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 2018030673, 9781496384133

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Table of contents :
Lippincott Illustrated Reviews Pharmacology, Seventh Edition
Half Title
Title Page
Copyright
In Memoriam
Contributing Authors
Contents
Chapter 1 Pharmacokinetics
Chapter 2 Drug-Receptor Interactions and Pharmacodynamics
Chapter 3 The Autonomic Nervous System
Chapter 4 Cholinergic Agonists
Chapter 5 Cholinergic Antagonists
Chapter 6 Adrenergic Agonists
Chapter 7 Adrenergic Antagonists
Chapter 8 Drugs for Neurodegenerative Diseases
Chapter 9 Anxiolytic and Hypnotic Drugs
Chapter 10 Antidepressants
Chapter 11 Antipsychotic Drugs
Chapter 12 Drugs for Epilepsy
Chapter 13 Anesthetics
Chapter 14 Opioids
Chapter 15 CNS Stimulants
Chapter 16 Antihypertensives
Chapter 17 Diuretics
Chapter 18 Drugs for Heart Failure
Chapter 19 Antiarrhythmics
Chapter 20 Antianginal Drugs
Chapter 21 Anticoagulants and Anti platelet Agents
Chapter 22 Drugs for Hyperlipidemia
Chapter 23 Pituitary and Thyroid
Chapter 24 Drugs for Diabetes
Chapter 25 Estrogens and Androgens
Chapter 26 Adrenal Hormones
Chapter 27 Drugs Affecting Bone Metabolism
Chapter 28 Principles of Antimicrobial Therapy
Chapter 29 Cell Wall Inhibitors
Chapter 30 Protein Synthesis Inhibitors
Chapter 31 Quinolones, Folic Acid Antagonists, and Urinary Tract Antiseptics
Chapter 32 Anti mycobacterial Drugs
Chapter 33 Antifungal Drugs
Chapter 34 Antiviral Drugs
Chapter 35 Anticancer Drugs
Chapter 36 Immunosuppressants
Chapter 37 Histamine and Serotonin
Chapter 38 Anti-inflammatory, Antipyretic, and Analgesic Agents
Chapter 39 Drugs for Disorders of the Respiratory System
Chapter 40 Gastrointestinal and Antiemetic Drugs
Chapter 41 Drugs for Urologic Disorders
Chapter 42 Drugs for Anemia
Chapter 43 Drugs for Dermatologic Disorders
Chapter 44 Clinical Toxicology
Index
Figure Credits
Chapter 45 Drugs of Abuse
Chapter 46 Antiprotozoal Drugs
Chapter 47 Anthelmintic Drugs

Citation preview

LippincotP Illustrated Reviews: Pharmacology Seventh Edition

Lippincott® Illustrated Reviews: Pharmacology Seventh Edition

Karen Whalen, PharmD, BCPS, FAPhA Clinical Professor Department of Pharmacotherapy and Translational Research College of Pharmacy University of Florida Gainesville, Florida

Collaborating Editors Carinda Feild, PharmD, FCCM Clinical Associate Professor Department of Pharmacotherapy and Translational Research College of Pharmacy University of Florida St. Petersburg, Florida

Rajan Radhakrishnan, BPharm, MSc, PhD Professor of Pharmacology College of Medicine Mohammed Bin Rashid University of Medicine and Health Sciences Dubai, United Arab Emirates

I)

Wolters Kluwer Philadelphia • Baltimore • New York • London Buenos Aires • Hong Kong • Sydney • Tokyo

Acquisitions Editor: Matt Hauber Development Editor: Andrea Vosburgh Editorial Coordinator: Kerry McShane Editorial Assistant: Brooks Phelps Production Project Manager: Barton Dudlick Design Coordinator: Stephen Druding Art Director: Jennifer Clements Manufacturing Coordinator: Margie Orzech Marketing Manager: Michael McMahon Prepress Vendor: SPi Global

Seventh Edition Copyright C 2019 Wolters Kluwer Copyright C 2015 Wolters Kluwer, C 2012 Wolters Kluwer Health I Lippincott Williams & Wilkins, Copyright C 2009 Lippincott Williams & Wilkins, a Wolters Kluwer business, Copyright C 2006, 2000 Lippincott Williams & Wilkins, Copyright C 1997 Lippincott-Raven Publishers, Copyright C 1992 J. B. Lippincott Company. All rights reserved. This book is protected by copyright. No part of this book may be reproduced or transmitted in any form or by any means, including as photocopies or scannedin or other electronic copies, or utilized by any information storage and retrieval system without written permission from the copyright owner, except for brief quotations embodied in critical articles and reviews. Materials appearing in this book prepared by individuals as part of their official duties as U.S. government employees are not covered by the above-mentioned copyright. To request permission, please contact Wolters Kluwer Health at Two Commerce Square, 2001 Market Street, Philadelphia, PA 191 03, via email at permissions@ lww.com, or via our website at lww.com (products and services). 987654321 Printed in China Library of Congress Cataloging-In-Publication Data Names: Whalen, Karen, editor. I Feild, Carinda, editor. I Radhakrishnan, Rajan, editor. Title: Pharmacology I [edited by] Karen Whalen ; collaborating editors, Carinda Feild, Rajan Radhakrishnan. Other titles: Pharmacology (Whalen) 1 Uppincott's illustrated reviews. Description: Seventh edition. 1 Philadelphia :Wolters Kluwer, [2019] 1 Series: Lippincott illustrated reviews I Includes bibliographical references and index. Identifiers: LCCN 2018030673 I ISBN 9781496384133 (pbk.) Subjects: I MESH: Pharmacology I Examination Questions I Outlines Classification: LCC RM301. 14 1 NLM av 18.2 1 DDC 615/.1 076--dc23 LC record available at https:l/lccn .loc.gov/2018030673

This work is provided "as is," and the publisher disclaims any and all warranties, express or implied, including any warranties as to accuracy, comprehensiveness, or currency of the content of this work. This work is no substitute for individual patient assessment based upon healthcare professionals' examination of each patient and consideration of, among other things, age, weight, gender, current or prior medical conditions, medication history, laboratory data and other factors unique to the patient. The publisher does not provide medical advice or guidance and this work is merely a reference tool. Healthcare professionals, and not the publisher, are solely responsible for the use of this work including all medical judgments and for any resulting diagnosis and treatments. Given continuous, rapid advances in medical science and health information, independent professional verification of medical diagnoses, indications, appropriate pharmaceutical selections and dosages, and treatment options should be made and healthcare professionals should consult a variety of sources. When prescribing medication, healthcare professionals are advised to consult the product information sheet (the manufacturer's package insert) accompanying each drug to verify, among other things, conditions of use, warnings and side effects and identify any changes in dosage schedule or contradictions, particularly if the medication to be administered is new, infrequently used or has a narrow therapeutic range. To the maximum extent permitted under applicable law, no responsibility is assumed by the publisher for any injury and/or damage to persons or property, as a matter of products liability, negligence law or otherwise, or from any reference to or use by any person of this work. LWW.com

In Memoriam Richard A. Harvey, PhD 1936--2017

Co-creator and series editor of the Lippincott Illustrated Reviews series, in collaboration with Pamela C. Champe, PhD (1945-2008). Illustrator and co-author of the first books in the series: Biochemistry, Pharmacology, and Microbiology and Immunology.

v

Contributing Authors Katherine Vogel Anderson, PharmD, BCACP Associate Professor Colleges of Pharmacy and Medicine University of Florida Gainesville, Florida

Kevin Cowart, PharmD, MPH, BCACP Assistant Professor College of Pharmacy University of South Florida Tampa, Florida

Shawn Anderson, PharmD, BCACP Clinical Pharmacy Specialist-Cardiology NF/SG Veterans Medical Center Adjunct Clinical Assistant Professor College of Pharmacy University of Florida Gainesville, Florida

Zachary L. Cox, PharmD Associate Professor College of Pharmacy Lipscomb University Heart Failure Clinical Pharmacist Vanderbilt University Medical Center Nashville, Tennessee

Angela K. Birnbaum, PhD Professor Department of Experimental and Clinical Pharmacology College of Pharmacy University of Minnesota Minneapolis, Minnesota Nancy Borja-Hart, PharmD Associate Professor The University of Tennessee Health Science Center College of Pharmacy Nashville, Tennessee Lindsey Childs-Kean, PharmD, MPH, BCPS Clinical Assistant Professor College of Pharmacy University of Florida Gainesville, Florida Jonathan c. Cho, PharmD, MBA Clinical Assistant Professor The University of Texas at Tyler Tyler, Texas Michelle Chung, PharmD Clinical Pharmacy Specialist-Cardiology NF/SG Veterans Medical Center Gainesville, Florida Jeannine M. Conway, PharmD Associate Professor College of Pharmacy University of Minnesota Minneapolis, Minnesota

Stacey Curtis, PharmD Clinical Assistant Professor College of Pharmacy University of Florida Gainesville, Florida Eric Dietrich, PharmD, BCPS Clinical Assistant Professor College of Pharmacy University of Florida Gainesville, Florida Lori Dupree, PharmD, BCPS Clinical Assistant Professor College of Pharmacy University of Florida Jacksonville, Florida Eric F. Egelund, PharmD, PhD Clinical Assistant Professor College of Pharmacy University of Florida Jacksonville, Florida Carinda Feild, PharmD, FCCM Clinical Associate Professor Department of Pharmacotherapy and Translational Research College of Pharmacy University of Florida St. Petersburg, Florida Chris Giordano, MD Associate Professor Department of Anesthesiology College of Medicine University of Florida Gainesville, Florida vii

viii

Contributing Authors Benjamin Gross, PharmD, MBA Associate Professor College of Pharmacy Lipscomb University Nashville, Tennessee Clinical Pharmacist Maury Regional Medical Group Columbia, Tennessee Jennifer Jebrock, PharmD, BCPS Liver and Gl Transplant Clinical Pharmacist Jackson Memorial Hospital Miami, Florida Sandhya Jinesh, BPharm, MS, PharmD, RPh Chief Pharmacist West Haven Pharmacy West Haven, Connecticut Jacqueline Jour)y, PharmD, BCPS Clinical Assistant Professor College of Pharmacy University of Florida Orlando, Florida Adonlce Khoury, PharmD, BCPS Clinical Assistant Professor College of Pharmacy University of Florida UF Health Shands Hospital Clinical Pharmacy Specialist Gainesville, Florida Jamie Kisgen, PharmD Pharmacotherapy Specialist-Infectious Diseases Sarasota Memorial Health Care System Sarasota, Florida

Brandon Lopez, MD Clinical Assistant Professor Department of Anesthesiology College of Medicine University of Florida Gainesville, Florida Paige May, PharmD, BCOP Oncology Pharmacy Specialist Malcom Randall VA Medical Center Clinical Assistant Professor University of Florida Gainesville, Florida Kyle Melin, PharmD, BCPS Assistant Professor School of Pharmacy University of Puerto Rico San Juan, Puerto Rico Shannon Miller, PharmD, BCACP Clinical Associate Professor College of Pharmacy University of Florida Orlando, Florida W. Cary Mobley, BS Pharmacy, PhD Clinical Associate Professor College of Pharmacy University of Florida Gainesville, Florida Cynthia Moreau, PharmD, BCACP Assistant Professor College of Pharmacy Nova Southeastern University Fort Lauderdale, Florida

Kenneth P. Klinker, PharmD Clinical Associate Professor College of Pharmacy University of Florida Gainesville, Florida

Carol Motycka, PharmD, BCACP Clinical Associate Professor College of Pharmacy University of Florida Jacksonville, Florida

Kourtney LaPlant, PharmD, BCOP Clinical Pharmacy Program Manager-Oncology Department of Veterans Affairs Gainesville, Florida

Joseph Pardo, PharmD, BCPS-AQ ID, AAHIVP Infectious Diseases Clinical Specialist North Florida/South Georgia Veterans Health System Gainesville, Florida

Robin Moorman Li, PharmD, BCACP, CPE Clinical Associate Professor College of Pharmacy University of Florida Jacksonville, Florida

Kristyn Pardo, PharmD, BCPS Ambulatory Care Clinical Specialist Department of Pharmacy North Florida/South Georgia VA Medical Center Gainesville, Florida

Contributing Authors

ix Charles A. Peloquin, PharmD Professor College of Pharmacy University of Florida Gainesville, Florida Joanna Perla, PhD Associate Professor College of Pharmacy University of Florida Gainesville, Florida

Rajan Radhakrishnan, BPharm, MSc, PhD Professor of Pharmacology College of Medicine Mohammed Bin Rashid University of Medicine and Health Sciences Dubai, United Arab Emirates Jane Revollo, PharmD, BCPS Kidney/Pancreas Transplant Clinical Pharmacist Jackson Memorial Hospital Miami, Florida Jose A. Rey, MS, PharmD, BCPP Professor Nova Southeastern University Davie, Florida Clinical Psychopharmacologist South Florida State Hospital Pembroke Pines, Florida Karen Sando, PharmD, BCACP, BC-ADM Associate Professor College of Pharmacy Nova Southeastern University Fort Lauderdale, Florida Elizabeth Sherman, PharmD Associate Professor Nova Southeastern University Fort Lauderdale, Florida HIV/AIDS Clinical Pharmacy Specialist Division of Infectious Disease Memorial Healthcare System Hollywood, Florida Kaylie Smith, PharmD Instructor College of Pharmacy University of Florida Gainesville, Florida

Dawn Sollee, PharmD Assistant Director Florida/USVI Poison Information Center-Jacksonville Associate Professor Department of Emergency Medicine College of Medicine University of Florida Jacksonville, Florida Joseph Spillane, PharmD, DABAT Courtesy Associate Professor Department of Emergency Medicine College of Medicine University of Florida Jacksonville, Florida Amy Talana, BS, PharmD Instructor College of Pharmacy University of Florida Gainesville, Florida Veena Venugopalan, PharmD Clinical Assistant Professor College of Pharmacy University of Florida Gainesville, Florida Karen Whalen, PharmD, BCPS, FAPhA Clinical Professor Department of Pharmacotherapy and Translational Research College of Pharmacy University of Florida Gainesville, Florida Emily Jaynes Winograd, PharmD Clinical Toxicology/Emergency Medicine Fellow Florida/USVI Poison Information Center-Jacksonville Jacksonville, Florida Marylee V. Worley, PharmD, BCPS Assistant Professor College of Pharmacy Nova Southeastern University Fort Lauderdale, Florida Venkata Yellepeddi, BPharm, PhD Associate Professor Department of Pediatrics School of Medicine University of Utah Salt Lake City, Utah

Reviewers Faculty Reviewers Ronald Bolen, RN, BSN, CFRN, CEN, CCRN, EMT·P Flight Nurse Vanderbilt University LifeFiight Nashville, Tennessee Mary G. Flanagan, MS, PA-C Associate Director PA Program Touro College New York, New York Eyad Qunalbl, PhD

Student Reviewers Sarah Corral Yewande Dayo Wanda Lal Lorenzo R. Sewanan Melissa M. Vega

Illustration and Graphic Design Michael Cooper Cooper Graphic www.cooper247.com Claire Hess hess2 Design Louisville, Kentucky

X

Contents Contributing Authors ...vii Reviewers ... x

UNIT 1: Principles of Drug Therapy Chapter 1 :

Pharmacokinetics .. .1 Venkata Yellepeddi

Chapter 2:

Drug-Receptor Interactions and Pharmacodynamics .. .23 Joanna Peris

UNIT II: Drugs Affecting the Autonomic Nervous System Chapter 3:

The Autonomic Nervous System ... 37 Rajan Radhakrishnan

Chapter 4:

Cholinergic Agonists ... 48 Rajan Radhakrishnan

Chapter 5:

Cholinergic Antagonists ... 62 Rajan Radhakrishnan and Carinda Feild

Chapter 6:

Adrenergic Agonists ... 73 Rajan Radhakrishnan

Chapter 7:

Adrenergic Antagonists .. .91 Rajan Radhakrishnan and Sandhya Jinesh

UNIT III: Drugs Affecting the Central Nervous System Chapter 8:

Drugs for Neurodegenerative Diseases .. .103 Jose A. Rey

Chapter 9:

Anxiolytic and Hypnotic Drugs ... 116 Jose A. Rey

Chapter 10: Antidepressants .. .128 Jose A. Rey Chapter 11: Antipsychotic Drugs .. .139 Jose A. Rey Chapter 12: Drugs for Epilepsy... 148 Jeannine M. Conway and Angela K. Birnbaum Chapter 13: Anesthetics .. .161 Brandon Lopez and Chris Giordano Chapter 14: Opioids ... 180 Robin Moorman Li Chapter 15: CNS Stimulants ... 194 Jose A. Rey

xi

xii

Contents

UNIT IV: Drugs Affecting the Cardiovascular System Chapter 16: Antihypertensives ... 203 Benjamin Gross Chapter 17: Diuretics ... 218 Zachary L. Cox Chapter 18: Drugs for Heart Failure ... 231 Shawn Anderson and Katherine Vogel Anderson Chapter 19: Antiarrhythmics ... 248 Shawn Anderson and Michelle Chung Chapter 20: Antianginal Drugs ... 259 Kristyn Pardo Chapter 21: Anticoagulants and Antiplatelet Agents ... 268 Katherine Vogel Anderson and Kaylie Smith Chapter 22: Drugs for Hyperlipidemia... 287 Karen Sando and Kevin Cowart

UNIT V: Drugs Affecting the Endocrine System Chapter 23: Pituitary and Thyroid ... 301 Shannon Miller and Karen Whalen Chapter 24: Drugs for Diabetes... 311 Karen Whalen and Cynthia Moreau Chapter 25: Estrogens and Androgens ... 326 Karen Whalen Chapter 26: Adrenal Hormones... 340 Shannon Miller and Karen Whalen Chapter 27: Drugs Affecting Bone Metabolism ... 348 Karen Whalen

UNIT VI: Chemotherapeutic Drugs Chapter 28: Principles of Antimicrobial Therapy... 355 Jamie Kisgen Chapter 29: Cell Wall Inhibitors... 368 Veena Venugopalan and Kenneth P. Klinker Chapter 30: Protein Synthesis lnhlbitors ... 384 Jacqueline Jourjy Chapter 31: Quinolones, Folic Acid Antagonists, and Urinary Tract Antiseptics ... 400 Kenneth P. Klinker and Joseph Pardo Chapter 32: Antimycobacterial Drugs ... 413 Charles A. Peloquin and Eric F. Egelund Chapter 33: Antifungal Drugs ... 423 Lindsey Childs-Kean Chapter 34: Antiviral Drugs ... 436 Elizabeth Sherman Chapter 35: Anticancer Drugs ... 454 Kourtney LaPlant and Paige May Chapter 36: lmmunosuppressants... 481 Jennifer Jebrock and Jane Revollo

Contents

UNIT VII: Special Topics in Pfuzrmacology Chapter 37: Histamine and Serotonin ... 493 Nancy Borja-Hart and Carol Motycka Chapter 38: Anti-inflammatory, Antipyretic, and Analgesic Agents ... 508 Eric Dietrich and Amy Talana Chapter 39: Drugs for Disorders of the Respiratory System ... 527 Kyle Melin Chapter 40: Gastrointestinal and Antiemetic Drugs ... 540 Carol Motycka and Adonice Khoury Chapter 41: Drugs for Urologic Disorders ... 557 Katherine Vogel Anderson and Kaylie Smith Chapter 42: Drugs for Anemia ... 565 Lori Dupree Chapter 43: Drugs for Dermatologic Disorders ... 572 Stacey Curtis and Cary Mobley Chapter 44: Clinical Toxicology ... 584 Dawn Sollee and Emily Jaynes Winograd lndex... l-1 Figure Credits ... C-1 Go to http://thePolnt.lww.com/actlvate and use the scratch-off code on the Inside cover this book to access the following electronic chapters: Chapter 45: Drugs of Abuse Carol Motycka and Joseph Spillane Chapter 46: Antiprotozoal Drugs Marylee V. Worley and Jonathan C. Cho Chapter 47: Anthelmintic Drugs Jonathan C. Cho and Marylee V. Worley

xiii

Pharmacokinetics Venkata Yellepeddi

I. OVERVIEW Pharmacokinetics refers to what the body does to a drug, whereas pharmacodynamics (see Chapter 2) describes what the drug does to the body. Four pharmacokinetic properties determine the onset, intensity, and duration of drug action (Figure 1.1 ):

Drug at site of administration

Absorption (input)

• Absorption: First, absorption from the site of administration permits entry of the drug (either directly or indirectly) into plasma. • Distribution: Second, the drug may reversibly leave the bloodstream and distribute into the interstitial and intracellular fluids. • Metabolism: Third, the drug may be biotransformed through metabolism by the liver or other tissues. • Elimination: Finally, the drug and its metabolites are eliminated from the body in urine, bile, or feces.

Using knowledge of pharmacokinetic parameters, clinicians can design optimal drug regimens, including the route of administration, dose, frequency, and duration of treatment.

II. ROUTES OF DRUG ADMINISTRATION The route of administration is determined by properties of the drug (for example, water or lipid solubility, ionization) and by the therapeutic objectives (for example, the need for a rapid onset, the need for long-term treatment, or restriction of delivery to a local site). Major routes of drug administration include enteral, parenteral, and topical, among others (Figure 1.2}. Figure 1.1 Schematic representation of drug absorption, distribution, metabolism, and elimination.

1

1. Pharmacokinetics

2 A. Enteral

Enteral administration {administering a drug by mouth) is the most common, convenient, and economical method of drug administration. The drug may be swallowed, allowing oral delivery, or it may be placed under the tongue {sublingual) or between the gums and cheek {buccal), facilitating direct absorption into the bloodstream. 1. Oral: Oral administration provides many advantages. Oral drugs are easily self-administered, and toxicities and/or overdose of oral drugs may be overcome with antidotes, such as activated charcoal. However, the pathways involved in oral drug absorption are the most complicated, and the low gastric pH inactivates some drugs. A wide range of oral preparations is available including enteric-coated and extended-release preparations.

~

Rectal -1.'1-...-rrl--+-____.:~-.

or

vaginal

Figure 1.2 Commonly used routes of drug administration. IV = intravenous; IM = intramuscular; SC = subcutaneous.

a. Enteric-coated preparations: An enteric coating is a chemical envelope that protects the drug from stomach acid, delivering it instead to the less acidic intestine, where the coating dissolves and releases the drug. Enteric coating is useful for certain drugs {for example, omeprazole) that are acid labile, and for drugs that are irritating to the stomach, such as aspirin. b. Extended-release preparations: Extended-release {abbreviated ER, XR, XL, SR, etc.) medications have special coatings or ingredients that control drug release, thereby allowing for slower absorption and prolonged duration of action. ER formulations can be dosed less frequently and may improve patient compliance. In addition, ER formulations may maintain concentrations within the therapeutic range over a longer duration, as opposed to immediaterelease dosage forms, which may result in larger peaks and troughs in plasma concentration. ER formulations are advantageous for drugs with short half-lives. For example, the half-life of oral morphine is 2 to 4 hours, and it must be administered six times daily to provide continuous pain relief. However, only two doses are needed when extended-release tablets are used. 2. Sublingual/buccal: The sublingual route involves placement of drug under the tongue. The buccal route involves placement of drug between the cheek and gum. Both the sublingual and buccal routes of absorption have several advantages, including ease of administration, rapid absorption, bypass of the harsh gastrointestinal {GI) environment, and avoidance of first-pass metabolism {see discussion of first-pass metabolism below).

3

II. Routes of Drug Administration B. Parenteral The parenteral route introduces drugs directly into the systemic circulation. Parenteral administration is used for drugs that are poorly absorbed from the Gl tract (for example, heparin) or unstable in the Gl tract (for example, insulin). Parenteral administration is also used for patients unable to take oral medications (unconscious patients) and in circumstances that require a rapid onset of action. Parenteral administration provides the most control over the dose of drug delivered to the body. However, this route of administration is irreversible and may cause pain, fear, local tissue damage, and infections. The four major parenteral routes are intravascular (intravenous or intra-arterial), intramuscular, subcutaneous, and intradermal (Figure 1.3).

Subcutaneous Intravenous injection injection Intramuscular Dermal injection injection

1. Intravenous (IV): IV injection is the most common parenteral route. It is useful for drugs that are not absorbed orally, such as the neuromuscular blocker rocuronium. IV delivery permits a rapid effect and a maximum degree of control over the amount of drug delivered. When injected as a bolus, the full amount of drug is delivered to the systemic circulation almost immediately. If administered as an IV infusion, the drug is infused over a longer period, resulting in lower peak plasma concentrations and an increased duration of circulating drug. 2. Intramuscular (IM): Drugs administered IM can be in aqueous solutions, which are absorbed rapidly, or in specialized depot preparations, which are absorbed slowly. Depot preparations often consist of a suspension of drug in a nonaqueous vehicle, such as polyethylene glycol. As the vehicle diffuses out of the muscle, drug precipitates at the site of injection. The drug then dissolves slowly, providing a sustained dose over an extended interval. 3. Subcutaneous (SC): Like IM injection, SC injection provides absorption via simple diffusion and is slower than the IV route. SC injection minimizes the risks of hemolysis or thrombosis associated with IV injection and may provide constant, slow, and sustained effects. This route should not be used with drugs that cause tissue irritation, because severe pain and necrosis may occur. 4. Intradermal (10): The intradermal (I D) route involves injection into the dermis, the more vascular layer of skin under the epidermis. Agents for diagnostic determination and desensitization are usually administered by this route.

Subcutaneous tissue--_.

200 c

'i c..... 0

§~

.. ... c

5 mg intravenous midazolam 100

E

a:"' ftl

30 60 Time (minutes)

Figure 1.3 A. Schematic representation of subcutaneous and intramuscular injection. B. Plasma concentrations of midazofam after intravenous and intramuscular injection.

90

4

1. Pharmacokinetics C. Other 1. Oral inhalation and nasal preparations: Both the oral inhalation and nasal routes of administration provide rapid delivery of drug across the large surface area of mucous membranes of the respiratory tract and pulmonary epithelium. Drug effects are almost as rapid as are those with IV bolus. Drugs that are gases (for example, some anesthetics) and those that can be dispersed in an aerosol are administered via inhalation. This route is effective and convenient for patients with respiratory disorders such as asthma or chronic obstructive pulmonary disease, because drug is delivered directly to the site of action, thereby minimizing systemic side effects. The nasal route involves topical administration of drugs directly into the nose, and it is often used for patients with allergic rhinitis.

Drug diffusing from reservoir into subcutaneous tissue

2. Intrathecal/intraventricular: The blood-brain barrier typically delays or prevents the absorption of drugs into the central nervous system (CNS). When local, rapid effects are needed, it is necessary to introduce drugs directly into the cerebrospinal fluid. 3. Topical: Topical application is used when a local effect of the drug is desired. 4. Transdermal: This route of administration achieves systemic effects by application of drugs to the skin, usually via a transdermal patch (Figure 1.4). The rate of absorption can vary markedly, depending on the physical characteristics of the skin at the site of application, as well as the lipid solubility of the drug.

Figure 1.4 A. Schematic representation of a transdermal patch. B. Transdermal nicotine patch applied to the arm.

5. Rectal: Because 50% of the drainage of the rectal region bypasses the portal circulation, the biotransformation of drugs by the liver is minimized with rectal administration. The rectal route has the additional advantage of preventing destruction of the drug in the Gl environment. This route is also useful if the drug induces vomiting when given orally, if the patient is already vomiting, or if the patient is unconscious. Rectal absorption is often erratic and incomplete, and many drugs irritate the rectal mucosa. Figure 1.5 summarizes characteristics of the common routes of administration, along with example drugs.

Ill. ABSORPTION OF DRUGS Absorption is the transfer of a drug from the site of administration to the bloodstream. The rate and extent of absorption depend on the environment where the drug is absorbed, chemical characteristics of the drug, and the route of administration (which influences bioavailability). Routes of administration other than intravenous may result in partial absorption and lower bioavailability.

5

Ill. Absorption of Drugs

ROUTE OF ADMINISTRATION

ABSORPTION PATTERN

ADVANTAGES

e v.riable;llffactH by IIWIIJ fllctal'l

01'111

• Umit.d absorption o f - drugs • Food 1M)' .rr.ct absorption • Plltlent mmpllance Is - r y • Drugs 1M)' ... m.taboiiDd Wore IIJRamk absarptlon

• O.pands on the drug: F- drugs (far example. nltrogtyurin) han rapid. direct systemic absorption Most drugs arratlcally or Incompletely absorbad

e BypaSS4111 fll'lt-pau llf'fKt • Bypasses destruction by stomllch acid • Drug stabllltJ malntalnad beca1111 the pH of saliva relatlwly neutral e May cauH Immediate pharmacological effacts

• Umlt.d to Clll'taln t)'pes of drugs • Umltecl to drugs that can be takl!n In small doses • May losa part of the drug dose If swallowed

• Absorption not raqulrad

• Can hawlmrnadlatl! .rr.cts • Ida! If dosed In large volumes e Sultab.. for Irritating substancas and cornpla mixtures • Valuable In el'llergeiiCJ situations • DoAga titration permlulb.. • ldaal for high molacular -lght proteins and peptide drugs

• Unsultab.. for olysubstancas • Bolus Injection may result In

-

lntnnMIHHII

-

lntl'llmuscular

• Depends on drug diluents:

·~

tiiiMb • AmGIIc:llllln llllf*llion

• Nltroglywr1n

• BupMJolpltlne

• Vilnmm)odrl

eHiparfn

adVWSI effacts

• Mollsubdancaa must ... slowly Injected • Strict uaptlc techniques naadad

• Suitable If drug volume Is moderate • Suitable far ollyvahldes and cartaln Irritating substances • Preferable to Intravenous If patient must salf-admlnlstar

• Affects certain lab tests (creatine kina sa) • Can be painful • Can cause Intramuscular hamormaga (pracluded during anticoagulation therapy)

• O.pands on drug diluants: Aq-ssolutlon: prompt Dtlpot praparatlons: slow and sustalnad

• Sultab.. for slow-ralaasa drugs • ldaal for soma p-ly llllubla suspensions

• P.aln or nacrosls If drug Is Irritating • Unsultab.. for drugs.clmlnlstarad In '-1evolu111es

• Systamlc absorption may occur; this is not always deslrabla

• Absorption Is rapid; can haw immediate effects eldul for gases • Effective far patients with respiratory problems • Dose can be titrated • Localized effect to target lungs; lower doses uHd compared to that with oral or parantaraladmlnlstratlon • Fewer systamk side effects

• Most addlcllva routa (drug can anter

eNIHiterol

the brain quickly) a P.at•nt may haft difficulty regulating dosa • Some patients may have difficulty using Inhaler~

• Flutictaone

• v.riable; affKted by 11dn condition, araa fill skin. and other factors

• Suitab.. wt..n local effKt of drug is

• Some 1ystemic .atsorption an OCitUr • Unsultab.. far drugs with high molecular w.lght or poor lipid llllubility

• Clalrirnazole

Aqueussolutlon: prompt O.pot praparatlons: slow and sustained

Subcutaneous

EXAMPLES

• Safast and mast mm111on. _...,t.and -nomical route of admlnlllrlltton

Sublingual

DISADVANTAGES

• Halop« chlorpromazine > clozapine. Which statement would have to be correct to conclude that the mechanism of antipsychotic effects for these drugs is via binding to D2 receptors? A. Haloperidol should have the lowest potency of the three antipsychotic drugs. B. D2 receptor binding should also be related to the potency of these drugs in causing Parkinson's-like adverse effects. C. A positive correlation should exist between the affinity of these drugs to bind to D2 receptors and their potency for antipsychotic actions. D. Clozapine would have to be more potent than chlorpromazine for decreasing psychosis. 2.7 If there were spare fl1-adrenergic receptors on cardiac muscle cells, which statement would be correct? A. The number of spare fl 1-adrenergic receptors determines the size of the maximum effect of the agonist epinephrine. B. Spare fl1 adrenergic receptors make the cardiac tissue less sensitive to epinephrine. C. A maximal effect of epinephrine is seen when only a portion of fl1 adrenergic receptors are occupied. D. Spare receptors are active even in the absence of epinephrine. 2.8 Which of the following up-regulates postsynaptic a1adrenergic receptors? A. Daily use of amphetamine that causes release of norepinephrine B. A disease that causes an increase in the activity of norepinephrine neurons C. Daily use of phenylephrine, an a1 receptor agonist D. Daily use of prazosin, an a1 receptor antagonist 2.9 Methylphenidate helps patients with attention deficit hyperactivity disorder (ADHD) maintain attention and perform better at school or work, with an EDso of 10 mg. However, methylphenidate can also cause significant nausea at higher doses (TD50 "' 30 mg). Which is correct regarding methylphenidate? A. The therapeutic index of methylphenidate is 3. B. The therapeutic index of methylphenidate is 0.3. C. Methylphenidate is more potent at causing nausea than treating ADHD. D. Methylphenidate is more efficacious at causing nausea than treating ADHD.

35 Correct answer = C. To conclude that the mechanism of antipsychotic effect for these drugs is via binding to D2 receptors, there should be a positive correlation between the affinity of the drugs for D2 receptors and their potency for antipsychotic actions. Haloperidol should have the highest antipsychotic potency and clozaplne the lowest. There Is no guarantee the therapeutic effects and adverse effects are mediated by the same receptor population; therefore, a different correlation may exist for the adverse effects and D2 receptor affinity.

Correct answer = C. Only a fraction of the total receptors need to be bound to elicit a maximum cellular response when spare receptors are present. The other choices do not accurately describe the effects of having spare receptors.

Correct answer= D. Up-regulation of receptors occurs when receptor activation is lower than normal, such as when the receptor Is continuously exposed to an antagonist for that receptor. Down-regulation of receptors occurs when receptor activation Is greater than normal because of continuous exposure to an agonist, as described in A, B, and C.

Correct answer = A. Therapeutic Index Is calculated by dividing TD50 by ED50 (30/10), making B incorrect. Cis incorrect because methylphenidate is more potent at treating ADHD (it takes a lower dose) than causing nausea. D. No information about efficacy is provided.

36

2. Drug-Receptor Interactions and Pharmacodynamics

2.10 Which is correct concerning the safety of using warfarin (with a small therapeutic index) versus penicillin (with a large therapeutic index)?

A. Warfarin is a safer drug because it has a low therapeutic index. B. Warfarin treatment has a high chance of resulting in dangerous adverse effects if bioavailability is altered. C. The high therapeutic index makes penicillin a safe drug for all patients. D. Penicillin treatment has a high chance of causing dangerous adverse effects if bioavailability is altered.

Correct answer = B. Agents with a low n (that is, drugs for which dose is critically important) are those drugs for which bioavailability critically alters the therapeutic and adverse effects. A is incorrect, because a drug with a low Tl is not generally considered to be safe. C Is Incorrect because a high Tl does not ensure safety across the entire patient population. D Is Incorrect because the hi!1J Tl makes it unlikely that bioavailability alters the incidence of therapeutic or adverse effects.

The Autonomic Nervous System Rajan Radhakrishnan

I. OVERVIEW The autonomic nervous system (ANS), along with the endocrine system, coordinates the regulation and integration of bodily functions. The endocrine system sends signals to target tissues by varying the levels of bloodborne hormones. By contrast, the nervous system exerts effects by the rapid transmission of electrical impulses over nerve fibers that terminate at effector cells, which specifically respond to the release of neuromediator substances. Drugs that produce their primary therapeutic effect by mimicking or altering the functions of the ANS are called autonomic drugs and are discussed in the following four chapters. The autonomic agents act either by stimulating portions of the ANS or by blocking the action of the autonomic nerves. This chapter outlines the fundamental physiology of the ANS and describes the role of neurotransmitters in the communication between extracellular events and chemical changes within the cell.

l NervousI System l I

Peripheral nervous system

Central nervous system

I Efferent division

Afferent division

Autonomic system

Somatic system

I

II. INTRODUCTION TO THE NERVOUS SYSTEM The nervous system is divided into two anatomical divisions: the central nervous system (CNS), which is composed of the brain and spinal cord, and the peripheral nervous system, which includes neurons located outside the brain and spinal cord-that is, any nerves that enter or leave the CNS (Figure 3.1 ). The peripheral nervous system is subdivided into the efferent and afferent divisions. The efferent neurons carry signals away from the brain and spinal cord to the peripheral tissues, and the afferent neurons bring information from the periphery to the CNS. Afferent neurons provide sensory input to modulate the function of the efferent division through reflex arcs or neural pathways that mediate a reflex action.

-Enteric - Parasympathetic - Sympathetic

Figure 3.1 Organization of the nervous system.

37

38

3. The Autonomic Nervous System A. Functional divisions within the nervous system Brainstem or spinal cord Cell body --+----~

&Inti Ionic tran1111tner



~

The efferent portion of the peripheral nervous system is further divided into two major functional subdivisions: the somatic nervous system and the ANS (Figure 3.1 ). The somatic efferent neurons are involved in the voluntary control of functions such as contraction of the skeletal muscles essential for locomotion. The ANS, conversely, regulates the everyday requirements of vital bodily functions without the conscious participation of the mind. Because of the involuntary nature of the ANS as well as its functions, it is also known as the visceral, vegetative, or involuntary nervous system. It is composed of efferent neurons that innervate visceral smooth muscle, cardiac muscle, vasculature, and the exocrine glands, thereby controlling digestion, cardiac output, blood flow, and glandular secretions. B. Anatomy of the ANS

NlluroeffKtor tran11111tter

Figure 3.2 Efferent neurons of the autonomic nervous system.

1. Efferent neurons: The ANS carries nerve impulses from the CNS to the effector organs through two types of efferent neurons: the preganglionic neurons and the postganglionic neurons (Figure 3.2). The cell body of the first nerve cell, the preganglionic neuron, is located within the CNS. The preganglionic neurons emerge from the brainstem or spinal cord and make a synaptic connection in ganglia (an aggregation of nerve cell bodies located in the peripheral nervous system). The ganglia function as relay stations between the preganglionic neuron and the second nerve cell, the postganglionic neuron. The cell body of the postganglionic neuron originates in the ganglion. It is generally nonmyelinated and terminates on effector organs, such as visceral smooth muscle, cardiac muscle, and the exocrine glands. 2. Afferent neurons: The afferent neurons (fibers) of the ANS are important in the reflex regulation of this system {for example, by sensing pressure in the carotid sinus and aortic arch) and in signaling the CNS to influence the efferent branch of the system to respond. 3. Sympathetic neurons: The efferent ANS is divided into the sympathetic and the parasympathetic nervous systems, as well as the enteric nervous system (Figure 3.1 ). Anatomically, the sympathetic and the parasympathetic neurons originate in the CNS and emerge from two different spinal cord regions (Figure 3.3). The preganglionic neurons of the sympathetic system come from the thoracic and lumbar regions (T1 to L2) of the spinal cord, and they synapse in two cord-like chains of ganglia that run close to and in parallel on each side of the spinal cord. The preganglionic neurons are short in comparison to the postganglionic ones. Axons of the postganglionic neuron extend from the ganglia to tissues they innervate and regulate (see Chapter 6). In most cases, the preganglionic nerve endings of the sympathetic nervous system are highly branched, enabling one preganglionic neuron to interact with many postganglionic neurons. This arrangement enables activation of numerous effector organs at the same time. [Note: The adrenal medulla, like the sympathetic ganglia, receives preganglionic fibers from the sympathetic system. The adrenal medulla, in response to stimulation by the ganglionic neurotransmitter acetylcholine, secretes epinephrine (adrenaline), and lesser amounts of norepinephrine, directly into the blood.]

39

II. Introduction to the Nervous System

EFFECTORS

SYMPATHETIC DIVISION Brain, brain stem, and spinal cord

Thoracic

Thoracic

~ Lum

Pancreas

~

Ii

'

I

C.~l.·.·_·_·_·_·_·_·_·_-~~~~~~ --!)>--------1 ~---i ..... .

I .·------------------I

'

'-·:

:

Bladder

-(·-v - - Sympathetic preganglionic fibers ••••••• Sympathetic postganglionic fibers - - Parasympathetic preganglionic fibers ••••••• Parasympathetic postganglionic fibers

Figure 3.3 Autonomic nervous system.

~--

>·····-,..,-

40

3. The Autonomic Nervous System 4. Parasympathetic neurons: The parasympathetic preganglionic fibers arise from cranial nerves Ill (oculomotor), VII (facial), IX (glossopharyngeal), and X (vagus), as well as from the sacral region (S2 to S4) of the spinal cord and synapse in ganglia near or on the effector organs. [Note: The vagus nerve accounts for 90% of preganglionic parasympathetic fibers. Postganglionic neurons from this nerve innervate most organs in the thoracic and abdominal cavity.] Thus, in contrast to the sympathetic system, the preganglionic fibers are long, and the postganglionic ones are short, with the ganglia close to or within the organ innervated. In most instances, there is a one-to-one connection between the preganglionic and postganglionic neurons, enabling discrete response of this system. 5. Enteric neurons: The enteric nervous system is the third division of the ANS. It is a collection of nerve fibers that innervate the gastrointestinal (GI) tract, pancreas, and gallbladder, and it constitutes the "brain of the gut." This system functions independently of the CNS and controls motility, exocrine and endocrine secretions, and microcirculation of the Gl tract. It is modulated by both the sympathetic and parasympathetic nervous systems. C. Functions of the sympathetic nervous system Although continually active to some degree (for example, in maintaining tone of vascular beds), the sympathetic division is responsible for adjusting in response to stressful situations, such as trauma, fear, hypoglycemia, cold, and exercise (Figure 3.4).

Red =Sympathetic actions Blue= Parasympathetic actions

LACRIMAL GLANDS Stimulation of tears

EYE Contraction of iris radial muscle (pupil dilates) Contraction of iris sphincter muscle (pupil contracts) Contraction of ciliary muscle (lens accommodates for near vision) TRACHEA AND BRONCHIOLES Dilation Constriction, increased secretions ADRENAL MEDULLA

Secretion of renin (~ 1 increases; a 1 decreases)

URETERS AND BLADDER Relaxation of detrusor; contraction ~ of trigone and sphincter Contraction of detrusor; relaxation of trigone and sphincter

SALIVARY GLANDS Thick, viscous secretion Copious, watery secretion

HEART Increased rate; increased contractility Decreased rate; decreased contractility

GASTROINTESTINAL SYSTEM Decreased muscle motility and tone; contraction of sphincters Increased muscle motility and tone GENITALIA (female) Relaxation of uterus BLOOD VESSELS (skeletal muscle) Dilation

GENITALIA (male) Stimulation of ejaculation Stimulation of erection

Figure 3.4 Actions of sympathetic and parasympathetic nervous systems on effector organs.

BLOOD VESSELS (skin, mucous membranes, and splanchnic area) Constriction

II. Introduction to the Nervous System 1. Effects of stimulation of the sympathetic division: The effect of sympathetic stimulation is an increase in heart rate and blood pressure, mobilization of energy stores, and increase in blood flow to skeletal muscles and the heart while diverting flow from the skin and internal organs. Sympathetic stimulation results in dilation of the pupils and bronchioles (Figure 3.4). It also reduces Gl motility and affects function of the bladder and sexual organs. 2. Fight or flight response: The changes experienced by the body during emergencies are referred to as the "fight or flighf' response (Figure 3.5). These reactions are triggered both by direct sympathetic activation of effector organs and by stimulation of the adrenal medulla to release epinephrine and lesser amounts of norepinephrine. Hormones released by the adrenal medulla directly enter the bloodstream and promote responses in effector organs that contain adrenergic receptors (see Chapter 6). The sympathetic nervous system tends to function as a unit and often discharges as a complete system, for example, during severe exercise or in reactions to fear (Figure 3.5). This system, with its diffuse distribution of postganglionic fibers, is involved in a wide array of physiologic activities. Although it is not essential for survival, it is essential in preparing the body to handle uncertain situations and unexpected stimuli.

41

"Fight-or-flight" stimulus

Sympathetic output (diffuse because postganglionic neurons may innervate more than one organ)

nRest-and-digestn stimulus

D. Functions of the parasympathetic nervous system The parasympathetic division is involved with maintaining homeostasis within the body. It is required for life, since it maintains essential bodily functions, such as digestion and elimination. The parasympathetic division usually acts to oppose or balance the actions of the sympathetic division and generally predominates the sympathetic system in "rest-and-digest" situations. Unlike the sympathetic system, the parasympathetic system never discharges as a complete system. If it did, it would produce massive, undesirable, and unpleasant symptoms, such as involuntary urination and defecation. Instead, parasympathetic fibers innervating specific organs such as the gut, heart, or eye are activated separately, and the system affects these organs individually. E. Role of the CNS in the control of autonomic functions Although the ANS is a motor system, it does require sensory input from peripheral structures to provide information on the current state of the body. This feedback is provided by streams of afferent impulses, originating in the viscera and other autonomically innervated structures that travel to integrating centers in the CNS, such as the hypothalamus, medulla oblongata, and spinal cord. These centers respond to stimuli by sending out efferent reflex impulses via the ANS.

Parasympathetic output (discrete because postganglionic neurons are not branched, but are directed to a specific organ)

Sympathetic and parasympathetic actions often oppose each other

Figure 3.5 Sympathetic and parasympathetic actions are elicited by different stimuli.

3. The Autonomic Nervous System

42

D AFFERENT INFORMATION Sensory input from the viscera: • Drop in blood pressure • Reduced stretch of baroreceptors in the aortic arch • Reduced frequency of afferent impulses to the medulla (brainstem)

1. Reflex arcs: Most of the afferent impulses are involuntarily translated into reflex responses. For example, a fall in blood pressure causes pressure-sensitive neurons (baroreceptors in the heart, vena cava, aortic arch, and carotid sinuses) to send fewer impulses to cardiovascular centers in the brain. This prompts a reflex response of increased sympathetic output to the heart and vasculature and decreased parasympathetic output to the heart, which results in a compensatory rise in blood pressure and heart rate (Figure 3.6). [Note: In each case, the reflex arcs of the ANS comprise a sensory (afferent) arm and a motor (efferent or effector) arm.] 2. Emotions and the ANS: Stimuli that evoke strong feelings, such as rage, fear, and pleasure, can modify activities of the ANS. F. Innervation by the ANS 1. Dual innervation: Most organs are innervated by both divisions of the ANS. Thus, vagal parasympathetic innervation slows the heart rate, and sympathetic innervation increases heart rate. Despite this dual innervation, one system usually predominates in controlling the activity of a given organ. For example, the vagus nerve is the predominant factor for controlling heart rate. The dual innervation of organs is dynamic, and fine-tuned continually to maintain homeostasis.

EJ

REFLEX RESPONSE

Efferent reflex impulses via the autonomic nervous system cause: elnhibition of parasympathetic and activation of sympathetic divisions elncreased peripheral resistance and cardiac output elncreased blood pressure

Figure 3.6 Baroreceptor reflex arc response to a decrease in blood pressure.

2. Sympathetic innervation: Although most tissues receive dual innervation, some effector organs, such as the adrenal medulla, kidney, pilomotor muscles, and sweat glands, receive innervation only from the sympathetic system. G. Somatic nervous system The efferent somatic nervous system differs from the ANS in that a single myelinated motor neuron, originating in the CNS, travels directly to skeletal muscle without the mediation of ganglia. As noted earlier, the somatic nervous system is under voluntary control, whereas the ANS is involuntary. Responses in the somatic division are generally faster than those in the ANS. H. Summary of differences between sympathetic, parasympathetic, and motor nerves Major differences in the anatomical arrangement of neurons lead to variations of the functions in each division (Figure 3.7). The sympathetic nervous system is widely distributed, innervating practically all effector systems in the body. By contrast, the distribution of the parasympathetic division is more limited. The sympathetic preganglionic fibers have a much broader influence than the parasympathetic fibers and synapse with a larger number of postganglionic fibers. This type of organization permits a diffuse discharge of the sympathetic nervous system. The parasympathetic division is more circumscribed, with mostly one-to-one interactions, and the ganglia are also close to, or within, organs they innervate. This limits the amount of branching that can be done by this division. [A notable exception is found in

43

Ill. Chemical Signaling Between Cells

PARASYMPATHETIC Thoracic and lumbar region of the spinal cord (thoracolumbar)

Sites of origin -

-

1-

Long preganglionic Short postganglionic

Short preganglionic Long postganglionic

Length offibers -

Location of ganglia

1-

Within or near effector organs

Close to the spinal cord -

1-

-

Preganglionic fiber branching

Extensive

Distribution

Minimal

Wide -

Type of response

Brain and sacral area of the spinal cord (craniosacral)

Limited 1-

Diffuse

Discrete

Figure 3.7 Characteristics of the sympathetic and parasympathetic nervous systems.

the myenteric plexus {major nerve supply to the Gl tract), where one preganglionic neuron has been shown to interact with 8000 or more postganglionic fibers.] The anatomical arrangement of the parasympathetic system results in the distinct functions of this division. The somatic nervous system innervates skeletal muscles. One somatic motor neuron axon is highly branched, and each branch innervates a single muscle fiber. Thus, one somatic motor neuron may innervate 100 muscle fibers. This arrangement leads to the formation of a motor unit. The lack of ganglia and the myelination of the motor nerves enable a fast response by the somatic nervous system.

Endocrine signaling

Q

Ill. CHEMICAL SIGNALING BETWEEN CELLS Neurotransmission in the ANS is an example of chemical signaling between cells. In addition to neurotransmission, other types of chemical signaling include the secretion of hormones and the release of local mediators {Figure 3.8).

A. Hormones Specialized endocrine cells secrete hormones into the bloodstream, where they travel throughout the body, exerting effects on broadly distributed target cells {see Chapters 23 through 26).

B. Local mediators Most cells secrete chemicals that act locally on cells in the immediate environment. Because these chemical signals are rapidly destroyed or removed, they do not enter the blood and are not distributed throughout the body. Histamine {see Chapter 37} and prostaglandins are examples of local mediators.

Target cell

Direct contact

mju~~pon

Slgnal ng ~Ta: cell

cells

Synaptic signaling

~arget

Nerve cell

I

~~

oell

Neurotransmitter

C. Neurotransmitters Communication between nerve cells, and between nerve cells and effector organs, occurs through the release of specific chemical signals {neurotransmitters) from the nerve terminals. The release is

Figure 3.8 Some commonly used mechanisms for transmission of regulatory signals between cells.

44

3. The Autonomic Nervous System triggered by arrival of the action potential at the nerve ending, leading to depolarization. An increase in intracellular Ca2 + initiates fusion of synaptic vesicles with the presynaptic membrane and release of their contents. The neurotransmitters rapidly diffuse across the synaptic cleft, or space (synapse), between neurons and combine with specific receptors on the postsynaptic (target) cell. 1. Membrane receptors: All neurotransmitters, and most hormones and local mediators, are too hydrophilic to penetrate the lipid bilayers of target cell plasma membranes. Instead, their signal is mediated by binding to specific receptors on the cell surface of target organs. [Note: A receptor is defined as a recognition site for a sub-

AUTONOMIC symr:thetlc innervation o adrenal medulla

A

Acetylcholine

~



cCf.:

Sympathetic

Acetylcholine

~



SOMATIC Parasympathetic

Nopnglla

Acetylcholine

~ Nkotlnlc receptor



Nicotinic receptor

Adrenal medulla

Epinephrine rele•secl Into the blood*

Norepinephrine

~......

Acetylcholine

Acetylcholine

~

~

~

receptor

receptor

Effedor organs



~ ::.-- receptor '

Skeletal muscle

Figure 3.9 Summary of the neurotransmitters released, types of receptors, and types of neurons within the autonomic and somatic nervous systems. Cholinergic neurons are shown in red and adrenergic neurons in blue. [Note: This schematic diagram does not show that the parasympathetic ganglia are close to or on the surface of the effector organs and that the postganglionic fibers are usually shorter than the preganglionic fibers. By contrast, the ganglia of the sympathetic nervous system are close to the spinal cord. The postganglionic fibers are long, allowing extensive branching to innervate more than one organ system. This allows the sympathetic nervous system to discharge as a unit.] *Epinephrine 80% and norepinephrine 20% released from adrenal medulla.

45

IV. Signal Transduction in the Effector Cell stance. It has a binding specificity and is coupled to processes that eventually evoke a response. Most receptors are proteins (see Chapter 2).]

r.WI Receptors coupled to lon W channels (lonotroplc receptors) Neuro-

2. Types of neurotransmitters: Although over 50 signal molecules in the nervous system have been identified, norepinephrine (and the closely related epinephrine), acetylcholine, dopamine, serotonin, histamine, glutamate, and y-aminobutyric acid are most commonly involved in the actions of therapeutically useful drugs. Each of these chemical signals binds to a specific family of receptors. Acetylcholine and norepinephrine are the primary chemical signals in the ANS, whereas a wide variety of neurotransmitters function in the CNS.

:lf~iar

II

~ me~~rane --~ \.

space

~·~ \

I

.1

".

/~~~

~~'tYJWiliiim!i .JJcr

Cytosol

Changes In membrana potential or ionic concentration within cell

3. Acetylcholine: The autonomic nerve fibers can be divided into two groups based on the type of neurotransmitter released. If transmission is mediated by acetylcholine, the neuron is termed cholinergic (Figure 3.9 and Chapters 4 and 5). Acetylcholine mediates the transmission of nerve impulses across autonomic ganglia in both the sympathetic and parasympathetic nervous systems. It is the neurotransmitter at the adrenal medulla. Transmission from the autonomic postganglionic nerves to the effector organs in the parasympathetic system, and a few sympathetic system organs, also involves the release of acetylcholine. In the somatic nervous system, transmission at the neuromuscular junction (the junction of nerve fibers and voluntary muscles) is also cholinergic (Figure 3.9).

cl-

transmltt.r

r.'WI 1.-1

Receptors coupled to adenylyl cyclase (rnetabotropic receptors) /?

IY

Q

Hormone or neurotransmitter

4. Norepinephrine and epinephrine: When norepinephrine is the neurotransmitter, the fiber is termed adrenergic (Figure 3.9 and Chapters 6 and 7). In the sympathetic system, norepinephrine mediates the transmission of nerve impulses from autonomic postganglionic nerves to effector organs. Epinephrine secreted by the adrenal medulla (not sympathetic neurons) also acts as a chemical messenger in the effector organs. [Note: A few sympathetic fibers, such as those involved in sweating, are cholinergic, and, for simplicity, they are not shown in Figure 3.9.]

Protain phosphorylation

P.:l 1.':11

Receptors coupled to diacylglycerol and inositol trisphosphate (metabotropic receptors) Hormone or neurotransmitter

IV. SIGNAL TRANSDUCTION IN THE EFFECTOR CELL The binding of chemical signals to receptors activates enzymatic processes within the cell membrane that ultimately results in a cellular response, such as the phosphorylation of intracellular proteins or changes in the conductivity of ion channels (see Chapter 2). A neurotransmitter can be thought of as a signal and a receptor as a signal detector and transducer. The receptors in the ANS effector cells are classified as adrenergic or cholinergic based on the neurotransmitters or hormones that bind to them. Epinephrine and norepinephrine bind to adrenergic receptors, and acetylcholine binds to cholinergic receptors. Cholinergic receptors are further classified as nicotinic or muscarinic. Some receptors, such as the postsynaptic cholinergic nicotinic receptors in skeletal muscle cells, are directly linked to membrane ion channels and are known as ionotropic receptors. Binding of neurotransmitter to ionotropic receptors directly affects ion permeability (Figure 3.10A).

Diacylglycerol

.JJ

Inositol trisphosphate

Figure 3.10 Three mechanisms whereby binding of a neurotransmitter leads to a cellular

effect.

46

3. The Autonomic Nervous System All adrenergic receptors and cholinergic muscarinic receptors are G protein-coupled receptors (metabotropic receptors). Metabotropic receptors mediate the effects of ligands by activating a second messenger system inside the cell. The two most widely recognized second messengers are the adenylyl cyclase system and the calcium/phosphatidylinositol system (Figure 3.1 08, C).

Study Questions Choose the ONE best answer. 3.1 Which is correct regarding the sympathetic nervous system? A. It generally mediates body functions in "rest-anddigesr mode. B. The neurotransmitter at the sympathetic ganglion is norepinephrine (NE). C. The neurotransmitter at the sympathetic ganglion is acetylcholine (ACh). D. Sympathetic neurons release ACh in the effector organs. 3.2 Why does the somatic nervous system enable a faster response compared to the ANS?

A. Somatic motor neurons have ganglia where neuro-

Correct answer = C. The neurotransmitter at the sympathetic and parasympathetic ganglia Is acetylcholine. The sympathetic system generally mediates body functions In "fight or flight" mode, and the parasympathetic system generally mediates body functions in "rest-and-digesf' mode. Sympathetic neurons release NE, and parasympathetic neurons release ACh in the effector cells.

Correct answer= D. Somatic motor neurons are myelinated and have no ganglia. This enables faster transmission in the somatic neurons.

transmission is mediated by ACh. B. Somatic motor neurons have ganglia where neurotransmission is mediated by NE. C. Somatic motor neurons are not myelinated. D. Somatic motor neurons are myelinated and do not have ganglia. 3.3 Which physiological change occurs when the parasympathetic system is activated?

A. Increase in heart rate B. Inhibition of lacrimation (tears) C. Dilation of the pupil (mydriasis) D. Increase in gastric motility 3.4 Which physiological change is expected when the sympathetic system is inhibited using a pharmacological agent? A. B. C. D.

Reduction in heart rate Increase in blood pressure Decrease in fluid secretions Constriction of blood vessels

3.5 Which is correct regarding activation of receptors on the effector organs in the ANS?

A. Acetylcholine activates muscarinic receptors. B. Acetylcholine activates adrenergic receptors. C. Epinephrine activates nicotinic receptors. D. Norepinephrine activates muscarinic receptors.

Correct answer = D. Activation of the parasympathetic system causes an increase in gastric motility, increase in fluid secretions, reduction In heart rate, and constriction of the pupil. In the "rest-and-dlgesr mode, the parasympathetic system Is more active, which helps with digestion.

Correct answer = A. Activation of the sympathetic system causes an increase in heart rate, increase in blood pressure, reduction or thickening of fluid secretions, and constriction of blood vessels. Therefore, Inhibition of the sympathetic system should theoretically cause a reduction in heart rate, decrease in blood pressure, Increase in fluid secretions, and relaxation of blood vessels.

Correct answer = A. Acetylcholine Is the neurotransmitter in the cholinergic system, and it activates both muscarinic and nicotinic cholinergic receptors, not adrenergic receptors. Norepinephrine and epinephrine activate adrenergic receptors, not muscarinic receptors.

Study Questions 3.6 Which statement concerning the parasympathetic nervous system is correct? A. The parasympathetic system often discharges as a single, functional system. B. The parasympathetic division is involved in near vision, movement of food, and urination. C. The postganglionic fibers of the parasympathetic division are long, compared to those of the sympathetic nervous system. D. The parasympathetic system controls the secretion of the adrenal medulla.

3. 7 Which is correct regarding neurotransmitters and neu rotransm ission? A. Neurotransmitters are released from the presynaptic nerve terminals. B. Arrival of an action potential in the postsynaptic cell triggers release of neurotransmitter. C. Intracellular calcium levels drop in the neuron before the release of neurotransmitter. D. Serotonin and dopamine are the primary neurotransmitters in the ANS.

3.8 An elderly man is brought to the emergency room after ingesting a large quantity of prazosin tablets, a drug that blocks a 1 adrenergic receptors, which mediate effects of epinephrine and norepinephrine on the blood vessels and urinary bladder. Which symptom is most likely to be seen in this patient? A. Reduced heart rate (bradycardia) B. Dilation of blood vessels (vasorelaxation) C. Increased blood pressure D. Reduction in urinary frequency

3.9 Which statement is correct regarding the autonomic nervous system? A. Afferent neurons carry impulses from the central nervous system (CNS) to the effector organs. B. Preganglionic neurons of the sympathetic system arise from the cranial nerves, as well as from the sacral region. C. When there is a sudden drop in blood pressure, the baroreceptors send signals to the brain to activate the parasympathetic system. D. The heart receives both sympathetic and parasympathetic innervation.

3.10 Which is correct regarding membrane receptors and signal transduction? A. ANS neurotransmitters bind to membrane receptors on the effector cells, which leads to intracellular events. B. Cholinergic muscarinic receptors are ionotropic receptors. C. Cholinergic nicotinic receptors are metabotropic receptors. D. Metabotropic receptors activate ion channels directly.

47 Correct answer = B. The parasympathetic nervous system maintains essential bodily functions, such as vision, movement of food, and urination. It uses acetylcholine, not norepinephrine, as a neurotransmitter, and it discharges as discrete fibers that are activated separately. The postganglionic fibers of the parasympathetic system are short compared to those of the sympathetic division. The adrenal medulla Is under the control of the sympathetic system.

Correct answer = A. Neurotransmitters are released from presynaptic neurons, triggered by the arrival of an action potential In the presynaptic neuron (not in the postsynaptic cell). When an action potential arrives in the presynaptic neuron, calcium enters the presynaptic neuron and calcium levels increase in the neuron before neurotransmitter is released. The main neurotransmitters in the ANS are norepinephrine and acetylcholine.

Correct answer = B. Activation of a., receptors causes vasoconstriction, reduction In urinary frequency, and an Increase in blood pressure, without a direct effect on the heart rate. It may cause reflex tachycardia (increase in heart rate) in some patients. Thus blockade of a., receptors could theoretically cause dilation of blood vessels, reduction in blood pressure, and increase in urinary frequency. It should not cause a reduction in heart rate.

Correct answer = D. The heart receives both sympathetic and parasympathetic innervation. Activation of sympathetic neurons increases the heart rate and force of contraction, and activation of parasympathetic neurons reduces the heart rate and force of contraction (slightly). Afferent neurons carry Impulses from the periphery to the CNS, and efferent neurons carry signals away from the CNS. Preganglionic neurons of the sympathetic system arise from thoracic and lumbar regions of the spinal cord, whereas the preganglionic neurons of the parasympathetic system arise from cranial nerves and the sacral region. When there is a sudden drop In blood pressure, the sympathetic system Is activated, not the parasympathetic system.

Correct answer = A. Neurotransmitters generally bind to membrane receptors on the postsynaptic effector cells and cause cellular effects. Acetylcholine (ACh) binds to cholinergic muscarinic receptors and activates the second messenger pathway in effector cells, which in turn causes cellular events. Receptors that are coupled to second messenger systems are known as metabotropic receptors. Metabotropic receptors do not directly activate ion channels. ACh also binds to cholinergic nicotinic receptors and activates ion channels on the effector cells. The receptors that directly activate ion channels are known as lonotroplc receptors.

Cholinergic Agonists Rajan Radhakrishnan

I. OVERVIEW DIRECT ACTING

Drugs affecting the autonomic nervous system (ANS) are divided into two groups according to the type of neuron involved in the mechanism of action. The cholinergic drugs, which are described in this and the following chapter, act on receptors activated by acetylcholine (ACh), whereas the adrenergic drugs (Chapters 6 and 7) act on receptors stimulated by norepinephrine or epinephrine. Cholinergic and adrenergic drugs act by either stimulating or blocking receptors of the ANS. Figure 4.1 summarizes cholinergic agonists discussed in this chapter.

Acetylcholine MIOCHOL-E Bethanecho/ URECHOLINE Carbachol MIOSTAT, ISOPTO CARBACHOL Cevime/ine EVOXAC Methacholine PROVOCHOLINE Nkotlne NICORETTE Pilocarpine SALAGEN, ISOPTO CARPINE INDIRECT ACTING (reversible)

II. THE CHOLINERGIC NEURON The preganglionic fibers terminating in the adrenal medulla, the autonomic ganglia (both parasympathetic and sympathetic), and the postganglionic fibers of the parasympathetic division use ACh as a neurotransmitter (Figure 4.2). The postganglionic sympathetic division of sweat glands also uses ACh. In addition, cholinergic neurons innervate the muscles of the somatic system and play an important role in the central nervous system (CNS).

A. Neurotransmlsslon at cholinergic neurons Neurotransmission in cholinergic neurons involves six sequential steps: 1) synthesis of ACh, 2) storage, 3) release, 4) binding of ACh to the receptor, 5) degradation of ACh in the synaptic cleft (the space between the nerve endings and adjacent receptors on nerves or effector organs), and 6) recycling of choline (Figure 4.3). 1. Synthesis of acetylcholine: Choline is transported from the extracellular fluid into the cytoplasm of the cholinergic neuron by an energy-dependent carrier system that cotransports sodium and can be inhibited by the drug hemicholinium. [Note: Choline has a quaternary nitrogen and carries a permanent positive charge and, thus, cannot diffuse through the membrane.] The uptake of choline is the rate-limiting step in ACh synthesis. Choline acetyltransferase catalyzes the reaction of choline with acetyl coenzyme A (CoA) to form ACh (an ester) in the cytosol.

48

Figure 4.1 Summary of cholinergic agonists.

49

II. The Cholinergic Neuron

AUTONOMIC Sympathetic Innervation of adrenal medulla

1

Sympathetic

SOMATIC Parasympathetk

Acetylcholine

Acetylcholine

Acetylcholine

~

~

~



6Nicotinic





Nicotinic

receptor

No ganglia

Nicotinic

receptor

Adrenal medulla

Epinaphrine and norepinephrine rel•sad into the blood

v

~

~ receptor

Norepinephrine

Acetylcholine

Acetylcholine

0......

~

~

receptor

~

~ receptor

• ~

Effector organs Figure 4.2 Sites of actions of cholinergic agonists in the autonomic and somatic nervous systems.

2. Storage of acetylcholine in vesicles: ACh is packaged and stored into presynaptic vesicles by an active transport process. The mature vesicle contains not only ACh but also adenosine triphosphate (ATP) and proteoglycan. Cotransmission from autonomic neurons is the rule rather than the exception. This means that most synaptic vesicles contain the primary neurotransmitter {here, ACh) as well as a cotransmitter (here, ATP) that increases or decreases the effect of the primary neurotransmitter. 3. Release of acetylcholine: When an action potential propagated by voltage-sensitive sodium channels arrives at a nerve ending, voltage-sensitive calcium channels on the presynaptic membrane open, causing an increase in the concentration of intracellular calcium. Elevated calcium levels promote the fusion of synaptic vesicles with the cell membrane and the release of contents into the synaptic space. This release can be blocked by botulinum toxin. In contrast, the toxin in black widow spider venom causes all the ACh stored in synaptic vesicles to empty into the synaptic gap.



Y

receptor -....::

Skeletal musde

50

4. Cholinergic Agonists

Choline -......,...._......_ Choline

•..

... y,A epinephrine> norepinephrine. The ~-adrenoceptors can be subdivided into three major subgroups, ~~~ ~. and ~3 , based on their affinities for adrenergic agonists and antagonists. P1 receptors have approximately equal affinities for epinephrine and norepinephrine, whereas ~ receptors have a higher affinity for epinephrine than

77

II. The Adrenergic Neuron for norepinephrine. Thus, tissues with a predominance of P2 receptors (such as the vasculature of skeletal muscle) are particularly responsive to the effects of circulating epinephrine released by the adrenal medulla. Binding of a neurotransmitter at any of the three types of p receptors results in activation of adenylyl cyclase and increased concentrations of cAMP within the cell.

a 2 Receptors Activation of the receptor decreases production of cAMP, leading to an inhibition of further release of norepinephrine from the neuron.

Synaptic vesicle

3. Distribution of receptors: Adrenergically innervated organs and tissues usually have a predominant type of receptor. For example, tissues such as the vasculature of skeletal muscle have both o:1 and P2 receptors, but the P2 receptors predominate. Other tissues may have one type of receptor almost exclusively. For example, the heart contains predominantly P1 receptors.

4. Characteristic responses mediated by adrenoceptors: It is useful to organize the physiologic responses to adrenergic stimulation according to receptor type, because many drugs preferentially stimulate or block one type of receptor. Figure 6.6 summarizes the most prominent effects mediated by the adrenoceptors. As a generalization, stimulation of o:1 receptors characteristically produces vasoconstriction (particularly in skin and abdominal viscera) and an increase in total peripheral resistance and blood pressure. Stimulation of P1 receptors characteristically causes cardiac stimulation (increase in heart rate and contractility), whereas stimulation of P2 receptors produces vasodilation (in skeletal muscle vascular beds) and smooth muscle relaxation. Pa Receptors are involved in lipolysis (along with P1), and also have effects on the detrusor muscle of the bladder.

5. Desensitization of receptors: Prolonged exposure to the catecholamines reduces the responsiveness of these receptors, a phenomenon known as desensitization. Three mechanisms have been suggested to explain this phenomenon: 1) sequestration of the receptors so that they are unavailable for interaction with the ligand; 2) down-regulation, that is, a disappearance of the receptors either by destruction or by decreased synthesis; and 3) an inability to couple to G-protein, because the receptor has been phosphorylated on the cytoplasmic side.

Membrane phospholnosltldes

0 DA~ ----={ ---y Ca

2

+

IP3

a 1 Receptors Activation of the receptor increases production of DAG and IP3, leading to an increase in intracellular calcium ions. Figure 6.5 Second messengers mediate the effects of a receptors. DAG =diacylglycerol; IP3 =inositol trisphosphate; ATP = adenosine triphosphate; cAMP = cyclic adenosine monophosphate.

ADRENOCEPTORS I

a, 1- Vasoconstriction 1-

Increased peripheral resistance

1- Increased blood pressure 1-

Mydriasis

I

a2 -

I

Inhibition of norepinephrine release

,..- Inhibition of acetylcholine release ~

Inhibition of insulin release

'- Increased closure of internal sphincter of the bladder

Figure 6.6 Major effects mediated by a- and j3-adrenoceptors.

Ji, f- Tachycardia

1- Increased lipolysis 1-

Increased myocardial contractility

I

Ji2 -

Vasodilation

-

Decreased peripheral resistance

-

Bronchodilation Increased muscle and liver glycogenolysis

-

~ Increased release

ofrenin

-

Increased release of glucagon

-

Relaxed uterme smooth muscle

I

78

6. Adrenergic Agonists

Ill. CHARACTERISTICS OF ADRENERGIC AGONISTS

OH H I / HOOCH-CH2-N ~

""-cH3

I Phenylephrine

O

OH H I / CH-CH-N I

""-

CH3

~

A. Catecholamines

CH3

Sympathomimetic amines that contain the 3,4-dihydroxybenzene group (such as epinephrine, norepinephrine, isoproterenol, and dopamine) are called catecholamines. These compounds share the following properties:

Ephedrine

OH H I / HOOCH-CH2- N HO

~

1. High potency: Catecholamines show the highest potency in directly activating a or preceptors.

""-H

I

2. Rapid inactivation: Catecholamines are metabolized by COMT postsynaptically and by MAO intraneuronally, by COMT and MAO in the gut wall, and by MAO in the liver. Thus, catecholamines have only a brief period of action when given parenterally, and they are inactivated (ineffective) when administered orally.

Norepinephrine

OH I

H /

HOOCH-CH2-N HO

~

I

""-cH 3

3. Poor penetration into the CNS: Catecholamines are polar and, therefore, do not readily penetrate into the CNS. Nevertheless, most catecholamines have some clinical effects (anxiety, tremor, and headaches) that are attributable to action on the CNS.

Epinephrine

OH I

HOOCH-CH2- N HO

~

I

Most adrenergic drugs are derivatives of p-phenylethylamine (Figure 6.7). Substitutions on the benzene ring or on the ethylamine side chains produce a variety of compounds with varying abilities to differentiate between a and p receptors and to penetrate the CNS. Two important structural features of these drugs are 1) the number and location of OH substitutions on the benzene ring and 2) the nature of the substituent on the amino nitrogen.

B. Noncatecholamines

H /

" CH / '

Isoproterenol

CH3

CH 3

Affinity for preceptors increases as group on the amine nitrogen gets larger.

DofHimine

Compounds lacking the catechol hydroxyl groups have longer halflives, because they are not inactivated by COMT. These include phenylephrine, ephedrine, and amphetamine (Figure 6.7). These agents are poor substrates for MAO (an important route of metabolism) and, thus, show a prolonged duration of action. Increased lipid solubility of many of the noncatecholamines (due to lack of polar hydroxyl groups) permits greater access to the CNS. C. Substitutions on the amine nitrogen The nature of the substituent on the amine nitrogen is important in determining p selectivity of the adrenergic agonist. For example, epinephrine, with a -cH 3 substituent on the amine nitrogen, is more potent at p receptors than norepinephrine, which has an unsubstituted amine. Similarly, isoproterenol, which has an isopropyl substituent -cH(CH 3 h on the amine nitrogen (Figure 6.7), is a strong p agonist with little a activity (Figure 6.4). D. Mechanism of action of adrenergic agonists

Figure 6.7 Structures of several important adrenergic agonists. Drugs containing the catechol ring are shown in yellow.

1. Direct-acting agonists: These drugs act directly on a or p receptors, producing effects similar to those that occur following stimulation of sympathetic nerves or release of epinephrine from the

79

IV. Direct-Acting Adrenergic Agonists adrenal medulla (Figure 6.8). Examples of direct-acting agonists include epinephrine, norepinephrine, isoproterenol, dopamine, and phenylephrine.

INDIRECT ACTION Drug enhances release of norepinephrine from vesicles.

2. Indirect-acting agonists: These agents may block the reuptake of norepinephrine or cause the release of norepinephrine from the cytoplasmic pools or vesicles of the adrenergic neuron (Figure 6.8). The norepinephrine then traverses the synapse and binds to a or ~ receptors. Examples of reuptake inhibitors and agents that cause norepinephrine release include cocaine and amphetamine, respectively.

MIXED ACTION

3. Mixed-action agonists: Ephedrine and its stereoisomer, pseudoephedrine, both stimulate adrenoceptors directly and enhance release of norepinephrine from the adrenergic neuron (Figure 6.8). SYNAPSE

IV. DIRECT-ACTING ADRENERGIC AGONISTS Direct-acting agonists bind to adrenergic receptors on effector organs without interacting with the presynaptic neuron. As a group, these agents are widely used in clinical practice. A. Epinephrine Epinephrine [ep-i-NEF-rin] is one of the four catecholamines (epinephrine, norepinephrine, dopamine, and dobutamine) commonly used in therapy. The first three are naturally occurring neurotransmitters, and the latter is a synthetic compound. In the adrenal medulla, norepinephrine is methylated to yield epinephrine, which is stored in chromaffin cells along with norepinephrine. On stimulation, the adrenal medulla releases about 80% epinephrine and 20% norepinephrine directly into the circulation. Epinephrine interacts with both a and ~receptors. At low doses, ~ effects (vasodilation) on the vascular system predominate, whereas at high doses, a effects (vasoconstriction) are the strongest.

1. Actions a. Cardiovascular: The major actions of epinephrine are on the cardiovascular system. Epinephrine strengthens the contractility of the myocardium (positive inotrope: ~ 1 action) and increases its rate of contraction (positive chronotrope: ~ 1 action). Therefore, cardiac output increases. These effects increase oxygen demands on the myocardium. Epinephrine activates ~ 1 receptors on the kidney to cause renin release. Renin is an enzyme involved in the production of angiotensin II, a potent vasoconstrictor. Epinephrine constricts arterioles in the skin, mucous membranes, and viscera (a effects), and it dilates vessels going to the liver and skeletal muscle (~2 effects). These combined effects result in a decrease in renal blood flow. Therefore, the cumulative effect is an increase in systolic blood pressure, coupled with a

POSTSYNAPTIC ' - - - - - - - - - - - , TARGET CELL DIRECT ACTION MEMBRANE

Drug directly activates receptor.

Figure 6.8 Sites of action of direct-, indirect-, and mixed-acting adrenergic agonists.

6. Adrenergic Agonists

80

Epinephrine increases

the rate and force of cardiac contraction. Infusion of epinephrine

·-...··- t -3& ... c

.. E

100

a.-

50

-

180

I!!

:II ...UICII I!! :I: a..e -gg

b. Respiratory: Epinephrine causes powerful bronchodilation by acting directly on bronchial smooth muscle (P2 action). It also inhibits the release of allergy mediators such as histamine from mast cells. c. Hyperglycemia: Epinephrine has a significant hyperglycemic effect because of increased glycogenolysis in the liver (P2 effect), increased release of glucagon (P2 effect), and a decreased release of insulin (a2 effect). d. Lipolysis: Epinephrine initiates lipolysis through agonist activity on the preceptors of adipose tissue. Increased levels of cAMP stimulate a hormone-sensitive lipase, which hydrolyzes triglycerides to free fatty acids and glycerol.

120

0

iii

slight decrease in diastolic pressure due to P2 receptor-mediated vasodilation in the skeletal muscle vascular bed (Figure 6.9).

60 High

2. Therapeutic uses

-cu I!~

Tlme(mln}

a. Bronchospasm: Epinephrine is the primary drug used in the emergency treatment of respiratory conditions when bronchoconstriction has resulted in diminished respiratory function. Thus, in treatment of anaphylactic shock, epinephrine is the drug of choice and can be lifesaving in this setting. Within a few minutes after subcutaneous administration, respiratory function greatly improves.

Systolic pressure is increased, and diastolic pressure is decreased.

b. Anaphylactic shock: Epinephrine is the drug of choice for the treatment of type I hypersensitivity reactions (including anaphylaxis) in response to allergens.

i; ·c·-

l!

Epinephrine

decreases the peripheral resistance.

c. Cardiac arrest: Epinephrine may be used to restore cardiac rhythm in patients with cardiac arrest.

Figure 6.9 Cardiovascular effects of intravenous infusion of low doses of epinephrine.

d. Local anesthesia: Local anesthetic solutions may contain low concentrations (for example, 1:100,000 parts) of epinephrine. Epinephrine greatly increases the duration of local anesthesia by producing vasoconstriction at the site of injection. Epinephrine also reduces systemic absorption of the local anesthetic and promotes local hemostasis.

Poor

Aerosol

tQ

penetration Into CNS

Figure 6.10 Pharmacokinetics of epinephrine. CNS = central nervous system.

e. Intraocular surgery: Epinephrine is used in the induction and maintenance of mydriasis during intraocular surgery. 3. Pharmacokinetics: Epinephrine has a rapid onset but a brief duration of action (due to rapid degradation). The preferred route for anaphylaxis in the outpatient setting is intramuscular (anterior thigh) due to rapid absorption. In emergencies, epinephrine is given intravenously (IV) for the most rapid onset of action. It may also be given subcutaneously, by endotracheal tube, or by inhalation (Figure 6.1 0). It is rapidly metabolized by MAO and COMT, and the metabolites metanephrine and vanillylmandelic acid are excreted in urine. 4. Adverse effects: Epinephrine can produce adverse CNS effects that include anxiety, fear, tension, headache, and tremor. It can trigger cardiac arrhythmias, particularly if the patient is receiving digoxin. Epinephrine can also induce pulmonary edema due

IV. Direct-Acting Adrenergic Agonists

81

to increased afterload caused by vasoconstrictive properties of the drug. Patients with hyperthyroidism may have an increased production of adrenergic receptors in the vasculature, leading to an enhanced response to epinephrine, and the dose must be reduced in these individuals. Inhalation anesthetics also sensitize the heart to the effects of epinephrine, which may lead to tachycardia. Epinephrine increases the release of endogenous stores of glucose. In diabetic patients, dosages of insulin may have to be increased. Nonselective ~-blockers prevent vasodilatory effects of epinephrine on ~2 receptors, leaving a receptor stimulation unopposed. This may lead to increased peripheral resistance and increased blood pressure. B. Norepinephrine Because norepinephrine [nor-ep-ih-NEF-rin] is the neurotransmitter in the adrenergic neurons, it should, theoretically, stimulate all types of adrenergic receptors. However, when administered in therapeutic doses, the a-adrenergic receptor is most affected.

Norepinephrine induces

reflex bradycardia.

Infusion of norepinephrine

1. Cardiovascular actions a. Vasoconstriction: Norepinephrine causes a rise in peripheral resistance due to intense vasoconstriction of most vascular beds, including the kidney (a1 effect). Both systolic and diastolic blood pressures increase (Figure 6.11 ). [Note: Norepinephrine causes greater vasoconstriction than epinephrine, because it does not induce compensatory vasodilation via ~2 receptors on blood vessels supplying skeletal muscles. The weak ~2 activity of norepinephrine also explains why it is not useful in the treatment of bronchospasm or anaphylaxis.] b. Baroreceptor reflex: Norepinephrine increases blood pressure, and this stimulates the baroreceptors, inducing a rise in vagal activity. The increased vagal activity produces a reflex bradycardia, which is sufficient to counteract the local actions of norepinephrine on the heart, although the reflex compensation does not affect the positive inotropic effects of the drug (Figure 6.11 ). When atropine, which blocks the transmission of vagal effects, is given before norepinephrine, stimulation of the heart by norepinephrine is evident as tachycardia.

.!c..1111·-E 1oo

.. ~! :~:

I!!

iia 1!!::1:

t

50

180

a. E 120 "I:IE

g-

iii

60

High

Low

2. Therapeutic uses: Norepinephrine is used to treat shock (for example, septic shock), because it increases vascular resistance and, therefore, increases blood pressure. It has no other clinically significant uses. 3. Pharmacokinetics: Norepinephrine is given IV for rapid onset of action. The duration of action is 1 to 2 minutes, following the end of the infusion. It is rapidly metabolized by MAO and COMT, and inactive metabolites are excreted in the urine. 4. Adverse effects: These are similar to epinephrine. In addition, norepinephrine is a potent vasoconstrictor and may cause blanching and sloughing of skin along an injected vein. If extravasation (leakage of drug from the vessel into tissues surrounding the injection site) occurs, it can cause tissue necrosis. It should not be administered in peripheral veins, if possible. Impaired circulation

15

Time(min)

Norepinephrine causes

increased systolic and diastolic pressure.

Norepinephrine constricts all

blood vessels, causing increased peripheral resistance.

Figure 6.11 Cardiovascular effects of intravenous infusion of norepinephrine.

82

6. Adrenergic Agonists

Isoproterenol causes vasodilation but strongly increases cardiac force and rate.

·- t 50

~-

I!!

180

:II

::a I!!::C ~E

120

gs iii

C. Isoproterenol Isoproterenol [eye-soe-proe-TER-e-nole] is a direct-acting synthetic catecholamine that stimulates both p,- and P2-adrenergic receptors. Its nonselectivity is a disadvantage and the reason why it is rarely used therapeutically. Its action on a receptors is insignificant. Isoproterenol produces intense stimulation of the heart (P1 effect), increasing heart rate, contractility, and cardiac output (Figure 6.12). It is as active as epinephrine in this action. Isoproterenol also dilates the arterioles of skeletal muscle (P2 effect), resulting in decreased peripheral resistance. Because of its cardiac stimulatory action, it may increase systolic blood pressure slightly, but it greatly reduces mean arterial and diastolic blood pressures (Figure 6.12). Isoproterenol is also a potent bronchodilator (P2 effect). The adverse effects of isoproterenol are similar to the p receptor-related side effects of epinephrine.

.. ·~c 100

.. E j!:II~ a;

from norepinephrine may be treated with the a receptor antagonist phentolamine. Alternatives to phentolamine include intradermal terbutaline and topical nitroglycerin.

60

D. Dopamine High

nme(mln} Isoproterenol causes

a significant decrease in peripheral resistance.

Dopamine [OOE-pa-meen], the immediate metabolic precursor of norepinephrine, occurs naturally in the CNS in the basal ganglia, where it functions as a neurotransmitter, as well as in the adrenal medulla. Dopamine can activate a- and p-adrenergic receptors. For example, at higher doses, it causes vasoconstriction by activating a1 receptors, whereas at lower doses, it stimulates p, cardiac receptors. In addition, 0 1 and 0 2 dopaminergic receptors, distinct from the a- and p-adrenergic receptors, occur in the peripheral mesenteric and renal vascular beds, where binding of dopamine produces vasodilation. 0 2 receptors are also found on presynaptic adrenergic neurons, where their activation interferes with norepinephrine release.

1. Actions Isoproterenol causes

markedly decreased diastolic pressure, with moderately increased systolic pressure.

Figure 6.12 Cardiovascular effects of intravenous infusion of isoproterenol.

a. Cardiovascular: Dopamine exerts a stimulatory effect on the p, receptors of the heart, having both positive inotropic and chronotropic effects (Figure 6.13). At very high doses, dopamine activates a1 receptors on the vasculature, resulting in vasoconstriction. b. Renal and visceral: Dopamine dilates renal and splanchnic arterioles by activating dopaminergic receptors, thereby increasing blood flow to the kidneys and other viscera (Figure 6.13). These receptors are not affected by a- or p-blocking drugs, and in the past, low-dose ("renal-dose") dopamine was often used in the prevention or treatment of acute renal failure. However, more recent data suggest there is limited clinical utility in the renal protective effects of dopamine. 2. Therapeutic uses: Dopamine can be used for cardiogenic and septic shock and is given by continuous infusion. It raises blood pressure by stimulating the p, receptors on the heart to increase cardiac output, and a1 receptors on blood vessels to increase total peripheral resistance. It enhances perfusion to the kidney and splanchnic areas, as described above. Increased blood flow to the kidney enhances

IV. Direct-Acting Adrenergic Agonists the glomerular filtration rate and causes diuresis. By contrast, norepinephrine can diminish blood supply to the kidney and may reduce renal function. Dopamine is also used to treat hypotension, severe heart failure, and bradycardia unresponsive to other treatments.

83

Isoproterenol

3. Adverse effects: An overdose of dopamine produces the same effects as sympathetic stimulation. Dopamine is rapidly metabolized by MAO or COMT, and its adverse effects {nausea, hypertension, and arrhythmias) are, therefore, short lived. E. Fenoldopam Fenoldopam [fen-OL-de-pam] is an agonist of peripheral dopamine D1 receptors. It is used as a rapid-acting vasodilator to treat severe hypertension in hospitalized patients, acting on coronary arteries, kidney arterioles, and mesenteric arteries. Fenoldopam is a racemic mixture, and the R-isomer is the active component. It undergoes extensive first-pass metabolism and has a 1a-minute elimination halflife after IV infusion. Headache, flushing, dizziness, nausea, vomiting, and tachycardia {due to vasodilation) may occur with this agent.

Bronchodilation

Peripheral vasodilation

F. Dobutamine Dobutamine [doe-BYOO-ta-meen] is a synthetic, direct-acting catecholamine that is primarily a P1 receptor agonist with minor P2 and a 1 effects. It increases heart rate and cardiac output with few vascular effects. Dobutamine is used to increase cardiac output in acute heart failure {see Chapter 18}, as well as for inotropic support after cardiac surgery. The drug increases cardiac output and does not elevate oxygen demands of the myocardium as much as other sympathomimetic drugs. Dobutamine should be used with caution in atrial fibrillation, because it increases atrioventricular {AV) conduction. Other adverse effects are similar to epinephrine. Tolerance may develop with prolonged use.

Increased cardiac output

G. Oxymetazoline Oxymetazoline [OX-ee-mee-TAZ-ih-leen] is a direct-acting synthetic adrenergic agonist that stimulates both a 1- and a 2 -adrenergic receptors. Oxymetazoline is found in many over-the-counter nasal spray decongestants, as well as in ophthalmic drops for the relief of redness of the eyes associated with swimming, colds, and contact lenses. Oxymetazoline directly stimulates a receptors on blood vessels supplying the nasal mucosa and conjunctiva, thereby producing vasoconstriction and decreasing congestion. It is absorbed in the systemic circulation regardless of the route of administration and may produce nervousness, headaches, and trouble sleeping. Local irritation and sneezing may occur with intranasal administration. Use for greater than 3 days is not recommended, as rebound congestion and dependence may occur.

Increased blood flow

Dopaminergic

Figure 6.13 H. Phenylephrine Phenylephrine [fen-iii-EF-reen] is a direct-acting, synthetic adrenergic drug that binds primarily to a1 receptors. Phenylephrine is a vasoconstrictor that raises both systolic and diastolic blood pressures. It has no effect on the heart itself but, rather, induces reflex bradycardia

Clinically important actions of isoproterenol and dopamine.

84

6. Adrenergic Agonists when given parenterally, making it useful in the treatment of paroxysmal supraventricular tachycardia. The drug is used to treat hypotension in hospitalized or surgical patients (especially those with a rapid heart rate). Large doses can cause hypertensive headache and cardiac irregularities. Phenylephrine acts as a nasal decongestant when applied topically or taken orally. Although data suggest it may not be as effective, phenylephrine has replaced pseudoephedrine in many oral decongestants, since pseudoephedrine has been misused to make methamphetamine. Phenylephrine is also used in ophthalmic solutions for mydriasis.

I. Mldodrlne Midodrine, a prodrug, is metabolized to the pharmacologically active desglymidodrine. It is a selective a1 agonist, which acts in the periphery to increase arterial and venous tone. Midodrine is indicated for the treatment of orthostatic hypotension. The drug should be given three times daily, with doses at 3- or 4-hour intervals. To avoid supine hypertension, doses within 4 hours of bedtime are not recommended. On•t of bronchodllatlon Duration of bronchodllatlon

Arfonnamollllll•••••e=> S®M~

. . . . . . . . .. . 0

10

5

Hours

Figure 6.14 Onset and duration of bronchodilation effects of inhaled adrenergic agonists.

J. Clonidine Clonidine [KLOE-ni-deen] is an ~ agonist used for the treatment of hypertension. It can also be used to minimize symptoms of withdrawal from opiates, tobacco smoking, and benzodiazepines. Both clonidine and the ~ agonist guanfacine [GWAHN-fa-seen] may be used in the management of attention deficit hyperactivity disorder. Clonidine acts centrally on presynaptic~ receptors to produce inhibition of sympathetic vasomotor centers, decreasing sympathetic outflow to the periphery. The most common side effects of clonidine are lethargy, sedation, constipation, and xerostomia. Abrupt discontinuation must be avoided to prevent rebound hypertension. Clonidine and another ~ agonist methyldopa are discussed with antihypertensives in Chapter 16.

K. Albuterol, metaproterenol, and terbutallne Albuterol [ai-BYOO-ter-ole], metaproterenol [MET-a-proe-TER-enol], and terbutaline [ter-BYOO-te-leen] are short-acting P2 agonists (SABAs) used primarily as bronchodilators and administered by a metered-dose inhaler (Figure 6.14). Albuterol is the SABA of choice for the management of acute asthma symptoms, because it is more selective for ~ receptors than metaproterenol. Inhaled terbuta/ine is no longer available in the United States, but is still used in other countries. Injectable terbutaline is used off-label as a uterine relaxant to suppress premature labor, and use for this indication should not exceed 72 hours. One of the most common side effects of these agents is tremor, but patients tend to develop tolerance to this effect. Other side effects include restlessness, apprehension, and anxiety. When these drugs are administered orally, they may cause tachycardia or arrhythmia (due to P1 receptor activation), especially in patients with underlying cardiac disease. Monoamine oxidase inhibitors (MAOis) also increase the risk of adverse cardiovascular effects, and concomitant use should be avoided.

V. Indirect-Acting Adrenergic Agonists

L. Salmeterol, formoterol, and indacaterol Salmeterol [sal-ME-ter-ole], formoterol [for-MOH-ter-ole], arformoterol(the [R,R]-enantiomerof formotero~, and indacatero/[IN-daKA-ter-ol] are long-acting 132 selective agonists (LABAs) used for the management of respiratory disorders such as asthma and chronic obstructive pulmonary disease (see Chapter 39). A single dose by a metered-dose inhalation device, such as a dry powder inhaler, provides sustained bronchodilation over 12 hours, compared with less than 3 hours for a/buterol. Unlike formoterol, however, salmeterol has a somewhat delayed onset of action (Figure 6.14). LABAs are not recommended as monotherapy for the treatment of asthma, because they have been shown to increase the risk of asthmarelated deaths; however, these agents are highly efficacious when combined with an asthma controller medication such as an inhaled corticosteroid.

M. Mirabegron Mirabegron [mir-a-BEG-ron] is a p3 agonist that relaxes the detrusor smooth muscle and increases bladder capacity. It is used for patients with overactive bladder. Mirabegron may increase blood pressure and should not be used in patients with uncontrolled hypertension. It increases levels of digoxin and inhibits the CYP2D6 isozyme, which may enhance the effects of other medications metabolized by this pathway (for example, metoprolo~.

V. INDIRECT-ACTING ADRENERGIC AGONISTS Indirect-acting adrenergic agonists cause the release, inhibitthe reuptake, or inhibit the degradation of epinephrine or norepinephrine (Figure 6.8). They potentiate the effects of epinephrine or norepinephrine produced endogenously, but do not directly affect postsynaptic receptors.

A. Amphetamine The marked central stimulatory action of amphetamine [am-FET-ameen] is often mistaken by drug abusers as its only action. However, the drug can also increase blood pressure significantly by a, agonist action on the vasculature, as well as P1 stimulatory effects on the heart. Its actions are mediated primarily through an increase in nonvesicular release of catecholamines such as dopamine and norepinephrine from nerve terminals. Thus, amphetamine is an indirect-acting adrenergic drug. The actions and therapeutic uses of amphetamine and its derivatives are discussed with CNS stimulants (see Chapter 15).

B. Tyramine Tyramine [TIE-ra-meen] is not a clinically useful drug, but it is important because it is found in fermented foods, such as aged cheese and Chianti wine. It is a normal by-product of tyrosine metabolism. Normally, it is oxidized by MAO in the gastrointestinal tract, but if the patient is taking MAOis, it can precipitate serious vasopressor

85

6. Adrenergic Agonists

86

episodes. Like amphetamines, tyramine can enter the nerve terminal and displace stored norepinephrine. The released catecholamine then acts on adrenoceptors. C. Cocaine

v-~

~ Anhythm;~

Cocaine [koe-KANE] is unique among local anesthetics in having the ability to block the sodium-chloride (Na+/CI-)--dependent norepinephrine transporter required for cellular uptake of norepinephrine into the adrenergic neuron. Consequently, norepinephrine accumulates in the synaptic space, resulting in enhanced sympathetic activity and potentiation of the actions of epinephrine and norepinephrine. Therefore, small doses of the catecholamines produce greatly magnified effects in an individual taking cocaine. In addition, the duration of action of epinephrine and norepinephrine is increased. Like amphetamines, it can increase blood pressure by a1 agonist actions and p stimulatory effects. Cocaine as a drug of abuse is discussed in Chapter 45.

Headache

VI. MIXED-ACTION ADRENERGIC AGONISTS

Hyperactivity

Insomnia

Nausea

Tremors

Figure 6.15 Some adverse effects observed with adrenergic agonists.

Ephedrine [eh-FED-rin] and pseudoephedrine [soo-doe-eh-FED-rin] are mixed-action adrenergic agents. They not only enhance release of stored norepinephrine from nerve endings (Figure 6.8) but also directly stimulate both a and p receptors. Thus, a wide variety of adrenergic actions ensue that are similar to those of epinephrine, although less potent. Ephedrine and pseudoephedrine are not catecholamines and are poor substrates for COMT and MAO. Therefore, these drugs have a long duration of action. Ephedrine and pseudoephedrine have excellent absorption after oral administration and penetrate the CNS, but pseudoephedrine has fewer CNS effects. Ephedrine is eliminated largely unchanged in urine, and pseudoephedrine undergoes incomplete hepatic metabolism before elimination in urine. Ephedrine raises systolic and diastolic blood pressures by vasoconstriction and cardiac stimulation and it is indicated in anesthesia-induced hypotension. Ephedrine produces bronchodilation, but it is less potent and slower acting than epinephrine or isoproterenol. It was previously used to prevent asthma attacks but has been replaced by more effective medications. Ephedrine produces a mild stimulation of the CNS. This increases alertness, decreases fatigue, and prevents sleep. It also improves athletic performance. [Note: The clinical use of ephedrine is declining because of the availability of better, more potent agents that cause fewer adverse effects. Ephedrine-containing herbal supplements (mainly ephedra-containing products) have been banned by the U.S. Food and Drug Administration because of life-threatening cardiovascular reactions.] Oral pseudoephedrine is primarily used to treat nasal and sinus congestion. Pseudoephedrine has been illegally used to produce methamphetamine. Therefore, products containing pseudoephedrine have certain restrictions and must be kept behind the sales counter in the United States. Important characteristics of the adrenergic agonists are summarized in Figures 6.15 to 6.17.

87

VI. Mixed-Action Adrenergic Agonists

TISSUE

RECEPTOR TYPE

ACTION

OPPOSING ACTIONS

Hurt • Sinus and AV

~1

• Conduction pathway

~1

• M,ofibrils

~1 -

I-

-

I-

Vascular smooth muscle

t t t -

Conduction velocity, autom1tidty

Cholinergic receptors

Contractility, 1utomaticity 1-

V111odilation

-

-

Bronchodilation

t

~1

t

~1,Jb

-

1-

1-

t

--

1-

1-

Motility

--

Cholinergic receptors 1-

Relaxation

lb -

1-

Cholinergic receptors 1-

~

lb

Gallbladder

lncn~ued contractllty Potassium uptaH; glycogt~nolysls Dllat• artliriH to skeletal muscle Tremor

--

1-

Cb-Adrenergic receptors

Relaxation

lb 1-

Gl tract

Lipolysis 1-

t

lb

Eye-ciliary muscle

Glycogenolysis and gluconeogenesis

-

1-

Skeletal muscle

a,-Adrenergic receptors 1-

lh.a1

Adipose tissue

Cholinergic receptors

Renin release

1-

Liver

a-Adrenergic receptors 1-

lb

Kidneys

Cholinergic receptors

-

lb

Bronchial smooth muscle

Automaticity

Cholinergic receptors 1-

Urinary bladder detrusor muscle

!b-Ib

Relaxation

Cholinergic receptors

Uterus

lb

Relaxation

Oxytocin

Figure 6.16 Summary of jl-adrenergic receptors. AV = atrioventricular; Gl = gastrointestinal.

6. Adrenergic Agonists

88

DRUG

RECEPTOR SPECIFICITY

Epinephrine

Uto «X2 PtoP2

THERAPEUTIC USES Anaphylactic shock Cardiac arrest In local anesthetics to Increase duration of action

1-

Norepinephrine