, producing a half-maximal response (ie, 50 receptors stimulate 50 effectors). Now imagine that the number of receptors increases tenfold to 1000 receptors but the total number of effectors remains constant. Most of the receptors are now spare in number. As a A

result, a much lower concentration of agonist suffices to occupy 50 of the 1000 receptors (5% of the receptors), and this same low concentration of agonist elicits a half-maximal response (50 of 100 effectors activated). Thus, it is possible to change the sensitivity of tissues with spare receptors by changing receptor number.

Competitive & Irreversible Antagonists Receptor antagonists bind to receptors but do not activate them; the primary action of antagonists is to reduce the effects of agonists (other drugs or endogenous regulatory molecules) that normally activate receptors. While antagonists are traditionally thought to have no functional effect in the absence of an agonist, some antagonists exhibit “inverse agonist” activity (see Chapter 1) because they also reduce receptor activity below basal levels observed in the absence of any agonist at all. Antagonist drugs are further divided into two classes depending on whether they act competitively or noncompetitively relative to an agonist present at the same time. In the presence of a fixed concentration of agonist, increasing concentrations of a competitive antagonist progressively inhibit the agonist response; high antagonist concentrations prevent the response almost completely. Conversely, sufficiently high concentrations of agonist can surmount the effect of a given concentration of the antagonist; that is, the Emax for the agonist remains the same for any fixed concentration of antagonist (Figure 2–3A). Because the antagonism is competitive, the presence of antagonist increases the agonist concentration required for a given degree of response, and so the agonist concentration-effect curve is shifted to the right. The concentration (C′) of an agonist required to produce a given effect in the presence of a fixed concentration ([I]) of competitive antagonist is greater than the agonist concentration (C) B

Agonist + competitive antagonist

Agonist alone

Agonist effect (E)

Agonist effect (E)

Agonist alone

Agonist + noncompetitive antagonist

C

C' = C (1 + [ l ] / K)

Agonist concentration

EC50 Agonist concentration

FIGURE 2–3  Changes in agonist concentration-effect curves produced by a competitive antagonist (A) or by an irreversible antagonist (B). In the presence of a competitive antagonist, higher concentrations of agonist are required to produce a given effect; thus the agonist concentration (C′) required for a given effect in the presence of concentration [I] of an antagonist is shifted to the right, as shown. High agonist concentrations can overcome inhibition by a competitive antagonist. This is not the case with an irreversible (or noncompetitive) antagonist, which reduces the maximal effect the agonist can achieve, although it may not change its EC50.

CHAPTER 2  Drug Receptors & Pharmacodynamics    25

required to produce the same effect in the absence of the antagonist. The ratio of these two agonist concentrations (called the dose ratio) is related to the dissociation constant (Ki) of the antagonist by the Schild equation: C′ [l] =1+ C Ki

Pharmacologists often use this relation to determine the Ki of a competitive antagonist. Even without knowledge of the relation between agonist occupancy of the receptor and response, the Ki can be determined simply and accurately. As shown in Figure 2–3, concentration-response curves are obtained in the presence and in the absence of a fixed concentration of competitive antagonist; comparison of the agonist concentrations required to produce identical degrees of pharmacologic effect in the two situations reveals the antagonist’s Ki. If C′ is twice C, for example, then [I] = Ki. For the clinician, this mathematical relation has two important therapeutic implications: 1. The degree of inhibition produced by a competitive antagonist depends on the concentration of antagonist. The competitive β-adrenoceptor antagonist propranolol provides a useful example. Patients receiving a fixed dose of this drug exhibit a wide range of plasma concentrations, owing to differences among individuals in the clearance of propranolol. As a result, inhibitory effects on physiologic responses to norepinephrine and epinephrine (endogenous adrenergic receptor agonists) may vary widely, and the dose of propranolol must be adjusted accordingly. 2. Clinical response to a competitive antagonist also depends on the concentration of agonist that is competing for binding to receptors. Again, propranolol provides a useful example: When this drug is administered at moderate doses sufficient to block the effect of basal levels of the neurotransmitter norepinephrine, resting heart rate is decreased. However, the increase in the release of norepinephrine and epinephrine that occurs with exercise, postural changes, or emotional stress may suffice to overcome this competitive antagonism. Accordingly, the same dose of propranolol may have little effect under these conditions, thereby altering therapeutic response. Conversely, the same dose of propranolol that is useful for treatment of hypertension in one patient may be excessive and toxic to another, based on differences between the patients in the amount of endogenous norepinephrine and epinephrine that they produce. The actions of a noncompetitive antagonist are different because, once a receptor is bound by such a drug, agonists cannot surmount the inhibitory effect irrespective of their concentration. In many cases, noncompetitive antagonists bind to the receptor in an irreversible or nearly irreversible fashion, sometimes by forming a covalent bond with the receptor. After occupancy of some proportion of receptors by such an antagonist, the number of remaining unoccupied receptors may be too low for the agonist (even at high concentrations) to elicit a response comparable to the previous maximal response (Figure 2–3B). If spare receptors are present, however, a lower dose of an irreversible antagonist may

leave enough receptors unoccupied to allow achievement of maximum response to agonist, although a higher agonist concentration will be required (Figures 2–2B and 2–2C; see section ReceptorEffector Coupling & Spare Receptors). Therapeutically, such irreversible antagonists present distinct advantages and disadvantages. Once the irreversible antagonist has occupied the receptor, it need not be present in unbound form to inhibit agonist responses. Consequently, the duration of action of such an irreversible antagonist is relatively independent of its own rate of elimination and more dependent on the rate of turnover of receptor molecules. Phenoxybenzamine, an irreversible α-adrenoceptor antagonist, is used to control the hypertension caused by catecholamines released from pheochromocytoma, a tumor of the adrenal medulla. If administration of phenoxybenzamine lowers blood pressure, blockade will be maintained even when the tumor episodically releases very large amounts of catecholamine. In this case, the ability to prevent responses to varying and high concentrations of agonist is a therapeutic advantage. If overdose occurs, however, a real problem may arise. If the α-adrenoceptor blockade cannot be overcome, excess effects of the drug must be antagonized “physiologically,” ie, by using a pressor agent that does not act via α adrenoceptors. Antagonists can function noncompetitively in a different way; that is, by binding to a site on the receptor protein separate from the agonist binding site; in this way, the drug can modify receptor activity without blocking agonist binding (see Chapter 1, Figures 1–2C and 1–2D). Although these drugs act noncompetitively, their actions are often reversible. Such drugs are called negative allosteric modulators because they act through binding to a different (ie, “allosteric”) site on the receptor relative to the classical (ie, “orthosteric”) site bound by the endogenous agonist to reduce activity of the receptor. Other allosteric modulators have the opposite effect: they increase receptor activity. Benzodiazepine drugs like diazepam, for example, bind to an allosteric site on ion channels that are physiologically activated by the neurotransmitter γ-aminobutyric acid (GABA). Benzodiazepines are considered positive allosteric modulators of GABA receptors because they potentiate (rather than inhibit) the ability of the orthosteric agonist (GABA) to increase channel conductance. A useful feature of this allosteric mechanism is that benzodiazepines have little activating effect on their own. This contributes to making benzodiazepines relatively safe in overdose unless combined with other sedating drugs. The concept of allosteric modulators also applies to proteins that lack any known orthosteric binding site. For example, ivacaftor binds to the cystic fibrosis transmembrane regulator (CFTR) ion channel that is mutated in cystic fibrosis. Some mutations that cause disease by rendering this channel hypoactive can be partially rescued by ivacaftor, despite CFTR having no known physiological agonist—and thus no (presently recognized) orthosteric binding site.

Partial Agonists Based on the maximal pharmacologic response that occurs when all receptors are occupied, agonists can be divided into two classes:

26    SECTION I  Basic Principles

partial agonists produce a lower response, at full receptor occupancy, than do full agonists. Partial agonists produce concentration-effect curves that resemble those observed with full agonists in the presence of an antagonist that irreversibly blocks some of the receptor sites (compare Figures 2–2 [curve D] and 2–4B). It is important to emphasize that the failure of partial agonists to produce a maximal response is not due to decreased affinity for binding to receptors. Indeed, a partial agonist’s inability to cause a maximal pharmacologic response, even when present at high concentrations that effectively saturate binding to all receptors, is indicated by the fact that partial agonists competitively inhibit the responses produced by full agonists (Figure 2–4). This mixed “agonist-antagonist” property of partial agonists can have both beneficial and deleterious effects in the clinic. For example, buprenorphine, a partial agonist of μ-opioid receptors, is a generally safer analgesic drug than morphine, a more efficacious partial agonist, and much safer than fentanyl which is a full agonist. This is because buprenorphine suppresses breathing upon binding opioid receptors (in ventilatory pacemaker neurons of the brainstem) less strongly than morphine, and much less strongly than fentanyl; breathing stops

Other Mechanisms of Drug Antagonism Not all mechanisms of antagonism involve interactions of drugs or endogenous ligands at a single type of receptor, and some types of antagonism do not involve a receptor protein at all. For example, protamine, a protein that is positively charged at physiologic pH, can be used clinically as a drug to counteract the effects of heparin, a nonprotein (glycosaminoglycan) anticoagulant drug that is negatively charged. In this case, one drug acts as a chemical antagonist of the other simply by ionic binding that makes the other drug unavailable to interact with proteins involved in blood clotting. B

100

1.0 0.8

80 60

Full agonist

Response

Percentage of maximal binding

A

if these receptors are activated too strongly. On the other hand, buprenorphine is effectively antianalgesic when administered in combination with more efficacious opioid drugs, due to the mixed agonist-antagonist effect. In addition, buprenorphine may precipitate a severe drug withdrawal reaction in opioid-dependent individuals, due to physiologic adaptations of the nervous system that are induced after prolonged or repeated drug exposure and effectively change the “set point” for sensitivity to opioids.

Partial agonist

40

Full agonist

0.6 0.4 0.2

20

Partial agonist

0.0

0 –10

–10

–8 –6 log (Partial agonist)

–8 –6 log (Full agonist or partial agonist)

C 1.0 Total response

Response

0.8

Full agonist component

0.6 0.4

Partial agonist component

0.2 0.0 –10

–8

–6

log (Partial agonist)

FIGURE 2–4  A: The percentage of receptor occupancy resulting from full agonist (present at a single concentration) binding to receptors in the presence of increasing concentrations of a partial agonist. Because the full agonist (blue line) and the partial agonist (green line) compete to bind to the same receptor sites, when occupancy by the partial agonist increases, binding of the full agonist decreases. B: When each of the two drugs is used alone and response is measured, occupancy of all the receptors by the partial agonist produces a lower maximal response than does similar occupancy by the full agonist. C: Simultaneous treatment with a single concentration of full agonist and increasing concentrations of the partial agonist produces the response patterns shown in the bottom panel. The fractional response caused by a single high concentration of the full agonist decreases as increasing concentrations of the partial agonist compete to bind to the receptor with increasing success; at the same time, the portion of the response caused by the partial agonist increases, while the total response—ie, the sum of responses to the two drugs (red line)—gradually decreases, eventually reaching the value produced by partial agonist alone (compare with B).

CHAPTER 2  Drug Receptors & Pharmacodynamics    27

Another type of antagonism is physiologic antagonism between endogenous regulatory pathways mediated by different receptors. For example, several catabolic actions of the glucocorticoid hormones lead to increased blood glucose levels, an effect that is physiologically opposed by insulin. Although glucocorticoids and insulin act on quite distinct receptor-effector systems, the clinician must sometimes administer insulin to oppose the hyperglycemic effects of a glucocorticoid hormone, whether the latter is elevated by endogenous synthesis (eg, a tumor of the adrenal cortex) or as a result of glucocorticoid therapy. In general, use of a drug as a physiologic antagonist produces effects that are less specific and less easy to control than are the effects of a receptor-specific antagonist. Thus, for example, to treat bradycardia caused by increased release of acetylcholine from vagus nerve endings, the clinician could use isoproterenol, a β-adrenoceptor agonist that increases heart rate by mimicking sympathetic stimulation of the heart. However, use of this physiologic antagonist would be less rational—and potentially more dangerous—than a receptor-specific antagonist such as atropine.

SIGNALING MECHANISMS & DRUG ACTION Until now we have considered receptor interactions and drug effects in terms of equations and concentration-effect curves. We must also understand the molecular mechanisms by which drugs act. We should also consider different structural families of receptor proteins, and this allows us to ask basic questions with important clinical implications:

1

2

3

R

R

•  Why do some drugs produce effects that persist for minutes, hours, or even days after the drug is no longer present? •  Why do responses to other drugs diminish rapidly with prolonged or repeated administration? •  How do cellular mechanisms for amplifying external chemical signals explain the phenomenon of spare receptors? •  Why do chemically similar drugs often exhibit extraordinary selectivity in their actions? •  Do these mechanisms provide targets for developing new drugs? Most transmembrane signaling is accomplished by a small number of different molecular mechanisms. Each type of mechanism has been adapted, through the evolution of distinctive protein families, to transduce many different signals. These protein families include receptors on the cell surface and within the cell, as well as enzymes and other components that generate, amplify, coordinate, and terminate postreceptor signaling by nonprotein chemical mediators in the cell that are collectively called second messengers. This section first discusses mechanisms for carrying chemical information across the plasma membrane and then discusses some examples of second messenger chemicals. Five basic mechanisms of transmembrane signaling are well understood (Figure 2–5). Each represents a different family of receptor protein and uses a different strategy to circumvent the barrier posed by the lipid bilayer of the plasma membrane. These strategies use (1) a lipid-soluble ligand that crosses the membrane and acts on an intracellular receptor; (2) a transmembrane receptor protein whose intracellular enzymatic activity is allosterically regulated by a ligand that binds to a site on the protein’s extracellular domain; (3) a transmembrane receptor that binds and stimulates an intracellular protein tyrosine kinase; (4) a ligand-gated transmembrane ion channel that can be induced to open or close by the binding

4

5

Drug Outside cell

R

Membrane

R

E G

Inside cell A

B

Y

Y~P

C

D

R

FIGURE 2–5  Known transmembrane signaling mechanisms: 1: A lipid-soluble chemical signal crosses the plasma membrane and acts on an intracellular receptor (which may be an enzyme or a regulator of gene transcription); 2: the signal binds to the extracellular domain of a transmembrane protein, thereby activating an enzymatic activity of its cytoplasmic domain; 3: the signal binds to the extracellular domain of a transmembrane receptor bound to a separate protein tyrosine kinase, which it activates; 4: the signal binds to and directly regulates the opening of an ion channel; 5: the signal binds to a cell-surface receptor linked to an effector enzyme by a G protein. (A, C, substrates; B, D, products; R, receptor; G, G protein; E, effector [enzyme or ion channel]; Y, tyrosine; P, phosphate.)

28    SECTION I  Basic Principles

of a ligand; and (5) a transmembrane receptor protein that stimulates a GTP-binding signal transducer protein (G protein), which in turn modulates production of an intracellular second messenger. Although the five established mechanisms do not account for all the chemical signals conveyed across cell membranes, they do transduce many of the most important signals exploited in pharmacotherapy.

Ligand-binding domain hsp90

Intracellular Receptors for Lipid-Soluble Agents Several biologic ligands are sufficiently lipid-soluble to cross the plasma membrane and act on intracellular receptors. One class of such ligands includes steroids (corticosteroids, mineralocorticoids, sex steroids, vitamin D) and thyroid hormone, whose receptors stimulate the transcription of genes by binding to specific DNA sequences (often called response elements) near the gene whose expression is to be regulated. These “gene-active” receptors belong to a protein family that evolved from a common precursor. Dissection of the receptors by recombinant DNA techniques has provided insights into their molecular mechanism. For example, binding of glucocorticoid hormone to its normal receptor protein relieves an inhibitory constraint on the transcription-stimulating activity of the protein. Figure 2–6 schematically depicts the molecular mechanism of glucocorticoid action: In the absence of hormone, the receptor is bound to hsp90, a protein that prevents normal folding of several structural domains of the receptor. Binding of hormone to the ligand-binding domain triggers release of hsp90. This allows the DNA-binding and transcription-activating domains of the receptor to fold into their functionally active conformations, so that the activated receptor can initiate transcription of target genes. The mechanism used by hormones that act by regulating gene expression has two therapeutically important consequences: 1. These hormones produce their effects after a characteristic lag period of 30 minutes to several hours—the time required for the synthesis of new proteins. This means that the gene-active hormones cannot be expected to alter a pathologic state within minutes (eg, glucocorticoids will not immediately relieve the symptoms of bronchial asthma). 2. The effects of these agents can persist for hours or days after their concentration has been reduced to zero. The persistence of effect is primarily due to the relatively slow turnover of most enzymes and proteins, which can remain active in cells for hours or days after they have been synthesized. Consequently, it means that the beneficial (or toxic) effects of a gene-active hormone usually decrease slowly when administration of the hormone is stopped.

Ligand-Regulated Transmembrane Enzymes Including Receptor Tyrosine Kinases This class of receptor molecules mediates the first steps in signaling by insulin, epidermal growth factor (EGF), platelet-derived

Steroid

hsp90

Transcriptionactivating domain DNA-binding domain

Altered transcription of specific genes

FIGURE 2–6  Mechanism of glucocorticoid action. The glucocorticoid receptor polypeptide is schematically depicted as a protein with three distinct domains. A heat-shock protein, hsp90, binds to the receptor in the absence of hormone and prevents folding into the active conformation of the receptor. Binding of a hormone ligand (steroid) causes dissociation of the hsp90 stabilizer and permits conversion to the active configuration. growth factor (PDGF), atrial natriuretic peptide (ANP), transforming growth factor-β (TGF-β), and many other trophic hormones. These receptors are polypeptides consisting of an extracellular hormone-binding domain and a cytoplasmic enzyme domain, which may be a protein tyrosine kinase, a serine kinase, or a guanylyl cyclase (Figure 2–7). In all these receptors, the two domains are connected by a hydrophobic segment of the polypeptide that resides in the lipid bilayer of the plasma membrane. The receptor tyrosine kinase signaling function begins with binding of ligand, typically a polypeptide hormone or growth factor, to the receptor’s extracellular domain. The resulting change in receptor conformation causes two receptor molecules to bind to one another (dimerize). This activates the tyrosine kinase enzyme activity present in the cytoplasmic domain of the dimer, leading to phosphorylation of the receptor as well as additional downstream signaling proteins. Activated receptors catalyze phosphorylation of tyrosine residues on different target signaling proteins, thereby allowing a single activated receptor complex to modulate a large number of biochemical processes.

CHAPTER 2  Drug Receptors & Pharmacodynamics    29

EGF molecules

+EGF –EGF

Outside

Inside

Y

Y

P

P Y

Y

S

S~P ATP

ADP

FIGURE 2–7  Mechanism of activation of the epidermal growth factor (EGF) receptor, a representative receptor tyrosine kinase. The receptor polypeptide has extracellular and cytoplasmic domains, depicted above and below the plasma membrane. Upon binding of EGF (circle), the receptor converts from its inactive monomeric state (left) to an active dimeric state (right), in which two receptor polypeptides bind noncovalently. The cytoplasmic domains become phosphorylated (P) on specific tyrosine residues (Y), and their enzymatic activities are activated, catalyzing phosphorylation of substrate proteins (S). Insulin, for example, uses a single class of tyrosine kinase receptors to trigger increased uptake of glucose and amino acids and to regulate metabolism of glycogen and triglycerides in the cell. Activation of the receptor in specific target cells drives a complex program of cellular events ranging from altered membrane transport of ions and metabolites to changes in the expression of many genes. Inhibitors of particular receptor tyrosine kinases are used in treating neoplastic disorders in which excessive growth factor signaling is often involved. Some of these inhibitors are monoclonal antibodies (eg, trastuzumab, cetuximab), which bind to the extracellular domain of a particular receptor and interfere with binding of growth factor. Other inhibitors are membrane-permeant small molecule chemicals (eg, gefitinib, erlotinib), which inhibit the receptor’s kinase activity in the cytoplasm. The intensity and duration of action of EGF, PDGF, and other agents that act via receptor tyrosine kinases are often limited by a process called receptor downregulation. This typically occurs by endocytosis of receptors from the cell surface followed by the degradation of internalized receptors (and their bound ligands). When this process occurs at a rate faster than de novo synthesis of receptors, the total number of cell-surface receptors is reduced (down-regulated), and the cell’s responsiveness to ligand is correspondingly diminished. A well-understood example is the EGF receptor tyrosine kinase, whose rate of internalization from the plasma membrane is greatly accelerated after activation by EGF; internalized receptors are subsequently delivered to lysosomes and proteolyzed. This downregulation process is essential physiologically to limit the strength and duration of the endogenous growth factor signal, and genetic mutations that interfere with the downregulation process cause excessive and prolonged responses that underlie or contribute to many forms of cancer. Endocytosis of

other receptor tyrosine kinases, most notably receptors for nerve growth factor, can serve a very different function. Internalized nerve growth factor receptors are not rapidly degraded but remain active in endocytic vesicles that move from the distal axon, where receptors are initially activated by nerve growth factor (released from the innervated tissue), into the neuron’s cell body. In the cell body, the growth factor signal is transduced to transcription factors regulating the expression of genes controlling cell survival. This process, effectively opposite to downregulation, transports a critical survival signal from its site of initiation to the site of a critical downstream signaling effect, and can do so over a remarkably long distance—up to a meter in some neurons. Other regulators of growth and differentiation, including TGF-β, act on another class of transmembrane receptor enzymes that phosphorylate serine and threonine residues. Atrial natriuretic peptide (ANP), an important regulator of blood volume and vascular tone, acts on a transmembrane receptor whose intracellular domain, a guanylyl cyclase, generates cGMP (see below).

Cytokine Receptors Cytokine receptors respond to a heterogeneous group of peptide ligands, which include growth hormone, erythropoietin, several kinds of interferon, and other regulators of growth and differentiation. These receptors use a mechanism (Figure 2–8) closely resembling that of receptor tyrosine kinases, except that in this case, the protein tyrosine kinase activity is not intrinsic to the receptor molecule. Instead, a separate protein tyrosine kinase, from the Januskinase (JAK) family, binds noncovalently to the receptor. As in the case of the EGF receptor, cytokine receptors dimerize after they bind the activating ligand, allowing the bound JAKs to become activated and to phosphorylate tyrosine residues on the receptor.

30    SECTION I  Basic Principles

Cytokine molecules

+ Cytokine

R

R

JAK

JAK

P~Y

R

R

Y~P

JAK JAK P~Y

STAT

Y~P P~Y

STAT

Y~P

STAT

STAT

FIGURE 2–8  Cytokine receptors, like receptor tyrosine kinases, have extracellular and intracellular domains and form dimers. However, after activation by an appropriate ligand, separate mobile protein tyrosine kinase molecules (JAK) are activated, resulting in phosphorylation of signal transducers and activation of transcription (STAT) molecules. STAT dimers then travel to the nucleus, where they regulate transcription. Phosphorylated tyrosine residues on the receptor’s cytoplasmic surface then set in motion a complex signaling dance by binding another set of proteins, called STATs (signal transducers and activators of transcription). The bound STATs are themselves phosphorylated by the JAKs, two STAT molecules dimerize (attaching to one another’s tyrosine phosphates), and finally the STAT/STAT dimer dissociates from the receptor and travels to the nucleus, where it regulates transcription of specific genes.

to sites on the α subunits, a conformational change occurs that results in the transient opening of a central aqueous channel, approximately 0.5 nm in diameter, through which sodium ions penetrate from the extracellular fluid to cause electrical depolarization of the cell. The structural basis for activating other

Ion Channels Many of the most useful drugs in clinical medicine act on ion channels. For ligand-gated ion channels, drugs often mimic or block the actions of natural agonists. Natural ligands of such receptors include acetylcholine, serotonin, GABA, and glutamate; all are synaptic transmitters. Each of their receptors transmits its signal across the plasma membrane by increasing transmembrane conductance of the relevant ion and thereby altering the electrical potential across the membrane. For example, acetylcholine causes the opening of the ion channel in the nicotinic acetylcholine receptor (nAChR), which allows Na+ to flow down its concentration gradient into cells, producing a localized excitatory postsynaptic potential—a depolarization. The nAChR is one of the best characterized of all cell-surface receptors for hormones or neurotransmitters (Figure 2–9). One form of this receptor is a pentamer made up of four different polypeptide subunits (eg, two α chains plus one β, one γ, and one δ chain). These polypeptides, each of which crosses the lipid bilayer four times, form a cylindrical structure that is approximately 10 nm in diameter but is impermeable to ions. When acetylcholine binds

Na+

ACh

α

γ

Outside

ACh δ α β

Inside

Na+

FIGURE 2–9  The nicotinic acetylcholine (ACh) receptor, a ligandgated ion channel. The receptor molecule is depicted as embedded in a rectangular piece of plasma membrane, with extracellular fluid above and cytoplasm below. Composed of five subunits (two α, one β, one γ, and one δ), the receptor opens a central transmembrane ion channel when ACh binds to sites on the extracellular domain of its α subunits.

CHAPTER 2  Drug Receptors & Pharmacodynamics    31

ligand-gated ion channels has been determined recently, and similar general principles apply, but there are differences in key details that may open new opportunities for drug design and action. For example, receptors that mediate excitatory neurotransmission at central nervous system synapses bind glutamate, a major excitatory neurotransmitter, through a large appendage domain that protrudes from the receptor and has been called a “flytrap” because it physically closes around the glutamate molecule; the glutamateloaded flytrap domain then moves as a unit to control pore opening. Drugs can regulate the activity of such glutamate receptors by binding to the flytrap domain, to surfaces on the membraneembedded portion around the pore, or within the pore itself. The time elapsed between the binding of the agonist to a ligand-gated channel and the cellular response can often be measured in milliseconds. The rapidity of this signaling mechanism is crucially important for moment-to-moment transfer of information across synapses. Ligand-gated ion channels can be regulated by multiple mechanisms, including phosphorylation and endocytosis. In some cases, such as the nicotinic synapse controlling the diaphragmatic muscles mediating ventilation, these mechanisms maintain a uniform response (ie, they are homeostatic). In other cases, such as at many synapses in the central nervous system, these mechanisms can produce long-term changes in the magnitude of the response and contribute to synaptic plasticity involved in learning and memory. Voltage-gated ion channels do not bind neurotransmitters directly but are controlled by membrane potential; such channels are also important drug targets. Drugs that regulate voltage-gated channels typically bind to a site of the receptor different from the charged amino acids that constitute the “voltage sensor” domain of the protein used for channel opening by membrane potential. For example, verapamil binds to a region in the pore of voltagegated calcium channels that are present in the heart and in vascular smooth muscle, inhibiting the ion conductance separately from the voltage sensor, producing antiarrhythmic effects, and reducing blood pressure without mimicking or antagonizing any known endogenous transmitter. Local anesthetics such as procaine work by inhibiting voltage-sensitive sodium channels expressed in sensory neurons, probably by binding to multiple sites on the channel. Other channels, such as the CFTR, are not strongly sensitive to either a known natural ligand or voltage but are still important drug targets. Lumacaftor binds CFTR and promotes its delivery to the plasma membrane after biosynthesis. Ivacaftor binds to a different site and enhances channel conductance. Both drugs act as allosteric modulators of the CFTR and are used in the treatment of cystic fibrosis, but each has a different effect.

G Proteins & Second Messengers Many extracellular ligands act by increasing the intracellular concentrations of second messengers such as cyclic adenosine-3′, 5′-monophosphate (cAMP), calcium ion, or the phosphoinositides (described below). In most cases, they use a transmembrane signaling system with three separate components. First, the extracellular ligand is selectively detected by a cell-surface receptor. The receptor in turn triggers the activation of a GTP-binding protein

Agonist

R

R*

Cell membrane

GDP G–GDP

GTP

E

G–GTP E* Pi

FIGURE 2–10  The guanine nucleotide-dependent activationinactivation cycle of G proteins. The agonist activates the receptor (R→R*), which promotes release of GDP from the G protein (G), allowing entry of GTP into the nucleotide binding site. In its GTP-bound state (G–GTP), the G protein regulates activity of an effector enzyme or ion channel (E→E*). The signal is terminated by hydrolysis of GTP, followed by return of the system to the basal unstimulated state. Open arrows denote regulatory effects. (Pi, inorganic phosphate.) (G protein) located on the cytoplasmic face of the plasma membrane. The activated G protein then changes the activity of an effector element, usually an enzyme or ion channel. This element then changes the concentration of the intracellular second messenger. For cAMP, the effector enzyme is adenylyl cyclase, a membrane protein that converts intracellular adenosine triphosphate (ATP) to cAMP. The corresponding G protein, Gs, stimulates adenylyl cyclase after being activated by hormones and neurotransmitters that act via specific Gs-coupled receptors. There are many examples of such receptors, including β adrenoceptors, glucagon receptors, thyrotropin receptors, and certain subtypes of dopamine and serotonin receptors. Gs and other G proteins rapidly activate their downstream effectors when bound by GTP, but they also have the ability to hydrolyze GTP (Figure 2–10); this hydrolysis reaction inactivates the G protein, and the rate of GTP hydrolysis is a major determinant of both the duration and amount of downstream responses. For example, a neurotransmitter such as norepinephrine may encounter its membrane receptor for only a few tens of milliseconds. When the encounter generates a GTP-bound Gs molecule, however, the duration of activation of adenylyl cyclase depends on the longevity of GTP binding to Gs rather than on the duration of norepinephrine’s binding to the receptor. Indeed, GTP-bound Gs may remain active for tens of seconds before it is inactivated by hydrolysis of the bound GTP to GDP, prolonging and enormously amplifying the original signal. The family of G proteins contains several functionally diverse subfamilies (Table 2–1), each of which mediates effects of a particular set of receptors to a distinctive group of effectors. Note that an endogenous ligand (eg, norepinephrine, acetylcholine, serotonin, many others not listed in Table 2–1) may bind and stimulate receptors that couple to different subsets of G proteins. The apparent promiscuity of such a ligand allows it to

32    SECTION I  Basic Principles

TABLE 2–1  G proteins and their receptors

Agonist

and effectors.

G Protein

Receptors for

Effector/Signaling Pathway

Gs

β-Adrenergic amines, histamine, serotonin, glucagon, and many other hormones

↑ Adenylyl cyclase →↑ cAMP

Gi1, Gi2, Gi3

Outside N II I

α2-Adrenergic amines, acetylcholine (muscarinic), opioids, serotonin, and many others

Several, including:   ↓ Adenylyl cyclase →↓ cAMP +   Open cardiac K channels →↓ heart rate

Golf

Odorants (olfactory epithelium)

↑ Adenylyl cyclase →↑ cAMP

Go

Neurotransmitters in brain (not yet specifically identified)

Not yet clear

Gq

Acetylcholine (muscarinic), bombesin, serotonin (5-HT2), and many others

↑ Phospholipase C →↑ IP3, diacylglycerol, cytoplasmic Ca2+

Gt1, Gt2

Photons (rhodopsin and color opsins in retinal rod and cone cells)

↑ cGMP phosphodiesterase →↓ cGMP (phototransduction)

VII VI

Inside

V

OH OH

elicit different G protein–dependent responses in different cells. For instance, the body responds to danger by using catecholamines (norepinephrine and epinephrine) both to increase heart rate and to induce constriction of blood vessels in the skin, by acting on Gs-coupled β adrenoceptors and Gq-coupled α1 adrenoceptors, respectively. Ligand promiscuity also offers opportunities in drug development (see Receptor Classes & Drug Development in the following text). Receptors that signal via G proteins are often called “G protein– coupled receptors” (GPCRs). GPCRs make up the largest receptor family and are also called “seven-transmembrane” (7TM) or “serpentine” receptors because the receptor polypeptide chain “snakes” across the plasma membrane seven times (Figure 2–11). Receptors for adrenergic amines, serotonin, acetylcholine (muscarinic but not nicotinic), many peptide hormones, odorants, and light receptors (in retinal rod and cone cells) all belong to the GPCR family. A few GPCRs (eg, GABAB and metabotropic glutamate receptors) require stable assembly into homodimers (complexes of two identical receptor polypeptides) or heterodimers (complexes of different isoforms) for functional activity. However, in contrast to tyrosine kinase and cytokine receptors, oligomerization is not universally required for GPCR activation, and many GPCRs are thought to function as monomers. GPCRs can bind agonists in a variety of ways, but they all appear to transduce signals across the plasma membrane in a similar way. Agonist binding (eg, a catecholamine or acetylcholine) stabilizes a conformational state of the receptor in which the cytoplasmic ends of the transmembrane helices spread apart by about 1 nm, opening a cavity in the receptor’s cytoplasmic surface that binds a critical regulatory surface of the G protein. This reduces nucleotide affinity

IV

C

HO

cAMP, cyclic adenosine monophosphate; cGMP, cyclic guanosine monophosphate; IP3, inositol-1,4,5-trisphosphate.

III

Ag

OH

G protein

FIGURE 2–11  Transmembrane topology of a typical “serpentine” GPCR. The receptor’s amino (N) terminal is extracellular (above the plane of the membrane), and its carboxyl (C) terminal intracellular, with the polypeptide chain “snaking” across the membrane seven times. The hydrophobic transmembrane segments (light color) are designated by Roman numerals (I–VII). Agonist (Ag) approaches the receptor from the extracellular fluid and binds to a site surrounded by the transmembrane regions of the receptor protein. G protein interacts with cytoplasmic regions of the receptor, especially around the third cytoplasmic loop connecting transmembrane regions V and VI. Lateral movement of these helices during activation exposes an otherwise buried cytoplasmic surface of the receptor that promotes guanine nucleotide exchange on the G protein and thereby activates the G protein, as discussed in the text. The receptor’s cytoplasmic terminal tail contains numerous serine and threonine residues whose hydroxyl (-OH) groups can be phosphorylated. This phosphorylation is associated with diminished receptor–G protein coupling and can promote receptor endocytosis. for the G protein, allowing GDP to dissociate and GTP to replace it (this occurs because GTP is normally present in the cytoplasm at much higher concentration than GDP). The GTP-bound form of G protein then dissociates from the receptor and can engage downstream mediators. Thus GPCR–G protein coupling involves coordinated conformational change in both proteins, allowing agonist binding to the receptor to effectively “drive” a nucleotide exchange reaction that “switches” the G protein from its inactive (GDP-bound) to active (GTP-bound) form. Figure 2–11 shows the main components schematically. Many high-resolution structures of GPCRs, and several of active-conformation GPCRs in complex with G protein, are available from the Protein Data Bank (www.rcsb.org). Such information provides deep insight into the actions and basis for specificity of existing GPCR-directed drugs, and it is beginning to be used to discover new drug leads through computational chemistry approaches.

Receptor Regulation G protein–mediated responses to drugs and hormonal agonists often attenuate with time (Figure 2–12A). After reaching an initial high level, the response (eg, cellular cAMP accumulation, Na+ influx, contractility, etc) diminishes over seconds or minutes, even

CHAPTER 2  Drug Receptors & Pharmacodynamics    33

A

Agonist

Response (cAMP)

1

2

3

4

1

5

2

Time Agonist in extracellular space

B

1

2 –OH

–OH

GRK –OH ATP

–OH –OH

–OH

5

P

Gs

P

Coated pit

P

β−Arr

3

4 6

P'ase

P

–OH –OH –OH

Lysosome

Endosomes

P P

FIGURE 2–12  Rapid desensitization, resensitization, and downregulation of β adrenoceptors. A: Response to a β-adrenoceptor agonist (ordinate) versus time (abscissa). (Numbers refer to the phases of receptor function in B.) Exposure of cells to agonist (indicated by the lightcolored bar) produces a cyclic AMP (cAMP) response. A reduced cAMP response is observed in the continued presence of agonist; this “desensitization” typically occurs within a few minutes. If agonist is removed after a short time (typically several to tens of minutes, indicated by broken line on abscissa), cells recover full responsiveness to a subsequent addition of agonist (second light-colored bar). This “resensitization” fails to occur, or occurs incompletely, if cells are exposed to agonist repeatedly or over a more prolonged time period. B: Agonist binding to receptors initiates signaling by promoting receptor interaction with G proteins (Gs) located in the cytoplasm (step 1 in the diagram). Agonist-activated receptors are phosphorylated by a G protein–coupled receptor kinase (GRK), preventing receptor interaction with Gs and promoting binding of a different protein, β-arrestin (β-Arr), to the receptor (step 2). The receptor-arrestin complex binds to coated pits, promoting receptor internalization (step 3). Dissociation of agonist from internalized receptors reduces β-Arr binding affinity, allowing dephosphorylation of receptors by a phosphatase (P’ase, step 4). Depending on the receptor, and on the agonist concentration achieved in the endosome, a second phase of G protein activation can occur internally before receptors recycle to the plasma membrane (step 5). Recycling of receptors serves to “resensitize” cellular responsiveness by restoring functional receptors at the cell surface, where they can initiate signaling again in response to agonist. The efficiency and rate of this recycling process depends on the GPCR, the physiological state of the cell, and on pharmacological variables including agonist concentration and duration of exposure. In general, repeated or prolonged agonist exposure favors the delivery of internalized receptors to lysosomes rather than their recycling to the cell surface (step 6), causing receptors to down-regulate and reducing, rather than recovering, cellular signaling responsiveness to agonist.

34    SECTION I  Basic Principles

in the continued presence of the agonist. In some cases, this desensitization phenomenon is rapidly reversible; a second exposure to agonist, if provided a few minutes after termination of the first exposure, can produce a response similar to that produced initially. In other cases, the desensitized state is more persistent, resulting in a longer-lasting suppression of the cell or tissue response. Multiple mechanisms contribute to desensitization of GPCRs. One well-understood mechanism involves phosphorylation of the receptor. The agonist-induced change in conformation of the β-adrenoceptor causes it not only to activate G protein, but also to recruit and activate a family of protein kinases called G protein–coupled receptor kinases (GRKs). GRKs phosphorylate serine and threonine residues in the receptor’s cytoplasmic tail (Figure 2–12B), diminishing the ability of activated β adrenoceptors to activate Gs and increasing the receptor’s affinity for binding a third protein, arrestin or β-arrestin. Binding of β-arrestin to the receptor further diminishes the receptor’s ability to interact with Gs, attenuating the cellular response (ie, stimulation of adenylyl cyclase as discussed below). Upon removal of agonist, phosphorylation by the GRK is terminated, β-arrestin can dissociate, and cellular phosphatases reverse the desensitized state and allow activation to occur again upon another encounter with agonist. For β adrenoceptors, and for many other GPCRs, β-arrestin can produce additional effects. One effect is to accelerate endocytosis of β adrenoceptors from the plasma membrane. This can down-regulate β adrenoceptors if receptors subsequently travel to lysosomes, by a process similar to the downregulation of EGF receptors. However, endocytosis of β adrenoceptors can also accelerate dephosphorylation of receptors by exposing them to phosphatase enzymes in endosomes (see Figure 2–12B). This enables receptors to return to the plasma membrane by recycling to signal again and, in some cases, it also enables receptors to initiate a second round of G protein activation from endosomes. In addition, β-arrestin may itself promote signaling by serving as a molecular scaffold that binds to other signaling proteins. Accordingly, β-arrestin can confer on GPCRs a great deal of flexibility in overall signaling and regulation. This may provide an opportunity to achieve additional selectivity in drug action through GPCRs, a concept called functional selectivity or agonist bias, whose clinical utility is presently under investigation.

Well-Established Second Messengers A.  Cyclic Adenosine Monophosphate (cAMP) Acting as an intracellular second messenger, cAMP mediates such hormonal responses as the mobilization of stored energy (the breakdown of carbohydrates in liver or triglycerides in fat cells stimulated by β-adrenomimetic catecholamines), conservation of water by the kidney (mediated by vasopressin), Ca2+ homeostasis (regulated by parathyroid hormone), and increased rate and contractile force of heart muscle (β-adrenomimetic catecholamines). It also regulates the production of adrenal and sex steroids (in response to corticotropin or follicle-stimulating hormone), relaxation of smooth muscle, and many other endocrine and neural processes. cAMP exerts most of its effects by stimulating cAMP-dependent protein kinases (Figure 2–13). These kinases are composed of a

Agonist

Gs

Rec

ATP

Membrane

AC

5'-AMP

cAMP PDE

R2 cAMP4

R2C2

2C* ATP

ADP S~P

S Pi P'ase

Response

FIGURE 2–13  The cAMP second messenger pathway. Key proteins include hormone receptors (Rec), a stimulatory G protein (Gs), catalytic adenylyl cyclase (AC), phosphodiesterases (PDE) that hydrolyze cAMP, cAMP-dependent kinases, with regulatory (R) and catalytic (C) subunits, protein substrates (S) of the kinases, and phosphatases (P’ase), which remove phosphates from substrate proteins. Open arrows denote regulatory effects. cAMP-binding regulatory (R) dimer and two catalytic (C) chains. When cAMP binds to the R dimer, active C chains are released to diffuse through the cytoplasm and nucleus, where they transfer phosphate from ATP to appropriate substrate proteins, often enzymes. The specificity of the regulatory effects of cAMP resides in the distinct protein substrates of the kinases that are expressed in different cells. For example, the liver is rich in phosphorylase kinase and glycogen synthase, enzymes whose reciprocal regulation by cAMP-dependent phosphorylation governs carbohydrate storage and release. When the hormonal stimulus stops, the intracellular actions of cAMP are terminated by an elaborate series of enzymes. cAMPstimulated phosphorylation of enzyme substrates is rapidly reversed by a diverse group of specific and nonspecific phosphatases. cAMP itself is degraded to 5′-AMP by several cyclic nucleotide phosphodiesterases (PDEs; see Figure 2–13). Milrinone, a selective inhibitor of type 3 phosphodiesterases that are expressed in cardiac muscle cells, has been used as an adjunctive agent in treating acute heart failure. Competitive inhibition of cAMP degradation is one way that caffeine, theophylline, and other methylxanthines produce their effects (see Chapter 20). B.  Phosphoinositides and Calcium Another well-studied second messenger system involves hormonal stimulation of phosphoinositide hydrolysis (Figure 2–14).

CHAPTER 2  Drug Receptors & Pharmacodynamics    35

Agonist

R

G

PIP2

PLC

IP3

DAG

PK-C* ATP

Ca2+

Membrane

S

CaM

ADP S~P

Pi E

CaM-E *

Response

FIGURE 2–14  The Ca2+-phosphoinositide signaling pathway. Key proteins include hormone receptors (R), a G protein (G), a phosphoinositide-specific phospholipase C (PLC), protein kinase C substrates of the kinase (S), calmodulin (CaM), and calmodulinbinding enzymes (E), including kinases, phosphodiesterases, etc. (PIP2, phosphatidylinositol-4,5-bisphosphate; DAG, diacylglycerol; IP3, inositol trisphosphate. Asterisk denotes activated state. Open arrows denote regulatory effects.) Some of the hormones, neurotransmitters, and growth factors that trigger this pathway bind to receptors linked to G proteins, whereas others bind to receptor tyrosine kinases. In all cases, the crucial step is stimulation of a membrane enzyme, phospholipase C (PLC), which splits a minor phospholipid component of the plasma membrane, phosphatidylinositol-4,5-bisphosphate (PIP2), into two second messengers, diacylglycerol (DAG) and inositol-1,4,5-trisphosphate (IP3 or InsP3). Diacylglycerol is confined to the membrane, where it activates a phospholipidand calcium-sensitive protein kinase called protein kinase C. IP3 is water-soluble and diffuses through the cytoplasm to trigger release of Ca2+ by binding to ligand-gated calcium channels in the limiting membranes of internal storage vesicles. Elevated cytoplasmic Ca2+ concentration resulting from IP3-promoted opening of these channels promotes the binding of Ca2+ to the calcium-binding protein calmodulin, which regulates activities of other enzymes, including calcium-dependent protein kinases. With its multiple second messengers and protein kinases, the phosphoinositide signaling pathway is much more complex than the cAMP pathway. For example, different cell types may contain one or more specialized calcium- and calmodulin-dependent kinases with limited substrate specificity (eg, myosin light-chain kinase) in addition to a general calcium- and calmodulindependent kinase that can phosphorylate a wide variety of protein substrates. Furthermore, at least nine structurally distinct types of protein kinase C have been identified. As in the cAMP system, multiple mechanisms damp or terminate signaling by this pathway. IP3 is inactivated by dephosphorylation;

diacylglycerol is either phosphorylated to yield phosphatidic acid, which is then converted back into phospholipids, or it is deacylated to yield arachidonic acid; Ca2+ is actively removed from the cytoplasm by Ca2+ pumps. These and other nonreceptor elements of the calciumphosphoinositide signaling pathway are of considerable importance in pharmacotherapy. For example, lithium ion, used in treatment of bipolar (manic-depressive) disorder, affects the cellular metabolism of phosphoinositides (see Chapter 29). C.  Cyclic Guanosine Monophosphate (cGMP) Unlike cAMP, the ubiquitous and versatile carrier of diverse messages, cGMP has established signaling roles in only a few cell types. In the retina, cGMP mediates vision and is destroyed by hydrolysis in response to light, mediated by a phosphodiesterase stimulated by a G protein coupled to the light-activated GPCR rhodopsin. In intestinal mucosa and vascular smooth muscle, the cGMP-based signal transduction mechanism closely parallels the cAMP-mediated signaling mechanism. Ligands detected by cell-surface receptors stimulate membrane-bound guanylyl cyclase to produce cGMP, and cGMP acts by stimulating a cGMP-dependent protein kinase. The actions of cGMP in these cells are terminated by enzymatic degradation of the cyclic nucleotide and by dephosphorylation of kinase substrates. Increased cGMP concentration causes relaxation of vascular smooth muscle by a kinase-mediated mechanism that results in dephosphorylation of myosin light chains (see Figure 12–2). In these smooth muscle cells, cGMP synthesis can be elevated by two transmembrane signaling mechanisms utilizing two different guanylyl cyclases. Atrial natriuretic peptide, a bloodborne peptide hormone, stimulates a transmembrane receptor by binding to its extracellular domain, thereby activating the guanylyl cyclase activity that resides in the receptor’s intracellular domain. The other mechanism mediates responses to nitric oxide (NO; see Chapter 19), which is generated in vascular endothelial cells in response to natural vasodilator agents such as acetylcholine and histamine. After entering the target cell, nitric oxide binds to and activates a cytoplasmic guanylyl cyclase (see Figure 19–2). A number of useful vasodilating drugs, such as nitroglycerin and sodium nitroprusside used in treating cardiac ischemia and acute hypertension, act by generating or mimicking nitric oxide. Other drugs produce vasodilation by inhibiting specific phosphodiesterases, thereby interfering with the metabolic breakdown of cGMP. One such drug is sildenafil, used in treating erectile dysfunction and pulmonary hypertension (see Chapter 12).

Interplay Among Signaling Mechanisms The calcium-phosphoinositide and cAMP signaling pathways oppose one another in some cells and are complementary in others. For example, vasopressor agents that contract smooth muscle act by IP3-mediated mobilization of Ca2+, whereas agents that relax smooth muscle often act by elevation of cAMP. In contrast, cAMP and phosphoinositide second messengers act together to stimulate glucose release from the liver.

36    SECTION I  Basic Principles

Isolation of Signaling Mechanisms The opposite of signal interplay is seen in some situations—an effective isolation of signaling according to location in the cell. For example, calcium signaling in the heart is highly localized because calcium released into the cytoplasm is rapidly sequestered by nearby calcium-binding proteins and is locally pumped from the cytoplasm into the sarcoplasmic reticulum. Even the second messenger cAMP can have surprisingly local effects, with signals mediated by the same messenger effectively isolated according to location. Here, it appears that signal isolation occurs by local hydrolysis of the second messenger by phosphodiesterase enzymes and by physical scaffolding of signaling pathway components into organized complexes that allow cAMP to transduce its local effects before hydrolysis. One mechanism by which phosphodiesterase inhibitor drugs produce toxic effects may be through “scrambling” local cAMP signals within the cell.

Phosphorylation: A Common Theme Almost all second messenger signaling involves reversible phosphorylation, which performs two principal functions in signaling: amplification and flexible regulation. In amplification, rather like GTP bound to a G protein, the attachment of a phosphoryl group to a serine, threonine, or tyrosine residue powerfully amplifies the initial regulatory signal by recording a molecular memory that the pathway has been activated; dephosphorylation erases the memory, taking a longer time to do so than is required for dissociation of an allosteric ligand. In flexible regulation, differing substrate specificities of the multiple protein kinases regulated by second messengers provide branch points in signaling pathways that may be independently regulated. In this way, cAMP, Ca2+, or other second messengers can use the presence or absence of particular kinases or kinase substrates to produce quite different effects in different cell types. Inhibitors of protein kinases have great potential as therapeutic agents, particularly in neoplastic diseases. Trastuzumab, an antibody that antagonizes growth factor signaling by the HER2 tyrosine kinase receptor (discussed earlier), is used for treating breast cancer. Imatinib, a small molecule inhibitor of the cytoplasmic tyrosine kinase Abl, is used for treating chronic myelogenous leukemia caused by a chromosomal translocation event that produces an inappropriate Bcr/Abl fusion protein with unregulated kinase activity.

RECEPTOR CLASSES & DRUG DEVELOPMENT The existence of a specific drug receptor is usually inferred from studying the structure-activity relationship of a group of structurally similar congeners of the drug that mimic or antagonize its effects. Thus, if a series of related agonists exhibits identical relative potencies in producing two distinct effects, it is likely that the two effects are mediated by similar or identical receptor molecules. In addition, if identical receptors mediate both effects, a competitive antagonist will inhibit both responses with the same Ki; a second competitive antagonist will inhibit both responses with its own

characteristic Ki. Thus, studies of the relation between structure and activity of a series of agonists and antagonists can identify a species of receptor that mediates a set of pharmacologic responses. Exactly the same experimental procedure can show that observed effects of a drug are mediated by different receptors. In this case, effects mediated by different receptors may exhibit different orders of potency among agonists and different Ki values for each competitive antagonist. Wherever we look, evolution has created many different receptors that function to mediate responses to any individual chemical signal. In some cases, the same chemical acts on completely different structural receptor classes. For example, acetylcholine uses ligand-gated ion channels (nicotinic AChRs) to initiate a fast (in milliseconds) excitatory postsynaptic potential (EPSP) in postganglionic neurons. Acetylcholine also activates a separate class of G protein–coupled receptors (muscarinic AChRs), which mediate slower (seconds to minutes) modulatory effects on the same neurons. In addition, each structural class usually includes multiple subtypes of receptor, often with significantly different signaling or regulatory properties. For example, many biogenic amines (eg, norepinephrine, acetylcholine, histamine, and serotonin) activate more than one receptor, each of which may activate a different G protein, as previously described (see also Table 2–1). The existence of many receptor classes and subtypes for the same endogenous ligand has created important opportunities for drug development. For example, propranolol, a selective antagonist of β adrenoceptors, can reduce an accelerated heart rate without preventing the sympathetic nervous system from causing vasoconstriction, an effect mediated by α1 adrenoceptors. The principle of drug selectivity may even apply to structurally identical receptors expressed in different cells, eg, receptors for steroids (see Figure 2–6). Different cell types express different accessory proteins, which interact with steroid receptors and change the functional effects of drug-receptor interaction. For example, tamoxifen is a drug that binds to steroid receptors naturally activated by estrogen. Tamoxifen acts as an antagonist on estrogen receptors expressed in mammary tissue but as an agonist on estrogen receptors in bone. Consequently, tamoxifen may be useful not only in the treatment of breast cancer but also in the prevention of osteoporosis by increasing bone density (see Chapters 40 and 42). Tamoxifen may create complications in postmenopausal women, however, by exerting an agonist action in the uterus, stimulating endometrial cell proliferation. New drug development is not confined to agents that act on receptors for extracellular chemical signals. Increasingly, pharmaceutical chemists are determining whether elements of signaling pathways distal to the receptors may also serve as targets of selective and useful drugs. We have already discussed drugs that act on phosphodiesterase and some intracellular kinases. Several new kinase inhibitors and modulators are presently in therapeutic trials, and there has been recent progress in developing inhibitors of GTP-binding transducer proteins that function downstream of tyrosine kinase growth factor receptors. This includes selective inhibitors for an activated form of K-Ras (G12C mutation) that is produced (due to somatic mutation) in many tumors and that causes a pathologic stimulation of growth factor signaling

CHAPTER 2  Drug Receptors & Pharmacodynamics    37

pathways in the absence of upstream receptor activation. These drugs are now used in the therapy of lung cancer.

RELATION BETWEEN DRUG DOSE & CLINICAL RESPONSE In this chapter, we have dealt with receptors as molecules and shown how receptors can quantitatively account for the relation between dose or concentration of a drug and pharmacologic responses, at least in an idealized system. When faced with a patient who needs treatment, the prescriber must make a choice among a variety of possible drugs and devise a dosage regimen that is likely to produce maximal benefit and minimal toxicity. To make rational therapeutic decisions, the prescriber must understand how drug-receptor interactions underlie the relations between dose and response in patients, the nature and causes of variation in pharmacologic responsiveness, and the clinical implications of selectivity of drug action.

Dose & Response in Patients A.  Graded Dose-Response Relations To choose among drugs and to determine appropriate doses of a drug, the prescriber must know the relative pharmacologic potency and maximal efficacy of the drugs in relation to the desired therapeutic effect. These two important terms, often confusing to students and clinicians, can be explained by referring to Figure 2–15, which depicts graded dose-response curves that relate the dose of four different drugs to the magnitude of a particular therapeutic effect. 1. Potency—Drugs A and B are said to be more potent than drugs C and D because of the relative positions of their doseresponse curves along the dose axis in Figure 2–15. Potency

A C

Response

D

B

Log drug dose

FIGURE 2–15  Graded dose-response curves for four drugs, illustrating different pharmacologic potencies and different maximal efficacies. (See text.)

refers to the concentration (EC50) or dose (ED50) of a drug required to produce 50% of that drug’s maximal effect. Thus, the pharmacologic potency of drug A in Figure 2–15 is less than that of drug B, a partial agonist because the EC50 of A is greater than the EC50 of B. Potency of a drug depends in part on the affinity (Kd) of receptors for binding the drug and in part on the efficiency with which drug-receptor interaction is coupled to response. Note that some doses of drug A can produce larger effects than any dose of drug B, despite the fact that we describe drug B as pharmacologically more potent. The reason for this is that drug A has a larger maximal efficacy (as described below). For therapeutic purposes, the potency of a drug should be stated in dosage units, usually in terms of a particular therapeutic end point (eg, 50 mg for mild sedation, 1 mcg/kg/min for an increase in heart rate of 25 bpm). Relative potency, the ratio of equi-effective doses (0.2, 10, etc), may be used in comparing one drug with another. 2. Maximal efficacy—This parameter reflects the limit of the dose-response relation on the response axis. Drugs A, C, and D in Figure 2–15 have equal maximal efficacy, and all have greater maximal efficacy than drug B. The maximal efficacy (sometimes referred to simply as efficacy) of a drug is obviously crucial for making clinical decisions when a large response is needed. It may be determined by the drug’s mode of interactions with receptors (as with partial agonists)* or by characteristics of the receptoreffector system involved. Thus, diuretics that act on one portion of the nephron may produce much greater excretion of fluid and electrolytes than diuretics that act elsewhere. In addition, the practical efficacy of a drug for achieving a therapeutic end point (eg, increased cardiac contractility) may be limited by the drug’s propensity to cause a toxic effect (eg, fatal cardiac arrhythmia) even if the drug could otherwise produce a greater therapeutic effect. B.  Shape of Dose-Response Curves Although the responses depicted in curves A, B, and C of Figure 2–15 approximate the shape of a simple Michaelis– Menten relation (transformed to a logarithmic plot), some clinical responses do not. Extremely steep dose-response curves (eg, curve D) may have important clinical consequences if the upper portion of the curve represents an undesirable extent of response (eg, coma caused by a sedative-hypnotic). Steep dose-response curves in patients can result from cooperative interactions of several different actions of a drug (eg, effects on brain, heart, and peripheral vessels, all contributing to lowering of blood pressure). * Note that “maximal efficacy,” used in a therapeutic context, does not have exactly the same meaning that the term denotes in the more specialized context of drug-receptor interactions described earlier in this chapter. In an idealized in vitro system, efficacy denotes the relative maximal efficacy of agonists and partial agonists that act via the same receptor. In therapeutics, efficacy denotes the extent or degree of an effect that can be achieved in the intact patient. Thus, therapeutic efficacy may be affected by the characteristics of a particular drug-receptor interaction, but it also depends on a host of other factors as noted in the text.

38    SECTION I  Basic Principles

C.  Quantal Dose-Effect Curves Graded dose-response curves of the sort described above have certain limitations in their application to clinical decision making. For example, such curves may be impossible to construct if the pharmacologic response is an either-or (quantal) event, such as prevention of convulsions, arrhythmia, or death. Furthermore, the clinical relevance of a quantitative dose-response relation in a single patient, no matter how precisely defined, may be limited in application to other patients, owing to the great potential variability among patients in severity of disease and responsiveness to drugs. Some of these difficulties may be avoided by determining the dose of drug required to produce a specified magnitude of effect in a large number of individual patients or experimental animals and plotting the cumulative frequency distribution of responders versus the log dose (Figure 2–16). The specified quantal effect may be chosen on the basis of clinical relevance (eg, relief of headache) or for preservation of safety of experimental subjects (eg, using low doses of a cardiac stimulant and specifying an increase in heart rate of 20 bpm as the quantal effect), or it may be an inherently quantal event (eg, death of an experimental animal). For most drugs, the doses required to produce a specified quantal effect in individuals are lognormally distributed; that is, a frequency distribution of such responses plotted against the log of the dose produces a gaussian normal curve of variation (colored areas; see Figure 2–16). When these responses are summated, the resulting cumulative frequency distribution constitutes a quantal dose-effect curve (or dose-percent curve) of the proportion or percentage of individuals who exhibit the effect plotted as a function of log dose.

Percent individuals responding

100

Cumulative percent exhibiting therapeutic effect

Cumulative percent dead at each dose

50 Percent requiring dose for a lethal effect

Percent requiring dose to achieve desired effect

1.25 2.5

5

ED50

10 20 40 80 160 320 640 Dose (mg) LD50

FIGURE 2–16  Quantal dose-effect plots. Shaded boxes (and the accompanying bell-shaped curves) indicate the frequency distribution of doses of drug required to produce a specified effect; that is, the percentage of animals that required a particular dose to exhibit the effect. The open boxes (and the corresponding colored curves) indicate the cumulative frequency distribution of responses, which are lognormally distributed.

The quantal dose-effect curve is often characterized by stating the median effective dose (ED50), which is the dose at which 50% of individuals exhibit the specified quantal effect. (Note that the abbreviation ED50 has a different meaning in this context from its meaning in relation to graded dose-effect curves, described in previous text.) Similarly, the dose required to produce a particular toxic effect in 50% of animals is called the median toxic dose (TD50). If the toxic effect is death of the animal, a median lethal dose (LD50) may be experimentally defined. Such values provide a convenient way of comparing the potencies of drugs in experimental and clinical settings: Thus, if the ED50s of two drugs for producing a specified quantal effect are 5 and 500 mg, respectively, then the first drug can be said to be 100 times more potent than the second for that particular effect. Similarly, one can obtain a valuable index of the selectivity of a drug’s action by comparing its ED50s for two different quantal effects in a population (eg, cough suppression versus sedation for opioid drugs). Quantal dose-effect curves may also be used to generate information regarding the margin of safety to be expected from a particular drug used to produce a specified effect. One measure, which relates the dose of a drug required to produce a desired effect to that which produces an undesired effect, is the therapeutic index. In animal studies, the therapeutic index is usually defined as the ratio of the TD50 to the ED50 for some therapeutically relevant effect. The precision possible in animal experiments may make it useful to use such a therapeutic index to estimate the potential benefit of a drug in humans. Of course, the therapeutic index of a drug in humans is almost never known with real precision; instead, drug trials and accumulated clinical experience often reveal a range of usually effective doses and a different (but sometimes overlapping) range of possibly toxic doses. The range between the minimum toxic dose and the minimum therapeutic dose is called the therapeutic window and is of greater practical value in choosing the dose for a patient. The clinically acceptable risk of toxicity depends critically on the severity of the disease being treated. For example, the dose range that provides relief from an ordinary headache in the majority of patients should be very much lower than the dose range that produces serious toxicity, even if the toxicity occurs in a small minority of patients. However, for treatment of a lethal disease such as Hodgkin lymphoma, the acceptable difference between therapeutic and toxic doses may be smaller. Finally, note that the quantal dose-effect curve and the graded dose-response curve summarize somewhat different sets of information, although both appear sigmoid in shape on a semilogarithmic plot (compare Figures 2–15 and 2–16). Critical information required for making rational therapeutic decisions can be obtained from each type of curve. Both curves provide information regarding the potency and selectivity of drugs; the graded dose-response curve indicates the maximal efficacy of a drug, and the quantal dose-effect curve indicates the potential variability of responsiveness among individuals.

Variation in Drug Responsiveness Individuals may vary considerably in their response to a drug; indeed, a single individual may respond differently to the same

CHAPTER 2  Drug Receptors & Pharmacodynamics    39

drug at different times during the course of treatment. Occasionally, individuals exhibit an unusual or idiosyncratic drug response, one that is infrequently observed in most patients. The idiosyncratic responses are usually caused by genetic differences in metabolism of the drug or by immunologic mechanisms, including allergic reactions. Quantitative variations in drug response are, in general, more common and more clinically important. An individual patient is hyporeactive or hyperreactive to a drug in that the intensity of effect of a given dose of drug is diminished or increased compared with the effect seen in most individuals. (Note: The term hypersensitivity usually refers to allergic or other immunologic responses to drugs.) With some drugs, the intensity of response to a given dose may change during the course of therapy; in these cases, responsiveness usually decreases as a consequence of continued drug administration, producing a state of relative tolerance to the drug’s effects. When responsiveness diminishes rapidly after administration of a drug, the response is said to be subject to tachyphylaxis. Even before administering the first dose of a drug, the prescriber should consider factors that may help in predicting the direction and extent of possible variations in responsiveness. These include the propensity of a particular drug to produce tolerance or tachyphylaxis as well as the effects of age, sex, body size, disease state, genetic factors, and simultaneous administration of other drugs. Four general mechanisms may contribute to variation in drug responsiveness among patients or within an individual patient at different times. A.  Alteration in Concentration of Drug That Reaches the Receptor As described in Chapter 3, patients may differ in the rate of absorption of a drug, in distributing it through body compartments, or in clearing the drug from the blood. By altering the concentration of drug that reaches relevant receptors, such pharmacokinetic differences may alter the clinical response. Some differences can be predicted on the basis of age, weight, sex, disease state, and liver and kidney function, and by testing specifically for genetic differences that may result from inheritance of a functionally distinctive complement of drug-metabolizing enzymes (see Chapters 4 and 5). Another important mechanism influencing drug availability is active transport of drug from the cytoplasm, mediated by a family of membrane transporters encoded by the so-called multidrug resistance (MDR) genes. For example, up-regulation of MDR gene-encoded transporter expression is a major mechanism by which tumor cells develop resistance to anticancer drugs. B.  Variation in Concentration of an Endogenous Receptor Ligand This mechanism contributes greatly to variability in responses to pharmacologic antagonists. Thus, propranolol, a β-adrenoceptor antagonist, markedly slows the heart rate of a patient whose endogenous catecholamines are elevated (as in pheochromocytoma) but does not affect the resting heart rate of a well-trained marathon runner. A partial agonist may exhibit even more dramatically

different responses: Saralasin, a weak partial agonist at angiotensin II receptors, lowers blood pressure in patients with hypertension caused by increased angiotensin II production and raises blood pressure in patients who produce normal amounts of angiotensin. C.  Alterations in Number or Function of Receptors Experimental studies have documented changes in drug response caused by increases or decreases in the number of receptor sites or by alterations in the efficiency of coupling of receptors to distal effector mechanisms. In some cases, the change in receptor number is caused by other hormones; for example, thyroid hormones increase both the number of β adrenoceptors in rat heart muscle and cardiac sensitivity to catecholamines. Similar changes probably contribute to the tachycardia of thyrotoxicosis in patients and may account for the usefulness of propranolol, a β-adrenoceptor antagonist, in ameliorating symptoms of this disease. In other cases, the agonist ligand itself induces a decrease in the number (eg, downregulation) or coupling efficiency (eg, desensitization) of its receptors. These mechanisms (discussed previously under Signaling Mechanisms & Drug Action) may contribute to two clinically important phenomena: first, tachyphylaxis or tolerance to the effects of some drugs (eg, biogenic amines and their congeners), and second, the “overshoot” phenomena that follow withdrawal of certain drugs. These phenomena can occur with either agonists or antagonists. An antagonist may increase the number of receptors in a critical cell or tissue by preventing downregulation caused by an endogenous agonist. When the antagonist is withdrawn, the elevated number of receptors can produce an exaggerated response to physiologic concentrations of agonist. Potentially disastrous withdrawal symptoms can result for the opposite reason when administration of an agonist drug is discontinued. In this situation, the number of receptors, which has been decreased by drug-induced downregulation, is too low for endogenous agonist to produce effective stimulation. For example, the withdrawal of clonidine (a drug whose α2-adrenoceptor agonist activity reduces blood pressure) can produce hypertensive crisis, probably because the drug down-regulates α2 adrenoceptors (see Chapter 11). The study of genetic factors determining drug response is called pharmacogenetics, and the use of gene sequencing or expression profile data to tailor therapies specific to an individual patient is called personalized or precision medicine. For example, somatic mutations affecting the tyrosine kinase domain of the epidermal growth factor receptor in lung cancers can confer enhanced sensitivity to kinase inhibitors such as gefitinib. This effect enhances the antineoplastic effect of the drug, and because the somatic mutation is specific to the tumor and not present in the host, the therapeutic index of these drugs can be significantly enhanced in patients whose tumors harbor such mutations. Genetic analysis can also predict drug resistance during treatment or identify new targets for therapy based on rapid mutation of the tumor in the patient. D.  Changes in Components of Response Distal to the Receptor Although a drug initiates its actions by binding to receptors, the response observed in a patient depends on the functional integrity of

40    SECTION I  Basic Principles

biochemical processes in the responding cell and physiologic regulation by interacting organ systems. Clinically, changes in these postreceptor processes represent the largest and most important class of mechanisms that cause variation in responsiveness to drug therapy. Before initiating therapy with a drug, the prescriber should be aware of patient characteristics that may limit the clinical response. These characteristics include the age and general health of the patient and—most importantly—the severity and pathophysiologic mechanism of the disease. The most important potential cause of failure to achieve a satisfactory response is that the diagnosis is wrong or physiologically incomplete. Drug therapy is most successful when it is accurately directed at the pathophysiologic mechanism responsible for the disease. When the diagnosis is correct and the drug is appropriate, an unsatisfactory therapeutic response can often be traced to compensatory mechanisms in the patient that respond to and oppose the beneficial effects of the drug. Compensatory increases in sympathetic nervous tone and fluid retention by the kidney, for example, can contribute to tolerance to antihypertensive effects of a vasodilator drug. In such cases, additional drugs may be required to achieve a useful therapeutic result.

Clinical Selectivity: Beneficial Versus Toxic Effects of Drugs Although we classify drugs according to their principal actions, it is clear that no drug causes only a single, specific effect. Why is this so? It is exceedingly unlikely that any kind of drug molecule will bind to only a single type of receptor molecule, if only because the number of potential receptors in every patient is astronomically large. Even if the chemical structure of a drug allowed it to bind to only one kind of receptor, the biochemical processes controlled by such receptors would take place in many cell types and would be coupled to many other biochemical functions; as a result, the patient and the prescriber would probably perceive more than one drug effect. Accordingly, drugs are only selective—rather than specific—in their actions, because they bind to one or a few types of receptor more tightly than to others and because these receptors control discrete processes that result in distinct effects. It is only because of their selectivity that drugs are useful in clinical medicine. Selectivity can be measured by comparing binding affinities of a drug to different receptors or by comparing ED50s for different effects of a drug in vivo. In drug development and in clinical medicine, selectivity is usually considered by separating effects into two categories: beneficial or therapeutic effects versus toxic or adverse effects. Pharmaceutical advertisements and prescribers occasionally use the term side effect, implying that the effect in question is insignificant or occurs via a pathway that is to one side of the principal action of the drug; such implications are frequently erroneous. A.  Beneficial and Toxic Effects Mediated by the Same Receptor-Effector Mechanism Much of the serious drug toxicity in clinical practice represents a direct pharmacologic extension of the therapeutic actions of the drug. In some of these cases (eg, bleeding caused by anticoagulant

therapy; hypoglycemic coma due to insulin), toxicity may be avoided by judicious management of the dose of drug administered, guided by careful monitoring of effect (measurements of blood coagulation or serum glucose) and aided by ancillary measures (avoiding tissue trauma that may lead to hemorrhage; regulation of carbohydrate intake). In still other cases, the toxicity may be avoided by not administering the drug at all, if the therapeutic indication is weak or if other therapy is available. In certain situations, a drug is clearly necessary and beneficial but produces unacceptable toxicity when given in doses that produce optimal benefit. In such situations, it may be necessary to add another drug to the treatment regimen. In treating hypertension, for example, administration of a second drug often allows the prescriber to reduce the dose and toxicity of the first drug (see Chapter 11). B.  Beneficial and Toxic Effects Mediated by Identical Receptors but in Different Tissues or by Different Effector Pathways Many drugs produce both their desired effects and adverse effects by acting on a single receptor type in different tissues. Examples discussed in this book include digitalis glycosides, which act by inhibiting Na+/K+-ATPase in cell membranes; methotrexate, which inhibits the enzyme dihydrofolate reductase; and glucocorticoid hormones. Three therapeutic strategies are used to avoid or mitigate this sort of toxicity. First, the drug should always be administered at the lowest dose that produces acceptable benefit. Second, adjunctive drugs that act through different receptor mechanisms and produce different toxicities may allow lowering the dose of the first drug, thus limiting its toxicity (eg, use of other immunosuppressive agents added to glucocorticoids in treating inflammatory disorders). Third, selectivity of the drug’s actions may be increased by manipulating the concentrations of drug available to receptors in different parts of the body, for example, by aerosol administration of a glucocorticoid to the bronchi in asthma. C.  Beneficial and Toxic Effects Mediated by Different Types of Receptors Therapeutic advantages resulting from new chemical entities with improved receptor selectivity were mentioned earlier in this chapter and are described in detail in later chapters. Many receptors, such as those for catecholamines, histamine, acetylcholine, and corticosteroids, and their associated therapeutic uses were discovered by analyzing effects of the physiologic chemical signals. This approach continues to be fruitful. For example, microRNAs (miRNAs), small RNAs that regulate protein expression by binding to protein-coding (messenger) RNAs, were linked recently to Duchenne muscular dystrophy. Current preclinical investigations include the potential utility of RNA-based therapy for this and other diseases. Other drugs were discovered by exploiting therapeutic or toxic effects of chemically similar agents observed in a clinical context. Examples include quinidine, the sulfonylureas, thiazide diuretics, tricyclic antidepressants, opioid drugs, and phenothiazine antipsychotics. Often such agents turn out to interact with receptors for endogenous substances (eg, opioids and phenothiazines for endogenous opioid and dopamine receptors, respectively). This approach

CHAPTER 2  Drug Receptors & Pharmacodynamics    41

is evolving toward understanding the structural details of how chemically similar agents differ in binding to receptors. For example, x-ray crystallography of β1 and β2 adrenoceptors shows that their orthosteric binding sites are identical; drugs discriminate between subtypes based on differences in traversing a divergent “vestibule” to access the orthosteric site. Many GPCRs have such passages, revealing a new basis for improving the selectivity of GPCR-targeted drugs. Thus, the propensity of drugs to bind to different classes of receptor sites is not only a potentially vexing problem in treating patients, but it also presents a continuing challenge to pharmacology and an opportunity for developing new and more useful drugs.

REFERENCES Brodlie M et al: Targeted therapies to improve CFTR function in cystic fibrosis. Genome Med 2015;7:101. Catterall WA, Lenaeus MJ, Gamal El-Din TM: Structure and pharmacology of voltage-gated sodium and calcium channels. Ann Rev Pharmacol Toxicol 2020;60:133.

Chen Q, Tesmer JJG: G protein-coupled receptor interactions with arrestins and GPCR kinases: the unresolved issue of signal bias. J Biol Chem 2022;298:102279. Dang CV et al: Drugging the ‘undruggable’ cancer targets. Nat Rev Cancer 2017;17:502. Gouaux E, MacKinnon R: Principles of selective ion transport in channels and pumps. Science 2005;310:1461. Hilger D et al: Structure and dynamics of GPCR signaling complexes. Nat Struct Mol Biol 2018;25:4. Irwin JJ, Shoichet BK: Docking screens for novel ligands conferring new biology. J Med Chem 2016;59:4103. Kenakin T: Biased receptor signaling in drug discovery. Pharmacol Rev 2019;71:267. Kovacs E et al: A structural perspective on the regulation of the epidermal growth factor receptor. Annu Rev Biochem 2015;84:739. Sprang SR: Activation of G proteins by GTP and the mechanism of Gα-catalyzed GTP hydrolysis. Biopolymers 2016;105:449. Terrar DA: Calcium signaling in the heart. Adv Exp Med Biol 2020;1131:395. Von Zastrow M, Sorkin A: Mechanisms for regulating and organizing receptor signaling by endocytosis. Annu Rev Biochem 2021;90:709.

C ASE STUDY ANSWER Propranolol, a β-adrenoceptor antagonist, is a useful antihypertensive agent because it reduces cardiac output and probably vascular resistance as well. However, it also prevents β-adrenoceptor–induced bronchodilation and therefore may precipitate bronchoconstriction in susceptible individuals. Calcium channel blockers such as verapamil also reduce blood pressure but, because they act on a different target, rarely cause bronchoconstriction or prevent bronchodilation. An alternative approach in this patient

would be to use a more highly selective adrenoceptor antagonist drug (such as metoprolol) that binds preferentially to the β1 subtype, which is a major β adrenoceptor in the heart, and has a lower affinity (ie, higher Kd) for binding the β2 subtype that mediates bronchodilation. Selection of the most appropriate drug or drug group for one condition requires awareness of the other conditions a patient may have and the receptor selectivity of the drug groups available.

C

H

3 A

P

T

E

R

Pharmacokinetics & Pharmacodynamics: Rational Dosing & the Time Course of Drug Action Nicholas H. G. Holford, MB, ChB, FRACP

C ASE STUDY An 85-year-old, 60-kg woman with a serum creatinine of 1.8 mg/dL has atrial fibrillation. A decision has been made to use digoxin to control the rapid heart rate. The target concentration of digoxin for the treatment of atrial

The goal of therapeutics is to achieve a desired beneficial effect with minimal adverse effects. When a medicine has been selected for a patient, the clinician must determine the dose that most closely achieves this goal. A rational approach to this objective combines the principles of pharmacokinetics with pharmacodynamics to understand the dose-effect relationship (Figure 3–1). Pharmacodynamics governs the concentration-effect part of the relationship, whereas pharmacokinetics deals with the dose-concentration part (Holford & Sheiner, 1981). The pharmacodynamic concepts of maximum response and sensitivity determine the magnitude of the effect at a particular concentration (see Emax and C50, Chapter 2; C50 is also known as EC50). The pharmacokinetic processes of input, distribution, and elimination determine how rapidly and for how long the target organ will be exposed to the drug. Figure 3–1 illustrates a fundamental hypothesis of pharmacology, namely, that a relationship exists between a beneficial or toxic effect of a drug and the concentration of the drug. This hypothesis has been documented for many drugs, as indicated by the target concentration column in Table 3–1. The target concentration is 42

fibrillation is 1 mg/mL. Tablets of digoxin are available that contain 62.5 micrograms (mcg) and 250 mcg. What maintenance dose would you recommend?

the concentration that reflects a balance between the beneficial and adverse effects. The apparent lack of such a relationship for some drugs does not weaken the basic hypothesis but points to the need to consider the time course of concentration at the actual site of pharmacologic effect (see below). Knowing the relationship between dose, drug concentration, and effects allows the clinician to take into account the various pathologic and physiologic features of a particular patient that make him or her different from the average individual in responding to a drug. The importance of pharmacokinetics and pharmacodynamics in patient care thus rests upon the improvement in therapeutic benefit and reduction in toxicity that can be achieved by application of these principles.

PHARMACOKINETICS The “standard” dose of a drug is based on trials in healthy subjects and patients with average ability to absorb, distribute, and eliminate the drug (see section Clinical Trials: The IND & NDA in Chapter 1).

CHAPTER 3  Pharmacokinetics & Pharmacodynamics: Rational Dosing & the Time Course of Drug Action      43

Dose of drug administered Input Distribution

Drug concentration in systemic circulation

Drug in tissues of distribution

Pharmacokinetics

Elimination Drug metabolized or excreted Drug concentration at site of action Pharmacologic effect Pharmacodynamics Clinical response Toxicity

Effectiveness

FIGURE 3–1  The relationship between dose and effect can be separated into pharmacokinetic (dose-concentration) and pharmacodynamic (concentration-effect) components. Concentration provides the link between pharmacokinetics and pharmacodynamics and is the focus of the target concentration approach to rational dosing. The three primary processes of pharmacokinetics are input, distribution, and elimination.

This dose will not be suitable for every patient. Several physiologic processes (eg, body size, maturation of organ function in neonates and infants) and pathologic processes (eg, heart failure, renal failure) may be used for dosage adjustment in individual patients. Individual differences in these physiological and pathological processes are associated with specific pharmacokinetic and pharmacodynamic properties (usually referred to as parameters) of the drug. The two basic pharmacokinetic parameters are volume of distribution, the measure of the apparent space in the body available to contain the drug, and clearance, the measure of the ability of the body to eliminate the drug. These parameters are illustrated schematically in Figure 3–2, where the volume of the beakers into which the drugs diffuse represents the volume of distribution, and the size of the outflow “drain” in Figures 3–2B and 3–2D represents the clearance.

of the physical volumes of the body (Table 3–2). Volume of distribution often exceeds any physical volume in the body because it is the volume apparently necessary to contain the amount of drug homogeneously at the concentration found in the blood, plasma, or water. Drugs with very high volumes of distribution have much higher concentrations in extravascular tissue than in the vascular compartment, ie, they are not homogeneously distributed. Drugs that are completely retained within the vascular compartment, on the other hand, would have a minimum possible volume of distribution equal to the plasma component in which they are distributed, eg, 0.04 L/kg body weight or 2.8 L/70 kg (see Table 3–2) for a drug that is restricted to the plasma compartment.

Volume of Distribution

Drug clearance concepts are similar to clearance concepts of renal physiology. Clearance of a drug is the factor that predicts the rate of elimination in relation to the drug concentration (C):

Volume of distribution (V) relates the amount of drug in the body to the concentration of drug (C) in blood or plasma:





(1)

The volume of distribution may be defined with respect to blood, plasma, or water (unbound drug), depending on the concentration used in equation (1) (C = Cb, Cp, or Cu). That the V calculated from equation (1) is an apparent volume may be appreciated by comparing the volumes of distribution of drugs such as digoxin or chloroquine (see Table 3–1) with some

Clearance





(2)

Clearance, like volume of distribution, may be defined with respect to blood (CLb), plasma (CLp), or unbound in water (CLu), depending on where and how the concentration is measured. It is important to note the additive character of clearance. Elimination of drug from the body may involve processes occurring in the kidney, the lung, the liver, and other organs. Dividing the rate of elimination at each organ by the concentration of drug yields

44    SECTION I  Basic Principles

TABLE 3−1  Pharmacokinetic and pharmacodynamic parameters for selected drugs in adults. (See Holford et al, 2013, for parameters in neonates and children.)

Drug

Oral Availability (F) (%)

Urinary Excretion (%)1

Bound in Plasma (%)

Clearance (L/h/70 kg)2

Volume of Distribution (L/70 kg)

Half-Life (h)

Target Concentration

Toxic Concentration

Acetaminophen

88

3

0

21

67

2

15 mg/L

>300 mg/L

Acyclovir

23

75

15

19.8

48

2.4

…

… 3

Amikacin

…

98

4

5.46

19

2.3

10 mg/L …

…

Amoxicillin

93

86

18

10.8

15

1.7

…

…

Amphotericin

…

4

90

1.92

53

18

…

…

Ampicillin

62

82

18

16.2

20

1.3

…

…

Aspirin

68

1

49

39

11

0.25

…

…

Atenolol

56

94

5

10.2

67

6.1

1 mg/L

…

Atropine

50

57

18

24.6

120

4.3

…

…

Captopril

65

38

30

50.4

57

2.2

50 ng/mL

…

Carbamazepine

70

1

74

5.34

98

15

6 mg/L

>9 mg/L

Cephalexin

90

91

14

18

18

0.9

…

…

Cephalothin

…

52

71

28.2

18

0.57

…

…

Chloramphenicol

80

25

53

10.2

66

2.7

…

…

Chlordiazepoxide

100

1

97

2.28

21

10

1 mg/L

…

Chloroquine

89

61

61

45

13,000

214

20 ng/mL

250 ng/mL

Chlorpropamide

90

20

96

0.126

6.8

33

…

…

Cimetidine

62

62

19

32.4

70

1.9

0.8 mg/L

…

Ciprofloxacin

60

65

40

25.2

130

4.1

…

…

Clonidine

95

62

20

12.6

150

12

1 ng/mL

…

Cyclosporine

30

1

98

23.9

244

15

200 ng/mL

>400 ng/mL

Diazepam

100

1

99

1.62

77

43

300 ng/mL

…

Digoxin

70

67

25

9

500

39

1 ng/mL

>2 ng/mL

Diltiazem

44

4

78

50.4

220

3.7

…

…

Disopyramide

83

55

2

5.04

41

6

3 mg/mL

>8 mg/mL

Enalapril

95

90

55

9

40

3

>0.5 ng/mL

…

Erythromycin

35

12

84

38.4

55

1.6

…

…

Ethambutol

77

79

5

36

110

3.1

…

>10 mg/L

Fluoxetine

60

3

94

40.2

2500

53

…

…

Furosemide

61

66

99

8.4

7.7

1.5

…

>25 mg/L 3

Gentamicin

…

76

10

4.7

20

3

3 mg/L

…

Hydralazine

40

10

87

234

105

1

100 ng/mL

…

Imipramine

40

2

90

63

1600

18

200 ng/mL

>1 mg/L

Indomethacin

98

15

90

8.4

18

2.4

1 mg/L

>5 mg/L

Labetalol

18

5

50

105

660

4.9

0.1 mg/L

…

Lidocaine

35

2

70

38.4

77

1.8

3 mg/L

>6 mg/L

Lithium

100

95

0

1.5

55

22

0.7 mEq/L

>2 mEq/L

Meperidine

52

12

58

72

310

3.2

0.5 mg/L

… (continued)

CHAPTER 3  Pharmacokinetics & Pharmacodynamics: Rational Dosing & the Time Course of Drug Action      45

TABLE 3−1  Pharmacokinetic and pharmacodynamic parameters for selected drugs in adults. (See Holford et al, 2013, for parameters in neonates and children.) (Continued)

Drug

Oral Availability (F) (%)

Urinary Excretion (%)1

Bound in Plasma (%)

Clearance (L/h/70 kg)2

Volume of Distribution (L/70 kg)

Half-Life (h)

Target Concentration

Toxic Concentration

Methotrexate

70

48

34

9

39

7.2

750 μM-h4,5

>950 μM-h

Metoprolol

38

10

11

63

290

3.2

25 ng/mL

…

Metronidazole

99

10

10

5.4

52

8.5

4 mg/L

…

Midazolam

44

56

95

27.6

77

1.9

…

…

Morphine

24

8

35

60

230

1.9

15 ng/mL

…

Nifedipine

50

0

96

29.4

55

1.8

50 ng/mL

…

Nortriptyline

51

2

92

30

1300

31

100 ng/mL

>500 ng/mL

Phenobarbital

100

24

51

0.258

38

98

15 mg/L

>30 mg/L

Phenytoin

90

2

89

Conc dependent5

45

Conc dependent6

10 mg/L

>20 mg/L

Prazosin

68

1

95

12.6

42

2.9

…

…

Procainamide

83

67

16

36

130

3

5 mg/L

>14 mg/L

Propranolol

26

1

87

50.4

270

3.9

20 ng/mL

…

Pyridostigmine

14

85

…

36

77

1.9

75 ng/mL

…

Quinidine

80

18

87

19.8

190

6.2

3 mg/L

>8 mg/L

Ranitidine

52

69

15

43.8

91

2.1

100 ng/mL

…

Rifampin

?

7

89

14.4

68

3.5

…

…

Salicylic acid

100

15

85

0.84

12

13

200 mg/L

>200 mg/L

Sulfamethoxazole

100

14

62

1.32

15

10

…

…

7

3

8

8

133

28

10 mcg/L

…

Tacrolimus

20

…

98

Terbutaline

14

56

20

14.4

125

14

2 ng/mL

…

Tetracycline

77

58

65

7.2

105

11

…

…

Theophylline

96

18

56

2.8

35

8.1

10 mg/L

>20 mg/L

Tobramycin

…

90

10

4.62

18

2.2

…

…

Tocainide

89

38

10

10.8

210

14

10 mg/L

…

Tolbutamide

93

0

96

1.02

7

5.9

100 mg/L

…

Trimethoprim

100

69

44

9

130

11

…

…

Tubocurarine

…

63

50

8.1

27

2

0.6 mg/L

…

Valproic acid

100

2

93

0.462

9.1

14

75 mg/L

>150 mg/L

Vancomycin

…

79

30

5.88

27

5.6

20 mg/L

…

Verapamil

22

3

90

63

350

4

…

…

Warfarin

93

3

99

0.192

9.8

37

…

…

Zidovudine

63

18

25

61.8

98

1.1

…

…

1

Assuming creatinine clearance 100 mL/min/70 kg.

2

Convert to mL/min by multiplying the number given by 16.6.

3

Average steady-state concentration.

4

Target area under the concentration-time curve after a single dose.

5

Can be estimated from measured C using CL = Vmax/(Km + C); Vmax = 415 mg/d, Km = 5 mg/L. See text.

6

Varies because of concentration-dependent clearance.

7

Bound in whole blood (%).

8

3

Based on whole blood standardized to hematocrit 45%.

46    SECTION I  Basic Principles

TABLE 3−2  Physical volumes (in L/kg body weight)

of some body compartments into which drugs may be distributed.

Concentration

A

Blood

0

Time

Extravascular volume

Blood

Extravascular volume

Blood

  Extracellular water (0.2 L/kg)

Larger water-soluble molecules: eg, gentamicin

  Plasma (0.04 L/kg)

Large protein molecules: eg, antibodies

Fat (0.2−0.35 L/kg)

Highly lipid-soluble molecules: eg, diazepam

Bone (0.07 L/kg)

Certain ions: eg, lead, fluoride

Time

the respective clearance at that organ. Added together, these separate clearances equal total systemic clearance: 0

Time













Concentration

D

Small water-soluble molecules: eg, ethanol

An average figure. Total body water in a young lean person might be 0.7 L/kg; in an obese person, 0.5 L/kg.

Concentration

C

  Total body water (0.6 L/kg1)

1

0

Blood

Examples of Drugs

Water

Concentration

B

Compartment and Volume

0

Time

FIGURE 3–2  Models of drug distribution and elimination. The effect of adding drug to the blood by rapid intravenous injection is represented by injecting a known amount of the agent into a beaker. The time course of the amount of drug in the beaker is shown in the graphs at the right. In the first example (A), there is no movement of drug out of the beaker, so the graph shows only a steep rise to a maximum followed by a plateau. In the second example (B), a route of elimination is present, and the graph shows a slow decay after a sharp rise to a maximum. Because the amount of agent in the beaker falls, the “pressure” driving the elimination process also falls, and the slope of the curve decreases. This is an exponential decay curve. In the third model (C), drug placed in the first compartment (“blood”) equilibrates rapidly with the second compartment (“extravascular volume”) and the amount of drug in “blood” declines exponentially to a new steady state. The fourth model (D) illustrates a more realistic combination of elimination mechanism and extravascular equilibration. The resulting graph shows an early distribution phase followed by the slower elimination phase. Note that the volume of fluid remains constant because of a fluid input at the same rate as elimination in (B) and (D).

(3a) (3b) (3c)



(3d)

“Other” tissues of elimination could include the lungs and additional sites of metabolism, eg, blood or muscle. The two major sites of drug elimination are the kidneys and the liver. Measurement of unchanged drug in the urine may be used to determine renal clearance. Within the liver, drug elimination occurs via biotransformation of parent drug to one or more metabolites, or excretion of unchanged drug into the bile, or both. Elimination of drug by the liver is difficult to measure directly, unlike renal elimination, so hepatic clearance is often assumed to be the difference between total systemic clearance and renal clearance. The pathways of biotransformation are discussed in Chapter 4. For most drugs, clearance is constant over the concentration range encountered in clinical settings, ie, elimination is not saturable, and the rate of drug elimination is directly proportional to concentration (rearranging equation [2]):



(4)

When elimination is directly proportional to C, this is called first-order elimination. When clearance is first-order, it can be estimated by calculating the area under the curve (AUC) of the timeconcentration profile after a dose. Clearance is calculated from the dose divided by the AUC. Note that this is a convenient form of calculation—not the definition of clearance.

CHAPTER 3  Pharmacokinetics & Pharmacodynamics: Rational Dosing & the Time Course of Drug Action      47





(5)

The maximum elimination capacity is Vmax, and Km is the drug concentration at which the rate of elimination is 50% of Vmax. At concentrations that are high relative to the Km, the elimination rate is almost independent of concentration—a state of “pseudozero order” elimination. If dosing rate exceeds elimination capacity, steady state cannot be achieved. The concentration will keep on rising as long as dosing continues. This pattern of capacitylimited elimination is important for three drugs in common use: ethanol, phenytoin, and aspirin. Clearance has no real meaning for drugs with capacity-limited elimination because it varies with concentration, and AUC should not be used to calculate clearance of such drugs. B.  Flow-Dependent Elimination In contrast to capacity-limited drug elimination, some drugs are cleared very readily by the organ of elimination, so that at any clinically realistic concentration of the drug, most of the drug in the blood perfusing the organ is eliminated on the first pass of the drug through the organ. The elimination of these drugs will thus depend primarily on the rate of drug delivery to the organ of elimination. Such drugs (see Table 4–7) can be called “high-extraction” drugs since they are almost completely extracted from the blood by the organ. Blood flow to the organ is the main determinant of drug delivery, but plasma protein binding and blood cell partitioning may also be important for extensively bound drugs that are highly extracted. C.  Large Molecules There are two aspects to the pharmacokinetics of proteins, often referred to as large molecules, when used as therapeutic agents. The first is that they all have much the same pharmacokinetics with a half-life of a couple of weeks. The second is that for some, but not all, the effect of the molecule is produced by binding to the target site. Elimination of the molecule is to some extent determined by the elimination of the target (eg, T cells). This is called target-mediated drug disposition. When target-mediated disposition occurs, the clearance of the molecule is increased and the half-life gets shorter. The time course of the effect of the molecule often follows the resulting changes in the time course of drug concentration.

Half-Life Half-life (t1/2) is the time required to change the amount of drug in the body by one-half during elimination (or during a constant infusion). In the simplest case—and the most useful in designing drug dosage regimens—the body may be considered as a single compartment (as illustrated in Figure 3–2B) of a size equal to the volume of distribution (V). The time course of drug in the body will depend on both the volume of distribution and the clearance:



(6)



Because drug elimination can be described by an exponential process, the time taken for a twofold decrease can be shown to be proportional to the natural logarithm of 2. The constant 0.7 in equation (6) is an approximation to the natural logarithm of 2. The elimination half-life is useful because it indicates the time required to attain 50% of steady state—or to decay 50% from steady-state conditions—after a change in the rate of drug input. Figure 3–3 shows the time course of drug accumulation during a constant-rate drug infusion and the time course of drug elimination after stopping an infusion that has reached steady state. Disease states can affect both of the physiologically related primary pharmacokinetic parameters: volume of distribution and clearance. A change in elimination half-life will not necessarily reflect a change in drug elimination. For example, patients with chronic renal failure have both decreased renal clearance of digoxin and a decreased volume of distribution; the increase in digoxin elimination half-life is not as great as might be expected based on the change in renal function. The decrease in volume of distribution is due to the decreased renal and skeletal muscle mass and consequent decreased tissue binding of digoxin to Na+/K+-ATPase.

100

Plasma concentration (% of steady state)

A.  Capacity-Limited Elimination For drugs that exhibit capacity-limited elimination (eg, phenytoin, ethanol), clearance does not remain constant but will vary depending on the concentration of drug that is achieved (see Table 3–1). Capacity-limited elimination is also known as mixed-order, saturable, nonlinear, and Michaelis-Menten elimination. It is associated with dose- or concentration-dependent clearance. Most drug elimination pathways by metabolism will become saturated if the dose and therefore the concentration are high enough. When blood flow to an organ does not limit elimination (see below), the relation between elimination rate and concentration (C) is expressed mathematically in equation (5):

75

Accumulation

50 Elimination

25 0

0

1

2

3 5 4 Time (half-lives)

6

7

8

FIGURE 3–3  The time course of drug accumulation and elimination. Solid line: Plasma concentrations reflecting drug accumulation during a constant-rate infusion of a drug. Fifty percent of the steady-state concentration is reached after one half-life, 75% after two half-lives, and over 90% after four half-lives. Dashed line: Plasma concentrations reflecting drug elimination after a constant-rate infusion of a drug had reached steady state. Fifty percent of the drug is lost after one half-life, 75% after two half-lives, etc. The “rule of thumb” that four half-lives must elapse after starting a drug-dosing regimen before full effects will be seen is based on the approach of the accumulation curve to over 90% of the final steady-state concentration.

48    SECTION I  Basic Principles

Many drugs will exhibit multicompartment pharmacokinetics (as illustrated in Figures 3–2C and 3–2D). Under these conditions, the “half-life” describing drug accumulation, as given in Table 3–1, will be greater than that calculated from equation (6).

Drug Accumulation Whenever drug doses are repeated, the drug will accumulate in the body until dosing stops. This is because it takes an infinite time (in theory) to eliminate all of a given dose. In practical terms, this means that if the dosing interval is shorter than four half-lives, accumulation will be detectable. Accumulation is inversely proportional to the fraction of the dose lost in each dosing interval. The fraction lost is 1 minus the fraction remaining just before the next dose. The fraction remaining can be predicted from the dosing interval and the half-life. A convenient index of accumulation is the accumulation factor:

TABLE 3−3  Routes of administration, bioavailability, and general characteristics.

Route

Bioavailability (%)

Characteristics

Intravenous (IV)

100 (by definition)

Most rapid onset

Intramuscular (IM)

75 to ≤100

Large volumes often feasible; may be painful

Subcutaneous (SC)

75 to ≤100

Smaller volumes than IM; may be painful

Oral (PO)

5 to × > 2.25 = EM, and >2.25 = UM (ultrarapid metabolizer). For more information regarding nomenclature, see https://www.pharmvar.org/genes.

CYP2D6 As described in Chapter 4, cytochrome P450 2D6 (CYP2D6) is involved in the metabolism of up to one-quarter of all drugs used clinically, including predominantly basic compounds such as β blockers, antidepressants, antipsychotics, and opioid analgesics. Similar to other polymorphic enzymes, four clinically defined metabolic phenotypes, ie, PMs, IMs, EMs, and UMs, are used to predict therapeutic and adverse responses following the administration of CYP2D6 substrates. The gene encoding CYP2D6 is highly polymorphic, with more than 100 alleles defined (https://www.pharmvar.org/gene/ CYP2D6); however, greater than 95% of phenotypes can be accounted for with just nine alleles, ie, CYP2D6 alleles *3, *4, *5, and *6 are nonfunctional; alleles *10, *17, and *41 have reduced function; and alleles *1 and *2 are fully functional. As with many polymorphisms, allele frequencies vary across populations (Table 5–1). Some genetic variants are shared among populations at similar allele frequencies, whereas others vary considerably.

CHAPTER 5  Pharmacogenomics    79

TABLE 5–1  Major alleles and frequencies in African, Asian, and European populations. Allele(s)1

dbSNP2 Number

Amino Acid

Function

Activity

Fraction in African Populations

 

*1

Reference

—

Normal

1.0

0.39

0.34

0.54

 

*1 × N

Gene duplication or multiplication

Increased expression

Increased

1.0 × N

0.015

0.0028

0.0080

 

*2

rs16947, rs1135840

R296C, S486T

Normal

1.0

0.20

0.13

0.27

 

*2 × N

Duplication or multiplication

Increased expression

Increased

1.0 × N

0.016

0.0038

0.013

 

*3

rs35742686

Frameshift

None

0.0

0.00030

0.00

0.013

 

*4

rs1065852, rs3892097

P34S, Splicing defect

None

0.0

0.034

0.0042

0.19

 

*5

—

No enzyme

None

0.0

0.061

0.056

0.027

 

*6

rs5030655

Frameshift

None

0.0

0.031

0.0002

0.0095

 

*10

rs1065852, rs1135840

P34S, S486T

Decreased

0.25

0.068

0.42

0.032

 

*17

rs28371706, rs16947, rs1135840

T107I, R296C, S486T

Decreased

0.5

0.20

0.0001

0.0032

 

*41

rs16947, rs1135840, rs28371725

R296C, S486T, Splicing defect

Decreased

0.5

0.11

0.020

0.086

 

*1

Reference

—

Normal

—

0.68

0.60

0.63

 

*2

rs4244285

Splicing defect

None

—

0.15

0.29

0.15

 

*3

rs4986893

W212X

None

—

0.0052

0.089

0.0042

 

*17

rs12248560

Increased expression

Increased

—

0.16

0.027

0.21

 

*1

Reference

—

Normal

—

 

 

 

 

*2

rs1799853

R144C

Decreased

—

0.03

0.00

0.13

 

*3

rs1057910

I359L

Decreased

—

0.02

0.04

0.07

 

*1

 

 

Normal

 

0.36

0.58

0.53

 

*4

rs2279343

K262R

Increased

 

0.0093

0.090

0.040

 

*6

rs2279343, rs3745274

K262R , Q172H

Decreased

 

0.34

0.20

0.20

 

*9

rs3745274

Q172H

Decreased

 

0.084

0.060

0.015

 

*18

rs28399499

I328T

None

 

0.052

0.00

0.00

 

*1

Reference

—

Normal

1.0

 

 

 

 

*2A

rs3918290

Splicing defect

None

0.0

0.0006

0.0037

0.0080

 

*13

rs55886062

I560S

None

0.0

0.00

0.00

0.0006

 

—

rs67376798

D949V

Decreased

0.5

0.0006

0.0005

0.00370

 

HapB3

rs56038477

E412E

Decreased

0.5

0.0018

0.0094

0.0204

 

*1

Reference

TA6

Normal

—

0.50

0.85

0.68

 

*28

rs8175347

TA7

Decreased

—

0.39

0.15

0.32

 

*36

rs8175347

TA5

Increased

—

0.066

0.00

0.00

 

*37

rs8175347

TA8

Decreased

—

0.036

0.00

0.0010

Gene

Fraction in Asian Populations

Fraction in European Populations

CYP2D6

CYP2C19

CYP2C9

CYP2B6

DPYD

UGT1A1

(continued)

80    SECTION I  Basic Principles

TABLE 5–1  Major alleles and frequencies in African, Asian, and European populations. (Continued) Allele(s)1

dbSNP2 Number

Amino Acid

Function

Activity

Fraction in African Populations

 

*1

Reference

—

Normal

—

0.94

0.98

0.96

 

*2

rs1800462

A80P

None

—

0.00079

0.00

0.0019

 

*3A

rs1800460, rs1142345

A154T, Y240C

None

—

0.0020

0.00012

0.036

 

*3B

rs1800460

A154T

None

—

0.00

0.00

0.00046

 

*3C

rs1142345

Y240C

None

—

0.050

0.016

0.0042

 

B

Reference

—

Normal

IV

—

—

—

 

A

rs1050829

N126D

Normal

III–IV

0.31–0.35

0.00

0.00–0.060

 

A- (rs1050829, rs1050828)

(N126D, V68M)

III

0.117

n/a

0.00

A- (rs1050829, rs137852328)

(N126D, R227L)

Decreased (5–10%)

A- (rs1050829, rs76723693)

(N126D, L323P)

 

Mediterranean (rs5030868)

S188P

Decreased (A) or 50% (DPYD*2A and c.1679T>G) compared with DPYD wild-type patients. The relative risk for severe fluoropyrimidine-related toxicity was reduced with genotype-guided dosing, eg, 1.31 (95% CI 0.63–2.73) compared with 2.87 (2.14–3.86) in the historic cohort for DPYD*2A carriers. CPIC recommendations for therapeutic regimens are shown in Table 5–2.

PHASE II ENZYMES As described in Chapter 4, phase II enzyme biotransformation reactions typically conjugate endogenous molecules, eg, sulfuric acid, glucuronic acid, and acetic acid, onto a wide variety of substrates in order to enhance their elimination from the body. Consequently, polymorphic phase II enzymes may diminish drug elimination and increase risks for toxicities. In this section, we describe key examples of polymorphic phase II enzymes and the pharmacologic consequence for selected prescription drugs.

Uridine 5′-Diphosphoglucuronosyl Transferase 1 (UGT1A1) The uridine 5′-diphospho- (UDP) glucuronosyltransferase 1A1 (UGT1A1) enzyme, encoded by the UGT1A1 gene, conjugates glucuronic acid onto small lipophilic molecules, eg, bilirubin, and a wide variety of therapeutic drug substrates so that they may be more readily excreted into bile (Chapter 4). The UGT1A1 gene locus has more than 30 defined alleles, some of which lead to reduced or completely abolished UGT1A1 function. Most

reduced function polymorphisms within the UGT1A1 gene locus are quite rare; however, the *28 allele is common across three major ethnic groups (see Table 5–1). Approximately 10% of European populations are homozygous carriers of the *28 allele, ie, UGT1A1 *28/*28 genotype, and are recognized clinically to have Gilbert syndrome. The *28 allele is characterized by an extra TA repeated in the proximal promoter region and is associated with reduced expression of the UGT1A1 enzyme. Clinically, Gilbert syndrome is generally benign; however, affected individuals may have 60–70% increased levels of circulating unconjugated bilirubin due to a ∼30% reduction in UGT1A1 activity. Individuals with the UGT1A1*28/*28 genotype are thus at an increased risk for adverse drug reactions with UGT1A1 drug substrates due to reduced biliary elimination. Example: Irinotecan is a topoisomerase I inhibitor prodrug and is indicated as first-line chemotherapy in combination with 5-FU and leucovorin for treatment of metastatic carcinoma of the colon or rectum (Chapter 54). Irinotecan is hydrolyzed by hepatic carboxylesterase enzymes to its cytotoxic metabolite, SN-38, which inhibits topoisomerase I and eventually leads to termination of DNA replication and cell death. The active SN-38 metabolite is responsible for the majority of therapeutic action as well as the dose-limiting bone marrow and gastrointestinal toxicities. Inactivation of SN-38 occurs via the polymorphic UGT1A1 enzyme, and carriers of the UGT1A1*6 and UGT1A1*28 polymorphisms are consequently at increased risk for severe life-threatening toxicities, eg, neutropenia and diarrhea, due to decreased clearance of the SN-38 metabolite.

Thiopurine S-Methyltransferase (TPMT) Thiopurine S-methyltransferase (TPMT) covalently attaches a methyl group onto aromatic and heterocyclic sulfhydryl compounds and is responsible for the pharmacologic deactivation of thiopurine drugs (Chapter 4). Genetic polymorphisms in the gene encoding TPMT may lead to three clinical TPMT activity phenotypes, ie, high, intermediate, and low activity, which are associated with differing rates of inactivation of thiopurine drugs and altered risks for toxicities. While the majority (86–97%) of the population inherits two functional TPMT alleles and has high TPMT activity, around 10% of Europeans and Africans inherit only one functional allele and are considered to have intermediate activity. Furthermore, about 0.3% of Europeans inherit two defective alleles and have very low to no TPMT activity (see Table 5–1). More than 90% of the phenotypic TPMT variability across populations can be accounted for with just three point mutations that are defined by four nonfunctional alleles, ie, TPMT*2, *3A, *3B, and *3C (see Table 5–2). Most commercial genotyping platforms test for these four common genetic biomarkers and are therefore able to identify individuals with reduced TPMT activity. Example: Three thiopurine drugs are used clinically, ie, azathioprine, 6-mercaptopurine (6-MP), and 6-thioguanine (6-TG). All share similar metabolic pathways and pharmacology. Azathioprine (a prodrug of 6-MP) and 6-MP are used for treating immunologic disorders, while 6-MP and 6-TG are important anticancer agents (Chapter 54). 6-MP and 6-TG may be activated by the salvage pathway enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRTase) to form 6-thioguanine nucleotides (TGNs),

86    SECTION I  Basic Principles

which are responsible for the majority of therapeutic efficacy as well as bone marrow toxicity. Alternatively, 6-MP and 6-TG may be inactivated by enzymes such as polymorphic TPMT and xanthine oxidase, leaving less available substrate to be activated by HGPRTase. The TPMT gene is a major determinant of thiopurine metabolism and exposure to cytotoxic 6-TGN metabolites and thiopurine-related toxicities. See Table 5–2 for recommended dosing strategies. Recent GWA studies have also implicated variants in the enzyme NUDT15, which catalyzes the hydrolysis of nucleotide diphosphates, as being associated with thiopurine intolerance in children from Japan, Singapore, and Guatemala.

OTHER ENZYMES G6PD Glucose 6-phosphate dehydrogenase (G6PD) is the first and rate-limiting step in the pentose phosphate pathway and supplies a significant amount of reduced NADPH in the body. In red blood cells (RBCs), where mitochondria are absent, G6PD is the exclusive source of NADPH and reduced glutathione, which play a critical role in the prevention of oxidative damage. Under normal conditions, G6PD in RBCs is able to detoxify unstable oxygen species while working at just 2% of its theoretical capacity. Following exposure to exogenous oxidative stressors, eg, infection, fava beans, and certain therapeutic drugs, G6PD activity in RBCs increases proportionately to meet NADPH demands and ultimately to protect hemoglobin from oxidation. Individuals with G6PD deficiency, defined as less than 60% enzyme activity, according to World Health Organization classification (Table 5–3), are at increased risk for abnormal RBC destruction, ie, hemolysis, due to reduced antioxidant capacity under oxidative pressures. The gene that encodes the G6PD enzyme is located on the X chromosome and is highly polymorphic, with more than 180 genetic variants identified that result in enzyme deficiency. Greater than 90% of variants are single-base substitutions in the coding region that produce amino acid changes, which result in unstable proteins with reduced enzyme activity. As with most X-linked traits, males with one reference X chromosome and females with

TABLE 5–3  Classification of G6PD deficiency (WHO Working Group, 1989).

World Health Organization Class

Level of Deficiency

Enzyme Activity

I

Severe

A polymorphism, are at increased risk for excessive anticoagulation following standard warfarin dosages. Furthermore, warfarin is administered as a racemic mixture of R- and S-warfarin, and patients with reduced-function CYP2C9

genotypes are at increased risk for bleeding due to decreased metabolic clearance of the more potent S-warfarin enantiomer. It is predicted that gene-based dosing may help optimize warfarin therapy management and minimize risks for adverse drug reactions.

■■ EPIGENOMICS Recently, epigenomics, which is the heritable patterns of gene expression not attributable to changes in the primary DNA sequence, has become an active area of research that may provide additional insights into the causes of variability in drug response. Epigenomic mechanisms that can regulate genes involved in pharmacokinetics or drug targets include DNA methylation and histone modifications. Although there is still much to be understood, epigenomics may contribute to our knowledge of diseases as well as our understanding of individual phenotypes such as acquired drug resistance.

■■ FUTURE DIRECTIONS Discoveries in pharmacogenomics are increasing as new technologies for genotyping are being developed and as access to patient DNA samples along with drug response information has accelerated. Increasingly, pharmacogenomics discoveries will move beyond single SNPs to multiple SNPs that inform both adverse and therapeutic responses. It is hoped that prescriber-friendly predictive models incorporating SNPs and other biomarkers as well as information on demographics, comorbidities, epigenetic signatures, and concomitant medications will be developed to aid in drug and dose selection. CPIC guidelines and FDA-stimulated product label changes will contribute to the accelerated translation of discoveries to clinical practice.

REFERENCES Altman RB, Whirl-Carrillo M, Klein TE: Challenges in the pharmacogenomic annotation of whole genomes. Clin Pharmacol Ther 2013;94:211. Bertilsson DL: Geographical/interracial differences in polymorphic drug oxidation. Clin Pharmacokinet 1995;29:192. Browning LA, Kruse JA: Hemolysis and methemoglobinemia secondary to rasburicase administration. Ann Pharmacother 2005;39:1932. Camptosar [irinotecan product label]. New York, NY: Pfizer Inc.; 2012. Cappellini MD, Fiorelli G: Glucose-6-phosphate dehydrogenase deficiency. Lancet 2008;371:64. Caudle KE et al: Clinical Pharmacogenetics Implementation Consortium guidelines for dihydropyrimidine dehydrogenase genotype and fluoropyrimidine dosing. Clin Pharmacol Ther 2013;94:640. Chasman DI et al: Genetic determinants of statin-induced low-density lipoprotein cholesterol reduction: The Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) trial. Circ Cardiovasc Genet 2012;5:257. Crews KR et al: Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for codeine therapy in the context of cytochrome P450 2D6 (CYP2D6) genotype. Clin Pharmacol Ther 2009;91:321. Daly AK et al: HLA-B*5701 genotype is a major determinant of drug-induced liver injury due to flucloxacillin. Nat Genet 2009;41:816. Elitek [rasburicase product label]. Bridgewater, NJ: Sanofi U.S. Inc.; 2009. Gammal RS et al: Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for UGT1A1 and atazanavir prescribing. Clin Pharmacol Ther 2016;99:363.

CHAPTER 5  Pharmacogenomics    91 Giacomini KM et al: International Transporter Consortium commentary on clinically important transporter polymorphisms. Clin Pharmacol Ther 2013;94:23. Howes RE et al: G6PD deficiency prevalence and estimates of affected populations in malaria endemic countries: A geostatistical model-based map. PLoS Med 2012;9:e1001339. Howes RE et al: Spatial distribution of G6PD deficiency variants across malariaendemic regions. Malaria J 2013;12:418. Johnson JA, Klein TE, Relling MV: Clinical implementation of pharmacogenetics: More than one gene at a time. Clin Pharmacol Ther 2013;93:384. Johnson JA et al: Clinical Pharmacogenetics Implementation Consortium guidelines for CYP2C9 and VKORC1 genotypes and warfarin dosing. Clin Pharmacol Ther 2009;90:625. Kim IS et al: ABCG2 Q141K polymorphism is associated with chemotherapyinduced diarrhea in patients with diffuse large B-cell lymphoma who received frontline rituximab plus cyclophosphamide/doxorubicin/vincristine/prednisone chemotherapy. Cancer Sci 2008;99:2496. Lai-Goldman M, Faruki H: Abacavir hypersensitivity: A model system for pharmacogenetic test adoption. Genet Med 2008;10:874. Lavanchy D: Evolving epidemiology of hepatitis C virus. Clin Microbiol Infect 2011;17:107. Matsuura K, Watanabe T, Tanaka Y: Role of IL28B for chronic hepatitis C treatment toward personalized medicine. J Gastroenterol Hepatol 2014;29:241. McDonagh EM et al: PharmGKB summary: Very important pharmacogene information for G6PD. Pharmacogenet Genomics 2012;22:219. Minucci A et al: Glucose-6-phosphate dehydrogenase (G6PD) mutations database: Review of the “old” and update of the new mutations. Blood Cell Mol Dis 2012;48:154. Moriyama T et al: NUDT15 polymorphisms alter thiopurine metabolism and hematopoietic toxicity. Nat Genet 2016;48:367. Muir AJ et al: Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for IFNL3 (IL28B) genotype and peginterferon alpha based regimens. Clin Pharmacol Ther 2014;95:141. Relling MV et al: Clinical Pharmacogenetics Implementation Consortium guidelines for thiopurine methyltransferase genotype and thiopurine dosing. Clin Pharmacol Ther 2009;89:387. Russmann S, Jetter A, Kullak-Ublick GA: Pharmacogenetics of drug-induced liver injury. Hepatology 2010;52:748. Scott SA et al: Clinical Pharmacogenetics Implementation Consortium guidelines for CYP2C19 genotype and clopidogrel therapy: 2013 update. Clin Pharmacol Ther 2013;94:317. Shin J: Clinical pharmacogenomics of warfarin and clopidogrel. J Pharmacy Pract 2012;25:428.

Swen JJ et al: Pharmacogenetics: From bench to byte—an update of guidelines. Clin Pharmacol Ther 2009;89:662. Tukey RH, Strassburg CP: Human UDP-glucuronosyltransferases: Metabolism, expression, and disease. Annu Rev Pharmacol Toxicol 2000;40:581. Tukey RH, Strassburg CP, Mackenzie PI: Pharmacogenomics of human UDPglucuronosyltransferases and irinotecan toxicity. Mol Pharmacol 2002;62:446. Wen CC et al: Genome-wide association study identifies ABCG2 (BCRP) as an allopurinol transporter and a determinant of drug response. Clin Pharmacol Ther 2015;97:518. WHO Working Group: Glucose-6-phosphate dehydrogenase deficiency. Bull World Health Org 1989;67:601. Wilke RA et al: The Clinical Pharmacogenomics Implementation Consortium: CPIC guideline for SLCO1B1 and simvastatin-induced myopathy. Clin Pharmacol Ther 2009;92:112. Xu J-M: Severe irinotecan-induced toxicity in a patient with UGT1A1*28 and UGT1A1*6 polymorphisms. World J Gastroenterol 2013;19:3899. Yang J et al: Influence of CYP2C9 and VKORC1 genotypes on the risk of hemorrhagic complications in warfarin-treated patients: A systematic review and meta-analysis. Int J Cardiol 2013;168:4234.

Reviews Campbell JM et al: Irinotecan-induced toxicity pharmacogenetics: An umbrella review of systematic reviews and meta-analyses. Pharmacogenomics J 2017;17:21. Flockhart DA, Huang SM: Clinical pharmacogenetics. In: Atkinson AJ et al (editors): Principles of Clinical Pharmacology, 3rd ed. Elsevier, 2012. Huang SM, Chen L, Giacomini KM: Pharmacogenomic mechanisms of drug toxicity. In: Atkinson AJ et al (editors): Principles of Clinical Pharmacology, 3rd ed. Elsevier, 2012. Meulendijks D et al: Improving safety of fluoropyrimidine chemotherapy by individualizing treatment based on dihydropyrimidine dehydrogenase activity: Ready for clinical practice? Cancer Treat Rev 2016;50:23. Relling MV, Giacomini KM: Pharmacogenetics. In: Brunton LL, Chabner BA, Knollmann BC (editors): Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 12th ed. McGraw Hill, 2011. Relling MV et al: Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for rasburicase therapy in the context of G6PD deficiency genotype. Clin Pharmacol Ther 2014;96:169. Zanger UM, Schwab M: Cytochrome P450 enzymes in drug metabolism: Regulation of gene expression, enzyme activities, and impact of genetic variation. Pharmacol Ther 2013;138:103.

C ASE STUDY ANSWER Atazanavir inhibits the polymorphic UGT1A1 enzyme, which mediates the conjugation of glucuronic acid with bilirubin. Decreased UGT1A1 activity results in the accumulation of unconjugated (indirect) bilirubin in blood and tissues. When levels are high enough, yellow discoloration of the eyes and skin, ie, jaundice, is the result. The plasma levels of indirect bilirubin concentrations are expected to increase to greater than 2.5 times the upper limit of normal (grade 3 or higher elevations) in approximately 40% of patients taking once-daily

atazanavir boosted with ritonavir and at least five times the upper limit of normal (grade 4 elevation) in approximately 4.8% of patients. Carriers of the UGT1A1 decreased-function alleles (*28/*28 or *28/*37) have reduced enzyme activity and have an increased risk of atazanavir discontinuation. Genotyping showed that the patient was homozygous for the UGT1A1*28 allele polymorphism. This probably led to the high levels of bilirubin and the subsequent discontinuation of atazanavir secondary to the adverse drug reaction of jaundice.

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SECTION II  AUTONOMIC DRUGS

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Introduction to Autonomic Pharmacology

H

6 A

P

T

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Todd W. Vanderah, PhD, & Bertram G. Katzung, MD, PhD

C ASE STUDY A 56-year-old woman is brought to the university eye center with a complaint of “loss of vision.” Because of visual impairment, she has lost her driver’s license and has fallen several times in her home. Examination reveals that her eyelids close involuntarily with a frequency and duration sufficient to prevent her from seeing her surroundings for more than brief moments at a time. When she holds her eyelids open with her fingers, she can see normally. She has no other muscle

The nervous system is anatomically divided into the central nervous system (CNS; the brain and spinal cord) and the peripheral nervous system (PNS; neuronal tissues outside the CNS). Functionally, the nervous system can be divided into two major subdivisions: autonomic and somatic. The autonomic nervous system (ANS) is largely independent (autonomous) in that its activities are not under direct conscious control. It is concerned primarily with control and integration of visceral functions necessary for life such as cardiac output, blood flow distribution, and digestion. Evidence is accumulating that the ANS, especially the vagus nerve, also influences immune function and some CNS functions such as seizure

dysfunction. A diagnosis of blepharospasm is made. Using a fine needle, several injections of botulinum toxin type A are made in the orbicularis oculi muscle of each eyelid. After observation in the waiting area, she is sent home. Two days later, she reports by telephone that her vision has improved dramatically. How did botulinum toxin improve her vision? How long can her vision be expected to remain normal after this single treatment?

discharge. Remarkably, some evidence indicates that autonomic nerves can also influence cancer development and progression. The efferent (motor) portion of the somatic subdivision is largely concerned with consciously controlled functions such as movement, respiration, and posture. Both the autonomic and the somatic systems have important afferent (sensory) inputs that provide information regarding the internal and external environments and modify motor output through reflex arcs of varying complexity. The nervous system has several properties in common with the endocrine system. These include high-level integration in the brain, the ability to influence processes in distant regions of the 93

94    SECTION II  Autonomic Drugs

body, and extensive use of negative feedback. Both systems use chemicals for the transmission of information; the nervous system also uses electrical signaling. In the nervous system, chemical transmission occurs between nerve cells and between nerve cells and their effector cells. Chemical transmission takes place through the release of small amounts of transmitter substances from the nerve terminals into the synaptic cleft. The transmitter crosses the cleft by diffusion and activates or inhibits the postsynaptic cell by binding to a specialized receptor molecule. In a few cases, retrograde transmission may occur from the postsynaptic cell to the presynaptic neuron terminal and modify its subsequent activity. By using drugs that mimic or block the actions of chemical transmitters, we can selectively modify many autonomic functions. These functions involve a variety of effector tissues, including cardiac muscle, smooth muscle, vascular endothelium, exocrine glands, and presynaptic nerve terminals. Autonomic drugs are

ACh

useful in many clinical conditions. Unfortunately, a very large number of drugs used for other purposes (eg, allergies, mental illness) have unwanted effects on autonomic function.

ANATOMY OF THE AUTONOMIC NERVOUS SYSTEM The ANS lends itself to division on anatomic grounds into two major portions: the sympathetic (thoracolumbar) division and the parasympathetic (traditionally craniosacral, but see Box: Sympathetic Sacral Outflow) division (Figure 6–1). Neurons in both divisions originate in nuclei within the CNS and give rise to preganglionic efferent fibers that exit from the brain stem or spinal cord and terminate in ganglia found in the periphery. The sympathetic preganglionic fibers leave the CNS through the thoracic,

N

Parasympathetic Cardiac and smooth muscle, gland cells, nerve terminals

ACh M

Medulla

N

ACh

Spinal cord

ACh M

N

ACh

NE α, β

Sympathetic Sweat glands

Sympathetic Cardiac and smooth muscle, gland cells, nerve terminals

N

ACh

NE, D

Sympathetic Renal vascular smooth muscle

α, D1

ACh N

Adrenal medulla

Epi, NE ACh N Somatic Skeletal muscle

Voluntary motor nerve

FIGURE 6–1  Schematic diagram comparing some anatomic and neurotransmitter features of autonomic and somatic motor nerves. Only the primary transmitter substances are shown. Parasympathetic ganglia are not shown because most are in or near the wall of the organ innervated. Cholinergic nerves are shown in blue, noradrenergic in red. Note that some sympathetic postganglionic fibers release acetylcholine rather than norepinephrine. Sympathetic nerves to the renal vasculature and kidney may release dopamine as well as norepinephrine during stress. The adrenal medulla, a modified sympathetic ganglion, receives sympathetic preganglionic fibers and releases epinephrine and norepinephrine into the blood. Not shown are the sacral preganglionic fibers that innervate the rectum, bladder, and genitalia. These fibers are probably sympathetic preganglionic nerves with cholinergic postganglionic fibers (see Box: Sympathetic Sacral Outflow). ACh, acetylcholine; D, dopamine; Epi, epinephrine; M, muscarinic receptors; N, nicotinic receptors; NE, norepinephrine.

CHAPTER 6  Introduction to Autonomic Pharmacology    95

lumbar, and (according to new information) sacral spinal nerves. The parasympathetic preganglionic fibers leave the CNS through the brainstem cranial nerves (cranial nerves three, seven, nine, and ten) as well as from the sacral spinal cord. Most thoracic and lumbar sympathetic preganglionic fibers leave the intermediate gray of the spinal cord, are short, and terminate in ganglia (collection of neuron cell bodies) located in the paravertebral chains that lie on either side of the spinal column. The remaining sympathetic preganglionic fibers are somewhat longer and terminate in prevertebral ganglia, which lie in front of the vertebrae, usually on the ventral surface of the aorta. From the ganglia, postganglionic sympathetic fibers run to, and terminate on, the tissues they innervate. Some preganglionic parasympathetic fibers terminate in parasympathetic ganglia located outside the organs they innervate, including the ciliary, pterygopalatine, submandibular, and otic ganglia. However, the majority of parasympathetic preganglionic fibers terminate on ganglion cells distributed diffusely or in networks in the walls of the innervated organs.

Several pelvic ganglia are innervated by sacral preganglionic nerves that are ontogenetically similar to sympathetic preganglionic fibers (see Box: Sympathetic Sacral Outflow). Note that the terms “sympathetic” and “parasympathetic” are anatomic designations and do not depend on the type of transmitter chemical released from the nerve endings nor on the kind of effect—excitatory or inhibitory— evoked by nerve activity. In addition to these clearly defined peripheral motor portions of the ANS, large numbers of afferent fibers run from the periphery to integrating centers, including the enteric plexuses in the gut, the autonomic ganglia, and the CNS. Many of the sensory pathways that end in the CNS terminate in the hypothalamus and medulla and evoke reflex motor activity that is carried to the effector cells by the efferent fibers described previously. There is increasing evidence that some of these sensory fibers also have peripheral motor functions. The enteric nervous system (ENS) is a large and highly organized collection of neurons located in the walls of the gastrointestinal (GI) system (Figure 6–2). With more than 150 million

Pseudomembranes

Sympathetic postganglionic fibers

EPAN

Serosa 5-HT

LM

ACh, CGRP IPAN MP

EN

NP

IN

NE ACh

CM

IPAN SMP

5-HT

5-HT SC EC

EN

NP

AC

NE NP

IN

5-HT EC

IPAN

IN

ACh

ACh, CGRP EN

• Deposition of fibrin in conjunctiva and mucous membranes

ACh

EC

SC

ACh

ACh NP

5-HT AC

SC

EC

EC

Lumen

FIGURE 6–2  A highly simplified diagram of the intestinal wall and some of the circuitry of the enteric nervous system (ENS). The ENS receives input from both the sympathetic and the parasympathetic systems and sends afferent impulses to sympathetic ganglia and to the central nervous system. Many transmitter or neuromodulator substances have been identified in the ENS; see Table 6–1. ACh, acetylcholine; AC, absorptive cell; CGRP, calcitonin gene-related peptide; CM, circular muscle layer; EC, enterochromaffin cell; EN, excitatory neuron; EPAN, extrinsic primary afferent neuron; 5-HT, serotonin; IN, inhibitory neuron; IPAN, intrinsic primary afferent neuron; LM, longitudinal muscle layer; MP, myenteric plexus; NE, norepinephrine; NP, neuropeptides; SC, secretory cell; SMP, submucosal plexus. Pseudomembrane is a layer of exudate resembling a membrane, formed on the surface of the skin or of a mucous membrane, especially the conjunctiva of the eye.

96    SECTION II  Autonomic Drugs

TABLE 6–1  Some of the transmitter substances found in autonomic nervous system, enteric nervous system, and nonadrenergic, noncholinergic neurons.1

Substance

Functions

Acetylcholine (ACh)

The primary transmitter at ANS ganglia, at the somatic neuromuscular junction, and at parasympathetic postganglionic nerve endings. A primary excitatory transmitter to smooth muscle and secretory cells in the ENS. Probably also the major neuron-to-neuron (“ganglionic”) transmitter in the ENS.

Adenosine triphosphate (ATP)

Acts as a transmitter or cotransmitter at many ANS-effector synapses.

Calcitonin gene-related peptide (CGRP)

Found with substance P in cardiovascular sensory nerve fibers. Present in some secretomotor ENS neurons and interneurons. A cardiac stimulant.

Cholecystokinin (CCK)

May act as a cotransmitter in some excitatory neuromuscular ENS neurons.

Dopamine

A modulatory transmitter in some ganglia and the ENS. Possibly a postganglionic sympathetic transmitter in renal blood vessels.

Enkephalin and related opioid peptides

Present in some secretomotor and interneurons in the ENS. Appear to inhibit ACh release and thereby inhibit peristalsis. May stimulate secretion.

Galanin

Present in secretomotor neurons; may play a role in appetite-satiety mechanisms.

GABA (γ-aminobutyric acid)

May have presynaptic effects on excitatory ENS nerve terminals. Has some relaxant effect on the gut. Probably not a major transmitter in the ENS.

Gastrin-releasing peptide (GRP)

Extremely potent excitatory transmitter to gastrin cells. Also known as mammalian bombesin.

Neuropeptide Y (NPY)

Found in many noradrenergic neurons. Present in some secretomotor neurons in the ENS and may inhibit secretion of water and electrolytes by the gut. Causes long-lasting vasoconstriction. It is also a cotransmitter in some parasympathetic postganglionic neurons.

Nitric oxide (NO)

A cotransmitter at inhibitory ENS and other neuromuscular junctions; may be especially important at sphincters. Cholinergic nerves innervating blood vessels appear to activate the synthesis of NO by vascular endothelium. NO is not stored, it is synthesized on demand by nitric oxide synthase, NOS; see Chapter 19.

Norepinephrine (NE)

The primary transmitter at most sympathetic postganglionic nerve endings.

Serotonin (5-HT)

An important transmitter or cotransmitter at excitatory neuron-to-neuron junctions in the ENS.

Substance P, related tachykinins

Substance P is an important sensory neurotransmitter in the ENS and elsewhere. Tachykinins appear to be excitatory cotransmitters with ACh at ENS neuromuscular junctions. Found with CGRP in cardiovascular sensory neurons. Substance P is a vasodilator (probably via release of nitric oxide).

Vasoactive intestinal peptide (VIP)

Excitatory secretomotor transmitter in the ENS; may also be an inhibitory ENS neuromuscular cotransmitter. A probable cotransmitter in many cholinergic neurons. A vasodilator (found in many perivascular neurons) and cardiac stimulant.

1

See Chapter 21 for transmitters found in the central nervous system.

neurons, it is sometimes considered a third division of the ANS. It is found in the wall of the GI tract from the esophagus to the distal colon and is involved in both motor and secretory activities of the gut. It is particularly important in the control of motor activity of the colon. The ENS includes the myenteric plexus (the plexus of Auerbach) and the submucous plexus (the plexus of Meissner). These neuronal networks receive preganglionic fibers from the parasympathetic system and postganglionic sympathetic axons. They also receive sensory input from within the wall of the gut. Fibers from the neuronal cell bodies in these plexuses travel forward, backward, and in a circular direction to the smooth muscle of the gut to control motility and to secretory cells in the mucosa. Sensory fibers transmit chemical and mechanical information from the mucosa and from stretch receptors to motor neurons in the plexuses and to postganglionic neurons in the sympathetic ganglia. For example, enteroendocrine epithelial cells in the mucosal layer synapse with vagal and other sensory fibers to send information regarding gut content chemicals to the CNS. This signaling appears to utilize glutamate for rapid transmission and peptides such as cholecystokinin for slower, longer-lasting

transmission. The parasympathetic and sympathetic fibers that synapse on enteric plexus neurons appear to play a modulatory role, as indicated by the observation that deprivation of input from both ANS divisions does not abolish GI activity. In fact, selective denervation may result in greatly enhanced motor activity. The ENS functions in a semiautonomous manner, using input from the motor outflow of the ANS for modulation of GI activity and sending sensory information back to the autonomic centers in the CNS. The ENS also provides the necessary synchronization of impulses that, for example, ensures forward, not backward, propulsion of gut contents and relaxation of sphincters when the gut wall contracts. The anatomy of autonomic synapses and junctions determines the localization of transmitter effects around nerve endings. Classic synapses such as the mammalian neuromuscular junction and most neuron-neuron synapses are relatively “tight” in that the nerve terminates in small boutons very close to the tissue innervated, so that the diffusion path from nerve terminal to postsynaptic receptors is very short. The effects are thus relatively rapid and localized.

CHAPTER 6  Introduction to Autonomic Pharmacology    97

In contrast, junctions between autonomic neuron terminals and effector cells (smooth muscle, cardiac muscle, glands) differ from classic synapses in that transmitter is often released from a chain of varicosities in the postganglionic nerve fiber in the region of

the smooth muscle cells rather than from boutons, and autonomic junctional clefts are wider than somatic synaptic clefts. Effects are thus slower in onset, and discharge of a single motor fiber often activates or inhibits many effector cells.

Sympathetic Sacral Outflow As noted in the previous editions of this book and other standard texts, it has long been believed that, like the cranial nerve cholinergic system described earlier, the cholinergic nerves that innervate the pelvic organs (rectum, bladder, and reproductive organs) are part of the parasympathetic nervous system. However, recent evidence (see Espinoza-Medina reference at the end of this chapter) suggests that the cholinergic preganglionic sacral fibers are actually derived from embryonic sympathetic precursor cells and that the postganglionic fibers innervated by them are therefore members of the sympathetic cholinergic class. This claim is based on several lines of evidence, as follows: (1) Cranial parasympathetic preganglionic neurons express the homeogene Phox2b and the transcription factors Tbx20, Tbx2, and Tbx3; thoracic sympathetic and sacral preganglionic neurons do

NEUROTRANSMITTER CHEMISTRY OF THE AUTONOMIC NERVOUS SYSTEM An important traditional classification of autonomic nerves is based on the primary transmitter molecules—acetylcholine or norepinephrine—released from their terminals and varicosities. A large number of peripheral ANS fibers synthesize and release acetylcholine; they are cholinergic fibers; that is, they work by synthesizing and releasing acetylcholine. As shown in Figure 6–1, these include all preganglionic efferent autonomic fibers and the somatic (nonautonomic) motor fibers to skeletal muscle as well. Thus, almost all efferent fibers leaving the CNS are cholinergic. In addition, most parasympathetic postganglionic and some sympathetic postganglionic fibers are cholinergic. A significant number of parasympathetic postganglionic neurons use nitric oxide or peptides as the primary transmitter or as cotransmitters with acetylcholine. Most postganglionic sympathetic fibers (see Figure 6–1) release norepinephrine (also known as noradrenaline); they are noradrenergic (often called simply “adrenergic”) fibers; that is, they work by releasing norepinephrine (noradrenaline). As noted, some sympathetic fibers release acetylcholine (eg, sweat gland innervation). Dopamine is a very important transmitter in the CNS, and it may be released by some peripheral sympathetic fibers under certain circumstances. Adrenal medullary cells, which are embryologically analogous to postganglionic sympathetic neurons, receive input from preganglionic sympathetic nerves and release a mixture of epinephrine and norepinephrine into the circulation. Finally, most autonomic nerves also release several cotransmitter substances (described in the following text), in addition to the primary transmitters just described. Five key features of neurotransmitter function provide potential targets for pharmacologic therapy: synthesis, storage, release,

not. Sacral preganglionic neurons do express transcription factor Foxp1, which is not expressed by cranial neurons. (2) Cranial parasympathetic preganglionic fibers exit the CNS via dorsolateral exit points; the sympathetic and sacral preganglionic nerves exit the spinal cord via ventral root exits. (3) At an early stage of development, cranial preganglionic neurons express the vesicular acetylcholine transporter (VAChT; VAT in Figure 6–3) but not nitric oxide synthase (NOS); sympathetic and sacral nerves at the same stage express NOS but not VAChT (even though they do express VAChT later in their development). These observations require independent confirmation but constitute strong evidence in favor of changing the traditional “craniosacral” synonym for the parasympathetic nervous system to “cranial autonomic” nervous system.

termination of action of the transmitter, and receptor effects. These processes are discussed next.

Cholinergic Transmission The terminals and varicosities of cholinergic neurons contain large numbers of small membrane-bound vesicles concentrated near the portion of the cell membrane facing the synapse (see Figure 6–3) as well as a smaller number of large dense-cored vesicles located farther from the synaptic membrane. The large vesicles contain a high concentration of peptide cotransmitters (Table 6–1), whereas the smaller clear vesicles contain most of the acetylcholine. Vesicles may be synthesized in the neuron cell body and carried to the terminal by axonal transport. They may also be recycled several times within the terminal after each exocytotic release of transmitter. Ultrafast neuronal firing appears to be supported by rapid recycling of clathrin-coated vesicles from endosomes in the nerve terminal. Vesicles are provided with vesicle-associated membrane proteins (VAMPs), which serve to align them with release sites on the inner neuronal cell membrane and participate in triggering the release of transmitter. The release site on the inner surface of the nerve terminal membrane contains synaptosomal nerve-associated proteins (SNAPs), which interact with VAMPs. VAMPs and SNAPs are collectively called fusion proteins. Acetylcholine (ACh) is synthesized in the cytoplasm from acetyl-CoA and choline through the catalytic action of the enzyme choline acetyltransferase (ChAT). Acetyl-CoA is synthesized in mitochondria, which are present in large numbers in the nerve ending. Choline is transported from the extracellular fluid into the neuron terminal by a sodium-dependent membrane choline transporter (CHT; see Figure 6–3). This symporter can be blocked by a group of research drugs called hemicholiniums.

98    SECTION II  Autonomic Drugs

Axon

Na+ CHT

Hemicholiniums

Choline

AcCoA + Choline ChAT Nerve terminal

H+

ACh

Vesamicol

VAT Heteroreceptor Calcium channel

ACh ATP, P

Ca2+

Presynaptic receptors

Acetylcholine autoreceptor

VAMPs

ACh ATP, P

Botulinum toxin

SNAPs

ACh Choline

Acetylcholinesterase

Acetate

Postsynaptic cell Cholinoceptors

Other receptors

FIGURE 6–3  Schematic illustration of a generalized cholinergic junction (not to scale). Choline is transported into the presynaptic nerve terminal by a sodium-dependent choline transporter (CHT). This transporter can be inhibited by hemicholinium drugs. In the cytoplasm, acetylcholine is synthesized from choline and acetyl-CoA (AcCoA) by the enzyme choline acetyltransferase (ChAT). Acetylcholine (ACh) is then transported into the storage vesicle by a vesicle-associated transporter (VAT), which can be inhibited by vesamicol. Peptides (P), adenosine triphosphate (ATP), and proteoglycan are also stored in the vesicle. Release of transmitters occurs when voltage-sensitive calcium channels in the terminal membrane are opened, allowing an influx of calcium. The resulting increase in intracellular calcium causes fusion of vesicles with the surface membrane and exocytotic expulsion of acetylcholine and cotransmitters into the junctional cleft (see text). This step can be blocked by botulinum toxin. Acetylcholine’s action is terminated by metabolism by the enzyme acetylcholinesterase. Receptors on the presynaptic nerve ending modulate transmitter release. SNAPs, synaptosomal nerve-associated proteins; VAMPs, vesicle-associated membrane proteins. Once synthesized, acetylcholine is transported from the cytoplasm into the vesicles by a vesicle-associated transporter (VAT) that is driven by proton efflux (see Figure 6–3). This antiporter can be blocked by the research drug vesamicol. Acetylcholine synthesis is a rapid process capable of supporting a very high rate

of transmitter release. Storage of acetylcholine is accomplished by the packaging of “quanta” of acetylcholine molecules (usually 1000–50,000 molecules in each vesicle). Most of the vesicular acetylcholine (a positively charged quaternary amine) is bound to negatively charged vesicular proteoglycan (VPG). (ACh is also

CHAPTER 6  Introduction to Autonomic Pharmacology    99

synthesized in lymphocytes and may play a role in immunologic reactions to viral infection.) Vesicles are concentrated on the inner surface of the nerve terminal facing the synapse through the interaction of so-called SNARE proteins on the vesicle (a subgroup of VAMPs called v-SNAREs, especially synaptobrevin) and on the inside of the terminal cell membrane (SNAPs called t-SNAREs, especially syntaxin and SNAP-25). Physiologic release of transmitter from the vesicles is dependent on extracellular calcium and occurs when an action potential reaches the terminal and triggers sufficient influx of calcium ions via N-type calcium channels. Calcium interacts with the VAMP synaptotagmin on the vesicle membrane and triggers fusion of the vesicle membrane with the terminal membrane and opening of a pore into the synapse. The opening of the pore and inrush of cations results in release of the acetylcholine from the proteoglycan and exocytotic expulsion into the synaptic cleft. One depolarization of a somatic motor nerve may release several hundred quanta into the synaptic cleft. One depolarization of an autonomic postganglionic nerve varicosity or terminal probably releases less and releases it over a larger area. In addition to acetylcholine, several cotransmitters are released at the same time

(see Table 6–1). The acetylcholine vesicle release process is blocked by botulinum toxin (BoNT) through the enzymatic cleavage of two amino acids from one or more of the fusion proteins, resulting in muscle paralysis. (Tetanus toxin [tetanospasmin, TeNT] blocks transmitter release by a similar cleavage of fusion proteins, but it does so mainly in inhibitory neurons of the spinal cord, thus resulting in spasm, rather than paralysis, of skeletal muscle.) After release from the presynaptic terminal, acetylcholine molecules may bind to and activate an acetylcholine receptor (cholinoceptor). Eventually (and usually very rapidly), all of the acetylcholine released diffuses within range of an acetylcholinesterase (AChE) molecule. AChE very efficiently splits acetylcholine into choline and acetate, neither of which has significant transmitter effect, and thereby terminates the action of the transmitter (see Figure 6–3). Most cholinergic synapses are richly supplied with acetylcholinesterase; the half-life of acetylcholine molecules in the synapse is therefore very short (a fraction of a second). Acetylcholinesterase is also found in other tissues, eg, red blood cells. (Other cholinesterases with a lower specificity for acetylcholine, including butyrylcholinesterase [pseudocholinesterase], are found in blood plasma, liver, glia, and many other tissues.)

Neurotransmitter Uptake Carriers As noted in Chapters 1, 4, and 5, several large families of transport proteins have been identified. The most important of these are the ABC (ATP-binding cassette) and SLC (solute carrier) transporter families. As indicated by the name, the ABC carriers use ATP for transport. The SLC proteins are cotransporters and, in most cases, use the movement of sodium down its concentration gradient as the energy source. Under some circumstances, they also transport transmitters in the reverse direction in a sodium-independent fashion. NET, SLC6A2, the norepinephrine transporter, is a member of the SLC family, as are similar transporters responsible for the reuptake of dopamine (DAT, SLC6A3) and 5-HT (serotonin, SERT, SLC6A4) into the neurons that release these transmitters. These

Adrenergic Transmission Adrenergic neurons (Figure 6–4) transport the precursor amino acid tyrosine into the nerve ending, convert it to dopa, and then synthesize a catecholamine transmitter (dopamine, norepinephrine, or epinephrine; Figure 6–5), and store it in membrane-bound vesicles. In most sympathetic postganglionic neurons, norepinephrine is the final product. In the adrenal medulla and certain areas of the brain, some norepinephrine is further converted to epinephrine. In dopaminergic neurons, synthesis terminates with dopamine. Several processes in these nerve terminals are potential sites of drug action. One of these, the conversion of tyrosine to dopa by tyrosine hydroxylase, is the rate-limiting step in catecholamine transmitter synthesis. It can be inhibited by the tyrosine analog metyrosine. A high-affinity antiporter for catecholamines located in the wall of the storage vesicle (vesicular monoamine transporter, VMAT) can be inhibited by the reserpine alkaloids. Reserpine and related

transport proteins are found in peripheral tissues and in the CNS wherever neurons using these transmitters are located. NET is important in the peripheral actions of cocaine and the amphetamines. In the CNS, NET, SERT, and DAT are important targets of several antidepressant drug classes (see Chapter 30) as well as cocaine and amphetamine use. The most important inhibitory transmitter in the CNS, γ-aminobutyric acid (GABA), is the substrate for at least three SLC transporters: GAT1, GAT2, and GAT3. GAT1 is the target of an antiseizure medication (see Chapter 24). The major excitatory CNS transmitter glutamate utilizes the excitatory amino acid transporter (EAAT) family, which are also SLC protein transporters.

drugs (tetrabenazine, deutetrabenazine) cause depletion of transmitter stores. Another transporter (norepinephrine transporter, NET) carries norepinephrine and similar molecules back into the cell cytoplasm from the synaptic cleft (see Figure 6–4; NET). NET is also commonly called uptake 1 or reuptake 1 and is partially responsible for the termination of synaptic activity. NET can be inhibited by cocaine, solriamfetol, and certain antidepressant drugs, resulting in an increase of transmitter activity in the synaptic cleft (see Box: Neurotransmitter Uptake Carriers). Release of the vesicular transmitter store from noradrenergic nerve endings is similar to the calcium-dependent process previously described for cholinergic terminals. In addition to the primary transmitter (norepinephrine), adenosine triphosphate (ATP), dopamine-β-hydroxylase, and peptide cotransmitters are simultaneously released from the same vesicles. Indirectly acting and mixed-action sympathomimetics, eg, tyramine,

100    SECTION II  Autonomic Drugs

Axon

Na+ A

Tyrosine

Tyr

Dopa Nerve terminal

Tyrosine hydroxylase Dopamine

Metyrosine

H+

Reserpine

VMAT Heteroreceptor

Presynaptic receptors

NE ATP, P

Calcium channel

Norepinephrine autoreceptor

Ca2+

VAMPs

NE, ATP, P

Bretylium, guanethidine

SNAPs

Cocaine, tricyclic antidepressants

NET

NE Diffusion

Postsynaptic cell Adrenoceptors

Other receptors

FIGURE 6–4  Schematic diagram of a generalized noradrenergic junction (not to scale). Tyrosine is transported into the noradrenergic nerve ending or varicosity by a sodium-dependent carrier (A). Tyrosine is converted to dopamine (see Figure 6–5 for details), and transported into the vesicle by the vesicular monoamine transporter (VMAT), which can be blocked by reserpine and tetrabenazine. The same carrier transports norepinephrine (NE) and several related amines into these vesicles. Dopamine is converted to NE in the vesicle by dopamine-β-hydroxylase. Physiologic release of transmitter occurs when an action potential opens voltage-sensitive calcium channels and increases intracellular calcium. Fusion of vesicles with the surface membrane results in expulsion of norepinephrine, cotransmitters, and dopamine-β-hydroxylase. Release can be blocked by drugs such as guanethidine and bretylium. After release, norepinephrine diffuses out of the cleft or is transported into the cytoplasm of the terminal by the norepinephrine transporter (NET), which can be blocked by cocaine and certain antidepressants, or into postjunctional or perijunctional cells. Regulatory receptors are present on the presynaptic terminal. SNAPs, synaptosome-associated proteins; VAMPs, vesicleassociated membrane proteins. amphetamines, and ephedrine, are capable of releasing stored transmitter from noradrenergic nerve endings by a calciumindependent process. These drugs are poor agonists (some are inactive) at adrenoceptors, but they are excellent substrates for

monoamine transporters. As a result, they are avidly taken up into noradrenergic nerve endings by NET. In the nerve ending, they are then transported by VMAT into the vesicles, displacing norepinephrine, which is subsequently expelled into the synaptic

CHAPTER 6  Introduction to Autonomic Pharmacology    101

OH

HO

Tyrosine –

Metyrosine

H

C

C

Cα NH2

H

H

O

L-Amino acid decarboxylase

Tyrosine hydroxylase OH

HO HO

Dopa

H

C

O

C

C

NH2

H

H

HO

Tyramine

H

H

C

C

H

H

NH2

Dopa decarboxylase

– COOH

Dopamine β-hydroxylase

HO HO

Dopamine

H

H

C

C

H

H

NH2 HO

Dopamine β-hydroxylase HO HO

H O

H

C

C

H

H

Norepinephrine

Octopamine

H O

H

C

C

H

H

NH2

Hydroxylase (from liver) NH2

Phenylethanolamine-N-methyltransferase HO HO

Epinephrine

H O

H

CH3

C

C

NH

H

H

FIGURE 6–5  Biosynthesis of catecholamines. The rate-limiting step, conversion of tyrosine to dopa, can be inhibited by metyrosine (α-methyltyrosine). The alternative pathway shown by the dashed arrows has not been found to be of physiologic significance in humans. However, tyramine and octopamine may accumulate in patients treated with monoamine oxidase inhibitors. (Reproduced with permission from Gardner DG, Shoback D: Greenspan’s Basic & Clinical Endocrinology, 9th ed. New York, NY: McGraw Hill; 2011.)

space by reverse transport via NET. Amphetamines also inhibit monoamine oxidase and have other effects that result in increased norepinephrine activity in the synapse. Their action does not require vesicle exocytosis. Norepinephrine and epinephrine can be metabolized by several enzymes, as shown in Figure 6–6. Because of the high activity of monoamine oxidase in the mitochondria of the nerve terminal, there is significant turnover of norepinephrine even in the resting terminal. Since the metabolic products are excreted in the urine, an estimate of catecholamine turnover can be obtained from measurement of total metabolites (sometimes referred to as “VMA and metanephrines”) in a 24-hour urine sample. However, metabolism

is not the primary mechanism for termination of action of norepinephrine physiologically released from noradrenergic nerves. Termination of noradrenergic transmission results from two processes: simple diffusion away from the receptor site (with eventual metabolism in the plasma or liver) and reuptake into the nerve terminal by NET (see Figure 6–4) or into perisynaptic glia or other cells.

Cotransmitters in Cholinergic & Adrenergic Nerves As previously noted, the vesicles of both cholinergic and adrenergic nerves contain other substances in addition to the primary

102    SECTION II  Autonomic Drugs

OH

OH HO

CH

HO

CH

HO

CH2

HO

CH2

HO

CH2

HO

CH2

NHCH3

NH2

Epinephrine

NH2

Norepinephrine AO

AO

O C

M

T

M

AO M

M

Dopamine

OH COMT

HO

CH

HO

C

COMT O

HO

CH2

HO

C

OH

O

CH3O

CH2

HO

CH2

OH

Dihydroxymandelic acid

Dihydroxyphenylacetic acid

NH2 3-Methoxytyramine

O C

AO M

CH

CH3O

OH CH3O

COMT

CH2

HO

HO

CH CH2

T

M

OH

CH3O HO

NH2

NHCH3 Metanephrine

Normetanephrine

CH2 C

O

OH Homovanillic acid

AO

M

AO

M

OH CH3O HO

CH C

O

OH 3-Methoxy-4-hydroxymandelic acid (VMA)

FIGURE 6–6 

Metabolism of catecholamines by catechol-O-methyltransferase (COMT) and monoamine oxidase (MAO). (Reproduced with permis-

sion from Gardner DG, Shoback D: Greenspan’s Basic & Clinical Endocrinology, 9th ed. New York, NY: McGraw Hill; 2011.)

transmitter, sometimes in the same vesicles and sometimes in a separate vesicle population. Some of the substances identified to date are listed in Table 6–1. Many of these substances are also primary transmitters in the nonadrenergic, noncholinergic nerves described in the text that follows. They appear to play several roles in the function of nerves that release acetylcholine or norepinephrine. In some cases, they provide a faster or slower action to supplement or modulate the effects of the primary transmitter. They also participate in feedback inhibition of the same and nearby nerve terminals. Growth of neurons and transmitter expression in specific neurons is a dynamic process. For example, neurotrophic factors released from target tissues influence growth and synapse formation by neurons. In addition, the transmitters released from a specific population of neurons can change in response to environmental factors such as the light-dark cycle.

AUTONOMIC RECEPTORS Historically, structure-activity analyses, with careful comparisons of the potency of series of autonomic agonist and antagonist analogs, led to the definition of different autonomic receptor subtypes, including muscarinic and nicotinic cholinoceptors, α, and β adrenoceptors, and dopamine receptors (Table 6–2). Subsequently, binding of isotope-labeled ligands permitted the purification and characterization of several of the receptor molecules. Molecular biology now provides techniques for the discovery and expression of genes that code for related receptors within these groups (see Chapter 2). The primary acetylcholine receptor subtypes were named after the alkaloids originally used in their identification: muscarine and nicotine, thus muscarinic and nicotinic receptors. In the case of

CHAPTER 6  Introduction to Autonomic Pharmacology    103

TABLE 6–2  Major autonomic receptor types. Receptor Name

Typical Locations

Result of Ligand Binding

  Muscarinic M1

CNS neurons, sympathetic postganglionic neurons, some presynaptic sites

Formation of IP3 and DAG, increased intracellular calcium

  Muscarinic M2

Myocardium, smooth muscle, some presynaptic sites; CNS neurons

Opening of potassium channels, inhibition of adenylyl cyclase

  Muscarinic M3

Exocrine glands, vessels (smooth muscle and endothelium); CNS neurons

Like M1 receptor-ligand binding

  Muscarinic M4

CNS neurons; possibly vagal nerve endings

Like M2 receptor-ligand binding

  Muscarinic M5

Vascular endothelium, especially cerebral vessels; CNS neurons

Like M1 receptor-ligand binding

  Nicotinic NN

Postganglionic neurons, some presynaptic cholinergic terminals; pentameric receptors typically contain α- and β-type subunits only (see Chapter 7)

Opening of Na , K channels, depolarization

  Nicotinic NM

Skeletal muscle neuromuscular end plates; pentameric receptors typically contain two α1- and β1-type subunits in addition to γ and δ subunits

Opening of Na+, K+ channels, depolarization

 Alpha1

Postsynaptic effector cells, especially smooth muscle

Formation of IP3 and DAG, increased intracellular calcium

 Alpha2

Presynaptic adrenergic nerve terminals, platelets, lipocytes, smooth muscle

Inhibition of adenylyl cyclase, decreased cAMP

 Beta1

Postsynaptic effector cells, especially heart, lipocytes, brain; presynaptic adrenergic and cholinergic nerve terminals, juxtaglomerular apparatus of renal tubules, ciliary body epithelium

Stimulation of adenylyl cyclase, increased cAMP

 Beta2

Postsynaptic effector cells, especially smooth muscle and cardiac muscle

Stimulation of adenylyl cyclase and increased cAMP. Activates cardiac Gi under some conditions.

 Beta3

Postsynaptic effector cells, especially lipocytes; heart

Stimulation of adenylyl cyclase and increased cAMP1

 D1 (DA1), D5

Brain; effector tissues, especially smooth muscle of the renal vascular bed

Stimulation of adenylyl cyclase and increased cAMP

 D2 (DA2)

Brain; effector tissues, especially smooth muscle; presynaptic nerve terminals

Inhibition of adenylyl cyclase; increased potassium conductance

 D3

Brain

Inhibition of adenylyl cyclase

 D4

Brain, cardiovascular system

Inhibition of adenylyl cyclase

Cholinoceptors

+

+

Adrenoceptors

Dopamine receptors

1

Cardiac β3-receptor function is poorly understood, but activation does not appear to result in stimulation of rate or force.

receptors associated with noradrenergic nerves, the use of the names of the agonists (noradrenaline, phenylephrine, isoproterenol, and others) was not practicable. Therefore, the term adrenoceptor is widely used to describe receptors that respond to catecholamines such as norepinephrine. By analogy, the term cholinoceptor denotes receptors (both muscarinic and nicotinic) that respond to acetylcholine. In North America, receptors were colloquially named after the nerves that usually innervate them; thus, adrenergic (or noradrenergic) receptors and cholinergic receptors. The general class of adrenoceptors can be further subdivided into `-adrenoceptor, a-adrenoceptor, and less thought of as an adrenoceptor, the dopamine-receptor types on the basis of both agonist and antagonist selectivity and on genomic grounds. Development of more selective blocking drugs has led to the naming of subclasses within these major types; for example, within the α-adrenoceptor class, α1 and α2 receptors differ in both agonist and antagonist selectivity. Examples of such selective drugs are given in the chapters that follow.

NONADRENERGIC, NONCHOLINERGIC (NANC) NEURONS It has been known for many years that autonomic effector tissues (eg, gut, airways, bladder) contain nerve fibers that do not show the histochemical characteristics of either cholinergic or adrenergic fibers. Both motor and sensory NANC fibers are present in these tissues. Although peptides are the most common transmitter substances found in these nerve endings, other substances, eg, nitric oxide synthase and purines, are also present in many nerve terminals (see Table 6–1). Capsaicin, a toxin derived from chili peppers, can cause the release of transmitter (especially substance P) from such neurons and, if given in high doses, destruction of the neuron. The enteric system in the gut wall (see Figure 6–2) is the most extensively studied system containing NANC neurons in addition to cholinergic and adrenergic fibers. In the small intestine,

104    SECTION II  Autonomic Drugs

for example, these neurons contain one or more of the following: nitric oxide synthase (which produces nitric oxide, NO), calcitonin gene-related peptide, cholecystokinin, dynorphin, enkephalins, gastrin-releasing peptide, 5-hydroxytryptamine (5-HT, serotonin), neuropeptide Y, somatostatin, substance P, and vasoactive intestinal peptide (VIP). Some neurons contain as many as five different transmitters. The sensory fibers in the nonadrenergic, noncholinergic systems are probably better termed “sensory-efferent” or “sensorylocal effector” fibers because, when activated by a sensory input, they are capable of releasing transmitter peptides from the sensory ending itself, from local axon branches, and from collaterals that terminate in the autonomic ganglia. These peptides are potent agonists in many autonomic effector tissues.

FUNCTIONAL ORGANIZATION OF AUTONOMIC ACTIVITY Autonomic function is integrated and regulated at many levels, from the CNS to the effector cells. Most regulation uses negative feedback, but several other mechanisms have been identified. Negative feedback is particularly important in the responses of the ANS to the administration of autonomic drugs.

Central Integration At the highest level—midbrain and medulla—the two divisions of the ANS and the endocrine system are integrated with each other, with sensory input, and with information from higher CNS centers, including the cerebral cortex. These interactions are such that early investigators called the parasympathetic system a trophotropic one (ie, leading to growth) used to “rest and digest” and the sympathetic system an ergotropic one (ie, leading to energy expenditure), which is activated for “fight or flight.” Although such terms offer little insight into the mechanisms involved, they do provide simple descriptions applicable to many of the actions of the systems (Table 6–3). For example, slowing of the heart and stimulation of digestive activity are typical energy-conserving and energy-storing actions of the parasympathetic system. In contrast, cardiac stimulation, increased blood sugar, and cutaneous vasoconstriction are responses produced by sympathetic discharge that are suited to fighting or surviving attack. At a more subtle level of interactions in the brain stem, medulla, and spinal cord, there are important cooperative interactions between the parasympathetic and sympathetic systems. For some organs, sensory fibers associated with the parasympathetic system exert reflex control over motor outflow in the sympathetic system. Thus, the sensory carotid sinus baroreceptor fibers in the glossopharyngeal nerve have a major influence on sympathetic outflow from the vasomotor center. This example is described in greater detail in the following text. Similarly, parasympathetic sensory fibers in the wall of the urinary bladder significantly influence sympathetic inhibitory outflow to that organ. Within the ENS, sensory fibers from the wall of the gut synapse on both preganglionic and postganglionic motor neurons that control intestinal smooth muscle and secretory cells (see Figure 6–2).

A. Integration of Cardiovascular Function Autonomic reflexes are particularly important in understanding cardiovascular responses to autonomic drugs. As indicated in Figure 6–7, the primary controlled variable in cardiovascular function is mean arterial pressure. In the absence of autonomic control, heart rate takes on an intrinsic value somewhat higher than normal resting rate—that is, resting heart rate in a transplanted human heart is 110–130 beats/min. This suggests that in the intact resting human, heart rate is dominated by parasympathetic tone, lowering the heart rate to the range of 70–80 beats/min. Changes in any variable contributing to mean arterial pressure (eg, a druginduced increase in peripheral vascular resistance) evoke powerful homeostatic secondary responses that tend to compensate for the directly evoked change. The homeostatic response may be sufficient to reduce the change in mean arterial pressure and to reverse the drug’s effects on heart rate. A slow infusion of norepinephrine provides a useful example. This agent produces direct effects on both vascular and cardiac muscle. It is a powerful vasoconstrictor and, by increasing peripheral vascular resistance, increases mean arterial pressure. In the absence of reflex control—in a patient who has had a heart transplant, for example—the drug’s effect on the heart is also stimulatory; that is, it increases heart rate and contractile force. However, in a subject with intact reflexes, the negative feedback response to increased mean arterial pressure causes decreased sympathetic outflow to the heart and a powerful increase in parasympathetic (vagus nerve) discharge at the cardiac pacemaker (sinoatrial [SA] node). This response is mediated by increased firing by the baroreceptor nerves of the carotid sinus and the aortic arch. Increased baroreceptor activity causes the decreased central sympathetic outflow and increased vagal outflow. As a result, the net effect of ordinary pressor doses of norepinephrine in a normal subject is to produce a marked increase in peripheral vascular resistance, an increase in mean arterial pressure, and often, a slowing of heart rate. Bradycardia, the reflex compensatory response elicited by this agent, is the exact opposite of the drug’s direct action; yet it is completely predictable if the integration of cardiovascular function by the ANS is understood. B. Presynaptic Regulation The principle of negative feedback control is also found at the presynaptic level of autonomic function. Important presynaptic feedback inhibitory control mechanisms have been shown to exist at most nerve endings. A well-documented mechanism involves the α2 receptor located on noradrenergic nerve terminals. This receptor is activated by norepinephrine and similar molecules; activation diminishes further release of norepinephrine from these nerve endings (Table 6–4). The mechanism of this G protein–mediated effect involves inhibition of the inward calcium current that causes vesicular fusion and transmitter release. Conversely, a presynaptic β receptor appears to facilitate the release of norepinephrine from some adrenergic neurons. Presynaptic receptors that respond to the primary transmitter substance released by the nerve ending are called autoreceptors. Autoreceptors are usually inhibitory, but in addition to the excitatory β receptors on noradrenergic fibers, many cholinergic fibers, especially somatic motor fibers, have excitatory nicotinic autoreceptors.

CHAPTER 6  Introduction to Autonomic Pharmacology    105

TABLE 6–3  Direct effects of autonomic nerve activity on some organ systems. Autonomic drug effects are similar but not identical (see text).

Effect of Sympathetic Activity Organ

Action

1

Receptor

Parasympathetic Activity 2

Action

Receptor2

Eye   Iris radial muscle

Contracts

α1

—

—

  Iris circular muscle

—

—

Contracts

M3

  Ciliary muscle

[Relaxes]

β

Contracts

M3

  Sinoatrial node

Accelerates

β1, β2

Decelerates

M2

  Ectopic pacemakers

Accelerates

β1, β2

—

—

 Contractility

Increases

β1, β2

Decreases (atria)

M2

  Skin, splanchnic vessels

Contracts

α

—

—

  Skeletal muscle vessels

Relaxes

β2

—

—

 

[Contracts]

α

—

—

 

Relaxes3

M3

—

—

 Endothelium of vessels in heart, brain, viscera

—

—

Synthesizes and releases EDRF4

M3, M55

Bronchiolar smooth muscle

Relaxes

β2

Contracts

M3

  Walls

Relaxes

α2,6 β2

Contracts7

M3

  Sphincters

Contracts

α1

Relaxes

M3

 Secretion

[Decreases]

α2

Increases

M3

  Bladder wall

Relaxes

β2

Contracts7

M3

 Sphincter

Contracts

α1

Relaxes

M3

  Uterus, pregnant

Relaxes

β2

—

…

 

Contracts

α

Contracts

M3

  Penis, seminal vesicles

Ejaculation

α

Erection

M

  Pilomotor smooth muscle

Contracts

α

—

—

  Sweat glands

 

 

—

—

  Eccrine

Increases

M

—

—

  Apocrine (stress)

Increases

α

—

—

 Liver

Gluconeogenesis

β2, α

—

—

 Liver

Glycogenolysis

β2, α

—

—

  Fat cells

Lipolysis

β3

—

—

 Kidney

Renin release

β1

—

—

Heart

Blood vessels

Gastrointestinal tract   Smooth muscle

Genitourinary smooth muscle

Skin

Metabolic functions

1

Less important actions are shown in brackets.

2

Specific receptor type: α, alpha; β, beta; M, muscarinic.

3

Vascular smooth muscle in skeletal muscle has sympathetic cholinergic dilator fibers.

4

The endothelium of most blood vessels releases EDRF (endothelium-derived relaxing factor), which causes marked vasodilation, in response to muscarinic stimuli. Parasympathetic fibers innervate muscarinic receptors in vessels in the viscera and brain, and sympathetic cholinergic fibers innervate skeletal muscle blood vessels. The muscarinic receptors in the other vessels of the peripheral circulation are not innervated and respond only to circulating muscarinic agonists. 5

Cerebral blood vessels dilate in response to M5 receptor activation.

6

Probably through presynaptic inhibition of parasympathetic activity.

7

The cholinergic innervation of the rectum and the genitourinary organs may be anatomically sympathetic; see Box: Sympathetic Sacral Outflow.

106    SECTION II  Autonomic Drugs

Autonomic feedback loop

VASOMOTOR CENTER

Sympathetic autonomic nervous system

Parasympathetic autonomic nervous system Baroreceptors +

Peripheral vascular resistance

Mean arterial pressure

Hormonal feedback loop

Cardiac output

–

+

+

Heart rate

+

Contractile force

Stroke volume

Venous tone

Venous return

Blood volume

Aldosterone

Renal blood flow/pressure

Renin

Angiotensin

FIGURE 6–7  Autonomic and hormonal control of cardiovascular function. Note that two feedback loops are present: the autonomic nervous system loop and the hormonal loop. The sympathetic nervous system directly influences four major variables: peripheral vascular resistance, heart rate, force, and venous tone. It also directly modulates renin production (not shown). The parasympathetic nervous system directly influences heart rate. In addition to its role in stimulating aldosterone secretion, angiotensin II directly increases peripheral vascular resistance and facilitates sympathetic effects (not shown). The net feedback effect of each loop is to compensate for changes in arterial blood pressure. Thus, decreased blood pressure due to blood loss would evoke increased sympathetic outflow and renin release. Conversely, elevated pressure due to the administration of a vasoconstrictor drug would cause reduced sympathetic outflow, reduced renin release, and increased parasympathetic (vagal) outflow.

TABLE 6–4  Autoreceptor, heteroreceptor, and modulatory effects on nerve terminals in peripheral synapses.1 Transmitter/Modulator

Receptor Type

Neuron Terminals Where Found

 Acetylcholine

M2, M4

Adrenergic, enteric nervous system

 Norepinephrine

Alpha2

Adrenergic

 Dopamine

D2; less evidence for D1

Adrenergic

  Serotonin (5-HT)

5-HT1, 5-HT2, 5-HT3

Cholinergic preganglionic

  ATP, ADP

P2Y

Adrenergic autonomic and ENS cholinergic neurons

 Adenosine

A1

Adrenergic autonomic and ENS cholinergic neurons

 Histamine

H3, possibly H2

H3 type identified on CNS adrenergic and serotonergic neurons

 Enkephalin

Delta (also mu, kappa)

Adrenergic, ENS cholinergic

  Neuropeptide Y

Y1, Y2 (NPY)

Adrenergic, some cholinergic

  Prostaglandin E1, E2

EP3

Adrenergic

 Epinephrine

Beta2

Adrenergic, somatic motor cholinergic

 Acetylcholine

N

Somatic motor cholinergic

  Angiotensin II

AT1

Adrenergic

Inhibitory effects

Excitatory effects

1

A provisional list. The number of transmitters and locations will undoubtedly increase with additional research.

CHAPTER 6  Introduction to Autonomic Pharmacology    107

Membrane potential

Preganglionic axon

Spike

0

Electrode Postganglionic neuron

IPSP

EPSP

mV

N

N

–100 Milliseconds

M2 Seconds

Slow EPSP

Late, slow EPSP

M1

Peptides

(Receptor types) Minutes

Time

FIGURE 6–8  Excitatory and inhibitory postsynaptic potentials (EPSP and IPSP) in an autonomic ganglion cell. The postganglionic neuron shown at the left with a recording electrode might undergo the membrane potential changes shown schematically in the recording. The response begins with two EPSP responses to nicotinic (N) receptor activation, the first not reaching threshold. The second, suprathreshold, EPSP evokes an action potential, which is followed by an IPSP, probably evoked by M2 receptor activation (with possible participation from dopamine receptor activation). The IPSP is, in turn, followed by a slower, M1-dependent EPSP, and this is sometimes followed by a still slower peptideinduced excitatory postsynaptic potential. Control of transmitter release is not limited to modulation by the transmitter itself. Nerve terminals also carry regulatory receptors that respond to many other substances. Such heteroreceptors may be activated by substances released from other nerve terminals that synapse with the nerve ending. For example, some vagal fibers in the myocardium synapse on sympathetic noradrenergic nerve terminals and inhibit norepinephrine release. Alternatively, the ligands for these receptors may diffuse to the receptors from the blood or from nearby tissues. Some of the transmitters and receptors identified to date are listed in Table 6–4. Presynaptic regulation by a variety of endogenous chemicals probably occurs at all synapses. C. Postsynaptic Regulation Postsynaptic regulation can be considered from two perspectives: modulation by previous activity at the primary receptor (which may up- or downregulate receptor number or desensitize receptors; see Chapter 2), and modulation by other simultaneous events. The first mechanism has been well documented in several receptor-effector systems. Up-regulation and down-regulation are known to occur in response to decreased or increased activation, respectively, of the receptors. An extreme form of up-regulation occurs after denervation of some tissues, resulting in denervation supersensitivity of the tissue to activators of that receptor type. In skeletal muscle, for example, nicotinic receptors are normally restricted to the end plate regions underlying somatic motor nerve terminals. Surgical or traumatic denervation results in marked proliferation of nicotinic cholinoceptors over all parts of the fiber, including areas not previously associated with any motor nerve junctions. A pharmacologic supersensitivity related to denervation supersensitivity occurs in autonomic effector tissues after administration of drugs that deplete transmitter stores and prevent activation of the postsynaptic receptors for a sufficient period of time. For example, prolonged administration of large doses of reserpine,

a norepinephrine depleter that blocks reuptake of norepinephrine into vesicles, can cause increased sensitivity of the smooth muscle and cardiac muscle effector cells served by the depleted sympathetic fibers. The second mechanism involves modulation of the primary transmitter-receptor event by actions evoked by the same or other transmitters acting on different postsynaptic receptors. Ganglionic transmission is a good example of this phenomenon (Figure 6–8). The postganglionic cells are activated (depolarized) as a result of binding of an appropriate ligand to a neuronal nicotinic (NN) acetylcholine receptor. The resulting fast excitatory postsynaptic potential (EPSP) evokes a propagated action potential if threshold is reached. This event is often followed by a small and slowly developing but longer-lasting hyperpolarizing afterpotential—a slow inhibitory postsynaptic potential (IPSP). This hyperpolarization involves opening of potassium channels by M2 cholinoceptors. The IPSP is followed by a small, slow excitatory postsynaptic potential caused by closure of potassium channels linked to M1 cholinoceptors. Finally, a late, very slow EPSP may be evoked by peptides released from other fibers. These slow potentials serve to modulate the responsiveness of the postsynaptic cell to subsequent primary excitatory presynaptic nerve activity. (See Chapter 21 for additional examples.)

PHARMACOLOGIC MODIFICATION OF AUTONOMIC FUNCTION Because transmission involves both similar (eg, ganglionic) and different (eg, effector cell receptor) mechanisms in different segments of the ANS, some drugs produce less selective effects, whereas others are highly specific in their actions. A summary of the steps in transmission of impulses, from the CNS to the autonomic effector cells, is presented in Table 6–5. Drugs that block action potential propagation (local anesthetics and some natural

108    SECTION II  Autonomic Drugs

TABLE 6–5  Steps in autonomic transmission: Effects of some drugs. Process Affected

Drug Example 1

Site

Action

Action potential propagation

Local anesthetics, tetrodotoxin, 2 saxitoxin

Nerve axons

Block voltage-gated sodium channels; block conduction

Transmitter synthesis

Hemicholiniums

Cholinergic nerve terminals: membrane

Block uptake of choline and slow ACh synthesis

 

α-Methyltyrosine (metyrosine)

Adrenergic nerve terminals and adrenal medulla: cytoplasm

Inhibits tyrosine hydroxylase and blocks synthesis of catecholamines

Transmitter storage

Vesamicol

Cholinergic terminals: VAT on vesicles

Prevents storage, depletes

 

Reserpine, tetrabenazine

Adrenergic terminals: VMAT on vesicles

Prevents storage, depletes

Transmitter release

Many

Nerve terminal membrane receptors

Modulate release

 

ω-Conotoxin GVIA4

Nerve terminal calcium channels

Reduces transmitter release

 

Amifampridine

Blocks nerve terminal K channels

Increases transmitter release by prolonging action potential and increasing calcium influx

 

Domoic acid

Nerve terminal kainate receptors (primarily CNS; see Chapter 21)

Modulates transmitter release by altering calcium influx/release

 

Botulinum toxin

Cholinergic vesicles

Prevents ACh release Causes explosive transmitter release

3

5

 

α-Latrotoxin

Cholinergic and adrenergic vesicles

 

Tyramine, amphetamine

Adrenergic nerve terminals

Promote transmitter release

Transmitter reuptake after release

Cocaine, tricyclic antidepressants, SNRI antidepressants6

Adrenergic nerve terminals, NET

Inhibit uptake; increase transmitter effect on postsynaptic receptors

Receptor activation or blockade

Norepinephrine

Receptors at adrenergic junctions

Binds and activates a receptors; causes contraction

 

Phentolamine

Receptors at adrenergic junctions

Binds α receptors; prevents activation

 

Isoproterenol

Receptors at adrenergic junctions

Binds β receptors; activates adenylyl cyclase

 

Propranolol

Receptors at adrenergic junctions

Binds β receptors; prevents activation

 

Nicotine

Receptors at nicotinic cholinergic junctions (autonomic ganglia, neuromuscular end plates)

Binds nicotinic receptors; opens ion channel in postsynaptic membrane

 

Tubocurarine

Neuromuscular end plates

Prevents activation of nicotinic receptors

 

Bethanechol

Receptors, parasympathetic effector cells (smooth muscle, glands)

Binds and activates muscarinic receptors

 

Atropine

Receptors, parasympathetic effector cells

Binds muscarinic receptors; prevents activation

Enzymatic inactivation of transmitter

Neostigmine

Cholinergic synapses (acetylcholinesterase)

Inhibits enzyme; prolongs and intensifies transmitter action after release

 

Tranylcypromine

Adrenergic nerve terminals (monoamine oxidase)

Inhibits enzyme; increases stored transmitter pool

1

Toxin of puffer fish, California newt.

2

Toxin of Gonyaulax (red tide organism).

3

Norepinephrine, dopamine, acetylcholine, angiotensin II, various prostaglandins, etc.

4

Toxin of marine snails of the genus Conus.

5

Black widow spider venom.

6

Serotonin, norepinephrine reuptake inhibitors.

NET, norepinephrine transporter; SNRI, serotonin-norepinephrine reuptake inhibitors; VAT, vesicle-associated transporter; VMAT, vesicular monoamine transporter.

toxins) are very nonselective in their action, since they act on a process that is common to all neurons. On the other hand, drugs that act on the biochemical processes involved in transmitter synthesis and storage are more selective, since the biochemistry of

each transmitter differs, eg, norepinephrine synthesis is very different from acetylcholine synthesis. Activation or blockade of effector cell receptors offers maximum flexibility and selectivity of effect attainable with currently available drugs: adrenoceptors are easily

CHAPTER 6  Introduction to Autonomic Pharmacology    109

distinguished from cholinoceptors. Furthermore, individual receptor subgroups can often be selectively activated or blocked within each major type. Some examples are given in Box: Pharmacology

of the Eye. Even greater selectivity may be attainable in the future using drugs that target post-receptor processes, eg, receptors for second messengers.

Pharmacology of the Eye The eye is an organ with multiple autonomic functions, controlled by several autonomic receptors. As shown in Figure 6–9, areas around the lens are the site of several autonomic effector tissues. These tissues include three muscles (pupillary dilator and constrictor muscles of the iris and the ciliary muscle) and the secretory epithelium of the ciliary body.

Parasympathetic nerve activity and muscarinic cholinomimetics mediate contraction of the circular pupillary constrictor muscle and of the ciliary muscle. Contraction of the pupillary constrictor muscle causes miosis, a reduction in pupil size. Miosis is usually present in patients exposed to large systemic or small topical doses of cholinomimetics, especially organophosphate

Cornea Canal of Schlemm Anterior chamber Trabecular meshwork

Dilator (α)

Sphincter (M)

Sclera Iris

Lens

Ciliary epithelium (β) Ciliary muscle (M)

FIGURE 6–9  Structures of the anterior chamber of the eye. Tissues with significant autonomic functions and the associated ANS receptors (α, β, M) are shown in this schematic diagram. Aqueous humor is secreted by the epithelium of the ciliary body, flows into the space in front of the iris, flows through the trabecular meshwork, and exits via the canal of Schlemm (arrow). Blockade of the β adrenoceptors associated with the ciliary epithelium causes decreased secretion of aqueous. Blood vessels (not shown) in the sclera are also under autonomic control and influence aqueous drainage. cholinesterase inhibitors. Ciliary muscle contraction causes accommodation of focus for near vision. Marked contraction of the ciliary muscle, which often occurs with cholinesterase inhibitor intoxication, is called cyclospasm. Ciliary muscle contraction also puts tension on the trabecular meshwork, opening its pores and facilitating outflow of the aqueous humor into the canal of Schlemm. Increased outflow reduces intraocular pressure, a very useful result in patients with glaucoma. All of these effects are prevented or reversed by muscarinic blocking drugs such as atropine.

Alpha adrenoceptors mediate contraction of the radially oriented pupillary dilator muscle fibers in the iris and result in mydriasis (an increase in pupil size). This occurs during sympathetic discharge and when α-agonist drugs such as phenylephrine are placed in the conjunctival sac. Beta adrenoceptors on the ciliary epithelium facilitate the secretion of aqueous humor. Blocking these receptors (with β-blocking drugs) reduces the secretory activity and reduces intraocular pressure, providing another therapy for glaucoma.

110    SECTION II  Autonomic Drugs

The next four chapters provide many more examples of this useful diversity of autonomic control processes.

REFERENCES Andersson K-E: Mechanisms of penile erection and basis for pharmacological treatment of erectile dysfunction. Pharmacol Rev 2011;63:811. Barrenschee M et al: SNAP-25 is abundantly expressed in enteric neuronal networks and upregulated by the neurotrophic factor GDNF. Histochem Cell Biol 2015;143:611. Biaggioni I: The pharmacology of autonomic failure: from hypotension to hypertension. Pharmacol Rev 2017;69:53. Birdsall NJM: Class A GPCR heterodimers: Evidence from binding studies. Trends Pharmacol Sci 2010;31:499. Burnstock G: Non-synaptic transmission at autonomic neuroeffector junctions. Neurochem Int 2008;52:14. Burnstock G: Purinergic signalling in the gut. Adv Exp Med Biol 2016;891:91. Centers for Disease Control and Prevention: Paralytic shellfish poisoning—Southeast Alaska, May-June 2011. MMWR Morb Mortal Wkly Rep 2011;60:1554. Dulcis D et al: Neurotransmitter switching in the adult brain regulates behaviour. Science 2013;340:449. Espinoza-Medina I et al: The sacral autonomic outflow is sympathetic. Science 2016;354:893. Fisher J: The neurotoxin domoate causes long-lasting inhibition of the kainate receptor GluK5 subunit. Neuropharmacology 2014;85:9. Furchgott RF: Role of endothelium in responses of vascular smooth muscle to drugs. Annu Rev Pharmacol Toxicol 1984;24:175. Galligan JJ: Ligand-gated ion channels in the enteric nervous system. Neurogastroenterol Motil 2002;14:611. Hills JM, Jessen KR: Transmission: γ-aminobutyric acid (GABA), 5-hydroxytryptamine (5-HT) and dopamine. In: Burnstock G, Hoyle CHV (editors): Autonomic Neuroeffector Mechanisms. Harwood Academic, 1992. Holzer P et al: Neuropeptide Y, peptide YY and pancreatic polypeptide in the gutbrain axis. Neuropeptides 2012;46:261. Johnston GR, Webster NR: Cytokines and the immunomodulatory function of the vagus nerve. Br J Anaesthesiol 2009;102:453. Langer SZ: Presynaptic receptors regulating transmitter release. Neurochem Int 2008;52:26.

Li YC, Kavalali ET: Synaptic vesicle-recycling machinery components as potential therapeutic targets. Pharmacol Rev 2017;69:142. Luther JA, Birren SJ: Neurotrophins and target interactions in the development and regulation of sympathetic neuron electrical and synaptic properties. Auton Neurosci 2009;151:46. Magnon C: Autonomic nerve development contributes to prostate cancer progression. Science 2013;341:1236361. Mikoshiba K: IP3 receptor/Ca2+ channel: From discovery to new signaling concepts. J Neurochem 2007;102:1426. Pirazzini M et al: Botulinum neurotoxins: Biology, pharmacology, and toxicology. Pharmacol Rev 2017;69:200. Raj SR, Coffin ST: Medical therapy and physical maneuvers in the treatment of the vasovagal syncope and orthostatic hypotension. Prog Cardiovasc Dis 2013;55:425. Rizo J: Staging membrane fusion. Science 2012;337:1300. Robertson D et al: Primer on the Autonomic Nervous System, 3rd ed. Academic Press, 2012. Shibasaki M, Crandall CG: Mechanisms and controllers of eccrine sweating in humans. Front Biosci (Schol Ed) 2011;2:685. Symposium: Gastrointestinal reviews. Curr Opin Pharmacol 2007;7:555. Tobin G, Giglio D, Lundgren O: Muscarinic receptor subtypes in the alimentary tract. J Physiol Pharmacol 2009;60:3. Vanderlaan RD et al: Enhanced exercise performance and survival associated with evidence of autonomic reinnervation in pediatric heart transplant recipients. Am J Transplant 2012;12:2157. Vernino S, Hopkins S, Wang Z: Autonomic ganglia, acetylcholine antibodies, and autoimmune gangliopathy. Auton Neurosci 2009;146:3. Verrier RL, Tan A: Heart rate, autonomic markers, and cardiac mortality. Heart Rhythm 2009;6(Suppl 11):S68. Watanabe S et al: Clathrin regenerates synaptic vesicles from endosomes. Nature 2014;515:228. Westfall DP, Todorov LD, Mihaylova-Todorova ST: ATP as a cotransmitter in sympathetic nerves and its inactivation by releasable enzymes. J Pharmacol Exp Ther 2002;303:439. Whittaker VP: Some currently neglected aspects of cholinergic function. J Mol Neurosci 2010;40:7.

C ASE STUDY ANSWER This case illustrates the overlap of autonomic pharmacology with somatic motor pharmacology through their use of a common transmitter. Blepharospasm and other manifestations of involuntary muscle spasm can be disabling and, in the case of large muscles, painful. Contraction of skeletal muscle is triggered by exocytotic release of acetylcholine

(ACh) from motor nerves in response to calcium influx at the nerve ending. Release of ACh can be reduced or blocked by botulinum toxin, which interferes with the fusion of nerve ending ACh vesicles with the nerve ending membrane (see text). Depending on dosage, botulinum blockade has an average duration of 1–3 months after a single administration.

C

Cholinoceptor-Activating & Cholinesterase-Inhibiting Drugs

H

7 A

P

T

E

R

Todd W. Vanderah, PhD

C ASE STUDY In late morning, a coworker brings 43-year-old JM to the emergency department because he is agitated and unable to continue picking vegetables. His gait is unsteady, and he walks with support from his colleague. JM has difficulty speaking and swallowing, his vision is blurred, and his eyes are filled with tears. His coworker notes that JM was working in a field

Acetylcholine-receptor (cholinoceptor) stimulants and cholinesterase inhibitors make up a large group of drugs that mimic acetylcholine (cholinomimetics) (Figure 7–1). Cholinoceptor stimulants are classified pharmacologically by their spectrum of action, depending on the type of receptor—muscarinic or nicotinic—that is activated. Cholinomimetics are also classified by their mechanism of action because some bind directly to (and activate) cholinoceptors, whereas others act indirectly by inhibiting the hydrolysis of endogenous acetylcholine.

SPECTRUM OF ACTION OF CHOLINOMIMETIC DRUGS Early studies of the parasympathetic nervous system showed that the alkaloid muscarine mimicked the effects of parasympathetic nerve discharge; that is, the effects were parasympathomimetic. Application of muscarine to ganglia and to autonomic effector tissues (smooth muscle, heart, exocrine glands) showed that the parasympathomimetic action of the alkaloid occurred through an action on receptors at effector cells (smooth muscle, glands), not

that had been sprayed early in the morning with a material that had the odor of sulfur. Within 3 hours after starting his work, JM complained of tightness in his chest that made breathing difficult, and he called for help before becoming disoriented. How would you proceed to evaluate and treat JM? What should be done for his coworker?

those in ganglia. The effects of acetylcholine itself and of other cholinomimetic drugs at autonomic neuroeffector junctions are called parasympathomimetic effects and are mediated by muscarinic receptors. In contrast, low concentrations of the alkaloid nicotine stimulated autonomic ganglia and skeletal muscle neuromuscular junctions but not autonomic effector cells. The ganglion and skeletal muscle receptors were therefore labeled nicotinic. When acetylcholine was later identified as the physiologic transmitter at both muscarinic and nicotinic receptors, both receptors were recognized as acetylcholine receptor subtypes. Cholinoceptors are members of either G protein-linked (muscarinic) or ion channel (nicotinic) families on the basis of their structure and transmembrane signaling mechanisms. Muscarinic receptors contain seven transmembrane domains whose third cytoplasmic loop is coupled to G proteins that function as transducers (see Figure 2–11). These receptors regulate the production of intracellular second messengers and modulate certain ion channels via their G proteins. Agonist selectivity is determined by the subtypes of muscarinic receptors and G proteins that are present in a given cell (Table 7–1). In native cells and in cell expression systems, muscarinic receptors form dimers or oligomers that are 111

112    SECTION II  Autonomic Drugs

Cholinoceptor stimulants

Nerve

Heart and Glands and smooth muscle endothelium

Alkaloids Direct-acting drugs

Receptors

Neuromuscular end plate, skeletal muscle

ACh

Nicotinic

Choline esters

FIGURE 7–1 

Reversible

Muscarinic

Autonomic ganglion cells

Indirect-acting drugs Irreversible

Central nervous system

The major groups of cholinoceptor-activating drugs, receptors, and target tissues. ACh, acetylcholine.

thought to function in receptor movement between the endoplasmic reticulum and plasma membrane as well as in signaling. Conceivably, agonist or antagonist ligands could signal by changing the quaternary structure of the receptor, that is, the ratio of monomeric to oligomeric receptors. Muscarinic receptors are integral proteins located in plasma membranes of cells in the central nervous system, in autonomic ganglia (see Figure 6–8), in organs innervated by parasympathetic nerves, and on some tissues that are not innervated by these nerves, (eg, endothelial cells of blood vessels) (see Table 7–1), as well as on tissues innervated by postganglionic sympathetic cholinergic nerves (eg, eccrine sweat glands, blood vessels in skeletal muscles of some animals).

Nicotinic receptors are part of a transmembrane polypeptide whose five subunits form cation-selective ion channels (see Figure 2–9). The five subunits are composed of different combinations of alpha, beta, gamma, delta, or epsilon subunits. These receptors are located in plasma membranes of postganglionic cells in all autonomic ganglia, of muscles innervated by somatic motor fibers, and of some central nervous system neurons (see Figure 6–1). Nonselective cholinoceptor stimulants in sufficient dosage can produce very diffuse and marked alterations in organ system function because acetylcholine has multiple sites of action where it initiates both excitatory and inhibitory effects. Fortunately, drugs are

TABLE 7–1  Subtypes and characteristics of cholinoceptors. Receptor Type

Other Names

Location

Structural Features

Postreceptor Mechanism

M1

 

Nerves

Seven transmembrane segments, Gq/11 protein-linked

IP3, DAG cascade

M2

Cardiac M2

Heart, nerves, smooth muscle

Seven transmembrane segments, Gi/o protein-linked

Inhibition of cAMP production, activation of K+ channels

M3

 

Glands, smooth muscle, endothelium

Seven transmembrane segments, Gq/11 protein-linked

IP3, DAG cascade

M4

 

CNS

Seven transmembrane segments, Gi/o protein-linked

Inhibition of cAMP production

M5

 

CNS

Seven transmembrane segments, Gq/11 protein-linked

IP3, DAG cascade

NM

Muscle type, end plate receptor

Skeletal muscle neuromuscular junction

Pentamer [(α1)2β1δγ)]

NN

Neuronal type, ganglion receptor

CNS, postganglionic cell body, dendrites

Pentamer with α and β subunits only, eg, (α4)2(β2)3 (CNS) or α3α5(β2)3 (ganglia)

1

Na+, K+ depolarizing ion channel

1

Na , K depolarizing ion channel

+

+

1 Pentameric structure in Torpedo electric organ and fetal mammalian muscle has two α1 subunits and one each of β1, δ, and γ subunits. The stoichiometry is indicated by subscripts, eg, [(α1)2 β1 δ γ]. In adult muscle, the γ subunit is replaced by an ε subunit. There are 12 neuronal nicotinic receptors with nine α (α2–α10) subunits and three (β2–β4) subunits. The subunit composition varies among different mammalian tissues.

DAG, diacylglycerol; IP3, inositol trisphosphate. Data from Millar NS, Gotti C: Diversity of vertebrate nicotinic acetylcholine receptors. Neuropharmacology 2009 Jan;56(1):237-246.

CHAPTER 7  Cholinoceptor-Activating & Cholinesterase-Inhibiting Drugs      113

available that have a degree of selectivity, so that desired effects can often be achieved while avoiding or minimizing adverse effects. Selectivity of action is based on several factors. Some drugs stimulate either muscarinic receptors or nicotinic receptors. Due to the nicotinic receptors being made up of five different subunits, some agents can stimulate nicotinic receptors at neuromuscular junctions preferentially and have less effect on nicotinic receptors in ganglia that consist of different subunits. Organ selectivity can also be achieved by using appropriate routes of administration (“pharmacokinetic selectivity”). For example, muscarinic stimulants can be administered topically to the surface of the eye to modify ocular function while minimizing systemic effects.

O H3C

O

CH2

CH2

N+

CH3 CH3 CH3

N+

CH3 CH3 CH3

Acetylcholine O H3C

C

O

CH

CH2

CH3 Methacholine (acetyl-a-methylcholine)

MODE OF ACTION OF CHOLINOMIMETIC DRUGS Direct-acting cholinomimetic agents bind to and activate muscarinic or nicotinic receptors (see Figure 7–1). Indirect-acting agents produce their primary effects by inhibiting acetylcholinesterase, which hydrolyzes acetylcholine to choline and acetic acid (see Figure 6–3). By inhibiting acetylcholinesterase, the indirect-acting drugs increase the endogenous acetylcholine concentration in synaptic clefts and neuroeffector junctions. The excess acetylcholine, in turn, stimulates cholinoceptors to evoke increased responses. These drugs act primarily where acetylcholine is physiologically released and are thus amplifiers of endogenous acetylcholine. Some cholinesterase inhibitors also inhibit butyrylcholinesterase (pseudocholinesterase). However, inhibition of butyrylcholinesterase plays little role in the action of indirect-acting cholinomimetic drugs because this enzyme is not important in the physiologic termination of synaptic acetylcholine action. However, butyrylcholinesterase serves as a biological scavenger to prevent or reduce the extent of cholinesterase inhibition by organophosphate agents (see Chapter 8). Some quaternary cholinesterase inhibitors have a modest direct action as well, eg, neostigmine, which activates neuromuscular nicotinic cholinoceptors directly in addition to blocking cholinesterase. Some individuals have a mutation in the BCHE gene that is expressed as a deficient butyrylcholinesterase produced by the liver, resulting in the inability to break down certain muscle relaxants (see Chapter 27) and anesthetics (see Chapter 25). These individuals can have a severe reaction including paralysis (and apnea) due to increased concentrations of the medications.

C

O H2N

C

O

CH2

CH2

N+

CH3 CH3 CH3

Carbachol (carbamoylcholine) O H2N

C

O

CH

CH2

N+

CH3

CH3 CH3 CH3

Bethanechol (carbamoyl-a-methylcholine)

FIGURE 7–2  Molecular structures of four choline esters. Acetylcholine and methacholine are acetic acid esters of choline and β-methylcholine, respectively. Carbachol and bethanechol are carbamic acid esters of the same alcohols. for receptor subtypes within either class. Development of subtypeselective allosteric modulators could be clinically useful.

Chemistry & Pharmacokinetics

■■ BASIC PHARMACOLOGY OF THE DIRECT-ACTING CHOLINOCEPTOR STIMULANTS

A. Structure Four important choline esters that have been studied extensively are shown in Figure 7–2. Their permanently charged quaternary ammonium group renders them relatively insoluble in lipids. Many naturally occurring and synthetic cholinomimetic drugs that are not choline esters have been identified; a few of these are shown in Figure 7–3. The muscarinic receptor is strongly stereoselective: (S)-bethanechol is almost 1000 times more potent than (R)-bethanechol.

The direct-acting cholinomimetic drugs can be divided on the basis of chemical structure into esters of choline (including acetylcholine) and alkaloids (such as muscarine and nicotine). Many of these drugs have effects on both receptors; acetylcholine is typical. A few of them are highly selective for the muscarinic or nicotinic receptor. However, none of the clinically useful drugs is selective

B.  Absorption, Distribution, and Metabolism Choline esters are poorly absorbed and poorly distributed into the central nervous system due to their hydrophilic nature. Although all are hydrolyzed in the gastrointestinal tract (and less active by the oral route), they differ markedly in their susceptibility to hydrolysis by cholinesterase. Acetylcholine is very rapidly hydrolyzed

114    SECTION II  Autonomic Drugs

Action chiefly muscarinic

Action chiefly nicotinic

HO

H3C

O

CH2

+

N

CH3 CH3 CH3

N

Muscarine

H3C

CH2

Nicotine

N

CH2

CH3

O

N

C6H5

N CH3

CH2

CH C6H5

Structures of some cholinomimetic alkaloids.

(see Chapter 6); large amounts must be infused intravenously to achieve concentrations sufficient to produce detectable effects. A large intravenous bolus injection has a brief effect, typically 5–20 seconds, whereas intramuscular and subcutaneous injections produce only local effects. Methacholine is more resistant to hydrolysis, and the carbamic acid esters carbachol and bethanechol are still more resistant to hydrolysis by cholinesterase and have correspondingly longer durations of action. The β-methyl group (methacholine, bethanechol) reduces the potency of these drugs at nicotinic receptors (Table 7–2) while they maintain activity at muscarinic receptors. The tertiary natural cholinomimetic alkaloids (pilocarpine, nicotine, lobeline) are well absorbed from most sites of administration. Nicotine, a liquid, is sufficiently lipid-soluble to be absorbed across the skin. Muscarine, a quaternary amine, is less completely absorbed from the gastrointestinal tract than the tertiary amines but is nevertheless toxic when ingested—eg, in certain mushrooms—and it even enters the brain. Lobeline is a plant derivative similar to nicotine. These amines are excreted chiefly by the kidneys. Acidification of the urine accelerates clearance of the tertiary amines (see Chapter 1).

TABLE 7–2  Properties of choline esters. Susceptibility to Cholinesterase

Muscarinic Action

Nicotinic Action

Acetylcholine chloride

++++

+++

+++

Methacholine chloride

+

++++

None

Carbachol chloride

Negligible

++

+++

Bethanechol chloride

Negligible

++

None

Choline Ester

CH2

Lobeline

Pilocarpine

FIGURE 7–3 

OH

O C

O

N

CH3

Pharmacodynamics A.  Mechanism of Action Activation of the parasympathetic nervous system modifies organ function by two major mechanisms. First, acetylcholine released from parasympathetic nerves activates muscarinic receptors on effector cells to alter organ function directly. Second, acetylcholine released from parasympathetic nerves interacts with muscarinic receptors on nerve terminals to modulate the release of their neurotransmitter. By this mechanism, acetylcholine release and circulating muscarinic agonists indirectly alter organ function by modulating the effects of the parasympathetic and sympathetic nervous systems and perhaps nonadrenergic, noncholinergic (NANC) systems. As indicated in Chapter 6, muscarinic receptor subtypes have been characterized by binding studies and cloned. Several cellular events occur when muscarinic receptors are activated, one or more of which might serve as second messengers for muscarinic activation. All muscarinic receptors appear to be of the G protein-coupled type (see Chapter 2 and Table 7–1). Muscarinic agonist binding to M1, M3, and M5 receptors activates the inositol trisphosphate (IP3), diacylglycerol (DAG) cascade. Some evidence implicates DAG in the opening of smooth muscle calcium channels; IP3 releases calcium from endoplasmic and sarcoplasmic reticulum. Muscarinic agonists also increase cellular cGMP concentrations. Activation of muscarinic receptors also increases potassium flux across cardiac cell membranes (Figure 7–4A) and decreases it in ganglion and smooth muscle cells. This effect is mediated by the binding of an activated G protein βγ subunit directly to the channel. Finally, activation of M2 and M4 muscarinic receptors inhibits adenylyl cyclase activity in tissues (eg, heart, intestine). Moreover, muscarinic agonists attenuate the activation of adenylyl cyclase and decrease cAMP concentration induced by hormones such as catecholamines. These muscarinic effects on cAMP concentrations reduce the physiologic response of the organ to stimulatory hormones.

CHAPTER 7  Cholinoceptor-Activating & Cholinesterase-Inhibiting Drugs      115 A Vagus nerve varicosity ACh ACh Acetylcholine autoreceptor

–

ACh

If

M 2R

IK, ACh

ICa

Cha n

nel

AC

α

+

γ β

γ

β

–

Gi /o

Sinoatrial nodal cell

α

ATP

cAMP

ATP

PKA∗

B

Somatic motor nerve

Skeletal muscle

ACh ACh

End plates

ACh

Choline Acetate

Action potential

Na

+

AChE

End plate

Channel closed

EPSP

Channel open

Excitation

Contraction

FIGURE 7–4  Muscarinic and nicotinic signaling. A: Muscarinic transmission to the sinoatrial node in heart. Acetylcholine (ACh) released from a varicosity of a postganglionic cholinergic axon interacts with a sinoatrial node cell muscarinic receptor (M2R) linked via Gi/o to K+ channel opening, which causes hyperpolarization, and to inhibition of cAMP synthesis. Reduced cAMP shifts the voltage-dependent opening of pacemaker channels (If ) to more negative potentials, and reduces the phosphorylation and availability of L-type Ca2+ channels (ICa). Released ACh also acts on an axonal muscarinic receptor (autoreceptor; see Figure 6–3) to cause inhibition of ACh release (autoinhibition). B: Nicotinic transmission at the skeletal neuromuscular junction. ACh released from the motor nerve terminal interacts with subunits of the pentameric nicotinic receptor to open it, allowing Na+ influx to produce an excitatory postsynaptic potential (EPSP). The EPSP depolarizes the muscle membrane, generating an action potential, and triggering contraction. Acetylcholinesterase (AChE) in the extracellular matrix hydrolyzes ACh.

116    SECTION II  Autonomic Drugs

The mechanism of nicotinic receptor activation has been studied in great detail, taking advantage of three factors: (1) the receptor is present in extremely high concentration in the membranes of organs of electric fish; (2) α-bungarotoxin, a component of certain snake venoms, binds tightly to the receptors and is readily labeled as a marker for isolation procedures; and (3) receptor activation results in easily measured electrical and ionic changes in the cells involved. The nicotinic receptor in muscle tissues (Figure 7–4B) is a pentamer of four types of glycoprotein subunits (β, δ, γ, or ε, and two α monomers) with a total molecular weight of about 250,000. The neuronal nicotinic receptor consists of α and/or β subunits only (see Table 7–1). Each subunit has four transmembrane segments. The nicotinic receptor has two agonist binding sites at the interfaces formed by the two α subunits and two adjacent subunits (β, γ, ε) (see Figure 27–1B). Agonist binding to the receptor sites causes a conformational change in the protein (channel opening) that allows sodium and potassium ions to diffuse rapidly down their concentration gradients (calcium ions may also carry charge through the nicotinic receptor ion channel). Binding of an agonist molecule by one of the two receptor sites only modestly increases the probability of channel opening; simultaneous binding of agonist by both of the receptor sites greatly enhances opening probability. Nicotinic receptor activation causes depolarization of the nerve cell or neuromuscular end plate membrane. In skeletal muscle, the depolarization initiates an action potential that propagates across the muscle membrane and causes contraction (see Figure 7–4B). Prolonged agonist occupancy of the nicotinic receptor abolishes the effector response; that is, the postganglionic neuron stops firing (ganglionic effect), and the skeletal muscle cell relaxes (neuromuscular end plate effect). Furthermore, the continued presence of the nicotinic agonist prevents electrical recovery of the postjunctional membrane. Thus, a state of “depolarizing blockade” occurs initially during persistent agonist occupancy of the receptor. Continued agonist occupancy is associated with return of membrane voltage to the resting level. The receptor becomes desensitized to the continuation of the agonist, resulting in a receptor state that is refractory to reversal by other agonists. As described in Chapter 27, this effect can be exploited to produce muscle paralysis. B.  Organ System Effects Most of the direct organ system effects of muscarinic cholinoceptor stimulants are readily predicted from knowledge of the effects of parasympathetic nerve stimulation (see Table 6–3) and the distribution of muscarinic receptors. Effects of a typical agent such as acetylcholine are listed in Table 7–3. The effects of nicotinic agonists are similarly predictable from knowledge of the physiology of the autonomic ganglia, central nervous system, and skeletal muscle motor end plate. 1. Eye—Muscarinic agonists instilled into the conjunctival sac cause contraction of the smooth muscle of the iris sphincter (resulting in miosis) and of the ciliary muscle (resulting in accommodation) via M3 receptors. As a result, the iris is pulled away from the angle of the anterior chamber, and the trabecular meshwork at the base of the ciliary muscle is

TABLE 7–3  Effects of direct-acting cholinoceptor stimulants.1

Organ

Response

Eye

 

  Sphincter muscle of iris

Contraction (miosis)

  Ciliary muscle

Contraction for near vision (accommodation)

Heart

 

  Sinoatrial node

Decrease in rate (negative chronotropy)

 Atria

Decrease in contractile strength (negative inotropy). Decrease in refractory period

  Atrioventricular node

Decrease in conduction velocity (negative dromotropy). Increase in refractory period

 Ventricles

Small decrease in contractile strength

Blood vessels

 

  Arteries, veins

Dilation (via EDRF). Constriction (high-dose direct effect)

Lung

 

  Bronchial muscle

Contraction (bronchoconstriction)

  Bronchial glands

Secretion

Gastrointestinal tract

 

 Motility

Increase

 Sphincters

Relaxation

 Secretion

Stimulation

Urinary bladder

 

 Detrusor

Contraction

  Trigone and sphincter

Relaxation

Glands

 

 Sweat, salivary, lacrimal, nasopharyngeal

Secretion

1

Only the direct effects are indicated; homeostatic responses to these direct actions may be important (see text). EDRF, endothelium-derived relaxing factor.

opened. Both effects facilitate aqueous humor outflow into the canal of Schlemm, which drains the anterior chamber and is beneficial in glaucoma. 2. Cardiovascular system—The primary cardiovascular effects of muscarinic agonists are reduction in peripheral vascular resistance and changes in heart rate depending on the dose. The direct effects listed in Table 7–3 are modified by important homeostatic reflexes, as described in Chapter 6 and depicted in Figure 6–7. Intravenous infusions of minimally effective doses of acetylcholine in humans (eg, 20–50 mcg/min) cause vasodilation, resulting in a reduction in blood pressure, often accompanied by a reflex increase in heart rate. Larger doses of acetylcholine produce bradycardia and decrease atrioventricular node conduction velocity in addition to causing hypotension. The direct cardiac actions of muscarinic stimulants include the following: (1) an increase in a potassium current (IK(ACh)) in the

CHAPTER 7  Cholinoceptor-Activating & Cholinesterase-Inhibiting Drugs      117

cells of the sinoatrial and atrioventricular nodes, in Purkinje cells, and also in atrial and ventricular muscle cells; (2) a decrease in the slow inward calcium current (ICa) in heart cells; and (3) a reduction in the hyperpolarization-activated current (If ) that underlies diastolic depolarization (see Figure 7–4A). All these actions are mediated by M2 receptors and contribute to slowing the pacemaker rate. Effects (1) and (2) cause hyperpolarization, reduce action potential duration, and decrease the contractility of atrial and ventricular cells. Predictably, knockout of M2 receptors eliminates the bradycardic effect of vagal stimulation and the negative chronotropic effect of carbachol on sinoatrial rate. The direct slowing of sinoatrial rate and atrioventricular conduction that is produced by muscarinic agonists is often opposed by reflex sympathetic discharge, elicited by the decrease in blood pressure (see Figure 6–7). The resultant sympathetic-parasympathetic interaction is complex because muscarinic modulation of sympathetic influences occurs by inhibition of norepinephrine release and by postjunctional cellular effects. Muscarinic receptors that are present on postganglionic parasympathetic nerve terminals allow neurally released acetylcholine to inhibit its own secretion. The neuronal muscarinic receptors need not be the same subtype as found on effector cells. Therefore, the net effect on heart rate depends on local concentrations of the agonist in the heart and in the vessels and on the level of reflex responsiveness. Parasympathetic innervation of the ventricles is much less extensive than that of the atria; activation of ventricular muscarinic receptors causes much less direct physiologic effect than that seen in atria. However, the indirect effects of muscarinic agonists on ventricular function are clearly evident during sympathetic nerve stimulation because of muscarinic modulation of sympathetic effects (“accentuated antagonism”). In the intact organism, intravascular injection of muscarinic agonists produces marked vasodilation. However, earlier studies of isolated blood vessels often showed a contractile response to these agents. It is now known that acetylcholine-induced vasodilation arises from activation of M3 receptors and requires the presence of intact endothelium (Figure 7–5). Muscarinic agonists

Tension

Unrubbed

via M3 release endothelium-derived relaxing factor (EDRF), identified as nitric oxide (NO), from the endothelial cells. The NO diffuses to adjacent vascular smooth muscle, where it activates guanylyl cyclase and increases cGMP, resulting in relaxation (see Figure 12–2). Isolated vessels prepared with the endothelium preserved consistently reproduce the vasodilation seen in the intact organism. The relaxing effect of acetylcholine was maximal at 3 ×  10−7  M (see Figure  7–5). This effect was eliminated in the absence of endothelium, and acetylcholine, at concentrations greater than 10−7 M, then caused contraction. This results from a direct effect of acetylcholine on vascular smooth muscle in which activation of M3 receptors stimulates IP3 production and releases intracellular calcium. Parasympathetic nerves can regulate arteriolar tone in vascular beds in thoracic and abdominal visceral organs. Acetylcholine released from postganglionic parasympathetic nerves relaxes coronary arteriolar smooth muscle via the NO/cGMP pathway in humans as described above. Damage to the endothelium, as occurs with atherosclerosis, eliminates this action, and acetylcholine is then able to contract arterial smooth muscle and produce vasoconstriction via an increase in the release of intracellular calcium. Parasympathetic nerve stimulation also causes vasodilation in cerebral blood vessels; however, the effect often appears as a result of NO released either from NANC (nitrergic) neurons or as a cotransmitter from cholinergic nerves. The relative contributions of cholinergic and NANC neurons to the vascular effects of parasympathetic nerve stimulation are not known for most viscera. Skeletal muscle receives sympathetic cholinergic vasodilator nerves, but the view that acetylcholine causes vasodilation in this vascular bed has not been verified experimentally. Nitric oxide, rather than acetylcholine, may be released from these neurons. However, this vascular bed responds to exogenous choline esters because of the presence of M3 receptors on endothelial and smooth muscle cells. The cardiovascular effects of all the choline esters are similar to those of acetylcholine—the main difference being in their potency and duration of action. Because of the resistance of methacholine,

Rubbed ACh –8 –7.5 –7 –6.5

ACh –8 –7.5

–6

W

–7 –6.5 NA –8

–6

W

NA –8

Time

FIGURE 7–5  Activation of endothelial cell muscarinic receptors by acetylcholine (ACh) releases endothelium-derived relaxing factor (nitric oxide), which causes relaxation of vascular smooth muscle precontracted with norepinephrine, 10−8 M. Removal of the endothelium by rubbing eliminates the relaxant effect and reveals contraction caused by direct action of ACh on vascular smooth muscle. (NA, noradrenaline [norepinephrine]; W, wash. Numbers indicate the log molar concentration applied at the time indicated.) (Reproduced with permission from Furchgott RF, Zawadzki JV: The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature. 1980; 288(5789):373-376.)

118    SECTION II  Autonomic Drugs

carbachol, and bethanechol to acetylcholinesterase, lower doses given intravenously are sufficient to produce effects similar to those of acetylcholine, and the duration of action of these synthetic choline esters is longer. The cardiovascular effects of most of the cholinomimetic natural alkaloids and the synthetic analogs also are generally similar to those of acetylcholine. Pilocarpine is an interesting exception to the above statement due to its affinity to M1 receptors. If given intravenously (an experimental exercise), it may produce hypertension after a brief initial hypotensive response. The longer-lasting hypertensive effect can be traced to sympathetic ganglionic discharge caused by activation of postganglionic cell membrane M1 receptors, which close K+ channels and elicit slow excitatory (depolarizing) postsynaptic potentials (see Figure 6–8). This effect, like the hypotensive effect, can be blocked by atropine, an antimuscarinic drug. 3. Respiratory system—Muscarinic stimulants contract the smooth muscle of the bronchial tree. In addition, the glands of the tracheobronchial mucosa are stimulated to secrete mucins, antimicrobial substances, and fluid. This combination of effects can occasionally cause symptoms, especially in individuals with asthma. The bronchoconstriction caused by muscarinic agonists is eliminated in knockout animals in which the M3 receptor has been mutated. 4. Gastrointestinal tract—Administration of muscarinic agonists, as in parasympathetic nervous system stimulation, increases the secretory and motor activity of the gut. The salivary and gastric glands are strongly stimulated; the pancreas and small intestinal glands are stimulated less so. Peristaltic activity is increased throughout the gut, and most sphincters are relaxed. Stimulation of contraction in this organ system involves depolarization of the smooth muscle cell membrane and increased calcium influx. Muscarinic agonists do not cause contraction of the ileum in mutant mice lacking M2 and M3 receptors. The M3 receptor is required for direct activation of smooth muscle contraction, whereas the M2 receptor reduces cAMP formation and relaxation caused by sympathomimetic drugs. 5. Genitourinary tract—Muscarinic agonists stimulate the detrusor muscle and relax the trigone and sphincter muscles of the bladder, thus promoting voiding. The function of M2 and M3 receptors in the urinary bladder appears to be the same as in intestinal smooth muscle. The human uterus is not notably sensitive to muscarinic agonists. 6. Miscellaneous secretory glands—Muscarinic agonists stimulate secretion by thermoregulatory sweat, lacrimal, and nasopharyngeal glands. 7. Central nervous system—The central nervous system contains both muscarinic and nicotinic receptors, the brain being relatively richer in muscarinic sites and the spinal cord containing a preponderance of nicotinic sites. The physiologic roles of these receptors are discussed in Chapter 21. All five muscarinic receptor subtypes have been detected in the central nervous system. The roles of M1 through M3 have been

analyzed by means of experiments in knockout mice. The M1 subtype is richly expressed in brain areas involved in cognition. Knockout of M1 receptors was associated with impaired neuronal plasticity in the forebrain, and pilocarpine did not induce seizures in M1 mutant mice. The central nervous system effects of the synthetic muscarinic agonist oxotremorine (tremor, hypothermia, and antinociception) were lacking in mice with homozygously mutated M2 receptors. Animals lacking M3 receptors, especially those in the hypothalamus, had reduced appetite and diminished body fat mass. Despite the smaller ratio of nicotinic to muscarinic receptors, nicotine and lobeline (see Figure 7–3) have important effects on the brain stem and cortex. Activation of nicotinic receptors occurs at presynaptic and postsynaptic loci. Presynaptic nicotinic receptors allow acetylcholine and nicotine to regulate the release of several neurotransmitters (glutamate, serotonin, GABA, dopamine, and norepinephrine). Acetylcholine regulates norepinephrine release via α3β4 nicotinic receptors in the hippocampus and inhibits acetylcholine release from neurons in the hippocampus and cortex. The α4β2 oligomer is the most abundant nicotinic receptor in the brain with modulation of hippocampal and hypothalamus function and may be involved with nicotine addiction. Chronic exposure to nicotine has a dual effect at nicotinic receptors: activation (depolarization) followed by desensitization. The former effect is associated with greater release of dopamine in the mesolimbic system of humans. This effect is thought to contribute to the mild alerting action and the addictive property of nicotine absorbed from tobacco. When the β2 subunits are deleted in reconstitution experiments, acetylcholine binding is reduced, as is the release of dopamine. The later desensitization of the nicotinic receptor is accompanied by increased high-affinity agonist binding and an upregulation of nicotinic binding sites, especially those of the α4β2 oligomer. Sustained desensitization may contribute to the benefits of nicotine replacement therapy in smoking cessation regimens. In high concentrations, nicotine induces tremor, emesis, and stimulation of the respiratory center. At still higher levels, nicotine causes convulsions, which may terminate in fatal coma. The lethal effects on the central nervous system and the fact that nicotine is readily absorbed form the basis for the use of nicotine and derivatives (neonicotinoids) as insecticides. The α7 subtype of nicotinic receptors (α7 nAChR) is detected in the central and peripheral nervous systems where it may function in cognition and pain perception. This nicotinic receptor subtype is a homomeric pentamer (α7)5 having five agonist binding sites at the interfaces of the subunits. Positive allosteric modulators (see Chapter 1) of the α7 receptor are being developed with a view to improving cognitive function in the treatment of schizophrenia. The presence of α7 nAChR on nonneuronal cells of the immune system has been suggested as a basis of anti-inflammatory actions. Acetylcholine or nicotine reduces the release of inflammatory cytokines via α7 nAChR on macrophages, microglia, and astrocytes. In human volunteers, transdermal nicotine reduced markers of inflammation caused by lipopolysaccharide. The antiinflammatory role of α7 nAChR has gained support from such data.

CHAPTER 7  Cholinoceptor-Activating & Cholinesterase-Inhibiting Drugs      119

8. Peripheral nervous system—Autonomic ganglia are important sites of nicotinic synaptic action. The α3 subtype is found in autonomic ganglia and is responsible for fast excitatory transmission. Beta2 and β4 subunits are usually present with the α3 subunit to form heteromeric subtypes in parasympathetic and sympathetic ganglia and in the adrenal medulla. Nicotinic agents cause marked activation of these nicotinic receptors and initiate action potentials in postganglionic neurons (see Figure 6–8). Nicotine itself has a somewhat greater affinity for neuronal than for skeletal muscle nicotinic receptors. Nicotine action is the same on both parasympathetic and sympathetic ganglia. Therefore, the initial response often resembles simultaneous discharge of both the parasympathetic and sympathetic nervous systems. In the case of the cardiovascular system, the effects of nicotine are chiefly sympathomimetic. Dramatic hypertension is produced by parenteral injection of nicotine; sympathetic tachycardia may alternate with a bradycardia mediated by vagal discharge. In the gastrointestinal and urinary tracts, the effects are largely parasympathomimetic: nausea, vomiting, diarrhea, and voiding of urine are commonly observed. Prolonged exposure may result in depolarizing blockade of the ganglia. Primary autoimmune autonomic failure provides a pathophysiologic example of the effects of suppression of nicotinic receptor function at autonomic ganglia. In some patients, neither diabetic neuropathy nor amyloidosis can account for the autonomic failure. In those individuals, circulating autoantibodies selective for the α3β4 nicotinic receptor subtype are present and cause orthostatic hypotension, reduced sweating, dry mouth and eyes, reduced baroreflex function, urinary retention, constipation, and erectile dysfunction. These signs of autonomic failure can be ameliorated by plasmapheresis, which also reduces the concentration of autoantibodies to the α3β4 nicotinic receptor. Deletion of either the α3 or the β2 and β4 subunits causes widespread autonomic dysfunction and blocks the action of nicotine in experimental animals. Humans deficient in α3 subunits are afflicted with microcystis (inadequate development of the urinary bladder), microcolon, and intestinal hypoperistalsis syndrome; urinary incontinence, urinary bladder distention, and mydriasis also occur. Neuronal nicotinic receptors are present on sensory nerve endings, especially afferent nerves in coronary arteries and the carotid and aortic bodies as well as on the glomus cells of the latter. Activation of these receptors by nicotinic stimulants and of muscarinic receptors on glomus cells by muscarinic stimulants elicits complex medullary responses, including respiratory alterations and vagal discharge. 9. Neuromuscular junction—The nicotinic receptors on the neuromuscular end plate apparatus are of (α1)2β1δε or (α1)2β1δγ and function similar but not identical to the receptors in the autonomic ganglia (see Table 7–1). Both types respond to acetylcholine and nicotine. (However, as noted in Chapter 8, the receptors differ in their structural requirements for nicotinic blocking drugs.) When a nicotinic agonist is applied directly (by iontophoresis or by intra-arterial injection), an immediate depolarization of the end plate results, caused by an increase in

permeability to sodium and potassium ions (see Figure 7–4B). The contractile response varies from disorganized fasciculations of independent motor units to a strong contraction of the entire muscle depending on the synchronization of depolarization of end plates throughout the muscle. Depolarizing nicotinic agents that are not rapidly hydrolyzed (like nicotine itself ) cause rapid development of depolarization blockade; transmission blockade persists even when the membrane has repolarized (discussed further in Chapters 8 and 27). This latter phase of block is manifested as flaccid paralysis in the case of skeletal muscle.

■■ BASIC PHARMACOLOGY OF THE INDIRECT-ACTING CHOLINOMIMETICS The actions of acetylcholine released from autonomic and somatic motor nerves are terminated by enzymatic hydrolysis of the molecule. Hydrolysis is accomplished by the action of acetylcholinesterase, which is present in high concentrations in cholinergic synapses. The indirect-acting cholinomimetics have their primary effect at the active site of this enzyme, although some also have direct actions at nicotinic receptors. The chief differences between members of the group are chemical and pharmacokinetic—their pharmacodynamic properties are almost identical.

Chemistry & Pharmacokinetics A. Structure There are three chemical groups of cholinesterase inhibitors: (1) simple alcohols bearing a quaternary ammonium group, eg, edrophonium; (2) carbamic acid esters of alcohols having quaternary or tertiary ammonium groups (carbamates, eg, neostigmine); and (3) organic derivatives of phosphoric acid (organophosphates, eg, echothiophate). Examples of the first two groups are shown in Figure 7–6. Edrophonium, neostigmine, and pyridostigmine are synthetic quaternary ammonium agents used in medicine. Physostigmine (eserine) is a naturally occurring tertiary amine, and rivastigmine is synthetic and of greater lipid solubility and is also used in therapeutics (Table 7–4). Donepezil is a synthesized piperidine derivative compound used to treat dementia. Carbaryl (carbaril) is typical of a large group of carbamate insecticides designed for very high lipid solubility, so that absorption into the insect and distribution to its central nervous system are very rapid. A few of the estimated 50,000 organophosphates are shown in Figure 7–7. Many of the organophosphates (echothiophate is an exception) are highly lipid-soluble liquids. Echothiophate, a thiocholine derivative, is of clinical value because it retains the very long duration of action of other organophosphates but is more stable in aqueous solution. Sarin is an extremely potent “nerve gas.” Parathion and malathion are thiophosphate (sulfur-containing phosphate) prodrugs that are inactive as such; they are converted to the phosphate derivatives in animals and plants and are used as insecticides.

120    SECTION II  Autonomic Drugs

[2]

[1] O

O

H3C N

C

CH3 CH3 CH3

+ N

O

H3C

H3C

NH

C

Carbaryl

Neostigmine O H3C N

C

O

CH3 O

CH3 C2H5 CH3

+N

HO

H N

N

CH3

CH3

Physostigmine

Edrophonium O

O N

O N

O

N O

Rivastigmine

Donepezil

FIGURE 7–6  Cholinesterase inhibitors. Neostigmine exemplifies the typical ester composed of carbamic acid ([1]) and a phenol bearing a quaternary ammonium group ([2]). Physostigmine, a naturally occurring carbamate, is a tertiary amine. Edrophonium is not an ester but binds to the active site of the enzyme. Carbaryl is used as an insecticide. B.  Absorption, Distribution, and Metabolism Absorption of the quaternary carbamates from the conjunctiva, skin, gut, and lungs is predictably poor, since their permanent charge renders them relatively insoluble in lipids. Thus, much

TABLE 7–4  Therapeutic uses and durations of action of cholinesterase inhibitors.

Group, Drug

Uses

Approximate Duration of Action

Alcohols Edrophonium

Myasthenia gravis, ileus, arrhythmias

5–15 minutes

Carbamates and related agents Neostigmine

Myasthenia gravis, ileus

0.5–4 hours

Pyridostigmine

Myasthenia gravis

4–6 hours

Physostigmine

For anticholinergic poisoning

0.5–2 hours

Rivastigmine

Mild to moderate Alzheimer dementia

8–10 hours

Donepezil

Alzheimer dementia

70–100 hours

Glaucoma

100 hours

Organophosphates Echothiophate

larger doses are required for oral administration than for parenteral injection. Distribution into the central nervous system is negligible. Physostigmine and rivastigmine, in contrast, are well absorbed from all sites and can be used topically in the eye (see Table 7–4). They are distributed into the central nervous system and are more toxic than the more polar quaternary carbamates. The carbamates are relatively stable in aqueous solution but can be metabolized by nonspecific esterases in the body as well as by cholinesterase. However, the duration of their effect is determined chiefly by the stability of the inhibitor-enzyme complex (see later Mechanism of Action section), not by metabolism or excretion. Donepezil is well absorbed and given orally with almost 100% bioavailability and is metabolized by liver enzymes and excreted in the urine. The organophosphate cholinesterase inhibitors (except for echothiophate) are well absorbed from the skin, lung, gut, and conjunctiva—thereby making them dangerous to humans and highly effective as insecticides. They are relatively less stable than the carbamates when dissolved in water and thus have a limited half-life in the environment (compared with another major class of insecticides, the halogenated hydrocarbons, eg, DDT). Echothiophate is highly polar and more stable than most other organophosphates. When prepared in aqueous solution for ophthalmic use, it retains activity for weeks. The thiophosphate insecticides (parathion, malathion, and related compounds) are quite lipid-soluble and are rapidly

CHAPTER 7  Cholinoceptor-Activating & Cholinesterase-Inhibiting Drugs      121

O

O H5C2

O

H5C2

O

P

CH2

S

CH2

+ N

CH3 CH3 CH3

H3C

CH

H3C

H5C2

O

O

P

O

O

NO2

O

Parathion

S H3C

O

H3C

O

F

Sarin

S O

P CH3

Echothiophate

H5C2

O

P

CH

O

Paraoxon

O

O S

P

C

O

C2H5

P

S

O CH2

C

Malathion

O

C2H5 Malaoxon

FIGURE 7–7  Structures of some organophosphate cholinesterase inhibitors. The dashed lines indicate the bond that is hydrolyzed in binding to the enzyme. The shaded ester bonds in malathion represent the points of detoxification of the molecule in mammals and birds.

absorbed by all routes. They must be activated in the body by conversion to the oxygen analogs (see Figure 7–7), a process that occurs rapidly in both insects and vertebrates. Malathion and a few other organophosphate insecticides are also rapidly metabolized by a carboxylase pathway to inactive products in birds and mammals but not in insects; these agents are therefore considered safe enough for sale to the general public. Unfortunately, fish cannot detoxify malathion, and significant numbers of fish have died from the heavy use of this agent on and near waterways. Parathion is not detoxified effectively in vertebrates; thus, it is considerably more dangerous than malathion to humans and livestock and is not available for general public use in the USA. All the organophosphates except echothiophate are distributed to all parts of the body, including the central nervous system. Therefore, central nervous system toxicity is an important component of poisoning with these agents.

Pharmacodynamics A.  Mechanism of Action Acetylcholinesterase is the primary target of these drugs, but butyrylcholinesterase is also inhibited. Acetylcholinesterase is an extremely active enzyme. In the initial catalytic step, acetylcholine binds to the enzyme’s active site and is hydrolyzed, yielding free choline and the acetylated enzyme. In the second step, the covalent acetyl-enzyme bond is split, with the addition of water (hydration). The entire process occurs in approximately 150 microseconds. All the cholinesterase inhibitors increase the concentration of endogenous acetylcholine at cholinoceptors by inhibiting acetylcholinesterase. However, the molecular details of their interaction

with the enzyme vary according to the three chemical subgroups mentioned above. The first group, of which edrophonium is the example, consists of quaternary alcohols. These agents reversibly bind electrostatically and by hydrogen bonds to the active site, thus preventing access of acetylcholine. The enzyme-inhibitor complex does not involve a covalent bond and is correspondingly short-lived (on the order of 2–10 minutes). The second group consists of carbamate esters, eg, neostigmine and physostigmine. These agents undergo a two-step hydrolysis sequence analogous to that described for acetylcholine. However, the covalent bond of the carbamoylated enzyme is considerably more resistant to the second (hydration) process, and this step is correspondingly prolonged (on the order of 30 minutes to 6 hours). The third group consists of the organophosphates. These agents also undergo initial binding and hydrolysis by the enzyme, resulting in a phosphorylated active site. The covalent phosphorusenzyme bond is extremely stable and hydrolyzes in water at a very slow rate (hundreds of hours). After the initial binding-hydrolysis step, the phosphorylated enzyme complex may undergo a process called aging. This process apparently involves the breaking of one of the oxygen-phosphorus bonds of the inhibitor and further strengthens the phosphorus-enzyme bond. The rate of aging varies with the particular organophosphate compound. For example, aging occurs within 10 minutes with the chemical warfare agent soman, but as much as 48 hours later with the drug VX (venomous agent X). If given before aging has occurred, strong nucleophiles like pralidoxime (PAM) are able to break the phosphorus-enzyme bond and can be used as “cholinesterase regenerator” drugs for organophosphate insecticide poisoning (see Chapter 8). Once aging has occurred, the enzyme-inhibitor complex is even more

122    SECTION II  Autonomic Drugs

stable and is more difficult to break, even with oxime regenerator compounds. The organophosphate inhibitors are sometimes referred to as “irreversible” cholinesterase inhibitors, and edrophonium, donepezil, and the carbamates are considered “reversible” inhibitors because of the marked differences in duration of action. However, the molecular mechanisms of action of the three groups do not support this simplistic description. B.  Organ System Effects The most prominent pharmacologic effects of cholinesterase inhibitors are on the cardiovascular and gastrointestinal systems, the eye, and the skeletal muscle neuromuscular junction (as described in the Case Study). Because the primary action is to amplify the actions of endogenous acetylcholine, the effects are similar (but not always identical) to the effects of the direct-acting cholinomimetic agonists. 1. Central nervous system—In low concentrations, the lipidsoluble cholinesterase inhibitors cause diffuse activation on the electroencephalogram and a subjective alerting response. In higher concentrations, they cause generalized convulsions, which may be followed by coma and respiratory arrest. 2. Eye, respiratory tract, gastrointestinal tract, urinary tract—The effects of the cholinesterase inhibitors on these organ systems, all of which are well innervated by the parasympathetic nervous system, are qualitatively quite similar to the effects of the direct-acting cholinomimetics (see Table 7–3). 3. Cardiovascular system—The cholinesterase inhibitors can increase activity in both sympathetic and parasympathetic ganglia supplying the heart and at the acetylcholine receptors on neuroeffector cells (cardiac and vascular smooth muscles) that receive cholinergic innervation. In the heart, the effects on the parasympathetic limb predominate. Thus, cholinesterase inhibitors such as edrophonium, physostigmine, or neostigmine mimic the effects of vagal nerve activation on the heart. Negative chronotropic, dromotropic, and inotropic effects are produced, and cardiac output falls. The fall in cardiac output is attributable to bradycardia, decreased atrial contractility, and some reduction in ventricular contractility. The latter effect occurs as a result of prejunctional inhibition of norepinephrine release as well as inhibition of postjunctional cellular sympathetic effects. Cholinesterase inhibitors have minimal effects by direct action on vascular smooth muscle because most vascular beds lack cholinergic innervation (coronary vasculature is an exception). At moderate doses, cholinesterase inhibitors cause an increase in systemic vascular resistance and blood pressure that is initiated at sympathetic ganglia in the case of quaternary nitrogen compounds and also at central sympathetic centers in the case of lipid-soluble agents. Atropine, acting in the central and peripheral nervous systems, can prevent the increase of blood pressure and the increased plasma norepinephrine. The net cardiovascular effects of moderate doses of cholinesterase inhibitors therefore consist of modest bradycardia, a fall in cardiac output, and an increased vascular resistance that results in a rise in blood pressure. (Thus, in patients with Alzheimer disease

who have hypertension, treatment with cholinesterase inhibitors requires that blood pressure be monitored to adjust antihypertensive therapy.) At high (toxic) doses of cholinesterase inhibitors, marked bradycardia occurs, cardiac output decreases significantly, and hypotension supervenes. 4. Neuromuscular junction—The cholinesterase inhibitors have important therapeutic and toxic effects at the skeletal muscle neuromuscular junction. Low (therapeutic) concentrations moderately prolong and intensify the actions of physiologically released acetylcholine. This increases the strength of contraction, especially in muscles weakened by curare-like neuromuscular blocking agents or by myasthenia gravis (an autoimmune disease that decreases functional neuromuscular nicotinic receptors). At higher concentrations, the accumulation of acetylcholine may result in fibrillation of muscle fibers. Antidromic firing of the motor neuron may also occur, resulting in fasciculations that involve an entire motor unit. With marked inhibition of acetylcholinesterase, depolarizing neuromuscular blockade occurs and that may be followed by a phase of nondepolarizing blockade as seen with succinylcholine (see Table 27–2 and Figure 27–7). Some quaternary carbamate cholinesterase inhibitors, eg, neostigmine and pyridostigmine, have an additional direct nicotinic agonist effect at the neuromuscular junction. This may contribute to the effectiveness of these agents as therapy for myasthenia.

■■ CLINICAL PHARMACOLOGY OF THE CHOLINOMIMETICS The major therapeutic uses of the cholinomimetics are to treat diseases of the eye (glaucoma, accommodative esotropia), the gastrointestinal and urinary tracts (postoperative atony, neurogenic bladder), and the neuromuscular junction (myasthenia gravis, curare-induced neuromuscular paralysis), and to treat patients with Alzheimer disease. Cholinesterase inhibitors are occasionally used in the treatment of atropine overdosage and, very rarely, in the therapy of certain atrial arrhythmias.

Clinical Uses A.  The Eye Glaucoma is a disease characterized by increased intraocular pressure. Muscarinic stimulants and cholinesterase inhibitors reduce intraocular pressure by causing contraction of the ciliary body so as to facilitate outflow of aqueous humor (see Figure 6–9). In the past, glaucoma was treated with either direct agonists (pilocarpine, methacholine, carbachol) or cholinesterase inhibitors (physostigmine, demecarium, echothiophate, isoflurophate). For chronic glaucoma, these drugs have been largely replaced by prostaglandin derivatives and topical β-adrenoceptor antagonists. Acute angle-closure glaucoma is a medical emergency that is frequently treated initially with drugs but usually requires surgery for permanent correction. Initial therapy often consists of a combination of a direct muscarinic agonist (eg, pilocarpine) and other drugs. Once the intraocular pressure is controlled and the danger of vision loss is diminished, the patient can be prepared

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for corrective surgery (laser iridotomy). Open-angle glaucoma and some cases of secondary glaucoma are chronic diseases that are not amenable to traditional surgical correction, although newer laser techniques appear to be useful. Other treatments for glaucoma are described in the Box: The Treatment of Glaucoma in Chapter 10 and in Table 10–3. Accommodative esotropia (strabismus caused by hypermetropic accommodative error) in young children is sometimes diagnosed and treated with cholinomimetic agonists. Dosage is similar to or higher than that used for glaucoma. B.  Gastrointestinal and Urinary Tracts In clinical disorders that involve depression of smooth muscle activity without obstruction, cholinomimetic drugs with direct or indirect muscarinic effects may be helpful. These disorders include postoperative ileus (atony or paralysis of the stomach or bowel following surgical manipulation) and congenital megacolon. Urinary retention may occur postoperatively or postpartum or may be secondary to spinal cord injury or disease (neurogenic bladder). Cholinomimetics were also sometimes used to increase the tone of the lower esophageal sphincter in patients with reflux esophagitis but proton-pump inhibitors are usually indicated (see Chapter 62). Of the muscarinic agonists, bethanechol is the most widely used for these disorders. For gastrointestinal problems, it is usually administered orally in a dose of 10–25 mg three or four times daily. In patients with urinary retention, bethanechol can be given subcutaneously in a dose of 5 mg and repeated in 30 minutes if necessary. Of the cholinesterase inhibitors, neostigmine is the most widely used for these applications. For paralytic ileus or atony of the urinary bladder, neostigmine can be given subcutaneously in a dose of 0.5–1 mg. If patients are able to take the drug by mouth, neostigmine can be given orally in a dose of 15 mg. In all of these situations, the clinician must be certain that there is no mechanical obstruction to outflow before using the cholinomimetic. Otherwise, the drug may exacerbate the problem, cause urine reflux into the kidneys, and possibly cause perforation as a result of increased pressure. Pilocarpine has long been used to increase salivary secretion. Cevimeline, a quinuclidine derivative of acetylcholine, is a newer direct-acting muscarinic agonist used for the treatment of dry mouth associated with Sjögren syndrome or caused by radiation damage of the salivary glands. C.  Neuromuscular Junction Myasthenia gravis is an autoimmune disease affecting skeletal muscle neuromuscular junctions. In this disease, antibodies are produced against the main immunogenic region found on α1 subunits of the nicotinic receptor-channel complex. Antibodies are detected in 85% of myasthenic patients. The antibodies reduce nicotinic receptor function by (1) cross-linking receptors, a process that stimulates their internalization and degradation; (2) causing lysis of the postsynaptic membrane; and (3) binding to the nicotinic receptor and inhibiting function. Frequent findings are ptosis, diplopia, difficulty in speaking and swallowing, and extremity weakness. Severe disease may affect all the muscles, including those necessary for respiration. The disease resembles the neuromuscular paralysis produced by d-tubocurarine and similar nondepolarizing neuromuscular blocking drugs (see Chapter 27). Patients with

myasthenia are exquisitely sensitive to the action of curariform drugs and other drugs that interfere with neuromuscular transmission, eg, aminoglycoside antibiotics. Cholinesterase inhibitors—but not direct-acting acetylcholine receptor agonists—are extremely valuable as therapy for myasthenia. Patients with ocular myasthenia may be treated with cholinesterase inhibitors alone (see Figure 7–4B). Patients having more widespread muscle weakness are also treated with immunosuppressant drugs (steroids, cyclosporine, and azathioprine). In some patients, the thymus gland is removed; very severely affected patients may benefit from administration of immunoglobulins and from plasmapheresis. Edrophonium is sometimes used as a diagnostic test for myasthenia. A 2-mg dose is injected intravenously after baseline muscle strength has been measured. If no reaction occurs after 45 seconds, an additional 8 mg may be injected. If the patient has myasthenia gravis, an improvement in muscle strength that lasts about 5 minutes can usually be observed. Clinical situations in which severe myasthenia (myasthenic crisis) must be distinguished from excessive drug therapy (cholinergic crisis) usually occur in very ill myasthenic patients and must be managed in hospital with adequate emergency support systems (eg, mechanical ventilators) available. Edrophonium can be used to assess the adequacy of treatment with the longer-acting cholinesterase inhibitors usually prescribed in patients with myasthenia gravis. If excessive amounts of cholinesterase inhibitor have been used, patients may become paradoxically weak because of nicotinic depolarizing blockade of the motor end plate. These patients may also exhibit symptoms of excessive stimulation of muscarinic receptors (abdominal cramps, diarrhea, increased salivation, excessive bronchial secretions, miosis, bradycardia). Small doses of edrophonium (1–2 mg intravenously) will produce no relief or even worsen weakness if the patient is receiving excessive cholinesterase inhibitor therapy. On the other hand, if the patient improves with edrophonium, an increase in cholinesterase inhibitor dosage may be indicated. Long-term therapy for myasthenia gravis is usually accomplished with pyridostigmine; neostigmine is an alternative. The doses are titrated to optimum levels based on changes in muscle strength. These drugs are relatively short-acting and therefore require frequent dosing (every 6 hours for pyridostigmine and every 4 hours for neostigmine; Table 7–4). Sustained-release preparations are available but should be used only at night and if needed. Longer-acting cholinesterase inhibitors such as the organophosphate agents are not used, because the dose requirement in this disease changes too rapidly to permit smooth control of symptoms with long-acting drugs. If muscarinic effects of such therapy are prominent, they can be controlled by the administration of antimuscarinic drugs such as atropine. Frequently, tolerance to the muscarinic effects of the cholinesterase inhibitors develops, so atropine treatment is not required. Neuromuscular blockade is frequently produced as an adjunct to surgical anesthesia, using nondepolarizing neuromuscular relaxants such as pancuronium and newer agents (see Chapter 27). After surgery, it is usually desirable to reverse this pharmacologic paralysis promptly. This can be easily accomplished with cholinesterase inhibitors; neostigmine and edrophonium are the drugs of choice. They are given intravenously or intramuscularly for

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prompt effect. Some snake venoms have curare-like effects, and the use of neostigmine as a nasal spray is under study to prevent respiratory arrest. Indirect ways of increasing acetylcholine release have been utilized in conditions like Lambert-Eaton myasthenic syndrome by altering the release of acetylcholine at the neuromuscular junction (see Box: Acetylcholine Release Modulators).

D. Heart The short-acting cholinesterase inhibitor edrophonium was used to treat supraventricular tachyarrhythmias, particularly paroxysmal supraventricular tachycardia. In this application, edrophonium has been replaced by newer drugs with different mechanisms (adenosine and the calcium channel blockers verapamil and diltiazem, see Chapter 14).

Acetylcholine Release Modulators Amifampridine and 4-aminopyridine (fampridine and dalfampridine) are potassium channel antagonists that block the efflux of potassium in nerve terminals and can result in prolonged action potentials. In the case of Lambert-Eaton myasthenic syndrome, in which antibodies are produced that interfere with proper voltage-gated Ca2+ (VGCa2+) channel function on the presynaptic nerve of the neuromuscular junction (Figure 7–8), there is a decrease in the amount of acetylcholine release at the neuromuscular junction that results in weakness. Amifampridine and 4-aminopyridine can be used to prolong the excitability by inhibiting the K+ efflux and slowing repolarization, resulting in more VGCa2+ activation. The

end result is increased acetylcholine release and increased strength. Amifampridine and 4-aminopyridine are both >90% bioavailable and are metabolized mainly by acetylation and excreted via the kidneys. Hence, genetic differences in acetylation rate or kidney function will alter the compounds’ efficacy and side effects. Amifampridine and 4-aminopyridine, due to effects on CNS and cardiac potassium channels, may increase seizure activity and may prolong cardiac QT interval. Hence they should not be used in individuals who have a history of seizures or epilepsy or in patients with known atrial fibrillation or long QT interval. Other adverse effects include tingling (paresthesias), numbness, and insomnia.

Neuromuscular Junction

Amifampridine & 4-Aminopyridine

Ca2+ Ca2+ VGCa2+

K+

Lambert-Eaton Myasthenic Syndrome

ACh = Choline Transporter

Acetylcholinesterase (AChE) Nicotinic Channel

Skeletal Muscle

FIGURE 7–8  Schematic illustration of a neuromuscular junction demonstrating how acetylcholine release modulators act in the autoimmune disease Lambert-Eaton myasthenic syndrome (LEMS). Amifampridine and 4-aminopyridine act on the nerve terminal by blocking potassium channels and helping to maintain a positive charge in the nerve terminal that increases the release of acetylcholine (ACh). VGCa2+, voltage-gated calcium channels.

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E.  Antimuscarinic Drug Intoxication Atropine intoxication is potentially lethal in children (see Chapter 8) and may cause prolonged severe behavioral disturbances and arrhythmias in adults. The tricyclic antidepressants, when taken in overdosage (often with suicidal intent), also cause severe muscarinic blockade (see Chapter 30). The muscarinic receptor blockade produced by all these agents is competitive in nature and can be overcome by increasing the amount of endogenous acetylcholine at the neuroeffector junctions. Theoretically, a cholinesterase inhibitor could be used to reverse these effects. Physostigmine has been used for this application because it enters the central nervous system and reverses the central as well as the peripheral signs of muscarinic blockade. However, as described below, physostigmine itself can produce dangerous central nervous system effects, and such therapy is therefore used only in patients with dangerous elevation of body temperature or very rapid supraventricular tachycardia (see also Chapter 58). F.  Central Nervous System Tacrine was the first drug with anticholinesterase and other cholinomimetic actions used for the treatment of mild to moderate Alzheimer disease. Tacrine’s efficacy is slight, and hepatic toxicity is significant. Donepezil, galantamine, and rivastigmine are newer, more selective, uncharged acetylcholinesterase inhibitors that appear to have the same marginal clinical benefit as tacrine but with less toxicity in treatment of cognitive dysfunction in Alzheimer patients. Donepezil may be given once daily because of its long half-life, and it lacks the hepatotoxic effect of tacrine. However, no trials directly comparing these drugs with tacrine have been reported. These drugs are discussed in Chapter 60.

Toxicity The toxic potential of the acetylcholine receptor stimulants varies markedly depending on their absorption, access to the central nervous system, and metabolism. A.  Direct-Acting Muscarinic Stimulants Drugs such as pilocarpine and the choline esters cause predictable signs of muscarinic excess when given in overdosage. These effects include nausea, vomiting, diarrhea, urinary urgency, salivation, sweating, cutaneous vasodilation, and bronchial constriction. The effects are all blocked competitively by atropine and its congeners. Certain mushrooms, especially those of the genus Inocybe, contain muscarinic alkaloids. Ingestion of these mushrooms causes typical signs of muscarinic excess within 15–30 minutes. These effects can be very uncomfortable but are rarely fatal. Treatment is with atropine, 1–2 mg parenterally. (Amanita muscaria, the first source of muscarine, contains very low concentrations of the alkaloid.) B.  Direct-Acting Nicotinic Stimulants Nicotine itself is the only common cause of this type of poisoning. (Varenicline toxicity is discussed elsewhere in this chapter.)

The acute toxicity of the alkaloid is well defined but much less important than the chronic effects associated with smoking. Nicotine was also used in insecticides but has been replaced by neonicotinoids, synthetic compounds that resemble nicotine only partially in structure. As nicotinic receptor agonists, neonicotinoids are more toxic for insects than for vertebrates. This advantage led to their widespread agricultural use to protect crops by coating the seeds with neonicotinoids. However, there is concern about the role of neonicotinoids in the collapse of bee colonies. In 2013 the European Commission imposed a 2-year ban on certain neonicotinoids (clothianidin, imidacloprid, thiamethoxam), and in 2018 the European Commission voted to permanently ban these three neonicotinoids for outdoor use. In 2016 the US Fish and Wildlife Service banned neonicotinoid use in wildlife refuges, and in 2019 the US Environment Protection Agency banned 12 different neonicotinoids, including the 3 listed above, due to their effect on bees and other pollinating insects. Neonicotinoids are suspected to contribute to colony collapse disorder because they suppress immunity against bee pathogens including the mite (Varroa destructor) that also serves as a vector for viruses and the Nosema species of fungi that parasitize the gut of bees. Research to ascertain the effect of neonicotinoids on pollinators such as bees and butterflies requires carefully controlled conditions. Neonicotinoid residues have a long half-life (5 months to 3 years) in the soil, and because they are systemic and enter the plant stem, leaves, and flowers, they can present a long-lasting hazard to pollinators. The Australian government’s report on neonicotinoids and honey bees recounts that Australia is one of a few countries that lack Varroa, which therefore provides an opportunity to test neonicotinoids in the absence of compounds used to treat this mite that contributes to bee pathology. 1. Acute toxicity—The fatal dose of nicotine is approximately 40 mg, or 1 drop of the pure liquid. This is the amount of nicotine in two regular cigarettes. Fortunately, most of the nicotine in cigarettes is destroyed by burning or escapes via the “sidestream” smoke. Ingestion of nicotine insecticides or of tobacco by infants and children is usually followed by vomiting, limiting the amount of the alkaloid absorbed. The toxic effects of a large dose of nicotine are simple extensions of the effects described previously. The most dangerous are (1) central stimulant actions, which cause convulsions and may progress to coma and respiratory arrest; (2) skeletal muscle end plate depolarization, which may lead to depolarization blockade and respiratory paralysis; and (3) hypertension and cardiac arrhythmias. Treatment of acute nicotine poisoning is largely symptomdirected. Muscarinic excess resulting from parasympathetic ganglion stimulation can be controlled with atropine. Central stimulation is usually treated with parenteral anticonvulsants such as diazepam. Neuromuscular blockade is not responsive to pharmacologic treatment and may require mechanical ventilation. Fortunately, nicotine is metabolized and excreted relatively rapidly. Patients who survive the first 4 hours usually recover completely if hypoxia and brain damage have not occurred.

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2. Chronic nicotine toxicity—The health costs of tobacco smoking to the smoker and its socioeconomic costs to the general public are still incompletely understood. However, the 1979 Surgeon General’s Report on Health Promotion and Disease Prevention stated that “cigarette smoking is clearly the largest single preventable cause of illness and premature death in the United States.” This statement has been supported by numerous subsequent studies. Unfortunately, the fact that most of the tobacco-associated diseases are delayed in onset reduces the health incentive to stop smoking. Clearly, the addictive power of cigarettes is directly related to their nicotine content. It is not known to what extent nicotine per se contributes to the other well-documented adverse effects of chronic tobacco use. It is highly probable that nicotine contributes to the increased risk of vascular disease and sudden coronary death associated with smoking. In addition, nicotine probably contributes to the high incidence of ulcer recurrences in smokers with peptic ulcer. These effects of smoking are not avoided by the use of electronic cigarettes (“vaping”) since only the nonnicotine components (“tars”) of tobacco are eliminated. The Centers for Disease Control and Prevention (CDC) report a significant increase in the use of electronic cigarettes, which deliver lower levels of carcinogens and therefore may decrease the risk of cancers due to traditional cigarette use. Thus the increase in electronic cigarette use may substantially decrease cardiovascular, lung cancer, and noncancer lung disease risks but increase the population with nicotine addiction and dependence. In 2019, a dramatic rise in acute lung injuries was reported, including several dozen deaths, due to the addition of tetrahydrocannabinol (THC) acetate ester and vitamin E acetate being added to the nicotine-containing and cannabiscontaining e-cigarettes. A significant number of cases occurred in young people because vaping is very popular in this vulnerable population. There are several approaches to help patients stop smoking. One approach is replacement therapy with nicotine in the form of gum, transdermal patch, nasal spray, or inhaler. All these forms have low abuse potential and are effective in patients motivated to stop smoking. Their action derives from slow absorption of nicotine that occupies α4β2 receptors in the central nervous system and reduces the desire to smoke and the pleasurable feelings of smoking. Another quite effective agent for smoking cessation is varenicline, a synthetic drug with partial agonist action at α4β2 nicotinic receptors. Varenicline also has antagonist properties that persist because of its long half-life and high affinity for the receptor; this prevents the stimulant effect of nicotine at presynaptic α4β2 receptors that causes release of dopamine. However, its use is limited by nausea and insomnia and also by exacerbation of psychiatric illnesses, including anxiety and depression. The incidence of adverse neuropsychiatric and cardiovascular events is reportedly low yet post-marketing surveillance continues. The efficacy of varenicline is superior to that of bupropion, an antidepressant (see Chapter 30) also approved for smoking cessation. Some of bupropion’s efficacy in smoking cessation therapy stems from its noncompetitive antagonism (see Chapter 2)

of nicotinic receptors where it displays some selectivity among neuronal subtypes. C.  Cholinesterase Inhibitors The acute toxic effects of the cholinesterase inhibitors, like those of the direct-acting agents, are direct extensions of their pharmacologic actions. The major source of such intoxications is pesticide use in agriculture and in the home. Approximately 100 organophosphate and 20 carbamate cholinesterase inhibitors are available in pesticides and veterinary vermifuges used in the USA. Cholinesterase inhibitors used in agriculture can cause slowly or rapidly developing symptoms, as described in the Case Study, which persist for days. The cholinesterase inhibitors used as chemical warfare agents (soman, sarin, VX) induce effects rapidly because of the large concentrations present. Acute intoxication must be recognized and treated promptly in patients with heavy exposure. The dominant initial signs are those of muscarinic excess: miosis, salivation, sweating, bronchial constriction, vomiting, and diarrhea. Central nervous system involvement (cognitive disturbances, convulsions, and coma) usually follows rapidly, accompanied by peripheral nicotinic effects, especially depolarizing neuromuscular blockade. Therapy always includes (1) maintenance of vital signs—respiration in particular may be impaired; (2) decontamination to prevent further absorption—this may require removal of all clothing and washing of the skin in cases of exposure to dusts and sprays; and (3) atropine parenterally in large doses, given as often as required to control signs of muscarinic excess. Therapy often also includes treatment with pralidoxime, as described in Chapter 8, and administration of benzodiazepines for seizures. Preventive therapy for cholinesterase inhibitors used as chemical warfare agents has been developed to protect soldiers and civilians. Personnel are given autoinjection syringes containing a carbamate, pyridostigmine, and atropine. Protection is provided by pyridostigmine, which, by prior binding to the enzyme, impedes binding of organophosphate agents and thereby prevents prolonged inhibition of cholinesterase. The protection is limited to the peripheral nervous system because pyridostigmine does not readily enter the central nervous system. Enzyme inhibition by pyridostigmine dissipates within hours (see Table 7–4), a duration of time that allows clearance of the organophosphate agent from the body. Chronic exposure to certain organophosphate compounds, including some organophosphate cholinesterase inhibitors, causes delayed neuropathy associated with demyelination of axons. Triorthocresyl phosphate, an additive in lubricating oils, is the prototype agent of this class. The effects are not caused by cholinesterase inhibition but rather by inhibition of neuropathy target esterase (NTE) whose symptoms (weakness of upper and lower extremities, unsteady gait) appear 1–2 weeks after exposure. Another nerve toxicity called intermediate syndrome occurs 1–4 days after exposure to organophosphate insecticides. This syndrome is also characterized by muscle weakness; its origin is not known but it appears to be related to cholinesterase inhibition.

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SUMMARY Drugs Used for Cholinomimetic Effects Subclass, Drug

Mechanism of Action

DIRECT-ACTING CHOLINE ESTERS   • Bethanechol Muscarinic agonist • negligible effect at nicotinic receptors

Effects Activates M1, M2, and M3 receptors in all peripheral tissues • causes increased secretion, smooth muscle contraction (except vascular smooth muscle relaxes), and changes in heart rate

Clinical Applications

Pharmacokinetics, Toxicities, Interactions

Postoperative and neurogenic ileus and urinary retention

Oral and parenteral, duration ~30 min • does not enter central nervous system (CNS) • Toxicity: Excessive parasympathomimetic effects, especially bronchospasm in asthmatics • Interactions: Additive with other parasympathomimetics

  • Carbachol: Nonselective muscarinic and nicotinic agonist; otherwise similar to bethanechol; used topically almost exclusively for glaucoma DIRECT-ACTING MUSCARINIC ALKALOIDS OR SYNTHETICS   • Pilocarpine Like bethanechol, Like bethanechol partial agonist

Glaucoma; Sjögren syndrome

Oral lozenge and topical • Toxicity & interactions: Like bethanechol

Medical use in smoking cessation • nonmedical use in smoking and in insecticides

Oral gum, patch for smoking cessation • Toxicity: Acutely increased gastrointestinal (GI) activity, nausea, vomiting, diarrhea • increased blood pressure • high doses cause seizures • long-term GI and cardiovascular risk factor • Interactions: Additive with CNS stimulants

  • Cevimeline: Synthetic M3-selective; similar to pilocarpine DIRECT-ACTING NICOTINIC AGONISTS   • Nicotine Agonist at both NN and NM receptors

Activates autonomic postganglionic neurons (both sympathetic and parasympathetic) and skeletal muscle neuromuscular end plates • enters CNS and activates NN receptors

  • Varenicline: Selective partial agonist at α4β2 nicotinic receptors; used exclusively for smoking cessation SHORT-ACTING CHOLINESTERASE INHIBITOR (ALCOHOL)   • Edrophonium Alcohol, binds briefly Amplifies all actions of ACh to active site of • increases parasympathetic acetylcholinesterase activity and somatic neuromuscular (AChE) and prevents transmission access of acetylcholine (ACh) INTERMEDIATE-ACTING CHOLINESTERASE INHIBITORS (CARBAMATES)   • Neostigmine Forms covalent Like edrophonium, but bond with AChE, longer-acting but hydrolyzed and released

Diagnosis and acute treatment of myasthenia gravis

Parenteral • quaternary amine • does not enter CNS • Toxicity: Parasympathomimetic excess • Interactions: Additive with parasympathomimetics

Myasthenia gravis • postoperative and neurogenic ileus and urinary retention

Oral and parenteral; quaternary amine, does not enter CNS. Duration 2–4 h • Toxicity & interactions: Like edrophonium

Obsolete • was used in glaucoma

Topical only • Toxicity: Brow ache, uveitis, blurred vision

  • Pyridostigmine: Like neostigmine, but longer-acting (4–6 h); used in myasthenia   • Physostigmine: Like neostigmine, but natural alkaloid tertiary amine; enters CNS   • Rivastigmine: Like neostigmine, but longer acting (8–10 h) and a tertiary amine that enters CNS LONG-ACTING CHOLINESTERASE INHIBITORS (ORGANOPHOSPHATES)   • Echothiophate

Like neostigmine, but released more slowly

Like neostigmine, but longer-acting

  • Malathion: Insecticide, relatively safe for mammals and birds because metabolized by other enzymes to inactive products; some medical use as ectoparasiticide   • Parathion, others: Insecticide, dangerous for all animals; toxicity important because of agricultural use and exposure of farm workers (see text)   • Sarin, others: “Nerve gas,” used exclusively in warfare and terrorism INDIRECT MODULATORS OF ACETYLCHOLINE RELEASE   • Amifampridine and Potassium channel Increases the excitability of 4-aminopyridine antagonist the presynaptic neuron in the neuromuscular junction, resulting in increased acetylcholine release

Lambert-Eaton myasthenic syndrome; congenital myasthenic syndromes

Oral, duration ~2.5 h • acetylation, then excreted via kidneys • Toxicity: seizure activity • may prolong cardiac QT interval • paresthesias • numbness • insomnia

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P R E P A R A T I O N S A V A I L A B L E GENERIC NAME AVAILABLE AS DIRECT-ACTING CHOLINOMIMETICS Acetylcholine Miochol-E Bethanechol Generic, Urecholine Carbachol     Ophthalmic (topical) Isopto Carbachol, Carboptic   Ophthalmic (intraocular) Miostat, Carbastat Cevimeline Generic, Evoxac Nicotine    Transdermal Generic, Nicoderm CQ, Nicotrol  Inhalation Nicotrol Inhaler, Nicotrol NS  Gum Generic, Commit, Nicorette Pilocarpine     Ophthalmic (drops)1, 2, 4, 6 Generic, Isopto Carpine  Ophthalmic sustained-release inserts Ocusert Pilo-20, Ocusert Pilo-40  Oral Salagen Varenicline Chantix CHOLINESTERASE INHIBITORS Donepezil Generic, Aricept Echothiophate Phospholine Edrophonium Generic, Tensilon Galantamine Generic, Reminyl, Razadyne Neostigmine Generic, Prostigmin Physostigmine Generic, Eserine Pyridostigmine Generic, Mestinon, Regonol Rivastigmine Exelon INDIRECT MODULATORS OF ACETYLCHOLINE RELEASE Amifampridine Ruzurgi, Firdapse 4-aminopyridine Fampridine, Ampyra (dalfampridine)

REFERENCES Aaron CK: Organophosphates and carbamates. In: Shannon MW, Borron SW, Burns MJ (editors): Haddad and Winchester’s Clinical Management of Poisoning and Drug Overdose, 4th ed. Philadelphia: Saunders, 2007:1171. Australian Pesticides and Veterinary Medicines Authority: Overview report: Neonicotinoids and the health of honey bees in Australia. 2014. https:// apvma.gov.au/node/18541. Benowitz N: Nicotine addiction. N Engl J Med 2010;362:2295. Brito-Zerón P et al: Primary Sjögren syndrome: An update on current pharmacotherapy options and future directions. Expert Opin Pharmacother 2013;14:279. Cahill K et al: Pharmacological interventions for smoking cessation: An overview and network meta-analysis. Cochrane Database Syst Rev 2013:5;CD009329.

Castellão-Santana LM et al: Tetanic facilitation of neuromuscular transmission by adenosine A2A and muscarinic M1 receptors is dependent on the uptake of choline via high-affinity transporters. Pharmacology 2019;103:38. Chen L: In pursuit of the high-resolution structure of nicotinic acetylcholine receptors. J Physiol 2010;588:557. Corradi J, Bourzat C: Understanding the bases of function and modulation of α7 nicotinic receptors: Implications for drug discovery. Mol Pharmacol 2016;90:288. Dineley KT et al: Nicotinic ACh receptors as therapeutic targets in CNS disorders. Trends Pharmacol Sci 2015;36:96. Ehlert FJ: Contractile role of M2 and M3 muscarinic receptors in gastrointestinal, airway and urinary bladder smooth muscle. Life Sci 2003;74:355. Ferré S et al: G protein-coupled receptor oligomerization revisited: Functional and pharmacological perspectives. Pharmacol Rev 2014;66:413. Giacobini E (editor): Cholinesterases and Cholinesterase Inhibitors. London: Martin Dunitz, 2000. Gilhus NE: Myasthenia gravis. N Engl J Med 2016;375:2570. Harvey RD, Belevych AE: Muscarinic regulation of cardiac ion channels. Br J Pharmacol 2003;139:1074. Judge S, Bever C: Potassium channel blockers in multiple sclerosis: Neuronal Kv channels and effects of symptomatic treatment. Pharmacol Ther 2006;111:224. Kim YB et al: Effects of neuromuscular presynaptic muscarinic M1 receptor blockade on rocuronium-induced neuromuscular blockade in immobilized tibialis anterior muscles. Clin Exp Pharmacol Physiol 2018;45:1309. Kirsch GE, Narahashi T: 3,4-diaminopyridine. A potent new potassium channel blocker. Biophys J 1978;22:507. Lamping KG et al: Muscarinic (M) receptors in coronary circulation. Arterioscler Thromb Vasc Biol 2004;24:1253. Lazartigues E et al: Spontaneously hypertensive rats cholinergic hyper-responsiveness: Central and peripheral pharmacological mechanisms. Br J Pharmacol 1999; 127:1657. Picciotto MR et al: It is not “either/or”: Activation and desensitization of nicotinic acetylcholine receptors both contribute to behaviors related to nicotine addiction and mood. Prog Neurobiol 2008;84:329. Richardson CE et al: Megacystis-microcolon-intestinal hypoperistalsis syndrome and the absence of the α3 nicotinic acetylcholine receptor subunit. Gastroenterology 2001;121:350. Sánchez-Bayo F et al: Are bee diseases linked to pesticides?—A brief review. Environ Int 2016;89-90:7. Schroeder C et al: Plasma exchange for primary autoimmune autonomic failure. N Engl J Med 2005;353:1585. Sharma G, Vijayaraghavan S: Nicotinic cholinergic signaling in hippocampal astrocytes involves calcium-induced calcium release from intracellular stores. Proc Natl Acad Sci USA 2001;98:4148. Shytle RD et al: Cholinergic modulation of microglial activation by α7 nicotinic receptors. J Neurochem 2004;89:337. Tarr TB et al: Synaptic pathophysiology and treatment of Lambert-Eaton myasthenic syndrome. Mol Neurobiol 2015;52:456. The Surgeon General: Smoking and Health. US Department of Health and Human Services, 1979. Tomizawa M, Casida JE: Neonicotinoid insecticide toxicology: Mechanisms of selective action. Annu Rev Pharmacol Toxicol 2005;45:247. Wess J et al: Muscarinic acetylcholine receptors: Mutant mice provide new insights for drug development. Nat Rev Drug Discov 2007;6:721. Wing VC et al: Measuring cigarette smoking-induced cortical dopamine release: A [11C]FLB-457 PET study. Neuropsychopharmacology 2015;40:1417.

C ASE STUDY ANSWER The patient’s presentation is characteristic of poisoning by organophosphate cholinesterase inhibitors (see Chapter 58). Ask the coworker if he can identify the agent used. Decontaminate the patient by removal of clothing and washing affected areas. Ensure an open airway and ventilate with oxygen. For muscarinic effects, administer atropine (0.5–5 mg) intravenously until signs of muscarinic excess (dyspnea, lacrimation,

confusion) subside. To treat nicotinic excess, infuse 2-PAM (initially a 1–2% solution in 15–30 min) followed by infusion of 1% solution (200–500 mg/h) until muscle fasciculations cease. Respiratory support is required because 2-PAM does not enter the central nervous system and may not reactivate “aged” organophosphate-cholinesterase complex. If needed, decontaminate the coworker and isolate all contaminated clothing.

C

Cholinoceptor-Blocking Drugs

H

8 A

P

T

E

R

Todd W. Vanderah, PhD

C ASE STUDY JH, a 63-year-old architect, complains of urinary symptoms to his family physician. He has hypertension, and during the last 8 years, he has been adequately managed with a thiazide diuretic and an angiotensin-converting enzyme inhibitor. During the same period, JH developed signs of benign prostatic hypertrophy, which eventually required prostatectomy

Cholinoceptor antagonists, like the agonists, are divided into muscarinic and nicotinic subgroups on the basis of their specific receptor affinities. Ganglion blockers and neuromuscular junction blockers make up the antinicotinic drugs. The ganglion-blocking drugs have little clinical use and are discussed at the end of this chapter. Neuromuscular blockers are heavily used and are discussed in Chapter 27. This chapter emphasizes drugs that block muscarinic acetylcholine receptors. Five subtypes of muscarinic receptors have been identified, primarily on the basis of data from ligand-binding and cDNAcloning experiments (see Chapters 6 and 7). A standard terminology (M1 through M5) for these subtypes is now in common use, and evidence—based mostly on selective agonists and antagonists— indicates that functional differences exist between several of these subtypes. The X-ray crystallographic structures of the M1–5 subtypes of muscarinic receptors have been reported. The structures of the M1–5 receptors are very similar in the inactive state with inverse agonist or antagonist bound to the receptor. The binding pocket for orthosteric ligands lies well within the plane of the plasma membrane, and the amino acids composing the site are conserved among muscarinic receptor subtypes. This observation underscores the difficulty in identifying subtype-selective ligands. A structure forming a “lid” separates the orthosteric binding site from an upper cavity termed the “vestibule” (Figure 8–1). The binding site for allosteric ligands is the extracellular vestibule. Among the receptor subtypes,

to relieve symptoms. He now complains that he has an increased urge to urinate as well as urinary frequency, and this has disrupted the pattern of his daily life. What do you suspect is the cause of JH’s problem? What information would you gather to confirm your diagnosis? What treatment steps would you initiate?

the extracellular vestibule is comprised of different amino acids that provide distinctive sites for binding by selective allosteric modulators. The M1 receptor subtype is located on central nervous system (CNS) neurons, autonomic postganglionic cell bodies, and many presynaptic sites. M2 receptors are located in the myocardium, smooth muscle organs, and some neuronal sites. M3 receptors are most common on effector cell membranes, especially glandular and smooth muscle cells. M4 and M5 receptors are less prominent and appear to play a greater role in the CNS than in the periphery with the M5 receptor potentially playing a role in drug addiction.

■■ BASIC PHARMACOLOGY OF THE MUSCARINIC RECEPTORBLOCKING DRUGS Muscarinic antagonists are sometimes called parasympatholytic because they block the effects of parasympathetic autonomic discharge. However, the term “antimuscarinic” is preferable. Naturally occurring compounds with antimuscarinic effects have been known and used for millennia as medicines, poisons, and cosmetics. Atropine is the prototype of these drugs. Many similar plant alkaloids are known, and hundreds of synthetic antimuscarinic compounds have been prepared. 129

130    SECTION II  Autonomic Drugs

(Figure 8–3) are often used for their effects on the eye or the CNS. Many antihistaminic (see Chapter 16), antipsychotic (see Chapter 29), and antidepressant (see Chapter 30) drugs have similar structures and, predictably, significant antimuscarinic effects. Quaternary amine antimuscarinic agents (see Figure 8–3) have been developed to produce more peripheral effects and reduced CNS effects.

Extracellular vestibule

B. Absorption Natural alkaloids and most tertiary antimuscarinic drugs are well absorbed from the gut and conjunctival membranes. When applied in a suitable vehicle, some (eg, scopolamine) are even absorbed across the skin (transdermal route). In contrast, only 10–30% of a dose of a quaternary antimuscarinic drug is absorbed after oral administration, reflecting the decreased lipid solubility of the charged molecule.

Tyr lid

Orthosteric binding site

FIGURE 8–1  Upper portion of the M3 receptor with a “lid” formed by tyrosine (Tyr) residues separating the cavity into an upper portion called the vestibule from the lower portion, with the orthosteric binding site depicted as occupied by tiotropium. The receptor is in black, tiotropium is in yellow, and the receptor surface is in green.  (Reproduced with permission from Kruse AC, Hu J, Pan AC, et al. Structure and dynamics of the M3 muscarinic acetylcholine receptor. Nature. 2012;482(7386):552-556.)

Chemistry & Pharmacokinetics A.  Source and Chemistry Atropine and its naturally occurring congeners are tertiary amine alkaloid esters of tropic acid (Figure 8–2). Atropine (hyoscyamine) is found in the plant Atropa belladonna, or deadly nightshade, and in Datura stramonium, also known as jimson-weed (Jamestown weed), sacred Datura, or thorn apple. Scopolamine (hyoscine) occurs in Hyoscyamus niger, or henbane, as the l(−) stereoisomer. Naturally occurring atropine is l(−)-hyoscyamine, but the compound readily racemizes, so the commercial material is racemic d,l-hyoscyamine. The l(−) isomers of both alkaloids are at least 100 times more potent than the d(+) isomers. A variety of semisynthetic and fully synthetic molecules have antimuscarinic effects. The tertiary members of these classes

N

[2] HOCH2 C C

O

O O

[1]

H Tropic acid

CH3

Base

FIGURE 8–2  The structure of atropine (oxygen [red] at [1] is missing) or scopolamine (oxygen present). In homatropine, the hydroxymethyl at [2] is replaced by a hydroxyl group, and the oxygen at [1] is absent.

C. Distribution Atropine and the other tertiary agents are widely distributed in the body. Significant levels are achieved in the CNS within 30 minutes to 1 hour, and this can limit the dose tolerated when the drug is taken for its peripheral effects. Scopolamine is rapidly and fully distributed into the CNS, where it has greater effects than most other antimuscarinic drugs. In contrast, the quaternary derivatives are poorly taken up by the brain and therefore are relatively free— at low doses—of CNS effects. D.  Metabolism and Excretion After administration, the elimination of atropine from the blood occurs in two phases: the half-life (t1/2) of the rapid phase is 2 hours and that of the slow phase is approximately 13 hours. About 50% of the dose is excreted unchanged in the urine. Most of the rest appears in the urine as hydrolysis and conjugation products. The drug’s effect on parasympathetic function declines rapidly in all organs except the eye. Effects on the iris and ciliary muscle persist for ≥72 hours.

Pharmacodynamics A.  Mechanism of Action Atropine causes reversible (surmountable) blockade (see Chapter 2) of cholinomimetic actions at muscarinic receptors; that is, blockade by a small dose of atropine can be overcome by a larger concentration of acetylcholine or equivalent muscarinic agonist. Mutation experiments suggest that aspartate in the third transmembrane segment of the heptahelical receptor forms an ionic bond with the nitrogen atom of acetylcholine; this amino acid is also required for binding of antimuscarinic drugs. When atropine binds to the muscarinic receptor, it prevents actions such as the release of inositol trisphosphate (IP3) and the inhibition of adenylyl cyclase that are caused by muscarinic agonists (see Chapter 7). Muscarinic antagonists were traditionally viewed as neutral compounds that occupied the receptor and prevented agonist binding. Recent evidence indicates that muscarinic receptors are constitutively active, and most drugs that block the actions of acetylcholine

CHAPTER 8  Cholinoceptor-Blocking Drugs    131

Quaternary amines for gastrointestinal and pulmonary applications (peptic disease, COPD): O C H C

O

CH2

O

CH2

+

N

CH3

C

N +

C3H7

O

O

C3H7

H3C

OH

Propantheline

CH3

Glycopyrrolate

Tertiary amines for peripheral applications: O CH2OH

CH2

CH

N

C

CH3

C2H5

COCH2CH2N

CH2

C2H5

N

O Dicyclomine (peptic disease, hypermotility)

Tropicamide (mydriatric, cycloplegic)

Tertiary amine for Parkinson disease:

Quaternary amine for use in asthma:

CH3

S

S

OH

C

N

CH3

N

O C

+

CH

O

O H

O

Tiotropium

FIGURE 8–3 

CH3

Benztropine

Structures of some semisynthetic and synthetic antimuscarinic drugs.

are inverse agonists (see Chapter 1) that shift the equilibrium to the inactive state of the receptor. Muscarinic blocking drugs that are antagonists or inverse agonists include atropine, pirenzepine, trihexyphenidyl, tiotropium, ipratropium, glycopyrrolate, dicyclomine, methscopolamine, as well as several experimental compounds, including AF-DX 116, AF-DX 384, 4-DAMP, ML381, and PCS1055 (Table 8–1). The effectiveness of antimuscarinic drugs varies with the tissue and with the source of agonist. Tissues most sensitive to atropine are the salivary, bronchial, and sweat glands. Secretion of acid by the gastric parietal cells is the least sensitive. In most tissues, antimuscarinic agents block exogenously administered cholinoceptor agonists more effectively than endogenously released acetylcholine.

Atropine is highly selective for muscarinic receptors. Its potency at nicotinic receptors is much lower, and actions at nonmuscarinic receptors are generally undetectable clinically. Atropine does not distinguish among the M1–M5 subgroups of muscarinic receptors. In contrast, other antimuscarinic drugs are moderately selective for one or another of these subgroups (see Table 8–1). Most synthetic antimuscarinic drugs are considerably less selective than atropine in interactions with nonmuscarinic receptors. For example, some quaternary amine antimuscarinic agents have significant ganglion-blocking actions (eg, propantheline), and others are potent histamine receptor blockers (eg, diphenhydramine). The antimuscarinic effects of other agents, eg, antipsychotic and antidepressant drugs, are noted as side effects and can be severe.

132    SECTION II  Autonomic Drugs

TABLE 8–1  Muscarinic receptor subgroups and their antagonists/inverse agonists. Subgroup Property

M1

M2

M3

M4

M5

Primary locations

Nerves

Heart, nerves, smooth muscle

Glands, smooth muscle, endothelium

Spleen, duodenum, small intestine, testis

Placenta, testis

Dominant effector system

↑ IP3, ↑ DAG

↓ cAMP, ↑ K+ channel current

↑ IP3, ↑ DAG

↓ cAMP, ↑ K+ channel current

↑ IP3, ↑ DAG

Antagonists

Pirenzepine, telenzepine, dicyclomine,1 trihexyphenidyl2

Gallamine, methoctramine, AF-DX 1164

4-DAMP, darifenacin, solifenacin, oxybutynin, tolterodine, tiotropium

AF-DX 384, dicyclomine, PCS1055

Xanomeline, ML381

Approximate dissociation constant5

 

 

 

 

 

 Atropine

1

1

1

1

1

 Pirenzepine

25

300

500

17

100

  AF-DX 116

2000

65

4000

>1000

>1000

 Darifenacin

70

55

8

22

10

3

4

1

In clinical use as an intestinal antispasmodic agent.

2

In clinical use in the treatment of Parkinson disease.

3

In clinical use as a neuromuscular blocking agent (obsolete).

4

Compound used in research only.

5

Relative to atropine. Smaller numbers indicate higher affinity.

AF-DX 116, 11-({2-[(diethylamino)methyl]-1-piperidinyl}acetyl)-5,11-dihydro-6H-pyrido-[2,3-b](1,4)benzodiazepine-6-one; DAG, diacylglycerol; IP3, inositol trisphosphate; 4-DAMP, 4-diphenylacetoxy-N-methylpiperidine.

Their relative selectivity for muscarinic receptor subtypes has not been defined. B.  Organ System Effects 1. Central nervous system—In the doses usually used, atropine has minimal stimulant effects on the CNS, especially the parasympathetic medullary centers, and a slower, longer-lasting sedative effect on the brain. Scopolamine has more marked central effects, producing drowsiness when given in recommended dosages and amnesia in sensitive individuals that may be mediated via the histamine H3 receptor. In toxic doses, scopolamine, and to a lesser degree atropine, can cause excitement, agitation, hallucinations, and coma. The tremor of Parkinson disease is reduced by centrally acting antimuscarinic drugs, and atropine—in the form of belladonna extract—was one of the first drugs used in the therapy of this disease. As discussed in Chapter 28, parkinsonian tremor and rigidity seem to result from a relative excess of cholinergic activity because of a deficiency of dopaminergic activity in the basal ganglia-striatum system. The combination of an antimuscarinic agent with a dopamine precursor drug (levodopa) can sometimes provide more effective therapy than either drug alone. These antimuscarinic agents also reduce extrapyramidal symptoms and dystonias due to typical antipsychotic medications. Vestibular disturbances thought to originate from the inner ear, especially motion sickness, appear to involve muscarinic (M3 and M4) cholinergic transmission and the production of endolymph. Scopolamine is often effective in preventing or reversing these disturbances.

2. Eye—The pupillary constrictor muscle (see Figure 6–9) depends on muscarinic (M3) acetylcholine receptor activation. This activation is blocked by topical atropine and other tertiary antimuscarinic drugs and results in unopposed sympathetic dilator activity and mydriasis. Dilated pupils were considered cosmetically desirable during the Renaissance and account for the name belladonna (“beautiful lady,” Italian) applied to the plant and its active extract because of the use of the extract as eye drops during that time. The second important ocular effect of antimuscarinic drugs is to weaken contraction of the ciliary muscle, or cycloplegia. Cycloplegia results in loss of the ability to accommodate; the fully atropinized eye cannot focus for near vision. Both mydriasis and cycloplegia are useful in ophthalmology. They are also potentially hazardous, since acute glaucoma may be induced in patients with a narrow anterior chamber angle. A third ocular effect of antimuscarinic drugs is to reduce lacrimal secretion. Patients occasionally complain of dry or “sandy” eyes when receiving large doses of antimuscarinic drugs. 3. Cardiovascular system—The sinoatrial node is very sensitive to muscarinic receptor blockade. Moderate to high therapeutic doses of atropine cause tachycardia in the innervated and spontaneously beating heart by blockade of vagal slowing. However, lower doses often result in initial bradycardia before the effects of peripheral vagal block become manifest (Figure 8–4). This slowing may be due to block of prejunctional M1 receptors (autoreceptors, see Figures 6–3 and 7–4A) on vagal postganglionic fibers that normally limit acetylcholine release in the sinus

CHAPTER 8  Cholinoceptor-Blocking Drugs    133

1.0

*

0.5

90

*

80

* Effect

70

*

60 50

0

Effect 0

1.2

*

Receptor occupancy 0.8

*

*

0.5

0.4

* 0

0.1 1 10 Atropine dose (mcg/kg)

100

0

0

0.1

1

10

1.0 100

* - M2-ChR occupancy (fraction)

Receptor occupancy

1.6

-

100

*

Salivary flow (g/min)

*

-

Heart rate (beats/min)

110

B

* - M2-ChR occupancy (fraction)

A 120

Atropine dose (mcg/kg)

FIGURE 8–4  Effects of increasing doses of atropine on heart rate (A) and salivary flow (B) compared with muscarinic receptor occupancy in humans. The parasympathomimetic effect of low-dose atropine is attributed to blockade of prejunctional muscarinic receptors that suppress acetylcholine release. (Reproduced with permission from Wellstein A, Pitschner HF. Complex dose-response curves of atropine in man explained by different functions of M1- and M2-cholinoceptors. Naunyn Schmiedebergs Arch Pharmacol. 1988;338(1):19-27.)

node and other tissues. The same mechanisms operate in the atrioventricular node; in the presence of high vagal tone, atropine can significantly reduce the PR interval of the electrocardiogram by blocking muscarinic receptors in the atrioventricular node. Muscarinic effects on atrial muscle are similarly blocked, but these effects are of no clinical significance except in atrial flutter and fibrillation. The ventricles are less affected by antimuscarinic drugs at therapeutic levels because of a lesser degree of vagal control. In toxic concentrations, the drugs can cause intraventricular conduction block that has been attributed to a local anesthetic action. Most blood vessels, except those in thoracic and abdominal viscera, receive no direct innervation from the parasympathetic system. However, parasympathetic nerve stimulation dilates coronary arteries, and sympathetic cholinergic nerves cause vasodilation in the skeletal muscle vascular bed (see Chapter 6). Atropine can block this vasodilation. Furthermore, almost all vessels contain endothelial muscarinic receptors that mediate vasodilation (see Chapter 7). These receptors are readily blocked by antimuscarinic drugs. At toxic doses, and in some individuals at normal doses, antimuscarinic agents cause cutaneous vasodilation, especially in the upper portion of the body. The mechanism is unknown. The net cardiovascular effects of atropine in patients with normal hemodynamics are not dramatic: Tachycardia may occur, but there is little effect on blood pressure. However, the cardiovascular effects of administered direct-acting muscarinic agonists are easily prevented. 4. Respiratory system—Both smooth muscle and secretory glands of the airway receive vagal innervation and contain muscarinic receptors. Even in normal individuals, administration of atropine can cause some bronchodilation and reduce

secretion. The effect is more significant in patients with airway disease, although the antimuscarinic drugs are not as useful as the β-adrenoceptor stimulants in the treatment of asthma (see Chapter 20). The effectiveness of nonselective antimuscarinic drugs in treating chronic obstructive pulmonary disease (COPD) is limited because block of autoinhibitory M2 receptors on postganglionic parasympathetic nerves can oppose the bronchodilation caused by block of M3 receptors on airway smooth muscle. Nevertheless, antimuscarinic agents selective for M3 receptors are valuable in some patients with asthma and in many with COPD. Antimuscarinic drugs are frequently used before the administration of inhalant anesthetics to reduce the accumulation of secretions in the trachea and the possibility of laryngospasm. 5. Gastrointestinal tract—Blockade of muscarinic receptors has dramatic effects on motility and some of the secretory functions of the gut. However, even complete muscarinic block cannot abolish activity in this organ system, since local hormones and noncholinergic neurons in the enteric nervous system (see Chapters 6 and 62) also modulate gastrointestinal function. As in other tissues, exogenously administered muscarinic stimulants are more effectively blocked than are the effects of parasympathetic (vagal) nerve activity. The removal of autoinhibition, a negative feedback mechanism by which neural acetylcholine suppresses its own release, might explain the lower efficacy of antimuscarinic drugs against the effects of endogenous acetylcholine. Antimuscarinic drugs have marked effects on salivary secretion; dry mouth occurs frequently in patients taking antimuscarinic drugs for Parkinson disease or urinary conditions (Figure 8–5). Gastric secretion is blocked less effectively: the volume and amount of

134    SECTION II  Autonomic Drugs

100

Percent change

80 Salivation 60 Heart rate

40 Micturition speed

20 0

Accommodation 0.5

1.0

2.0 mg

Atropine dose (log scale)

FIGURE 8–5  Effects of subcutaneous injection of atropine on salivation, speed of micturition (voiding), heart rate, and accommodation in normal adults. Note that salivation is the most sensitive of these variables, accommodation the least. (Data from Herxheimer A: A comparison of some atropine-like drugs in man with particular reference to their end-organ specificity. Br J Pharmacol Chemother 1958 Jun;13(2):184-192.)

acid, pepsin, and mucin are all reduced, but large doses of atropine may be required. Basal secretion is blocked more effectively than that stimulated by food, nicotine, or alcohol. Pirenzepine and a more potent analog, telenzepine, reduce gastric acid secretion with fewer adverse effects than atropine and other less selective agents. This was thought to result from a selective blockade of excitatory M1 muscarinic receptors on vagal ganglion cells innervating the stomach, as suggested by their high ratio of M1 to M3 affinity (see Table 8–1). However, carbachol was found to stimulate gastric acid secretion in M1 receptor knockout animals; M3 receptors were implicated and pirenzepine opposed this effect of carbachol, an indication that pirenzepine is selective but not specific for M1 receptors. The mechanism of vagal regulation of gastric acid secretion likely involves multiple muscarinic receptor–dependent pathways. Pirenzepine and telenzepine are investigational in the USA. Pancreatic and intestinal secretion are little affected by atropine; these processes are primarily under hormonal rather than vagal control. Gastrointestinal smooth muscle motility is affected from the stomach to the colon. In general, antimuscarinic drugs diminish the tone and propulsive movements; the walls of the viscera are relaxed. Therefore, gastric emptying time is prolonged, and intestinal transit time is lengthened. Diarrhea due to overdosage with parasympathomimetic agents is readily stopped using antimuscarinics, and even diarrhea caused by nonautonomic agents can usually be temporarily controlled. However, intestinal “paralysis” induced by antimuscarinic drugs is temporary; local mechanisms within the enteric nervous system usually reestablish at least some peristalsis after 1–3 days of antimuscarinic drug therapy. 6. Genitourinary tract—The antimuscarinic action of atropine and its analogs relaxes smooth muscle of the ureters and

bladder wall and slows voiding (see Figure 8–5). This action is useful in the treatment of spasm induced by mild inflammation, surgery, and certain neurologic conditions, but it can precipitate urinary retention in men who have prostatic hyperplasia (see following section, Clinical Pharmacology of the Muscarinic Receptor-Blocking Drugs). Long-term use of antimuscarinics can lead to impotence since acetylcholine acting at muscarinic receptors plays a role in smooth muscle relaxation in genital erectile tissue. The antimuscarinic drugs have no significant effect on the uterus. 7. Sweat glands —Atropine suppresses thermoregulatory sweating. Sympathetic cholinergic fibers innervate eccrine sweat glands, and their muscarinic receptors are readily accessible to antimuscarinic drugs. In adults, body temperature is elevated by this effect only if large doses are administered, but in infants and children, even ordinary doses may cause “atropine fever.”

■■ CLINICAL PHARMACOLOGY OF THE MUSCARINIC RECEPTORBLOCKING DRUGS Therapeutic Applications The antimuscarinic drugs have applications in several of the major organ systems and in the treatment of poisoning by muscarinic agonists. A.  Central Nervous System Disorders 1. Parkinson disease—The treatment of Parkinson disease (see Chapter 28) is often an exercise in polypharmacy, since no single agent is fully effective over the course of the disease. Most antimuscarinic drugs promoted for this application (see Table 28–1) were developed before levodopa became available. Their use is accompanied by all of the adverse effects described below, but the drugs remain useful as adjunctive therapy for reducing resting tremor in some patients. 2. Motion sickness—Certain vestibular disorders respond to antimuscarinic drugs (and to antihistaminic agents with antimuscarinic effects). Scopolamine is one of the oldest remedies for seasickness and is as effective as recently introduced agents. It can be given by injection or by mouth or as a transdermal patch. The patch formulation produces significant blood levels over 48–72 hours. Useful doses by any route usually cause significant sedation and dry mouth. B.  Ophthalmologic Disorders Accurate measurement of refractive error in uncooperative patients, eg, young children, requires ciliary paralysis. Also, mydriasis greatly facilitates ophthalmoscopic examination of the retina. Therefore, antimuscarinic agents, administered topically as eye drops or ointment, are very helpful in doing a complete examination. For adults and older children, the shorter-acting drugs are preferred (Table 8–2). For younger children, the greater efficacy

CHAPTER 8  Cholinoceptor-Blocking Drugs    135

TABLE 8–2  Antimuscarinic drugs used in ophthalmology.

Drug

Duration of Effect

Usual Concentration (%)

Atropine

5–6 days

0.5–1

Scopolamine

3–7 days

0.25

Homatropine

12–24 hours

2–5

Cyclopentolate

3–6 hours

0.5–2

Tropicamide

15–60 min

0.5–1

of atropine is sometimes necessary, but the possibility of antimuscarinic poisoning is correspondingly increased. Drug loss from the conjunctival sac via the nasolacrimal duct into the nasopharynx can be diminished by the use of the ointment form rather than drops. Formerly, ophthalmic antimuscarinic drugs were selected from the tertiary amine subgroup to ensure good penetration after conjunctival application. However, glycopyrrolate, a quaternary agent, is as rapid in onset and as long-lasting as atropine. Antimuscarinic drugs should never be used for the sole purpose of mydriasis unless cycloplegia or prolonged action is required. Alpha-adrenoceptor stimulant drugs, eg, phenylephrine, produce a short-lasting mydriasis that is usually sufficient for funduscopic examination (see Chapter 9). A second ophthalmologic use is to prevent synechia (adhesion) formation in uveitis and iritis. The longer-lasting preparations, especially homatropine, are valuable for this indication. C.  Respiratory Disorders The use of atropine became part of routine preoperative medication when anesthetics such as ether were used, because these irritant anesthetics markedly increased airway secretions and were associated with frequent episodes of laryngospasm. Preanesthetic injection of atropine or scopolamine could prevent these hazardous effects. Scopolamine also produces significant amnesia for the events associated with surgery and obstetric delivery, an adverse effect that was considered desirable. On the other hand, urinary retention and intestinal hypomotility following surgery were often exacerbated by antimuscarinic drugs. Newer inhalational anesthetics are far less irritating to the airways. Patients with COPD, a condition that occurs more frequently in older patients, particularly chronic smokers, benefit from bronchodilators, especially antimuscarinic agents. Ipratropium, tiotropium (see Figure 8–3), aclidinium, and umeclidinium, synthetic analogs of atropine, are used as inhalational drugs in COPD either alone or in combination with a long-acting β-adrenoceptor agonist. The aerosol route of administration has the advantage of maximal concentration at the bronchial target tissue with reduced systemic effects. This application is discussed in greater detail in Chapter 20. Tiotropium (t1/2 25 hours) and umeclidinium (t1/2 11 hours) have a longer bronchodilator action than ipratropium (t1/2 2 hours) and can be given once daily because they dissociate slowly from M3 receptors. Aclidinium (t1/2 6 hours) is administered twice daily. Glycopyrrolate (t1/2 1.2 hours) is now available in inhalational form for twice-daily treatment of COPD. Tiotropium

reduces the incidence of COPD exacerbations and is a useful adjunct in pulmonary rehabilitation to increase exercise tolerance. The hyperactive neural bronchoconstrictor reflex present in most individuals with asthma is mediated by the vagus, acting on muscarinic receptors on bronchial smooth muscle cells. Ipratropium and tiotropium are also used as inhalational drugs in asthma. D.  Cardiovascular Disorders Marked reflex vagal discharge sometimes accompanies the pain of myocardial infarction (eg, vasovagal attack) and may depress sinoatrial or atrioventricular node function sufficiently to impair cardiac output. Parenteral atropine or a similar antimuscarinic drug is appropriate therapy in this situation. Rare individuals without other detectable cardiac disease have hyperactive carotid sinus reflexes and may experience faintness or even syncope as a result of vagal discharge in response to pressure on the neck, eg, from a tight collar. Such individuals may benefit from the judicious use of atropine or a related antimuscarinic agent. Pathophysiology can influence muscarinic activity in other ways as well. Circulating autoantibodies against the second extracellular loop of cardiac M2 muscarinic receptors have been detected in some patients with idiopathic dilated cardiomyopathy and those afflicted with Chagas disease caused by the protozoan Trypanosoma cruzi. Patients with Graves disease (hyperthyroidism) also have such autoantibodies that may facilitate the development of atrial fibrillation since these antibodies tend to act like agonists. These antibodies exert parasympathomimetic actions on the heart that are prevented by atropine. In animals immunized with a peptide from the second extracellular loop of the M2 receptor, the antibody is an allosteric modulator of the receptor. Although their role in the pathology of heart diseases is unknown, these antibodies have provided clues to the molecular basis of receptor activation because their site of action differs from the orthosteric site where acetylcholine binds (see Chapter 2) and they favor the formation of receptor dimers. E.  Gastrointestinal Disorders Antimuscarinic agents were used for peptic ulcer disease in the USA but are now obsolete for this indication (see Chapter 62). Antimuscarinic agents can provide some relief in the treatment of common traveler’s diarrhea and other mild or self-limited conditions of hypermotility. They are often combined with an opioid antidiarrheal drug, an extremely effective therapy. In this combination, however, the very low dosage of the antimuscarinic drug functions primarily to discourage abuse of the opioid agent. The classic combination of atropine with diphenoxylate, a nonanalgesic congener of meperidine, is available under many names (eg, Lomotil) in both tablet and liquid form (see Chapter 62). F.  Urinary Disorders Atropine and other antimuscarinic drugs have been used to provide symptomatic relief in the treatment of urinary urgency caused by minor inflammatory bladder disorders (Table 8–3). However, specific antimicrobial therapy is essential in bacterial cystitis. In the human urinary bladder, M2 and M3 receptors are expressed predominantly with the M3 subtype mediating direct activation

136    SECTION II  Autonomic Drugs

TABLE 8–3  Antimuscarinic drugs used in

gastrointestinal and genitourinary conditions.

Drug

Usual Dosage

Quaternary amines

 

 Anisotropine

50 mg tid

 Clidinium

2.5 mg tid–qid

 Mepenzolate

25–50 mg qid

 Methscopolamine

2.5 mg qid

 Oxyphenonium

5–10 mg qid

 Propantheline

15 mg qid

 Trospium

20 mg bid

Tertiary amines

 

 Atropine

0.4 mg tid–qid

 Darifenacin

7.5 mg daily

 Dicyclomine

10–20 mg qid

 Oxybutynin

5 mg tid

 Scopolamine

0.4 mg tid

 Solifenacin

5 mg daily

 Tolterodine

2 mg bid

of contraction. As in intestinal smooth muscle, the M2 subtype appears to act indirectly by inhibiting relaxation by norepinephrine and epinephrine. Receptors for acetylcholine on the urothelium (the epithelial lining of the urinary tract) and on afferent nerves as well as the detrusor muscle provide a broad basis for the action of antimuscarinic drugs in the treatment of overactive bladder. Oxybutynin, which is somewhat selective for M3 receptors, is used to relieve bladder spasm after urologic surgery, eg, prostatectomy. It is also valuable in reducing involuntary voiding in patients with neurologic disease, eg, children with meningomyelocele. Oral oxybutynin or instillation of the drug by catheter into the bladder in such patients appears to improve bladder capacity and continence and to reduce infection and renal damage. Transdermally applied oxybutynin or its oral extended-release formulation reduces the need for multiple daily doses. Trospium, a nonselective antagonist, has been approved and is comparable in efficacy and adverse effects to oxybutynin. Darifenacin and solifenacin are antagonists that have greater selectivity for M3 receptors than oxybutynin or trospium. Darifenacin and solifenacin, M3-selective antimuscarinics, have the advantage of once-daily dosing because of their long half-lives. Tolterodine, an M2- and M3-selective antimuscarinic, and fesoterodine, an M3-selective antimuscarinic that is a prodrug, are available for use in adults with urinary incontinence. They have many of the qualities of darifenacin and solifenacin and are available in extended-release tablets. Propiverine, a newer antimuscarinic agent with efficacy comparable to other muscarinic antagonists, has been approved for urinary incontinence in Europe but not in the USA. The convenience of the newer and longer-acting drugs has not been

accompanied by improvements in overall efficacy or by reductions in adverse effects such as dry mouth. Muscarinic antagonists have an adjunct role in therapy of benign prostatic hypertrophy when bladder symptoms (increased urinary frequency) occur. Treatment with an α-adrenoceptor antagonist combined with a muscarinic antagonist resulted in a greater reduction in bladder storage problems and urinary frequency than treatment with an α-adrenoceptor antagonist alone. An alternative treatment for urinary incontinence refractory to antimuscarinic drugs is intrabladder injection of botulinum toxin A. Botulinum toxin A is reported to reduce urinary incontinence for several months after a single treatment by interfering with the co-release of ATP with neuronal acetylcholine (see Figure 6–3). Blockade of the activation by ATP of purinergic receptors on sensory nerves in the urothelium may account for a large part of this effect. Botulinum toxin has been approved for use in patients who do not tolerate or are refractory to antimuscarinic drugs. Imipramine, a tricyclic antidepressant drug with strong antimuscarinic actions, has long been used to reduce incontinence in institutionalized elderly patients. It is moderately effective but causes significant CNS toxicity. Antimuscarinic agents have also been used in urolithiasis to relieve the painful ureteral smooth muscle spasm caused by passage of the stone. However, their usefulness in this condition is debatable. G.  Cholinergic Poisoning Severe cholinergic excess is a medical emergency, especially in rural communities where cholinesterase inhibitor insecticides are commonly used and in cultures where wild mushrooms are frequently eaten. The potential use of cholinesterase inhibitors as chemical warfare “nerve gases” also requires an awareness of the methods for treating acute poisoning (see Chapter 58). 1. Antimuscarinic therapy—Both the nicotinic and the muscarinic effects of the cholinesterase inhibitors can be life-threatening. Unfortunately, there is no effective method for directly reversing the nicotinic effects of cholinesterase inhibition, because nicotinic agonists and antagonists cause blockade of transmission (see Chapter 27). To reverse the muscarinic effects, a tertiary (not quaternary) amine drug must be used (preferably atropine) to treat the CNS effects as well as the peripheral effects of the organophosphate inhibitors. Large doses of atropine may be needed to oppose the muscarinic effects of extremely potent agents like parathion and chemical warfare nerve gases: 1–2 mg of atropine sulfate may be given intravenously every 5–15 minutes until signs of effect (dry mouth, reversal of miosis) appear. The drug may have to be given many times, since the acute effects of the cholinesterase inhibitor may last 24–48 hours or longer. In this life-threatening situation, as much as 1 g of atropine per day may be required for as long as 1 month for full control of muscarinic excess. 2. Cholinesterase regenerator compounds—A second class of compounds, composed of substituted oximes capable of regenerating active enzyme from the organophosphoruscholinesterase complex, also is available to treat organophosphorus

CHAPTER 8  Cholinoceptor-Blocking Drugs    137

O +N

C

NOH

CH3 Pralidoxime

H3C

C H3C

C

NOH

Diacetylmonoxime

poisoning. These oxime agents include pralidoxime (PAM), diacetylmonoxime (DAM), obidoxime, and others. Organophosphates cause phosphorylation of the serine OH group at the active site of cholinesterase. The oxime group (=NOH) has a very high affinity for the phosphorus atom, for which it competes with serine OH. These oximes can hydrolyze the phosphorylated enzyme and regenerate active enzyme from the organophosphorus-cholinesterase complex if the complex has not “aged” (see Chapter 7). Pralidoxime is the most extensively studied—in humans—of the agents shown and the only one available for clinical use in the USA. It is most effective in regenerating the cholinesterase associated with skeletal muscle neuromuscular junctions. Pralidoxime and obidoxime are ineffective in reversing the central effects of organophosphate poisoning because each has positively charged quaternary ammonium groups that prevent entry into the CNS. Diacetylmonoxime, on the other hand, crosses the blood-brain barrier and, in experimental animals, can regenerate some of the CNS cholinesterase. Pralidoxime is administered by intravenous infusion, 1–2 g given over 15–30 minutes. In spite of the likelihood of aging of the phosphate-enzyme complex, recent reports suggest that administration of multiple doses of pralidoxime over several days may be useful in severe poisoning. In excessive doses, pralidoxime can induce neuromuscular weakness and other adverse effects. Pralidoxime is not recommended for the reversal of inhibition of acetylcholinesterase by carbamate inhibitors. Further details of treatment of anticholinesterase toxicity are given in Chapter 58. A third approach to protection against excessive acetylcholinesterase inhibition is pretreatment with intermediate-acting enzyme inhibitors that transiently occupy the active site to prevent binding of the much longer-acting organophosphate inhibitor. This prophylaxis can be achieved with pyridostigmine but is reserved for situations in which possibly lethal poisoning is anticipated, eg, chemical warfare (see Chapter 7). Simultaneous use of atropine is required to control muscarinic excess. The use of biological scavengers has emerged as an adjunct to oximes in the reactivation of acetylcholinesterase inactivated by organophosphates. Human acetylcholinesterase, acting catalytically, increased the effectiveness of PAM in reactivating the enzyme. Butyrylcholinesterase can achieve the same effect, but it acts stoichiometrically, and thus large amounts of this bioscavenger are required. (Another use for butyrylcholinesterase is in the treatment of cocaine toxicity because butyrylcholinesterase displays cocaine hydrolase activity. The catalytic efficiency of human butyrylcholinesterase against cocaine has been increased by mutation of the enzyme such that it can prevent the effect of a lethal dose of cocaine in experimental animals.)

Mushroom poisoning has traditionally been divided into rapidonset and delayed-onset types. The rapid-onset type is usually apparent within 30 minutes to 2 hours after ingestion of the mushrooms and can be caused by a variety of toxins. Some of these produce simple upset stomach; others can have disulfiram-like effects; some cause hallucinations; and a few mushrooms (eg, Inocybe species) can produce signs of muscarinic excess: nausea, vomiting, diarrhea, urinary urgency, sweating, salivation, and sometimes bronchoconstriction. Parenteral atropine, 1–2 mg, is effective treatment in such intoxications. Despite its name, Amanita muscaria contains not only muscarine (the alkaloid was named after the mushroom), but also numerous other alkaloids, including antimuscarinic agents, and ingestion of A muscaria often causes signs of atropine poisoning, not muscarine excess. Delayed-onset mushroom poisoning, usually caused by Amanita phalloides, Amanita virosa, Galerina autumnalis, or Galerina marginata, manifests its first symptoms 6–12 hours after ingestion. Although the initial symptoms usually include nausea and vomiting, the major toxicity involves hepatic and renal cellular injury by amatoxins that inhibit RNA polymerase. Atropine is of no value in this form of mushroom poisoning (see Chapter 58). H.  Other Applications Hyperhidrosis (excessive sweating) is sometimes reduced by antimuscarinic agents, eg, propantheline bromide. However, relief is incomplete at best, probably because apocrine rather than eccrine glands are usually involved.

Adverse Effects Treatment with atropine or its congeners directed at one organ system almost always induces undesirable effects in other organ systems. Thus, mydriasis and cycloplegia are adverse effects when an antimuscarinic agent is used to reduce gastrointestinal secretion or motility, even though they are therapeutic effects when the drug is used in ophthalmology. At higher concentrations, atropine causes block of all parasympathetic functions. However, atropine is a remarkably safe drug in adults. Atropine poisoning has occurred as a result of attempted suicide, but most cases are due to attempts to induce hallucinations. Poisoned individuals manifest dry mouth, mydriasis, tachycardia, hot and flushed skin, agitation, and delirium for as long as 1 week. Body temperature is frequently elevated. These effects are memorialized in the adage, “dry as a bone, blind as a bat, red as a beet, mad as a hatter.” Unfortunately, children, especially infants, are very sensitive to the hyperthermic effects of atropine. Although accidental administration of more than 400 mg has been followed by recovery, deaths have followed doses as small as 2 mg. Therefore, atropine should be considered a highly dangerous drug when overdose occurs in infants or children. Overdoses of atropine or its congeners are generally treated symptomatically (see Chapter 58). Poison control experts discourage the use of physostigmine or another cholinesterase inhibitor to reverse the effects of atropine overdose because symptomatic management is more effective and less dangerous. When physostigmine

138    SECTION II  Autonomic Drugs

is deemed necessary, small doses are given slowly intravenously (1–4 mg in adults, 0.5–1 mg in children). Symptomatic treatment may require temperature control with cooling blankets and seizure control with diazepam. Poisoning caused by high doses of quaternary antimuscarinic drugs is associated with all of the peripheral signs of parasympathetic blockade but few or none of the CNS effects of atropine. These more polar drugs may cause significant ganglionic blockade, however, with marked orthostatic hypotension (see below). Treatment of the antimuscarinic effects, if required, can be carried out with a quaternary cholinesterase inhibitor such as neostigmine. Control of hypotension may require the administration of a sympathomimetic drug such as phenylephrine. Recent evidence indicates that some centrally acting drugs (tricyclic antidepressants, selective serotonin reuptake inhibitors, anti-anxiety agents, antihistamines) with antimuscarinic actions impair memory and cognition in older patients.

Contraindications Contraindications to the use of antimuscarinic drugs are relative, not absolute. Obvious muscarinic excess, especially that caused by cholinesterase inhibitors, can always be treated with atropine. Antimuscarinic drugs are contraindicated in patients with glaucoma, especially angle-closure glaucoma. Even systemic use of moderate doses may precipitate angle closure (and acute glaucoma) in patients with shallow anterior chambers. In elderly men, antimuscarinic drugs should always be used with caution and should be avoided in those with a history of prostatic hyperplasia. Because the antimuscarinic drugs slow gastric emptying, they may increase symptoms in patients with gastric ulcer, and therefore, nonselective antimuscarinic agents should never be used to treat acid-peptic disease (see Chapter 62).

■■ BASIC & CLINICAL PHARMACOLOGY OF THE GANGLION-BLOCKING DRUGS Ganglion-blocking agents competitively block the action of acetylcholine and similar agonists at neuronal nicotinic receptors of both parasympathetic and sympathetic autonomic ganglia. Some members of the group also block the ion channel that is gated by the nicotinic cholinoceptor. The ganglion-blocking drugs are important and used in pharmacologic and physiologic research because they can block all autonomic outflow. However, their lack of selectivity confers such a broad range of undesirable effects that they have limited clinical use.

Chemistry & Pharmacokinetics All ganglion-blocking drugs of interest are synthetic amines. Tetraethylammonium (TEA), the first to be recognized as having this action, has a very short duration of action. Hexamethonium (“C6”) was developed and was introduced clinically as the first drug effective for management of hypertension. As shown in

CH3

CH3 CH3

+

N

CH2

CH2

CH2

CH2

CH2

CH2

CH3

+N

CH3

CH3

Hexamethonium CH2

CH3 CH3 CH3 NH CH3

CH3

CH2

CH2

Mecamylamine

CH2

CH3

CH3

Tetraethylammonium

CH3 CH3

N+

CH3

N+

O CH2

CH2

O

C

CH3

CH3

Acetylcholine

FIGURE 8–6  Some ganglion-blocking drugs. Acetylcholine is shown for reference. Figure 8–6, there is an obvious relationship between the structures of the agonist acetylcholine and the nicotinic antagonists tetraethylammonium and hexamethonium. Decamethonium, the “C10” analog of hexamethonium, is a depolarizing neuromuscular blocking agent. Mecamylamine, a secondary amine, was developed to improve the degree and extent of absorption from the gastrointestinal tract because the quaternary amine ganglion-blocking compounds were poorly and erratically absorbed after oral administration. Trimethaphan, a short-acting, polar, ganglion-blocking drug, is no longer available for clinical use.

Pharmacodynamics A.  Mechanism of Action Ganglionic nicotinic receptors, like those of the skeletal muscle neuromuscular junction, are subject to both depolarizing and nondepolarizing blockade (see Chapters 7 and 27). Nicotine itself, carbamoylcholine, and even acetylcholine (if amplified with a cholinesterase inhibitor) can produce depolarizing ganglion block. Drugs now used as ganglion-blocking drugs are classified as nondepolarizing competitive antagonists. Blockade can be surmounted by increasing the concentration of an agonist, eg, acetylcholine. However, hexamethonium actually produces most of its blockade by occupying sites in or on the nicotinic ion channel, not by occupying the cholinoceptor itself. B.  Organ System Effects 1. Central nervous system—Mecamylamine, unlike the quaternary amine agents and trimethaphan, crosses the blood-brain barrier and readily enters the CNS. Sedation, tremor, choreiform movements, and mental aberrations have been reported as effects of mecamylamine.

CHAPTER 8  Cholinoceptor-Blocking Drugs    139

2. Eye—The ganglion-blocking drugs cause a predictable cycloplegia with loss of accommodation because the ciliary muscle receives innervation primarily from the parasympathetic nervous system. The effect on the pupil is not so easily predicted, since the iris receives both sympathetic innervation (mediating pupillary dilation) and parasympathetic innervation (mediating pupillary constriction). Ganglionic blockade often causes moderate dilation of the pupil because parasympathetic tone usually dominates this tissue. 3. Cardiovascular system—Blood vessels receive chiefly vasoconstrictor fibers from the sympathetic nervous system; therefore, ganglionic blockade causes a marked decrease in arteriolar and venomotor tone. The blood pressure may fall precipitously because both peripheral vascular resistance and venous return are decreased (see Figure 6–7). Hypotension is especially marked in the upright position (orthostatic or postural hypotension), because postural reflexes that normally prevent venous pooling are blocked. Cardiac effects include diminished contractility and, because the sinoatrial node is usually dominated by the parasympathetic nervous system, a moderate tachycardia. 4. Gastrointestinal tract—Secretion is reduced, although not enough to treat peptic disease effectively. Motility is profoundly inhibited, and constipation can be marked. 5. Other systems—Genitourinary smooth muscle is partially dependent on autonomic innervation for normal function.

Therefore, ganglionic blockade causes hesitancy in urination and may precipitate urinary retention in men with prostatic hyperplasia. Sexual function is impaired in that both erection and ejaculation may be prevented by moderate doses. Thermoregulatory sweating is reduced by the ganglion-blocking drugs. However, hyperthermia is not a problem except in very warm environments, because cutaneous vasodilation is usually sufficient to maintain a normal body temperature. 6. Response to autonomic drugs—Patients receiving ganglionblocking drugs are fully responsive to autonomic drugs acting on muscarinic, α-, and β-adrenoceptors because these effector cell receptors are not blocked. In fact, responses may be exaggerated or even reversed (eg, intravenously administered norepinephrine may cause tachycardia rather than bradycardia), because homeostatic reflexes, which normally moderate autonomic responses, are absent.

Clinical Applications & Toxicity Ganglion blocking drugs are used rarely because more selective autonomic blocking agents are available. Mecamylamine blocks central nicotinic receptors and has been advocated as a possible adjunct with the transdermal nicotine patch to reduce nicotine craving in patients attempting to quit smoking. The toxicity of the ganglion-blocking drugs is limited to the autonomic effects already described. For most patients, these effects are intolerable except for acute use.

SUMMARY  Drugs with Anticholinergic Actions Subclass, Drug

Mechanism of Action

MOTION SICKNESS DRUGS   •  Scopolamine Competitive antagonism at muscarinic receptors, additional 5HT3 antagonist mechanism in CNS GASTROINTESTINAL DISORDERS Competitive antagonism at M1 and M4 receptors

  •  Dicyclomine

Pharmacokinetics, Toxicities, Interactions

Effects

Clinical Applications

Reduces vertigo, postoperative nausea

Prevention of motion sickness and postoperative nausea and vomiting

Transdermal patch used for motion sickness • IM injection for postoperative use • Toxicity: Tachycardia, blurred vision, xerostomia, delirium • Interactions: With other antimuscarinics

Reduces smooth muscle and secretory activity of gut

Irritable bowel syndrome, minor diarrhea

Available in oral and parenteral forms • short t½ but action lasts up to 6 h • Toxicity: Tachycardia, confusion, urinary retention, increased intraocular pressure • Interactions: With other antimuscarinics

Causes mydriasis and cycloplegia

Retinal examination; prevention of synechiae after surgery

Used as drops • long (5–6 days) action • Toxicity: Increased intraocular pressure in closed-angle glaucoma • Interactions: With other antimuscarinics

  •  Hyoscyamine: Longer duration of action OPHTHALMOLOGY   •  Atropine

Competitive antagonism at all M receptors

  •  Homatropine: Shorter duration of action (12–24 h) than atropine   •  Cyclopentolate: Shorter duration of action (3–6 h)   •  Tropicamide: Shortest duration of action (15–60 min) (continued)

140    SECTION II  Autonomic Drugs

Subclass, Drug

Mechanism of Action

RESPIRATORY (ASTHMA, COPD) Competitive, nonselective antagonist at M receptors

  • Ipratropium

Pharmacokinetics, Toxicities, Interactions

Effects

Clinical Applications

Reduces or prevents bronchospasm

Prevention and relief of acute episodes of bronchospasm

Aerosol canister, up to qid • Toxicity: Xerostomia, cough • Interactions: With other antimuscarinics

Urge incontinence; postoperative spasms

Oral, IV, patch formulations • Toxicity: Tachycardia, constipation, increased intraocular pressure, xerostomia • Patch: Pruritus • Interactions: With other antimuscarinics

  •  Tiotropium, aclidinium, and umeclidinium: Longer duration of action; used once daily URINARY   •  Oxybutynin

Slightly M3-selective muscarinic antagonist

Reduces detrusor smooth muscle tone, spasms

  •  Darifenacin, solifenacin, fesoterodine, and tolterodine: Tertiary amines with somewhat greater selectivity for M3 receptors   •  Trospium: Quaternary amine with less CNS effect CHOLINERGIC POISONING Nonselective competitive antagonist at all muscarinic receptors in CNS and periphery

  •  Atropine

  •  Pralidoxime

Very high affinity for phosphorus atom but does not enter CNS

Blocks muscarinic excess at exocrine glands, heart, smooth muscle

Mandatory antidote for severe cholinesterase inhibitor poisoning

Intravenous infusion until antimuscarinic signs appear • continue as long as necessary • Toxicity: Insignificant as long as AChE inhibition continues

Regenerates active AChE; can relieve skeletal muscle end plate block

Usual antidote for early-stage (48 h) cholinesterase inhibitor poisoning

Intravenous every 4–6 h • Toxicity: Can cause muscle weakness in overdose

AChE, acetylcholinesterase; CNS, central nervous system; COPD, chronic obstructive pulmonary disease; IM, intramuscular.

P R E P A R A T I O N S GENERIC NAME

A V A I L A B L E

AVAILABLE AS

ANTIMUSCARINIC ANTICHOLINERGIC DRUGS* Aclidinium Tudorza Pressair Atropine Generic Belladonna alkaloids, extract, Generic or tincture Botulinum toxin A Botox Clidinium Generic, Quarzan, others Cyclopentolate Generic, Cyclogyl, others Darifenacin Generic, Enablex Dicyclomine Generic, Bentyl, others Fesoterodine Toviaz Flavoxate Generic, Urispas Glycopyrrolate Generic, Robinul (systemic) Seebri Neohaler (oral inhalation) Homatropine Generic, Isopto Homatropine, others l-Hyoscyamine Anaspaz, Cystospaz-M, Levsin, others Ipratropium Generic, Atrovent Mepenzolate Cantil *

GENERIC NAME Methscopolamine Oxybutynin Propantheline Scopolamine  Oral  Ophthalmic  Transdermal Solifenacin Tiotropium Tolterodine Tropicamide

AVAILABLE AS Generic, Pamine Generic, Ditropan, Gelnique, others Generic, Pro-Banthine, others   Generic Isopto Hyoscine Transderm Scop Vesicare Spiriva Generic, Detrol Generic, Mydriacyl Ophthalmic, others Trospium Generic, Sanctura Umeclidinium Incruse Ellipta GANGLION BLOCKERS Mecamylamine Vecamyl CHOLINESTERASE REGENERATOR Pralidoxime Generic, Protopam

Antimuscarinic drugs used in parkinsonism are listed in Chapter 28.

REFERENCES Brodde OE et al: Presence, distribution and physiological function of adrenergic and muscarinic receptor subtypes in the human heart. Basic Res Cardiol 2001;96:528. Cahill K et al: Pharmacological interventions for smoking cessation: An overview and network meta-analysis. Cochrane Database Syst Rev 2013;5:CD009329.

Carrière I et al: Drugs with anticholinergic properties, cognitive decline, and dementia in an elderly general population. Arch Intern Med 2009; 169:1317. Casaburi R et al: Improvement in exercise tolerance with the combination of tiotropium and pulmonary rehabilitation in patients with COPD. Chest 2005;127:809.

CHAPTER 8  Cholinoceptor-Blocking Drugs    141 Chapple CR et al: A comparison of the efficacy and tolerability of solifenacin succinate and extended release tolterodine at treating overactive bladder syndrome: Results of the STAR trial. Eur Urol 2005;48:464. Cohen JS et al: Dual therapy strategies for COPD: The scientific rationale for LAMA+LABA. Int J Chron Obstruct Pulmon Dis 2016;11:785. Ehlert FJ, Pak KJ, Griffin MT: Muscarinic agonists and antagonists: Effects on gastrointestinal function. In: Fryer AD et al (editors): Muscarinic Receptors. Handb Exp Pharmacol 2012;208:343. Filson CP et al: The efficacy and safety of combined therapy with α-blockers and anticholinergics for men with benign prostatic hyperplasia: A meta-analysis. J Urol 2013;190:2013. Fowler CJ, Griffiths D, de Groat WC: The neural control of micturition. Nat Rev Neurosci 2008;9:453. Giovannini MG et al: Effects of histamine H3 receptor agonists and antagonists on cognitive performance and scopolamine-induced amnesia. Behav Brain Res 1999;104:147. Kranke P et al: The efficacy and safety of transdermal scopolamine for the prevention of postoperative nausea and vomiting: A quantitative systematic review. Anesth Analg 2002;95:133. Kruse AC et al: Muscarinic acetylcholine receptors: Novel opportunities for drug development. Nat Rev Drug Discov 2014;13:549. Lawrence GW, Aoki KR, Dolly JO: Excitatory cholinergic and purinergic signaling in bladder are equally susceptible to botulinum neurotoxin A consistent with corelease of transmitters from efferent fibers. J Pharmacol Exp Ther 2010;334:1080. Marquardt K: Mushrooms, amatoxin type. In: Olson K (editor): Poisoning & Drug Overdose, 6th ed. New York: McGraw Hill, 2012. Moriya H et al: Affinity profiles of various muscarinic antagonists for cloned human muscarinic acetylcholine receptor (mAChR) subtypes and mAChRs in rat heart and submandibular gland. Life Sci 1999;64:2351.

Profita M et al: Smoke, choline acetyltransferase, muscarinic receptors, and fibroblast proliferation in chronic obstructive pulmonary disease. J Pharmacol Exp Ther 2009;329:753. Rai BP et al: Anticholinergic drugs versus non-drug active therapies for nonneurogenic overactive bladder syndrome in adults. Cochrane Database Syst Rev 2012;12:CD003193. Tauterman CS et al: Molecular basis for the long duration of action and kinetic selectivity of tiotropium for the muscarinic M3 receptor. J Med Chem 2013;56:8746. Thai DM et al: Crystal structures of the M1 and M4 muscarinic acetylcholine receptors. Nature 2016;335:2016. Vuckovic Z et al: Crystal structure of the M5 muscarinic acetylcholine receptor. Proc Natl Acad Sci U S A 2019;116:26001. Wallukat G, Schimke I: Agonistic autoantibodies directed against G-protein-coupled receptors and their relationship to cardiovascular diseases. Semin Immunopathol 2014;36:351. Young JM et al: Mecamylamine: New therapeutic uses and toxicity/risk profile. Clin Ther 2001;23:532. Zhang L et al: A missense mutation in the CHRM2 gene is associated with familial dilated cardiomyopathy. Circ Res 2008;102:1426.

Treatment of Anticholinesterase Poisoning Nachon F et al: Progress in the development of enzyme-based nerve agent bioscavengers. Chem Biol Interact 2013;206:536. Thiermann H et al: Pharmacokinetics of obidoxime in patients poisoned with organophosphorus compounds. Toxicol Lett 2010;197:236. Weinbroum AA: Pathophysiological and clinical aspects of combat anticholinesterase poisoning. Br Med Bull 2005;72:119.

C ASE STUDY ANSWER JH’s symptoms are often displayed by patients following prostatectomy to relieve significant obstruction of bladder outflow. Urge incontinence can occur in patients whose prostatic hypertrophy caused instability of the detrusor muscle. JH should be advised that urinary incontinence and urinary

frequency can diminish with time after prostatectomy as detrusor muscle instability subsides. JH can be helped by daily administration of a single tablet of extended-release tolterodine (4 mg/d) or oxybutynin (5–10 mg/d). A transdermal patch containing oxybutynin (3.9 mg/d) also is available.

C

H

9 A

P

T

E

R

Adrenoceptor Agonists & Sympathomimetic Drugs Italo Biaggioni, MD*, & Vsevolod V. Gurevich, PhD

C ASE STUDY A 68-year-old man presents with a complaint of lightheadedness on standing that is worse after meals and in hot environments. Symptoms started about 4 years ago and have slowly progressed to the point that he is disabled. He has fainted several times but always recovers consciousness almost as soon as he falls. Other symptoms include slight worsening of constipation, urinary retention out of proportion to prostate size, and decreased sweating. He is otherwise healthy with no history of hypertension, diabetes, or Parkinson disease. Because of urinary retention, he was placed on the α1A antagonist tamsulosin, but the fainting spells got worse. Physical examination is unremarkable except for a blood pressure of 167/84 mm Hg supine and

The sympathetic nervous system is an important regulator of virtually all organ systems. This is particularly evident in the regulation of blood pressure. As illustrated in the case study, the sympathetic nervous system is required to maintain blood pressure stable even under relatively minor situations of stress. For example, during standing, the gravitational pooling of blood in the lower body triggers sympathetic stimulation that causes the release of norepinephrine from nerve terminals, which then activates adrenoceptors on postsynaptic sites (see Chapter 6) to restore blood pressure. Also, in response to more stressful situations (eg, hypoglycemia), sympathetic activation causes the adrenal medulla to release epinephrine, which is then transported in the blood to target tissues. In other

*

The author thanks David Robertson, MD, for his contributions to previous versions of this chapter. 142

106/55 mm Hg standing. There was an inadequate compensatory increase in heart rate (from 84 to 88 bpm), considering the magnitude of orthostatic hypotension. There is no evidence of peripheral neuropathy or parkinsonian features. Laboratory examinations are negative except for a low plasma norepinephrine (98 pg/mL; normal for his age 250–400 pg/mL). A diagnosis of pure autonomic failure is made, based on the clinical picture and the absence of drugs that could induce orthostatic hypotension and diseases commonly associated with autonomic neuropathy (eg, diabetes, Parkinson disease). What precautions should this patient observe in using sympathomimetic drugs? Can such drugs be used in his treatment?

words, epinephrine acts as a hormone, whereas norepinephrine acts as a neurotransmitter. Both have a role in the “fight or flight” response that characterizes sympathetic activation. Drugs that mimic the actions of epinephrine or norepinephrine have traditionally been termed sympathomimetic drugs. The sympathomimetics can be grouped by mode of action and by the spectrum of receptors that they activate. Some of these drugs (e.g., norepinephrine and epinephrine) are direct agonists; they directly interact with and activate adrenoceptors. Others are indirect agonists because their actions are dependent on their ability to enhance the actions of endogenous catecholamines by (1) inducing the release of catecholamines by displacing them from adrenergic nerve endings (e.g., the mechanism of action of tyramine), (2) decreasing the clearance of catecholamines by inhibiting their neuronal reuptake (e.g., the mechanism of action of cocaine and certain antidepressants), or (3) preventing the enzymatic metabolism

CHAPTER 9  Adrenoceptor Agonists & Sympathomimetic Drugs     143

of norepinephrine (monoamine oxidase and catechol-O-methyltransferase inhibitors). Some drugs have both direct and indirect actions. Both types of sympathomimetics, direct and indirect, ultimately cause activation of adrenoceptors, leading to some or all of the characteristic effects of endogenous catecholamines. The pharmacologic effects of direct agonists depend on the route of administration, their relative affinity for adrenoceptor subtypes, and the relative expression of these receptor subtypes in target tissues. The pharmacologic effects of indirect sympathomimetics are greater under conditions of increased sympathetic activity and norepinephrine release.

to G proteins that regulate various effector proteins. Each G protein is a heterotrimer consisting of α, β, and γ subunits. G proteins are classified on the basis of their distinctive α subunits. G proteins of particular importance for adrenoceptor function include Gs, the stimulatory G protein of adenylyl cyclase; Gi and Go, the inhibitory G proteins of adenylyl cyclase; and Gq and G11, the G proteins coupling α receptors to phospholipase C. The activation of G protein-coupled receptors by catecholamines promotes the dissociation of guanosine diphosphate (GDP) from the α subunit of the corresponding G protein. Guanosine triphosphate (GTP) then binds to this G protein, and the α subunit dissociates from the βγ subunit. The activated GTP-bound α subunit then regulates the activity of its effector. Effectors of adrenoceptor-activated α subunits include adenylyl cyclase, phospholipase C, and ion channels. The α subunit is inactivated by hydrolysis of the bound GTP to GDP and phosphate, and the subsequent reassociation of the α subunit with the βγ subunit. The βγ subunits have additional independent effects, acting on a variety of effectors such as ion channels and enzymes. Adrenoceptors were originally characterized pharmacologically by their relative affinities for agonists; α receptors have the comparative potencies epinephrine ≥ norepinephrine >> isoproterenol, and β receptors have the comparative potencies isoproterenol > epinephrine ≥ norepinephrine. Molecular cloning further identified distinct subtypes of these receptors (Table 9–1).

■■ MOLECULAR PHARMACOLOGY UNDERLYING THE ACTIONS OF SYMPATHOMIMETIC DRUGS The effects of catecholamines are mediated by cell-surface receptors. Adrenoceptors are typical G protein-coupled receptors (GPCRs; see Chapter 2). The receptor protein has an extracellular N-terminus, traverses the membrane seven times (transmembrane domains) forming three extracellular and three intracellular loops, and has an intracellular C-terminus (Figure 9–1). They are coupled Agonist

Phospholipase C

Gq

Ptdlns 4,5P2

{ β

DAG

γ αq

Alpha1 receptor

+

αq*

GDP

GTP

Ca2+-dependent protein kinase +

PKC

Activated PKC

IP3 +

Free calcium

Stored calcium

Activated protein kinase

FIGURE 9–1  Activation of α1 responses. Stimulation of α1 receptors by catecholamines leads to the activation of a Gq-coupling protein. The activated α subunit (αq*) of this G protein activates the effector, phospholipase C, which leads to the release of IP3 (inositol 1,4,5-trisphosphate) and DAG (diacylglycerol) from phosphatidylinositol 4,5-bisphosphate (PtdIns 4,5P2). IP3 stimulates the release of sequestered stores of calcium, leading to an increased concentration of cytoplasmic Ca2+. Ca2+ may then activate Ca2+-dependent protein kinases, which in turn phosphorylate their substrates. DAG activates protein kinase C (PKC). GDP, guanosine diphosphate; GTP, guanosine triphosphate. See text for additional effects of α1-receptor activation.

144    SECTION II  Autonomic Drugs

TABLE 9–1  Adrenoceptor types and subtypes. Receptor

Agonist

Antagonist

G Protein

Effects

Gene on Chromosome

`1 type

Phenylephrine

Prazosin

Gq

↑ IP3, DAG common to all

 

  α1A

 

Tamsulosin

 

 

C8

 

 

 

 

C5

  α1B   α1D

1

 

 

 

 

C20

`2 type

Clonidine

Yohimbine

Gi

↓ cAMP common to all

 

  α2A

Oxymetazoline

 

 

 

C10

  α2B

 

Prazosin

 

 

C2

  α2C

 

Prazosin

 

 

C4

a type

Isoproterenol

Propranolol

Gs

↑ cAMP common to all

 

  a1

Dobutamine

Betaxolol

 

 

C10

  a2

Albuterol

Butoxamine

 

 

C5

  a3

Mirabegron

 

 

 

C8

Dopamine type

Dopamine

 

 

 

 

 D1

Fenoldopam

 

Gs

↑ cAMP

C5

 D2

Bromocriptine

 

Gi

↓ cAMP

C11

 D3

 

 

Gi

↓ cAMP

C3

 D4

 

Clozapine

Gi

↓ cAMP

C11

 D5

 

 

Gs

↑ cAMP

C4

1

Initially an “α1C” receptor was described but was later recognized to be identical to the α1A receptor. To avoid confusion, the nomenclature now omits α1C.

Nomenclature: The adrenoreceptors (and the genes that encode them) are also known by the abbreviation ADR, followed by the type (ADRA, ADRB) and subtype (ADRA1A, ADRA1B, etc). The corresponding nomenclature for the dopamine receptors is DRD1, DRD2, etc.

Likewise, the endogenous catecholamine dopamine produces a variety of biologic effects that are mediated by interactions with specific dopamine receptors (see Table 9–1). These receptors are particularly important in the brain (see Chapters 21, 28, and 29) and in the splanchnic and renal vasculature. Molecular cloning has identified several distinct genes encoding five receptor subtypes: two D1-like receptors that activate adenylate cyclase (D1 and D5), and three D2-like receptors that inhibit adenylate cyclase (D2, D3, and D4). Further complexity exists because alternative splicing produces D2 receptor isoforms, and D2 receptors might also form oligo- and heterodimers. These subtypes may have importance for understanding the efficacy and adverse effects of novel antipsychotic drugs (see Chapter 29).

Receptor Types

influx of calcium across the cell’s plasma membrane. IP3 is sequentially dephosphorylated, which ultimately leads to the formation of free inositol. DAG cooperates with Ca2+ in activating protein kinase C (PKC), which modulates activity of many signaling pathways. In addition, α1 receptors activate signal transduction pathways that stimulate tyrosine kinases such as mitogen-activated protein kinases (MAP kinases) and polyphosphoinositol-3-kinase (PI-3-kinase). Alpha2 receptors are coupled to the inhibitory regulatory protein Gi (Figure 9–2) that reduces adenylyl cyclase activity and lowers intracellular levels of cyclic adenosine monophosphate (cAMP). It is likely that not only the α subunit of Gi, but also its βγ subunits, contribute to inhibition of adenylyl cyclase. It is also likely that α2 receptors are coupled to other signaling pathways that regulate ion channels and enzymes involved in signal transduction.

A.  Alpha Receptors Alpha1 receptors are coupled via G proteins of the Gq family to phospholipase C. This enzyme hydrolyzes polyphosphoinositides, leading to the formation of inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG) (see Table 9–1 and Figure 9–1). IP3 promotes the release of sequestered Ca2+ from intracellular stores, which increases cytoplasmic free Ca2+ concentrations that activate various calcium-dependent protein kinases and other calmodulinregulated proteins. Activation of these receptors may also increase

B.  Beta Receptors All three receptor subtypes (β1, β2, and β3) are coupled to the stimulatory regulatory protein Gs, which activates adenylyl cyclase to increase intracellular levels of cAMP (see Table 9–1 and Figure 9–2). Cyclic AMP is the second messenger that mediates most of the actions of β-receptors; in the liver cAMP mediates a cascade of events culminating in the activation of glycogen phosphorylase; in the heart, it increases the influx of calcium across the cell membrane; whereas in smooth muscle it promotes

CHAPTER 9  Adrenoceptor Agonists & Sympathomimetic Drugs     145

Agonist

Agonist

Adenylyl cyclase

GS

Gi

{

{ βγ

GS

β

αS Beta receptor

αS*

+

–

αi

αi*

GDP

GTP

GTP

GDP

γ

GDP GTP

GTP GDP

Alpha2 receptor

ATP cAMP Enzyme

+

ATP +

2C

R2C2 protein kinase

ADP Enzyme-PO4

2R

Biologic effect

FIGURE 9–2  Activation and inhibition of adenylyl cyclase by agonists that bind to catecholamine receptors. Binding to β adrenoceptors stimulates adenylyl cyclase by activating the stimulatory G protein, Gs, which leads to the dissociation of its α subunit charged with GTP. This activated αs subunit directly activates adenylyl cyclase, resulting in an increased rate of synthesis of cAMP. Alpha2-adrenoceptor ligands inhibit adenylyl cyclase by causing dissociation of the inhibitory G protein, Gi, into its subunits—ie, an activated αi subunit charged with GTP and a β-γ unit. The mechanism by which these subunits inhibit adenylyl cyclase is uncertain. cAMP binds to the regulatory subunit (R) of cAMP-dependent protein kinase, leading to the liberation of active catalytic subunits (C) that phosphorylate specific protein substrates and modify their activity. These catalytic units also phosphorylate the cAMP response element binding protein (CREB), which modifies gene expression. See text for other actions of β and α2 adrenoceptors. relaxation through phosphorylation of myosin light-chain kinase to an inactive form (see Figure 12–1). Some actions of β adrenoceptors may be mediated through different intracellular signaling pathways, via exchange proteins activated by cAMP rather than conventional protein kinase A (PKA), or via coupling to Gs but independent of cAMP, or coupling to Gq proteins and activation of MAP kinases. The β3 adrenoceptor is a lower-affinity receptor compared with β1 and β2 receptors but is more resistant to desensitization. It is found in several tissues, but its physiologic or pathologic role in humans is not clear. Beta3 receptors are expressed in the detrusor muscle of the bladder and induce its relaxation, and the selective β3 agonist mirabegron is used clinically for the treatment of symptoms of overactive bladder (urinary urgency and frequency). C.  Dopamine Receptors The D1 receptor is typically associated with the stimulation of adenylyl cyclase (see Table 9–1); for example, D1 receptor–induced

smooth muscle relaxation is presumably due to cAMP accumulation in the smooth muscle of those vascular beds in which dopamine is a vasodilator. D2 receptors have been found to inhibit adenylyl cyclase activity, open potassium channels, and decrease calcium influx.

Adrenoceptor Polymorphisms Since elucidation of the sequences of the genes encoding adrenoceptors, it has become clear that there are relatively common genetic polymorphisms (variations in the gene sequence) for many of these receptor subtypes in humans. Distinct polymorphisms may be inherited together, in combinations termed haplotypes. Genetic polymorphisms can result in changes in critical amino acids that may alter the function of the receptor in ways that are clinically relevant. Some polymorphisms have been shown to alter susceptibility to diseases such as heart failure, modify the propensity of a receptor to desensitize, or modulate therapeutic responses

146    SECTION II  Autonomic Drugs

to drugs in diseases such as asthma. In many other cases, studies have reported inconsistent results as to the pathophysiologic importance of polymorphisms.

Receptor Regulation Responses mediated by adrenoceptors are not fixed and static. The magnitude of the response depends on the number and function of adrenoceptors on the cell surface and on the regulation of these receptors by catecholamines themselves, other hormones and drugs, age, and a number of disease states (see Chapter 2). These changes may modify the magnitude of a tissue’s physiologic response to catecholamines and can be important clinically during the course of treatment. One of the best-studied examples of receptor regulation is the desensitization of adrenoceptors that may occur after exposure to catecholamines and other sympathomimetic drugs. After a cell or tissue has been exposed for a period of time to an agonist, that tissue often becomes less responsive to further stimulation by that agent (see Figure 2–12). Other terms such as tolerance, refractoriness, and tachyphylaxis also have been used to describe desensitization. This process has potential clinical significance because it may limit the therapeutic response to sympathomimetic agents. Many mechanisms have been found to contribute to desensitization. Some mechanisms occur relatively slowly, over the course of hours or days, and these typically involve transcriptional or translational changes in the receptor protein level, or its transport to the cell surface. Other mechanisms of desensitization occur quickly, within minutes. Rapid modulation of receptor function in desensitized cells may involve critical covalent modification of the receptor, association of these receptors with other proteins, or changes in their subcellular location. There are two major categories of desensitization of responses mediated by G protein-coupled receptors. Homologous desensitization refers to loss of responsiveness exclusively of the receptors that have been exposed to repeated or sustained activation by an agonist. Heterologous desensitization refers to the process by which desensitization of one receptor by its agonists also results in desensitization of another receptor that has not been directly activated by the agonist in question. A major mechanism of desensitization that occurs rapidly involves phosphorylation of receptors by members of the G protein-coupled receptor kinase (GRK) family, of which there are seven in most mammals, with four subtypes (GRK2, GRK3, GRK5, and GRK6) being ubiquitously expressed. Specific adrenoceptors become substrates for these kinases only when they are bound to an agonist. This mechanism is an example of homologous desensitization because it specifically affects only agonistoccupied receptors. Phosphorylation of these receptors enhances their affinity for arrestins, a family of four proteins, of which the two nonvisual arrestin subtypes are widely expressed. Upon binding of arrestin, the capacity of the receptor to activate G proteins is blunted, likely as a result of steric hindrance, as suggested by the crystal structures of GPCR complexes with G proteins and arrestins (see Figure 2–12). Arrestin then interacts with clathrin and clathrin adaptor

AP2, leading to endocytosis of the receptor. In addition to their role in the desensitization process, arrestins can trigger G proteinindependent signaling pathways. Receptor desensitization may also be mediated by second-messenger feedback. For example, β adrenoceptors stimulate cAMP accumulation, which leads to activation of PKA; PKA can phosphorylate residues on β receptors, resulting in inhibition of receptor function. For the β2 receptor, PKA phosphorylation occurs on serine residues in the third cytoplasmic loop of the receptor. Similarly, activation of PKC by Gq-coupled receptors may lead to phosphorylation of this class of G protein-coupled receptors. PKA phosphorylation of the β2 receptor also switches its G protein preference from Gs to Gi, further reducing cAMP response. This second-messenger feedback mechanism has been termed heterologous desensitization because activated PKA or PKC may phosphorylate any structurally similar receptor with the appropriate consensus sites for phosphorylation by these enzymes—e.g., the elevation of cAMP by activation of other receptors can trigger PKA phosphorylation of β receptors.

Receptor Selectivity Selectivity means that a drug preferentially activates one subgroup of receptors at concentrations that have little or no effect on another subgroup. However, selectivity is not usually absolute (nearly absolute selectivity has been termed specificity), and at higher concentrations, a drug may also interact with related classes of receptors. The clinical effects of a given drug may depend not only on its selectivity to adrenoceptor types, but also on the relative expression of receptor subtypes in a given tissue. Examples of clinically useful sympathomimetic agonists that are relatively selective for α1-, α2-, and β-adrenoceptor subgroups are compared with some nonselective agents in Table 9–2.

TABLE 9–2  Relative receptor affinities.  

Relative Receptor Affinities

Alpha agonists

 

  Phenylephrine, methoxamine

α1 > α2 >>>>> β

  Clonidine, methylnorepinephrine

α2 > α1 >>>>> β

Mixed alpha and beta agonists

 

 Norepinephrine

α1 = α2; β1 >> β2

 Epinephrine

α1 = α2; β1 = β2

Beta agonists

1

 

 Dobutamine

1

β1 > β2 >>>> α

 Isoproterenol

β1 = β2 >>>> α

 Albuterol, terbutaline, metaproterenol, ritodrine

β2 >> β1 >>>> α

Dopamine agonists

 

 Dopamine 

D1 = D2 >> β >> α

 Fenoldopam 

D1 >> D2

See text.

CHAPTER 9  Adrenoceptor Agonists & Sympathomimetic Drugs     147

Even though each receptor subtype is coupled to a G protein that mediates most of its intracellular signaling (see Table 9–1), in many cases a receptor can be coupled to other G proteins, or signal through both G protein-dependent and G protein-independent pathways. This observation has prompted the concept of developing biased agonists that selectively activate one of the signaling pathways (see Box: Therapeutic Potential of Biased Agonists at Beta Receptors). There is also interest in discovering allosteric modulators of receptor function, i.e., ligands that bind to the receptor at a site different from the agonist binding site and modulate the response to the agonist.

Therapeutic Potential of Biased Agonists at Beta Receptors Traditional β agonists like epinephrine activate cardiac β1 receptors, increasing heart rate and cardiac workload through coupling with G proteins. This can be deleterious in situations such as myocardial infarction. Beta1 receptors are also coupled through G protein-independent signaling pathways involving β-arrestin, which are thought to be cardioprotective. A “biased” agonist could potentially activate only the cardioprotective, β-arrestin–mediated signaling (and not the G protein–mediated signals that lead to greater cardiac workload). Such a biased agonist would be of great therapeutic potential in situations such as myocardial infarction or heart failure. In asthma, there is interest in developing biased agonists that are effective bronchial muscle relaxants but are not subject to desensitization. Biased agonists potent enough to reach these therapeutic goals have not yet been developed.

The Norepinephrine Transporter When norepinephrine is released into the synaptic cleft, it binds to postsynaptic adrenoceptors to elicit the expected physiologic effect. However, just as the release of neurotransmitters is a tightly regulated process, the mechanisms for removal of neurotransmitter must also be highly effective. The norepinephrine transporter (NET) is the principal route by which this occurs. It is particularly efficient in the synapses of the heart, where up to 90% of released norepinephrine is removed by the NET. Remaining synaptic norepinephrine may escape into the extrasynaptic space and enter the bloodstream or be taken up into extraneuronal cells and metabolized by catechol-O-methyltransferase. In other sites such as the vasculature, where synaptic structures are less well developed, removal by NET may still be 60% or more. The NET, often situated on the presynaptic neuronal membrane, pumps the synaptic norepinephrine back into the neuron cell cytoplasm. In the cell, this norepinephrine may reenter the vesicles or undergo metabolism through monoamine oxidase to dihydroxyphenylglycol (DHPG). Elsewhere in the body similar transporters remove dopamine (dopamine transporter, DAT), serotonin (serotonin transporter, SERT), and other neurotransmitters. The NET,

surprisingly, has equivalent affinity for dopamine as for norepinephrine, and it can sometimes clear dopamine in brain areas where DAT is low, like the cortex. Blockade of the NET, e.g., by the nonselective psychostimulant cocaine or the NET-selective agents atomoxetine or reboxetine, impairs this primary site of norepinephrine removal and thus synaptic norepinephrine levels rise, leading to greater stimulation of α and β adrenoceptors. In the periphery this effect may produce a clinical picture of sympathetic activation, but it is often counterbalanced by concomitant stimulation of α2 adrenoceptors in the brain stem that reduces sympathetic activation. The function of the norepinephrine and dopamine transporters is complex, and drugs can interact with the NET to actually reverse the direction of transport and induce the release of intraneuronal neurotransmitter. This is illustrated in Figure 9–3. Under normal circumstances (panel A), presynaptic NET (red) inactivates and recycles norepinephrine (NE, red) released by vesicular fusion. In panel B, amphetamine (black) acts as both an NET substrate and a reuptake blocker, eliciting reverse transport and blocking normal uptake, thereby increasing NE levels in and beyond the synaptic cleft. In panel C, agents such as methylphenidate and cocaine (hexagons) block NET-mediated NE reuptake and enhance NE signaling.

■■ MEDICINAL CHEMISTRY OF SYMPATHOMIMETIC DRUGS Phenylethylamine may be considered the parent compound from which sympathomimetic drugs are derived (Figure 9–4). This compound consists of a benzene ring with an ethylamine side chain. The presence of –OH groups at the 3 and 4 positions of the benzene ring yields sympathomimetic drugs collectively known as catecholamines. Additional substitutions made on (1) the benzene ring, (2) the terminal amino group, and (3) the α or β carbons produce catechols with different affinity for α and β receptors, from almost pure α agonists (methoxamine) to almost pure β agonists (isoproterenol). In addition to determining relative affinity to receptor subtypes, chemical structure also determines the pharmacokinetic properties and bioavailability of these molecules. A.  Substitution on the Benzene Ring Maximal α and β activity is found with catecholamines, i.e., drugs having –OH groups at the 3 and 4 positions on the benzene ring. The absence of one or the other of these groups dramatically reduces the potency of these drugs. For example, phenylephrine (Figure 9–5) is much less potent than epinephrine; its affinity to α receptors is decreased approximately 100-fold, but because its β activity is almost negligible except at very high concentrations, it is a selective α agonist. On the other hand, the presence of –OH groups make catecholamines subject to inactivation by catechol-O-methyltransferase (COMT), and because this enzyme is found in the gut and liver, catecholamines are not active orally (see Chapter 6). Absence of one or both –OH groups on the phenyl ring increases

148    SECTION II  Autonomic Drugs

A

B

Postganglionic sympathetic nerve ending NET

NET

NE

VMAT

Amphetamine

VMAT

NE

NET

NET

Reversed transport

NE

NE

Effector cell

Effector cell

C

NET

VMAT

Cocaine NE

NET

Blocked transport NE

Effector cell

FIGURE 9–3  Pharmacologic targeting of monoamine transporters. Commonly used drugs such as antidepressants, amphetamines, and cocaine target monoamine (norepinephrine, dopamine, and serotonin) transporters with different potencies. A shows the mechanism of reuptake of norepinephrine (NE) back into the noradrenergic neuron via the norepinephrine transporter (NET), where a proportion is sequestered in presynaptic vesicles through the vesicular monoamine transporter (VMAT). B and C show the effects of amphetamine and cocaine on these pathways. See text for details. the bioavailability after oral administration and prolongs the duration of action. Furthermore, absence of ring –OH groups tends to increase the distribution of the molecule to the central nervous system (CNS). For example, ephedrine and amphetamine (see Figure 9–5) are orally active, have a prolonged duration of action, and produce central nervous system effects not typically observed with the catecholamines. Methamphetamine (“crystal meth,” a common drug of abuse) can be synthesized by simple dehydroxylation of ephedrine, which led to the restriction of over-the-counter distribution of its isomer pseudoephedrine. B.  Substitution on the Amino Group Increasing the size of alkyl substituents on the amino group tends to increase β-receptor activity. For example, methyl substitution

on norepinephrine (yielding epinephrine) enhances activity at β2 receptors, and isopropyl substitution (yielding isoproterenol) increases β activity further. Conversely, the larger the substituent on the amino group, the lower is the activity at α receptors; for example, isoproterenol is very weak at α receptors. Beta2-selective agonists generally require a large amino substituent group. C.  Substitution on the Alpha Carbon Substitutions at the α carbon (e.g., ephedrine and amphetamine; see Figure 9–5) block oxidation by monoamine oxidase (MAO), thus prolonging the duration of action of these drugs. Alphamethyl compounds are also called phenylisopropylamines. In addition to their resistance to oxidation by MAO, some phenylisopropylamines have an enhanced ability to displace catecholamines

CHAPTER 9  Adrenoceptor Agonists & Sympathomimetic Drugs     149

HO 3

HO

2

4

1 5

Catechol

6

β CH2

α CH2

NH2

Phenylethylamine

HO

HO OH

OH

CH

HO

CH2

NH2

CH

HO

Norepinephrine

CH2

NH

CH3

Epinephrine

HO

HO OH CH

HO

CH3 CH2

NH

CH

HO

CH2

CH2

NH2

CH3

Isoproterenol

FIGURE 9–4 

Dopamine

Phenylethylamine and some important catecholamines. Catechol is shown for reference.

from storage sites in noradrenergic nerves (see Chapter 6). Therefore, a portion of their activity is dependent on the presence of normal norepinephrine stores in the body; they are indirectly acting sympathomimetics. D.  Substitution on the Beta Carbon Direct-acting agonists typically have a β-hydroxyl group, although dopamine does not. In addition to facilitating activation of adrenoceptors, this hydroxyl group may be important for storage of sympathomimetic amines in synaptic vesicles.

CH3O

HO

CH CH

CH2

NH

CH3

OH

Phenylephrine

CH

CH

OH

CH3

Ephedrine

OH OCH3

CH

NH2

CH3

Methoxamine

NH

CH3

CH2

CH

NH2

CH3

Amphetamine

FIGURE 9–5  Some examples of noncatecholamine sympathomimetic drugs. The isopropyl group is highlighted in color. Methamphetamine is amphetamine with one of the amine hydrogens replaced by a methyl group.

ORGAN SYSTEM EFFECTS OF SYMPATHOMIMETIC DRUGS Cardiovascular System General outlines of the cellular actions of sympathomimetics are presented in Tables 6–3 and 9–3. Sympathomimetics have prominent cardiovascular effects because of widespread distribution of α and β adrenoceptors in the heart, blood vessels, and neural and hormonal systems involved in blood pressure regulation. The effects of sympathomimetic drugs on blood pressure can be explained on the basis of their effects on heart rate, myocardial function, arterial vascular resistance, and venous return (see Figure 6–7 and Table 9–4). The endogenous catecholamines, norepinephrine and epinephrine, have complex cardiovascular effects because they activate both α and β receptors. It is easier to understand these actions by first describing the cardiovascular effect of sympathomimetics that are selective for a given adrenoceptor. A.  Effects of Alpha1-Receptor Activation Alpha1 receptors are widely expressed in vascular beds, and their activation leads to arterial and venous vasoconstriction. Their direct effect on cardiac function is of relatively less importance. Phenylephrine and midodrine are selective α1 agonists, and their administration increases peripheral arterial resistance (arterial vasoconstriction) and decreases venous capacitance (venous constriction). The enhanced arterial resistance usually leads to a dose-dependent rise in blood pressure (Figure 9–6). In the presence of normal cardiovascular reflexes, the rise in blood pressure elicits a baroreceptor-mediated increase in vagal tone with slowing of the heart rate, which may be quite

150    SECTION II  Autonomic Drugs

TABLE 9–3  Distribution of adrenoceptor subtypes. Type

Tissue

Actions

α1

Most vascular smooth muscle (innervated)

Contraction

 

Pupillary dilator muscle

Contraction (dilates pupil)

 

Pilomotor smooth muscle

Erects hair

 

Prostate

Contraction

 

Heart

Increases force of contraction

α2

Postsynaptic CNS neurons

Probably multiple

 

Platelets

Aggregation

 

Adrenergic and cholinergic nerve terminals

Inhibits transmitter release

 

Some vascular smooth muscle

Contraction

 

Fat cells

Inhibits lipolysis

β1

Heart, juxtaglomerular cells

Increases force and rate of contraction; increases renin release

β2

Respiratory, uterine, and vascular smooth muscle

Promotes smooth muscle relaxation

 

Skeletal muscle

Promotes potassium uptake

 

Human liver

Activates glycogenolysis

β3

Bladder

Relaxes detrusor muscle

 

Fat cells

Activates lipolysis

D1

Smooth muscle

Dilates renal blood vessels

D2

Nerve endings

Modulates transmitter release

marked (Figure 9–7). However, cardiac output may not diminish in proportion to this reduction in rate, because the improved venous return increases stroke volume. Furthermore, direct α-adrenoceptor stimulation of the heart may have a modest positive inotropic action.

It is important to note that any effect these agents have on blood pressure is counteracted by compensatory autonomic baroreflex mechanisms aimed at restoring homeostasis. The magnitude of the restraining effect is quite dramatic. If baroreflex function is removed

TABLE 9–4  Cardiovascular responses to sympathomimetic amines.  

Phenylephrine

Epinephrine

Isoproterenol

Vascular resistance (tone)

 

 

 

  Skin, mucous membranes (α)

↑↑

↑↑

0

  Skeletal muscle (β2, α)

↑

↓ or ↑

↓↓

  Renal (α, D1)

↑

↑

↓ 1

  Splanchnic (α, β)

↑↑

↓ or ↑

↓

  Total peripheral resistance

↑↑↑

↓ or ↑1

↓↓

  Venous tone (α, β)

↑

↑

↓

Cardiac

 

 

 

  Contractility (β1)

0 or ↑

↑↑↑

↑↑↑

  Heart rate (predominantly β1)

↓↓ (vagal reflex)

↑ or ↓

↑↑↑

  Stroke volume

0, ↓, ↑

↑

↑

  Cardiac output

↓

↑

↑↑

Blood pressure

 

 

 

 Mean

↑↑

↑

↓

 Diastolic

↑↑

↓ or ↑1

↓↓

 Systolic

↑↑

↑↑

0 or ↓

  Pulse pressure

0

↑↑

↑↑

1

Small doses decrease, large doses increase.

↑ = increase; ↓ = decrease; 0 = no change.

CHAPTER 9  Adrenoceptor Agonists & Sympathomimetic Drugs     151

190/145 BP

145/100 160

HR

170 Phenylephrine 190/124

BP

135/90

HR

180

160/82

175/110

210 Epinephrine

BP

145/95

130/50 95/28

HR

150

Isoproterenol

240

FIGURE 9–6  Effects of an α-selective (phenylephrine), β-selective (isoproterenol), and nonselective (epinephrine) sympathomimetic, given as an intravenous bolus injection to a dog. Reflexes are blunted but not eliminated in this anesthetized animal. BP, blood pressure; HR, heart rate. by pretreatment with the ganglionic blocker trimethaphan, the pressor effect of phenylephrine is increased approximately 10-fold, and bradycardia is no longer observed (see Figure 9–7), confirming that the decrease in heart rate was reflex in nature rather than a direct effect of α1-receptor activation. Patients who have an impairment of autonomic function (due to pure autonomic failure as in the case study or to more common conditions such as diabetic autonomic neuropathy) exhibit this extreme hypersensitivity to most pressor and depressor stimuli, including medications. This is to a large extent due to failure of baroreflex buffering. Such patients may have exaggerated increases in heart rate or blood pressure when taking sympathomimetics. This, however, can be used as an advantage in their treatment. The α1 agonist midodrine is commonly used to ameliorate orthostatic hypotension in these patients. There are major differences in receptor types predominantly expressed in the various vascular beds (see Table 9–4). The skin vessels have predominantly α receptors and constrict in response to epinephrine and norepinephrine, as do the splanchnic vessels. Vessels in skeletal muscle may constrict or dilate depending on whether α or β receptors are activated. The blood vessels of the nasal mucosa express α receptors, and local vasoconstriction induced by sympathomimetics explains their decongestant action (see Therapeutic Uses of Sympathomimetic Drugs). B.  Effects of Alpha2-Receptor Activation Selective α2 adrenoceptors agonists, such as clonidine, act in the CNS to reduce sympathetic activity (“central sympatholytics”) and

are used in the treatment of hypertension (see Chapter 11). Alpha2 adrenoreceptors are also present in the vasculature, and their activation leads to vasoconstriction. This effect, however, is observed only when α2 agonists are given locally, by rapid intravenous injection or in very high oral doses. When given systemically, these vascular effects are obscured by the central sympatholytic effects of α2 receptors. In patients with pure autonomic failure, characterized by neural degeneration of postganglionic noradrenergic fibers, clonidine may increase blood pressure because the central sympatholytic effects of clonidine become irrelevant whereas the peripheral vasoconstriction remains intact. C.  Effects of Beta-Receptor Activation The cardiovascular effects of β-adrenoceptor activation are exemplified by the response to the nonselective β agonist isoproterenol, which activates both β1 and β2 receptors. Stimulation of β receptors in the heart increases cardiac output by increasing contractility and by direct activation of the sinus node to increase heart rate. Beta agonists also decrease peripheral resistance by activating β2 receptors, leading to vasodilation of certain vascular beds (see Table 9–4). The net effect is to maintain or slightly increase systolic pressure and to lower diastolic pressure, so that mean blood pressure is decreased (see Figure 9–6). The cardiac effects of β agonists are determined largely by β1 receptors (although β2 and α receptors also may be involved, especially in heart failure). The prototypical β1-selective agonist is dobutamine. Beta1-receptor activation in the heart results in

152    SECTION II  Autonomic Drugs

80

100

0

0

BP 100 mm Hg

100

HR bpm

Phe 75 mcg

Phe 7.5 mcg 0

0 Intact

Ganglionic blockade

FIGURE 9–7  Effects of ganglionic blockade on the response to phenylephrine (Phe) in a human subject. Left: The cardiovascular effect of the selective α agonist phenylephrine when given as an intravenous bolus to a subject with intact autonomic baroreflex function. Note that the increase in blood pressure (BP) is associated with a baroreflex-mediated compensatory decrease in heart rate (HR). Right: The response in the same subject after autonomic reflexes were abolished by the ganglionic blocker trimethaphan. Note that resting blood pressure is decreased and heart rate is increased by trimethaphan because of sympathetic and parasympathetic withdrawal (HR scale is different). In the absence of baroreflex buffering, approximately a 10-fold lower dose of phenylephrine is required to produce a similar increase in blood pressure. Note also the lack of compensatory decrease in heart rate. increased calcium influx in cardiac cells with both electrical and mechanical consequences. Beta1 activation in the sinoatrial node increases pacemaker activity and heart rate (positive chronotropic effect). Beta1 stimulation in the atrioventricular node increases conduction velocity (positive dromotropic effect) and decreases the refractory period. Beta1 activation also increases intrinsic myocardial contractility (positive inotropic effect) and accelerates relaxation. Physiologic stimulation of the heart by catecholamines, therefore, increases heart rate and cardiac output, and it tends to increase coronary blood flow because of coronary vasodilation. Excessive stimulation of ventricular muscle and Purkinje cells can result in ventricular arrhythmias. Expression of β3 adrenoceptors has been detected in the human heart and may be up-regulated in disease states, but the relevance of this finding is not clear. D.  Effects of Dopamine-Receptor Activation Intravenous administration of dopamine promotes vasodilation of renal, splanchnic, coronary, cerebral, and perhaps other resistance vessels, via activation of D1 receptors. Activation of the D1 receptors in the renal vasculature may also induce natriuresis. The renal effects of dopamine have been used clinically to improve perfusion to the kidney in situations of oliguria (abnormally low

urinary output). The activation of presynaptic D2 receptors suppresses norepinephrine release, but it is unclear if this contributes to cardiovascular effects of dopamine. Dopamine, however, can activate adrenoreceptors at higher concentrations. At low doses, the vasodilatory effects of dopamine receptors predominate, and peripheral resistance decreases. At moderate doses dopamine activates β1 receptors in the heart, causing an increase in heart rate and in contractility. At higher doses dopamine activates vascular α receptors, leading to vasoconstriction, including in the renal vascular bed. Consequently, high rates of infusion of dopamine may mimic the actions of epinephrine.

Noncardiac Effects of Sympathomimetics Adrenoceptors are distributed in virtually all organ systems. This section focuses on those actions that explain the therapeutic uses of sympathomimetics or their adverse effects. A more detailed description of the therapeutic use of sympathomimetics is given later in this chapter. Activation of β2 receptors in bronchial smooth muscle leads to bronchodilation, and β2 agonists are important in the treatment of asthma (see Chapter 20 and Table 9–3).

CHAPTER 9  Adrenoceptor Agonists & Sympathomimetic Drugs     153

In the eye, the radial pupillary dilator muscle of the iris contains α receptors; activation by drugs such as phenylephrine causes mydriasis (see Figure 6–9). Alpha2 agonists increase the outflow of aqueous humor from the eye and can be used clinically to reduce intraocular pressure. In contrast, β agonists have little effect, but β antagonists decrease the production of aqueous humor and are used in the treatment of glaucoma (see Chapter 10). In genitourinary organs, the bladder base, urethral sphincter, and prostate contain α1A receptors that mediate contraction and therefore promote urinary continence. This effect explains why α1A antagonists are useful in the management of symptoms of urinary flow obstruction and, conversely, why urinary retention is a potential adverse effect of administration of the α1 agonist midodrine. Alpha-receptor activation in the ductus deferens, seminal vesicles, and prostate plays a role in normal ejaculation and in the detumescence of erectile tissue that normally follows ejaculation. This explains why abnormal ejaculation can be seen as an adverse effect of α1A antagonists. The salivary glands contain adrenoceptors that regulate the secretion of amylase and water, and α2 agonists, e.g., clonidine, produce symptoms of dry mouth. It is likely that CNS effects are responsible for this side effect, although peripheral effects may contribute. The apocrine sweat glands, located on the palms of the hands and a few other areas, are nonthermoregulatory glands that respond to psychological stress and adrenoceptor stimulation with increased sweat production. (The diffusely distributed thermoregulatory eccrine sweat glands are regulated by sympathetic cholinergic postganglionic nerves that activate muscarinic cholinergic receptors; see Chapter 6.) Sympathomimetic drugs have important effects on intermediary metabolism. Activation of β adrenoceptors in fat cells leads to increased lipolysis with enhanced release of free fatty acids and glycerol into the blood. Beta3 adrenoceptors play a role in mediating this response in animals, but their role in humans is not clear. Experimentally, the β3 agonist mirabegron stimulates brown adipose tissue in humans. The potential importance of this finding is that brown fat cells (“good fat”) are thermogenic and thus have a positive metabolic function. Brown adipose tissue is present in neonates, but only remnant amounts are normally found in adult humans. Therefore, it is not clear whether β3 agonists can be used therapeutically for the treatment of obesity. Human fat cells also contain α2 receptors that inhibit lipolysis by decreasing intracellular cAMP. Sympathomimetic drugs enhance glycogenolysis in the liver, which leads to increased glucose release into the circulation. In the human liver, the effects of catecholamines are probably mediated mainly by β receptors, although α1 receptors also may play a role. Activation of β2 adrenoceptors by endogenous epinephrine or by sympathomimetic drugs promotes the uptake of potassium into cells, leading to a fall in extracellular potassium. This may result in a fall in the plasma potassium concentration during stress or protect against a rise in plasma potassium during exercise. Blockade of these receptors may accentuate the rise in plasma potassium that occurs during exercise. On the other hand, epinephrine has been used to treat hyperkalemia in certain

conditions, but alternatives are more commonly used. Beta receptors and α2 receptors that are expressed in pancreatic islets tend to increase and decrease insulin secretion, respectively, although the major regulator of insulin release is the plasma concentration of glucose. Catecholamines are important endogenous regulators of hormone secretion from a number of glands. As mentioned above, insulin secretion is stimulated by β receptors and inhibited by α2 receptors. Similarly, renin secretion is stimulated by β1 and inhibited by α2 receptors; indeed, β-receptor antagonist drugs may lower blood pressure in patients with hypertension at least in part by lowering plasma renin. Adrenoceptors also modulate the secretion of parathyroid hormone, calcitonin, thyroxine, and gastrin; however, the physiologic significance of these control mechanisms is probably limited. At high concentrations, epinephrine and related agents cause leukocytosis, in part by promoting demargination of sequestered white blood cells back into the general circulation. The action of sympathomimetics on the CNS varies dramatically, depending on their ability to cross the blood-brain barrier. The catecholamines are almost completely excluded by this barrier, and subjective CNS effects are noted only at the highest rates of infusion. These effects have been described as ranging from “nervousness” to “an adrenaline rush” or “a feeling of impending disaster.” Furthermore, peripheral effects of β-adrenoceptor agonists such as tachycardia and tremor are similar to the somatic manifestations of anxiety. In contrast, noncatecholamines with indirect actions, such as amphetamines, which readily enter the CNS from the circulation, produce qualitatively very different effects on the nervous system. These actions vary from mild alerting, with improved attention to boring tasks; through elevation of mood, insomnia, euphoria, and anorexia; to full-blown psychotic behavior. These effects are not necessarily mediated by adrenoceptor activation, and they may represent enhancement of dopamine-mediated processes or other effects of these drugs in the CNS.

SPECIFIC SYMPATHOMIMETIC DRUGS Endogenous Catecholamines Epinephrine (adrenaline) is released from the adrenal medulla to act as a circulating hormone. Epinephrine is an agonist at both α and β receptors. It is therefore a very potent vasoconstrictor and cardiac stimulant. The rise in systolic blood pressure that occurs after epinephrine release or administration is caused by its positive inotropic and chronotropic actions on the heart (predominantly β1 receptors) and the vasoconstriction induced in many vascular beds (α receptors). Epinephrine also activates β2 receptors in some vessels (e.g., skeletal muscle blood vessels), leading to vasodilation. Consequently, total peripheral resistance may actually fall, explaining the fall in diastolic pressure that is seen with epinephrine injection (see Figure 9–6 and Table 9–4). Activation of β2 receptors in skeletal muscle contributes to increased blood flow during exercise. Norepinephrine (levarterenol, noradrenaline) is an agonist at both α1 and α2 receptors. Norepinephrine also activates β1 receptors with potency similar to epinephrine, but it has relatively little

154    SECTION II  Autonomic Drugs

effect on β2 receptors. Consequently, norepinephrine increases peripheral resistance and both diastolic and systolic blood pressure. Compensatory baroreflex activation tends to overcome the direct positive chronotropic effects of norepinephrine; however, the positive inotropic effects on the heart are maintained. Dopamine is the immediate precursor in the synthesis of norepinephrine (see Figure 6–5). Its cardiovascular effects were described above. Endogenous dopamine may have more important effects in regulating sodium excretion and renal function. It is an important neurotransmitter in the CNS and is involved in the reward stimulus relevant to addiction. Its deficiency in the basal ganglia leads to Parkinson disease, which is treated with its precursor levodopa. Dopamine receptors are also targets for antipsychotic drugs.

BETA1-SELECTIVE HO HO

CH2

CH2

NH

HO

CH2

CH2

CH

Dobutamine

HO

Direct-Acting Sympathomimetics Phenylephrine was discussed previously when describing the actions of a relatively pure α1 agonist (see Table 9–2). Because it is not a catechol derivative (see Figure 9–5), it is not inactivated by COMT and has a longer duration of action than the catecholamines. It is an effective mydriatic and decongestant and can be used to raise the blood pressure (see Figure 9–6). Midodrine is a prodrug that is enzymatically hydrolyzed to desglymidodrine, a selective α1-receptor agonist. The peak concentration of desglymidodrine is achieved about 1 hour after midodrine is administered orally. The primary indication for midodrine is the treatment of orthostatic hypotension, typically due to impaired autonomic nervous system function. Midodrine increases upright blood pressure and improves orthostatic tolerance, but it may cause hypertension when the subject is supine. Alpha2-selective agonists decrease blood pressure through actions in the CNS that reduce sympathetic tone (“sympatholytics”) even though direct application to a blood vessel may cause vasoconstriction. Such drugs (e.g., clonidine, methyldopa, guanfacine, guanabenz) are useful in the treatment of hypertension (and some other conditions) and are discussed in Chapter 11. Sedation is a recognized side effect of these drugs, but in some situations it may be beneficial. For example, tizanidine is used as a centrally acting muscle relaxant, and dexmedetomidine is used as a sedative to reduce requirements for opioids for pain control, and to induce sedation in an intensive care setting or in preparation for anesthesia. On the other hand, newer α2 agonists (with activity also at imidazoline receptors) with fewer CNS side effects are available outside the USA for the treatment of hypertension (moxonidine, rilmenidine). Short-acting central sympatholytics like clonidine and tizanidine have the disadvantage that they can be associated with rebound hypertension and their effects wear off. This can be particularly relevant to tizanidine, which is marketed as a muscle relaxant and prescribed by physicians who do not realize that it can be as effective an antihypertensive as clonidine. Oxymetazoline is a direct-acting α agonist used as a topical decongestant because of its ability to promote constriction of the vessels in the nasal mucosa and conjunctiva. Isoproterenol (isoprenaline) is a very potent β-receptor agonist and has little effect on α receptors. Thus, the drug has positive

CH3

BETA2-SELECTIVE

CH

CH2

NH

C(CH3)3

OH HO

FIGURE 9–8 

Terbutaline

Examples of β1- and β2-selective agonists.

chronotropic and inotropic actions and is a potent vasodilator. These actions lead to a marked increase in cardiac output that explains a slight increase in systolic pressure but a decrease in diastolic and mean arterial pressure (see Table 9–4 and Figure 9–6). Beta subtype-selective agonists are very important because the separation of β1 and β2 effects (see Table 9–2), although incomplete, is sufficient to reduce adverse effects in several clinical applications. Beta1-selective agents (Figure 9–8) increase cardiac output without lowering diastolic blood pressure because they do not activate vasodilator β2 receptors. Dobutamine was initially considered a relatively β1-selective agonist, but its actions are more complex. Its chemical structure resembles dopamine, but its actions are mediated mostly by activation of α and β receptors. Clinical formulations of dobutamine are a racemic mixture of (–) and (+) isomers, each with contrasting activity at α1 and α2 receptors. The (+) isomer is a potent β1 agonist and an α1-receptor antagonist. The (–) isomer is a potent α1 agonist, which is capable of causing significant vasoconstriction when given alone. The resultant cardiovascular effects of dobutamine reflect this complex pharmacology. Dobutamine has a positive inotropic action caused by the isomer with predominantly β-receptor activity. It has relatively greater inotropic than chronotropic effect compared with isoproterenol. Activation of α1 receptors probably explains why peripheral resistance does not decrease significantly. Beta2-selective agents (see Figure 9–8) have achieved an important place in the treatment of asthma and are discussed in Chapter 20.

Mixed-Acting Sympathomimetics Ephedrine is present in various plants and has been used in China for more than 2000 years; it was introduced into Western medicine

CHAPTER 9  Adrenoceptor Agonists & Sympathomimetic Drugs     155

in 1924 as the first orally active sympathomimetic drug. Ma huang, a popular herbal medication (see Chapter 64), contains ephedrine and multiple other ephedrine-like alkaloids. Because ephedrine is a noncatechol phenylisopropylamine (see Figure 9–5), it has high bioavailability and a relatively long duration of action—hours rather than minutes. The ability of ephedrine to activate β receptors probably accounted for its earlier use in asthma. Because it gains access to the CNS, it is a mild stimulant. The US Food and Drug Administration (FDA) has banned the sale of ephedra-containing dietary supplements because of safety concerns. Pseudoephedrine, one of four ephedrine enantiomers, has been available over the counter as a component of many decongestant mixtures. However, the use of pseudoephedrine as a precursor in the illicit manufacture of methamphetamine has led to restrictions on the amount of drug that can be purchased.

INDIRECT-ACTING SYMPATHOMIMETICS As noted previously, indirect-acting sympathomimetics can have one of two different mechanisms (see Figure 9–3). First, they may enter the sympathetic nerve ending and displace stored catecholamine transmitter. Such drugs have been called amphetamine-like or “displacers.” Second, they may inhibit the reuptake of released transmitter by interfering with the action of the norepinephrine transporter, NET. A. Amphetamine-Like Amphetamine is a racemic mixture of phenylisopropylamine (see Figure 9–5) that is important chiefly because of its use and misuse as a CNS stimulant (see Chapter 32). Pharmacokinetically, it is similar to ephedrine; however, amphetamine enters the CNS even more readily, where it has marked stimulant effects on mood and alertness and a depressant effect on appetite. Its d-isomer is more potent than the l-isomer. Amphetamine’s actions are mediated through the release of norepinephrine and, to some extent, dopamine. Methamphetamine (N-methylamphetamine) is very similar to amphetamine, with an even higher ratio of central to peripheral actions. Methylphenidate is an amphetamine variant whose major pharmacologic effects and abuse potential are similar to those of amphetamine. Methylphenidate may be effective in children with attention deficit hyperactivity disorder (see Therapeutic Uses of Sympathomimetic Drugs). Modafinil and armodafinil are psychostimulants that differ from amphetamine in structure, neurochemical profile, and behavioral effects. Their mechanism of action is not fully known. They inhibit both norepinephrine and dopamine transporters, and increase synaptic concentrations not only of norepinephrine and dopamine, but also of serotonin and glutamate, while decreasing γ-aminobutyric acid (GABA) levels. They are used primarily to improve wakefulness in narcolepsy and some other conditions. Their use can be associated with increases in blood pressure and heart rate, although these are usually mild (see Therapeutic Uses of Sympathomimetic Drugs).

TABLE 9–5  Foods reputed to have a high content

of tyramine or other sympathomimetic agents.

Food

Tyramine Content of an Average Serving

Beer

4–45 mg

Broad beans, fava beans

Negligible (but contains dopamine)

Cheese, natural or aged

Nil to 130 mg (cheddar, Gruyère, and Stilton especially high)

Chicken liver

Nil to 9 mg

Chocolate

Negligible (but contains phenylethylamine)

Sausage, fermented (eg, salami, pepperoni, summer sausage)

Nil to 74 mg

Smoked or pickled fish (eg, pickled herring)

Nil to 198 mg

Wine (red)

Nil to 3 mg

Yeast (eg, dietary brewer’s yeast supplements)

2–68 mg

Note: In a patient taking an irreversible monoamine oxidase (MAO) inhibitor drug, 20–50 mg of tyramine in a meal may increase the blood pressure significantly (see also Chapter 30: Antidepressant Agents). Note that only cheese, sausage, pickled fish, and yeast supplements contain sufficient tyramine to be consistently dangerous. This does not rule out the possibility that some preparations of other foods might contain significantly greater than average amounts of tyramine. Amounts in mg as per regular food portion.

Tyramine (see Figure 6–5) is a normal byproduct of tyrosine metabolism in the body. It is an indirect sympathomimetic, inducing the release of catecholamines from noradrenergic neurons. Tyramine can be produced in high concentrations in protein-rich foods by decarboxylation of tyrosine during fermentation (Table 9–5) but is normally inactive when taken orally because it is readily metabolized by MAO in the liver (i.e., low bioavailability because of a very high first-pass effect). In patients treated with MAO inhibitors—particularly inhibitors of the MAO-A isoform—the sympathomimetic effect of tyramine may be greatly intensified, leading to marked increases in blood pressure. This occurs because of increased bioavailability of tyramine and increased neuronal stores of catecholamines. Patients taking MAO inhibitors should avoid tyramine-containing foods (aged cheese, cured meats, and pickled food). There are differences in the effects of various MAO inhibitors on tyramine bioavailability, and isoform-specific or reversible enzyme antagonists may be safer (see Chapters 28 and 30). B.  Catecholamine Reuptake Inhibitors Many inhibitors of the amine transporters for norepinephrine, dopamine, and serotonin are used clinically. Although specificity is not absolute, some are highly selective for one of the transporters. Many antidepressants, particularly the older tricyclic antidepressants, can inhibit norepinephrine and serotonin reuptake to different degrees. Some antidepressants of this class, particularly imipramine, can induce orthostatic hypotension presumably by their clonidine-like effect or by blocking α1 receptors, but the mechanism remains unclear.

156    SECTION II  Autonomic Drugs

Atomoxetine is a selective inhibitor of the norepinephrine reuptake transporter. Its actions, therefore, are mediated by potentiation of norepinephrine levels in noradrenergic synapses. It is used in the treatment of attention deficit disorders (see below). Reboxetine (investigational in the USA) has similar characteristics to atomoxetine but is used mainly for major depression disorder. Because reuptake inhibitors potentiate norepinephrine actions, there is concern about their cardiovascular safety. Norepinephrine reuptake is particularly important in the heart, especially during sympathetic stimulation, and this explains why atomoxetine and other norepinephrine reuptake inhibitors can cause orthostatic tachycardia. In general, however, atomoxetine produces few cardiovascular effects. This may be explained because atomoxetine has a clonidine-like effect in the CNS to decrease sympathetic outflow that may counteract the potentiating effects of norepinephrine in the periphery. In rare patients with autonomic failure due to impairment in CNS regulatory centers, the sympatholytic effects of atomoxetine are lost and blood pressure is increased by its peripheral effects. Pharmacoepidemiologic studies have not found significant adverse cardiovascular events associated with the use of norepinephrine reuptake inhibitors and other medications used to treat attention deficit hyperactivity disorders in children and young adults. However, in patients with a history of cardiovascular disease the use of sibutramine, a serotonin and norepinephrine reuptake inhibitor, was associated with a small increase in cardiovascular events, including strokes. For this reason, it was taken off the market as an appetite suppressant. It is not clear if this concern applies to other serotonin and norepinephrine reuptake inhibitors widely used as antidepressants (venlafaxine, desvenlafaxine, and duloxetine; see Chapter 30), and no increase in cardiovascular risk has been reported with duloxetine. Milnacipran, another serotonin and norepinephrine transporter blocker, is approved for the treatment of pain in fibromyalgia (see Chapter 30). Cocaine is a local anesthetic with a peripheral sympathomimetic action that results from inhibition of transmitter reuptake at noradrenergic synapses (see Figure 9–3). It readily enters the CNS and produces an amphetamine-like psychological effect that is shorter lasting and more intense than amphetamine. The major action of cocaine in the CNS is to inhibit dopamine reuptake into neurons in the “pleasure centers” of the brain. These properties and the fact that a rapid onset of action can be obtained when smoked, snorted, or injected have made cocaine a heavily abused drug (see Chapter 32). It is interesting that dopamine-transporter knockout mice still self-administer cocaine, suggesting that cocaine may have additional pharmacologic targets.

Dopamine Agonists Levodopa, which is converted to dopamine in the body, and dopamine agonists with central actions are of considerable value in the treatment of Parkinson disease and prolactinemia. These agents are discussed in Chapters 28 and 37. Fenoldopam is a D1-receptor agonist that selectively leads to peripheral vasodilation in some vascular beds. The primary indication for fenoldopam is in the intravenous treatment of severe hypertension (see Chapter 11).

THERAPEUTIC USES OF SYMPATHOMIMETIC DRUGS Cardiovascular Applications In keeping with the critical role of the sympathetic nervous system in the control of blood pressure, a major area of application of the sympathomimetics is in cardiovascular conditions. A.  Treatment of Acute Hypotension Acute hypotension may occur in a variety of settings such as severe hemorrhage, decreased blood volume, cardiac arrhythmias, neurologic disease, adverse reactions or overdose of medications such as antihypertensive drugs, and infections. If cerebral, renal, and cardiac perfusion is maintained, hypotension itself does not usually require vigorous direct treatment. Rather, placing the patient in the recumbent position and ensuring adequate fluid volume while the primary problem is determined and treated is usually the correct course of action. The use of sympathomimetic drugs merely to elevate a blood pressure that is not an immediate threat to the patient may increase morbidity. However, sympathomimetics may be required in cases of sustained hypotension with evidence of tissue hypoperfusion. Shock is a complex acute cardiovascular syndrome that results in a critical reduction in perfusion of vital tissues and a wide range of systemic effects. Shock is usually associated with hypotension, an altered mental state, oliguria, and metabolic acidosis. If untreated, shock usually progresses to a refractory deteriorating state and death. The three major forms of shock are septic, cardiogenic, and hypovolemic. Volume replacement and treatment of the underlying disease are the mainstays of the treatment of shock. If vasopressors are needed, adrenergic agonists with both α and β activity are preferred. Pure β-adrenergic stimulation increases blood flow but also increases the risk of myocardial ischemia. Pure α-adrenergic stimulation increases vascular tone and blood pressure but can also decrease cardiac output and impair tissue blood flow. Norepinephrine provides an acceptable balance and is considered the vasopressor of first choice: it has predominantly α-adrenergic properties, but its modest β-adrenergic effects help to maintain cardiac output. Administration generally results in a clinically significant increase in mean arterial pressure, with little change in heart rate or cardiac output. Dopamine has no advantage over norepinephrine because it is associated with a higher incidence of arrhythmias and mortality. However, dobutamine is arguably the inotropic agent of choice when increased cardiac output is needed. B.  Chronic Orthostatic Hypotension On standing, gravitational forces induce venous pooling, resulting in decreased venous return. Normally, a decrease in blood pressure is prevented by reflex sympathetic activation with increased heart rate, and peripheral arterial and venous vasoconstriction. Impairment of autonomic reflexes that regulate blood pressure can lead to chronic orthostatic hypotension. This is more often due to medications that can interfere with autonomic function (e.g., α blockers for the treatment of urinary retention), diabetes and

CHAPTER 9  Adrenoceptor Agonists & Sympathomimetic Drugs     157

other diseases causing peripheral autonomic neuropathies, and less commonly, primary degenerative disorders of the autonomic nervous system, as in the case study described at the beginning of the chapter. Increasing peripheral resistance is one of the strategies to treat chronic orthostatic hypotension, and drugs activating α receptors can be used for this purpose. Midodrine, an orally active α1 agonist, is frequently used for this indication. Other sympathomimetics, such as oral ephedrine or phenylephrine, can be tried. A more recent approach to treat orthostatic hypotension is droxidopa, a synthetic (L-threo-dihydroxyphenylserine, L-DOPS) molecule that is converted to norepinephrine by the aromatic L-amino acid decarboxylase (dopa-decarboxylase), the same enzyme that converts L-dopa to dopamine in the treatment of Parkinson disease, and is now approved for the treatment of orthostatic hypotension. C.  Cardiac Applications Epinephrine is used during resuscitation from cardiac arrest. Current evidence indicates that it improves the chance of returning to spontaneous circulation, but it is less clear that it improves survival or long-term neurologic outcomes. Dobutamine is used as a pharmacologic cardiac stress test. Dobutamine augments myocardial contractility and promotes coronary and systemic vasodilation. These actions lead to increased heart rate and increased myocardial work and can reveal areas of ischemia in the myocardium that are detected by echocardiogram or nuclear medicine techniques. Dobutamine can thus be used in patients unable to perform an exercise stress test. D.  Inducing Local Vasoconstriction Reduction of local or regional blood flow is desirable for achieving hemostasis during surgery, for reducing diffusion of local anesthetics away from the site of administration, and for reducing mucous membrane congestion. In each instance, α-receptor activation is desired, and the choice of agent depends on the maximal efficacy required, the desired duration of action, and the route of administration. Effective pharmacologic hemostasis is often necessary for facial, oral, and nasopharyngeal surgery. Epinephrine is usually applied topically in nasal packs (for epistaxis) or in a gingival string (for gingivectomy). Cocaine is still sometimes used for nasopharyngeal surgery because it combines a hemostatic effect with local anesthesia. Combining α agonists with some local anesthetics greatly prolongs their duration of action; the total dose of local anesthetic (and the probability of systemic toxicity) can therefore be reduced. Epinephrine, 1:100,000 or 1:200,000, is the favored agent for this application. Systemic effects on the heart and peripheral vasculature may occur even with local drug administration but are usually minimal. Use of epinephrine with local anesthesia of acral vascular beds (digits, nose, and ears) has not been advised because of fear of ischemic necrosis. Recent studies suggest that it can be used (with caution) for this indication. Alpha agonists can be used topically as mucous membrane decongestants to reduce the discomfort of allergic rhinitis or the common cold. These effects are mediated by activation of

α receptors in the vasculature reducing blood flow in the nasal mucosa, thus reducing its volume. Phenylephrine and the longer-acting oxymetazoline are used in over-the-counter nasal decongestants. Unfortunately, rebound hyperemia (“rhinitis medicamentosa”) may follow the use of these agents, and repeated topical use of high drug concentrations may result in ischemic changes in the mucous membranes, probably as a result of vasoconstriction of nutrient arteries. Oral administration of agents such as ephedrine and pseudoephedrine can provide a longer duration of action but at the cost of greater potential for cardiac and CNS effects.

Pulmonary Applications One of the most important uses of sympathomimetic drugs is in the therapy of asthma and chronic obstructive pulmonary disease (COPD; discussed in more detail in Chapter 20). Beta2-selective drugs (albuterol, metaproterenol, terbutaline) are used for this purpose to reduce the adverse effects that would be associated with β1 stimulation. Short-acting preparations can be used only transiently for acute treatment of asthma symptoms. For chronic asthma treatment in adults, long-acting β2 agonists should be used only in combination with steroids because their use in monotherapy has been associated with increased mortality. Long-acting β2 agonists are also used in patients with COPD. Indacaterol, olodaterol, and vilanterol are newer ultralong β2 agonists that are used with once-a-day dosing in the treatment of COPD. Nonselective drugs are now rarely used because they are likely to have more adverse effects than the selective drugs.

Anaphylaxis Anaphylactic shock and related immediate (type I) IgE-mediated reactions affect both the respiratory and the cardiovascular systems. The syndrome of bronchospasm, mucous membrane congestion, angioedema, and severe hypotension usually responds rapidly to the parenteral administration of epinephrine, 0.3–0.5 mg (0.3–0.5 mL of a 1:1000 epinephrine solution). Intramuscular injection may be the preferred route of administration, since skin blood flow (and hence systemic drug absorption from subcutaneous injection) is unpredictable in hypotensive patients. In some patients with impaired cardiovascular function, intravenous injection of epinephrine may be required. The use of epinephrine for anaphylaxis precedes the era of controlled clinical trials, but extensive experimental and clinical experience supports its use as the agent of choice. Epinephrine activates α, β1, and β2 receptors, all of which may be important in reversing the pathophysiologic processes underlying anaphylaxis. It is recommended that patients at risk for anaphylaxis carry epinephrine in an autoinjector (EpiPen, Auvi-Q) for self-administration.

Ophthalmic Applications Phenylephrine is an effective mydriatic agent frequently used to facilitate examination of the retina. It is also a useful decongestant for minor allergic hyperemia and itching of the conjunctival membranes. Sympathomimetics administered as ophthalmic drops are

158    SECTION II  Autonomic Drugs

also useful in localizing the lesion in Horner syndrome. (See Box: An Application of Basic Pharmacology to a Clinical Problem.) Glaucoma responds to a variety of sympathomimetic and sympathoplegic drugs. (See Box: The Treatment of Glaucoma, in Chapter 10.) Both α2-selective agonists (apraclonidine and brimonidine) and β-blocking agents (timolol and others) are common topical therapies for glaucoma.

Genitourinary Applications As noted above, β2-selective agents (eg, terbutaline) relax the pregnant uterus. In the past, these agents were used to suppress premature labor. However, meta-analysis of older trials and a randomized study suggest that β-agonist therapy has no significant benefit on perinatal infant mortality and may increase maternal morbidity.

Central Nervous System Applications The amphetamines have a mood-elevating (euphoriant) effect; this effect is the basis for the widespread abuse of this drug group (see Chapter 32). The amphetamines also have an alerting, sleepdeferring action that is manifested by improved attention to repetitive tasks and by acceleration and desynchronization of the electroencephalogram. A therapeutic application of this effect is in the treatment of narcolepsy. Modafinil and armodafinil, newer amphetamine substitutes, are approved for use in narcolepsy and are claimed to have fewer disadvantages (excessive mood changes, insomnia, and abuse potential) than amphetamine in this condition. Amphetamines have appetite-suppressing effects, but there is no evidence that long-term improvement in weight control can be achieved with amphetamines alone, especially when administered for a relatively short course. A final application of the CNSactive sympathomimetics is in the attention deficit hyperactivity

disorder (ADHD), a behavioral syndrome consisting of short attention span, hyperkinetic physical behavior, and learning problems. Some patients with this syndrome respond well to low doses of methylphenidate and related agents. Extended-release formulations of methylphenidate may simplify dosing regimens and increase adherence to therapy, especially in school-age children. Slow or continuous-release preparations of the α2 agonists clonidine and guanfacine also are effective in children with ADHD. The norepinephrine reuptake inhibitor atomoxetine is also used in ADHD. Clinical trials suggest that modafinil may also be useful in ADHD, but because the safety profile in children has not been defined, it has not gained approval by the FDA for this indication.

Additional Therapeutic Uses Although the primary use of the α2 agonist clonidine is in the treatment of hypertension (see Chapter 11), the drug has been found to have efficacy in the treatment of diarrhea in diabetics with autonomic neuropathy, perhaps because of its ability to enhance salt and water absorption from the intestine. In addition, clonidine has efficacy in diminishing craving for narcotics and alcohol during withdrawal and may facilitate cessation of cigarette smoking. Clonidine has also been used to diminish menopausal hot flushes. Dexmedetomidine is an α2 agonist used for sedation under intensive care circumstances and during anesthesia (see Chapter 25). It blunts the sympathetic response to surgery, which may be beneficial in some situations. It lowers opioid requirements for pain control and does not depress ventilation. Clonidine is also sometimes used as a premedication before anesthesia. Tizanidine is an α2 agonist closely related to clonidine that is used as a “central muscle relaxant” (see Chapter 27), but many physicians are not aware of its cardiovascular actions, which may lead to unanticipated adverse effects such as orthostatic hypotension followed by rebound hypertension.

An Application of Basic Pharmacology to a Clinical Problem Horner syndrome is a condition—usually unilateral—that results from interruption of the sympathetic nerves to the face. This translates clinically with vasodilation, ptosis, miosis, and loss of sweating on the affected side. The syndrome can be caused by either a preganglionic or a postganglionic lesion, and knowledge of the location of the lesion (preganglionic or postganglionic) helps determine the optimal therapy. A localized lesion in a nerve causes degeneration of the distal portion of that fiber and loss of transmitter contents from the degenerated nerve ending—without affecting neurons innervated by the fiber. Therefore, a preganglionic lesion leaves the postganglionic adrenergic neuron intact, whereas a postganglionic lesion results in degeneration of the adrenergic nerve endings and loss of stored catecholamines from them. Because

indirectly acting sympathomimetics require normal stores of catecholamines, such drugs can be used to test for the presence of normal adrenergic nerve endings. The iris, because it is easily visible and responsive to topical sympathomimetics, is a convenient assay tissue in the patient. If the lesion of Horner syndrome is postganglionic, indirectly acting sympathomimetics (e.g., cocaine, hydroxyamphetamine) will not dilate the abnormally constricted pupil because catecholamines have been lost from the nerve endings in the iris. In contrast, the pupil dilates in response to phenylephrine, which acts directly on the α receptors on the smooth muscle of the iris. A patient with a preganglionic lesion, on the other hand, shows a normal response to both drugs, since the postganglionic fibers and their catecholamine stores remain intact in this situation.

CHAPTER 9  Adrenoceptor Agonists & Sympathomimetic Drugs     159

SUMMARY  Sympathomimetic Drugs Subclass, Drug

Mechanism of Action

Effects

Clinical Applications

Pharmacokinetics, Toxicities, Interactions

`1 AGONISTS   •  Midodrine

 

 

 

 

Activates phospholipase C, resulting in increased intracellular calcium and vasoconstriction

Vascular smooth muscle contraction increasing blood pressure (BP)

Orthostatic hypotension

Oral • prodrug converted to active drug with a 1-h peak effect • Toxicity: Supine hypertension, piloerection (goose bumps), and urinary retention

  •  Phenylephrine: Can be used IV for short-term maintenance of BP in acute hypotension and intranasally to produce local vasoconstriction as a decongestant `2 AGONISTS

 

 

 

 

  •  Clonidine

Inhibits adenylyl cyclase and interacts with other intracellular pathways

Vasoconstriction is masked by central sympatholytic effect, which lowers BP

Hypertension

Oral • transdermal • peak effect 1–3 h • t1/2 of oral drug ~12 h • produces dry mouth and sedation

       

•  α-Methyldopa, guanfacine, and guanabenz: Also used as central sympatholytics •  Dexmedetomidine: Prominent sedative effects and used in anesthesia •  Tizanidine: Used as a muscle relaxant •  Apraclonidine and brimonidine: Used topically in glaucoma to reduce intraocular pressure

a1 AGONISTS

 

 

 

 

  •  Dobutamine1

Activates adenylyl cyclase, increasing myocardial contractility

Positive inotropic effect

Cardiogenic shock, acute heart failure

IV • requires dose titration to desired effect

A2 AGONISTS

 

 

 

 

  •  Albuterol

Activates adenylyl cyclase

Bronchial smooth muscle dilation

Asthma

Inhalation • duration 4–6 h • Toxicity: Tremor, tachycardia

  •  See other β2 agonists in Chapter 20 A3 AGONISTS

 

 

 

 

  •  Mirabegron

Activates adenylyl cyclase

Reduces bladder tone

Urinary urgency

Oral • duration 50 h • Toxicity: Possible hypertension

DOPAMINE AGONISTS D1 AGONISTS  

 

 

 

  •  Fenoldopam

Activates adenylyl cyclase

Vascular smooth muscle relaxation

Hypertensive emergency

Requires dose titration to desired effect

D2 AGONISTS

  Inhibits adenylyl cyclase and interacts with other intracellular pathways

  Mimics dopamine actions in the CNS

  Parkinson disease, prolactinemia

  Oral • Toxicity: Nausea, headache, orthostatic hypotension

  •  Bromocriptine

  •  See other D2 agonists in Chapters 28 and 37 1

Dobutamine has other actions in addition to β1-agonist effect. See text for details.

160    SECTION II  Autonomic Drugs

P R E P A R A T I O N S GENERIC NAME Amphetamine, racemic mixture 1:1:1:1 mixtures of amphetamine sulfate, amphetamine aspartate, dextroamphetamine sulfate, and dextroamphetamine saccharate Apraclonidine Armodafinil Brimonidine Dexmedetomidine Dexmethylphenidate Dextroamphetamine Dobutamine Dopamine Droxidopa Ephedrine Epinephrine

Fenoldopam

A V A I L A B L E*

AVAILABLE AS Generic Adderall

Iopidine Nuvigil Alphagan Precedex Focalin Generic, Dexedrine Generic, Dobutrex Generic, Intropin Northera Generic Generic, Adrenalin Chloride, Primatene Mist, Bronkaid Mist, EpiPen, Auvi-Q Corlopam

GENERIC NAME Hydroxyamphetamine Isoproterenol Metaraminol Methamphetamine Methylphenidate Midodrine Mirabegron Modafinil Naphazoline Norepinephrine Olodaterol Oxymetazoline Phenylephrine Pseudoephedrine Tetrahydrozoline Tizanidine Xylometazoline

AVAILABLE AS Paremyd (includes 0.25% tropicamide) Generic, Isuprel Aramine Desoxyn Generic, Ritalin, Ritalin-SR ProAmatine Myrbetriq Provigil Generic, Privine Generic, Levophed Striverdi Respimat Generic, Afrin, Neo-Synephrine 12 Hour, Visine LR Generic, Neo-Synephrine Generic, Sudafed Generic, Visine Zanaflex Generic, Otrivin

*

α2 Agonists used in hypertension are listed in Chapter 11. β2 Agonists used in asthma are listed in Chapter 20. Norepinephrine transporter inhibitors are listed in Chapter 30.

REFERENCES Cooper WO et al: ADHD drugs and serious cardiovascular events in children and young adults. N Engl J Med 2011;265:1896. Cotecchia S: The α1-adrenergic receptors: Diversity of signaling networks and regulation. J Recept Signal Transduct Res 2010;30:410. Guvercih VV, Guverich EV: GPCR signaling regulation: the role of GRKs and arrestins. Front Pharmacol 2019;10:125. Gurevich VV, Gurevich EV: Biased GPCR signaling: possible mechanisms and inherent limitations. Pharmacol Ther 2020;211:107540. Hikino K et al: A meta-analysis of the influence of ADRB2 genetic polymorphisms on albuterol (salbutamol) therapy in patients with asthma. Br J Clin Pharmacol 2021;87:1708. Hollenberg SM: Vasoactive drugs in circulatory shock. Am J Respir Crit Care Med 2011;183:847. Johnson JA, Liggett SB: Cardiovascular pharmacogenomics of adrenergic receptor signaling: clinical implications and future directions. Clin Pharmacol Ther 2011;89:366.

Johnson M: Molecular mechanisms of β2-adrenergic receptor function, response, and regulation. J Allergy Clin Immunol 2006;117:18. Minzenberg MJ, Carter CS: Modafinil: A review of neurochemical actions and effects on cognition. Neuropsychopharmacology 2008;33:1477. Sandilands AJ, O’Shaughnessy KM: The functional significance of genetic variation within the beta-adrenoceptor. Br J Clin Pharmacol 2005;60:235. Schena G, Caplan MJ: Everything you always wanted to know about β3-AR * (*but were afraid to ask). Cells 2019;8:357. Seyedabadi M et al: Receptor-arrestin interactions: the GPCR perspective. Biomolecules. 2021;11:218. Simons FE: Anaphylaxis. J Allergy Clin Immunol 2008;121:S402. Soar J. Epinephrine for cardiac arrest: knowns, unknowns and controversies. Curr Opin Crit Care. 2020;26:590. Vincent J-L, De Backer D: Circulatory shock. N Engl J Med 2013;369:1726. Wisler JW et al: Biased G protein-coupled receptor signaling. Changing the paradigm of drug discovery. Circulation 2018;137:2315.

C ASE STUDY ANSWER The clinical picture is that of autonomic failure. The best indicator of this is the profound drop in orthostatic blood pressure without an adequate compensatory increase in heart rate. Pure autonomic failure is a neurodegenerative disorder selectively affecting peripheral autonomic fibers. Patients’ blood pressure is critically dependent on whatever residual sympathetic tone they have, hence the symptomatic worsening of orthostatic hypotension that occurred when this

patient was given the α1A blocker tamsulosin. Conversely, these patients are hypersensitive to the pressor effects of α agonists and other sympathomimetics. For example, the α agonist midodrine can increase blood pressure significantly at doses that have no effect in normal subjects and can be used to treat their orthostatic hypotension. Caution should be observed in the use of sympathomimetics (including overthe-counter agents) and sympatholytic drugs.

10 C

Adrenoceptor Antagonist Drugs

H

A

P

T

E

R

Italo Biaggioni, MD*

C ASE STUDY A 38-year-old man has been experiencing palpitations and headaches. He enjoyed good health until 1 year ago when spells of rapid heartbeat began. These became more severe and were eventually accompanied by throbbing headaches and drenching sweats. Physical examination revealed a blood pressure of 150/90 mm Hg and heart rate of 88 bpm. During the physical examination, palpation of the abdomen

Catecholamines play a role in many physiologic and pathophysiologic responses, as described in Chapter 9. Drugs that block their receptors, therefore, have important effects, some of which are of great clinical value. These effects vary dramatically according to the drug’s selectivity for α and β receptors. The classification of α and β adrenoceptors subtypes and the effects of activating these receptors are discussed in Chapters 6 and 9. Blockade of peripheral dopamine receptors is of limited clinical importance at present. In contrast, modulation of central nervous system (CNS) dopamine receptors is very important, as discussed in Chapters 21, 28, and 29. This chapter deals with pharmacologic antagonist drugs whose major effect is to occupy α or β receptors and prevent their activation by catecholamines and related agonists. Nonselective α antagonists are used in the treatment of pheochromocytoma (tumors that secrete catecholamines), and α1-selective antagonists are used in primary hypertension and benign prostatic hyperplasia. Beta-receptor antagonist drugs are useful in a much wider variety of clinical conditions and are firmly established in the treatment of hypertension, ischemic heart disease, arrhythmias, endocrinologic and neurologic disorders, glaucoma, and other conditions. *

The author thanks David Robertson, MD, for his contributions to previous versions of this chapter.

elicited a sudden and typical episode, with a rise in blood pressure to 210/120 mm Hg, heart rate to 122 bpm, profuse sweating, and facial pallor. This was accompanied by severe headache. What is the likely cause of his episodes? What caused the blood pressure and heart rate to rise so high during the examination? What treatments might help this patient?

■■ BASIC PHARMACOLOGY OF THE ALPHA-RECEPTOR ANTAGONIST DRUGS Mechanism of Action Alpha-receptor antagonists may be reversible or irreversible in their interaction with these receptors. Reversible antagonists dissociate from receptors, and the block can be overcome with sufficiently high concentrations of agonists; irreversible drugs do not dissociate and cannot be surmounted. Phentolamine and prazosin (Figure 10–1) are examples of reversible antagonists. Phenoxybenzamine forms a reactive ethyleneimonium intermediate (see Figure 10–1) that covalently binds to α receptors, resulting in irreversible blockade. Figure 10–2 illustrates the effects of a reversible drug in comparison with those of an irreversible agent. As discussed in Chapters 1 and 2, the duration of action of a reversible antagonist is largely dependent on the half-life of the drug in the body and the rate at which it dissociates from its receptor: The shorter the half-life, the less time it takes for the effects of the drug to dissipate. In contrast, the effects of an irreversible antagonist may persist long after the drug has been cleared from the plasma. 161

162    SECTION II  Autonomic Drugs

HO CH3 N N

CH2

O

CH2

CH

C

CH2

R1

CI

N N H

H 3C

CH2

N R2

CH2

Phentolamine

CH2

Phenoxybenzamine

+

+CI–

CH2

Active (ethyleneimonium) intermediate O

N N

CH3O

N

C O

N

CH3O NH2

Prazosin O

CH2

CH2

O

CH2

CH3

NH

CH

SO2NH2

CH2

CH3

O

CH3

Tamsulosin

FIGURE 10–1 

Structure of several α-receptor–blocking drugs.

Competitive antagonist

Irreversible antagonist 100

Control 50 10 µmol/L

Percent of maximum tension

Percent of maximum tension

100

Control 50

0.4 µmol/L 0.8 µmol/L

20 µmol/L 0

2.4

20

160

Norepinephrine (µmol/L)

0

1.2

10

80

Norepinephrine (µmol/L)

FIGURE 10–2  Dose-response curves to norepinephrine in the presence of two different α-adrenoceptor–blocking drugs. The tension produced in isolated strips of cat spleen, a tissue rich in α receptors, was measured in response to graded doses of norepinephrine. Left: Tolazoline, a reversible blocker, shifted the curve to the right without decreasing the maximum response when present at concentrations of 10 and 20 μmol/L. Right: Dibenamine, an analog of phenoxybenzamine and irreversible in its action, reduced the maximum response attainable at both concentrations tested. (Reproduced with permission from Bickerton RK: The response of isolated strips of cat spleen to sympathomimetic drugs and their antagonists. J Pharmacol Exp Ther 1963;142:99-110.)

CHAPTER 10  Adrenoceptor Antagonist Drugs     163

In the case of phenoxybenzamine, the restoration of tissue responsiveness after extensive α-receptor blockade is dependent on synthesis of new receptors, which may take several days. The rate of return of α1-adrenoceptor responsiveness may be particularly important in patients who have a sudden cardiovascular event or who become candidates for urgent surgery.

for gravitational pooling of blood in the lower body. Thus, α adrenoceptor antagonists can cause orthostatic hypotension by blocking sympathetically-mediated peripheral arterial vasoconstriction and splanchnic capacitance venoconstriction. Because β receptors are unopposed, this is associated with a compensatory baroreflex-mediated tachycardia.

Pharmacologic Effects

B.  Other Effects Blockade of α receptors in noncardiac tissues elicits miosis (small pupils) and nasal stuffiness. Alpha1 receptors are expressed in the base of the bladder and the prostate, and their blockade decreases resistance to the flow of urine. Alpha blockers, therefore, are used therapeutically for the treatment of urinary retention due to prostatic hyperplasia (see below).

A.  Cardiovascular Effects Because arteriolar and venous tone are determined to a large extent by α receptors on vascular smooth muscle, α-receptor antagonist drugs cause a lowering of peripheral vascular resistance and blood pressure (Figure 10–3). These drugs can prevent the pressor effects of usual doses of α agonists; indeed, in the case of agonists with both α and β2 effects (eg, epinephrine), selective α-receptor antagonism may convert a pressor to a depressor response (see Figure 10–3); it illustrates how the activation of both α and β receptors in the vasculature may lead to opposite responses, and that blockade of α adrenoceptors unmasks the effects of epinephrine on β receptors. Alpha-receptor antagonists (Table 10–1) block sympathetic-mediated vasoconstriction, causing a decrease in blood pressure. The fall in blood pressure is greater in situations when blood pressure depends on increased sympathetic activity. This may occur, for example, on standing when blood pressure is maintained by sympathetic activation to compensate

BP

135/85

HR

160

SPECIFIC AGENTS Phenoxybenzamine binds covalently to α receptors, causing irreversible blockade of long duration (14–48 hours or longer). It is somewhat selective for α1 receptors but less so than prazosin (see Table 10–1). The drug also inhibits reuptake of released norepinephrine by presynaptic adrenergic nerve terminals. Phenoxybenzamine also blocks histamine (H1), acetylcholine, and serotonin receptors (see Chapter 16), but the pharmacologic actions of phenoxybenzamine are primarily related to antagonism of α-receptor–mediated events.

128/50

200 Phentolamine 190/124 BP

HR

160/82

175/110

135/90

210

180

Epinephrine before phentolamine

BP

HR

125/85

100/35

190 210 Epinephrine after phentolamine

FIGURE 10–3  Top: Effects of phentolamine, an α-receptor–blocking drug, on blood pressure in an anesthetized dog. Epinephrine reversal is demonstrated by tracings showing the response to epinephrine before (middle) and after (bottom) phentolamine. All drugs given intravenously. BP, blood pressure; HR, heart rate.

164    SECTION II  Autonomic Drugs

TABLE 10–1  Relative selectivity of antagonists for adrenoceptors.

Drugs

Receptor Affinity

Alpha antagonists

 

  Prazosin, terazosin, doxazosin

α1 >>>> α2

 Phenoxybenzamine

α1 > α2

 Phentolamine

α1 = α2

  Yohimbine, tolazoline

α2 >> α1

Mixed antagonists

 

  Labetalol, carvedilol

β1 = β2 ≥ α1 > α2

Beta antagonists

 

 Metoprolol, acebutolol, alprenolol, atenolol, betaxolol, celiprolol, esmolol, nebivolol

β1 >>> β2

 Propranolol, carteolol, nadolol, penbutolol, pindolol, timolol

β1 = β2

 Butoxamine

β2 >>> β1

The most significant effect is attenuation of catecholamine-induced vasoconstriction. While phenoxybenzamine causes relatively little fall in blood pressure in normal individuals in the supine position (when sympathetic tone is low), it reduces blood pressure when sympathetic tone is high, eg, as a result of upright posture or because of reduced blood volume. Phenoxybenzamine is absorbed after oral administration, although bioavailability is low; its other pharmacokinetic properties are not well known. Phenoxybenzamine is almost exclusively used in the treatment of pheochromocytoma (see below). Most adverse effects of phenoxybenzamine derive from its α-receptor– blocking action; the most important are orthostatic hypotension and tachycardia. Nasal stuffiness and inhibition of ejaculation also occur. Since phenoxybenzamine enters the CNS, it may cause fatigue, sedation, and nausea. Phentolamine is a potent competitive antagonist at both α1 and α2 receptors (see Table 10–1). Phentolamine reduces peripheral resistance through blockade of α1 receptors and possibly α2 receptors on vascular smooth muscle. Its cardiac stimulation is due to antagonism of presynaptic α2 receptors (leading to enhanced release of norepinephrine from sympathetic nerves) and sympathetic activation from baroreflex mechanisms. Phentolamine also has minor inhibitory effects at serotonin receptors and agonist effects at muscarinic and H1 and H2 histamine receptors. Phentolamine’s principal adverse effects are related to compensatory cardiac stimulation, which may cause severe tachycardia, arrhythmias, and myocardial ischemia. Phentolamine is only available for intravenous administration and is now rarely used for the treatment of pheochromocytoma and other hypertensive emergencies. Prazosin, terazosin, and doxazosin are highly selective for α1 receptors. These drugs dilate both arterial and venous vascular smooth muscle, as well as smooth muscle in the prostate, due to blockade of α1 receptors. They are used as second-line treatment for hypertension (see Chapter 11) and in men with urinary retention

symptoms due to benign prostatic hyperplasia (BPH). Prazosin is extensively metabolized in humans; because of metabolic degradation by the liver, only about 50% of the drug is available after oral administration. The half-life is approximately 3 hours. Terazosin has high bioavailability but is extensively metabolized in the liver, with only a small fraction of unchanged drug excreted in the urine. The half-life of terazosin is 9–12 hours. Doxazosin has a longer half-life of about 22 hours. It has moderate bioavailability and is extensively metabolized, with very little parent drug excreted in urine or feces. Tamsulosin is a competitive α1 antagonist with a structure quite different from that of most other α1-receptor blockers. It has high bioavailability and a half-life of 9–15 hours. It is metabolized extensively in the liver. Tamsulosin has higher affinity for α1A and α1D receptors than for the α1B subtype. This results in greater potency in inhibiting contraction in prostate smooth muscle, which is mediated by the α1A subtype versus vascular smooth muscle. Therefore, compared with other antagonists, tamsulosin has less effect on standing blood pressure in patients. Nevertheless, caution is appropriate in using any α antagonist in patients with diminished sympathetic nervous system function. Recent epidemiologic studies suggest an increased risk of orthostatic hypotension shortly after initiation of treatment. Patients on tamsulosin undergoing cataract surgery have a higher risk of the intraoperative floppy iris syndrome (IFIS), characterized by the billowing of a flaccid iris, propensity for iris prolapse, and progressive intraoperative pupillary constriction. These effects increase the risk of cataract surgery, and some recommend stopping tamsulosin for several weeks before cataract surgery, but the benefits of discontinuing the drug have not been proven.

OTHER ALPHA-ADRENOCEPTOR ANTAGONISTS Alfuzosin is an α1-selective quinazoline derivative that is approved for use in BPH. It has a bioavailability of about 60%, is extensively metabolized, and has an elimination half-life of about 5 hours. It may increase risk of QT prolongation in susceptible individuals. Silodosin resembles tamsulosin in blocking the α1A receptor and is also used in the treatment of BPH. Indoramin is another α1selective antagonist that also has efficacy as an antihypertensive. It is not available in the USA. Urapidil is an α1 antagonist (its primary effect) that also has weak α2-agonist and 5-HT1A-agonist actions and weak antagonist action at β1 receptors. It is used in Europe as an antihypertensive agent and for BPH. Labetalol and carvedilol have both α1-selective and β-antagonistic effects; they are discussed below. Neuroleptic drugs such as chlorpromazine and haloperidol are potent dopamine receptor antagonists but are also antagonists at α receptors. Similarly, the antidepressant trazodone has the capacity to block α1 receptors. This action probably contributes to some of their adverse effects, particularly orthostatic hypotension. Ergot derivatives, eg, ergotamine and dihydroergotamine, cause reversible α-receptor blockade, probably via a partial agonist action (see Chapter 16).

CHAPTER 10  Adrenoceptor Antagonist Drugs     165

Pheochromocytoma Pheochromocytoma is a tumor of the adrenal medulla or sympathetic ganglion cells. The tumor secretes catecholamines, especially norepinephrine and epinephrine. Patients with this tumor have many symptoms and signs of catecholamine excess, including intermittent or sustained hypertension, headaches, palpitations, and increased sweating. Release of stored catecholamines from pheochromocytomas may occur in response to physical pressure, chemical stimulation, or spontaneously. The patient in the case study at the beginning of this chapter had a left adrenal pheochromocytoma that was identified by imaging. In addition, he had elevated plasma and urinary norepinephrine, epinephrine, and their metabolites, normetanephrine and metanephrine. The diagnosis of pheochromocytoma is confirmed on the basis of elevated plasma or urinary levels of norepinephrine, epinephrine, metanephrine, and normetanephrine (see Chapter 6). Once diagnosed biochemically, techniques to localize a pheochromocytoma include computed tomography and magnetic resonance imaging scans and scanning with radiomarkers such as 131 I-meta-iodobenzylguanidine (MIBG), a norepinephrine transporter substrate that is taken up by tumor cells and is therefore a useful imaging agent to identify the site of pheochromocytoma. Alpha-receptor antagonists are most useful in the preoperative management of patients with pheochromocytoma (Figure 10–4). The major clinical use of phenoxybenzamine is in the management of pheochromocytoma. Its administration in the preoperative period helps to control hypertension and tends to reverse chronic changes resulting from excessive catecholamine secretion such as plasma volume contraction. Furthermore, it may prevent the blood pressure surges that can occur by manipulation of the tumor during surgery. Oral doses of 10 mg/d can be increased at intervals of several days until hypertension is controlled, for 1–3 weeks before surgery. A dosage of less than 100 mg/d is usually sufficient to achieve adequate α-receptor blockade, but doses up to 240 mg/d may be needed in some patients. Hypertension

Supine Standing

220 200 180 160 140 120 100 80 60 40 20 0

mg/d

■■ CLINICAL PHARMACOLOGY OF THE ALPHA-RECEPTOR– BLOCKING DRUGS

240

Blood pressure (mm Hg)

Yohimbine is an α2-selective antagonist. It is sometimes used in the treatment of orthostatic hypotension because it promotes norepinephrine release through blockade of α2 receptors in both the CNS (increasing central sympathetic activation) and the periphery (promoting norepinephrine release from noradrenergic fibers. Because it is its pharmacologic opposite, yohimbine reverses the antihypertensive effects of α2-adrenoceptor agonists such as clonidine. It is used in veterinary medicine to reverse anesthesia produced by xylazine, an α2 agonist. It was once widely used to treat male erectile dysfunction but has been superseded by phosphodiesterase-5 inhibitors like sildenafil (see Chapter 12), and was taken off the market in the USA solely for financial reasons. It is available as a “nutritional” supplement and through compounding pharmacies.

80 40 0

Dibenzyline

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Weeks

FIGURE 10–4  Effects of phenoxybenzamine (Dibenzyline) on blood pressure in a patient with pheochromocytoma. Dosage of the drug was begun in the fourth week as shown by the shaded bar. Supine systolic and diastolic pressures are indicated by the circles, and the standing pressures by triangles and the hatched area. Note that the α-blocking drug dramatically reduced blood pressure. The reduction in orthostatic hypotension, which was marked before treatment, is probably due to normalization of blood volume, a variable that is sometimes markedly reduced in patients with longstanding pheochromocytoma-induced hypertension. (From Annals of Internal Medicine, Engelman E, Sjoerdsma A: Chronic medical therapy for pheochromocytoma, 61(2):229. Copyright © 1964. All Rights Reserved. Reprinted with the permission of American College of Physicians, Inc.)

in patients with pheochromocytoma may also respond to reversible α1-selective antagonists or to conventional calcium channel antagonists. Observational studies suggest that controlling hypertension without phenoxybenzamine to avoid delaying surgery is an alternative approach that can be safely implemented. Beta antagonists should not be used prior to establishing effective α-receptor blockade, since unopposed β-receptor blockade could theoretically cause blood pressure elevation from increased vasoconstriction. Beta-receptor antagonists may be required after α-receptor blockade has been instituted to reverse the cardiac effects of excessive catecholamines. Phenoxybenzamine can be very useful in the chronic treatment of inoperable or metastatic pheochromocytoma. Pheochromocytoma is sometimes treated with metyrosine (α-methyltyrosine), the α-methyl analog of tyrosine. This agent is a competitive inhibitor of tyrosine hydroxylase, the rate-limiting step in the synthesis of dopamine, norepinephrine, and epinephrine (see Figure 6–5). Metyrosine is especially useful in symptomatic

166    SECTION II  Autonomic Drugs

patients with inoperable or metastatic pheochromocytoma. Because it has access to the CNS, metyrosine can cause extrapyramidal effects due to reduced dopamine levels.

Hypertensive Emergencies The α-adrenoceptor antagonist drugs have limited application in the management of hypertensive emergencies, but labetalol has been used in this setting (see Chapter 11). In theory, α-adrenoceptor antagonists are most useful when increased blood pressure reflects excess circulating concentrations of α agonists, eg, in pheochromocytoma, overdosage of sympathomimetic drugs, or clonidine withdrawal. However, other drugs are generally preferable because considerable experience is necessary to use α-adrenoceptor antagonist drugs safely in these settings.

Chronic Hypertension Members of the prazosin family of α1-selective antagonists are efficacious drugs in the treatment of mild to moderate systemic hypertension (see Chapter 11). They are generally well tolerated, but they are not usually recommended as first-line treatment or monotherapy for hypertension because other classes of antihypertensives are more effective in preventing heart failure and stroke. Their major adverse effect is orthostatic hypotension, which may be severe after the first few doses but is otherwise uncommon unless patients have impaired autonomic reflexes. Orthostatic changes in blood pressure should be checked routinely in any patient being treated for hypertension. Nonselective α antagonists are not used in primary hypertension.

Peripheral Vascular Disease Alpha-receptor–blocking drugs do not seem to be effective in the treatment of peripheral vascular occlusive disease characterized by morphologic changes that limit flow in the vessels. Occasionally, individuals with Raynaud phenomenon and other conditions involving excessive reversible vasospasm in the peripheral circulation do benefit from prazosin or phenoxybenzamine, although calcium channel blockers may be preferable for most patients.

Urinary Obstruction Benign prostatic hyperplasia is common in older men. Various surgical treatments are effective in relieving the urinary symptoms of BPH; however, drug therapy is efficacious in many patients. The mechanism of action in improving urine flow involves partial reversal of smooth muscle contraction in the enlarged prostate and in the bladder base. It has been suggested that some α1-receptor antagonists may have additional effects on cells in the prostate that help improve symptoms. Prazosin, doxazosin, and terazosin are all efficacious in patients with BPH. These drugs are particularly useful in patients who also have hypertension. Subtype-selective α1A-receptor antagonists like tamsulosin may have improved efficacy and safety in treating this disease because this is the receptor subtype most important for

smooth muscle contraction in the prostate. As indicated above, even though tamsulosin has less blood pressure–lowering effect, it should be used with caution in patients susceptible to orthostatic hypotension and should not be used in patients undergoing eye surgery. Selective α1 antagonists are also used in urolithiasis to induce ureteral dilation and facilitate the expulsion of kidney stones. It appears that this approach is less effective for smaller (5 mm or smaller) than for larger stones (>5 mm).

Applications of Alpha2 Antagonists Alpha2 antagonists have relatively little clinical usefulness. Prescription drugs with this mechanism are no longer available, but extracts from the bark of the yohimbine tree are sold as dietary and health supplements, allegedly to treat erectile dysfunction, even though their efficacy is questionable.

■■ BASIC PHARMACOLOGY OF THE BETA-RECEPTOR ANTAGONIST DRUGS Beta-receptor antagonists share the common feature of antagonizing the effects of catecholamines at β adrenoceptors. Most β-blocking drugs in clinical use are pure antagonists; that is, the occupancy of a β receptor by such a drug causes no activation of the receptor. However, some are partial agonists; that is, they cause partial activation of the receptor, albeit less than that caused by the full agonists epinephrine and isoproterenol. As described in Chapter 2, partial agonists inhibit the activation of β receptors in the presence of high catecholamine concentrations but moderately activate the receptors in the absence of endogenous agonists. Finally, evidence suggests that some β blockers (eg, betaxolol, metoprolol) are inverse agonists—drugs that stabilize the inactive conformation of β receptors, reducing the proportion of active receptors, but the clinical significance of this property is not known. Chemically, most β-receptor antagonist drugs (Figure 10–5) resemble isoproterenol to some degree (see Figure 9–4), even though they have opposite actions. The β-receptor–blocking drugs differ in their relative affinities for β1 and β2 receptors (see Table 10–1). Some have a higher affinity for β1 than for β2 receptors, and this selectivity may have important clinical implications. Since none of the clinically available β-receptor antagonists are absolutely specific for β1 receptors, the selectivity is dose-related; it tends to diminish at higher drug concentrations.

Pharmacokinetic Properties of the Beta-Receptor Antagonists A. Absorption Most of the drugs in this class are well absorbed after oral administration; peak concentrations occur 1–3 hours after ingestion.

CHAPTER 10  Adrenoceptor Antagonist Drugs     167

O

CH2

CH

CH2

NH

CH(CH3)2

O

CH2

OH

CH2

Propranolol

CH2

CH

CH2

NH

CH(CH3)2

OH

CH2

O

CH

CH2

O

CH3

Metoprolol

NH

CH(CH3)2

O O

OH

CH2

N

CH

CH2

NH

C(CH3)3

OH N

N S

N

Timolol

H

Pindolol HO

CH

CH2

NH

CH

CH2

O

CH2

CH2

CH

CH2

NH

CH(CH3)2

OH

CH3 O C

O

NH2 CH2

OH

C

NH2

Labetalol

Atenolol

OH O

CH

OH CH2

NH

CH2

F

O

CH F

Nebivolol

FIGURE 10–5 

Structures of some β-receptor antagonists.

Sustained-release preparations of propranolol and metoprolol are available.

β antagonists with the exception of betaxolol, penbutolol, pindolol, and sotalol.

B. Bioavailability Propranolol undergoes extensive hepatic (first-pass) metabolism; its bioavailability is relatively low (Table 10–2). The proportion of drug reaching the systemic circulation increases as the dose is increased, suggesting that hepatic extraction mechanisms may become saturated. A major consequence of the low bioavailability of propranolol is that oral administration of the drug leads to much lower drug concentrations than are achieved after intravenous injection of the same dose. Because the first-pass effect varies among individuals, there is great individual variability in the plasma concentrations achieved after oral propranolol. For the same reason, bioavailability is limited to varying degrees for most

C.  Distribution and Clearance The β antagonists are rapidly distributed and have large volumes of distribution. Propranolol and penbutolol are quite lipophilic and readily cross the blood-brain barrier (see Table 10–2). Most β antagonists have half-lives in the range of 3–10 hours. A major exception is esmolol, which is rapidly hydrolyzed and has a halflife of approximately 10 minutes. Propranolol and metoprolol are extensively metabolized in the liver, with little unchanged drug appearing in the urine. The CYP2D6 genotype is a major determinant of interindividual differences in metoprolol plasma clearance (see Chapters 4 and 5). Poor metabolizers exhibit threefold to tenfold higher plasma concentrations after administration of

168    SECTION II  Autonomic Drugs

TABLE 10–2  Properties of several beta-receptor–blocking drugs. Drugs

Selectivity

Partial Agonist Activity

Local Anesthetic Action

Lipid Solubility

Elimination Half-life

Approximate Bioavailability

Acebutolol

β1

Yes

Yes

Low

3–4 hours

50

Atenolol

β1

No

No

Low

6–9 hours

40

Betaxolol

β1

No

Slight

Low

14–22 hours

90

Bisoprolol

β1

No

No

Low

9–12 hours

80

Carteolol

None

Yes

No

Low

6 hours

85

1

Carvedilol

None

No

No

Moderate

7–10 hours

25–35

Celiprolol

β1

Yes

No

Low

4–5 hours

70

Esmolol

2

β1

No

No

Low

10 minutes

0

Labetalol

None

Yes

Yes

Low

5 hours

30

Metoprolol Tartrate

β1

No

Yes

Moderate

3–4 hours

Metoprolol Succinate

β1

No

Yes

Moderate

~20 hours

50–70

Nadolol

None

No

No

Low

14–24 hours

33

Nebivolol

β1

?

4

No

Low

11–30 hours

12–96

Penbutolol

None

Yes

No

High

5 hours

>90

Pindolol

None

Yes

Yes

Moderate

3–4 hours

90

Propranolol

None

No

Yes

High

3.5–6 hours

305

Sotalol

None

No

No

Low

12 hours

90

Timolol

None

No

No

Moderate

4–5 hours

50

1

50 3

1

Carvedilol and labetalol also cause α1-adrenoceptor blockade.

2

Not available in the USA.

3

Apparent half-life prolonged by extended-release preparation.

4

β3 agonist.

5

Bioavailability is dose-dependent.

metoprolol than extensive metabolizers. Atenolol, celiprolol, and pindolol are less completely metabolized. Nadolol is excreted unchanged in the urine and has the longest half-life of any available β antagonist (up to 24 hours). The half-life of nadolol is prolonged in renal failure. The elimination of drugs such as propranolol may be prolonged in the presence of liver disease, diminished hepatic blood flow, or hepatic enzyme inhibition. It is notable that the pharmacodynamic effects of these drugs are sometimes prolonged well beyond the time predicted from half-life data.

Pharmacodynamics of the Beta-Receptor Antagonist Drugs Most of the effects of these drugs are due to occupation and blockade of β receptors. However, some actions may be due to other effects, including partial agonist activity at β receptors and local anesthetic membrane stabilizing effects, which differ among the β blockers (see Table 10–2). A.  Effects on the Cardiovascular System Beta-blocking drugs given chronically lower blood pressure in patients with hypertension (see Chapter 11). The mechanisms involved are not fully understood but probably include suppression of renin release and effects in the CNS. These drugs do not usually cause hypotension in healthy individuals with normal blood pressure.

Beta-receptor antagonists have prominent effects on the heart (Figure 10–6). The negative inotropic and chronotropic effects reflect the role of adrenoceptors in regulating these functions. Slowed atrioventricular conduction with an increased PR interval is a related result of adrenoceptor blockade in the atrioventricular node. In the vascular system, β-receptor blockade opposes β2mediated vasodilation. This may acutely lead to a rise in peripheral resistance from unopposed α-receptor–mediated effects as the sympathetic nervous system discharges in response to lowered blood pressure due to the fall in cardiac output. Beta-receptor antagonists are very valuable in the treatment of angina (see Chapter 12), for chronic heart failure (see Chapter 13), and following myocardial infarction (see Chapter 14). The beneficial effects in these situations are related to blockade of the deleterious effects of catecholamines in the heart. Overall, although the acute effects of these drugs may include a rise in peripheral resistance, chronic drug administration leads to a fall in peripheral resistance in patients with hypertension. This effect may be related to inhibition of renin release. B.  Effects on the Respiratory Tract Blockade of the β2 receptors in bronchial smooth muscle may lead to an increase in airway resistance, particularly in patients with asthma. Beta1-receptor antagonists such as metoprolol and atenolol have an advantage over nonselective β antagonists when blockade

CHAPTER 10  Adrenoceptor Antagonist Drugs     169

Propranolol 0.5 mg/kg 1 mcg/kg Epinephrine

1 mcg/kg Epinephrine

Cardiac contractile force 200 Arterial pressure (mm Hg)

100

2

0 Heart rate (beats/min)

200

1 min

1 Aortic flow (L/min) 0

100

FIGURE 10–6  The effect in an anesthetized dog of the injection of epinephrine before and after propranolol. In the presence of a β-receptor–blocking agent, epinephrine no longer augments the force of contraction (measured by a strain gauge attached to the ventricular wall) nor increases cardiac rate. Blood pressure is still elevated by epinephrine because vasoconstriction is not blocked. (Reproduced with permission from Shanks RG. The pharmacology of beta sympathetic blockade. Am J Cardiol. 1966;18(3):308-316.)

of β1 receptors in the heart is desired and β2-receptor blockade is undesirable. However, no currently available β1-selective antagonist is sufficiently specific to completely avoid interactions with β2 adrenoceptors. Consequently, these drugs should generally be avoided in patients with asthma. However, some patients with chronic obstructive pulmonary disease (COPD) may tolerate β1selective blockers, and the benefits, for example in patients with concomitant ischemic heart disease, may outweigh the risks. C.  Effects on the Eye Beta-blocking agents reduce intraocular pressure, especially in glaucoma. The likely mechanism usually is decreased aqueous humor production. (See Clinical Pharmacology and Box: The Treatment of Glaucoma.) D.  Metabolic and Endocrine Effects Beta-receptor antagonists inhibit sympathetic nervous system stimulation of lipolysis. The effects on carbohydrate metabolism are less clear, although glycogenolysis in the human liver is at least partially inhibited after β2-receptor blockade. Use of β-receptor antagonists can be detrimental in response to hypoglycemia, a significant clinical concern in the treatment of patients with diabetes. In part, this is because patients on β-blockers are less able to recognize the warning symptoms of hypoglycemia which includes tachycardia. Glucagon is the primary hormone used to combat hypoglycemia; it is unclear to what extent β antagonists impair recovery from hypoglycemia, but they should be used with caution in insulin-dependent diabetic patients. This may be particularly important in diabetic patients with inadequate glucagon reserve and in pancreatectomized patients since catecholamines may be the major factors in stimulating glucose release from the liver in response to hypoglycemia. Beta1-receptor–selective drugs may be less prone to inhibit recovery from hypoglycemia. The chronic use of β-adrenoceptor antagonists has been associated with increased plasma concentrations of very-low-density

lipoproteins (VLDL) and decreased concentrations of HDL cholesterol. Both of these changes are potentially unfavorable in terms of risk of cardiovascular disease. Although low-density lipoprotein (LDL) concentrations generally do not change, there is a variable decline in the HDL cholesterol/LDL cholesterol ratio that may increase the risk of coronary artery disease. These changes tend to occur with both selective and nonselective β blockers, although they may be less likely to occur with β blockers possessing intrinsic sympathomimetic activity (partial agonists). Beta receptor antagonists also reduce resting energy expenditure, which can contribute to weight gain. In summary, β-receptor antagonists have negative metabolic effects that can discourage its use. However, newer β–blockers such as metoprolol, carvedilol, bisoprolol, and nebivolol are less likely to have negative metabolic effects. Furthermore, the beneficial effects of these drugs, when used in patients in whom they are indicated, such as heart failure, usually overweight these concerns. E.  Effects Not Related to Beta-Blockade Antagonists with partial b-agonist activity (pindolol and others noted in Table 10-2) may be desirable to prevent untoward effects such as precipitation of asthma or excessive bradycardia. However, these drugs may not be as effective as the pure antagonists in secondary prevention of myocardial infarction. Clinical trials of partial β-agonist drugs in hypertension have not confirmed increased benefit. Local anesthetic action, also known as “membrane-stabilizing” action, is a prominent effect of several β blockers (see Table 10–2). This action is the result of typical local anesthetic blockade of sodium channels (see Chapter 26) and can be demonstrated experimentally in isolated neurons, heart muscle, and skeletal muscle membrane. However, it is unlikely that this effect is important clinically, since the concentration in plasma usually achieved by these routes is too low for the anesthetic effects to be evident. Some β-receptor antagonists have a–blocking effects (carvedilol, labetalol), or promote nitric oxide production (nebivolol), as

170    SECTION II  Autonomic Drugs

discussed below. Sotalol is a nonselective β-receptor antagonist that lacks local anesthetic action but has marked class III antiarrhythmic effects, reflecting potassium channel blockade (see Chapter 14).

SPECIFIC AGENTS (SEE TABLE 10–2) Propranolol is the prototypical β-blocking drug. As noted above, it has low and dose-dependent bioavailability. A long-acting form of propranolol is available, with absorption of the drug occurring over a 24-hour period. The drug has negligible effects at α and muscarinic receptors; however, it may block some serotonin receptors in the brain, although the clinical significance is unclear. It has no detectable partial agonist action at β receptors.

Metoprolol, atenolol, and several other drugs (see Table 10–2) are members of the b1-selective group. These agents may be safer in patients who experience bronchoconstriction in response to propranolol. Since their β1 selectivity is rather modest, they should be used with great caution, if at all, in patients with a history of asthma. However, in selected patients with COPD, the benefits may exceed the risks, eg, in patients with myocardial infarction. Beta1-selective antagonists may be preferable in patients with diabetes or peripheral vascular disease when therapy with a β blocker is required, since β2 receptors are probably important in liver (recovery from hypoglycemia) and blood vessels (vasodilation). Celiprolol* is a β1-selective antagonist with a modest capacity to activate β2 receptors. There is limited evidence suggesting that celiprolol may have less adverse bronchoconstrictor effect in asthma and may even promote bronchodilation.

The Treatment of Glaucoma Glaucoma is a major cause of blindness. The primary manifestation is increased intraocular pressure, which initially can be asymptomatic. Without treatment, increased intraocular pressure results in damage to the retina and optic nerve, with restriction of visual fields and, eventually, blindness. Intraocular pressure is easily measured as part of the routine ophthalmologic examination. Two major types of glaucoma are recognized: open-angle and closed-angle (also called narrow-angle). The closed-angle form is associated with a shallow anterior chamber, in which a dilated iris can occlude the outflow drainage pathway at the angle between the cornea and the ciliary body (see Figure 6–9). This form is associated with acute and painful increases of pressure, which must be controlled on an emergency basis with drugs

or prevented by surgical removal of part of the iris (iridectomy). The open-angle form of glaucoma is a chronic condition, and treatment is largely pharmacologic. Because intraocular pressure is a function of the balance between fluid input and drainage out of the eye, topical medications work either by reducing aqueous humor secretion (α agonists, β blockers, carbonic anhydrase inhibitors) or by enhancing aqueous outflow (prostaglandin F2α analogs, cholinomimetics, rho kinase inhibitors), as shown in Table 10–3. Topical prostaglandins are currently considered the drugs of choice to initiate treatment because they are effective and have a low adverse effect profile. Beta blockers are still commonly used in combination therapy and in patients who cannot afford prostaglandins.

TABLE 10–3  Topical drugs used in open-angle glaucoma.

*

Drugs

Mechanism

Comments

Beta Blockers

 

 

 Timolol, betaxolol, carteolol, levobunolol, metipranolol

Decreased aqueous secretion from the ciliary epithelium

Use with caution in patients with bradycardia, heart block, heart failure, asthma, or obstructive airway disease

Alpha2 agonists

 

 

  Apraclonidine, brimonidine

Decreased aqueous secretion and increased outflow

May be associated with greater incidence of adverse effects

Cholinomimetics

 

 

  Pilocarpine, carbachol

Ciliary muscle contraction and opening trabecular meshwork leading to increased outflow

Higher incidence of topical adverse effects

Prostaglandins

 

 

  L atanoprost, bimatoprost, travoprost, unoprostone, tafluprost

Increased outflow

Advantage of once-daily dosing, few adverse effects

Carbonic anhydrase inhibitors*

 

 

  Dorzolamide, brinzolamide

Decreased aqueous secretion

Not as effective as other drugs

Rho kinase inhibitors

 

 

  Netarsudil

Increased outflow

Relatively new drug, less long-term experience

Oral preparations are also available (acetazolamide and methazolamide) but can produce systemic adverse effects.

CHAPTER 10  Adrenoceptor Antagonist Drugs     171

Esmolol is an ultra-short–acting b1-selective adrenoceptor antagonist. The structure of esmolol contains an ester linkage; esterases in red blood cells rapidly metabolize esmolol to a metabolite that has a low affinity for β receptors. Consequently, esmolol has a short half-life (about 10 minutes) and duration of action, so that steady-state concentrations are achieved quickly during continuous infusions of esmolol and the therapeutic actions of the drug are terminated rapidly when its infusion is discontinued. Esmolol may be safer to use than longer-acting antagonists in critically ill patients who require a β-adrenoceptor antagonist. Esmolol is useful in controlling supraventricular arrhythmias, arrhythmias associated with thyrotoxicosis, perioperative hypertension, and myocardial ischemia in acutely ill patients. Pindolol, acebutolol, penbutolol, carteolol, oxprenolol,* and celiprolol* are of interest because they have partial b-agonist activity. Although these partial agonists may be less likely to cause bradycardia and abnormalities in plasma lipids than pure antagonists, the overall clinical significance of intrinsic sympathomimetic activity remains uncertain. Pindolol also antagonizes 5-HT1A serotonin receptors, and may potentiate the action of traditional antidepressant medications. Acebutolol is also a β1-selective antagonist. Nebivolol is the most highly selective β1-adrenergic receptor blocker, although some of its metabolites do not have this level of specificity. Nebivolol has the additional quality of eliciting vasodilation by promoting endothelial nitric oxide production. Nebivolol may increase insulin sensitivity and does not adversely affect lipid profile. At equivalent beta blocking effects, nebivolol is not associated with the decrease in insulin sensitivity and increase in oxidative stress produced by metoprolol in patients with the metabolic syndrome. Other β-blocking drugs cause vasodilation by antagonizing α-adrenoceptors. Labetalol is a reversible adrenoceptor antagonist available as a racemic mixture of two pairs of chiral isomers (the molecule has two centers of asymmetry). The (S,S)- and (R,S)isomers are nearly inactive, the (S,R)-isomer is a potent α blocker, and the (R,R)-isomer is a potent β blocker. Labetalol’s affinity for α receptors is less than that of phentolamine, but labetalol is α1selective. Its β-blocking potency is somewhat lower than that of propranolol. Hypotension induced by labetalol is accompanied by less tachycardia than occurs with phentolamine and similar α blockers. Carvedilol, medroxalol,* and bucindolol* are nonselective β-receptor antagonists with some capacity to block α1-adrenergic receptors. Carvedilol antagonizes the actions of catecholamines more potently at β receptors than at α1 receptors. The drug has a half-life of 6–8 hours. It is extensively metabolized in the liver, and stereoselective metabolism of its two isomers is observed. Since metabolism of (R)-carvedilol is influenced by polymorphisms in CYP2D6 activity and by drugs that inhibit this enzyme’s activity (such as quinidine and fluoxetine, see Chapter 4), drug interactions may occur. Carvedilol also appears to attenuate oxygen free radical–initiated lipid peroxidation and to inhibit vascular smooth *

Not available in the USA.

muscle mitogenesis independently of adrenoceptor blockade. These effects may contribute to the clinical benefits of the drug in chronic heart failure (see Chapter 13). Timolol is a nonselective β blocker without local anesthetic activity, a characteristic that is advantageous when given topically in the eye in the treatment of glaucoma because chronic anesthesia of the cornea, eliminating its protective reflexes, would be undesirable. Nadolol is noteworthy for its very long duration of action; its spectrum of action is similar to that of timolol. Levobunolol (nonselective) and betaxolol (β1-selective) are also used for topical ophthalmic application in glaucoma; the latter drug may be less likely to induce bronchoconstriction than nonselective antagonists. Carteolol is a nonselective β-receptor antagonist. Butoxamine is a selective β2-blocking drug used in research. Beta2-antagonists have not been actively developed because there is no obvious clinical application for them; none is available for clinical use.

■■ CLINICAL PHARMACOLOGY OF THE BETA-RECEPTOR–BLOCKING DRUGS Hypertension Classic β-adrenoceptor antagonists are effective antihypertensive medications, but are not indicated as first line treatment for essential hypertension because other classes of drugs are superior in preventing stroke, particularly in patients older than 60 years. It is unclear if newer vasodilating β-adrenoceptor antagonists share the same limitation. Beta-adrenoceptor antagonists may be indicated in hypertension in special populations in whom “cardioprotection” is desirable, such as those with heart failure with reduced ejection fraction and those with coronary artery disease. Use of these agents is discussed in greater detail in Chapter 11.

Ischemic Heart Disease Beta-adrenoceptor antagonists are first-line therapy in symptomatic management of patients with chronic stable angina (see Chapter 12). The beneficial effects are due to blockade of cardiac β receptors, resulting in decreased cardiac work, slowing and regularization of the heart rate, and reduction in oxygen demand. (Figure 10–7). Multiple large-scale prospective studies indicate that in addition to symptomatic relief, β-adrenoceptor antagonists reduce infarct size and acute mortality when given early during acute myocardial infarct. In this setting, relative contraindications include bradycardia, hypotension, moderate or severe left ventricular failure, shock, heart block, and active airways disease. They also improve survival when given chronically to patients who have had myocardial infarction or to those with heart failure with reduced ejection fraction (Figure 10-8). The β1-adrenoceptor antagonist metoprolol is commonly used for this purpose. Atenolol and timolol are also effective. Atenolol has the disadvantage that it is cleared by the kidney and its dose has to be adjusted in patients with renal failure.

172    SECTION II  Autonomic Drugs

Drama

Comedy

Documentary

Heart rate

110

90

70

50 10

50

30

70

90

110

Time (min)

FIGURE 10–7  Heart rate in a patient with ischemic heart disease measured by telemetry while watching television. Measurements were begun 1 hour after receiving placebo (upper line, red) or 40 mg of oxprenolol (lower line, blue), a nonselective β antagonist with partial agonist activity. Not only was the heart rate decreased by the drug under the conditions of this experiment, it also varied much less in response to stimuli. (Reproduced with permission from Taylor SH. Oxprenolol in clinical practice. Am J Cardiol. 1983;52(9):34D-42D.)

Cardiac Arrhythmias Beta antagonists are often effective in the treatment of both supraventricular and ventricular arrhythmias (see Chapter 14). It has been suggested that the improved survival following myocardial infarction in patients using β antagonists (see Figure 10–8) is due to suppression of arrhythmias. By increasing the atrioventricular nodal refractory period, β antagonists slow ventricular response rates in atrial flutter and fibrillation. These drugs can also reduce ventricular ectopic beats, particularly if the ectopic activity has

0.30

Placebo Timolol

0.25

Heart Failure Clinical trials have demonstrated that at least three β antagonists— metoprolol, bisoprolol, and carvedilol—are effective in reducing mortality in selected patients with chronic heart failure. In some patients, administration of these drugs may worsen acute congestive heart failure, but most patients tolerate treatment initiation with gradual dose increments. Although mechanisms are uncertain, there appear to be beneficial effects on myocardial remodeling and in decreasing the risk of sudden death (see Chapter 13).

Other Cardiovascular Disorders

0.20

Beta-receptor antagonists have been found to increase stroke volume in some patients with obstructive cardiomyopathy. This beneficial effect is thought to result from the slowing of ventricular ejection and decreased outflow resistance. Beta antagonists are indicated in the treatment of dissecting aortic aneurysms.

0.15 0.10 0.05 0

been precipitated by catecholamines. Esmolol is particularly useful against acute perioperative arrhythmias because it has a short duration of action and can be given parenterally. Sotalol has antiarrhythmic effects involving ion channel blockade in addition to its β-blocking action; these are discussed in Chapter 14.

0

12

24

36

48

60

72

Time (months)

FIGURE 10–8  Effects of β-blocker therapy on life-table cumulated rates of mortality from all causes over 6 years among 1884 patients surviving myocardial infarctions. Patients were randomly assigned to treatment with placebo (blue bar) or timolol (red bar).

Glaucoma (See Box: The Treatment of Glaucoma) Systemic administration of β-blocking drugs for other indications was found serendipitously to reduce intraocular pressure in patients with glaucoma. Subsequently, it was found that topical administration also reduces intraocular pressure. The mechanism appears to involve reduced production of aqueous humor by the ciliary body,

CHAPTER 10  Adrenoceptor Antagonist Drugs     173

which is physiologically activated by cAMP. Timolol and related β antagonists are suitable for local use in the eye because they lack local anesthetic properties. Beta antagonists appear to have an efficacy comparable to that of epinephrine or pilocarpine in open-angle glaucoma and are far better tolerated by most patients. While the maximal daily dose applied locally (1 mg) is small compared with the systemic doses commonly used in the treatment of hypertension or angina (10–60 mg), sufficient timolol may be absorbed from the eye to cause serious adverse effects on the heart and airways in susceptible individuals. Topical timolol may interact with orally administered verapamil and increase the risk of heart block. Betaxolol, carteolol, levobunolol, and metipranolol are also approved for the treatment of glaucoma. Betaxolol has the potential advantage of being β1-selective; to what extent this potential advantage might diminish systemic adverse effects remains to be determined. The drug apparently has caused worsening of pulmonary symptoms in some patients.

Hyperthyroidism Excessive catecholamine action is an important aspect of the pathophysiology of hyperthyroidism (see Chapter 38), and β antagonists can reduce palpitations, tachycardia, tremulousness, and anxiety. They are recommended in patients diagnosed with hyperthyroidism unless a contraindication exists. Propranolol has been used extensively in patients with thyroid storm (severe hyperthyroidism); it is used cautiously in patients with this condition to control supraventricular tachycardias that often precipitate heart failure.

Neurologic Diseases Propranolol, metoprolol, and timolol reduce the frequency and intensity of migraine headache. Other β-receptor antagonists with preventive efficacy include atenolol and nadolol. The mechanism is not known. Since sympathetic activity may enhance skeletal muscle tremor, it is not surprising that β antagonists have been found to reduce certain tremors (see Chapter 28). The somatic manifestations of anxiety may respond dramatically to low doses of propranolol, particularly when taken prophylactically. For example, benefit has been found in musicians with performance anxiety (“stage fright”). Propranolol may contribute to the symptomatic treatment of alcohol withdrawal in some patients.

Miscellaneous Beta-receptor antagonists have been found to diminish portal vein pressure in patients with cirrhosis. There is evidence that both propranolol and nadolol decrease the incidence of the first episode of bleeding from esophageal varices and decrease the mortality rate associated with bleeding in patients with cirrhosis. Nadolol in combination with isosorbide mononitrate appears to be more efficacious than sclerotherapy in preventing rebleeding in patients who have previously bled from esophageal varices. Variceal band ligation in combination with a β antagonist may be more efficacious. The potential beneficial effects of β blockers in preventing bleeding have to be balanced with the potential reduction in cardiac output and reduced blood pressure. Infantile hemangiomas are the most common vascular tumors of infancy, and propranolol has been found to reduce their

volume, color, and elevation in infants younger than 6 months and children up to 5 years of age. A retrospective analysis found improved survival of patients with melanoma treated with immunotherapy who happened to be taking nonselective β blockers, but not in patients taking β1–selective antagonists or no β blockers. The significance of this finding is not yet clear. Similar putative beneficial effect have been reported in patients with breast cancer, in part because β blockers may prevent chemotherapy-induced cardiomyopathy.

CHOICE OF A BETA-ADRENOCEPTOR ANTAGONIST DRUG In general, β1-selective antagonists are preferred in patients with asthma, COPD, diabetes mellitus, or peripheral vascular disease. Beta blockers with intrinsic sympathetic activity may be preferred in patients with resting bradycardia. Vasodilating β blockers may be preferred in patients with heart failure or hypertension. As with other medications, patient compliance may be improved by using drugs with a longer half-life.

CLINICAL TOXICITY OF THE BETARECEPTOR ANTAGONIST DRUGS The major adverse effects of β-receptor antagonist drugs relate to the predictable consequences of β blockade. Beta2-receptor blockade associated with the use of nonselective agents commonly causes worsening of preexisting asthma and other forms of airway obstruction. β1-selective drugs have fewer adverse effects on airways than nonselective β antagonists, and they can be used, but very cautiously, in patients with reactive airway disease. Nonselective β blockers can induce peripheral vasoconstriction. Clinical symptoms can range from a sensation of cold extremities in individuals with otherwise normal circulation, to worsening of claudication in patients with peripheral vascular disease. They can also worsen Raynaud phenomenon. Beta1-selective antagonists are generally better tolerated in patients with mild to moderate peripheral vascular disease, but caution is required in patients with severe peripheral vascular disease or vasospastic disorders. Slowing of the resting heart rate and development of sinus bradycardia are the main pharmacological effects of β blockade, and even β blockers with intrinsic sympathetic activity are contraindicated in patients with symptomatic bradycardia and sinus node dysfunction. Beta blockers slow atrioventricular (AV) node conduction and can induce or worsen heart block, leading to potentially serious bradyarrhythmias. Beta-receptor blockade depresses myocardial contractility and excitability. In patients with abnormal myocardial function, cardiac output may be dependent on sympathetic drive. If this stimulus is removed by β blockade, cardiac decompensation may ensue. Thus, caution must be exercised in starting a β-receptor antagonist in patients with compensated heart failure, but this should not deter their use; only a minority of patients with stable heart failure decompensate after cautious initiation of β blockers, and long-term use of these drugs has been shown to reduce mortality in

174    SECTION II  Autonomic Drugs

these patients. Beta blockers may interact with the calcium antagonist verapamil; severe hypotension, bradycardia, heart failure, and cardiac conduction abnormalities have all been described. These adverse effects may even arise in susceptible patients taking a topical (ophthalmic) β blocker and oral verapamil. Epinephrine is a critical hormone involved in the counterregulatory response to hypoglycemia. β blockers can not only mask the early adrenergic warning symptoms of hypoglycemia (tachycardia, sweating and anxiety), but may delay recovery to normoglycemia. Therefore, it is not advisable to use β antagonists in insulin-dependent diabetic patients who suffer from frequent hypoglycemic episodes if alternative therapies are available. Beta1selective antagonists offer some advantage in these patients, since the rate of recovery from hypoglycemia may be faster compared with that in diabetics receiving nonselective β-adrenoceptor antagonists. There is considerable potential benefit from these drugs in diabetics after a myocardial infarction, so the balance of risk versus benefit must be evaluated in individual patients.

Fatigue, depression, and sexual dysfunction have been historically considered common adverse effects of β blockers, and these effects were thought to be less common with nonlipophilic drugs (eg, atenolol). A systematic review of the results of randomized trials, however, suggests that the risk of these effects, while present, is lower than previously thought. The use of β blockers is associated with a small increase in body weight and mild negative changes in metabolism and lipids, with a small increase in triglycerides and a decrease in HDL. These effects are not seen with vasodilating β blockers. Acute withdrawal of β blockers can lead to sudden onset of tachycardia and exacerbation of ischemic symptoms, and even precipitation of acute myocardial infarction. The mechanism of this effect might involve up-regulation of the number of β receptors in response to chronic exposure to an antagonist. This phenomenon can be prevented by gradual dose tapering rather than abrupt cessation when these drugs are discontinued, especially when using drugs with short half-lives.

SUMMARY  Sympathetic Antagonists Subclass, Drug

Mechanism of Action

Effects

Clinical Applications

Pharmacokinetics, Toxicities, Interactions

ALPHA-ADRENOCEPTOR ANTAGONISTS   • Phenoxybenzamine

Irreversibly blocks α1 and α2 • indirect baroreflex activation

Lowers blood pressure (BP) • heart rate (HR) rises due to baroreflex activation

Pheochromocytoma • high catecholamine states

  • Phentolamine

Reversibly blocks α1 and α2

Blocks α-mediated vasoconstriction, lowers BP, increases HR (baroreflex)

Pheochromocytoma

  • Prazosin

Block α1, but not α2

Lower BP

Hypertension • benign prostatic hyperplasia

Larger depressor effect with first dose may cause orthostatic hypotension

Slightly selective for α1A

α1A blockade may relax prostatic smooth muscle more than vascular smooth muscle Raises BP and HR

Benign prostatic hyperplasia

Orthostatic hypotension may be less common with this subtype

Male erectile dysfunction • hypotension

May cause anxiety • excess pressor effect if norepinephrine transporter is blocked

Lowers BP with limited HR increase

Hypertension

Oral, parenteral • Toxicity: Less tachycardia than other α1 agents

Lower HR and BP • reduce renin

Oral, parenteral • Toxicity: Bradycardia • worsened asthma • fatigue • vivid dreams • cold hands Toxicity: Bradycardia • fatigue • vivid dreams • cold hands

Toxicity: Asthma provocation

  • Doxazosin   • Terazosin   • Tamsulosin

  • Yohimbine

Blocks α2 • elicits increased central sympathetic activity • increased norepinephrine release

  • Labetalol (see carvedilol section below)

β > α1 block

BETA-ADRENOCEPTOR ANTAGONISTS   • Propranolol Block β1 and β2

Block β1 > β2

Lower HR and BP • reduce renin • may be safer in asthma

Hypertension • angina pectoris • arrhythmias • migraine • hyperthyroidism • glaucoma (topical timolol) Angina pectoris • hypertension • arrhythmias • glaucoma (topical betaxolol)

Blocks β2 > β1

Increases peripheral resistance

No clinical indication

  • Nadolol   • Timolol   • Metoprolol   • Atenolol   • Betaxolol   • Nebivolol   • Butoxamine1

Irreversible blocker • duration > 1 day • Toxicity: Orthostatic hypotension • tachycardia • myocardial ischemia Half-life ~45 min after IV injection

(continued)

CHAPTER 10  Adrenoceptor Antagonist Drugs     175

Pharmacokinetics, Toxicities, Interactions

Subclass, Drug

Mechanism of Action

Effects

Clinical Applications

  •  Pindolol

β1, β2, with intrinsic sympathomimetic (partial agonist) effect

Lower BP • modestly lower HR

Hypertension • arrhythmias • migraine • may avoid worsening of bradycardia

Oral • Toxicity: Fatigue • vivid dreams • cold hands

β > α1 block

 

Heart failure

Oral, long half-life • Toxicity: Fatigue

β1 > β2

Very brief cardiac β blockade

Rapid control of BP and arrhythmias, thyrotoxicosis, and myocardial ischemia intraoperatively

Parenteral only • half-life ~10 min • Toxicity: Bradycardia • hypotension

Lowers BP • may elicit extrapyramidal effects (due to decreased dopamine in CNS)

Pheochromocytoma

Toxicity: Extrapyramidal symptoms • orthostatic hypotension • crystalluria

  •  Acebutolol   •  Carteolol   •  Bopindolol1   •  Oxprenolol1   •  Celiprolol1   •  Penbutolol   •  Carvedilol   •  Medroxalol1   • Bucindolol1 (see labetalol above)   •  Esmolol

TYROSINE HYDROXYLASE INHIBITOR   •  Metyrosine Blocks tyrosine hydroxylase • reduces synthesis of dopamine, norepinephrine, and epinephrine 1

Not available in the USA.

P R E P A R A T I O N S

A V A I L A B L E*

GENERIC NAME AVAILABLE AS ALPHA BLOCKERS Alfuzosin Generic, Uroxatral Doxazosin Generic, Cardura Phenoxybenzamine Generic, Dibenzyline Phentolamine Generic Prazosin Generic, Minipress Silodosin Generic, Rapaflo Tamsulosin Generic, Flomax Terazosin Generic, Hytrin Tolazoline Generic, Priscoline BETA BLOCKERS Acebutolol Generic, Sectral Atenolol Generic, Tenormin Betaxolol    Oral Generic, Kerlone  Ophthalmic Generic, Betoptic Bisoprolol Generic, Zebeta Carteolol    Oral Generic, Cartrol *

In the USA.

GENERIC NAME  Ophthalmic Carvedilol Esmolol Labetalol Levobunolol

AVAILABLE AS Generic, Ocupress Generic, Coreg Generic, Brevibloc Generic, Normodyne, Trandate Generic, Betagan Liquifilm, others Metipranolol Generic, OptiPranolol Metoprolol Generic, Lopressor, Toprol Nadolol Generic, Corgard Nebivolol Bystolic Penbutolol Levatol Pindolol Generic, Visken Propranolol Generic, Inderal Sotalol Generic, Betapace Timolol    Oral Generic, Blocadren  Ophthalmic Generic, Timoptic TYROSINE HYDROXYLASE INHIBITOR Metyrosine Demser

176    SECTION II  Autonomic Drugs

REFERENCES Ambrosio G et al: β-Blockade with nebivolol for prevention of acute ischaemic events in elderly patients with heart failure. Heart 2011;97:209. Ayers K et al: Differential effects of nebivolol and metoprolol on insulin sensitivity and plasminogen activator inhibitor in the metabolic syndrome. Hypertension 2012;59:893. Bird ST et al: Tamsulosin treatment for benign prostatic hyperplasia and risk of severe hypotension in men aged 40-85 years in the United States: Risk window analyses using between and within patient methodology. BMJ 2013;347:f6320. Campschroer T et al: Alpha-blockers as medical expulsive therapy for ureteral stones. Cochrane Database Syst Rev 2018;4:CD008509. Danesh A, Gottschalk PCH: Beta-blockers for migraine prevention: a review article. Curr Treat Options Neurol. 2019;21:20. De Nunzio C et al: Erectile dysfunction and lower urinary tract symptoms. Curr Urol Rep 2018;19:61. Fusco et al: Alpha 1-blockers improve benign prostatic obstruction in men with lower urinary tract symptoms: A systematic review and meta-analysis of urodynamic studies. Eur Urol 2016;69:1091. Joseph P et al: The evolution of beta-blockers in coronary artery disease and heart failure. J Am Coll Cardiol 2019;74:672. Mancia G et al: Individualized beta-blocker treatment for high blood pressure dictated by medical comorbidities: indications beyond the 2018 European Society of Cardiology/European Society of Hypertension Guidelines. Hypertension 2022;79:1153.

Macca L et al: Update on treatment of infantile hemangiomas: what’s new in the last five years? Front Pharmacol 2022;13:879602 Negri L et al: Timolol 0.1% in glaucomatous patients: efficacy, tolerance, and quality of life. J Ophthalmol 2019:4146124. Neumann HPH et al: Pheochromocytoma and paraganglioma. N Engl J Med 2019;381:552. Nocentini A, Supuran CT: Adrenergic agonists and antagonists as patent review (2013-2019). Exp Opin Ther Pat 2019;29:805. Okamoto LE et al: Nebivolol, but not metoprolol lowers blood pressure in nitric oxide-sensitive human hypertension. Hypertension 2014;64:1241. Olawi N et al: Nebivolol in the treatment of arterial hypertension. Basic Clin Pharmacol Toxicol 2019;125:189. Phadke S, Clamon G: Beta blockade as adjunctive breast cancer therapy: A review. Crit Rev Oncol Hematol 2016;138:173. Raj SR et al: Propranolol decreases tachycardia and improves symptoms in the postural tachycardia syndrome: Less is more. Circulation 2009;120:725. Shah P et al: Meta-analysis comparing usefulness of beta blockers to preserve left ventricular function during anthracycline therapy. Am J Cardiol 2019;124:789. Shanker V: Essential tremor: diagnosis and management. Br Med J 2019;366:I4485 Shibao C et al: Comparative efficacy of yohimbine against pyridostigmine for the treatment of orthostatic hypotension in autonomic failure. Hypertension 2010;56:847. Suissa S, Ernst P: Beta-blockers in COPD: A methodological review of the observational studies. COPD 2018;15:520.

C ASE STUDY ANSWER The patient had a pheochromocytoma. This tumor secretes catecholamines, especially norepinephrine and epinephrine, resulting in increases in blood pressure (via α1 receptors) and heart rate (via β1 receptors). The pheochromocytoma was in the left adrenal gland and was diagnosed by elevated plasma fractionated metanephrines (catecholamine metabolites). The left adrenal tumor was identified by computer tomography and by meta-iodobenzylguanidine (MIBG) imaging, which labels tissues that have norepinephrine transporters on their cell surface (see text). In addition, he had elevated plasma and urinary norepinephrine, epinephrine, and their

metabolites. The pressor episode during the physical examination was likely triggered by external pressure as the physician palpated the abdomen. His profuse sweating was typical and partly due to α1 receptors, although the mechanism of sweating in pheochromocytoma has never been fully explained. Treatment would consist of preoperative pharmacologic control of blood pressure with α antagonists, and normalization of blood volume which is often significantly reduced, followed by surgical resection of the tumor. Control of blood pressure may be necessary during surgery as manipulation of the tumor may lead to catecholamine discharge.

SECTION III  CARDIOVASCULAR-RENAL DRUGS

11

C

Antihypertensive Agents Neal L. Benowitz, MD

H

A

P

T

E

R

CASE STUDY A 35-year-old man presents with a blood pressure of 140/90 mm Hg. He has been generally healthy, is sedentary, drinks several cocktails per day, and does not smoke cigarettes. He has a family history of hypertension, and his father died of a myocardial infarction at age 55. Physical examination

Hypertension is the most common cardiovascular disease and the most common reason for physician office visits. Using National Health and Nutrition Examination Survey (NHANES) data from 2017 to 2018, and a definition of ≥130/90 mm Hg recommended by the 2017 ACC/AHA High Blood Pressure Clinical Practice Guideline, hypertension was found in 45% of American adults and 74% of adults age 60 years or older. The prevalence varies with age, race, education, and many other variables. Sustained arterial hypertension damages blood vessels in kidney, heart, and brain and leads to an increased incidence of renal failure, coronary disease, heart failure, stroke, and dementia. More than 50% of deaths from coronary heart disease and stroke occur in people with hypertension. Effective pharmacologic lowering of blood pressure has been shown to prevent damage to blood vessels and to substantially reduce morbidity and mortality rates. However, NHANES found that, unfortunately, only one-half of Americans with hypertension had adequate blood pressure control. Many effective drugs

is remarkable only for moderate obesity. Total cholesterol is 220, and high-density lipoprotein (HDL) cholesterol level is 40 mg/dL. Fasting glucose is 105 mg/dL. Chest X-ray is normal. Electrocardiogram shows left ventricular hypertrophy. How would you treat this patient?

are available. Knowledge of their antihypertensive mechanisms and sites of action allows accurate prediction of efficacy and toxicity. The rational use of these agents, alone or in combination, can lower blood pressure with minimal risk of serious toxicity in most patients.

HYPERTENSION & REGULATION OF BLOOD PRESSURE Diagnosis The diagnosis of hypertension is based on repeated, reproducible measurements of elevated blood pressure (Table 11–1). Blood pressure may be elevated in the office but not at home (“white coat hypertension”), so it is best to confirm a diagnosis of hypertension with home or ambulatory blood pressure measurement. The diagnosis serves primarily as a prediction of consequences 177

178    SECTION III  Cardiovascular-Renal Drugs

TABLE 11–1  Blood pressure in adults. Blood Pressure

(Systolic [mm Hg]/ Diastolic [mm Hg]

Low

70–90/40–60

Normal

90–120/60–80

Elevated

120–129/80

Hypertension

 

Stage I

130–139/80–90

Stage II

>140/>90

for the patient; it seldom includes a statement about the cause of hypertension. Epidemiologic studies indicate that the risks of damage to kidney, heart, and brain are directly related to the extent of blood pressure elevation. Even mild hypertension (blood pressure 130/80 mm Hg) increases the risk of eventual end-organ damage. Starting at 115/75 mm Hg, cardiovascular disease risk doubles with each increment of 20/10 mm Hg throughout the blood pressure range. Both systolic hypertension and diastolic hypertension are associated with end-organ damage; so-called isolated systolic hypertension is not benign. The risks—and therefore the urgency of instituting therapy—increase in proportion to the magnitude of blood pressure elevation. The risk of end-organ damage at any level of blood pressure or age is greater in African Americans and relatively less in premenopausal women than in men. Other risk factors include smoking, including exposure to secondhand smoke; diabetes; metabolic syndrome including obesity, dyslipidemia; physical inactivity; manifestations of end-organ damage at the time of diagnosis; and a family history of cardiovascular disease. It should be noted that the diagnosis of hypertension depends on measurement of blood pressure and not on symptoms reported by the patient. In fact, hypertension is usually asymptomatic until overt end-organ damage is imminent or has already occurred.

Etiology of Hypertension A specific cause of hypertension can be established in only 10–15% of patients. Patients in whom no specific cause of hypertension can be found are said to have essential or primary hypertension. Patients with a specific etiology are said to have secondary hypertension. It is important to consider specific causes in each case, however, because some of them are amenable to definitive surgical treatment: renal artery constriction, coarctation of the aorta, pheochromocytoma, Cushing disease, and primary aldosteronism. In most cases, elevated blood pressure is associated with an overall increase in resistance to flow of blood through arterioles, whereas cardiac output is usually normal. Meticulous investigation of autonomic nervous system function, baroreceptor reflexes, the renin-angiotensin-aldosterone system, and the kidney has failed to identify a single abnormality as the cause of increased peripheral vascular resistance in essential hypertension. It appears, therefore,

that elevated blood pressure is usually caused by a combination of several (multifactorial) abnormalities. Epidemiologic evidence points to genetic factors, psychological stress, environmental and dietary factors (increased salt and decreased potassium or calcium intake), alcohol consumption, and obesity as contributing to the development of hypertension. Increase in blood pressure with aging does not occur in populations with low daily sodium intake. Patients with labile hypertension appear more likely than normal controls to have blood pressure elevations after salt loading. The heritability of essential hypertension is estimated to be about 30%. Mutations in several genes have been linked to various rare causes of hypertension, but most hypertension appears to be polygenic. Functional variations of the genes for angiotensinogen, angiotensin-converting enzyme (ACE), the angiotensin II receptor, the β2 adrenoceptor, α adducin (a cytoskeletal protein), uromodulin (modulator of renal electrolyte transport), and others appear to contribute to some cases of essential hypertension.

Normal Regulation of Blood Pressure According to the hydraulic equation, arterial blood pressure (BP) is directly proportionate to the product of the blood flow (cardiac output, CO) and the resistance to passage of blood through precapillary arterioles (peripheral vascular resistance, PVR): BP = CO × PVR

Physiologically, in both normal and hypertensive individuals, blood pressure is maintained by moment-to-moment regulation of cardiac output and peripheral vascular resistance, exerted at three anatomic sites (Figure 11–1): arterioles, postcapillary venules (capacitance vessels), and heart. A fourth anatomic control site, the kidney, contributes to maintenance of blood pressure by regulating the volume of intravascular fluid. Baroreflexes, mediated by autonomic nerves, act in combination with humoral mechanisms, including the renin-angiotensin-aldosterone system, to coordinate

2. Capacitance Venules

3. Pump output Heart

CNS– Sympathetic nerves 4. Volume Kidneys

1. Resistance Arterioles

Renin

Aldosterone

FIGURE 11–1 

Angiotensin

Anatomic sites of blood pressure control.

CHAPTER 11  Antihypertensive Agents    179

function at these four control sites and to maintain normal blood pressure. Finally, local release of vasoactive substances from vascular endothelium may also be involved in the regulation of vascular resistance. For example, endothelin-1 (see Chapter 17) constricts and nitric oxide (see Chapter 19) dilates blood vessels. Blood pressure in a hypertensive patient is controlled by the same mechanisms that are operative in normotensive subjects. Regulation of blood pressure in hypertensive patients differs from healthy patients in that the baroreceptors and the renal blood volume-pressure control systems appear to be “set” at a higher level of blood pressure. All antihypertensive drugs act by interfering with these normal mechanisms, which are reviewed below. A.  Postural Baroreflex Baroreflexes are responsible for rapid, moment-to-moment adjustments in blood pressure, such as in transition from a reclining to an upright posture (Figure 11–2). Central sympathetic neurons arising from the vasomotor area of the medulla are tonically active. Carotid baroreceptors are stimulated by the stretch of the vessel walls brought about by the internal pressure (arterial blood pressure). Baroreceptor activation inhibits central sympathetic discharge. Conversely, reduction in stretch results in a reduction in baroreceptor activity. Thus, in the case of a transition to upright posture, baroreceptors sense the reduction in arterial pressure that results from pooling of blood in the veins below the level of the heart as reduced wall stretch, and sympathetic discharge is disinhibited. The reflex increase in sympathetic outflow acts through nerve endings to increase peripheral vascular resistance (constriction of arterioles) and cardiac output (direct stimulation of the heart and constriction of capacitance vessels, which increases venous return to the heart), thereby restoring normal blood pressure. The same baroreflex acts in response to any event that lowers arterial pressure, including a primary reduction in peripheral

vascular resistance (eg, caused by a vasodilating agent) or a reduction in intravascular volume (eg, due to hemorrhage or to loss of salt and water via the kidney). B.  Renal Response to Decreased Blood Pressure By controlling blood volume, the kidney is primarily responsible for long-term blood pressure control. A reduction in renal perfusion pressure causes intrarenal redistribution of blood flow and increased reabsorption of salt and water. In addition, decreased pressure in renal arterioles as well as sympathetic neural activity (via β adrenoceptors) stimulates production of renin, which increases production of angiotensin II (see Figure 11–1 and Chapter 17). Angiotensin II causes (1) direct constriction of resistance vessels and (2) stimulation of aldosterone synthesis in the adrenal cortex, which increases renal sodium absorption and intravascular blood volume. Vasopressin released from the posterior pituitary gland also plays a role in maintenance of blood pressure through its ability to regulate water reabsorption by the kidney (see Chapters 15 and 17).

■■ BASIC PHARMACOLOGY OF ANTIHYPERTENSIVE AGENTS All antihypertensive agents act at one or more of the four anatomic control sites depicted in Figure 11–1 and produce their effects by interfering with normal mechanisms of blood pressure regulation. A useful classification of these agents categorizes them according to the principal regulatory site or mechanism on which they act (Figure 11–3). Because of their common mechanisms of action, drugs within each category tend to produce a similar spectrum of toxicities. The categories include the following:

IC 2. Nucleus of the tractus solitarius Brainstem

CP

Sensory fiber

X XI

Inhibitory interneurons

Arterial blood pressure

XII 3. Vasomotor center

Spinal cord

FIGURE 11–2 

1. Baroreceptor in carotid sinus

Vessel wall Motor fibers 5

4. Autonomic ganglion

5. Sympathetic nerve ending

Baroreceptor reflex arc. CP, cerebellar peduncle; IC, inferior colliculus.

6

6. α or β receptor

180    SECTION III  Cardiovascular-Renal Drugs

Vasomotor center Methyldopa Clonidine Guanabenz Guanfacine Sympathetic nerve terminals Guanethidine Guanadrel Reserpine

Sympathetic ganglia β-Receptors of heart

Trimethaphan

Propranolol and other β blockers Angiotensin receptors of vessels Losartan and other angiotensin receptor blockers

α-Receptors of vessels

Vascular smooth muscle

Prazosin and other α1 blockers

Hydralazine Verapamil and other calcium channel Minoxidil blockers Nitroprusside Fenoldopam Diazoxide β-Receptors of juxtaglomerular cells that release renin

Kidney tubules Thiazides, etc

Metoprolol and other β blockers

Angiotensinconverting enzyme Angiotensin II

Angiotensin I Captopril and other ACE inhibitors

FIGURE 11–3 

Renin

Angiotensinogen

Aliskiren

Sites of action of the major classes of antihypertensive drugs.

1. Diuretics, which lower blood pressure by depleting the body of sodium and reducing blood volume and perhaps by other mechanisms. 2. Agents that block production or action of renin or angiotensin and thereby reduce peripheral vascular resistance and (potentially) blood volume. 3. Direct vasodilators, which reduce pressure by relaxing vascular smooth muscle, thus dilating resistance vessels and—to varying degrees—increasing capacitance as well. 4. Sympathoplegic agents, which lower blood pressure by reducing peripheral vascular resistance, inhibiting cardiac function, and increasing venous pooling in capacitance vessels. (The latter two effects reduce cardiac output.) These agents are further subdivided according to their putative sites of action in the sympathetic reflex arc (see below).

The fact that these drug groups act by different mechanisms permits the combination of drugs from two or more groups with increased efficacy and, in some cases, decreased toxicity. (See Box: Resistant Hypertension & Polypharmacy.)

DRUGS THAT ALTER SODIUM & WATER BALANCE Dietary sodium restriction has been known for many years to decrease blood pressure in hypertensive patients. With the advent of diuretics, sodium restriction was thought to be less important. However, there is now general agreement that dietary control of blood pressure is a relatively nontoxic therapeutic measure and may even be preventive. Even modest dietary sodium restriction lowers blood pressure (though to varying extents) in many hypertensive persons.

CHAPTER 11  Antihypertensive Agents    181

Resistant Hypertension & Polypharmacy Many patients with hypertension require two or more drugs acting by different mechanisms (polypharmacy). According to some estimates, up to 40% of patients may respond inadequately even to two agents and are considered to have “resistant hypertension.” Some of these patients have treatable secondary hypertension that has been missed, but most do not, and three or more drugs are required. One rationale for polypharmacy in hypertension is that most drugs evoke compensatory regulatory mechanisms for maintaining blood pressure (see Figures 6–7 and 11–1), which may markedly limit their effect. For example, vasodilators such as hydralazine cause a significant decrease in peripheral vascular resistance, but evoke a strong compensatory tachycardia and salt and water retention (Figure 11–4) that are capable of almost completely reversing their effect. The addition of a β blocker prevents the tachycardia; addition of a diuretic (eg, hydrochlorothiazide) prevents the salt and water retention. In effect, all three drugs increase the sensitivity of the cardiovascular system to each other’s actions. A second reason is that some drugs have only modest maximum efficacy but reduction of long-term morbidity mandates their use. Many studies of angiotensin-converting enzyme (ACE) inhibitors report a maximal lowering of blood pressure of less than 10 mm Hg. In patients with more severe hypertension (pressure >160/100 mm Hg), this is inadequate to prevent all the

Mechanisms of Action & Hemodynamic Effects of Diuretics Diuretics lower blood pressure primarily by depleting body sodium stores. Initially, diuretics reduce blood pressure by reducing blood volume and cardiac output; peripheral vascular resistance may increase. After 6–8 weeks, cardiac output returns toward normal while peripheral vascular resistance declines. Sodium is believed to contribute to vascular resistance by increasing vessel stiffness and neural reactivity, possibly related to altered sodium-calcium exchange with a resultant increase in intracellular calcium. These effects are reversed by diuretics or dietary sodium restriction. Diuretics are effective in lowering blood pressure by 10–15 mm Hg in most patients, and diuretics alone often provide adequate treatment for mild or moderate essential hypertension. In more severe hypertension, diuretics are used in combination with sympathoplegic and vasodilator drugs to control the tendency toward sodium retention caused by these agents. Vascular responsiveness—ie, the ability to either constrict or dilate—is diminished by sympathoplegic and vasodilator drugs, so that the vasculature behaves like an inflexible tube. As a consequence, blood pressure becomes exquisitely sensitive to blood volume. Thus, in severe hypertension, when multiple drugs are used, blood pressure may be well controlled when blood volume is 95% of normal but much too high when blood volume is 105% of normal.

sequelae of hypertension, but ACE inhibitors have important long-term benefits in preventing or reducing renal disease in diabetic persons and in reduction of heart failure. Finally, the toxicity of some effective drugs prevents their use at maximally effective doses. Two approaches to treating hypertension can be considered. One may start with monotherapy, and if hypertension does not respond adequately to a regimen of one drug, a second drug from a different class with a different mechanism of action and different pattern of toxicity is added. If the response is still inadequate and compliance is known to be good, a third drug should be added. Another increasingly common approach is to use small doses of drugs two or three dugs (for example a diuretic, ACE inhibitor, or angiotensin reception blocker and/or a calcium channel blocker). If three drugs (usually including a diuretic) are inadequate, other causes of resistant hypertension such as excessive dietary sodium intake, use of nonsteroidal antiinflammatory or stimulant drugs, or the presence of secondary hypertension should be considered. In some instances, an additional drug may be necessary, and mineralocorticoid antagonists, such as spironolactone, have been found to be particularly useful. Occasionally patients are resistant to four or more drugs, and nonpharmacologic approaches have been considered. A promising treatments that is still under investigation, particularly for patients with advanced kidney disease, is renal denervation.

Use of Diuretics The sites of action within the kidney and the pharmacokinetics of various diuretic drugs are discussed in Chapter 15. Thiazide diuretics are appropriate for most patients with mild or moderate hypertension and normal renal and cardiac function. Chlorthalidone may be more effective than hydrochlorothiazide since it has a longer duration of action yet a recent study has shown that hydrochlorothiazide was equally effective compared to chlorthalidone with respect to cardiovascular outcomes over time in people 65 years or older. More powerful diuretics (eg, those acting on the loop of Henle) such as furosemide, bumetanide, and torsemide are necessary in severe hypertension, when multiple drugs with sodium-retaining properties are used; in renal insufficiency, when glomerular filtration rate is less than 30–40 mL/min; and in cardiac failure or cirrhosis, in which sodium retention is marked. Recent studies indicate that chlorthalidone can be effective in lowering blood pressure even in patients with advanced chronic kidney disease. Potassium-sparing diuretics are useful both to avoid excessive potassium depletion and to enhance the natriuretic effects of other diuretics. Aldosterone receptor antagonists in particular also have a favorable effect on cardiac function in people with heart failure and as polypharmacy in patients with resistant hypertension. Some pharmacokinetic characteristics and the initial and usual maintenance dosages of diuretics are listed in Table 11–2.

182    SECTION III  Cardiovascular-Renal Drugs

Vasodilator drugs

Decreased systemic vascular resistance

1

Decreased renal sodium excretion

Increased sympathetic nervous system outflow

Decreased arterial pressure 2

1

Increased renin release 2

Increased aldosterone

Increased angiotensin II

Sodium retention, increased plasma volume

Increased systemic vascular resistance

Increased arterial pressure

Increased heart rate

2 Increased cardiac contractility

Increased cardiac output

FIGURE 11–4  diuretics.

2

Compensatory responses to vasodilators; basis for combination therapy with β blockers and diuretics. Effect blocked by β blockers.

Although thiazide diuretics are more natriuretic at higher doses (up to 100–200 mg of hydrochlorothiazide), when used as a single agent, lower doses (25–50 mg) exert as much antihypertensive effect as do higher doses. In contrast to thiazides, the blood pressure response to loop diuretics continues to increase at doses many times greater than the usual therapeutic dose.

Toxicity of Diuretics In the treatment of hypertension, the most common adverse effect of diuretics (except for potassium-sparing diuretics) is potassium depletion. Although mild degrees of hypokalemia are tolerated well by many patients, hypokalemia may be hazardous in persons taking digitalis, those who have chronic arrhythmias, or those with acute myocardial infarction or left ventricular dysfunction. Potassium loss is coupled to reabsorption of sodium, and restriction of dietary sodium intake therefore minimizes potassium loss. Diuretics may also cause magnesium depletion, impair glucose tolerance, and increase serum lipid concentrations. Diuretics increase uric acid concentrations and may precipitate gout. The use of low doses minimizes these adverse metabolic effects without impairing the antihypertensive action. Potassium-sparing diuretics may produce hyperkalemia, particularly in patients with renal insufficiency and

Decreased venous capacitance

1

Effect blocked by

those taking ace inhibitors or angiotensin receptor blockers; spironolactone (a steroid) is associated with gynecomastia.

INHIBITORS OF ANGIOTENSIN Renin, angiotensin, and aldosterone play important roles in some people with essential hypertension. Approximately 20% of patients with essential hypertension have inappropriately low and 20% have inappropriately high plasma renin activity. Blood pressure of patients with high-renin hypertension responds well to drugs that interfere with the system, supporting a role for excess renin and angiotensin in this population.

Mechanism & Sites of Action Renin release from the kidney cortex is stimulated by reduced renal arterial pressure, sympathetic neural stimulation, and reduced sodium delivery or increased sodium concentration at the distal renal tubule (see Chapter 17). Renin acts upon angiotensinogen to yield the inactive precursor decapeptide angiotensin I. Angiotensin I is then converted, primarily by endothelial ACE, to the arterial vasoconstrictor octapeptide angiotensin II (Figure 11–5), which is in turn converted in the adrenal gland to

CHAPTER 11  Antihypertensive Agents    183

TABLE 11–2  Pharmacokinetic characteristics and dosage of selected oral antihypertensive drugs.

Drug

Half-life (h)

Bioavailability (percent)

Suggested Initial Dose

Usual Maintenance Dose Range

Reduction of Dosage Required in Moderate Renal Insufficiency1

Amlodipine

35

65

2.5 mg/d

5–10 mg/d

No

Atenolol

6

60

50 mg/d

50–100 mg/d

Yes

2

Benazepril

0.6

35

5–10 mg/d

20–40 mg/d

Yes

Captopril

2.2

65

50–75 mg/d

75–150 mg/d

Yes

Chlorthalidone

40–60

65

25 mg/d

25–50 mg/d

No

Clonidine

8–12

95

0.2 mg/d

0.2–1.2 mg/d

Yes

Diltiazem

3.5

40

120–140 mg/d

240–360 mg/d

No

Hydralazine

1.5–3

25

40 mg/d

40–200 mg/d

No

Hydrochlorothiazide

12

70

25 mg/d

25–50 mg/d

No

Lisinopril

12

25

10 mg/d

10–80 mg/d

Yes

3

Losartan

1–2

36

50 mg/d

25–100 mg/d

No

Methyldopa

2

25

1 g/d

1–2 g/d

No

Metoprolol

3–7

40

50–100 mg/d

200–400 mg/d

No

Minoxidil

4

90

5–10 mg/d

40 mg/d

No

4

Nebivolol

12

Nd

5 mg/d

10–40 mg/d

No

Nifedipine

2

50

30 mg/d

30–60 mg/d

No

Prazosin

3–4

70

3 mg/d

10–30 mg/d

No

Propranolol

3–5

25

80 mg/d

80–480 mg/d

No

Reserpine

24–48

50

0.25 mg/d

0.25 mg/d

No

Verapamil

4–6

22

180 mg/d

240–480 mg/d

No

1

Creatinine clearance ≥30 mL/min. Many of these drugs do require dosage adjustment if creatinine clearance falls below 30 mL/min.

2

The active metabolite of benazepril has a half-life of 10 hours.

3

The active metabolite of losartan has a half-life of 3–4 hours.

4

Nd, not determined.

angiotensin III. Angiotensin II can also be converted to angiotensin III in the brain by the enzyme aminopeptidase A. Brain angiotensin III exerts tonic control on blood pressure and is implicated in development of hypertension in animals. Angiotensin II has vasoconstrictor and sodium-retaining activity. Angiotensin II and III both stimulate aldosterone release. Angiotensin may contribute to maintaining high vascular resistance in hypertensive states associated with high plasma renin activity, such as renal arterial stenosis, some types of intrinsic renal disease, and malignant hypertension, as well as in essential hypertension after treatment with sodium restriction, diuretics, or vasodilators. However, even in low-renin hypertensive states, these drugs can lower blood pressure (see below). A parallel system for angiotensin generation exists in several other tissues (eg, heart) and may be responsible for trophic changes such as cardiac hypertrophy. The converting enzyme involved in tissue angiotensin II synthesis is also inhibited by ACE inhibitors. Three currently marketed classes of drugs act specifically on the renin-angiotensin system: ACE inhibitors; the competitive inhibitors of angiotensin at its receptors (angiotensin receptor blockers or ARBs), including losartan and other nonpeptide antagonists;

and aliskiren, an orally active renin antagonist (see Chapter 17). A fourth group of drugs, the aldosterone receptor inhibitors (eg, spironolactone, eplerenone), is discussed with the diuretics. In addition, β blockers, as noted earlier, can reduce renin secretion. The experimental drug firibastat inhibits brain aminopeptidase and has been shown to lower blood pressure in hypertensive overweight patients.

ANGIOTENSIN-CONVERTING ENZYME (ACE) INHIBITORS Captopril and other drugs in this class inhibit the converting enzyme peptidyl dipeptidase that hydrolyzes angiotensin I to angiotensin II and (under the name plasma kininase) inactivates bradykinin, a potent vasodilator that works at least in part by stimulating release of nitric oxide and prostacyclin. The hypotensive activity of captopril results from both an inhibitory action on the renin-angiotensin system and a stimulating action on the kallikrein-kinin system (see Figure 11–5). The latter mechanism has been demonstrated by showing that a bradykinin receptor

184    SECTION III  Cardiovascular-Renal Drugs

Kininogen

Angiotensinogen

Renin

Kallikrein – Aliskiren Bradykinin

Angiotensin I

Increased prostaglandin synthesis

Angiotensin-converting enzyme (kininase II) – Angiotensin II

ACE inhibitors

Inactive metabolites

ARBs –

–

Vasoconstriction

Vasodilation

Aldosterone secretion –

Increased peripheral vascular resistance

Increased sodium and water retention

Increased blood pressure

Spironolactone, eplerenone Decreased peripheral vascular resistance

Decreased blood pressure

FIGURE 11–5  Sites of action of drugs that interfere with the renin-angiotensin-aldosterone system. ACE, angiotensin-converting enzyme; ARBs, angiotensin receptor blockers.

antagonist, icatibant (see Chapter 17), blunts the blood pressure– lowering effect of captopril. Enalapril is an oral prodrug that is converted by hydrolysis to a converting enzyme inhibitor, enalaprilat, with effects similar to those of captopril. Enalaprilat itself is available only for intravenous use, primarily for hypertensive emergencies. Lisinopril is a lysine derivative of enalaprilat. Benazepril, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril, and trandolapril are other long-acting members of the class. All except lisinopril are prodrugs, like enalapril, and are converted to the active agents by hydrolysis, primarily in the liver. Angiotensin II inhibitors lower blood pressure principally by decreasing peripheral vascular resistance. Cardiac output and heart rate are not significantly changed. Unlike direct vasodilators, these agents do not result in reflex sympathetic activation and can be used safely in persons with ischemic heart disease. The absence of reflex tachycardia may be due to downward resetting of the baroreceptors or to enhanced parasympathetic activity. Although converting enzyme inhibitors are most effective in conditions associated with high plasma renin activity, there is no good correlation among subjects between plasma renin activity

and antihypertensive response. Accordingly, renin profiling is unnecessary. ACE inhibitors have a particularly useful role in treating patients with chronic kidney disease because they diminish proteinuria and stabilize renal function (even in the absence of lowering of blood pressure). This effect is particularly valuable in diabetes, and these drugs are now recommended in diabetes even in the absence of hypertension. These benefits probably result from improved intrarenal hemodynamics, with decreased glomerular efferent arteriolar resistance and a resulting reduction of intraglomerular capillary pressure. ACE inhibitors have also proved to be extremely useful in the treatment of heart failure and as treatment after myocardial infarction, and there is evidence that ACE inhibitors reduce the incidence of diabetes in patients with high cardiovascular risk (see Chapter 13).

Pharmacokinetics & Dosage Captopril’s pharmacokinetic parameters and dosing recommendations are listed in Table 11–2. Peak concentrations of enalaprilat, the active metabolite of enalapril, occur 3–4 hours after dosing

CHAPTER 11  Antihypertensive Agents    185

with enalapril. The half-life of enalaprilat is about 11 hours. Typical doses of enalapril are 10–20 mg once or twice daily. Lisinopril has a half-life of 12 hours. Doses of 10–80 mg once daily are effective in most patients. All of the ACE inhibitors except fosinopril and moexipril are eliminated primarily by the kidneys; doses of these drugs should be reduced in patients with renal insufficiency.

TABLE 11–3  Mechanisms of action of vasodilators.

Toxicity Severe hypotension can occur after initial doses of any ACE inhibitor in patients who are hypovolemic as a result of diuretics, salt restriction, or gastrointestinal fluid loss. Other adverse effects common to all ACE inhibitors include acute renal failure (particularly in patients with bilateral renal artery stenosis or stenosis of the renal artery of a solitary kidney), hyperkalemia, dry cough sometimes accompanied by wheezing, and angioedema. Hyperkalemia is more likely to occur in patients with renal insufficiency or diabetes. Bradykinin and substance P seem to be responsible for the cough and angioedema seen with ACE inhibition. ACE inhibitors are contraindicated during the second and third trimesters of pregnancy because of the risk of fetal hypotension, anuria, and renal failure, sometimes associated with fetal malformations or death. Recent evidence also implicates first-trimester exposure to ACE inhibitors in increased teratogenic risk. Captopril, particularly when given in high doses to patients with renal insufficiency, may cause neutropenia or proteinuria. Minor toxic effects seen more typically include altered sense of taste, allergic skin rashes, and drug fever, which may occur in up to 10% of patients. Important drug interactions include those with potassium supplements or potassium-sparing diuretics, which can result in hyperkalemia. Nonsteroidal anti-inflammatory drugs may impair the hypotensive effects of ACE inhibitors by blocking bradykininmediated vasodilation, which is at least in part prostaglandin mediated.

ANGIOTENSIN RECEPTOR-BLOCKING AGENTS Losartan and valsartan were the first marketed blockers of the angiotensin II type 1 (AT1) receptor. Azilsartan, candesartan, eprosartan, irbesartan, olmesartan, and telmisartan are also available. They have no effect on bradykinin metabolism and are therefore more selective blockers of angiotensin effects than ACE inhibitors. They also have the potential for more complete inhibition of angiotensin action compared with ACE inhibitors because there are enzymes other than ACE that are capable of generating angiotensin II. Angiotensin receptor blockers provide benefits similar to those of ACE inhibitors in patients with heart failure and chronic kidney disease. Losartan’s pharmacokinetic parameters are listed in Table 11–2. The adverse effects are generally similar to those described for ACE inhibitors, including the hazard of use during pregnancy. Cough and angioedema can occur but are uncommon. In the past, angiotensin receptor-blocking drugs were most commonly used in patients who had adverse reactions such as cough or angioedema with ACE inhibitors, but now many

Mechanism

Examples

Release of nitric oxide from drug or endothelium

Nitroprusside, hydralazine, 1 nitrates, histamine, acetylcholine

Reduction of calcium influx

Verapamil, diltiazem, nifedipine1

Hyperpolarization of cell membranes through opening of potassium channels

Minoxidil, diazoxide

Activation of dopamine receptors

Fenoldopam

1

See Chapter 12.

clinicians prefer to begin with angiotensin receptor blockers to avoid such adverse reactions. Combinations of ACE inhibitors and angiotensin receptor blockers or aliskiren, which had once been considered useful for more complete inhibition of the renin-angiotensin system, are not recommended due to toxicity demonstrated in recent clinical trials. Valsartan in combination with sacubitril (a neprilysin inhibitor) is marketed for heart failure.

VASODILATORS Mechanism & Sites of Action This class of drugs includes the oral vasodilators, hydralazine and minoxidil, which are used for long-term outpatient therapy of hypertension; the parenteral vasodilators, nitroprusside and fenoldopam, which are used to treat hypertensive emergencies; the calcium channel blockers, which are used in both circumstances; and the nitrates, which are used mainly in ischemic heart disease but sometimes also in hypertensive emergencies (Table 11–3). Chapter 12 contains additional discussion of vasodilators. All the vasodilators that are useful in hypertension relax smooth muscle of arterioles, thereby decreasing systemic vascular resistance. Sodium nitroprusside and the nitrates also relax veins. Decreased arterial resistance and decreased mean arterial blood pressure elicit compensatory responses, mediated by baroreceptors and the sympathetic nervous system (see Figure 11–4), as well as increases in renin, angiotensin, and aldosterone. Because sympathetic reflexes are intact, vasodilator therapy does not cause orthostatic hypotension or sexual dysfunction. Vasodilators work best in combination with other antihypertensive drugs that oppose the compensatory cardiovascular responses. (See Box: Resistant Hypertension & Polypharmacy.)

HYDRALAZINE Hydralazine, a hydrazine derivative, dilates arterioles but not veins. It has been available for many years, although it was initially thought not to be particularly effective because tachyphylaxis to its antihypertensive effects developed rapidly. The benefits of combination therapy are now recognized, and hydralazine may be used more effectively, particularly in severe hypertension. The combination of hydralazine with nitrates is effective in heart failure and

186    SECTION III  Cardiovascular-Renal Drugs

should be considered in patients with both hypertension and heart failure, especially in patients who are intolerant to angiotensin inhibiting drugs.

with renal failure and severe hypertension, who do not respond well to hydralazine. O

Pharmacokinetics & Dosage Hydralazine is well absorbed and rapidly metabolized by the liver during the first pass, so that bioavailability is low (averaging 25%) and variable among individuals. It is metabolized in part by acetylation at a rate that appears to be bimodally distributed in the population (see Chapter 4). As a consequence, rapid acetylators have greater first-pass metabolism, lower blood levels, and less antihypertensive benefit from a given dose than do slow acetylators. The half-life of hydralazine ranges from 1.5 to 3 hours, but vascular effects persist longer than do blood concentrations, possibly due to avid binding to vascular tissue. N

N

H2N

NH2

N N

Minoxidil

Pharmacokinetics & Dosage Pharmacokinetic parameters of minoxidil are listed in Table 11–2. Even more than with hydralazine, the use of minoxidil is associated with reflex sympathetic stimulation and sodium and fluid retention. Minoxidil must be used in combination with a β blocker and a diuretic.

N N H

NH2

Hydralazine

Usual dosage ranges from 40 to 200 mg/d. The higher dosage was selected as the dose at which there is a small possibility of developing the lupus erythematosus-like syndrome described in the next section. However, higher dosages result in greater vasodilation and may be used if necessary. Dosing two or three times daily provides smooth control of blood pressure.

Toxicity The most common adverse effects of hydralazine are headache, nausea, anorexia, palpitations, sweating, and flushing. In patients with ischemic heart disease, reflex tachycardia and sympathetic stimulation may provoke angina or ischemic arrhythmias. With dosages of 400 mg/d or more, there is a 10–20% incidence— chiefly in persons who slowly acetylate the drug—of a syndrome characterized by arthralgia, myalgia, skin rashes, and fever that resembles lupus erythematosus. The syndrome is not associated with renal damage and is reversed by discontinuance of hydralazine. Peripheral neuropathy and drug fever are other serious but uncommon adverse effects.

Toxicity Tachycardia, palpitations, angina, and edema are observed when doses of co-administered β blockers and diuretics are inadequate. Headache, sweating, and hypertrichosis (the latter particularly bothersome in women) are relatively common. Minoxidil illustrates how one person’s toxicity may become another person’s therapy. Topical minoxidil (as Rogaine) is used as a stimulant to hair growth for correction of baldness.

SODIUM NITROPRUSSIDE Sodium nitroprusside is a powerful parenterally administered vasodilator that is used in treating hypertensive emergencies as well as severe heart failure. Nitroprusside dilates both arterial and venous vessels, resulting in reduced peripheral vascular resistance and venous return. The action occurs as a result of activation of guanylyl cyclase, either via release of nitric oxide or by direct stimulation of the enzyme. The result is increased intracellular cGMP, which relaxes vascular smooth muscle (see Figure 12–2). In the absence of heart failure, blood pressure decreases, owing to decreased vascular resistance, whereas cardiac output does not change or decreases slightly. In patients with heart failure and low cardiac output, output often increases owing to afterload reduction. +

NO

MINOXIDIL –

Minoxidil is a very efficacious orally active vasodilator. The effect results from the opening of potassium channels in smooth muscle membranes by minoxidil sulfate, the active metabolite. Increased potassium permeability stabilizes the membrane at its resting potential and makes contraction less likely. Like hydralazine, minoxidil dilates arterioles but not veins. Because of its greater potential antihypertensive effect, minoxidil should replace hydralazine when maximal doses of the latter are not effective or in patients

CN–

CN

Fe2+ CN–

CN– CN– Nitroprusside

CHAPTER 11  Antihypertensive Agents    187

Pharmacokinetics & Dosage Nitroprusside is a complex of iron, cyanide groups, and a nitroso moiety. It is rapidly metabolized by uptake into red blood cells with release of nitric oxide and cyanide. Cyanide in turn is metabolized by the mitochondrial enzyme rhodanese, in the presence of a sulfur donor, to the less toxic thiocyanate. Thiocyanate is distributed in extracellular fluid and slowly eliminated by the kidney. Nitroprusside rapidly lowers blood pressure, and its effects disappear within 1–10 minutes after discontinuation. The drug is given by intravenous infusion. Sodium nitroprusside in aqueous solution is sensitive to light and must therefore be made up fresh before each administration and covered with opaque foil. Infusion solutions should be changed after several hours. Dosage typically begins at 0.5 mcg/kg/min and may be increased up to 10 mcg/kg/min as necessary to control blood pressure. Higher rates of infusion, if continued for more than an hour, may result in toxicity. Because of its efficacy and rapid onset of effect, nitroprusside should be administered by infusion pump and arterial blood pressure continuously monitored via intraarterial recording.

Toxicity Other than excessive blood pressure lowering, the most serious toxicity is related to accumulation of cyanide; metabolic acidosis, arrhythmias, excessive hypotension, and death have resulted. In a few cases, toxicity after relatively low doses of nitroprusside suggested a defect in cyanide metabolism. Administration of sodium thiosulfate as a sulfur donor facilitates metabolism of cyanide. Hydroxocobalamin combines with cyanide to form the nontoxic cyanocobalamin. Both have been advocated for prophylaxis or treatment of cyanide poisoning during nitroprusside infusion. Thiocyanate may accumulate over the course of prolonged administration, usually several days or more, particularly in patients with renal insufficiency who do not excrete thiocyanate at a normal rate. Thiocyanate toxicity is manifested as weakness, disorientation, psychosis, muscle spasms, and convulsions, and the diagnosis is confirmed by finding serum concentrations greater than 10 mg/dL. Rarely, delayed hypothyroidism occurs, owing to thiocyanate inhibition of iodide uptake by the thyroid. Methemoglobinemia during infusion of nitroprusside has also been reported.

DIAZOXIDE Diazoxide is an effective and relatively long-acting potassium channel opener that causes hyperpolarization in smooth muscle and pancreatic β cells. Because of its arteriolar dilating property, it was formerly used parenterally to treat hypertensive emergencies. Injection of diazoxide results in a rapid fall in systemic vascular resistance and mean arterial blood pressure. Injectable diazoxide is no longer available in the USA. Diazoxide also inhibits insulin release from the pancreas (probably by opening potassium

channels in the beta cell membrane) and is used at present in the USA to treat hypoglycemia caused by hyperinsulinism secondary to insulinoma. N

CH3 CI

NH S O2 Diazoxide

Pharmacokinetics & Dosage Oral dosage for hypoglycemia is 3–8 mg/kg/d in three divided doses, with a maximum of 15 mg/kg/d. Diazoxide is similar chemically to the thiazide diuretics but has no diuretic activity. It is bound extensively to serum albumin and to vascular tissue. Diazoxide is partially metabolized; its metabolic pathways are not well characterized. The remainder is excreted unchanged. Its halflife is approximately 24 hours, but the relationship between blood concentration and hypotensive action is not well established. The blood pressure-lowering effect after a rapid injection is established within 5 minutes and lasts for 4–12 hours. When diazoxide was first marketed for use in hypertension, a dose of 300 mg by rapid injection was recommended. It appears, however, that excessive hypotension can be avoided by beginning with smaller doses (50–150 mg). If necessary, doses of 150 mg may be repeated every 5–15 minutes until blood pressure is lowered satisfactorily. Alternatively, diazoxide may be administered by intravenous infusion at rates of 15–30 mg/min. Because of reduced protein binding, smaller doses should be administered to persons with chronic renal failure. The hypotensive effects of diazoxide are also greater when patients are pretreated with β blockers to prevent the reflex tachycardia and associated increase in cardiac output.

Toxicity The most significant toxicity from parenteral diazoxide has been excessive hypotension, resulting from the original recommendation to use a fixed dose of 300 mg in all patients. Such hypotension has resulted in stroke and myocardial infarction. The reflex sympathetic response can provoke angina, electrocardiographic evidence of ischemia, and cardiac failure in patients with ischemic heart disease, and diazoxide should be avoided in this situation. Occasionally, hyperglycemia complicates diazoxide use, particularly in persons with renal insufficiency. In contrast to the structurally related thiazide diuretics, diazoxide causes renal salt and water retention. However, because the drug is used for short periods only, this is rarely a problem.

FENOLDOPAM Fenoldopam is a peripheral arteriolar dilator used for hypertensive emergencies and postoperative hypertension. It acts primarily as an agonist of dopamine D1 receptors, resulting in dilation of

188    SECTION III  Cardiovascular-Renal Drugs

peripheral arteries and natriuresis. The commercial product is a racemic mixture with the (R)-isomer mediating the pharmacologic activity. Fenoldopam is rapidly metabolized, primarily by conjugation. Its half-life is 10 minutes. The drug is administered by continuous intravenous infusion. Fenoldopam is initiated at a low dosage (0.1 mcg/kg/min), and the dose is then titrated upward every 15 or 20 minutes to a maximum dose of 1.6 mcg/kg/min or until the desired blood pressure reduction is achieved. As with other direct vasodilators, the major toxicities are reflex tachycardia, headache, and flushing. Fenoldopam also increases intraocular pressure and should be avoided in patients with glaucoma.

CALCIUM CHANNEL BLOCKERS In addition to their antianginal (see Chapter 12) and antiarrhythmic effects (see Chapter 14), calcium channel blockers also reduce peripheral resistance and blood pressure. The mechanism of action in hypertension (and, in part, in angina) is inhibition of calcium influx into arterial smooth muscle cells. Verapamil, diltiazem, and the dihydropyridine family (amlodipine, felodipine, isradipine, nicardipine, nifedipine, nisoldipine, nimodipine, and nitrendipine [the latter two not available in the USA]) are all equally effective in lowering blood pressure. Clevidipine is a newer member of this group that is formulated for intravenous use only. Hemodynamic differences among calcium channel blockers may influence the choice of a particular agent. Amlodipine and the other dihydropyridine agents are more selective as vasodilators and have less cardiac depressant effect than verapamil and diltiazem. Reflex sympathetic activation with slight tachycardia maintains or increases cardiac output in most patients given dihydropyridines. Verapamil has the greatest depressant effect on the heart and may decrease heart rate and cardiac output. Diltiazem has intermediate actions. The pharmacology and toxicity of these drugs are discussed in more detail in Chapter 12. Doses of calcium channel blockers used in treating hypertension are similar to those used in treating angina. Some epidemiologic studies reported an increased risk of myocardial infarction or mortality in patients receiving short-acting nifedipine for hypertension. It is therefore recommended that short-acting oral dihydropyridines not be used for hypertension. Sustained-release calcium blockers or calcium blockers with long half-lives provide smoother blood pressure control and are more appropriate for treatment of chronic hypertension. Intravenous nicardipine and clevidipine are available for the treatment of hypertension when oral therapy is not feasible; parenteral verapamil and diltiazem can also be used for the same indication. Nicardipine is typically infused at rates of 2–15 mg/h. Clevidipine is infused starting at 1–2 mg/h and progressing to 4–6 mg/h. It has a rapid onset of action and has been used in acute hypertension occurring during surgery. Oral short-acting nifedipine has been used in emergency management of severe hypertension.

DRUGS THAT ALTER SYMPATHETIC NERVOUS SYSTEM FUNCTION In many patients, hypertension is initiated and sustained at least in part by sympathetic neural activation. In patients with moderate to severe hypertension, drug regimens that include an agent that inhibits function of the sympathetic nervous system may be needed for optimal blood pressure control. Drugs in this group are classified according to the site at which they impair the sympathetic reflex arc (see Figure 11–2). This neuroanatomic classification explains prominent differences in cardiovascular effects of drugs and allows the clinician to predict interactions of these drugs with one another and with other drugs. The subclasses of sympathoplegic drugs exhibit different patterns of potential toxicity. Drugs that lower blood pressure by actions on the central nervous system tend to cause sedation and mental depression and may produce disturbances of sleep, including nightmares. Drugs that act by inhibiting transmission through autonomic ganglia (ganglion blockers) produce toxicity from inhibition of parasympathetic regulation, in addition to profound sympathetic blockade, and are no longer used. Drugs that act chiefly by reducing release of norepinephrine from sympathetic nerve endings cause effects that are similar to those of surgical sympathectomy, including inhibition of ejaculation, and hypotension that is increased by upright posture and after exercise. Drugs that block postsynaptic adrenoceptors produce a more selective spectrum of effects depending on the class of receptor to which they bind. Finally, one should note that all of the agents that lower blood pressure by altering sympathetic function can elicit compensatory effects through mechanisms that are not dependent on adrenergic nerves. Thus, the antihypertensive effect of any of these agents used alone may be limited by retention of sodium by the kidney and expansion of blood volume. For this reason, sympathoplegic antihypertensive drugs are most effective when used concomitantly with a diuretic.

CENTRALLY ACTING SYMPATHOPLEGIC DRUGS Centrally acting sympathoplegic drugs were once widely used in the treatment of hypertension. With the exception of clonidine, these drugs are rarely used today.

Mechanisms & Sites of Action These agents reduce sympathetic outflow from vasomotor centers in the brain stem but allow these centers to retain or even increase their sensitivity to baroreceptor control. Accordingly, the antihypertensive and toxic actions of these drugs are generally less dependent on posture than are the effects of drugs that act directly on peripheral sympathetic neurons. Methyldopa (l-α-methyl-3,4-dihydroxyphenylalanine) is an analog of l-dopa and is converted to α-methyldopamine and α-methylnorepinephrine; this pathway directly parallels the

CHAPTER 11  Antihypertensive Agents    189

synthesis of norepinephrine from dopa illustrated in Figure 6–5. Alpha-methylnorepinephrine is stored in adrenergic nerve vesicles, where it stoichiometrically replaces norepinephrine, and is released by nerve stimulation to interact with postsynaptic adrenoceptors. However, this replacement of norepinephrine by a false transmitter in peripheral neurons is not responsible for methyldopa’s antihypertensive effect, because the α-methylnorepinephrine released is an effective agonist at the α adrenoceptors that mediate peripheral sympathetic constriction of arterioles and venules. In fact, methyldopa’s antihypertensive action appears to be due to stimulation of central α adrenoceptors by α-methylnorepinephrine or α-methyldopamine. The antihypertensive action of clonidine, a 2-imidazoline derivative, was discovered in the course of testing the drug for use as a nasal decongestant. After intravenous injection, clonidine produces a brief rise in blood pressure followed by more prolonged hypotension. The pressor response is due to direct stimulation of α adrenoceptors in arterioles. The drug is classified as a partial agonist at α receptors because it also inhibits pressor effects of other α agonists. The hypotensive effect of clonidine is exerted at α adrenoceptors in the medulla of the brain. In animals, the hypotensive effect of clonidine is prevented by central administration of α antagonists. Clonidine reduces sympathetic and increases parasympathetic tone, resulting in blood pressure lowering and bradycardia. The reduction in pressure is accompanied by a decrease in circulating catecholamine levels. These observations suggest that clonidine sensitizes brain stem vasomotor centers to inhibition by baroreflexes. Thus, studies of clonidine and methyldopa suggest that normal regulation of blood pressure involves central adrenergic neurons that modulate baroreceptor reflexes. Clonidine and α-methylnorepinephrine bind more tightly to α2 than to α1 adrenoceptors. As noted in Chapter 6, α2 receptors are located on presynaptic adrenergic neurons as well as some postsynaptic sites. It is possible that clonidine and α-methylnorepinephrine act in the brain to reduce norepinephrine release onto relevant receptor sites. Alternatively, these drugs may act on postsynaptic α2 adrenoceptors to inhibit activity of appropriate neurons. Finally, clonidine also binds to a nonadrenoceptor site, the imidazoline receptor, which may also mediate antihypertensive effects. Methyldopa and clonidine produce slightly different hemodynamic effects: clonidine lowers heart rate and cardiac output more than does methyldopa. This difference suggests that these two drugs do not have identical sites of action. They may act primarily on different populations of neurons in the vasomotor centers of the brain stem. Guanabenz and guanfacine are centrally active antihypertensive drugs that share the central α-adrenoceptor–stimulating effects of clonidine. They do not appear to offer any advantages over clonidine and are rarely used.

METHYLDOPA Methyldopa was widely used in the past but is now used primarily for hypertension during pregnancy. It lowers blood pressure chiefly by reducing peripheral vascular resistance, with a variable reduction in heart rate and cardiac output.

Most cardiovascular reflexes remain intact after administration of methyldopa, and blood pressure reduction is not markedly dependent on posture. Postural (orthostatic) hypotension sometimes occurs, particularly in volume-depleted patients. One potential advantage of methyldopa is that it causes reduction in renal vascular resistance. OH

HO

HO

CH2

C

O

C

NH2

CH3 α-Methyldopa (α-methyl group in color)

Pharmacokinetics & Dosage Pharmacokinetic characteristics of methyldopa are listed in Table 11–2. Methyldopa enters the brain via an aromatic amino acid transporter. The usual oral dose of methyldopa produces its maximal antihypertensive effect in 4–6 hours, and the effect can persist for up to 24 hours. Because the effect depends on accumulation and storage of a metabolite (α-methylnorepinephrine) in the vesicles of nerve endings, the action persists after the parent drug has disappeared from the circulation.

Toxicity The most common undesirable effect of methyldopa is sedation, particularly at the onset of treatment. With long-term therapy, patients may complain of persistent mental lassitude and impaired mental concentration. Nightmares, mental depression, vertigo, and extrapyramidal signs may occur but are relatively infrequent. Lactation, associated with increased prolactin secretion, can occur both in men and in women treated with methyldopa. This toxicity is probably mediated by inhibition of dopaminergic mechanisms in the hypothalamus. Other important adverse effects of methyldopa are development of a positive Coombs test (occurring in 10–20% of patients undergoing therapy for longer than 12 months), which sometimes makes cross-matching blood for transfusion difficult and rarely is associated with hemolytic anemia, as well as hepatitis and drug fever. Discontinuation of the drug usually results in prompt reversal of these abnormalities.

CLONIDINE Blood pressure lowering by clonidine results from reduction of cardiac output due to decreased heart rate and relaxation of capacitance vessels, as well as a reduction in peripheral vascular resistance. CI N NH N CI Clonidine

190    SECTION III  Cardiovascular-Renal Drugs

Reduction in arterial blood pressure by clonidine is accompanied by decreased renal vascular resistance and maintenance of renal blood flow. As with methyldopa, clonidine reduces blood pressure in the supine position and only rarely causes postural hypotension. Pressor effects of clonidine are not observed after ingestion of therapeutic doses of clonidine, but severe hypertension can complicate a massive overdose.

Pharmacokinetics & Dosage Typical pharmacokinetic characteristics are listed in Table 11–2. Clonidine is lipid-soluble and rapidly enters the brain from the circulation. Because of its relatively short half-life and the fact that its antihypertensive effect is directly related to blood concentration, oral clonidine must be given twice a day (or as a patch, below) to maintain smooth blood pressure control. However, as is not the case with methyldopa, the dose-response curve of clonidine is such that increasing doses are more effective (but also more toxic). A transdermal preparation of clonidine that reduces blood pressure for 7 days after a single application is also available. This preparation appears to produce less sedation than clonidine tablets but may be associated with local skin reactions.

Toxicity Dry mouth and sedation are common. Both effects are centrally mediated and dose-dependent and coincide temporally with the drug’s antihypertensive effect. Clonidine should not be given to patients who are at risk for mental depression and should be withdrawn if depression occurs during therapy. Concomitant treatment with tricyclic antidepressants may block the antihypertensive effect of clonidine. The interaction is believed to be due to α-adrenoceptor–blocking actions of the tricyclics. Withdrawal of clonidine after protracted use, particularly with high dosages (more than 1 mg/d), can result in life-threatening hypertensive crisis mediated by increased sympathetic nervous activity. Patients exhibit nervousness, tachycardia, headache, and sweating after omitting one or two doses of the drug. Because of the risk of severe hypertensive crisis when clonidine is suddenly withdrawn, all patients who take clonidine should be warned of this possibility. If the drug must be stopped, it should be done gradually while other antihypertensive agents are being substituted. Treatment of the hypertensive crisis consists of reinstitution of clonidine therapy or administration of α- and β-adrenoceptor–blocking agents.

GANGLION-BLOCKING AGENTS Historically, drugs that block activation of postganglionic autonomic neurons by acetylcholine were among the first agents used in the treatment of hypertension. Most such drugs are no longer available clinically because of intolerable toxicities related to their primary action (see below).

Ganglion blockers competitively block nicotinic cholinoceptors on postganglionic neurons in both sympathetic and parasympathetic ganglia. In addition, these drugs may directly block the nicotinic acetylcholine channel, in the same fashion as neuromuscular nicotinic blockers. The adverse effects of ganglion blockers are direct extensions of their pharmacologic effects. These effects include both sympathoplegia (excessive orthostatic hypotension and sexual dysfunction) and parasympathoplegia (constipation, urinary retention, precipitation of glaucoma, blurred vision, dry mouth, etc). These severe toxicities are the major reason for the abandonment of ganglion blockers for the therapy of hypertension.

ADRENERGIC NEURON-BLOCKING AGENTS These drugs lower blood pressure by preventing normal physiologic release of norepinephrine from postganglionic sympathetic neurons. They have significant toxicity and are now rarely used.

Guanethidine Guanethidine is no longer available in the USA but may be used elsewhere. In high enough doses, guanethidine can produce profound sympathoplegia. Guanethidine can thus produce all of the toxicities expected from “pharmacologic sympathectomy,” including marked postural hypotension, diarrhea, and impaired ejaculation. Because of these adverse effects, guanethidine is now rarely used. Guanethidine is too polar to enter the central nervous system. As a result, this drug has none of the central effects seen with many of the other antihypertensive agents described in this chapter. Guanadrel is a guanethidine-like drug that is no longer used in the USA. Bethanidine and debrisoquin, antihypertensive agents not available for clinical use in the USA, are similar. A.  Mechanism and Sites of Action Guanethidine inhibits the release of norepinephrine from sympathetic nerve endings (see Figure 6–4). This effect is probably responsible for most of the sympathoplegia that occurs in patients. Guanethidine is transported across the sympathetic nerve membrane by the same mechanism that transports norepinephrine itself (NET, uptake 1), and uptake is essential for the drug’s action. Once guanethidine has entered the nerve, it is concentrated in transmitter vesicles, where it replaces norepinephrine and causes a gradual depletion of norepinephrine stores in the nerve ending. B.  Pharmacokinetics and Dosage Because of guanethidine’s long half-life (5 days), the onset of sympathoplegia is gradual (maximal effect in 1–2 weeks), and sympathoplegia persists for a comparable period after cessation of therapy. The dose should not ordinarily be increased at intervals shorter than 2 weeks.

CHAPTER 11  Antihypertensive Agents    191

C. Toxicity Therapeutic use of guanethidine is often associated with symptomatic postural hypotension and hypotension following exercise, particularly when the drug is given in high doses. Guanethidineinduced sympathoplegia in men may be associated with delayed or retrograde ejaculation (into the bladder). Guanethidine commonly causes diarrhea, which results from increased gastrointestinal motility due to parasympathetic predominance in controlling the activity of intestinal smooth muscle. Interactions with other drugs may complicate guanethidine therapy.

Reserpine Reserpine, an alkaloid extracted from the roots of an Indian plant, Rauwolfia serpentina, was one of the first effective drugs used on a large scale in the treatment of hypertension. Because of adverse effects, it was rarely used and is no longer available in the USA. A.  Mechanism and Sites of Action Reserpine blocks the ability of aminergic transmitter vesicles to take up and store biogenic amines, probably by interfering with the vesicular membrane-associated transporter (VMAT, see Figure 6–4). This effect occurs throughout the body, resulting in depletion of norepinephrine, dopamine, and serotonin in both central and peripheral neurons. Chromaffin granules of the adrenal medulla are also depleted of catecholamines, although to a lesser extent than are the vesicles of neurons. Reserpine’s effects on adrenergic vesicles appear irreversible; trace amounts of the drug remain bound to vesicular membranes for many days. Depletion of peripheral amines probably accounts for much of the beneficial antihypertensive effect of reserpine, but a central component cannot be ruled out. Reserpine readily enters the brain, and depletion of cerebral amine stores causes sedation, mental depression, and parkinsonism symptoms. At lower doses used for treatment of mild hypertension, reserpine lowers blood pressure by a combination of decreased cardiac output and decreased peripheral vascular resistance. B.  Pharmacokinetics and Dosage See Table 11–2. C. Toxicity At the low doses usually administered, reserpine produces little postural hypotension. Most of the unwanted effects of reserpine result from actions on the brain or gastrointestinal tract. High doses of reserpine characteristically produce sedation, lassitude, nightmares, and severe mental depression; occasionally, these occur even in patients receiving low doses (0.25 mg/d). Much less frequently, ordinary low doses of reserpine produce extrapyramidal effects resembling Parkinson disease, probably as a result of dopamine depletion in the corpus striatum. Patients with a history of mental depression should not receive reserpine, and the drug should be stopped if depression appears.

Reserpine rather often produces mild diarrhea and gastrointestinal cramps and increases gastric acid secretion. The drug should not be given to patients with a history of peptic ulcer.

ADRENOCEPTOR ANTAGONISTS The detailed pharmacology of α- and β-adrenoceptor blockers is presented in Chapter 10.

BETA-ADRENOCEPTOR–BLOCKING AGENTS Of the large number of β blockers tested, most have been shown to be effective in lowering blood pressure. The pharmacologic properties of several of these agents differ in ways that may confer therapeutic benefits in certain clinical situations.

Propranolol Propranolol was the first β blocker shown to be effective in hypertension and ischemic heart disease. Propranolol has now been largely replaced by cardioselective β blockers such as metoprolol. All β-adrenoceptor–blocking agents are useful for lowering blood pressure in mild to moderate hypertension. In severe hypertension, β blockers are especially useful in preventing the reflex tachycardia that often results from treatment with direct vasodilators. Beta blockers have been shown to reduce mortality after a myocardial infarction and some also reduce mortality in patients with heart failure; they are particularly advantageous for treating hypertension in patients with these conditions (see Chapter 13). A.  Mechanism and Sites of Action Propranolol’s efficacy in treating hypertension as well as most of its toxic effects result from nonselective β blockade. Propranolol decreases blood pressure primarily as a result of a decrease in cardiac output. Other β blockers may decrease cardiac output or decrease peripheral vascular resistance to various degrees, depending on cardioselectivity and partial agonist activities. Propranolol inhibits the stimulation of renin production by catecholamines (mediated by β1 receptors). It is likely that propranolol’s antihypertensive effect is due in part to depression of the reninangiotensin-aldosterone system. Although most effective in patients with high plasma renin activity, propranolol also reduces blood pressure in hypertensive patients with normal or even low renin activity. Beta blockers might also act on peripheral presynaptic β adrenoceptors to reduce sympathetic vasoconstrictor nerve activity. In mild to moderate hypertension, propranolol produces a significant reduction in blood pressure without prominent postural hypotension. B.  Pharmacokinetics and Dosage See Table 11–2. Resting bradycardia and a reduction in the heart rate during exercise are indicators of propranolol’s β-blocking effect, and changes in these parameters may be used as guides for

192    SECTION III  Cardiovascular-Renal Drugs

regulating dosage. Propranolol can be administered twice daily, and slow-release once-daily preparations are available.

Patients with reduced renal function should receive correspondingly reduced doses of nadolol and carteolol.

C. Toxicity The principal toxicities of propranolol result from blockade of cardiac, vascular, or bronchial β receptors and are described in more detail in Chapter 10. The most important of these predictable extensions of the β1-blocking action occur in patients with bradycardia or cardiac conduction disease, and those of the β2-blocking action occur in patients with asthma, peripheral vascular insufficiency, and diabetes. When β blockers are discontinued after prolonged regular use, some patients experience a withdrawal syndrome, manifested by nervousness, tachycardia, increased intensity of angina, and increase of blood pressure. Myocardial infarction has been reported in a few patients. Although the incidence of these complications is probably low, β blockers should not be discontinued abruptly. The withdrawal syndrome may involve up-regulation or supersensitivity of β adrenoceptors.

Pindolol, Acebutolol, & Penbutolol

Metoprolol & Atenolol Metoprolol and atenolol, which are cardioselective, are the most widely used β blockers in the treatment of hypertension. Metoprolol is approximately equipotent to propranolol in inhibiting stimulation of β1 adrenoceptors such as those in the heart but 50to 100-fold less potent than propranolol in blocking β2 receptors. Relative cardioselectivity is advantageous in treating hypertensive patients who also suffer from asthma, diabetes, or peripheral vascular disease. Although cardioselectivity is not complete, metoprolol causes less bronchial constriction than propranolol at doses that produce equal inhibition of β1-adrenoceptor responses. Metoprolol is extensively metabolized by CYP2D6 with high first-pass metabolism. The drug has a relatively short half-life of 4–6 hours, but the extended-release preparation can be dosed once daily (see Table 11–2). Sustained-release metoprolol is effective in reducing mortality from heart failure and is particularly useful in patients with hypertension and heart failure. Atenolol is not extensively metabolized and is excreted primarily in the urine with a half-life of 6 hours; it is usually dosed once daily. Atenolol has been found to be less effective than metoprolol in preventing the complications of hypertension. A possible reason for this difference is that once-daily dosing does not maintain adequate blood levels of atenolol. The usual dosage is 50–100 mg/d. Patients with reduced renal function should receive lower doses.

Nadolol, Carteolol, Betaxolol, & Bisoprolol Nadolol and carteolol, nonselective β-receptor antagonists, are not appreciably metabolized and are excreted to a considerable extent in the urine. Betaxolol and bisoprolol are β1-selective blockers that are primarily metabolized in the liver but have long halflives. Because of these relatively long half-lives, these drugs can be administered once daily. Nadolol is usually begun at a dosage of 40 mg/d, carteolol at 2.5 mg/d, betaxolol at 10 mg/d, and bisoprolol at 5 mg/d. Increases in dosage to obtain a satisfactory therapeutic effect should take place no more often than every 4 or 5 days.

Pindolol, acebutolol, and penbutolol are partial agonists, ie, β blockers with some intrinsic sympathomimetic activity. They lower blood pressure but are rarely used in hypertension.

Labetalol, Carvedilol, & Nebivolol These drugs have both β-blocking and vasodilating effects. Labetalol is formulated as a racemic mixture of four isomers (it has two centers of asymmetry). Two of these isomers—the (S,S)- and (R,S)-isomers—are relatively inactive, a third (S,R)- is a potent α blocker, and the last (R,R)- is a potent β blocker. Labetalol has a 3:1 ratio of β:α antagonism after oral dosing. Blood pressure is lowered by reduction of systemic vascular resistance (via α blockade) without significant alteration in heart rate or cardiac output. Because of its combined α- and β-blocking activity, labetalol is useful in treating the hypertension of pheochromocytoma and hypertensive emergencies. Oral daily doses of labetalol range from 200 to 2400 mg/d. Labetalol is given as repeated intravenous bolus injections of 20–80 mg to treat hypertensive emergencies. Carvedilol, like labetalol, is administered as a racemic mixture. The S(-) isomer is a nonselective β-adrenoceptor blocker, but both S(-) and R(+) isomers have approximately equal α-blocking potency. The isomers are stereoselectively metabolized in the liver, which means that their elimination half-lives may differ. The average half-life is 7–10 hours. The usual starting dosage of carvedilol for ordinary hypertension is 6.25 mg twice daily. Carvedilol reduces mortality in patients with heart failure and is therefore particularly useful in patients with both heart failure and hypertension. Nebivolol is a β1-selective blocker with vasodilating properties that are not mediated by α blockade. d-Nebivolol has highly selective β1-blocking effects, while the l-isomer causes vasodilation; the drug is marketed as a racemic mixture. The vasodilating effect may be due to an increase in endothelial release of nitric oxide via induction of endothelial nitric oxide synthase. The hemodynamic effects of nebivolol therefore differ from those of pure β blockers in that peripheral vascular resistance is acutely lowered (by nebivolol) as opposed to increased acutely (by the older agents). Nebivolol is extensively metabolized and has active metabolites. The half-life is 10–12 hours, but the drug can be given once daily. Dosing is generally started at 5 mg/d, with dose escalation as high as 40 mg/d, if necessary. The efficacy of nebivolol is similar to that of other antihypertensive agents, but several studies report fewer adverse effects.

Esmolol Esmolol is a β1-selective blocker that is rapidly metabolized via hydrolysis by red blood cell esterases. It has a short halflife (9–10 minutes) and is administered by intravenous infusion. Esmolol is generally administered as a loading dose (0.5–1 mg/kg), followed by a constant infusion. The infusion is typically started at 50–150 mcg/kg/min, and the dose increased

CHAPTER 11  Antihypertensive Agents    193

every 5 minutes, up to 300 mcg/kg/min, as needed to achieve the desired therapeutic effect. Esmolol is used for management of intraoperative and postoperative hypertension, and sometimes for hypertensive emergencies, particularly when hypertension is associated with tachycardia or when there is concern about toxicity such as aggravation of severe heart failure, in which case a drug with a short duration of action that can be discontinued quickly is advantageous.

PRAZOSIN & OTHER ALPHA1 BLOCKERS Mechanism & Sites of Action Prazosin, terazosin, and doxazosin produce most of their antihypertensive effects by selectively blocking α1 receptors in arterioles and venules. These agents produce less reflex tachycardia when lowering blood pressure than do nonselective α antagonists such as phentolamine. Alpha1-receptor selectivity allows norepinephrine to exert unopposed negative feedback (mediated by presynaptic α2 receptors) on its own release (see Chapter 6); in contrast, phentolamine blocks both presynaptic and postsynaptic α receptors, with the result that reflex activation of sympathetic neurons by phentolamine’s effects produces greater release of transmitter onto β receptors and correspondingly greater cardioacceleration. Alpha blockers reduce arterial pressure by dilating both resistance and capacitance vessels. As expected, blood pressure is reduced more in the upright than in the supine position. Retention of salt and water occurs when these drugs are administered without a diuretic. The drugs are more effective when used in combination with other agents, such as a β blocker and a diuretic, than when used alone. Owing to their beneficial effects in men with prostatic hyperplasia and bladder obstruction symptoms, these drugs are used primarily in men with concurrent hypertension and benign prostatic hyperplasia.

Pharmacokinetics & Dosage Pharmacokinetic characteristics of prazosin are listed in Table 11–2. Terazosin is also extensively metabolized but undergoes very little first-pass metabolism and has a half-life of 12 hours. Doxazosin has an intermediate bioavailability and a half-life of 22 hours. Terazosin can often be given once daily, with doses of 5–20 mg/d. Doxazosin is usually given once daily starting at 1 mg/d and progressing to 4 mg/d or more as needed. Although long-term treatment with these α blockers causes relatively little postural hypotension, a precipitous drop in standing blood pressure develops in some patients shortly after the first dose is absorbed. For this reason, the first dose should be small and should be administered at bedtime. Although the mechanism of this first-dose phenomenon is not clear, it occurs more commonly in patients who are salt- and volume-depleted. Aside from the first-dose phenomenon, the reported toxicities of the α1 blockers are relatively infrequent and mild. These include dizziness, palpitations, headache, and lassitude. Some patients develop a positive test for antinuclear factor in serum while on prazosin therapy, but this has not been associated with rheumatic symptoms.

The α1 blockers do not adversely and may even beneficially affect plasma lipid profiles, but this action has not been shown to confer any benefit on clinical outcomes.

OTHER ALPHA-ADRENOCEPTOR– BLOCKING AGENTS The nonselective agents, phentolamine and phenoxybenzamine, are useful in diagnosis and treatment of pheochromocytoma and in other clinical situations associated with exaggerated release of catecholamines (eg, phentolamine may be combined with a β blocker to treat the clonidine withdrawal syndrome, described previously). Their pharmacology is described in Chapter 10.

■■ CLINICAL PHARMACOLOGY OF ANTIHYPERTENSIVE AGENTS Hypertension presents a unique problem in therapeutics. It is usually a lifelong disease that causes few symptoms until the advanced stage. For effective treatment, medicines that may be expensive and sometimes produce adverse effects must be consumed daily. Thus, the physician must establish with certainty that hypertension is persistent and requires treatment and must exclude secondary causes of hypertension that might be treated by definitive surgical procedures. Persistence of hypertension, particularly in persons with mild elevation of blood pressure, should be established by finding an elevated blood pressure with multiple measurements on at least three different office visits. Home or ambulatory blood pressure monitoring may be the best predictor of risk and therefore of need for therapy in mild hypertension, and is recommended for initial evaluation of all patients. Isolated systolic hypertension and hypertension in the elderly also benefit from therapy. Once the presence of hypertension is established, the question of whether to treat with medications and which drugs to use must be considered. The level of blood pressure, the age of the patient, the severity of organ damage (if any) due to high blood pressure, and the cardiovascular risk factors all must be considered. Current guidelines suggest treating people with medications for blood pressure of 140/90 mm Hg or greater if 10-year cardiovascular disease risk is less than 10%, and treatment at or above 130/80 if 10-year risk is 10% or greater. Assessment of renal function and the presence of proteinuria are useful in antihypertensive drug selection. Treatment thresholds and goals are described in Table 11–1. At this stage, the patient must be educated about the nature of hypertension and the importance of treatment so that he or she can make an informed decision regarding therapy. Once the decision is made to treat, a therapeutic regimen must be developed. Selection of drugs is dictated by the level of blood pressure, the presence and severity of end-organ damage, and the presence of other diseases. Severe high blood pressure with lifethreatening complications requires more rapid treatment with more efficacious drugs. Most patients with essential hypertension, however, have had elevated blood pressure for months or years, and therapy is best initiated in a gradual fashion.

194    SECTION III  Cardiovascular-Renal Drugs

Education about the natural history of hypertension and the importance of treatment adherence as well as potential adverse effects of drugs is essential. Obesity should be treated, and drugs that increase blood pressure (sympathomimetic decongestants, nonsteroidal anti-inflammatory drugs, estrogen-containing oral contraceptives, stimulant drug abuse, and some herbal medications) should be eliminated if possible. Follow-up visits should be frequent enough to convince the patient that the physician thinks the illness is serious. With each follow-up visit, the importance of treatment should be reinforced and questions concerning dosing or side effects of medication encouraged. Other factors that may improve compliance are simplifying dosing regimens and having the patient monitor blood pressure at home.

OUTPATIENT THERAPY OF HYPERTENSION The initial step in treating hypertension may be nonpharmacologic. Sodium restriction may be effective treatment for some patients with mild hypertension. Weight reduction has been shown to normalize blood pressure in up to 75% of overweight patients with mild to moderate hypertension. Dietary sodium restriction should be recommended. The average American diet contains about 200 mEq of sodium per day. A reasonable dietary goal in treating hypertension is 70–100 mEq of sodium per day, which can be achieved by not salting food during or after cooking and by avoiding processed foods that contain large amounts of sodium. Eating a diet rich in fruits, vegetables, and low-fat dairy products with a reduced content of saturated and total fat, and moderation of alcohol intake (no more than two drinks per day) also lower blood pressure. Both the DASH (Dietary Approach to Stop Hypertension) and more recently the Chinese Heart-Healthy Diet have been demonstrated to reduce blood pressure in hypertensive adults. Using salt that substitutes potassium for some of the sodium reduces blood pressure and risk of future cardiovascular events. Regular exercise has been shown in some but not all studies to lower blood pressure in hypertensive patients. For pharmacologic management of mild hypertension, blood pressure can be normalized in many patients with a single drug, although it is becoming more common to see the use of lowdose combination pharmacotherapy to improve effectiveness and reduce adverse effects. Most patients with moderate to severe hypertension require two or more antihypertensive medications (see Box: Resistant Hypertension & Polypharmacy). Thiazide diuretics, ACE inhibitors, angiotensin receptor blockers, and calcium channel blockers have all been shown to reduce complications of hypertension and may be used for initial drug therapy. There has been concern that diuretics, by adversely affecting the serum lipid profile or impairing glucose tolerance, may add to the risk of coronary disease, thereby offsetting the benefit of blood pressure reduction. However, a large clinical trial comparing different classes of antihypertensive mediations for initial therapy found that chlorthalidone (a thiazide diuretic) was as effective as other agents in reducing coronary heart disease death and nonfatal

myocardial infarction, and was superior to amlodipine in preventing heart failure and superior to lisinopril in preventing stroke. Beta blockers are less effective in reducing cardiovascular events and are currently not recommended as first-line treatment for uncomplicated hypertension. The presence of concomitant disease should influence selection of antihypertensive drugs because two diseases may benefit from a single drug. For example, drugs that inhibit the renin-angiotensin system are particularly useful in patients with diabetes or evidence of chronic kidney disease with proteinuria. Beta blockers or calcium channel blockers are useful in patients who also have angina; diuretics, ACE inhibitors, angiotensin receptor blockers, β blockers, or hydralazine combined with nitrates in patients who also have heart failure; and α1 blockers in men who have benign prostatic hyperplasia. Race may also affect drug selection: African Americans respond better on average to diuretics and calcium channel blockers than to β blockers and ACE inhibitors. Chinese patients are more sensitive to the effects of β blockers and may require lower doses. Drugs with different sites of action can be combined to effectively lower blood pressure while minimizing toxicity. If three drugs are required, combining a diuretic, an ACE inhibitor or angiotensin receptor blocker, and a calcium channel blocker is often effective. If a fourth drug is needed, a sympathoplegic agent such as a β blocker or clonidine should be considered. In the USA, fixed-dose drug combinations containing a β blocker, plus an ACE inhibitor or angiotensin receptor blocker, plus a thiazide; and a calcium channel blocker plus an ACE inhibitor are available. In recent studies, fixed low-dose triple combination treatment such as with telmisartan 20 mg, amlodipine 2.5 mg, and chlorthalidone 12.5 mg once daily demonstrated a high degree of efficacy in moderate hypertension with minimal side effects. Fixed three-drug combination tablets are not currently available in the USA. Fixeddose combinations have the drawback of not allowing for titration of individual drug doses but have the advantage of allowing fewer pills to be taken, potentially enhancing compliance. Assessment of blood pressure during office visits should include measurement of recumbent, sitting, and standing pressures. An attempt should be made to normalize blood pressure in the posture or activity level that is customary for the patient. Although there is still some debate about how much blood pressure should be lowered, the Systolic Blood Pressure Intervention Trial (SPRINT) and several meta-analyses suggest a target systolic blood pressure of 120 mm Hg for patients at high cardiovascular risk. Systolic hypertension (>150 mm Hg in the presence of normal diastolic blood pressure) is a strong cardiovascular risk factor in people older than 60 years of age and should be treated. Recent advances in outpatient treatment include home blood pressure telemonitoring with pharmacist case management, which has been shown to improve blood pressure control. In addition to noncompliance with medication, causes of failure to respond to drug therapy include excessive sodium intake and inadequate diuretic therapy with excessive blood volume, and drugs such as tricyclic antidepressants, nonsteroidal anti-inflammatory drugs, over-the-counter sympathomimetics, abuse of stimulants (amphetamine or cocaine), or excessive doses of caffeine and oral

CHAPTER 11  Antihypertensive Agents    195

contraceptives that can interfere with actions of some antihypertensive drugs or directly raise blood pressure.

the syndrome may progress over a period of 12–48 hours to convulsions, stupor, coma, and even death.

MANAGEMENT OF HYPERTENSIVE EMERGENCIES

Treatment of Hypertensive Emergencies

Despite the large number of patients with chronic hypertension, hypertensive emergencies are relatively rare. Marked or sudden elevation of blood pressure may be a serious threat to life, however, and prompt control of blood pressure is indicated. Most frequently, hypertensive emergencies occur in patients whose hypertension is severe and poorly controlled and in those who suddenly discontinue antihypertensive medications.

Clinical Presentation & Pathophysiology Hypertensive emergencies include hypertension associated with vascular damage (termed malignant hypertension) and hypertension associated with hemodynamic complications such as heart failure, stroke, or dissecting aortic aneurysm. The underlying pathologic process in malignant hypertension is a progressive arteriopathy with inflammation and necrosis of arterioles. Vascular lesions occur in the kidney, which releases renin, which in turn stimulates production of angiotensin and aldosterone, which further increase blood pressure. Hypertensive encephalopathy is a classic feature of malignant hypertension. Its clinical presentation consists of severe headache, mental confusion, and apprehension. Blurred vision, nausea and vomiting, and focal neurologic deficits are common. If untreated,

The general management of hypertensive emergencies requires monitoring the patient in an intensive care unit with continuous recording of arterial blood pressure. Fluid intake and output must be monitored carefully, and body weight measured daily as an indicator of total body fluid volume during the course of therapy. Parenteral antihypertensive medications are used to lower blood pressure rapidly (within a few hours); as soon as reasonable blood pressure control is achieved, oral antihypertensive therapy should be substituted because this allows smoother long-term management of hypertension. The goal of treatment in the first few hours or days is not complete normalization of blood pressure because chronic hypertension is associated with autoregulatory changes in cerebral blood flow. Thus, rapid normalization of blood pressure may lead to cerebral hypoperfusion and brain injury. Rather, blood pressure should be lowered by about 25%, maintaining diastolic blood pressure at no less than 100–110 mm Hg. Subsequently, blood pressure can be reduced to normal using oral medications over several weeks. The parenteral drugs used to treat hypertensive emergencies include sodium nitroprusside, nitroglycerin, labetalol, calcium channel blockers, fenoldopam, and hydralazine. Esmolol is often used to manage intraoperative and postoperative hypertension. Diuretics such as furosemide are administered to prevent the volume expansion that typically occurs during administration of powerful vasodilators.

SUMMARY  Drugs Used in Hypertension Subclass, Drug

Pharmacokinetics, Toxicities, Interactions

Mechanism of Action

Effects

Clinical Applications

  • Thiazides: Hydrochlorothiazide, chlorthalidone   • Loop diuretics: Furosemide

Block Na/Cl transporter in renal distal convoluted tubule Block Na/K/2Cl transporter in renal loop of Henle

Reduce blood volume and poorly understood vascular effects Like thiazides • greater efficacy

Hypertension, mild heart failure

 

Severe hypertension, heart failure

See Chapter 15

  • Spironolactone, eplerenone

Block aldosterone receptor in renal collecting tubule

Increase Na and decrease K excretion • poorly understood reduction in heart failure mortality

Aldosteronism, heart failure, hypertension

 

Reduce angiotensin II levels • reduce vasoconstriction and aldosterone secretion • increase bradykinin

Hypertension • heart failure, diabetes

Oral • Toxicity: Cough, angioedema • hyperkalemia • renal impairment • teratogenic

Same as ACE inhibitors but no increase in bradykinin

Hypertension • heart failure

Oral • Toxicity: Same as ACE inhibitors but less cough and angioedema

DIURETICS

ANGIOTENSIN-CONVERTING ENZYME (ACE) INHIBITORS   •  Captopril, many others Inhibit angiotensinconverting enzyme

ANGIOTENSIN RECEPTOR BLOCKERS (ARBs)   •  Losartan, many others Block AT1 angiotensin receptors

(continued)

196    SECTION III  Cardiovascular-Renal Drugs

Subclass, Drug

Pharmacokinetics, Toxicities, Interactions

Mechanism of Action

Effects

Clinical Applications

Inhibits enzyme activity of renin

Reduces angiotensin I and II and aldosterone

Hypertension

Oral • Toxicity: Hyperkalemia, renal impairment • potential teratogen

Reduce central sympathetic outflow • reduce norepinephrine release from noradrenergic nerve endings

Hypertension • clonidine also used in withdrawal from abused drugs

Oral • clonidine also as patch • Toxicity: sedation • methyldopa hemolytic anemia—withdrawal syndrome with sudden discontinuation of high-dose clonidine treatment

Blocks vesicular amine transporter in noradrenergic nerves and depletes transmitter stores Interferes with amine release and replaces norepinephrine in vesicles

Reduces all sympathetic effects, especially cardiovascular, and reduce blood pressure

Hypertension but rarely used

Oral • long duration (days) • Toxicity: Psychiatric depression, gastrointestinal disturbances

Same as reserpine

Same as reserpine

Severe orthostatic hypotension • sexual dysfunction • availability limited

Selectively block α1 adrenoceptors

Prevent sympathetic vasoconstriction • reduce prostatic smooth muscle tone

Hypertension • benign prostatic hyperplasia

Oral • Toxicity: Orthostatic hypotension

Block β1 receptors; carvedilol also blocks α receptors; nebivolol also releases nitric oxide

Prevent sympathetic cardiac stimulation • reduce renin secretion

Hypertension • heart failure • coronary disease

See Chapter 10

Nonselective block of L-type calcium channels

Reduce cardiac rate and output • reduce vascular resistance

Hypertension, angina, arrhythmias

See Chapter 12

Block vascular calcium channels > cardiac calcium channels Causes nitric oxide release Metabolite opens K channels in vascular smooth muscle

Reduce vascular resistance

Hypertension, angina

See Chapter 12

Vasodilation • reduces vascular resistance • arterioles more sensitive than veins • reflex tachycardia

Hypertension • minoxidil also used to treat hair loss

Oral • Toxicity: Angina, tachycardia • Hydralazine: Lupus-like syndrome • Minoxidil: Hypertrichosis

PARENTERAL AGENTS   • Nitroprusside

Releases nitric oxide

Powerful vasodilation

  • Fenoldopam

Activates D1 receptors

  • Diazoxide

Opens K channels

Hypertensive emergencies • diazoxide now used only in hypoglycemia

Parenteral • short duration • Toxicity: Excessive hypotension, shock

  • Labetalol

α, β blocker

RENIN INHIBITOR   •  Aliskiren

SYMPATHOPLEGICS, CENTRALLY ACTING   •  Clonidine, methyldopa

Activate α2 adrenoceptors

SYMPATHETIC NERVE TERMINAL BLOCKERS   •  Reserpine

  • Guanethidine, guanadrel ` BLOCKERS   •  Prazosin   •  Terazosin   •  Doxazosin a BLOCKERS   •  Metoprolol, others   •  Carvedilol   •  Nebivolol

  • Propranolol: Nonselective prototype β blocker   • Metoprolol and atenolol: Very widely used β1-selective blockers VASODILATORS   • Verapamil   • Diltiazem   • Nifedipine, amlodipine, other dihydropyridines   • Hydralazine   • Minoxidil

CHAPTER 11  Antihypertensive Agents    197

P R E P A R A T I O N S

A V A I L A B L E

GENERIC NAME AVAILABLE AS BETA-ADRENOCEPTOR BLOCKERS Acebutolol Generic, Sectral Atenolol Generic, Tenormin Betaxolol Generic, Kerlone Bisoprolol Generic, Zebeta Carvedilol Generic, Coreg Esmolol Generic, Brevibloc Labetalol Generic, Normodyne, Trandate Metoprolol Generic, Lopressor, Toprol-XL Nadolol Generic, Corgard Nebivolol Bystolic Penbutolol Levatol Pindolol Generic, Visken Propranolol Generic, Inderal, Inderal LA Timolol Generic, Blocadren CENTRALLY ACTING SYMPATHOPLEGIC DRUGS Clonidine Generic, Catapres, Catapres-TTS Guanabenz Generic, Wytensin Guanfacine Generic, Tenex Methyldopa Generic, Methyldopate HCl POSTGANGLIONIC SYMPATHETIC NERVE TERMINAL BLOCKERS Guanadrel Hylorel Guanethidine Ismelin Reserpine Generic ALPHA 1 -SELECTIVE ADRENOCEPTOR BLOCKERS Doxazosin Generic, Cardura Prazosin Generic, Minipress Terazosin Generic, Hytrin GANGLION-BLOCKING AGENTS Mecamylamine Generic (orphan drug for Tourette syndrome) VASODILATORS USED IN HYPERTENSION Diazoxide Hyperstat IV, Proglycem (oral for insulinoma) Fenoldopam Corlopam Hydralazine Generic, Apresoline Minoxidil Generic, Loniten  Topical Rogaine

REFERENCES Agarwal R et al: Chlorthalidone for hypertension in advanced chronic kidney disease. N Engl J Med 2021;385:2507. Appel LJ et al: Intensive blood-pressure control in hypertensive chronic kidney disease. N Engl J Med 2010;363:918. Arguedas JA et al: Blood pressure targets for hypertension in people with diabetes mellitus. Cochrane Database Syst Rev 2013;10:CD008277. Aronow WS et al: ACCF/AHA 2011 expert consensus document on hypertension in the elderly: A report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents. Circulation 2011;123:2434. Benetos A et al: Hypertension management in older and frail older patients. Circ Res 2019;124:1045.

GENERIC NAME AVAILABLE AS Nitroprusside Generic, Nitropress CALCIUM CHANNEL BLOCKERS Amlodipine Generic, Norvasc Clevidipine Cleviprex Diltiazem Generic, Cardizem, Cardizem CD, Cardizem SR, Dilacor XL Felodipine Generic, Plendil Isradipine Generic, DynaCirc, Dynacirc CR Nicardipine Generic, Cardene, Cardene SR, Cardene (IV) Nifedipine Generic, Adalat, Procardia, Adalat CC, Procardia-XL Nisoldipine Generic, Sular Verapamil Generic, Calan, Isoptin, Calan SR, Verelan ANGIOTENSIN-CONVERTING ENZYME INHIBITORS Benazepril Generic, Lotensin Captopril Generic, Capoten Enalapril Generic, Vasotec, Enalaprilat (parenteral) Fosinopril Generic, Monopril Lisinopril Generic, Prinivil, Zestril Moexipril Generic, Univasc Perindopril Generic, Aceon Quinapril Generic, Accupril Ramipril Generic, Altace Trandolapril Generic, Mavik ANGIOTENSIN RECEPTOR BLOCKERS Azilsartan Edarbi Candesartan Generic, Atacand Eprosartan Generic, Teveten Irbesartan Generic, Avapro Losartan Generic, Cozaar Olmesartan Benicar Telmisartan Generic, Micardis Valsartan Diovan RENIN INHIBITOR Aliskiren Tekturna

Bress AP et al: Potential cardiovascular disease events prevented with adoption of the 2017 American College of Cardiology/American Heart Association Blood Pressure Guideline. Circulation 2019;139:24. Calhoun DA et al: Resistant hypertension: Diagnosis, evaluation, and treatment: A scientific statement from the American Heart Association Professional Education Committee of the Council for High Blood Pressure Research. Circulation 2008;117:e510. Carey RM et al: Guideline-driven management of hypertension: an evidence-based update. Circ Res 2021;128:827. Diao D et al: Pharmacotherapy for mild hypertension. Cochrane Database Syst Rev 2012;8:CD006742. Ellison DH, Welling P: Insights into salt handling and blood pressure. N Engl J Med 2021;385:1981.

198    SECTION III  Cardiovascular-Renal Drugs Ettehad D et al: Blood pressure lowering for prevention of cardiovascular disease and death: A systematic review and meta-analysis. Lancet 2016;387:957–67. Ferdinand KC et al: Efficacy and safety of firibastat, a first-in-class brain aminopeptidase A inhibitor, in hypertensive overweight patients of multiple ethnic origins. Circulation 2019;140:138. Flint AC et al: Effect of systolic and diastolic blood pressure on cardiovascular outcomes. N Engl J Med 2019 Jul 18;381(3):243–251. doi: 10.1056/ NEJMoa1803180. Garjón J et al: First-line combination therapy versus first-line monotherapy for primary hypertension. Cochrane Database Syst Rev 2020;2:CD010316. Greene MF, Williams WW: Treating hypertension in pregnancy. N Engl J Med 2022;386:1846. He FJ et al: Effect of longer term modest salt reduction on blood pressure: Cochrane systematic review and meta-analysis of randomised trials. BMJ 2013;346:f1325. Hripcsak G et al: Comparison of cardiovascular and safety outcomes of chlorthalidone vs hydrochlorothiazide to treat hypertension. JAMA Intern Med 2020;180:542. Ishani A, et al: Chlorthalidone vs. Hydrochlorothiazide for Hypertension– Cardiovascular Events. NEJM 2022;387(26)2401-2410. James PA et al: 2014 evidence-based guideline for the management of high blood pressure in adults: Report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA 2014;311:507. Kandzari DE et al: Effect of renal denervation on blood pressure in the presence of antihypertensive drugs: 6-month efficacy and safety results from the SPYRAL HTN-ON MED proof-of-concept randomised trial. Lancet 2018;391:2346. Krause T et al: Management of hypertension: Summary of NICE guidance. BMJ 2011;343:d4891. Lv J et al: Antihypertensive agents for preventing diabetic kidney disease. Cochrane Database Syst Rev 2012;12:CD004136. Mancia GF et al: 2013 practice guidelines for the management of arterial hypertension of the European Society of Hypertension (ESH) and the European Society of Cardiology (ESC): ESH/ESC Task Force for the Management of Arterial Hypertension. J Hypertens 2013;31:1925. Margolis KL et al: Effect of home blood pressure telemonitoring and pharmacist management on blood pressure control: A cluster randomized clinical trial. JAMA 2013;310:46. Marik PE, Varon J: Hypertensive crises: Challenges and management. Chest 2007;131:1949. Mente A et al: Associations of urinary sodium excretion with cardiovascular events in individuals with and without hypertension: A pooled analysis of data from four studies. Lancet 2016;388:465. Muntner P et al: Trends in blood pressure control among US adults with hypertension, 1999-2000 to 2017-2018. JAMA 2020;324:1190. Muntner P et al: Measurement of blood pressure in humans: a scientific statement from the American Heart Association. Hypertension 2019;73:e35. Musini VM et al: Pharmacotherapy for hypertension in adults 60 years or older. Cochrane Database Syst Rev 2019;6:CD000028. Neal B et al: Effect of salt substitution on cardiovascular events and death. N Engl J Med 2021;385:1067. Nwankwo T et al: Hypertension among adults in the United States: National Health and Nutrition Examination Survey, 2011-2012. NCHS Data Brief 2013;133:1. Olde Engberink RHG et al: Effects of thiazide-type and thiazide-like diuretics on cardiovascular events and mortality: Systematic review and meta-analysis. Hypertension 2015;65:1033. Padilla Ramos A, Varon J: Current and newer agents for hypertensive emergencies. Curr Hypertens Rep 2014;16:450. Peixoto AJ: Acute severe hypertension. N Engl J Med 2019;381:1843. Reboussin DM et al: Systematic Review for the 2017 ACC/AHA/AAPA/ABC/ ACPM/AGS/ APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation 2018;138:e595.

Rossignol P et al: The double challenge of resistant hypertension and chronic kidney disease. Lancet 2015;386:1588. Roush GC, Sica DA: Diuretics for hypertension: A review and update. Am J Hypertens 2016;29:1130. Sacks FM, Campos H: Dietary therapy in hypertension. N Engl J Med 2010; 362:2102. Saiz LC et al: Blood pressure targets for the treatment of people with hypertension and cardiovascular disease. Cochrane Database Syst Rev 2020;9:CD010315. Sharma P et al: Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers for adults with early (stage 1 to 3) non-diabetic chronic kidney disease. Cochrane Database Syst Rev 2011;10:CD007751. SPRINT Research Group: A randomized trial of intensive versus standard bloodpressure control. N Engl J Med 2015;373:2103. SPRINT Research Group, Lewis CE, et al: Final report of a trial of intensive versus standard blood-pressure control. N Engl J Med 2021;384:1921. Taler SJ: Initial treatment of hypertension. N Engl J Med 2018;378:636. Thompson AM et al: Antihypertensive treatment and secondary prevention of cardiovascular disease events among persons without hypertension: A metaanalysis. JAMA 2011;305:913. Unger T et al: 2020 International Society of Hypertension Global Hypertension Practice Guidelines. Hypertension 2020;75:1334. Viera AJ et al: Does this adult patient have hypertension?: The Rational Clinical Examination Systematic Review. JAMA 2021;326:339. Wang Y et al: Effects of cuisine-based Chinese heart-healthy diet in lowering blood pressure among adults in China: multicenter, single-blind, randomized, parallel controlled feeding trial. Circulation 2022;146:303. Weber MA et al: Clinical practice guidelines for the management of hypertension in the community: A statement by the American Society of Hypertension and the International Society of Hypertension. J Hypertens 2014;32:3. Webster R et al: Fixed low-dose triple combination antihypertensive medication vs usual care for blood pressure control in patients with mild to moderate hypertension in Sri Lanka: A randomized clinical trial. JAMA 2018;320:566. Whelton PK et al: 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ ASPC/NMA/ PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation 2018;138:e484. Whelton PK et al: Sodium, blood pressure, and cardiovascular disease: Further evidence supporting the American Heart Association sodium reduction recommendations. Circulation 2012;126:2880. Whelton PK et al: Harmonization of the American College of Cardiology/ American Heart Association and European Society of Cardiology/European Society of Hypertension Blood Pressure/Hypertension Guidelines: Comparisons, Reflections, and Recommendations. J Am Coll Cardiol 2022;80:1192. Williams B et al: 2018 ESC/ESH Guidelines for the management of arterial hypertension. Eur Heart J 2018;39:3021. Williamson JD et al: Intensive vs standard blood pressure control and cardiovascular disease outcomes in adults aged >/=75 years: A randomized clinical trial. JAMA 2016;315:2673. Wiysonge CS, Opie LH: β-Blockers as initial therapy for hypertension. JAMA 2013;310:1851. Wright JM, Musini VM, Gill R: First-line drugs for hypertension. Cochrane Database Syst Rev 2018;4:CD001841. Xie W et al: Blood pressure-lowering drugs and secondary prevention of cardiovascular disease: Systematic review and meta-analysis. J Hypertens 2018;36:1256. Xie X et al: Effects of intensive blood pressure lowering on cardiovascular and renal outcomes: Updated systematic review and meta-analysis. Lancet 2016;387:435. Yang WY et al: Association of office and ambulatory blood pressure with mortality and cardiovascular outcomes. JAMA 2019;322:409.

CHAPTER 11  Antihypertensive Agents    199

C ASE STUDY ANSWER According to the 2017 American College of Cardiology/ American Heart Association High Blood Pressure Clinical Practice Guidelines, this patient has stage 2 hypertension (see Table 11–1). The first question in management is how urgent it is to treat the hypertension. Cardiovascular risk factors in this man include family history of early coronary disease and elevated cholesterol. Evidence of end-organ impact includes left ventricular hypertrophy on electrocardiogram. The strong family history suggests that this patient has essential hypertension. However, the patient should undergo the usual screening tests including renal function, thyroid function, and serum electrolyte measurements. An echocardiogram should also be considered to determine whether the patient has left ventricular hypertrophy secondary to valvular or other structural heart disease as opposed to hypertension.

Initial management in this patient can be behavioral, including dietary changes and aerobic exercise. However, most patients like this will require medication. Thiazide diuretics in low doses are inexpensive, have relatively few side effects, and are effective in many patients with mild hypertension. Other first-line agents include angiotensinconverting enzyme inhibitors, angiotensin receptor blockers, and calcium channel blockers. Beta blockers might be considered if the patient had coronary disease or had labile hypertension. Either single agent or a combination of two agents in low doses should be prescribed and the patient reassessed in a month. If additional agents are needed, one should be a thiazide diuretic. Once blood pressure is controlled, patients should be followed periodically to reinforce the need for compliance with both lifestyle changes and medications.

12 C

H

A

P

T

E

R

Vasodilators & the Treatment of Angina Pectoris & Coronary Syndromes Bertram G. Katzung, MD, PhD

C ASE STUDY A 67-year-old woman presents in the emergency department of a small rural hospital with a history of chest pain and shortness of breath while watching television. While nasal oxygen is administered and an ECG is recorded, blood is drawn for high-sensitivity troponin measurement. Her husband provides the history that she has a history of exercise-induced angina pectoris and has taken nitroglycerin for relief in the past. Two doses of nitroglycerin have not relieved her pain on this occasion. She smokes and has

Ischemic heart disease is one of the most common cardiovascular diseases in developed countries, and angina pectoris is the most common condition involving tissue ischemia in which vasodilator drugs are used. The name angina pectoris denotes chest pain caused by accumulation of metabolites resulting from myocardial ischemia. The organic nitrates, eg, nitroglycerin, are the mainstay of therapy for the immediate relief of angina. Another group of vasodilators, the calcium channel blockers, is also important, especially for prophylaxis, and a blockers, which are not vasodilators, are also useful in prophylaxis. Several newer drugs are available, including drugs that alter myocardial ion currents and selective cardiac rate inhibitors. The most common cause of angina is atheromatous obstruction of the large coronary vessels (coronary artery disease, CAD). Inadequate blood flow in the presence of CAD results in effort angina, also known as classic angina. Diagnosis is usually made on the basis of the history and stress testing, sometimes supplemented 200

a history of hyperlipidemia with elevated “bad cholesterol” (low-density lipoprotein [LDL]) and hypertension. Her father survived a “heart attack” at age 55, and an uncle died of some cardiac disease at age 60. On physical examination, the patient’s blood pressure is 145/90 mm Hg, and her heart rate is 100 bpm. The ECG shows no ST elevation, but ST depression is present in several leads. Assuming that a dioagnosis of acute coronary syndrome (ACS) is correct, what treatment should be implemented?

by coronary angiography. Some patients have typical symptoms of angina in spite of normal epicardial coronary vessels. Previously labeled “coronary syndrome X,” this condition is coronary microvascular dysfunction. Both types of angina are associated with diminished coronary fractional flow reserve, the fractional increase in coronary flow that can be achieved by maximal coronary dilation. Transient spasm of localized portions of these vessels, usually associated with underlying atheromas, can also cause significant myocardial ischemia and pain (vasospastic or variant angina). Vasospastic angina is also called Prinzmetal angina. Diagnosis is usually made on the basis of history but can be confirmed by tests that provoke temporary spasm. The primary cause of angina pectoris is an imbalance between the oxygen requirement of the heart and the oxygen supplied to it via the coronary vessels. In effort angina, the imbalance occurs when the myocardial oxygen requirement increases, especially

CHAPTER 12  Vasodilators & the Treatment of Angina Pectoris & Coronary Syndromes     201

during exercise, and coronary blood flow does not increase proportionately. The resulting ischemia with accumulation of acidic metabolites usually leads to pain. In fact, coronary flow reserve is frequently impaired in such patients because of endothelial dysfunction, which results in impaired vasodilation. As a result, ischemia may even occur at a lower level of myocardial oxygen demand. In some individuals, the ischemia is not always accompanied by pain, resulting in “silent” or “ambulatory” ischemia. In variant angina, oxygen delivery decreases as a result of reversible coronary vasospasm, which also causes ischemia and pain. Unstable angina, an acute coronary syndrome (ACS), is said to be present when episodes of angina occur at rest and there is an increase in the severity, frequency, and duration of chest pain in patients with previously stable angina or an event occurs without prior history of angina. Unstable angina is caused by episodes of increased epicardial coronary artery resistance or small platelet clots occurring in the vicinity of an atherosclerotic plaque. In most cases, formation of labile partially occlusive thrombi at the site of a fissured or ulcerated plaque is the mechanism for reduction in flow. Inflammation may be a risk factor, because patients taking tumor necrosis factor inhibitors appear to have a lower risk of myocardial infarction. The course and the prognosis of unstable angina are variable, but this subset of acute coronary syndrome is associated with a high risk of myocardial infarction and death and is considered a medical emergency. In theory, the imbalance between oxygen delivery and myocardial oxygen demand can be corrected by decreasing oxygen demand or by increasing delivery (by increasing coronary flow). In effort angina, oxygen demand can be reduced by decreasing cardiac work or, according to some studies, by shifting myocardial metabolism to substrates that require less oxygen per unit of adenosine triphosphate (ATP) produced. In variant angina, on the other hand, spasm of coronary vessels can be reversed by nitrate or calcium channel-blocking vasodilators. In unstable angina, vigorous measures are taken to achieve both—increase oxygen delivery (by medical or physical interventions) and decrease oxygen demand. Lipid-lowering drugs have become extremely important in the longterm treatment of atherosclerotic disease (see Chapter 35).

PATHOPHYSIOLOGY OF ANGINA Determinants of Myocardial Oxygen Demand The major determinants of myocardial oxygen requirement are listed in Table 12–1. The effects of arterial blood pressure and venous pressure are mediated through their effects on myocardial wall stress. As a consequence of its continuous activity, the heart’s oxygen needs are relatively high, and it extracts approximately 75% of the available oxygen even in the absence of stress. The myocardial oxygen requirement increases when there is an increase in heart rate, contractility, arterial pressure, or ventricular volume. These hemodynamic alterations occur during physical exercise and sympathetic discharge, which often precipitate angina in patients with obstructive coronary artery disease. Drugs that reduce cardiac size, rate, or force reduce cardiac oxygen demand. Thus, vasodilators, β blockers, and calcium blockers

TABLE 12–1  Hemodynamic determinants of

myocardial oxygen consumption.

Wall stress   Intraventricular pressure   Ventricular radius (volume)   Wall thickness Heart rate Contractility

have predictable benefits in angina. A small, late component of sodium current helps to maintain the long plateau and prolong the calcium current of myocardial action potentials. Drugs that block this late sodium current can indirectly reduce calcium influx and consequently reduce cardiac contractile force. The heart favors fatty acids as a substrate for energy production. However, oxidation of fatty acids requires more oxygen per unit of ATP generated than oxidation of carbohydrates. Therefore, drugs that shift myocardial metabolism toward greater use of glucose (fatty acid oxidation inhibitors), at least in theory, may reduce the oxygen demand without altering hemodynamics.

Determinants of Coronary Blood Flow & Myocardial Oxygen Supply In the normal heart, increased demand for oxygen is met by augmenting coronary blood flow. Because coronary flow drops to near zero during systole, coronary blood flow is directly related to the aortic diastolic pressure and the duration of diastole. Therefore, the duration of diastole becomes a limiting factor for myocardial perfusion during tachycardia. Coronary blood flow is inversely proportional to coronary vascular resistance. Resistance is determined mainly by intrinsic factors, including metabolic products and autonomic activity, and can be modified—in normal coronary vessels—by various pharmacologic agents. Damage to the endothelium of coronary vessels has been shown to alter their ability to dilate and to increase coronary vascular resistance.

Determinants of Vascular Tone Peripheral arteriolar and venous tone (vascular smooth muscle tension) both play a role in determining myocardial wall stress (see Table 12–1). Arteriolar tone directly controls peripheral vascular resistance and thus arterial blood pressure. In systole, intraventricular pressure must exceed aortic pressure to eject blood; arterial blood pressure thus determines the left ventricular systolic wall stress in an important way. Venous tone determines the capacity of the venous circulation and controls the amount of blood sequestered in the venous system versus the amount returned to the heart. Venous tone thereby determines the right ventricular diastolic wall stress. The regulation of smooth muscle contraction and relaxation is shown schematically in Figure 12–1. The mechanisms of action of the major types of vasodilators are listed in Table 11–3. As shown in Figures 12–1 and 12–2, drugs may relax vascular smooth muscle in several ways:

202    SECTION III  Cardiovascular-Renal Drugs

2+

Ca

Ca2+ channel blockers

–

K+

Ca2+ ATP

Calmodulin

β2 agonists

+ Ca2+ -Calmodulin complex

cAMP

+

+

MLCK(PO4)2

Myosin-LC kinase (MLCK)

MLCK*

+

+ Myosin light chains (myosin-LC)

Myosin-LC

Myosin-LC-PO4 Actin

cGMP

– Contraction

ROCK

Relaxation

Vascular smooth muscle cell

FIGURE 12–1  A simplified diagram of smooth muscle contraction and the site of action of calcium channel-blocking drugs. Contraction is triggered (red arrows) by influx of calcium (which can be blocked by calcium channel blockers) through transmembrane calcium channels. The calcium combines with calmodulin to form a complex that converts the enzyme myosin light-chain kinase to its active form (MLCK*). The latter phosphorylates the myosin light chains, thereby initiating the interaction of myosin with actin. Other proteins, including calponin and 2+ caldesmon (not shown), inhibit the ATPase activity of myosin during the relaxation of smooth muscle. Interaction with the Ca -calmodulin complex reduces their interaction with myosin during the contraction cycle. Beta2 agonists (and other substances that increase cAMP) may cause relaxation in smooth muscle (blue arrows) by accelerating the inactivation of MLCK and by facilitating the expulsion of calcium from the cell (not shown). cGMP facilitates relaxation by the mechanism shown in Figure 12–2. ROCK, Rho kinase.

1. Increasing cGMP: cGMP facilitates the dephosphorylation of myosin light chains, preventing the interaction of myosin with actin. Nitric oxide (NO) is an effective activator of soluble guanylyl cyclase and acts mainly through increasing cGMP. Important molecular donors of nitric oxide include nitroprusside (used in hypertensive emergencies, see Chapter 11) and the organic nitrates used in angina. Atherosclerotic disease may diminish endogenous endothelial NO synthesis, thus making the vascular smooth muscle more dependent upon exogenous sources of NO. 2. Decreasing intracellular Ca2+: Calcium channel blockers predictably cause vasodilation because they reduce intracellular Ca2+, a major modulator of the activation of myosin light chain kinase (see Figure 12–1) in smooth muscle. Beta blockers and calcium channel blockers also reduce Ca2+ influx in cardiac muscle fibers, thereby reducing rate, contractility, and oxygen requirement under most circumstances.

3. Stabilizing or preventing depolarization of the vascular smooth muscle cell membrane: The membrane potential of excitable cells is stabilized near the resting potential by increasing potassium permeability. cGMP may increase permeability of Ca2+-activated K+ channels. Potassium channel openers, such as minoxidil sulfate (see Chapter 11), increase the permeability of K+ channels, probably ATP-dependent K+ channels. Certain agents used elsewhere and under investigation in the United States (eg, nicorandil) may act, in part, by this mechanism. 4. Increasing cAMP in vascular smooth muscle cells: As shown in Figure 12–1, an increase in cAMP increases the rate of inactivation of myosin light chain kinase, the enzyme responsible for triggering the interaction of actin with myosin in these cells. This appears to be the mechanism of vasodilation caused by β2 agonists, drugs that are not used in angina (because they cause too much cardiac stimulation), and by fenoldopam, a D1 agonist used in hypertensive emergencies.

CHAPTER 12  Vasodilators & the Treatment of Angina Pectoris & Coronary Syndromes     203

Blood vessel lumen

Capillary endothelial cells

Interstitium

Nitrates Nitrites

Arginine

eNOS

Nitric oxide (NO)

Ca2+

Guanylyl cyclase Ca2+

NO +

Vascular smooth muscle cell

–

SNOs

MLCK*

GTP

GC*

+ Myosin light chains (myosin-LC)

mtALDH2

cGMP

PDE

Nitrates Nitrites Sildenafil

GMP

+ Myosin-LC

Myosin-LC-PO4 Actin

– ROCK Contraction

Relaxation

FIGURE 12–2  Mechanism of action of nitrates, nitrites, and other substances that increase the concentration of nitric oxide (NO) in vascular smooth muscle cells. Steps leading to relaxation are shown with blue arrows. MLCK*, activated myosin light-chain kinase (see Figure 12–1). Nitrosothiols (SNOs) appear to have non-cGMP-dependent effects on potassium channels and Ca2+-ATPase. eNOS, endothelial nitric oxide synthase; GC*, activated guanylyl cyclase; mtALDH2, mitochondrial aldehyde dehydrogenase-2; PDE, phosphodiesterase; ROCK, Rho kinase.

■■ BASIC PHARMACOLOGY OF DRUGS USED TO TREAT ANGINA Drug Action in Angina The three drug groups traditionally used in angina (organic nitrates, calcium channel blockers, and β blockers) decrease myocardial oxygen requirement by decreasing one or more of the major determinants of oxygen demand (heart size, heart rate, blood pressure, and contractility). In some patients, the nitrates and the calcium channel blockers may cause a redistribution of coronary flow and increase oxygen delivery to ischemic tissue. In variant angina, these two drug groups also increase myocardial oxygen delivery by reversing coronary artery spasm. The nitrates are used for relief of

acute episodes of anginal pain and for prophylaxis. Because of their slow onset of action, calcium channel blockers and β blockers are used for prophylaxis. Newer drugs are discussed later.

NITRATES & NITRITES Chemistry Diets rich in inorganic nitrates are known to have a small blood pressure–lowering action but are of no value in angina. The agents useful in angina are simple organic nitric and nitrous acid esters of polyalcohols. Nitroglycerin is the prototype of the group and has been used in cardiovascular conditions for over 160 years. Although nitroglycerin is used in the manufacture of dynamite,

204    SECTION III  Cardiovascular-Renal Drugs

the formulations used in medicine are not explosive. The conventional sublingual tablet form of nitroglycerin may lose potency when stored as a result of volatilization and adsorption to plastic surfaces. Therefore, it should be kept in tightly closed glass containers. Nitroglycerin is not sensitive to light. All therapeutically active agents in the nitrate group appear to have identical mechanisms of action and similar toxicities, although development of tolerance may vary. Therefore, pharmacokinetic factors govern the choice of agent and mode of therapy when using the nitrates. H2C

O

NO2

HC

O

NO2

H2C

O

NO2

Nitroglycerin (Glyceryl trinitrate)

Pharmacokinetics The liver contains a high-capacity organic nitrate reductase that removes nitrate groups in a stepwise fashion from the parent molecule and ultimately inactivates the drug. Therefore, oral bioavailability of the traditional organic nitrates (eg, nitroglycerin and isosorbide dinitrate) is low (typically 6 hours). This drug has also been reported to reduce pulmonary hypertension in experimental animals. Other routes of administration available for nitroglycerin include transdermal and buccal absorption from slow-release preparations (described below). Amyl nitrite and related nitrites are highly volatile liquids. Amyl nitrite is available in fragile glass ampules (“poppers”) packaged in a protective cloth covering. The ampule can be crushed with the fingers, resulting in rapid release of vapors inhalable through the cloth covering. The inhalation route provides very rapid absorption and, like the sublingual route, avoids the hepatic first-pass effect. Because of its unpleasant odor and extremely short duration of action, amyl nitrite is now obsolete for angina. Once absorbed, the unchanged organic nitrate compounds have half-lives of only 2–8 minutes. The partially denitrated metabolites have much longer half-lives (up to 3 hours). Of the nitroglycerin metabolites (two dinitroglycerins and two mononitro forms), the 1,2-dinitro derivative has significant vasodilator efficacy and probably provides most of the therapeutic effect of orally administered nitroglycerin. The 5-mononitrate metabolite

of isosorbide dinitrate is an active metabolite of the latter drug and is available for oral use as isosorbide mononitrate. It has a bioavailability of 100%. Excretion, primarily in the form of glucuronide derivatives of the denitrated metabolites, is largely by way of the kidney.

Pharmacodynamics A.  Mechanism of Action in Smooth Muscle After more than a century of study, the mechanism of action of nitroglycerin is partially understood. There is general agreement that the drug must be bioactivated with the release of nitric oxide. Unlike nitroprusside (Chapter 11) and some other direct nitric oxide donors, nitroglycerin activation requires enzymatic action. Nitroglycerin can be denitrated by glutathione S-transferase in smooth muscle and other cells. A mitochondrial enzyme, aldehyde dehydrogenase isoform 2 (ALDH2) and possibly isoform 3 (ALDH3), appears to be key in the activation and release of nitric oxide from nitroglycerin and pentaerythritol tetranitrate. Different enzymes may be involved in the denitration of isosorbide dinitrate and mononitrate. Free nitrite ion is released, which is then converted to nitric oxide (see Chapter 19). Nitric oxide (probably complexed with cysteine) combines with the heme group of soluble guanylyl cyclase, activating that enzyme and causing an increase in cGMP. As shown in Figure 12–2, formation of cGMP represents a first step toward smooth muscle relaxation. The production of prostaglandin E or prostacyclin (PGI2) and membrane hyperpolarization may also be involved. There is no evidence that autonomic receptors are involved in the primary nitrate response. However, autonomic reflex responses, evoked when hypotensive doses are given, are common and may be significant. As described in the following text, tolerance is another important consideration in the use of nitrates. Although tolerance may be caused in part by a decrease in tissue sulfhydryl groups, eg, on cysteine, tolerance can be only partially prevented or reversed with a sulfhydrylregenerating agent. Increased generation of free radicals during nitrate therapy may be another important mechanism of tolerance. Some evidence suggests that diminished availability of calcitonin gene-related peptide (CGRP, a potent vasodilator) is also associated with nitrate tolerance. Nicorandil and several other antianginal agents not available in the United States appear to combine the activity of nitric oxide release with a direct potassium channel-opening action resulting in smooth muscle hyperpolarization, thus providing an additional mechanism for causing vasodilation. B.  Organ System Effects Nitroglycerin relaxes all types of smooth muscle regardless of the cause of the preexisting muscle tone (Figure 12–3). It has practically no direct effect on cardiac or skeletal muscle. 1. Vascular smooth muscle—All segments of the vascular system from large arteries through large veins relax in response to nitroglycerin. Most evidence suggests a gradient of response, with veins responding at the lowest concentrations and arteries

CHAPTER 12  Vasodilators & the Treatment of Angina Pectoris & Coronary Syndromes     205

A

B 10 mN

10 mN

K+

NE

NE

K+ NTG

K+

10 min 10 mN

C NE NTG 10 min 10 mN

K+ Verapamil

FIGURE 12–3  Effects of vasodilators on contractions of human vein segments studied in vitro. A shows contractions induced by two vasoconstrictor agents, norepinephrine (NE) and potassium (K+). B shows the relaxation induced by nitroglycerin (NTG), 4 µmol/L. The relaxation is prompt. C shows the relaxation induced by verapamil, 2.2 µmol/L. The relaxation is slower but more sustained. mN, millinewtons, a measure of force. (Adapted with permission from Mikkelsen E, Andersson KE, Bengtsson B: Effects of verapamil and nitroglycerin on contractile responses to potassium and noradrenaline in isolated human peripheral veins. Acta Pharmacol Toxicol (Copenh). 1978;42(1):14-22.)

at slightly higher ones. The epicardial coronary arteries are sensitive, but concentric atheromas can prevent significant dilation. On the other hand, eccentric lesions permit an increase in flow when nitrates relax the smooth muscle on the side away from the lesion. Arterioles and precapillary sphincters are dilated least, partly because of reflex responses and partly because different vessels vary in their ability to release nitric oxide from the drug. A primary direct result of an effective dose of nitroglycerin is marked relaxation of veins with increased venous capacitance and decreased ventricular preload. Pulmonary vascular pressures and heart size are significantly reduced. In the absence of heart failure, cardiac output is reduced. Because venous capacitance is increased, orthostatic hypotension may be marked and syncope can result. Dilation of large epicardial coronary arteries may improve oxygen delivery in the presence of eccentric atheromas or collateral vessels. Temporal artery pulsations and a throbbing headache associated with meningeal artery pulsations are common effects of nitroglycerin and amyl nitrite. In heart failure, preload is often abnormally high; the nitrates and other vasodilators, by reducing preload, may have a beneficial effect on cardiac output in this condition (see Chapter 13). The indirect effects of nitroglycerin consist of those compensatory responses evoked by baroreceptors and hormonal mechanisms responding to decreased arterial pressure (see Figure 6–7); this often results in tachycardia and increased cardiac contractility. Retention of salt and water may also be significant, especially with intermediate- and long-acting nitrates. These compensatory responses contribute to the development of nitrate tolerance. In normal subjects without coronary disease, nitroglycerin can induce a significant, if transient, increase in total coronary blood

flow. In contrast, there is no evidence that total coronary flow is increased in patients with angina due to atherosclerotic obstructive coronary artery disease. However, some studies suggest that redistribution of coronary flow from normal to ischemic regions may play a role in nitroglycerin’s therapeutic effect. Nitroglycerin also exerts a weak negative inotropic effect on the heart via nitric oxide. 2. Other smooth muscle organs—Relaxation of smooth muscle of the bronchi, gastrointestinal tract (including biliary system), and genitourinary tract has been demonstrated experimentally. Because of their brief duration, these actions of the nitrates are rarely of any clinical value. During recent decades, the use of amyl nitrite and isobutyl nitrite (not nitrates) by inhalation as recreational (sex-enhancing) drugs has become popular with some people. Nitrites readily release nitric oxide in erectile tissue as well as vascular smooth muscle and activate guanylyl cyclase. The resulting increase in cGMP causes dephosphorylation of myosin light chains and relaxation (see Figure 12–2), which enhances erection. This pharmacologic approach to erectile dysfunction is discussed in the Box: Drugs Used in the Treatment of Erectile Dysfunction. 3. Action on platelets—Nitric oxide released from nitroglycerin stimulates guanylyl cyclase in platelets as in smooth muscle. The increase in cGMP that results is responsible for a decrease in platelet aggregation. Unfortunately, recent prospective trials have established no survival benefit when nitroglycerin is used in acute myocardial infarction. In contrast, intravenous nitroglycerin may be of value in acute coronary syndrome, in part through its action on platelets.

206    SECTION III  Cardiovascular-Renal Drugs

4. Other effects—Nitrite ion (not nitrate ion) reacts with hemoglobin (which contains ferrous iron) to produce methemoglobin (by oxidation of ferrous to ferric iron). Because methemoglobin has a very low affinity for oxygen, large doses of nitrites can result in pseudocyanosis, tissue hypoxia, and death. Fortunately, the plasma concentration of nitrite resulting from even large doses of organic and inorganic nitrates is too low to cause significant methemoglobinemia in adults. In nursing infants, the intestinal flora is capable of converting significant amounts of inorganic nitrate (sometimes present, eg, in well water) to nitrite ion. In addition, sodium nitrite is used as a curing agent for meats, eg, corned beef. Thus, inadvertent exposure to large amounts of nitrite ion can occur and may produce serious toxicity. One therapeutic application of this otherwise toxic effect of nitrite has been discovered. Cyanide poisoning results from

complexing and inactivation of cytochrome iron by the CN− ion. Methemoglobin iron has a very high affinity for CN−; thus, administration of sodium nitrite (NaNO2) soon after cyanide exposure regenerates active cytochrome. The cyanomethemoglobin produced can be further detoxified by the intravenous administration of sodium thiosulfate (Na2S2O3); this results in formation of thiocyanate ion (SCN−), a less toxic ion that is readily excreted. Methemoglobinemia, if excessive, can be treated by giving methylene blue intravenously. This antidote for cyanide poisoning (inhaled amyl nitrite plus intravenous sodium nitrite, followed by intravenous sodium thiocyanate and, if needed, methylene blue) is now being replaced by hydroxocobalamin, a form of vitamin B12, which also has a very high affinity for cyanide ion and combines with it to generate cyanocobalamin, another form of vitamin B12, and free cytochrome.

Drugs Used in the Treatment of Erectile Dysfunction Erectile dysfunction in men has long been the subject of research (by both amateur and professional scientists) and is heavily promoted on the internet by quacks. Among the substances used in the past and generally discredited are “Spanish Fly” (a bladder and urethral irritant), yohimbine (an α2 antagonist; see Chapter 10), nutmeg, and mixtures containing lead, arsenic, or strychnine. Substances currently favored by practitioners of herbal medicine but of dubious value include ginseng and kava. Scientific studies of the process have shown that erection requires relaxation of the nonvascular smooth muscle of the corpora cavernosa. This relaxation permits inflow of blood at nearly arterial pressure into the sinuses of the cavernosa, and it is the pressure of the blood that causes erection. (With regard to other aspects of male sexual function, ejaculation requires intact sympathetic motor function, while orgasm involves independent superficial and deep sensory nerves.) Physiologic erection occurs in response to the release of nitric oxide from nonadrenergic-noncholinergic nerves (see Chapter 6) associated with parasympathetic discharge. Thus, parasympathetic motor innervation must be intact and nitric oxide synthesis must be active. (A similar process occurs in female erectile tissues.) Certain other smooth muscle relaxants—eg, PGE1 analogs or α-adrenoceptor antagonists—if present in high enough concentration, can independently cause sufficient cavernosal relaxation to result in erection. As noted in the text, nitric oxide activates guanylyl cyclase, which increases the concentration of cGMP, and the latter second messenger stimulates the dephosphorylation of myosin light chains (see Figure 12–2) and relaxation of the smooth muscle. Thus, any drug that increases cGMP might be of value in erectile dysfunction if normal innervation is present. Sildenafil (Viagra) and congeners act to increase cGMP by inhibiting its breakdown by phosphodiesterase isoform 5 (PDE-5). Three similar PDE-5 inhibitors (PDE-5I),

tadalafil, vardenafil, and avanafil, are available. These drugs have been very successful in the marketplace because they can be taken orally. However, they are of little or no value in men with loss of potency due to cord injury or other damage to innervation and in men lacking libido. Furthermore, PDE-5Is potentiate the action of nitrates used for angina, and severe hypotension and a few myocardial infarctions have been reported in men taking a nitrate plus a PDE-5I. It is recommended that at least 6 hours pass between use of a nitrate and the ingestion of PDE-5 inhbitors. PDE-5Is also have effects on color vision, causing difficulty in blue-green discrimination. It is important to be aware that numerous nonprescription mail-order products that contain sildenafil analogs such as hydroxythiohomosildenafil and sulfoaildenafil have been marketed as “male enhancement” agents. These products are not approved by the Food and Drug Administration (FDA) and incur the same risk of dangerous interactions with nitrates as the approved agents. PDE-5 inhibitors have also been studied for possible use in other conditions. Clinical studies show distinct benefit in some patients with pulmonary arterial hypertension but not in patients with advanced idiopathic pulmonary fibrosis. The drugs have possible benefit in systemic hypertension, cystic fibrosis, and benign prostatic hyperplasia. Both sildenafil and tadalafil are currently approved for pulmonary hypertension. Preclinical studies suggest that sildenafil may be useful in preventing apoptosis and cardiac remodeling after ischemia and reperfusion. The drug most commonly used for erectile dysfunction in patients who do not respond to PDE-5Is is alprostadil, a PGE1 analog (see Chapter 18) that can be injected directly into the cavernosa or placed in the urethra as a minisuppository, from which it diffuses into the cavernosal tissue. Phentolamine can be used by injection into the cavernosa. These drugs will cause erection in most men who do not respond to PDE-5Is.

CHAPTER 12  Vasodilators & the Treatment of Angina Pectoris & Coronary Syndromes     207

Toxicity & Tolerance A.  Acute Adverse Effects The major acute toxicities of organic nitrates are direct extensions of therapeutic vasodilation: orthostatic hypotension, tachycardia, and throbbing headache. Glaucoma, once thought to be a contraindication, does not worsen, and nitrates can be used safely in the presence of increased intraocular pressure. Nitrates are contraindicated, however, if intracranial pressure is elevated. Rarely, transdermal nitroglycerin patches have ignited when external defibrillator electroshock was applied to the chest of patients in ventricular fibrillation. Such patches should be removed before use of external defibrillation to prevent superficial burns. B. Tolerance With continuous exposure to nitrates, isolated smooth muscle may develop complete tolerance (tachyphylaxis), and the intact human becomes progressively more tolerant when long-acting preparations (oral, transdermal) or continuous intravenous infusions are used for more than a few hours without interruption. The mechanisms by which tolerance develops are not completely understood. As previously noted, diminished release of nitric oxide resulting from reduced bioactivation may be partly responsible for tolerance to nitroglycerin. Supplementation of cysteine may partially reverse tolerance, suggesting that reduced availability of sulfhydryl donors may play a role. Systemic compensation also plays a role in tolerance in the intact human. Initially, significant sympathetic discharge occurs, and after 1 or more days of therapy with long-acting nitrates, retention of salt and water may partially reverse the favorable hemodynamic changes initially caused by nitroglycerin. Tolerance does not occur equally with all nitric oxide donors. Nitroprusside, for example, retains activity over long periods. Other organic nitrates appear to be less susceptible than nitroglycerin to the development of tolerance. In cell-free systems, soluble guanylate cyclase is inhibited, possibly by nitrosylation of the enzyme, only after prolonged exposure to exceedingly high nitroglycerin concentrations. In contrast, treatment with antioxidants that protect ALDH2 and similar enzymes appears to prevent or reduce tolerance. This suggests that tolerance is a function of diminished bioactivation of organic nitrates and, to a lesser degree, a loss of soluble guanylate cyclase responsiveness to nitric oxide. Continuous exposure to high levels of nitrates can occur in the chemical industry, especially where explosives are manufactured. When contamination of the workplace with volatile organic nitrate compounds is severe, workers find that upon starting their work week (Monday), they suffer headache and transient dizziness (Monday disease). After a day or so, these symptoms disappear owing to the development of tolerance. Over the weekend, when exposure to the chemicals is eliminated, tolerance disappears, so symptoms recur each Monday. Other hazards of industrial exposure, including dependence, have been reported. There is no evidence that physical dependence develops as a result of the therapeutic use of short-acting nitrates for angina, even in large doses.

C.  Carcinogenicity of Nitrate and Nitrite Derivatives Nitrosamines are small molecules with the structure R2–N–NO formed from the combination of nitrates and nitrites with amines. Some nitrosamines are powerful carcinogens in animals, apparently through conversion to reactive derivatives. Although there is no direct proof that these agents cause cancer in humans, there is a strong epidemiologic correlation between the incidence of esophageal and gastric carcinoma and the nitrate content of food in certain cultures. Nitrosamines are also found in tobacco and in cigarette smoke. There is no evidence that the small doses of nitrates used in the treatment of angina result in significant body levels of nitrosamines.

Mechanisms of Clinical Effect The beneficial and deleterious effects of nitrate-induced vasodilation are summarized in Table 12–2. A.  Nitrate Effects in Angina of Effort Decreased venous return to the heart and the resulting reduction of intracardiac volume are important beneficial hemodynamic effects of nitrates. Arterial pressure also decreases. Decreased intraventricular pressure and left ventricular volume are associated with decreased wall tension (Laplace relation) and decreased myocardial oxygen requirement. In rare instances, a paradoxical increase in myocardial oxygen demand may occur as a result of excessive reflex tachycardia and increased contractility. Intracoronary, intravenous, or sublingual nitrate administration consistently increases the caliber of the large epicardial coronary arteries except where blocked by concentric atheromas. Coronary arteriolar resistance tends to decrease, though to a lesser extent. However, nitrates administered by the usual systemic routes may decrease overall coronary blood flow (and myocardial oxygen consumption) if cardiac output is reduced due to decreased venous return.

TABLE 12–2  Beneficial and deleterious effects of nitrates in the treatment of angina.

Effect

Mechanism and Result

Potential beneficial effects   Decreased ventricular volume   Decreased arterial pressure

Decreased work and myocardial oxygen requirement

  Decreased ejection time  Vasodilation of epicardial coronary arteries

Relief of coronary artery spasm

  Increased collateral flow

Improved perfusion of ischemic myocardium

 Decreased left ventricular diastolic pressure

Improved subendocardial perfusion

Potential deleterious effects   Reflex tachycardia

Increased myocardial oxygen requirement; decreased diastolic perfusion time and coronary perfusion

  Reflex increase in contractility

Increased myocardial oxygen requirement

208    SECTION III  Cardiovascular-Renal Drugs

The reduction in oxygen demand is the major mechanism for the relief of effort angina. B.  Nitrate Effects in Variant Angina Nitrates benefit patients with variant angina by relaxing the smooth muscle of the epicardial coronary arteries and relieving coronary artery spasm. C.  Nitrate Effects in Acute Coronary Syndromes Nitrates are also useful in the treatment of the acute coronary syndrome of unstable angina, but the precise mechanism for their beneficial effects is not clear. Because both increased coronary vascular tone and increased myocardial oxygen demand can precipitate rest angina in these patients, nitrates may exert their beneficial effects both by dilating the epicardial coronary arteries and by simultaneously reducing myocardial oxygen demand. As previously noted, nitroglycerin also decreases platelet aggregation, and this effect may be important in acute coronary syndrome.

Clinical Use of Nitrates Some of the forms of nitroglycerin and its congeners and their doses are listed in Table 12–3. Because of its rapid onset of action

TABLE 12–3  Nitrate and nitrite drugs used in the treatment of angina. Dose

Duration of Action

 Nitroglycerin, sublingual

0.15–1.2 mg

10–30 minutes

 Isosorbide dinitrate, sublingual

2.5–5 mg

10–60 minutes

 Amyl nitrite, inhalant (obsolete)

0.18–0.3 mL

3–5 minutes

 Nitroglycerin, oral sustained-action

6.5–13 mg per 6–8 hours

6–8 hours

 Nitroglycerin, 2% ointment, transdermal

1–1.5 inches per 4 hours

3–6 hours

 Nitroglycerin, slow-release, buccal

1–2 mg per 4 hours

3–6 hours

 Nitroglycerin, slow-release patch, transdermal

10–25 mg per 24 hours (one patch per day)

8–10 hours

 Isosorbide dinitrate, sublingual

2.5–10 mg per 2 hours

1.5–2 hours

 Isosorbide dinitrate, oral

10–60 mg per 4–6 hours

4–6 hours

 Isosorbide dinitrate, chewable oral

5–10 mg per 2–4 hours

2–3 hours

 Isosorbide mononitrate, oral

20 mg per 12 hours

6–10 hours

 Pentaerythritol tetranitrate (PETN)

50 mg per 12 hours

10–12 hours

Drug Short-acting

Long-acting

(1–3 minutes), sublingual nitroglycerin is the most frequently used agent for the immediate treatment of angina. Because its duration of action is short (not exceeding 20–30 minutes), it is not suitable for maintenance therapy. The onset of action of intravenous nitroglycerin is also rapid (minutes), but its hemodynamic effects are quickly reversed when the infusion is stopped. Clinical use of intravenous nitroglycerin is therefore restricted to the treatment of severe, recurrent rest angina. Slowly absorbed preparations of nitroglycerin include a buccal form, oral preparations, and several transdermal forms. These formulations have been shown to provide blood concentrations for long periods but, as noted above, this may lead to the development of tolerance. The hemodynamic effects of sublingual or chewable isosorbide dinitrate and the oral organic nitrates are similar to those of nitroglycerin given by the same routes. Although transdermal administration may provide blood levels of nitroglycerin for 24 hours or more, the beneficial hemodynamic effects usually do not persist for more than 8–10 hours. The clinical efficacy of slow-release forms of nitroglycerin in maintenance therapy of angina is thus limited by the development of tolerance. Therefore, a nitrate-free period of at least 8 hours between doses of long-acting and slowrelease forms should be observed to prevent tolerance.

OTHER NITRO-VASODILATORS Nicorandil is a nicotinamide nitrate ester that has vasodilating properties in normal coronary arteries but more complex effects in patients with angina. Studies in isolated myocytes indicate that the drug activates an Na+/Ca2+ exchanger and reduces intracellular Ca2+ overload. Clinical studies suggest that it reduces both preload and afterload. It also provides some myocardial protection via preconditioning by activation of cardiac KATP channels. One large trial showed a significant reduction in relative risk of fatal and nonfatal coronary events in patients receiving the drug. Nicorandil is currently approved for use in the treatment of angina in Europe and Japan but has not been approved in the USA. Molsidomine is a prodrug that is converted to a nitric oxide–releasing metabolite. It is said to have efficacy comparable to that of the organic nitrates and is not subject to tolerance. Recent studies suggest that it may reduce cerebral vasospasm in stroke.

CALCIUM CHANNEL-BLOCKING DRUGS It has been known since the late 1800s that transmembrane calcium influx is necessary for the contraction of smooth and cardiac muscle. The discovery of a calcium channel in cardiac muscle was followed by the finding of several different types of calcium channels in different tissues (Table 12–4). The discovery of these channels made possible the measurement of the transmembrane calcium current, ICa, and subsequently, the development of clinically useful blocking drugs. Although the blockers currently available for clinical use in cardiovascular conditions are exclusively L-type calcium channel blockers, selective blockers of other types of calcium channels are under investigation. Certain antiseizure drugs are thought to act, at least in part,

CHAPTER 12  Vasodilators & the Treatment of Angina Pectoris & Coronary Syndromes     209

TABLE 12–4  Properties of several voltage-activated calcium channels. Properties of the Calcium Current

Blocked By

Cardiac, skeletal, smooth muscle, neurons (CaV1.4 is found in retina), endocrine cells, bone

Long, large, high threshold

Verapamil, DHPs, Cd , ω-aga-IIIA

CaV3.1–CaV3.3

Heart, neurons

Short, small, low threshold

sFTX, flunarizine, Ni (CaV3.2 only), 1 mibefradil

N

CaV2.2

Neurons, sperm2

Short, high threshold

Ziconotide,3 gabapentin,4 ω-CTXGVIA, ω-aga-IIIA, Cd2+

P/Q

CaV2.1

Neurons

Long, high threshold

ω-CTX-MVIIC, ω-aga-IVA

R

CaV2.3

Neurons, sperm2

Pacemaking

SNX-482, ω-aga-IIIA

Type

Channel Name

Where Found

L

CaV1.1–CaV1.4

T

2+

2+

1

Antianginal drug withdrawn from market.

2

Channel types associated with sperm flagellar activity may be of the Catsper 1–4 variety.

3

Synthetic snail peptide analgesic (see Chapter 31).

4

Antiseizure agent (see Chapter 24).

DHPs, dihydropyridines (eg, nifedipine); sFTX, synthetic funnel web spider toxin; ω-CTX, conotoxins extracted from several marine snails of the genus Conus; ω-aga-IIIA and ω-agaIVA, toxins of the funnel web spider, Agelenopsis aperta; SNX-482, a toxin of the African tarantula, Hysterocrates gigas.

through calcium channel (especially T-type) blockade in neurons (see Chapter 24).

Chemistry & Pharmacokinetics Verapamil, the first clinically useful member of this group, was the result of attempts to synthesize more active analogs of papaverine, a vasodilator alkaloid found in the opium poppy. Since then, dozens of agents of varying structure have been found to have the same pharmacologic action (Table 12–5). Three chemically dissimilar calcium channel blockers are shown in Figure 12–4. Nifedipine is the prototype of the dihydropyridine family of calcium channel blockers; dozens of molecules in this family have been investigated, and several are currently approved in the USA for angina, hypertension, and other indications.

The calcium channel blockers are orally active agents and are characterized by high first-pass effect, high plasma protein binding, and extensive metabolism. Verapamil and diltiazem are also used by the intravenous route.

Pharmacodynamics A.  Mechanism of Action The voltage-gated L type is the dominant type of calcium channel in cardiac and smooth muscle and is known to contain several drug receptors. It consists of α1 (the larger, pore-forming subunit), α2, β, γ, and δ subunits. Four variant α1 subunits have been recognized. Nifedipine and other dihydropyridines have been demonstrated to bind to one site on the α1 subunit, whereas verapamil and diltiazem appear to bind to closely related but not identical

TABLE 12–5  Clinical pharmacology of some calcium channel–blocking drugs. Drug

Oral Bioavailability (%)

Half-Life (hours)

Indication

Dosage

 Amlodipine

65–90

30–50

Angina, hypertension

5–10 mg orally once daily

 Felodipine

15–20

11–16

Hypertension, Raynaud phenomenon

5–10 mg orally once daily

 Isradipine

15–25

8

Hypertension

2.5–10 mg orally twice daily

 Nicardipine

35

2–4

Angina, hypertension

20–40 mg orally every 8 hours

 Nifedipine

45–70

4

Angina, hypertension, Raynaud phenomenon

3–10 mcg/kg IV; 20–40 mg orally every 8 hours

 Nisoldipine

cardiac channels

  •  Amlodipine, felodipine, other dihydropyridines: Like nifedipine but slower onset and longer duration (up to 12 h or more) MISCELLANEOUS   •  Ranolazine

Inhibits late sodium current in heart • also may modify fatty acid oxidation at much higher doses

Reduces cardiac oxygen demand • fatty acid oxidation modification could improve efficiency of cardiac oxygen utilization

  •  Ivabradine: Inhibitor of sinoatrial pacemaker; reduction of heart rate reduces oxygen demand   •  Trimetazidine, allopurinol, perhexiline, fasudil: See text

Prophylaxis of angina

Oral, duration 6–8 h • Toxicity: QT interval prolongation (but no increase of torsades de pointes), nausea, constipation, dizziness • Interactions: Inhibitors of CYP3A increase ranolazine concentration and duration of action

CHAPTER 12  Vasodilators & the Treatment of Angina Pectoris & Coronary Syndromes     217

P R E P A R A T I O N S A V A I L A B L E GENERIC NAME AVAILABLE AS NITRATES & NITRITES Amyl nitrite Generic Isosorbide dinitrate (oral, oral sustained Generic, Isordil release, sublingual) Isosorbide mononitrate Ismo, others Nitroglycerin (sublingual, buccal, Generic, others oral sustained release, parenteral, transdermal patch, topical ointment) CALCIUM CHANNEL BLOCKERS Amlodipine Generic, Norvasc, AmVaz Clevidipine (approved only for use in Cleviprex hypertensive emergencies) Diltiazem (oral, oral sustained release, Generic, Cardizem parenteral) Felodipine Generic, Plendil Isradipine (oral, oral controlled release) DynaCirc Nicardipine (oral, oral sustained release, Cardene, others parenteral) Nifedipine (oral, oral extended release) Adalat, Procardia, others Nisoldipine Sular Verapamil (oral, oral sustained release, Generic, Calan, Isoptin parenteral) BETA BLOCKERS See Chapter 10 SODIUM CHANNEL BLOCKERS Ranolazine Ranexa DRUGS FOR ERECTILE DYSFUNCTION Avanafil Stendra Sildenafil Viagra, Revatio Tadalafil Cialis, Adcirca Vardenafil Levitra DRUGS FOR PERIPHERAL ARTERY DISEASE Cilostazol Generic, Pletal Pentoxifylline Generic, Trental

REFERENCES Bairey Merz CN et al: Ischemia and no obstructive coronary artery disease (INOCA): Developing evidence-based therapies and research agenda for the next decade. Circulation 2017;135:1075. Bhatt DL et al: Diagnosis and treatment of acute coronary syndromes. A review. JAMA 2022;327:662. Borer JS: Clinical effect of ‘pure’ heart rate slowing with a prototype If inhibitor: Placebo-controlled experience with ivabradine. Adv Cardiol 2006;43:54. Brozovitch FV et al: Mechanisms of vascular smooth muscle contraction and the basis for pharmacologic treatment of smooth muscle disorders. Pharmacol Rev 2016;68:476. Burashnikov A et al: Ranolazine effectively suppresses atrial fibrillation in the setting of heart failure. Circ Heart Fail 2014;7:627. Carmichael P, Lieben J: Sudden death in explosives workers. Arch Environ Health 1963;7:50. Catterall WA, Swanson TM: Structural basis for pharmacology of voltage-gated sodium and calcium channels. Mol Pharmacol 2015;88:141.

Chaitman BR et al: Effects of ranolazine, with atenolol, amlodipine, or diltiazem on exercise tolerance and angina frequency in patients with severe chronic angina: A randomized controlled trial. JAMA 2004;291:309. Chang C-R, Sallustio B, Horowitz JD: Drugs that affect cardiac metabolism: Focus on perhexiline. Cardiovasc Drugs Ther 2016;30:399. Chen Z, Zhang J, Stamler JS: Identification of the enzymatic mechanism of nitroglycerin bioactivation. Proc Natl Acad Sci 2002;99:8306. Cooper-DeHoff RM, Chang S-W, Pepine CJ: Calcium antagonists in the treatment of coronary artery disease. Curr Opin Pharmacol 2013;13:301. Fearon WF et al: Fractional flow reserve-guided PCI as compared with coronary bypass surgery. N Engl J Med 2022;386:128. Fihn SD et al: Guideline for the diagnosis and management of patients with stable ischemic heart disease: Executive summary. Circulation 2012;126:3097. Goldman L et al: Comparative reproducibility and validity of systems for assessing cardiovascular functional class: Advantages of a new specific activity scale. Circulation 1981;64:1227. Husted SE, Ohman EM: Pharmacological and emerging therapies in the treatment of chronic angina. Lancet 2015;386:691. Ignarro LJ et al: Mechanism of vascular smooth muscle relaxation by organic nitrates, nitrites, nitroprusside, and nitric oxide: Evidence for the involvement of S-nitrosothiols as active intermediates. J Pharmacol Exp Ther 1981;218:739. Joshi PH, de Lemos JA: Diagnosis and management of stable angina. A review. JAMA 2021;325:1765. Kannam JP, Aroesty JM, Gersh BJ: Overview of the management of stable angina pectoris. UpToDate, 2019. http://www.uptodate.com. Kast R et al: Cardiovascular effects of a novel potent and highly selective asaindolebased inhibitor of Rho-kinase. Br J Pharmacol 2007;152:1070. Lacinova L: Voltage-dependent calcium channels. Gen Physiol Biophys 2005;24(Suppl 1):1. Li H, Föstermann U: Uncoupling of endothelial NO synthesis in atherosclerosis and vascular disease. Curr Opin Pharmacol 2013;13:161. McGillian MM et al: Isosorbide mononitrate in heart failure with preserved ejection fraction. N Engl J Med 2015;373:2314. McGillian MM et al: Management of patients with refractory angina: Canadian Cardiovascular Society/Canadian Pain Society joint guidelines. Can J Cardiol 2012;28(Suppl2):S20. McLaughlin VV et al: Expert consensus document on pulmonary hypertension. J Am Coll Cardiol 2009;53:1573. Moss AJ et al: Ranolazine shortens repolarization in patients with sustained inward sodium current due to type-3 long QT syndrome. J Cardiovasc Electrophysiol 2008;19:1289. Münzel T et al: Physiology and pathophysiology of vascular signaling controlled by guanosine 3’,5’-cyclic monophosphate-dependent protein kinase. Circulation 2003;108:2172. Münzel T, Gori T: Nitrate therapy and nitrate tolerance in patients with coronary artery disease. Curr Opin Pharmacol 2013;13:251. Ohman EM: Clinical practice. Chronic stable angina. N Engl J Med 2016;374:1167. Peng J, Li Y-J: New insights into nitroglycerin effects and tolerance: Role of calcitonin gene-related peptide. Eur J Pharmacol 2008;586:9. Rajendra NS et al: Mechanistic insights into the therapeutic use of high-dose allopurinol in angina pectoris. J Am Coll Cardiol 2011;58:820. Sayed N et al: Nitroglycerin-induced S-nitrosylation and desensitization of soluble guanylyl cyclase contribute to nitrate tolerance. Circ Res 2008;103:606. Simons M, Laham RJ: New therapies for angina pectoris. UpToDate 2019. http:// uptodate.com. Stevens S et al: Pentaerythritol tetranitrate in vivo treatment improves oxidative stress and vascular dysfunction by suppression of endothelin-1 signaling in monocrotaline-induced pulmonary hypertension. Oxid Med Cell Longev 2017; 2017:4353462. Stone GW et al: A prospective natural-history study of coronary atherosclerosis. N Engl J Med 2011;364:226. Triggle DJ: Calcium channel antagonists: Clinical uses—Past, present and future. Biochem Pharmacol 2007;74:1. Wei J et al: Coronary microvascular dysfunction causing cardiac ischemia in women. JAMA 2019;322:2334.

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C ASE STUDY ANSWER The case described is typical of acute coronary syndrome without STEMI (ST elevation myocardial infarction). Her chest pain is due to transient and possibly reversible inadequate coronary flow, probably due to rupture of an atheromatous plaque and clotting in an epicardial coronary artery. Immediate treatment to restore coronary flow is indicated. If available,

percutaneous coroanary intervention (PCI) is optimal. If PCI is not available in this rural hospital, lysis of the clot should be attempted immediately with a fibrinolytic drug such as alteplase (Chapter 34). Admission to the intensive care unit is indicated, and transfer to a hospital where PCI is available also should be considered if her condition worsens.

13

C

Drugs Used in Heart Failure Bertram G. Katzung, MD, PhD

H

A

P

T

E

R

C ASE STUDY A 60-year-old woman notices shortness of breath with exertion while working long hours in her bakery. She has a 20-year history of poorly controlled hypertension. The shortness of breath is accompanied by onset of swelling of the feet and ankles and increasing fatigue. On physical examination in the clinic, she is found to be mildly short of breath lying down but feels better sitting upright. Pulse is 100 bpm and regular, and blood pressure is 165/100 mm

Heart failure occurs when cardiac output is inadequate to provide the oxygen needed by the body. It is a highly lethal condition, with a 5-year mortality rate conventionally said to be about 50%. The most common cause of heart failure in the USA is coronary artery disease, with hypertension also an important factor. Two major types of failure may be distinguished. Almost 50% of younger patients have systolic failure, with reduced mechanical pumping action (contractility) and reduced ejection fraction (HFrEF). The remaining group has diastolic failure, with stiffening and loss of adequate relaxation playing a major role in reducing filling and cardiac output. Ejection fraction may be normal (preserved, HFpEF) in diastolic failure even though stroke volume is significantly reduced. The proportion of patients with diastolic failure increases with age. Because other cardiovascular conditions (especially myocardial infarction) are now being treated more effectively, more patients are surviving long enough for heart failure to develop, making heart failure one of the cardiovascular conditions that is actually increasing in prevalence in some countries. Like coronary artery disease, heart failure is disproportionately represented in underserved populations. Heart failure is a progressive disease that is characterized by a gradual reduction in cardiac performance, punctuated in many patients by episodes of acute decompensation, often requiring hospitalization. Treatment is therefore directed at two somewhat different goals: (1) reducing symptoms and slowing progression as

Hg. Crackles are noted at both lung bases, and her jugular venous pressure is elevated. The liver is enlarged, and there is 3+ edema of the ankles and feet. An echocardiogram shows an enlarged, poorly contracting heart with a left ventricular ejection fraction of about 30% (normal: 60%). The presumptive diagnosis is stage C, class III heart failure with reduced ejection fraction (HFrEF). What treatment is indicated?

much as possible during relatively stable periods and (2) managing acute episodes of decompensated failure. These factors are discussed in Clinical Pharmacology of Drugs Used in Heart Failure. Although it is believed that the primary defect in early systolic heart failure resides in the excitation-contraction coupling machinery of the myocardium, the clinical condition also involves many other processes and organs, including the baroreceptor reflex, the sympathetic nervous system, the kidneys, angiotensin II and other peptides, aldosterone, and apoptosis of cardiac cells. Recognition of these factors has resulted in a variety of drug treatment strategies (Table 13–1) that constitute the current standard of care. A rare form of amyloid cardiomyopathy, transthyretin amyloid cardiomyopathy (ATTR-CM), is associated with heart failure and can be treated with a small molecule oral drug, tafamidis. Large clinical trials have shown that therapy directed at noncardiac targets is more valuable in the long-term treatment of heart failure than traditional positive inotropic agents (cardiac glycosides [digitalis]). Large trials have also shown that angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), certain β blockers, aldosterone receptor antagonists, combined angiotensin receptor blocker plus neprilysin inhibitor (ARNI), and probably SGLT2 inhibitor therapies are the only agents in current use that actually prolong life and reduce hospitalizations in patients with chronic heart failure. These strategies are useful in both systolic and diastolic failure. 219

220    SECTION III  Cardiovascular-Renal Drugs

TABLE 13–1  Therapies used in heart failure. Chronic Systolic Heart Failure

Acute Heart Failure

Diuretics

Diuretics

Aldosterone receptor antagonists

Vasodilators

Angiotensin-converting enzyme inhibitors

Beta agonists

Angiotensin receptor blockers

Bipyridines

SGLT2 inhibitors

Natriuretic peptide

Beta blockers Cardiac glycosides

Left ventricular assist device

Vasodilators, neprilysin inhibitor Resynchronization and cardioverter therapy

Smaller studies support the use of the hydralazine-nitrate combination in African Americans and the use of ivabradine in patients with persistent tachycardia despite optimal management. Positive inotropic drugs, on the other hand, are helpful mainly in acute systolic failure. Cardiac glycosides also reduce symptoms in chronic systolic heart failure. In large clinical trials to date, other positive inotropic drugs have usually reduced survival in chronic failure or had no benefit, and their use is discouraged.

Control of Normal Cardiac Contractility The vigor of contraction of heart muscle is determined by several processes that lead to the movement of actin and myosin filaments in the cardiac sarcomere (Figure 13–1). Ultimately, contraction results from the interaction of activator calcium (during systole) with the actin-troponin-tropomyosin system, thereby triggering the actin-myosin interaction. This activator calcium is released from the sarcoplasmic reticulum (SR). The amount released depends on the amount stored in the SR and on the amount of trigger calcium that enters the cell during the plateau of the action potential. A.  Sensitivity of the Contractile Proteins to Calcium and Other Contractile Protein Modifications The determinants of calcium sensitivity, ie, the curve relating the shortening of cardiac myofibrils to the cytoplasmic calcium concentration, are incompletely understood, but several types of drugs can be shown to affect calcium sensitivity in vitro. Levosimendan is a drug that increases calcium sensitivity (it may also inhibit phosphodiesterase) and reduces symptoms in models of heart failure. Several reports suggest that omecamtiv mecarbil (CK-1827452) alters the rate of transition of myosin from a low-actin-binding state to a strongly actin-bound, force-generating state and improves ejection fraction in the failing heart. This action might increase contractility without increasing energy consumption, ie, increase efficiency. B.  Amount of Calcium Released from the Sarcoplasmic Reticulum A small rise in free cytoplasmic calcium, brought about by calcium influx during the action potential, triggers the opening of

calcium-gated, ryanodine-sensitive (RyR2) calcium channels in the membrane of the cardiac SR and the rapid release of a large amount of the ion into the cytoplasm in the vicinity of the actin-troponintropomyosin complex. The amount released is proportional to the amount stored in the SR and the amount of trigger calcium that enters the cell through the cell membrane. (Ryanodine is a potent negative inotropic plant alkaloid that interferes with the release of calcium through cardiac SR channels.) C. Amount of Calcium Stored in the Sarcoplasmic Reticulum The SR membrane contains a very efficient calcium uptake transporter known as the sarcoplasmic endoplasmic reticulum Ca2+ATPase (SERCA). This pump maintains free cytoplasmic calcium at very low levels during diastole by pumping calcium into the SR. SERCA is normally inhibited by phospholamban; phosphorylation of phospholamban by protein kinase A (activated, eg, by cAMP produced in response to β-adrenoceptor activation) removes this inhibition. (Some evidence suggests that SERCA activity is impaired in heart failure.) The amount of calcium sequestered in the SR is thus determined, in part, by the amount accessible to this transporter and the activity of the sympathetic nervous system. This in turn is dependent on the balance of calcium influx (primarily through the voltage-gated membrane L-type calcium channels) and calcium efflux, the amount removed from the cell (primarily via the sodium-calcium exchanger [NCX], a transporter in the cell membrane). The amount of Ca2+ released from the SR depends on the response of the RyR channels to trigger Ca2+. D.  Amount of Trigger Calcium The amount of trigger calcium that enters the cell depends on the concentration of extracellular calcium, the availability of membrane calcium channels, and the duration of their opening. As described in Chapters 6 and 9, sympathomimetics cause an increase in calcium influx through an action on these channels. Conversely, the calcium channel blockers (see Chapter 12) reduce this influx and depress contractility. E.  Activity of the Sodium-Calcium Exchanger This antiporter (NCX) uses the inward movement of three sodium ions to move one calcium ion against its concentration gradient from the cytoplasm to the extracellular space. Extracellular concentrations of these ions are much less labile than intracellular concentrations under physiologic conditions. The sodium-calcium exchanger’s ability to carry out this transport is thus strongly dependent on the intracellular concentrations of both ions, especially sodium. F. Intracellular Sodium Concentration and Activity of Na+/K+-ATPase Na+/K+-ATPase, by removing intracellular sodium, is the major determinant of sodium concentration in the cell. The sodium influx through voltage-gated channels, which occurs as a normal part of almost all cardiac action potentials, is another determinant, although the amount of sodium that enters with each action

CHAPTER 13  Drugs Used in Heart Failure     221

Myofibril syncytium

Digoxin

– Interstitium Cell membrane

Na+/K+-ATPase

Cav–L

NCX

ATP K+

– +

Na+

Cytoplasm Ca2+ channel blockers

Ca2+

β agonists

Trigger Ca2+ ATP

SERCA

CalS CalS Ca2+

Sarcoplasmic reticulum

Ca2+

Ca2+

CalS CalS

RyR

CalS

ATP

Ca2+ sensitizers

Ca2+

Ca2+

+

Z

+ Actin-tropomyosintroponin

Myosin

Myosin activators

Sarcomere

FIGURE 13–1  Schematic diagram of a cardiac muscle sarcomere, with sites of action of several drugs that alter contractility. (Mitochondria, which are critical for the generation of ATP, are omitted for simplicity.) Na+/K+-ATPase, the sodium pump, is the site of action of cardiac glycosides. NCX is the sodium-calcium exchanger. Cav-L is the voltage-gated, L-type calcium channel. SERCA (sarcoplasmic endoplasmic reticulum Ca2+-ATPase) is a calcium transporter ATPase that pumps calcium into the sarcoplasmic reticulum. CalS is calcium bound to calsequestrin, a highcapacity Ca2+-binding protein. RyR (ryanodine RyR2 receptor) is a calcium-activated calcium channel in the membrane of the SR that is triggered to release stored calcium. Z is the Z-line, which delimits the sarcomere. Calcium sensitizers act at the actin-troponin-tropomyosin complex where activator calcium brings about the contractile interaction of actin and myosin. Black arrows represent processes that initiate contraction or support basal tone. Green arrows represent processes that promote relaxation.

222    SECTION III  Cardiovascular-Renal Drugs

potential is much less than 1% of the total intracellular sodium. Na+/K+-ATPase appears to be the primary target of digoxin and other cardiac glycosides.

Cardiac output

Pathophysiology of Heart Failure Heart failure is a syndrome with many causes that may involve one or both ventricles. Normal cardiac output is ~5 L/min/70 kg body weight. Cardiac output is usually below this normal value in failure (“low-output” failure). Systolic dysfunction, with reduced cardiac output and significantly reduced ejection fraction (EF 60%), is typical of acute failure, especially that resulting from myocardial infarction. Diastolic dysfunction often occurs as a result of hypertrophy and stiffening of the myocardium, and although cardiac output is reduced, ejection fraction may be normal. Heart failure due to diastolic dysfunction does not usually respond optimally to positive inotropic drugs. “High-output” failure is a rare form of heart failure. In this condition, the demands of the body are so great that even increased cardiac output is insufficient. High-output failure can result from hyperthyroidism, beriberi, anemia, or arteriovenous shunts. This form of failure responds poorly to the drugs discussed in this chapter and should be treated by correcting the underlying cause. The primary signs and symptoms of all types of heart failure include tachycardia, decreased exercise tolerance, shortness of breath, and cardiomegaly. Peripheral and pulmonary edema (the congestion of congestive heart failure) are often but not always present. Decreased exercise tolerance with rapid muscular fatigue is the major direct consequence of diminished cardiac output. The other manifestations result from the attempts by the body to compensate for the intrinsic cardiac defect. Neurohumoral (extrinsic) compensation involves two major mechanisms (previously presented in Figure 6–7)—the sympathetic nervous system and the renin-angiotensin-aldosterone hormonal response—plus several others. Some of the detrimental as well as beneficial features of these compensatory responses are illustrated in Figure 13–2. The baroreceptor reflex appears to be reset, with a lower sensitivity to arterial pressure, in patients with heart failure. As a result, baroreceptor sensory input to the vasomotor center is reduced even at normal pressures; sympathetic outflow is increased, and parasympathetic outflow is decreased. Increased sympathetic outflow causes tachycardia, increased cardiac contractility, and increased vascular tone. Vascular tone is further increased by angiotensin II and endothelin, a potent vasoconstrictor released by vascular endothelial cells. Vasoconstriction increases afterload, which further reduces ejection fraction and cardiac output. The result is a vicious cycle that is characteristic of heart failure (Figure 13–3). Neurohumoral antagonists and vasodilators attempt to reduce heart failure mortality by interrupting the cycle and slowing the downward spiral. After a relatively short exposure to increased sympathetic drive, complex down-regulatory changes in the cardiac β1adrenoceptor–G protein-effector system take place that result in diminished stimulatory effects. Beta2 receptors are not downregulated and may develop increased coupling to the inositol 1,4,5-trisphosphate–diacylglycerol (IP3-DAG) cascade. It has also

Carotid sinus firing

Renal blood flow

Sympathetic discharge

Renin release

Angiotensin II Force Rate Preload

Afterload

Remodeling

Cardiac output (via compensation)

FIGURE 13–2  Some compensatory responses (orange boxes) that occur during congestive heart failure. In addition to the effects shown, sympathetic discharge facilitates renin release, and angiotensin II increases norepinephrine release by sympathetic nerve endings (dashed arrows). been suggested that cardiac β3 receptors (which do not appear to be down-regulated in failure) may mediate negative inotropic effects. Excessive β activation can lead to leakage of calcium from the SR via RyR channels and contributes to stiffening of the ventricles and arrhythmias. Reuptake of Ca2+ into the SR by SERCA may also be impaired. Prolonged β activation also increases caspases, the enzymes responsible for apoptosis. Increased angiotensin II

CO

Cardia cp

1

erform

CO NE, A ET

EF

ance

2

CO NE, A ET

B

EF

Afterload Afterload

NE, A ET

EF

Afterload Time

FIGURE 13–3  Vicious spiral of progression of heart failure. Decreased cardiac output (CO) activates production of neurohormones (NE, norepinephrine; AII, angiotensin II; ET, endothelin), which cause vasoconstriction and increased afterload. This further reduces ejection fraction (EF) and CO, and the cycle repeats. The downward spiral is continued until a new steady state is reached in which CO is lower and afterload is higher than is optimal for normal activity. Circled points 1, 2, and B represent points on the ventricular function curves depicted in Figure 13–4.

CHAPTER 13  Drugs Used in Heart Failure     223

Pathophysiology of Cardiac Performance Cardiac performance is a function of four primary factors: 1. Preload: When some measure of left ventricular performance such as stroke volume or stroke work is plotted as a function of left ventricular filling pressure or end-diastolic fiber length, the resulting graph is termed the left ventricular function curve (Figure 13–4). The ascending limb (BNP Ring cleavage

NPR-C

NPR-C

NPR-B GC-B

NPR-B GC-B

NPR-A GC-A

NPR-A GC-A

ANP=BNP

Signaling?

NEP

Endocytosis

ANP=CNP>BNP Tail cleavage

Peptide degradation

IDE

Intracellular

FIGURE 17–7  Natriuretic hormone receptors, intracellular signaling, and degradation processes. The expression above each receptor indicates the relative affinities of the three peptides, ANP, BNP, and CNP. GC-A, guanylate cyclase type A; GC-B, guanylate cyclase type B; IDE, insulin degrading enzyme; NEP, neprilysin. (Adapted from Volpe M, Carnovali M, Mastromarino V: The natriuretic peptides system in the pathophysiology of heart failure: From molecular basis to treatment, Clin Sci. 2016 Jan;130(2):57-77.)

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internalized, the peptide is degraded enzymatically, and the receptor is returned to the cell surface.

CLINICAL ROLE OF NATRIURETIC PEPTIDES In heart failure, release of ANP and BNP is increased in response to cardiac stretch. This represents a compensatory response that ultimately fails to prevent the sodium and water retention caused by activation of the renin-angiotensin and other neurohormonal systems. The increases in ANP and BNP are proportional to the severity of the disease, and measurement of their plasma levels (or MR-proANP or NT-proBNP) has significant diagnostic and prognostic value. Indeed, BNP and NT-proBNP are regarded by some as the gold standard for the diagnosis and stratification of heart failure, and their use is recommended by ACC/AHA guidelines. Atrial fibrillation (AFib) is the most common cardiac arrhythmia and an important risk factor for ischemic stroke. Plasma natriuretic peptide levels are frequently increased in patients with AFib and an association between elevated ANP and the incidence of AFib and stroke has been reported. It has been recommended that natriuretic peptide, MR-proANP, or NT-proBNP levels be measured as part of the routine evaluation of patients with AFib. Successful treatment of AFib with catheter ablation is accompanied by decreased plasma ANP, and pretreatment plasma ANP may predict the effectiveness of the treatment. Increased release of natriuretic peptides during AFib may cause natriuresis and diuresis. As noted above, ANP and BNP participate in the regulation of whole body metabolism. Furthermore, epidemiological studies suggest that these peptides are involved in some metabolic diseases. For example, natriuretic peptide deficiency may contribute to the etiology of obesity, metabolic syndrome, and type 2 diabetes. Thus the natriuretic peptide system may underlie, in part, the link between metabolic and cardiovascular disease.

Therapeutic Applications Natriuretic peptides can be administered as recombinant ANP (carperitide), recombinant BNP (nesiritide), or ularitide, the synthetic form of urodilatin (see above). These peptides produce vasodilation and natriuresis and have been investigated for the treatment of congestive heart failure. Nesiritide is approved for the treatment of decompensated acute heart failure (see Chapter 13). Ularitide demonstrated beneficial effects in animal models of heart failure and in phase 1 and 2 studies in heart failure patients. However, despite inducing hemodynamic improvements and beneficial effects on renal function, dyspnea, myocardial structure, and endothelin levels, ularitide did not reduce long-term cardiovascular mortality in patients with acute heart failure. M-ANP is a novel synthetic 40-amino acid peptide which consists of the native 28-amino acid core of ANP with a 12-amino acid extended C-terminus. M-ANP activates particulate guanylyl cyclase with equal potency to ANP and is highly resistant to

degradation by neprilysin. It has potential for the treatment of acute hypertension. The circulating levels of natriuretic peptides can also be increased by drugs that inhibit their breakdown by neprilysin. The resulting increase in ANP and BNP causes natriuresis and vasodilation, as well as a compensatory increase in renin secretion and plasma ANG II levels. Because of the increase in ANG II, these peptides are not effective as monotherapy in the treatment of heart failure. However, these observations led to the development of drugs that combine neprilysin inhibition with an ACE inhibitor in order to prevent the increase in plasma ANG II, or with an ARB to block the actions of ANG II. Drugs that combine neprilysin inhibition with ACE inhibition, known as vasopeptidase inhibitors, include omapatrilat, sampatrilat, and fasidotrilat. Omapatrilat, which received the most attention, lowers blood pressure in animal models of hypertension as well as in hypertensive patients, and improves cardiac function in patients with heart failure. Unfortunately, omapatrilat causes a significant incidence of angioedema and cough, apparently as a result of decreased metabolism of bradykinin, and is not approved for clinical use. The combination of an ANG II receptor antagonist with a neprilysin inhibitor (ARNI) increases endogenous natriuretic peptide levels while simultaneously blocking the effects of the increase in plasma ANG II. The first-in-class ARNI, sacubitril-valsartan, is a single molecule composed of the neprilysin inhibitor prodrug sacubitril and the ANG II receptor antagonist valsartan. In healthy subjects, sacubitril-valsartan increased plasma ANP and cGMP levels in combination with increases in plasma renin and ANG II levels. Clinical trials in patients with heart failure demonstrated several beneficial effects of sacubitril-valsartan, and it has proved superior to ACE inhibition or angiotensin receptor blockade in reducing the risk of death and hospitalization from heart failure (Figure 17–8). Side effects include hypotension, hyperkalemia, renal impairment, and angioedema, the latter possibly due to increased bradykinin levels. Sacubitril-valsartan, marketed under the brand name Entresto, is approved by the FDA for the treatment of heart failure with reduced ejection fraction (see Chapter 13). It is not approved for heart failure with preserved ejection fraction. In patients with acute myocardial infarction, sacubitril-valsartan did not decrease the incidence of death when compared to ramipril alone. Sacubitril-valsartan has been shown to lower blood pressure in patients with essential hypertension, comparing favorably with valsartan. Increasing natriuretic peptide levels with sacubitril-valsartan could also be a useful strategy in the treatment of metabolic disease. Achondroplasia is a rare genetic disease that inhibits endochondral ossification, resulting in short stature and other health complications. CNP is known to increase endochondral ossification and improve skeletal growth, and this has led to the use of CNP analogs to treat the disease. Vosoritide is a 39-amino acid CNP analog with an extended plasma half-life due to increased resistance to neprilysin. In children with achondroplasia, once-daily subcutaneous administration of vosoritide resulted in a sustained increase in growth velocity for up to 42 months. This was accompanied by an increase in urinary

CHAPTER 17  Vasoactive Peptides    327

Angiotensin antagonist

ACE inhibitor

Sacubitrilvalsartan

% Decrease in mortality

0%

–10%

–20%

–30%

–40%

FIGURE 17–8  Comparison of the decrease in mortality produced by an angiotensin receptor antagonist, a converting enzyme inhibitor, and the combined angiotensin receptor antagonist-neprilysin inhibitor sacubitril-valsartan (Entresto) in patients with heart failure. Results for the three drugs are from separate trials. Each bar represents the drug effect versus placebo. (Adapted from Volpe M, Carnovali M, Mastromarino V: The natriuretic peptides system in the pathophysiology of heart failure: From molecular basis to treatment, Clin Sci 2016;130(2):57-77.)

cyclic GMP. Side effects included a transient reduction in blood pressure. TransCon CNP is a 38-amino acid CNP analog conjugated to a polyethylene glycol carrier, designed to provide sustained systemic CNP levels during subcutaneous administration. In mice and monkeys, transCon CNP produced a sustained increase in plasma CNP-38 and was more effective in stimulating bone growth than either unconjugated CNP-38 or vosoritide. There was no reduction in blood pressure. This prodrug is in clinical development for the treatment of achondroplasia.

■■ VASOACTIVE INTESTINAL PEPTIDE Vasoactive intestinal peptide (VIP) is a 28-amino-acid peptide that belongs to the glucagon-secretin family of peptides. VIP is widely distributed in the central and peripheral nervous systems, where it functions as one of the major peptide neurotransmitters. It is present in cholinergic presynaptic neurons in the central nervous system, and in peripheral peptidergic neurons innervating diverse tissues including the heart, lungs, gastrointestinal and urogenital tracts, skin, eyes, ovaries, and thyroid gland. Many blood vessels are innervated by VIP neurons. VIP is also present in key organs of the immune system including the thymus, spleen, and lymph nodes. Although VIP is present in blood, where it undergoes rapid degradation, it does not appear to function as a hormone. VIP participates in a wide variety of biologic functions including metabolic processes, secretion of endocrine and exocrine glands, cell differentiation, smooth muscle relaxation, and modulation of the immune response. VIP exerts significant effects on the cardiovascular system. It produces marked vasodilation in most vascular beds and in this regard is more potent on a molar basis than acetylcholine. In the heart, VIP causes coronary vasodilation and exerts positive inotropic and chronotropic effects. It may thus participate in

the regulation of coronary blood flow, cardiac contraction, and heart rate. The effects of VIP are mediated by two G protein–coupled receptors, VPAC1 and VPAC2. Both receptors are widely distributed in the central nervous system and in the heart, blood vessels, and other tissues. VIP has a high affinity for both receptor subtypes. Binding of VIP to its receptors results in activation of adenylyl cyclase and formation of cAMP, which is responsible for the vasodilation and many other effects of the peptide. Other actions may be mediated by inositol trisphosphate synthesis and calcium mobilization. VIP can also bind with low affinity to the VIP-like peptide pituitary adenylyl cyclase-activating peptide receptor, PAC1. In view of its potent vasodilator action, VIP has potential for the treatment of systemic and pulmonary hypertension and heart failure, but this is limited by its short half-life in the circulation. However, PB1046 (Vasomera), a stable long-acting form of VIP that is selective for VPAC2 receptors, has been developed. Vasomera reduces blood pressure in animal models of hypertension, pulmonary arterial hypertension, and heart failure, and has been shown to be safe and well tolerated after single subcutaneous or intravenous injection in phase 1 studies in patients with essential hypertension. It has received orphan drug designation for the treatment of pulmonary arterial hypertension and cardiomyopathy associated with dystrophinopathies.

■■ SUBSTANCE P Substance P (SP) belongs to the tachykinin family of peptides, which share the common carboxyl terminal sequence Phe-GlyLeu-Met. Other members of this family are neurokinins A and B, and three endokinins, hemokinin-1 and endokinins A and B. SP is an undecapeptide, while neurokinins A and B are decapeptides. SP is widely distributed in the central and peripheral nervous systems and in the cardiovascular system. It is also present in

328    SECTION IV  Drugs with Important Actions on Smooth Muscle

the gastrointestinal tract, where it may function as a transmitter in the enteric nervous system and as a paracrine agent (see Chapter 6). SP is the most important member of the tachykinin family. It exerts a variety of central actions that implicate the peptide in stress, anxiety, depression, nausea, and emesis. It is present in peripheral afferent pain fibers and participates in nociception. SP causes contraction of venous, intestinal, and bronchial smooth muscle. It stimulates secretion by the salivary glands and causes diuresis and natriuresis by the kidneys. It has been implicated in immune system regulation and inflammation. SP participates in the regulation of the cardiovascular system at both the central and peripheral levels. In the central nervous system, SP-containing nerve fibers are present in cardiovascular centers in the brain and spinal cord. In the heart, SP-containing fibers are present in both atrial and ventricular myocardium. Intravenous infusion of SP induces a dose-dependent increase in cardiac output, mostly due to increased stroke volume. In the vascular system, SP-containing nerve fibers are located around blood vessels, particularly those of the gut and skin. Vasodilation is the predominant vascular action of SP. It apparently results from an action on the vascular endothelium mediated by nitric oxide or other endothelium-derived factors. In some vascular beds, SP causes vasoconstriction. The actions of SP and neurokinins A and B are mediated by three Gq protein–coupled tachykinin receptors designated NK1, NK2, and NK3, which exhibit different affinities for the tachykinins. SP is the preferred ligand for the NK1 receptor, which is widespread throughout the body and is the predominant tachykinin receptor in the human brain. Neurokinins A and B also possess considerable affinity for this receptor but display the highest affinity for NK2 and NK3. Most of the central and peripheral effects of SP including vasodilation are mediated by NK1 receptors. In some cells SP binding leads to activation of phospholipase C; in others it activates adenylyl cyclase. Several nonpeptide NK1 receptor antagonists have been developed. These compounds are highly selective and orally active, and enter the brain. Recent clinical trials have shown that these antagonists may be useful in treating depression and other disorders and in preventing chemotherapy-induced emesis. The first of these to be approved for the prevention of chemotherapy-induced and postoperative nausea and vomiting is aprepitant (see Chapter 62). Fosaprepitant is a prodrug that is converted to aprepitant after intravenous administration and may be a useful parenteral alternative to oral aprepitant. The SP-NK1 system has also been implicated in cancer. SP and NK1 receptors are present in a variety of tumor cells, and NK1 receptor antagonists exert an antitumor action. Thus, drugs such as aprepitant may have potential as anticancer agents. A role for NK1 antagonists in the treatment of cardiovascular disease has not been identified. Novel selective nonpeptide NK2 antagonists include saredutant, nepadutant, and ibodutant. They have undergone clinical testing for the treatment of respiratory and gastrointestinal disorders as well as anxiety, but their use is limited by their low efficacy.

■■ NEUROTENSIN Neurotensin (NT) is a tridecapeptide that was first isolated from the hypothalamus but subsequently found to be present in the gastrointestinal tract. It is also present in the blood, heart, lungs, liver, pancreas, and spleen. NT is synthesized as part of a larger precursor, pro-NT/NMN, that also contains neuromedin N, a six-amino-acid NT-like peptide. In the brain, processing of the precursor leads primarily to the formation of NT and neuromedin N; these are released together from nerve endings. In the gut, processing leads mainly to the formation of NT and a larger peptide that contains the neuromedin N sequence at the carboxyl terminal. Both peptides are secreted into the circulation after ingestion of food. Most of the activity of NT is mediated by the six amino acids at the C-terminus, NT(8-13). Like many other neuropeptides, NT serves a dual function as a neurotransmitter or neuromodulator in the central nervous system. When administered centrally, NT exerts potent effects including hypothermia, antinociception, and modulation of dopamine and glutamate neurotransmission. There are close associations between NT and dopamine systems, and NT may be involved in clinical disorders involving dopamine pathways such as schizophrenia, Parkinson disease, and drug abuse. Consistent with this, it has been shown that central administration of NT in rodents produces effects similar to those produced by antipsychotic drugs. NT also participates in cardiovascular regulation. NT-containing nerve fibers make close contact with atrial and ventricular myocytes, the cardiac conduction system, and coronary vessels. NT-containing fibers are also present in the ascending aorta, aortic arch, and pulmonary veins. Intravenous administration of NT produces tachycardia, vasodilation, and hypotension. It affects coronary vascular tone, blood flow in cutaneous and adipose tissues and the gastrointestinal tract, and venous smooth muscle tone. It may also participate in cardiovascular reflexes. There is evidence that the NT-induced decrease in blood pressure is involved in acute circulatory disorders such as shock. For example, elevated levels of NT have been found in patients with septic and cardiogenic shock and may contribute to the hypotension. Other peripheral actions of NT include increased vascular permeability, increased secretion of several anterior pituitary hormones, hyperglycemia, inhibition of gastric acid and pepsin secretion, and inhibition of gastric motility. Actions on the immune system have also been described. The effects of NT are mediated by three subtypes of NT receptors, designated NTR1, NTR2, and NTR3, also known as NTS1, NTS2, and NTS3. NTR1 and NTR2 belong to the Gq protein– coupled superfamily. NTR1 has a higher affinity for NT than NTR2 and is the major mediator of the diverse effects of NT. The NTR3 receptor is a single-transmembrane protein that is structurally unrelated to NTR1 or NTR2. It belongs to a family of sorting proteins and is therefore known as NTR3/sortilin. The potential use of NT as an antipsychotic agent has been hampered by its rapid degradation in the circulation and inability to cross the blood-brain barrier. However, a series of analogs of NT(8-13) that exert antipsychotic-like activity in animal studies has been developed. These agonists include NT69L, which

CHAPTER 17  Vasoactive Peptides    329

binds with high affinity to NTR1 and NTR2; and NT79, which preferentially binds to NTR2. Another agonist, PD149163, has improved metabolic stability. In addition to their possible role as antipsychotic drugs, these agonists may be useful in the treatment of pain, psychostimulant abuse, and Parkinson disease. Potential adverse effects include hypothermia and hypotension. Development of tolerance to some of the effects of the agonists may occur. NT receptors can be blocked with the nonpeptide antagonists SR142948A and meclinertant (SR48692). SR142948A is a potent antagonist of the hypothermia and analgesia produced by centrally administered NT. It also blocks the cardiovascular effects of systemic NT.

■■ CALCITONIN GENE-RELATED PEPTIDE Calcitonin gene-related peptide (CGRP) is a member of the calcitonin family of peptides that also includes calcitonin, adrenomedullin, and amylin. In humans, CGRP exists in two isoforms termed α-CGRP and β-CGRP. α-CGRP is a 37-amino acid peptide formed by alternative splicing of the calcitonin/CGRP gene on chromosome 11. β-CGRP, which is encoded in a separate gene in the same region, differs in three amino acids. α-CGRP and β-CGRP have similar biological activity but α-CGRP is the principal form. Like calcitonin, CGRP is present in large quantities in the C cells of the thyroid gland. It is also distributed widely in the central and peripheral nervous systems, cardiovascular and respiratory systems, and gastrointestinal tract. In the cardiovascular system, CGRP-containing neuronal fibers are more abundant around arteries than around veins and in atria than in ventricles. CGRP fibers are associated with most smooth muscles of the gastrointestinal tract. CGRP is found with substance P (see above) in some of these regions and with acetylcholine in others. When CGRP is injected into the central nervous system, it produces a variety of effects, including hypertension and suppression of feeding. When injected into the systemic circulation, the peptide causes hypotension, tachycardia, and a positive inotropic effect. The hypotensive action of CGRP results from the potent vasodilator action of the peptide; indeed, CGRP is the most potent vasodilator yet discovered. It dilates multiple vascular beds and increases cutaneous, renal, and coronary blood flow, the coronary circulation being particularly sensitive. The vasodilation results in part from increased nitric oxide production in endothelial cells which in turn acts to relax the underlying vascular smooth muscle. The biological effects of CGRP are mainly mediated by the CGRP receptor, a complex composed of the G protein–coupled calcitonin-like receptor (CLR) and a single transmembrane domain protein, receptor activity-modifying protein 1 (RAMP1). Some CGRP effects are mediated by the amylin-1 receptor (AMY1), a complex consisting of the calcitonin receptor (CTR) and RAMP1. Both receptors are expressed throughout the central nervous, cardiovascular, and other systems. Despite its cardiovascular actions, CGRP does not appear to participate in the physiologic regulation of blood pressure.

However, it might play a protective role in cardiovascular diseases including hypertension, where it may counteract the reninangiotensin and sympathetic nervous systems, and in heart failure, where it could alleviate cardiac hypertrophy, inflammation, and apoptosis. Indeed, an acylated α-CGRP analog with a longer halflife than the native peptide has shown promising results in animal models of hypertension and heart failure. There is now considerable evidence that release of CGRP from trigeminal nerves plays a central role in the pathophysiology of migraine (see Chapter 16). The peptide is released during migraine attacks, and successful treatment of migraine with a selective serotonin agonist normalizes cranial CGRP levels. Intravenous administration of CGRP can induce migraine-like headaches in migraineurs. Peptide and nonpeptide antagonists of the CGRP receptor have been developed. CGRP8-37 was used extensively to investigate the actions of CGRP but displays affinity for other related receptors including those for adrenomedullin (see below). Smaller, nonpeptide CGRP receptor antagonists target the interface between CLR and RAMP1, making them more selective for the CGRP receptor. Examples are the “gepants,” olcegepant and telcagepant. They are effective in the treatment of migraine, but their development was limited by concerns regarding liver toxicity. A second generation of gepants includes ubrogepant, rimegepant, and atogepant. Ubrogepant and rimegepant are approved for acute treatment of migraine, while rimegepant and atogepant can be used for migraine prevention. Vazegepant is a new intranasal gepant being investigated as an acute treatment for migraine. Monoclonal antibodies targeting CGRP or its receptor have been developed. To date, four such monoclonal antibodies have been developed and tested in humans: erenumab, which targets the extracellular domain of the CGRP receptor; and eptinezumab, fremanezumab, and galcanezumab, which target CGRP. These drugs are effective and have a good safety and tolerability profile but must be given subcutaneously and are very expensive. In view of the cardioprotective effects of CGRP noted above, it will be important to monitor the cardiovascular effects of these anti-migraine drugs. No adverse effects have been reported to date.

■■ ADRENOMEDULLIN Adrenomedullin (AM) was discovered in human adrenal medullary pheochromocytoma tissue. It is a 52-amino acid peptide with a six-amino acid disulfide ring and a C-terminal amide, both of which are required for activity. Like CGRP, AM is a member of the calcitonin family of peptides. A related 47-amino acid peptide called adrenomedullin 2 or intermedin has been identified in humans and other mammals where it is expressed in several organs including the heart and kidneys. AM is synthesized as the 185-amino acid preproAM which is cleaved, ultimately forming mature AM, proAM N-terminal 20 peptide (PAMP), and mid-regional AM (MR-proAM). It is expressed in virtually all tissues of the body, the highest levels occurring in the adrenal medulla, kidneys, cardiac atria, and lungs. AM is present in the hypothalamus where it may participate in the central control of blood pressure by increasing sympathetic outflow.

330    SECTION IV  Drugs with Important Actions on Smooth Muscle

It is present in the circulation, the main source apparently being the vasculature. Plasma AM is metabolized by peptidases including neprilysin, resulting in a half-life of approximately 22 minutes. Intravenous infusion of AM causes marked vasodilation which results from a direct action on resistance vessels and leads to decreased peripheral resistance and arterial pressure. The fall in blood pressure in turn elicits compensatory increases in heart rate, cardiac output, and plasma norepinephrine and renin levels. AM also acts on the kidneys to cause diuresis and natriuresis. Other actions include positive inotropy, inhibition of cardiomyocyte hypertrophy and proliferation, and reduced collagen production in cardiac fibroblasts. The actions of AM are mediated by two receptors, AM1 and AM2. These receptors are formed by heterodimerization of the calcitonin receptor-like receptor (CLR) with RAMP2 and RAMP3, respectively, in a manner analogous to the formation of the CGRP receptor. The receptors are distributed widely in the body. They are present in vascular endothelial and smooth muscle cells, and AM-induced vasodilation results from actions on both. In endothelial cells, AM increases NO production, which subsequently causes dilation of the adjacent smooth muscle cells. In vascular smooth muscle cells, AM increases cAMP levels resulting in activation of protein kinase A and, in turn, vasodilation. In addition to binding to AM1 and AM2 receptors, AM has significant affinity for the CGRP receptor. Circulating AM levels increase in a number of pathologic states, including sepsis, heart failure, essential and pulmonary hypertension, myocardial infarction, and renal failure. Plasma AM and MR-proAM levels increase in proportion to the severity of these diseases and show promise as prognostic markers. The roles of AM in these states remain to be defined, but it is currently thought that the peptide may serve a protective role, mitigating cardiovascular overload and injury by virtue of its vasodilator and natriuretic activity. Studies have shown that AM exerts beneficial hemodynamic, endocrine, and myocardial effects in animal models and in patients with heart failure. Drugs are available to block or prolong the actions of AM. Its vasodilator action can be blocked by the receptor antagonist AM(22-52). AM can be administered intravenously as the native peptide but its effectiveness is limited by its short half-life (22 minutes). PEGylation at the N-terminus extends the halflife while leaving the C-terminus free to bind to AM receptors. Adrecizumab is a humanized, monoclonal, non-neutralizing antibody against the N-terminus of AM. The C-terminus of antibody-bound AM remains exposed, permitting receptor binding without activation. The antibody has a half-life of 15 days. Adrecizumab partly inhibits AM signaling, but following administration of the antibody, there is a marked increase in plasma AM so that there is a net increase in AM activity in the blood. The mechanism of this increase is not clear but it has been proposed that the antibody translocates AM from the interstitium to the blood. The resulting decrease in interstitial AM would reduce its direct vasodilatory action on vascular smooth muscle, while the increase in AM in the blood (mostly antibody-bound) could help stabilize the endothelial barrier. ADZ demonstrated a promising safety profile in phase 1 studies and a phase 2 study is in progress. It is increasingly seen as a potential adjunct therapy to restore endothelial function in septic shock.

■■ RELAXIN Relaxin (RLX) is a member of the relaxin family of peptides (RXFPs) which, in humans, comprises three peptides RLX-1, RLX-2, and RLX-3. They are members of the insulin superfamily, being structurally related to insulin with A and B chains connected by two disulfide bonds. RLX-2 is the major form of RLX in the circulation where it has a short half-life. RLX is an important hormone of pregnancy, being responsible for vasodilation and increased cardiac output. However, there is now a large body of evidence that its actions extend well beyond those concerned with reproduction. For example, RLX is produced not only in the reproductive system but also in the brain, heart, kidneys, lungs, and liver. Circulating RLX levels are increased in diseases including pulmonary arterial hypertension, heart failure, prostate cancer, and atrial fibrillation. Intravenous administration of RLX causes systemic and renal vasodilation, resulting in increased cardiac output, and renal blood flow and glomerular filtration rate. It also reduces collagen synthesis and causes beneficial remodeling of the vasculature. These actions are mediated primarily by the relaxin family peptide receptor-1 (RXFP1), a G protein–coupled receptor that is expressed in brain, liver, kidneys, lungs, and cardiovascular system. Multiple signaling pathways include NO, cGMP, and cAMP (Figure 17–9). The beneficial effects of RLX can be mimicked by serelaxin (RLX030) a recombinant form of the human RLX peptide. In addition to causing systemic and renal vasodilation, serelaxin

Serelaxin RXFP1

Gαs

Gαi

cAMP

Gαo

NO

MMPs

Endothelium

TIMPs

Altered gene regulation

TGFβ

Vasodilation

Collagen synthesis Collagen degradation

Smooth Muscle

Fibrosis

FIGURE 17–9  Mechanism of action of the relaxin analog, serelaxin. RXFP1, relaxin family peptide receptor-1; MMP, matrix metalloproteinase; TIMP, tissue inhibitor of metalloproteinase.  (Adapted from Yandrapalli S, Jolly G, Biswas M, et al. Newer hormonal pharmacotherapies for heart failure, Expert Rev Endocrinol Metab 2018 Jan;13(1):35-49.)

CHAPTER 17  Vasoactive Peptides    331

delivered intravenously has been reported to exert multiple beneficial effects on the cardiovascular system including suppression of arrhythmia and inflammation and reversal of fibrosis. Unfortunately, extended phase III clinical trials for the treatment of acute heart failure were generally negative. Recently, RLX mimetics with longer half-lives and lower cost have been developed. B7-33 is a peptide consisting of residues 7-33 of the B chain of RLX. It reduces cardiac and renal fibrosis in rodent models. A newer drug, ML290 is a non-peptide agonist of the RXFP1 receptor. It exerts antifibrotic effects in a human hepatic cell line and has potential for the treatment of cardiovascular disease, at least in the short term. Another member of the relaxin family of peptides is insulinlike 3 peptide (INSL3). It is expressed mainly in the gonads and acts through relaxin family peptide receptor-2 (RXFP2). This peptide and its receptor are closely related to RLX and RXFP1 but they appear to be concerned more with reproduction and bone and muscle metabolism.

■■ UROCORTINS Urocortins (UCNs) are members of the corticotropin-releasing hormone (CRH) family of peptides, which in mammals comprises CRH and three UCNs: UCN1 (40 amino acids), UCN2 (39), and UCN3 (38). UCNs are widely expressed throughout the central nervous system and in the cardiovascular, digestive, and immune systems, kidneys, adrenals, and other tissues. They are present in the circulation and urine. In the central nervous system, UCNs are involved in anxiety, depression, and drug abuse. UCN2 participates in the control of gastric emptying via sympathetic pathways and may contribute to the control of the hypothalamic-pituitary-adrenal axis. UCN3 contributes to the control of food intake. In the periphery, UCNs exert actions on the cardiovascular, gastrointestinal, and reproductive systems, and in the adrenal medulla. Systemic administration of UCN2 in healthy volunteers increases heart rate and cardiac output, and decreases peripheral resistance and diastolic and mean arterial pressure. Intra-arterial forearm infusion of UCN2 causes vasodilation which is at least partly mediated by NO. All three UCNs cause renal vasodilation. UCNs modulate the actions of other vasoactive peptides including ANG II, endothelins, and natriuretic peptides. They also exert complex actions on endothelial cell function, with most evidence suggesting an endothelial-protective role. UCNs act via two G protein–coupled receptors, CRHR1 and CRHR2. UCN1 activates both receptors but has a higher affinity for CRHR2. UCN2 and UCN3 bind specifically to CRHR2. CRHR1 is preferentially expressed in the brain and pituitary while CRHR2 is expressed in discrete brain regions and peripheral organs including all chambers of the heart, and endothelial and smooth muscle cells of arteries and veins.

Role in Heart Failure Plasma levels of UCN2 are elevated in patients with heart failure and might serve as a biomarker for the diagnosis and prognosis of

this disease. However, UCN2 does not appear to have any additional value over NT-proBNP. Several studies have demonstrated beneficial effects of UCNs in heart failure. Intravenous administration of UCN2 in patients with congestive heart failure produced cardiovascular changes generally similar to those in healthy subjects, ie, increased cardiac output, vasodilation, and decreased blood pressure. In patients with acute decompensated heart failure, administration of UCN2 increased heart rate and cardiac output, and decreased peripheral vascular resistance and arterial pressure. Administration of UCN3 in patients with stable heart failure increased cardiac index and decreased systemic vascular resistance and diastolic pressure with no significant changes in heart rate or systolic pressure.

Role in Pulmonary Hypertension Expression of UCN2 and CRHR2 has been reported to increase in right ventricular tissue of patients with right ventricular failure and in rats with a model of pulmonary hypertension. Chronic infusion of UCN2 attenuated pulmonary arterial hypertension and right ventricular dysfunction in the rat model. Taken together these observations suggest that UCNs have potential for the diagnosis and treatment of heart failure and pulmonary hypertension. They may also be beneficial in other diseases including ischemic heart disease and systemic hypertension. UCN3 is available as the investigational drug stresscopin (RT-400). It is in phase II development as a peptide infusion therapy for acute decompensated heart failure.

■■ VASOACTIVE PEPTIDES: SUMMARY AND PERSPECTIVE The vasoactive peptides are a diverse group of chemical messengers that participate in the control of cardiovascular function. They are not only important in physiological regulation but also cause or contribute to cardiovascular disease, and are thus important targets for drug development. From the physiological point of view, the vasoconstrictors play an important role in defending blood pressure and volume against hypotension and hypovolemia by virtue of their actions on the cardiovascular system and kidneys. Important players here include ANG II, vasopressin, and the endothelins. From the pathological standpoint, excessive secretion of the peptides can, by the same actions, cause or exacerbate cardiovascular diseases such as hypertension, heart failure, and kidney disease. For this reason, a wide variety of drugs that block the formation of the peptides (e.g., renin and ACE inhibitors) or antagonize their receptors (e.g., ANG II receptor blockers) has been developed. The vasodilators play a quite different role, being concerned more with defending against hypervolemia and maintaining optimal blood flow. This is largely accomplished by increasing renal sodium and water excretion, dilating blood vessels, and, in some cases, increasing cardiac output. Of significance here are the natriuretic peptides, which also play a protective role in disease states. For example, in heart failure, ANP and BNP are released in an

332    SECTION IV  Drugs with Important Actions on Smooth Muscle

attempt to counter the overactive renin-angiotensin and sympathetic nervous systems. Other vasodilator peptides exert a similar protective action, although their roles are less well defined. In view of the beneficial effects of the vasodilators, considerable attention has been directed to developing drugs that mimic or enhance their actions. The use of the native peptides is generally limited by their short half-lives, but they can be helpful in shortterm therapy. Another approach is to increase the circulating levels

of the peptides with an inhibitor of the peptidases that metabolize the peptides, e.g., sacubitril. However, elevated levels of some of the peptides may produce undesirable effects including cough (bradykinin) and vasoconstriction (ANG II). A solution to this problem is to combine the peptidase inhibitor with a drug that blocks the unwanted effect of the peptide. An example of such a combination, sacubitril/valsartan, has proved to be of value in the treatment of heart failure.

SUMMARY  Drugs that Interact with Vasoactive Peptide Systems Subclass, Drug

Mechanism of Action

ANGIOTENSIN RECEPTOR ANTAGONISTS   • Valsartan Selective competitive antagonist of angiotensin AT1 receptors

Effects

Clinical Applications

Arteriolar dilation • decreased aldosterone secretion • increased sodium and water excretion

Hypertension

  • Eprosartan, irbesartan, candesartan, olmesartan, telmisartan: Similar to valsartan ANGIOTENSIN RECEPTOR AGONISTS   • Angiotensin II AT1 (and AT2) receptor agonist   • Compound 21 AT2 receptor agonist CONVERTING ENZYME INHIBITORS   • Enalapril Inhibits conversion of angiotensin I to angiotensin II

Increased blood pressure Beneficial cardiovascular effects

Vasodilatory shock Potential for treatment of cardiovascular disease

Arteriolar dilation • decreased aldosterone secretion • increased sodium and water excretion

Hypertension • heart failure

  • Captopril and many others: Similar to enalapril RENIN INHIBITOR   • Aliskiren

Inhibits catalytic activity of renin

Arteriolar dilation • decreased aldosterone secretion • increased sodium and water excretion

Hypertension

KININ INHIBITORS   • Icatibant

Selective antagonist of kinin B2 receptors

Blocks effects of kinins on pain, hyperalgesia, and inflammation

Hereditary angioedema

  • Cinryze, Berinert: Plasma C1 esterase inhibitors, decrease bradykinin formation, used in hereditary angioedema   • Ecallantide: Plasma kallikrein inhibitor   •  Donidalorsen: Inhibits production of plasma prekallikrien VASOPRESSIN AGONISTS   • Arginine vasopressin

Agonist of vasopressin V1 (and V2) receptors

Vasoconstriction

Vasodilatory shock

  • Selepressin, terlipressin: More selective for V1a receptor

 

 

VASOPRESSIN ANTAGONISTS   • Conivaptan Antagonist of vasopressin V1 and V2 receptors

Vasodilation

Potential use in hypertension and heart failure • hyponatremia

NATRIURETIC PEPTIDE AGONISTS   • Nesiritide, Carperitide, Agonists of natriuretic peptide receptors M-ANP

Increased sodium and water excretion • vasodilation

Potential use in acute hypertension and heart failure

  • Vosoritide

Increased endochondral ossification

Achondroplasia

  • Relcovaptan, SRX251: Increased selectivity for V1 receptor   • Tolvaptan: Increased selectivity for V2 receptor

Agonist of C-type natriuretic peptide receptor

  • Ularitide: Synthetic form of urodilatin (continued)

CHAPTER 17  Vasoactive Peptides    333

Subclass, Drug

Mechanism of Action

Effects

Clinical Applications

COMBINED ANGIOTENSIN-CONVERTING ENZYME/NEPRILYSIN INHIBITORS (VASOPEPTIDASE INHIBITORS)   • Omapatrilat

Decreases breakdown of natriuretic peptides and formation of angiotensin II

1

Vasodilation • increased sodium and water excretion

Hypertension • heart failure

Vasodilation • increased sodium and water excretion

Heart failure • hypertension1

ENDOTHELIN ANTAGONISTS   • Bosentan, macitentan Nonselective antagonists of endothelin ETA and ETB receptors

Vasodilation

Pulmonary arterial hypertension

  • Sparsentan

Vasodilation

  • Sampatrilat, fasidotrilat: Similar to omapatrilat COMBINED ANGIOTENSIN RECEPTOR ANTAGONIST/NEPRILYSIN INHIBITOR   • Sacubitril/valsartan

Decreases breakdown of natriuretic peptides and blocks angiotensin II receptors

Combined ETA/AT1 antagonist

  • Sitaxsentan, ambrisentan: Selective antagonists of ETA receptors COMBINED ENDOTHELIN-CONVERTING ENZYME/NEPRILYSIN INHIBITOR   • SLV306, daglutril Blocks formation of endothelins and breakdown of natriuretic peptides

Vasodilation • increased sodium and water excretion

Heart failure • hypertension1

Selective agonist of VPAC2 receptors

Vasodilation • multiple metabolic, endocrine, and other effects

Essential and pulmonary hypertension • cardiomyopathy1

  • Aprepitant

Selective antagonist of tachykinin NK1 receptors

Blocks several central nervous system effects of substance P

Prevention of chemotherapyinduced nausea and vomiting

  • Saredutant, nepadutant, ibodutant

Selective antagonists of tachykinin NK2 receptors

VASOACTIVE INTESTINAL PEPTIDE AGONIST   • PB1046, Vasomera SUBSTANCE P ANTAGONISTS

Potential for treatment of respiratory and gastrointestinal disorders and anxiety

  • Fosaprepitant: Prodrug that is converted to aprepitant NEUROTENSIN AGONISTS   • PD149163, NT69L, NT79

Agonists of central neurotensin receptors

NEUROTENSIN ANTAGONIST   • Meclinertant Antagonist of central and peripheral neurotensin receptors CALCITONIN GENE-RELATED PEPTIDE AGONIST   • Acylated alpha-CGRP Agonist of CGRP receptors CALCITONIN GENE-RELATED PEPTIDE ANTAGONISTS   • Telcagepant, Antagonists of the calcitonin gene-related olcegepant peptide (CGRP) receptor   • Ubrogepant, Second-generation CGRP receptor rimegepant, atogepant antagonists   • Erenumab Monoclonal antibody against the CGRP receptor   • Eptinezumab, Monoclonal antibodies against CGRP fremanezumab, galcanezumab

Interact with central dopamine systems

Potential for treatment of schizophrenia and Parkinson disease

Blocks some central and peripheral (vasodilator) actions of neurotensin

None identified

Mimics beneficial cardiovascular effects of CGRP

Potential for treatment of hypertension and heart failure

Blocks some central and peripheral (vasodilator) actions of CGRP Blocks some central and peripheral (vasodilator) actions of CGRP

Migraine1

Partly inhibits adrenomedullin signaling Increases plasma adrenomedullin levels

Septic shock

Migraine Migraine prevention and treatment

ADRENOMEDULLIN ANTAGONIST   • Adrecizumab

Monoclonal antibody against adrenomedullin receptors

1

(continued)

334    SECTION IV  Drugs with Important Actions on Smooth Muscle

Subclass, Drug

Mechanism of Action

Effects

Clinical Applications

Blocks vasoconstrictor response to neurotensin

Potential antiobesity agent

Vasodilation and other cardiovascular actions

Potential for treatment of heart failure and other cardiovascular diseases

Vasodilation and other cardiovascular effects

Acute heart failure1

Blocks vasoconstrictor action of urotensin

Potential for treatment of diabetic renal failure and asthma1

NEUROPEPTIDE Y ANTAGONISTS   • BIBP3226

Selective antagonist of neuropeptide Y1 receptors

  • BIIE0246: Selective for Y2 receptor   • MK-0557: Selective for Y5 receptor RELAXIN AGONISTS   • Serelaxin

Agonist of relaxin family peptide receptor-1

  • B7-33, ML290: Longer half-lives than serelaxin UROCORTIN AGONIST   • Stresscopin, RT-400

Agonist of urocortin receptors

UROTENSIN ANTAGONISTS   • Palosuran Antagonist of urotensin receptors   • GSK1440115: More potent than palosuran 1

Undergoing preclinical or clinical evaluation.

P R E P A R A T I O N S GENERIC NAME

A V A I L A B L E

AVAILABLE AS ANGIOTENSIN II

Angiotensin II

Giapreza

ANGIOTENSIN-CONVERTING ENZYME INHIBITORS  

(SEE CHAPTER 11) ANGIOTENSIN RECEPTOR BLOCKERS

 

(SEE CHAPTER 11) RENIN INHIBITOR

Aliskiren

Tekturna

GENERIC NAME AVAILABLE AS COMBINED NEPRILYSIN INHIBITOR / ANGIOTENSIN RECEPTOR ANTAGONIST Sacubitril/valsartan Erenumab

Aimovig

Fremanezumab

Ajovy

Galcanezumab

Emgality

Ubrogepant

Firazyr

Ambrisentan

Letairis

Bosentan

Tracleer

Epoprostenol

Flolan, Veletri

Iloprost

Ventavis

Vaprisol

Macitentan

Opsumit

Samsca

Nintedanib

Ofev

Pirfenidone

Esbriet

Riociguat

Adempas

Selexipag

Uptravi

Treprostinil

Tyvaso, Remodulin

KALLIKREIN INHIBITORS C1 esterase inhibitor, human

Cinryze, Berinert

Ecallantide

Kalbitor AVP RECEPTOR ANTAGONISTS

Conivaptan Tolvaptan

SUBSTANCE P ANTAGONIST Aprepitant

Emend NATRIURETIC PEPTIDE AGONIST

Nesiritide

Ubrelvy DRUGS USED IN PULMONARY HYPERTENSION

KININ INHIBITOR Icatibant

Entresto CGRP ANTAGONISTS

Natrecor

CHAPTER 17  Vasoactive Peptides    335

REFERENCES Vasoconstrictors Angiotensin Abadir P et al: Topical reformulation of valsartan for treatment of chronic diabetic wounds. J Invest Dermatol 2018;138:434. Bjerre HL et al: The role of aliskiren in the management of hypertension and major cardiovascular outcomes: A systematic review and meta-analysis. J Hum Hypertens 2019;33:795. Bussard RL, Busse LW: Angiotensin II: A new therapeutic option for vasodilatory shock. Ther Clin Risk Manag 2018;14:1287. Busse PJ, Christiansen SC: Hereditary angioedema. N Engl J Med 2020;382:1136. Chow BS, Allen TJ: Angiotensin II type 2 receptor (AT2R) in renal and cardiovascular disease. Clin Sci (Lond) 2016;130:1307. Cruz Rodriguez JB, Cu C, Siddiqui T. Narrative review in the current role of angiotensin receptor-neprilysin inhibitors. Ann Transl Med 2021;9:518. Danser AH: The role of the (pro)renin receptor in hypertensive disease. Am J Hypertens 2015;28:1187. Friis UG et al: Regulation of renin secretion by renal juxtaglomerular cells. Eur J Physiol 2013;465:25. Karnik SS et al: International Union of Basic and Clinical Pharmacology. XCIX. Angiotensin receptors: Interpreters of pathophysiological angiotensinergic stimuli [corrected]. Pharmacol Rev 2015;67:754. Miller AJ, Arnold AC: The renin-angiotensin system in cardiovascular autonomic control: Recent developments and clinical implications. Clin Auton Res 2019;29:231. Packer M: Are healthcare systems now ready to adopt sacubitril/valsartan as the preferred approach to inhibiting the renin-angiotensin system in chronic heart failure? The culmination of a 20-year journey. Eur Heart J. 2019;40:3353. Patel S, Hussain T: Dimerization of AT2 and Mas receptors in control of blood pressure. Curr Hypertens Rep 2018;20:41. Ramkumar N, Kohan DE: The (pro)renin receptor: An emerging player in hypertension and metabolic syndrome. Kidney Int 2019;95:1041. Ranjbar R et al: The potential therapeutic use of renin-angiotensin system inhibitors in the treatment of inflammatory diseases. J Cell Physiol 2019;234:2277. Vaduganathan M et al: Renin-angiotensin-aldosterone system inhibitors in patients with covid-19. N Engl J Med 2020;382:1653. Wieruszewski PM et al: Angiotensin II Infusion for Shock: A multicenter study of postmarketing use. Chest 2021;159:596. Xu Y et al. Effect of angiotensin-neprilysin versus renin-angiotensin system inhibition on renal outcomes: a systematic review and meta-analysis. Front Pharmacol 2021;12:604017.

Vasopressin Asfar P et al: Selepressin in septic shock: A step toward decatecholaminization? Crit Care Med 2016;44:234. Boucheix OB et al: Selepressin, a new V1A receptor agonist: Hemodynamic comparison to vasopressin in dogs. Shock 2013;39:533. Jentzer JC, Hollenberg SM. Vasopressor and inotrope therapy in cardiac critical care. J Intensive Care Med 2021;36:843. Kunkes JH et al: Vasopressin therapy in cardiac surgery. J Card Surg 2019;34:20. Palmer BF: Vasopressin receptor antagonists. Curr Hypertens Rep 2015;17:510.

Endothelins Correale M et al: Endothelin-receptor antagonists in the management of pulmonary arterial hypertension: Where do we stand? Vasc Health Risk Manag 2018;14:253. Davenport AP et al: Endothelin. Pharmacol Rev 2016;68:357. Haryono A et al. Endothelin and the cardiovascular system: the long journey and where we are going. Biology (Basel) 2022;11:759. Maguire JJ, Davenport AP: Endothelin@25—new agonists, antagonists, inhibitors and emerging research frontiers: IUPHAR Review 12. Br J Pharmacol 2014;171:5555. Pulido T et al: Macitentan and morbidity and mortality in pulmonary arterial hypertension. N Engl J Med 2013;369:809.

Sidharta PN, van Giersbergen PL, Dingemanse J: Safety, tolerability, pharmacokinetics, and pharmacodynamics of macitentan, an endothelin receptor antagonist, in an ascending multiple-dose study in healthy subjects. J Clin Pharmacol 2013;53:1131.

Neuropeptide Y Saraf R et al: Neuropeptide Y is an angiogenic factor in cardiovascular regeneration. Eur J Pharmacol 2016;776:64. Tan CMJ et al: The role of neuropeptide Y in cardiovascular health and disease. Front Physiol 2018;9:1281. Thorsell A, Mathé AA: Neuropeptide Y in alcohol addiction and affective disorders. Front Endocrinol (Lausanne) 2017;8:178. Zhu P et al: The role of neuropeptide Y in the pathophysiology of atherosclerotic cardiovascular disease. Int J Cardiol 2016;220:235.

Urotensin Chatenet D et al: Update on the urotensinergic system: New trends in receptor localization, activation, and drug design. Front Endocrinol 2013;3:1. Cheriyan J et al: The effects of urotensin II and urantide on forearm blood flow and systemic haemodynamics in humans. Br J Clin Pharmacol 2009;68:518. Portnoy A et al: Effects of urotensin II receptor antagonist, GSK1440115, in asthma. Front Pharmacol 2013;4:54. Sun SL, Liu LM: Urotensin II: An inflammatory cytokine. J Endocrinol. 2019;240:R107. Svistunov AA et al: Urotensin II: Molecular mechanisms of biological activity. Curr Protein Pept Sci 2018;19:924. Vaudry H et al: International Union of Basic and Clinical Pharmacology. XCII. Urotensin II, urotensin II-related peptide, and their receptor: From structure to function. Pharmacol Rev 2015;67:214.

Vasodilators Kinins Bork K: A decade of change: Recent developments in pharmacotherapy of hereditary angioedema (HAE). Clin Rev Allergy Immunol 2016;51:183. Dutra RC: Kinin receptors: Key regulators of autoimmunity. Autoimmun Rev 2017;16:192. Farkas H, Köhalmi KV: Icatibant for the treatment of hereditary angioedema with C1-inhibitor deficiency in adolescents and in children aged over 2 years. Expert Rev Clin Immunol 2018;14:447. Fijen LM et al. Inhibition of prekallikrein for hereditary angioedema. N Engl J Med 2022;386:1026. Girolami JP et al. Kinins and kinin receptors in cardiovascular and renal diseases. Pharmaceuticals (Basel) 2021;14:240. Longhurst HJ et al: Real-world outcomes in hereditary angioedema: First experience from the Icatibant Outcome Survey in the United Kingdom. Allergy Asthma Clin Immunol 2018;14:28. Qadri F, Bader M: Kinin B1 receptors as a therapeutic target for inflammation. Expert Opin Ther Targets 2018;22:31. Taddei S, Bortolotto L: Unraveling the pivotal role of bradykinin in ACE inhibitor activity. Am J Cardiovasc Drugs 2016;16:309.

Natriuretic Peptides Anker SD et al: Ularitide for the treatment of acute decompensated heart failure: From preclinical to clinical studies. Eur Heart J 2015;36:715. Baba M, Yoshida K, Ieda M. Clinical applications of natriuretic peptides in heart failure and atrial fibrillation. Int J Mol Sci 2019;20. Berntsson J et al: Pro-atrial natriuretic peptide and prediction of atrial fibrillation and stroke: The Malmo Preventive Project. Eur J Prev Cardiol 2017;24:788. Breinholt VM et al: TransCon CNP, a sustained-release C-Type Natriuretic Peptide prodrug, a potentially safe and efficacious new therapeutic modality for the treatment of comorbidities associated with FGFR3-related skeletal dysplasias. J Pharmacol Exp Ther. 2019;370:459. Cannone V et al: Atrial natriuretic peptide: A molecular target of novel therapeutic approaches to cardio-metabolic disease. Int J Mol Sci 2019;20:3265.

336    SECTION IV  Drugs with Important Actions on Smooth Muscle Castiglione V et al. Biomarkers for the diagnosis and management of heart failure. Heart Fail Rev 2022;2:625. Hanigan S, DiDomenico RJ: Emerging therapies for acute and chronic heart failure: Hope or hype? J Pharm Pract 2016;29:46. Hijazi Z et al: Cardiac biomarkers and left ventricular hypertrophy in relation to outcomes in patients with atrial fibrillation: experiences from the RE-LY trial. J Am Heart Assoc 2019;8:e010107. Jhund PS, McMurray JJ: The neprilysin pathway in heart failure: A review and guide on the use of sacubitril/valsartan. Heart 2016;102:1342. Matsuo A et al: Natriuretic peptides in human heart: Novel insight into their molecular forms, functions, and diagnostic use. Peptides 2019;111:3. Nakanishi K et al: Pre-procedural serum atrial natriuretic peptide levels predict left atrial reverse remodeling after catheter ablation in patients with atrial fibrillation. JACC Clin Electrophysiol 2016;2:151. Packer M et al: Effect of ularitide on cardiovascular mortality in acute heart failure. N Engl J Med 2017;376:1956. Pfeffer MA et al. Angiotensin receptor-neprilysin inhibition in acute myocardial infarction. N Engl J Med 2021;385:1845. Prenner SB et al: Role of angiotensin receptor-neprilysin inhibition in heart failure. Curr Atheroscler Rep 2016;18:48. Saito Y: Roles of atrial natriuretic peptide and its therapeutic use. J Cardiol 2010;56:262. Savarirayan R et al: C-Type natriuretic peptide analogue therapy in children with achondroplasia. N Engl J Med 2019;381:25. Solomon, SD et al: Angiotensin receptor neprilysin inhibition in heart failure with preserved ejection fraction: Rationale and design of the PARAGON-HF trial. JACC Heart Fail 2017;5:471. Tanase DM et al: Natriuretic peptides in heart failure with preserved left ventricular ejection fraction: From molecular evidences to clinical implications. Int J Mol Sci. 2019;20:2629. Tsiachris D et al: Biomarkers determining prognosis of atrial fibrillation ablation. Curr Med Chem 2019;26:925. Vilela-Martin JF: Spotlight on valsartan-sacubitril fixed-dose combination for heart failure: The evidence to date. Drug Des Devel Ther 2016;10:1627. Volpe M et al: The natriuretic peptides system in the pathophysiology of heart failure: From molecular basis to treatment. Clin Sci (Lond) 2016;130:57.

Vasoactive Intestinal Peptide Paulis L et al: New developments in the pharmacological treatment of hypertension: Dead-end or a glimmer at the horizon? Curr Hypertens Rep 2015;17:557. White CM et al: Therapeutic potential of vasoactive intestinal peptide and its receptors in neurological disorders. CNS Neurol Disord Drug Targets 2010;9:661.

Substance P Garcia-Recio S, Gascon P: Biological and pharmacological aspects of the NK1receptor. Biomed Res Int 2015;2015:495704. Jung HJ, Priefer R. Tachykinin NK2 antagonist for treatments of various disease states. Auton Neurosci 2021;235:102865. Khorasani S et al. The immunomodulatory effects of tachykinins and their receptors. J Cell Biochem 2020;121:3031. Mistrova E et al: Role of substance P in the cardiovascular system. Neuropeptides 2016;58:41. Munoz M, Covenas R: Involvement of substance P and the NK-1 receptor in cancer progression. Peptides 2013;48C:1.

Neurotensin Boules M et al: Diverse roles of neurotensin agonists in the central nervous system. Front Endocrinol 2013;4:36. Hwang JI et al: Phylogenetic history, pharmacological features, and signal transduction of neurotensin receptors in vertebrates. Ann N Y Acad Sci 2009;1163:169. Iyer MR, Kunos G. Therapeutic approaches targeting the neurotensin receptors. Expert Opin Ther Pat 2021;3:361. Konno N: Neurotensin. In: Takei Y, Ando H, Tsutsui K (editors): Handbook of Hormones: Comparative Endocrinology for Basic and Clinical Research. Elsevier, 2016. Osadchii OE: Emerging role of neurotensin in regulation of the cardiovascular system. Eur J Pharmacol 2015;762:184.

Calcitonin Gene-Related Peptide Ailani J et al. Atogepant for the preventive treatment of migraine. N Engl J Med 2021;385:695. Aubdool AA et al: A novel alpha-calcitonin gene-related peptide analogue protects against end-organ damage in experimental hypertension, cardiac hypertrophy, and heart failure. Circulation 2017;136:367. Caronna E, Starling AJ. Update on preventive treatment of migraine. Neurol Clin 2021;39:1. Hay DL, Walker CS: CGRP and its receptors. Headache 2017;57:625. Kee Z, Kodji X, Brain SD: The role of calcitonin gene related peptide (CGRP) in neurogenic vasodilation and its cardioprotective effects. Front Physiol 2018;9:1249. Tajti J et al: Migraine and neuropeptides. Neuropeptides 2015;2:19. Tiseo C et al: How to integrate monoclonal antibodies targeting the calcitonin gene-related peptide or its receptor in daily clinical practice. J Headache Pain 2019;20:49. Wrobel Goldberg S, Silberstein SD: Targeting CGRP: A new era for migraine treatment. CNS Drugs 2015;29:443.

Adrenomedullin Deniau B et al. Adrecizumab: an investigational agent for the biomarker-guided treatment of sepsis. Expert Opin Investig Drugs 2021;30:95. Geven C, Kox M, Pickkers P: Adrenomedullin and adrenomedullin-targeted therapy as treatment strategies relevant for sepsis. Front Immunol 2018;9:292. Kato J, Kitamura K: Bench-to-bedside pharmacology of adrenomedullin. Eur J Pharmacol 2015;764:140. Koyama T et al: Adrenomedullin-RAMP2 system in vascular endothelial cells. J Atheroscler Thromb 2015;22:647. Nishikimi T, Nakagawa Y: Adrenomedullin as a biomarker of heart failure. Heart Fail Clin 2018;14:49. Tsuruda T et al: Adrenomedullin: Continuing to explore cardioprotection. Peptides 2019;111:47. Voors AA et al: Adrenomedullin in heart failure: Pathophysiology and therapeutic application. Eur J Heart Fail 2019;21:163. Watkins HA et al: Receptor activity-modifying proteins 2 and 3 generate adrenomedullin receptor subtypes with distinct molecular properties. J Biol Chem 2016;291:11657.

Relaxin Ghosh RK et al: Serelaxin in acute heart failure: Most recent update on clinical and preclinical evidence. Cardiovasc Ther 2017;35:55. Jelinic M et al: From pregnancy to cardiovascular disease: Lessons from relaxindeficient animals to understand relaxin actions in the vascular system. Microcirculation 2019;26:e12464. Kanai AJ et al: Relaxin and fibrosis: Emerging targets, challenges, and future directions. Mol Cell Endocrinol 2019;487:66. Martin B et al: Cardioprotective actions of relaxin. Mol Cell Endocrinol 2019;487:45. Martins RC et al. Relaxin and the cardiovascular system: from basic science to clinical practice. Curr Mol Med 2020;20:167. Ng HH et al: Relaxin and extracellular matrix remodeling: Mechanisms and signaling pathways. Mol Cell Endocrinol 2019;487:59. Ng TM et al: Relaxin for the treatment of acute decompensated heart failure: Pharmacology, mechanisms of action, and clinical evidence. Cardiol Rev 2016;24:194. Patil NA et al: Relaxin family peptides: Structure-activity relationship studies. Br J Pharmacol 2017;174:950. Summers RJ: Recent progress in the understanding of relaxin family peptides and their receptors. Br J Pharmacol 2017;174:915.

Urocortins Adao R et al: Urocortin-2 improves right ventricular function and attenuates pulmonary arterial hypertension. Cardiovasc Res 2018;114:1165. Chatzaki E et al: Do urocortins have a role in treating cardiovascular disease? Drug Discov Today 2019;24:279. Grieco P, Gomez-Monterrey I: Natural and synthetic peptides in the cardiovascular diseases: An update on diagnostic and therapeutic potentials. Arch Biochem Biophys 2019;662:15.

CHAPTER 17  Vasoactive Peptides    337 Kovacs DK et al. Assessment of clinical data on urocortins and their therapeutic potential in cardiovascular diseases: A systematic review and meta-analysis. Clin Transl Sci 2021;14:2461. Rademaker MT, Richards AM: Urocortins: Actions in health and heart failure. Clin Chim Acta 2017;474:76. Stenmark KR, Graham BB: Urocortin 2: Will a drug targeting both the vasculature and the right ventricle be the future of pulmonary hypertension therapy? Cardiovasc Res 2018;114:1057.

General Lo CCW, Moosavi SM, Bubb KJ: The regulation of pulmonary vascular tone by neuropeptides and the implications for pulmonary hypertension. Front Physiol 2018;9:1167.

Oparil S, Schmieder RE: New approaches in the treatment of hypertension. Circ Res 2015;116:1074. Perrin S et al: New pharmacotherapy options for pulmonary arterial hypertension. Expert Opin Pharmacother 2015;16:2113. Raghu GB et al: Effect of recombinant human pentraxin 2 vs placebo on change in forced vital capacity in patients with idiopathic pulmonary fibrosis: A randomized clinical trial. JAMA 2018;319:2299. Sommer N et al. Current and future treatments of pulmonary arterial hypertension. Br J Pharmacol 2021;178:6. Yandrapalli S et al: Newer hormonal pharmacotherapies for heart failure. Expert Rev Endocrinol Metab 2018;13:35.

C ASE STUDY ANSWER Enalapril lowers blood pressure by blocking the conversion of angiotensin I to angiotensin II (ANG II). Since converting enzyme also inactivates bradykinin, enalapril increases bradykinin levels, and this is responsible for adverse side effects such as cough and angioedema. This problem might be avoided by using a renin inhibitor, eg, aliskiren, or an ANG II

receptor antagonist, eg, valsartan, instead of an angiotensinconverting enzyme inhibitor, to block the renin-angiotensin system. A β-adrenoceptor-blocking drug might also be tried since, in addition to their cardiac action, these drugs can inhibit renin secretion.

18 C

H

A

P

T

E

R

The Eicosanoids: Prostaglandins, Thromboxanes, Leukotrienes, & Related Compounds John Hwa, MD, PhD, & Kathleen Martin, PhD*

C ASE STUDY A 40-year-old woman presented to her doctor with a 6-month history of increasing shortness of breath. This was associated with poor appetite and ankle swelling. On physical examination, she had elevated jugular venous distention, a soft tricuspid regurgitation murmur, clear lungs, and mild peripheral edema. An echocardiogram revealed tricuspid regurgitation, severely elevated

The eicosanoids are oxygenation (oxidation) products of polyunsaturated 20-carbon long-chain fatty acids (eicosa, Greek for “twenty”). They are ubiquitous in the animal kingdom and are also found in a variety of plants. They constitute a very large family of compounds that are highly potent and display an extraordinarily wide spectrum of important biologic activities. Thus, the eicosanoid ligands, their specific receptors, their synthetic enzymes and inhibitors, and their plant and fish oil precursors, are therapeutic targets for a growing list of conditions.

*

The authors thank Emer M. Smyth, PhD, and Garret A. FitzGerald, MD, for their contributions to previous editions of this chapter. 338

pulmonary pressures, and right ventricular enlargement. Cardiac catheterization confirmed the severely elevated pulmonary pressures. She was commenced on appropriate therapies. Which of the eicosanoid agonists have been demonstrated to reduce both morbidity and mortality in patients with such a diagnosis? What are the modes of action?

ARACHIDONIC ACID & OTHER POLYUNSATURATED PRECURSORS Arachidonic acid (AA) (5,8,11,14-eicosatetraenoic acid), the most abundant of the eicosanoid precursors, is a 20-carbon (C20) polyunsaturated fatty acid containing four double bonds (C20:4(5,8,11,14)). Linoleic acid, an essential fatty acid, is converted to linolenic acid, followed by conversion to AA. The first double bond in AA occurs at 6 carbons from the methyl end, defining AA as an omega-6 fatty acid (C20:4(ω–6) or C20:4-6). AA must first be released or mobilized from the sn-2 position of membrane phospholipids by one or more lipases of the phospholipase A2 (PLA2) type (Figure 18–1) for eicosanoid synthesis to occur. The phospholipase A2 superfamily consists of over 30 isoforms classified into several families, contributing to arachidonate

CHAPTER 18  The Eicosanoids: Prostaglandins, Thromboxanes, Leukotrienes, & Related Compounds     339

Arachidonic acid esterified in membrane phospholipids

Free radicals

Diverse physical, chemical, inflammatory, and mitogenic stimuli

Phospholipase A2 Isoprostanes

Epoxyeicosatrienoic acids (EETs) 9

8

Cytochrome P450

6

1

5

COOH

AA (20:4 cis D5,8,11,14) 20 11

12

14

15

Lipoxygenases (LOX)

Cyclooxygenases (COX)

HETEs Leukotrienes Lipoxins

FIGURE 18–1 

19

Prostaglandins Prostacyclin Thromboxane

Prostanoids

Pathways of arachidonic acid (AA) release and metabolism.

release from membrane lipids. The major two families are cytosolic PLA2 (cPLA2) and secretory PLA2 (sPLA2), both of which are calcium-dependent. Others include calcium-independent PLA2 (iPLA2); platelet-activating factor acetylhydrolase (PAF-AH); lysosomal PLA2 (LPLA2); PLA/acyltransferase (PLAAT); and α/β hydrolase (ABHD). Chemical and physical stimuli activate the Ca2+-dependent translocation of cPLA2 to the plasma membrane, where it releases arachidonate for metabolism to eicosanoids. While

ACRONYMS AA

Arachidonic acid

COX

Cyclooxygenase

DHET

Dihydroxyeicosatrienoic acid

EET

Epoxyeicosatrienoic acid

HETE

Hydroxyeicosatetraenoic acid

HPETE

Hydroxyperoxyeicosatetraenoic acid

LTB, LTC

Leukotriene B, C, etc

LOX

Lipoxygenase

LXA, LXB

Lipoxin A, B

NSAID

Nonsteroidal anti-inflammatory drug

PGE, PGF

Prostaglandin E, F, etc

PLA, PLC

Phospholipase A, C

TXA, TXB

Thromboxane A, B

cPLA2 dominates in the acute release of AA, inducible sPLA2 contributes under conditions of sustained or intense stimulation of AA production. In contrast, under non-stimulated conditions, AA liberated by iPLA2 is reincorporated into cell membranes, so there is negligible eicosanoid biosynthesis. AA can also be released from phospholipase C-generated diacylglycerol esters by the action of diacylglycerol and monoacylglycerol lipases. Following mobilization, AA is oxygenated by four separate routes: enzymatically via the cyclooxygenase (COX), lipoxygenase, and P450 epoxygenase pathways; and nonenzymatically via the isoeicosanoid pathway (see Figure 18–1). Among factors determining the type of eicosanoid synthesized are (1) the substrate lipid species, (2) the cell stimulus, and (3) the cell type. The cell type-specific production of eicosanoids is largely determined by the presence of downstream “synthases” (ie, thromboxane versus prostacyclin synthase) that metabolize COX-derived endoperoxide to distinct eicosanoids. Distinct but related products can be formed from precursors other than AA. For example, an omega-6 fatty acid such as homo-γ-linoleic acid (C20:3–6), in comparison to the omega-3 fatty acid eicosapentaenoic acid (C20:5–3), yields products that differ quantitatively and qualitatively from those derived from AA. This serves as the basis for dietary manipulation of eicosanoid generation using fatty acids obtained from cold-water fish or from plants as nutritional supplements. For example, thromboxane (TXA2), a powerful vasoconstrictor and platelet agonist, is synthesized from AA via the COX pathway. COX metabolism of eicosapentaenoic acid

340    SECTION IV  Drugs with Important Actions on Smooth Muscle

(an omega-3 fatty acid) yields TXA3, which is relatively inactive. 3-Series prostaglandins, such as prostaglandin E3 (PGE3), can also act as partial agonists or antagonists, thereby having reduced activity in comparison to their AA-derived 2-series counterparts. Similarly, eicosapentaenoic acid can be metabolized to prostaglandin I3, which serves as a full agonist for the prostacyclin receptor. The hypothesis that dietary eicosapentaenoic acid (omega-3 fatty acid) substitution for arachidonate could reduce the incidence of cardiovascular disease and cancer via the production of 3-series prostanoids is an area of intense study. In December 2019, the FDA approved the use of icosapent ethyl (Vascepa) (an eicosapentaenoic omega-3 fatty acid) as adjunctive therapy (e.g., add on to statin) to reduce cardiovascular risk in adults with elevated triglyceride levels (Chapter 41).

SYNTHESIS OF EICOSANOIDS Products of Prostaglandin Endoperoxide Synthases (Cyclooxygenases) Two unique COX isozymes convert AA into prostaglandin endoperoxides. PGH synthase-1 (COX-1) is expressed constitutively in most cells. In contrast, PGH synthase-2 (COX-2) is readily inducible, its expression levels being dependent on the stimulus. COX-2 is an immediate early-response gene product that is markedly up-regulated by shear stress, growth factors, tumor promoters, and inflammatory cytokines, consistent with the presence of multiple regulatory motifs in the promoter and 3′ untranslated regions of the COX-2 gene for several transcription factors, including NFκB, a key regulator of inflammatory gene expression. Put simply, COX-1 generates prostanoids for “housekeeping” functions, such as gastric epithelial cytoprotection, whereas COX-2 is the major source of prostanoids in inflammation and cancer. However, there are additional physiologic and pathophysiologic processes in which each enzyme is uniquely involved, and others in which they function coordinately. For example, endothelial COX-2 is the primary source of vascular prostacyclin (PGI2), whereas renal COX2-derived prostanoids are important for normal renal development and maintenance of function. Nonsteroidal anti-inflammatory drugs (NSAIDs; see Chapter 36) exert their therapeutic effects through inhibition of the COXs. Most older NSAIDs like indomethacin, sulindac, meclofenamate, and ibuprofen nonselectively inhibit both COX-1 and COX-2, whereas the selective COX-2 inhibitors follow the order celecoxib = diclofenac = meloxicam = etodolac < valdecoxib 1500 eosinophils/μL).

Anti-TSLP Therapy The most recent monoclonal antibody approved for severe asthma treatment is tezepelumab-ekko, which is a subcutaneous injection administered every 4 weeks. Its target, TSLP, is an epithelial cytokine; blocking it decreases several downstream inflammationassociated cytokines (IgE, Il-5, and IL-13) and biomarkers (peripheral and airway submucosal eosinophils and fractional exhalation of nitric oxide).

FUTURE DIRECTIONS OF ASTHMA THERAPY The term “asthma” encompasses a heterogeneous collection of disorders, some of which are poorly responsive to corticosteroid treatment. The existence of different forms or subtypes of asthma has actually long been recognized, as implied by the use of modifying terms to describe asthma in particular patients. More rigorous description of asthma phenotypes, based on cluster analysis of multiple clinical, physiologic, and laboratory features, including analysis of blood and sputum inflammatory cell assessments, has identified as many as five different asthma phenotypes. The key question raised by this approach is whether the phenotypes respond differently to available asthma treatments. The demonstration of differences in the pattern of gene expression in the airway epithelium of asthmatic and healthy subjects is persuasive evidence of the existence of different asthma phenotypes requiring different approaches to therapy. Compared with healthy controls, half of the asthmatic participants overexpressed genes for periostin, CLCA1, and serpinB2, genes known to be upregulated in airway epithelial cells by IL-13, a signature cytokine of T2 lymphocytes. The other half of the asthmatic participants

did not. These findings suggest that fundamentally different pathophysiologic mechanisms exist even among patients with mild asthma. The participants with overexpression of genes upregulated by IL-13 are referred to as having a “T2-high molecular phenotype” of asthma. The other subjects, who did not overexpress these genes, are described as having a “non-T2” or “T2-low” molecular phenotype. The T2-high asthmatic subjects on average tended to have more sputum eosinophilia and blood eosinophilia, positive skin test results, higher levels of IgE, and greater expression of certain mucin genes. The response to ICS treatment of these two groups was quite different. Eight weeks of treatment with an ICS improved forced expiratory volume in 1 second (FEV1) only in the T2-high subjects. The implications of these findings are far reaching because they indicate that perhaps as many as half of patients with mild to moderate asthma do not respond to ICS therapy with an improvement in lung function. These data do not address whether there is differential response to ICS in symptoms or exacerbation frequency between T2-low and high. Current research focuses on further exploring molecular phenotypes in asthma and in finding effective treatments for each group. An NIH-sponsored prospective, double-blind multicenter trial was recently completed to compare mometasone (an ICS) and tiotropium (an antimuscarinic) in subjects with mild asthma characterized as T2-high or non-T2-high by analysis of their induced sputum samples for eosinophil number. This trial demonstrated that although subjects with T2-high asthma had a better response to mometasone than tiotropium, subjects with T2-low asthma did not respond better to one agent vs the other. Further studies are needed to determine if the benefit of either of these agents in T2-low asthma is superior to placebo. Another advance for T2-low asthma is the finding that low-dose azithromycin, given to adults with poorly controlled asthma already on a combination of inhaled corticosteroids and long-acting bronchodilators, reduced exacerbation frequency and improved quality of life equally in both eosinophilic (ie, T2-high) and non-eosinophilic (ie, T2-low) asthma. Advances in the development of novel not yet on market bronchodilators (eg, soluble guanylyl cyclase agonists and Ste20like kinase inhibitors) also has the potential to improve the treatment of asthma across phenotypes. The pace of advance in the scientific description of the immunopathogenesis of asthma has spurred the development of many new therapies that target different sites in the immune cascade. Beyond the monoclonal antibodies directed against cytokines (IL-4, IL-5, IL-13, and TSLP) already reviewed (see Table  20–1), these include antagonists of cell adhesion molecules, protease inhibitors, and immunomodulators aimed at shifting CD4 lymphocytes from the Th2 to the Th1 subtype or at selective inhibition of the subset of Th2 lymphocytes directed against particular antigens. Among the monoclonal antibodies in development is daclizumab, a humanized antibody that binds the CD25 subunit of the IL-2 receptor. As these new therapies are developed, it will become increasingly important to identify biomarkers of specific phenotypes of asthma that are most likely to benefit from specific therapies. This will enable truly personalized asthma therapy.

376    SECTION IV  Drugs with Important Actions on Smooth Muscle

■■ CLINICAL PHARMACOLOGY OF DRUGS USED IN THE TREATMENT OF ASTHMA National and international guidelines for asthma emphasize the need for adjusting the intensity of asthma therapy to the underlying severity of the disease and the level of control achieved by the patient’s current treatment (https://www.nhlbi.nih.gov/ health-pro/guidelines/current/asthma-guidelines; ginasthma.org). An underlying principle common to these guidelines is that asthma should be considered in two time domains. In the present domain, asthma is important for the symptoms and impairments it causes— cough, nocturnal awakenings, and shortness of breath that interfere with the ability to exercise or to pursue desired activities. For mild asthma, occasional inhalation of a bronchodilator may be all that is needed to control these symptoms. For more severe asthma, treatment with a long-term controller, like an ICS, is necessary to relieve symptoms and restore function. The second domain of asthma is the risk it presents of future events, such as exacerbations or progressive loss of pulmonary function. Satisfaction with the ability to control symptoms and maintain function by frequent use of an inhaled β2 agonist does not mean that the risk of future events is also controlled. In fact, use of two or more canisters of an inhaled β agonist per month is a marker for increased risk of asthma fatality. The challenges of assessing severity and adjusting therapy for these two domains of asthma are different. For relief of distress in the present domain, the key information is obtained by asking specific questions about the frequency and severity of symptoms, the frequency of rescue use of an inhaled β agonist, the frequency of nocturnal awakenings, and the ability to exercise, and by measuring lung function with spirometry. The best predictor of the risk for future exacerbations is the frequency and severity of their occurrence in the past. Without such a history, estimation of risk is more difficult. In general, patients with poorly controlled symptoms have a heightened risk of exacerbations in the future, but some patients seem unaware of the severity of their airflow obstruction (sometimes described as “poor perceivers”) and can be identified only by measurement of pulmonary function. Reductions in FEV1 correlate with heightened risk of future attacks of asthma. Other possible markers of heightened risk are unstable pulmonary function (large variations in FEV1 from visit to visit, large change with bronchodilator treatment), extreme bronchial reactivity, high numbers of eosinophils in blood or sputum, and high levels of nitric oxide in exhaled air. Assessment of these features may identify patients who need increases in therapy for protection against future exacerbations.

BRONCHODILATORS Bronchodilators, eg, inhaled albuterol, are rapidly effective, safe, and inexpensive. Many patients with only occasional symptoms of asthma require no more than an inhaled bronchodilator taken on an as-needed basis. If symptoms require this “rescue” therapy more

than twice a week, nocturnal symptoms occur more than twice a month, or the FEV1 is less than 80% of predicted, additional treatment is needed. The treatment first recommended is a low dose of an ICS, although a leukotriene receptor antagonist may be used as an alternative. An important caveat for patients with mild asthma is that although the risk of a severe, life-threatening attack is low, it is not zero. All patients with asthma should be instructed in a simple action plan for severe, frightening attacks: to take up to four puffs of albuterol every 20 minutes over 1 hour. If no improvement is noted after the first four puffs, additional treatments should be taken while on the way to an emergency department or other higher level of care. With the goal of improving outcomes on a population level, the non-zero risk of a life-threatening attack led one set of international guidelines (Global Initiative for Asthma) to recommend that all patients with asthma, however mild, should take doses of ICS at least on an as-needed basis; ie, every time a dose of bronchodilator is taken. Nonetheless, major guidelines diverge on this recommendation given the unclear benefit of ICS for all individuals with the mildest forms of asthma.

MUSCARINIC ANTAGONISTS Inhaled muscarinic antagonists have so far earned a limited place in the treatment of asthma. The effects of short-acting agents (eg, ipratropium bromide) on baseline airway resistance are nearly as great as, but no greater than, those of the sympathomimetic drugs, so they are used largely as alternative therapies for patients intolerant of β-adrenoceptor agonists. The airway effects of antimuscarinic and sympathomimetic drugs given in full doses have been shown to be additive only in reducing hospitalization rates in patients with severe airflow obstruction who present for emergency care. The long-acting antimuscarinic (LAMA) agent tiotropium, added to an ICS in asthma, is likely as effective as the addition of an LABA. The addition of tiotropium to combined ICS and LABA therapy can increase lung function and reduce exacerbations in individuals with persistent airflow obstruction, more bronchodilator responsiveness, higher symptom burden, and a history of exacerbations. As a treatment for COPD, LAMAs improve functional capacity, presumably through their action as bronchodilators, and reduce the frequency of exacerbations through currently unknown mechanisms. Studies have provided mixed data as to whether LAMAs can slow the rate of decline of lung function in COPD.

CORTICOSTEROIDS If asthmatic symptoms occur frequently, or if significant airflow obstruction persists despite bronchodilator therapy, inhaled corticosteroids should be started. For patients with severe symptoms or severe airflow obstruction (eg, FEV1 85%) • peak concentrations in 4–6 h • low (35%) plasma protein binding • t1/2 6–10 h • metabolized in liver by carboxylesterase 1; no active metabolites • metabolite mostly excreted in urine (~70%)

Lennox-Gastaut syndrome, focal seizures

Toxicity: Somnolence, vomiting, pyrexia, diarrhea • Interactions: Not metabolized via P450 enzymes, but there may be interactions with other antiseizure medications

GABAPENTINOIDS   •  Gabapentin

α2δ ligand

Bioavailability 50%, decreasing with increasing doses • peak concentrations in 2–3 h • not bound to plasma proteins • not metabolized; 100% excreted unchanged in urine • t1/2 5–9 h

Focal seizures; neuropathic pain; postherpetic neuralgia; anxiety

Toxicity: Somnolence, dizziness, ataxia • Interactions: Minimal

  •  Pregabalin

α2δ ligand

Nearly complete (~90%) absorption • peak concentrations in 1–2 h • not bound to plasma proteins • not metabolized; 98% excreted unchanged in urine • t1/2 4.5–7 h

Focal seizures; neuropathic pain; postherpetic neuralgia; fibromyalgia; anxiety

Toxicity: Somnolence, dizziness, ataxia • Interactions: Minimal

Positive allosteric modulator of GABAA receptors • reduces excitatory synaptic responses

Nearly complete (>90%) absorption • peak concentrations in 0.5–4 h • modest (55%) plasma protein binding • extensively metabolized in liver; no active metabolites; 20–25% excreted unchanged in urine • t1/2 75–140 h Nearly complete (>90%) absorption • minimal (10%) plasma protein binding • peak concentrations in 2–6 h • extensively metabolized in liver; 2 active metabolites (phenobarbital and phenylethylmalonamide); 65% excreted unchanged in urine • t1/2 10–25 h

Focal seizures, generalized tonic-clonic seizures, myoclonic seizures, neonatal seizures; sedation

Toxicity: Sedation, cognitive impairment, ataxia, hyperactivity • Interactions: Valproate, carbamazepine, felbamate, phenytoin, cyclosporine, felodipine, lamotrigine, nifedipine, nimodipine, steroids, theophylline, verapamil, others Toxicity: Sedation, cognitive impairment, ataxia, hyperactivity • Interactions: Similar to phenobarbital

Nearly complete (>90%) absorption • peak concentrations in 3–7 h • not bound to plasma proteins • extensively metabolized in liver; no active metabolites; 20% excreted unchanged in urine • t1/2 20–60 h

Absence seizures

Toxicity: Nausea, headache, dizziness, lethargy • Interactions: Valproate, phenobarbital, phenytoin, carbamazepine, rifampicin

Nearly complete (>90%) oral or rectal absorption • peak concentrations in 1–1.5 h • IV for status epilepticus • highly (95–98%) bound to plasma proteins • extensively metabolized by CYP3A4 and CYP2C19 to N-desmethyldiazepam and other active metabolites • t1/2 of N-desmethyldiazepam up to 100 h Bioavailability >80% • peak concentrations in 1–4 h • highly (86%) bound to plasma proteins • extensively metabolized in liver by CYP3A4; no active metabolites • t1/2 12–56 h

Status epilepticus, acute repetitive seizures (seizure clusters); sedation, anxiety, muscle relaxation (muscle spasms, spasticity), acute alcohol withdrawal

Toxicity: Sedation • Interactions: Additive with sedative-hypnotics

Absence seizures, myoclonic seizures, infantile spasms

Toxicity: Similar to diazepam • Interactions: Additive with sedative-hypnotics

  •  Rufinamide

BARBITURATES   •  Phenobarbital

  •  Primidone

Sodium channel blocker-like but converted to phenobarbital

ABSENCE SEIZURE–SPECIFIC   •  Ethosuximide Inhibit low-threshold calcium channels (T-type)

Generalized tonic-clonic seizures, focal seizures

BENZODIAZEPINES   •  Diazepam

Positive allosteric modulator of GABAA receptors

  •  Clonazepam

Positive allosteric modulator of GABAA receptors

(continued)

460    SECTION V  Drugs That Act in the Central Nervous System

Type, Drug   •  Clobazam

Mechanism of Action Positive allosteric modulator of GABAA receptors

Pharmacokinetics

Clinical Applications

Toxicities, Interactions

Bioavailability >95% • protein binding 80–90% • extensively metabolized to N-desmethylclobazam, which is pharmacologically active • parent: t1/2 10–30 h • N-desmethyl metabolite: t1/2 36–46 h

Focal seizures, seizures associated with LennoxGastaut syndrome and Dravet syndrome

Toxicity: Somnolence, sedation, lethargyInteractions: Increases levels of phenytoin and carbamazepine; cannabidiol increases levels of N-desmethylclobazam

  •  Lorazepam: Used for status epilepticus; rapidly conjugated to lorazepam glucuronide, which is inactive; t1/2 12 h   • Midazolam: Used for status epilepticus and acute repetitive seizures (seizure clusters); water soluble at pH 90%) • no food effect • 22–25% bound to plasma proteins, primarily albumin • 40–50% excreted unchanged in urine • t1/2 20–23 h

Focal seizures; seizures associated with LennoxGastaut syndrome

Toxicity: Anorexia, nausea, vomiting, insomnia, anxiety, weight loss, dizziness, headache, somnolence, aplastic anemia, hepatic failure • Interactions: Increases phenytoin, valproate and phenobarbital; reduces carbamazepine but increases carbamazepine epoxide; phenytoin, carbamazepine, and phenobarbital reduce felbamate concentrations

POTASSIUM CHANNEL OPENER   • Retigabine Opens KCNQ (ezogabine) potassium channels

AMPA RECEPTOR BLOCKER   •  Perampanel

CANNABINOID   • Cannabidiol (sesame oil formulation)

CARBAMATE   •  Felbamate

(continued)

CHAPTER 24  Antiseizure Medications    461

Mechanism of Action

Pharmacokinetics

Clinical Applications

Toxicities, Interactions

Sodium channel blocker; low-efficacy positive allosteric modulator of GABAA receptors

Well absorbed (>88%) • no food effect • peak concentrations in 1–4 h • >60% bound to plasma proteins, primarily albumin • extensively metabolized in liver • t1/2 50–60 h

Focal seizures

Toxicity: Somnolence, dizziness, fatigue, balance disorder, gait disturbance, dysarthria, nystagmus, and ataxia; DRESS; short QT interval • Interactions: Increases phenytoin; may also increase phenobarbital and N-desmethylclobazam; decreases carbamazepine, lamotrigine

AROMATIC ALLYLIC ALCOHOL   •  Stiripentol Positive allosteric modulator of GABAA receptors; increases clobazam and norclobazam levels

Used in combination with clobazam or valproate • bioavailability 30% • t1/2 4.5–13 h (dose-dependent) • highly (>99%) bound to plasma proteins • metabolized in liver

Dravet syndrome (USA: adjunctive use in conjunction with clobazam; European Union: adjunctive use in conjunction with clobazam and valproate)

Toxicity: Sedation/drowsiness, reduced appetite, slowing of mental function, ataxia, diplopia, nausea, and abdominal pain

Bioavailability 68–74% • no food effect • peak concentration 3–5 h • t1/2 20 h • metabolized to norfenfluramine by CYP1A2, CYP2B6, CYP2D6

Convulsive seizures associated with Dravet syndrome; atonic seizures associated with LennoxGastaut syndrome

Toxicity: Decreased appetite, diarrhea, fatigue • Interactions: concomitant stiripentol increases fenfluramine exposure and reduces norfenfluramine exposure; fenfluramine does not affect valproate, stiripentol, clobazam, or norclobazam

Type, Drug   •  Cenobamate

SUBSTITUTED AMPHETAMINE   •  Fenfluramine Serotonin release

P R E P A R A T I O N S GENERIC NAME Brivaracetam Cannabidiol Carbamazepine forms  Carbamazepine  Carbamazepine extended release

  Carbamazepine injection Cenobamate Clobazam Clonazepam forms   Clonazepam tablet

 Clonazepam orally disintegrating tablet   Clonazepam oral solution   Clonazepam injection Clorazepate dipotassium Corticotropin Diazepam forms  Diazepam  Diazepam oral solution concentrate

Interactions: Clobazam, valproate; also carbamazepine, phenobarbital, phenytoin

A V A I L A B L E

AVAILABLE AS Generic, Briviact Epidiolex   Generic, Tegretol, Epitol, Teril Generic, Tegretol-XR, Carbatrol, Equetro, Curatil Prolonged-Release Carnexiv (discontinued in USA) Xcopri, Ontozry Generic, Onfi, Sympazan   Generic, Klonopin, Rivatril, Rivotril, Antelepsin, Clonotril, Iktorivil, others Generic Generic, Rivotril oral solution (not available USA) Generic, Rivotril injection (not available in USA) Generic, Tranxene Acthar Gel   Generic, Valium, others Generic, Diazepam Intensol

GENERIC NAME   Diazepam injection   Diazepam rectal gel   Diazepam intranasal Eslicarbazepine acetate Ethosuximide Ethotoin Everolimus Felbamate Fenfluramine Fosphenytoin sodium injection Gabapentin Gabapentin enacarbil Ganaxolone Lacosamide forms  Lacosamide   Lacosamide injection Lamotrigine forms  Lamotrigine   Lamotrigine extended release Levetiracetam forms  Levetiracetam  Levetiracetam extended release   Levetiracetam injection

AVAILABLE AS Generic Diastat Acudial Valtoco Aptiom, Stedesa Generic, Zarontin Peganone (discontinued in USA) Afinitor Generic, Felbatol Fintepla Generic, Cerebyx Generic, Neurontin, Gralise Horizant Ztalmy   Generic, Vimpat Generic, Vimpat injection   Generic, Lamictal Generic, Lamictal XR   Generic, Keppra, Spritam Generic, Keppra XR, Elepsia XR Generic, Keppra injection (continued)

462    SECTION V  Drugs That Act in the Central Nervous System

GENERIC NAME Lorazepam forms  Lorazepam  Lorazepam oral solution concentrate   Lorazepam injection Mephenytoin Methsuximide Midazolam forms  Midazolam hydrochloride injection  Midazolam hydrochloride syrup  Midazolam oromucosal solution (buccal)   Midazolam nasal spray Oxcarbazepine Pentobarbital sodium injection Perampanel Phenobarbital forms  Phenobarbital   Phenobarbital sodium injection Phenytoin sodium forms   Phenytoin sodium extended

AVAILABLE AS   Generic, Ativan Generic, Lorazepam Intensol Generic, Ativan injection Mesantoin (discontinued in USA) Celontin   Generic, Versed, Seizalam Generic Epistatus, Buccolam Nayzilam, Nasolam Generic, Trileptal, Oxtellar XR Generic, Nembutal Sodium injection Fycompa   Generic, Luminal Sodium, others Generic, Sezaby   Generic, Dilantin, Phenytek

REFERENCES Ettinger AB, Argoff CE: Use of antiepileptic drugs for non-epileptic conditions: Psychiatric disorders and chronic pain. Neurotherapeutics 2007;4:75. French JA et al: Development of new treatment approaches for epilepsy: Unmet needs and opportunities. Epilepsia 2013;54(Suppl 4):3. Glauser TA et al: Ethosuximide, valproic acid, and lamotrigine in childhood absence epilepsys. N Engl J Med 2010;362:790. Grover EH et al: Treatment of convulsive status epilepticus. Curr Treat Options Neurol 2016;18:11. Haut SR: Seizure clusters: Characteristics and treatment. Curr Opin Neurol 2015;28:143. Kaminski RM et al: SV2A is a broad-spectrum anticonvulsant target: Functional correlation between protein binding and seizure protection in models of both partial and generalized epilepsy. Neuropharmacology 2008;54:715. Kapur J et al: Randomized trial of three anticonvulsant medications for status epilepticus. N Engl J Med 2019;381:2103. Kienitz R et al: Benzodiazepines in the management of seizures and status epilepticus: a review of routes of delivery, pharmacokinetics, efficacy, and tolerability. CNS Drugs 2022;36:951. Klein P et al: Suicidality risk of newer antiseizure medications: a meta-analysis. JAMA Neurol 2021;78:1118. Löscher W et al: Synaptic vesicle glycoprotein 2A ligands in the treatment of epilepsy and beyond. CNS Drugs 2016;30:1055. Meldrum BS, Rogawski MA: Molecular targets for antiepileptic drug development. Neurotherapeutics 2007;4:18. Patsalos PN: Antiepileptic Drug Interactions. A Clinical Guide. Springer International Publishing, 2016. Patsalos PN: Drug interactions with the newer antiepileptic drugs (AEDs)—Part 1: Pharmacokinetic and pharmacodynamic interactions between AEDs. Clin Pharmacokinet 2013;52:927. Patsalos PN et al: Therapeutic drug monitoring of antiepileptic drugs in epilepsy: A 2018 update. Ther Drug Monit 2018;40(5):526.

GENERIC NAME   Phenytoin sodium injectable Pregabalin forms  Pregabalin   Pregabalin extended release Primidone Retigabine (ezogabine) Rufinamide Stiripentol Tiagabine Topiramate forms  Topiramate   Topiramate extended release Trimethadione Valproate/valproic acid forms   Valproic acid  Divalproex sodium delayed release  Divalproex sodium extended release  Valproate sodium injection Vigabatrin Zonisamide

AVAILABLE AS Generic, phenytoin sodium injection   Generic, Lyrica Generic, Lyrica CR Generic, Mysoline Potiga, Trobalt (discontinued) Generic, Banzel Diacomit Generic, Gabitril   Generic, Topamax, Eprontia Generic, Trokendi XR, Qudexy XR Tridione (discontinued)   Generic, Depakene Generic, Depakote Generic, Depakote ER Generic, Depacon Generic, Sabril, Vigradone Generic, Zonegran, Zonisade

Porter RJ et al: AED mechanisms and principles of drug treatment. In: Stefan H, Theodore W (editors): Handbook of Clinical Neurology, 3rd series, Epilepsies Part 2: Treatment. Elsevier, 2012. Reimers A et al: Reference ranges for antiepileptic drugs revisited: A practical approach to establish national guidelines. Drug Des Devel Ther 2018;12:271. Rosenfeld WE et al: Efficacy of cenobamate by focal seizure subtypes: Post-hoc analysis of a phase 3, multicenter, open-label study. Epilepsy Res 2022;183: 106940. Rogawski MA et al: Current understanding of the mechanism of action of the antiepileptic drug lacosamide. Epilepsy Res 2015;110:189. Rogawski MA, Hanada T: Preclinical pharmacology of perampanel, a selective non-competitive AMPA receptor antagonist. Acta Neurol Scand 2013; 127(Suppl 197):19. Rogawski MA et al: Mechanisms of action of antiseizure drugs and the ketogenic diet. Cold Spring Harb Perspect Med 2016;6:a022780. Sánchez Fernández I et al: Meta-analysis and cost-effectiveness of second-line antiepileptic drugs for status epilepticus. Neurology 2019;92:e2339. Sills GJ, Rogawski MA: Mechanisms of action of currently used antiseizure drugs. Neuropharmacology 2020;168:107966. Steinhof BJ et al: Efficacy and safety of adjunctive perampanel for the treatment of refractory partial seizures: A pooled analysis of three phase III studies. Epilepsia 2013;54:1481. Vélez-Ruiz NJ, Pennell PB: Issues for women with epilepsy. Neurol Clin 2016;34:411. Wilcox KS et al: Issues related to development of new anti-seizure treatments. Epilepsia 2013;54(Suppl 4):24. Xie X et al: Electrophysiological and pharmacological properties of the human brain type IIA Na+ channel expressed in a stable mammalian cell line. Pflugers Arch 2001;441:425. Xie X, Hagan RM: Cellular and molecular actions of lamotrigine: Possible mechanisms of efficacy in bipolar disorder. Neuropsychobiology 1998; 38:119.

CHAPTER 24  Antiseizure Medications    463

C ASE STUDY ANSWER Lamotrigine was gradually added to the regimen to a dosage of 200 mg bid. Since then, the patient has been seizure-free for almost 2 years but now comes to the office for a medication review. Gradual discontinuation of levetiracetam is

planned if the patient continues to do well for another year, although risk of recurrent seizures is always present when medications are withdrawn.

25 C

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General Anesthetics Helge Eilers, MD, & Spencer Yost, MD

C ASE STUDY An elderly man with type 2 diabetes mellitus and ischemic pain in a lower extremity is scheduled for femoral-to-popliteal artery bypass surgery. He has a history of hypertension and coronary artery disease with symptoms of stable angina. He can walk only half a block before pain in his legs forces him to stop. He has a 50-pack-year smoking history but stopped 2 years ago. Medications include atenolol, atorvastatin, and hydrochlorothiazide.

For centuries, humans relied on natural medicines and physical methods to control surgical pain. Historical texts describe the sedative effects of cannabis, henbane, mandrake, and opium poppy. Physical methods such as cold, nerve compression, carotid artery occlusion, and cerebral concussion were also employed, with variable effectiveness. Although surgery was performed under ether anesthesia as early as 1842, the first public demonstration of surgical general anesthesia in 1846 is generally accepted as the start of the modern era of anesthesia. For the first time, physicians had a reliable means to keep their patients from experiencing pain during surgical procedures. The neurophysiologic state produced by general anesthetics is characterized by five primary effects: unconsciousness, amnesia, analgesia, inhibition of autonomic reflexes, and skeletal muscle relaxation. None of the currently available anesthetic agents used alone can achieve all five of these desired effects well. An ideal anesthetic drug should also induce rapid, smooth loss of consciousness, be rapidly reversible upon discontinuation, and possess a wide margin of safety. The modern practice of anesthesiology relies on the use of combinations of intravenous and inhaled drugs (balanced anesthesia techniques) to take advantage of the favorable properties of each agent while minimizing their adverse effects. The choice of anesthetic technique is determined by the type of diagnostic, therapeutic, or surgical intervention that the patient needs. 464

The nurse in the preoperative holding area obtains the following vital signs: temperature 36.8°C (98.2°F), blood pressure 168/100 mm Hg, heart rate 78 bpm, oxygen saturation by pulse oximeter 96% while breathing room air; he reports pain 5/10 in the right lower leg after walking into the hospital. What anesthetic agents will you choose for his anesthetic plan? Why? Does the choice of anesthetic make a difference?

For  minor superficial surgery or invasive diagnostic procedures, oral or parenteral sedatives can be combined with local anesthetics in a technique termed monitored anesthesia care (MAC) (see Box: Sedation & Monitored Anesthesia Care, and Chapter 26). This approach can provide profound analgesia, while retaining the patient’s ability to maintain a patent airway and to respond to verbal commands. For more invasive surgical procedures, anesthesia may begin with a preoperative benzodiazepine, be induced with a rapidly acting intravenous drug (eg, propofol or thiopental), and be maintained with inhaled agents (eg, volatile agents, nitrous oxide), intravenous drugs (eg, propofol, opioid analgesics), or both.

MECHANISM OF GENERAL ANESTHETIC ACTION General anesthetics have been in successful clinical use for more than 175 years, yet their mechanism of action remains unknown. The principal effect that is common to all anesthetic agents is suppression of the normal activity of the central nervous system (CNS). Initial research focused on identifying a single biologic site of action for these drugs. This “unitary theory” of anesthetic action has been supplanted by a more complex model of molecular targets located at multiple levels of the CNS. Ongoing research has

CHAPTER 25  General Anesthetics    465

focused on cellular, molecular, and network sites to understand the mechanism of general anesthesia. Anesthetics affect neurons at various cellular locations, but the primary focus has been on the synapse. A presynaptic action may alter the release of neurotransmitters, whereas a postsynaptic effect may change the frequency or amplitude of impulses exiting the synapse. The cumulative effect of these actions may produce strengthened inhibition or diminished excitation within key areas of the CNS. Studies on isolated spinal cord tissue have demonstrated that excitatory transmission is impaired more strongly by anesthetics than inhibitory effects are potentiated. The principal molecular targets of anesthetic action that have been studied are neuronal ion channels that mediate impulse conduction in the CNS. Chloride channels (γ-aminobutyric acid-A [GABAA] and glycine receptors) and potassium channels (K2P, possibly KV, and KATP channels) remain the primary inhibitory ion channels considered possible sites of anesthetic action. Excitatory ion channel targets include those activated by acetylcholine (nicotinic and muscarinic receptors), by glutamate (amino3-hydroxy-5-methyl-4-isoxazol-propionic acid [AMPA], kainate, and N-methyl-d-aspartate [NMDA] receptors), or by serotonin (5-HT2 and 5-HT3 receptors). Figure 25–1 depicts the relation of these inhibitory and excitatory targets of anesthetics within the context of the nerve terminal.

Recently, researchers using new investigational tools such as extended array electroencephalography and functional magnetic resonance imaging have focused on neural networks within the brain that are altered by general anesthetics (see Box: What Does Anesthesia Represent & How Does It Work? for more details). Nevertheless, the principal barrier to understanding the mechanism of action of anesthetic agents is the lack of a coherent, widely accepted explanation for how CNS neuronal activity gives rise to the fundamental properties of brain function such as memory, sensation, emotion, and consciousness.

■■ INHALED ANESTHETICS A clear distinction should be made between gaseous and volatile anesthetics, both of which are administered by inhalation. Gaseous anesthetics (nitrous oxide, xenon) have high vapor pressures and low boiling points so that they are in gas form at room temperature. In contrast, volatile anesthetics (halothane, isoflurane, desflurane, sevoflurane) have lower vapor pressures and relatively higher boiling points so that they are liquids at room temperature (20°C) and sea-level ambient pressure. The physical characteristics of volatile anesthetics determine that they need to be administered using precision vaporizers. Figure 25–2 shows the chemical structures of important, clinically used, inhaled anesthetics.

Sedation & Monitored Anesthesia Care Many diagnostic and minor therapeutic surgical procedures can be performed without general anesthesia (GA) using sedationbased anesthetic techniques. In this setting, regional (nerve block) or local anesthesia supplemented with a benzodiazepine or propofol with or without opioid analgesics (or ketamine) will allow a patient to tolerate superficial surgical or interventional procedures. This anesthetic technique is known as monitored anesthesia care, abbreviated as MAC, and should not be confused with the minimal alveolar concentration for the comparison of potencies of inhaled anesthetics (see text and Box: What Does Anesthesia Represent & How Does It Work?). The technique typically begins with intravenous midazolam to produce anxiolysis, amnesia, and mild sedation, followed by a titrated, variablerate propofol infusion (to provide moderate to deep levels of sedation). A potent opioid analgesic or ketamine may be added to blunt pain associated with the injection of local anesthesia and the procedure itself. Another approach, used primarily by non-anesthesiologists, is called conscious sedation. This technique produces alleviation of anxiety and pain with less alteration of the level of consciousness by using smaller doses of sedative medications. In this state, the patient retains the ability to maintain a patent airway and remains responsive to verbal commands. Using intravenous anesthetic drugs such as benzodiazepines and/or opioid analgesics (eg, fentanyl) in conscious sedation protocols carries the added advantage of being rapidly reversible by specific receptor

antagonist drugs (flumazenil and naloxone, respectively) if a particular patient displays unusual sensitivity to them. MAC or conscious sedation can also help supplement regional anesthesia techniques such as peripheral nerve blocks or neuraxial anesthesia. A specialized form of sedation is occasionally required for critically ill patients in the intensive care unit (ICU) that require invasive cardiopulmonary support such as mechanical ventilation or extracorporeal membrane oxygenation (ECMO). In this situation, sedative-hypnotic drugs and low doses of intravenous anesthetic infusions may be combined. Propofol, fentanyl, and dexmedetomidine are popular choices for this indication. Deep sedation is similar to a light state of general anesthesia characterized by decreased consciousness from which the patient is not easily aroused. The transition from deep sedation to general anesthesia is fluid and can be difficult to define. Because deep sedation is accompanied by loss of verbal responsiveness, protective airway reflexes, and the ability to maintain a patent airway, this state may be indistinguishable from general anesthesia. A practitioner with expertise in airway management (anesthesiologist or nurse anesthetist) must be present. Intravenous agents used in deep sedation protocols mainly include the sedative-hypnotics propofol and midazolam, sometimes in combination with potent opioid analgesics or ketamine, depending on the level of pain associated with the surgery or procedure.

466    SECTION V  Drugs That Act in the Central Nervous System

Presynaptic neuron

A

Action potential

GABA or Glycine

Anesthetics

Cl

K+

GABAA Cl– receptor

–

K+

K+

+

K

Glycine receptor

K+ K+

Cl– Cl–

–

channel

Cl–

K+

Cl– Cl – Cl Cl–

Cl– Cl–

K+

K+ Postsynaptic neuron

Presynaptic neuron

B

Action potential

Glutamate or ACh

Anesthetics

Na+ Ca2+ nACh receptor

Na+

Ca2+ Na+ Na+

Ca2+ Ca2+

Na+

NMDA receptor

Mg2+ Ca2+

Ca2+ Mg2+ Na+ Na+ Mg2+ Ca2+ Na+ Mg2+

Na+

Ca2+ Na+ Postsynaptic neuron

FIGURE 25–1  Putative targets of anesthetic action. Anesthetic drugs may (A) enhance inhibitory synaptic activity or (B) diminish excitatory activity. ACh, acetylcholine; GABAA, γ-aminobutyric acid-A.

PHARMACOKINETICS Inhaled anesthetics, both volatile and gaseous, are taken up through gas exchange in the alveoli of the lung for distribution to the effect compartments within the body. The kinetic goal of delivering anesthetic gases this way is to rapidly achieve an

effective concentration of the agent at the lung:blood interface. When this equilibrium is reached we presume that the effect site concentration within the CNS (brain and spinal cord) has also been reached. Several factors determine how quickly the alveolar and subsequent CNS concentrations change.

CHAPTER 25  General Anesthetics    467

O N

N

Nitrous oxide

F

F

Br

C

C

F

Cl

H

H

F

F

C

C

Cl

F O

C

H

F

F Enflurane

Halothane

Xe Xenon

F

F

H

C

C

F

F O

C

Cl

H

F

Isoflurane F F

C

C

F

F

H

C

C

F

H O

C

F

F

C

F

H

C F

Desflurane

FIGURE 25–2 

O

F

F

F

H

H

F

Sevoflurane

Chemical structures of inhaled anesthetics.

Uptake & Distribution A. Factors Controlling Uptake 1. Inspired concentration and ventilation—The driving force for uptake of an inhaled anesthetic into the body is the ratio between inspired and alveolar concentration. The most important

parameter that can be controlled by the anesthesiologist to change alveolar concentration quickly is the inspired concentration or partial pressure. The partial pressure is the fraction of a gas mixture that a particular component comprises. For example, a mixture of gases that may be delivered by an anesthesia machine—70% nitrous oxide, 29% oxygen, and 1% isoflurane at normal barometric pressure (760 mm Hg)—contains partial pressures of 532 mm Hg nitrous oxide, 220 mm Hg oxygen, and 7.6 mm Hg isoflurane. The partial pressure of anesthetic in the inspired gas mixture determines the maximum partial pressure that can be achieved in the alveoli as well as the rate of rise of the partial pressure in the alveoli. To accelerate induction, the anesthesiologist increases the inspired anesthetic partial pressure to create a steeper gradient between inspired and alveolar partial pressure. This fractional rise of anesthetic partial pressure during induction is expressed as a ratio of alveolar concentration (FA) over inspired concentration (FI); the faster FA/FI approaches 1 (representing inspired-to-alveolar equilibrium), the faster anesthesia onset will be during inhaled induction of anesthesia. The other parameter under control of the anesthesiologist that directly determines the rate of rise of FA/FI is alveolar ventilation. By increasing the tidal volume and respiratory rate the anesthesiologist can quickly deliver a larger mass of anesthetic agent to the alveoli of the lung. The tendency for a given inhaled anesthetic to pass from the gas phase of the alveoli into pulmonary capillary blood is determined by the blood:gas partition coefficient (see the following section Solubility and Table 25–1). As increased ventilation supplies more anesthetic molecules to the alveoli, a highly soluble anesthetic (blood:gas partition coefficient >1) will traverse the alveolar capillary membrane and be taken up by the pulmonary flow, preventing a rise in its alveolar partial pressure. Thus, increased ventilation will replenish the alveolar anesthetic concentration for a highly soluble anesthetic but is not necessary for an anesthetic with low solubility. Therefore, an increase in ventilation accelerates the rise in alveolar partial pressure of an anesthetic with low blood solubility very little, but can significantly increase the partial pressure of agents with moderate to high blood solubility such as halothane. As seen in Figure 25–3, a fourfold increase in the ventilation rate almost doubles the FA/FI ratio

TABLE 25–1  Pharmacologic properties of inhaled anesthetics. Anesthetic

Blood:Gas Partition Coefficient1

Brain:Blood Partition Coefficient1

Minimal Alveolar Concentration (MAC) (%)2

Metabolism

Comments

Nitrous oxide

0.47

1.1

>100

None

Incomplete anesthetic; rapid onset and recovery

Desflurane

0.42

1.3

6–7

enflurane > sevoflurane > isoflurane > desflurane > nitrous oxide (see Table 25–1). Nitrous oxide is not metabolized by human tissues. However, bacteria in the gastrointestinal tract may be able to break down the nitrous oxide molecule.

PHARMACODYNAMICS Organ System Effects of Inhaled Anesthetics A. CNS Effects Anesthetic potency is currently described by the minimal alveolar concentration (MAC) required to prevent a response to a surgical incision (see Box: What Does Anesthesia Represent & How Does It Work?). This parameter was first described by investigators in the 1960s and remains the best clinical guide for administering inhaled anesthetics, especially since improved medical technology can now provide instantaneous, accurate determination of gas concentrations. Inhaled anesthetics (and intravenous anesthetics, discussed later) decrease the metabolic activity of the brain. Decreased cerebral metabolic rate (CMR) generally causes a reduction in blood flow within the brain. However, volatile anesthetics may also produce cerebral vasodilation, which can increase cerebral blood flow. The net effect on cerebral blood flow (increase, decrease, or no change) depends on the concentration of anesthetic delivered. At 0.5 MAC, the reduction in CMR is greater than the vasodilation caused by anesthetics, so cerebral blood flow is decreased. Conversely, at 1.5 MAC, vasodilation by the anesthetic is greater than the reduction in CMR, so cerebral blood flow is increased. In between, at 1.0 MAC, the effects are balanced and cerebral blood flow is unchanged. An increase in cerebral blood flow is clinically undesirable in patients who have increased intracranial pressure because of brain tumor, intracranial hemorrhage, or head injury. Therefore, administration of high concentrations of volatile anesthetics is best avoided in patients with increased intracranial pressure. Hyperventilation can be used to attenuate this response—decreasing the Paco2 (the partial pressure of carbon dioxide in arterial blood) through hyperventilation causes cerebral vasoconstriction. If the patient is hyperventilated before the volatile agent is started, the increase in intracranial pressure can be minimized. Nitrous oxide can increase cerebral blood flow and cause increased intracranial pressure. This effect is most likely caused by activation of the sympathetic nervous system (as described below). Therefore, nitrous oxide may be combined with other agents (intravenous anesthetics) or techniques (hyperventilation) that reduce cerebral blood flow in patients with increased intracranial pressure. Potent inhaled anesthetics produce a basic pattern of change to brain electrical activity as recorded by standard electroencephalography (EEG). Isoflurane, desflurane, sevoflurane, halothane, and enflurane produce initial activation of the EEG at low doses and then slowing of electrical activity up to doses of 1.0–1.5 MAC. At higher concentrations, EEG suppression increases to the point of electrical silence with isoflurane at 2.0–2.5 MAC. Isolated epileptic-like patterns may also be seen between 1.0 and 2.0 MAC, especially with sevoflurane and enflurane, but frank clinical seizure activity has been observed only with enflurane. Nitrous oxide used alone causes fast electrical oscillations emanating from the frontal cortex at doses associated with analgesia and depressed consciousness.

CHAPTER 25  General Anesthetics    471

What Does Anesthesia Represent & How Does It Work? Anesthetic action has three principal components: immobility, amnesia, and unconsciousness. The exact cellular, molecular, or physiologic mechanisms for producing these effects are largely unknown.

Immobility Immobility is the easiest anesthetic end point to measure. Edmond Eger and colleagues introduced the concept of minimal alveolar concentration (MAC) to quantify the potency of an inhalational anesthetic. They defined 1.0 MAC as the alveolar partial pressure of an inhalational anesthetic at which 50% of a population of unparalyzed patients remained immobile at the time of abdominal surgery skin incision. Anesthetic immobility is mediated primarily by neural inhibition within the spinal cord but may also include inhibited nociceptive transmission to the brain. This concept is the most convenient measure by which anesthesiologists compare the potency of inhaled agents and guide the conduct of patient anesthesia.

Amnesia The ablation of memory occurs in several locations in the CNS, including the hippocampus, amygdala, prefrontal cortex, and regions of the sensory and motor cortices. Memory researchers differentiate two types of remembrance that should be abolished under anesthesia: (1) explicit memory, ie, specific awareness or consciousness under anesthesia; and (2) implicit

Traditionally, anesthetic effects on the brain produce four stages or levels of increasing depth of CNS depression (Guedel’s signs, derived from observations of the effects of inhaled diethyl ether): Stage I—analgesia: The patient initially experiences analgesia without amnesia. Later in stage I, both analgesia and amnesia are produced. Stage II—excitement: During this stage, the patient appears delirious and may vocalize but is completely amnesic. Respiration is rapid, and heart rate and blood pressure increase. Duration and severity of this light stage of anesthesia are shortened by rapidly increasing the concentration of the agent. Stage III—surgical anesthesia: This stage begins with slowing of respiration and heart rate and extends to complete cessation of spontaneous respiration (apnea). Four planes of stage III are described based on changes in ocular movements, eye reflexes, and pupil size, indicating increasing depth of anesthesia. Stage IV—medullary depression: This deep stage of anesthesia represents severe depression of the CNS, including the vasomotor center in the medulla and respiratory center in the brainstem. Without circulatory and respiratory support, death would rapidly ensue in stage IV. B. Cardiovascular Effects Halothane, enflurane, isoflurane, desflurane, and sevoflurane all depress normal cardiac contractility (halothane and enflurane more so than isoflurane, desflurane, and sevoflurane). As a result,

memory, the unconscious acquisition of information under adequate levels of anesthesia. Their studies have found that formation of both types of memory is reliably prevented at low MAC values (0.2–0.4 MAC). Prevention of explicit memory (awareness) has spurred the development of monitors such as the bispectral index, patient state index, electroencephalogram (EEG), and entropy monitor of auditory evoked potentials to help recognize inadequate depth of anesthesia.

Unconsciousness The ability of anesthetic drugs to abolish consciousness requires action at anatomic locations responsible for the formation of human consciousness. Neuroscientists studying consciousness identify three regions in the brain involved in generating personal awareness: the cerebral cortical hemispheres, the thalamus, and the reticular activating system. Neural pathways emanating from these regions seem to synchronize as an interacting system to produce the mental state in which humans are awake, aware, and perceiving. Our current state of understanding supports the following framework: sensory stimuli conducted through the reticular formation of the brainstem into supratentorial signaling loops, connecting the thalamus with various regions of the cortex, are the foundation of consciousness. These neural pathways involved in the development of consciousness are reversibly disrupted by anesthetic agents.

all volatile agents tend to decrease mean arterial pressure in direct proportion to their alveolar concentration. With halothane and enflurane, the reduced arterial pressure is caused primarily by myocardial depression (reduced cardiac output) and there is little change in systemic vascular resistance. In contrast, isoflurane, desflurane, and sevoflurane produce greater vasodilation with minimal effect on cardiac output. These differences may have important implications for patients with heart failure. Because isoflurane, desflurane, and sevoflurane better preserve cardiac output as well as reduce preload (ventricular filling) and afterload (systemic vascular resistance), these agents may be better choices for patients with impaired myocardial function. Nitrous oxide also depresses myocardial function in a concentration-dependent manner. This depression may be significantly offset by a concomitant activation of the sympathetic nervous system resulting in preservation of cardiac output. Therefore, administration of nitrous oxide in combination with the more potent volatile anesthetics can minimize circulatory depressant effects by both anesthetic-sparing and sympathetic-activating actions. Because all inhaled anesthetics produce a dose-dependent decrease in arterial blood pressure, activation of autonomic nervous system reflexes may trigger increased heart rate. However, halothane, enflurane, and sevoflurane have little effect on heart rate, probably because they attenuate baroreceptor input into the autonomic nervous system. Desflurane and isoflurane significantly

472    SECTION V  Drugs That Act in the Central Nervous System

increase heart rate because they cause less depression of the baroreceptor reflex. In addition, desflurane can trigger transient sympathetic activation—with elevated catecholamine levels—to cause marked increases in heart rate and blood pressure during administration of high desflurane concentrations or when desflurane concentrations are changed rapidly. Inhaled anesthetics tend to reduce myocardial oxygen consumption, which reflects depression of normal cardiac contractility and decreased arterial blood pressure. In addition, inhaled anesthetics produce coronary vasodilation. The net effect of decreased oxygen demand and increased coronary flow (oxygen supply) is improved myocardial oxygenation. However, other factors, such as surgical stimulation, intravascular volume status, blood oxygen levels, and withdrawal of perioperative β blockers, may tilt the oxygen supply-demand balance toward myocardial ischemia in specific patients.

early recovery period can continue to depress the compensatory increase in ventilation normally caused by hypoxia. Inhaled anesthetics also depress mucociliary function in the airway. During prolonged exposure to inhaled anesthetics, mucus pooling may result in atelectasis and the development of postoperative respiratory complications, including hypoxemia, mucous plugging, and respiratory infections.

C. Respiratory Effects All volatile anesthetics possess varying degrees of bronchodilating properties, an effect of value in patients with active wheezing and in status asthmaticus. However, airway irritation, which may provoke coughing or breath-holding, is induced by the pungency of some volatile anesthetics. The pungency of isoflurane and desflurane makes these agents less suitable for induction of anesthesia in patients with active bronchospasm. These reactions rarely occur with halothane and sevoflurane, which are considered nonpungent. Therefore, the bronchodilating action of halothane and sevoflurane makes them the agents of choice in patients with underlying airway problems. Nonpungency and rapid increases in alveolar anesthetic concentration also make sevoflurane an excellent choice for smooth and rapid inhalation inductions in pediatric and adult patients. Nitrous oxide is also nonpungent and can facilitate inhalational induction of anesthesia in a patient with bronchospasm. The control of breathing is significantly affected by inhaled anesthetics. With the exception of nitrous oxide, all inhaled anesthetics in current use cause a dose-dependent decrease in tidal volume and an increase in respiratory rate, resulting in a rapid, shallow breathing pattern. However, the increase in respiratory rate varies among agents and does not fully compensate for the decrease in tidal volume, resulting in decreased alveolar ventilation. In addition, all volatile anesthetics are respiratory depressants, as defined by a reduced ventilatory response to increased levels of carbon dioxide in the blood. The degree of ventilatory depression varies among the volatile agents, with isoflurane and enflurane being the most depressant. By this hypoventilation mechanism, all volatile anesthetics increase the resting level of Paco2 in spontaneously breathing patients. Volatile anesthetics also raise the apneic threshold (Paco2 level below which apnea occurs through lack of CO2-driven respiratory stimulation) and decrease the ventilatory response to hypoxia. Clinically, the respiratory depressant effects of anesthetics are overcome by assisting (controlling) ventilation mechanically. The ventilatory depression produced by inhaled anesthetics may be counteracted by surgical stimulation; however, low, subanesthetic concentrations of volatile anesthetic present after surgery in the

E. Hepatic Effects Volatile anesthetics cause a concentration-dependent decrease in portal vein blood flow that parallels the decline in cardiac output produced by these agents. However, total hepatic blood flow may be relatively preserved as hepatic artery blood flow to the liver may increase or stay the same. Although transient changes in liver function tests may occur following exposure to volatile anesthetics, persistent elevation in liver enzymes is rare except following repeated exposures to halothane (see section Toxicity of Anesthetic Agents).

D. Renal Effects Inhaled anesthetics tend to decrease glomerular filtration rate (GFR) and urine flow. Renal blood flow may also be decreased by some agents, but filtration fraction is increased, implying that autoregulatory control of efferent arteriole tone helps compensate and limits the reduction in GFR. In general these anesthetic effects are minor compared with the stress of surgery itself and usually reversible after discontinuation of the anesthetic.

F. Effects on Uterine Smooth Muscle Nitrous oxide appears to have little effect on uterine musculature. However, the halogenated anesthetics are potent uterine muscle relaxants and produce this effect in a concentration-dependent fashion. This pharmacologic effect can be helpful when profound uterine relaxation is required for intrauterine fetal manipulation or manual extraction of a retained placenta during delivery. However, it can also lead to increased uterine bleeding after delivery when uterine contraction is desired.

Toxicity of Anesthetic Agents A. Acute Toxicity Volatile anesthetics have a narrow therapeutic range and must be administered in a well-controlled, monitored setting by trained practitioners. When delivered in this way the risk of acute organ injury is low. The effects described below are rare or of historical interest only. However, concern over neurotoxicity of volatile anesthetics, especially in the developing brain is an active area of research. 1. Nephrotoxicity—Metabolism of enflurane and sevoflurane may generate compounds that are potentially nephrotoxic. Although their metabolism can liberate nephrotoxic fluoride ions, significant renal injury has been reported only for enflurane with prolonged exposure. The insolubility and rapid elimination of sevoflurane may prevent toxicity. This drug may be degraded by carbon dioxide absorbents in anesthesia machines to form a

CHAPTER 25  General Anesthetics    473

nephrotoxic vinyl ether compound termed “compound A,” which, in high concentrations, has caused proximal tubular necrosis in rats. Nevertheless, there have been no reports of renal injury in humans receiving sevoflurane anesthesia. Moreover, exposure to sevoflurane does not produce any change in standard markers of renal function. 2. Hematotoxicity—Prolonged exposure to nitrous oxide decreases methionine synthase activity, which theoretically could cause megaloblastic anemia. Megaloblastic bone marrow changes have been observed in patients after 12-hour exposure to 50% nitrous oxide. Chronic exposure of dental personnel to nitrous oxide in inadequately ventilated dental operating suites is a potential occupational hazard. All inhaled anesthetics can produce some carbon monoxide (CO) from their interaction with strong bases in dry carbon dioxide absorbers. CO binds to hemoglobin with high affinity, reducing oxygen delivery to tissues. Desflurane produces the most CO, and intraoperative formation of CO has been reported. CO production can be avoided simply by using fresh carbon dioxide absorbent and by preventing its complete desiccation. 3. Malignant hyperthermia—Malignant hyperthermia is a heritable genetic disorder of skeletal muscle that occurs in susceptible individuals exposed to volatile anesthetics while undergoing general anesthesia (see Chapter 16 and Table 16–4). The depolarizing muscle relaxant succinylcholine may also trigger malignant hyperthermia. The malignant hyperthermia syndrome consists of muscle rigidity, hyperthermia, rapid onset of tachycardia and hypercapnia, hyperkalemia, and metabolic acidosis following exposure to one or more triggering agents. Malignant hyperthermia is a rare but important cause of anesthetic morbidity and mortality. A specific biochemical abnormality—an increase in free cytosolic calcium concentration in skeletal muscle cells—may be the underlying cellular basis of malignant hyperthermia. Treatment includes administration of dantrolene (to reduce calcium release from the sarcoplasmic reticulum) and appropriate measures to reduce body temperature and restore electrolyte and acid-base balance (see Chapters 16 and 27). A new formulation of dantrolene with improved solubility has become available that can speed the treatment of this rare but potentially fatal reaction. Malignant hyperthermia susceptibility is characterized by genetic heterogeneity, and several predisposing clinical myopathies have been identified. It has been associated with mutations in the gene coding for the skeletal muscle ryanodine receptor (RyR1, the calcium release channel on the sarcoplasmic reticulum), and mutant alleles of the gene encoding the α1 subunit of the human skeletal muscle l-type voltage-dependent calcium channel. However, the genetic loci identified to date account for less than 50% of malignant hyperthermia-susceptible individuals, and genetic testing cannot definitively determine malignant hyperthermia susceptibility. Currently, the most reliable test to establish susceptibility is the in vitro caffeine-halothane contracture test using skeletal muscle biopsy samples. Genetic counseling is recommended for family members of a person who has experienced a documented malignant hyperthermia reaction in the operating room.

4. Hepatotoxicity (halothane hepatitis)—Hepatic dysfunction following surgery and general anesthesia is most likely caused by hypovolemic shock, infection conferred by blood transfusion, or other surgical stresses rather than by volatile anesthetic toxicity. However, a small subset of individuals previously exposed to halothane developed fulminant hepatic failure. The incidence of severe hepatotoxicity following exposure to halothane was estimated to be in the range of 1 in 20,000–35,000. The mechanisms underlying halothane hepatotoxicity remain unclear, but studies in animals implicate the formation of reactive metabolites that either cause direct hepatocellular damage (eg, free radicals) or initiate immune-mediated responses. Cases of hepatitis following exposure to other volatile anesthetics, including enflurane, isoflurane, and desflurane, have rarely been reported. 5. Neurotoxicity—Neuronal toxicity of volatile anesthesia in young infants whose brains are still undergoing neurogenesis is an emerging concern, first identified in animal studies. In vitro studies have also found increased levels of apoptosis in cultured neurons exposed to clinical levels of volatile anesthetics. Human data is difficult to obtain but a recently reported epidemiologic study that followed a cohort of children receiving either general anesthesia or nerve block anesthesia for hernia repair in the first 3 months of life found no difference in IQ testing at 5 years of age. The neurotoxicity of longer or multiple exposures to volatile anesthetics is unknown. B. Chronic Toxicity 1. Mutagenicity, teratogenicity, and reproductive effects—Under normal conditions, inhaled anesthetics including nitrous oxide are neither mutagens nor carcinogens in patients. Nitrous oxide can be directly teratogenic in animals under conditions of extremely high exposure. Halothane, enflurane, isoflurane, desflurane, and sevoflurane may be teratogenic in rodents as a result of physiologic changes associated with the anesthesia rather than through a direct teratogenic effect. The most consistent finding in surveys conducted to determine the reproductive success of female operating room personnel who may have low-level chronic exposure to anesthetic agents has been a questionably higher-than-expected incidence of miscarriages. However, there are several problems in interpreting these studies. The association of obstetric problems with surgery and anesthesia in pregnant patients is also an important consideration. In the United States, at least 50,000 pregnant women each year undergo anesthesia and surgery for indications unrelated to pregnancy. The risk of abortion is clearly higher following this experience. It is not obvious, however, whether the underlying disease, surgery, anesthesia, or a combination of these factors is the cause of the increased risk. 2. Carcinogenicity—Epidemiologic studies suggested an increase in the cancer rate in operating room personnel who were exposed to trace concentrations of anesthetic agents. However, no study has demonstrated the existence of a causal relationship between anesthetics and cancer. Many other factors might account for the questionably positive results seen after a careful review of

474    SECTION V  Drugs That Act in the Central Nervous System

epidemiologic data. Anesthesia machines are now equipped with gas scavenging systems to remove concentrations of anesthetics administered to patients, and operating rooms rely on high air exchange rates to remove trace concentrations of anesthetics released from anesthesia machines.

ENVIRONMENTAL IMPACT OF INHALED ANESTHETICS The primary inhalational anesthetics in clinical use, sevoflurane, isoflurane, desflurane, and nitrous oxide, are known to act as greenhouse gases but their contribution to global temperature rise and climate change are considered small compared with other industrial processes. In current practice these gases are administered to patients, exhaled with little metabolism, and then collected by anesthesia machine scavenging systems for venting out of the building directly into the atmosphere. By their intrinsic chemical nature these compounds are hundreds to thousands of times more potent than carbon dioxide (CO2) in their global warming potential. Moreover, each of these gases possess widely varying atmospheric lifetimes. For example, the tropospheric lifetime of sevoflurane, isoflurane, desflurane, and nitrous oxide are 1.4, 3.6, 10, and 114 years, respectively. The medical use of nitrous oxide for anesthesia has been estimated to represent 1–3% of the annual U.S. nitrous oxide emission. Because of this increased awareness, clinical guidelines for decreasing the amount of inhaled anesthetics used have been proposed. The current trend is to use the agents in ultra-low total gas flow techniques (0.5–1.0 liter per minute), to avoid adding nitrous oxide as a carrier admixture gas with room air, and to restrict the use of desflurane.

■■ INTRAVENOUS ANESTHETICS Intravenous nonopioid anesthetics play an essential role in the practice of modern anesthesia. They are used to facilitate rapid induction of anesthesia and have replaced inhalation as the preferred method of anesthesia induction in most settings except for pediatric anesthesia. Intravenous agents are also commonly used to provide sedation during monitored anesthesia care and for patients in ICU settings. With the introduction of propofol, intravenous anesthesia also became a good option for the maintenance of anesthesia. However, similar to the inhaled agents, the currently available intravenous anesthetics are not ideal anesthetic drugs in the sense of producing all and only the five desired effects (unconsciousness, amnesia, analgesia, inhibition of autonomic reflexes, and skeletal muscle relaxation). Therefore, balanced anesthesia employing multiple drugs (inhaled anesthetics, sedative-hypnotics, opioids, neuromuscular blocking drugs) is generally used to achieve the desired combination of effects while minimizing unwanted effects. The intravenous anesthetics used for induction of general anesthesia are lipophilic and preferentially partition into highly perfused lipophilic tissues (brain, spinal cord), which accounts for their rapid onset of action. Regardless of the extent and speed

of their metabolism, termination of the effect of a single bolus is determined by redistribution of the drug into less perfused and inactive tissues such as skeletal muscle and fat. Thus, all drugs used for induction of anesthesia have similar durations of action when administered as a single bolus dose despite significant differences in their metabolism. Figure 25–6 shows the chemical structures of common clinically used intravenous anesthetics. Table 25–2 lists pharmacokinetic properties of these and other intravenous agents.

PROPOFOL In most countries, propofol is the drug most frequently administered for the induction of anesthesia, and it has largely replaced barbiturates in this setting. Because its pharmacokinetic profile allows for continuous infusions, propofol is a good alternative to inhaled anesthetics for maintenance of anesthesia and is also a common choice for sedation in the setting of monitored anesthesia care. When used during maintenance of anesthesia, propofol infusion can be supplemented with intravenous opioids and neuromuscular blockers as needed to completely avoid the use of inhaled anesthetics (total intravenous anesthesia, TIVA). Alternatively, a propofol infusion might be used to reduce the required concentration of inhaled anesthetics so that undesired effects can be minimized. Increasingly, propofol is also used for sedation in the ICU as well as conscious sedation and short-duration general anesthesia in locations outside the operating room (eg, interventional radiology suites, emergency department; see Box: Sedation & Monitored Anesthesia Care, earlier). Propofol (2,6-diisopropylphenol) is an alkyl phenol with hypnotic properties that is chemically distinct from other groups of intravenous anesthetics (see Figure 25–6). Because of its poor solubility in water, it is formulated as an emulsion containing 10% soybean oil, 2.25% glycerol, and 1.2% lecithin, the major component of the egg yolk phosphatide fraction. Hence, susceptible patients may experience allergic reactions. The solution appears milky white and slightly viscous, has a pH of approximately 7, and has a propofol concentration of 1% (10 mg/mL). In some countries, a 2% formulation is available. Although retardants of bacterial growth are added to the formulations, solutions should be used as soon as possible (unused drug must be discarded 12 hours after opening the vial), and proper sterile technique is essential. The addition of metabisulfite in one of the formulations has raised concern regarding its use in patients with reactive airway disease (eg, asthma) or sulfite allergies. The presumed mechanism of action of propofol is through potentiation of the chloride current mediated through the GABAA receptor complex.

Pharmacokinetics Propofol is rapidly metabolized in the liver; the resulting watersoluble compounds are presumed to be inactive and are excreted through the kidneys. Plasma clearance is high and exceeds hepatic blood flow, indicating the importance of extrahepatic metabolism, which presumably occurs in the lungs and may account for

CHAPTER 25  General Anesthetics    475

H

O

N

CH3

N

C2H5

S

N CH

N H

O

CH2

CH2

CH3

CH3

N

Cl

Thiopental

F

N O C2H5OC

Midazolam

CH(CH3)2

N

OH

CHCH3

Cl

CH(CH3)2 Propofol HN O CH3

Etomidate

Ketamine

FIGURE 25–6 

Chemical structures of some intravenous anesthetics.

the elimination of up to 30% of a bolus dose of the drug (see Table 25–2). The recovery from propofol is more complete, with less “hangover” than that observed with thiopental, likely due to the high plasma clearance. However, as with other intravenous drugs, transfer of propofol from the plasma (central) compartment and the associated termination of drug effect after a single bolus dose are mainly the result of redistribution from highly perfused (brain) to less-well-perfused (skeletal muscle) compartments (Figure 25–7). As with other intravenous agents, awakening after an induction dose of propofol usually occurs within

8–10 minutes. The kinetics of propofol (and other intravenous anesthetics) after a single bolus dose or continuous infusion are best described by means of a three-compartment model. Such models have been used as the basis for developing systems of target-controlled infusions. The context-sensitive half-time of a drug describes the elimination half-time after discontinuation of a continuous infusion as a function of the duration of the infusion. It is an important parameter in assessing the suitability of a drug for use as maintenance anesthetic. The context-sensitive half-time of propofol

TABLE 25–2  Pharmacokinetic properties of intravenous anesthetics. Drug

Induction Dose (mg/kg IV)

Duration of Action (min)

Dexmedetomidine

NA

NA

Diazepam

0.3–0.6

15–30

Etomidate

0.2–0.3

3–8

Ketamine

1–2

5–10

Lorazepam

0.03–0.1

60–120

Methohexital

1–1.5

4–7

Midazolam

0.1–0.3

15–20

Propofol

1–2.5

Thiopental

3–5

Vdss (L/kg)

t½ Distribution (min)

Protein Binding (%)

CL (mL/kg/min)

t½ Elimination (h)

2–3

6

94

10–30

2–3

0.7–1.7

…

98

0.2–0.5

20–50

2.5–4.5

2–4

77

18–25

2.9–5.3

3.1

11–16

12

12–17

2–4

0.8–1.3

3–10

98

0.8–1.8

11–22

2.2

5–6

73

11

4

1.1–1.7

7–15

94

6.4–11

1.7–2.6

3–8

2–10

2–4

97

20–30

4–23

5–10

2.5

2–4

83

3.4

11

Note: The duration of action reflects the duration after a typical single IV dose given for induction of anesthesia. Data are for average adult patients. CL, clearance; NA, not applicable; Vdss, volume of distribution at steady state.

476    SECTION V  Drugs That Act in the Central Nervous System

oxygen (CMRO2), which decreases intracranial pressure (ICP) and intraocular pressure; the magnitude of these changes is comparable to that of thiopental. Although propofol can produce a desired decrease in ICP, the combination of reduced cerebral blood flow and reduced mean arterial pressure due to peripheral vasodilation can critically decrease cerebral perfusion pressure. When administered in large doses, propofol produces burst suppression in the EEG, an end point that has been used when administering intravenous anesthetics for neuroprotection during neurosurgical procedures. Evidence from animal studies suggests that propofol’s neuroprotective effects during focal ischemia are similar to those of thiopental and isoflurane.

100 Blood Lean tissues

Percent of dose

80 Brain and viscera

60 40

Fat

20 0

0.125

0.5 1

4

16

64

256

Time (min)

FIGURE 25–7  Redistribution of thiopental after an intravenous bolus administration. The redistribution curves for bolus administration of other intravenous anesthetics are similar, explaining the observation that recovery times are the same despite remarkable differences in metabolism. Note that the time axis is not linear. is brief, even after a prolonged infusion, and therefore, recovery occurs relatively promptly (Figure 25–8).

Organ System Effects

Context-sensitive half-time (min)

A. CNS Effects Propofol acts as hypnotic but does not have analgesic properties. Although the drug leads to a general suppression of CNS activity, excitatory effects such as twitching or spontaneous movement are occasionally observed during induction of anesthesia. These effects may resemble seizure activity; however, most studies support an anticonvulsant effect of propofol, and the drug may be safely administered to patients with seizure disorders. Propofol decreases cerebral blood flow and the cerebral metabolic rate for

150 Thiopental

100

Midazolam 50

Ketamine Propofol Etomidate

0 0

1

2

3

4

5

6

7

8

9

Infusion duration (h)

FIGURE 25–8  The context-sensitive half-time of common intravenous anesthetics. Even after a prolonged infusion, the half-time of propofol is relatively short, which makes propofol the preferred choice for intravenous maintenance of anesthesia. Ketamine and etomidate have similar characteristics, but their use is limited by other effects.

B. Cardiovascular Effects Compared with other induction drugs, propofol produces the most pronounced decrease in systemic blood pressure; this is a result of profound vasodilation in both arterial and venous circulations leading to reductions in preload and afterload. This effect on systemic blood pressure is more pronounced with increased age, in patients with reduced intravascular fluid volume, and with rapid injection. Because the hypotensive effects are further augmented by the inhibition of the normal baroreflex response, the vasodilation only leads to a small increase in heart rate. In fact, profound bradycardia and asystole after the administration of propofol have been described in healthy adults despite prophylactic anticholinergic drugs. C. Respiratory Effects Propofol is a potent respiratory depressant and generally produces apnea after an induction dose. A maintenance infusion reduces minute ventilation through reductions in tidal volume and respiratory rate, with the effect on tidal volume being more pronounced. In addition, the ventilatory response to hypoxia and hypercapnia is reduced. Propofol causes a greater reduction in upper airway reflexes than thiopental does, which makes it well suited for instrumentation of the airway, such as placement of a laryngeal mask airway. D. Other Effects Although propofol, unlike volatile anesthetics, does not augment neuromuscular block, studies have found good intubating conditions after propofol induction without the use of neuromuscular blocking agents. Unexpected tachycardia occurring during propofol anesthesia should prompt laboratory evaluation for possible metabolic acidosis (propofol infusion syndrome). An interesting and desirable side effect of propofol is its antiemetic activity. Pain on injection is a common complaint and can be reduced by premedication with an opioid or coadministration with lidocaine. Dilution of propofol and the use of larger veins for injection can also reduce the incidence and severity of injection pain.

Clinical Uses & Dosage The most common use of propofol is to facilitate induction of general anesthesia by bolus injection of 1–2.5 mg/kg IV. Increasing age, reduced cardiovascular reserve, or premedication with benzodiazepines or opioids reduces the required induction dose;

CHAPTER 25  General Anesthetics    477

children require higher doses (2.5–3.5 mg/kg IV). Generally, titration of the induction dose helps to prevent severe hemodynamic changes. Propofol is often used for maintenance of anesthesia either as part of a balanced anesthesia regimen in combination with volatile anesthetics, nitrous oxide, sedative-hypnotics, and opioids or as part of a total intravenous anesthetic technique, usually in combination with opioids. Therapeutic plasma concentrations for maintenance of anesthesia normally range between 3 and 8 mcg/mL (typically requiring a continuous infusion rate between 100 and 200 mcg/kg/min) when combined with nitrous oxide or opioids. In many countries (other than the United States), propofol is frequently administered utilizing target-controlled infusion (TCI). TCI uses pharmacokinetic models based on patient characteristics (height, weight, gender, and age) to control an infusion pump based on target plasma concentrations entered by the anesthesiologist. The models incorporate context-sensitive halftime and automatically set the infusion rate to reach or maintain the target concentration entered, thereby replacing the manual administration of the boluses and infusion estimated by the anesthesiologist. Data suggest that induction using TCI provides better hemodynamic stability. TCI is often combined with the use of the bispectral index (BIS) or other monitors of processed EEG signals. Pharmacologic models also exist for other drugs such as opioid analgesics and allow TCI application for multiple drugs. When used for sedation of mechanically ventilated patients in the ICU or for sedation during procedures, the required plasma concentration is 1–2 mcg/mL, which can be achieved with a continuous infusion at 25–75 mcg/kg/min. Because of its pronounced respiratory depressant effect and narrow therapeutic range, propofol should be administered only by individuals trained in airway management. Subanesthetic doses of propofol can be used to treat postoperative nausea and vomiting (10–20 mg IV as bolus or 10 mcg/kg/ min as an infusion).

FOSPROPOFOL As previously noted, injection pain during administration of propofol is often perceived as severe, and the lipid emulsion has several disadvantages. Intense research has focused on finding alternative formulations or related drugs that would address some of these problems. Fospropofol is a water-soluble prodrug of propofol, is rapidly metabolized by alkaline phosphatase, and produces propofol, phosphate, and formaldehyde. The formaldehyde is metabolized by aldehyde dehydrogenase in the liver and in erythrocytes. The available fospropofol formulation is a sterile, aqueous, colorless, and clear solution that is supplied in a single-dose vial at a concentration of 35 mg/mL under the trade name Lusedra.

Pharmacokinetics & Organ System Effects Because the active compound is propofol and fospropofol is a prodrug that requires metabolism to form propofol, the pharmacokinetics are more complex than for propofol itself. Multicompartment models with two compartments for fospropofol and three for propofol have been used to describe the kinetics.

The effect profile of fospropofol is similar to that of propofol, but onset and recovery are prolonged compared with propofol because the prodrug must first be converted into an active form. Although patients receiving fospropofol do not appear to experience the injection pain typical of propofol, a common adverse effect is the experience of paresthesia, often in the perianal region, which occurs in up to 74% of patients. The mechanism for this effect is unknown.

Clinical Uses & Dosage Fospropofol is approved for sedation during monitored anesthesia care. Supplemental oxygen must be administered to all patients receiving the drug. As with propofol, airway compromise is a major concern. Hence, it is recommended that fospropofol be administered only by personnel trained in airway management. The recommended standard dosage is an initial bolus dose of 6.5 mg/kg IV followed by supplemental doses of 1.6 mg/kg IV as needed. For patients weighing more than 90 kg or less than 60 kg, 90 or 60 kg should be used to calculate the dose, respectively. The dose should be reduced by 25% in patients older than 65 years and in those with an American Society of Anesthesiologists status of 3 or 4.

BARBITURATES This section focuses on the use of thiopental and methohexital for induction of general anesthesia; however, these barbiturate hypnotics have been largely replaced as induction agents by propofol. Other barbiturates and general barbiturate pharmacology are discussed in Chapter 22. The anesthetic effect of barbiturates presumably involves a combination of enhancement of inhibitory transmission and inhibition of excitatory neurotransmission (see Figure 25–1). Although the effects on inhibitory transmission probably result from activation of the GABAA receptor complex, the effects on excitatory transmission are less well understood.

Pharmacokinetics Thiopental and methohexital undergo hepatic metabolism, mostly by oxidation but also by N-dealkylation, desulfuration, and destruction of the barbituric acid ring structure. Barbiturates should not be administered to patients with acute intermittent porphyria because they increase the production of porphyrins through stimulation of aminolevulinic acid synthetase. Methohexital has a shorter elimination half-time than thiopental due to its larger plasma clearance (see Table 25–2), leading to a faster and more complete recovery after bolus injection. Although thiopental is metabolized more slowly and has a long elimination halftime, recovery after a single bolus injection is comparable to that of methohexital and propofol because it depends on redistribution to inactive tissue sites rather than on metabolism (Figure 25–7). However, if administered through repeated bolus injections or continuous infusion, recovery will be markedly prolonged because elimination will depend on metabolism under these circumstances (see also context-sensitive half-time, Figure 25–8).

478    SECTION V  Drugs That Act in the Central Nervous System

Organ System Effects A. CNS Effects Barbiturates produce dose-dependent CNS depression ranging from sedation to general anesthesia when administered as bolus injections. They do not produce analgesia; instead, some evidence suggests they may reduce the pain threshold, causing hyperalgesia. Barbiturates are potent cerebral vasoconstrictors and produce predictable decreases in cerebral blood flow, cerebral blood volume, and ICP. As a result, they decrease CMRO2 consumption in a dose-dependent manner up to a dose at which they suppress all EEG activity. The ability of barbiturates to decrease ICP and CMRO2 makes these drugs useful in the management of patients with space-occupying intracranial lesions. They may provide neuroprotection from focal cerebral ischemia (stroke, surgical retraction, temporary clips during aneurysm surgery), but likely will not reduce the injury after global cerebral ischemia (eg, from cardiac arrest). Except for methohexital, barbiturates decrease electrical activity on the EEG and can be used as anticonvulsants. In contrast, methohexital activates epileptic foci and may therefore be useful to facilitate electroconvulsive therapy or during the identification of epileptic foci during surgery. B. Cardiovascular Effects The decrease in systemic blood pressure associated with administration of barbiturates for induction of anesthesia is primarily due to peripheral vasodilation and is usually smaller than the blood pressure decrease associated with propofol. There are also direct negative inotropic effects on the heart. However, inhibition of the baroreceptor reflex is less pronounced than with propofol; thus, compensatory increases in heart rate limit the decrease in blood pressure and make it transient. The depressant effects on systemic blood pressure are increased in patients with hypovolemia, cardiac tamponade, cardiomyopathy, coronary artery disease, or cardiac valvular disease because such patients are less able to compensate for the effects of peripheral vasodilation. Hemodynamic effects are also more pronounced with larger doses and rapid injection. C. Respiratory Effects Barbiturates are respiratory depressants, and a usual induction dose of thiopental or methohexital typically produces transient apnea, which will be more pronounced if other respiratory depressants are also administered. Barbiturates lead to decreased minute ventilation through reduced tidal volumes and respiratory rate and also decrease the ventilatory responses to hypercapnia and hypoxia. Resumption of spontaneous breathing after an anesthetic induction dose of a barbiturate is characterized by a slow breathing rate and decreased tidal volume. Suppression of laryngeal reflexes and cough reflexes is probably not as profound as after an equianesthetic propofol administration, which makes barbiturates an inferior choice for airway instrumentation in the absence of neuromuscular blocking drugs. Furthermore, stimulation of the upper airway or trachea (eg, by secretions, laryngeal mask airway, direct laryngoscopy, tracheal intubation) during inadequate depression of airway reflexes may result in laryngospasm or bronchospasm. This phenomenon is not unique to barbiturates but is true whenever the dose of the anesthetic drug is inadequate to suppress the airway reflexes.

D. Other Effects Accidental intra-arterial injection of barbiturates results in excruciating pain and intense vasoconstriction, often leading to severe tissue injury involving gangrene. Approaches to treatment include blockade of the sympathetic nervous system (eg, stellate ganglion block) in the involved extremity. If extravasation occurs, some authorities recommend local injection of the area with 0.5% lidocaine (5–10 mL) in an attempt to dilute the barbiturate concentration. Life-threatening allergic reactions to barbiturates are rare, with an estimated occurrence of 1 in 30,000 patients. However, barbiturate-induced histamine release occasionally is seen.

Clinical Uses & Dosage The principal clinical use of thiopental (3–5 mg/kg IV) or methohexital (1–1.5 mg/kg IV) is for induction of anesthesia (unconsciousness), which usually occurs in less than 30 seconds. Patients may experience a garlic or onion taste after administration. Solutions of thiopental sodium for intravenous injection have a pH range of 10–11 to maintain stability. Rapid co-injection with depolarizing and nondepolarizing muscle relaxants, which have much lower pH, may cause precipitation of insoluble thiopentone acid. Barbiturates such as methohexital (20–30 mg/kg) may be administered per rectum to facilitate induction of anesthesia in mentally challenged patients and uncooperative pediatric patients. When a barbiturate is administered with the goal of neuroprotection, an isoelectric EEG indicating maximal reduction of CMRO2 has traditionally been used as the end point. More recent data demonstrating equal protection after smaller doses have challenged this practice. The use of smaller doses is less frequently associated with hypotension, thus making it easier to maintain adequate cerebral perfusion pressure, especially in the setting of increased ICP.

BENZODIAZEPINES Benzodiazepines commonly used in the perioperative period include midazolam, lorazepam, and less frequently, diazepam. Benzodiazepines are unique among the group of intravenous anesthetics in that their action can readily be terminated by administration of their selective antagonist, flumazenil. Their most desired effects are anxiolysis and anterograde amnesia, which are extremely useful for premedication. The chemical structure and pharmacodynamics of the benzodiazepines are discussed in detail in Chapter 22.

Pharmacokinetics in the Anesthesia Setting The highly lipid-soluble benzodiazepines rapidly enter the CNS, which accounts for their rapid onset of action, followed by redistribution to inactive tissue sites and subsequent termination of the drug effect. Additional information regarding the pharmacokinetics of the benzodiazepines may be found in Chapter 22. Despite its prompt passage into the brain, midazolam is considered to have a slower effect-site equilibration time than propofol

CHAPTER 25  General Anesthetics    479

and thiopental. In this regard, intravenous doses of midazolam should be sufficiently spaced to permit the peak clinical effect to be recognized before a repeat dose is considered. Midazolam has the shortest context-sensitive half-time, which makes it the only one of the three benzodiazepine drugs suitable for continuous infusion (see Figure 25–8).

Organ System Effects A. CNS Effects Benzodiazepines decrease CMRO2 and cerebral blood flow but to a smaller extent than propofol or the barbiturates. There appears to be a ceiling effect for benzodiazepine-induced decreases in CMRO2 as evidenced by midazolam’s inability to produce an isoelectric EEG. Patients with decreased intracranial compliance demonstrate little or no change in ICP after the administration of midazolam. Although neuroprotective properties have not been shown for benzodiazepines, these drugs are potent anticonvulsants used in the treatment of status epilepticus, alcohol withdrawal, and local anesthetic-induced seizures. The CNS effects of benzodiazepines can be promptly terminated by administration of the selective benzodiazepine antagonist flumazenil, which improves their safety profile. B. Cardiovascular Effects If used for the induction of anesthesia, midazolam produces a greater decrease in systemic blood pressure than comparable doses of diazepam. These changes are most likely due to peripheral vasodilation inasmuch as cardiac output is not changed. Similar to other intravenous induction agents, midazolam’s effect on systemic blood pressure is exaggerated in hypovolemic patients. C. Respiratory Effects Benzodiazepines alone produce minimal depression of ventilation, although transient apnea may follow rapid intravenous administration of midazolam for induction of anesthesia, especially in the presence of opioid premedication. Benzodiazepines decrease the ventilatory response to carbon dioxide, but this effect is not usually significant if they are administered alone. More severe respiratory depression can occur when benzodiazepines are administered together with opioids. Another problem affecting ventilation is airway obstruction induced by the hypnotic effects of benzodiazepines, especially in patients at risk for obstructive sleep apnea. D. Other Effects Pain during intravenous and intramuscular injection and subsequent thrombophlebitis are most pronounced with diazepam and reflect the poor water solubility of this benzodiazepine, which requires an organic solvent in the formulation. Despite its better solubility, eliminating the need for an organic solvent, midazolam may also produce pain on injection. Allergic reactions to benzodiazepines are rare to nonexistent.

Clinical Uses & Dosage Benzodiazepines are most commonly used for preoperative medication, intravenous sedation, and suppression of seizure activity.

Less frequently, midazolam and diazepam may also be used to induce general anesthesia. The slow onset and prolonged duration of action of lorazepam limit its usefulness as preoperative medication or for induction of anesthesia, especially when rapid and sustained awakening at the end of surgery is desirable. Although flumazenil (8–15 mcg/kg IV) may be useful for treating patients experiencing delayed awakening, its duration of action is brief (about 20 minutes) and resedation may occur. The amnestic, anxiolytic, and sedative effects of benzodiazepines make this class of drugs the most popular choice for preoperative medication. Midazolam (1–2 mg IV) is effective for premedication, sedation during regional anesthesia, and brief therapeutic procedures. Midazolam has a more rapid onset, with greater amnesia and less postoperative sedation, than diazepam. Midazolam is also the most commonly used oral premedication for children; 0.5 mg/kg administered orally 30 minutes before induction of anesthesia provides reliable sedation and anxiolysis in children without producing delayed awakening. The synergistic effects between benzodiazepines and other drugs, especially opioids and propofol, can be used to achieve better sedation and analgesia but may also greatly enhance their combined respiratory depression and may lead to airway obstruction or apnea. Because benzodiazepine effects are more pronounced with increasing age, dose reduction and careful titration may be necessary in elderly patients. General anesthesia can be induced by the administration of midazolam (0.1–0.3 mg/kg IV), but the onset of unconsciousness is slower than after the administration of thiopental, propofol, or etomidate. Delayed awakening is a potential disadvantage, limiting the usefulness of benzodiazepines for induction of general anesthesia despite their advantage of less pronounced circulatory effects.

ETOMIDATE Etomidate (see Figure 25–6) is an intravenous anesthetic with hypnotic but not analgesic effects and is often chosen for its minimal hemodynamic effects. Although its pharmacokinetics are favorable, endocrine side effects limit its use for continuous infusions. Etomidate is a carboxylated imidazole derivative that is poorly soluble in water and is therefore supplied as a 2 mg/mL solution in 35% propylene glycol. The solution has a pH of 6.9 and does not cause problems with precipitation as thiopental does. Etomidate appears to have GABA-like effects and seems to act primarily through potentiation of GABAA-mediated chloride current, like most other intravenous anesthetics.

Pharmacokinetics An induction dose of etomidate produces rapid onset of anesthesia, and recovery depends on redistribution to inactive tissue sites, comparable to thiopental and propofol. Metabolism is primarily by ester hydrolysis to inactive metabolites, which are then excreted in urine (78%) and bile (22%). Less than 3% of an administered dose of etomidate is excreted as unchanged drug in urine. Clearance of etomidate is about five times that of thiopental, as reflected

480    SECTION V  Drugs That Act in the Central Nervous System

by a shorter elimination half-time (see Table  25–2). The duration of action is linearly related to the dose, with each 0.1 mg/ kg providing about 100 seconds of unconsciousness. Because of etomidate’s minimal effects on hemodynamics and short contextsensitive half-time, larger doses, repeated boluses, or continuous infusions can safely be administered. Etomidate, like most other intravenous anesthetics, is highly protein bound (77%), primarily to albumin.

Organ System Effects A. CNS Effects Etomidate is a potent cerebral vasoconstrictor, as reflected by decreases in cerebral blood flow and ICP. These effects are similar to those produced by comparable doses of thiopental. Despite its reduction of CMRO2, etomidate has failed to show neuroprotective properties in animal studies, and human studies are lacking. The frequency of excitatory spikes on the EEG after the administration of etomidate is greater than with thiopental. Similar to methohexital, etomidate may activate seizure foci, manifested as fast activity on the EEG, making it a useful drug in the setting of electroconvulsive therapy. In addition, spontaneous movements characterized as myoclonus occur in more than 50% of patients receiving etomidate, and this myoclonic activity may be associated with seizure-like activity on the EEG. B. Cardiovascular Effects A characteristic and desired feature of induction of anesthesia with etomidate is cardiovascular stability after bolus injection. In this regard, decrease in systemic blood pressure is modest or absent and principally reflects a decrease in systemic vascular resistance. Therefore, the systemic blood pressure–lowering effects of etomidate are probably exaggerated in the presence of hypovolemia, and the patient’s intravascular fluid volume status should be optimized before induction of anesthesia. Etomidate produces minimal changes in heart rate and cardiac output. Its depressant effects on myocardial contractility are minimal at concentrations used for induction of anesthesia. C. Respiratory Effects The depressant effects of etomidate on ventilation are less pronounced than those of barbiturates, although apnea may occasionally follow rapid intravenous injection of the drug. Depression of ventilation may be exaggerated when etomidate is combined with inhaled anesthetics or opioids. D. Endocrine Effects Etomidate causes adrenocortical suppression by producing a dosedependent inhibition of 11β-hydroxylase, an enzyme necessary for the conversion of cholesterol to cortisol (see Figure 39–1). This suppression lasts 4–8 hours after an induction dose of the drug. Despite concerns regarding this finding, no outcome studies have demonstrated an adverse effect when etomidate is given in a bolus dose. However, because of its endocrine effects, etomidate is not used as continuous infusion.

Clinical Uses & Dosage Etomidate is an alternative to propofol and barbiturates for the rapid intravenous induction of anesthesia, especially in patients with compromised myocardial contractility. After a standard induction dose (0.2–0.3 mg/kg IV), the onset of unconsciousness is comparable to that achieved by thiopental and propofol. Similar to propofol, during intravenous injection of etomidate, there is a high incidence of pain, which may be followed by venous irritation. Involuntary myoclonic movements are also common but may be masked by the concomitant administration of neuromuscular blocking drugs. Awakening after a single intravenous dose of etomidate is rapid, with little evidence of any residual depressant effects. Etomidate does not produce analgesia, and postoperative nausea and vomiting may be more common than after the administration of thiopental or propofol.

KETAMINE Ketamine (see Figure 25–6) is a partially water-soluble and highly lipid-soluble phencyclidine derivative differing from most other intravenous anesthetics in that it produces significant analgesia. The characteristic state observed after an induction dose of ketamine is known as “dissociative anesthesia,” a cataleptic state wherein the patient’s eyes often remain open with a slow nystagmic gaze. Of the two stereoisomers, the S(+) form is more potent than the R(−) isomer, but only the racemic mixture of ketamine is available as an injection drug in the USA. A formulation of S(+) ketamine (Esketamine) for intranasal administration was recently approved by the FDA for the treatment of acute depression (see Chapter 30). Ketamine’s mechanism of action is complex, but the major effect is probably produced through inhibition of the NMDA receptor complex.

Pharmacokinetics The high lipid solubility of ketamine ensures a rapid onset of its effect. As with other intravenous induction drugs, the effect of a single bolus injection is terminated by redistribution to inactive tissue sites. Metabolism occurs primarily in the liver and involves N-demethylation by the cytochrome P450 system. Norketamine, the primary active metabolite, is less potent (one third to one fifth the potency of ketamine) and is subsequently hydroxylated and conjugated into water-soluble inactive metabolites that are excreted in urine. Ketamine is the only intravenous anesthetic that has low protein binding (see Table 25–2).

Organ System Effects If ketamine is administered as the sole anesthetic, amnesia is not as complete as with the other intravenous anesthetics. Reflexes are often preserved, but it cannot be assumed that patients are able to protect the upper airway. The eyes remain open and the pupils are moderately dilated with a nystagmic gaze. Frequently, lacrimation and salivation are increased, and premedication with an anticholinergic drug may be indicated to limit this effect.

CHAPTER 25  General Anesthetics    481

A. CNS Effects In contrast to other intravenous anesthetics, ketamine is considered to be a cerebral vasodilator that increases cerebral blood flow, as well as CMRO2. For these reasons, ketamine has traditionally not been recommended for use in patients with intracranial pathology, especially increased ICP. Nevertheless, these perceived undesirable effects on cerebral blood flow may be blunted by the maintenance of normocapnia. Despite the potential to produce myoclonic activity, ketamine is considered an anticonvulsant and may be recommended for treatment of status epilepticus when more conventional drugs are ineffective. Unpleasant emergence reactions after administration are the main factor limiting ketamine’s use. Such reactions may include vivid colorful dreams, hallucinations, out-of-body experiences, and increased and distorted visual, tactile, and auditory sensitivity. These reactions can be associated with fear and confusion, but a euphoric state may also be induced, which explains the potential for abuse of the drug. Children usually have a lower incidence of and less severe emergence reactions. Combination with a benzodiazepine may be indicated to limit the unpleasant emergence reactions and also increase amnesia. B. Cardiovascular Effects Ketamine can produce transient but significant increases in systemic blood pressure, heart rate, and cardiac output, presumably by centrally mediated sympathetic stimulation. These effects, which are associated with increased cardiac workload and myocardial oxygen consumption, are not always desirable and can be blunted by coadministration of benzodiazepines, opioids, or inhaled anesthetics. Although the mechanism is more controversial, ketamine is also considered to be a direct myocardial depressant. This property is usually masked by the stimulation of the sympathetic nervous system but may become apparent in critically ill patients with limited ability to increase their sympathetic nervous system activity. C. Respiratory Effects Ketamine is not thought to produce significant respiratory depression. When it is used as a single drug, the respiratory response to hypercapnia is preserved and blood gases remain stable. Transient hypoventilation and, in rare cases, a short period of apnea can follow rapid administration of a large intravenous dose for induction of anesthesia. The ability to protect the upper airway in the presence of ketamine cannot be assumed despite the presence of active airway reflexes. Especially in children, the risk for laryngospasm due to increased salivation must be considered; this risk can be reduced by premedication with an anticholinergic drug. Ketamine relaxes bronchial smooth muscle and may be helpful in patients with reactive airways and in the management of patients experiencing bronchoconstriction.

many cases despite the unpleasant psychomimetic effects. Moreover, ketamine can be administered by multiple routes (intravenous, intramuscular, oral, rectal, epidural), thus making it a useful option for premedication in mentally challenged and uncooperative pediatric patients. Induction of anesthesia can be achieved with ketamine, 1–2 mg/kg intravenously or 4–6 mg/kg intramuscularly. Although the drug is not commonly used for maintenance of anesthesia, its short context-sensitive half-time makes ketamine a candidate for this purpose. For example, general anesthesia can be achieved with the infusion of ketamine, 15–45 mcg/kg/min, plus 50–70% nitrous oxide or by ketamine alone, 30–90 mcg/kg/min. Small bolus doses of ketamine (0.2–0.8 mg/kg IV) may be useful during regional anesthesia when additional analgesia is needed (eg, cesarean delivery under neuraxial anesthesia with an insufficient regional block). Ketamine provides effective analgesia without compromise of the airway. An infusion of a subanalgesic dose of ketamine (3–5 mcg/kg/min) during general anesthesia and in the early postoperative period may be useful to augment opioid analgesia and reduce opioid tolerance and opioid-induced hyperalgesia. The use of ketamine has always been limited by its unpleasant psychotomimetic side effects, but its unique features make it a very valuable alternative in certain settings, mostly because of the potent analgesia with minimal respiratory depression. Most recently, it has become popular as an adjunct administered at subanalgesic doses to limit or reverse opioid tolerance, especially in patients with chronic pain.

DEXMEDETOMIDINE Dexmedetomidine is a highly selective α2-adrenergic agonist. Recognition of the usefulness of α2 agonists is based on observations of decreased anesthetic requirements in patients receiving chronic clonidine therapy. The effects of dexmedetomidine can be antagonized with α2-antagonist drugs. Dexmedetomidine is the active S-enantiomer of medetomidine, a highly selective α2-adrenergic agonist imidazole derivative that is used in veterinary medicine. Dexmedetomidine is water soluble and available as a parenteral formulation.

Pharmacokinetics Dexmedetomidine undergoes rapid hepatic metabolism involving N-methylation and hydroxylation, followed by conjugation. Metabolites are excreted in the urine and bile. Clearance is high, and the elimination half-time is short (see Table 25–2). However, there is a significant increase in the context-sensitive half-time from 4 minutes after a 10-minute infusion to 250 minutes after an 8-hour infusion.

Clinical Uses & Dosage

Organ System Effects

Its unique properties, including profound analgesia, stimulation of the sympathetic nervous system, bronchodilation, and minimal respiratory depression, make ketamine an important alternative to the other intravenous anesthetics and a desirable adjunct in

A. CNS Effects Dexmedetomidine produces its selective α2-agonist effects through activation of CNS α2 receptors. Hypnosis presumably results from stimulation of α2 receptors in the locus coeruleus, and

482    SECTION V  Drugs That Act in the Central Nervous System

the analgesic effect originates at the level of the spinal cord. The sedative effect produced by dexmedetomidine has a different quality than that produced by other intravenous anesthetics in that it more completely resembles a physiologic sleep state through activation of endogenous sleep pathways. Dexmedetomidine is likely to be associated with a decrease in cerebral blood flow without significant changes in ICP and CMRO2. It has the potential to lead to the development of tolerance and dependence. B. Cardiovascular Effects Dexmedetomidine infusion results in moderate decreases in heart rate and systemic vascular resistance and, consequently, a decrease in systemic blood pressure. A bolus injection may produce a transient increase in systemic blood pressure and pronounced decrease in heart rate, an effect that is probably mediated through activation of peripheral α2 adrenoceptors. Bradycardia associated with dexmedetomidine infusion may require treatment. Heart block, severe bradycardia, and asystole have been observed and may result from unopposed vagal stimulation. The response to anticholinergic drugs is unchanged. C. Respiratory Effects The effects of dexmedetomidine on the respiratory system are a small to moderate decrease in tidal volume and very little change in the respiratory rate. The ventilatory response to carbon dioxide is unchanged. Although the respiratory effects are mild, upper airway obstruction as a result of sedation is possible. In addition, dexmedetomidine has a synergistic sedative effect when combined with other sedative-hypnotics.

In addition to their use as part of a balanced anesthesia regimen, opioids in large doses have been used in combination with large doses of benzodiazepines to achieve a general anesthetic state, particularly in patients with limited circulatory reserve who undergo cardiac surgery. When administered in large doses, potent opioids such as fentanyl can induce chest wall (and laryngeal) rigidity, thereby acutely impairing mechanical ventilation. Furthermore, large doses of potent opioids may speed up the development of tolerance and complicate postoperative pain management.

CURRENT CLINICAL PRACTICE The practice of clinical anesthesia requires integrating the pharmacology and the known adverse effects of these potent drugs with the pathophysiologic state of individual patients. Every case tests the ability of the anesthesiologist to produce the depth of anesthesia required to allow invasive surgery to proceed and to achieve this safely despite frequent major medical problems.

AWARENESS DURING ANESTHESIA As described in this chapter inhalational and intravenous agents are used alone and in combination to induce the depression of central nervous system function that allows patients to undergo painful procedures. The job of the anesthesiologist is to gauge the intensity of the noxious stimulus and deliver the appropriate amount and combination of agents to render the patient unaware of stimulus. During light and even deep sedation it is not uncommon for patients to have some memory of events.

Clinical Uses & Dosage Dexmedetomidine is principally used for the short-term sedation of intubated and ventilated patients in an ICU setting. In the operating room, dexmedetomidine may be used as an adjunct to general anesthesia or to provide sedation, eg, during awake fiberoptic tracheal intubation or regional anesthesia. When administered during general anesthesia, dexmedetomidine (0.5–1 mcg/kg loading dose over 10–15 minutes, followed by an infusion of 0.2–0.7 mcg/kg/h) decreases the dose requirements for inhaled and injected anesthetics. Awakening and the transition to the postoperative setting may benefit from dexmedetomidine-produced sedative and analgesic effects without respiratory depression.

P R E P A R A T I* O N S A V A I L A B L E GENERIC NAME Desflurane Dexmedetomidine Diazepam Droperidol Enflurane Etomidate Fospropofol Halothane Isoflurane Ketamine Lorazepam Methohexital Midazolam Nitrous oxide (gas, supplied in blue cylinders) Propofol Sevoflurane Thiopental

OPIOID ANALGESICS IN ANESTHESIA Opioids are analgesic agents and are distinct from general anesthetics and hypnotics. Even when high doses of opioid analgesics are administered, recall cannot be prevented reliably unless hypnotic agents such as benzodiazepines are also used. Opioid analgesics are routinely used to achieve postoperative analgesia and intraoperatively as part of a balanced anesthesia regimen as described earlier (see Intravenous Anesthetics). Their pharmacology and clinical use are described in greater detail in Chapter 31.

*

AVAILABLE AS Suprane Precedex Generic, Valium Generic, Inapsine Enflurane, Ethrane Generic, Amidate Lusedra Generic, Fluothane Generic, Forane, Terrell Generic, Ketalar Generic, Ativan Generic, Brevital Generic, Versed Generic Generic, Diprivan Generic, Ultane Pentothal

See Chapter 31 for names of opioid agents used in anesthesia.

CHAPTER 25  General Anesthetics    483

REFERENCES Allaert SE et al: First trimester anesthesia exposure and fetal outcome. A review. Acta Anaesthesiol Belg 2007;58:119. Eger EI II: Uptake and distribution. In: Miller RD (editor): Anesthesia, 8th ed. Churchill Livingstone, 2015. Fraga M et al: The effects of isoflurane and desflurane on intracranial pressure, cerebral perfusion and cerebral arteriovenous oxygen content difference in normocapnic patients with supratentorial brain tumors. Anesthesiology 2003;98:1085. Fragen RJ: Drug Infusions in Anesthesiology. Lippincott Williams & Wilkins, 2005. Hirshey Dirksen SJ et al: Future directions in malignant hyperthermia research and patient care. Anesth Analg 2011;113:1108. Mashour GA: Top-down mechanisms of anesthetic-induced unconsciousness. Front Syst Neurosci 2014;8:1. O’Leary JD, Orser BA: Neurodevelopment after general anaesthesia in infants. Lancet 2019;393:614.

Olkkola KT, Ahonen J: Midazolam and other benzodiazepines. Handb Exp Pharmacol 2008;182:335. Reves JG et al: Intravenous anesthetics. In: Miller RD (editor): Anesthesia, 7th ed. Churchill Livingstone, 2010. Ryan SM, Nielsen CJ: Global warming potential of inhaled anesthetics: Application to clinical use. Anesth Analg 2010;111:92. Rudolph U et al: Sedatives, anxiolytics, and amnestics. In: Evers AS, Maze M (editors): Anesthetic Pharmacology: Physiologic Principles and Clinical Practice. Churchill Livingstone, 2004. Stoelting R, Hillier S: Barbiturates. In: Stoelting RK, Hillier SC (editors): Pharmacology and Physiology in Anesthetic Practice. Lippincott Williams & Wilkins, 2005. Struys MMR et al: The history of target-controlled infusion. Anesth Analg 2016;122:56.

C ASE STUDY ANSWER This patient presents with significant underlying cardiac risk and is scheduled to undergo major stressful surgery. Balanced anesthesia would begin with intravenous agents that cause minimal changes in blood pressure and heart rate such as a lowered dose of propofol or etomidate, combined with potent analgesics such as fentanyl (see Chapter 31) to block undesirable stimulation of autonomic reflexes. Maintenance of anesthesia could incorporate inhaled anesthetics that ensure unconsciousness and amnesia, additional intravenous agents to provide intraoperative and postoperative analgesia, and, if needed, neuromuscular blocking drugs (see Chapter 27) to induce muscle relaxation. The choice

of inhaled agent(s) would be made based on the desire to maintain sufficient myocardial contractility, systemic blood pressure, and cardiac output for adequate perfusion of critical organs throughout the operation. If the patient’s ischemic pain has been chronic and severe, a low-dose ketamine infusion may be administered for additional pain control. Rapid emergence from the combined effects of the chosen anesthetic drugs, which would facilitate the patient’s return to a baseline state of heart function, breathing, and mentation, can be attained by understanding the known pharmacokinetic properties of the anesthetic agents as presented in this chapter.

26 C

H

A

P

T

E

R

Local Anesthetics Mohab M. Ibrahim, MD, PhD, & Tally M. Largent-Milnes, PhD

C ASE STUDY A 67-year-old woman is scheduled for elective total knee arthroplasty. What local anesthetic agents would be most appropriate if surgical anesthesia were to be administered using a spinal or an epidural technique, and what potential

Simply stated, local anesthesia refers to loss of sensation in a limited region of the body. This is accomplished by disruption of afferent neural traffic via inhibition of impulse generation or propagation. Such blockade may bring with it other physiologic changes such as muscle paralysis and suppression of somatic or visceral reflexes, and these effects might be desirable or undesirable depending on the particular circumstances. Nonetheless, in most cases, it is the loss of sensation, or at least the achievement of localized analgesia, that is the primary goal. Although local anesthetics are often used as analgesics, it is their ability to provide complete loss of all sensory modalities that is their distinguishing characteristic. The contrast with general anesthesia should be obvious, but it is perhaps worthwhile to emphasize that with local anesthesia the drug is delivered directly to the target organ, and the systemic circulation serves only to diminish or terminate its effect. Local anesthesia can also be produced by various chemical or physical means. However, in routine clinical practice, it is achieved with a rather narrow spectrum of compounds, and recovery is normally spontaneous, predictable, and without residual effects. The development of these compounds has a rich history (see Box: Historical Development of Local Anesthesia), punctuated by serendipitous observations, delayed starts, and an evolution driven more by concerns for safety than improvements in efficacy.

484

complications might arise from their use? What anesthetics would be most appropriate for providing postoperative analgesia via an indwelling epidural or peripheral nerve catheter?

■■ BASIC PHARMACOLOGY OF LOCAL ANESTHETICS Chemistry Most local anesthetic agents consist of a lipophilic group (eg, an aromatic ring) connected by an intermediate chain via an ester or amide to an ionizable group (eg, a tertiary amine) (Table 26–1). In addition to the general physical properties of the molecules, specific stereochemical configurations are associated with differences in the potency of stereoisomers (eg, levobupivacaine, ropivacaine). Because ester links are more prone to hydrolysis than amide links, esters usually have a shorter duration of action. Local anesthetics are weak bases and are usually made available clinically as salts to increase solubility and stability. In the body, they exist either as the uncharged base or as a cation (see Chapter 1, section Ionization of Weak Acids and Weak Bases). The relative proportions of these two forms are governed by their pKa and the pH of the body fluids according to the Henderson-Hasselbalch equation, which can be expressed as: pKa = pH – log [base]/[conjugate acid]

If the concentration of base and conjugate acid are equal, the second portion of the right side of the equation drops out, as log 1 = 0, leaving: pKa = pH (when base concentration = conjugate acid concentration)

CHAPTER 26  Local Anesthetics    485

TABLE 26–1  Structure and properties of some ester and amide local anesthetics.1  

Structure

Potency (Procaine = 1)

Duration of Action

2

Medium

1

Short

16

Long

Surface use only

 

4

Medium

2

Medium

16

Long

16

Long

nf2

Medium

Esters Cocaine

O

CH3

O

N

C

CH3

O C

O

Procaine (Novocain)

O C

H2N

C2H5 O

CH2

CH2

N C2H5

Tetracaine (Pontocaine)

O

CH3

C

HN

O

CH2

CH2

N CH3

C4H9

Benzocaine

O C

H2N

O

CH2

CH3

Amides Lidocaine (Xylocaine)

CH3 O NH

C

C2H5 CH2

N C2H5

CH3

Mepivacaine (Carbocaine, Isocaine)

CH3 O NH

C N

CH3

Bupivacaine (Marcaine), Levobupivacaine (Chirocaine)

CH3

CH3 O NH

C N

CH3

Ropivacaine (Naropin)

C4H9

CH3 O NH

C N

CH3

Articaine

CH3 NH S

1

C3H7 O

CH3

C

CH

NH

C3H7

O C

OCH

Other chemical types are available including ethers (pramoxine), ketones (dyclonine), and phenetidine derivatives (phenacaine).

2

Data not found.

486    SECTION V  Drugs That Act in the Central Nervous System

Historical Development of Local Anesthesia Although the numbing properties of cocaine were recognized for centuries, one might consider September 15, 1884, to mark the “birth of local anesthesia.” Based on work performed by Carl Koller, cocaine’s numbing effect on the cornea was demonstrated before the Ophthalmological Congress in Heidelberg, ushering in the era of surgical local anesthesia. Unfortunately, with widespread use came recognition of cocaine’s significant central nervous system (CNS) and cardiac toxicity, which along with its addiction potential, tempered enthusiasm for this application. As the early investigator Mattison commented, “the risk of untoward results have robbed this peerless drug of much favor in the minds of many surgeons, and so deprived them of a most valued ally.” As cocaine was known to be a benzoic acid ester, the search for alternative local anesthetics focused on this class of compounds, resulting in the identification of benzocaine shortly before the turn of the last century. However, benzocaine proved to have limited utility due to its marked hydrophobicity, and was thus relegated to topical anesthesia, a use for which it still finds limited application in current clinical practice. The first useful injectable local anesthetic, procaine, was introduced shortly thereafter by Einhorn, and its structure has served as the template for the development of the most commonly used modern local anesthetics. The three basic structural elements of these compounds can be appreciated by review of Table 26–1: an aromatic ring, conferring lipophilicity; an ionizable tertiary amine, conferring hydrophilicity; and an intermediate chain connecting these via an ester or amide linkage. One of procaine’s limitations was its short duration of action, a drawback overcome with the introduction of tetracaine in 1928. Unfortunately, tetracaine demonstrated significant toxicity when employed for high-volume peripheral blocks, ultimately reducing its common usage to spinal anesthesia. Both procaine and tetracaine shared another drawback: their ester linkage

Thus, pKa can be seen as an effective way to consider the tendency for compounds to exist in a charged or uncharged form, ie, the lower the pKa, the greater the percentage of uncharged weak bases at a given pH. Because the pKa of most local anesthetics is in the range of 7.5–9.0, the charged, cationic form will constitute the larger percentage at physiologic pH. A glaring exception is benzocaine, which has a pKa around 3.5, and thus exists solely as the nonionized base under normal physiologic conditions. This issue of ionization is of critical importance because the cationic form is the most active at the receptor site. However, the story is a bit more complex, because the receptor site for local anesthetics is at the inner vestibule of the sodium channel, and the charged form of the anesthetic penetrates biologic membranes poorly. Thus, the uncharged form is important for cell penetration. After penetration into the cytoplasm, equilibration leads to formation and binding of the charged cation at the sodium channel, and hence the production of a clinical effect (Figure 26–1). Drug may also reach the receptor laterally through what has been

conferred instability, and particularly in the case of procaine, the free aromatic acid released during ester hydrolysis of the parent compound was believed to be the source of relatively frequent allergic reactions. Löfgren and Lundqvist circumvented the problem of instability with the introduction of lidocaine in 1948. Lidocaine was the first in a series of amino-amide local anesthetics that would come to dominate the second half of the 20th century. Lidocaine had a longer (and more favorable) duration of action than procaine, and less systemic toxicity than tetracaine. To this day, it remains one of the most versatile and widely used anesthetics. Nonetheless, some applications required more prolonged block than that afforded by lidocaine, a pharmacologic void that was filled with the introduction of bupivacaine, a more lipophilic and more potent anesthetic. Unfortunately, bupivacaine was found to have greater propensity for significant effects on cardiac conduction and function, which at times proved lethal. Recognition of this potential for cardiac toxicity led to changes in anesthetic practice, and significant toxicity became sufficiently rare for it to remain a widely used anesthetic for nearly every regional technique in modern clinical practice. Nonetheless, this inherent cardiotoxicity would drive developmental work leading to the introduction of two additions to the anesthetic armamentarium, levobupivacaine and ropivacaine. The former is the S(–) enantiomer of bupivacaine, which has less affinity for cardiac sodium channels than its R(+) counterpart. Ropivacaine, another S(–) enantiomer, shares this reduced affinity for cardiac sodium channels, while being slightly less potent than bupivacaine or levobupivacaine. However, despite the reduced channel affinity, a recent advisory panel of the American Society of Regional Anesthesia concluded that in most clinical settings ropivacaine and bupivacaine probably have similar toxicity when administered on an equipotent basis.

Extracellular

Sodium LA+H+ channel

LAH+

LA

Intracellular LA+H+

LAH+

FIGURE 26–1  Schematic diagram depicting paths of local anesthetic (LA) to receptor sites. Extracellular anesthetic exists in equilibrium between charged and uncharged forms. The charged cation penetrates lipid membranes poorly; intracellular access is thus achieved by passage of the uncharged form. Intracellular re-equilibration results in formation of the more active charged species, which binds to the receptor at the inner vestibule of the sodium channel. Anesthetic may also gain access more directly by diffusing laterally within the membrane (hydrophobic pathway).

CHAPTER 26  Local Anesthetics    487

termed the hydrophobic pathway. As a clinical consequence, local anesthetics are less effective when they are injected into infected tissues because the low extracellular pH favors the charged form, with less of the neutral base available for diffusion across the membrane. Conversely, adding bicarbonate to a local anesthetic—a strategy sometimes used in clinical practice—will raise the effective concentration of the nonionized form and thus shorten the onset time of a regional block.

Pharmacokinetics When local anesthetics are used for local, peripheral, and central neuraxial anesthesia—their most common clinical applications— systemic absorption, distribution, and elimination serve only to diminish or terminate their effect. Thus, classic pharmacokinetics plays a lesser role than with systemic therapeutics, yet remains important to the anesthetic’s duration and critical to the potential development of adverse reactions, specifically cardiac and CNS toxicity. Some pharmacokinetic properties of the commonly used amide local anesthetics are summarized in Table 26–2. The pharmacokinetics of the ester-based local anesthetics have not been extensively studied owing to their rapid breakdown in plasma (elimination half-life lidocaine > mepivacaine > ropivacaine ≈ bupivacaine and levobupivacaine (slowest). As a result, toxicity from amide-type local anesthetics is more likely to occur in patients with hepatic disease. For example, the average elimination half-life of lidocaine may be increased from 1.6 hours in normal patients (t½, see Table 26–2) to more than 6 hours in patients with severe liver disease. Many other drugs used in anesthesia are metabolized by the same P450 isozymes, and concomitant administration of these competing drugs may slow the hepatic metabolism of the local anesthetics. Decreased hepatic elimination of local anesthetics would also be anticipated in patients with

reduced hepatic blood flow. For example, the hepatic elimination of lidocaine in patients anesthetized with volatile anesthetics (which reduce liver blood flow) is slower than in patients anesthetized with intravenous anesthetic techniques. Delayed metabolism due to impaired hepatic blood flow may likewise occur in patients with heart failure.

Pharmacodynamics A. Mechanism of Action 1. Membrane potential—The primary mechanism of action of local anesthetics is blockade of voltage-gated sodium channels (see Figure 26–1). The excitable membrane of nerve axons, like the membrane of cardiac muscle (see Chapter 14) and neuronal cell bodies (see Chapter 21), maintains a resting transmembrane potential of –90 to –60 mV. During excitation, the sodium channels open, and a fast, inward sodium current quickly depolarizes the membrane toward the sodium equilibrium potential (+40 mV). As a result of this depolarization process, the sodium channels close (inactivate) and potassium channels open. The outward flow of potassium repolarizes the membrane toward the potassium equilibrium potential (about –95 mV); repolarization returns the sodium channels to the rested state with a characteristic recovery time that determines the refractory period. The transmembrane ionic gradients are maintained by the sodium pump. These ionic fluxes are similar to, but simpler than, those in heart muscle, and local anesthetics have similar effects in both tissues. 2. Sodium channel isoforms—Each sodium channel consists of a single alpha subunit containing a central ion-conducting pore associated with accessory beta subunits. The pore-forming alpha subunit is actually sufficient for functional expression, but the kinetics and voltage dependence of channel gating are modified by the beta subunit. A variety of different sodium channels have been characterized by electrophysiologic recording, and subsequently isolated and cloned, while mutational analysis has allowed for identification of the essential components of the local anesthetic binding site. Nine members of a mammalian family of sodium channels have been so characterized and classified as Nav1.1–Nav1.9, where the chemical symbol represents the primary ion, the subscript denotes the physiologic regulator (in this case voltage), the initial number denotes the gene, and the number following the period indicates the particular isoform. 3. Channel blockade—Biologic toxins such as batrachotoxin, aconitine, veratridine, and some scorpion venoms bind to receptors within the channel and prevent inactivation. This results in prolonged influx of sodium through the channel and depolarization of the resting potential. The marine toxins tetrodotoxin (TTX) and saxitoxin have clinical effects that largely resemble those of local anesthetics (ie, block of conduction without a change in the resting potential). However, in contrast to the local anesthetics, the toxin binding site is located near the extracellular surface. The sensitivity of these channels to TTX varies, and subclassification based on this pharmacologic sensitivity has important physiologic and therapeutic implications. Six of the aforementioned channels

CHAPTER 26  Local Anesthetics    489

are sensitive to nanomolar concentration of this biotoxin (TTX-S), while three are resistant (TTX-R). Such differences, along with their variable neuronal distribution, raise the possibility of targeting specific neuronal subpopulations. Such fine-tuned analgesic therapy has the theoretical potential of providing effective analgesia, while limiting the significant adverse effects produced by nonspecific sodium channel blockers. When progressively increasing concentrations of a local anesthetic are applied to a nerve fiber, the threshold for excitation increases, impulse conduction slows, the rate of rise of the action potential declines, action potential amplitude decreases, and, finally, the ability to generate an action potential is completely abolished. These progressive effects result from binding of the local anesthetic to more and more sodium channels. If the sodium current is blocked over a critical length of the nerve, propagation across the blocked area is no longer possible. In myelinated nerves, the critical length appears to be two to three nodes of Ranvier. At the minimum dose required to block propagation, the resting potential is not significantly altered. The blockade of sodium channels by most local anesthetics is both voltage- and time-dependent: Channels in the rested state, which predominate at more negative membrane potentials, have a much lower affinity for local anesthetics than activated (open state) and inactivated channels, which predominate at more positive membrane potentials (see Figure 14–10). Therefore, the effect of a given drug concentration is more marked in rapidly firing axons than in resting fibers (Figure 26–3). Between successive action potentials, a portion of the sodium channels will recover from the local anesthetic block (see Figure 14–10). The recovery from drug-induced block is 10–1000 times slower than the recovery of channels from normal inactivation (as shown for the cardiac membrane in Figure 14–4). As a result, the refractory period is lengthened and the nerve conducts fewer action potentials.

Sodium current

Time

1

25

2 3

3 2

nA

1

Use

1 ms

FIGURE 26–3  Effect of repetitive activity on the block of sodium current produced by a local anesthetic in a myelinated axon. A series of 25 pulses was applied, and the resulting sodium currents (downward deflections) are superimposed. Note that the current produced by the pulses rapidly decreased from the first to the 25th pulse. A long rest period after the train resulted in recovery from block, but the block could be reinstated by a subsequent train. nA, nanoamperes. (Reproduced with permission from Courtney KR: Mechanism of frequencydependent inhibition of sodium currents in frog myelinated nerve by the lidocaine derivative GEA. J Pharmacol Exp Ther. 1975;195(2):225–236.)

Elevated extracellular calcium partially antagonizes the action of local anesthetics owing to the calcium-induced increase in the surface potential on the membrane (which favors the low-affinity rested state). Conversely, increases in extracellular potassium depolarize the membrane potential and favor the inactivated state, enhancing the effect of local anesthetics. 4. Other effects—Currently used local anesthetics bind to the sodium channel with low affinity and poor specificity, and there are multiple other sites for which their affinity is nearly the same as that for sodium channel binding. Thus, at clinically relevant concentrations, local anesthetics are potentially active at countless other channels (eg, potassium and calcium), enzymes (eg, adenylyl cyclase, carnitine-acylcarnitine translocase), and receptors (eg, N-methyl-d-aspartate [NMDA], G protein-coupled, 5-HT3, neurokinin-1 [substance P receptor]). The role that such ancillary effects play in achievement of local anesthesia appears to be important but is poorly understood. Further, interactions with these other sites are likely the basis for numerous differences between the local anesthetics with respect to anesthetic effects (eg, differential block) and toxicities that do not parallel anesthetic potency, and thus are not adequately accounted for solely by blockade of the voltage-gated sodium channel. The actions of circulating local anesthetics at such diverse sites exert a multitude of effects, some of which go beyond pain control, including some that are also potentially beneficial. For example, there is evidence to suggest that the blunting of the stress response and improvements in perioperative outcome that may occur with epidural anesthesia derive in part from an action of the anesthetic beyond its sodium channel block. Circulating local anesthetics also demonstrate antithrombotic effects, including having an impact on coagulation, platelet aggregation, and the microcirculation, as well as modulation of inflammation. B. Structure-Activity Characteristics of Local Anesthetics The smaller and more highly lipophilic local anesthetics have a faster rate of interaction with the sodium channel receptor. As previously noted, potency is also positively correlated with lipid solubility. Lidocaine, procaine, and mepivacaine are more water soluble than tetracaine, bupivacaine, and ropivacaine. The latter agents are more potent and have longer durations of local anesthetic action. These long-acting local anesthetics also bind more extensively to proteins and can be displaced from these binding sites by other protein-bound drugs. In the case of optically active agents (eg, bupivacaine), the R(+) isomer can usually be shown to be slightly more potent than the S(–) isomer (levobupivacaine). C. Neuronal Factors Affecting Block 1. Differential block—Since local anesthetics are capable of blocking all nerves, their actions are not limited to the desired loss of sensation from sites of noxious (painful) stimuli. With central neuraxial techniques (spinal or epidural), motor paralysis may impair respiratory activity, and autonomic nerve blockade may promote hypotension. Further, while motor paralysis may be desirable during surgery, it may be a disadvantage in other settings. For example, motor weakness occurring as a consequence of

490    SECTION V  Drugs That Act in the Central Nervous System

epidural anesthesia during obstetrical labor may limit the ability of the patient to bear down (ie, “push”) during delivery. Similarly, when used for postoperative analgesia, weakness may hamper ability to ambulate without assistance and pose a risk of falling, while residual autonomic blockade may interfere with bladder function, resulting in urinary retention and the need for bladder catheterization. These issues are particularly problematic in the setting of ambulatory (same-day) surgery, which represents an ever-increasing percentage of surgical caseloads. 2. Intrinsic susceptibility of nerve fibers—Nerve fibers differ significantly in their susceptibility to local anesthetic blockade. It has been traditionally taught, and still often cited, that local anesthetics preferentially block smaller diameter fibers first because the distance over which such fibers can passively propagate an electrical impulse is shorter. However, a variable proportion of large fibers are blocked prior to the disappearance of the small fiber component of the compound action potential. Most notably, myelinated nerves tend to be blocked before unmyelinated nerves of the same diameter. For example, preganglionic B fibers are blocked before the smaller unmyelinated C fibers involved in pain transmission (Table 26–3). Another important factor underlying differential block derives from the state- and use-dependent mechanism of action of local anesthetics. Blockade by these drugs is more marked at higher frequencies of depolarization. Sensory (pain) fibers have a high firing rate and relatively long action potential duration. Motor fibers fire at a slower rate and have a shorter action potential duration. As type A delta and C fibers participate in high-frequency pain transmission, this characteristic may favor blockade of these fibers earlier and with lower concentrations of local anesthetics. The potential impact of such effects mandates cautious interpretation of non-physiologic experiments evaluating intrinsic susceptibility of nerves to conduction block by local anesthetics. 3. Anatomic arrangement—In addition to the effect of intrinsic vulnerability to local anesthetic block, the anatomic organization of the peripheral nerve bundle may impact the onset and susceptibility of its components. As one would predict based on the necessity of having proximal sensory fibers join the nerve trunk

last, the core will contain sensory fibers innervating the most distal sites. Anesthetic placed outside the nerve bundle will thus reach and anesthetize the proximal fibers located at the outer portion of the bundle first, and sensory block will occur in sequence from proximal to distal.

■■ CLINICAL PHARMACOLOGY OF LOCAL ANESTHETICS Local anesthetics can provide highly effective analgesia in welldefined regions of the body. The most common routes of administration include a topical application (eg, nasal mucosa), wound or incision site infiltration, injection in the vicinity of peripheral nerve endings or major nerve trunks, and injection into the epidural or subarachnoid spaces surrounding the spinal cord (Figure  26–4). In addition, recent clinical practice has seen the development of truncal blocks that target fascial planes (eg, transversus abdominis or erector spinae), as well as expansion of the use of local infiltration anesthesia (LIA), particularly in the setting of total joint arthroplasty.

Clinical Block Characteristics In clinical practice, there is generally an orderly evolution of block components beginning with sympathetic transmission and progressing to temperature, pain, light touch, and finally motor block. This is most readily appreciated during the onset of spinal anesthesia, where a spatial discrepancy can be detected in modalities, the most vulnerable components achieving greater dermatomal (cephalad) spread. Thus, loss of the sensation of cold (often assessed by a wet alcohol sponge) will be roughly two segments above the analgesic level for pinprick, which in turn will be roughly two segments rostral to loss of light touch recognition. However, because of the anatomic considerations noted earlier for peripheral nerve trunks, onset with peripheral blocks is more variable, and proximal motor weakness may precede the onset of more distal sensory loss. Additionally, the anesthetic solution is not generally deposited evenly around a nerve bundle, and longitudinal spread and radial penetration into the nerve trunk are far from uniform.

TABLE 26–3  Relative size and susceptibility of different types of nerve fibers to local anesthetics. Fiber Type

Function

Diameter (µm)

Myelination

Conduction Velocity (m/s)

Sensitivity to Block

 Alpha

Proprioception, motor

12–20

Heavy

70–120

+

 Beta

Touch, pressure

5–12

Heavy

30–70

++

 Gamma

Muscle spindles

3–6

Heavy

15–30

++

 Delta

Pain, temperature

2–5

Heavy

5–25

+++

Type B

Preganglionic autonomic

35 minutes). Drugs eliminated by the liver tend to have shorter half-lives and durations of action (Table 27–1). All steroidal muscle relaxants are metabolized to their 3-hydroxy, 17-hydroxy, or 3,17-dihydroxy products in the liver. The 3-hydroxy metabolites are usually 40–80% as potent as the parent drug. Under normal circumstances, metabolites are not formed in sufficient

502    SECTION V  Drugs That Act in the Central Nervous System

O CH3

OC CH3

N

O

H

CH3

+

CH3

H

H

N+ CH3

H

H

CH3CO

H

H

H

Pancuronium O C CH3

CH3

N

CH3CO

H

H

+

N

CH3

H

H

H O H

CH3

O

H

H

Vecuronium O CH3 CH3

N+

CH3

CH3

N

CH3 +

N

H H

CH3CO

OC

N

CH3 CH3

H

H

O

Pipecuronium O CH3

C CH3

O H

O N

H

CH3 H

HO

H

N+

H

H H

CH2

CH

CH2

H

Rocuronium

FIGURE 27–4 

Structures of steroid neuromuscular blocking drugs (steroid nucleus in color). These agents are all nondepolarizing muscle relaxants.

quantities to produce a significant degree of neuromuscular blockade during or after anesthesia. However, if the parent compound is administered for several days in the ICU setting, the 3-hydroxy metabolite may accumulate and cause prolonged paralysis because it has a longer half-life than the parent compound. The remaining metabolites possess minimal neuromuscular blocking properties. The intermediate-acting steroid muscle relaxants (eg, vecuronium and rocuronium) tend to be more dependent on

biliary excretion or hepatic metabolism for their elimination. These muscle relaxants are more commonly used clinically than the long-acting steroid-based drugs (eg, pancuronium). The duration of action of these relaxants may be prolonged significantly in patients with impaired liver function. Atracurium (see Figure 27–3) is an intermediate-acting isoquinoline nondepolarizing muscle relaxant that is no longer in widespread clinical use. In addition to hepatic metabolism, atracurium is inactivated by a form of spontaneous breakdown known as Hofmann elimination. The main breakdown products are laudanosine and a related quaternary acid, neither of which possesses neuromuscular blocking properties. Laudanosine is slowly metabolized by the liver and has a longer elimination half-life (ie, 150 minutes). It readily crosses the blood-brain barrier, and high blood concentrations may cause seizures and an increase in the volatile anesthetic requirement. During surgical anesthesia, blood levels of laudanosine typically range from 0.2 to 1 mcg/mL; however, with prolonged infusions of atracurium in the ICU, laudanosine blood levels may exceed 5 mcg/mL. Atracurium has several stereoisomers, and the potent isomer cisatracurium has become one of the most common muscle relaxants in use today. Although cisatracurium resembles atracurium, it has less dependence on hepatic inactivation, produces less laudanosine, and is much less likely to release histamine. From a clinical perspective, cisatracurium has all the advantages of atracurium with fewer adverse effects. Therefore, cisatracurium has virtually replaced atracurium in clinical practice. Gantacurium represents a new class of nondepolarizing neuromuscular blockers, called asymmetric mixed onium chlorofumarates. It is degraded nonenzymatically by adduction of the amino acid cysteine and ester bond hydrolysis. Gantacurium is currently in phase 3 clinical trials and not yet available for widespread clinical use. Preclinical and clinical data indicate gantacurium has a rapid onset of effect and predictable duration of action (very short, similar to succinylcholine) that can be reversed with neostigmine or more quickly (within 1–2 minutes), with administration of l-cysteine. At doses above three times the ED95, cardiovascular adverse effects (eg, hypotension) have occurred, probably due to histamine release. No bronchospasm or pulmonary vasoconstriction has been reported at these higher doses. B. Depolarizing Relaxant Drugs The extremely short duration of action of succinylcholine (5–10 minutes) is due to its rapid hydrolysis by butyrylcholinesterase and pseudocholinesterase in the liver and plasma, respectively. Plasma cholinesterase metabolism is the predominant pathway for succinylcholine elimination. The primary metabolite of succinylcholine, succinylmonocholine, is rapidly broken down to succinic acid and choline. Because plasma cholinesterase has an enormous capacity to hydrolyze succinylcholine, only a small percentage of the original intravenous dose ever reaches the neuromuscular junction. In addition, because there is little if any plasma cholinesterase at the motor end plate, a succinylcholineinduced blockade is terminated by its diffusion away from the end plate into extracellular fluid. Therefore, the circulating levels

CHAPTER 27  Skeletal Muscle Relaxants    503

TABLE 27–1  Pharmacokinetic and dynamic properties of neuromuscular blocking drugs. Drug

Elimination

Clearance (mL/kg/min)

Approximate Duration of Action (minutes)

Approximate Potency Relative to Tubocurarine

6.6

20–35

1.5

Isoquinoline derivatives Atracurium

Spontaneous1

Cisatracurium

Mostly spontaneous

5–6

25–44

1.5

Tubocurarine

Kidney (40%)

2.3–2.4

>50

1

Pancuronium

Kidney (80%)

1.7–1.8

>35

6

Rocuronium

Liver (75–90%) and kidney

2.9

20–35

0.8

Vecuronium

Liver (75–90%) and kidney

3–5.3

20–35

6

Plasma ChE2 (100%)

>100

>8

0.4

Steroid derivatives

Depolarizing agent Succinylcholine 1

Nonenzymatic and enzymatic hydrolysis of ester bonds.

2

Butyrylcholinesterase (pseudocholinesterase).

of plasma cholinesterase influence the duration of action of succinylcholine by determining the amount of the drug that reaches the motor end plate. Neuromuscular blockade produced by succinylcholine can be prolonged in patients with an abnormal genetic variant of plasma cholinesterase. The dibucaine number is a measure of the ability of a patient to metabolize succinylcholine and can be used to identify at-risk patients. Under standardized test conditions, dibucaine inhibits the normal enzyme by 80% and the abnormal enzyme by only 20%. Many genetic variants of plasma cholinesterase have been identified, although the dibucaine-related variants are the most important. Given the rarity of these genetic variants, plasma cholinesterase testing is not a routine clinical procedure but may be indicated for patients with a family history of plasma cholinesterase deficiency. Another reasonable strategy is to avoid the use of succinylcholine where practical in patients with a possible family history of plasma cholinesterase deficiency.

Mechanism of Action The interactions of drugs with the acetylcholine receptor-end plate channel have been described at the molecular level. Several modes of action of drugs on the receptor are illustrated in Figure 27–5. A. Nondepolarizing Relaxant Drugs All the neuromuscular blocking drugs in current use in the USA except succinylcholine are classified as nondepolarizing agents. Although it is no longer in widespread clinical use, d-tubocurarine is considered the prototype neuromuscular blocker. When small doses of nondepolarizing muscle relaxants are administered, they act predominantly at the nicotinic receptor site by competing with acetylcholine. The least potent nondepolarizing relaxants (eg, rocuronium) have the fastest onset and the shortest duration of action. In larger doses, nondepolarizing drugs can enter the pore of the ion channel (see Figure  27–5)

to produce a more intense motor blockade. This action further weakens neuromuscular transmission and diminishes the ability of the acetylcholinesterase inhibitors (eg, neostigmine, edrophonium, pyridostigmine) to antagonize the effect of nondepolarizing muscle relaxants. Nondepolarizing relaxants can also block prejunctional sodium channels. As a result of this action, muscle relaxants interfere with the mobilization of acetylcholine at the nerve ending and cause fade of evoked nerve twitch contractions (Figure 27–6 and described below). One consequence of the surmountable nature of the postsynaptic blockade produced by nondepolarizing muscle relaxants is the fact that tetanic stimulation (rapid delivery of electrical stimuli to a peripheral nerve) releases a large quantity of acetylcholine and is followed by transient posttetanic facilitation of the twitch strength (ie, relief of blockade). An important clinical consequence of this principle is the reversal of residual blockade by cholinesterase inhibitors. The characteristics of a nondepolarizing neuromuscular blockade are summarized in Table 27–2 and Figure 27–6. B. Depolarizing Relaxant Drugs 1. Phase I block (depolarizing)—Succinylcholine is the only clinically useful depolarizing blocking drug. Its neuromuscular effects are like those of acetylcholine except that succinylcholine produces a longer effect at the myoneural junction. Succinylcholine reacts with the nicotinic receptor to open the channel and cause depolarization of the motor end plate, and this in turn spreads to the adjacent membranes, causing transient contractions of muscle motor units. Data from single-channel recordings indicate that depolarizing blockers can enter the channel to produce a prolonged “flickering” of the ion conductance (Figure 27–7). Because succinylcholine is not metabolized effectively at the synapse, the depolarized membranes remain depolarized and unresponsive to subsequent impulses (ie, a state of depolarizing blockade). Furthermore, because excitation-contraction coupling requires end plate repolarization (“repriming”) and repetitive

504    SECTION V  Drugs That Act in the Central Nervous System

ACh Choline Acetate

Acetylcholine Nondepolarizing blocker Depolarizing blocker Na+

AChE

End plate

Channel closed

Channel open normal

ACh Choline Acetate

Na+ AChE

End plate

Channel closed

Channel open blocked

FIGURE 27–5  Schematic diagram of the interactions of drugs with the acetylcholine receptor on the end plate channel (structures are purely symbolic). Top: The action of the normal agonist, acetylcholine (red) in opening the channel. Bottom, left: A nondepolarizing blocker, eg, rocuronium (yellow), is shown as preventing the opening of the channel when it binds to the receptor. Bottom, right: A depolarizing blocker, eg, succinylcholine (blue), both occupying the receptor and blocking the channel. Normal closure of the channel gate is prevented, and the blocker may move rapidly in and out of the pore. Depolarizing blockers may desensitize the end plate by occupying the receptor and causing persistent depolarization. An additional effect of drugs on the end plate channel may occur through changes in the lipid environment surrounding the channel (not shown). General anesthetics and alcohols may impair neuromuscular transmission by this mechanism. firing to maintain muscle tension, a flaccid paralysis results. In contrast to the nondepolarizing drugs, this so-called phase I (depolarizing) block is augmented, not reversed, by cholinesterase inhibitors. The characteristics of a depolarizing neuromuscular blockade are summarized in Table 27–2 and Figure 27–6. 2. Phase II block (desensitizing)—With prolonged exposure to succinylcholine, the initial end plate depolarization decreases, and the membrane becomes repolarized. Despite this repolarization, the membrane cannot easily be depolarized again because it is desensitized. The mechanism for this desensitizing phase is unclear, but some evidence indicates that channel block may become more important than agonist action at the receptor in phase II of succinylcholine’s neuromuscular blocking action. Regardless of the mechanism, the channels behave as if they are in a prolonged closed state (see Figure 27–6). Later in phase II, the characteristics of the blockade are nearly identical to those of a nondepolarizing block (ie, a nonsustained twitch response to a tetanic stimulus) (see Figure 27–6), with possible reversal by acetylcholinesterase inhibitors.

■■ CLINICAL PHARMACOLOGY OF NEUROMUSCULAR BLOCKING DRUGS Skeletal Muscle Paralysis Before the introduction of neuromuscular blocking drugs, profound skeletal muscle relaxation for intracavitary operations could be achieved only by producing levels of volatile (inhaled) anesthesia deep enough to produce profound depressant effects on the cardiovascular and respiratory systems. The adjunctive use of neuromuscular blocking drugs makes it possible to achieve adequate muscle relaxation for all types of surgical procedures without the cardiorespiratory depressant effects produced by deep anesthesia.

Assessment of Neuromuscular Transmission Monitoring the effect of muscle relaxants during surgery (and recovery following the administration of cholinesterase

CHAPTER 27  Skeletal Muscle Relaxants    505

No Drug

Nondepolarizing Block

Train-of-four

Fade

TOF-R = 1.0

TOF-R = 0.4

Double burst

Posttetanic potentiation

*

PTC = >6

Depolarizing Block Phase I

Phase II

Constant but diminished TOF-R = 1.0

Fade TOF-R = 0.4

Fade

No fade

Fade

Present

Absent

Present

PTC = 3

*

PTC = 3

*

*

FIGURE 27–6  Muscle contraction responses to different patterns of nerve stimulation used in monitoring skeletal muscle relaxation. The alterations produced by a nondepolarizing blocker and depolarizing and desensitizing blockade by succinylcholine are shown. In the train-offour (TOF) pattern, four stimuli are applied at 2 Hz. The TOF ratio (TOF-R) is calculated from the strength of the fourth contraction divided by that of the first. In the double-burst pattern, three stimuli are applied at 50 Hz, followed by a 700 ms rest period and then repeated. In the posttetanic potentiation pattern, several seconds of 50 Hz stimulation are applied, followed by several seconds of rest and then by single stimuli at a slow rate (eg, 0.5 Hz). The number of detectable posttetanic twitches is the posttetanic count (PTC),* first posttetanic contraction. inhibitors) typically involves the use of a device that produces transdermal electrical stimulation of one of the peripheral nerves to the hand or facial muscles and recording of the evoked contractions (ie, twitch responses). The motor responses to different patterns of peripheral nerve stimulation can be recorded in the operating room during the procedure (see Figure 27–6). The standard approach for monitoring the clinical effects of muscle

relaxants during surgery uses peripheral nerve stimulation to elicit motor responses, which are visually observed by the anesthesiologist. The three most commonly used patterns include (1) single-twitch stimulation, (2)  train-of-four (TOF) stimulation, and (3) tetanic stimulation. Two other modalities are also available to monitor neuromuscular transmission: double-burst stimulation and posttetanic count.

TABLE 27–2  Comparison of a typical nondepolarizing muscle relaxant (rocuronium) and a depolarizing muscle relaxant (succinylcholine).

 

 

Succinylcholine

 

Rocuronium

Phase I

Phase II

Administration of tubocurarine

Additive

Antagonistic

Augmented1

Administration of succinylcholine

Antagonistic

Additive

Augmented

1

Effect of neostigmine

Antagonistic

Augmented

Antagonistic

Initial excitatory effect on skeletal muscle

None

Fasciculations

None

Response to a tetanic stimulus

Unsustained (fade)

Sustained2 (no fade)

Unsustained (fade)

Posttetanic facilitation

Yes

No

Yes

Rate of recovery

30–60 min

4–8 min

>20 min

3

1

It is not known whether this interaction is additive or synergistic (super additive).

2

The amplitude is decreased, but the response is sustained.

3

1

The rate depends on the dose and on the completeness of neuromuscular blockade.

3

506    SECTION V  Drugs That Act in the Central Nervous System

4 pA 25 ms

FIGURE 27–7  Action of succinylcholine on single-channel end plate receptor currents in frog muscle. Currents through a single AChR channel were recorded using the patch clamp technique. The upper trace was recorded in the presence of a low concentration of succinylcholine; the downward deflections represent openings of the channel and passage of inward (depolarizing) current. The lower trace was recorded in the presence of a much higher concentration of succinylcholine and shows prolonged “flickering” of the channel as it repetitively opens and closes or is “plugged” by the drug. (Reproduced with permission from Marshall CG, Ogden DC, Colquhoun D. The actions of suxamethonium (succinyldicholine) as an agonist and channel blocker at the nicotinic receptor of frog muscle. J Physiol. 1990;428:155–174.)

With single-twitch stimulation, a single supramaximal electrical stimulus is applied to a peripheral nerve at frequencies from 0.1  Hz to 1.0 Hz. The higher frequency is often used during induction and reversal to more accurately determine the peak (maximal) drug effect. TOF stimulation involves four successive supramaximal stimuli given at intervals of 0.5 second (2 Hz). Each stimulus in the TOF causes the muscle to contract, and the relative magnitude of the response of the fourth twitch compared with the first twitch is the TOF ratio. With a depolarizing block, all four twitches are reduced in a dose-related fashion. With a nondepolarizing block, the TOF ratio decreases (“fades”) and is inversely proportional to the degree of blockade. During recovery from nondepolarizing block, the amount of fade decreases and the TOF ratio approaches 1.0. Recovery to a TOF ratio greater than 0.7 is typically necessary for resumption of spontaneous ventilation. However, complete clinical recovery from a nondepolarizing block is considered to require a TOF greater than 0.9. Fade in the TOF response after administration of succinylcholine signifies the development of a phase II block. Tetanic stimulation consists of a very rapid (30–100 Hz) delivery of electrical stimuli for several seconds. During a nondepolarizing neuromuscular block (and a phase II block after succinylcholine), the response is not sustained, and fade of the twitch responses is observed. Fade in response to tetanic stimulation is normally considered a presynaptic event. However, the degree of fade depends primarily on the degree of neuromuscular blockade. During a partial nondepolarizing blockade, tetanic nerve stimulation is followed by an increase in the posttetanic twitch response, so-called posttetanic facilitation of neuromuscular transmission. During intense neuromuscular blockade, there is no response to either tetanic or posttetanic stimulation. As the intensity of the block diminishes, the response to posttetanic twitch stimulation reappears. The reappearance of the first response to twitch stimulation after tetanic stimulation reflects the duration of profound

(clinical) neuromuscular blockade. To determine the posttetanic count, 5 seconds of 50 Hz tetany is applied, followed by 3 seconds of rest, followed by 1 Hz pulses for about 10 seconds (10 pulses). The counted number of muscle twitches provides an estimation of the depth of blockade. For instance, a posttetanic count of 2 suggests no twitch response (by TOF) for about 20–30 minutes, and a posttetanic count of 5 correlates to a no-twitch response (by TOF) of about 10–15 minutes (see Figure 27–6, bottom panel). The double-burst stimulation pattern is another mode of electrical nerve stimulation developed with the goal of allowing for manual detection of residual neuromuscular blockade when it is not possible to record the responses to single-twitch, TOF, or tetanic stimulation. In this pattern, three nerve stimuli are delivered at 50 Hz followed by a 700 ms rest period and then by two or three additional stimuli at 50 Hz. It is easier to detect fade in the responses to double-burst stimulation than to TOF stimulation. The absence of fade in response to double-burst stimulation implies that clinically significant residual neuromuscular blockade does not exist. A more quantitative approach to neuromuscular monitoring involves monitoring using a force transducer for measuring the evoked response (ie, movement) of the thumb to TOF stimulation over the ulnar nerve at the wrist. This device has the advantage of being integrated in the anesthesia machine and also provides a more accurate graphic display of the percentage of fade to TOF stimulation. A. Nondepolarizing Relaxant Drugs During anesthesia, administration of tubocurarine, 0.1–0.4 mg/kg IV, initially causes motor weakness, followed by the skeletal muscles becoming flaccid and inexcitable to electrical stimulation (Figure 27–8). In general, larger muscles (eg, abdominal, trunk, paraspinous, diaphragm) are more resistant to neuromuscular blockade and recover more rapidly than smaller muscles (eg, facial, foot,

CHAPTER 27  Skeletal Muscle Relaxants    507

Isoflurane (1.25 MAC) 1 min 23 min

Tubocurarine (3 mg/m2)

Halothane (1.25 MAC)

1 min 11 min

Tubocurarine (6 mg/m2)

FIGURE 27–8  Neuromuscular blockade from tubocurarine during equivalent levels of isoflurane and halothane anesthesia in patients. Note that isoflurane augments the block far more than does halothane. MAC, minimal alveolar concentration. hand). The diaphragm is usually the last muscle to be paralyzed. Assuming that ventilation is adequately maintained, no adverse effects occur with skeletal muscle paralysis. When administration of muscle relaxants is discontinued, recovery of muscles usually occurs in reverse order, with the diaphragm regaining function first. The pharmacologic effect of tubocurarine, 0.3 mg/kg IV, usually lasts 45–60 minutes. However, subtle evidence of residual muscle paralysis detected using a neuromuscular monitor may last for another hour, increasing the likelihood of adverse outcomes, eg, aspiration and decreased hypoxic drive. Potency and duration of action of the other nondepolarizing drugs are shown in Table 27–1. In addition to the duration of action, the most important property distinguishing the nondepolarizing relaxants is the time to onset of the blocking effect, which determines how rapidly the patient’s trachea can be intubated. Of the currently available nondepolarizing drugs, rocuronium has the most rapid onset time (60–120 seconds).

B. Depolarizing Relaxant Drugs Following the administration of succinylcholine, 0.75–1.5 mg/kg IV, transient muscle fasciculations occur over the chest and abdomen within 30 seconds, although general anesthesia and the prior administration of a small dose of a nondepolarizing muscle relaxant tend to attenuate them. As paralysis develops rapidly (70 years). Conversely, patients with severe burns and those with upper motor neuron disease are resistant to nondepolarizing muscle relaxants. This desensitization is probably caused by proliferation of extrajunctional receptors, which results in an increased dose requirement for the nondepolarizing relaxant to block a sufficient number of receptors.

Reversal of Nondepolarizing Neuromuscular Blockade The cholinesterase inhibitors effectively antagonize the neuromuscular blockade caused by nondepolarizing drugs. Their general pharmacology is discussed in Chapter 7. Neostigmine and pyridostigmine antagonize nondepolarizing neuromuscular

blockade by increasing the availability of acetylcholine at the motor end plate, mainly by inhibition of acetylcholinesterase. To a lesser extent, these cholinesterase inhibitors also increase the release of this transmitter from the motor nerve terminal. In contrast, edrophonium antagonizes neuromuscular blockade purely by inhibiting acetylcholinesterase activity. Edrophonium has a more rapid onset of action but may be less effective than neostigmine in reversing the effects of nondepolarizing blockers in the presence of profound neuromuscular blockade. These differences are important in determining recovery from residual block, the neuromuscular blockade remaining after completion of surgery and movement of the patient to the recovery room. Unsuspected residual block may result in hypoventilation, leading to hypoxia and even apnea, especially if patients have received central depressant medications in the early recovery period. Sugammadex is a reversal agent approved for rapid reversal of the steroid neuromuscular blocking agents rocuronium and vecuronium. Although it has been in clinical use in Europe since 2008, its approval in the USA was delayed because of concerns that it causes a low incidence of anaphylaxis and hypersensitivity reactions. Sugammadex is a modified g-cyclodextrin (a large ring structure with 16 polar hydroxyl groups facing inward and 8 polar carboxyl groups facing outward) that binds tightly to rocuronium in a 1:1 ratio. By binding to plasma rocuronium, sugammadex decreases the free plasma concentration and establishes a concentration gradient for rocuronium to diffuse away from the neuromuscular junction back into the circulation, where it is quickly bound by free sugammadex. Currently, three dose ranges are recommended for sugammadex: 2 mg/kg to reverse shallow neuromuscular blockade (spontaneous recovery has reached the second twitch in TOF stimulation), 4 mg/kg to reverse deeper blockade (1–2 posttetanic count and no response to TOF stimulation), and 16 mg/kg for immediate reversal following administration of a single dose of 1.2 mg/kg of rocuronium. In patients with normal renal function (defined as a creatinine clearance [CrCl] > 80 mL/min), the sugammadexrocuronium complex is typically excreted unchanged in the urine within 24 hours. In patients with renal insufficiency, complete urinary elimination may take much longer. The plasma half-life of sugammadex in patients with renal impairment increases significantly as CrCl is reduced. In mild to moderate renal insufficiency (CrCl between 30 and 80 mL/min), the half-life varies between 4 and 6 hours. This increases dramatically in patients with severe renal impairment (CrCl > 30 mL/min), in whom the half-life is extended to 19 hours. The ability to dialyze sugammadex is variable, although some studies have demonstrated the ability to dialyze it using a high-flux method. Therefore, sugammadex is not recommended for use in patients with severe renal impairment unless absolutely necessary. Sugammadex is associated with a few significant adverse reactions. Most importantly, sugammadex may cause anaphylaxis, which occurred in 0.3% of patients who received the 16 mg/kg dose in the US Food and Drug Administration (FDA) studies. Hypersensitivity reactions, such as nausea, pruritus, and urticaria,

510    SECTION V  Drugs That Act in the Central Nervous System

are more common than anaphylaxis, and also occur more frequently with higher doses of sugammadex. Other significant adverse reactions include marked bradycardia that may progress to cardiac arrest within minutes of administration and coagulopathy, with an approximately 25% elevation of activated partial thromboplastin time and prothrombin time/international normalized ratio values that may last up to 1 hour. Because sugammadex binds the steroidal neuromuscular blocking agents rocuronium and vecuronium, it is not surprising that it can also block other steroidal drugs. The two most important of these drugs are progesterone-based contraceptives and the selective estrogen receptor modulator toremifene. When sugammadex is administered to a woman who is taking hormonal contraceptives that contain progesterone, the progesterone may be bound by sugammadex, and the efficacy of the contraceptive is decreased as if the woman missed one or two doses. The manufacturer recommends that an alternative nonhormonal contraceptive be used for 7 days following sugammadex administration. Sugammadex also very tightly binds toremifene, which may be used to treat metastatic breast cancer (see Chapter 40). Not only will the efficacy of toremifene be reduced, but displacement of rocuronium from sugammadex may result, and prolonged neuromuscular blockade could occur.

Uses of Neuromuscular Blocking Drugs A. Surgical Relaxation One of the most important applications of the neuromuscular blockers is in facilitating intracavitary surgery, especially in intraabdominal and intrathoracic procedures. B. Endotracheal Intubation By relaxing the pharyngeal and laryngeal muscles, neuromuscular blocking drugs facilitate laryngoscopy and placement of an endotracheal tube. Endotracheal tube placement ensures an adequate airway and minimizes the risk of pulmonary aspiration during general anesthesia. C. Control of Ventilation In critically ill patients who have ventilatory failure from various causes (eg, severe bronchospasm, pneumonia, chronic obstructive airway disease), it may be necessary to control ventilation to provide adequate gas exchange and to prevent atelectasis. In the ICU, neuromuscular blocking drugs are frequently administered to reduce chest wall resistance (ie, improve thoracic compliance), decrease oxygen utilization, and improve ventilator synchrony. D. Treatment of Convulsions Neuromuscular blocking drugs (ie, succinylcholine) are occasionally used to attenuate the peripheral (motor) manifestations of convulsions associated with status epilepticus, local anesthetic toxicity, or electroconvulsive therapy. Although this approach is effective in eliminating the muscular manifestations of the seizures, it has no effect on the central processes because neuromuscular blocking drugs do not cross the blood-brain barrier.

■■ SPASMOLYTIC & ANTISPASMODIC DRUGS Skeletal muscle relaxants include neuromuscular blockers, spasmolytics, and antispasmodics. Spasmolytics and antispasmodics are used to treat two conditions: spasms from peripheral musculoskeletal conditions (antispasmodics) and spasticity from upper motor neuron lesions (spasmolytics). Spasticity presents as intermittent or sustained involuntary contraction of skeletal muscle, causing stiffness that interferes with mobility and speech. It is characterized by an increase in tonic stretch reflexes and flexor muscle spasms (ie, increased basal muscle tone) together with muscle weakness. It is often associated with spinal injury, cerebral palsy, multiple sclerosis, and stroke. The mechanisms underlying clinical spasticity appear to involve not only the stretch reflex arc itself but also higher centers in the CNS, with damage to descending pathways in the spinal cord resulting in hyperexcitability of the alpha motor neurons in the cord. The important components involved in these processes are shown in Figure 27–9. Pharmacologic therapy may ameliorate some of the symptoms of spasticity by modifying the stretch reflex arc or by interfering directly with skeletal muscle (ie, excitation-contraction coupling). Drugs that modify the reflex arc may modulate excitatory or inhibitory synapses (see Chapter 21). Thus, to reduce the hyperactive stretch reflex, it is desirable to reduce the activity of the Ia fibers that excite the primary motor neuron or to enhance the activity of the inhibitory internuncial neurons. These structures are shown in greater detail in Figure 27–10.

Interneuron

Ia neuron

Alpha motor neurons

Gamma motor neuron

Striated muscle Spindle

Sensory ending

Spindle (intrafusal) muscle fiber

FIGURE 27–9  Schematic illustration of the structures involved in the stretch reflex (right half ) showing innervation of extrafusal (striated muscle) fibers by alpha motor neurons and of intrafusal fibers (within muscle spindle) by gamma motor neurons. The left half of the diagram shows an inhibitory reflex arc, which includes an intercalated inhibitory interneuron. (Reproduced with permission from Waxman SG: Clinical Neuroanatomy, 26th ed. New York, NY: McGraw Hill; 2009.)

CHAPTER 27  Skeletal Muscle Relaxants    511

Inhibitory interneuron Tizanidine Corticospinal pathway Baclofen

α2

–

–

GABAB

Glu GABA Motor neuron

GABAB AMPA

–

α2

–

Muscle

GABAA

– Dantrolene

Benzodiazepines Action potentials

FIGURE 27–10  Postulated sites of spasmolytic action of tizanidine (α2), benzodiazepines (GABAA), and baclofen (GABAB) in the spinal cord. Tizanidine may also have a postsynaptic inhibitory effect. Dantrolene acts on the sarcoplasmic reticulum in skeletal muscle. Glu, glutamatergic neuron. A variety of pharmacologic agents described as depressants of the spinal “polysynaptic” reflex arc (eg, barbiturates [phenobarbital] and glycerol ethers [mephenesin]) have been used to treat these conditions of excess skeletal muscle tone. However, as illustrated in Figure 27–10, nonspecific depression of synapses involved in the stretch reflex could reduce the desired GABAergic inhibitory activity, as well as the excitatory glutamatergic transmission. Currently available drugs can provide significant relief from painful muscle spasms, but they are less effective in improving meaningful function (eg, mobility and return to work).

spasmolytics (eg, midazolam), but clinical experience with them is limited. Meprobamate and carisoprodol are sedatives that have been used as central muscle relaxants, although evidence for their efficacy without sedation is lacking. Carisoprodol is a schedule IV drug; it is metabolized to meprobamate, which is also a schedule IV drug. Withdrawal of carisoprodol and meprobamate after extensive use elicits physical withdrawal, with anxiety, tremors, muscle twitching, insomnia, and auditory and visual hallucinations.

Diazepam

Baclofen

As described in Chapter 22, benzodiazepines facilitate the action of GABA in the CNS. Diazepam acts at GABAA synapses, and its action in reducing spasticity is at least partly mediated in the spinal cord because it is somewhat effective in patients with cord transection. Although diazepam can be used in patients with muscle spasm of almost any origin (including local muscle trauma), it also produces sedation at the doses required to reduce muscle tone. The initial dosage is 4 mg/d, and it is gradually increased to a maximum of 60 mg/d. Other benzodiazepines have been used as

Baclofen (p-chlorophenyl-GABA) was designed to be an orally active GABA-mimetic agent and is an agonist at GABAB receptors. Activation of these receptors by baclofen results in hyperpolarization by three distinct actions: (1) closure of presynaptic calcium channels, (2) increased postsynaptic K+ conductance, and (3) inhibition of dendritic calcium influx channels. Through reduced release of excitatory transmitters in both the brain and the spinal cord, baclofen suppresses activity of Ia sensory afferents, spinal interneurons, and motor neurons (see Figure 27–10). Baclofen may

512    SECTION V  Drugs That Act in the Central Nervous System

also reduce pain in patients with spasticity, perhaps by inhibiting the release of substance P (neurokinin 1) in the spinal cord. CI

CH CH2

CH2

NH2

COOH

Baclofen

Baclofen is at least as effective as diazepam and tizanidine (discussed below) in reducing spasticity and is less sedating than diazepam. Baclofen does not reduce overall muscle strength as much as dantrolene. It is rapidly and completely absorbed after oral administration and has a plasma half-life of 3–4 hours. Dosage is started at 15 mg twice daily, increasing as tolerated to 100 mg daily. Studies have confirmed that intrathecal catheter administration of baclofen can control severe spasticity and muscle pain that is not responsive to medication by other routes of administration. Owing to the poor egress of baclofen from the spinal cord, peripheral symptoms are rare. Therefore, higher central concentrations of the drug may be tolerated. Partial tolerance to the effect of the drug may occur after several months of therapy but can be overcome by upward dosage adjustments to maintain the beneficial effect. This tolerance was not confirmed in a recent study and decreased response may represent unrecognized catheter malfunctions. Although a major disadvantage of this therapeutic approach is the difficulty of maintaining the drug delivery catheter in the subarachnoid space, risking an acute withdrawal syndrome upon treatment interruption, long-term intrathecal baclofen therapy can improve the quality of life for patients with severe spastic disorders. Adverse effects of high-dose baclofen include excessive somnolence, respiratory depression, and coma. Patients can become tolerant to the sedative effect with chronic administration. Increased seizure activity has been reported in epileptic patients. Withdrawal from baclofen must be done very slowly. Baclofen should be used with caution during pregnancy; although there are no reports of baclofen directly causing human fetal malformations, animal studies using high doses show that it causes impaired sternal ossification and omphalocele. Oral baclofen has been studied in many other medical conditions, including patients with intractable low back pain, stiff person syndrome, trigeminal neuralgia, cluster headache, intractable hiccups, tic disorder, gastroesophageal reflux disease, and cravings for alcohol, nicotine, and cocaine (see Chapter 32). Efficacy of oral baclofen has not been established in patients with stroke, Parkinson disease, or cerebral palsy.

TIZANIDINE As noted in Chapter 11, α2-adrenoceptor agonists such as clonidine and other imidazoline compounds have a variety of effects on the CNS that are not fully understood. Among these effects is the ability to reduce muscle spasm. Tizanidine is a congener

of clonidine that has been studied for its spasmolytic actions. Tizanidine has significant α2-agonist effects, but it reduces spasticity in experimental models at doses that cause fewer cardiovascular effects than clonidine or dexmedetomidine. Tizanidine has approximately one tenth to one fifteenth of the blood pressurelowering effects of clonidine. Neurophysiologic studies in animals and humans suggest that tizanidine reinforces both presynaptic and postsynaptic inhibition in the cord. It also inhibits nociceptive transmission in the spinal dorsal horn. Tizanidine’s actions are believed to be mediated via restoration of inhibitory suppression of the group II spinal interneurons without inducing any changes in intrinsic muscle properties. Clinical trials with oral tizanidine report efficacy in relieving muscle spasm comparable to diazepam, baclofen, and dantrolene. Tizanidine causes markedly less muscle weakness but produces a different spectrum of adverse effects, including drowsiness, hypotension in 16–33%, dizziness, dry mouth, asthenia, and hepatotoxicity, requiring monitoring of liver function, blood pressure, and renal function. The drowsiness can be managed by taking the drug at night. Tizanidine displays linear pharmacokinetics, and dosage requirements vary considerably among patients. Treatment is initiated at 2 mg every 6–8 hours and can be titrated up to a maximum of 36 mg/d. Dosage must be adjusted in patients with hepatic or renal impairment. Tizanidine is involved in drug-drug interactions; plasma levels increase in response to CYP1A2 inhibition. Conversely, tizanidine induces CYP11A1 activity, which is responsible for converting cholesterol to pregnenolone. In addition to its effectiveness in spastic conditions, tizanidine also appears to be effective for management of chronic migraine. Abrupt withdrawal should be avoided because it results in rebound hypertension, tachycardia, and increased spasms.

OTHER CENTRALLY ACTING SPASMOLYTIC DRUGS Gabapentin is an antiepileptic drug (see Chapter 24) that has shown considerable promise as a spasmolytic agent in several studies involving patients with multiple sclerosis. Pregabalin is a newer analog of gabapentin that may also prove useful in relieving painful disorders that involve a muscle spasm component. Progabide and glycine have also been found in preliminary studies to reduce spasticity. Progabide is a GABAA and GABAB agonist and has active metabolites, including GABA itself. Glycine is another inhibitory amino acid neurotransmitter (see Chapter  21) that appears to possess pharmacologic activity when given orally and readily passes the blood-brain barrier. Idrocilamide and riluzole are newer drugs for the treatment of amyotrophic lateral sclerosis (ALS) that appear to have spasm-reducing effects, possibly through inhibition of glutamatergic transmission in the CNS, although several other mechanisms have been proposed—such as stabilizing the inactivated state of voltage-dependent sodium channels.

CHAPTER 27  Skeletal Muscle Relaxants    513

BOTULINUM TOXIN

DANTROLENE Dantrolene is a hydantoin derivative related to phenytoin that has a unique mechanism of spasmolytic activity. In contrast to the centrally acting drugs, dantrolene reduces skeletal muscle strength by interfering with excitation-contraction coupling in the muscle fibers. The normal contractile response involves release of calcium from its stores in the sarcoplasmic reticulum (see Figures 13–1 and 27–10). This activator calcium brings about the tensiongenerating interaction of actin with myosin. Calcium is released from the sarcoplasmic reticulum via a calcium channel, called the ryanodine receptor (RyR) channel because the plant alkaloid ryanodine combines with a receptor on the channel protein. In the case of the skeletal muscle RyR1 channel, ryanodine facilitates the open configuration.

HN O

N

N

CH O

The therapeutic use of botulinum toxin (BoNT) for ophthalmic purposes and for local muscle spasm was mentioned in Chapter 6. This neurotoxin produces chemodenervation and local paralysis when injected into a muscle. Seven immunologically distinct toxins share homologous subunits. The single-chain polypeptide BoNT has little activity until it is cleaved into a heavy chain (100  kDa) and a light chain (50 kDa). The light chain, a zinc-dependent protease, prevents release of acetylcholine by interfering with vesicle fusion, through proteolytically cleaving SNAP*-25 (BoNT-A, BoNT-E) or synaptobrevin-2 (BoNT-B, BoNT-D, BoNT-F). Local facial injections of botulinum toxin are widely used for the short-term treatment (1–3 months per treatment) of wrinkles associated with aging around the eyes and mouth. Local injection of botulinum toxin has also become a useful treatment for generalized spastic disorders (eg, cerebral palsy). Most clinical studies to date have involved administration in one or two limbs, and the benefits appear to persist for weeks to several months after a single treatment. BoNT has virtually replaced anticholinergic medications used in the treatment of dystonia. More recently, FDA approval was granted for treatment of incontinence due to overactive bladder and for chronic migraine. Most studies have used several formulations of type A BoNT, but type B is also available. Adverse effects include respiratory tract infections, muscle weakness, urinary incontinence, falls, fever, and pain. While immunogenicity is currently of much less concern than in the past, experts still recommend that injections not be administered more frequently than every 3 months. Studies to determine safety of more frequent administration are underway. Besides occasional complications, a major limitation of BoNT treatment is its high cost. In addition, post-marketing reports of systemic and potentially fatal effects from spread of the toxin, generated a black box warning. The risk is greatest for children treated for spasticity, but toxicity can occur in adults as well.

O NO2

Dantrolene

Dantrolene interferes with the release of activator calcium through this sarcoplasmic reticulum calcium channel by binding to the RyR1 and blocking the opening of the channel. Motor units that contract rapidly are more sensitive to the drug’s effects than are slower-responding units. Cardiac muscle and smooth muscle are minimally depressed because the release of calcium from their sarcoplasmic reticulum involves a different RyR channel (RyR2). Treatment with dantrolene is usually initiated with 25 mg daily as a single dose, increasing to a maximum of 100 mg four times daily as tolerated. Only about one-third of an oral dose of dantrolene is absorbed, and the elimination half-life of the drug is approximately 8 hours. Major adverse effects are generalized muscle weakness, sedation, and occasionally hepatitis. A special application of dantrolene is in the treatment of malignant hyperthermia, a rare heritable disorder that can be triggered by a variety of stimuli, including general anesthetics (eg, volatile anesthetics) and neuromuscular blocking drugs (eg, succinylcholine; see also Chapter 16). Patients at risk for this condition have a hereditary alteration in Ca2+-induced Ca2+ release via the RyR1 channel or impairment in the ability of the sarcoplasmic reticulum to sequester calcium via the Ca2+ transporter (see Figure 27–10). Several mutations associated with this risk have been identified. After administration of one of the triggering agents, there is a sudden and prolonged release of calcium, with massive muscle contraction, lactic acid production, and increased body temperature. Prompt treatment is essential to control acidosis and body temperature and to reduce calcium release. The latter is accomplished by administering intravenous dantrolene, starting with a dose of 1 mg/kg IV, and repeating as necessary to a maximum dose of 10 mg/kg.

ANTISPASMODICS: DRUGS USED TO TREAT ACUTE LOCAL MUSCLE SPASM A large number of less well-studied, centrally active drugs (eg, carisoprodol, chlorzoxazone, cyclobenzaprine, metaxalone, methocarbamol, and orphenadrine) are promoted for the relief of acute muscle spasm caused by local tissue trauma or muscle strains. It has been suggested that these drugs act primarily at the level of the brainstem. Cyclobenzaprine may be regarded as the prototype of the group. Cyclobenzaprine is structurally related to the tricyclic antidepressants and produces antimuscarinic side effects. It is ineffective in treating muscle spasm due to cerebral palsy or spinal cord injury. As a result of its strong antimuscarinic actions, cyclobenzaprine may cause significant sedation, as well as confusion and transient visual hallucinations. The dosage of cyclobenzaprine for acute injury-related muscle spasm is 20–40 mg/d orally in divided doses. This drug class carries risks of significant adverse events and abuse potential.

514    SECTION V  Drugs That Act in the Central Nervous System

SUMMARY  Skeletal Muscle Relaxants Subclass, Drug

Mechanism of Action

DEPOLARIZING NEUROMUSCULAR BLOCKING AGENT   •  Succinylcholine Agonist at nicotinic acetylcholine (ACh) receptors, especially at neuromuscular junctions • depolarizes • may stimulate ganglionic nicotinic ACh and cardiac muscarinic ACh receptors

Pharmacokinetics, Toxicities, Interactions

Effects

Clinical Applications

Initial depolarization causes transient contractions, followed by prolonged flaccid paralysis • depolarization is then followed by repolarization that is also accompanied by paralysis

Placement of endotracheal tube at start of anesthetic procedure • rarely, control of muscle contractions in status epilepticus

Rapid metabolism by plasma cholinesterase • normal duration ∼5 min • Toxicities: Arrhythmias • hyperkalemia • transient increased intra-abdominal, intraocular pressure • postoperative muscle pain

Prolonged relaxation for surgical procedures • superseded by newer nondepolarizing agents

Renal excretion • duration, ∼40–60 min • Toxicities: Histamine release • hypotension • prolonged apnea

Prolonged relaxation for surgical procedures • relaxation of respiratory muscles to facilitate mechanical ventilation in intensive care unit Like cisatracurium • useful in patients with renal impairment

Not dependent on renal or hepatic function • duration ∼25–45 min • Toxicities: Prolonged apnea but less toxic than atracurium

Severe spasticity due to cerebral palsy, multiple sclerosis, stroke Chronic spasm due to cerebral palsy, stroke, spinal cord injury • acute spasm due to muscle injury Spasm due to multiple sclerosis, stroke, amyotrophic lateral sclerosis

Oral, intrathecal • Toxicities: Sedation, weakness; rebound spasticity upon abrupt withdrawal Hepatic metabolism • duration ∼12–24 h • Toxicities: See Chapter 22

Acute spasm due to muscle injury • inflammation

Hepatic metabolism • duration, ∼4–6 h • Toxicities: Strong antimuscarinic effects

NONDEPOLARIZING NEUROMUSCULAR BLOCKING AGENTS   •  d-Tubocurarine

Competitive antagonist at nACh receptors, especially at neuromuscular junctions

  •  Cisatracurium

Similar to tubocurarine

  •  Rocuronium

Similar to cisatracurium

Prevents depolarization by ACh, causes flaccid paralysis • can cause histamine release with hypotension • weak block of cardiac muscarinic ACh receptors Like tubocurarine but lacks histamine release and antimuscarinic effects

Like cisatracurium but slight antimuscarinic effect

Hepatic metabolism • duration ∼20–35 min • Toxicities: Like cisatracurium

  •  Vecuronium: Intermediate duration; metabolized in liver CENTRALLY ACTING SPASMOLYTIC DRUGS   •  Baclofen GABAB agonist, facilitates spinal inhibition of motor neurons   •  Diazepam Facilitates GABAergic transmission in central nervous system (see Chapter 22)   •  Tizanidine α2-Adrenoceptor agonist in the spinal cord

Pre- and postsynaptic inhibition of motor output Increases interneuron inhibition of primary motor afferents in spinal cord • central sedation Pre- and postsynaptic inhibition of reflex motor output

Oral • renal and hepatic elimination • duration 3–6 h • Toxicities: Weakness, sedation, hypotension, hepatotoxicity (rare), rebound hypertension upon abrupt withdrawal

CENTRALLY ACTING ANTISPASMODIC DRUGS   •  Cyclobenzaprine

Poorly understood inhibition of muscle stretch reflex in spinal cord

Reduction in hyperactive muscle reflexes • antimuscarinic effects

  • Methocarbamol, orphenadrine, others: Like cyclobenzaprine with varying degrees of antimuscarinic effect. Class side effect: strong central nervous system depression; note carisoprodol is a schedule IV drug. DIRECT-ACTING MUSCLE RELAXANTS 2+   •  Dantrolene Blocks RyR1 Ca -release channels in the sarcoplasmic reticulum of skeletal muscle

Reduces actin-myosin interaction • weakens skeletal muscle contraction

IV: Malignant hyperthermia • Oral: Spasm due to cerebral palsy, spinal cord injury, multiple sclerosis

IV, oral • duration 4–6 h • Toxicities: Muscle weakness • Black box warning: hepatotoxicity

  • Botulinum toxin

Flaccid paralysis

Upper and lower limb spasm due to cerebral palsy, multiple sclerosis; cervical dystonia, overactive bladder, migraine, hyperhidrosis

Direct injection into muscle • duration 2–3 months • Toxicities: Muscle weakness, falls • Black box warning: potential spread of toxin leading to excessive weakness reported after use for cerebral palsy with spasticity

Inhibits synaptic exocytosis through clipping of vesicle fusion proteins in presynaptic nerve terminal

CHAPTER 27  Skeletal Muscle Relaxants    515

P R E P A R A T I O N S A V A I L A B L E GENERIC NAME AVAILABLE AS NEUROMUSCULAR BLOCKING DRUGS Atracurium Generic Cisatracurium Generic, Nimbex Pancuronium Generic Rocuronium Generic, Zemuron Succinylcholine Generic, Anectine, Quelicin Tubocurarine Generic Vecuronium Generic, Norcuron REVERSAL AGENTS Neostigmine Generic Edrophonium Generic Sugammadex Bridion SPASMOLYTICS, ANTISPASMODICS Baclofen Generic, Gablofen, Lioresal Botulinum toxin type A Botox, Dysport, Xeomin Botulinum toxin type B Myobloc Carisoprodol Generic, Soma Chlorzoxazone Generic Cyclobenzaprine Generic, Amrix, Fexmid, Flexeril Dantrolene Generic, Dantrium, Revonto Diazepam Generic, Valium, Diastat Gabapentin Generic, Fanatrex FusePaq, Gabarone, Gralise, Neurontin   Note: This drug is labeled for use only in epilepsy and postherpetic neuralgia. Metaxalone Generic, Skelaxin Methocarbamol Generic, Robaxin Orphenadrine Generic, Antiflex, Banflex, Norflex, Flexoject, Flexon, Mio-Rel, Myolin, Norflex Injectable, Orfro, Orphenate Riluzole Generic, Rilutek, Tiglutik  Note: This drug is labeled only for use in amyotrophic lateral sclerosis. Tizanidine Generic, Zanaflex

REFERENCES Neuromuscular Blockers Belmont MR et al: Clinical pharmacology of GW280430A in humans. Anesthesiology 2004;100:768. Brull SJ, Murphy GS: Residual neuromuscular block: Lessons unlearned. Part II: Methods to reduce the risk of residual weakness. Anesth Analg 2010;111:129. Bryson HM, Fulton B, Benfield P: Riluzole. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential in amyotrophic lateral sclerosis. Drugs 1996;52:549. Cammu G et al: Dialysability of sugammadex and its complex with rocuronium in intensive care patients with severe renal impairment. Br J Anaes 2012;109:382. De Boer HD et al: Reversal of rocuronium-induced (1.2 mg/kg) profound neuromuscular blockade by sugammadex. Anesthesiology 2007;107:239. Gibb AJ, Marshall IG: Pre- and postjunctional effects of tubocurarine and other nicotinic antagonists during repetitive stimulation in the rat. J Physiol 1984;351:275. Hemmerling TM, Russo G, Bracco D: Neuromuscular blockade in cardiac surgery: An update for clinicians. Ann Card Anaesth 2008;11:80.

Hirsch NP: Neuromuscular junction in health and disease. Br J Anaesth 2007; 99:132. Kampe S et al: Muscle relaxants. Best Prac Res Clin Anesthesiol 2003;17:137. Lee C: Structure, conformation, and action of neuromuscular blocking drugs. Br J Anaesth 2001;87:755. Lee C et al: Reversal of profound neuromuscular block by sugammadex administered three minutes after rocuronium. Anesthesiology 2009;110:1020. Lien CA et al: Fumarates: Unique nondepolarizing neuromuscular blocking agents that are antagonized by cysteine. J Crit Care 2009;24:50. Llauradó S et al: Sugammadex ideal body weight dose adjusted by level of neuromuscular blockade in laparoscopic bariatric surgery. Anesthesiology 2012; 117:93. Mace SE: Challenges and advances in intubation: Rapid sequence intubation. Emerg Med Clin North Am 2008;26:1043. Marshall CG, Ogden DC, Colquhoun D: The actions of suxamethonium (succinyldicholine) as an agonist and channel blocker at the nicotinic receptor of frog muscle. J Physiol (Lond) 1990;428:155. Martyn JA: Neuromuscular physiology and pharmacology. In: Miller RD (editor): Anesthesia, 7th ed. Churchill Livingstone, 2010. Meakin GH: Recent advances in myorelaxant therapy. Paed Anaesthesia 2001;11:523. Murphy GS, Brull SJ: Residual neuromuscular block: Lessons unlearned. Part I: Definitions, incidence, and adverse physiologic effects of residual neuromuscular block. Anesth Analg 2010;111:120. Naguib M: Sugammadex: Another milestone in clinical neuromuscular pharmacology. Anesth Analg 2007;104:575. Naguib M, Brull SJ: Update on neuromuscular pharmacology. Curr Opin Anaesthesiol 2009;22:483. Naguib M, Kopman AF, Ensor JE: Neuromuscular monitoring and postoperative residual curarisation: A meta-analysis. Br J Anaesth 2007;98:302. Naguib M et al: Advances in neurobiology of the neuromuscular junction: Implications for the anesthesiologist. Anesthesiology 2002;96:202. Nicholson WT, Sprung J, Jankowski CJ: Sugammadex: A novel agent for the reversal of neuromuscular blockade. Pharmacotherapy 2007;27:1181. Pavlin JD, Kent CD: Recovery after ambulatory anesthesia. Curr Opin Anaesthesiol 2008;21:729. Puhringer FK et al: Reversal of profound, high-dose rocuronium-induced neuromuscular blockade by sugammadex at two different time points. Anesthesiology 2008;109:188. Sacan O, Klein K, White PF: Sugammadex reversal of rocuronium-induced neuromuscular blockade: A comparison with neostigmine-glycopyrrolate and edrophonium-atropine. Anesth Analg 2007;104:569. Savarese JJ et al: Preclinical pharmacology of GW280430A (AV430A) in the rhesus monkey and in the cat: A comparison with mivacurium. Anesthesiology 2004;100:835. Sine SM: End-plate acetylcholine receptor: Structure, mechanism, pharmacology, and disease. Physiol Rev 2012;92:1189. Staals LM et al: Reduced clearance of rocuronium and sugammadex in patients with severe to end-stage renal failure: A pharmacokinetic study. Br J Anaesth 2010;104:31. Sugammadex: BRIDION (sugammadex) Injection, for intravenous use initial U.S. Approval: 2015. http://www.accessdata.fda.gov/drugsatfda_docs/label/ 2015/022225lbl.pdf. Sunaga H et al: Gantacurium and CW002 do not potentiate muscarinic receptormediated airway smooth muscle constriction in guinea pigs. Anesthesiology 2010;112:892. Viby-Mogensen J: Neuromuscular monitoring. In: Miller RD (editor): Anesthesia, 5th ed. Churchill Livingstone, 2000.

Spasmolytics BOTOX (onabotulinumtoxinA) for injection, for intramuscular, intradetrusor, or intradermal use. https://www.accessdata.fda.gov/drugsatfda_docs/label/ 2011/103000s5232lbl.pdf Caron E, Morgan R, Wheless JW: An unusual cause of flaccid paralysis and coma: Baclofen overdose. J Child Neurol 2014;29:555. Corcia P, Meininger V: Management of amyotrophic lateral sclerosis. Drugs 2008;68:1037.

516    SECTION V  Drugs That Act in the Central Nervous System Cutter NC et al: Gabapentin effect on spasticity in multiple sclerosis: A placebo-controlled, randomized trial. Arch Phys Med Rehabil 2000; 81:164. Draulans N et al: Intrathecal baclofen in multiple sclerosis and spinal cord injury: Complications and long-term dosage evolution. Clin Rehabil 2013;27:1137. Gracies JM, Singer BJ, Dunne JW: The role of botulinum toxin injections in the management of muscle overactivity of the lower limb. Disabil Rehabil 2007;29:1789. Groves L, Shellenberger MK, Davis CS: Tizanidine treatment of spasticity: A metaanalysis of controlled, double-blind, comparative studies with baclofen and diazepam. Adv Ther 1998;15:241. Jankovic J: Medical treatment of dystonia. Mov Disord 2013;28:1001. Kheder A, Nair KPS: Spasticity: Pathophysiology, evaluation and management. Pract Neurol 2012;12:289. Krause T et al: Dantrolene—A review of its pharmacology, therapeutic use and new developments. Anaesthesia 2004;59:364. 2+ Lopez JR et al: Effects of dantrolene on myoplasmic free [Ca ] measured in vivo in patients susceptible to malignant hyperthermia. Anesthesiology 1992;76:711. Lovell BV, Marmura MJ: New therapeutic developments in chronic migraine. Curr Opin Neurol 2010;23:254. Malanga G, Reiter RD, Garay E: Update on tizanidine for muscle spasticity and emerging indications. Expert Opin Pharmacother 2008;9:2209.

Mast N, Linger M, Pikuleva IA: Inhibition and stimulation of activity of purified recombinant CYP11A1 by therapeutic agents. Mol Cell Endocrinol 2013;371:100. Mirbagheri MM, Chen D, Rymer WZ: Quantification of the effects of an alpha-2 adrenergic agonist on reflex properties in spinal cord injury using a system identification technique. J Neuroeng Rehabil 2010;7:29. Neuvonen PJ: Towards safer and more predictable drug treatment—Reflections from studies of the First BCPT Prize awardee. Basic Clin Pharmacol Toxicol 2012;110:207. Nolan KW, Cole LL, Liptak GS: Use of botulinum toxin type A in children with cerebral palsy. Phys Ther 2006;86:573. Reeves RR, Burke RS: Carisoprodol: Abuse potential and withdrawal syndrome. Curr Drug Abuse Rev 2010;3:33. Ronan S, Gold JT: Nonoperative management of spasticity in children. Childs Nerv Syst 2007;23:943. Ross JC et al: Acute intrathecal baclofen withdrawal: A brief review of treatment options. Neurocrit Care 2011;14:103. Vakhapova V, Auriel E, Karni A: Nightly sublingual tizanidine HCl in multiple sclerosis: Clinical efficacy and safety. Clin Neuropharmacol 2010;33:151. Verrotti A et al: Pharmacotherapy of spasticity in children with cerebral palsy. Pediatr Neurol 2006;34:1. Ward AB: Spasticity treatment with botulinum toxins. J Neural Transm 2008;115:607. Zanaflex Capsules™ Package insert. Prescribing information. Acorda Therapeutics, 2006.

C ASE STUDY ANSWER This patient presents problems that make her management more difficult than the average. She is at higher risk of difficulty with airway management because of obesity, and both obesity and diabetes raise the risk of aspiration. Therefore, the decision to use an endotracheal tube for her airway management is reasonable. As the case progresses, you are experiencing difficulty with mask ventilation, and the decision to abort the procedure and awaken the patient is probably the best response. In order to do so, the neuromuscular blockade must be fully reversed so she will be able to breathe on her own once awakened. There are two options for reversal of neuromuscular blockade with rocuronium (and with vecuronium): sugammadex, or neostigmine combined with glycopyrrolate. Sugammadex would be the most appropriate agent. As described in Chapter 7, neostigmine works to increase the level of acetylcholine at the neuromuscular junction by inhibiting the enzymatic breakdown of acetylcholine. Glycopyrrolate (Chapter 8) is given to block the bradycardia associated with increased cholinergic activity. However, if the patient is still fully relaxed with rocuronium, neostigmine will not sufficiently increase

acetylcholine to allow full reversal. In contrast, sugammadex actively binds rocuronium and removes it from the neuromuscular junction. In order to fully reverse an intubating dose of rocuronium, a sugammadex dose of 16 mg/kg should be administered. This will reverse the effect of rocuronium within 1.5–3.0 minutes. Sugammadex is renally cleared, so it should not be used in patients in renal failure (creatinine clearance less than 30 mL/min) unless absolutely necessary. This patient has insulin-dependent diabetes, so her creatinine clearance may be abnormally low. If this were the case, the benefit of sugammadex would still outweigh its potential risk. In addition, some studies have found that sugammadex may be dialyzable, and could therefore be removed by that method if needed. This patient is also taking an oral contraceptive agent, and it would be necessary to counsel her that sugammadex may interfere with the efficacy of that agent and the FDA recommends use of another method of contraception for the following 7 days. Other issues that may occur with sugammadex use include anaphylaxis, especially when using the maximum dose of 16 mg/kg, marked bradycardia, hypotension, nausea and vomiting, and headache.

28 C

Pharmacologic Management of Parkinsonism & Other Movement Disorders

H

A

P

T

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R

Michael J. Aminoff, MD, DSc, FRCP

C ASE STUDY A 76-year-old retired banker complains of a shuffling gait with occasional falls over the last year. He has developed a stooped posture, drags his left leg when walking, and is unsteady on turning. He remains independent in all activities of daily living, but he has become more forgetful and occasionally sees his long-deceased father in his bedroom. Examination reveals hypomimia, hypophonia, a slight rest tremor of the right hand and chin, mild rigidity, and impaired rapid alternating movements in all limbs. Neurologic and general examinations are otherwise normal. What is the likely diagnosis and prognosis?

Several types of abnormal movement are recognized. Tremor consists of a rhythmic oscillatory movement around a joint and is best characterized by its relation to activity. Tremor at rest is characteristic of parkinsonism, when it is often associated with rigidity and an impairment of voluntary activity. Tremor may occur during maintenance of sustained posture (postural tremor) or during movement (intention tremor). A conspicuous postural tremor is the cardinal feature of benign essential or familial tremor. Intention tremor occurs in patients with a lesion of the brainstem or cerebellum, especially when the superior cerebellar peduncle is involved; it may also occur as a manifestation of toxicity from alcohol or certain other drugs. Chorea consists of irregular, unpredictable, involuntary muscle jerks that occur in different parts of the body and impair voluntary activity. In some instances, the proximal muscles of the limbs

The patient is started on a dopamine agonist, and the dose is gradually built up to the therapeutic range. Was this a good choice of medications? Six months later, the patient and his wife return for followup. It now becomes apparent that he is falling asleep at inappropriate times, such as at the dinner table, and when awake, he spends much of the time in arranging and rearranging the table cutlery or in picking at his clothes. To what is his condition due, and how should it be managed? Would you recommend surgical treatment?

are most severely affected, and because the abnormal movements are then particularly violent, the term ballismus has been used to describe them. Chorea may be hereditary or acquired and may occur as a complication of a number of general medical disorders and of therapy with certain drugs. Abnormal movements may be slow and writhing in character (athetosis) and, in some instances, are so sustained that they are more properly regarded as abnormal postures (dystonia). Athetosis or dystonia may occur with perinatal brain damage, with focal or generalized cerebral lesions, as an acute complication of certain drugs, as an accompaniment of diverse neurologic disorders, or as an isolated inherited phenomenon of uncertain cause known as isolated generalized torsion dystonia or dystonia musculorum deformans. Various genetic loci have been reported depending on the age of onset, mode 517

518    SECTION V  Drugs That Act in the Central Nervous System

of inheritance, and response to dopaminergic therapy. The physiologic basis is uncertain, and treatment is unsatisfactory. Patients with dystonia commonly have psychiatric complications, such as depression, that affect the quality of life. These may be secondary to the dystonia or a nonmotor manifestation of the underlying disorder. Tics are sudden coordinated abnormal movements that tend to occur repetitively, particularly about the face and head, especially in children, and can be suppressed voluntarily for short periods of time. Common tics include repetitive sniffing or shoulder shrugging. Tics may be single or multiple and transient or chronic. Gilles de la Tourette syndrome is characterized by chronic multiple tics; its pharmacologic management is discussed at the end of this chapter. Many of the movement disorders have been attributed to disturbances of the basal ganglia. The basic circuitry of the basal ganglia involves three interacting neuronal loops that include the cortex and thalamus as well as the basal ganglia themselves (Figure  28–1). However, the precise function of these anatomic structures is not yet fully understood, and it is not possible to relate individual symptoms to involvement at specific sites.

Cortex

+

Glutamate +

– Dopamine

Striatum + Dopamine –

Substantia nigra (pars compacta)

GABA Enkephalin

Globus pallidus (external) Indirect pathway –

Direct pathway

GABA GABA Substance P

Subthalamic nucleus – Glutamate +

Globus pallidus (internal) Substantia nigra (pars reticulata)

–

GABA Thalamus (ventrolateralventroanterior nuclei)

FIGURE 28–1  Functional circuitry between the cortex, basal ganglia, and thalamus. The major neurotransmitters are indicated. In Parkinson disease, there is degeneration of the pars compacta of the substantia nigra, leading to overactivity in the indirect pathway (red) and increased glutamatergic activity by the subthalamic nucleus.

■■ PARKINSONISM & PARKINSON DISEASE Parkinsonism is characterized by a combination of rigidity, bradykinesia, tremor, and postural instability that can occur for a variety of reasons but is usually idiopathic (Parkinson disease or paralysis agitans). Bradykinesia should be present before a diagnosis of Parkinson disease is made. Focal dystonic features may be present. Cognitive decline occurs in many patients as the disease advances. Other nonmotor symptoms include affective disorders (anxiety or depression); confusion, cognitive impairment, or personality changes; apathy; fatigue; abnormalities of autonomic function (eg, sphincter or sexual dysfunction, dysphagia and choking, sweating abnormalities, sialorrhea, or disturbances of blood pressure regulation); sleep disorders; and sensory complaints or pain. The disease is incurable, is generally progressive, and leads to increasing disability with time, but pharmacologic treatment may relieve motor symptoms and improve the quality of life for many years. Patients with Parkinson disease may develop hyposmia, constipation, depression, anxiety, or rapid-eye-movement (REM) sleep behavior disorder in a preclinical phase before onset of the motor disturbance. Parkinsonism may also have a hereditary basis, may follow exposure to various toxins (eg, manganese dusts, carbon disulfide, carbon monoxide), may develop after multiple subcortical whitematter infarcts or recurrent head injury (as in boxers), and may occur in association with other neurologic disorders.

Pathogenesis The pathogenesis of Parkinson disease seems to relate to a combination of impaired degradation of proteins, intracellular protein accumulation and aggregation, oxidative stress, mitochondrial damage, inflammatory cascades, and apoptosis. Studies in twins suggest that genetic factors are important, especially when the disease occurs in patients under age 50. Recognized genetic abnormalities account for 10–15% of cases. Mutations of the α-synuclein gene at 4q21 or duplication and triplication of the normal synuclein gene are associated with Parkinson disease, which is now widely recognized as a synucleinopathy. Mutations of the leucine-rich repeat kinase 2 (LRRK2) gene at 12cen, and the UCHL1 gene may also cause autosomal dominant parkinsonism. Mutations in the parkin gene (6q25.2–q27) cause early-onset, autosomal recessive, familial parkinsonism, or sporadic juvenile-onset parkinsonism. Several other genes or chromosomal regions have been associated with familial forms of the disease. Environmental or endogenous toxins may also be important in the etiology of the disease. Epidemiologic studies reveal that cigarette smoking, coffee, anti-inflammatory drug use, and high serum uric acid levels are protective, whereas the incidence of the disease is increased in those working in teaching, health care, or farming, and in those with lead or manganese exposure or with vitamin D deficiency. The finding of Lewy bodies (intracellular inclusion bodies containing α-synuclein) in fetal dopaminergic cells transplanted into the brain of parkinsonian patients some years previously has provided some support for suggestions that Parkinson disease may represent a prion disease.

CHAPTER 28  Pharmacologic Management of Parkinsonism & Other Movement Disorders     519

Normal Substantia nigra

Corpus striatum

Dopamine Acetylcholine

GABA

Parkinsonism

FIGURE 28–2  Schematic representation of the sequence of neurons involved in parkinsonism. A simplified version of the involved circuitry is shown. Top: Dopaminergic neurons (red) originating in the substantia nigra normally inhibit the GABAergic output from the striatum, whereas cholinergic neurons (green) exert an excitatory effect. Bottom: In parkinsonism, there is a selective loss of dopaminergic neurons (dashed, red). Staining for α-synuclein has revealed that pathology is more widespread than previously recognized, developing initially in the olfactory nucleus and the medulla or lower brainstem (stage 1 of Braak scale), then higher in the medulla and the pons of the brainstem (stage 2), extending to the midbrain and in particular the substantia nigra (stage 3), the mesocortex and thalamus (stage 4), the neocortex (stage 5), and then spreading more extensively in the neocortex (stage 6). The motor features of Parkinson disease develop at stage 3 on the Braak scale. The normally high concentration of dopamine in the basal ganglia of the brain is reduced in parkinsonism, and pharmacologic attempts to restore dopaminergic activity with levodopa and dopamine agonists alleviate many of the motor features of the disorder. An alternative but complementary approach has been to restore the normal balance of cholinergic and dopaminergic influences on the basal ganglia with antimuscarinic drugs. The pathophysiologic basis for these therapies is that in idiopathic parkinsonism, there is a loss of dopaminergic neurons in the substantia nigra that normally inhibit the output of GABAergic cells in the corpus striatum (Figure 28–2). Drugs that induce parkinsonian syndromes either are dopamine receptor antagonists (eg, antipsychotic agents; see Chapter 29) or lead to the destruction of the dopaminergic nigrostriatal neurons (eg, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine [MPTP]; see below). Various other neurotransmitters, such as norepinephrine, are also depleted in the brain in parkinsonism, but these deficiencies are of uncertain clinical relevance.

LEVODOPA Dopamine does not cross the blood-brain barrier and if given into the peripheral circulation has no therapeutic effect in parkinsonism. However, (–)-3-(3,4-dihydroxyphenyl)-l-alanine (levodopa),

the immediate metabolic precursor of dopamine, does enter the brain (via an l-amino acid transporter, LAT), where it is decarboxylated to dopamine (see Figure 6–5). Several noncatecholamine dopamine receptor agonists have also been developed and may lead to clinical benefit, as discussed in the text that follows. Dopamine receptors are discussed in detail in Chapters 21 and 29. They exist in five subtypes. D1 and D5 receptors are classified as the D1 receptor family based on genetic and biochemical factors; D2, D3, and D4 are grouped as belonging to the D2 receptor family. Dopamine receptors of the D1 type are located in the pars compacta of the substantia nigra and presynaptically on striatal axons coming from cortical neurons and from dopaminergic cells in the substantia nigra. The D2 receptors are located postsynaptically on striatal neurons and presynaptically on axons in the substantia nigra belonging to neurons in the basal ganglia. The benefits of dopaminergic antiparkinsonism drugs appear to depend mostly on stimulation of the D2 receptors. However, D1-receptor stimulation may also be required for maximal benefit, and one of the newer drugs is D3 selective. Dopamine agonist or partial agonist ergot derivatives such as lergotrile and bromocriptine that are powerful stimulators of the D2 receptors have antiparkinsonism properties, whereas certain dopamine blockers that are selective D2 antagonists can induce parkinsonism.

Chemistry Dopa is the amino acid precursor of dopamine and norepinephrine (discussed in Chapter 6). Its structure is shown in Figure 28–3. Levodopa is the levorotatory stereoisomer of dopa.

Pharmacokinetics Levodopa is rapidly absorbed from the small intestine, but its absorption depends on the rate of gastric emptying and the pH of the gastric contents. Ingestion of food delays the appearance of levodopa in the plasma. Moreover, certain amino acids from ingested food can compete with the drug for absorption from the gut and for transport from the blood to the brain. Plasma concentrations usually peak between 1 and 2 hours after an oral dose, and the plasma half-life is usually between 1 and 3 hours, although it varies considerably among individuals. About two-thirds of the dose appears in the urine as metabolites within 8 hours of an oral dose, the main metabolic products being 3-methoxy-4-hydroxyphenyl acetic acid (homovanillic acid, HVA) and dihydroxyphenylacetic acid (DOPAC). Unfortunately, only about 1–3% of administered levodopa actually enters the brain unaltered; the remainder is metabolized extracerebrally, predominantly by decarboxylation to dopamine, which does not penetrate the blood-brain barrier. Accordingly, levodopa must be given in large amounts when used alone. However, when given in combination with a dopa decarboxylase inhibitor that does not penetrate the blood-brain barrier, the peripheral metabolism of levodopa is reduced, plasma levels of levodopa are higher, plasma half-life is longer, and more dopa is available for entry into the brain (Figure 28–4). Indeed, concomitant administration of a peripheral dopa decarboxylase inhibitor such as carbidopa may reduce the daily requirements of levodopa by approximately 75%.

520    SECTION V  Drugs That Act in the Central Nervous System

HO

CH2

COOH

CH NH2

HO Dihydroxyphenylalanine (DOPA) CH3 HO

CH2

COOH

C

NH2

NH HO Carbidopa

CH3 CH2

CH

N

CH2

C

CH

CH3 Selegiline

O2N

CH

C

N

C

C O

N

CH2CH3 CH2CH3

HO OH Entacapone

FIGURE 28–3 

Some drugs used in the treatment of parkinsonism.

Clinical Use The best results of levodopa treatment are obtained in the first few years of treatment. This is sometimes because the daily dose of levodopa must be reduced over time to avoid adverse effects at doses that were well tolerated initially. Some patients become less responsive to levodopa, perhaps because of loss of dopaminergic nigrostriatal nerve terminals or some pathologic process directly involving striatal dopamine receptors. For such reasons, the benefits of levodopa treatment often begin to diminish after about 3 or 4 years of therapy, regardless of the initial therapeutic response. Although levodopa therapy does not stop the progression of parkinsonism, its early initiation lowers the mortality rate. However, long-term therapy may lead to a number of problems in management such as the on-off phenomenon discussed below. The most appropriate time to introduce levodopa therapy must therefore be determined individually. When levodopa is used, it is generally given in combination with carbidopa (see Figure 28–3), a peripheral dopa decarboxylase inhibitor, which reduces peripheral conversion to dopamine. Combination treatment is started with a small dose, eg, carbidopa 25 mg, levodopa 100 mg three times daily, and gradually increased.

It should be taken 30–60 minutes before meals. Most patients ultimately require carbidopa 25 mg, levodopa 250 mg three or four times daily. Some physicians prefer to keep treatment with this agent at a low level (eg, carbidopa-levodopa 25/100 three times daily) when possible, and if necessary, to add a dopamine agonist, in the belief that this reduces the risk of development of response fluctuations. However, the occurrence of response fluctuations probably depends on disease progression rather than pharmacologic management, and any benefit of dopamine agonists in this regards is probably because they are less effective than levodopa. A controlled-release formulation of carbidopa-levodopa is available and may be helpful in patients with established response fluctuations or as a means of reducing dosing frequency. Even more helpful for response fluctuations is an extended-release formulation (Rytary) that consists of capsules containing beads that release carbidopa and levodopa (present in a 1:4 ratio) at different rates over a prolonged time as they dissolve in the stomach. It is substituted for the regular (immediate-release) formulation using dosing guidelines provided by its manufacturer (Table 28–1). A formulation of carbidopa-levodopa (10/100, 25/100, 25/250) that disintegrates in the mouth and is swallowed with the saliva (Parcopa) is available commercially and is best taken about 1 hour before meals. The combination (Stalevo) of levodopa, carbidopa, and a catechol-O-methyltransferase (COMT) inhibitor (entacapone) is discussed in a later section. Finally, therapy by infusion of carbidopa-levodopa into the duodenum or upper jejunum appears to be safe and is superior to a number of oral combination therapies in patients with advanced levodopa-responsive parkinsonism with response fluctuations. A permanent access tube is inserted via a percutaneous endoscopic gastrostomy in patients who have responded well to carbidopa-levodopa gel administered through a nasoduodenal tube. A morning bolus (100–300 mg of levodopa) is delivered via a portable infusion pump, followed by a continuous maintenance dose (40–120 mg/h), with supplemental bolus doses as required. Levodopa can ameliorate many of the clinical motor features of parkinsonism, but it is particularly effective in relieving bradykinesia and any disabilities resulting from it. When it is first introduced, about one third of patients respond very well and one third less well. Most of the remainder either are unable to tolerate the medication or simply do not respond at all, especially if they do not have classic Parkinson disease.

Adverse Effects A. Gastrointestinal Effects When levodopa is given without a peripheral decarboxylase inhibitor, anorexia and nausea and vomiting occur in about 80% of patients. These adverse effects can be minimized by taking the drug in divided doses, with or immediately after meals, and by increasing the total daily dose very slowly. Antacids taken 30–60 minutes before levodopa may also be beneficial. The vomiting has been attributed to stimulation of the chemoreceptor trigger zone located in the brainstem but outside the blood-brain barrier. Fortunately, tolerance to this emetic effect develops in many patients. If not, an additional dose of carbidopa (Lodosyn; 25 mg) taken

CHAPTER 28  Pharmacologic Management of Parkinsonism & Other Movement Disorders     521

Levodopa alone 100%

30%

1–3%

Brain

Blood Levodopa dose

Gut

70%

27–29%

Metabolism in the GI tract

Peripheral tissues (toxicity)

Levodopa with carbidopa 100% Levodopa dose

60% Blood

Gut

40%

Metabolism in the GI tract

10%

Brain

50%

Peripheral tissues (toxicity)

FIGURE 28–4  Fate of orally administered levodopa and the effect of carbidopa, estimated from animal data. The width of each pathway indicates the absolute amount of the drug at each site, whereas the percentages shown denote the relative proportion of the administered dose. The benefits of co-administration of carbidopa include reduction of the amount of levodopa required for benefit and of the absolute amount diverted to peripheral tissues and an increase in the fraction of the dose that reaches the brain. GI, gastrointestinal. (Data from Nutt JG, Fellman JH: Pharmacokinetics of levodopa. Clin Neuropharmacol 1984;7(1):35-49.)

TABLE 28-1  Substitution of Rytary for immediaterelease carbidopa/levodopa.

1

Current Levodopa Total Daily Dose (mg)

Rytary Dose (Carbidopa/ 1 Levodopa) (mg)

Zero

23.75/95, 1 cap TID

400–549

23.75/95, 3 caps TID

550–749

23.75/95, 4 caps QID

750–949

36.25/145, 3 caps TID

950–1249

48.75/195, 3 caps TID

1250 or more

48.75/195, 4 caps TID or

 

61.25/245, 3 caps TID

Dose levels recommended by the manufacturers.

with the regular carbidopa-levodopa dose is often helpful, even though the usual maximum requirement of carbidopa is 75 mg daily. Domperidone (not available in the USA) may also relieve persistent nausea, as may ondansetron. Antiemetics such as phenothiazines should be avoided because they reduce the antiparkinsonism effects of levodopa and may exacerbate the disease. When levodopa is given in combination with carbidopa, adverse gastrointestinal effects are much less frequent and troublesome, occurring in less than 20% of cases, so that patients can tolerate proportionately higher doses. B. Cardiovascular Effects A variety of cardiac arrhythmias have been described in patients receiving levodopa, including tachycardia, ventricular extrasystoles, and rarely, atrial fibrillation. This effect has been attributed to

522    SECTION V  Drugs That Act in the Central Nervous System

increased catecholamine formation peripherally. The incidence of such arrhythmias is low, even in the presence of established cardiac disease, and may be reduced still further if the levodopa is taken in combination with a peripheral decarboxylase inhibitor. Postural hypotension is common, but often asymptomatic, and tends to diminish with continuing treatment. However, it sometimes develops later in the disease course. Hypertension may also occur, especially in the presence of nonselective monoamine oxidase inhibitors or sympathomimetics or when massive doses of levodopa are being taken. C. Behavioral Effects A wide variety of adverse mental effects have been reported, including depression, anxiety, agitation, insomnia, somnolence, sleep attacks, confusion, delusions, hallucinations, nightmares, euphoria, and other changes in mood or personality. Such adverse effects are more common in patients taking levodopa in combination with a decarboxylase inhibitor rather than levodopa alone, presumably because higher levels are reached in the brain. They may be precipitated by intercurrent illness or surgery. It may be necessary to reduce or withdraw the medication. Several atypical antipsychotic agents that have low affinity for dopamine D2 receptors (clozapine, olanzapine, quetiapine, and risperidone; see Chapter 29) are now available and may be particularly helpful in counteracting such behavioral complications. Pimavanserin (34 mg daily), a selective serotonin 5-HT2A inverse agonist, is also helpful for treating the hallucinations and delusions of Parkinson disease psychosis. It should not be used for dementia-related psychosis and should be avoided in patients with QT prolongation. Confusion and hallucinations developing in parkinsonian patients is more likely due to treatment with anticholinergic agents, amantadine, or dopamine agonists rather than to levodopa. The dopamine dysregulation syndrome is characterized by compulsive overuse of dopaminergic medication as well as by other impulsive behaviors; such impulse control disorders are more common with dopamine agonists than levodopa and are discussed later. Management involves the close regulation of dopaminergic intake. Punding designates the performance of stereotyped, complex, but purposeless motor activity, such as sorting or lining up various objects or repetitive grooming behavior. It responds to reduction in dose of dopaminergic agents or to atypical antipsychotic agents. D. Dyskinesias and Response Fluctuations Dyskinesias occur in up to 80% of patients receiving levodopa therapy for more than 10 years. The character of dopa dyskinesias varies between patients but tends to remain constant in individual patients. Choreoathetosis of the face and distal extremities is the most common presentation. The development of dyskinesias is dose related, but there is considerable individual variation in the dose required to produce them. Their pathogenesis is unclear, but they may relate to an unequal distribution of striatal dopamine. Dopaminergic denervation plus chronic pulsatile stimulation of dopamine receptors with levodopa has been associated with development of dyskinesias. A lower incidence of dyskinesias occurs

when levodopa is administered continuously (eg, intraduodenally or intrajejunally) and with drug delivery systems that enable a more continuous delivery of dopaminergic medication. Reduction of levodopa dose or the dose of adjunctive medications (discussed later) will alleviate dyskinesias in many instances, but motor symptoms of parkinsonism then worsen. Much less commonly, dyskinesias occur as patients respond to levodopa and again as the benefit wears off, and these “diphasic dyskinesias” may be best managed by dividing the daily dose into more frequent smaller doses or by replacing some of the levodopa with a dopamine receptor agonist. Mild dyskinesias require no treatment. Amantadine may help to reduce more troublesome dyskinesias, as may clozapine; a number of other compounds are being studied as possible antidyskinetic agents. Certain fluctuations in clinical response to levodopa occur with increasing frequency as treatment continues. In some patients, these fluctuations relate to the timing of levodopa intake (wearing-off reactions or end-of-dose akinesia). In other instances, fluctuations in clinical state are unrelated to the timing of doses (on-off phenomenon). In the on-off phenomenon, off-periods of marked akinesia alternate over the course of a few hours with on-periods of improved mobility but often marked dyskinesia. These fluctuations may be helped by talking the main protein meal in the evening rather than during the day, by adjustments to levodopa dose and dosing interval, and by the use of longeracting formulations of levodopa and adjunctive medications. An inhaled formulation of levodopa also is available commercially for the intermittent treatment of off-periods. Surgical treatment should be considered (discussed later). For patients with severe off-periods who are unresponsive to other measures, subcutaneously injected apomorphine may provide temporary benefit but may increase dyskinesias. The on-off phenomenon is most likely to occur in patients who responded well to treatment initially. The exact mechanism is unknown. E. Miscellaneous Adverse Effects Mydriasis may occur and may precipitate an attack of acute glaucoma in some patients. Other reported but rare adverse effects include various blood dyscrasias; a positive Coombs’ test with evidence of hemolysis; hot flushes; aggravation or precipitation of gout; abnormalities of smell or taste; brownish discoloration of saliva, urine, or vaginal secretions; priapism; and mild—usually transient—elevations of blood urea nitrogen and of serum transaminases, alkaline phosphatase, and bilirubin.

Drug Holidays A drug holiday (discontinuance of the drug for 3–21 days) may temporarily improve responsiveness to levodopa and alleviate some of its adverse effects but is usually of little help in the management of the on-off phenomenon. Furthermore, a drug holiday carries the risks of aspiration pneumonia, venous thrombosis, pulmonary embolism, and depression resulting from the immobility accompanying severe parkinsonism. For these reasons and because of the temporary nature of any benefit, drug holidays are not recommended.

CHAPTER 28  Pharmacologic Management of Parkinsonism & Other Movement Disorders     523

Drug Interactions Pharmacologic doses of pyridoxine (vitamin B6) enhance the extracerebral metabolism of levodopa and may therefore prevent its therapeutic effect unless a peripheral decarboxylase inhibitor is also taken. Levodopa should not be given to patients taking monoamine oxidase A inhibitors or within 2 weeks of their discontinuance because such a combination can lead to hypertensive crises.

Contraindications Levodopa should not be given to psychotic patients because it may exacerbate the mental disturbance. It is also contraindicated in patients with angle-closure glaucoma, but those with chronic open-angle glaucoma may be given levodopa if intraocular pressure is well controlled and can be monitored. When combined with carbidopa, the risk of cardiac dysrhythmia is slight, even in patients with cardiac disease. Patients with active peptic ulcer must be managed carefully, since gastrointestinal bleeding has occasionally occurred with levodopa. Because levodopa is a precursor of skin melanin and conceivably may activate malignant melanoma, it should be used with particular care in patients with a history of melanoma or with suspicious undiagnosed skin lesions; such patients should be monitored regularly by a dermatologist.

DOPAMINE RECEPTOR AGONISTS Drugs acting directly on postsynaptic dopamine receptors may have a beneficial effect in addition to that of levodopa (Figure  28–5). Unlike levodopa, they do not require enzymatic conversion to an active metabolite, act directly on the postsynaptic dopamine receptors, have no potentially toxic metabolites, and do not compete with other substances for active transport into the blood and across the blood-brain barrier. Moreover, drugs selectively affecting certain (but not all) dopamine receptors may have more limited adverse effects than levodopa. Several dopamine agonists have antiparkinsonism activity. The older dopamine agonists (bromocriptine and pergolide) are ergot (ergoline) derivatives (see Chapter 16) and are rarely—if ever—used to treat parkinsonism. Their side effects are of more concern than those of the newer agents (pramipexole and ropinirole). There is no evidence that one agonist is superior to another; individual patients, however, may respond to one but not another of these agents. Moreover, their duration of action varies and is lengthened by extended-release preparations. Apomorphine is a potent dopamine agonist but is discussed separately in a later section in this chapter because it is used primarily as a rescue drug for patients with disabling response fluctuations to levodopa. Dopamine agonists have been used as first-line therapy for Parkinson disease, and their use is associated with a lower incidence of the response fluctuations and dyskinesias that occur with long-term levodopa therapy. Dopaminergic therapy is therefore often initiated with a dopamine agonist, although, compared

Pramipexole, ropinirole

+

Selegiline, rasagiline

Dopamine receptors

Tolcapone

+

– MAO-B

DOPAC

+

Bromocriptine, pergolide

– Dopamine

COMT

3-MT

DOPA decarboxylase L-DOPA L-amino acid transporter

Brain Blood-brain barrier Periphery 3-OMD

COMT

L-DOPA

Dopamine DOPA decarboxylase

–

–

Entacapone, tolcapone

Carbidopa

Adverse effects

FIGURE 28–5  Pharmacologic strategies for dopaminergic therapy of Parkinson disease. Drugs and their effects are indicated (see text). COMT, catechol-O-methyltransferase; DOPAC, dihydroxyphenylacetic acid; L-DOPA, levodopa; MAO, monoamine oxidase; 3-MT, 3-methoxytyramine; 3-OMD, 3-O-methyldopa. with levodopa, the agonists generally provide less symptomatic benefit and are more likely to cause mental side effects, somnolence, and edema. In other instances, a low dose of carbidopa plus levodopa (eg, Sinemet, 25/100 three times daily) is introduced, and a dopamine agonist is then added. In either case, the dose of the dopamine agonist is built up gradually depending on response and tolerance. Dopamine agonists may also be given to patients with parkinsonism who are taking levodopa and who have end-of-dose akinesia or on-off phenomenon or are becoming resistant to treatment with levodopa. In such circumstances, it is generally necessary to lower the dose of levodopa to prevent intolerable adverse effects. The response to a dopamine agonist is generally disappointing in patients who have never responded to levodopa.

Bromocriptine Bromocriptine is a D2 agonist; its structure is shown in Table 16–7. This drug has been widely used to treat Parkinson disease in the past but is now rarely used for this purpose. The usual daily dose of bromocriptine for parkinsonism varies between 7.5 and 30 mg. To minimize adverse effects, the dose is built up slowly over 2 or 3 months depending on response or the development of adverse reactions.

524    SECTION V  Drugs That Act in the Central Nervous System

Pergolide

CH3

CH2

CH2

Pergolide, another ergot derivative, directly stimulates both D1 and D2 receptors. It too has been widely used for parkinsonism but is no longer available in the United States because its use has been associated with the development of valvular heart disease. It is nevertheless still used in some countries.

CH3

CH2

CH2

N

CH2

CH2

O N Ropinirole

Pramipexole Pramipexole is not an ergot derivative, but it has preferential affinity for the D3 receptor. It is effective as monotherapy for mild parkinsonism and is also helpful in patients with advanced disease, permitting the dose of levodopa to be reduced and smoothing out response fluctuations. Pramipexole may ameliorate affective symptoms. A possible neuroprotective effect has been suggested by its ability to scavenge hydrogen peroxide and enhance neurotrophic activity in mesencephalic dopaminergic cell cultures. CH3

CH2

CH2

NH

S

NH2

N Pramipexole

Pramipexole is rapidly absorbed after oral administration, reaching peak plasma concentrations in approximately 2 hours, and is excreted largely unchanged in the urine. It is started at a dosage of 0.125 mg three times daily, doubled after 1 week, and again after another week. Further increments in the daily dose are by 0.75 mg at weekly intervals, depending on response and tolerance. Most patients require between 0.5 and 1.5 mg three times daily. Renal insufficiency may necessitate dosage adjustment. An extended-release preparation is now available and is taken once daily at a dose equivalent to the total daily dose of standard pramipexole. The extended-release preparation is generally more convenient for patients and avoids swings in blood levels of the drug over the day.

Rotigotine The dopamine agonist rotigotine, delivered daily through a skin patch, is approved for treatment of early Parkinson disease. It supposedly provides more continuous dopaminergic stimulation than oral medication in early parkinsonism; its efficacy in more advanced disease is less clear. Benefits and side effects are similar to those of other dopamine agonists but reactions may also occur at the application site and are sometimes serious. Treatment is usually started with the 2 mg/24 hours patch and titrated weekly as necessary by increasing the patch size to 4 mg/24 hours and then to 6 mg/24 hours.

Adverse Effects of Dopamine Agonists A. Gastrointestinal Effects Anorexia and nausea and vomiting may occur when a dopamine agonist is introduced and can be minimized by taking the medication with meals. Constipation, dyspepsia, and symptoms of reflux esophagitis may also occur. Bleeding from peptic ulceration has been reported. B. Cardiovascular Effects Postural hypotension may occur, particularly at the initiation of therapy. Painless digital vasospasm is a dose-related complication of long-term treatment with the ergot derivatives (bromocriptine or pergolide). When cardiac arrhythmias occur, they are an indication for discontinuing treatment. Peripheral edema is sometimes problematic. Cardiac valvulopathy may occur with pergolide.

Ropinirole

C. Dyskinesias Abnormal movements similar to those introduced by levodopa may occur and are reversed by reducing the total dose of dopaminergic drugs being taken.

Another nonergoline derivative, ropinirole (now available in a generic preparation) is a relatively pure D2 receptor agonist that is effective as monotherapy in patients with mild disease and as a means of smoothing the response to levodopa in patients with more advanced disease and response fluctuations. It is introduced at 0.25 mg three times daily, and the total daily dose is then increased by 0.75 mg at weekly intervals until the fourth week and by 1.5 mg thereafter. In most instances, a dosage between 2 and 8 mg three times daily is necessary. Ropinirole is metabolized by CYP1A2; other drugs metabolized by this isoform may significantly reduce its clearance. A prolonged-release preparation taken once daily is available.

D. Mental Disturbances Confusion, hallucinations, delusions, and other psychiatric reactions may develop as a feature of Parkinson disease or as complications of dopaminergic treatment and are more common and severe with dopamine receptor agonists than with levodopa. They tend to occur earlier in older patients and become more common as the disease advances. There appears to be no difference between the various dopamine agonists in their ability to induce these disorders. They may respond to atypical antipsychotic agents such as clozapine, olanzapine, quetiapine, and risperidone or to pimavanserin.

CHAPTER 28  Pharmacologic Management of Parkinsonism & Other Movement Disorders     525

Disorders of impulse control may occur either as an exaggeration of a previous tendency or as a new phenomenon and may lead to compulsive gambling, shopping, betting, sexual activity, and other behaviors (see Chapter 32). Their prevalence varies in different reports but may be as high as 45% in parkinsonian patients treated with dopamine agonists. They relate to activation of D2 or D3 dopamine receptors in the mesocorticolimbic system, may occur with one dopamine agonist and not another, and may occur at any time after the initiation of treatment. They have been associated with increasing dose and duration of treatment; in some patients, a dose reduction may ameliorate them. They resolve on withdrawal of the offending medication. Impulse control disorders are generally under-reported by patients and their families and often unrecognized by health care professionals. Risk factors include an impulsive personality, a history of drug use or other addictive behaviors, and a family history of gambling disorders. A withdrawal syndrome develops in occasional patients tapered off a dopamine agonist. It consists of a combination of distressing physical and psychological symptoms that are refractory to levodopa and other dopaminergic medications, that may persist for months or longer, and for which no other cause can be found. Anxiety, agitation, panic attacks, depression, suicidal ideation, irritability, fatigue, postural hypotension, nausea, vomiting, diaphoresis, and drug cravings may occur. Risk factors include impulse control behavior disorders and higher dopamine agonist dosage. There is no effective treatment. The dopamine agonist should be reintroduced and tapered more gradually if possible. Treatment with dopamine agonists should not be stopped abruptly, because doing so may rarely lead to an akinetic (parkinsonian) crisis or to a syndrome resembling neuroleptic malignant syndrome (discussed later). E. Miscellaneous Headache, nasal congestion, increased arousal, pulmonary infiltrates, pleural and retroperitoneal fibrosis, and erythromelalgia are other reported adverse effects of the ergot-derived dopamine agonists. Erythromelalgia consists of red, tender, painful, swollen feet and, occasionally, hands, at times associated with arthralgia; symptoms and signs clear within a few days of withdrawal of the causal drug. In rare instances, an uncontrollable tendency to fall asleep at inappropriate times has occurred, particularly in patients receiving pramipexole or ropinirole; this requires discontinuation of the medication.

Contraindications Dopamine agonists are contraindicated in patients with a history of psychotic illness or recent myocardial infarction, or with active peptic ulceration. The ergot-derived agonists are best avoided in patients with peripheral vascular disease.

MONOAMINE OXIDASE INHIBITORS Two types of monoamine oxidase have been distinguished in the nervous system. Monoamine oxidase A metabolizes norepinephrine, serotonin, and dopamine; monoamine oxidase B metabolizes

dopamine selectively. Selegiline (deprenyl) (see Figure 28–3), a selective irreversible inhibitor of monoamine oxidase B at normal doses (at higher doses it inhibits monoamine oxidase A as well), retards the breakdown of dopamine (see Figure 28–5); in consequence, it enhances and prolongs the antiparkinsonism effect of levodopa (thereby allowing the dose of levodopa to be reduced) and may reduce mild on-off or wearing-off phenomena. It is therefore used as adjunctive therapy for patients with a declining or fluctuating response to levodopa. The standard dose of selegiline is 5 mg with breakfast and 5 mg with lunch. Selegiline may cause insomnia when taken later during the day. Selegiline has only a minor therapeutic effect on parkinsonism when given alone. Studies in animals suggest that it may reduce disease progression, but trials to test the effect of selegiline on the progression of parkinsonism in humans have yielded ambiguous results. The findings in a large multicenter study were taken to suggest a beneficial effect in slowing disease progression but may simply have reflected a symptomatic response. Rasagiline, another monoamine oxidase B inhibitor, is more potent than selegiline in preventing MPTP-induced parkinsonism and is being used as monotherapy for early treatment in patients with mild symptoms. The standard dosage is 1 mg/d. Rasagiline is also used as adjunctive therapy at a dosage of 0.5 or 1 mg/d to prolong the effects of carbidopa-levodopa in patients with advanced disease and response fluctuations. A large double-blind, placebocontrolled, delayed-start study (the ADAGIO trial) to evaluate whether it had neuroprotective benefit (ie, slowed the disease course) yielded unclear results: a daily dose of 1 mg met all the end points of the study and did seem to slow disease progression, but a 2-mg dose failed to do so. These findings are difficult to explain, and the decision to use rasagiline for neuroprotective purposes therefore remains an individual one. A third monoamine oxidase B inhibitor, safinamide, has been used to reduce response fluctuations in patients taking carbidopalevodopa, diminishing off-periods in patients with wearing-off effect or on-off phenomena. It is not effective as monotherapy for Parkinson disease. The starting dose is 50 mg orally once daily, increased after 2 weeks to 100 mg once daily. Monoamine oxidase B inhibitors should not be taken by patients receiving meperidine, tramadol, methadone, propoxyphene, cyclobenzaprine, or St. John’s wort. The antitussive dextromethorphan should also be avoided by patients taking one of the monoamine oxidase B inhibitors; indeed, it is wise to advise patients to avoid all over-the-counter cold preparations. Rasagiline, selegiline, or safinamide should not be taken with other monoamine oxidase inhibitors and should be used with care in patients receiving tricyclic antidepressants or serotonin reuptake inhibitors because of the theoretical risk of acute toxic interactions of the serotonin syndrome type (see Chapter 16), but this is rarely encountered in practice. The adverse effects of levodopa, especially dyskinesias, mental changes, nausea, and sleep disorders, may be increased by these drugs. Hypertension may be precipitated or aggravated. The combined administration of levodopa and an inhibitor of both forms of monoamine oxidase (ie, a nonselective inhibitor) must be avoided, because it may lead to hypertensive crises, probably due to the peripheral accumulation of norepinephrine.

526    SECTION V  Drugs That Act in the Central Nervous System

CATECHOL-O-METHYLTRANSFERASE INHIBITORS Inhibition of dopa decarboxylase is associated with compensatory activation of other pathways of levodopa metabolism, especially catechol-O-methyltransferase (COMT), and this increases plasma levels of 3-O-methyldopa (3-OMD). Elevated levels of 3-OMD have been associated with a poor therapeutic response to levodopa, perhaps in part because 3-OMD competes with levodopa for an active carrier mechanism that governs its transport across the intestinal mucosa and the blood-brain barrier. Selective COMT inhibitors such as tolcapone and entacapone also prolong the action of levodopa by diminishing its peripheral metabolism (see Figure 28–5). Levodopa clearance is decreased, and relative bioavailability of levodopa is thus increased. Neither the time to reach peak concentration nor the maximal concentration of levodopa is increased. These agents may be helpful in patients receiving levodopa who have developed response fluctuations, leading to a smoother response, more prolonged on-time, and the option of reducing total daily levodopa dose. There is no benefit in taking a COMT inhibitor either alone or with levodopa as initial therapy for parkinsonism. Tolcapone and entacapone are both widely available, but entacapone is generally preferred because it has not been associated with hepatotoxicity. The pharmacologic effects of tolcapone and entacapone are similar, and both are rapidly absorbed, bound to plasma proteins, and metabolized before excretion. However, tolcapone has both central and peripheral effects, whereas the effect of entacapone is peripheral. The half-life of both drugs is approximately 2 hours, but tolcapone is slightly more potent and has a longer duration of action. Tolcapone is taken in a standard dosage of 100 mg three times daily; some patients require a daily dose of twice that amount. By contrast, entacapone (200 mg) needs to be taken with each dose of levodopa, up to six times daily. Opicapone (Ongentys) is a newer long-acting, peripherally selective, catechol-O-methyl transferase inhibitor that is taken once daily at bedtime, in a 50-mg dose. As with the other COMT inhibitors, it decreases the duration of daily off-periods and increases on-time in patients with a fluctuating response to levodopa. Adverse effects of the COMT inhibitors relate in part to increased levodopa exposure and include dyskinesias, nausea, and confusion. It is often necessary to lower the daily dose of levodopa by about 30% in the first 48 hours to avoid or reverse such complications. Other adverse effects include diarrhea, abdominal pain, orthostatic hypotension, sleep disturbances, and an orange discoloration of the urine. Tolcapone may cause an increase in liver enzyme levels and has been associated rarely with death from acute hepatic failure; accordingly, it should not be used in patients with abnormal liver function test results. Its use in the USA requires signed patient consent (as provided in the product labeling) plus monitoring of liver function tests every 2–4 weeks during the first 6 months and periodically but less frequently thereafter. The medication should be withdrawn and not reintroduced if hepatic damage becomes evident. No such toxicity has been reported with entacapone.

The commercial preparation named Stalevo consists of a combination of levodopa with both carbidopa and entacapone. It is available in three strengths: Stalevo 50 (50 mg levodopa plus 12.5  mg carbidopa and 200 mg entacapone), Stalevo 100 (100  mg, 25 mg, and 200 mg, respectively), and Stalevo 150 (150 mg, 37.5 mg, and 200 mg, respectively). Use of this preparation simplifies the drug regimen and requires the consumption of fewer tablets than otherwise. The combination agent may provide greater symptomatic benefit than carbidopa-levodopa alone. However, despite the convenience of a single combination preparation, use of Stalevo rather than carbidopa-levodopa has been associated with earlier occurrence and increased frequency of dyskinesia. There is no evidence that the use of Stalevo is associated with an increased risk for cardiovascular events (myocardial infarction, stroke, cardiovascular death).

APOMORPHINE Subcutaneous injection of apomorphine hydrochloride (Apokyn), a potent nonergoline dopamine agonist that interacts with postsynaptic D2 receptors in the caudate nucleus and putamen, is effective for the temporary relief (“rescue”) of off-periods of akinesia in patients on optimized dopaminergic therapy. It is rapidly taken up in the blood and then the brain, leading to clinical benefit that begins within about 10 minutes of injection and persists for up to 2 hours. The optimal dose is identified by administering increasing test doses until adequate benefit is achieved or a maximum of 0.6 mL (6 mg) is reached, with the supine and standing blood pressures monitored before injection and then every 20 minutes for an hour after it. Most patients require a dose of 0.3–0.6 mL (3–6 mg), and this should be given usually no more than about three times daily, but occasionally up to five times daily. Apomorphine can also be given as continuous therapy by infusion to reduce off-time and response fluctuations. Nausea is often troublesome, especially at the initiation of apomorphine treatment; accordingly, oral pretreatment with the antiemetic trimethobenzamide (300 mg three times daily) for 3 days is recommended before apomorphine is introduced and is then continued for at least 1 month, if not indefinitely. Other adverse effects include dyskinesias, drowsiness, insomnia, chest pain, sweating, hypotension, syncope, constipation, diarrhea, mental or behavioral disturbances, panniculitis, and bruising at the injection site. Apomorphine should be prescribed only by physicians familiar with its potential complications and interactions. It should not be used in patients taking serotonin 5-HT3 antagonists because severe hypotension may result.

AMANTADINE Amantadine, an antiviral agent, was by chance found to have relatively weak antiparkinsonism properties. Its mode of action in parkinsonism is unclear, but it may potentiate dopaminergic function by influencing the synthesis, release, or reuptake of dopamine. It has been reported to antagonize the effects of adenosine at adenosine A2A receptors, which may inhibit D2 receptor function.

CHAPTER 28  Pharmacologic Management of Parkinsonism & Other Movement Disorders     527

Release of catecholamines from peripheral stores has also been documented. Amantadine is an antagonist of the NMDA-type glutamate receptor, suggesting an antidyskinetic effect. It is available in an immediate-release formulation (Symmetrel; standard dose, 100 mg orally two or three times daily) and extended-release formulations (Gocovri, once daily at bedtime; Osmolex, 129–322 mg once daily in the morning).

Pharmacokinetics Peak plasma concentrations of amantadine are reached 1–4 hours after an oral dose of the immediate-release preparation. The plasma half-life is between 2 and 4 hours, with most of the drug being excreted unchanged in the urine.

Clinical Use Amantadine is less efficacious than levodopa, and its benefits may be short-lived, often disappearing after only a few weeks of treatment. Nevertheless, during that time it may favorably influence the bradykinesia, rigidity, and tremor of parkinsonism. Amantadine may also help in reducing iatrogenic dyskinesias in patients with advanced disease.

Adverse Effects Amantadine has several undesirable central nervous system effects, all of which can be reversed by stopping the drug. These include restlessness, depression, suicidal ideation, irritability, impulse-control disorders, somnolence, insomnia, agitation, excitement, hallucinations, confusion, and psychosis. Overdosage may produce an acute toxic psychosis. With doses several times higher than recommended, convulsions have occurred. Livedo reticularis sometimes occurs in patients taking amantadine and usually clears within 1 month after the drug is withdrawn. Other dermatologic reactions have also been described. Peripheral edema, another well-recognized complication, is not accompanied by signs of cardiac, hepatic, or renal disease and responds to diuretics. Other adverse reactions to amantadine include headache, heart failure, postural hypotension, urinary retention, and gastrointestinal disturbances (eg, anorexia, nausea, constipation, and dry mouth). Amantadine should be used with caution in patients with a history of seizures, heart failure, or moderate or severe renal disease. Discontinuation of the medication should be gradual, as abrupt withdrawal may lead to an acute confusional state, hyperpyrexia, and abrupt worsening of parkinsonism.

ISTRADEFYLLINE Istradefylline is an analog of caffeine and a selective antagonist of the adenosine A2A receptor. It can be taken orally (20 or 40 mg daily) to reduce off-periods and improve motor function in patients taking carbidopa-levodopa. Side effects include dyskinesias, dizziness, constipation, nausea, hallucinations, and sleeplessness. Hallucinations, psychoses, or impulsive or compulsive behaviors may necessitate dose reductions or discontinuation of the drug.

TABLE 28-2  Some drugs with antimuscarinic

properties used in parkinsonism.

Drug

Usual Daily Dose (mg)

Benztropine mesylate

1–6

Biperiden

2–12

Orphenadrine

150–400

Procyclidine

7.5–30

Trihexyphenidyl

6–20

ACETYLCHOLINE-BLOCKING DRUGS Several centrally acting antimuscarinic preparations are available that differ in their potency and in their efficacy in different patients. Some of these drugs were discussed in Chapter 8. These agents may improve the tremor and rigidity of parkinsonism but have little effect on bradykinesia. They are more effective than placebo. Some of the more commonly used drugs are listed in Table 28–2.

Clinical Use Treatment is started with a low dose of one of the drugs in this category, the dosage gradually being increased until benefit occurs or until adverse effects limit further increments. If patients do not respond to one drug, a trial with another member of the drug class is warranted and may be successful.

Adverse Effects Antimuscarinic drugs have several undesirable central nervous system and peripheral effects (see Chapter 8) and are poorly tolerated by the elderly or cognitively impaired. Dyskinesias occur in rare cases. Acute suppurative parotitis sometimes occurs as a complication of dryness of the mouth. If medication is to be withdrawn, this should be accomplished gradually rather than abruptly to prevent acute exacerbation of parkinsonism. For contraindications to the use of antimuscarinic drugs, see Chapter 8.

SURGICAL PROCEDURES Ablative surgical procedures for parkinsonism have generally been replaced by functional, reversible lesions induced by highfrequency deep brain stimulation, which has a lower morbidity. Stimulation of the subthalamic nucleus or globus pallidus by an implanted electrode and stimulator has yielded good results for the management of the clinical fluctuations or the dyskinesias occurring in moderate parkinsonism. The anatomic substrate for such therapy is indicated in Figure 28–1. Such procedures are contraindicated in patients with secondary or atypical parkinsonism, dementia, or failure to respond to dopaminergic medication. The level of antiparkinsonian medication can often be reduced in patients undergoing deep brain stimulation, and this may help to

528    SECTION V  Drugs That Act in the Central Nervous System

ameliorate dose-related adverse effects of medication. Patients with medically refractory tremor-predominant parkinsonism who are reluctant to undergo surgery may respond to focused ultrasound thalamotomy. In a controlled trial of the transplantation of dopaminergic tissue (fetal substantia nigra tissue), symptomatic benefit occurred in younger (less than 60 years old) but not older parkinsonian patients. In another trial, benefits were inconsequential. Furthermore, uncontrollable dyskinesias occurred in some patients in both studies, perhaps from a relative excess of dopamine from continued fiber outgrowth from the transplant. Additional basic studies are required before further trials of cellular therapies—in particular, stem cell therapies—are undertaken, and such approaches therefore remain investigational.

NEUROPROTECTIVE THERAPY Among the compounds that have been investigated as potential neuroprotective agents to slow disease progression are antioxidants, antiapoptotic agents, glutamate antagonists, intraparenchymally administered glial-derived neurotrophic factor, and anti-inflammatory drugs. None of these agents has been shown to be effective in this context, however, and their use for therapeutic purposes is not indicated at this time. Specifically, coenzyme Q10, creatine, pramipexole, and pioglitazone have not been found to be effective despite early hopes to the contrary. The urate precursor inosine, and isradipine, a dihydropyridine calcium-channel blocker with relatively high affinity for Cav1.3 channels, also failed to show benefit in randomized controlled trials. The possibility that rasagiline has a protective effect was discussed earlier. Other agents currently being studied as disease-modifying agents include deferiprone (a potent iron chelator) and exenatide, a glucagon-like peptide-1 (GLP-1) receptor agonist (see Chapter  41) that affects various cellular processes likely to be involved in the etiology of Parkinson disease. Active and passive immunization against α-synuclein or an α-synuclein-mimicking peptide is also being explored. The procedures are generally well-tolerated, without treatment-associated adverse events other than mild injection-site reactions, and lead to generation of antibodies against α-synuclein. Recent work suggests that an assay for misfolded α-synuclein in the spinal fluid has high sensitivity and specificity in distinguishing Parkinson disease from healthy controls and may serve as a useful biomarker of the disease, even before it becomes manifest clinically. If confirmed, this would permit those at risk of the disease to start protective treatment before they become symptomatic.

GENE THERAPY Several phase 1 (safety) or phase 2 trials of gene therapy for Parkinson disease have been completed in the USA. All trials involved infusion into the striatum of adeno-associated virus type

2 as the vector for the gene. The genes were for glutamic acid decarboxylase (GAD, to facilitate synthesis of GABA, an inhibitory neurotransmitter), infused into the subthalamic nucleus to cause inhibition; for aromatic acid decarboxylase (AADC), infused into the putamen to increase metabolism of levodopa to dopamine; and for neurturin (a growth factor that may enhance the survival of dopaminergic neurons), infused into the putamen. All agents were deemed safe. A phase 2 study of the GAD gene has been completed and the results are encouraging, but one for neurturin infused into the substantia nigra as well as the putamen was disappointing. In a phase 1b trial of AADC in moderately advanced disease, motor function and quality of life stabilized or improved, and medication requirements were reduced in some patients. The results of a European study involving bilateral intrastriatal delivery of ProSavin, a lentiviral vector-based gene therapy with three genes (decarboxylase, tyrosine hydroxylase, and GTPcyclohydrolase 1) aimed at restoring local and continuous dopamine production in patients with advanced Parkinson disease, have also been encouraging.

THERAPY FOR NONMOTOR MANIFESTATIONS Persons with cognitive decline may respond to rivastigmine (1.5–6 mg twice daily), memantine (5–10 mg daily), or donepezil (5–10 mg daily) (see Chapter 60); with affective disorders to antidepressants or anxiolytic agents (see Chapter 30); with psychosis to atypical antipsychotic agents or pimavanserin; with excessive daytime sleepiness to modafinil (100–400 mg in the morning) (see Chapter 9); and with bladder and bowel disorders to appropriate symptomatic therapy (see Chapter 8).

GENERAL COMMENTS ON DRUG MANAGEMENT OF PATIENTS WITH PARKINSONISM Parkinson disease generally follows a progressive course. Moreover, the benefits of levodopa therapy often diminish as the disease advances, and serious adverse effects may complicate long-term levodopa treatment. Nevertheless, dopaminergic therapy at a relatively early stage may be most effective in alleviating motor symptoms of parkinsonism and may also favorably affect the mortality rate due to the disease. Therefore, several strategies have evolved for optimizing dopaminergic therapy, as summarized in Figure 28–5. Symptomatic treatment of mild parkinsonism is probably best avoided until there is some degree of disability or functional limitation or until symptoms begin to impact the patient’s lifestyle or cause significant social impairment. When symptomatic treatment becomes necessary, a trial of rasagiline, selegiline, amantadine, or an antimuscarinic drug (in young patients) may be worthwhile. With disease progression, dopaminergic therapy becomes necessary. This can conveniently

CHAPTER 28  Pharmacologic Management of Parkinsonism & Other Movement Disorders     529

be initiated with either carbidopa-levodopa therapy or a dopamine agonist, either alone or in combination, although an agonist is best avoided in patients older than 70 or when risk factors for impulse control disorders are present. Carbidopalevodopa is the most effective symptomatic treatment of the motor disturbances of parkinsonism. Physical therapy is helpful in improving mobility. In patients with severe parkinsonism and long-term complications of levodopa therapy such as the on-off phenomenon, a trial of treatment with the newer extended-release formulation of carbidopa-levodopa (Rytary), a COMT inhibitor, or rasagiline may be helpful. Regulation of dietary protein intake may also improve response fluctuations. Deep brain stimulation is often helpful in patients with response fluctuations or dyskinesias who fail to respond adequately to these measures. Treating patients who are young or have mild parkinsonism with rasagiline may delay disease progression and merits consideration, although evidence of benefit is incomplete.

DRUG-INDUCED PARKINSONISM Reserpine and the related drugs tetrabenazine, deutetrabenazine, and valbenazine deplete biogenic monoamines from their storage sites, whereas haloperidol, metoclopramide, and the phenothiazines block dopamine receptors. These drugs may therefore produce a parkinsonian syndrome, usually within 3 or 4 months after introduction. The disorder tends to be symmetric, with inconspicuous tremor, but this is not always the case. The syndrome is related to high dosage and clears over several weeks or months after withdrawal. If treatment is necessary, antimuscarinic agents are preferred. Levodopa is of no help if neuroleptic drugs are continued and may in fact aggravate the mental disorder for which antipsychotic drugs were prescribed originally. In 1983, a drug-induced form of parkinsonism was discovered in individuals who attempted to synthesize and use a narcotic drug related to meperidine but actually synthesized and self-administered MPTP, as discussed in the Box: MPTP & Parkinsonism.

ATYPICAL PARKINSONISM SYNDROMES Several disorders characterized by parkinsonism differ from classic Parkinson disease because of inconspicuous tremor, symmetry of the neurologic findings, and the presence of additional findings (eg, dysautonomia, cerebellar deficits, eye movement abnormalities, or early cognitive and behavioral changes). These disorders include multisystem atrophy, progressive supranuclear palsy, corticobasal degeneration (in which parkinsonism may be markedly asymmetric), and diffuse Lewy body disease. The prognosis is worse than for Parkinson disease, and the response to antiparkinsonian treatment may be limited. Treatment is symptomatic.

OTHER MOVEMENT DISORDERS Tremor Tremor consists of rhythmic oscillatory movements. Physiologic postural tremor, which is a normal phenomenon, is enhanced in amplitude by anxiety, fatigue, thyrotoxicosis, and intravenous epinephrine or isoproterenol. Propranolol reduces its amplitude and, if administered intra-arterially, prevents the response to isoproterenol in the perfused limb, presumably through some peripheral action. Certain drugs—especially the bronchodilators, valproate, tricyclic antidepressants, and lithium—may produce a dose-dependent exaggeration of the normal physiologic tremor that is reversed by discontinuing the drug. Although the tremor produced by sympathomimetics such as terbutaline (a bronchodilator) is blocked by propranolol, which antagonizes both β1 and β2 receptors, it is not blocked by metoprolol, a β1-selective antagonist; this suggests that such tremor is mediated mainly by the β2 receptors. Essential tremor is a postural tremor, sometimes familial with autosomal dominant inheritance, which is clinically similar to physiologic tremor. Dysfunction of β1 receptors has been implicated in some instances, since the tremor may respond dramatically to standard doses of metoprolol as well as to propranolol. The tremor may involve the hands, head, voice, and—much less commonly—the legs. Patients may become functionally limited or socially withdrawn, quality of life is affected, and some patients report being seriously disabled by the tremor. The most useful therapeutic approach is with propranolol, but whether the response depends on a central or peripheral action is unclear. The pharmacokinetics, pharmacologic effects, and adverse reactions of propranolol are discussed in Chapter 10. Total daily doses of propranolol on the order of 120 mg or more (range, 60–320 mg) are usually required, divided into two doses; reported adverse effects have been few. Propranolol should be used with caution in patients with heart failure, heart block, asthma, depression, or hypoglycemia. Other adverse effects include fatigue, malaise, lightheadedness, and impotence. Patients can be instructed to take their own pulse and call the physician if significant bradycardia develops. Long-acting propranolol is also effective and is preferred by many patients because of its convenience. Some patients prefer to take a single dose of propranolol when they anticipate their tremor is likely to be exacerbated, for example, by social situations. Metoprolol is sometimes useful in treating tremor when patients have concomitant pulmonary disease that contraindicates use of propranolol. Drugs potentiating GABAA receptors in the central nervous system (such as phenobarbital, primidone, topiramate, and benzodiazepines) also improve tremor, but phenobarbital is not used clinically because of its sedating effect. Primidone (an antiepileptic drug; see Chapter 24), in gradually increasing doses up to 250 mg three times daily, is also effective in providing symptomatic control in some cases. Patients with tremor are very sensitive to primidone and often cannot tolerate the doses used to treat seizures; they should be started on 50 mg once daily and the daily dose increased by 50 mg every 2 weeks depending on response. In many instances, a dose of 125 mg two or three times daily is sufficient.

530    SECTION V  Drugs That Act in the Central Nervous System

MPTP & Parkinsonism Reports in the early 1980s of a rapidly progressive form of parkinsonism in young persons opened a new area of research in the etiology and treatment of parkinsonism. The initial report described apparently healthy young people who attempted to support their opioid habit with a meperidine analog synthesized by an amateur chemist. They unwittingly self-administered 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and subsequently developed a very severe form of parkinsonism. MPTP is a protoxin that is converted by monoamine oxidase + + B to N-methyl-4-phenylpyridinium (MPP ). MPP is selectively taken up by cells in the substantia nigra through an active mechanism normally responsible for dopamine reuptake. MPP+ inhibits mitochondrial complex I, thereby inhibiting oxidative phosphorylation. The interaction of MPP+ with complex

Topiramate, another antiepileptic drug, may also be helpful in a dose of 400 mg daily, built up gradually. Alprazolam (in doses up to 3 mg daily) or gabapentin (100–2400 mg/d; typically 1200 mg/d) is helpful in some patients. Gabapentin binds to the α2δ subunit of calcium channels. It produces less consistent relief of tremor but is associated with fewer side effects than primidone. Other patients are helped by intramuscular injections of botulinum toxin, but dose-dependent weakness may complicate symptomatic benefit. Thalamic stimulation by an implanted electrode and stimulator is worthwhile in advanced cases refractory to pharmacotherapy. Thalamotomy by magnetic resonance imaging-guided focused ultrasound or stereotactic radiosurgery is also effective in reducing upper-extremity tremor. Diazepam, chlordiazepoxide, mephenesin, and antiparkinsonism agents have been advocated in the past but are generally of little benefit. Small quantities of alcohol may suppress essential tremor for a short time but should not be recommended as a treatment strategy because of possible behavioral and other complications of alcohol. Intention tremor is present during movement but not at rest; sometimes it occurs as a toxic manifestation of alcohol or drugs such as phenytoin. Withdrawal or reduction in dosage provides dramatic relief. There is no satisfactory pharmacologic treatment for intention tremor due to other neurologic disorders. Rest tremor is usually due to parkinsonism.

I probably leads to cell death and thus to striatal dopamine depletion and parkinsonism. Recognition of the effects of MPTP suggested that spontaneously occurring Parkinson disease may result from exposure to an environmental toxin that is similarly selective in its target. However, no such toxin has yet been identified. It also suggested a successful means of producing an experimental model of Parkinson disease in animals, especially nonhuman primates. This model is useful in the development of new antiparkinsonism drugs. Pretreatment of exposed animals with a monoamine oxidase B inhibitor such as selegiline prevents the conversion of MPTP to MPP+ and thus protects against the occurrence of parkinsonism. This observation has provided one reason to believe that selegiline or rasagiline may retard the progression of Parkinson disease in humans.

Huntington disease is characterized by progressive chorea and dementia that usually begin in adulthood. The development of chorea seems to be related to an imbalance of dopamine, acetylcholine, GABA, and perhaps other neurotransmitters in the basal ganglia (Figure 28–6). Pharmacologic studies indicate that chorea results from functional overactivity in dopaminergic nigrostriatal pathways, perhaps because of increased responsiveness of postsynaptic dopamine receptors or deficiency of a neurotransmitter that normally antagonizes dopamine. Drugs that impair dopaminergic neurotransmission, either by depleting central monoamines (eg, reserpine, tetrabenazine, deutetrabenazine, valbenazine) or

Normal Substantia nigra

Corpus striatum

Dopamine Acetylcholine

GABA

Huntington disease

Huntington Disease Huntington disease is an autosomal dominant inherited disorder caused by an abnormality (expansion of a CAG trinucleotide repeat that codes for a polyglutamine tract) of the huntingtin gene on chromosome 4. An autosomal recessive form may also occur. Huntington disease-like (HDL) disorders are not associated with an abnormal CAG trinucleotide repeat number of the huntingtin gene. Autosomal dominant (HDL1, 20pter-p12; HDL2, 16q24.3) and recessive forms (HDL3, 4p15.3) occur.

FIGURE 28–6  Schematic representation of the sequence of neurons involved in Huntington chorea. The complex anatomic circuitry has been simplified. Top: Dopaminergic neurons (red) originating in the substantia nigra normally inhibit the output of the spiny GABAergic neurons from the striatum, whereas cholinergic neurons (green) exert an excitatory effect. Bottom: In Huntington chorea, some cholinergic neurons may be lost, but even more GABAergic neurons (black) degenerate.

CHAPTER 28  Pharmacologic Management of Parkinsonism & Other Movement Disorders     531

by blocking dopamine receptors (eg, phenothiazines, butyrophenones), often alleviate chorea, whereas dopamine-like drugs such as levodopa tend to exacerbate it. Both GABA and the enzyme (glutamic acid decarboxylase) concerned with its synthesis are markedly reduced in the basal ganglia of patients with Huntington disease, and GABA receptors are usually implicated in inhibitory pathways. There is also a significant decline in concentration of choline acetyltransferase, the enzyme responsible for synthesizing acetylcholine, in the basal ganglia of these patients. These findings may be of pathophysiologic significance and have led to attempts to alleviate chorea by enhancing central GABA or acetylcholine activity, but with disappointing results. Consequently, the most commonly used drugs for controlling dyskinesia in patients with Huntington disease are still those that interfere with dopamine activity. With all the latter drugs, however, reduction of abnormal movements may be associated with iatrogenic parkinsonism. Tetrabenazine (12.5–50 mg orally three times daily) depletes cerebral dopamine and reduces the severity of chorea. It has less troublesome adverse effects than reserpine, which has also been used for this purpose. Tetrabenazine is metabolized by cytochrome P450 (CYP2D6), and genotyping has therefore been recommended to determine metabolizer status (CYP2D6 expression) in patients needing doses exceeding 50 mg/d. For poor metabolizers, the maximum recommended dose is 50 mg daily (25 mg/dose); otherwise, a maximum dose of 100 mg daily can be used. Treatment with postsynaptic dopamine receptor blockers such as phenothiazines and butyrophenones may also be helpful. Haloperidol is started in a small dose, eg, 1 mg twice daily, and increased every 4 days depending on the response. If haloperidol is not helpful, treatment with increasing doses of fluphenazine in a similar dose, eg, 1 mg twice daily, sometimes helps. Several recent reports suggest that olanzapine may also be useful; the dose varies with the patient, but 10 mg daily is often sufficient, although doses as high as 30 mg daily are sometimes required. The pharmacokinetics and clinical properties of these drugs are considered in greater detail elsewhere in this book. Selective serotonin reuptake inhibitors may reduce depression, aggression, and agitation. However, strong CYP2D6 inhibitors should be used with caution, as it may be necessary to decrease the dose of tetrabenazine taken concurrently. Deutetrabenazine is a selective inhibitor of the vesicular monoamine 2 transporter (VMAT2) that modulates dopamine stores. It seems as effective as tetrabenazine for treating the chorea of Huntington disease and improving overall motor function, and may have fewer side effects. The dose is built up weekly from 6 mg daily to a maximum of 24 mg twice daily with food (18 mg twice daily in poor CYP2DG metabolizers). It may cause agitation, restlessness, and parkinsonism. Other adverse effects are sedation, dry mouth, diarrhea, insomnia, and fatigue. QT prolongation may occur. Deutetrabenazine is contraindicated in patients on monoamine oxidase inhibitors, reserpine, or tetrabenazine, and in those who are severely depressed or suicidal. Valbenazine, discussed later, is also now approved for treating chorea in patients with Huntington disease. Other important aspects of management include genetic counseling, speech therapy, physical and occupational therapy, dysphagia precautions, and provision of social services.

Other Forms of Chorea Benign hereditary chorea is inherited (usually autosomal dominant; possibly also autosomal recessive) or arises spontaneously. Chorea develops in early childhood and does not progress during adult life; dementia does not occur. In patients with TITF-1 gene mutations, thyroid and pulmonary abnormalities may also be present (brain-thyroid-lung syndrome). Familial chorea may also occur as part of the chorea-acanthocytosis syndrome, together with orolingual tics, vocalizations, cognitive changes, seizures, peripheral neuropathy, and muscle atrophy; serum β-lipoproteins are normal. Mutations of the gene encoding chorein at 9q21 may be causal. Treatment of these hereditary disorders is symptomatic. Tetrabenazine (0.5 mg/kg/d for children and 37.5 mg/d for adults) may improve chorea in some instances. The efficacy in this context of the newer selective VMAT2 blockers deutetrabenazine and valbenazine is unclear. Treatment is directed at the underlying cause when chorea occurs as a complication of general medical disorders such as thyrotoxicosis, polycythemia vera rubra, systemic lupus erythematosus, hypocalcemia, and hepatic cirrhosis. Drug-induced chorea is managed by withdrawal of the offending substance, which may be levodopa, an antimuscarinic drug, amphetamine, lithium, phenytoin, or an oral contraceptive. Neuroleptic drugs may also produce an acute or tardive dyskinesia (discussed below). Sydenham’s chorea is temporary and usually so mild that pharmacologic management of the dyskinesia is unnecessary, but dopamine-blocking drugs are effective in suppressing it.

Ballismus The biochemical basis of ballismus is unknown, but the pharmacologic approach to management is the same as for chorea. Treatment with tetrabenazine, haloperidol, perphenazine, or other dopamine-blocking drugs may be helpful.

Athetosis & Dystonia The physiologic basis of these disorders is unknown, and there is no satisfactory medical treatment for them. A subset of patients respond well to levodopa medication (dopa-responsive dystonia), which is therefore worthy of trial. Occasional patients with dystonia may respond to diazepam, amantadine, antimuscarinic drugs (in high dosage), carbamazepine, baclofen, haloperidol, or phenothiazines. A trial of these pharmacologic approaches is worthwhile, though often not successful. Patients with focal dystonias such as blepharospasm or torticollis often benefit from injection of botulinum toxin into the overactive muscles. Deep brain stimulation may be helpful in medically intractable cases. The role of repetitive transcranial magnetic stimulation and transcranial direct current stimulation to induce plastic changes in the brain is being explored.

Tics The pathophysiologic basis of tics is unknown. Chronic multiple tics (Gilles de la Tourette syndrome) may require symptomatic treatment if the disorder is severe or is having a significant impact on the patient’s life. Education of patients, family, and teachers

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is important. Comprehensive behavioral intervention may help adults with Tourette syndrome. Pharmacologic therapy may be necessary when tics interfere with social life or otherwise impair activities of daily living. Treatment is with drugs that block dopamine receptors or deplete dopamine stores, such as fluphenazine, pimozide, and tetrabenazine. These drugs reduce the frequency and intensity of tics by about 60%. Pimozide, a dopamine receptor antagonist, may be helpful in patients as a first-line treatment or in those who are either unresponsive to or intolerant of the other agents mentioned. Treatment is started at 1 mg/d, and the dosage is increased by 1 mg every 5 days; most patients require 7–16 mg/d. It has similar side effects to haloperidol but may cause irregularities of cardiac rhythm. Haloperidol has been used for many years to treat tic disorders. Patients are better able to tolerate this drug if treatment is started with a small dosage (eg, 0.25 or 0.5 mg daily) and then increased gradually (eg, by 0.25 mg every 4 or 5 days) over the following weeks depending on response and tolerance. Most patients ultimately require a total daily dose of 3–8 mg. Adverse effects include extrapyramidal movement disorders, sedation, dryness of the mouth, blurred vision, and gastrointestinal disturbances. Deutetrabenazine and aripiprazole (see Chapter 29) have also been found effective in treating tics. Valbenazine has failed to provide significant benefit compared to placebo. Ecopipam, a novel dopamine D1 receptor blocker, produced significant reduction in tic severity in children with Tourette syndrome in a phase 2b randomized controlled clinical trial. The drug was well tolerated and further studies are planned. Although not approved by the US Food and Drug Administration (FDA) for the treatment of tics or Tourette syndrome, certain α2-adrenergic agonists may be preferred as an initial treatment because they are less likely to cause extrapyramidal side effects than neuroleptic agents. Clonidine reduces motor or vocal tics in about 50% of children so treated. It may act by reducing activity in noradrenergic neurons in the locus coeruleus. It is introduced at a dose of 2–3 mcg/kg/d, increasing after 2 weeks to 4 mcg/kg/d and then, if required, to 5 mcg/ kg/d. It may cause an initial transient fall in blood pressure. The most common adverse effect is sedation; other adverse effects include reduced or excessive salivation and diarrhea. Guanfacine, another α2-adrenergic agonist, has also been used. Both of these drugs may be particularly helpful for behavioral symptoms, such as impulse control disorders. Atypical antipsychotics, such as risperidone and aripiprazole, may be especially worthwhile in patients with significant behavioral problems. Clonazepam, baclofen, topiramate, and carbamazepine have also been used to treat tics in preference to dopamine receptor blockers with their potential side effects. The pharmacologic properties of these drugs are discussed elsewhere in this book. Injection of botulinum toxin A at the site of problematic tics is sometimes helpful when these are focal simple tics. Treatment of any associated attention deficit disorder (eg, with clonidine patch, guanfacine, pemoline, methylphenidate, or dextroamphetamine) or obsessive-compulsive disorder (with selective serotonin reuptake inhibitors or clomipramine) may be required.

Deep brain stimulation is sometimes worthwhile in otherwise intractable cases.

Drug-Induced Dyskinesias Levodopa or dopamine agonists produce diverse dyskinesias as a dose-related phenomenon in patients with Parkinson disease; dose reduction reverses them. Chorea may also develop in patients receiving phenytoin, carbamazepine, amphetamines, lithium, and oral contraceptives, and it resolves with discontinuance of the offending medication. Dystonia has resulted from administration of dopaminergic agents, lithium, serotonin reuptake inhibitors, carbamazepine, and metoclopramide; and postural tremor from theophylline, caffeine, lithium, valproic acid, thyroid hormone, tricyclic antidepressants, and isoproterenol. The pharmacologic basis of the acute dyskinesia or dystonia sometimes precipitated by the first few doses of a phenothiazine is not clear. In most instances, parenteral administration of an antimuscarinic drug such as benztropine (2 mg intravenously), diphenhydramine (50 mg intravenously), or biperiden (2–5 mg intravenously or intramuscularly) is helpful, whereas in other instances diazepam (10 mg intravenously) alleviates the abnormal movements. Tardive dyskinesia, a disorder characterized by a variety of abnormal movements, is a common complication of long-term neuroleptic or metoclopramide drug treatment (see Chapter 29). Its precise pharmacologic basis is unclear. A reduction in dose of the offending medication, a dopamine receptor blocker, commonly worsens the dyskinesia, whereas an increase in dose may suppress it. The drugs most likely to provide immediate symptomatic benefit are those interfering with dopaminergic function, either by depletion (eg, reserpine, tetrabenazine) or receptor blockade (eg, phenothiazines, butyrophenones). Paradoxically, the receptor-blocking drugs are the ones that also cause the dyskinesia. Deutetrabenazine and valbenazine are selective inhibitors of VMAT2, which modulates dopamine release, and both ameliorate tardive dyskinesia. Deutetrabenazine was discussed earlier. Valbenazine is started in a dose of 40 mg once daily for 1 week and then increased to 80 mg once daily. Somnolence and QT prolongation may occur. Adverse effects include anticholinergic effects, impaired balance and falls, headache, akathisia, arthralgia, and nausea and vomiting. Valbenazine should not be used with monoamine oxidase inhibitors; its dose should be reduced in patients receiving a strong inhibitor of CYP2D6 (eg, paroxetine, fluoxetine) or CYP3A4 (eg, carbamazepine, phenytoin). Tardive dystonia is usually segmental or focal; generalized dystonia is less common and occurs in younger patients. Treatment is the same as for tardive dyskinesia, but anticholinergic drugs may also be helpful; focal dystonias may also respond to local injection of botulinum A toxin. Tardive akathisia is treated similarly to drug-induced parkinsonism. Rabbit syndrome, another neuroleptic-induced disorder, is manifested by rhythmic vertical movements about the mouth; it may respond to anticholinergic drugs. Because the tardive syndromes that develop in adults are often irreversible and have no satisfactory treatment, care must be taken

CHAPTER 28  Pharmacologic Management of Parkinsonism & Other Movement Disorders     533

to reduce the likelihood of their occurrence. Antipsychotic medication should be prescribed only when necessary and should be withheld periodically to assess the need for continued treatment and to unmask incipient dyskinesia. Thioridazine, a phenothiazine with a piperidine side chain, is an effective antipsychotic agent that seems less likely than most to cause extrapyramidal reactions, perhaps because it has little effect on dopamine receptors in the striatal system. Finally, antimuscarinic drugs should not be prescribed routinely in patients receiving neuroleptics, because the combination may increase the likelihood of dyskinesia. Neuroleptic malignant syndrome is a rare complication of treatment with neuroleptics and certain antiemetic agents (such as metoclopramide and promethazine). A somewhat similar syndrome may occur with withdrawal of dopaminergic therapy in parkinsonian patients. It is characterized by rigidity, fever, changes in mental status, and autonomic dysfunction (see Table 16–4). Symptoms typically develop over 1–3 days (rather than minutes to hours as in malignant hyperthermia) and may occur at any time during treatment. The serum creatine kinase level is increased to very high levels. Treatment includes withdrawal of antipsychotic drugs, lithium, and anticholinergics; reduction of body temperature; and rehydration. A markedly elevated blood pressure should be lowered. Benzodiazepines (diazepam or lorazepam) help in reducing agitation. Dantrolene, dopamine agonists, levodopa, or amantadine may also be helpful, but there is a high mortality rate (up to 20%) with neuroleptic malignant syndrome.

Restless Legs Syndrome Restless legs syndrome is characterized by an unpleasant creeping discomfort that seems to arise deep within the legs and occasionally the arms. Symptoms occur particularly when patients are relaxed, especially when they are lying down or sitting, and they lead to an urge to move about. Such symptoms may delay the onset of sleep. A sleep disorder associated with periodic movements during sleep may also occur. The cause is unknown, but the disorder is especially common among pregnant women and also among uremic or diabetic patients with neuropathy. In most patients, no obvious predisposing cause is found, but several genetic loci have been associated with it. Symptoms may resolve with correction of coexisting irondeficiency anemia or a low-normal serum ferritin level, or with avoidance of caffeine, sleep deprivation, and various medications that can provoke or exacerbate them, such as serotonergic antidepressants, neuroleptics, metoclopramide, and antihistamines. They often respond to pharmacologic agents. Dopaminergic therapy can be initiated with long-acting dopamine agonists (eg, oral pramipexole 0.125–0.75 mg or ropinirole 0.25–4.0 mg once daily) or with the rotigotine skin patch to avoid the augmentation that may be associated especially with carbidopa-levodopa (25/100 or 50/200 taken about 1 hour before bedtime). Augmentation refers to the earlier onset or enhancement of symptoms; earlier onset of symptoms at rest; and a briefer response to medication. When augmentation occurs with levodopa, a dopamine agonist should be substituted. If it occurs in patients receiving an agonist, the daily dose should be divided, another agonist tried, or other

medications substituted. Dopamine agonist therapy may be associated with development of impulse control disorders. Gabapentin is effective in reducing the severity of restless legs syndrome and is taken once or twice daily (in the evening and before sleep). The starting dose is 300 mg daily, building up depending on response and tolerance (to approximately 1800 mg daily). Oral gabapentin enacarbil (600 or 1200 mg once daily) or pregabalin (150–300 mg daily, in divided doses) may also help. Clonazepam, 1 mg daily, is also sometimes worthwhile, especially for those with intermittent symptoms. When opiates are required, those with long half-lives or low addictive potential should be used. Oxycodone is often effective; the dose is individualized.

Wilson Disease A recessively inherited disorder of copper metabolism due to mutations in the copper-transporting gene, ATP7B, Wilson disease is characterized biochemically by reduced serum copper and ceruloplasmin concentrations, with increased urinary copper excretion; pathologically by markedly increased concentration of copper in the brain and viscera; and clinically by hepatic, neurologic, and psychiatric dysfunction. Neurologic signs include tremor, choreiform movements, rigidity and hypokinesia (parkinsonism), ataxia, cognitive changes, and dysarthria and dysphagia. Siblings of affected patients should be screened for asymptomatic Wilson disease. Kayser-Fleischer rings, brownish deposits of copper in Descemet membrane in the cornea, are seen in virtually all patients with neurologic abnormalities and in approximately half of those with only hepatic manifestations. Treatment should start promptly, even in presymptomatic cases, continue indefinitely, and be monitored by laboratory tests and neurologic examination. It involves the removal of excess copper, followed by maintenance of copper balance. Dietary copper should also be kept below 2 mg daily. Penicillamine (dimethylcysteine) has been used for many years as the primary agent to remove copper. It is a chelating agent that forms a ring complex with copper (see Chapter 57). It is readily absorbed from the gastrointestinal tract and rapidly excreted in the urine. A common starting dose in adults is 500 mg three or four times daily. After remission occurs, it may be possible to lower the maintenance dose, generally to not less than 1 g daily, which must thereafter be continued indefinitely. Adverse effects include nausea and vomiting, nephrotic syndrome, a lupus-like syndrome, pemphigus, myasthenia, arthropathy, optic neuropathy, and various blood dyscrasias. In about 10% of instances, neurologic worsening occurs with penicillamine. Treatment should be monitored by frequent urinalysis and complete blood counts and serum creatinine determination. Patients receiving penicillamine should also take pyridoxine, 25 mg daily, unless it is part of the penicillamine formulation, to prevent pyridoxine deficiency. Trientine hydrochloride, another chelating agent, is preferred by many over penicillamine because of the lesser likelihood of drug reactions or neurologic worsening. It may be used in a daily dose of 1–1.5 g. Trientine appears to have few adverse effects other than mild anemia due to iron deficiency in a few patients.

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Tetrathiomolybdate may be better than trientine for preserving neurologic function in patients with neurologic involvement and is taken both with and between meals. It is currently undergoing clinical trials (phase 3) and is not yet commercially available or approved by the FDA. Zinc acetate administered orally increases the fecal excretion of copper and can be used in combination with these other agents. The dose is 50 mg three times a day. Zinc sulfate (200 mg/d orally) has also been used to decrease copper absorption. Zinc blocks copper absorption from the gastrointestinal tract by induction of

intestinal cell metallothionein. Its main advantage is its low toxicity compared with that of other anticopper agents, although it may cause gastric irritation when introduced. Liver transplantation is sometimes necessary to restore hepatic function and ameliorate portal hypertension when medical treatment is inadequate. Its role in the management of patients with primarily neurologic manifestations is unclear. In such patients survival is poorer but transplantation has been proposed as rescue therapy in patients with neurologic involvement resistant to anticopper therapies.

SUMMARY  Drugs Used for Selected Movement Disorders Subclass, Drug

Mechanism of Action

LEVODOPA AND COMBINATIONS   •  Levodopa Transported into the central nervous system (CNS) and converted to dopamine (which does not enter the CNS); also converted to dopamine in the periphery

Effects Ameliorates all motor symptoms of Parkinson disease and causes significant peripheral dopaminergic effects (see text)

Clinical Applications

Pharmacokinetics, Toxicities, Interactions

Parkinson disease: Most efficacious therapy but not always used as the first drug due to development of disabling response fluctuations over time

Oral • ∼6–8 h effect • Toxicity: Gastrointestinal upset, arrhythmias, dyskinesias, on-off and wearing-off phenomena, behavioral disturbances • Interactions: Use with carbidopa greatly diminishes required dosage and is now standard • use with COMT or MAO-B inhibitors prolongs duration of effect

  • Levodopa + carbidopa (Sinemet, others): Carbidopa inhibits peripheral metabolism of levodopa to dopamine and reduces required dosage and toxicity; carbidopa does not enter CNS   •  Levodopa + carbidopa + entacapone (Stalevo): Entacapone is a catechol-O-methyltransferase (COMT) inhibitor (see below) DOPAMINE AGONISTS   •  Pramipexole

Direct agonist at D3 receptors, nonergot

Reduces symptoms of parkinsonism • smooths out fluctuations in levodopa response

Parkinson disease: Can be used as initial therapy • also effective in on-off phenomenon

Oral • ∼8 h effect • Toxicity: Nausea and vomiting, postural hypotension, dyskinesias, confusion, impulse control disorders, sleepiness

  •  Ropinirole: Similar to pramipexole; nonergot; relatively pure D2 agonist   •  Bromocriptine: Ergot derivative; potent agonist at D2 receptors; more toxic than pramipexole or ropinirole; now rarely used for antiparkinsonian effect   •  Apomorphine: Nonergot; subcutaneous route useful for rescue treatment in levodopa-induced dyskinesia; high incidence of nausea and vomiting MONOAMINE OXIDASE (MAO) INHIBITORS   •  Rasagiline Inhibits MAO-B selectively; higher doses also inhibit MAO-A

Increases dopamine stores in neurons; may have neuroprotective effects

Parkinson disease: Adjunctive to levodopa • smooths levodopa response

Oral • Toxicity & interactions: May cause serotonin syndrome with meperidine, and theoretically also with selective serotonin reuptake inhibitors, tricyclic antidepressants

  •  Selegiline: Like rasagiline, adjunctive use with levodopa; may be less potent than rasagiline   •  Safinamide: Also used as adjunct to levodopa in patients with response fluctuations COMT INHIBITORS   •  Entacapone

Inhibits COMT in periphery • does not enter CNS

Reduces metabolism of levodopa and prolongs its action

Parkinson disease

Oral • Toxicity: Increased levodopa toxicity • nausea, dyskinesias, confusion

  •  Tolcapone: Like entacapone but enters CNS; some evidence of hepatotoxicity, elevation of liver enzymes   •  Opicapone: Taken once daily ANTIMUSCARINIC AGENTS   •  Benztropine Antagonist at M receptors in basal ganglia

Reduces tremor and rigidity • little effect on bradykinesia

Parkinson disease

Oral • Toxicity: Typical antimuscarinic effects– sedation, mydriasis, urinary retention, constipation, confusion, dry mouth

  •  Biperiden, orphenadrine, procyclidine, trihexyphenidyl: Similar antimuscarinic agents with CNS effects (continued)

CHAPTER 28  Pharmacologic Management of Parkinsonism & Other Movement Disorders     535

Subclass, Drug

Mechanism of Action

DRUGS USED IN HUNTINGTON DISEASE   • Tetrabenazine, Deplete amine transmitters, deutetrabenazine, especially dopamine, from reserpine nerve endings

Effects Reduce chorea severity

Clinical Applications

Pharmacokinetics, Toxicities, Interactions

Huntington disease • other applications, see Chapter 11

Oral • Toxicity: Hypotension, sedation, depression, diarrhea • deutetrabenazine is the least toxic

  •  Haloperidol, fluphenazine, other neuroleptics, olanzapine: Dopamine receptor blockers, sometimes helpful DRUGS USED IN TOURETTE SYNDROME   • Pimozide, Block central D2 receptors haloperidol

Reduce vocal and motor tic frequency, severity

Tourette syndrome • other applications, see Chapter 11

Oral • Toxicity: Parkinsonism, other dyskinesias • sedation • blurred vision • dry mouth • gastrointestinal disturbances • pimozide may cause cardiac rhythm disturbances

  •  Clonidine, guanfacine: Effective in ∼50% of patients; see Chapter 11 for basic pharmacology   •  Phenothiazines, atypical antipsychotics, tetrabenazine, deutetrabenazine, clonazepam, carbamazepine, topiramate: Often of value

P R E P A R A T I O N S A V A I L A B L E GENERIC NAME Amantadine Apomorphine Benztropine Biperiden Bromocriptine Carbidopa Carbidopa/levodopa Carbidopa/levodopa/entacapone Deutetrabenazine Entacapone Levodopa Opicapone Orphenadrine Penicillamine Pergolide* Pramipexole Procyclidine Rasagiline Ropinirole Safinamide Selegiline (deprenyl) Tetrabenazine Tolcapone Trientine Trihexyphenidyl Valbenazine *

AVAILABLE AS Generic, Gocovri, Osmolex ER, Symmetrel Apokyn Generic, Cogentin Akineton Generic, Parlodel Lodosyn Generic, Parcopa, Rytary, Sinemet Generic, Stalevo Austedo Generic, Comtan Dopar, Inbrija, others Ongentys Generic, various Cuprimine, Depen Permax, other Generic, Mirapex Kemadrin Azilect Generic, Requip, Requip XL Xadago Emsam Xenazine Tasmar Syprine Generic, Artane, others Ingrezza

Not available in the United States.

REFERENCES Ahmad A, Torrazza-Perez E, Schilsky ML: Liver transplantation for Wilson disease. Handb Clin Neurol 2017;142:193. Armstrong MJ, Okun MS: Diagnosis and treatment of Parkinson disease: A review. JAMA 2020;323:548.

Bashir H, Jankovic J: Deutetrabenazine for the treatment of Huntington’s chorea. Expert Rev Neurother 2018;18:625. Bledsoe IO et al: Treatment of dystonia: Medications, neurotoxins, neuromodulation, and rehabilitation. Neurotherapeutics 2020;17:1622. Bloem BR et al: Parkinson’s disease. Lancet 2021;397:2284. Bond AE et al: Safety and efficacy of focused ultrasound thalamotomy for patients with medication-refractory, tremor-dominant Parkinson disease: A randomized clinical trial. JAMA Neurol 2017;74:1412. Christine CW et al: Magnetic resonance imaging-guided phase 1 trial of putaminal AADC gene therapy for Parkinson’s disease. Ann Neurol 2019;85:704. Clark LN, Louis ED: Essential tremor. Handb Clin Neurol 2018;147:229. Corvol JC et al: Longitudinal analysis of impulse control disorders in Parkinson disease. Neurology 2018;91:e189. Członkowska A, Litwin T: Wilson disease—currently used anticopper therapy. Handb Clin Neurol 2017;142:181. Dean M, Sung VW: Review of deutetrabenazine: A novel treatment for chorea associated with Huntington’s disease. Drug Des Devel Ther 2018;12:313. Farber RH et al: Clinical development of valbenazine for tics associated with Tourette syndrome. Expert Rev Neurother 2021;21:393. Ferreira JJ, et al: MDS evidence-based review of treatments for essential tremor. Mov Disord 2019;34:950. Ghosh R, Tabrizi SJ: Huntington disease. Handb Clin Neurol 2018;147:255. Gilbert DL et al: Ecopipam, a D1 receptor antagonist, for treatment of Tourette syndrome in children: A randomized, placebo-controlled crossover study. Mov Disord 2018;33:1272. Gossard TR et al: Restless legs syndrome: Contemporary diagnosis and treatment. Neurotherapeutics 2021;18:140. Haubenberger D, Hallett M: Essential tremor. N Engl J Med 2018;378:1802. Hedera P: Wilson’s disease: A master of disguise. Parkinsonism Relat Disord 2019;59:140. Hopfner F, Deuschl G: Managing essential tremor. Neurotherapeutics 2020;17:1603. Horn S et al: Pimavanserin versus quetiapine for the treatment of psychosis in Parkinson’s disease and dementia with Lewy bodies. Parkinsonism Relat Disord 2019;69:119. Katzenschlager R et al: Apomorphine subcutaneous infusion in patients with Parkinson’s disease with persistent motor fluctuations (TOLEDO): A multicentre, double-blind, randomised, placebo-controlled trial. Lancet Neurol 2018;17:749. Kieburtz K, Reilmann R, Olanow CW: Huntington’s disease: Current and future therapeutic prospects. Mov Disord 2018;33:1033. Kogan M et al: Deep brain stimulation for Parkinson disease. Neurosurg Clin N Am 2019;30:137. Lorincz MT: Wilson disease and related copper disorders. Handb Clin Neurol 2018;147:279. Mittur A, Gupta S, Modi NB: Pharmacokinetics of Rytary®, an extended-release capsule formulation of carbidopa-levodopa. Clin Pharmacokinet 2017;56:999.

536    SECTION V  Drugs That Act in the Central Nervous System Paik J: Levodopa inhalation powder: A review in Parkinson’s disease. Drugs 2020; 80:821. Palfi S et al: Long-term follow-up of a phase I/II study of ProSavin, a lentiviral vector gene therapy for Parkinson’s disease. Hum Gene Ther Clin Dev 2018;29:148. Pringsheim T et al: Practice guideline recommendations summary: Treatment of tics in people with Tourette syndrome and chronic tic disorders. Neurology 2019;92:896. Quezada J, Coffman KA: Current approaches and new developments in the pharmacological management of Tourette syndrome. CNS Drugs 2018;32:33. Ramirez-Zamora A, Ostrem JL: Globus pallidus interna or subthalamic nucleus deep brain stimulation for Parkinson disease: A review. JAMA Neurol 2018;75:367. Rodrigues FB et al: Deep brain stimulation for dystonia. Cochrane Database Syst Rev 2019;1:CD012405. Schaefer SM, Vives Rodriguez A, Louis ED: Brain circuits and neurochemical systems in essential tremor: Insights into current and future pharmacotherapeutic approaches. Expert Rev Neurother 2018;18:101. Schapira AH et al: Assessment of safety and efficacy of safinamide as a levodopa adjunct in patients with Parkinson disease and motor fluctuations: A randomized clinical trial. JAMA Neurol 2017;74:216. Scott LJ: Opicapone: A review in Parkinson’s disease. CNS Drugs 2021;35:121. Siderowf A et al: Assessment of heterogeneity among participants in the Parkinson’s Progression Markers Initiative cohort using α-synuclein seed amplification: A cross-sectional study. Lancet Neurol 2023;22:407.

Simpson DM et al: Practice guideline update summary: Botulinum neurotoxin for the treatment of blepharospasm, cervical dystonia, adult spasticity, and headache: Report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology 2016;86:1818. Singer HS: Tics and Tourette syndrome. Continuum (Minneap Minn) 2019; 25:936. Stocchi F et al: Initiating levodopa/carbidopa therapy with and without entacapone in early Parkinson disease: The STRIDE-PD study. Ann Neurol 2010;68:18. Torti M, Vacca L, Stocchi F: Istradefylline for the treatment of Parkinson’s disease: Is it a promising strategy? Expert Opin Pharmacother. 2018;19:1821. Trenkwalder C et al: Comorbidities, treatment, and pathophysiology in restless legs syndrome. Lancet Neurol 2018;17:994. Van Holst RJ et al: Brain imaging studies in pathological gambling. Curr Psychiatry Rep 2010;12:418. Vijayakumar D, Jankovic J: Drug-induced dyskinesias (2 parts). Drugs 2016;76:759 and 779. Volpicelli-Daley L, Brundin P: Prion-like propagation of pathology in Parkinson disease. Handb Clin Neurol 2018;153:321. Xu W et al: Deep brain stimulation for Tourette’s syndrome. Transl Neurodegener 2020;9:4. Yu XX, Fernandez HH: Dopamine agonist withdrawal syndrome: A comprehensive review. J Neurol Sci 2017;374:53. Zucconi M et al: An update on the treatment of restless legs syndrome/Willis-Ekbom disease: Prospects and challenges. Expert Rev Neurother 2018;18:705.

C ASE STUDY ANSWER The history is suggestive of parkinsonism, but the inconspicuous tremor and early cognitive changes raise the possibility of atypical parkinsonism rather than classic Parkinson disease. The prognosis of these disorders is worse than that of classic Parkinson disease. Given the cognitive changes and his age, the use of a dopamine agonist was unwise, as these agents are more likely than levodopa to exacerbate

or precipitate behavioral and cognitive disturbances. Sleep attacks may occur spontaneously but are especially noted in patients receiving dopamine agonists. The patient has also developed punding, which is a recognized adverse effect of dopaminergic medication. Surgical treatment (deep brain stimulation) is contraindicated in patients with cognitive changes or atypical parkinsonism.

29 C

Antipsychotic Agents & Lithium

H

A

P

T

E

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Charles DeBattista, MD*

C ASE STUDY A 19-year-old male student is brought into the clinic by his mother, who has been concerned about her son’s erratic behavior and strange beliefs. He destroyed a TV because he felt the TV was sending harassing messages to him. In addition, he reports hearing voices telling him that family members are trying to poison his food. As a result, he is not eating. After a diagnosis is made, haloperidol is prescribed at a gradually increasing dose on an outpatient basis. The drug improves the patient’s positive symptoms but ultimately causes intolerable adverse effects including severe akathisia.

■■ ANTIPSYCHOTIC AGENTS Antipsychotic drugs are able to reduce psychotic symptoms in a wide variety of conditions, including schizophrenia, bipolar disorder, psychotic depression, psychoses associated with dementia, and drug-induced psychoses. They are also able to improve mood and reduce anxiety and sleep disturbances, but they are not the treatment of choice when these symptoms are the primary disturbance in nonpsychotic patients. A neuroleptic is a subtype of antipsychotic drug that produces a high incidence of extrapyramidal side effects (EPS) at clinically effective doses, or catalepsy in laboratory animals. The second-generation or “atypical” antipsychotic drugs are now the most widely used type of antipsychotic drug.

*

The author thanks Herbert Meltzer, MD, PhD, for his contributions to prior editions of this chapter.

Although more costly, lurasidone is then prescribed, which, over the course of several weeks of treatment, improves his symptoms and is tolerated by the patient. What signs and symptoms would support an initial diagnosis of schizophrenia? In the treatment of schizophrenia, what benefits do the second-generation antipsychotic drugs offer over the traditional agents such as haloperidol? In addition to the management of schizophrenia, what other clinical indications warrant consideration of the use of drugs nominally classified as antipsychotics?

History Reserpine and chlorpromazine were the first drugs found to be useful to reduce psychotic symptoms in schizophrenia. Reserpine was used only briefly for this purpose and is no longer of interest as an antipsychotic agent. Chlorpromazine is a neuroleptic agent; that is, it produces catalepsy in rodents and EPS in humans. The discovery that its antipsychotic action was related to dopamine (D or DA)receptor blockade led to the identification of other compounds as antipsychotics between the 1950s and 1970s. The discovery of clozapine in 1959 led to the realization that antipsychotic drugs need not cause EPS in humans at clinically effective doses. Clozapine was called an “atypical” antipsychotic drug because of this dissociation; it produces fewer EPS at equivalent antipsychotic doses in humans and laboratory animals. As a result, there has been a major shift in clinical practice away from typical or first-generation antipsychotic drugs toward the use of an ever-increasing number of atypical or second-generation drugs, which have other advantages as well. The introduction of antipsychotic drugs led to massive changes in disease management, including brief instead of life-long hospitalizations. 537

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These drugs have also proved to be of great value in studying the pathophysiology of schizophrenia and other psychoses. It should be noted that schizophrenia and bipolar disorder are no longer believed by many to be separate disorders but rather to be part of a continuum of brain disorders with psychotic features.

Nature of Psychosis & Schizophrenia The term psychosis denotes a variety of mental disorders that are characterized by the inability to distinguish between what is real and what is not: the presence of delusions (false beliefs); various types of hallucinations, usually auditory or visual, but sometimes tactile or olfactory; and grossly disorganized thinking in a clear sensorium. Schizophrenia is a particular kind of psychosis characterized mainly by a clear sensorium but a marked thinking and perceptual disturbance. Schizophrenia is the most common psychotic disorder, present in about 1% of the population and responsible for approximately half of long-term psychiatric hospitalizations. Psychosis is not unique to schizophrenia and is not present in all patients with schizophrenia at all times. Schizophrenia is considered to be a neurodevelopmental disorder. This implies that structural and functional changes in the brain are present even in utero in some patients, or that they develop during childhood and adolescence, or both. Twin, adoption, and family studies have established that schizophrenia is a genetic disorder with high heritability. No single gene is involved. Current theories involve multiple genes with common and rare mutations, including large deletions and insertions (copy number variations), combining to produce a very variegated clinical presentation and course.

THE SEROTONIN HYPOTHESIS OF SCHIZOPHRENIA The discovery that indole hallucinogens such as LSD (lysergic acid diethylamide) and mescaline are serotonin (5-HT) agonists led to the search for endogenous hallucinogens in the urine, blood, and brains of patients with schizophrenia. This proved fruitless, but the identification of many 5-HT-receptor subtypes led to the pivotal discovery that 5-HT2A-receptor and possibly 5-HT2C stimulation was the basis for the hallucinatory effects of these agents. It has been found that 5-HT2A-receptor blockade is a key factor in the mechanism of action of the main class of second-generation antipsychotic drugs, of which clozapine is the prototype and which includes, in order of their introduction around the world, melperone, risperidone, zotepine, blonanserin, olanzapine, quetiapine, ziprasidone, aripiprazole, sertindole, paliperidone, iloperidone, asenapine, lurasidone, cariprazine, and brexpiprazole. These drugs are inverse agonists of the 5-HT2A receptor; that is, they block the constitutive activity of these receptors. These receptors modulate the release of dopamine, norepinephrine, glutamate, GABA, and acetylcholine, among other neurotransmitters in the cortex, limbic region, and striatum. Stimulation of 5-HT2A receptors leads to depolarization of glutamate neurons, but also stabilization of N-methyl-d-aspartate (NMDA) receptors on postsynaptic neurons. It has been found that hallucinogens can modulate the stability of a complex consisting of 5-HT2A and NMDA receptors.

5-HT2C-receptor stimulation provides a further means of modulating cortical and limbic dopaminergic activity. Stimulation of 5-HT2C receptors leads to inhibition of cortical and limbic dopamine release. Many atypical antipsychotic drugs, eg, clozapine, asenapine, and olanzapine, are 5-HT2C inverse agonists. 5-HT2C agonists are currently being studied as antipsychotic agents.

THE DOPAMINE HYPOTHESIS OF SCHIZOPHRENIA The dopamine hypothesis for schizophrenia was the second neurotransmitter-based concept to be developed but is no longer considered adequate to explain all aspects of schizophrenia, especially the cognitive impairment. Nevertheless, it is still highly relevant to understanding the major dimensions of schizophrenia, such as positive (hallucinations, delusions) and negative symptoms (emotional blunting, social withdrawal, lack of motivation), cognitive impairment, and possibly depression. It is also essential to understanding the mechanisms of action of most and probably all antipsychotic drugs. Several lines of evidence suggest that excessive limbic dopaminergic activity plays a role in psychosis. (1) Many antipsychotic drugs strongly block postsynaptic D2 receptors in the central nervous system, especially in the mesolimbic and striatal-frontal system; this includes partial dopamine agonists, such as aripiprazole, brexpiprazole, and bifeprunox. (2) Drugs that increase dopaminergic activity, such as levodopa, amphetamines, and bromocriptine and apomorphine, either aggravate schizophrenia psychosis or produce psychosis de novo in some patients. (3) Dopamine-receptor density has been found postmortem to be increased in the brains of schizophrenics who have not been treated with antipsychotic drugs. (4) Some but not all postmortem studies of schizophrenic subjects have reported increased dopamine levels and D2-receptor density in the nucleus accumbens, caudate, and putamen. (5) Imaging studies have shown increased amphetamine-induced striatal dopamine release, increased baseline occupancy of striatal D2 receptors by extracellular dopamine, and other measures consistent with increased striatal dopamine synthesis and release. However, the dopamine hypothesis is far from a complete explanation of all aspects of schizophrenia. Diminished cortical or hippocampal dopaminergic activity has been suggested to underlie the cognitive impairment and negative symptoms of schizophrenia. Postmortem and in vivo imaging studies of cortical, limbic, nigral, and striatal dopaminergic neurotransmission in schizophrenic subjects have reported findings consistent with diminished dopaminergic activity in these regions. Decreased dopaminergic innervation in medial temporal cortex, dorsolateral prefrontal cortex, and hippocampus and decreased levels of DOPAC, a metabolite of dopamine, in the anterior cingulate have been reported in postmortem studies. Imaging studies have found increased prefrontal D1-receptor levels that correlated with working memory impairments. The fact that several of the atypical antipsychotic drugs have much less effect on D2 receptors and yet are effective in schizophrenia has redirected attention to the role of other dopamine receptors and to nondopamine receptors. Serotonin receptors—particularly the 5-HT2A-receptor subtype—may mediate synergistic effects or

CHAPTER 29  Antipsychotic Agents & Lithium      539

protect against the extrapyramidal consequences of D2 antagonism. As a result of these considerations, the direction of research has changed to a greater focus on compounds that may act on several transmitter-receptor systems, eg, serotonin and glutamate. The atypical antipsychotic drugs share the property of weak D2-receptor antagonism and more potent 5-HT2A-receptor blockade.

THE GLUTAMATE HYPOTHESIS OF SCHIZOPHRENIA Glutamate is the major excitatory neurotransmitter in the brain (see Chapter 21). Phencyclidine (PCP) and ketamine are noncompetitive inhibitors of the NMDA receptor that exacerbate both cognitive impairment and psychosis in patients with schizophrenia. PCP and a related drug, MK-801, increase locomotor activity and, acutely or chronically, a variety of cognitive impairments in rodents and primates. These effects are widely employed as a means to develop novel antipsychotic and cognitive-enhancing drugs. Selective 5-HT2A antagonists, as well as atypical antipsychotic drugs, are much more potent than D2 antagonists in blocking these effects of PCP and MK-801. This was the starting point for the hypothesis that hypofunction of NMDA receptors, located on GABAergic interneurons, leading to diminished inhibitory influences on neuronal function, contributed to schizophrenia. The diminished GABAergic activity can induce disinhibition of downstream glutamatergic activity,

Phenothiazine derivatives

which can lead to hyperstimulation of cortical neurons through nonNMDA receptors. Preliminary evidence suggests that LY2140023, a drug that acts as an agonist of the metabotropic 2/3 glutamate receptor (mGLuR2/3), may be effective in schizophrenia. The NMDA receptor, an ion channel, requires glycine for full activation. It has been suggested that in patients with schizophrenia, the glycine site of the NMDA receptor is not fully saturated. There have been several trials of high doses of glycine to promote glutamatergic activity, but the results are far from convincing. Currently, glycine transport inhibitors are in development as possible psychotropic agents. Ampakines are drugs that potentiate currents mediated by AMPA-type glutamate receptors. In behavioral tests, ampakines are effective in correcting behaviors in various animal models of schizophrenia and depression. They protect neurons against neurotoxic insults, in part by mobilizing growth factors such as brainderived neurotrophic factor (BDNF, see also Chapter 30).

BASIC PHARMACOLOGY OF ANTIPSYCHOTIC AGENTS Chemical Types A number of chemical structures have been associated with antipsychotic properties. The drugs can be classified into several groups as shown in Figures 29–1 and 29–2.

Thioxanthene derivative

S

(7)

S

Phenothiazine nucleus

(2)

(2)

N (10)

C

Substituting C for N in the nucleus

(9)

Aliphatic side chain

Chlorpromazine

(2)

Cl

Thioridazine

(2)

SCH3 (10)

(10)

CH2

CH2 CH2 N

Thiothixene

(CH3)2

(2)

SO2N(CH3)2

(9) CH

CH2 CH2

CH2 CH2 N

N

CH3

N CH3

Piperazine side chain

Butyrophenone Trifluoperazine

(2)

CF3

(10) CH2 CH2 CH2

N

N

CH3

O F

C

CH2 CH2

CH2

N

Cl OH

Perphenazine

(2)

CI

(10) CH2 CH2 CH2

N

N

CH2

CH2 OH

Fluphenazine

(2)

CF3

(10)

N

N

CH2

CH2 OH

CH2 CH2 CH2

Haloperidol

FIGURE 29–1  Structural formulas of some older antipsychotic drugs: phenothiazines, thioxanthenes, and butyrophenones. Only representative members of each type are shown.

540    SECTION V  Drugs That Act in the Central Nervous System

O NH F

O O

N

CH

CH2

CH3

N

N

F

Molindone

Pimozide

N

N

N

CH3

N

CI

N

CH3

N

CI

O

N H

Loxapine

Clozapine

CH3

CH2

CH2

N

N O

CH2

CH2CH3

CH2 N H

N

CH2

CH2

N

N

CH2

O

CH2

CH2OH

N

N O S

Quetiapine

F

Risperidone

CH3 N S

N N

N

N

O N H

Cl

N CH3 N H

S

Ziprasidone

Olanzapine CI

CI N

N

CH2(CH2)2CH2O

N H

O

Aripiprazole

FIGURE 29–2 

Structural formulas of some newer antipsychotic drugs.

A. Phenothiazine Derivatives Three subfamilies of phenothiazines, based primarily on the side chain of the molecule, were once the most widely used of the antipsychotic agents. Aliphatic derivatives (eg, chlorpromazine) and piperidine derivatives (eg, thioridazine) are the least potent. These drugs produce more sedation and weight gain. Piperazine derivatives are more potent (effective in lower doses) but not necessarily more efficacious. The piperazine derivatives are also more selective in their pharmacologic effects (Table 29–1).

The National Institute of Mental Health (NIMH)-funded Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) reported that perphenazine, a piperazine derivative, was as effective as atypical antipsychotic drugs, with the modest exception of olanzapine, and concluded that first-generation antipsychotic drugs are the treatment of choice for schizophrenia based on their lower cost. However, there were numerous flaws in the design, execution, and analysis of this study, leading to it having only modest impact on clinical practice. In particular, it

CHAPTER 29  Antipsychotic Agents & Lithium      541

TABLE 29–1  Antipsychotic drugs: Relation of chemical structure to potency and toxicities. Drug

D2/5-HT2A Ratio1

Clinical Potency

Extrapyramidal Toxicity

Sedative Action

Hypotensive Actions

 Aliphatic

Chlorpromazine

High

Low

Medium

High

High

 Piperazine

Fluphenazine

High

High

High

Low

Very low

Thioxanthene

Thiothixene

Very high

High

Medium

Medium

Medium

Butyrophenone

Haloperidol

Medium

High

Very high

Low

Very low

Dibenzodiazepine

Clozapine

Very low

Medium

Very low

Low

Medium

2

Chemical Class Phenothiazines

Benzisoxazole

Risperidone

Very low

High

Low

Low

Low

Thienobenzodiazepine

Olanzapine

Low

High

Very low

Medium

Low

Dibenzothiazepine

Quetiapine

Low

Low

Very low

Medium

Low to medium

Dihydroindolone

Ziprasidone

Low

Medium

Very low

Low

Very low

Dihydrocarbostyril

Aripiprazole

Medium

High

Very low

Very low

Low

1

Ratio of affinity for D2 receptors to affinity for 5-HT2A receptors.

2

At dosages below 8 mg/d.

failed to consider issues such as dosage of olanzapine, inclusion of treatment resistant patients, encouragement of patients to switch medications inherent in the design, risk for tardive dyskinesia following long-term use of even low-dose typical antipsychotics, and the necessity of large sample sizes in equivalency studies. B. Thioxanthene Derivatives This group of drugs is exemplified primarily by thiothixene. C. Butyrophenone Derivatives This group, of which haloperidol is the most widely used, has a very different structure from those of the two preceding groups. Haloperidol, a butyrophenone, is the most widely used first-generation antipsychotic drug, despite its high level of EPS relative to other typical antipsychotic drugs. Diphenylbutylpiperidines are closely related compounds. The butyrophenones and congeners tend to be more potent and to have fewer autonomic effects but greater extrapyramidal effects than phenothiazines (see Table 29–1). D. Miscellaneous Structures Pimozide and molindone are first-generation antipsychotic drugs. There is no significant difference in efficacy between these newer typical and the older typical antipsychotic drugs. E. Second-Generation Antipsychotic Drugs Clozapine, asenapine, olanzapine, quetiapine, paliperidone, risperidone, sertindole, ziprasidone, zotepine, brexpiprazole, cariprazine, lurasidone, and aripiprazole are second-generation antipsychotic drugs (some of which are shown in Figure 29–2). Clozapine is the prototype. Paliperidone is 9-hydroxyrisperidone, the active metabolite of risperidone. Risperidone is rapidly converted to 9-hydroxyrisperidone in vivo in most patients, except for about 10% of patients who are poor metabolizers. Sertindole is approved in some European countries but not in the USA.

These drugs have complex pharmacology, but they share a greater ability to alter 5-HT2A-receptor activity than to interfere with D2-receptor action. In most cases, they act as partial agonists at the 5-HT1A receptor, which produces synergistic effects with 5-HT2A receptor antagonism. Most are also either 5-HT6 or 5-HT7 receptor antagonists. Sulpride and sulpiride constitute another class of atypical agents. They have equivalent potency for D2 and D3 receptors, but they are also 5-HT7 antagonists. They dissociate EPS and antipsychotic efficacy. However, they also produce marked increases in serum prolactin levels and are not as free of the risk of tardive dyskinesia as are drugs such as clozapine and quetiapine. They are not approved in the USA. Cariprazine represents another type of second-generation agent. In addition to D2/5-HT2 antagonism, cariprazine is also a D3 partial agonist with selectivity for the D3 receptor. Cariprazine’s selectivity for the D3 receptor may be associated with greater effects on the negative symptoms of schizophrenia. This drug was approved in 2015 in the USA. F. Glutamatergic Antipsychotics No glutamate-specific agents are currently approved for the treatment of schizophrenia. However, several agents are in late clinical testing. Among these is bitopertin, a glycine transporter 1 (GlyT1) inhibitor. As noted earlier, glycine is a required co-agonist with glutamate at NMDA receptors. Initial phase 2 studies indicated that bitopertin used adjunctively with standard antipsychotics significantly improved negative symptoms of schizophrenia, but subsequent trials have been disappointing. Sarcosine (N-methylglycine), another GlyT1 inhibitor, in combination with a standard antipsychotic has also shown benefit in improving both negative and positive symptoms of schizophrenia in acutely ill as well as in patients with more chronic schizophrenia. Another class of investigational antipsychotic agents includes the metabotropic glutamate receptor agonists. Eight metabotropic

542    SECTION V  Drugs That Act in the Central Nervous System

glutamate receptors are divided into three groups: group I (mGluR1,5), group II (mGluR2,3), and group III (mGluR4,6,7,8). mGluR2,3 inhibits glutamate release presynaptically. Several mGluR2,3 agents are being investigated in the treatment of schizophrenia. One agent, pomaglumetad methionil, showed antipsychotic efficacy in early phase 2 trials, but subsequent trials failed to show benefit in either positive or negative symptoms of schizophrenia. Other metabotropic glutamate receptor agonists are being explored for the treatment of negative and cognitive symptoms of schizophrenia.

Pharmacokinetics A. Absorption and Distribution Most antipsychotic drugs are readily but incompletely absorbed. Furthermore, many undergo significant first-pass metabolism. Thus, oral doses of chlorpromazine and thioridazine have systemic availability of 25–35%, whereas haloperidol, which has less first-pass metabolism, has an average systemic availability of about 65%. Most antipsychotic drugs are highly lipid soluble and protein bound (92–99%). They tend to have large volumes of distribution (usually more than 7 L/kg). They generally have a much longer clinical duration of action than would be estimated from their plasma half-lives. This is paralleled by prolonged occupancy of D2 dopamine receptors in the brain by the typical antipsychotic drugs. Metabolites of chlorpromazine may be excreted in the urine weeks after the last dose of chronically administered drug. Longacting injectable formulations may cause some blockade of D2 receptors 3–6 months after the last injection. Time to recurrence of psychotic symptoms is highly variable after discontinuation of antipsychotic drugs. The average time for relapse in stable patients with schizophrenia who discontinue their medication is 6 months. Clozapine is an exception in that relapse after discontinuation is usually rapid and severe. Thus, clozapine should never be discontinued abruptly unless clinically needed because of adverse effects such as myocarditis or agranulocytosis, which are true medical emergencies. B. Metabolism Most antipsychotic drugs are almost completely metabolized by oxidation or demethylation, catalyzed by liver microsomal cytochrome P450 enzymes. CYP2D6, CYP1A2, and CYP3A4 are the major isoforms involved (see Chapter 4). Drug-drug interactions should be considered when combining antipsychotic drugs with various other psychotropic drugs or drugs—such as ketoconazole—that inhibit various cytochrome P450 enzymes. At the typical clinical doses, antipsychotic drugs do not usually interfere with the metabolism of other drugs.

Pharmacodynamics The first phenothiazine antipsychotic drugs, with chlorpromazine as the prototype, proved to have a wide variety of central nervous system, autonomic, and endocrine effects. Although efficacy of these drugs is primarily driven by D2-receptor blockade, their

adverse actions were traced to blocking effects at a wide range of receptors including α adrenoceptors and muscarinic, H1 histaminic, and 5-HT2 receptors. A. Dopaminergic Systems Five dopaminergic systems or pathways are important for understanding schizophrenia and the mechanism of action of antipsychotic drugs. The first pathway—the one most closely related to behavior and psychosis—is the mesolimbic-mesocortical pathway, which projects from cell bodies in the ventral tegmentum in separate bundles of axons to the limbic system and neocortex. The second system—the nigrostriatal pathway—consists of neurons that project from the substantia nigra to the dorsal striatum, which includes the caudate and putamen; it is involved in the coordination of voluntary movement. Blockade of the D2 receptors in the nigrostriatal pathway is responsible for EPS. The third pathway—the tuberoinfundibular system—arises in the arcuate nuclei and periventricular neurons and releases dopamine into the pituitary portal circulation. Dopamine released by these neurons physiologically inhibits prolactin secretion from the anterior pituitary. The fourth dopaminergic system—the medullary-periventricular pathway—consists of neurons in the motor nucleus of the vagus whose projections are not well defined. This system may be involved in eating behavior. The fifth pathway—the incertohypothalamic pathway—forms connections from the medial zona incerta to the hypothalamus and the amygdala. It appears to regulate the anticipatory motivational phase of copulatory behavior in rats. After dopamine was identified as a neurotransmitter in 1959, it was shown that its effects on electrical activity in central synapses and on production of the second messenger cAMP synthesized by adenylyl cyclase could be blocked by antipsychotic drugs such as chlorpromazine, haloperidol, and thiothixene. This evidence led to the conclusion in the early 1960s that these drugs should be considered dopamine-receptor antagonists and was a key factor in the development of the dopamine hypothesis of schizophrenia described earlier in this chapter. The antipsychotic action is now thought to be produced (at least in part) by their ability to block the effect of dopamine (D2 receptors inhibit the activity of adenylyl cyclase in the mesolimbic system). B. Dopamine Receptors and Their Effects At present, five dopamine receptors have been described, consisting of two separate families, the D1-like (D1, D5) and D2-like (D2, D3, D4) receptor groups. The D1 receptor is coded by a gene on chromosome 5, increases cAMP by Gs-coupled activation of adenylyl cyclase, and is located mainly in the putamen, nucleus accumbens, and olfactory tubercle and cortex. The other member of this family, D5, is coded by a gene on chromosome 4, also increases cAMP, and is found in the hippocampus and hypothalamus. The therapeutic potency of antipsychotic drugs does not correlate with their affinity for binding to the D1 receptor (Figure  29–3, top) nor did a selective D1 antagonist prove to be an effective antipsychotic in patients with schizophrenia. The D2 receptor is coded on chromosome 11, decreases cAMP

CHAPTER 29  Antipsychotic Agents & Lithium      543

(by Gi-coupled inhibition of adenylyl cyclase), and inhibits calcium channels but opens potassium channels. It is found both pre- and postsynaptically on neurons in the caudate-putamen, nucleus accumbens, and olfactory tubercle. A second member of this family, the D3 receptor, also coded by a gene on chromosome 11, is thought to also decrease cAMP and is located in the frontal cortex, medulla, and midbrain. D4 receptors also decrease cAMP and are concentrated in the cortex. The first-generation antipsychotic agents block D2 receptors stereoselectively for the most part, and their binding affinity is very strongly correlated with clinical antipsychotic and extrapyramidal potency (Figure 29–3, bottom). In vivo imaging studies

K (mol/L) on 3H-SCH 23390 binding

10–5 D1

Clebopride

Sulpiride Molindone

10–6 Chlorpromazine

Spiperone

Clozapine

10–7 Haloperidol

Thioridazine

Fluphenazine Trifluperazine 10–8 Flupenthixol

IC50 (mol/L) on 3H-haloperidol binding

10–7 Promazine Chlorpromazine Trazodone Clozapine Molindone Thioridazine Moperone Prochlorperazine Trifluperazine Thiothixene

D2 10–8

10–9

Haloperidol Droperidol

Fluphenazine

Pimozide

Trifluperidol

Benperidol 10–10

0.1

Spiroperidol 1

10

100

1000

Range and average clinical dose for controlling schizophrenia (mg/d)

FIGURE 29–3  Correlations between the therapeutic potency of antipsychotic drugs and their affinity for binding to dopamine D1 (top) or D2 receptors (bottom). Potency is indicated on the horizontal axes; it decreases to the right. Binding affinity for D1 receptors was measured by displacing the selective D1 ligand SCH 23390; affinity for D2 receptors was similarly measured by displacing the selective D2 ligand haloperidol. Binding affinity decreases upward. (Reproduced with permission from Seeman P: Dopamine receptors and the dopamine hypothesis of schizophrenia. Synapse 1987;1(2):133-152.)

of D2-receptor occupancy indicate that for antipsychotic efficacy, the typical antipsychotic drugs must be given in sufficient doses to achieve at least 60% occupancy of striatal D2 receptors. This is not required for some second-generation antipsychotic drugs such as clozapine and olanzapine, which are effective at lower occupancy levels of 30–50%, most likely because of their concurrent high occupancy of 5-HT2A receptors. The first-generation antipsychotic drugs produce EPS when the occupancy of striatal D2 receptors reaches 80% or higher. Positron emission tomography (PET) studies with aripiprazole show very high occupancy of D2 receptors, but this drug does not cause EPS because it is a partial D2-receptor agonist. Aripiprazole also gains therapeutic efficacy through its 5-HT2A antagonism and possibly 5-HT1A partial agonism. These findings have been incorporated into the dopamine hypothesis of schizophrenia. However, additional factors complicate interpretation of dopamine receptor data. For example, dopamine receptors exist in both high- and low-affinity forms, and it is not known whether schizophrenia or the antipsychotic drugs alter the proportions of receptors in these two forms. It has not been convincingly demonstrated that antagonism of any dopamine receptor other than the D2 receptor plays a role in the action of antipsychotic drugs. Selective and relatively specific D1-, D3-, and D4-receptor antagonists have been tested repeatedly with no evidence of antipsychotic action. Most of the newer atypical antipsychotic agents and some of the traditional ones have a higher affinity for the 5-HT2A receptor than for the D2 receptor (see Table 29–1), suggesting an important role for the serotonin 5-HT system in the etiology of schizophrenia and the action of these drugs. C. Novel Pharmacodynamic Targets While currently available antipsychotics predominately act on the D2 receptor, there are at least 2 current agents that appear to have little affinity for the D2 receptor; clozapine and pimavanserin. Pimavanserin is primarily a 5HT2 antagonist approved for the treatment of psychosis in Parkinson’s disease while clozapine also is a 5HT2 antagonist with differential effects on D1-D4 receptors. While that available antipsychotics have proven extremetly helpful in mitigating positive psychotic symptoms including hallucinations and delusions that often have intolerable side effects and have not been particularly effective in treating negative and cognitive symptoms. Two drugs in late-stage development with a novel pharmacodynamic profile offer some hope of treating patients for whom the currenly available agents have proven ineffective or too difficult to tolerate. Xenomeline is a muscarine M1/M4 agonist while Ulotaront is a Trace Amine Associated Receptor -1 agonist (TAAR-1). Both of these drugs have shown efficacy in the treatment of schizophrenia and lack the EPS and metabolic side effects of first- and second-generation antipsychotics. In addition, Xenomaline has shown benefit for treating cognitive symptoms of schizophrenia and both drugs may have benefits for treating negative symptoms. Xenomaline is expected to undergo FDA review in 2023 for possible approval while ulotarant has been given a breakthrough designation by the FDA for the treatment of schizophrenia and is expected to seek approval by 2024.

544    SECTION V  Drugs That Act in the Central Nervous System

D. Differences among Antipsychotic Drugs Although almost all effective antipsychotic drugs block D2 receptors, the degree of this blockade in relation to other actions on receptors varies considerably among drugs. Vast numbers of ligand-receptor binding experiments have been performed in an effort to discover a single receptor action that would best predict antipsychotic efficacy. A summary of the relative receptor-binding affinities of several key agents in such comparisons illustrates the difficulty in drawing simple conclusions from such experiments: Chlorpromazine: α1 = 5-HT2A > D2 > D1 Haloperidol: D2 > α1 > D4 > 5-HT2A > D1 > H1 Clozapine: D4 = α1 > 5-HT2A > D2 = D1 Olanzapine: 5-HT2A > H1 > D4 > D2 > α1 > D1 Aripiprazole: D2 = 5-HT2A > D4 > α1 = H1 >> D1 Quetiapine: H1 > α1 > M1,3 > D2 > 5-HT2A

Thus, most of the second-generation and some first-generation antipsychotic agents are at least as potent in inhibiting 5-HT2 receptors as they are in inhibiting D2 receptors. Aripiprazole and brexpiprazole appear to be partial agonists of D2 receptors. Varying degrees of antagonism of α2 adrenoceptors are also seen with risperidone, clozapine, olanzapine, quetiapine, and aripiprazole. Current research is directed toward discovering novel antipsychotic compounds that either are more selective for the mesolimbic system (to reduce their effects on the extrapyramidal system) or have effects on central neurotransmitter receptors—such as those for acetylcholine and excitatory amino acids—that have been proposed as new targets for antipsychotic action. In contrast to the difficult search for receptors responsible for antipsychotic efficacy, the differences in receptor effects of various antipsychotics do explain many of their toxicities (Tables 29–1 and 29–2). In particular, extrapyramidal toxicity appears to be consistently associated with high D2 potency.

TABLE 29–2  Adverse pharmacologic effects of antipsychotic drugs.

Type

Manifestations

Mechanism

Autonomic nervous system

Loss of accommodation, dry mouth, difficulty urinating, constipation

Muscarinic cholinoceptor blockade

 

Orthostatic hypotension, impotence, failure to ejaculate

α-Adrenoceptor blockade

Central nervous system

Parkinson syndrome, akathisia, dystonias

Dopamine-receptor blockade

 

Tardive dyskinesia

Supersensitivity of dopamine receptors

 

Toxic-confusional state

Muscarinic blockade

Endocrine system

Amenorrheagalactorrhea, infertility, impotence

Dopamine-receptor blockade resulting in hyperprolactinemia

Other

Weight gain

Possibly combined H1 and 5-HT2 blockade

E. Psychological Effects Most antipsychotic drugs cause unpleasant subjective effects in nonpsychotic individuals. The mild to severe EPS, including akathisia, sleepiness, restlessness, and autonomic effects, are unlike any associated with more familiar sedatives or hypnotics. Nevertheless, low doses of some of these drugs, particularly quetiapine, are used to promote sleep onset and maintenance, although there is no approved indication for such usage. People without psychiatric illness given antipsychotic drugs, even at low doses, experience impaired performance as judged by a number of psychomotor and psychometric tests. Psychotic individuals, however, may actually show improvement in their performance as the psychosis is alleviated. The ability of the second-generation antipsychotic drugs to improve some domains of cognition in patients with schizophrenia and bipolar disorder is controversial. Some individuals experience marked improvement, and for that reason, cognition should be assessed in all patients with schizophrenia and a trial of an atypical agent considered, even if positive symptoms are well controlled by firstgeneration agents. F. Electroencephalographic Effects Antipsychotic drugs produce shifts in the pattern of electroencephalographic (EEG) frequencies, usually slowing them and increasing their synchronization. The slowing (hypersynchrony) is sometimes focal or unilateral, which may lead to erroneous diagnostic interpretations. Both the frequency and the amplitude changes induced by psychotropic drugs are readily apparent and can be quantitated by sophisticated electrophysiologic techniques. Some antipsychotic agents lower the seizure threshold and induce EEG patterns typical of seizure disorders; however, with careful dosage titration, most can be used safely in epileptic patients. G. Endocrine Effects Older typical antipsychotic drugs, as well as risperidone and paliperidone, produce elevations of prolactin (see Adverse Effects, below). Newer antipsychotics such as olanzapine, quetiapine, aripiprazole, and brexpiprazole cause no or minimal increases of prolactin and reduce the risks of extrapyramidal system dysfunction and tardive dyskinesia, reflecting their diminished D2 antagonism. H. Cardiovascular Effects The low-potency phenothiazines frequently cause orthostatic hypotension and tachycardia. Mean arterial pressure, peripheral resistance, and stroke volume are decreased. These effects are predictable from the autonomic actions of these agents (see Table 29–2). Abnormal electrocardiograms have been recorded, especially with thioridazine. Changes include prolongation of QT interval and abnormal configurations of the ST segment and T waves. These changes are readily reversed by withdrawing the drug. Since thioridazine is associated with torsades de pointes and an increased risk of sudden death, the branded drug was removed from the market in 2005, and its use currently is as a second-line agent if other drugs have proved intolerable or ineffective.

CHAPTER 29  Antipsychotic Agents & Lithium      545

Among the newest antipsychotics, prolongation of the QT or QTc interval has received much attention. Because this was believed to indicate an increased risk of dangerous arrhythmias, ziprasidone and quetiapine are accompanied by warnings. There is, however, no evidence that this has actually translated into increased incidence of arrhythmias. The atypical antipsychotics are also associated with a metabolic syndrome that may increase the risk of coronary artery disease, stroke, and hypertension.

CLINICAL PHARMACOLOGY OF ANTIPSYCHOTIC AGENTS INDICATIONS A. Psychiatric Indications Schizophrenia is the primary indication for antipsychotic agents. However, in the last decade, the use of antipsychotics in the treatment of mood disorders such as type 1 bipolar disorder (BD-1), psychotic depression, and treatment-resistant depression has eclipsed their use in the treatment of schizophrenia. Catatonic forms of schizophrenia are best managed by intravenous benzodiazepines. Antipsychotic drugs may be needed to treat psychotic components of that form of the illness after catatonia has ended, and they remain the mainstay of treatment for this condition. Unfortunately, many patients show little response, and virtually none shows a complete response. Antipsychotic drugs are also indicated for schizoaffective disorders, which share characteristics of both schizophrenia and affective disorders. No fundamental difference between these two diagnoses has been reliably demonstrated. It is most likely that they are part of a continuum with bipolar psychotic disorder. The psychotic aspects of the illness require treatment with antipsychotic drugs, which may be used with other drugs such as antidepressants, lithium, or valproic acid. The manic phase in bipolar affective disorder often requires treatment with antipsychotic agents, although lithium or valproic acid supplemented with high-potency benzodiazepines (eg, lorazepam or clonazepam) may suffice in milder cases. Controlled trials support the efficacy of monotherapy with second-generation antipsychotics in the acute phase (up to 4 weeks) of mania. In addition, several second-generation antipsychotics are approved in the maintenance treatment of bipolar disorder. They appear more effective in preventing mania than in preventing depression. As mania subsides, the antipsychotic drug may be withdrawn, although maintenance treatment with atypical antipsychotic agents has become more common. Nonmanic excited states may also be managed by antipsychotics, often in combination with benzodiazepines. An increasingly common use of antipsychotics is in the monotherapy of acute bipolar depression and the adjunctive use of antipsychotics with antidepressants in the treatment of unipolar depression. Several antipsychotics are now approved by the US Food and Drug Administration (FDA) in the management of bipolar depression including quetiapine, lurasidone, and cariprazine, lumateperone and olanzapine (in a combination formulation with

fluoxetine). The antipsychotics appear more consistently effective than antidepressants in the treatment of bipolar depression and also do not increase the risk of inducing mania or increasing the frequency of bipolar cycling. Likewise, several antipsychotics, including aripiprazole, quetiapine, brexpiprazole, and olanzapine (with fluoxetine), are now approved in the adjunctive treatment of unipolar depression. Although many drugs are combined with antidepressants in the adjunctive treatment of major depression, antipsychotic agents are the only class of agents that have been formally evaluated for FDA approval for this purpose. Residual symptoms and partial remission are common, with antipsychotics showing consistent benefit in improving overall antidepressant response. Some of the intramuscular antipsychotics have been approved for the control of agitation associated with bipolar disorder and schizophrenia. Antipsychotics such as haloperidol have long been used in the ICU setting to manage agitation in delirious and postsurgical patients. The intramuscular forms of ziprasidone, olanzapine, and aripiprazole have been shown to improve agitation within 1–2 hours, with fewer extrapyramidal symptoms than typical agents such as haloperidol. An alternative to antipsychotics, also now approved for the management of agitation in bipolar disorder and schizophrenia, is a sublingual analog of etomidate, dexmedetomidate. Etomidate has long been used as an anesthetic, and dexmetetomidate is a sulingual film that that can be given as an alternative or an oral or IM antipsychotic. Dexmetedomidate does not carry the EPS risks of acute antipsychotics. Sedation and dry mouth have been the most common side effects in clinical trials. Other indications for the use of antipsychotics include Tourette syndrome and possibly disturbed behavior in patients with Alzheimer disease. However, controlled trials of antipsychotics in the management of behavioral symptoms in dementia patients have generally not demonstrated efficacy. Furthermore, second-generation as well as some first-generation antipsychotics have been associated with increased mortality in these patients. Antipsychotics are not indicated for the treatment of various withdrawal syndromes, eg, opioid withdrawal. In small doses, antipsychotic drugs have been promoted (wrongly) for the relief of anxiety associated with minor emotional disorders. The antianxiety sedatives (see Chapter 22) are preferred in terms of both safety and acceptability to patients. Psychotic symptoms associated with Parkinson disease represent a clinical challenge. Medications such as levodopa that treat the symptoms of Parkinson disease can also exacerbate psychotic symptoms. Likewise, antipsychotics that can treat the psychotic symptoms can significantly worsen the other symptoms of Parkinson disease. In 2016, a new type of antipsychotic was approved for the treatment of psychosis in Parkinson disease. Pimavanserin is a selective serotonin inverse agonist. As such, it has no dopamine antagonist properties and is not associated with EPS. Pimavanserin is currently being investigated as an adjunctive treatment in schizophrenia. Irritability and behavioral dyscontrol in patients with autism spectrum disorders (ASD) can be challenging for care providers and patients alike. Two antipsychotics, risperidone and aripiprazole, are approved to treat irritability in ASD patients.

546    SECTION V  Drugs That Act in the Central Nervous System

No medications, however, are known to treat and correct the core symptoms of ASD. B. Nonpsychiatric Indications Most older first-generation antipsychotic drugs, with the exception of thioridazine, have a strong antiemetic effect. This action is due to dopamine-receptor blockade, both centrally (in the chemoreceptor trigger zone of the medulla) and peripherally (on receptors in the stomach). Some drugs, such as prochlorperazine and benzquinamide, are promoted solely as antiemetics. Phenothiazines with shorter side chains have considerable H1-receptor-blocking action and have been used for relief of pruritus or, in the case of promethazine, as preoperative sedatives. The butyrophenone droperidol is used in combination with the opioid fentanyl in neuroleptanesthesia. Droperidol has doseassociated risk of QT prolongation and has been removed from some markets. The use of these drugs in anesthesia practice is described in Chapter 25.

Drug Choice Choice among antipsychotic drugs is based mainly on differences in adverse effects and possible differences in efficacy. In addition, cost and the availability of a given agent on drug formularies also influence the choice of a specific antipsychotic. Because use of the older drugs is still common, especially for patients treated in the

public sector, knowledge of such agents as chlorpromazine and haloperidol remains relevant. Thus, one should be familiar with one member of each of the three subfamilies of phenothiazines, a member of the thioxanthene and butyrophenone group, and all of the newer compounds—clozapine, risperidone, olanzapine, quetiapine, ziprasidone, lurasidone, iloperidone, asenapine, cariprazine, lumateperone, and aripiprazole. Each may have special advantages for selected patients. A representative group of antipsychotic drugs is presented in Table 29–3. For approximately 70% of patients with schizophrenia, and probably for a similar proportion of patients with bipolar disorder with psychotic features, first- and second-generation antipsychotic drugs are of equal efficacy for treating positive symptoms. However, the evidence favors second-generation drugs for benefit for negative symptoms and cognition, for diminished risk of tardive dyskinesia and other forms of EPS, and for lesser increases in prolactin levels. Some of the second-generation antipsychotic drugs produce more weight gain and increases in lipids than some first-generation drugs. A small percentage of patients develop diabetes mellitus, most often seen with clozapine and olanzapine. Ziprasidone is the second-generation drug causing the least weight gain. Risperidone, lurasidone, brexpiprazole, paliperidone, and aripiprazole usually produce small increases in weight and lipids. Asenapine and quetiapine have an intermediate effect. Clozapine and olanzapine frequently result in large increases in weight and lipids. Thus, these

TABLE 29–3  Some representative antipsychotic drugs. Drug Class

Drug

Advantages

Disadvantages

 Aliphatic

Chlorpromazine1

Generic, inexpensive

Many adverse effects, especially autonomic

 Piperidine

Thioridazine2

Slight extrapyramidal syndrome; generic

800 mg/d limit; no parenteral form; cardiotoxicity

Phenothiazines

3

 Piperazine

Fluphenazine

Depot form also available (enanthate, decanoate)

Possible increased tardive dyskinesia

Thioxanthene

Thiothixene

Parenteral form also available; possible decreased tardive dyskinesia

Uncertain

Butyrophenone

Haloperidol

Parenteral form also available; generic

Severe extrapyramidal syndrome

Dibenzoxazepine

Loxapine

Possible no weight gain

Uncertain

Dibenzodiazepine

Clozapine

May benefit treatment-resistant patients; little extrapyramidal toxicity

May cause agranulocytosis in up to 2% of patients; dose-related lowering of seizure threshold

Benzisoxazole

Risperidone

Broad efficacy; little or no extrapyramidal system dysfunction at low doses

Extrapyramidal system dysfunction and hypotension with higher doses

Thienobenzodiazepine

Olanzapine

Effective against negative as well as positive symptoms; little or no extrapyramidal system dysfunction

Weight gain; dose-related lowering of seizure threshold

Dibenzothiazepine

Quetiapine

Similar to olanzapine; perhaps less weight gain

May require high doses if there is associated hypotension; short t½ and twice-daily dosing

Dihydroindolone

Ziprasidone

Perhaps less weight gain than clozapine, parenteral form available

QTc prolongation

Dihydrocarbostyril

Aripiprazole

Lower weight gain liability, long half-life, novel mechanism potential

Uncertain, novel toxicities possible

1

Other aliphatic phenothiazines: promazine, triflupromazine.

2

Other piperidine phenothiazines: piperacetazine, mesoridazine.

3

Other piperazine phenothiazines: acetophenazine, perphenazine, carphenazine, prochlorperazine, trifluoperazine.

CHAPTER 29  Antipsychotic Agents & Lithium      547

drugs should be considered as second-line drugs unless there is a specific indication. That is the case with clozapine, which at high doses (300–900 mg/d) is effective in the majority of patients with schizophrenia refractory to other drugs, provided that treatment is continued for up to 6 months. Case reports and several clinical trials suggest that high-dose olanzapine, ie, doses of 30–45 mg/d, may also be efficacious in refractory schizophrenia when given over a 6-month period. Clozapine is the only second-generation antipsychotic drug approved to reduce the risk of suicide in patients with history of schizophrenia. Patients with schizophrenia who have made life-threatening suicide attempts should be seriously evaluated for switching to clozapine. New antipsychotic drugs have been shown in some trials to be more effective than older ones for treating negative symptoms. The floridly psychotic form of the illness accompanied by uncontrollable behavior probably responds equally well to all potent antipsychotics but is still frequently treated with older drugs that offer intramuscular formulations for acute and chronic treatment. Moreover, the low cost of the older drugs contributes to their widespread use despite their risk of adverse EPS effects. Several of the newer antipsychotics, including clozapine, risperidone, and olanzapine, show superiority over haloperidol in terms of overall response in some controlled trials. More comparative studies with aripiprazole are needed to evaluate its relative efficacy. Moreover, the superior adverse-effect profile of the newer agents and low to absent risk of tardive dyskinesia suggest that these should provide the first line of treatment. Generic forms of many secondgeneration drugs including clozapine, olanzapine, aripiprazole, risperidone, and quetiapine have become available, and cost of these drugs is much less of a consideration than it once was. The best guide for selecting a drug for an individual patient is the patient history of past responses to drugs. At present, clozapine is limited to those patients who have failed to respond to substantial doses of conventional antipsychotic drugs. The agranulocytosis and seizures associated with this drug prevent more widespread use. Risperidone’s improved adverse-effect profile (compared with that of haloperidol) at dosages of 6 mg/d or less and the apparently lower risk of tardive dyskinesia have contributed to its widespread use. Olanzapine and quetiapine may have even lower risks and have also achieved widespread use. At this writing, aripiprazole is the most commonly prescribed second-generation antipsychotic in the USA due to a relatively favorable side effect profile and aggressive marketing.

Dosage The range of effective dosages among various antipsychotic agents is broad. Therapeutic margins are substantial. At appropriate dosages, antipsychotics—with the exception of clozapine and perhaps olanzapine—are of equal efficacy in broadly selected groups of patients. However, some patients who fail to respond to one drug may respond to another; for this reason, several drugs may have to be tried to find the one most effective for an individual patient. Patients who have become refractory to two or three antipsychotic agents given in substantial doses become candidates for treatment with clozapine or high-dose olanzapine. Thirty to fifty percent of

TABLE 29–4  Dose relationships of antipsychotics.  

Minimum Effective Therapeutic Dose (mg)

Usual Range of Daily Doses (mg)

Chlorpromazine

100

100–1000

Thioridazine

100

100–800

Trifluoperazine

5

5–60

Perphenazine

10

8–64

Fluphenazine

2

2–60

Thiothixene

2

2–120

Haloperidol

2

2–60

Loxapine

10

20–160

Molindone

10

20–200

Clozapine

50

300–600

Cariprazine

1.5

1.5–4.5

Olanzapine

5

10–30

Quetiapine

150

150–800

Risperidone

4

4–16

Ziprasidone

40

80–160

Aripiprazole

10

10–30

Lumateperone

42

42

patients previously refractory to standard doses of other antipsychotic drugs respond to these drugs. In such cases, the increased risk of clozapine can well be justified. Some dosage relationships between various antipsychotic drugs, as well as possible therapeutic ranges, are shown in Table 29–4.

Parenteral Preparations Well-tolerated parenteral forms of the high-potency older drugs haloperidol and fluphenazine are available for rapid initiation of treatment as well as for maintenance treatment in noncompliant patients. Since the parenterally administered drugs may have much greater bioavailability than the oral forms, doses should be only a fraction of what might be given orally, and the manufacturer’s literature should be consulted. Fluphenazine decanoate and haloperidol decanoate are suitable for long-term parenteral maintenance therapy in patients who cannot or will not take oral medication. In addition, newer long-acting injectable (LAI) second-generation antipsychotics are now available, including formulations of risperidone, olanzapine, aripiprazole, and paliperidone. For some patients, the newer LAI drugs may be better tolerated than the older depot injectables.

Dosage Schedules Antipsychotic drugs are often given in divided daily doses, titrating to an effective dosage Some others, such as lumateperone are given once a day while many clinicians dose more sedating medications such as quetiapine or olanzapine primarily at night. The low end of the dosage range in Table 29–4 should be tried for at least several weeks. After an effective daily dosage has been defined

548    SECTION V  Drugs That Act in the Central Nervous System

for an individual patient, doses can be given less frequently. Oncedaily doses, usually given at night, are feasible for many patients during chronic maintenance treatment. Simplification of dosage schedules leads to better compliance.

Maintenance Treatment A very small minority of schizophrenic patients may recover from an acute episode and require no further drug therapy for prolonged periods. In most cases, the choice is between “as needed” increased doses or the addition of other drugs for exacerbations versus continual maintenance treatment with full therapeutic dosage. The choice depends on social factors such as the availability of family or friends familiar with the early symptoms of relapse and ready access to care.

Drug Combinations Combining antipsychotic drugs confounds evaluation of the efficacy of the drugs being used. Use of combinations, however, is widespread, with more emerging experimental data supporting such practices. Tricyclic antidepressants or, more often, selective serotonin reuptake inhibitors (SSRIs) are often used with antipsychotic agents for symptoms of depression complicating schizophrenia. The evidence for the usefulness of this polypharmacy is minimal. Electroconvulsive therapy (ECT) is a useful adjunct for antipsychotic drugs, not only for treating mood symptoms, but for positive symptom control as well. Electroconvulsive therapy can augment clozapine when maximum doses of clozapine are ineffective. In contrast, adding risperidone to clozapine is not beneficial. Lithium or valproic acid is sometimes added to antipsychotic agents with benefit to patients who do not respond to the latter drugs alone. There is some evidence that lamotrigine is more effective than any of the other mood stabilizers for this indication (see below). It is uncertain whether instances of successful combination therapy represent misdiagnosed cases of mania or schizoaffective disorder. Benzodiazepines may be useful for patients with anxiety symptoms or insomnia not controlled by antipsychotics.

Adverse Reactions Most of the unwanted effects of antipsychotic drugs are extensions of their known pharmacologic actions (see Tables 29–1 and 29–2), but a few effects are allergic in nature, and some are idiosyncratic. A. Behavioral Effects The older typical antipsychotic drugs are unpleasant to take. Many patients stop taking these drugs because of the adverse effects, which may be mitigated by giving small doses during the day and the major portion at bedtime. A “pseudodepression” that may be due to drug-induced akinesia usually responds to cautious treatment with antiparkinsonism drugs. Other pseudodepressions may be due to higher doses than needed in a partially remitted patient, in which case decreasing the dose may relieve the symptoms. Toxic-confusional states may occur with very high doses of drugs that have prominent antimuscarinic actions.

B. Neurologic Effects Extrapyramidal reactions occurring early during treatment with older agents include typical Parkinson syndrome, akathisia (uncontrollable restlessness), and acute dystonic reactions (spastic retrocollis or torticollis). Parkinsonism can be treated, when necessary, with conventional antiparkinsonism drugs of the antimuscarinic type or, in rare cases, with amantadine. (Levodopa should never be used in these patients.) Parkinsonism may be self-limiting, so an attempt to withdraw antiparkinsonism drugs should be made every 3–4 months. Akathisia and dystonic reactions also respond to such treatment, but many clinicians prefer to use a sedative antihistamine with anticholinergic properties, eg, diphenhydramine, which can be given either parenterally or orally. Tardive dyskinesia, as the name implies, is a late-occurring syndrome of abnormal choreoathetoid movements. It is the most important unwanted effect of antipsychotic drugs. It has been proposed that it is caused by a relative cholinergic deficiency secondary to supersensitivity of dopamine receptors in the caudate-putamen. The prevalence varies enormously, but tardive dyskinesia is estimated to have occurred in 20–40% of chronically treated patients before the introduction of the newer atypical antipsychotics. Early recognition is important, since advanced cases may be difficult to reverse. Any patient with tardive dyskinesia treated with a firstgeneration antipsychotic drug or possibly risperidone or paliperidone could be switched to quetiapine or clozapine, the second-generation agents with the least likelihood of causing tardive dyskinesia. Most authorities agree that the first step should be to discontinue or slowly reduce the dose of the current antipsychotic agent or switch to one of the newer atypical agents. A logical second step would be to eliminate all drugs with central anticholinergic action, particularly antiparkinsonism drugs and tricyclic antidepressants. These two steps are often enough to bring about improvement. In 2017, the first vesicular monoamine transporter type-2 (VMAT-2) inhibitor, valbenazine, was approved for the treatment of tardive dyskinesia. It was joined by deutetrabenazine, a second VMAT-2 agent in 2018. The VMAT-2 inhibitors selectively bind to the transporter to decrease dopamine to release in a reversible manner. Tardive dyskinesia is thought to be the result of postsynaptic dopamine hypersensitivity, and VMAT-2 inhibitors are more selective for dopamine than other monoamines. In the clinical trials leading to FDA approval, between 40% and 60% of patients were rated to be much or very much improved in their tardive dyskinesia. The most common side effects of valbenazine and deutetrabenazine are fatigue, somnolence, and headaches. Gastrointestinal side effects and akathisia also have been reported with the VMAT-2 inhibitors. Less commonly, QT prolongation also has been reported with both valbenazine and deutetrabenazine. Seizures, though recognized as a complication of chlorpromazine treatment, were so rare with the high-potency older drugs as to merit little consideration. However, de novo seizures may occur in 2–5% of patients treated with clozapine. Use of an anticonvulsant is able to control seizures in most cases. C. Autonomic Nervous System Effects Most patients are able to tolerate the antimuscarinic adverse effects of antipsychotic drugs. Those who are made too uncomfortable

CHAPTER 29  Antipsychotic Agents & Lithium      549

or who develop urinary retention or other severe symptoms can be switched to an agent without significant antimuscarinic action. Orthostatic hypotension or impaired ejaculation—common complications of therapy with chlorpromazine or mesoridazine— should be managed by switching to drugs with less marked adrenoceptor-blocking actions. D. Metabolic and Endocrine Effects Weight gain is very common, especially with clozapine and olanzapine, and requires monitoring of food intake, especially carbohydrates. Hyperglycemia may develop, but whether secondary to weight gain-associated insulin resistance or to other mechanisms remains to be clarified. Hyperlipidemia may occur. The management of weight gain, insulin resistance, and increased lipids should include monitoring of weight at each visit and measurement of fasting blood sugar and lipids at 3- to 6-month intervals. Measurement of hemoglobin A1C may be useful when it is impossible to be sure of obtaining a fasting blood sugar. Diabetic ketoacidosis has been reported in a few cases. The triglyceride:HDL ratio should be less than 3.5 in fasting samples. Levels higher than that indicate increased risk of atherosclerotic cardiovascular disease. Hyperprolactinemia in women results in the amenorrheagalactorrhea syndrome and infertility; in men, loss of libido, impotence, and infertility may result. Hyperprolactinemia may cause osteoporosis, particularly in women. If dose reduction is not indicated, or is ineffective in controlling this pattern, switching to an atypical agent that does not raise prolactin levels, eg, aripiprazole, may be indicated. E. Toxic or Allergic Reactions Agranulocytosis, cholestatic jaundice, and skin eruptions occur rarely with the high-potency antipsychotic drugs currently used. In contrast to other antipsychotic agents, clozapine causes agranulocytosis in a small but significant number of patients— approximately 1–2% of those treated. This serious, potentially fatal effect can develop rapidly, usually between the 6th and 18th weeks of therapy. It is not known whether it represents an immune reaction, but it appears to be reversible upon discontinuance of the drug. Because of the risk of agranulocytosis, patients receiving clozapine must have weekly blood counts for the first 6 months of treatment and every 3 weeks thereafter. F. Ocular Complications Deposits in the anterior portions of the eye (cornea and lens) are a common complication of chlorpromazine therapy. They may accentuate the normal processes of aging of the lens. Thioridazine is the only antipsychotic drug that causes retinal deposits, which in advanced cases may resemble retinitis pigmentosa. The deposits are usually associated with “browning” of vision. The maximum daily dose of thioridazine has been limited to 800 mg/d to reduce the possibility of this complication. G. Cardiac Toxicity Thioridazine in doses exceeding 300 mg daily is almost always associated with minor abnormalities of T waves that are easily reversible.

Overdoses of thioridazine are associated with major ventricular arrhythmias, eg, torsades de pointes, cardiac conduction block, and sudden death; it is not certain whether thioridazine can cause these same disorders when used in therapeutic doses. In view of possible additive antimuscarinic and quinidinelike actions with various tricyclic antidepressants, thioridazine should be combined with the latter drugs only with great care. Among the atypical agents, ziprasidone carries the greatest risk of QT prolongation and therefore should not be combined with other drugs that prolong the QT interval, including thioridazine, pimozide, and group 1A or 3 antiarrhythmic drugs. Clozapine is sometimes associated with myocarditis and must be discontinued if myocarditis manifests. Sudden death due to arrhythmias is common in schizophrenia. It is not always drugrelated, and there are no studies that definitively show increased risk with particular drugs. Monitoring of QTc prolongation has proved to be of little use unless the values increase to more than 500 ms and this is manifested in multiple rhythm strips or a Holter monitor study. A 20,000-patient study of ziprasidone versus olanzapine showed minimal or no increased risk of torsades de pointes or sudden death in patients who were randomized to ziprasidone. H. Use in Pregnancy; Dysmorphogenesis Although antipsychotic drugs appear to be relatively safe in pregnancy, a small increase in teratogenic risk could be missed. Questions about whether to use these drugs during pregnancy and whether to abort a pregnancy in which the fetus has already been exposed must be decided individually. If a pregnant woman could manage to be free of antipsychotic drugs during pregnancy, this would be desirable because of their effects on the neurotransmitters involved in neurodevelopment. I. Neuroleptic Malignant Syndrome This life-threatening disorder occurs in patients who are extremely sensitive to the extrapyramidal effects of antipsychotic agents (see also Chapter 16). The initial symptom is marked muscle rigidity. If sweating is impaired, as it often is during treatment with anticholinergic drugs, fever may ensue, often reaching dangerous levels. The stress leukocytosis and high fever associated with this syndrome may erroneously suggest an infectious process. Autonomic instability, with altered blood pressure and pulse rate, is often present. Muscle-type creatine kinase levels are usually elevated, reflecting muscle damage. This syndrome is believed to result from an excessively rapid blockade of postsynaptic dopamine receptors. A severe form of extrapyramidal syndrome follows. Early in the course, vigorous treatment of the extrapyramidal syndrome with antiparkinsonism drugs is worthwhile. Muscle relaxants, particularly diazepam, are often useful. Other muscle relaxants, such as dantrolene, or dopamine agonists, such as bromocriptine, have been reported to be helpful. If fever is present, cooling by physical measures should be tried. Various minor forms of this syndrome are now recognized. Switching to an atypical drug after recovery is indicated.

550    SECTION V  Drugs That Act in the Central Nervous System

Drug Interactions Antipsychotics produce more important pharmacodynamic than pharmacokinetic interactions because of their multiple effects. Additive effects may occur when these drugs are combined with others that have sedative effects, α-adrenoceptor-blocking action, anticholinergic effects, and—for thioridazine and ziprasidone— quinidine-like action. A variety of pharmacokinetic interactions have been reported, but none are of major clinical significance.

Overdoses Poisonings with antipsychotic agents (unlike tricyclic antidepressants) are rarely fatal, with the exception of those due to mesoridazine and thioridazine (which are no longer available in the USA). In general, drowsiness proceeds to coma, with an intervening period of agitation. Neuromuscular excitability may be increased and proceed to convulsions. Pupils are miotic, and deep tendon reflexes are decreased. Hypotension and hypothermia are the rule, although fever may be present later in the course. The lethal effects of mesoridazine and thioridazine are related to induction of ventricular tachyarrhythmias. Patients should be given the usual “ABCD” treatment for poisonings (see Chapter 58) and treated supportively. Management of overdoses of thioridazine and mesoridazine, which are complicated by cardiac arrhythmias, is similar to that for tricyclic antidepressants (see Chapter 30).

Psychosocial Treatment & Cognitive Remediation Patients with schizophrenia need psychosocial support based around activities of daily living, including housing, social activities, returning to school, obtaining the optimal level of work they may be capable of, and restoring social interactions. Unfortunately, funding for this crucial component of treatment has been minimized in recent years. Case management and therapy services are a vital part of the treatment program that should be provided to patients with schizophrenia. First-episode patients are particularly needful of this support because they often deny their illness and are noncompliant with medication.

Benefits & Limitations of Drug Treatment As noted at the beginning of this chapter, antipsychotic drugs have had a major impact on psychiatric treatment. First, they have shifted the vast majority of patients from long-term hospitalization to the community. For many patients, this shift has provided a better life under more humane circumstances and in many cases has made life possible without frequent use of physical restraints. For others, the tragedy of an aimless existence is now being played out in the streets of our communities rather than in mental institutions. Second, these antipsychotic drugs have markedly shifted psychiatric thinking to a more biologic orientation. Partly because of research stimulated by the effects of these drugs on schizophrenia, we now know much more about central nervous system

physiology and pharmacology than was known before the introduction of these agents. However, despite much research, schizophrenia remains a scientific mystery and a personal disaster for the patient. Although most schizophrenic patients obtain some degree of benefit from these drugs—in some cases substantial benefit— none is made well by them.

■■ LITHIUM, MOOD-STABILIZING DRUGS, & OTHER TREATMENT FOR BIPOLAR DISORDER Bipolar disorder, once known as manic-depressive illness, was conceived of as a psychotic disorder distinct from schizophrenia at the end of the 19th century. Before that, both of these disorders were considered part of a continuum. The weight of the evidence today indicates that there is profound overlap in these disorders. However, there are pathophysiologically important differences, and some drug treatments are differentially effective in these disorders. According to DSM-IV, they are separate disease entities while research continues to define the dimensions of these illnesses and their genetic and other biologic markers. Lithium was the first agent shown to be useful in the treatment of the manic phase of bipolar disorder that was not also an antipsychotic drug. Lithium is sometimes used adjunctively in schizophrenia. Lithium continues to be used for acute-phase illness as well as for prevention of recurrent manic and depressive episodes. A group of mood-stabilizing drugs that are also anticonvulsant agents has become more widely used than lithium. It includes carbamazepine and valproic acid for the treatment of acute mania and for prevention of its recurrence. Lamotrigine is approved for prevention of recurrence. Gabapentin, oxcarbazepine, and topiramate are sometimes used to treat bipolar disorder but are not approved by the FDA for this indication. Aripiprazole, chlorpromazine, olanzapine, quetiapine, risperidone, and ziprasidone are approved by the FDA for treatment of the manic phase of bipolar disorder. Olanzapine plus fluoxetine in combination and quetiapine are approved for treatment of bipolar depression.

Nature of Bipolar Affective Disorder Bipolar affective disorder occurs in 1–3% of the adult population. It may begin in childhood, but most cases are first diagnosed in the third and fourth decades of life. The key symptoms of bipolar disorder in the manic phase are expansive or irritable mood, hyperactivity, impulsivity, disinhibition, diminished need for sleep, racing thoughts, psychotic symptoms in some (but not all) patients, and cognitive impairment. Depression in bipolar patients is phenomenologically similar to that of major depression, with the key features being depressed mood, diurnal variation, sleep disturbance, anxiety, and sometimes, psychotic symptoms. Mixed manic and depressive symptoms are also seen. Patients with bipolar disorder are at high risk for suicide. The sequence, number, and intensity of manic and depressive episodes are highly variable. The cause of the mood swings

CHAPTER 29  Antipsychotic Agents & Lithium      551

characteristic of bipolar affective disorder is unknown, although a preponderance of catecholamine-related activity may be present. Drugs that increase this activity tend to exacerbate mania, whereas those that reduce activity of dopamine or norepinephrine relieve mania. Acetylcholine or glutamate also may be involved. The nature of the abrupt switch from mania to depression experienced by some patients is uncertain. Bipolar disorder has a strong familial component, and there is abundant evidence that bipolar disorder is genetically determined. Many of the genes that increase vulnerability to bipolar disorder are common to schizophrenia, but some genes appear to be unique to each disorder. Genome-wide association studies of psychotic bipolar disorder have shown replicated linkage to chromosomes 8p and 13q. Several candidate genes have shown association with bipolar disorder with psychotic features and with schizophrenia. These include genes for dysbindin, DAOA/G30, disrupted-inschizophrenia-1 (DISC-1), and neuregulin 1.

BASIC PHARMACOLOGY OF LITHIUM Lithium was first used therapeutically in the mid-19th century in patients with gout. It was briefly used as a substitute for sodium chloride in hypertensive patients in the 1940s but was banned after it proved too toxic for use without monitoring. In 1949, Cade discovered that lithium was an effective treatment for bipolar disorder, engendering a series of controlled trials that confirmed its efficacy as monotherapy for the manic phase of bipolar disorder.

Pharmacokinetics Lithium is a small monovalent cation. Its pharmacokinetics are summarized in Table 29–5.

Pharmacodynamics Despite considerable investigation, the biochemical basis for mood stabilizer therapies including lithium and anticonvulsant mood stabilizers is not clearly understood. Lithium directly inhibits two signal transduction pathways. It both suppresses inositol signaling through depletion of intracellular inositol and inhibits

TABLE 29–5  Pharmacokinetics of lithium. Absorption

Virtually complete within 6–8 hours; peak plasma levels in 30 minutes to 2 hours

Distribution

In total body water; slow entry into intracellular compartment. Initial volume of distribution is 0.5 L/kg, rising to 0.7–0.9 L/kg; some sequestration in bone. No protein binding.

Metabolism

None

Excretion

Virtually entirely in urine. Lithium clearance about 20% of creatinine. Plasma half-life about 20 hours.

Target plasma concentration

0.6–1.4 mEq/L

Dosage

0.5 mEq/kg/d in divided doses

glycogen synthase kinase-3 (GSK-3), a multifunctional protein kinase. GSK-3 is a component of diverse intracellular signaling pathways. These include signaling via insulin/insulin-like growth factor, brain-derived neurotrophic factor (BDNF), and the Wnt pathway. Lithium-induced inhibition of GSK-3 results in reduction of phosphorylation of β-catenin, which allows β-catenin to accumulate and translocate to the nucleus. There, β-catenin facilitates transcription of a variety of proteins. The pathways that are facilitated by the accumulation of β-catenin via GSK-3 inhibition modulate energy metabolism, provide neuroprotection, and increase neuroplasticity. Studies on the enzyme prolyl oligopeptidase and the sodium myoinositol transporter support an inositol depletion mechanism for the mood-stabilizer action. Valproic acid may indirectly reduce GSK-3 activity and can up-regulate gene expression through inhibition of histone deacetylase. Valproic acid also inhibits inositol signaling through an inositol depletion mechanism. There is no evidence of GSK-3 inhibition by carbamazepine, a second antiepileptic mood stabilizer. In contrast, this drug alters neuronal morphology through an inositol depletion mechanism, as seen with lithium and valproic acid. The mood stabilizers may also have indirect effects on neurotransmitters and their release. A. Effects on Electrolytes and Ion Transport Lithium is closely related to sodium in its properties. It can substitute for sodium in generating action potentials and in Na+-Na+ exchange across the membrane. At therapeutic concentrations (~1 mEq/L), it does not significantly affect the Na+-Ca2+ exchanger or the Na+/K+-ATPase pump. B. Effects on Second Messengers Some of the enzymes affected by lithium are listed in Table 29–6. One of the best-defined effects of lithium is its action

TABLE 29–6  Enzymes affected by lithium at therapeutic concentrations.

Enzyme

Enzyme Function; Action of Lithium

Inositol monophosphatase

The rate-limiting enzyme in inositol recycling; inhibited by lithium, resulting in depletion of substrate for IP3 production (Figure 29–4)

Inositol polyphosphate 1-phosphatase

Another enzyme in inositol recycling; inhibited by lithium, resulting in depletion of substrate for IP3 production (Figure 29–4)

Bisphosphate nucleotidase

Involved in AMP production; inhibited by lithium; may be target that results in lithiuminduced nephrogenic diabetes insipidus

Fructose 1,6-biphosphatase

Involved in gluconeogenesis; inhibition by lithium of unknown relevance

Phosphoglucomutase

Involved in glycogenolysis; inhibition by lithium of unknown relevance

Glycogen synthase kinase-3

Constitutively active enzyme that appears to limit neurotrophic and neuroprotective processes; lithium inhibits

AMP, adenosine monophosphate; IP3, inositol 1,4,5-trisphosphate.

552    SECTION V  Drugs That Act in the Central Nervous System

Receptor PIP

PIP2

G PLC

PI Inositol

−

DAG

IP3 IP1

IP2

−

Effects

Lithium

FIGURE 29–4 

Effect of lithium on the IP3 (inositol trisphosphate) and DAG (diacylglycerol) second-messenger system. The schematic diagram shows the synaptic membrane of a neuron. (PI, inorganic phosphate; PIP2, phosphatidylinositol-4,5-bisphosphate; PLC, phospholipase C; G, coupling protein; Effects, activation of protein kinase C, mobilization of intracellular Ca2+, etc.) Lithium, by inhibiting the recycling of inositol substrates, may cause the depletion of the second-messenger source PIP2 and therefore reduce the release of IP3 and DAG. Lithium may also act by other mechanisms (see text).

on inositol phosphates. Early studies of lithium demonstrated changes in brain inositol phosphate levels, but the significance of these changes was not appreciated until the second-messenger roles of inositol-1,4,5-trisphosphate (IP3) and diacylglycerol (DAG) were discovered. As described in Chapter 2, inositol trisphosphate and diacylglycerol are important second messengers for both α-adrenergic and muscarinic transmission. Lithium inhibits inositol monophosphatase (IMPase) and other important enzymes in the normal recycling of membrane phosphoinositides, including conversion of IP2 (inositol diphosphate) to IP1 (inositol monophosphate) and the conversion of IP1 to inositol (Figure 29–4). This block leads to a depletion of free inositol and ultimately of phosphatidylinositol-4,5-bisphosphate (PIP2), the membrane precursor of IP3 and DAG. Over time, the effects of transmitters on the cell diminish in proportion to the amount of activity in the PIP2-dependent pathways. The activity of these pathways is postulated to be markedly increased during a manic episode. Treatment with lithium would be expected to diminish activity in these circuits. Studies of noradrenergic effects in isolated brain tissue indicate that lithium can inhibit norepinephrine-sensitive adenylyl cyclase. Such an effect could relate to both its antidepressant and its antimanic effects. The relationship of these effects to lithium’s actions on IP3 mechanisms is currently unknown. Because lithium affects second-messenger systems involving both activation of adenylyl cyclase and phosphoinositol turnover, it is not surprising that G proteins also are found to be affected. Several studies suggest that lithium may uncouple receptors from their G proteins; indeed, two of lithium’s most common side effects, polyuria and subclinical hypothyroidism, may be due to uncoupling of the vasopressin and thyroid-stimulating hormone (TSH) receptors from their G proteins. The major current working hypothesis for lithium’s therapeutic mechanism of action supposes that its effects on phosphoinositol turnover, leading to an early relative reduction of myoinositol

in human brain, are part of an initiating cascade of intracellular changes. Effects on specific isoforms of protein kinase C may be most relevant. Alterations of protein kinase C-mediated signaling alter gene expression and the production of proteins implicated in long-term neuroplastic events that could underlie long-term mood stabilization.

CLINICAL PHARMACOLOGY OF LITHIUM Bipolar Affective Disorder Until the late 1990s, lithium carbonate was the universally preferred treatment for bipolar disorder, especially in the manic phase. With the approval of valproate, aripiprazole, olanzapine, quetiapine, risperidone, and ziprasidone for this indication, a smaller percentage of bipolar patients now receive lithium. This trend is reinforced by the slow onset of action of lithium, which has often been supplemented with concurrent use of antipsychotic drugs or potent benzodiazepines in severely manic patients. The overall success rate for achieving remission from the manic phase of bipolar disorder can be as high as 80% but lower among patients who require hospitalization. A similar situation applies to maintenance treatment, which is about 60% effective overall but less in severely ill patients. These considerations have led to increased use of combined treatment in severe cases. After mania is controlled, the antipsychotic drug may be stopped and benzodiazepines and lithium continued as maintenance therapy. The depressive phase of manic-depressive disorder often requires concurrent use of other agents including antipsychotics such as quetiapine or lurasidone. Antidepressants have not shown consistent utility and may be destabilizing. Tricyclic antidepressant agents have been linked to precipitation of mania, with more rapid cycling of mood swings, although most patients do not show this effect. Similarly, selective norepinephrine-serotonin reuptake inhibitor (SNRI) agents (see Chapter 30) have been associated with higher rates of switching to mania than some other antidepressants. Selective serotonin reuptake inhibitors are less likely to induce mania but may have limited efficacy. Bupropion has shown some promise but—like tricyclic antidepressants—may induce mania at higher doses. As shown in recent controlled trials, the anticonvulsant lamotrigine is effective for some patients with bipolar depression, but results have been inconsistent. For some patients, however, one of the older monoamine oxidase inhibitors may be the antidepressant of choice. Quetiapine and the combination of olanzapine plus fluoxetine have been approved for use in bipolar depression. Unlike antipsychotic or antidepressant drugs, which exert several actions on the central or autonomic nervous system, lithium ion at therapeutic concentrations is devoid of autonomic blocking effects and of activating or sedating effects, although it can produce nausea and tremor. Most important is that the prophylactic use of lithium can prevent both mania and depression. Many experts believe that the aggressive marketing of newer drugs has inappropriately produced a shift to drugs that are less effective than lithium for substantial numbers of patients.

CHAPTER 29  Antipsychotic Agents & Lithium      553

Other Applications

Drug Interactions

Recurrent depression with a cyclic pattern is controlled by either lithium or imipramine, both of which are superior to placebo. Lithium is also among the better-studied agents used to augment standard antidepressant response in acute major depression in those patients who have had inadequate response to monotherapy. For this application, concentrations of lithium at the lower end of the recommended range for bipolar disorder appear to be adequate. Schizoaffective disorder, another condition with an affective component characterized by a mixture of schizophrenic symptoms and depression or excitement, is treated with antipsychotic drugs alone or combined with lithium. Various antidepressants are added if depression is present. Lithium alone is rarely successful in treating schizophrenia, but adding lithium to an antipsychotic may salvage an otherwise treatment-resistant patient. Carbamazepine may work equally well when added to an antipsychotic drug.

Renal clearance of lithium is reduced about 25% by diuretics (eg, thiazides), and doses may need to be reduced by a similar amount. A similar reduction in lithium clearance has been noted with several of the newer nonsteroidal anti-inflammatory drugs that block synthesis of prostaglandins. This interaction has not been reported for either aspirin or acetaminophen. All neuroleptics tested to date, with the possible exception of clozapine and the newer atypical antipsychotics, may produce more severe extrapyramidal syndromes when combined with lithium.

Monitoring Treatment Clinicians rely on measurements of serum lithium concentrations for assessing both the dosage required for treatment of acute mania and for prophylactic maintenance. These measurements are customarily taken 10–12 hours after the last dose, so all data in the literature pertaining to these concentrations reflect this interval. An initial determination of serum lithium concentration should be obtained about 5 days after the start of treatment, at which time steady-state conditions should have been attained. If the clinical response suggests a change in dosage, simple arithmetic (new dose equals present dose times desired blood level divided by present blood level) should produce the desired level. The serum concentration attained with the adjusted dosage can be checked after another 5 days. Once the desired concentration has been achieved, levels can be measured at increasing intervals unless the schedule is influenced by intercurrent illness or the introduction of a new drug into the treatment program.

Maintenance Treatment The decision to use lithium as prophylactic treatment depends on many factors: the frequency and severity of previous episodes, a crescendo pattern of appearance, and the degree to which the patient is willing to follow a program of indefinite maintenance therapy. Patients with a history of two or more mood cycles or any clearly defined bipolar I diagnosis are probable candidates for maintenance treatment. It has become increasingly evident that each recurrent cycle of bipolar illness may leave residual damage and worsen the long-term prognosis of the patient. Thus, there is greater consensus among experts that maintenance treatment be started as early as possible to reduce the frequency of recurrence. Although some patients can be maintained with serum levels as low as 0.6 mEq/L, the best results have been obtained with higher levels, such as 0.9 mEq/L.

Adverse Effects & Complications Many adverse effects associated with lithium treatment occur at varying times after treatment is started. Some are harmless, but it is important to be alert to adverse effects that may signify impending serious toxic reactions. A. Neurologic and Psychiatric Adverse Effects Tremor is one of the most common adverse effects of lithium treatment, and it occurs with therapeutic doses. Propranolol and atenolol, which have been reported to be effective in essential tremor, also alleviate lithium-induced tremor. Other reported neurologic abnormalities include choreoathetosis, motor hyperactivity, ataxia, dysarthria, and aphasia. Psychiatric disturbances at toxic concentrations are generally marked by mental confusion and withdrawal. Appearance of any new neurologic or psychiatric symptoms or signs is a clear indication for temporarily stopping treatment with lithium and for close monitoring of serum levels. B. Decreased Thyroid Function Lithium probably decreases thyroid function in most patients exposed to the drug, but the effect is reversible or nonprogressive. Few patients develop frank thyroid enlargement, and fewer still show symptoms of hypothyroidism. Although initial thyroid testing followed by regular monitoring of thyroid function has been proposed, such procedures are not cost-effective. Obtaining a serum TSH concentration every 6–12 months, however, is prudent. C. Nephrogenic Diabetes Insipidus and Other Renal Adverse Effects Polydipsia and polyuria are common but reversible concomitants of lithium treatment, occurring at therapeutic serum concentrations. The principal physiologic lesion involved is loss of responsiveness to antidiuretic hormone (nephrogenic diabetes insipidus). Lithium-induced diabetes insipidus is resistant to vasopressin but responds to amiloride (see Chapter 15). Extensive literature has accumulated concerning other forms of renal dysfunction during long-term lithium therapy, including chronic interstitial nephritis and minimal-change glomerulopathy with nephrotic syndrome. Some instances of decreased glomerular filtration rate have been encountered but no instances of marked azotemia or renal failure.

554    SECTION V  Drugs That Act in the Central Nervous System

Patients receiving lithium should avoid dehydration and the associated increased concentration of lithium in urine. Periodic tests of renal concentrating ability should be performed to detect changes.

ion, it is dialyzed readily. Both peritoneal dialysis and hemodialysis are effective, although the latter is preferred.

D. Edema Edema is a common adverse effect of lithium treatment and may be related to some effect of lithium on sodium retention. Although weight gain may be expected in patients who become edematous, water retention does not account for the weight gain observed in up to 30% of patients taking lithium.

VALPROIC ACID

E. Cardiac Adverse Effects The bradycardia-tachycardia (“sick sinus”) syndrome is a definite contraindication to the use of lithium because the ion further depresses the sinus node. T-wave flattening is often observed on the electrocardiogram but is of questionable significance. F. Use during Pregnancy Renal clearance of lithium increases during pregnancy and reverts to lower levels immediately after delivery. A patient whose serum lithium concentration is in a good therapeutic range during pregnancy may develop toxic levels after delivery. Special care in monitoring lithium levels is needed at these times. Lithium is transferred to nursing infants through breast milk, in which it has a concentration about one third to one half that of serum. Lithium toxicity in newborns is manifested by lethargy, cyanosis, poor suck and Moro reflexes, and perhaps hepatomegaly. The Issue of lithium-induced dysmorphogenesis is not settled. An earlier report suggested an increase in cardiac anomalies— especially Ebstein anomaly—in lithium babies, and it is listed as such in Table 59–1 in this book. However, more recent data suggest that lithium carries a relatively low risk of teratogenic effects. Further research is needed in this important area. G. Miscellaneous Adverse Effects Transient acneiform eruptions have been noted early in lithium treatment. Some of them subside with temporary discontinuance of treatment and do not recur with its resumption. Folliculitis is less dramatic and probably occurs more frequently. Leukocytosis is always present during lithium treatment, probably reflecting a direct effect on leukopoiesis rather than mobilization from the marginal pool. This adverse effect has now become a therapeutic effect in patients with low leukocyte counts.

Overdoses Therapeutic overdoses of lithium are more common than those due to deliberate or accidental ingestion of the drug. Therapeutic overdoses are usually due to accumulation of lithium resulting from some change in the patient’s status, such as diminished serum sodium, use of diuretics, or fluctuating renal function. Since the tissues will have already equilibrated with the blood, the plasma concentrations of lithium may not be excessively high in proportion to the degree of toxicity; any value over 2 mEq/L must be considered as indicating likely toxicity. Because lithium is a small

Valproic acid (valproate), discussed in detail in Chapter 24 as an antiepileptic, has been demonstrated to have antimanic effects and is now being widely used for this indication in the USA. (Gabapentin is not effective, leaving the mechanism of antimanic action of valproate unclear.) Overall, valproic acid shows efficacy equivalent to that of lithium during the early weeks of treatment. It is significant that valproic acid has been effective in some patients who have failed to respond to lithium. For example, mixed states and rapid cycling forms of bipolar disorder may be more responsive to valproate than to lithium. Moreover, its side-effect profile is such that one can rapidly increase the dosage over a few days to produce blood levels in the apparent therapeutic range, with nausea being the only limiting factor in some patients. The starting dosage is 750 mg/d, increasing rapidly to the 1500–2000 mg range with a recommended maximum dosage of 60 mg/kg/d. Combinations of valproic acid with other psychotropic medications likely to be used in the management of either phase of bipolar illness are generally well tolerated. Valproic acid is an appropriate first-line treatment for mania, although it is not clear that it will be as effective as lithium as a maintenance treatment in all subsets of patients. Many clinicians advocate combining valproic acid and lithium in patients who do not fully respond to either agent alone.

CARBAMAZEPINE Carbamazepine has been considered to be a reasonable alternative to lithium when the latter is less than optimally efficacious. However, the pharmacokinetic interactions of carbamazepine and its tendency to induce the metabolism of CYP3A4 substrates make it a more difficult drug to use with other standard treatments for bipolar disorder. The mode of action of carbamazepine is unclear, and oxcarbazepine is not effective. Carbamazepine may be used to treat acute mania and also for prophylactic therapy. Adverse effects (discussed in Chapter 24) are generally no greater and sometimes less than those associated with lithium. Carbamazepine may be used alone or, in refractory patients, in combination with lithium or, rarely, valproate. The use of carbamazepine as a mood stabilizer is similar to its use as an anticonvulsant (see Chapter 24). Dosage usually begins with 200 mg twice daily, with increases as needed. Maintenance dosage is similar to that used for treating epilepsy, ie, 800–1200 mg/d. Plasma concentrations between 3 and 14 mg/L are considered desirable, although the optimal therapeutic range has not been established. Blood dyscrasias have figured prominently in the adverse effects of carbamazepine when it is used as an anticonvulsant, but they have not been a major problem with its use as a mood stabilizer. Overdoses of carbamazepine are a major emergency and should generally be managed like overdoses of tricyclic antidepressants (see Chapter 58).

CHAPTER 29  Antipsychotic Agents & Lithium      555

OTHER DRUGS Lamotrigine is approved as a maintenance treatment for bipolar disorder. Although not effective in treating acute mania, it appears effective in reducing the frequency of recurrent depressive cycles and may have some utility in the treatment of bipolar depression.

A number of novel agents are under investigation for bipolar depression, including riluzole, a neuroprotective agent that is approved for use in amyotrophic lateral sclerosis; ketamine, a noncompetitive NMDA antagonist previously discussed as a drug believed to model schizophrenia but thought to act by producing relative enhancement of AMPA receptor activity; and AMPA receptor potentiators.

SUMMARY  Antipsychotic Drugs & Lithium Subclass, Drug PHENOTHIAZINES   •  Chlorpromazine   •  Fluphenazine   •  Thioridazine

Mechanism of Action

Pharmacokinetics, Toxicities, Interactions

Effects

Clinical Applications

Blockade of D2 receptors >> 5-HT2A receptors

α-Receptor blockade (fluphenazine least) • muscarinic (M)-receptor blockade (especially chlorpromazine and thioridazine) • H1-receptor blockade (chlorpromazine, thiothixene) • central nervous system (CNS) depression (sedation) • decreased seizure threshold • QT prolongation (thioridazine)

Psychiatric: schizophrenia (alleviate positive symptoms), bipolar disorder (manic phase) • nonpsychiatric: antiemesis, preoperative sedation (promethazine) • pruritus

Oral and parenteral forms, long halflives with metabolism-dependent elimination • Toxicity: Extensions of effects on α and M receptors • blockade of dopamine receptors may result in akathisia, dystonia, parkinsonian symptoms, tardive dyskinesia, and hyperprolactinemia

Blockade of D2 receptors >> 5-HT2A receptors

Some α blockade, but minimal M-receptor blockade and much less sedation than the phenothiazines

Schizophrenia (alleviates positive symptoms), bipolar disorder (manic phase), Huntington chorea, Tourette syndrome

Oral and parenteral forms with metabolism-dependent elimination • Toxicity: Extrapyramidal dysfunction is major adverse effect

Some α blockade (clozapine, risperidone, ziprasidone) and M-receptor blockade (clozapine, olanzapine) • variable H1-receptor blockade (all)

Schizophrenia—improve both positive and negative symptoms • bipolar disorder (olanzapine or risperidone adjunctive with lithium) • agitation in Alzheimer and Parkinson patients (low doses) • major depression (aripiprazole)

Toxicity: Agranulocytosis (clozapine), diabetes (clozapine, olanzapine), hypercholesterolemia (clozapine, olanzapine), hyperprolactinemia (risperidone), QT prolongation (ziprasidone), weight gain (clozapine, olanzapine)

No significant antagonistic actions on autonomic nervous system receptors or specific CNS receptors • no sedative effects

Bipolar affective disorder— prophylactic use can prevent mood swings between mania and depression

Oral absorption, renal elimination • half-life 20 h • narrow therapeutic window (monitor blood levels) • Toxicity: Tremor, edema, hypothyroidism, renal dysfunction, dysrhythmias • pregnancy category D • Interactions: Clearance decreased by thiazides and some NSAIDs

See Chapter 24

Valproic acid is increasingly used as first choice in acute mania • carbamazepine and lamotrigine are also used both in acute mania and for prophylaxis in depressive phase

Oral absorption • once-daily dosing • carbamazepine forms active metabolite • lamotrigine and valproic acid form conjugates • Toxicity: Hematotoxicity and induction of P450 drug metabolism (carbamazepine), rash (lamotrigine), tremor, liver dysfunction, weight gain, inhibition of drug metabolism (valproic acid)

THIOXANTHENE   •  Thiothixene

BUTYROPHENONE   •  Haloperidol

SECOND-GENERATION ANTIPSYCHOTICS   •  Aripiprazole Blockade of 5-HT2A   •  Brexpiprazole receptors > blockade of   •  Cariprazine D2 receptors   •  Clozapine   •  Lurasidone Lumateperone   •  Olanzapine   •  Quetiapine   •  Risperidone   •  Ziprasidone LITHIUM

Mechanism of action uncertain • suppresses inositol signaling and inhibits glycogen synthase kinase-3 (GSK-3), a multifunctional protein kinase

OTHER AGENTS FOR BIPOLAR DISORDER   •  Carbamazepine Mechanism of action in   •  Lamotrigine bipolar disorder unclear   •  Valproic acid (see Chapter 24 for putative actions in seizure disorders)

556    SECTION V  Drugs That Act in the Central Nervous System

P R E P A R A T I O N S A V A I L A B L E GENERIC NAME AVAILABLE AS ANTIPSYCHOTIC AGENTS Aripiprazole Abilify Asenapine Saphris, Secuado Brexpiprazole Rexulti Cariprazine Vraylar Chlorpromazine Generic, Thorazine Clozapine Generic, Clozaril, others Fluphenazine Generic Fluphenazine decanoate Generic, Prolixin Decanoate Haloperidol Generic, Haldol Haloperidol ester Haldol Decanoate Iloperidone Fanapt Loxapine Adasuve Lumateperone Caplyta Lurasidone Latuda Molindone Moban Olanzapine Generic, Zyprexa Paliperidone Invega Perphenazine Generic, Trilafon Pimavanserin Nuplazid Pimozide Orap Prochlorperazine Generic, Compazine Quetiapine Generic, Seroquel Risperidone Generic, Risperdal Thioridazine Generic, Mellaril Thiothixene Generic, Navane Trifluoperazine Generic, Stelazine Ziprasidone Generic, Geodon MOOD STABILIZERS Carbamazepine Generic, Tegretol Divalproex Generic, Depakote Lamotrigine Generic, Lamictal Lithium carbonate Generic, Eskalith Topiramate Generic, Topamax Valproic acid Generic, Depakene

REFERENCES Antipsychotic Drugs Bhattacharjee J, El-Sayeh HG: Aripiprazole versus typical antipsychotic drugs for schizophrenia. Cochrane Database Syst Rev 2008;16(3):CD006617. Blair HA. Lumateperone: First Approval. Drugs. 2020 Mar;80(4):417-423. doi: 10.1007/s40265-020-01271-6. PMID: 32060882. Caccia S et al: A new generation of antipsychotics: Pharmacology and clinical utility of cariprazine in schizophrenia. Ther Clin Risk Manag 2013;9:319. Chue P: Glycine reuptake inhibition as a new therapeutic approach in schizophrenia: Focus on the glycine transporter 1 (GlyT1). Curr Pharm Des 2013;19:1311. Citrome L: A review of the pharmacology, efficacy and tolerability of recently approved and upcoming oral antipsychotics: An evidence-based medicine approach. CNS Drugs 2013;27:879. Citrome L: Cariprazine: Chemistry, pharmacodynamics, pharmacokinetics, and metabolism, clinical efficacy, safety, and tolerability. Expert Opin Drug Metab Toxicol 2013;9:193.

Citrome L: Cariprazine in bipolar disorder: Clinical efficacy, tolerability, and place in therapy. Adv Ther 2013;30:102. Citrome L: Cariprazine in schizophrenia: Clinical efficacy, tolerability, and place in therapy. Adv Ther 2013;30:114. Correll CU et al: Efficacy of brexpiprazole in patients with acute schizophrenia: Review of three randomized, double-blind, placebo-controlled studies. Schizophr Res 2016;174:82. Coyle JT: Glutamate and schizophrenia: Beyond the dopamine hypothesis. Cell Mol Neurobiol 2006;26:365. Durgam S et al: An 8-week randomized, double-blind, placebo-controlled evaluation of the safety and efficacy of cariprazine in patients with bipolar I depression. Am J Psychiatry 2016;173:271. Durgam S et al: Cariprazine in acute exacerbation of schizophrenia: A fixed-dose, phase 3, randomized, double-blind, placebo- and active-controlled trial. J Clin Psychiatry 2015;76:e1574. Edinoff A, Wu N, deBoisblanc C, Feltner CO, Norder M, Tzoneva V, Kaye AM, Cornett EM, Kaye AD, Viswanath O, Urits I. Lumateperone for the Treatment of Schizophrenia. Psychopharmacol Bull. 2020 Sep 14;50(4):32-59. PMID: 33012872; PMCID: PMC7511146. Escamilla MA, Zavala JM: Genetics of bipolar disorder. Dialogues Clin Neurosci 2008;10:141. Fava M et al: Adjunctive brexpiprazole in patients with major depressive disorder and irritability: An exploratory study. J Clin Psychiatry 2016;77:1695. Fountoulakis KN, Vieta E: Treatment of bipolar disorder: A systematic review of available data and clinical perspectives. Int J Neuropsychopharmacol 2008;11:999. Freudenreich O, Goff DC: Antipsychotic combination therapy in schizophrenia: A review of efficacy and risks of current combinations. Acta Psychiatr Scand 2002;106:323. Glassman AH: Schizophrenia, antipsychotic drugs, and cardiovascular disease. J Clin Psychiatry 2005;66(Suppl 6):5. Grunder G, Nippius H, Carlsson A: The “atypicality” of antipsychotics: A concept re-examined and re-defined. Nat Rev Drug Discov 2009;8:197. Haddad PM, Anderson IM: Antipsychotic-related QTc prolongation, torsade de pointes and sudden death. Drugs 2002;62:1649. Harrison PJ, Weinberger DR: Schizophrenia genes, gene expression, and neuropathology: On the matter of their convergence. Mol Psychiatry 2005;10:40. Hashimoto K et al: Glutamate modulators as potential therapeutic drugs in schizophrenia and affective disorders. Eur Arch Psychiatry Clin Neurosci 2013;263:367. Herman EJ et al: Metabotropic glutamate receptors for new treatments in schizophrenia. Handb Exp Pharmacol 2012;213:297. Hermanowicz S, Hermanowicz N: The safety, tolerability and efficacy of pimavanserin tartrate in the treatment of psychosis in Parkinson’s disease. Expert Rev Neurother 2016;16:625. Hovelsø N et al: Therapeutic potential of metabotropic glutamate receptor modulators. Curr Neuropharmacol 2012;10:12. Javitt DC: Glycine transport inhibitors in the treatment of schizophrenia. Handb Exp Pharmacol 2012;213:367. Kane JM et al: Overview of short- and long-term tolerability and safety of brexpiprazole in patients with schizophrenia. Schizophr Res 2016;174:93. Karam CS et al: Signaling pathways in schizophrenia: Emerging targets and therapeutic strategies. Trend Pharmacol Sci 2010;31:381. Lao KS et al: Tolerability and safety profile of cariprazine in treating psychotic disorders, bipolar disorder and major depressive disorder: A systematic review with meta-analysis of randomized controlled trials. CNS Drugs 2016;30:1043. Lieberman JA et al: Antipsychotic drugs: Comparison in animal models of efficacy, neurotransmitter regulation, and neuroprotection. Pharmacol Rev 2008;60:358. Lieberman JA et al: Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 2005;353:1209. McKeage K, Plosker GL: Amisulpride: A review of its use in the management of schizophrenia. CNS Drugs 2004;18:933. Meltzer HY: Treatment of schizophrenia and spectrum disorders: Pharmacotherapy, psychosocial treatments, and neurotransmitter interactions. Biol Psychiatry 1999;46:1321. Meltzer HY, Massey BW: The role of serotonin receptors in the action of atypical antipsychotic drugs. Curr Opin Pharmacol 2011;11:59.

CHAPTER 29  Antipsychotic Agents & Lithium      557 Meltzer HY et al: A randomized, double-blind comparison of clozapine and highdose olanzapine in treatment-resistant patients with schizophrenia. J Clin Psychiatry 2008;69:274. Newcomer JW, Haupt DW: The metabolic effects of antipsychotic medications. Can J Psychiatry 2006;51:480. Pimavanserin (Nuplazid) for Parkinson’s disease psychosis. Med Lett Drugs Ther 2016;58:74. Preskorn SH, Zeller S, Citrome L, Finman J, Goldberg JF, Fava M, Kakar R, De Vivo M, Yocca FD, Risinger R. Effect of Sublingual Dexmedetomidine vs Placebo on Acute Agitation Associated With Bipolar Disorder: A Randomized Clinical Trial. JAMA. 2022 Feb 22;327(8):727-736. doi: 10.1001/ jama.2022.0799. PMID: 35191924; PMCID: PMC8864508. Schwarz C et al: Valproate for schizophrenia. Cochrane Database Syst Rev 2008;3:CD004028. Urichuk L et al: Metabolism of atypical antipsychotics: Involvement of cytochrome p450 enzymes and relevance for drug-drug interactions. Curr Drug Metab 2008;9:410. Walsh T et al: Rare structural variants disrupt multiple genes in neurodevelopmental pathways in schizophrenia. Science 2008;320:539. Zhang A et al: Recent progress in development of dopamine receptor subtypeselective agents: Potential therapeutics for neurological and psychiatric disorders. Chem Rev 2007;107:274.

Mood Stabilizers Baraban JM et al: Second messenger systems and psychoactive drug action: Focus on the phosphoinositide system and lithium. Am J Psychiatry 1989;146:1251. Bowden CL, Singh V: Valproate in bipolar disorder: 2000 onwards. Acta Psychiatr Scand Suppl 2005;426:13. Catapano LA, Manji HK: Kinases as drug targets in the treatment of bipolar disorder. Drug Discov Today 2008;13:295. Fountoulakis KN, Vieta E: Treatment of bipolar disorder: A systematic review of available data and clinical perspectives. Int J Neuropsychopharmacol 2008;11:999. Jope RS: Anti-bipolar therapy: Mechanism of action of lithium. Mol Psychiatry 1999;4:117. Mathew SJ et al: Novel drugs and therapeutic targets for severe mood disorders. Neuropsychopharmacology 2008;33:2080. Quiroz JA et al: Emerging experimental therapeutics for bipolar disorder: Clues from the molecular pathophysiology. Mol Psychiatry 2004;9:756. Vieta E, Sanchez-Moreno J: Acute and long-term treatment of mania. Dialogues Clin Neurosci 2008;10:165. Yatham LN et al: Third generation anticonvulsants in bipolar disorder: A review of efficacy and summary of clinical recommendations. J Clin Psychiatry 2002;63:275.

C ASE STUDY ANSWER Schizophrenia is characterized by a disintegration of thought processes and emotional responsiveness. Symptoms commonly include auditory hallucinations, paranoid or bizarre delusions, disorganized thinking and speech, and social and occupational dysfunction. For many patients, first-generation (eg, haloperidol) and secondgeneration agents (eg, risperidone) are of equal efficacy for treating positive symptoms. Second-generation agents

are often more effective for treating negative symptoms and cognitive dysfunction and have lower risk of tardive dyskinesia and hyperprolactinemia. Other indications for the use of selected antipsychotics include bipolar disorder, psychotic depression, Tourette syndrome, disturbed behavior in patients with Alzheimer disease, and, in the case of older drugs (eg, chlorpromazine), treatment of emesis and pruritus.

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Antidepressant Agents Charles DeBattista, MD

C ASE STUDY A 47-year-old woman presents to her primary care physician with a chief complaint of fatigue. She indicates that she was promoted to senior manager in her company approximately 11 months earlier. Although her promotion was welcome and came with a sizable raise in pay, it resulted in her having to move away from an office and group of colleagues she very much enjoyed. In addition, her level of responsibility increased dramatically. The patient reports that for the last 7 weeks, she has been waking up at 3 am every night and been unable to go back to sleep. She dreads the day and the stresses of the workplace. As a consequence, she is not eating as well as she might and has dropped 7% of her body weight in the last 3 months. She also reports being so stressed that she breaks down crying in the office occasionally and has been calling in sick frequently. When she comes home, she finds she is less motivated to attend to chores around the

The diagnosis of depression still rests primarily on the clinical interview. Major depressive disorder (MDD) is characterized by depressed mood most of the time for at least 2 weeks or loss of interest or pleasure in most activities, or both. In addition, depression is characterized by disturbances in sleep and appetite as well as deficits in cognition and energy. Thoughts of guilt, worthlessness, and suicide are common. Coronary artery disease, diabetes, and stroke appear to be more common in depressed patients, and depression may considerably worsen the prognosis for patients with a variety of comorbid medical conditions. According to the Centers for Disease Control and Prevention, antidepressants are consistently among the three most commonly prescribed classes of medications in the USA. The wisdom of such widespread use of antidepressants is debated. However, it is clear that American physicians have been increasingly inclined to use 558

house and has no motivation, interest, or energy to pursue recreational activities that she once enjoyed such as hiking. She describes herself as “chronically miserable and worried all the time.” Her medical history is notable for chronic neck pain from a motor vehicle accident for which she is being treated with tramadol and meperidine. In addition, she is on hydrochlorothiazide and propranolol for hypertension. The patient has a history of one depressive episode after a divorce that was treated successfully with fluoxetine. Medical workup including complete blood cell count, thyroid function tests, and a chemistry panel reveals no abnormalities. She is started on fluoxetine for a presumed major depressive episode and referred for cognitive behavioral psychotherapy. What CYP450 and pharmacodynamic interactions might be associated with fluoxetine use in this patient? Which class of antidepressants would be contraindicated in this patient?

antidepressants to treat a host of conditions and that patients have been increasingly receptive to their use. The primary indication for antidepressant agents is the treatment of MDD. Major depression, with a lifetime prevalence of around 17% in the USA and a point prevalence of 5%, is associated with substantial morbidity and mortality. MDD represents one of the most common causes of disability in the developed world. In addition, major depression is commonly associated with a variety of medical conditions—from chronic pain to coronary artery disease. When depression coexists with other medical conditions, the patient’s disease burden increases, and the quality of life—and often the prognosis for effective treatment—decreases significantly. Some of the growth in antidepressant use may be related to the broad application of these agents for conditions other than

CHAPTER 30  Antidepressant Agents    559

major depression. For example, antidepressants have received US Food and Drug Administration (FDA) approvals for the treatment of panic disorder, generalized anxiety disorder (GAD), post-traumatic stress disorder (PTSD), and obsessive-compulsive disorder (OCD). In addition, antidepressants are commonly used to treat pain disorders such as neuropathic pain and the pain associated with fibromyalgia. Some antidepressants are used for treating premenstrual dysphoric disorder (PMDD), mitigating the vasomotor symptoms of menopause, and treating stress urinary incontinence. Thus, antidepressants have a broad spectrum of use in medical practice. However, their primary use remains the treatment for MDD.

PATHOPHYSIOLOGY OF MAJOR DEPRESSION There has been a marked shift in the last decade in our understanding of the pathophysiology of major depression. In addition to the older idea that a deficit in function or amount of monoamines (the monoamine hypothesis) is central to the biology of depression, there is evidence that neurotrophic and endocrine factors play a major role (the neurotrophic hypothesis). Histologic

studies, structural and functional brain imaging research, genetic findings, and steroid research all suggest a complex pathophysiology for MDD with important implications for drug treatment.

Neurotrophic Hypothesis There is substantial evidence that nerve growth factors such as brain-derived neurotrophic factor (BDNF) are critical in the regulation of neural plasticity, resilience, and neurogenesis. The evidence suggests that depression is associated with the loss of neurotrophic support and that effective antidepressant therapies increase neurogenesis and synaptic connectivity in cortical areas such as the hippocampus. BDNF is thought to exert its influence on neuronal survival and growth effects by activating the tyrosine kinase receptor B in both neurons and glia (Figure 30–1). Several lines of evidence support the neurotrophic hypothesis. Animal and human studies indicate that stress and pain are associated with a drop in BDNF levels and that this loss of neurotrophic support contributes to atrophic structural changes in the hippocampus and perhaps other areas such as the medial frontal cortex and anterior cingulate. The hippocampus is known to be important in both contextual memory and regulation of the hypothalamic-pituitary-adrenal (HPA) axis. Likewise, the

Dendritic sprouts

BDNF

BDNF

BDNF

Monoamines

Monoamines Glutamate Others

CREB

BDNF

CREB

Glutamate Others

– Glucocorticoids Treated state

Depressed state A

B

FIGURE 30–1  The neurotrophic hypothesis of major depression. Changes in trophic factors (especially brain-derived neurotrophic factor, BDNF) and hormones appear to play a major role in the development of major depression (A). Successful treatment results in changes in these factors (B). CREB, cAMP response element-binding (protein); BDNF, brain-derived neurotrophic factor. (Reproduced with permission from Nestler EJ, Barrot M, DiLeone RJ, Eisch AJ, Gold SJ, Monteggia LM. Neurobiology of depression. Neuron 2002 Mar 28;34(1):13-25.)

560    SECTION V  Drugs That Act in the Central Nervous System

anterior cingulate plays a role in the integration of emotional stimuli and attention functions, whereas the medial orbital frontal cortex is also thought to play a role in memory, learning, and emotion. Over 30 structural imaging studies suggest that major depression is associated with a 5–10% loss of volume in the hippocampus, although some studies have not replicated this finding. Depression and chronic stress states have also been associated with a substantial loss of volume in the anterior cingulate and medial orbital frontal cortex. Loss of volume in structures such as the hippocampus also appears to increase as a function of the duration of illness and the amount of time that the depression remains untreated. Another source of evidence supporting the neurotrophic hypothesis of depression comes from studies of the direct effects of BDNF on emotional regulation. Direct infusion of BDNF into the midbrain, hippocampus, and lateral ventricles of rodents has an antidepressant-like effect in animal models. Moreover, all known classes of antidepressants are associated with an increase in BDNF levels in animal models with chronic (but not acute) administration. This increase in BDNF levels is consistently associated with increased neurogenesis in the hippocampus in these animal models. Other interventions thought to be effective in the treatment of major depression, including electroconvulsive therapy, also appear to robustly stimulate BDNF levels and hippocampus neurogenesis in animal models. Human studies seem to support the animal data on the role of neurotrophic factors in stress states. Depression appears to be associated with a drop in BDNF levels in the cerebrospinal fluid and serum as well as with a decrease in tyrosine kinase receptor B activity. Conversely, administration of antidepressants increases BDNF levels in clinical trials and may be associated with an increase in hippocampus volume in some patients. Much evidence supports the neurotrophic hypothesis of depression, but not all evidence is consistent with this concept. Animal studies in BDNF knockout mice have not always suggested an increase in depressive or anxious behaviors that would be expected with a deficiency of BDNF. In addition, some animal studies have found an increase in BDNF levels after some types of social stress and an increase rather than a decrease in depressive behaviors with lateral ventricle injections of BDNF. A proposed explanation for the discrepant findings on the role of neurotrophic factors in depression is that there are polymorphisms for BDNF that may yield very different effects. Mutations in the BDNF gene have been found to be associated with altered anxiety and depressive behavior in both animal and human studies. Thus, the neurotrophic hypothesis continues to be intensely investigated and has yielded new insights and potential targets in the treatment of MDD.

Monoamines & Other Neurotransmitters The monoamine hypothesis of depression (Figure 30–2) suggests that depression is related to a deficiency in the amount or function of cortical and limbic serotonin (5-HT), norepinephrine (NE), and dopamine (DA).

Evidence to support the monoamine hypothesis comes from several sources. It has been known for many years that reserpine treatment, which is known to deplete monoamines, is associated with depression in a subset of patients. Similarly, depressed patients who respond to serotonergic antidepressants such as fluoxetine often rapidly suffer relapse when given diets free of tryptophan, a precursor of serotonin synthesis. Patients who respond to noradrenergic antidepressants such as desipramine are less likely to relapse on a tryptophan-free diet. Moreover, depleting catecholamines in depressed patients who have previously responded to noradrenergic agents likewise tends to be associated with relapse. Administration of an inhibitor of norepinephrine synthesis is also associated with a rapid return of depressive symptoms in patients who respond to noradrenergic but not necessarily in patients who had responded to serotonergic antidepressants. Another line of evidence supporting the monoamine hypothesis comes from genetic studies. A functional polymorphism exists for the promoter region of the serotonin transporter gene, which regulates how much of the transporter protein is available. Subjects who are homozygous for the s (short) allele may be more vulnerable to developing major depression and suicidal behavior in response to stress. In addition, homozygotes for the s allele may also be less likely to respond to and tolerate serotonergic antidepressants. Conversely, subjects with the l (long) allele tend to be more resistant to stress and may be more likely to respond to serotonergic antidepressants. Studies of depressed patients have sometimes shown an alteration in monoamine function. For example, some studies have found evidence of alteration in serotonin receptor numbers (5-HT1A and 5-HT2C) or norepinephrine (α2) receptors in depressed and suicidal patients, but these findings have not been consistent. A reduction in the primary serotonin metabolite 5-hydroxyindoleacetic acid in the cerebrospinal fluid is associated with violent and impulsive behavior, including violent suicide attempts. However, this finding is not specific to major depression and is associated more generally with violent and impulsive behavior. Finally, perhaps the most convincing line of evidence supporting the monoamine hypothesis is the fact that (at the time of this writing) all available antidepressants appear to have significant effects on the monoamine system. All classes of antidepressants appear to enhance the synaptic availability of 5-HT, norepinephrine, or dopamine. Attempts to develop antidepressants that work on other neurotransmitter systems have not been effective to date. The monoamine hypothesis, like the neurotrophic hypothesis, is at best incomplete. Many studies have not found an alteration in function or levels of monoamines in depressed patients. In addition, some candidate antidepressant agents under study do not act directly on the monoamine system. In addition to the monoamines, the excitatory neurotransmitter glutamate appears to be important in the pathophysiology of depression. A number of studies of depressed patients have found elevated glutamate content in the cerebrospinal fluid of depressed patients and decreased glutamine/glutamate ratios in their plasma. In addition, postmortem studies have revealed significant increases in the frontal and dorsolateral prefrontal cortex of depressed patients. Likewise, structural neuroimaging

CHAPTER 30  Antidepressant Agents    561

Serotonergic

Noradrenergic

Tryptophan

Tyrosine

Tryptophan hydroxylase

Tyrosine hydroxylase

Serotonin

Norepinephrine Presynaptic axon

α

βγ

MAO-A Metabolites

α βγ

5-HT 1B

α2 Adrenoceptor

γ α β

Serotonin receptors 5-HT 1A

SERT

α

NET

β γ G

α PLC

i

Gs

IP3 , DAG

cAMP

Postsynaptic neuron

βγ

AC ATP

PKA

PKC

Cytoplasm CREB Nucleus

FIGURE 30–2  The amine hypothesis of major depression. Depression appears to be associated with changes in serotonin or norepinephrine signaling in the brain (or both) with significant downstream effects. Most antidepressants cause changes in amine signaling. AC, adenylyl cyclase; CREB, cAMP response element-binding (protein); DAG, diacyl glycerol; 5-HT, serotonin; IP3, inositol trisphosphate; MAO, monoamine oxidase; NET, norepinephrine transporter; PKC, protein kinase C; PLC, phospholipase C; SERT, serotonin transporter. studies have consistently found volumetric changes in the brain areas of depressed patients in which glutamate neurons and their connections are most abundant, including the amygdala and hippocampus. Antidepressants are known to impact glutamate neurotransmission in a variety of ways. For example, chronic antidepressant use is associated with reducing glutamatergic transmission, including the presynaptic release of glutamate in the hippocampus and cortical

areas. Similarly, the chronic administration of antidepressants significantly reduces depolarization-evoked release of glutamate in animal models. Stress is known to enhance the release of glutamate in rodents, and antidepressants inhibit stress-induced presynaptic release of glutamate in these models. Given the effect of antidepressants on the glutamate system, there has been a growing interest in the development of pharmaceutical agents that might modulate the glutamate system. Ketamine

562    SECTION V  Drugs That Act in the Central Nervous System

and esketamine (the (S) + enantiomer of ketamine) are both potent, high-affinity, noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonists but have many other pharmacodynamic properties (see below). Esketamine was approved as an adjunctive treatment for resistant major depression in 2019. In 2022, the combination of bupropion and dextromethorphan also was approved for the treatment of major depression. Among the putative mechanisms of action proposed for dextromethorphan is as an NMDA antagonist as well as actions on the sigma-1 receptor. In addition, a number of other NMDA receptor antagonists, partial antagonists, and metabotropic glutamate receptor modulators (see Chapter 29) are under investigation as potential antidepressants.

Neuroendocrine Factors in the Pathophysiology of Depression Depression is associated with a number of hormonal abnormalities. Among the most replicated of these findings are abnormalities in the HPA axis in patients with MDD. For example, MDD is associated with elevated cortisol levels (see Figure 30–1), nonsuppression of adrenocorticotropic hormone (ACTH) release in the dexamethasone suppression test, and chronically elevated levels of corticotropin-releasing hormone. The significance of these HPA abnormalities is unclear, but they are thought to indicate a dysregulation of the stress hormone axis. More severe types of depression, such as psychotic depression, tend to be associated with HPA abnormalities more commonly than milder forms of major depression. It is well known that both exogenous glucocorticoids and endogenous elevation of cortisol are associated with mood symptoms and cognitive deficits similar to those seen in MDD. Thyroid dysregulation also has been reported in depressed patients. Up to 25% of depressed patients are reported to have abnormal thyroid function. These abnormalities include a blunting of response of thyrotropin to thyrotropin-releasing hormone and elevations in circulating thyroxine during depressed states. Clinical hypothyroidism often presents with depressive symptoms, which resolve with thyroid hormone supplementation. Thyroid hormones are also commonly used in conjunction with standard antidepressants to augment therapeutic effects of the latter. Finally, sex steroids also are implicated in the pathophysiology of depression. Estrogen deficiency states, which occur in the postpartum and postmenopausal periods, are thought to play a role in the etiology of depression in some women. Likewise, severe testosterone deficiency in men is sometimes associated with depressive symptoms. Hormone replacement therapy in hypogonadal men and women may be associated with an improvement in mood and depressive symptoms.

receptors are found in high density in the hippocampus. Binding of these hippocampal glucocorticoid receptors by cortisol during chronic stress states such as major depression may decrease BDNF synthesis and may result in volume loss in stress-sensitive regions such as the hippocampus. The chronic activation of monoamine receptors by antidepressants appears to have the opposite effect of stress and results in an increase in BDNF transcription. In addition, activation of monoamine receptors appears to down-regulate the HPA axis and may normalize HPA function. One of the weaknesses of the monoamine hypothesis is the fact that amine levels increase immediately with antidepressant use, but maximum beneficial effects of most antidepressants are not seen for many weeks. The time required to synthesize neurotrophic factors has been proposed as an explanation for this delay of antidepressant effects. Appreciable protein synthesis of products such as BDNF typically takes 2 weeks or longer and coincides with the clinical course of antidepressant treatment.

■■ BASIC PHARMACOLOGY OF ANTIDEPRESSANTS CHEMISTRY & SUBGROUPS The currently available antidepressants make up a remarkable variety of chemical types. These differences and the differences in their molecular targets provide the basis for distinguishing several subgroups.

Integration of Hypotheses Regarding the Pathophysiology of Depression

A. Selective Serotonin Reuptake Inhibitors The selective serotonin reuptake inhibitors (SSRIs) represent a chemically diverse class of agents that have as their primary action the inhibition of the serotonin transporter (SERT; Figure 30–3). Fluoxetine was introduced in the United States in 1988 and quickly became one of the most commonly prescribed medications in medical practice. The development of fluoxetine emerged out of the search for chemicals that had high affinity for monoamine receptors but lacked the affinity for histamine, acetylcholine, and α adrenoceptors that is seen with the tricyclic antidepressants (TCAs). There are currently six available SSRIs, and they are the most common antidepressants in clinical use. In addition to their use in major depression, SSRIs have indications in GAD, PTSD, OCD, panic disorder, PMDD, and bulimia. Fluoxetine, sertraline, and citalopram exist as isomers and are formulated in the racemic forms, whereas paroxetine and fluvoxamine are not optically active. Escitalopram is the (S) enantiomer of citalopram. As with all antidepressants, SSRIs are highly lipophilic. The popularity of SSRIs stems largely from their ease of use, safety in overdose, relative tolerability, cost (all are available as generic products), and broad spectrum of uses.

The several pathophysiologic hypotheses just described are not mutually exclusive. It is evident that the monoamine, neuroendocrine, and neurotrophic systems are interrelated in important ways. For example, HPA and steroid abnormalities may contribute to suppression of transcription of the BDNF gene. Glucocorticoid

B. Serotonin-Norepinephrine Reuptake Inhibitors Two classes of antidepressants act as combined serotonin and norepinephrine reuptake inhibitors: selective serotoninnorepinephrine reuptake inhibitors (SNRIs) and TCAs.

CHAPTER 30  Antidepressant Agents    563

F3C O

O

CH CH2CH2NHCH3

O

CH2 F

Paroxetine

Fluoxetine

N

H N

O

C O CH2CH2CH2N

NHCH3

CH3 CH3

CI CI

F Citalopram, escitalopram

FIGURE 30–3 

Sertraline

Structures of several selective serotonin reuptake inhibitors (SSRIs).

1. Selective serotonin-norepinephrine reuptake inhibitors— The SNRIs include venlafaxine, its metabolite desvenlafaxine, duloxetine, and levomilnacipran. Levomilnacipran is the active enantiomer of a racemic SNRI, milnacipran. Milnacipran has been approved for the treatment of fibromyalgia in the USA and has been used in the treatment of depression in Europe for many years. In addition to their use in major depression, SNRIs have applications in the treatment of pain disorders including neuropathies and fibromyalgia. SNRIs are also used in the treatment of generalized anxiety, stress urinary incontinence, and vasomotor symptoms of menopause. N

CH3 CH3

HO RO R = CH3 : Venlafaxine R = H : Desvenlafaxine

SNRIs are chemically unrelated to each other. Venlafaxine was discovered in the process of evaluating chemicals that inhibit binding of imipramine. Venlafaxine’s in vivo effects are similar to those of imipramine but with a more favorable adverse-effect profile. All SNRIs bind the serotonin (SERT) and norepinephrine (NET) transporters, as do the TCAs. However, unlike the TCAs, the SNRIs do not have much affinity for other receptors. Venlafaxine and desvenlafaxine are bicyclic compounds, whereas duloxetine is a three-ring structure unrelated to the TCAs. Milnacipran contains a cyclopropane ring and is provided as a racemic mixture.

S CH

CH2

CH2

NHCH3

O

Duloxetine

2. Tricyclic antidepressants—The TCAs were the dominant class of antidepressants until the introduction of SSRIs in the 1980s and 1990s. Nine TCAs are available in the USA, and they all have an iminodibenzyl (tricyclic) core (Figure 30–4). The chemical differences between the TCAs are relatively subtle. For example, the prototype TCA imipramine and its metabolite, desipramine, differ by only a methyl group in the propylamine side chain. However, this minor difference results in a substantial change in their pharmacologic profiles. Imipramine is highly anticholinergic and is a relatively strong serotonin as well as norepinephrine reuptake inhibitor. In contrast, desipramine is much less anticholinergic and is a more potent and somewhat more selective norepinephrine reuptake inhibitor than is imipramine. At present, the TCAs are used primarily in depression that is unresponsive to more commonly used antidepressants such as the SSRIs or SNRIs. Their loss of popularity stems in large part from relatively poorer tolerability compared with newer agents, difficulty of use, and lethality in overdose. Other uses for TCAs include the treatment of pain conditions, enuresis, and insomnia.

564    SECTION V  Drugs That Act in the Central Nervous System

O

R2

N

C

C

R1

R1

R1: = CH(CH2)2N(CH3)2

R1: = CH(CH2)2N(CH3)2

Amitriptyline

Doxepin

R1 R1:–(CH2)3N(CH3)2 R2: H Imipramine

R1: = CH(CH2)2NHCH3

R1: = (CH2)3NHCH3 R2: H

Nortriptyline

Desipramine R1 R1: = (CH2)3N(CH3)2

R1: = (CH2)3NCH3

R2: – Cl

Protriptyline

Clomipramine R1: = CH2CH(CH)3CH2N(CH3)2 R2: – H Trimipramine

FIGURE 30–4 

Structures of some tricyclic antidepressants (TCAs).

C. 5-HT2 Receptor Modulators Two antidepressants are thought to act primarily as antagonists at the 5-HT2 receptor: trazodone and nefazodone. Trazodone’s structure includes a triazolo moiety that is thought to impart antidepressant effects. Its primary metabolite, m-chlorophenylpiperazine (m-cpp), is a potent 5-HT2 antagonist. Trazodone was among the most commonly prescribed antidepressants until it was supplanted by the SSRIs in the late 1980s. The most common use of trazodone in current practice is as an unlabeled hypnotic, since it is highly sedating and not associated with tolerance or dependence. Nefazodone is chemically related to trazodone. Its primary metabolites, hydroxynefazodone and m-cpp, are both inhibitors of the 5-HT2 receptor. Nefazodone received an FDA black box warning in 2001 implicating it in hepatotoxicity, including lethal cases of hepatic failure. Although still available generically, nefazodone is no longer commonly prescribed. The primary indications for both nefazodone and trazodone are major depression, although both have also been used in the treatment of anxiety disorders.

N O

N N

CH2

CH2

CH2

N

N Cl

Trazodone

CH3CH2 N O CH2 CH2 N

N CH2 CH2 CH2 N O

N CI

Nefazodone

Vortioxetine is a newer agent that acts as an antagonist of the 5-HT3, 5-HT7, and 5-HT1D receptors, a partial agonist of the 5-HT1B receptor, and an agonist of the 5-HT1A receptor. It also inhibits the serotonin transporter, but its actions are not primarily related to SERT inhibition and it is therefore not classified as an SSRI. Vortioxetine has demonstrated efficacy in major depression in a number of controlled clinical studies. In addition, vortioxetine is approved in Europe and the USA to treat cognitive dysfunction associated with depression. D. Tetracyclic and Unicyclic Antidepressants A number of antidepressants do not fit neatly into the other classes. Among these are bupropion, mirtazapine, amoxapine, vilazodone, and maprotiline (Figure 30–5). Bupropion has a unicyclic aminoketone structure. Its unique structure results in a different side-effect profile than most antidepressants (described below). Bupropion somewhat resembles amphetamine in chemical structure and, like the stimulant, has central nervous system (CNS) activating properties. Mirtazapine was introduced in 1994 and, like bupropion, is one of the few antidepressants not commonly associated with

CHAPTER 30  Antidepressant Agents    565

NH

N

CH2 N

CH2

NH

CH3

Cl

C

O Amoxapine

CH3

CH2

Maprotiline

N CI N

N

O C

CH

NH

C(CH3)3

CH3 Mirtazapine

FIGURE 30–5 

Bupropion

Structures of the tetracyclics, amoxapine, maprotiline, and mirtazapine and the unicyclic, bupropion.

sexual effects. It has a tetracyclic chemical structure and belongs to the piperazino-azepine group of compounds. Mirtazapine, amoxapine, and maprotiline have tetracyclic structures. Amoxapine is the N-demethylated metabolite of loxapine, an older antipsychotic drug. Amoxapine and maprotiline share structural similarities and side effects comparable to the TCAs. As a result, these tetracyclics are not commonly prescribed in current practice. Their primary use is in MDD that is unresponsive to other agents. Vilazodone has a multiring structure that allows it to bind potently to the serotonin transporter but minimally to the dopamine and norepinephrine transporter. E. Monoamine Oxidase Inhibitors Arguably the first modern class of antidepressants, monoamine oxidase inhibitors (MAOIs) were introduced in the 1950s but are now rarely used in clinical practice because of toxicity and potentially lethal food and drug interactions. Their primary use now is in the treatment of depression unresponsive to other antidepressants. However, MAOIs have also been used historically to treat anxiety states, including social anxiety and panic disorder. In addition, selegiline is used in the treatment of Parkinson disease (see Chapter 28). Current MAOIs include the hydrazine derivatives phenelzine and isocarboxazid and the nonhydrazines tranylcypromine, selegiline, and moclobemide (the latter is not available in the USA). The hydrazines and tranylcypromine bind irreversibly and nonselectively with MAO-A and B, whereas other MAOIs may have more selective or reversible properties. Some of the MAOIs such as tranylcypromine resemble amphetamine in chemical structure, whereas other MAOIs such as selegiline have amphetamine-like metabolites. As a result, these MAOIs tend to have substantial CNS-stimulating effects.

CH2

CH2

NH

NH2

Phenelzine

CH

CH

NH2

CH2 Tranylcypromine

F. NMDA Receptor Antagonists Esketamine became the first non-monoamine-specific agent approved in the adjunctive treatment of major depression in 2019. Esketamine is the (S)-enantiomer of racemic ketamine that has been in use since early 1960s. Ketamine was developed in 1962 as a short-acting analog of phencyclidine. Phencyclidine proved to be unsuitable for use as an anesthetic because of its tendency to produce a prolonged delirium. Thus, phencyclidine never was approved for use in humans although it did become a drug of abuse (PCP, “angel dust”). In contrast to phencyclidine, ketamine has been approved since 1970 in the USA and used in anesthesia and critical care medicine to provide sedation without the degree of cardiorespiratory suppression found in some anesthetics. Observations beginning around 2006 led to an interest in the off-label use of ketamine in treatment-resistant depression. The advantages over existing antidepressants include rapid onset (often within 24 hours) and ketamine’s efficacy in patients who had not responded to standard antidepressants. Disadvantages include a short duration of activity (5–7 days), IV route of administration, a tendency to produce dissociative symptoms, and risk of abuse. Esketamine was developed

566    SECTION V  Drugs That Act in the Central Nervous System

as an intranasal preparation for use in treatment-resistant depression. It may have somewhat fewer dissociative effects than ketamine but has a similar side-effect profile. Esketamine has also been studied as a rapid treatment for acute suicidal ideation and is currently under review for this second indication. Dextromethorphan, which is a moderate NMDA antagonist, has been available as an antitussive agent since the 1950s. In 2022 it was approved in combination with bupropion as a rapidly acting treatment for depression. In addition to its NMDA antagonism, dextromethorphan has other pharmacodynamic properties that could contribute to antidepressant effects including some serotonin reuptake–blocking activity, as well as alpha-2 noradrenergic, sigma-1, and even modest mu-opioid agonism. Dextromethorphan, like PCP and ketamine, has been abused although not at the levels of the dissociative anesthetics. A number of small studies since 2011 have suggested a possible role for dextromethorphan in the treatment of depression. However, dextromethorphan is rapidly metabolized via the CYP2D6 pathway, rendering it difficult to achieve adequate serum levels. Quinidine is a CYP2D6 inhibitor that has been combined with dextromethorphan and was approved in 2010 for the treatment of pseudobulbar affect. Studies of the combination of quinidine combined with dextromethorphan, including a phase 2 program, did not demonstrate consistent efficacy. The combination of dextromethorphan with an approved antidepressant, bupropion, which also is a CYP2D6 inhibitor, made pharmacodynamic and pharmacodynamic sense. The combination was proven effective in the treatment of depression in both a phase 2 and phase 3 program, leading to FDA approval in 2022. G. Allosteric Modulators of GABAA Brexanolone (allopregnanolone) is a member of a new class of neurosteroid antidepressants that are thought to act primarily on the GABA system. Allopregnanolone is a derivative of progesterone and like other GABAA agents is thought to have anxiolytic and anticonvulsant properties. Brexanolone has been studied as a rapidly acting IV antidepressant in women with postpartum depression and is administered as a 60-hour IV infusion. Like ketamine and esketamine, brexanolone acts rapidly with evidence of response by 60 hours. Unlike ketamine and esketamine, the effect appears durable at least 30 days after infusion and is not associated with dissociative symptoms or risk of abuse. In late 2018, an FDA advisory panel voted to 17 to 1 to support approval of brexanolone as the first drug indicated for the treatment of postpartum depression. Other modulators of GABAA include zuranolone (Sage 217), which is being evaluated as an oral drug for general major depression and ganaxolone, which is being evaluated in the treatment of PTSD.

PHARMACOKINETICS The antidepressants share several pharmacokinetic features (Table  30–1). Most have fairly rapid oral absorption, achieve peak plasma levels within 2–3 hours, are tightly bound to plasma proteins, undergo hepatic metabolism, and are renally cleared.

However, even within classes, the pharmacokinetics of individual antidepressants varies considerably. A. Selective Serotonin Reuptake Inhibitors The prototype SSRI, fluoxetine, differs from other SSRIs in some important respects (see Table 30–1). Fluoxetine is metabolized to an active product, norfluoxetine, which may have plasma concentrations greater than those of fluoxetine. The elimination half-life of norfluoxetine is about three times longer than fluoxetine and contributes to the longest half-life of all the SSRIs. As a result, fluoxetine has to be discontinued 4 weeks or longer before an MAOI can be administered to mitigate the risk of serotonin syndrome. Fluoxetine and paroxetine are potent inhibitors of the CYP2D6 isoenzyme, and this contributes to potential drug interactions (see Drug Interactions). In contrast, fluvoxamine is an inhibitor of CYP3A4, whereas citalopram, escitalopram, and sertraline have more modest CYP interactions. B. Serotonin-Norepinephrine Reuptake Inhibitors 1. Selective serotonin-norepinephrine reuptake inhibitors— Venlafaxine is extensively metabolized in the liver via the CYP2D6 isoenzyme to O-desmethylvenlafaxine (desvenlafaxine). Both have similar half-lives of about 8–11 hours. Despite the relatively short half-lives, both drugs are available in formulations that allow once-daily dosing. Venlafaxine and desvenlafaxine have the lowest protein binding of all antidepressants (27–30%). Unlike most antidepressants, desvenlafaxine is conjugated and does not undergo extensive oxidative metabolism. At least 45% of desvenlafaxine is excreted unchanged in the urine compared with 4–8% of venlafaxine. Duloxetine is well absorbed and has a half-life of 12–15 hours but is dosed once daily. It is tightly bound to protein (97%) and undergoes extensive oxidative metabolism via CYP2D6 and CYP1A2. Hepatic impairment significantly alters duloxetine levels unlike desvenlafaxine. Both milnacipran and levomilnacipran are well absorbed after oral dosing. Both have shorter half-lives and lower protein binding than venlafaxine (see Table 30–1). Milnacipran and levomilnacipran are largely excreted unchanged in the urine. Levomilnacipran also undergoes desethylation via 3A3/4. 2. Tricyclic antidepressants—The TCAs tend to be well absorbed and have long half-lives (see Table 30–1). As a result, most are dosed once daily at night because of their sedating effects. TCAs undergo extensive metabolism via demethylation, aromatic hydroxylation, and glucuronide conjugation. Only about 5% of TCAs are excreted unchanged in the urine. The TCAs are substrates of the CYP2D6 system, and the serum levels of these agents tend to be substantially influenced by concurrent administration of drugs such as fluoxetine. In addition, genetic polymorphism for CYP2D6 may result in low or extensive metabolism of the TCAs. The secondary amine TCAs, including desipramine and nortriptyline, lack active metabolites and have fairly linear kinetics. These TCAs have a wide therapeutic window, and serum levels are reliable in predicting response and toxicity.

CHAPTER 30  Antidepressant Agents    567

TABLE 30–1  Pharmacokinetic profiles of selected antidepressants. Class, Drug

Bioavailability (%)

Plasma t1/2 (hours)

Active Metabolite t1/2 (hours)

Volume of Distribution (L/kg)

Protein Binding (%)

SSRIs

 

 

 

 Citalopram

80

33–38

ND

15

80

 Escitalopram

80

27–32

ND

12–15

80

 Fluoxetine

70

48–72

180

12–97

95

 Fluvoxamine

90

14–18

14–16

25

80

 Paroxetine

50

20–23

ND

28–31

94

 Sertraline

45

22–27

62–104

20

98

SNRIs

 

 

 

 

 

 Duloxetine

50

12–15

ND

10–14

97

 Milnacipran

85–90

6–8

ND

5–6

13

 Venlafaxine

1

 

 

45

8–11

9–13

4–10

27

Tricyclics

 

 

 

 

 

 Amitriptyline

45

31–46

20–92

5–10

90

 Clomipramine

50

19–37

54–77

7–20

97

 Imipramine

40

9–24

14–62

15–30

84

5-HT modulators

 

 

 

 

 

 Nefazodone

20

2–4

ND

0.5–1

99

 Trazodone

95

3–6

ND

1–3

96

 Vortioxetine

75

66

ND

ND

98

Tetracyclics and unicyclic

 

 

 

 

 

 Amoxapine

ND

7–12

5–30

0.9–1.2

85

 Bupropion

70

11–14

15–25

20–30

85

 Maprotiline

70

43–45

ND

23–27

88

 Mirtazapine

50

20–40

20–40

3–7

85

 Vilazodone

72

25

ND

ND

ND

MAOIs

 

 

 

 

 

 Phenelzine

ND

11

ND

ND

ND

 Selegiline

4

8–10

9–11

8–10

99

NMDA antagonists

 

 

 

 

 

 Esketamine

48

7–12

8

709

45

  Dextromethorphan + bupropion

20–68

15–22

33–45

ND

60–84

GABAA modulators

 

 

 

 

 

 Brexanolone

100 (IV)

12

ND

3

99

1

Desvenlafaxine has similar properties but is less completely metabolized.

MAOIs, monoamine oxidase inhibitors; ND, no data found; SNRIs, serotonin-norepinephrine reuptake inhibitors; SSRIs, selective serotonin reuptake inhibitors.

C. 5-HT Receptor Modulators Trazodone and nefazodone are rapidly absorbed and undergo hepatic metabolism. Both drugs are bound to protein and have limited bioavailability because of extensive metabolism. Because of their short half-lives split dosing is generally required when these drugs are used as antidepressants. However, trazodone is often prescribed as a single dose at night as a hypnotic in lower doses than are used in the treatment of depression. Both trazodone and nefazodone have active metabolites that also exhibit 5-HT2 antagonism. Nefazodone is a potent inhibitor of the CYP3A4 system

and may interact with drugs metabolized by this enzyme (see Drug Interactions). Vortioxetine is not a potent inhibitor of CYP isoenzymes. However, it is extensively metabolized through oxidation by CYP2D6 and other isoenzymes and then undergoes subsequent glucuronic acid conjugation. It is tightly bound to protein and has linear and dose-proportional pharmacokinetics. D. Tetracyclic and Unicyclic Agents Bupropion is rapidly absorbed and has a mean protein binding of 85%. It undergoes extensive hepatic metabolism and has a

568    SECTION V  Drugs That Act in the Central Nervous System

substantial first-pass effect. It has three active metabolites including hydroxybupropion; the latter is being developed as an antidepressant. Bupropion has a biphasic elimination with the first phase lasting about 1 hour and the second phase lasting 14 hours. Amoxapine is also rapidly absorbed with protein binding of about 85%. The half-life is variable, and the drug is often given in divided doses. Amoxapine undergoes extensive hepatic metabolism. One of the active metabolites, 7-hydroxyamoxapine, is a potent D2 blocker and is associated with antipsychotic effects. Maprotiline is similarly well absorbed orally and 88% bound to protein. It undergoes extensive hepatic metabolism. Mirtazapine is demethylated followed by hydroxylation and glucuronide conjugation. Several CYP isozymes are involved in the metabolism of mirtazapine, including 2D6, 3A4, and 1A2. The half-life of mirtazapine is 20–40 hours, and it is usually dosed once in the evening because of its sedating effects. Vilazodone is well absorbed (see Table 30–1), and absorption is increased when it is given with a fatty meal. It is extensively metabolized by CYP3A4 with minor contributions by CYP2C19 and CYP2D6. Only 1% of vilazodone is excreted unchanged in the urine.

22 hours after 8 days of administration. In CYP2D6 extensive metabolizers, approximately 37–52% of the orally administered dose of dextromethorphan is recovered in the urine. Less than 2% of the administered dose is excreted as unchanged parent drug in the urine. In CYP2D6 poor metabolizers, a higher percentage is recovered in the urine.

E. Monoamine Oxidase Inhibitors The different MAOIs are metabolized via different pathways but tend to have extensive first-pass effects that may substantially decrease bioavailability. Tranylcypromine is ring hydroxylated and N-acetylated, whereas acetylation appears to be a minor pathway for phenelzine. Selegiline is N-demethylated and then hydroxylated. The MAOIs are well absorbed from the gastrointestinal tract. Because of the prominent first-pass effects and their tendency to inhibit MAO in the gut (resulting in tyramine pressor effects), alternative routes of administration are being developed. For example, selegiline is available in both transdermal and sublingual forms that bypass both gut and liver. These routes decrease the risk of food interactions and provide substantially increased bioavailability.

As previously noted, all currently available antidepressants enhance monoamine neurotransmission by one of several mechanisms. The most common mechanism is inhibition of the activity of SERT, NET, or both monoamine transporters (Table 30–2). Antidepressants that inhibit SERT, NET, or both include the SSRIs and SNRIs (by definition) and the TCAs. Another mechanism for increasing the availability of monoamines is inhibition of their enzymatic degradation (by the MAOIs). Additional strategies for enhancing monoamine effects include binding presynaptic autoreceptors (mirtazapine) or specific postsynaptic receptors (5-HT2 antagonists and mirtazapine). Ultimately, the increased availability of monoamines for binding in the synaptic cleft results in a cascade of events that enhance the transcription of some proteins and the inhibition of others. It is the net production of these proteins, including BDNF, glucocorticoid receptors, β adrenoceptors, and other proteins, that appears to determine the benefits as well as the toxicity of a given agent.

F. NMDA Receptor Antagonists The pharmacokinetics of racemic ketamine (usually given IV) and esketamine (intranasal) are similar but differ in part as a function of different routes of administration. Intranasal esketamine is 48% bioavailable, while bioavailability of IV ketamine is complete. Esketamine has a terminal half-life of 7–12 hours while its major metabolite, noresketamine, has a half-life of about 8 hours. IV ketamine has a half-life of approximately 3 hours. The time to reach maximum plasma concentration for intranasal esketamine is 20–40 minutes from the last nasal spray. Less than 1% of esketamine is excreted unchanged, with 78% of all metabolites found in the urine and 2% in feces. Racemic IV ketamine is cleared rapidly (95 L/h/70 kg), with 91% of the dose recovered in urine and 3% in feces. Bupropion and a putative NMDA antagonist, dextromethorphan, have been combined in an extended-release formulation for the treatment of depression. Bupropion inhibits the metabolism of dextromethorphan via CYP2D6. Peak serum levels are achieved for the combination tablet in 3 hours, and the tablet has a t½ of

G. GABAA Modulators IV brexanolone is extensively metabolized by non-CYP450 routes including glucuronidation, sulfation, and ketoreduction. Only 1% of the dose is excreted unchanged, with 47% of the metabolites found in the urine and 42% in the feces. The drug is heavily bound to protein (99%) and is extensively distributed to tissues, with a volume of distribution of 3 L/kg. The terminal half-life of brexanolone is about 9 hours with continuous administration over 60 hours. However, the initial half-life of brexanolone is only about 40 minutes, consistent with its rapid sedating effects.

PHARMACODYNAMICS

A. Selective Serotonin Reuptake Inhibitors The serotonin transporter (SERT) is a glycoprotein with 12 transmembrane regions embedded in the axon terminal and cell body membranes of serotonergic neurons. When extracellular serotonin binds to receptors on the transporter, conformational changes occur in the transporter and serotonin, Na+, and Cl− are moved into the cell. Binding of intracellular K+ then results in the release of serotonin inside the cell and return of the transporter to its original conformation. SSRIs allosterically inhibit the transporter by binding the SERT receptor at a site other than the serotonin binding site. At therapeutic doses, about 80% of the activity of the transporter is inhibited. Functional polymorphisms exist for SERT that determine the activity of the transporter (see Table 30–2). SSRIs have modest effects on other neurotransmitters. Unlike TCAs and SNRIs, there is little evidence that SSRIs have

CHAPTER 30  Antidepressant Agents    569

TABLE 30–2  Blocking effects of some antidepressant drugs on several receptors and transporters. ACh M

`1

H1

5-HT2

Amitriptyline

+++

+++

++

Amoxapine

+

++

+

Bupropion

0

0

Citalopram, escitalopram

0

0

Clomipramine

+

Desipramine

+

Doxepin Fluoxetine

Antidepressant

NET

SERT

0/+

+

++

+++

++

+

0

0

0/+

0

0

 

0

+++

++

+

+

+

+++

+

+

0/+

+++

+

++

+++

+++

0/+

+

+

0

0

0

0/+

0

+++

Fluvoxamine

0

0

0

0

0

+++

Imipramine

++

+

+

0/+

+

++

Maprotiline

+

+

++

0/+

++

0

Mirtazapine

0

0

+++

+

+

0

Nefazodone

0

+

0

++

0/+

+

Nortriptyline

+

+

+

+

++

+

Paroxetine

+

0

0

0

+

+++

Protriptyline

+++

+

+

+

+++

+

Sertraline

0

0

0

0

0

+++

Trazodone

0

++

0/+

++

0

+

Trimipramine

++

++

+++

0/+

0

0

Venlafaxine

0

0

0

0

+

++

ND

ND

ND

ND

+

+++

1

Vortioxetine 1

Vortioxetine is an agonist or partial agonist at 5-HT1A and 5-HT1B receptors, an antagonist at 5-HT3 and 5-HT7 receptors, and an inhibitor of SERT.

ACh M, acetylcholine muscarinic receptor; α1, alpha1-adrenoceptor; H1, histamine1 receptor; 5-HT2, serotonin 5-HT2 receptor; ND, no data found; NET, norepinephrine transporter; SERT, serotonin transporter. 0/+, minimal affinity; +, mild affinity; ++, moderate affinity; +++, high affinity.

prominent effects on β adrenoceptors or the norepinephrine transporter, NET. Binding to the serotonin transporter is associated with tonic inhibition of the dopamine system, although there is substantial interindividual variability in this effect. The SSRIs do not bind aggressively to histamine, muscarinic, or other receptors. B. Drugs That Block Both Serotonin and Norepinephrine Transporters A large number of antidepressants have mixed inhibitory effects on both serotonin and norepinephrine transporters. The newer agents in this class (venlafaxine and duloxetine) are termed SNRIs; those in the older group are termed TCAs on the basis of their structures. The NET is structurally very similar to the 5-HT transporter. Like the serotonin transporter, it is a 12-transmembrane domain complex that allosterically binds SNRIs and TCAs. The NET also has a moderate affinity for dopamine. 1. Serotonin-norepinephrine reuptake inhibitors—SNRIs bind both the serotonin and the norepinephrine transporters. Venlafaxine is a weak inhibitor of NET, whereas desvenlafaxine, duloxetine, milnacipran, and levomilnacipran are more balanced inhibitors of both SERT and NET. Nonetheless, the

affinity of most SNRIs tends to be much greater for SERT than for NET. The SNRIs differ from the TCAs in that they lack the potent antihistamine, α-adrenergic blocking, and anticholinergic effects of the TCAs. As a result, the SNRIs tend to be favored over the TCAs in the treatment of MDD and pain syndromes because of their better tolerability. 2. Tricyclic antidepressants—The TCAs resemble the SNRIs in function, and their antidepressant activity is thought to relate primarily to their inhibition of 5-HT and norepinephrine reuptake. Within the TCAs, there is considerable variability in affinity for SERT versus NET. For example, clomipramine has relatively very little affinity for NET but potently binds SERT. This selectivity for the serotonin transporter contributes to clomipramine’s known benefits in the treatment of OCD. On the other hand, the secondary amine TCAs, desipramine and nortriptyline, are relatively more selective for NET. Although the tertiary amine TCA imipramine has more serotonin effect initially, its metabolite, desipramine, then balances this effect with more NET inhibition. Common adverse effects of the TCAs, including dry mouth and constipation, are attributable to the potent antimuscarinic

570    SECTION V  Drugs That Act in the Central Nervous System

effects of many of these drugs. The TCAs also tend to be potent antagonists of the histamine H1 receptor. TCAs such as doxepin are sometimes prescribed as hypnotics and used in treatments for pruritus because of their antihistamine properties. The blockade of α adrenoceptors can result in substantial orthostatic hypotension, particularly in older patients. C. 5-HT Receptor Modulators The principal action of both nefazodone and trazodone appears to be blockade of the 5-HT2A receptor. Inhibition of this receptor in both animal and human studies is associated with substantial antianxiety, antipsychotic, and antidepressant effects. Conversely, agonists of the 5-HT2A receptor, eg, lysergic acid (LSD) and mescaline, are often hallucinogenic and anxiogenic. The 5-HT2A receptor is a G protein-coupled receptor and is distributed throughout the neocortex. Nefazodone is a weak inhibitor of both SERT and NET but is a potent antagonist of the postsynaptic 5-HT2A receptor, as are its metabolites. Trazodone is also a weak but selective inhibitor of SERT with little effect on NET. Its primary metabolite, m-cpp, is a potent 5-HT2 antagonist, and much of trazodone’s benefits as an antidepressant might be attributed to this effect. Trazodone also has weak to moderate presynaptic α-adrenergic–blocking properties and is a modest antagonist of the H1 receptor. As described above, vortioxetine has multimodal effects on a variety of 5-HT receptors and is an allosteric inhibitor of SERT. It has no known direct activity on norepinephrine or dopamine receptors. D. Tetracyclic and Unicyclic Antidepressants The actions of bupropion remain poorly understood. Bupropion and its major metabolite hydroxybupropion are modest to moderate inhibitors of norepinephrine and dopamine reuptake in animal studies. However, these effects seem less than are typically associated with antidepressant benefit. A more significant effect of bupropion is presynaptic release of catecholamines. In animal studies, bupropion appears to substantially increase the presynaptic availability of norepinephrine, and dopamine to a lesser extent. Bupropion has virtually no direct effects on the serotonin system. Mirtazapine has a complex pharmacology. It is an antagonist of the presynaptic α2 autoreceptor and enhances the release of both norepinephrine and 5-HT. In addition, mirtazapine is an antagonist of 5-HT2 and 5-HT3 receptors. Finally, mirtazapine is a potent H1 antagonist, which is associated with the drug’s sedative effects. The actions of amoxapine and maprotiline resemble those of TCAs such as desipramine. Both are potent NET inhibitors and less potent SERT inhibitors. In addition, both possess anticholinergic properties. Unlike the TCAs or other antidepressants, amoxapine is a moderate inhibitor of the postsynaptic D2 receptor. As such, amoxapine possesses some antipsychotic properties. Vilazodone is a potent serotonin reuptake inhibitor and a partial agonist of the 5-HT1A receptor. Partial agonists of the 5-HT1A receptor such as buspirone are thought to have mild to moderate antidepressant and anxiolytic properties.

E. Monoamine Oxidase Inhibitors MAOIs act by mitigating the actions of monoamine oxidase in the neuron and increasing monoamine content. There are two forms of monoamine oxidase. MAO-A is present in both dopamine and norepinephrine neurons and is found primarily in the brain, gut, placenta, and liver; its primary substrates are norepinephrine, epinephrine, and serotonin. MAO-B is found primarily in serotonergic and histaminergic neurons and is distributed in the brain, liver, and platelets. MAO-B acts primarily on dopamine, tyramine, phenylethylamine, and benzylamine. Both MAO-A and -B metabolize tryptamine. MAOIs are classified by their specificity for MAO-A or -B and whether their effects are reversible or irreversible. Phenelzine and tranylcypromine are examples of irreversible, nonselective MAOIs. Moclobemide is a reversible and selective inhibitor of MAO-A but is not available in the USA. Moclobemide can be displaced from MAO-A by tyramine, and this mitigates the risk of food interactions. In contrast, selegiline is an irreversible MAO-B–specific agent at low doses. Selegiline is useful in the treatment of Parkinson disease at these low doses, but at higher doses it becomes a nonselective MAOI similar to other agents. F. NMDA Receptor Antagonists While ketamine and esketamine are thought to act primarily as noncompetitive antagonists of the NMDA receptor, these drugs have multiple other pharmacodynamic actions that could contribute to efficacy in depression and other disorders. These include interactions with opioid receptors, monoaminergic receptors, cholinergic receptors, and voltage-sensitive Ca2+ channels. Despite its use as an anesthetic, ketamine does not appear to act on GABA receptors. The effects of ketamine and esketamine on monoamines are not as well established as NMDA effects. Most but not all studies suggest that ketamine can significantly increase dopaminergic activity through dopamine reuptake inhibition. This dopaminergic effect would be consistent with the euphoric and psychotomimetic effects of the drug. In addition, ketamine is thought to enhance the activity of descending serotonergic pathways that may be important in both the antidepressant and analgesic properties of the drug. G. GABAA Receptor Modulators Brexanolone has been proposed to reset dysregulated brain function in depressive episodes through modulation of the GABAA receptor. GABAA receptors are ligand-gated, chloride-conducting ion channels (Chapter 22) that have been shown to mediate inhibition of neural networks including those associated with limbic overactivity in major depression. Brexanolone is a positive allosteric modulator of GABAA receptors both pre- and postsynaptically. As such it induces rapid phasic and tonic inhibition of multiple GABA networks responsible for regulating and maintaining those networks. Brexanolone is also thought to increase tonic inhibition through effects on GABA trafficking to and from neuronal surfaces and laterally between synaptic and extrasynaptic locations. Zuranolone (Sage 217) is similar and is in phase 2 trials.

CHAPTER 30  Antidepressant Agents    571

■■ CLINICAL PHARMACOLOGY OF ANTIDEPRESSANTS Clinical Indications A. Depression The FDA indication for the use of the antidepressants in the treatment of major depression is fairly broad. Most antidepressants are approved for both acute and long-term treatment of major depression. Acute episodes of MDD tend to last about 6–14 months untreated, but at least 20% of episodes last 2 years or longer. The goal of acute treatment of MDD is remission of all symptoms. Since antidepressants may not achieve their maximum benefit for 1–2 months or longer, it is not unusual for a trial of therapy to last 8–12 weeks at therapeutic doses. The antidepressants are successful in achieving remission in about 30–40% of patients within a single trial of 8–12 weeks. If an inadequate response is obtained, therapy is often switched to another agent or augmented by addition of another drug. For example, bupropion, an atypical antipsychotic, or mirtazapine might be added to an SSRI or SNRI to augment antidepressant benefit if monotherapy is unsuccessful. Seventy to eighty percent of patients are able to achieve remission with sequenced augmentation or switching strategies. Once an adequate response is achieved, continuation therapy is recommended for a minimum of 6–12 months to reduce the substantial risk of relapse. Approximately 85% of patients who have a single episode of MDD will have at least one recurrence in a lifetime. Many patients have multiple recurrences, and these recurrences may progress to more serious, chronic, and treatment-resistant episodes. Thus, it is not unusual for patients to require maintenance treatment to prevent recurrences. Although maintenance treatment studies of more than 5 years are uncommon, long-term studies with TCAs, SNRIs, and SSRIs suggest a significant protective benefit when given chronically. Thus, it is commonly recommended that patients be considered for long-term maintenance treatment if they have had two or more serious MDD episodes in the previous 5 years or three or more serious episodes in a lifetime. It is not clear whether antidepressants are useful for all subtypes of depression. For example, patients with bipolar depression may not benefit much from antidepressants even when added to mood stabilizers. In fact, the antidepressants are sometimes associated with switches into mania or more rapid cycling. There has also been some debate about the overall efficacy of antidepressants in unipolar depression, with some meta-analyses showing large effects and others showing more modest effects. Although this debate is not likely to be settled immediately, there is little debate that antidepressants have important benefits for most patients. Psychotherapeutic interventions such as cognitive behavioral therapy appear to be as effective as antidepressant treatment for mild to moderate forms of depression. However, cognitive behavioral therapy tends to take longer to be effective and is generally more expensive than antidepressant treatment. Psychotherapy is often combined with antidepressant treatment, and the combination appears more effective than either strategy alone.

B. Anxiety Disorders After major depression, anxiety disorders represent the most common application of antidepressants. A number of SSRIs and SNRIs have been approved for all the major anxiety disorders, including PTSD, OCD, social anxiety disorder, GAD, and panic disorder. Panic disorder is characterized by recurrent episodes of brief overwhelming anxiety, which often occur without a precipitant. Patients may begin to fear having an attack, or they avoid situations in which they might have an attack. In contrast, GAD is characterized by a chronic, free-floating anxiety and undue worry that tends to be chronic in nature. Although older antidepressants and drugs of the sedative-hypnotic class are still occasionally used for the treatment of anxiety disorders, SSRIs and SNRIs have largely replaced them. The benzodiazepines (see Chapter 22) provide much more rapid relief of both generalized anxiety and panic than do any of the antidepressants. However, the antidepressants appear to be at least as effective as, and perhaps more effective than, benzodiazepines in the long-term treatment of these anxiety disorders. Furthermore, antidepressants do not carry the risks of dependence and tolerance that may occur with the benzodiazepines. OCD is known to respond to serotonergic antidepressants. It is characterized by repetitive anxiety-provoking thoughts (obsessions) or repetitive behaviors (compulsions) aimed at reducing anxiety. Clomipramine and several of the SSRIs are approved for the treatment of OCD, and they are moderately effective. Behavior therapy is usually combined with the antidepressant for additional benefits. Social anxiety disorder is an uncommonly diagnosed but a fairly common condition in which patients experience severe anxiety in social interactions. This anxiety may limit their ability to function adequately in their jobs or interpersonal relationships. Several SSRIs and venlafaxine are approved for the treatment of social anxiety. The efficacy of the SSRIs in the treatment of social anxiety is greater in some studies than their efficacy in the treatment of MDD. PTSD is manifested when a traumatic or life-threatening event results in intrusive anxiety-provoking thoughts or imagery, hypervigilance, nightmares, and avoidance of situations that remind the patient of the trauma. SSRIs are considered first-line treatment for PTSD and can benefit a number of symptoms including anxious thoughts and hypervigilance. Other treatments, including psychotherapeutic interventions, are usually required in addition to antidepressants. C. Pain Disorders Antidepressants possess analgesic properties independent of their mood effects. TCAs have been used in the treatment of neuropathic and other pain conditions since the 1960s. Medications that possess both norepinephrine and 5-HT reuptake blocking properties are often useful in treating pain disorders. Ascending corticospinal monoamine pathways appear to be important in the endogenous analgesic system. In addition, chronic pain conditions are commonly associated with major depression. TCAs continue to be commonly used for some of these conditions, and SNRIs

572    SECTION V  Drugs That Act in the Central Nervous System

are increasingly used. In 2010, duloxetine was approved for the treatment of chronic joint and muscle pain. As mentioned earlier, milnacipran is approved for the treatment of fibromyalgia in the USA and for MDD in other countries. Other SNRIs, eg, desvenlafaxine, are being investigated for a variety of pain conditions from postherpetic neuralgia to chronic back pain.

Bupropion may have some benefits in treating obesity. Nondepressed, obese patients treated with bupropion were able to lose somewhat more weight and maintain the loss relative to a similar population treated with placebo. However, the weight loss was not robust, and there appear to be more effective options for weight loss (see Chapter 16).

D. Premenstrual Dysphoric Disorder Approximately 5% of women in the child-bearing years will have prominent mood and physical symptoms during the late luteal phase of almost every cycle; these may include anxiety, depressed mood, irritability, insomnia, fatigue, and a variety of other physical symptoms. These symptoms are more severe than those typically seen in premenstrual syndrome (PMS) and can be quite disruptive to vocational and interpersonal activities. The SSRIs are known to be beneficial to many women with PMDD, and fluoxetine and sertraline are approved for this indication. Treating for 2 weeks out of the month in the luteal phase may be as effective as continuous treatment. The rapid effects of SSRIs in PMDD may be associated with rapid increases in pregnenolone levels.

G. Other Uses for Antidepressants Antidepressants are used for many other on- and off-label applications. Enuresis in children is an older labeled use for some TCAs, but they are less commonly used now because of their side effects. The SNRI duloxetine is approved in Europe for the treatment of urinary stress incontinence. Many of the serotonergic antidepressants appear to be helpful for treating vasomotor symptoms in perimenopause. Desvenlafaxine is under consideration for FDA approval for the treatment of these vasomotor symptoms, and studies have suggested that SSRIs, venlafaxine, and nefazodone also may provide benefit. Although serotonergic antidepressants are commonly associated with inducing sexual adverse effects, some of these effects might prove useful for some sexual disorders. For example, SSRIs are known to delay orgasm in some patients. For this reason, SSRIs are sometimes used to treat premature ejaculation. In addition, bupropion has been used to treat sexual adverse effects associated with SSRI use, although its efficacy for this use has not been consistently demonstrated in controlled trials.

E. Smoking Cessation Bupropion was approved in 1997 as a treatment for smoking cessation. Approximately twice as many people treated with bupropion as with placebo have a reduced urge to smoke. In addition, patients taking bupropion appear to experience fewer mood symptoms and possibly less weight gain while withdrawing from nicotine dependence. Bupropion appears to be about as effective as nicotine patches in smoking cessation. The mechanism by which bupropion is helpful in this application is unknown, but the drug may mimic nicotine’s effects on dopamine and norepinephrine and may inhibit nicotinic receptors. Nicotine is also known to have antidepressant effects in some people, and bupropion may substitute for this effect. Other antidepressants also may have a role in the treatment of smoking cessation. Nortriptyline has been shown to be helpful in smoking cessation, but the effects have not been as consistent as those seen with bupropion. F. Eating Disorders Bulimia nervosa and anorexia nervosa are potentially devastating disorders. Bulimia is characterized by episodic intake of large amounts of food (binges) followed by ritualistic purging through emesis, the use of laxatives, or other methods. Medical complications of the purging, such as hypokalemia, are common and dangerous. Anorexia is a disorder in which reduced food intake results in a loss of weight of 15% or more of ideal body weight, and the person has a morbid fear of gaining weight and a highly distorted body image. Anorexia is often chronic and may be fatal in 10% or more of cases. Antidepressants appear to be helpful in the treatment of bulimia but not anorexia. Fluoxetine was approved for the treatment of bulimia in 1996, and other antidepressants have shown benefit in reducing the binge-purge cycle. The primary treatment for anorexia at this time is refeeding, family therapy, and cognitive behavioral therapy.

CHOOSING AN ANTIDEPRESSANT The choice of an antidepressant depends first on the indication. Not all conditions are equally responsive to all antidepressants. However, in the treatment of MDD, it is difficult to demonstrate that one antidepressant is consistently more effective than another. Thus, the choice of an antidepressant for the treatment of depression rests primarily on practical considerations such as cost, availability, adverse effects, potential drug interactions, the patient’s history of response or lack thereof, and patient preference. Other factors such as the patient’s age, gender, and medical status also may guide antidepressant selection. For example, older patients are particularly sensitive to the anticholinergic effects of the TCAs. On the other hand, the CYP3A4-inhibiting effects of the SSRI fluvoxamine may make this a problematic choice in some older patients because fluvoxamine may interact with many other medications that an older patient may require. There is some suggestion that female patients may respond to and tolerate serotonergic better than noradrenergic or TCA antidepressants, but the data supporting this gender difference have not been consistent. Patients with narrow-angle glaucoma may have an exacerbation with noradrenergic antidepressants, whereas bupropion and other antidepressants are known to lower the seizure threshold in epilepsy patients. At present, SSRIs are the most commonly prescribed first-line agents in the treatment of both MDD and anxiety disorders. Their popularity comes from their ease of use, tolerability, and safety in overdose. The starting dose of the SSRIs is usually the same as

CHAPTER 30  Antidepressant Agents    573

the therapeutic dose for most patients, and so titration may not be required. In addition, most SSRIs are now generically available and inexpensive. Other agents, including the SNRIs, bupropion, and mirtazapine, also are reasonable first-line agents for the treatment of MDD. Bupropion, mirtazapine, and nefazodone are the antidepressants with the least association with sexual adverse effects and are often prescribed for this reason. However, bupropion is not thought to be effective in the treatment of the anxiety disorders and may be poorly tolerated in anxious patients. The primary indication for bupropion is in the treatment of major depression, including seasonal (winter) depression. Off-label uses of bupropion include the treatment of attention deficit hyperactivity disorder (ADHD), and bupropion is commonly combined with other antidepressants to augment therapeutic response. The primary indication for mirtazapine is in the treatment of major depression. However, its strong antihistamine properties have contributed to its occasional use as a hypnotic and as an adjunctive treatment to more activating antidepressants. The TCAs and MAOIs are now relegated to second- or thirdline treatments for MDD. Both the TCAs and the MAOIs are potentially lethal in overdose, require titration to achieve a therapeutic dose, have serious drug interactions, and have many troublesome adverse effects. As a consequence, their use in the treatment of MDD or anxiety is now reserved for patients who have been unresponsive to other agents. Clearly, there are patients whose depression responds only to MAOIs or TCAs. Thus, TCAs and MAOIs are probably underused in treatment-resistant depressed patients. The use of antidepressants outside the treatment of MDD tends to require specific agents. For example, the TCAs and SNRIs appear to be useful in the treatment of pain conditions, but other antidepressant classes appear to be far less effective. SSRIs and the highly serotonergic TCA clomipramine are effective in the treatment of OCD, but noradrenergic antidepressants have not proved to be as helpful for this condition. Bupropion and nortriptyline have usefulness in the treatment of smoking cessation, but SSRIs have not been proven useful. Thus, outside the treatment of depression, the choice of antidepressant is primarily dependent on the known benefit of a particular antidepressant or class for a particular indication.

TABLE 30–3  Antidepressant dose ranges. Usual Therapeutic Dosage (mg/d)

Drug SSRIs

 

 Citalopram

20–60

 Escitalopram

10–30

 Fluoxetine

20–60

 Fluvoxamine

100–300

 Paroxetine

20–60

 Sertraline

50–200

SNRIs

 

 Venlafaxine

75–375

 Desvenlafaxine

50–200

 Duloxetine

40–120

 Milnacipran

100–200

Tricyclics

 

 Amitriptyline

150–300

 Clomipramine

100–250

 Desipramine

150–300

 Doxepin

150–300

 Imipramine

150–300

 Nortriptyline

50–150

 Protriptyline

15–60

  Trimipramine maleate

150–300

5-HT2 antagonists

 

 Nefazodone

300–500

 Trazodone

150–300

Tetracyclics and unicyclics

 

 Amoxapine

150–400

 Bupropion

200–450

 Maprotiline

150–225

 Mirtazapine

15–45

MAOIs

 

 Isocarboxazid

30–60

 Phenelzine

45–90

DOSING

 Selegiline

20–50

 Tranylcypromine

30–60

The optimal dose of an antidepressant depends on the indication and on the patient. For SSRIs, SNRIs, and a number of newer agents, the starting dose for the treatment of depression is usually a therapeutic dose (Table 30–3). Patients who show little or no benefit after at least 4 weeks of treatment may benefit from a higher dose even though it has been difficult to show a clear advantage for higher doses with SSRIs, SNRIs, and other newer antidepressants. The dose is generally titrated to the maximum dosage recommended or to the highest dosage tolerated if the patient is not responsive to lower doses. Some patients may benefit from doses lower than the usual minimum recommended therapeutic dose. TCAs and MAOIs typically require titration to a therapeutic

NMDA antagonists

 

  Esketamine (intranasal)

56–84

  Ketamine (IV)

0.5 mg/kg/h

  Dextromethorphan + bupropion

Bup 105 mg/Dex 45 mg BID

GABAA modulators

 

  Brexanolone (IV)

30–90 mcg/kg/h

MAOIs, monoamine oxidase inhibitors; SNRIs, serotonin-norepinephrine reuptake inhibitors; SSRIs, selective serotonin reuptake inhibitors.

574    SECTION V  Drugs That Act in the Central Nervous System

dosage over several weeks. Dosing of the TCAs may be guided by monitoring TCA serum levels. Some anxiety disorders may require higher doses of antidepressants than are used in the treatment of major depression. For example, patients treated for OCD often require maximum or somewhat higher than maximum recommended MDD doses to achieve optimal benefits. Likewise, the minimum dose of paroxetine for the effective treatment of panic disorder is higher than the minimum dose required for the effective treatment of depression. In the treatment of pain disorders, modest doses of TCAs are often sufficient. For example, 25–50 mg/d of imipramine might be beneficial in the treatment of pain associated with a neuropathy, but this would be a subtherapeutic dose in the treatment of MDD. In contrast, SNRIs are usually prescribed in pain disorders at the same doses used in the treatment of depression.

ADVERSE EFFECTS Although some potential adverse effects are common to all antidepressants, most of their adverse effects are specific to a subclass of agents and to their pharmacodynamic effects. An FDA warning applied to all antidepressants is the risk of increased suicidality in patients younger than 25. The warning suggests that use of antidepressants is associated with suicidal ideation and gestures, but not completed suicides, in up to 4% of patients under 25 who were prescribed antidepressants in clinical trials. This rate is about twice the rate seen with placebo treatment. For those over 25, there is either no increased risk or a reduced risk of suicidal thoughts and gestures on antidepressants, particularly after age 65. Although a small minority of patients may experience a treatment-emergent increase in suicidal ideation with antidepressants, the absence of treatment of a major depressive episode in all age groups is a particularly important risk factor in completed suicides. A. Selective Serotonin Reuptake Inhibitors The adverse effects of the most commonly prescribed antidepressants—the SSRIs—can be predicted from their potent inhibition of SERT. SSRIs enhance serotonergic tone, not just in the brain but throughout the body. Increased serotonergic activity in the gut is commonly associated with nausea, gastrointestinal upset, diarrhea, and other gastrointestinal symptoms. Gastrointestinal adverse effects usually emerge early in the course of treatment and tend to improve after the first week. Increasing serotonergic tone at the level of the spinal cord and above is associated with diminished sexual function and interest. As a result, at least 30–40% of patients treated with SSRIs report loss of libido, delayed orgasm, or diminished arousal. The sexual effects often persist as long as the patient remains on the antidepressant but may diminish with time. Other adverse effects related to the serotonergic effects of SSRIs and vortioxetine include an increase in headaches and insomnia or hypersomnia. Some patients gain weight while taking SSRIs, particularly paroxetine. Sudden discontinuation of short half-life

SSRIs such as paroxetine and sertraline is associated with a discontinuation syndrome in some patients characterized by dizziness, paresthesias, and other symptoms beginning 1 or 2 days after stopping the drug and persisting for 1 week or longer. Most antidepressants are category C agents by the FDA teratogen classification system. There is an association of paroxetine with cardiac septal defects in first trimester exposures. Thus, paroxetine is a category D agent. Other possible associations of SSRIs with post-birth complications, including pulmonary hypertension, have not been clearly established. B. Serotonin-Norepinephrine Reuptake Inhibitors and Tricyclic Antidepressants SNRIs have many of the serotonergic adverse effects associated with SSRIs. In addition, SNRIs may also have noradrenergic effects, including increased blood pressure and heart rate, and CNS activation, such as insomnia, anxiety, and agitation. The hemodynamic effects of SNRIs tend not to be problematic in most patients. A dose-related increase in blood pressure has been seen more commonly with the immediate-release form of venlafaxine than with other SNRIs. Likewise, there are more reports of cardiac toxicity with venlafaxine overdose than with either the other SNRIs or SSRIs. Duloxetine is rarely associated with hepatic toxicity in patients with a history of liver damage. All the SNRIs have been associated with a discontinuation syndrome resembling that seen with SSRI discontinuation. The primary adverse effects of TCAs have been described in the previous text. Anticholinergic effects are perhaps the most common. These effects include dry mouth, constipation, urinary retention, blurred vision, and confusion. They are more common with tertiary amine TCAs such as amitriptyline and imipramine than with the secondary amine TCAs desipramine and nortriptyline. The potent α-blocking property of TCAs often results in orthostatic hypotension. H1 antagonism by the TCAs is associated with weight gain and sedation. The TCAs are class 1A antiarrhythmic agents (see Chapter 14) and are arrhythmogenic at higher doses. Sexual effects are common, particularly with highly serotonergic TCAs such as clomipramine. The TCAs have a prominent discontinuation syndrome characterized by cholinergic rebound and flulike symptoms. C. 5-HT Receptor Modulators The most common adverse effects associated with the 5-HT2 antagonists are sedation and gastrointestinal disturbances. Sedative effects, particularly with trazodone, can be quite pronounced. Thus, it is not surprising that the treatment of insomnia is currently the primary application of trazodone. The gastrointestinal effects appear to be dose-related and are less pronounced than those seen with SNRIs or SSRIs. Sexual effects are uncommon with nefazodone or trazodone treatment as a result of the relatively selective serotonergic effects of these drugs on the 5-HT2 receptor rather than on SERT. However, trazodone has rarely been associated with inducing priapism. Both nefazodone and trazodone are α-blocking agents and may result in a dose-related orthostatic hypotension in some patients. Nefazodone has been associated with hepatotoxicity, including rare fatalities and cases

CHAPTER 30  Antidepressant Agents    575

of fulminant hepatic failure requiring transplantation. The rate of serious hepatotoxicity with nefazodone has been estimated at 1 in 250,000 to 1 in 300,000 patient-years of nefazodone treatment. As with the SSRIs, the most common adverse effects of vortioxetine are serotonergic and include dose-dependent gastrointestinal effects, particularly nausea, as well as sexual dysfunction. Higher doses of vortioxetine tend to increase the rate of GI and sexual side effects. The teratogenic risks of vortioxetine are not known but like most other antidepressants, it is considered a category C agent. D. Tetracyclics and Unicyclics Amoxapine is sometimes associated with a parkinsonian syndrome due to its D2-blocking action. Mirtazapine has significant sedative effect. Maprotiline has a moderately high affinity for NET and may cause TCA-like adverse effects and, rarely, seizures. Bupropion is occasionally associated with agitation, insomnia, and anorexia. Vilazodone may have somewhat higher rates of gastrointestinal upset, including diarrhea and nausea, than the SSRIs. E. Monoamine Oxidase Inhibitors The most common adverse effects of the MAOIs leading to discontinuation of these drugs are orthostatic hypotension and weight gain. In addition, the irreversible nonselective MAOIs are associated with the highest rates of sexual effects of all the antidepressants. Anorgasmia is fairly common with therapeutic doses of some MAOIs. The amphetamine-like properties of some MAOIs contribute to activation, insomnia, and restlessness in some patients. Phenelzine tends to be more sedating than either selegiline or tranylcypromine. Confusion is also sometimes associated with higher doses of MAOIs. Because they block metabolism of tyramine and similar ingested amines, MAOIs may cause dangerous interactions with certain foods and with serotonergic drugs (see Interactions). Finally, MAOIs have been associated with a sudden discontinuation syndrome manifested in a delirium-like presentation with psychosis, excitement, and confusion. F. NMDA Receptor Antagonists The adverse effects of ketamine and esketamine are consistent with their pharmacologic profile. The short-term adverse effects of these drugs include sedation, dissociation, hypertension, nausea, tachycardia, and cognitive impairment. Most of these effects occur in close proximity to the administration of the drug and usually dissipate in minutes to hours. In the registration trials for esketamine, 8–17% of patients had a systolic blood pressure increase of >40 mm Hg and >25 mm Hg diastolic in the first 1.5 hours after administration. Up to 75% of patients had dissociative symptoms (eg, depersonalization, derealization, out-of-body experiences, distortions of time), although these tended to be most common in the first 2 hours of administration. Therefore, the esketamine prescribing protocol will require that patients be observed in the clinic for at least 2 hours after administration.

Ketamine has been a significant drug of abuse in some parts of the world, notably in parts of China and southeast Asia. Long-term abuse of ketamine has been associated with dependence, psychotomimetic effects (including auditory and visual hallucinations and paranoid delusions), and bladder inflammation and ulcerations. In the long-term depression trials with intranasal esketamine given intermittently (twice weekly for 4 weeks, once weekly for 4 weeks, and once every other week thereafter), there have not been cases of addiction, bladder ulcerations, or other long-term side effects seen in ketamine abusers. Dextromethorphan has more rarely been abused at higher doses. In clinical trials of the combination pill with bupropion approved for depression, an increase in anxiety was the only side effect that led to discontinuation at rates higher than 1% (2% of trial participants). The most common side effects of the combination pill were dizziness, headaches, dry mouth, and diarrhea. G. GABAA Receptor Modulators The most common adverse effects of IV brexanolone in clinical trials were headaches, dizziness, and somnolence. About 27% of patients in the postpartum depression trials experienced sedation compared with 14% of the placebo-treated patients. Brexanolone has a terminal half-life of about 12 hours, and the sedation did not appear to persist after the infusion stopped. There was a rare adverse effect of syncope and loss of consciousness in 4 patients (1.4%) during the infusion, which resolved with discontinuation of the infusion. Another 4% of patients had excessive sedation or near loss of consciousness relieved by the discontinuation of the infusion. Overall, the rate of adverse events in the brexanolone group was about the same as the rate in the placebo group, and SERT inhibition (amoxapine, maprotiline) • increased release of norepinephrine, 5-HT (mirtazapine)

Presynaptic release of catecholamines but no effect on 5-HT (bupropion) • amoxapine and maprotiline resemble TCAs

Major depression • smoking cessation (bupropion) • sedation (mirtazapine) • amoxapine and maprotiline rarely used

Extensive metabolism in liver • Toxicity: Lowers seizure threshold (amoxapine, bupropion); sedation and weight gain (mirtazapine) • Interactions: CYP2D6 inhibitor (bupropion)

TETRACYCLICS, UNICYCLIC   •  Bupropion   •  Amoxapine   •  Maprotiline   •  Mirtazapine

(continued)

CHAPTER 30  Antidepressant Agents    579

Subclass, Drug

Mechanism of Action

MONOAMINE OXIDASE INHIBITORS (MAOIs)   •  Phenelzine Blockade of MAO-A and   •  Tranylcypromine MAO-B (phenelzine,   •  Selegiline nonselective) • MAO-B irreversible selective MAO-B inhibition (low-dose selegiline)

NMDA RECEPTOR ANTAGONISTS   •  Ketamine (off-label) Noncompetitive antagonism   •  Esketamine at the NMDA receptor Bupropion + dextromethorphan NE agonist, DA reuptake inhibitor, NMDA antagonist, sigma-1 agonist GABAA RECEPTOR MODULATORS   •  Brexanolone Positive allosteric modulator of the GABAA chloride channel, binding site distinct from benzodiazepine site

P R E P A R A T I O N S

Clinical Applications

Transdermal formulation of selegiline achieves levels that inhibit MAO-A

Major depression unresponsive to other drugs • Parkinson disease (selegiline)

Very slow elimination • Toxicity: Hypotension, insomnia • Interactions: Hypertensive crisis with tyramine, other indirect sympathomimetics • serotonin syndrome with serotonergic agents, meperidine

Anesthesia; possible increase in serotonergic activity, dopaminergic activity Combination tablet for major depression

Ketamine: anesthesia Esketamine: refractory depression (outside USA: anesthesia)

Ketamine: IV Esketamine: nasal inhalation, rapid onset of action • Toxicity: Dissociative symptoms, possible abuse, BP increase

Unclear: possibly replaces endogenous allopregnanolone, which decreases markedly after delivery

Postpartum depression only

IV infusion over 60 hours • Toxicity: Excessive sedation, possible loss of consciousness

A V A I L A B L E

GENERIC NAME AVAILABLE AS SELECTIVE SEROTONIN REUPTAKE INHIBITORS Citalopram Generic, Celexa Escitalopram Generic, Lexapro Fluoxetine Generic, Prozac, Prozac Weekly Fluvoxamine* Generic Paroxetine Generic, Paxil Sertraline Generic, Zoloft SEROTONIN NOREPINEPHRINE REUPTAKE INHIBITORS Desvenlafaxine Pristiq Duloxetine Generic, Cymbalta Levomilnacipran Fetzima Milnacipran† Savella Venlafaxine Generic, Effexor 5-HT RECEPTOR MODULATORS Nefazodone Generic Trazodone Generic, Desyrel Vortioxetine Trintellix TRICYCLICS Amitriptyline Generic, Elavil Amoxapine Generic Generic, Anafranil Clomipramine* Desipramine Generic, Norpramin *

Labeled only for obsessive-compulsive disorder.

†

Labeled only for fibromyalgia.

‡

Labeled only for postpartum depression.

Pharmacokinetics, Toxicities, Interactions

Effects

Doxepin

GENERIC NAME

AVAILABLE AS Generic, Sinequan

Imipramine Nortriptyline Protriptyline

Generic, Tofranil Generic, Pamelor Generic, Vivactil

Trimipramine

Surmontil

TETRACYCLIC AND UNICYCLIC AGENTS Amoxapine Bupropion Maprotiline Mirtazapine

Generic Generic, Wellbutrin Generic Generic, Remeron

Vilazodone

Viibryd MONOAMINE OXIDASE INHIBITORS

Isocarboxazid Phenelzine

Marplan Generic, Nardil

Selegiline Tranylcypromine

Generic, Eldepryl Generic, Parnate NMDA RECEPTOR MODULATORS

Esketamine Bupropion + dextromethorphan

Spravato, Ketanest Auvelity

GABA A RECEPTOR MODULATORS Brexanolone

‡

Zulresso

580    SECTION V  Drugs That Act in the Central Nervous System

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Gutman DA, Owens MJ: Serotonin and norepinephrine transporter binding profile of SSRIs. Essent Psychopharmacol 2006;7:35. Tabuteau H et al: Effect of AXS-05 (dextromethorphan-bupropion) in major depressive disorder: a randomized double-blind controlled trial. Am J Psychiatry 2022;179:490. Harrison J et al: The effects of vortioxetine on cognitive function in patients with major depressive disorder (MDD): A meta-analysis of three randomized controlled trials. Int J Neuropsychopharmacol 2016;19:pyw055. Hirschfeld RM: Antidepressants in long-term therapy: A review of tricyclic antidepressants and selective serotonin reuptake inhibitors. Acta Psychiatr Scand Suppl 2000;403:35. Hirschfeld RM: History and evolution of the monoamine hypothesis of depression. J Clin Psychiatry 2000;61(Suppl 6):4. Holma KM et al: Long-term outcome of major depressive disorder in psychiatric patients is variable. J Clin Psychiatry 2008;69:196. Jann MW, Slade JH: Antidepressant agents for the treatment of chronic pain and depression. Pharmacotherapy 2007;27:1571. Kalia M: Neurobiological basis of depression: An update. Metabolism 2005; 54(5 Suppl 1):24. Kozisek ME et al: Brain-derived neurotrophic factor and its receptor tropomyosinrelated kinase B in the mechanism of action of antidepressant therapies. Pharmacol Ther 2008;117:30. Krystal JH et al: Rapid-acting glutamatergic antidepressants: The path to ketamine and beyond. Biol Psychiatry 2013;73:1133. Laughren TP et al: Vilazodone: Clinical basis for the US Food and Drug Administration’s approval of a new antidepressant. J Clin Psychiatry 2011; 72:1166. Lesch KP, Gutknecht L: Pharmacogenetics of the serotonin transporter. Prog Neuropsychopharmacol Biol Psychiatry 2005;29:1062. Majeed A et al: Efficacy of dextromethorphan for the treatment of depression: a systematic review of preclinical and clinical trials. Expert Opin Emerg Drugs 2021;26:63. Mago R et al: Safety and tolerability of levomilnacipran ER in major depressive disorder: Results from an open-label, 48-week extension study. Clin Drug Investig 2013;33:761. Maletic V et al: Neurobiology of depression: An integrated view of key findings. Int J Clin Pract 2007;61:2030. Manji HK et al: The cellular neurobiology of depression. Nat Med 2001;7:541. Mathews DC, Zarate CA Jr: Current status of ketamine and related compounds for depression. J Clin Psychiatry 2013;74:516. McCleane G: Antidepressants as analgesics. CNS Drugs 2008;22:139. McEwen BS: Glucocorticoids, depression, and mood disorders: Structural remodeling in the brain. Metabolism 2005;54(5 Suppl 1):20. Montgomery SA et al: Efficacy and safety of levomilnacipran sustained release in moderate to severe major depressive disorder: A randomized, doubleblind, placebo-controlled, proof-of-concept study. J Clin Psychiatry 2013; 74:363. Nestler EJ et al: Neurobiology of depression. Neuron 2002;34:13. Pace TW et al: Cytokine-effects on glucocorticoid receptor function: Relevance to glucocorticoid resistance and the pathophysiology and treatment of major depression. Brain Behav Immun 2007;21:9. Pilc A et al: Glutamate-based antidepressants: Preclinical psychopharmacology. Biol Psychiatry 2013;73:1125. Sakinofsky I: Treating suicidality in depressive illness. Part 2: Does treatment cure or cause suicidality? Can J Psychiatry 2007;52(6 Suppl 1):85S. Schatzberg AF et al: Manual of Clinical Psychopharmacology, 6th ed. American Psychiatric Publishing, 2007. Shapiro JR et al: Bulimia nervosa treatment: A systematic review of randomized controlled trials. Int J Eat Disord 2007;40:321. Soomro GM et al: Selective serotonin reuptake inhibitors (SSRIs) versus placebo for obsessive compulsive disorder (OCD). Cochrane Database Syst Rev 2008;1:CD001765. Stein MB, Stein DJ: Social anxiety disorder. Lancet 2008;371(9618):1115. Stone EA et al: A final common pathway for depression? Progress toward a general conceptual framework. Neurosci Biobehav Rev 2008;32:508. Thase ME et al: A meta-analysis of randomized, placebo-controlled trials of vortioxetine for the treatment of major depressive disorder in adults. Eur Neuropsychopharmacol 2016;26:979.

CHAPTER 30  Antidepressant Agents    581 Tuccori M et al: Use of selective serotonin reuptake inhibitors during pregnancy and risk of major and cardiovascular malformations: An update. Postgrad Med 2010;122:49. Warden D et al: The STAR*D Project results: A comprehensive review of findings. Curr Psychiatry Rep 2007;9:449. Wheeler BW et al: The population impact on incidence of suicide and non-fatal self harm of regulatory action against the use of selective serotonin reuptake

inhibitors in under 18s in the United Kingdom: Ecological study. Br Med J 2008;336(7643):542. Wilson KL et al: Persistent pulmonary hypertension of the newborn is associated with mode of delivery and not with maternal use of selective serotonin reuptake inhibitors. Am J Perinatol 2011;28:19. Yu S et al: Neuronal actions of glucocorticoids: Focus on depression. J Steroid Biochem Mol Biol 2008;108:300.

C ASE STUDY ANSWER The patient has previously responded to fluoxetine, so this drug is an obvious choice. However, she is taking other drugs and fluoxetine, the prototype SSRI, has a number of pharmacokinetic and pharmacodynamic interactions. Fluoxetine is a CYP450 2D6 inhibitor and thus can inhibit the metabolism of 2D6 substrates such as propranolol and other β blockers; tricyclic antidepressants; tramadol; opioids such as methadone, codeine, and oxycodone; antipsychotics such as haloperidol and thioridazine; and many other drugs. This inhibition of metabolism can result in significantly higher plasma levels of the concurrent drug, and this may lead to an increase in adverse reactions associated with that drug.

As a potent inhibitor of the serotonin transporter, fluoxetine is associated with a number of pharmacodynamic interactions involving serotonergic neurotransmission. The combination of tramadol with fluoxetine has occasionally been associated with a serotonin syndrome, characterized by diaphoresis, autonomic instability, myoclonus, seizures, and coma. The combination of fluoxetine with an MAOI is contraindicated because of the risk of a fatal serotonin syndrome. In addition, meperidine is specifically contraindicated in combination with an MAOI. An interaction with hydrochlorothiazide is not likely.

31

C

H

A

P

T

E

R

Opioid Agonists & Antagonists Mark A. Schumacher, MD, PhD, Allan I. Basbaum, PhD, & Ramana K. Naidu, MD*

C ASE STUDY A 48-year-old man with a body mass index (BMI) of 33 (obesity) and history of obstructive sleep apnea presents to the emergency department with severe back pain following a fall from a ladder.

Morphine, the prototypic opioid agonist, has been used throughout history to relieve acute severe pain with remarkable efficacy. The opium poppy is the source of crude opium from which Sertürner in 1803 isolated morphine, the pure alkaloid, naming it after Morpheus, the Greek god of dreams. It remains the standard against which all drugs that have strong analgesic action are compared. These drugs are collectively known as opioids and include not only the natural and semisynthetic alkaloid derivatives from opium but also synthetic surrogates, other opioid-like drugs whose actions are blocked by the nonselective antagonist naloxone, plus several endogenous peptides that interact with the different subtypes of opioid receptors.

■■ BASIC PHARMACOLOGY OF THE OPIOIDS Source Opium, the source of morphine, is obtained from the poppy, Papaver somniferum and P album. After incision, the poppy seed pod exudes a white substance that turns into a brown gum that is crude opium. Opium contains many alkaloids, the principal

*

In memory of Walter (Skip) Way, MD.

582

He complains of severe pain without loss of consciousness or focal neurologic deficits. What is the most appropriate immediate treatment for his pain? Are any special precautions needed?

one being morphine, which is present in a concentration of about 10%. Codeine can also be found in opium and is synthesized commercially from morphine.

Classification & Chemistry The term opioid describes all compounds that work at opioid receptors. The term opiate specifically describes the naturally occurring alkaloids: morphine, codeine, thebaine, and papaverine. In contrast, narcotic was originally used to describe sleep-inducing medications, but in the United States, its usage has shifted into a legal term. Opioid drugs include full agonists, partial agonists, and antagonists–measures of intrinsic activity or efficacy. Morphine is a full agonist at the µ (mu)-opioid receptor, the major analgesic opioid receptor (Table 31–1). Opioids may also differ in receptor-binding affinity. For example, morphine exhibits a greater binding affinity at the μ-opioid receptor than does codeine. Other opioid receptor subtypes include d (delta) and κ (kappa) nociception/opioidreceptor-like subtype 1 (ORL-1) receptors. Simple substitution of an allyl group on the nitrogen of the full agonist morphine plus addition of a single hydroxyl group results in naloxone, a strong μ-receptor antagonist. The structures of some of these compounds are shown later in this chapter. Some opioids, eg, nalbuphine, a mixed agonist-antagonist, are capable of producing an agonist (or partial agonist) effect at one opioid receptor subtype and an antagonist effect at another. The receptor-activating properties and

CHAPTER 31  Opioid Agonists & Antagonists    583

TABLE 31–1  Opioid receptor subtypes, their

functions, and their endogenous peptide affinities.

Receptor Subtype

Functions

Endogenous Opioid Peptide Affinity

μ(mu)

Supraspinal and spinal analgesia; sedation; inhibition of respiration; slowed gastrointestinal transit; modulation of hormone and neurotransmitter release

Endorphins > enkephalins > dynorphins

δ(delta)

Supraspinal and spinal analgesia; modulation of hormone and neurotransmitter release

Enkephalins > endorphins and dynorphins

κ(kappa)

Supraspinal and spinal analgesia; psychotomimetic effects; slowed gastrointestinal transit

Dynorphins > > endorphins and enkephalins

affinities of opioid analgesics can be manipulated by pharmaceutical chemistry; in addition, certain opioid analgesics are modified in the liver, resulting in compounds with greater analgesic action. Chemically, the opioids derived from opium are phenanthrene derivatives and include four or more fused rings, while most of the synthetic opioids are simpler molecules.

Endogenous Opioid Peptides Opioid alkaloids (eg, morphine) produce analgesia through actions at central nervous system (CNS) receptors that also respond to certain endogenous peptides with opioid-like pharmacologic properties. The general term currently used for these endogenous substances is endogenous opioid peptides. Three families of endogenous opioid peptides have been described: the endorphins, the pentapeptide enkephalins (methionine-enkephalin [met-enkephalin] and leucine-enkephalin [leu-enkephalin]), and the dynorphins. These three families of endogenous opioid peptides have overlapping affinities for opioid receptors (see Table 31–1). The endogenous opioid peptides are derived from three precursor proteins: prepro-opiomelanocortin (POMC), preproenkephalin (proenkephalin A), and preprodynorphin (proenkephalin B). POMC contains the met-enkephalin sequence, β-endorphin, and several nonopioid peptides, including adrenocorticotropic hormone (ACTH), β-lipotropin, and melanocyte-stimulating hormone. Preproenkephalin contains six copies of met-enkephalin and one copy of leu-enkephalin. Leu- and met-enkephalin have slightly higher affinity for the δ (delta) than for the μ-opioid receptor (see Table 31–1). Preprodynorphin yields several active opioid peptides that contain the leu-enkephalin sequence. These are dynorphin A, dynorphin B, and α and β neoendorphins. Painful stimuli can evoke release of endogenous opioid peptides under the stress associated with pain or the anticipation of pain, and they diminish the perception of pain. In contrast to the analgesic role of leu- and met-enkephalin, an analgesic action of dynorphin A—through its binding to κ-opioid receptors—remains controversial. Dynorphin A is also found in

the dorsal horn of the spinal cord. Increased levels of dynorphin occur in the dorsal horn after tissue injury and inflammation. This elevated dynorphin level is proposed to increase pain and induce a state of long-lasting sensitization and hyperalgesia. The pronociceptive action of dynorphin in the spinal cord appears to be independent of the opioid receptor system. Beyond their role in pain, κ-opioid receptor agonists can also function as antipruritic agents. The principal receptor for this novel system is the G protein– coupled orphanin opioid-receptor–like subtype 1 (ORL1). Its endogenous ligand has been termed nociceptin by one group of investigators and orphanin FQ by another group. This ligandreceptor system is currently known as the N/OFQ system. Nociceptin is structurally similar to dynorphin except for the absence of an N-terminal tyrosine; it acts only at the ORL1 receptor, now known as NOP. The N/OFQ system is widely expressed in the CNS and periphery, reflecting its equally diverse biology and pharmacology. As a result of experiments using highly selective NOP receptor ligands, the N/OFQ system has been implicated in both pro- and antinociceptive activity as well as in the modulation of drug reward, learning, mood, anxiety, and cough processes, and of Parkinsonism.

Pharmacokinetics of Exogenous Opioids Properties of clinically important opioids are summarized in Table 31–2. A. Absorption Most opioid analgesics are well absorbed when given by subcutaneous, intramuscular, and oral routes. However, because of the first-pass effect, the oral dose of the opioid (eg, morphine) to elicit a therapeutic effect may need to be much higher than the parenteral dose. As there is considerable interpatient variability in first-pass opioid metabolism, prediction of an effective oral dose is difficult. Certain analgesics such as codeine and oxycodone are effective orally because they have reduced first-pass metabolism. By avoiding first-pass metabolism, nasal insufflation of certain opioids can rapidly result in therapeutic blood levels. Other routes of opioid administration include oral mucosa via lozenges, and the transdermal route via patches. The latter can provide delivery of potent analgesics over days. B. Distribution The uptake of opioids by various organs and tissues is a function of both physiologic and chemical factors. Although all opioids bind to plasma proteins with varying affinity, the drugs rapidly leave the blood compartment and localize in highest concentrations in highly perfused tissues such as the brain, lungs, liver, kidneys, and spleen. Drug concentrations in skeletal muscle may be much lower, but this tissue serves as the main reservoir because of its greater bulk. Even though blood flow to fatty tissue is much lower than to the highly perfused tissues, accumulation can be very important, particularly after frequent high-dose administration or continuous infusion of highly lipophilic opioids that are slowly metabolized, eg, fentanyl.

584    SECTION V  Drugs That Act in the Central Nervous System

TABLE 31–2  Common opioid analgesics. Receptor Effects1 κ

Approximately Equivalent Dose (mg)

Oral: Parenteral Potency Ratio

Duration of Analgesia (hours)

Maximum Efficacy

+

10

Low

4–5

High

+++

1.5

Low

4–5

High

+++

1.5

Low

3–4

High

Methadone

+++

3

10

High

4–6

High

Meperidine

+++

60–100

Medium

2–4

High

Fentanyl

+++

0.1

Low

1–1.5

High

Sufentanil

+++

0.02

Parenteral only

1–1.5

High

Alfentanil

+++

Titrated

Parenteral only

0.25–0.75

High

Remifentanil

+++

Titrated4

Parenteral only

0.055

High

Levorphanol

+++

2–3

High

4–5

High

Codeine

±

30–60

High

3–4

Low

±

5–10

Medium

4–6

Moderate

++

4.5

Medium

3–4

Mod–High

Generic Name

μ

Morphine2

+++

Hydromorphone Oxymorphone

6

Hydrocodone Oxycodone

1

2,7

δ

+

+

Pentazocine

±

+

30–50

Medium

3–4

Moderate

Nalbuphine

−

++

10

Parenteral only

3–6

High

Buprenorphine

±

−

0.3

Low

4–8

High

Butorphanol

±

+++

2

Parenteral only

3–4

High

−

+++, +++, +, strong agonist; ±, partial or weak agonist; −, antagonist.

2

Available in sustained-release forms, morphine (MS Contin); oxycodone (OxyContin).

3

No consensus—may have higher potency.

4

Administered as an infusion at 0.025–0.2 mcg/kg/min.

5

Duration is dependent on a context-sensitive half-time of 3–4 minutes.

6

Available in tablets containing acetaminophen (Norco, Vicodin, Lortab, others).

7

Available in tablets containing acetaminophen (Percocet); aspirin (Percodan).

C. Metabolism The opioids are converted in large part to polar metabolites (mostly glucuronides), which are then readily excreted by the kidneys. For example, morphine, which contains free hydroxyl groups, is primarily conjugated to morphine-3-glucuronide (M3G), a compound with neuroexcitatory properties. The neuroexcitatory effects of M3G do not appear to be mediated by μ receptors and are under further study. In contrast, approximately 10% of morphine is metabolized to morphine-6-glucuronide (M6G), an active metabolite with analgesic potency four to six times that of its parent compound. However, these relatively polar metabolites have limited ability to cross the blood-brain barrier and probably do not contribute significantly to the usual CNS effects of a single dose of morphine. Importantly, accumulation of these metabolites may produce unexpected adverse effects in patients with renal failure or when exceptionally large doses of morphine are administered or high doses are administered over long periods. This can result in M3G-induced CNS excitation (seizures) or enhanced and prolonged opioid action produced by M6G. CNS uptake of M3G and, to a lesser extent, M6G can be enhanced by co-administration of probenecid or of drugs that inhibit the P-glycoprotein drug transporter.

1. Hepatic P450 metabolism—Hepatic oxidative metabolism is the primary route of degradation of the phenylpiperidine opioids (fentanyl, meperidine, alfentanil, sufentanil) and eventually leaves only small quantities of the parent compound unchanged for excretion. However, accumulation of a demethylated metabolite of meperidine, normeperidine, may occur in patients with decreased renal function and in those receiving multiple high doses of the drug. In high concentrations, normeperidine may cause seizures. In contrast, no active metabolites of fentanyl have been reported. The P450 isozyme CYP3A4 metabolizes fentanyl by N-dealkylation in the liver. CYP3A4 is also present in the mucosa of the small intestine and contributes to the first-pass metabolism of fentanyl when it is taken orally. Codeine, oxycodone, and hydrocodone undergo metabolism in the liver by P450 isozyme CYP2D6, resulting in the production of metabolites of greater potency. For example, codeine is demethylated to morphine, which is then conjugated. Hydrocodone is metabolized to hydromorphone and, like morphine, hydromorphone is conjugated, yielding hydromorphone-3-glucuronide (H3G), which has CNS excitatory properties. Hydromorphone cannot form a 6-glucuronide metabolite. Similarly, oxycodone

CHAPTER 31  Opioid Agonists & Antagonists    585

is metabolized to oxymorphone, which is then conjugated to oxymorphone-3-glucuronide (O3G). Genetic polymorphism of CYP2D6 has been documented and linked to the variation in analgesic and adverse responses seen among patients. In contrast, the metabolites of oxycodone and hydrocodone may be of minor consequence; the parent compounds are currently believed to be directly responsible for the majority of their analgesic actions. However, oxycodone and its metabolites can accumulate under conditions of renal failure and have been associated with prolonged action and sedation. In the case of codeine, conversion to morphine may be of greater importance because codeine itself has relatively low affinity for opioid receptors. As a result, some patients (so-called poor metabolizers) may experience no significant analgesic effect. In contrast, there have been case reports of an exaggerated response to codeine due to enhanced metabolic conversion to morphine (ie, ultrarapid metabolizers; see Chapters 4 and 5) resulting in respiratory depression and death. For this reason, routine use of codeine, especially in pediatric age groups, is now being eliminated in the United States. The synthetic opioid methadone is metabolized through several CYP450 pathways, in part accounting for its highly variable bioavailability. The most important hepatic pathway for metabolism is CYP2B6. Although genetic testing of CYP450 pathways is not common, these tests are available and becoming cheaper. Over the next several decades, personalized medicine will help patients who need opioids (and their prescribers) understand which opioids may not be good options for them. 2. Plasma esterase metabolism—Esters (eg, heroin, remifentanil) are rapidly hydrolyzed by common plasma and tissue esterases. Heroin (diacetylmorphine) is hydrolyzed to monoacetylmorphine and finally to morphine, which is then conjugated with glucuronic acid. D. Excretion Polar metabolites, including glucuronide conjugates of opioid analgesics, are excreted mainly in the urine. Small amounts of unchanged drug may also be found in the urine. In addition, glucuronide conjugates are found in the bile, but enterohepatic circulation represents only a small portion of the excretory process of these polar metabolites. In patients with renal impairment the effects of active polar metabolites should be considered before the administration of potent opioids such as morphine or hydromorphone—especially when given at high doses—due to the risk of sedation and respiratory depression.

Pharmacodynamics A. Mechanism of Action Opioid agonists produce analgesia by binding to specific G  protein–coupled receptors (GPCRs) that are located in brain and spinal cord regions involved in the transmission and modulation of pain (Figure 31–1). Some effects may be mediated by opioid receptors on peripheral sensory nerve endings.

1. Receptor types—As noted previously, three major classes of opioid receptors (μ, δ, and κ) have been identified in various nervous system sites and in other tissues (see Table 31–1). Each of the three major receptors has now been cloned. All are members of the G protein–coupled family of receptors and show significant amino acid sequence homologies. Multiple receptor subtypes have been proposed based on pharmacologic criteria, including μ1, μ2; δ1, δ2; and κ1, κ2, and κ3. However, genes encoding only one subtype from each of the μ, δ, and κ receptor families have thus far been isolated and characterized. One plausible explanation is that μ-receptor subtypes arise from alternate splice variants of a common gene. This idea has been supported by the identification of receptor splice variants in mice and humans, and a recent report pointed to the selective association of a μ-opioid receptor splice variant (MOR1D) with the induction of itch rather than the suppression of pain. Since an opioid may function with different potencies as an agonist, partial agonist, or antagonist at more than one receptor class or subtype, it is not surprising that these agents are capable of diverse pharmacologic effects. 2. Cellular actions—At the molecular level, opioid receptors form a family of proteins that physically couple to G proteins and through this interaction affect ion channel gating, modulate intracellular Ca2+ disposition, and alter protein phosphorylation (see Chapter 2). The opioids have two well-established direct Gi/0 protein–coupled actions on neurons: (1) they close voltage-gated Ca2+ channels on presynaptic nerve terminals and thereby reduce transmitter release, and (2) they open K+ channels and hyperpolarize and thus inhibit postsynaptic neurons. Figure  31–1 schematically illustrates these effects. The presynaptic action— depressed transmitter release—has been demonstrated for a large number of neurotransmitters, including glutamate, the principal excitatory amino acid released from nociceptive nerve terminals, as well as acetylcholine, norepinephrine, serotonin, and substance P. 3. Relation of physiologic effects to receptor type—The majority of currently available opioid analgesics act primarily at the μ-opioid receptor (see Table 31–2). Analgesia and the euphoriant, respiratory depressant, and physical dependence properties of morphine result principally from actions at μ receptors. In fact, the μ receptor was originally defined using the relative potencies for clinical analgesia of a series of opioid alkaloids. However, opioid analgesic effects are complex and include interaction with δ and κ receptors. This is supported in part by the study of genetic knockouts of the μ, δ, and κ genes in mice. The development of μ-receptor–selective agonists could be clinically useful if their side-effect profiles (respiratory depression, risk of dependence) were more favorable than those found with current μ-receptor agonists, such as morphine. Although morphine does act at κ and δ receptor sites, it is unclear to what extent this contributes to its analgesic action. The endogenous opioid peptides differ from most of the alkaloids in their affinity for the δ and κ receptors (see Table 31–1).

586    SECTION V  Drugs That Act in the Central Nervous System

Biased Ligand

MOR

M

Ca++

M

M MOR M

K+ –

Pain stimulus

+

Gi/o

Periphery

Analgesia

MOR

Respiratory depression Constipation Tolerance

Primary afferent fiber

–

MOR α2

Glutamate

K+

Neuropeptide

–

–

Ca2+ Dorsal horn spinal cord

MOR

NMDA NK1

+

AMPA

Secondary afferent neuron

K+

FIGURE 31–1  Potential receptor mechanisms of analgesic drugs. The primary afferent neuron (cell body not shown) originates in the periphery and carries pain signals to the dorsal horn of the spinal cord, where it synapses via glutamate and neuropeptide transmitters with the secondary neuron. Pain stimuli can be attenuated in the periphery (under inflammatory conditions) by opioids acting at μ-opioid receptors (MOR) or blocked in the afferent axon by local anesthetics (not shown). Action potentials reaching the dorsal horn can be attenuated at the presynaptic ending by opioids and calcium blockers (ziconotide), by α2 agonists, and possibly, by drugs that increase synaptic concentrations of norepinephrine by blocking reuptake (tapentadol). Opioids also inhibit the postsynaptic neuron, as do certain neuropeptide antagonists acting at tachykinin (NK1) and other neuropeptide receptors. Inset: Morphine (M) binds and activates the μ-opioid receptor (MOR) coupling to Gi/o-mediated calcium channel inhibition and potassium channel activation. Analgesia (left) and β-arrestin–mediated side effects: respiratory depression, constipation, and tolerance (right). Biased ligand (closed triangle) targets a structural aspect of the MOR that facilitates Gi/o coupling (analgesia) over β-arrestin (side effects).

CHAPTER 31  Opioid Agonists & Antagonists    587

In an effort to develop opioid analgesics with a reduced incidence of respiratory depression or propensity for addiction and dependence, compounds that show preference for κ-opioid receptors have been developed. Butorphanol and nalbuphine have shown some clinical success as analgesics, but they can cause dysphoric reactions and have limited potency. It is of interest that butorphanol has also been shown to cause significantly greater analgesia in women than in men. In fact, gender-based differences in analgesia mediated by μ- and δ-receptor activation have been widely reported. Another approach to improve the therapeutic window of drugs that target opioid receptors is to develop opioid-like molecules that are analgesic but have significantly reduced adverse side effects (respiratory depression, constipation, and dependence). This effort is driven by structural studies of the mu opioid receptor that revealed different amino acid sequences, through which ligand binding to GPCRs influences multiple downstream signaling pathways. For example, morphine exerts its analgesic action via Gi/o signaling, but adverse side effects are proposed to occur by engaging the β-arrestin pathway. To avoid the latter pathway, “biased agonists” have been developed that are biased toward Gi signaling (see Figure 31–1, inset). Comparable studies have targeted biased agonist development of kappa opioid receptor agonists that lack the dysphoric effects typical of KOR agonists but retain analgesic efficacy as well as profound anti-pruritogenic effects. Complementary to this approach are the synergistic combinations of opioids that also target peripheral opioid receptors. In light of reports that these biased agonists may, in fact, represent partial agonists, like buprenorphine, caution in interpreting the mechanism of action of these novel opioids is advised. Another means to reduce opioid side-effects is based on reports of heterodimerization of different opioid receptors, eg, of the mu (MOR) and delta (DOR) opioid receptor. In this case, a hybrid MOR agonist and DOR antagonist retained analgesic action in the tail flick test, but tolerance and dependence were reduced compared to morphine. Other studies have reported heterodimerization between MOR and nonopioid receptors, eg, the nociceptin/ orphanin F/Q receptor (NOP). Interestingly, a bifunctional peptide-based hybrid that exerts an agonist action at the MOR and the NOP produced significant analgesic effects with reduced adverse effects. More recently, heterodimers were identified between the MOR and the Gal1 subtype of galanin receptors, contributing a major source of dopamine to nucleus accumbens–mediated reward. Such MOR-GAL1 heterodimers have been implicated in the relatively low-rewarding properties of methadone compared with morphine. The implication is that development of opioid analgesics that preferentially target the MOR-GAL1 heterodimer may provide analgesia with significantly reduced misuse potential. Of course, an alternative is to identify peripheral or CNS sites where selective targeting can increase the therapeutic window. To this end, recent studies reported that targeting the mu opioid receptor in the lateral habenula can exert significant analgesic actions without reward. Moreover, a rewarding effect only occurred in a pain model, presumably as a consequence of pain relief that may involve regulation of mesolimbic dopaminergic circuitry. 4. Receptor distribution and neural mechanisms of analgesia—Opioid receptor–binding sites have been localized

Somatosensory cortex

ACG

Thalamus VPL

C

Amygdala

Parabrachial nucleus Medulla/pons

DRG

B Dorsal horn Spinal cord

A Primary afferent nociceptor terminals

FIGURE 31–2  Putative sites of action of opioid analgesics. Sites of action on the afferent pain transmission pathway from the periphery to the higher centers are shown. (A) Direct action of opioids on inflamed or damaged peripheral tissues (see Figure 31–1 for detail). (B) Inhibition also occurs in the spinal cord (see Figure 31–1). (C) Possible site of action in the amygdala. ACG, anterior cingulate gyrus; DRG, dorsal root ganglion, VPL, ventral posterolateral nucleus of the thalamus. autoradiographically with high-affinity radioligands and with antibodies to unique peptide sequences in each receptor subtype. All three major receptors are present in subregions of the central nervous system including the dorsal horn of the spinal cord. Receptors are present both on spinal cord pain transmission neurons and on the primary afferents that relay the pain message to them (Figure 31–2, sites A and B). Although opioid agonists directly inhibit dorsal horn pain transmission neurons, they also inhibit the release of excitatory transmitters from the primary afferents. Although there are reports that heterodimerization of the μ-opioid and δ-opioid receptors contributes to μ-agonist efficacy (eg, inhibition of presynaptic voltage-gated calcium channel activity), a recent study using a transgenic mouse that expresses a δ-receptor–enhanced green fluorescent protein (eGFP) fusion protein showed little overlap of μ receptor and δ receptor in dorsal root ganglion neurons. Importantly, the μ receptor is associated with TRPV1 and peptide (substance P)-expressing nociceptors, whereas δ-receptor expression predominates in the nonpeptidergic population of nociceptors, including many primary afferents with myelinated axons. This finding is consistent with the action of intrathecal μ-receptor– and δ-receptor–selective ligands

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that are found to block heat versus mechanical pain processing, respectively. An association of the δ but not the μ receptor with large diameter mechanoreceptive afferents has been described. To what extent the differential expression of the μ receptor and δ receptor in the dorsal root ganglia is characteristic of neurons throughout the CNS remains to be determined. The fact that opioids exert a powerful analgesic effect directly on the spinal cord has been exploited clinically by direct application of opioid agonists to the spinal cord. This spinal action provides a regional analgesic effect while reducing the unwanted respiratory depression, nausea and vomiting, and sedation that may occur from the supraspinal actions of systemically administered opioids. Under most circumstances, opioids are given systemically and thus act simultaneously at multiple sites. These include not only the ascending pathways of pain transmission beginning with specialized peripheral sensory terminals that transduce painful stimuli (see Figure 31–2) but also descending (modulatory) pathways (Figure  31–3). At these sites, as at others, opioids directly

Higher centers

Cortex

Midbrain A − Periaqueductal gray

Medulla/pons B − Rostral ventral medulla

Spinal cord C − Dorsal horn Action potentials

Opioid receptor (MOR)

GABA

GABAA receptor Descending inhibitory neuron

Action potentials

FIGURE 31–3  Brainstem local circuitry underlying the modulating effect of μ-opioid receptor (MOR)–mediated analgesia on descending pathways. The pain-inhibitory neuron is indirectly activated by opioids (exogenous or endogenous), which inhibit an inhibitory (GABAergic) interneuron. This results in enhanced inhibition of nociceptive processing in the dorsal horn of the spinal cord (see Figure 31–4).

FIGURE 31–4  Opioid analgesic action on the descending inhibitory pathway. Sites of action of opioids on pain-modulating neurons in the midbrain and medulla including the midbrain periaqueductal gray area (A), rostral ventral medulla (B), and the locus coeruleus indirectly control pain transmission pathways by enhancing descending inhibition to the dorsal horn (C). inhibit neurons; yet this action results in the activation of descending inhibitory neurons that send processes to the spinal cord and inhibit pain transmission neurons. This activation has been shown to result from the inhibition of inhibitory neurons in several locations (Figure 31–4). Taken together, interactions at these sites increase the overall analgesic effect of opioid agonists. Moreover, when pain-relieving opioid drugs are given systemically, they presumably act on neuronal circuits normally regulated by endogenous opioids. However, as morphine exerts its action mainly at the mu receptor, while enkephalins engage both mu and delta receptors, it is likely that different analgesia-mediating circuits may be activated by exogenous and endogenous opioids. Animal and human clinical studies demonstrate that both endogenous and exogenous opioids can also produce analgesia at sites outside the CNS. Pain associated with inflammation seems especially sensitive to these peripheral opioid actions. The presence of functional μ receptors on the peripheral terminals of sensory neurons supports this hypothesis. Furthermore, activation of peripheral μ receptors results in a decrease in sensory neuron activity and transmitter release. The endogenous release of β-endorphin produced by immune cells within injured or inflamed tissue represents one source of physiologic peripheral μ-receptor activation. Intra-articular administration of opioids,

CHAPTER 31  Opioid Agonists & Antagonists    589

eg, following arthroscopic knee surgery, has shown some clinical benefit for up to 24 hours. For this reason, opioids selective for a peripheral site of action may be useful adjuncts in the treatment of inflammatory pain (see Box: Ion Channels & Novel Analgesic Targets). Such compounds could have the additional benefit of reducing unwanted effects such as nausea. Also of interest is a recent report that a fentanyl analog that preferentially acts within an acidic environment (namely, diseased colon) can produce analgesia without the typical adverse side effects (constipation and respiratory depression). Interestingly, this compound produces reward that appears to be secondary to its peripheral pain-relieving properties. 5. Tolerance and dependence—With frequently repeated therapeutic doses of morphine or its surrogates, there is a gradual loss in effectiveness; this loss of effectiveness is termed tolerance. Attempts to reproduce the original analgesic response require a larger dose to be administered (with variable success). Along with tolerance, physical dependence develops. Physical dependence is defined as a characteristic withdrawal or abstinence syndrome when a drug is stopped or an antagonist is administered (see also Chapter 32). The mechanism of development of opioid tolerance and physical dependence is poorly understood, but persistent activation of μ receptors such as occurs with the treatment of severe chronic pain appears to play a primary role in its induction and maintenance. Current concepts have shifted away from tolerance being driven by a simple up-regulation of the cyclic adenosine monophosphate (cAMP) system. Although this process is associated with tolerance, it is not sufficient to explain it. A second hypothesis for the development of opioid tolerance and dependence is based on the concept of receptor recycling. Normally, activation of μ receptors

by endogenous ligands results in receptor endocytosis followed by resensitization and recycling of the receptor to the plasma membrane (see Chapter 2). However, using genetically modified mice, research now shows that the failure of morphine to induce endocytosis of the μ-opioid receptor is an important component of tolerance and dependence. In further support of this idea, methadone, a μ-receptor agonist used for the treatment of opioid tolerance and dependence, induces receptor endocytosis. This suggests that maintenance of normal sensitivity of μ receptors requires reactivation by endocytosis and recycling. The concept of receptor uncoupling has also gained prominence. Under this hypothesis, tolerance results from a dysfunction of structural interactions between the μ receptor and G proteins, second-messenger systems, and their target ion channels. Uncoupling and recoupling of μ receptor function are likely linked to receptor recycling. Recent studies demonstrate that receptor internalization of GPCRs is not merely a step in recycling to the membrane or of receptor degradation. Rather, several G protein receptors, after their internalization, can reside and remain functional in cytoplasmic endosomes. This has been demonstrated for pronociceptive ligands (eg, CGRP, substance P, PAR2) and most recently for the delta opioid receptor, which could be engaged by ligands from patient-derived inflamed colon. The NMDAreceptor ion channel complex is also a significant contributor to tolerance development and maintenance. Consistent with this mechanism, NMDA-receptor antagonists such as ketamine can block tolerance development, in part by reducing descending medullary pain facilitatory mechanisms. These studies emphasize that the development of novel NMDA-receptor antagonists or other strategies to recouple μ receptors to their target ion channels provides hope for achieving a clinically effective means to prevent or reverse opioid analgesic tolerance.

Ion Channels & Novel Analgesic Targets Even the most severe acute pain (lasting hours to days) can usually be controlled—with significant but tolerable adverse effects— using currently available analgesics, especially the opioids. However, chronic pain (lasting months to years) and especially pain arising from neuropathic causes are not very satisfactorily managed with opioids. It is now known that in chronic pain, receptors on sensory nerve terminals in the periphery contribute to increased excitability of these sensory endings (peripheral sensitization). The hyperexcitable sensory neuron bombards the spinal cord, leading to increased excitability and synaptic alterations in the dorsal horn (central sensitization). Such changes are likely important contributors to chronic inflammatory and neuropathic pain states. In the effort to discover better analgesic drugs for chronic pain, renewed attention is being paid to the molecular basis of peripheral sensory transduction. Potentially important ion channels associated with the primary afferent nociceptor include

members of the transient receptor potential family, notably the capsaicin receptor TRPV1 (which is activated by multiple noxious stimuli such as heat, protons, and products of inflammation) and TRPA1, activated by inflammatory mediators, TRPM8, the receptor for menthol-mediated topical analgesia, and P2X receptors (which are responsive to purines released from tissue damage). Special subtypes of voltage-gated sodium channels (Nav 1.7, 1.8, 1.9) are uniquely associated with nociceptive neurons in dorsal root ganglia. Lidocaine and mexiletine, which are useful in some chronic pain states, may act by blocking this class of channels. Certain centipede toxins appear to selectively inhibit Nav 1.7 channels and may also be useful in the treatment of chronic pain. Genetic polymorphisms of Nav 1.7 are associated with either absence (congenital insensitivity to pain) or predisposition to pain (erythromelalgia or paroxysmal extreme pain disorder), and there may be a direct link between expressed levels of Nav 1.7 and enkephalin in sensory ganglia. Nav 1.9 is

590    SECTION V  Drugs That Act in the Central Nervous System

also currently under study as a therapeutic target. Because of the importance of their peripheral sites of action, therapeutic strategies that deliver agents that block peripheral pain transduction or transmission have been introduced in the form of transdermal patches and balms. In addition, products that systemically target peripheral TRPV1, TRPA1, TRPM8, and sodium channel function are in development. Intrathecal administration of ziconotide, a blocker of voltage-gated N-type calcium channels, is approved for producing analgesia in patients with refractory chronic pain. Ziconotide is a synthetic peptide related to the marine snail toxin Ω-conotoxin, which selectively blocks N-type calcium channels. Gabapentin/pregabalin, anticonvulsants that act at the α2δ1 subunit of voltage-gated calcium channels, are effective treatments for neuropathic (nerve injury) pain and reduce opioid requirements postoperatively (see Chapter 24). N-methyl-d-aspartate (NMDA) receptors appear to play a very important role in central sensitization at both spinal and supraspinal levels. Although certain NMDA antagonists have demonstrated anti-hyperalgesic and analgesic activity (eg, ketamine), it has been difficult to find agents with an acceptably low profile of adverse effects or neurotoxicity. However, ketamine infused at very small doses reduces hyperalgesia and can reduce opioid requirements under conditions of opioid tolerance, eg, after

6. Opioid-induced hyperalgesia (OIH)—In addition to the development of tolerance, persistent administration of opioid analgesics can increase the sensation of pain, resulting in a state of hyperalgesia. This phenomenon can be produced with several opioid analgesics, including morphine, fentanyl, and remifentanil. Some studies have implicated a microglial-expressed opioid receptor or a metabolite of morphine that binds a microglialexpressed TL4 receptor in OIH. In contrast, an earlier report demonstrated that both opioid tolerance and OIH can be prevented by selective deletion of the MOR from primary sensory neurons, not from microglia. Spinal dynorphin and activation of the bradykinin and NMDA receptors have also emerged as important candidates for the mediation of opioid-induced hyperalgesia. This is one more reason why continuously administered opioids for chronic noncancer pain has been questioned. B. Organ System Effects of Morphine and Its Surrogates The actions described below for morphine, the prototypic opioid agonist, can also be observed with other opioid agonists, partial agonists, and those with mixed receptor effects. Characteristics of specific members of these groups are discussed below. 1. Central nervous system effects—The principal effects of opioid analgesics with affinity for μ receptors are on the CNS; the more important ones include analgesia, euphoria, sedation, and respiratory depression. With repeated use, a high degree of tolerance occurs to all of these effects (Table 31–3).

major abdominal and spinal surgery. GABA and acetylcholine (through nicotinic receptors) appear to control the central synaptic release of several transmitters involved in nociception. Use of antibodies that bind nerve growth factor (NGF) has been shown to block inflammatory and back pain, but approval of their clinical use may be limited due to safety concerns. Finally, work on cannabinoids and vanilloids and their receptors suggests that Δ9-tetrahydrocannabinol (THC) as well as cannabidiol (CBD) and other minor cannabinoids, which act on CB1 cannabinoid receptors and interact with the TRPV1 capsaicin receptor under certain circumstances, can synergize with μ-receptor agonists to produce analgesia. As our understanding of peripheral and central pain transduction improves, additional therapeutic targets and strategies will become available. Combined with our present knowledge of opioid analgesics, a “multimodal” approach to pain therapy is paramount. Multimodal analgesia involves the administration of multiple agents (eg, COX-inhibitors or nonsteroidal anti-inflammatory drugs [NSAIDs], gabapentinoids (in select patients), and selective norepinephrine receptor inhibitors with complementary mechanisms of action to provide analgesia that is superior to that provided by an individual compound. Another benefit of multimodal analgesia is reduced opioid requirements with fewer serious adverse effects.

a. Analgesia—Pain consists of both sensory and affective (emotional) components. Opioid analgesics are unique in that they can reduce both aspects of the pain experience. In contrast, nonsteroidal anti-inflammatory analgesic drugs, eg, ibuprofen, have no significant effect on the emotional aspects of pain. b. Euphoria—Typically, patients or intravenous drug users who receive intravenous morphine experience a pleasant floating sensation with lessened anxiety and distress. However, dysphoria, an unpleasant state characterized by restlessness and malaise, also may occur.

TABLE 31–3  Degrees of tolerance that may develop to some of the effects of the opioids.

High

Moderate

Minimal or None

Analgesia

Bradycardia

Miosis

Euphoria, dysphoria

Constipation

Mental clouding

Convulsions

Sedation Respiratory depression Antidiuresis Nausea and vomiting Cough suppression

CHAPTER 31  Opioid Agonists & Antagonists    591

c. Sedation—Drowsiness and clouding of mentation are common effects of opioids. There is little or no amnesia. Sleep is induced by opioids more frequently in the elderly than in young, healthy individuals. Ordinarily, the patient can be easily aroused from this sleep. However, the combination of morphine with other central depressant drugs such as the sedative-hypnotics may result in very deep sleep. In standard analgesic doses, morphine (a phenanthrene) disrupts normal rapid eye movement (REM) and non-REM sleep patterns. This disrupting effect is probably characteristic of all opioids. In contrast to humans, a number of other species (cats, horses, cows, pigs) may manifest excitation rather than sedation when given opioids. These paradoxical effects are at least partially dose-dependent. d. Respiratory depression—All of the opioid analgesics can produce significant respiratory depression by inhibiting brainstem respiratory mechanisms. Alveolar Paco2 may increase, but the most reliable indicator of this depression is a depressed response to a carbon dioxide challenge. The respiratory depression is dose-related and is influenced significantly by the degree of sensory input occurring at the time. For example, it is possible to partially overcome opioid-induced respiratory depression by a variety of stimuli. When strongly painful stimuli that have prevented the depressant action of a large dose of an opioid are relieved, respiratory depression may suddenly become marked. A small to moderate decrease in respiratory function, as measured by Paco2 elevation, may be well tolerated in the patient without prior respiratory impairment. However, in individuals with increased intracranial pressure, asthma, chronic obstructive pulmonary disease, or cor pulmonale, this decrease in respiratory function may not be tolerated. Opioid-induced respiratory depression remains one of the most difficult clinical challenges in the treatment of severe pain. Ongoing research to overcome this problem is focused on μ-receptor pharmacology, serotonin signaling pathways in the brainstem respiratory control centers, and agonist ligands biased toward Gi/o coupling. e. Cough suppression—Suppression of the cough reflex is a wellrecognized action of opioids. Codeine in particular has been used to advantage in persons suffering from pathologic cough. However, cough suppression by opioids may allow accumulation of secretions and thus lead to airway obstruction and atelectasis. f. Miosis—Constriction of the pupils is seen with virtually all opioid agonists. Miosis is a pharmacologic action to which little or no tolerance develops, even in highly tolerant addicts (see Table 31–3); thus, it is valuable in the diagnosis of opioid overdose. This action, which can be blocked by opioid antagonists, is mediated by parasympathetic pathways, which, in turn, can be blocked by atropine. g. Truncal rigidity—Several opioids can intensify tone in the large trunk muscles. It was originally believed that truncal rigidity involved a spinal cord action of these drugs, but a supraspinal action is likely. Truncal rigidity reduces thoracic compliance and thus interferes with ventilation. The effect is most apparent when high doses of the highly lipid-soluble opioids (eg, fentanyl,

sufentanil, alfentanil, remifentanil) are rapidly administered intravenously. Truncal rigidity may be overcome by administration of an opioid antagonist, which of course will also antagonize the analgesic action of the opioid. Preventing truncal rigidity while preserving analgesia requires the concomitant use of neuromuscular blocking agents. h. Nausea and vomiting—The opioid analgesics can activate the brainstem chemoreceptor trigger zone to produce nausea and vomiting. As ambulation seems to increase the incidence of nausea and vomiting there may also be a vestibular component in this effect. i. Temperature—Homeostatic regulation of body temperature is mediated in part by the action of endogenous opioid peptides in the brain. For example, administration of μ-opioid receptor agonists, such as morphine to the anterior hypothalamus produces hyperthermia, whereas administration of κ agonists induces hypothermia. j. Sleep architecture—Although the mechanism by which opioids interact with circadian rhythm is unclear, they can decrease the percentage of stage 3 and 4 sleep, which may result in fatigue and other sleep disorders, including sleep-disordered breathing and central sleep apnea. 2. Peripheral effects a. Cardiovascular system—Most opioids have no significant direct effects on the heart and, other than bradycardia, no major effects on cardiac rhythm. Meperidine is an exception to this generalization because its antimuscarinic action can result in tachycardia. Blood pressure is usually well maintained in subjects receiving opioids unless the cardiovascular system is stressed, in which case hypotension may occur. This hypotensive effect is probably due to peripheral arterial and venous dilation, which has been attributed to a number of mechanisms including central depression of vasomotor-stabilizing mechanisms and release of histamine. No consistent effect on cardiac output is seen, and the electrocardiogram is not significantly affected. However, caution should be exercised in patients with decreased blood volume, because the above mechanisms make these patients susceptible to hypotension. Opioid analgesics affect cerebral circulation minimally except when Pco2 rises as a consequence of respiratory depression. Increased Pco2 leads to cerebral vasodilation associated with a decrease in cerebral vascular resistance, an increase in cerebral blood flow, and an increase in intracranial pressure. b. Gastrointestinal tract—Constipation has long been recognized as an effect of opioids, an effect that does not diminish with continued use. That is, tolerance does not develop to opioid-induced constipation (see Table 31–3). Opioid receptors exist in high density in the gastrointestinal tract, and the constipating effects of the opioids are mediated through an action on the enteric nervous system (see Chapter 6) as well as the CNS. In the stomach, motility (rhythmic contraction and relaxation) may decrease but tone (persistent contraction) may increase—particularly in the central portion; gastric secretion

592    SECTION V  Drugs That Act in the Central Nervous System

of hydrochloric acid is decreased. Small intestine resting tone is increased, with periodic spasms, but the amplitude of nonpropulsive contractions is markedly decreased. In the large intestine, propulsive peristaltic waves are diminished and tone is increased; this delays passage of the fecal mass and allows increased absorption of water, which leads to constipation. The large bowel actions are the basis for the use of opioids in the management of diarrhea, and constipation is a major problem in the use of opioids for control of severe cancer pain. As described later, a new generation of agents designed to block or reverse opioid-induced constipation has been introduced. c. Biliary tract—The opioids contract biliary smooth muscle, which can result in biliary colic. The sphincter of Oddi may constrict, resulting in reflux of biliary and pancreatic secretions and elevated plasma amylase and lipase levels. d. Renal—Renal function is depressed by opioids. It is believed that in humans this is chiefly due to decreased renal plasma flow. In addition, μ receptor opioids have an antidiuretic effect in humans. Mechanisms may involve both the CNS and peripheral sites. Opioids also enhance renal tubular sodium reabsorption. The role of opioid-induced changes in antidiuretic hormone (ADH) release is controversial. Ureteral and bladder tone are increased by therapeutic doses of the opioid analgesics. Increased sphincter tone may precipitate urinary retention, especially in postoperative patients. Occasionally, ureteral colic caused by a renal calculus is made worse by opioid-induced increase in ureteral tone. e. Uterus—The opioid analgesics may prolong labor. Although the mechanism for this action is unclear, both μ- and κ-opioid receptors are expressed in human uterine muscle. Fentanyl and meperidine (pethidine) inhibit uterine contractility but only at supraclinical concentrations; morphine had no reported effects. In contrast, the κ agonist [3H]-D-ala2,L-met5enkephalinamide (DAMEA) inhibits contractility in human uterine muscle strips. f. Endocrine—Opioids stimulate the release of ADH, prolactin, and somatotropin but inhibit the release of luteinizing hormone (see Table 31–1). These effects suggest that endogenous opioid peptides, through effects in the hypothalamus, modulate these systems. Patients receiving chronic opioid therapy can have low testosterone resulting in decreased libido, energy, and mood. Women can experience dysmenorrhea or amenorrhea. g. Pruritus—The opiates, such as morphine and codeine, produce flushing and warming of the skin accompanied sometimes by sweating, urticaria, and itching. Although peripheral histamine release is an important contributor, all opioids can cause pruritus via a central (spinal cord and medullary) action on pruritoceptive neural circuits. When opioids are administered to the neuraxis by the spinal or epidural route, their usefulness may be limited by intense pruritus over the lips and torso. The incidence of opioid-induced pruritus via the neuraxial route is high, estimated at 70–100%. Of interest, the κ agonist/partial μ antagonist

nalbuphine and the selective κ agonist nalfurafine have proved effective and in some countries have been approved for the management of itch. Nalfurafine importantly is a highly biased κ agonist that does not produce the dysphoria typical of κ receptor agonists. As to mechanism, a recent preclinical study implicated a κ opioid receptor–expressing medullospinal inhibitory circuit in these controls. On the other hand, with respect to pain regulation, other studies underscore the complex contribution of the κ receptor. Indeed, κ antagonists reportedly can attenuate pain in a preclinical migraine model. h. Immune—The opioids modulate the immune system by effects on lymphocyte proliferation, antibody production, angioneogenesis, and chemotaxis. In addition, leukocytes migrate to the site of tissue injury and release opioid peptides, which in turn help counter inflammatory pain. However, natural killer cell cytolytic activity and lymphocyte proliferative responses to mitogens are usually inhibited by opioids, which may play a role in tumor progression. Although the mechanisms involved are complex, activation of central opioid receptors could mediate a significant component of the changes observed in peripheral immune function. These effects are mediated by the sympathetic nervous system in the case of acute administration and by the hypothalamic-pituitary-adrenal system in the case of prolonged administration of opioids.

■■ CLINICAL PHARMACOLOGY OF THE OPIOID ANALGESICS Successful management of pain is a challenging task that begins with assessment of and an attempt to understand the source and magnitude of the pain. Pain is an unpleasant sensory and emotional experience with many layers of complexity. The amount of pain experienced by the patient is often measured by means of a pain numeric rating scale (NRS) or less frequently by marking a line on a 100-mm visual analog scale (VAS, which is more commonly used in research), as well as the verbal rating scale (VRS) with word descriptors ranging from no pain to excruciating pain. In each case, values indicate the magnitude of pain as mild (1–3), moderate (4–6), or severe (7–10). A similar scale can be used with children (Face, Legs, Activity, Cry, Consolability [FLACC] or Wong-Baker scales) and with patients who cannot speak; the Wong-Baker scale depicts five faces ranging from smiling (no pain) to crying (maximum pain). The Brief Pain Inventory is a series of questions regarding the severity of pain. Functional scales include the Oswestry Disability Index or the World Health Organization Disability Assessment Scale 2.0. There are specialized scales for patients with specific conditions including rheumatoid arthritis and dementia. More comprehensive questionnaires such as the McGill Pain Questionnaire address the multiple facets of pain including both the affective and sensory experience. For a patient in severe acute pain, administration of an opioid analgesic is usually considered a primary part of the overall management plan. Determining the route of administration

CHAPTER 31  Opioid Agonists & Antagonists    593

(oral, parenteral, neuraxial), duration of drug action, ceiling effect (maximal intrinsic activity), duration of therapy, potential for adverse effects, and the patient’s past experience with opioids, including their genetics, social history, and family history, all should be addressed. One of the main principles in this process is to establish analgesic treatment goals before initiation of therapy. Just as important is the principle that following delivery of the therapeutic plan, its effectiveness must be monitored and reevaluated frequently, and the plan modified as necessary. Use of opioid drugs in acute situations should be contrasted with their use in chronic pain management, in which a multitude of other factors must be considered, including the development of tolerance, dependence, and the rarer cases of diversion or misuse.

Clinical Use of Opioid Analgesics A. Analgesia Severe, acute pain is usually relieved with opioid analgesics having high intrinsic activity (see Table 31–2), whereas sharp, intermittent pain does not appear to be as effectively controlled. The pain associated with cancer and other terminal illnesses typically involves a combination of mechanisms, must be treated aggressively, and often requires a multidisciplinary approach for effective management. Such conditions may require continuous use of potent opioid analgesics when cancer is active and/or invasive and when the conditions are associated with risk of tolerance and dependence. Importantly, use of multimodal analgesic strategies can reduce these risks. However, this should not be used as a barrier to providing patients with the best possible care and quality of life. The World Health Organization Ladder (see http://www.who. int/cancer/palliative/painladder/en/) was created in 1986 to promote awareness of the optimal treatment of pain for individuals with cancer and has helped improve pain care for cancer patients worldwide. Research in the hospice setting has also demonstrated that fixed-interval administration of opioid medication (ie, a regular dose at a scheduled time) is more effective in achieving pain relief than dosing on demand. Dosage forms of opioids that allow slower (sustained) release of the drug are now available, eg, sustained-release forms of morphine (MS Contin) and oxycodone (OxyContin). Their purported advantage is a longer and more stable level of analgesia. However, there is little to no evidence of the superiority of long-term (>3–6 months) use of sustainedrelease opioids to manage chronic noncancer or chronic low back, hip, or knee pain for 12 months when compared with nonopioid analgesic strategies. Alternately, attempts to control chronic pain with opioids alone may lead to excessive use, dependence and risk of opioid use disorder (OUD), overdose, and death (see Box: Educating Opioid Prescribers). If disturbances of gastrointestinal function prevent the use of oral sustained-release morphine, then a fentanyl transdermal system (fentanyl patch) can be used over long periods. Furthermore, buccal transmucosal fentanyl can be used for short episodes of breakthrough cancer pain (see Alternative Routes of Administration). Administration of strong opioids by nasal insufflation also is efficacious, and nasal preparations are now available in

some  countries. Opioid analgesics are often used during obstetric labor. Because opioids cross the placental barrier and reach the fetus, care must be taken to minimize neonatal depression. If it occurs, immediate injection of the antagonist naloxone will reverse the depression. The phenylpiperidine drugs (eg, meperidine) appear to produce less depression, particularly respiratory depression, in newborn infants than does morphine; this may justify their use in obstetric practice. The acute, severe pain of renal and biliary colic often requires a strong agonist opioid for adequate relief. However, the druginduced increase in smooth muscle tone may cause a paradoxical increase in pain secondary to increased spasm. B. Acute Pulmonary Edema The relief produced by intravenous morphine in patients with dyspnea from pulmonary edema associated with left ventricular heart failure is remarkable. Proposed mechanisms include reduced anxiety (perception of shortness of breath) and reduced cardiac preload (reduced venous tone) and afterload (decreased peripheral resistance). However, if respiratory depression is a problem, a diuretic (furosemide) may be preferred for the treatment of pulmonary edema. On the other hand, morphine can be particularly useful when treating painful myocardial ischemia with pulmonary edema. C. Cough Suppression of cough can be obtained at doses lower than those needed for analgesia. However, in recent years, the use of opioid analgesics to allay cough has diminished largely because of the availability of a number of effective synthetic compounds that are neither analgesic nor addictive. These agents are discussed below. D. Diarrhea Diarrhea from almost any cause can be controlled with the opioid analgesics, but if diarrhea is associated with infection, such use must not substitute for appropriate treatment. Crude opium preparations (eg, paregoric) were used in the past to control diarrhea, but now synthetic surrogates with more selective gastrointestinal effects and few or no CNS effects, eg, diphenoxylate or loperamide, are used. Several preparations are available specifically for this purpose (see Chapter 62). E. Shivering Although all opioid agonists have some propensity to reduce shivering, meperidine is reported to have the most pronounced anti-shivering properties. Meperidine apparently blocks shivering mainly through an action on subtypes of the α2 adrenoceptor. F. Applications in Anesthesia The opioids are frequently used as premedicant drugs before anesthesia and surgery because of their sedative, anxiolytic, and analgesic properties. They are also used intraoperatively as a part of induction, maintenance, and preparation for postoperative analgesia. Opioids are most commonly used in cardiovascular surgery and other types of high-risk surgery in which a primary goal is to

594    SECTION V  Drugs That Act in the Central Nervous System

minimize cardiovascular depression. In such situations, mechanical respiratory assistance must be provided. Because of their direct action on the neurons of the superficial dorsal horn of the spinal cord, opioids can also be used as regional analgesics, by administration into the epidural or subarachnoid spaces of the spinal column. A number of studies have demonstrated that long-lasting analgesia with minimal adverse effects can be achieved by epidural administration of 3–5 mg of morphine, followed by slow infusion through a catheter placed in the epidural space. It was initially assumed that the epidural application of opioids might selectively produce analgesia without impairment of motor, autonomic, or sensory functions other than pain. However, respiratory depression can occur after the drug is injected into the epidural space and may require reversal with naloxone. Effects such as pruritus and nausea and vomiting are common after epidural and subarachnoid administration of opioids and may also be reversed with naloxone. The use of epidural opioids in combination with dilute solutions of local anesthetics is common practice for postoperative analgesia following thoracic and abdominal operations and can reduce the amount of systemic opioids, thereby reducing other opioid-related side effects such as sedation or constipation. In rare cases, chronic pain management specialists may elect to implant surgically a programmable infusion pump connected to a spinal catheter for continuous infusion of opioids and/or other analgesic compounds in chronic or cancer pain management. G. Alternative Routes of Administration Patient-controlled analgesia (PCA) is widely used for the management of breakthrough pain. With PCA, the patient controls a parenteral (usually intravenous) infusion device by pressing a button to deliver a preprogrammed dose of the desired opioid analgesic, called the demand dose. A programmable lockout interval prevents administration of another dose for a set period of time. In addition, the pumps can be programmed with a continuous or basal infusion (which should generally be avoided due to safety concerns unless directed by an experienced provider) and the 1-hour lockout dose (the maximum amount of drug that can be delivered in 1 hour). Claims of better patient satisfaction are supported by well-designed clinical trials, making this approach very useful in postoperative pain control. However, healthcare personnel must be very familiar with the use of PCAs to avoid overdosage secondary to misuse or improper programming. There is a proven risk of PCA-associated respiratory depression and hypoxia that requires careful monitoring of vital signs and sedation level, and provision of supplemental oxygen. Continuous pulse oximetry is recommended for patients receiving PCA-administered opioids; this is not a fail-safe method for early detection of hypoventilation or apnea but rather serves as a safety net for an unrecognized adverse event. Monitoring of ventilation is ideal but is often inadequate. The risk of sedation is increased if medications with sedative properties, such as benzodiazepines and certain types of antiemetics, are concurrently prescribed. Rectal suppositories of morphine and hydromorphone have been used when oral and parenteral routes are undesirable.

The transdermal fentanyl patch is the most common full opioid agonist in transdermal application and is indicated primarily for the management of persistent unremitting cancer pain. It can provide more consistent blood levels of drug and potentially better pain control while avoiding the need for repeated or continuous parenteral (intravenous) injections. This may be especially important in patients unable to receive opioids via the enteral route due to limited GI function. Because of the complication of fentanyl-induced respiratory depression, the FDA recommends that introduction of a transdermal fentanyl patch (25 mcg/h) be reserved for patients with an established oral morphine requirement of at least 60 mg/d for 1 week or more. Extreme caution must be exercised in any patient initiating therapy or undergoing a dose increase because the peak effects may not be realized until 24–48 hours after patch application. Another alternative to parenteral administration is the buccal transmucosal route, which uses a fentanyl citrate lozenge or “lollipop” mounted on a stick for breakthrough cancer pain. The inclusion of the transdermal fentanyl patch for the treatment of chronic noncancer pain is associated with an increased risk of respiratory depression, tolerance, dependence, and opioid use disorder. Evidence is lacking for its superiority over nonopioid analgesic strategies in the treatment of chronic non-cancer pain and is often reserved for patients unable to be administered or absorb enteral opioid analgesics. The buprenorphine patch (Butrans) is an example of the transdermal delivery of a mixed agonist-antagonist for the treatment of chronic pain in addition to opioid maintenance or detoxification. The intranasal route avoids repeated parenteral drug injections and the first-pass metabolism of orally administered drugs. Butorphanol is the only opioid currently available in the USA in a nasal formulation, but more are expected.

Toxicity & Undesired Effects Direct toxic effects of the opioid analgesics that are extensions of their acute pharmacologic actions include respiratory depression, nausea, vomiting, and constipation (Table 31–4). Tolerance, dependence, diagnosis and treatment of overdosage, and contraindications must be considered.

TABLE 31–4  Adverse effects of the opioid analgesics. Adverse Effects with Acute Use

Adverse Effects with Chronic Use

Respiratory depression

Hypogonadism

Nausea/vomiting

Immunosuppression

Pruritus

Increased feeding

Urticaria

Increased growth hormone secretion

Constipation

Withdrawal effects

Urinary retention

Tolerance, dependence

Delirium

Abuse, addiction

Sedation

Hyperalgesia

Myoclonus

Impairment while driving

Seizures

CHAPTER 31  Opioid Agonists & Antagonists    595

A. Tolerance and Dependence Drug dependence of the opioid type is marked by a relatively specific withdrawal or abstinence syndrome. Just as there are pharmacologic differences between the various opioids, there are reported differences in psychological dependence and the severity of withdrawal effects. Administration of an opioid antagonist to an opioid-dependent person is followed by brief but severe withdrawal symptoms (see antagonist-precipitated withdrawal, below). The potential for physical and psychological dependence of the partial agonist-antagonist opioids appears to be less than that of the strong agonist drugs. 1. Opioid tolerance—Opioid tolerance is the phenomenon whereby repeated doses of opioids have a diminishing analgesic effect. Clinically, it has been described as an increasing opioid dose requirement to achieve the analgesia observed at the initiation of opioid administration. Although development of tolerance begins with the first dose of an opioid, tolerance may not become clinically manifest until after 2–3 weeks of frequent exposure to ordinary therapeutic doses. Nevertheless, perioperative and critical care use of ultrapotent opioid analgesics such as remifentanil have been shown to induce opioid tolerance within hours. Tolerance develops most readily when potent opioids are given at short intervals and is minimized by giving small amounts of drug with longer intervals between doses. Although a high degree of tolerance may develop to the analgesic, sedating, and respiratory depressant effects of opioid agonists (see Table 31–3), it is still possible to produce respiratory arrest in a tolerant (or nontolerant) person with clinically used doses of opioid analgesics—especially if concurrently administered with sedating drugs such as benzodiazepines. Tolerance also develops to the antidiuretic, emetic, and hypotensive effects but not to the miotic, convulsant, and constipating actions. Following discontinuation of opioids, loss of tolerance to the sedating and respiratory effects of opioids is variable and difficult to predict. However, tolerance to the emetic effects may persist for several months after withdrawal of the drug. Therefore, opioid tolerance differs by effect, drug, time, and the individual (genetic-epigenetic factors). Tolerance also develops to analgesics with mixed receptor effects but to a lesser extent than to the agonists. Adverse effects such as hallucinations, sedation, hypothermia, and respiratory depression are reduced after repeated administration of the mixed receptor drugs. However, tolerance to the latter agents does not generally include cross-tolerance to the agonist opioids. It is also important to note that tolerance does not develop to the antagonist actions of the mixed agents or to those of the pure antagonists. Cross-tolerance is an extremely important characteristic of the opioids, ie, patients tolerant to morphine often show a reduction in analgesic response to other agonist opioids. This is particularly true of those agents with primarily μ-receptor agonist activity. Morphine and its congeners exhibit cross-tolerance not only with respect to their analgesic actions but also to their euphoriant, sedative, and respiratory effects. However, the cross-tolerance existing among the μ-receptor agonists can often be partial or incomplete. This clinical observation has led to the concept of “opioid rotation,” which has been used for many years in the treatment of cancer pain. A patient who is experiencing decreasing effectiveness

of one opioid analgesic regimen is “rotated” to a different opioid analgesic (eg, morphine to hydromorphone; hydromorphone to methadone) and typically experiences significantly improved analgesia at a reduced overall equivalent dosage. Another approach is to recouple opioid receptor function as described previously through the use of adjunctive nonopioid agents. NMDA-receptor antagonists (eg, ketamine) have shown promise in preventing or reversing opioid-induced hyperalgesia and tolerance in animals and humans. Use of ketamine is increasing because well-controlled studies have shown clinical efficacy in reducing postoperative pain and opioid requirements in opioid-tolerant patients. Agents that independently enhance μ-receptor recycling may also hold promise for improving analgesia in the opioid-tolerant patient. 2. Dependence—The development of physical dependence is an invariable accompaniment of tolerance to repeated administration of an opioid of the μ type. Failure to continue administering the drug results in a characteristic withdrawal or abstinence syndrome that reflects an exaggerated rebound from the acute pharmacologic effects of the opioid. The signs and symptoms of withdrawal include rhinorrhea, lacrimation, yawning, chills, gooseflesh (piloerection), hyperventilation, hyperthermia, mydriasis, muscular aches, vomiting, diarrhea, anxiety, and hostility. The number and intensity of the signs and symptoms are largely dependent on the degree of physical dependence that has developed. Administration of an opioid at this time suppresses abstinence signs and symptoms almost immediately. The time of onset, intensity, and duration of abstinence syndrome depend on the drug previously used and may be related to its biologic half-life. With fentanyl, heroin, or morphine withdrawal signs may start within 6–10 hours after the last dose. Peak effects are seen at 36–48 hours, after which most of the signs and symptoms gradually subside. By 5 days, most of the effects have disappeared, but some may persist for months. In the case of meperidine, the withdrawal syndrome largely subsides within 24 hours, whereas with methadone several days are required to reach the peak of the abstinence syndrome, and it may last as long as 2 weeks. The slower subsidence of methadone effects is associated with a less intense immediate syndrome, and this is the basis for its use in the detoxification of heroin addicts. However, despite the loss of physical dependence on the opioid, craving for it may persist. In addition to methadone, buprenorphine and the α2 agonist clonidine are FDA-approved treatments for opioid analgesic detoxification (see Chapter 32). A transient, explosive abstinence syndrome—antagonistprecipitated withdrawal—can be induced in a subject physically dependent on opioids by administering naloxone, another antagonist, or even a partial μ agonist such as buprenorphine. Within seconds to minutes after injection of the antagonist naloxone, signs and symptoms similar to those seen after abrupt discontinuance appear, peaking in 10–20 minutes and largely subsiding after 1 hour. Even in the case of methadone, the antagonist-precipitated abstinence syndrome may be very severe. In the case of agents with mixed effects, withdrawal signs and symptoms can be induced after repeated administration followed by abrupt discontinuance of pentazocine, cyclazocine, or nalorphine, but the syndrome appears to be somewhat different from

596    SECTION V  Drugs That Act in the Central Nervous System

that produced by morphine and other agonists. Anxiety, loss of appetite and body weight, tachycardia, chills, increase in body temperature, and abdominal cramps have been noted. 3. Addiction—As defined by the American Society of Addiction Medicine, addiction is a primary, chronic disease of brain reward, motivation, memory, and related circuitry. Dysfunction in these circuits leads to characteristic biologic, psychological, and social manifestations. This is reflected in an individual’s pathologic pursuit of reward and relief through substance use and other behaviors. Addiction is characterized by inability to abstain, impairment in behavioral control exhibited by a compulsion to use, craving, diminished recognition of significant problems with one’s behaviors and interpersonal relationships, use despite consequences, and a dysfunctional emotional response (see Chapter 32). The risk of inducing dependence and, potentially, addiction is clearly an important consideration in the therapeutic use of opioid drugs. Although opioids administered to treat acute painful conditions such as trauma or surgical intervention are widely accepted as effective, recent reports suggest that even brief periprocedural exposures can increase the risk of long-term use. Therefore, certain principles should be observed by the clinician to minimize the potential harm presented by opioid-induced respiratory depression, dependence, misuse, or abuse: •  Consider using nonopioid analgesics whenever possible. Especially in chronic management, consider using other types of analgesics or compounds exhibiting less pronounced withdrawal symptoms on discontinuance. •  Frequently evaluate continuing analgesic therapy and the patient’s need for opioids. •  Establish therapeutic goals before starting opioid therapy. This tends to limit the potential for physical dependence. The patient and his or her family should be included in this process. •  Once an effective dose is established, attempt to limit dosage to this level. This goal is facilitated by use of a written treatment contract that specifically prohibits early refills and having multiple prescribing physicians. •  Discuss the rights, responsibilities, and roles of patients and providers regarding controlled substances. Educate about safe opioid storage and disposal. Difficult decisions may need to be made about availability and use of opioid reversal medication (naloxone) for overdose, the proposed duration of opioid therapy, and the need for tapering or discontinuing opioid therapy. B. Diagnosis and Treatment of Opioid Overdosage Intravenous injection of naloxone dramatically reverses coma due to opioid overdose but not that due to other CNS depressants. Use of the antagonist should not, of course, delay the institution of other therapeutic measures, especially respiratory support. (See also The Opioid Antagonists, below, and Chapter 58.) The initial epidemic of prescription opioid overuse has been accompanied by an increase in heroin-related deaths and now an even greater wave of overdose deaths in the United States driven by synthetics such as fentanyl. For this reason, attention is being directed to make naloxone via

intranasal and intramuscular routes widely available, including as over-the-counter formulations. With ever-increasing rates of ultrapotent synthetic opioids such as fentanyl-laced products illicitly being distributed in the USA, repeated doses of naloxone may be needed, with 10-fold higher doses, to reverse respiratory depression. C. Contraindications and Cautions in Therapy 1. Use of pure agonists with weak partial agonists—When a weak partial agonist such as pentazocine is given to a patient also receiving a full agonist (eg, morphine), there is a risk of diminishing analgesia or even inducing a state of withdrawal; thus combining a full agonist with partial agonist opioids should be avoided. 2. Use in patients with head injuries—Carbon dioxide retention caused by respiratory depression results in cerebral vasodilation. In patients with elevated intracranial pressure, this may lead to lethal alterations in brain function. 3. Use during pregnancy—In pregnant women who are chronically using opioids, the fetus may become physically dependent in utero and manifest withdrawal symptoms in the early postpartum period. Daily doses of heroin, fentanyl, and/or polysubstance exposure taken by the mother can result in a withdrawal syndrome in the infant, including irritability, shrill crying, diarrhea, or even seizures. As a result of the opioid epidemic in the USA and other countries, the incidence of these events has dramatically increased. Recognition of the condition known as neonatal abstinence syndrome (NAS) is aided by a careful history, physical examination, and use of validated tools and severity scales. Treatment protocols have evolved and include symptom-based treatment guidelines ranging from increased nonpharmacologic approaches to opioid replacement therapy with morphine or possibly methadone or buprenorphine. Nonopioid adjuncts such as clonidine also have been utilized with positive effect. NAS care plans may also need modification given the possibility of neonatal exposure to multiple nonopioid drugs from the mother. 4. Use in patients with impaired pulmonary function— In patients with borderline respiratory reserve, the depressant properties of the opioid analgesics may lead to acute respiratory failure. 5. Use in patients with impaired hepatic or renal function—Because morphine and its congeners are metabolized primarily in the liver, their use in patients in prehepatic coma may be questioned. Half-life is prolonged in patients with impaired renal function, and morphine and its active glucuronide metabolite may accumulate; dosage can often be reduced in such patients. 6. Use in patients with endocrine disease—Patients with adrenal insufficiency (Addison disease) and those with hypothyroidism (myxedema) may have prolonged and exaggerated responses to opioids.

Drug Interactions Because seriously ill or hospitalized patients may require a large number of drugs, there is always a possibility of drug interactions

CHAPTER 31  Opioid Agonists & Antagonists    597

TABLE 31–5  Opioid drug interactions. Drug Group

Interaction with Opioids

Sedative-hypnotics

Increased central nervous system depression, particularly respiratory depression.

Antipsychotic agents

Increased sedation. Variable effects on respiratory depression. Accentuation of cardiovascular effects (antimuscarinic and a-blocking actions).

Monoamine oxidase inhibitors

Relative contraindication to all opioid analgesics and antitussives because of the high incidence of hyperpyrexic coma; hypertension also has been reported.

when the opioid analgesics are administered. Table 31–5 lists some of these drug interactions and the reasons for not combining the named drugs with opioids.

■■ SPECIFIC AGENTS The following section describes the most important and widely used opioid analgesics, along with features peculiar to specific agents. Data about doses approximately equivalent to 10 mg of intramuscular morphine, oral versus parenteral efficacy, duration of analgesia, and intrinsic activity (maximum efficacy) are presented in Table 31–2.

STRONG AGONISTS Phenanthrenes Morphine, hydromorphone, and oxymorphone are strong agonists useful in treating severe pain. These prototypic agents have been described in detail above. 10 17

CH3

N CH2

1

CH2 7 HO

3

O

6

OH

Morphine

Heroin (diamorphine, diacetylmorphine) is potent and fastacting, but its use is prohibited in the USA and Canada. Doubleblind studies have not supported the claim that heroin is more effective than morphine in relieving severe pain, at least when given by the intramuscular route.

Phenylheptylamines Methadone has undergone a dramatic revival as a potent and clinically useful analgesic. It can be administered by the oral, intravenous, subcutaneous and rectal routes. It is well absorbed from the

gastrointestinal tract, and its bioavailability, although variable, far exceeds that of oral morphine.

N

O

Methadone

Methadone is not only a potent μ-receptor agonist but its racemic mixture of d- and l-methadone isomers can also block both NMDA receptors and monoaminergic reuptake transporters. These nonopioid receptor properties may help explain its ability to relieve difficult-to-treat pain (neuropathic, cancer pain), especially when a previous trial of morphine has failed. In this regard, when analgesic tolerance or intolerable side effects have developed with the use of increasing doses of morphine or hydromorphone in progressive cancer pain, “opioid rotation” to methadone has provided superior analgesia at 10–20% of the morphine-equivalent daily dose. In contrast to its use in suppressing symptoms of opioid withdrawal, use of methadone as an analgesic typically requires administration at more frequent intervals (eg, 8 hours). However, given methadone’s highly variable pharmacokinetics and long halflife (∼25–52 hours), the initial administration period (loading phase) should be closely monitored to avoid potentially harmful adverse effects, especially respiratory depression. Because methadone is metabolized by CYP2B6 and CYP3A4 isoforms in the liver, inhibition of its metabolic pathway or hepatic dysfunction has also been associated with overdose effects, including respiratory depression or prolonged QT-based cardiac arrhythmias. Methadone has been widely used in the treatment of opioid use disorders. Tolerance and physical dependence develop more slowly with methadone than with morphine. The withdrawal signs and symptoms occurring after abrupt discontinuance of methadone are often milder, although more prolonged, than those of morphine. In many cases, these properties make methadone a useful drug for detoxification and for maintenance of chronic relapsing opioid use disorder. For detoxification of a heroin-dependent person, low doses of methadone (5–10 mg orally) have been given two or three times daily for 2 or 3 days to lessen the subsequent withdrawal syndrome. For maintenance therapy of the opioid recidivist, tolerance to 50–100 mg/d of oral methadone may be deliberately produced; in this state, opioid craving is diminished and there is a crosstolerance to heroin to limit the addiction-reinforcing effects of heroin. One rationale of maintenance programs is that blocking the reinforcement obtained from illicit opioids removes the drive to obtain them, thereby reducing criminal activity and making the user more amenable to psychiatric and rehabilitative therapy. The pharmacologic basis for the use of methadone in maintenance programs is sound, and the sociologic basis is rational.

598    SECTION V  Drugs That Act in the Central Nervous System

The concurrent administration of methadone to heroin addicts known to be recidivists has been questioned because of the increased risk of overdose death secondary to respiratory arrest. As the number of patients prescribed methadone for persistent pain has increased, so, too, has the incidence of accidental overdose and complications related to respiratory depression. Variability in methadone metabolism, protein binding, distribution, and nonlinear opioid dose conversion all play a role in adverse events. Buprenorphine, a partial μ-receptor agonist with long-acting properties, has been found to be effective in opioid detoxification and maintenance programs and is associated with a lower risk of such overdose fatalities. To increase the access of persons with OUD, in the USA, a provider with a controlled substance DEA license may prescribe buprenorphine for OUD. With the increase in access and legalization of cannabis products in many states in the USA, some authorities have suggested the use of cannabis as a treatment for OUD or to facilitate tapering of opioids. However, there is no strong evidence to support these proposals.

Phenylpiperidines Fentanyl is one of the most widely used agents in the family of synthetic opioids. The fentanyl subgroup now includes sufentanil, alfentanil, and remifentanil in addition to the parent compound, fentanyl. An extremely potent analog, carfentanil, is used in veterinary medicine for sedating large mammals, eg, elephants. Adulteration of street heroin and counterfeit prescription analgesic pills with fentanyl, carfentanil, or related synthetics has been responsible for a dramatic increase of unintended overdoses and deaths. O N

C

CH2

CH3

N CH2

CH2

C6H5

Fentanyl

Among the phenylpiperidines, these opioids differ mainly in their potency and biodisposition. Sufentanil is five to seven times more potent than fentanyl. Carfentanil is approximately 100 times more potent than fentanyl. Alfentanil is considerably less potent than fentanyl but acts more rapidly and has a markedly shorter duration of action. Remifentanil is metabolized very rapidly by blood and nonspecific tissue esterases, making its pharmacokinetic and pharmacodynamic half-lives extremely short. Such properties are useful when these compounds are used in anesthesia practice. Although fentanyl is now the predominant analgesic in the phenylpiperidine class, meperidine continues to be used. This older opioid has significant antimuscarinic effects, which may be a contraindication if tachycardia would be a problem. Meperidine

is also reported to have a negative inotropic action on the heart. In addition, it has the potential for producing seizures secondary to accumulation of its metabolite, normeperidine, in patients receiving high doses or with concurrent renal failure. Given this undesirable profile, use of meperidine as a first-line analgesic is becoming increasingly rare.

Morphinans Levorphanol is a synthetic opioid analgesic closely resembling morphine and has μ-, δ-, and κ-opioid agonist actions, serotoninnorepinephrine reuptake inhibition, and NMDA receptor antagonist properties.

MILD TO MODERATE AGONISTS Phenanthrenes Codeine, dihydrocodeine, and hydrocodone have lower binding affinity to μ-opioid receptors than morphine and often have adverse effects that limit the maximum tolerated dose when one attempts to achieve analgesia comparable to that of morphine. Oxycodone is more potent and is prescribed alone in higher doses as immediate-release or controlled-release forms for the treatment of moderate to severe pain. Combinations of hydrocodone or oxycodone with acetaminophen are the predominant formulations of orally administered analgesics in the United States for the treatment of mild to moderate pain. Since each controlledrelease tablet of oxycodone contains a large quantity of oxycodone to allow for prolonged action, those intent on abusing the old formulation have extracted crushed tablets and injected high doses, resulting in misuse and possible fatal overdose. In 2010, the FDA approved a new formulation of the controlled-release form of oxycodone that reportedly prevents the tablets from being cut, broken, chewed, crushed, or dissolved to release more oxycodone. It is hoped that this new formulation will lead to less misuse by snorting or injection. The FDA is now requiring a Risk Evaluation and Mitigation Strategy (REMS) that will include the issuance of a medication guide to patients and a requirement for prescriber education regarding the appropriate use of opioid analgesics in the treatment of pain. (See Box: Educating Opioid Prescribers.) CH3

N CH2 CH2 H3C

O

O

OH

Codeine

Phenylheptylamines Propoxyphene is chemically related to methadone but has extremely low analgesic activity. Its low efficacy makes it unsuitable, even in combination with aspirin, for severe pain.

CHAPTER 31  Opioid Agonists & Antagonists    599

The increasing incidence of deaths associated with its use and misuse caused it to be withdrawn in the United States.

Phenylpiperidines Diphenoxylate and its metabolite, difenoxin, are not used for analgesia but for the treatment of diarrhea. They are scheduled for minimal control (difenoxin is Schedule IV or V, depending on formulation; diphenoxylate Schedule V; see inside front cover) because the likelihood of their misuse is remote. The poor solubility of the compounds limits their use for parenteral injection. As antidiarrheal drugs, they are used in combination with atropine. The atropine is added in a concentration too low to have a significant antidiarrheal effect but is presumed to further reduce the likelihood of misuse. Loperamide is a phenylpiperidine derivative used to control diarrhea. Due to action on peripheral μ-opioid receptors and lack of effect on CNS receptors, investigations are ongoing as to whether it could be an effective analgesic. Its potential for misuse

is considered very low because of its limited access to the brain. It is therefore available without a prescription. The usual dose with all of these antidiarrheal agents is two tablets to start and then one tablet after each diarrheal stool.

OPIOIDS WITH MIXED RECEPTOR ACTIONS Partial agonists may be used in situations where patients may benefit from the profile of the drug compared with full agonists. An example would be for patients who find full μ agonists to be too “strong” and therefore prefer a partial agonist. Care should be taken to administer any partial agonist or drug with mixed opioid receptor actions to patients receiving pure opioid agonists because of the unpredictability of both drugs’ effects; reduction of analgesia or precipitation of an explosive abstinence syndrome may result.

Educating Opioid Prescribers—The Opioid Epidemic The treatment of chronic pain is a difficult biopsychosocial problem, and prescribers of opioids have been caught between a number of competing forces in their attempts to relieve pain and suffering. The USA is the largest user of prescription opioids of any country and continues to experience an epidemic of opioid-related harm and death that has worsened under the SARS- COVID pandemic. Drug overdose is now the leading cause of injury-related deaths in the USA. Following a tidal wave of opioid prescriptions driven by subsequent opioid use disorder (OUD), more than 68,000 died from an opioid overdose in 2020, a leap from nearly 50,000 opioid-related deaths in 2019 and more than 16,000 deaths related to prescription opioids (wonder.cdc. gov). Overall, more than 100,000 deaths from 2020–2021 are attributed to drug overdose with opioids as the primary cause. The line between deaths from illicit versus prescription opioids is blurred since some patients may choose to cross from one opioid to another. In contrast, in several countries the medical use of opioids is prohibited or severely limited, resulting in unmanaged pain after surgery or trauma and near the end of life. Forces that have influenced excessive prescribing of opioids for chronic noncancer pain in the USA include aggressive marketing of opioids, misleading industry-led education on the abuse and addiction potential of opioids, an unjustified assumption of the superiority of opioids over nonopioid therapies for the treatment of chronic noncancer pain, and a paucity of safe, effective, and affordable (covered or reimbursed by insurance) analgesic strategies that have low abuse potential. These findings prompted the Centers for Disease Control (CDC) to create the first Opioid Prescribing Guidelines for Primary Care Prescribers caring for patients with chronic noncancer pain in 2016 that was revised in 2022 (https://www.cdc.gov/mmwr/volumes/71/rr/rr7103a1 .htm?s_cid=rr7103a1.htm_w. The US Health and Human Services

Interagency Task Force also completed a “Pain Management Best Practices” guide (https://www.hhs.gov/sites/default/files/overview-pmtf-final-report-fact-sheet_508.pdf that integrates input from a comprehensive consortium of governmental and nongovernmental health professional societies. The FDA has also instituted training programs such as a risk evaluation and mitigation strategy (REMS) program for all potent opioid prescribing to help providers better understand potential benefits versus risks of prescription opioids. State medical boards in the USA are establishing their own regulations in addition to creating prescription drug monitoring programs (PDMPs). The US Drug Enforcement Agency has focused efforts on illicit practices and distribution patterns with concerns about diversion. Major efforts to expand research in this domain are now supported through the National Institutes of Health program Helping End Addiction Long Term (HEAL). Litigation of the opioid and drug distribution industry is underway to obtain resources to support prevention and treatment and of OUD in the USA. Prescribers are advised to learn about the local, state, and national guidelines and laws for the prescribing and monitoring of patients on opioids. A major concern from 2015 to 2019 data has been the number of fentanyl- and heroin-related deaths in persons suffering from OUD. This has resulted from opioids (counterfeit prescription pills, heroin) dealt “on the street” that have been adulterated with the much more potent fentanyl to increase effect. While law-enforcement efforts have been made to reduce supply, it may be more effective to reduce demand. Paramount in such reduction will be the use of multimodal nonopioid strategies in the management of chronic noncancer pain, appropriate opioid tapering, access to opioid maintenance programs, investment in addiction medicine, and development of analgesics without abuse liability.

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Phenanthrenes As noted above, buprenorphine is a potent and long-acting phenanthrene derivative that is a partial μ-receptor agonist (low intrinsic activity) and an antagonist at the δ and κ receptors and is therefore referred to as a mixed agonist-antagonist. Although buprenorphine is used as an analgesic, it can antagonize the action of more potent μ agonists such as morphine. Buprenorphine also binds to ORL1, the orphanin receptor. Whether this property also participates in opposing μ receptor function is under study. Administration by the sublingual route is preferred to avoid significant first-pass effect. Buprenorphine’s long duration of action is due to its slow dissociation from μ receptors. This property renders its effects resistant to naloxone reversal. Buprenorphine was approved by the FDA in 2002 for the management of opioid dependence, and studies suggest it is as effective as methadone for the management of opioid withdrawal and detoxification in programs that include counseling, psychosocial support, and direction by physicians qualified under the Drug Addiction Treatment Act. In the USA, a special Drug Enforcement Administration (DEA) waiver and training were needed to legally prescribe buprenorphine for addiction. In contrast to methadone, high-dose administration of buprenorphine results in a μ-opioid antagonist action, limiting its properties of analgesia and respiratory depression. However, buprenorphine formulations can still cause serious respiratory depression and death, particularly when extracted and injected intravenously in combination with benzodiazepines or used with other CNS depressants (ie, sedatives, antipsychotics, or alcohol). Buprenorphine is also available combined with naloxone, a pure μ-opioid antagonist (as Suboxone), to help prevent its diversion for illicit intravenous misuse. A slow-release transdermal patch preparation that releases drug over a 1-week period also is available (Butrans). The FDA has also approved an implanted buprenorphine rod (Probuphine) that lasts for 6 months and is meant to deter misuse. Psychotomimetic effects, with hallucinations, nightmares, and anxiety, have been reported after use of drugs with mixed agonist-antagonist actions. The management of acute postsurgical pain may be challenging in the patient who is on chronic buprenorphine, as its high affinity for the μ-opioid receptor may render commonly used opioid agonists ineffective for pain management. The current recommendation is for these patients to continue their buprenorphine and employ nonopioid modalities to the greatest degree while educating patients on expectations. In certain cases where the surgical intervention is expected to result in severe postoperative pain not manageable with ongoing buprenorphine, a supervised reduction by tapering the dose may be indicated prior to surgery but rarely if ever should be stopped. Taken together, higher doses of opioids may be needed in situations where pain is severe and concurrent regional anesthetic techniques (nerve blocks) are not available. Patients need to be monitored for risk of relapse and ideally be followed closely by an addiction medicine specialist or counselor. Kratom, an extract from the leaves of Mitragyna speciosa, has come into public view with various claims of its efficacy in opioid tapering or opioid replacement therapy. Although very limited preclinical research on its component alkaloids, mitragynine and 7-hydroxymitragynine, suggests that they can act as partial

μ-receptor agonists, a multitude of other effects and harms have been associated with kratom (Salmonella bacterial poisoning, hallucinations, seizures, coma, and death). Given the lack of proven benefit and increasing reports of harm, kratom is not considered either safe or effective. Nevertheless, additional studies on kratom may reveal important mechanistic insights useful for future therapeutic development. Pentazocine (a benzomorphan) and nalbuphine are other examples of opioid analgesics with mixed agonist-antagonist properties. Nalbuphine is a strong κ-receptor agonist and a partial μ-receptor antagonist; it is given parenterally. At higher doses there seems to be a definite ceiling—not noted with morphine—to the respiratory depressant effect. Unfortunately, when respiratory depression does occur, it may be relatively resistant to naloxone reversal due to its greater affinity for the receptor than naloxone. Nalbuphine is equipotent to morphine for analgesia and, at lower doses, can sometimes be effective for pruritus caused by opioids and nonopioids.

Morphinans Butorphanol produces analgesia equivalent to nalbuphine but appears to produce more sedation at equianalgesic doses. Butorphanol is considered to be predominantly a κ agonist. However, it may also act as a partial agonist or antagonist at the μ receptor.

Benzomorphans Pentazocine is a κ agonist with weak μ-antagonist or partial agonist properties. It is the oldest mixed agent available. It may be used orally or parenterally. However, because of its irritant properties, the injection of pentazocine subcutaneously is not recommended.

MISCELLANEOUS Tramadol is a centrally acting analgesic whose mechanism of action is also dependent on the ability of the parent drug and its metabolites to block serotonin and norepinephrine reuptake. Because its analgesic effect is only weakly antagonized by naloxone, it is thought to depend less on its low-affinity binding to the μ receptor for therapeutic activity. The recommended dosage is 50–100 mg orally four times daily; however, its systemic concentration and analgesic effect are dependent on its variable metabolism by CYP2D6 polymorphisms. Toxicity includes association with seizures; the drug is relatively contraindicated in patients with a history of epilepsy and for use with other drugs that lower the seizure threshold. Another serious risk is the development of serotonin syndrome, especially if selective serotonin reuptake inhibitor antidepressants are being administered (see Chapter  16). Other adverse effects include nausea and dizziness, but these symptoms typically abate after several days of therapy. No clinically significant effects on respiration or the cardiovascular system have thus far been reported when used as monotherapy. Given the fact that the analgesic action of tramadol is largely independent of μ-receptor action, tramadol has been considered as an adjunct in the treatment of neuropathic pain; however, this is based on low-quality studies of short duration.

CHAPTER 31  Opioid Agonists & Antagonists    601

Tapentadol is an analgesic with modest μ-opioid receptor affinity and significant norepinephrine reuptake-inhibiting action. In animal models, its analgesic effects were only moderately reduced by naloxone but strongly reduced by an α2-adrenoceptor antagonist. Furthermore, its binding to the norepinephrine transporter (NET, see Chapter 6) was stronger than that of tramadol, whereas its binding to the serotonin transporter (SERT) was less than that of tramadol. Tapentadol was approved in 2008 and has been shown to be as effective as oxycodone in the treatment of moderate to severe pain but with a reduced profile of gastrointestinal complaints such as nausea. Clinical studies are ongoing to determine if the lack of active metabolites and lower risk of serotonin syndrome with tapentadol will translate to an improvement in analgesia with reduced adverse effects.

THE OPIOID ANTAGONISTS The pure opioid antagonist drugs naloxone, naltrexone, and nalmefene are morphine derivatives with bulkier substituents at the N17 position. These agents have a relatively high affinity for μ-opioid binding sites. They have lower affinity for the other receptors but can also reverse agonists at δ and κ sites. CH

CH2

CH2

HO

CH2 HO

ANTITUSSIVES The opioid analgesics are among the most effective drugs available for the suppression of cough. This effect is often achieved at doses below those necessary to produce analgesia. The receptors involved in the antitussive effect appear to differ from those associated with the other actions of opioids. For example, the antitussive effect is also produced by stereoisomers of opioid molecules that are devoid of analgesic effects and addiction liability (see below). The physiologic mechanism of cough is complex, and little is known about the specific mechanism of action of the opioid antitussive drugs. It appears likely that both central and peripheral effects play a role. The opioid derivatives most commonly used as antitussives are dextromethorphan, codeine, levopropoxyphene, and noscapine (levopropoxyphene and noscapine are not available in the USA). They should be used with caution in patients taking monoamine oxidase inhibitors (see Table 31–5). Antitussive preparations usually also contain expectorants to thin and liquefy respiratory secretions. Importantly, due to increasing reports of death in young children taking dextromethorphan in formulations of over-the-counter “cold/cough” medications, its use in children younger than 6 years of age has been banned by the FDA. Moreover, because of variations in the metabolism of codeine, its use for any purpose in young children is being reconsidered. Dextromethorphan is the dextrorotatory stereoisomer of a methylated derivative of levorphanol. It is purported to be free of addictive properties and produces less constipation than codeine. The usual antitussive dose is 15–30 mg three or four times daily. It is available in many over-the-counter products. Dextromethorphan has also been found to enhance the analgesic action of morphine and presumably other μ-receptor agonists. However, misuse of its purified (powdered) form has been reported to lead to serious adverse events including death. Codeine, as noted, has a useful antitussive action at doses lower than those required for analgesia. Thus, 15 mg is usually sufficient to relieve cough. Levopropoxyphene is the stereoisomer of the weak opioid agonist dextropropoxyphene. It is devoid of opioid effects, although sedation has been described as a side effect. The usual antitussive dose is 50–100 mg every 4 hours.

CH2

N

O

O Naloxone

Pharmacokinetics Naloxone is usually given by injection and has a short duration of action (1–2 hours) when given by this route. Metabolic disposition is chiefly by glucuronide conjugation like that of the agonist opioids with free hydroxyl groups. Naltrexone is well absorbed after oral administration but may undergo rapid firstpass metabolism. It has a half-life of 10 hours, and a single oral dose of 100 mg blocks the effects of injected heroin for up to 48 hours. Nalmefene, the newest of these agents, is a derivative of naltrexone but is available only for intravenous administration. Like naloxone, nalmefene is used for opioid overdose but has a longer half-life (8–10 hours).

Pharmacodynamics When given in the absence of an agonist drug, these antagonists are almost inert at doses that produce marked antagonism of agonist opioid effects. When given intravenously to a morphine-treated subject, the antagonist completely and dramatically reverses the opioid effects within 1–3 minutes. In individuals who are acutely depressed by an overdose of an opioid, the antagonist effectively normalizes respiration, level of consciousness, pupil size, bowel activity, and awareness of pain. In dependent subjects who appear normal while taking opioids, naloxone or naltrexone almost instantaneously precipitates an abstinence syndrome. There is no tolerance to the antagonistic action of these agents, nor does withdrawal after chronic administration precipitate an abstinence syndrome.

Clinical Use Naloxone is a pure antagonist and is preferred over older weak agonist-antagonist agents that had been used primarily as antagonists, eg, nalorphine and levallorphan. The major application of naloxone is in the treatment of acute opioid overdose (see also Chapter 58). It is very important that the relatively short duration of action of naloxone be borne in mind,

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because a severely depressed patient may recover after a single dose of naloxone and appear normal, only to relapse into coma after 1–2 hours. The usual initial dose of naloxone is 0.1–0.4 mg intravenously for life-threatening respiratory and CNS depression. Maintenance is with the same drug, 0.4–0.8 mg given intravenously, and repeated as needed—or provided as a continuous infusion under monitored conditions. Multiple doses of naloxone in excess of 0.8 mg per dose have been required to reverse respiratory depression induced by overdose of illicit fentanyl and its analogs. In using naloxone in the severely opioid-depressed newborn, it is important to start with doses of 5–10 mcg/kg and to consider a second dose of up to a total of 25 mcg/kg if no response is noted. Low-dose naloxone (0.04 mg) has an increasing role in the treatment of adverse effects that are commonly associated with intravenous or epidural opioids. Careful titration of the naloxone dosage can often eliminate the itching, nausea, and vomiting while sparing the analgesia. For this purpose, oral naloxone, and modified analogs of naloxone and naltrexone, have been approved by the FDA. Analogs include methylnaltrexone bromide and naldemedine for the treatment of constipation in patients with opioid-induced constipation (OIC) with chronic noncancer pain and late-stage advanced illness—and naloxegol, naldemedine,

and alvimopan for the treatment of postoperative ileus following bowel resection surgery. Methylnaltrexone has a quaternary amine preventing it from crossing the blood-brain barrier. Naloxegol is pegylated naloxone, which limits penetration into the CNS and through peripheral μ-antagonism mitigates constipation. Naldemedine and alvimopan are considered peripheral μ-receptor antagonists. The principal mechanism for the selective therapeutic effect of these agents is peripheral enteric μ-receptor antagonism with minimal CNS penetration. Because of its long duration of action, naltrexone has been proposed as a maintenance drug for addicts in treatment programs. A single dose given on alternate days blocks virtually all of the effects of a dose of heroin. More recently, a depot formulation of naltrexone has been developed offering extended release over weeks to months. There is evidence that naltrexone decreases the craving for alcohol in chronic alcoholics by increasing baseline β-endorphin release, and it has been approved by the FDA for this purpose (see Chapter 23). Naltrexone also facilitates abstinence from nicotine (cigarette smoking) with reduced weight gain. In fact, a combination of naltrexone plus bupropion (Chapter 16) may also offer an effective and synergistic strategy for weight loss.

SUMMARY  Opioids, Opioid Substitutes, and Opioid Antagonists Subclass, Drug

Mechanism of Action

Effects

Clinical Applications

Pharmacokinetics, Toxicities

Strong μ-receptor agonists • variable affinity for δ and κ receptors

Analgesia • relief of anxiety • sedation • slowed gastrointestinal transit

Severe pain • adjunct in anesthesia (fentanyl, morphine) • pulmonary edema (morphine only) • maintenance in rehabilitation programs (methadone only)

First-pass effect • duration 1–4 h except methadone, 4–6 h • Toxicity: Respiratory depression • severe constipation • addiction liability • convulsions

Like strong agonists • weaker effects

Mild-moderate pain • cough (codeine)

Like strong agonists, toxicity dependent on genetic variation of metabolism

Like strong agonists but can antagonize their effects • also reduces craving for alcohol Similar to buprenorphine

Moderate pain • some maintenance rehabilitation programs Moderate pain

Long duration of action 4–8 h • may precipitate abstinence syndrome Like buprenorphine

Reduces cough reflex • dextromethorphan, levopropoxyphene not analgesic

Acute debilitating cough

Duration 30–60 min • Toxicity: Minimal when taken as directed

OPIOID AGONISTS   •  Morphine   •  Methadone   •  Fentanyl

         

•  Hydromorphone, oxymorphone: Like morphine in efficacy, but higher potency •  Meperidine: Strong agonist with anticholinergic effects •  Oxycodone: Dose-dependent analgesia •  Sufentanil, alfentanil, remifentanil: Like fentanyl but shorter durations of action •  Carfentanil: Like fentanyl but much more potent

  •  Codeine   •  Hydrocodone

Less efficacious than morphine • can antagonize strong agonists

MIXED OPIOID AGONIST-ANTAGONISTS   •  Buprenorphine Partial μ agonist • κ antagonist   •  Nalbuphine ANTITUSSIVES   •  Dextromethorphan

κ Agonist • μ antagonist

Poorly understood but strong and partial μ agonists are also effective antitussives

  •  Codeine, levopropoxyphene: Similar to dextromethorphan in antitussive effect (continued)

CHAPTER 31  Opioid Agonists & Antagonists    603

Subclass, Drug OPIOID ANTAGONISTS   •  Naloxone

Mechanism of Action

Effects

Clinical Applications

Antagonist at μ, δ, and κ receptors

Rapidly antagonizes all opioid effects

Opioid overdose

Pharmacokinetics, Toxicities Duration 1–2 h (may have to be repeated when treating overdose) • Toxicity: Precipitates abstinence syndrome in dependent users

  • Naltrexone, nalmefene: Like naloxone but longer durations of action (10 h); naltrexone is used in maintenance programs and can block heroin effects for up to 48 h; naltrexone is also used for alcohol and nicotine dependence; when combined with bupropion, may be effective in weight-loss programs   • Alvimopan, methylnaltrexone bromide, naldemedine: Potent µ antagonists with poor entry into the central nervous system; can be used to treat severe opioid-induced constipation without precipitating an abstinence syndrome OTHER ANALGESICS USED IN MODERATE PAIN   •  Tapentadol Moderate μ agonist, strong NET inhibitor

Analgesia

Moderate pain

Duration 4–6 h • Toxicity: Headache; nausea and vomiting; possible dependence

  •  Tramadol

Analgesia

Moderate pain • adjunct to opioids in chronic pain syndromes

Duration 4–6 h • Toxicity: Seizures • risk of serotonin syndrome

Mixed effects: weak μ agonist, moderate SERT inhibitor, weak NET inhibitor

NET, norepinephrine reuptake transporter; SERT, serotonin reuptake transporter.

P R E P A R A T I O N S

A V A I L A B L E*

GENERIC NAME AVAILABLE AS ANALGESIC OPIOIDS Alfentanil Generic, Alfenta Buprenorphine Buprenex, others, Butrans (transdermal) Butorphanol Generic, Stadol, Stadol NS (nasal) Codeine (sulfate or phosphate) Generic Fentanyl Generic, Duragesic (transdermal); Fentanyl Buccal, Fentanyl Actiq (lozenge) Hydromorphone Generic, Dilaudid, others Levomethadyl acetate† Orlaam Morphine sulfate   Oral, rectal, parenteral Generic  Oral sustained-release Avinza, Kadian capsules  Oral extended-release Embeda capsules (morphine sulfate/ naltrexone HCl) Nalbuphine Generic, Nubain Oxycodone Generic, OxyContin (sustained release) Oxymorphone Generic, Numorphan, others Pentazocine Talwin Remifentanil Generic, Ultiva Sufentanil Generic, Sufenta *

Antidiarrheal opioid preparations are listed in Chapter 62.

†

Orphan drug approved only for the treatment of narcotic addiction.

‡

GENERIC NAME

AVAILABLE AS

OTHER ANALGESICS Tapentadol Nucynta Tramadol Generic, Ultram, others Ziconotide Prialt ANALGESIC COMBINATIONS ‡ Codeine/acetaminophen Generic, Tylenol with Codeine, others Codeine/aspirin Generic, Empirin Compound, others Hydrocodone/acetaminophen Generic, Norco, Vicodin, Lortab, others Hydrocodone/ibuprofen Vicoprofen Oxycodone/acetaminophen Generic, Percocet, Tylox, others Oxycodone/aspirin Generic, Percodan OPIOID ANTAGONISTS Alvimopan Entereg Methylnaltrexone Relistor Naldemedine Symproic Nalmefene Revex Naloxone Generic, Narcan Naltrexone Generic, ReVia, Depade, Vivitrol ANTITUSSIVES Codeine Generic Dextromethorphan Generic, Benylin DM, Delsym, others

Dozens of combination products are available; only a few of the most commonly prescribed are listed here. Codeine combination products available in several strengths are usually denoted No. 2 (15 mg codeine), No. 3 (30 mg codeine), and No. 4 (60 mg codeine). Prescribers should be aware of the possible danger of renal and hepatic injury with acetaminophen, aspirin, and nonsteroidal anti-inflammatory drugs contained in these analgesic combinations.

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C ASE STUDY ANSWER In this case of severe pain following a traumatic fall, treatment may require the administration of a potent intravenous opioid analgesic such as morphine, hydromorphone, or fentanyl; however, concurrent use of nonopioid analgesics (such as ketamine) and other nonopioid multimodal analgesic strategies (NSAIDs) often reduce or eliminate opioid requirements and risk of respiratory failure. Given the history of obstructive sleep apnea, before an additional dose of an opioid analgesic is administered, it is expected that the

patient will require frequent reevaluation of both the severity of his pain and the presence of potential adverse effects. Reevaluation of his level of consciousness, respiratory rate, fractional oxygen saturation, and other vital parameters can help achieve the goal of pain relief and minimize respiratory depression. Concurrent use of sedative agents such as benzodiazepines should be avoided if possible as they greatly increase the risk of respiratory depression, obstruction, and failure.

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Drugs of Abuse Christian Lüscher, MD

C ASE STUDY A 15-year-old high school student was brought to the emergency department after his parents found him in his room staring at the ceiling and visibly frightened. Earlier that evening, he attended a party but was depressed because his girlfriend just broke up with him. His parents are also worried about a change in his behavior over the last few months. He is failing this year at school and has stopped playing soccer. He has lost interest in school, at times seems depressed, and tells his parents that his pocket money is not sufficient.

Drugs are abused (used in ways that are not medically approved) because they cause strong feelings of euphoria. However, repetitive exposure induces widespread adaptive changes in the brain. As a consequence, drug use may become compulsive—the hallmark of addiction.

■■ BASIC NEUROBIOLOGY OF DRUG ABUSE DEPENDENCE VERSUS ADDICTION There is a conceptual and mechanistic separation of “dependence” and “addiction.” The older term “physical dependence” is now denoted as dependence, whereas “psychological dependence” is more simply called addiction. Every addictive drug causes its own characteristic spectrum of acute effects, but they all induce strong feelings of euphoria

606

When questioned by the intern, he reports that space-cookies were served at the party. He also says that smoking marijuana has become a habit (three to four joints a week) but denies consumption of alcohol and other drugs. How do you explain the state he was found in? What is the difference between hashish and marijuana? What may be the link to his poor performance at school? Do all drug users necessarily use several drugs?

and reward. With repetitive exposure, addictive drugs induce adaptive changes such as tolerance (ie, escalation of dose to maintain effect). Once the abused drug is no longer available, signs of withdrawal become apparent. A combination of such signs, referred to as the withdrawal syndrome, defines dependence. Dependence is not always a correlate of drug abuse—it can also occur with many classes of nonpsychoactive drugs, eg, sympathomimetic vasoconstrictors and bronchodilators, and organic nitrate vasodilators. Addiction, on the other hand, consists of compulsive, relapsing drug use despite negative consequences, at times triggered by cravings that occur in response to contextual cues (see Box: Animal Models in Addiction Research). Although dependence invariably occurs with chronic exposure, only a small percentage of subjects develop a compulsion, lose control, and become addicted. For example, very few patients who receive opioids as analgesics desire the drug after withdrawal. And only one person out of six becomes addicted within 10 years of first use of cocaine. Conversely, relapse is very common in addicts after a successful withdrawal when, by definition, they are no longer dependent.

CHAPTER 32  Drugs of Abuse    607

ADDICTIVE DRUGS INCREASE THE LEVEL OF DOPAMINE (DA): REINFORCEMENT To understand the long-term changes induced by drugs of abuse, their initial molecular and cellular targets must be identified. A combination of approaches in animals and humans, including functional imaging, has revealed the mesolimbic dopamine system as the prime target of addictive drugs. This system originates in the ventral tegmental area (VTA), a tiny structure at the tip of the brainstem, which projects to the nucleus accumbens (NAc), the amygdala, the hippocampus, and the prefrontal cortex (Figure 32–1). Most projection neurons of the VTA are dopamine-producing neurons. When the dopamine neurons of the VTA begin to fire in bursts, large quantities of dopamine are released in the nucleus accumbens and the prefrontal cortex. Early animal studies pairing electrical stimulation of the VTA with operant responses (eg, lever pressing) that result in strong reinforcement established the central role of the mesolimbic dopamine system in reward processing. Direct application of drugs into the VTA also acts as a strong reinforcer, and systemic

mPFC

vHippo LHb

D1 D2

VP RMTg

NAc

LDT BLA

VTA

FIGURE 32–1  Major connections of the mesolimbic dopamine system in the brain. Schematic diagram of the brain illustrating that the dopamine projections (red) originate in the ventral tegmental area (VTA) and target the nucleus accumbens (NAc), prefrontal cortex (mPFC), basolateral amygdala (BLA), and ventral pallidum (VP). Neurons in the NAc fall into two classes, one expressing type 1 dopamine receptors (D1s) and the other expressing type 2 receptors (D2s). Both classes contain GABAergic projection neurons (green); the D1R neurons send their axons to both the VP and the VTA (where they target primarily the GABA interneurons), whereas the D2R neurons send their axons selectively to the VP. The NAc is also a site of convergence of excitatory projections from the mPFC, the ventral hippocampus (vHippo), and the BLA. The midbrain dopamine neurons receive a direct excitatory input (blue) from the lateral dorsal tegmentum (LDT), while the GABA neurons of the rostromedial tegmentum (RMTg) at the tail of the VTA are excited by neurons from the lateral habenula (LHb), typically when an aversive stimulus occurs. The projection from the orbitofrontal cortex (OFC) to the dorsal striatum (DS) has been implicated in compulsive drug seeking and taking. The ventral and dorsal parts of the striatum are connected by reciprocal, spiraling connections.

administration of drugs of abuse causes the release of dopamine. Even direct activation of dopamine neurons is sufficient to drive reinforcement and elicit adaptive behavioral changes typically observed with addictive drugs. These very selective interventions use optogenetic methods. Blue light is delivered in a freely moving mouse through light guides to activate channelrhodopsin, a light-gated cation channel that is artificially expressed in dopamine neurons. As a result, mice will “self-administer” light to activate VTA dopamine neurons. After several pairings with a specific environment, a long-lasting place preference is established. Once the light is no longer available, a seeking behavior is observed (but no actual withdrawal syndrome). Finally, some mice will self-stimulate even if they have to endure a punishment (e.g. light electric shock). Conversely, inhibition of VTA dopamine neurons or activation of upstream inhibitory cells causes aversion. Classifying the VTA dopamine neurons based on their activity in response to a rewarding or aversive stimulus suggests distinct groups. The dopamine neurons located in the lateral part of the VTA projecting to the lateral shell of the NAc respond strongly to an unexpected reward and are the prime target of addictive drugs, which also target the medial VTA. As a general rule, all addictive drugs elicit dopamine transients in the mesolimbic system. Dopamine also peaks in response to unexpected natural rewards and may thus code for the difference between expected and actual rewards. A very appealing hypothesis posits that dopamine constitutes a learning signal and addictive drugs, by their sheer pharmacological power, an excessive learning signal (see Box: The Dopamine Hypothesis of Addiction), which eventually biases decisions in favor of drug consumption, even when associated with major negative consequences. Each addictive drug activates the mesolimbic system via its specific molecular target, engaging distinct cellular mechanisms to increase dopamine levels. The first class of drugs directly stimulates the dopamine neurons. This is the case for nicotine, which binds to excitatory nicotinic receptors expressed on the cell body of dopamine neurons. The second class interferes with the reuptake of dopamine (eg, cocaine) or promotes nonvesicular release (eg, amphetamines). This happens in NAc and the VTA itself because dopamine neurons also express somatodendritic transporters, which normally clear dopamine released by the dendrites. Although drugs of this class also affect transporters of other monoamines (norepinephrine, serotonin), action on the dopamine transporter remains central for addiction. This is consistent with the observations that antidepressants that block serotonin and norepinephrine uptake, but not dopamine uptake, do not cause addiction even after prolonged use. The third mechanism is indirect, whereby the drugs inhibit γ-aminobutyric acid (GABA) neurons that act as local inhibitory interneurons (eg, opioids, cannabis). The three groups also differ by the molecular targets the drug binds to. For example, members of the last group bind to Gio protein–coupled receptors, typically of the Gio family, that inhibit neurons through postsynaptic hyperpolarization and lower presynaptic transmitter release probability. By contrast, direct activation uses ionotropic receptors or ion channels, and all reuptake blockers interfere with the dopamine transporter (Table 32–1 and Figure 32–2).

608    SECTION V  Drugs That Act in the Central Nervous System

Animal Models in Addiction Research Many of the recent advances in addiction research have been made possible by the use of animal models. Since drugs of abuse are not only rewarding but also reinforcing, an animal will learn a behavior (eg, press a lever) when paired with drug administration. In such a self-administration paradigm, the number of times an animal is willing to press the lever in order to obtain a single dose reflects the strength of reinforcement and is therefore a measure of the motivation of the animal. Observing withdrawal signs specific for rodents (eg, escape jumps or “wet-dog” shakes after abrupt termination of chronic morphine administration) allows the quantification of dependence. When this aversive state is avoided, negative reinforcement may result (ie, the individual takes the drug to avoid withdrawal). Behavioral tests for addiction in rodents certainly do not capture the complexity of the disease. However, it is possible to model core components of addiction, for example, by monitoring behavioral sensitization and conditioned place preference. In the first test, an increase in locomotor activity is observed with intermittent drug exposure and may reflect enhanced incentive saliency. The latter tests for the preference of a particular environment associated with drug exposure by measuring the time an animal spends in the compartment where a drug was received compared with the compartment where only saline was injected (conditioned place preference). Both tests have in common that they are sensitive to cue-conditioned effects of addictive drugs. Subsequent exposures to the environment without the drug lead to extinction of the place preference, which can be reinstated with a low dose of

the drug or the presentation of a conditioned stimulus. These persistent changes serve as a model of relapse and have been linked to synaptic plasticity of excitatory transmission in the ventral tegmental area, nucleus accumbens, and prefrontal cortex (see also Box: The Dopamine Hypothesis of Addiction). More sophisticated tests rely on self-administration of the drug, in which a rat or a mouse has to press a lever in order to obtain an injection of, for example, cocaine. Once the animal has learned the association with a conditioned stimulus (eg, light or brief sound), the simple presentation of the cue elicits drug seeking. Using an apparatus with two levers, one can demonstrate strong motivation for drug seeking. In this test the animal has to press the lever for a random duration, only after which the second lever is presented that then allows to self-administer the drug. Prolonged self-administration of addictive drugs over weeks, particularly when using intermittent access schedules, elicits behaviors in some rodents that more closely resemble human addiction. Such “addicted” rodents are very strongly motivated to seek cocaine, continue looking for the drug even when no longer available, and self-administer cocaine despite negative consequences, such as punishment in the form of an electric foot shock. The latter is a reflection of compulsion, which occurs only in a fraction of animals, reminiscent of the observation that only some drug users will become addicted, while many can maintain a recreational consumption. While there is little evidence for addicted animals in the wild, these findings suggest that addiction is a disease that does not respect species boundaries once drugs become available.

TABLE 32–1  The mechanistic classification of drugs of abuse.1 Name

Main Molecular Target

Pharmacology

Effect on Dopamine (DA) Neurons

RR2

Drugs That Activate G Protein–Coupled Receptors Opioids

μ-OR (Gio)

Agonist

Disinhibition

4

Cannabinoids

CB1R (Gio)

Agonist

Disinhibition

2

γ-Hydroxybutyric acid (GHB)

GABABR (Gio)

Weak agonist

Disinhibition

?

LSD, mescaline, psilocybin

5-HT2AR (Gq)

Partial agonist

—

1

Agonist

Excitation

4

Excitation, disinhibition (?)

3

Drugs That Bind to Ionotropic Receptors and Ion Channels Nicotine

nAChR (α4β2)

Alcohol

GABAAR, 5-HT3R, nAChR, NMDAR, Kir3 channels

Benzodiazepines

GABAAR

Positive modulator

Disinhibition

3

Phencyclidine, ketamine

NMDAR

Antagonist

—

1

Drugs That Bind to Transporters of Biogenic Amines Cocaine

DAT, SERT, NET

Inhibitor

Blocks DA uptake

5

Amphetamine

DAT, NET, SERT, VMAT

Reverses transport

Blocks DA uptake, synaptic depletion

5

Ecstasy

SERT > DAT, NET

Reverses transport

Blocks DA uptake, synaptic depletion

?

5-HTxR, serotonin receptor; CB1R, cannabinoid-1 receptor; DAT, dopamine transporter; GABA, γ-aminobutyric acid; Kir3 channels, G protein–coupled inwardly rectifying potassium channels; LSD, lysergic acid diethylamide; μ-OR, μ-opioid receptor; nAChR, nicotinic acetylcholine receptor; NET, norepinephrine transporter; NMDAR, N-methyl-d-aspartate receptor; R, receptor; SERT, serotonin transporter; VMAT, vesicular monoamine transporter; ? indicates data not available. 1

Drugs fall into one of three categories, targeting either G protein–coupled receptors, ionotropic receptors or ion channels, or biogenic amine transporters.

2

RR, relative risk of addiction; 1 = nonaddictive; 5 = highly addictive.

CHAPTER 32  Drugs of Abuse    609

FIGURE 32–2  Neuropharmacological classification of addictive drugs by cellular mechanism engaged (see text and Table 32–1). DA, dopamine; GABA, γ-aminobutyric acid; GHB, γ-hydroxybutyric acid; GPCRs, G protein–coupled receptors; THC, Δ9-tetrahydrocannabinol.

DEPENDENCE: TOLERANCE & WITHDRAWAL With chronic exposure to addictive drugs, the brain shows signs of adaptation. For example, if morphine is used at short intervals, the dose has to be progressively increased over the course of several days to maintain rewarding or analgesic effects. This phenomenon is called tolerance. It may become a serious problem because of increasing side effects—eg, respiratory depression— that do not show as much tolerance and may lead to overdoserelated fatalities. Tolerance to opioids may be due to a reduction of the concentration of a drug or a shorter duration of action in a target system (pharmacokinetic tolerance). Alternatively, it may involve changes in μ-opioid receptor function (pharmacodynamic tolerance). Many μ-opioid receptor agonists promote robust receptor phosphorylation that triggers the recruitment of the adaptor protein β-arrestin, causing G proteins to uncouple from the receptor and internalize within minutes (see Chapter 2). Since this decreases signaling, it is tempting to explain tolerance by such a mechanism. However, morphine, which strongly induces tolerance, does not recruit β-arrestins and fails to promote receptor internalization (see Chapter 31). Conversely, other agonists that drive receptor internalization very efficiently induce only modest tolerance. Based on these observations, it has been hypothesized that desensitization and receptor internalization protect the cell from overstimulation. In this model, morphine, by failing to trigger receptor endocytosis, disproportionally stimulates adaptive processes, which eventually cause tolerance. Although the molecular identity of these processes

is still under investigation, they may be similar to the ones involved in withdrawal (see below). Adaptive changes become fully apparent once drug exposure is terminated. This state is called withdrawal and is observed to varying degrees after chronic exposure to most drugs of abuse. Withdrawal from opioids in humans is particularly strong (described below). Studies in rodents have added significantly to our understanding of the neural and molecular mechanisms that underlie dependence. For example, signs of dependence, as well as analgesia and reward (positive reinforcement), are abolished in genome-wide knockout mice lacking the μ-opioid receptor (Chapter 31), but not in mice lacking other opioid receptors (δ, κ). If μ-opioid receptors are selectively deleted on VTA GABA neurons of the VTA, positive reinforcement is lost, but not dependence. Such mice will still show withdrawal upon abrupt termination of opioid exposure, indicating that circuits of dependence are distinct. An input from the periventricular thalamus to the nucleus accumbens, conveying an aversive state during withdrawal, has been implicated. On the molecular level, dependence may involve adaptation of receptor signaling. μ-opioid receptors initially inhibit adenylyl cyclase; this inhibition becomes weaker after several days of repeated exposure. The reduction of the inhibition of adenylyl cyclase is due to a counteradaptation of the enzyme system during exposure to the drug, which results in the overproduction of cAMP during subsequent withdrawal. Several mechanisms exist for this adenylyl cyclase compensatory response, including upregulation of transcription of the enzyme. Increased cAMP concentrations strongly activate the transcription factor cyclic AMP response element binding protein (CREB), leading to the regulation of downstream genes.

610    SECTION V  Drugs That Act in the Central Nervous System

The Dopamine Hypothesis of Addiction In the earliest version of the hypothesis described in this chapter, mesolimbic dopamine was believed to be the neurochemical correlate of pleasure and reward. However, during the past decades, experimental evidence has led to several revisions. Phasic dopamine release may actually code for the prediction error of reward rather than the reward itself. This distinction is based on pioneering observations in monkeys that dopamine neurons in the ventral tegmental area (VTA) are most efficiently activated by a reward (eg, a few drops of fruit juice) that is not anticipated. When the animal learns to predict the occurrence of a reward (eg, by pairing it with a stimulus such as a sound), dopamine neurons stop responding to the reward itself (juice), but increase their firing rate when the conditioned stimulus (sound) occurs. Finally, if reward is predicted but not delivered (sound but no juice), dopamine neurons become silent. In other words, the mesolimbic system continuously scans the reward situation. It increases its activity when reward is larger than expected and shuts down when a promised reward is omitted, thus coding for the prediction error of reward. Tonic release of dopamine in turn may reflect motivation. Under physiologic conditions the phasic mesolimbic dopamine signal could represent a learning signal responsible for reinforcing constructive behavioral adaptation (eg, learning to press a lever for food). Indeed, animals that cannot synthesize dopamine because key enzymes have been ablated genetically show unconditioned reflexes and can execute previously learned behavior, but hardly acquire new responses. Addictive drugs, by directly increasing dopamine, would generate a strong but inappropriate learning signal, thus hijacking the reward system and leading to pathologic reinforcement. As a consequence, over time, through several intermediate steps, behavior may become compulsive in some individuals; that is, decisions are strongly biased in favor of actions to seek and take drugs. This is the hallmark of addiction. This appealing hypothesis has been challenged by the intriguing observation that mice genetically modified to lack the primary molecular target of cocaine, the dopamine transporter

ADDICTION: A DISEASE OF MALADAPTIVE LEARNING Addiction is characterized by a high motivation to obtain and use a drug despite negative consequences. With time, drug use becomes compulsive (“wanting without liking”). Addiction is a recalcitrant, chronic, and stubbornly relapsing disease that is very difficult to treat. The central problem is that even after successful withdrawal and prolonged drug-free periods, addicted individuals have a high risk of relapsing. Relapse is typically triggered by three conditions: re-exposure to the addictive drug, stress, or a context that recalls prior drug use. It appears that when paired with drug use, a neutral

DAT, still self-administer the drug. Only when transporters of other biogenic amines are also knocked out does cocaine completely lose its rewarding properties. However, in DAT–/– mice, in which basal synaptic dopamine levels are high, cocaine still leads to increased dopamine release, presumably because other cocaine-sensitive monoamine transporters (NET, SERT) are able to clear some dopamine. When cocaine is given, these transporters are also inhibited and dopamine is again increased. As a consequence of this substitution among monoamine transporters, fluoxetine (a selective serotonin reuptake inhibitor, see Chapter 30) becomes addictive in DAT–/– mice. This concept is supported by evidence showing that deletion of the cocaine-binding site on DAT leaves basal dopamine levels unchanged but abolishes the rewarding effect of cocaine. The dopamine hypothesis of addiction has also been challenged by the observation that salient stimuli that are not rewarding (they may actually even be aversive and therefore negative reinforcers) also activate a subpopulation of dopamine neurons in the VTA. The neurons that are activated by aversive stimuli preferentially project to the prefrontal cortex and the tail of the striatum, while the dopamine neurons inhibited by aversive stimuli are those that mostly target the nucleus accumbens. These recent findings suggest that in parallel to the reward system, a system for aversion-learning originates in the VTA. Regardless of the many roles of dopamine under physiologic conditions, all addictive drugs significantly increase its concentration in target structures of the mesolimbic projection, in particular in the dorsomedial shell of the NAc. This suggests that high levels of dopamine may actually be at the origin of the adaptive changes that underlie dependence and addiction, a concept that is now supported by novel techniques that allow controlling the activity of dopamine neurons in vivo. In fact manipulations that drive sustained activity of VTA dopamine neurons cause the same cellular adaptations and behavioral changes typically observed with addictive drug exposure, including late-stage symptoms such as persistence of self-stimulation during punishment.

stimulus may undergo a switch and motivate (“trigger”) addictionrelated behavior. This phenomenon may involve synaptic plasticity in the target nuclei of the mesolimbic projection (eg, projections from the medial prefrontal cortex and the ventral hippocampus to the neurons of the nucleus accumbens that express the d1 receptors). Several recent studies suggest that the recruitment of circuits in the dorsal striatum is responsible for compulsion. This switch may depend on synaptic plasticity in the nucleus accumbens of the ventral striatum (Figure 32–3), where mesolimbic dopamine afferents converge with glutamatergic afferents to modulate their function. If dopamine release codes for the prediction error of reward (see Box: The Dopamine Hypothesis of Addiction), pharmacologic stimulation of the mesolimbic dopamine system

CHAPTER 32  Drugs of Abuse    611

FIGURE 32–3  Rules of synaptic plasticity in the striatum. The tripartite synapse between glutamatergic afferents, the GABAergic medium spiny neurons, and the ascending axons of VTA dopamine neurons can undergo several forms of synaptic plasticity. In cells that express the Gs-coupled D1 receptor, dopamine favors the appearance of long-term potentiation (LTP), while long-term depression (LTD) is inhibited. Conversely in D2 receptor-expressing cells, dopamine when released at the same time as glutamate causes LTD and opposes LTP. These rules apply when dopamine is released at the same time as afferent glutamate and may explain the predominant effect of addictive drugs. (Data from Shen W, et al: Dichotomous dopaminergic control of striatal synaptic plasticity, Science 2008;321:848.)

will generate an unusually strong learning signal. Unlike natural rewards, addictive drugs continue to increase dopamine even when reward is expected. Such overriding of the prediction error signal may eventually be responsible for the usurping of memory processes by addictive drugs. The involvement of learning and memory systems in addiction is also suggested by clinical studies. For example, the role of context in relapse is supported by the fact that soldiers who became addicted to heroin during the Vietnam War had significantly better outcomes when treated after their return home, compared with addicts who remained in the environment where they had taken the drug. In other words, cravings may recur at the presentation of contextual cues (eg, people, places, or drug paraphernalia). Current research therefore focuses on the effects of drugs on associative forms of synaptic plasticity, such as long-term potentiation (LTP), which underlie learning and memory (see Box: Synaptic Plasticity, Altered Circuit Function, & Addiction). Non-substance-dependent disorders, such as pathologic gambling and compulsive shopping, share many clinical features of addiction. Several lines of arguments suggest that they also share the underlying neurobiological mechanisms. This conclusion is supported by the clinical observation that, as an adverse effect of dopamine agonist medication, patients with Parkinson disease may become pathologic gamblers. Other patients may develop a compulsion for recreational activities, such as shopping, binge eating, or hypersexuality. Although large-scale studies are not yet available, an estimated one in seven parkinsonian patients develops

an addiction-like behavior when receiving dopamine agonists (see Chapter 28). Large individual differences exist also in vulnerability to substance-related addiction. Whereas one person may become “hooked” after a few doses, others may be able to use a drug occasionally during their entire lives without ever having difficulty in stopping. Even in the case of drugs that induce dependence in all subjects, only a percentage of users progress to addiction. For example, a retrospective analysis shows that after several decades of cocaine abuse, only 20% become addicted. With cannabis, the fraction is only 10%, while heroin leads to approximately 30% of users becoming addicts. A similar percentage for cocaine is also observed in rats and mice that have extended access to the drug. With dopamine neuron self-stimulation, the fraction of mice that resist punishment is approximately 50%. Recent studies in rats suggest that impulsivity or excessive anxiety may be crucial traits that represent a risk for addiction. The transition to addiction is determined by a combination of environmental and genetic factors. Heritability of addiction, as determined by comparing monozygotic with dizygotic twins, is relatively modest for cannabinoids but higher for cocaine. It is of interest that the relative risk for addiction (addiction liability) of a drug (see Table 32–1) correlates with its heritability, suggesting that the neurobiologic basis of addiction common to all drugs is what is being inherited. Further genomic analysis indicates that numerous, perhaps even hundreds of alleles need to function in combination to produce the phenotype. However, identification of the genes involved remains elusive. Although some

612    SECTION V  Drugs That Act in the Central Nervous System

substance-specific candidate genes have been identified (eg, alcohol dehydrogenase, nicotinic acetylcholine receptor subunits), current research focuses on genes implicated in the neurobiologic mechanisms common to all addictive drugs. An appealing idea is the contribution of epigenetics as a determinant of addiction vulnerability. This scenario is supported by the observation that the fraction of

transition to compulsion in genetically homogeneous mice is similar to that observed in humans. Cocaine regulates posttranslational modifications of histones, DNA methylation, and signaling via noncoding RNAs, which eventually may have an impact on behavior. The cellular mechanism involved and the relationship to synaptic plasticity are currently under investigation.

Synaptic Plasticity, Altered Circuit Function, & Addiction Long-term potentiation (LTP) and long-term depression (LTD) are forms of experience-dependent synaptic plasticity that is induced by activating glutamate receptors of the N-methyld-aspartate (NMDA) type. Since NMDA receptors are blocked by magnesium at negative potentials, their activation requires the concomitant release of glutamate (presynaptic activity) onto a receiving neuron that is depolarized (postsynaptic activity). Correlated pre- and postsynaptic activity durably enhances synaptic efficacy and triggers the formation of new connections. In contrast, weak correlated activity (eg, postsynaptic neurons firing before the presynaptic cell) leads to LTD. Because associativity is a critical component, LTP and LTD have become leading candidate mechanisms underlying learning and memory. They can be elicited at glutamatergic synapses of the mesolimbic reward system and are modulated by dopamine. The dopamine receptors dictate the rules of synaptic plasticity. In D1R-expressing cells, a surge of dopamine favors LTP of excitatory afferents but blocks LTD. Conversely in D2R-expressing neurons, dopamine release concomitant to glutamate transmission leads to the depression of the latter and inhibits LTP. Drugs of abuse therefore interfere with LTP and LTD at sites of convergence of dopamine and glutamate projections, leading to drug-evoked synaptic plasticity. Exposure

NONADDICTIVE DRUGS OF ABUSE Some drugs of abuse do not lead to addiction. This is the case for substances that alter perception without causing sensations of reward and euphoria, such as psychedelics and dissociative anesthetics (see Table 32–1). Unlike addictive drugs, which primarily target the mesolimbic dopamine system, these agents primarily target cortical and thalamic circuits. Lysergic acid diethylamide (LSD), for example, activates the serotonin 5-HT2A receptor in the prefrontal cortex, acutely enhancing glutamatergic transmission onto pyramidal neurons for the duration of the presence of the drug. These excitatory afferents mainly come from the thalamus and carry sensory information of varied modalities, which may constitute a link to enhanced perception. Phencyclidine (PCP) and ketamine produce a feeling of separation of mind and body (which is why they are called dissociative anesthetics) and, at higher doses, stupor and coma. The principal mechanism of action is a use-dependent inhibition of glutamate receptors of the NMDA type. High doses of dextromethorphan, an over-the-counter cough

to an addictive drug thus typically triggers a potentiation of excitatory afferents onto D1R-expressing neurons. Dopamine also potentiates GABAA receptor-mediated inhibition of the GABA neurons in the VTA and the ventral pallidum (VP), both primary targets of the medium spiny neurons of the nucleus accumbens. As a consequence, the excitability of dopamine neurons is increased, the synaptic calcium sources altered, and the rules for subsequent LTP inverted. In the nucleus accumbens, drug-evoked synaptic plasticity appears with some delay on D1 receptor-expressing neurons, which are the ones projecting back to the VTA to control the activity of the GABA neurons as well as to the VP. Manipulations in mice that prevent or reverse drug-evoked plasticity in vivo also have effects on persistent changes of drug-associated behavioral sensitization or cue-induced drug seeking, providing more direct evidence for a causal role of synaptic plasticity in drug-adaptive behavior. The strengthening of the projection from the orbitofrontal cortex to the dorsal striatum may be a neural correlate of compulsion in those animals that self-stimulate the VTA dopamine neurons or take a drug even when punished. Together, a circuit model of staged drug-evoked synaptic plasticity is emerging, whereby various symptoms are caused by changes in specific projections, eventually combining into addiction.

suppressant, can also elicit a dissociative state. This effect is mediated by a rather nonselective action on serotonin reuptake, and opioid, acetylcholine, and NMDA receptors. The classification of NMDA antagonists as nonaddictive drugs was based on early assessments, which, in the case of PCP, have recently been questioned. Animal research shows that PCP can increase mesolimbic dopamine concentrations and has some reinforcing properties in rodents. Ketamine also increases dopamine and leads to weak reinforcement but not to long-lasting adaptation, because NMDA receptor blockage precludes the induction of drug-evoked synaptic plasticity. Addiction liability is thus believed to be low, but not zero. Concurrent effects on both thalamocortical and mesolimbic systems also exist for other addictive drugs. Psychosis-like symptoms can be observed with cannabinoids, amphetamines, and cocaine, which may reflect their effects on thalamocortical structures. For example, cannabinoids, in addition to their documented effects on the mesolimbic dopamine system, also enhance excitation in cortical circuits through presynaptic inhibition of GABA release.

CHAPTER 32  Drugs of Abuse    613

Hallucinogens and NMDA antagonists, even if they do not produce dependence or addiction, can still have long-term effects. Flashbacks of altered perception can occur years after LSD use. Moreover, chronic use of PCP may lead to an irreversible schizophrenia-like psychosis.

■■ BASIC PHARMACOLOGY OF DRUGS OF ABUSE Since all addictive drugs increase dopamine concentrations in the target structures of the mesolimbic projections, we classify them based on the underlying cellular mechanism (see Table 32–1 and Figure 32–2). The first group includes nicotine, which through its ionotropic receptor stimulates dopamine neurons. The second group comprises cocaine, amphetamines, and ecstasy, which all bind to monoamine transporters and lead to increased dopamine levels independent of their effect on neuron firing. The third group contains opioids, cannabinoids, γ-hydroxybutyric acid (GHB), and benzodiazepines, which exert their action through Gio protein– coupled receptors and ionotropic receptors and cause disinhibition of dopamine neurons. Alcohol, which has several molecular targets, increases dopamine through a still unknown mechanism. Drugs such as psychedelics do not increase dopamine, are not addictive, and are classified based on their molecular target.

DRUGS THAT EXCITE DOPAMINE NEURONS NICOTINE In terms of numbers affected, nicotine addiction exceeds all other forms of addiction, touching more than 50% of all adults in some countries. Nicotine exposure occurs primarily through smoking of tobacco, which causes associated diseases that are responsible for many preventable deaths. The chronic use of chewing tobacco and snuff tobacco is also addictive. Nicotine is a selective agonist of the nicotinic acetylcholine receptor (nAChR) that is normally activated by acetylcholine (see Chapters 6 and 7). Based on nicotine’s enhancement of cognitive performance and the association of Alzheimer dementia with a loss of ACh-releasing neurons from the nucleus basalis of Meynert, nAChRs are believed to play an important role in many cognitive processes. The rewarding effect of nicotine requires involvement of the VTA, in which nAChRs are expressed on dopamine neurons. When nicotine excites projection neurons, dopamine is released in the nucleus accumbens and the prefrontal cortex, thus fulfilling the dopamine requirement of addictive drugs. α4β2-containing channels in the VTA are the nAChRs mediating the rewarding effects of nicotine. This statement is based on the observation that knockout mice deficient for the β2 subunit lose interest in self-administering nicotine, and that in these mice, this behavior can be restored through an in vivo transfection of the β2 subunits in neurons of the VTA. Electrophysiologic evidence suggests that homomeric nAChRs made exclusively of α7 subunits

also contribute to the reinforcing effects of nicotine. These receptors are mainly expressed on synaptic terminals of excitatory afferents projecting onto the dopamine neurons. They also contribute to nicotine-evoked dopamine release and the long-term changes induced by the drugs related to addiction (eg, long-term synaptic potentiation of excitatory inputs). Nicotine withdrawal is mild compared with opioid withdrawal and involves irritability and problems sleeping. However, nicotine is among the most addictive drugs (relative risk 4), and relapse after attempted cessation is very common.

Treatment Treatments for nicotine addiction include nicotine itself in forms that are slowly absorbed and several other drugs. Nicotine that is chewed, inhaled, or transdermally delivered can be substituted for the nicotine in cigarettes, thus slowing the pharmacokinetics and eliminating the many complications associated with the toxic substances found in tobacco smoke. Recently, two partial agonists of α4β2-containing nAChRs have been characterized: the plantextract cytisine and its synthetic derivative varenicline. Both work by occupying nAChRs on dopamine neurons of the VTA, thus preventing nicotine from exerting its action. Varenicline may impair the capacity to drive and has been associated with suicidal ideation. The antidepressant bupropion is approved for nicotine cessation therapy. It is most effective when combined with behavioral therapies. Many countries have banned smoking in public places to create smoke-free environments. This important step not only reduces passive smoking and the hazards of secondhand smoke but also the risk that ex-smokers will be exposed to smoke, which as a contextual cue, may trigger relapse.

DRUGS THAT INTERFERE WITH DOPAMINE REUPTAKE Cocaine The prevalence of cocaine abuse remains a major public health problem worldwide. Cocaine is highly addictive (relative risk = 5), and its use is associated with a number of complications. Cocaine is an alkaloid found in the leaves of Erythroxylum coca, a shrub indigenous to the Andes. For more than 100 years, it has been extracted and used in clinical medicine, mainly as a local anesthetic and to dilate pupils in ophthalmology. Sigmund Freud famously proposed its use to treat depression and alcohol dependence, but addiction quickly brought an end to these ideas. Cocaine hydrochloride is a water-soluble salt that can be injected or absorbed by any mucosal membrane (eg, nasal snorting). When heated in an alkaline solution, it is transformed into the free base, “crack cocaine,” which can then be smoked. Inhaled crack cocaine is rapidly absorbed in the lungs and penetrates swiftly into the brain, producing an almost instantaneous “rush.” In the peripheral nervous system, cocaine inhibits voltagegated sodium channels, thus blocking initiation and conduction of action potentials (see Chapter 26). This mechanism, underlying

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Cocaine

Amphetamine

VMAT Amph

DA

DAT

DAT

DAT DA

DA

Cocaine

DA Amph

DA

FIGURE 32–4  Mechanism of action of cocaine and amphetamine on synaptic terminal of dopamine (DA) neurons. Left: Cocaine inhibits the dopamine transporter (DAT), decreasing DA clearance from the synaptic cleft and causing an increase in extracellular DA concentration. Right: Since amphetamine (Amph) is a substrate of the DAT, it competitively inhibits DA transport. In addition, once in the cell, amphetamine interferes with the vesicular monoamine transporter (VMAT) and impedes the filling of synaptic vesicles. As a consequence, vesicles are depleted and cytoplasmic DA increases. This leads to a reversal of DAT direction, strongly increasing nonvesicular release of DA, and further increasing extracellular DA concentrations. its effect as a local anesthetic, seems responsible for neither the acute rewarding nor the addictive effects. In the central nervous system, cocaine blocks the uptake of dopamine, noradrenaline, and serotonin through their respective transporters. The block of the dopamine transporter (DAT), which increases dopamine concentrations in the nucleus accumbens, has been implicated in the rewarding effects of cocaine (Figure 32–4). In fact, the rewarding effects of cocaine are abolished in mutant mice with a cocaineinsensitive DAT. The activation of the sympathetic nervous system results mainly from blockage of the norepinephrine transporter (NET) and leads to an acute increase in arterial pressure, tachycardia, and often, ventricular arrhythmias. Users typically lose their appetite, are hyperactive, and sleep little. Cocaine exposure increases the risk for intracranial hemorrhage, ischemic stroke, myocardial infarction, and seizures. Cocaine overdose may lead to hyperthermia, coma, and death. In the 1970s, when crack-cocaine appeared in the USA, it was suggested that the drug is particularly harmful to the fetus in addicted pregnant women. The term “crack-baby” was used to describe a specific syndrome of the newborn, and the mothers faced harsh legal consequences. The followup of the children, now adults, does not confirm a drug-specific handicap in cognitive performance. Moreover, in this population, the percentage of drug-users is comparable to controls matched for socioeconomic environment. Susceptible individuals may become dependent and addicted after only a few exposures to cocaine. Although a withdrawal syndrome is reported, it is not as strong as that observed with opioids. Tolerance may develop, but in some users, a reverse tolerance is observed; that is, they become sensitized to small doses of cocaine. This behavioral sensitization is in part contextdependent. Cravings are very strong and underlie the very high addiction liability of cocaine. To date, no specific antagonist is available, and the management of intoxication remains supportive. Developing a pharmacologic treatment for cocaine addiction is a top priority.

AMPHETAMINES Amphetamines are a group of synthetic, indirect-acting sympathomimetic drugs that cause the release of endogenous biogenic amines, such as dopamine and norepinephrine (see Chapters  6 and  9). Amphetamine, methamphetamine, and their many derivatives exert their effects by reversing the action of biogenic amine transporters at the plasma membrane. Amphetamines are substrates of these transporters and are taken up into the cell (see Figure 32–4). Once in the cell, amphetamines interfere with the vesicular monoamine transporter (VMAT; see Figure 6–4), depleting synaptic vesicles of their neurotransmitter content. As a consequence, levels of dopamine (or other transmitter amine) in the cytoplasm increase and quickly become sufficient to cause release into the synapse by reversal of the plasma membrane DAT. Normal vesicular release of dopamine consequently decreases (because synaptic vesicles contain less transmitter), whereas nonvesicular release increases. Similar mechanisms apply for other biogenic amines (serotonin and norepinephrine). Together with GHB and ecstasy, amphetamines are often referred to as “club drugs” because they are increasingly popular in the club scene. They are often produced in small clandestine laboratories, which makes their precise chemical identification difficult. They differ from ecstasy chiefly in the context of use: intravenous administration and “hard-core” addiction are far more common with amphetamines, especially methamphetamine. In general, amphetamines lead to elevated catecholamine levels that increase arousal and reduce sleep, whereas the effects on the dopamine system mediate euphoria but may also cause abnormal movements and precipitate psychotic episodes. Effects on serotonin transmission may play a role in the hallucinogenic and anorexigenic functions as well as in the hyperthermia often caused by amphetamines. Unlike many other abused drugs, amphetamines are neurotoxic. The exact mechanism is not known, but neurotoxicity

CHAPTER 32  Drugs of Abuse    615

depends on the NMDA receptor and affects mainly serotonin and dopamine neurons. Amphetamines are typically taken initially in pill form by abusers, but can also be smoked or injected. Heavy users often progress rapidly to intravenous administration. Within hours after oral ingestion, amphetamines increase alertness and cause euphoria, agitation, and confusion. Bruxism (tooth grinding) and skin flushing may occur. Effects on heart rate may be minimal with some compounds (eg, methamphetamine), but with increasing dosage these agents often lead to tachycardia and dysrhythmias. Hypertensive crisis and vasoconstriction may lead to stroke. Spread of HIV and hepatitis infection in inner cities has been closely associated with needle sharing by intravenous users of methamphetamine. With chronic use, amphetamine tolerance may develop, leading to dose escalation. Withdrawal consists of dysphoria, drowsiness (in some cases, insomnia), and general irritability.

ECSTASY (MDMA) Ecstasy is the name of a class of drugs that includes a large variety of derivatives of the amphetamine-related compound methylenedioxymethamphetamine (MDMA). MDMA was originally used in some forms of psychotherapy, but no medically useful effects were documented. This is perhaps not surprising, because the main effect of ecstasy appears to be to foster feelings of intimacy and empathy without impairing intellectual capacities. Today, MDMA and its many derivatives are often produced in small quantities in ad hoc laboratories and distributed at parties or “raves,” where it is taken orally. Ecstasy therefore is the prototypic designer drug and, as such, is increasingly popular. Similar to the amphetamines, MDMA causes release of biogenic amines by reversing the action of their respective transporters. It has a preferential affinity for the serotonin transporter (SERT) and therefore most strongly increases the extracellular concentration of serotonin. This release is so profound that there is a marked intracellular depletion for 24 hours after a single dose. With repetitive administration, serotonin depletion may become permanent, which has triggered a debate on its neurotoxicity. Although direct proof from animal models for neurotoxicity remains weak, several studies report long-term cognitive impairment in heavy users of MDMA. In contrast, there is a wide consensus that MDMA has several acute adverse effects, in particular hyperthermia, which along with dehydration (eg, caused by an all-night dance party) may be fatal. Other complications include serotonin syndrome (mental status change, autonomic hyperactivity, and neuromuscular abnormalities; see Chapter 16) and seizures. Following warnings about the dangers of MDMA, some users have attempted to compensate for hyperthermia by drinking excessive amounts of water, causing water intoxication involving severe hyponatremia, seizures, and even death. Withdrawal is marked by a mood “offset” characterized by depression lasting up to several weeks. There have also been reports of increased aggression during periods of abstinence in chronic MDMA users.

Taken together, the evidence for irreversible damage to the brain, although not completely convincing, implies that even occasional recreational use of MDMA cannot be considered safe.

■■ DRUGS THAT DISINHIBIT DOPAMINE NEURONS OPIOIDS Opioids may have been the first drug abused in human history and are still among the most commonly used for nonmedical purposes.

Pharmacology & Clinical Aspects As described in Chapter 31, opioids comprise a large family of endogenous and exogenous agonists at three G protein–coupled receptors: the μ-, κ-, and δ-opioid receptors. Although all three receptors couple to inhibitory G proteins (ie, they all inhibit adenylyl cyclase and activate K+ channels), they have distinct, sometimes even opposing effects, mainly because of the cell type-specific expression throughout the brain. In the VTA, for example, μ-opioid receptors are selectively expressed on GABA neurons (which they inhibit), whereas κ-opioid receptors are expressed on and inhibit dopamine neurons. This may explain why μ-opioid agonists cause euphoria, whereas κ agonists induce dysphoria. In line with the latter observations, the rewarding effects of morphine are absent in knockout mice lacking μ receptors but persist when either of the other opioid receptors are ablated. In the VTA, μ opioids cause an inhibition of GABAergic inhibitory interneurons, which leads to a disinhibition of dopamine neurons, particularly those that project to the medial shell of the nucleus accumbens. The most commonly abused μ opioids include morphine, heroin (diacetylmorphine, which is rapidly metabolized to morphine), codeine, and oxycodone. The very potent synthetic opioid fentanyl (which within minutes saturates opioid receptors at a dose 100× lower than morphine) has become a widely abused drug because of its rapid onset and ease of distribution. Because of its pharmacokinetic properties it is among the most dangerous drugs and accounts for many deaths by overdose. Meperidine (also known as pethidine) is commonly abused among health professionals. All of these drugs induce strong tolerance and dependence, which increases the risk of transition to addiction by negative reinforcement. Positive and negative reinforcing effects of opioids both depend on μ receptors. In genetically modified mice lacking this receptor, no withdrawal is observed once chronic opioid exposure is terminated. In humans, the withdrawal syndrome may be very severe (except for codeine) and includes intense dysphoria, nausea or vomiting, muscle aches, lacrimation, rhinorrhea, mydriasis, piloerection, sweating, diarrhea, yawning, and fever. Beyond the withdrawal syndrome, which usually lasts no longer than a few days, some individuals who have received opioids as analgesics to treat acute pain develop addiction. Despite this

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fact, opioid addiction has become a major public health issue in some countries, particularly the USA and Canada. The reason for this epidemic has been identified as careless, widespread chronic prescription of pain killers such as oxycodone to patients, who eventually switched to heroin or other illicit opioids. The relative risk of addiction is 4 out of 5 on a scale of 1 (nonaddictive) to 5 (highly addictive).

Treatment The opioid antagonist naloxone reverses the effects of a dose of morphine or heroin within minutes. This may be lifesaving in the case of an overdose, given typically IV or IM, but also as a nasal spray that can be applied by nonmedical personnel (see Chapters 31 and 58). Naloxone administration also provokes an acute withdrawal (precipitated abstinence) syndrome in a dependent person, which limits compliance. The half-life of naloxone is shorter than morphine (1 h and 2–4 h, respectively), which is why repeated administrations may be necessary. In treating opioid addiction, a longer-acting opioid (eg, methadone, buprenorphine, extended-release morphine sulfate) is often substituted for the shorter-acting, more rewarding opioid (eg, heroin). For substitution therapy, methadone is given orally once daily, facilitating supervised intake. The use of a partial agonist (buprenorphine) and the much longer half-life (methadone, extended-release morphine sulfate, and buprenorphine) may also have some beneficial effects (eg, weaker drug sensitization, which typically requires intermittent exposures), but it is essential to realize that abrupt termination of methadone administration also precipitates a withdrawal syndrome; that is, the subject on substitution therapy remains dependent. Levomethadone, a preparation containing only the active enantiomer, has similar kinetics and effects as methadone, but lower side effects, particularly when cardiac repolarization is perturbed (long QT interval in the electrocardiogram). The use of buprenorphine may be limited by the withdrawal syndrome observed at the beginning of the therapy. Some countries (eg, Canada, Denmark, Netherlands, United Kingdom, Switzerland) allow substitution of medical heroin for street heroin. A follow-up of a cohort of addicts who received heroin injections in a controlled setting and had access to counseling indicates that addicts under heroin substitution have an improved health status and are better integrated in society. The current opioid crisis in the USA has become a leading cause of death in young adults and more than 2 million individuals are dependent.

CANNABINOIDS Endogenous cannabinoids that act as neurotransmitters include 2-arachidonyl glycerol (2-AG) and anandamide, both of which bind to CB1 receptors (see also Chapter 63). These very lipidsoluble compounds are released at the postsynaptic somatodendritic membrane, and diffuse through the extracellular space to bind at presynaptic CB1 receptors, where they inhibit the release of either glutamate or GABA. Because of this backward signaling, endocannabinoids are called retrograde messengers. In the

hippocampus, the release of endocannabinoids from pyramidal neurons selectively affects inhibitory transmission and may contribute to the induction of synaptic plasticity during learning and memory formation. Exogenous cannabinoids, eg, in marijuana, which when smoked contains thousands of organic and inorganic chemical compounds, exert their pharmacologic effects through active substances, including Δ9-tetra-hydrocannabinol (THC), a powerful psychoactive substance. Like opioids, THC causes disinhibition of dopamine neurons, mainly by presynaptic inhibition of GABA neurons in the VTA. The half-life of THC is about 4 hours. The onset of effects of THC after smoking marijuana occurs within minutes and reaches a maximum after 1–2 hours. The most prominent effects are euphoria and relaxation. Users also report feelings of well-being, grandiosity, and altered perception of passage of time. Dose-dependent perceptual changes (eg, visual distortions), drowsiness, diminished coordination, and memory impairment may occur. Cannabinoids can also create a dysphoric state and, in rare cases following the use of very high doses, eg, in hashish, result in visual hallucinations, depersonalization, and frank psychotic episodes. Additional effects of THC, eg, increased appetite, attenuation of nausea, decreased intraocular pressure, and relief of chronic pain, have led to the use of cannabinoids in medical therapeutics. The justification of medicinal use of marijuana was comprehensively examined more than 20 years ago. Today, medical use of botanical marijuana has been legalized in 25 states and the District of Columbia. Nevertheless this continues to be a controversial issue, mainly because of the fear that cannabinoids may serve as a gateway to the consumption of “hard” drugs or cause schizophrenia in individuals with a predisposition. Chronic exposure to marijuana leads to dependence, which is revealed by a distinctive, but mild and short-lived withdrawal syndrome that includes restlessness, irritability, mild agitation, insomnia, nausea, and cramping. The relative risk for addiction is 2. The synthetic Δ9-THC analog dronabinol is a US Food and Drug Administration (FDA)-approved cannabinoid agonist currently marketed in the USA and some European countries. Nabilone, an older commercial Δ9-THC analog, was recently reintroduced in the USA to treat chemotherapy-induced emesis. Cannabidiol (CBD) is an active ingredient in marijuana, with low addiction liability, that is legal in all states and most western countries. It may benefit some forms of epilepsy, anxiety, insomnia, and chronic pain. Major side effects include nausea, fatigue, and enhanced blood thinning (particularly in patients receiving anticoagulants). CBD is a low-affinity agonist at CB1/ CB2 receptors, but it also binds to other (orphan) GPCRs and can affect serotonin and opioid signaling. Nabiximols (trade name Sativex) is a botanical drug obtained by standard extraction. Its active principles are Δ9-THC and CBD. Initially only marketed in the United Kingdom, it is now widely available to treat symptoms of multiple sclerosis. In the USA, nabiximols is in phase III testing for cancer pain. The cannabinoid system will likely emerge as an essential drug target in the future because of its apparent involvement in several therapeutically desirable effects.

CHAPTER 32  Drugs of Abuse    617

GAMMA-HYDROXYBUTYRIC ACID Gamma-hydroxybutyric acid (GHB, or sodium oxybate for its salt form) is produced during the metabolism of GABA, but the function of this endogenous agent is unknown at present. The pharmacology of GHB is complex because there are two distinct binding sites. The protein that contains a high-affinity binding site (1 μM) for GHB has been cloned, but its involvement in the cellular effects of GHB at pharmacologic concentrations remains unclear. The low-affinity binding site (1 mM) has been identified as the GABAB receptor. In mice that lack GABAB receptors, even very high doses of GHB have no effect; this suggests that GABAB receptors are the sole mediators of GHB’s pharmacologic action. GHB was first synthesized in 1960 in France and introduced as a general anesthetic. Because of its narrow safety margin and its addictive potential, it is not available in the USA for this purpose. Sodium oxybate (GHB sodium salt) can, however, be prescribed

to treat narcolepsy and to decrease daytime sleepiness and episodes of cataplexy through a mechanism unrelated to the reward system. Before causing sedation and coma, GHB causes euphoria, enhanced sensory perceptions, a feeling of social closeness, and amnesia. These properties have made it a popular “club drug” that goes by colorful street names such as “liquid ecstasy,” “grievous bodily harm,” or “date rape drug.” As the latter name suggests, GHB has been used in date rapes because it is odorless and can be readily dissolved in beverages. It is rapidly absorbed after ingestion and reaches a maximal plasma concentration 20–30 minutes after ingestion of a 10–20 mg/kg dose. The elimination half-life is about 30 minutes and leaves the recipient amnesic for events during the drug’s duration of action. Although GABAB receptors are expressed on all neurons of the VTA, GABA neurons are much more sensitive to GHB than are dopamine neurons (Figure 32–5). This is reflected by the EC50s, which differ by about one order of magnitude, as a result of the difference in coupling efficiency of the GABAB receptor and the

Opioids MOR GABA Ca VGCC

DA

2+

Kir3 MOR

GABA

Ca2+

K+

MOR

βγ

βγ

THC CB1R GABA GABAA R

DA

GHB GABAB DA GABA

FIGURE 32–5  Disinhibition of dopamine (DA) neurons in the ventral tegmental area (VTA) through drugs that act via Gio-coupled receptors. Top: Opioids target μ-opioid receptors (MORs) that in the VTA are located exclusively on γ-aminobutyric acid (GABA) neurons. MORs are expressed on the presynaptic terminal of these cells and the somatodendritic compartment of the postsynaptic cells. Each compartment has distinct effectors (insets). G protein-βγ-mediated inhibition of voltage-gated calcium channels (VGCC) is the major mechanism in the presynaptic terminal. Conversely, in dendrites MORs activate K channels. Together the pre- and postsynaptic mechanisms reduce transmitter release and suppress activity, ultimately taking away the inhibition by the GABA neurons. Middle: Δ9-tetrahydrocannabinol (THC) and other cannabinoids mainly act through presynaptic inhibition. Bottom: Gamma-hydroxybutyric acid (GHB) targets GABAB receptors, which are located on both cell types. However, GABA neurons are more sensitive to GHB than are DA neurons, leading to disinhibition at concentrations typically obtained with recreational use. CB1R, cannabinoid receptors.

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potassium channels responsible for the hyperpolarization. Because GHB is a weak agonist, only GABA neurons are inhibited at the concentrations typically obtained with recreational use. This feature may underlie the reinforcing effects of GHB and the basis for addiction to the drug. At higher doses, however, GHB also hyperpolarizes dopamine neurons, eventually completely inhibiting dopamine release. Such an inhibition of the VTA may in turn preclude its activation by other addictive drugs and may explain why GHB might have some usefulness as an “anticraving” compound, particularly in the treatment of alcoholism.

BENZODIAZEPINES Benzodiazepines are commonly prescribed as anxiolytics and sleep medications. They represent a definite risk for abuse, which has to be weighed against their beneficial effects. Some persons abuse benzodiazepines for their euphoriant effects, but most often, abuse occurs concomitant with other drugs, eg, to attenuate anxiety during withdrawal from opioids. Benzodiazepine dependence is very common, and diagnosis of addiction is probably often missed. Withdrawal from benzodiazepines occurs within days of stopping the medication and varies as a function of the half-life of elimination. Symptoms include irritability, insomnia, phonophobia and photophobia, depression, muscle cramps, and even seizures. Typically, these symptoms taper off within 1–2 weeks. Benzodiazepines are positive modulators of the GABAA receptor, increasing both single-channel conductance and open-channel probability. GABAA receptors are pentameric structures consisting of α, β, and γ subunits (see Chapter 22). GABA receptors on dopamine neurons of the VTA lack α1, a subunit isoform that is present in GABA neurons nearby (ie, interneurons). Because of this difference, unitary synaptic currents in interneurons are larger than those in dopamine neurons, and when this difference is amplified by benzodiazepines, interneurons fall silent. GABA is no longer released, and benzodiazepines lose their effect on dopamine neurons, ultimately leading to disinhibition of the dopamine neurons. The rewarding effects of benzodiazepines are, therefore, mediated by α1-containing GABAA receptors expressed on VTA neurons. Receptors containing α5 subunits seem to be required for tolerance to the sedative effects of benzodiazepines, and studies in humans link α2β3-containing receptors to alcohol dependence (the GABAA receptor is also a target of alcohol; see following text). Taken together, a picture is emerging linking GABAA receptors that contain the α1 subunit isoform to their addiction liability. By extension, α1-sparing compounds, which at present remain experimental and are not approved for human use, may eventually be preferred to treat anxiety disorders because of their reduced risk of induced addiction. Barbiturates, which preceded benzodiazepines as the most commonly abused sedative-hypnotics (after ethanol), are now rarely prescribed to outpatients and therefore constitute a less common prescription drug problem than they did in the past. Street sales of barbiturates, however, continue. Management of barbiturate withdrawal and addiction is similar to that of benzodiazepines.

DRUGS WITH MULTIPLE MECHANISMS OF ACTION ALCOHOL Alcohol (ethanol, see Chapter 23) is regularly used by most of the population in many Western countries. Although only a minority becomes dependent and addicted, abuse is a severe public health problem because of the social costs and many diseases associated with alcoholism.

Pharmacology The pharmacology of alcohol is complex, and no single receptor mediates all of its effects. On the contrary, alcohol alters the function of several receptors and cellular functions, including GABAA receptors, Kir3/GIRK channels, adenosine reuptake (through the equilibrative nucleoside transporter, ENT1), the glycine receptor, NMDA receptor, and 5-HT3 receptor. They are all, with the exception of ENT1, either ionotropic receptors or ion channels. It is not clear which of these targets is responsible for the increase of dopamine release from the mesolimbic reward system. The inhibition of ENT1 is probably not responsible for the rewarding effects (ENT1 knockout mice drink more than controls) but seems to be involved in alcohol dependence through an accumulation of adenosine, stimulation of adenosine A2 receptors, and ensuing enhanced CREB signaling. Dependence becomes apparent 6–12 hours after cessation of heavy drinking as a withdrawal syndrome that may include tremor (mainly of the hands), nausea and vomiting, excessive sweating, agitation, and anxiety. In some individuals, this is followed by visual, tactile, and auditory hallucinations 12–24 hours after cessation. Generalized seizures may manifest after 24–48 hours. Finally, 48–72 hours after cessation, an alcohol withdrawal delirium (delirium tremens) may become apparent in which the person hallucinates, is disoriented, and shows evidence of autonomic instability. Delirium tremens is associated with 5–15% mortality.

Treatment Treatment of ethanol withdrawal is supportive and relies on benzodiazepines, taking care to use compounds such as oxazepam and lorazepam, which are not as dependent on oxidative hepatic metabolism as most other benzodiazepines. In patients in whom monitoring is not reliable and liver function is adequate, a longeracting benzodiazepine such as chlordiazepoxide is preferred. As in the treatment of all chronic drug abuse problems, heavy reliance is placed on psychosocial approaches to alcohol addiction. This is perhaps even more important for the alcoholic patient because of the ubiquitous presence of alcohol in many social contexts. The pharmacologic treatment of alcohol addiction is limited, although several compounds, with different goals, have been used. Therapy is discussed in Chapter 23.

INHALANTS Inhalant abuse is defined as recreational exposure to chemical vapors, such as nitrites, ketones, and aliphatic and aromatic hydrocarbons. These substances are present in a variety of

CHAPTER 32  Drugs of Abuse    619

household and industrial products that are inhaled by “sniffing,” “huffing,” or “bagging.” Sniffing refers to inhalation from an open container, huffing to the soaking of a cloth in the volatile substance before inhalation, and bagging to breathing in and out of a paper or plastic bag filled with fumes. It is common for novices to start with sniffing and progress to huffing and bagging as addiction develops. Inhalant abuse is particularly prevalent in children and young adults. The exact mechanism of action of most volatile substances remains unknown. Altered function of ionotropic receptors and ion channels throughout the central nervous system has been demonstrated for a few. Nitrous oxide, for example, binds to NMDA receptors, and fuel additives enhance GABAA receptor function. Most inhalants produce euphoria; increased excitability of the VTA has been documented for toluene and may underlie its addiction risk. Other substances, such as amyl nitrite (“poppers”), primarily produce smooth muscle relaxation and enhance erection but are not addictive. With chronic exposure to the aromatic hydrocarbons (eg, benzene, toluene), toxic effects can be observed in many organs, including white matter lesions in the central nervous system. Management of overdose remains supportive.

NON-ADDICTIVE DRUGS OF ABUSE LSD, MESCALINE, & PSILOCYBIN LSD, mescaline, and psilocybin are commonly called psychedelics because of their ability to alter consciousness, so one senses stimuli that are not present. They induce, often in an unpredictable way, perceptual symptoms, including shape and color distortion. Psychosis-like manifestations (depersonalization, hallucinations, distorted time perception) have led some to classify these drugs as psychotomimetics. They also produce somatic symptoms (dizziness, nausea, paresthesias, and blurred vision). Some users have reported intense reexperiencing of perceptual effects (flashbacks) up to several years after the last drug exposure. Psychedelics differ from most other drugs described in this chapter in that they induce neither dependence nor addiction. However, repetitive exposure still leads to rapid tolerance (also called tachyphylaxis). Animals do not self-administer hallucinogens, suggesting that they are not rewarding to them. Additional studies show that these drugs also fail to stimulate dopamine release, further supporting the idea that only drugs that activate the mesolimbic dopamine system are addictive. Instead, hallucinogens increase glutamate release in the cortex, presumably by enhancing excitatory afferent input via presynaptic serotonin receptors (eg, 5-HT2A,B) from the thalamus. Resolution of the 3D structure of an LSD-bound 5-HT2B receptor reveals an unusual attachment mode, explaining the slow kinetics of the molecule. LSD is an ergot alkaloid. After synthesis, blotter paper or sugar cubes are sprinkled with the liquid and allowed to dry. When LSD is swallowed, psychoactive effects typically appear after 30 minutes and last 6–12 hours. During this time, subjects have impaired ability to make rational judgments and understand common dangers, which puts them at risk for accidents and personal injury. In adults, a typical dose is 20–30 mcg. LSD is not considered neurotoxic, but like most ergot alkaloids, it may lead to

strong contractions of the uterus that can induce abortion (see Chapter 16). The main molecular target of LSD and other hallucinogens is the 5-HT2A receptor. This receptor couples to G proteins of the Gq type and generates inositol trisphosphate (IP3), leading to a release of intracellular calcium. Although hallucinogens, and LSD in particular, have been proposed for several therapeutic indications, efficacy remains elusive pending the outcome of ongoing clinical studies (for historical reasons often being carried out in Switzerland) for cluster headache, depression, and alcohol use disorder.

KETAMINE & PHENCYCLIDINE (PCP) Ketamine and PCP were developed as general anesthetics (see Chapter 25), but only ketamine is still used for this application, and more recently as an antidepressant (see Chapter 30). Both drugs, along with others, are now classified as “club drugs” and sold under names such as “angel dust,” “Hog,” and “Special K.” They owe their effects to their use-dependent, noncompetitive antagonism of the NMDA receptor. The effects of these substances became apparent when patients undergoing surgery reported unpleasant vivid dreams and hallucinations after anesthesia. Ketamine and PCP are white crystalline powders in their pure forms, but on the street they are also sold as liquids, capsules, or pills, which can be snorted, ingested, injected, or smoked. Psychedelic effects last for about 1 hour and also include increased blood pressure, impaired memory function, and visual alterations. At high doses, unpleasant out-of-body and neardeath experiences have been reported. Although ketamine and PCP do not cause dependence and addiction (relative risk = 1), chronic exposure, particularly to the latter, may lead to long-lasting psychosis closely resembling schizophrenia, which may persist beyond drug exposure. Surprisingly, intravenous administration of ketamine can eliminate episodes of depression within hours (see Chapter 30), in strong contrast to selective serotonin reuptake inhibitors and other antidepressants, which usually take weeks to act. The antidepressive mechanism is believed to involve the antagonism of NMDA receptors. An alternate explanation may involve hydroxynorketamine, a metabolite of ketamine, that targets AMPA receptors to exert the antidepressant effect. Recent findings suggest that ketamine dampens the NMDA receptor dependent burst activity of neurons of the lateral habenula, which leads to a weak disinhibition of the ventral tegmental area. Additional work implicates a disinhibitory circuit in the anterior cingulate cortex. While one ketamine preparation (eg, esketamine, the S-enantiomer, introduced in Germany in 1997 as an anesthetic) has received FDA approval to treat depression in adults, a limitation may be the transient nature of the effect, which wears off within days even with repetitive administration.

■■ CLINICAL PHARMACOLOGY OF DEPENDENCE & ADDICTION No single pharmacologic treatment (even in combination with behavioral interventions) efficiently eliminates addiction. This is not to say that addiction is irreversible. Pharmacologic interventions

620    SECTION V  Drugs That Act in the Central Nervous System

may in fact, be useful at all stages of the disease. This is particularly true in the case of a massive overdose, in which reversal of drug action may be a lifesaving measure. However, FDA-approved antagonists are available only for opioids and benzodiazepines. Pharmacologic interventions may also alleviate the withdrawal syndrome, particularly after opioid exposure. On the assumption that withdrawal reflects—at least in part—hyperactivity of central adrenergic systems, the α2-adrenoceptor agonist clonidine (also used as a centrally active antihypertensive drug; see Chapter 11) has been used with some success to attenuate withdrawal. Today, most clinicians prefer to manage opioid withdrawal by very slowly tapering the administration of long-acting opioids. Another widely accepted treatment is substitution of a legally available agonist that acts at the same receptor as the abused drug. This approach has been approved for opioids and nicotine. For example, heroin addicts may receive methadone to replace heroin; smoking addicts may receive nicotine continuously via a transdermal patch system to replace smoking. In general, a rapid-acting substance is replaced with one that acts or is absorbed more slowly. Some substitution therapies employ a partial agonist (eg, buprenorphine), which, however, may trigger withdrawal. Substitution treatments are largely justified by the benefits of reducing associated health risks, the reduction of drug-associated crime, and better social integration. Although dependence persists, the goal is, with the support of behavioral interventions, to motivate drug users to gradually reduce the dose and become abstinent. The biggest challenge is the treatment of addiction itself. Several approaches have been proposed, but all remain experimental. One approach is to pharmacologically reduce cravings.

The μ-opioid receptor antagonist and partial agonist naltrexone is FDA-approved for this indication in opioid and alcohol addiction. Its effect is modest and may involve a modulation of endogenous opioid systems. Clinical trials are currently being conducted with a number of drugs, including the high-affinity GABAB-receptor agonist baclofen, and initial results have shown a significant reduction of craving. This effect may be mediated by the inhibition of the dopamine neurons of the VTA, which is possible at baclofen concentrations obtained by oral administration because of its very high affinity for the GABAB receptor. Rimonabant is an inverse agonist of the CB1 receptor that behaves like an antagonist of cannabinoids. It was developed for smoking cessation and to facilitate weight loss. Because of frequent adverse effects—most notably severe depression carrying a substantial risk of suicide—this drug is no longer used clinically. It was initially used in conjunction with diet and exercise for obese patients (body mass index above 30 kg/m2). While the cellular mechanism of rimonabant remains to be elucidated, data in rodents convincingly demonstrate that this compound can reduce self-administration in naive as well as drug-experienced animals. While still experimental, the emergence of a circuit model for addiction has prompted interest in neuromodulatory interventions, such as deep brain stimulation (DBS) or transcranial magnetic stimulation (TMS). Inspired by optogenetic “treatments” in rodent models of addiction, novel protocols have been proposed for DBS in the nucleus accumbens or TMS of the prefrontal cortex. Case studies seem to confirm the potential of such approaches, but controlled clinical studies are lacking.

SUMMARY  Drugs Used to Treat Dependence and Addiction Subclass, Drug

Mechanism of Action

Effects

Clinical Applications

Reverses the acute effects of opioids; can precipitate severe abstinence syndrome Blocks effects of illicit opioids

Opioid overdose

Slow-acting agonist of μ-opioid receptor

Acute effects similar to morphine (see text)

Substitution therapy for opioid addicts

  •  Levomethadone

“Enantiopure” methadone containing only the left-enantiomer of the molecule

Similar to morphine and methadone, but at half the dose of the latter

Substitution therapy

  •  Morphine sulphate

A salt containing morphine sulfate pentahydrate

Slow-release version with a longer action than morphine

Substitution therapy

OPIOID RECEPTOR ANTAGONIST Nonselective antagonist of opioid receptors

  •  Naloxone

  •  Naltrexone SYNTHETIC OPIOID   •  Methadone

Antagonist of opioid receptors

Treatment of alcoholism, opioid addiction

Pharmacokinetics, Toxicities, Interactions Effect much shorter than morphine (1–2 h); therefore several injections required Half-life 10 h (oral); 5–10 days (depot injection)

High oral bioavailability • half-life highly variable among individuals (range 4–130 h) • Toxicity: Respiratory depression, constipation, miosis, tolerance, dependence, arrhythmia, and withdrawal symptoms Less toxic compared to racemic methadone, particularly related to cardiac adverse effects (long QT interval)

(continued)

CHAPTER 32  Drugs of Abuse    621

Subclass, Drug

Mechanism of Action

Pharmacokinetics, Toxicities, Interactions

Effects

Clinical Applications

PARTIAL m-OPIOID RECEPTOR AGONIST   •  Buprenorphine Partial agonist at μ-opioid receptors

Attenuates acute effects of morphine

Oral substitution therapy for opioid addicts

Long half-life (40 h) • formulated together with naloxone to avoid illicit IV injections

NICOTINIC RECEPTOR PARTIAL AGONIST   •  Varenicline Partial agonist of nicotinic acetylcholine receptor of the α4β2-type

Occludes “rewarding” effects of smoking • heightened awareness of colors

Smoking cessation

Toxicity: Nausea and vomiting, seizures, psychiatric changes

Enhances GABAergic synaptic transmission; attenuates withdrawal symptoms (tremor, hallucinations, anxiety) in alcoholics • prevents withdrawal seizures

Delirium tremens

Half-life 4–15 h • pharmacokinetics not affected by decreased liver function

May interfere with forms of synaptic plasticity that depend on NMDA receptors

Treatment of alcoholism • effective only in combination with counseling

Toxicity: Allergic reactions, arrhythmia, and low or high blood pressure, headaches, insomnia, and impotence • hallucinations, particularly in elderly patients

Decreases neurotransmitter release at GABAergic and glutamatergic synapses

Approved in Europe from 2006 to 2008 to treat obesity, then withdrawn because of major side effects • smoking cessation has never been approved, but remains an off-label indication

Toxicity: Major depression, including increased risk of suicide

  •  Cytisine: Natural analog (extracted from laburnum flowers) of varenicline BENZODIAZEPINES   •  Oxazepam, others

Positive modulators of the GABAA receptors, increase frequency of channel opening

  •  Lorazepam: Alternate to oxazepam with similar properties N-METHYL-d-ASPARTATE (NMDA) ANTAGONIST   •  Acamprosate

Antagonist of NMDA glutamate receptors

CANNABINOID RECEPTOR INVERSE AGONIST   •  Rimonabant CB1 receptor inverse agonist

REFERENCES General Hancock DB et al: Human genetics of addiction: New insights and future directions. Current Psychiatry Rep 2018;20, doi:10.1007/s11920-018-0873-3. Lüscher C, Janak PH: Consolidating the circuit model for addiction. Annu Rev Neurosci 2021;44:173. Lüscher C, Robbins TW, Everitt BJ: The transition to compulsion in addiction. Nat Rev Neurosci 2020;21:247. Nestler EJ, Lüscher C: The molecular basis of drug addiction: Linking epigenetic to synaptic and circuit mechanisms. Neuron 2019;102:48. Pascoli V et al: Stochastic synaptic plasticity underlying compulsion in a model of addiction. Nature 2018;564:366. Redish AD, Jensen S, Johnson A: A unified framework for addiction: Vulnerabilities in the decision process. Behav Brain Sci 2008;31:461.

Pharmacology of Drugs of Abuse Benowitz NL: Nicotine addiction. N Engl J Med 2010;362:2295. Corre J et al: Dopamine neurons projecting to medial shell of the nucleus accumbens drive heroin reinforcement. eLife 2018;7:e39945.

Simmler LD et al: Dual action of ketamine confines addiction liability. Nature 2022;608:368. Maskos U et al: Nicotine reinforcement and cognition restored by targeted expression of nicotinic receptors. Nature 2005;436:103. Morton J: Ecstasy: Pharmacology and neurotoxicity. Curr Opin Pharmacol 2005;5:79. Nichols DE: Hallucinogens. Pharmacol Ther 2004;101:131. Shen W et al: Dichotomous dopaminergic control of striatal synaptic plasticity. Science 2008;321:848. Snead OC, Gibson KM: Gamma-hydroxybutyric acid. N Engl J Med 2005;352:2721. Sulzer D et al: Mechanisms of neurotransmitter release by amphetamines: A review. Prog Neurobiol 2005;75:406. Tan KR et al: Neural basis for addictive properties of benzodiazepines. Nature 2010;463:769.

622    SECTION V  Drugs That Act in the Central Nervous System

C ASE STUDY ANSWER When found by his parents, the patient was having visual hallucinations of colorful insects. Hallucinations are often caused by a cannabis overdose, especially when hashish is ingested. The slower kinetics of oral cannabis are more difficult to control compared to smoking marijuana. The poor learning performance may be due to the interference of

exogenous cannabis with endocannabinoids that fine-tune synaptic transmission and plasticity. While probably not fulfilling the criteria for addiction at present, the patient is at risk as epidemiologic studies show that drug abuse typically begins in late adolescence. The fact that he is not yet using other drugs is a positive sign.

SECTION VI  DRUGS USED TO TREAT DISEASES OF THE BLOOD, INFLAMMATION, & GOUT

33

C

Agents Used in Cytopenias; Hematopoietic Growth Factors

H

A

P

T

E

R

James L. Zehnder, MD, & Lacrisha J. Go, DNP, FNP-C*

C ASE STUDY A 25-year-old woman who has been on a strict vegan diet for the past 2 years presents with increasing numbness and paresthesias in her extremities, generalized weakness, a sore tongue, and gastrointestinal discomfort. Physical examination reveals a pale woman with diminished vibration sensation, diminished spinal reflexes, and extensor plantar reflexes (Babinski sign). Examination of her oral cavity reveals atrophic glossitis, in which the tongue appears deep red in color and abnormally smooth and shiny due to atrophy of the lingual papillae. Laboratory testing reveals a macrocytic anemia based on a hematocrit of 30% (normal

Hematopoiesis, the production from undifferentiated stem cells of circulating erythrocytes, platelets, and leukocytes, is a remarkable process that produces more than 200 billion new blood cells *

The authors acknowledge the contributions of the previous author of this chapter, Susan B. Masters, PhD.

for women, 37–48%), a hemoglobin concentration of 9.4 g/dL, an erythrocyte mean cell volume (MCV) of 123 fL (normal, 84–99 fL), an erythrocyte mean cell hemoglobin concentration (MCHC) of 34% (normal, 31–36%), and a low reticulocyte count. Further laboratory testing reveals a normal serum folate concentration and a serum vitamin B12 (cobalamin) concentration of 98 pg/mL (normal, 250–1100 pg/mL). Once megaloblastic anemia was identified, why was it important to measure serum concentrations of both folic acid and cobalamin? Should this patient be treated with oral or parenteral vitamin B12?

per day in the normal person and even greater numbers of cells in persons with conditions that cause loss or destruction of blood cells. In adults, the hematopoietic machinery resides primarily in the bone marrow and requires a constant supply of three essential nutrients—iron, vitamin B12, and folic acid—as well as the presence of hematopoietic growth factors, proteins that regulate 623

624    SECTION VI  Drugs Used to Treat Diseases of the Blood, Inflammation, & Gout

the proliferation and differentiation of hematopoietic cells. Inadequate supplies of either the essential nutrients or the growth factors result in deficiency of functional blood cells. Anemia, a deficiency in oxygen-carrying erythrocytes, is the most common deficiency and several forms are easily treated. Sickle cell anemia, a condition resulting from a genetic alteration in the hemoglobin molecule, is common but is not easily treated. It is discussed in the Box: Sickle Cell Disease and Hydroxyurea. Thrombocytopenia and neutropenia are not rare, and some forms are amenable to drug therapy. In this chapter, we first consider the treatment of anemia due to deficiency of iron, vitamin B12, or folic acid; we then turn to the medical use of hematopoietic growth factors to combat anemia, thrombocytopenia, and neutropenia, and to support stem cell transplantation.

■■ AGENTS USED IN ANEMIAS IRON Basic Pharmacology Iron deficiency is the most common cause of chronic anemia. Like other forms of chronic anemia, iron deficiency anemia leads to pallor, fatigue, dizziness, exertional dyspnea, and other generalized symptoms of tissue hypoxia. The cardiovascular adaptations to chronic anemia—tachycardia, increased cardiac output,

vasodilation—can worsen the condition of patients with underlying cardiovascular disease. Iron forms the nucleus of the iron-porphyrin heme ring, which together with globin chains forms hemoglobin. Hemoglobin reversibly binds oxygen and provides the critical mechanism for oxygen delivery from the lungs to other tissues. In the absence of adequate iron, small erythrocytes with insufficient hemoglobin are formed, giving rise to microcytic hypochromic anemia. Ironcontaining heme is also an essential component of myoglobin, cytochromes, and other proteins with diverse biologic functions.

Pharmacokinetics Free inorganic iron is extremely toxic, but iron is required for essential proteins such as hemoglobin; therefore, evolution has provided an elaborate system for regulating iron absorption, transport, and storage (Figure 33–1). The system uses specialized transport, storage, ferrireductase, and ferroxidase proteins whose concentrations are controlled by the body’s demand for hemoglobin synthesis and adequate iron stores (Table 33–1). A peptide called hepcidin, produced primarily by liver cells, serves as a key central regulator of the system. Nearly all of the iron used to support hematopoiesis is reclaimed from catalysis of the hemoglobin in senescent or damaged erythrocytes. Normally, only a small amount of iron is lost from the body each day, so dietary requirements are small and easily fulfilled by the iron available in a wide variety of foods. However, in special populations with either increased iron requirements

Sickle Cell Disease and Hydroxyurea Sickle cell disease is a genetic cause of hemolytic anemia, a form of anemia due to increased erythrocyte destruction, instead of the reduced mature erythrocyte production seen with iron, folic acid, and vitamin B12 deficiency. Patients with sickle cell disease are homozygous for the aberrant β-hemoglobin S (HbS) allele (substitution of valine for glutamic acid at amino acid 6 of β-globin) or heterozygous for HbS and a second mutated β-hemoglobin gene such as hemoglobin C (HbC) or β-thalassemia. Sickle cell disease has an increased prevalence in individuals of African descent because the heterozygous trait confers resistance to malaria. In the majority of patients with sickle cell disease, anemia is not the primary presenting problem; the anemia is generally well compensated even though such individuals have a chronically low hematocrit (20–30%), a low serum hemoglobin level (7–10 g/dL), and an elevated reticulocyte count. Instead, the primary problem is that deoxygenated HbS chains form polymeric structures that dramatically change erythrocyte shape, reduce deformability, and elicit membrane permeability changes that further promote hemoglobin polymerization. Abnormal erythrocytes aggregate in the microvasculature—where oxygen tension is low and hemoglobin is deoxygenated—and cause veno-occlusive damage. In the musculoskeletal system, this results in characteristic, extremely severe bone and joint pain. In the cerebral vascular system, it causes ischemic stroke. Damage

to the spleen increases the risk of infection, particularly by encapsulated bacteria such as Streptococcus pneumoniae. In the pulmonary system, there is an increased risk of infection, and in adults, an increase in embolism and pulmonary hypertension. Supportive treatment includes analgesics, antibiotics, pneumococcal vaccination, and blood transfusions. In addition, the cancer chemotherapeutic drug hydroxyurea (hydroxycarbamide) reduces veno-occlusive events. It is approved in the United States for treatment of adults with recurrent sickle cell crises and approved in Europe in adults and children with recurrent vasoocclusive events. As an anticancer drug used in the treatment of chronic and acute myelogenous leukemia, hydroxyurea inhibits ribonucleotide reductase and thereby depletes deoxynucleoside triphosphate and arrests cells in the S phase of the cell cycle (see Chapter 54). In the treatment of sickle cell disease, hydroxyurea acts through poorly defined pathways to increase the production of fetal hemoglobin γ (HbF), which interferes with the polymerization of HbS. Clinical trials have shown that hydroxyurea decreases painful crises in adults and children with severe sickle cell disease. Its adverse effects include hematopoietic depression, gastrointestinal effects, and teratogenicity in pregnant women. More recently, voxelotor, an oral drug that binds HbS and reduces sickling by increasing its affinity for oxygen, has received accelerated approval from the FDA.

CHAPTER 33  Agents Used in Cytopenias; Hematopoietic Growth Factors     625 4 Spleen, other tissues macrophage

Blood Senescent RBC

1 Gut lumen

Intestinal epithelial cells Hgb F

Hgb

Hgb Tf

HCP1

FP Fe3+

F

DB

FP

– Hepcidin FP

Fe2+

DMT1

–

– – Erythroferrone

Hepcidin TfR

F

Heme RBC production

Fe

2 Bone marrow erythrocyte precursor

TfR

3 Hepatocyte

FIGURE 33–1  Absorption, transport, and storage of iron. Intestinal epithelial cells actively absorb inorganic iron via the divalent metal transporter 1 (DMT1) and heme iron via the heme carrier protein 1 (HCP1). Iron that is absorbed or released from absorbed heme iron in the intestine (1) is actively transported into the blood by ferroportin (FP) and stored as ferritin (F). In the blood, iron is transported by transferrin (Tf ) to erythroid precursors in the bone marrow for synthesis of hemoglobin (Hgb) in red blood cells (RBC) (2); or to hepatocytes for storage as ferritin (3). The transferrin-iron complex binds to transferrin receptors (TfR) in erythroid precursors and hepatocytes and is internalized. After release of iron, the TfR-Tf complex is recycled to the plasma membrane and Tf is released. Macrophages that phagocytize senescent erythrocytes (RBC) reclaim the iron from the RBC hemoglobin and either export it or store it as ferritin (4). Hepatocytes use several mechanisms to take up iron and store the iron as ferritin. High hepatic iron stores increase hepcidin synthesis, and hepcidin inhibits ferroportin; low hepatocyte iron and increased erythroferrone inhibits hepcidin and enhances iron absorption via ferroportin. Ferrous iron (Fe2+), blue 3+ diamonds, squares; ferric iron (Fe ), red; DB, duodenal cytochrome B; F, ferritin. (Modified from Trevor A: Pharmacology Examination & Board Review, 9th ed. New York, NY: McGraw Hill; 2010.)

(eg, growing children, pregnant women) or increased losses of iron (eg, menstruating women), iron requirements can exceed normal dietary supplies, and iron deficiency can develop. A. Absorption The average American diet contains 10–15 mg of elemental iron daily. A normal individual absorbs 5–10% of this iron, or about 0.5–1 mg daily. Iron is absorbed in the duodenum and proximal jejunum, although the more distal small intestine can absorb iron if necessary. Iron absorption increases in response to low iron stores or increased iron requirements. Total iron absorption increases to 1–2 mg/d in menstruating women and may be as high as 3–4 mg/d in pregnant women. Iron is available in a wide variety of foods but is especially abundant in meat. The iron in meat protein can be efficiently absorbed,

because heme iron in meat hemoglobin and myoglobin can be absorbed intact without first having to be dissociated into elemental iron (see Figure 33–1). Iron in other foods, especially vegetables and grains, is often tightly bound to organic compounds and is much less available for absorption. Nonheme iron in foods and iron in inorganic iron salts and complexes must be reduced by a ferrireductase to ferrous iron (Fe2+) before it can be absorbed by intestinal mucosal cells. Iron crosses the luminal membrane of the intestinal mucosal cell by two mechanisms: active transport of ferrous iron by the divalent metal transporter DMT1, and absorption of iron complexed with heme (see Figure 33–1). Together with iron split from absorbed heme, the newly absorbed iron can be actively transported into the blood across the basolateral membrane by a transporter known as ferroportin and oxidized to ferric iron (Fe3+)

626    SECTION VI  Drugs Used to Treat Diseases of the Blood, Inflammation, & Gout

TABLE 33–1  Iron distribution in normal adults.1 Iron Content (mg) Men

Women

Hemoglobin

3050

1700

Myoglobin

 430

 300

Enzymes

  10

   8

Transport (transferrin)

   8

   6

Storage (ferritin and other forms)

 750

 300

Total

4248

2314

1

Values are based on data from various sources and assume that normal men weigh 80 kg and have a hemoglobin level of 16 g/dL and that normal women weigh 55 kg and have a hemoglobin level of 14 g/dL. Reproduced with permission from Wyngaarden JB, Smith LH: Cecil Textbook of Medicine, 18th ed. Philadelphia, PA: Saunders/Elsevier; 1988.

by the ferroxidase hephaestin. The liver-derived hepcidin inhibits intestinal cell iron release by binding to ferroportin and triggering its internalization and destruction. Excess iron is stored in intestinal epithelial cells as ferritin, a water-soluble complex consisting of a core of ferric hydroxide covered by a shell of a specialized storage protein called apoferritin. B. Transport Iron is transported in the plasma bound to transferrin, a β-globulin that can bind two molecules of ferric iron (see Figure 33–1). The transferrin-iron complex enters maturing erythroid cells by a specific receptor mechanism. Transferrin receptors—integral membrane glycoproteins present in large numbers on proliferating erythroid cells—bind and internalize the transferrin-iron complex through the process of receptor-mediated endocytosis. In endosomes, the ferric iron is released, reduced to ferrous iron, and transported by DMT1 into the cytoplasm, where it is funneled into hemoglobin synthesis or stored as ferritin. The transferrin-transferrin receptor complex is recycled to the cell membrane, where the transferrin dissociates and returns to the plasma. This process provides an efficient mechanism for supplying the iron required by developing red blood cells. Increased erythropoiesis is associated with an increase in the number of transferrin receptors on developing erythroid cells and a reduction in hepatic hepcidin release. Iron store depletion and iron deficiency anemia are associated with an increased concentration of serum transferrin. C. Storage In addition to the storage of iron in intestinal mucosal cells, iron is also stored, primarily as ferritin, in macrophages in the liver, spleen, and bone, and in parenchymal liver cells (see Figure 33–1). The mobilization of iron from macrophages and hepatocytes is primarily controlled by hepcidin regulation of ferroportin activity. Low hepcidin concentrations result in iron release from these storage sites; high hepcidin concentrations inhibit iron release. Ferritin is detectable in serum. Since the ferritin present in serum is in equilibrium with storage ferritin in reticuloendothelial tissues, the serum ferritin level can be used to estimate total body iron stores.

D. Elimination There is no mechanism for excretion of iron. Small amounts are lost in the feces by exfoliation of intestinal mucosal cells, and trace amounts are excreted in bile, urine, and sweat. These losses account for no more than 1 mg of iron per day. Because the body’s ability to excrete iron is so limited, regulation of iron balance must be achieved by changing intestinal absorption and storage of iron in response to the body’s needs. As noted below, impaired regulation of iron absorption leads to serious pathology.

Clinical Pharmacology A. Indications for the Use of Iron The only clinical indication for the use of iron preparations is the treatment or prevention of iron deficiency anemia. This manifests as a hypochromic, microcytic anemia in which the erythrocyte mean cell volume (MCV) and the mean cell hemoglobin concentration are low (Table 33–2). Iron deficiency is commonly seen in populations with increased iron requirements. These include infants, especially premature infants; children during rapid growth periods; pregnant and lactating women; and patients with chronic kidney disease who lose erythrocytes at a relatively high rate during hemodialysis and also form them at a high rate as a result of treatment with the erythrocyte growth factor erythropoietin (see below). Inadequate iron absorption also can cause iron deficiency. This is seen after gastrectomy and in patients with severe small bowel disease that results in generalized malabsorption. The most common cause of iron deficiency in adults is blood loss. Menstruating women lose about 30 mg of iron with each menstrual period; women with heavy menstrual bleeding may lose much more. Thus, many premenopausal women have low iron stores or even iron deficiency. In men and postmenopausal women, the most common site of blood loss is the gastrointestinal tract.

TABLE 33–2  Distinguishing features of the nutritional anemias.

Nutritional Deficiency

Type of Anemia

Laboratory Abnormalities

Iron

Microcytic, hypochromic with MCV