USMLE Step 1 Pharmacology Review Flash Cards [1st ed.] 9780071804370

Table of contents :
Cover
Title Page
Copyright Page
Contents
Preface
Acknowledgements
About the Author
Section 1 Autonomic Pharmacology
Section 2 Cardiovascular Pharmacology
Section 3 Neuropharmacology
Section 4 Antibiotics
Section 5 Pharmacokinetic and Pharmacodynamic Principles
Figures and Tables

Citation preview

ADDITIONAL RESOURCES To access the additional content included only with purchase of USMLE Step 1 Pharmacology Flashcards, please follow the directions below: • Use your web browser to go to: www.langetextbooks.com/crisp. • You will now have access to the USMLE Step 1 Pharmacology Flashcards Lecture Series by Terriann Crisp.

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USMLE Step 1 Pharmacology Flashcards Terriann Crisp, PhD Crisp Enterprises: Pharmacology Instruction and Consultation, LLC Ankeny, Iowa

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

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Notice Medicine is an ever-changing science. As new research and clinical experience broaden our knowledge, changes in treatment and drug therapy are required. The authors and the publisher of this work have checked with sources believed to be reliable in their efforts to provide information that is complete and generally in accord with the standards accepted at the time of publication. However, in view of the possibility of human error or changes in medical sciences, neither the authors nor the publisher nor any other party who has been involved in the preparation or publication of this work warrants that the information contained herein is in every respect accurate or complete, and they disclaim all responsibility for any errors or omissions or for the results obtained from use of the information contained in this work. Readers are encouraged to confirm the information contained herein with other sources. For example and in particular, readers are advised to check the product information sheet included in the package of each drug they plan to administer to be certain that the information contained in this work is accurate and that changes have not been made in the recommended dose or in the contraindications for administration. This recommendation is of particular importance in connection with new or infrequently used drugs.

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Copyright © 2015 by McGraw-Hill Education. All rights reserved. Except as permitted under the United States Copyright Act of 1976, no part of this publication may be reproduced or distributed in any form or by any means, or stored in a database or retrieval system, without the prior written permission of the publisher, with the exception that the program listings may be entered, stored, and executed in a computer system, but they may not be reproduced for publication. ISBN: 978-0-07-180437-0 MHID: 0-07-180437-4 The material in this eBook also appears in the print version of this title: ISBN: 978-0-07-179963-8, MHID: 0-07-179963-X. eBook conversion by codeMantra Version 1.0 All trademarks are trademarks of their respective owners. Rather than put a trademark symbol after every occurrence of a trademarked name, we use names in an editorial fashion only, and to the benefit of the trademark owner, with no intention of infringement of the trademark. Where such designations appear in this book, they have been printed with initial caps. McGraw-Hill Education eBooks are available at special quantity discounts to use as premiums and sales promotions or for use in corporate training programs. To contact a representative, please visit the Contact Us page at www.mhprofessional.com. TERMS OF USE This is a copyrighted work and McGraw-Hill Education and its licensors reserve all rights in and to the work. Use of this work is subject to these terms. Except as permitted under the Copyright Act of 1976 and the right to store and retrieve one copy of the work, you may not decompile, disassemble, reverse engineer, reproduce, modify, create derivative works based upon, transmit, distribute, disseminate, sell, publish or sublicense the work or any part of it without McGraw-Hill Education’s prior consent. You may use the work for your own noncommercial and personal use; any other use of the work is strictly prohibited. Your right to use the work may be terminated if you fail to comply with these terms. THE WORK IS PROVIDED “AS IS.” McGRAW-HILL EDUCATION AND ITS LICENSORS MAKE NO GUARANTEES OR WARRANTIES AS TO THE ACCURACY, ADEQUACY OR COMPLETENESS OF OR RESULTS TO BE OBTAINED FROM USING THE WORK, INCLUDING ANY INFORMATION THAT CAN BE ACCESSED THROUGH THE WORK VIA HYPERLINK OR OTHERWISE, AND EXPRESSLY DISCLAIM ANY WARRANTY, EXPRESS OR IMPLIED, INCLUDING BUT NOT LIMITED TO IMPLIED WARRANTIES OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE. McGraw-Hill Education and its licensors do not warrant or guarantee that the functions contained in the work will meet your requirements or that its operation will be uninterrupted or error free. Neither McGraw-Hill Education nor its licensors shall be liable to you or anyone else for any inaccuracy, error or omission, regardless of cause, in the work or for any damages resulting therefrom. McGraw-Hill Education has no responsibility for the content of any information accessed through the work. Under no circumstances shall McGraw-Hill Education and/or its licensors be liable for any indirect, incidental, special, punitive, consequential or similar damages that result from the use of or inability to use the work, even if any of them has been advised of the possibility of such damages. This limitation of liability shall apply to any claim or cause whatsoever whether such claim or cause arises in contract, tort or otherwise.

Contents Preface Acknowledgments About the Author

ix xi xiii

Section 1

Autonomic Pharmacology

Section 2

Cardiovascular Pharmacology

20–66

Section 3

Neuropharmacology

67–95

1–19

Section 4

Antibiotics

Section 5

Pharmacokinetic and Pharmacodynamic Principles

96–110

Figures and Tables

111–128 129–158

vii

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Preface The USMLE Step 1 Pharmacology Flashcard Series and the companion PowerPoint presentations are intended to clearly and succinctly review high-yield USMLE Step 1 pertinent information on 5 major areas of Medical Pharmacology. Emphasis is placed on drug mechanism(s) of action, clinical indications, and major adverse drug reactions/toxicities. Section I reviews USMLE-relevant information on Autonomic Pharmacology. In both the flash card series and PowerPoint presentations, beautifully-drawn artwork is provided in figures and tables to help emphasize and explain critical points. This will be especially helpful for those students who tend to be visual learners. Section II covers important areas of Cardiovascular Pharmacology. Multiple figures are provided to explain the mechanisms of action and clinical indications of these critically important agents. For medical students preparing for the USMLE Step 1, all 5 sections of this flash card series were designed to provide the most high-yield pharmacological information available, and cardiovascular pharmacology is certainly one of the most important areas of the examination. Section III reviews the highest yield information available in Neuropharmacology, which is another of the most essential modules on the USMLE Step 1. Dr. Crisp has scoured through the most respected pharmacology textbooks available to bring neuropharmacology to life for those students who might have had difficulty putting this information together by themselves. Her intent is to help students make sense of vast amounts of neuropharmacological information by compressing it into more tenable parts. In Section IV, the Antibiotics are discussed along with mnemonics to help students remember the names of the numerous drugs comprising this section (e.g., the ‘flox’ drugs are fluoroquinolones etc.). Dr. Crisp has succinctly incorporated the high-yield mechanisms of action, clinical indications, and adverse drug reactions ix

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for each of the major classes of antibiotics. Medical students taking the USMLE Step 1 will need to be especially skilled at identifying microbiological infections and bacterial cultures. Understanding the appropriate antimicrobial treatment regimens and drug mechanisms will be paramount on the examination. In the final Section V, important Pharmacokinetic and Pharmacodynamic Principles will be described along with USMLE Step 1 relevant examples. Students will be expected to understand the principles underlying cytochrome P-450 (CYP) inducers and inhibitors, zero- versus first-order kinetics, and the use of the Henderson-Hasselbalch equation to explain behavior of weak acids and weak bases in different pH environments in the body. It is our hope that this information will help students competently succeed on the Step 1 examination and move on toward a successful and rewarding career in medicine.

x

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Acknowledgments “If I have seen further than others, it is by standing on the shoulders of giants.” …Sir Isaac Newton As scientists, no one person is solely responsible for important discoveries or scientific advances and I am certainly no exception. Mentors, colleagues, and role models have helped to inspire and guide me through my training and profession. Throughout a 30-year career in medical education, I have worked with some outstanding mentors and friends, including Dr. Michael E. Trulson, Dr. David J. Smith, Dr. Laurie Brown-Croyts, Drs. Robert and Betty Bush, Dr. Gary Rankin, Dr. Edward P. Finnerty, Dr. Daniel Deavers, Dr. Wayne Terry, Dr. Traci Ann Bush, Phyllis and John Griffith, and many others. I publicly offer my deepest respect and gratitude to these individuals for their forbearance, patience, and tutelage. I also want to thank my amazing family for their continued support and faith.

xi

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About the Author

Dr. Terriann Crisp has served as an academic pharmacologist for almost 30 years. She earned her Ph.D. from Marshall University School of Medicine in 1985 prior to completing a postdoctoral research fellowship at Robert C. Byrd Health Sciences Center. Dr. Crisp worked through the academic ranks as a professor of medical pharmacology at Northeast Ohio Medical University College of Medicine and later at Des Moines University.

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Autonomic Pharmacology

. . . ---_-_-_-_-_ .. . . ._-_-_-_-_,,--, . . .-_-_-_ . . ___._...._-_-_-_-_,--. . . .-_-_-_ . . ___._...._-_-_-_-_,--. . . .-_-_-_ . . ___.__-_-_-_-_,--. . . . .-----=-~-=--=--=-=.--, . . . ~::::::::::::~====.-, . r-~::::::::::::==::::'.======::.-, . . ;:-.::::.::::.::::.::::.::::_ . ...._-_-_-_-_-_,,--. . . . --------~' .. -:..-::..-::..-=..-=.--, Location of Muscarinic, Nicotinic and Adrenergic (a and~) Receptors

Drugs Affecting the Cholinergic Nerve Terminal (Figure 2)

Drugs Affecting the Adrenergic Nerve Terminal (Figure 3)

Important Muscarinic Receptor Agonist Actions

Clinical Indications of Muscarinic Agonists (Figure 4)

Clinical Indications of AChEis (Figune 4)

Clinlcal Jndications for Muscarinic Blocking Drugs (.Antimuscarinics)

Adverse Drug Reactions of the Antimuscarinics

Effects of a-1 and a-2 Adrenoceptor Activation

(Continued)

Autonomic Pharmacology (Cont'd.)

Effects of β-1 and β-2 Adrenoceptor Activation

Signal Transduction Mechanisms for α- and βAdrenoceptors

Clinical Uses of α-1 Adrenergic Agonists

Clinical Uses of α-2 Adrenergic Agonists

Clinical Uses of β-1 and β-2 Adrenergic Agonists

Indirect-Acting Sympathomimetics

Clinical Uses of α-1 and α-2 Receptor Antagonists

Clinical Uses of Nonselective β-1 and β-2 Adrenoceptor Antagonists

Clinical Uses of β-1 “Cardioselective” β-Blockers

1

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SECTION 1

Location of Muscarinic, Nicotinic and Adrenergic (α and β) Receptors Muscarinic receptors (M2 and M3 sites) are located on target tissues on smooth muscle, the eye, the cardiac muscle, and the exocrine glands (Figure 1). Nicotinic cholinoceptors are located on postganglionic parasympathetic and sympathetic fibers, the adrenal medulla (NN), and skeletal muscle cells (NM).

2

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α-adrenoceptors can be found on postsynaptic effector cells in the ciliary epithelium of the eye, vasculature smooth muscle, and the glands (Figure 1). β1-adrenoceptors are located on cardiac cells and the juxtaglomerular tissue of the kidney. β2-adrenoceptors can be found on the bronchial and the vasculature smooth muscle, the uterus, and the pancreatic islet cells.

2

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SECTION 1

Drugs Affecting the Cholinergic Nerve Terminal (Figure 2) Acetylcholine (ACh) is an endogenous agonist at muscarinic and nicotinic cholinoceptors. Hemicholinium blocks the reuptake of choline by inhibiting the Na+-dependent choline transporter (blocks ACh synthesis). Vesamicol blocks the vesicle-associated transporter (VAT), inhibiting the vesicular transport of ACh (blocks ACh storage). Botulinum toxin (Botox) blocks exocytotic release of ACh by proteolytic degradation of soluble N-ethylmaleimide-sensitive factor activating protein receptor (SNARE) proteins (i.e., synaptobrevin) in the vesicles and the plasma membrane that are important for vesicular fusion and exocytosis.

3

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Acetylcholinesterase (AChE) is the endogenous enzyme that terminates the action of ACh. Edrophonium, Neostigmine, Parathion, and Soman are AChE inhibitors (AChEIs) that block the enzymatic activity of AChE.

3

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SECTION 1

Drugs Affecting the Adrenergic Nerve Terminal (Figure 3) Reserpine inhibits the vesicular monoamine transporter (VMAT), blocking the vesicular transport of dopamine (DA), norepinephrine (NE), and other biogenic amines (5-HT). Reserpine acts in the central nervous system (CNS) and peripheral nervous system (PNS). The monoamine oxidase inhibitors (MAOIs), phenelzine and tranylcypromine, block the enzymatic activity of intracellular monoamine oxidase (MAO), increasing the levels of NE, DA, and 5-HT inside the nerve terminal.

4

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Guanethidine inhibits Ca2+-dependent exocytosis of NE from the presynaptic terminal. Guanethidine does not cross the blood-brain barrier, but acts as a sympathoplegic agent and inhibits the release of NE from sympathetic nerve endings. Cocaine blocks the reuptake of DA (in CNS) and NE (mostly PNS) into the presynaptic terminal. Amphetamine enters the terminal through the reuptake transporter and indirectly increases synaptic concentrations of DA or NE in the CNS and PNS by reversing the transport mechanism.

4

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SECTION 1

Important Muscarinic Receptor Agonist Actions Eye—miosis and accommodation (contraction for near vision) Lung—bronchoconstriction and bronchial gland secretion Gastrointestinal (GI) tract—increased motility and acid secretion Heart—SA node—decreased rate (negative chronotropic effect), decreased AV conduction (negative dromotropic effect), and minimal decrease in ventricular contractility (negative inotropic effect)

5

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Vasculature—vasodilation (sympathetic action) Urinary bladder—contraction of detrusor muscle (urination) and relaxation of trigone and sphincter Glands—SLUDE (mnemonic): salivation/sweating, lacrimation (tears), urination, defecation, and emesis (nausea and vomiting)

5

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SECTION 1

Clinical Indications of Muscarinic Agonists (Figure 4) Carbachol—decreases intraocular pressure in patients with glaucoma by increasing the diameter of the canal of Schlemm and increasing the drainage of aqueous humor. Pilocarpine—used clinically to treat glaucoma (increases the diameter of the canal of Schlemm); increases the drainage of aqueous humor. Bethanechol—treats urinary retention (the “U” in SLUDE stands for urination)

6

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Methacholine—used in diagnostic tests to detect familial dysautonomia (doses of methacholine having no effect in normal individuals produce significant miosis in patients with dysautonomia). Methacholine is also used as a diagnostic test for asthma (bronchial hyper-reactivity) and in the chloride sweat test for diagnosing cystic fibrosis.

N

ACh

ACh M

Smooth muscle, cardiac muscle and endocrine glands

Medulla

Muscarinic cholinoceptors in the periphery are upregulated after damage to the parasympathetic nerve, inducing supersensitivity and miosis.

6

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SECTION 1

Clinical Indications of Acetylcholinesterase Inhibitors (Figure 4) Neostigmine—myasthenia gravis, reversal of tubocurarine-induced neuromuscular blockade Pyridostigmine and Ambenonium—myasthenia gravis Demecarium, Physostigmine, and Echothiophate—glaucoma Donepezil, Rivastigmine and Galantamine—CNS AChEIs used to treat memory loss in patients with Alzheimers

7

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Edrophonium—differentiation between “cholinergic crisis” and “myasthenic crisis” Physostigmine—reverses antimuscarinic toxicity in the CNS and peripheral nervous system (from atropine-like drugs, tricyclic antidepressants, phenothiazines, and other drugs with antimuscarinic actions)

7

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SECTION 1

Clinical Indications for Muscarinic Blocking Drugs (Antimuscarinics) Atropine—antispasmodic, decrease secretions, management of overdose of AChEIs, antidiarrheal, ophthalmology Tropicamide—ophthalmology (topical) Ipratropium and Tiotropium—asthma and chronic obstructive pulmonary disease (COPD) (inhalational), no CNS entry

8

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Scopolamine—used in motion sickness, causes sedation, and short-term memory block Benztropine and Trihexyphenidyl—lipid-soluble (CNS entry); used in Parkinsonism and to treat acute extrapyramidal symptoms induced by antipsychotics

8

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SECTION 1

Adverse Drug Reactions of the Antimuscarinics Dry mouth Visual disturbances—cycloplegia (paralysis of accommodation), photophobia, and blurred vision Constipation Difficulty in urination Elevated body temperature Dry hot skin

9

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Note of Importance Many classes of drugs block muscarinic cholinoceptors and may induce antimuscarinic side effects, including the tricyclic antidepressants (TCA), phenothiazine antipsychotics (chlorpromazine), antiarrhythmic agents (quinidine), amantadine (an antiviral agent and DA-releaser used in Parkinson disease), and meperidine (an opiate).

9

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SECTION 1

Effects of α-1 and α-2 Adrenoceptor Activation α-1 Mediated Effects Contraction of radial muscle in eye (dilation of pupil—mydriasis) Contraction of arterial and venous smooth muscle (vasoconstriction) Ejaculation

10

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α-2 Mediated Effects Inhibition of sympathetic outflow from CNS Contraction of arterial and venous smooth muscle (vasoconstriction) Inhibition of lipolysis Inhibition of insulin secretion from the pancreas

10

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SECTION 1

Effects of β-1 and β-2 Adrenoceptor Activation β-1 Mediated Effects (mostly in heart and kidney) Increase automaticity—HR (positive chronotropic effect) Increase conduction velocity (positive dromotropic effect) Increase contractility (positive inotropic effect) Increase renin secretion

11

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β-2 Mediated Effects Relaxation of bronchial smooth muscle (bronchodilation) Relaxation of vascular smooth muscle (vasodilation) Increase glycogenolysis, gluconeogenesis Relaxation of uterine smooth muscle Increase insulin secretion from the pancreas

11

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SECTION 1

Signal Transduction Mechanisms for α- and β-Adrenoceptors α-1 Adrenoceptors Phospholipase C activation (Gq-coupled), ↑ release of inositol triphosphate (IP3) and diacylglycerol (DAG) IP3-↑ intracellular Ca2+ DAG-activates Protein Kinase C

12

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α-2 Adrenoceptors Gi-coupled; inhibition of adenylate cyclase, ↓ cAMP β-1, β-2, and D-1 Adrenoceptors GS-coupled; activation of adenylate cyclase, ↑ cAMP

12

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SECTION 1

Clinical Uses of α-1 Adrenergic Agonists α-1 Adrenergic Agonists Phenylephrine—vasoconstriction-induced decongestant action treats nasal congestion Methoxamine—used to treat nasal congestion and postural hypotension DA, NE, and EPI (catecholamines)—all have affinity for the α-1 adrenoceptor EPI – α-1, α-2, β-1, and β-2 agonist • prolongs the duration of action of local anesthetics • treats anaphylactic shock • counteracts complete heart block and cardiac arrest NE – α-1, α-2, and β-1 agonist • vasoconstriction, used to treat hypotension

13

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DA – α-1, α-2, β-1, and D-1 agonist properties • treats patients with cardiogenic circulatory failure • maintains glomerular filtration rate (GFR) and is used to sustain renal blood flow in CHF patients with impaired renal function (via interacting with D1 receptors in the kidney vasculature). • intermediate doses of DA will increase cardiac contractility

13

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SECTION 1

Clinical Uses of α-2 Adrenergic Agonists α-2 Adrenergic Agonists Clonidine—stimulates α-2 adrenoceptors in the brainstem—↓ blood pressure by inhibiting the release of sympathetic transmitters (NE) in periphery, ↓ PVR, and ↓ blood pressure. Clonidine—diminishes the effects of an overactive sympathetic nervous system in patients withdrawing from narcotics, alcohol, and tobacco. α-Methyldopa—converted to α-methyl NE in the CNS; centrally active mechanism same as clonidine; preferable agent for treating hypertension in pregnancy.

14

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Note of Importance Antihypertensive medications are used to treat hypertension in women who are not pregnant (e.g., ACEIs and ARBs). However, these agents can potentially cause adverse drug reaction to the fetus. α-Methyldopa is indicated in pregnancy.

14

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SECTION 1

Clinical Uses of β-1 and β-2 Adrenergic Agonists Non-selective β-1 and β-2 Adrenergic Agonists Isoproterenol—bronchodilation, once used to treat asthma. β-1 Selective Adrenergic Agonists Dobutamine—↑ contractility of the heart; used for acute treatment of congestive heart failure (CHF) and short-term treatment of cardiac decompensation post-myocardial infarction (MI)

15

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β-2 Selective Adrenergic Agonists Albuterol—bronchodilator used for the treatment of asthma and COPD Terbutaline—bronchodilator used for the treatment of asthma and COPD Metaproterenol—bronchodilator used for the treatment of asthma and COPD Salmeterol—long-acting bronchodilator used for the treatment of asthma and COPD Ritodrine—inhibits uterine contraction to prevent premature labor (tocolytic agent)

15

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SECTION 1

Indirect-Acting Sympathomimetics Specific Drugs The pharmacological actions of these drugs are generally due to their ability to ↑ the release of NE. Sympathetic-like effects include vasoconstriction (↑ BP) and ↑ HR. Amphetamine—CNS stimulant that releases NE in the periphery; induces vasoconstriction (↑ BP) and ↑ HR. (In CNS, amphetamine ↑ release of both DA and NE.) Tyramine—an amino acid contained in certain foods (processed meat, aged cheese, and soy sauce, vegetables such as beets, broccoli, eggplant, fava beans, lima beans, and navy beans) and drinks (unpasteurized beer, some red, and sparkling wines)

16

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Tyramine—produces its pharmacological effects by releasing NE in the periphery, causing vasoconstriction (↑ BP) and ↑ HR. Ephedrine—(mixed-acting sympathomimetic)—has agonist actions α- and β-adrenoceptors. Also increases the release of NE from sympathetic neurons.

16

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SECTION 1

Clinical Uses of α-1 and α-2 Receptor Antagonists Non-selective α-1 and α-2 Antagonists Phentolamine—treats pheochromocytoma (adrenal medullary tumor that secretes large quantities of catecholamines into the circulation) and hypertension Phenoxybenzamine—pheochromocytoma Selective α-1 Receptor Antagonists Prazosin—hypertension; facilitates urine flow in patients with BPH (first-dose hypotension) Doxazosin—hypertension; facilitates urine flow in patients with benign prostatic hyperplasia (BPH)

17

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Terazosin—hypertension; facilitates urine flow in patients with BPH Tamsulosin—treats BPH by relaxing the smooth muscle in the prostate, which facilitates micturition. Minimal affinity for vascular α-1 receptor. Selective α-2 Receptor Antagonists No specific FDA-approved clinical use

17

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SECTION 1

Clinical Uses of Nonselective β-1 and β-2 Adrenoceptor Antagonists Nonselective β-1 and β-2 Antagonists (note the ‘olol’ in spelling) Propranolol—used in acute MI to prevent recurrence; relieves angina, palpitations, and syncope in patients with hypertrophic obstructive cardiomyopathy; treats supraventricular arrhythmias, hyperthyroidism and is used in migraine prophylaxis Nadolol—useful in hypertension angina pectoris, cardiac arrhythmias, and migraine prophylaxis (unlabeled use) Timolol—post-MI to prevent recurrence; useful for treating glaucoma (by preventing the synthesis of aqueous humor)

18

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Pindolol—(partial agonist; ISA properties) treats hypertension in patients with diabetes, peripheral vascular disease (Raynaud disease), and bronchoconstrictive disorders (asthma and COPD) Labetalol—(competitive antagonist at both α-1 and β-1 and β-2 adrenoceptors)—treats chronic hypertension and angina. Used to reverse cocaine overdose

18

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SECTION 1

Clinical Uses of β-1 “Cardioselective” β-Blockers Cardioselective β-1-blockers Acebutolol—has ISA properties • partial agonist with greater agonist than antagonist effects at β-2 sites • treats hypertension in patients with diabetes, peripheral vascular disease (Raynaud’s), and bronchoconstrictive disorders (asthma and COPD) Atenolol—useful for treating hypertension, arrhythmias, and angina pectoris; also reduces the risk of heart complications following myocardial infarction Esmolol—administered IV (rapid onset and short duration); used during surgery to prevent or treat tachycardia; useful in severe postoperative hypertension; suitable for use when cardiac output, heart rate, and blood pressure are increased

19

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Metoprolol—↓ mortality in patients with stable CHF, ↓ remodeling Carvedilol—also blocks α-1 adrenoceptors; ↓ mortality in patients with CHF (inhibits O2 free radical–initiated lipid peroxidation and vascular smooth muscle mitogenesis; ↓ remodeling) Bisoprolol—↓ mortality in patients with stable CHF, ↓ remodeling

19

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Cardiovascular Pharmacology

List of Antihypertensive Agents (Figures 5)

Antihypertensive Drugs Interfering with Storage Vesicles

Antihypertensive Centrally Active a-2 Agonists (Figures 5 and 6)

Antihypertensive a-1

Antihypertensive ~-Blockers

Antagonists

Antihwertensive Ca 2 Ohannel Blockers

1, Antihypertensive Direct-Acting Vasodila tors (Figures 7 and 8)

Antihypertensive Angiotensin Converting Enzyme Inhibitors (Figure 9)

Angiotensin Receptor Blockers and Renin Antagonist (Figure 9)

(Continued)

20

Cardiovascular Pharmacology (Cont'd.)

Diuretics — Antihypertensive Agents (Figure 10; Table 1)

Other Antihypertensive Agents

Antihypertensive Drugs in Comorbid Conditions

Classification of Antiarrhythmic Agents (Figures 11–14)

Antiarrhythmic Agents

Treatment of Congestive Heart Failure

Antianginal Pharmacology

‘Pharm-Man’ Says… Antianginal Pharmacology

Diuretics (Figure 10, Table 1)

DiureticInduced Changes in Body pH

Drugs to Treat Lipid Disorders

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SECTION 2

List of Antihypertensive Agents (Figure 5) Drugs Interfering with Storage Vesicles Reserpine Guanadrel Drugs Altering Sympathetic Nervous System Activity α-2 agonists—Clonidine, α-Methyldopa (Figure 6) α-antagonist—Prazosin, Doxazosin, Terazosin, Tamsulosin β-blockers—Metoprolol, Acebutolol, Atenolol Calcium Channel Blockers Nifedipine, Amlodipine, Felodipine, Verapamil, Diltiazem Direct-acting Vasodilators (Figure 7) Hydralazine, Diazoxide, Minoxidil, Nitroprusside

21

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Angiotensin Converting Enzyme Inhibitors (ACEIs) and Angiotensin Receptor Blockers (ARBs) Captopril, Enalapril, Lisinopril (ACEIs) Losartan, Valsartan (ARBs) Diuretics Thiazides—Hydrochlorothiazide, Chlorthalidone, Metolazone, Indapamide Loop diuretics—Furosemide, Ethacrynic Acid, Bumetanide Bosentan Treats pulmonary artery hypertension Antihypertensive Drugs in Comorbid Conditions

21

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SECTION 2

Antihypertensive Drugs Interfering with Storage Vesicles Drugs Interfering with Central and Peripheral Adrenergic Storage Vesicles Reserpine—referred to as a “sympathoplegic” agent because it paralyzes the sympathetic nervous system. Reserpine easily crosses the blood-brain barrier (BBB). Mechanism of Action Reserpine binds to storage vesicles in central and peripheral neurons and destroys the vesicular membrane-associated transporter (VMAT2). Storage vesicles can no longer concentrate and store NE, DA, and 5-HT. NE, DA, and 5-HT leak into the cytoplasm and are metabolized by MAO (Figures 3 and 5). Recovery of function requires synthesis of new storage vesicles, which takes days to weeks after discontinuation of the drug. Reserpine lowers BP by a combination of ↓ CO and ↓ TPR (↓ NE in periphery).

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Adverse Drug Reactions • Sedation and inability to concentrate or perform complex tasks. • Suicidal ideation and depression (reserpine must be discontinued at the first sign of depression).

(Continued)

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SECTION 2

Antihypertensive Drugs Interfering with Storage Vesicles Drugs Interfering with Adrenergic Storage Vesicles Guanethidine—produces profound sympathoplegia (rarely used clinically but mechanisms are important to recognize for the USMLE) Mechanism of Action Guanethidine does not cross the BBB, so it does not produce suicidal ideation like reserpine. Guanethidine accumulates into sympathetic nerve endings by the NET reuptake pump, concentrates in transmitter vesicles, and causes a gradual depletion of NE from sympathetic nerve endings (Figures 3 and 5). Guanethidine ↓ BP by ↓ CO and ↓ TPR • Uptake through the NET is essential for the antihypertensive actions of guanethidine. If tricyclic antidepressants are administered to patients taking guanethidine, the antihypertensive effects of guanethidine are blocked and severe hypertension may occur.

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Adverse Drug Reactions • postural hypotension • delayed or retrograde ejaculation

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SECTION 2

Antihypertensive Centrally Active Alpha-2 Agonists (Figures 5 and 6) Centrally Active Alpha-2 Agonists Clonidine—centrally acting α-2 agonist α–Methyldopa—converted to α-methyl NE in the CNS Mechanism of Action (Figure 6) These drugs act on α-2 adrenoceptors in the vasomotor center of the brainstem—decrease sympathetic nervous system activity (and ↓ NE release from periphery)—↓ CO, ↓ TPR

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Clinical Uses Mild-to-moderate hypertension (α-Methyldopa is used for hypertension management in pregnancy) Opiate withdrawal (clonidine patch) Adverse Drug Reactions Positive Coombs test (α-Methyldopa), CNS depression, edema Rebound hypertension following abrupt withdrawal of clonidine—treat with phentolamine (α-antagonist) and propranolol (β-blocker)

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SECTION 2

Antihypertensive α-1 Antagonists α-1 Antagonists Prazosin Doxazosin Terazosin Tamsulosin—greater potency (and affinity) in inhibiting contraction in prostate smooth muscle versus vascular smooth muscle Mechanism of Action Block α-1 adrenoceptors in the periphery—↓ arteriolar and venous resistance, ↓ BP Clinical Uses Hypertension BPH (tamsulosin—relaxes smooth muscle in the prostate)

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Adverse Drug Reactions • “First-dose syncope”—severe orthostatic hypotension occurs within 30 to 90 minutes (or longer) of the initial dose of the drug (tolerance develops after the first few doses) • Reflex tachycardia • Advantage—favorable effect on lipid profile (↓ LDL, ↑ HDL)

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SECTION 2

Antihypertensive β-Blockers β-Blockers Propranolol Metoprolol Atenolol Labetalol—a competitive α-1 and β-antagonist Pindolol—intrinsic sympathomimetic activity (ISA) agent (partial agonist with greater agonist than antagonist actions at β-2 sites) Acebutolol—ISA agent Mechanism of Action ↓ CO and ↓ renin release

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Adverse Drug Reactions Unfavorable lipid profile (β-blockers ↑ LDL and ↓ HDL). Use nonselective β-blockers with caution in patients with diabetes, peripheral vasculature disease (Raynaud’s disease), or asthma/COPD. Use ISA drugs (Pindolol or Acebutolol) or cardioselective agents (Acebutolol, Atenolol, or Metoprolol) in patients with diabetes, peripheral vasculature disease (Raynaud’s disease) or asthma/COPD.

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SECTION 2

Antihypertensive Ca2+ Channel Blockers Calcium Channel Blockers (Figure 5) Nifedipine—dihydropyridine Amlodipine—dihydropyridine Felodipine—dihydropyridine Verapamil Diltiazem

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Mechanism of Action/Uses • The Ca2+ channel blockers block activated and inactivated L-type calcium channels. • The Ca2+ channel blockers are equally efficacious at lowering blood pressure. • Nifedipine and the other dihydropyridine agents are more selective as vasodilators (little or no direct cardio-depressant effects). Adverse Drug Reactions • Dihydropyridines (nifedipine)—reflex ↑ HR or CO

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SECTION 2

Antihypertensive Direct-Acting Vasodilators (Figure 7 and Figure 8) Direct-Acting Vasodilators Hydralazine—↓ BP by ↑ nitric oxide (NO) release; ↓ TPR via arteriolar dilation Minoxidil—↓ BP by opening K+ channels and hyperpolarizes vascular smooth muscle Nitroprusside (parenterally available)—used in hypertensive emergencies; ↓ TPR by releasing NO, which activates the guanylyl cyclase–cyclic GMP–PKG pathway, leading to vasodilation of both arterioles and venules (Figures 7 and 8) Adverse Drug Reactions • rarely use direct-acting vasodilators as sole therapy of hypertension (Figure 7). These drugs may induce compensatory reflex tachycardia and fluid retention. Hydralazine—SLE-like syndrome in slow acetylators Reflex tachycardia and fluid retention (treat with β-blockers and diuretics) Minoxidil—Hypertrichosis (excessive hair growth); reflex tachycardia and fluid retention

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Nitroprusside—cyanide toxicity—treat with sodium thiosulfate or sodium nitrite; reflex tachycardia and fluid retention Note of Interest: Keep in mind: One man’s side effect can be another man’s therapy. Topical minoxidil is indicated for use in male-pattern baldness.

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SECTION 2

Antihypertensive Angiotensin Converting Enzyme Inhibitors (Figure 9) Angiotensin Converting Enzyme Inhibitors (the “prils”) Captopril Enalapril Lisinopril The angiotensin converting enzymes (ACEs) prevent: • vasoconstriction by blocking the formation of angiotensin II • fluid retention by blocking aldosterone release from the adrenal cortex, and • the degradation of bradykinin, facilitating vasodilation.

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• The ACEIs are useful in treating patients with chronic kidney disease because they diminish proteinuria and stabilize renal function (particularly valuable in diabetes). • ACEIs and angiotensin receptor blockers (ARBs)—DOC for treating patients with CHF; ACEIs and ARBs ↓ preload and ↓ afterload, slowing ventricular dilation (↓ remodeling).

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SECTION 2

Angiotensin Receptor Blockers and Renin Antagonist (Figure 9) Angiotensin Receptor Blockers (“sartans”) Losartan Valsartan Eprosartan • The ARBs decrease PVR by competitively blocking Angiotensin II at A1 receptors. Provide similar clinical benefits as the ACEIs in patients with heart failure and chronic kidney disease. • The ARBs do not interfere with bradykinin metabolism (do not induce a dry cough). • The angiotensin II receptor (AT1) is a Gq G-protein coupled receptor. When angiotensin II interacts with the AT1 receptor, it activates phospholipase C to produce diacylglycerol and inositol-1,4,5-triphosphate (IP3). Blocked by ARBs.

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Renin Antagonist – Aliskiren (Figure 9) • Aliskiren is a direct renin inhibitor, ↓ conversion of angiotensinogen to angiotensin I. • Used to treat hypertension (alone or in combination with other antihypertensive drugs).

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SECTION 2

Diuretics—Antihypertensive Agents (Figure 10, Table 1) Thiazides ↓ blood volume, ↓ BP. The thiazides inhibit the reabsorption of NaCl in the distal convoluted tubule, producing diuresis. The thiazides also ↑ Ca2+ reabsorption and are used to treat kidney stones (nephrolithiasis). Hydrochlorothiazide Chlorthalidone Metolazone Indapamide Loop Diuretics ↓ blood volume, ↓ BP. Block the luminal Na+/K+/2Cl– transporter in the ascending limb of the loop of Henle (Figure 10, Table 1). The loops also ↑ Mg2+ and Ca2+ excretion and are used to treat hypercalcemia. Furosemide Ethacrynic Acid—no sulfa group Bumetanide

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Adverse Drug Effects • Hypokalemia • Hyperuricemia; loops and thiazides may precipitate gouty arthritis attacks • Loops and thiazides—↑ Na+ delivery to the collecting duct where it is reabsorbed into the blood, ↑ secretion and excretion of K+ and H+, inducing hypokalemia and metabolic alkalosis (“Diuretic-Induced Changes in Body pH” in the Diuretic section below). • Loop diuretics may cause a dose-related and reversible hearing loss (more common in patients receiving other ototoxic agents such as aminoglycoside antibiotics).

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SECTION 2

Other Antihypertensive Agents Bosentan An endothelin antagonist used to treat pulmonary arterial hypertension. Mechanism of Action/Uses • Stimulation of endothelin receptors causes vasoconstriction. • Bosentan blocks both ETA and ETB endothelin receptors on vascular endothelium and smooth muscle, inducing vasodilation (↑ affinity for the ETA endothelin receptor subtype). • Used to treat pulmonary artery hypertension

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SECTION 2

Antihypertensive Drugs in Comorbid Conditions Indication

Drugs to be Used

Hypertension and angina

β-Blockers, CCBs

Hypertension and diabetes

ACEIs, ARBs

Hypertension and BPH

α-Blockers (tamsulosin)

Hypertension and post-MI

β-Blockers

Hypertension and CHF

ACEIs, ARBs

Hypertension and hyperlipidemias

α-Blockers, CCBs, ACEIs/ARBs

ACEI, angiotensin converting enzyme inhibitor; ARB, angiotensin receptor blocker; BPH, benign prostatic hyperplasia; CCB, calcium channel blockers; CHF, congestive heart failure; MI, myocardial infarction.

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SECTION 2

Classification of Antiarrhythmic Agents (Figures 11–14) Antiarrhythmic agents reduce ectopic pacemaker activity and modify conduction in re-entry circuits to disable circus movement (Figure 11). The pharmacologic mechanisms currently available for accomplishing these goals are: Na+ channel blockade (Class I) β-blockade (Class II) K+ blockade (Class III) Ca2+ channel blockade (Class IV) Class I (Na+ Channel Blockers) Ia—Quinidine, Procainamide, Disopyramide Ib—Lidocaine, Phenytoin Ic—Flecainide Propafenone—Proarrhythmic (Table 2—Specific Antiarrhythmic Drug Contraindications)

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Class II (β-Blockers) Propranolol Acebutolol Carvedilol Labetalol Bisoprolol

(Continued)

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Classification of Antiarrhythmic Agents (Figures 11–14) Class III (K+ Channel Blockers) Amiodarone Sotalol Ibutilide Class IV (Ca2+ Channel Blockers) Verapamil Diltiazem

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Class V Antiarrhythmics Adenosine Magnesium sulfate—treats torsades de pointes Digoxin Atropine

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Antiarrhythmic Agents Class Ia Na+ Channel Blockers Quinidine Mechanism of Action/Uses • Na+ and K+-channel blocker, ↑ action potential duration (APD) and ↑ the effective refractory period (ERP) Antimuscarinic effects (↑ HR, dry mouth, blurred vision, GI upset). When treating atrial fibrillation, addition of low-dose digoxin ↓s HR and ↓s AV nodal conduction. Quinidine has α-blocking properties (vasodilation) • Clinical use in atrial and ventricular arrhythmias (Figure 11)

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Adverse Drug Effects • Cinchonism (headache, dizziness, and tinnitus) • Prolongation of the QT-interval—torsades de pointes Drug Interactions • Quinidine displaces digoxin from tissue-binding sites, enhancing digoxin toxicity.

(Continued)

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Antiarrhythmic Agents Class Ia Na+ Channel Blockers (Continued) Procainamide Disopyramide Mechanism of Action/Uses • Similar to Quinidine (Na+ channel blockers in cardiac myocytes) Clinical use in atrial and ventricular arrhythmias (Figures 11–13)

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Adverse Drug Effects • Procainamide is metabolized via N-acetyltransferase to N-acetyl procainamide (NAPA). Slow acetylators develop a systemic lupus erythematosus (SLE)-like syndrome with chronic use, consisting of arthralgia and arthritis, pleuritis, pericarditis, or parenchymal pulmonary disease (characterized by a dry, unproductive cough and dyspnea on exertion). • Excessive accumulation of NAPA has been implicated in torsades de pointes. • Class 1a Na+ channel blockers have antimuscarinic properties (↑ HR). A drug that slows AV conduction (digoxin) may be administered with disopyramide when treating atrial flutter or fibrillation. • Disopyramide has a strong negative inotropic action and may aggravate heart failure.

(Continued)

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Antiarrhythmic Agents Class Ib Antiarrhythmic Agents Lidocaine Phenytoin Mexiletine—orally-available congener of lidocaine Mechanism of Action/Uses • Block sodium channel in the inactivated state (Figure 14). • Class Ib drugs suppress spontaneous depolarizations and re-entry mechanisms in ventricular tissue

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• Preferential action on ischemic (partially depolarized) tissue – useful for treating digoxininduced arrhythmias, ventricular arrhythmias post-MI and post-open heart surgery. • Shortens the ERP and APD within the His-Purkinje system. Adverse Drug Effects • Phenytoin causes gingival hyperplasia.

(Continued)

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Antiarrhythmic Agents Class Ic Antiarrhythmic Agents (Table 2) Flecainide Encainide http://www.ncbi.nlm.nih.gov/pubmed/1900101 Mechanism of Action/Uses The Class 1c agents are potent blockers of Na+ and K+. Useful in atrial fibrillation in patients without CAD.

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Adverse Drug Effects • Proarrhythmic Acceleration of ventricular rate in patients with atrial flutter Increased frequency of re-entrant ventricular tachycardia Increased mortality in patients post-MI

(Continued)

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SECTION 2

Antiarrhythmic Agents Class II (β-blockers) (Figure 12) Propranolol Acebutolol Carvedilol Labetalol Bisoprolol

0 Phase 0 −20

Phase 3

−40 −60 −80 −100

Phase 4

r ake cem t Pa urren c Na+,

Ca2+ / K+ Slow Ca2+ current Delayed rectifier K+ current

Mechanism of Action/Uses Cardiac action potentials in slow-response fibers • β-adrenoceptor blockers ↓ the slope of phase 4, ↓ SA and ↓ AV nodal conduction (useful in terminating re-entrant arrhythmias involving the AV node) • In acutely ischemic tissue, β-blockers increase the energy required to induce cardiac arrhythmias and are efficacious at controlling ventricular response in atrial fibrillation or flutter. • β-blockers prevent recurrent infarction and sudden death in patients recovering from acute myocardial infarction (drug of choice post-MI) 40

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Adverse Drug Reactions • Non-cardioselective and non-ISA β-blockers can induce bronchospasm, aggravation of CHF, worsen symptoms of peripheral vascular disease and mask symptoms of hypoglycemia in diabetic patients

(Continued)

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Antiarrhythmic Agents Class III (K+ channel blockers) Amiodarone Sotalol Ibutilide Mechanism of Action/Uses • K+ channel blockers can prolong repolarization in cardiac myocytes, ↑ the refractory period. • Amiodarone has a biologic t½ of approximately 100 days and possesses pharmacodynamic properties of class I, II, III, and IV antiarrhythmic agents. Sotalol is also a β-blocker. • These drugs are K+ channel blockers that ↑ action potential duration and ↓ automaticity. These agents treat both atrial and ventricular arrhythmias. • Ibutilide used for acute termination of atrial flutter and fibrillation (available IV), and converts atrial fibrillation to sinus rhythm in patients after cardiac surgery and in those with the Wolff–Parkinson–White syndrome.

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Adverse Drug Reactions • Amiodarone adverse effects include pulmonary fibrosis, blue pigmentation of the skin (“smurf skin”), corneal microdeposits, phototoxicity, hypo- and hyperthyroidism, hepatic necrosis, and ↑ risk of the risk of torsades de pointes. • Dronedarone is a non-iodinated derivative of amiodarone with adrenergic blocking properties and a shorter t½ ( NE uptake inhibitor • Nortriptyline and Desipramine—NE > 5-HT uptake inhibitor • Amitriptyline is also used to treat neuropathic pain • Imipramine is used to treat enuresis

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Adverse Drug Reactions • Cardiotoxic effects of the TCAs—life threatening quinidine-like effects on cardiac conduction (Na+-channel blocking properties ↑ QRS complex, torsades de pointes; syncope). No more than a 1-week supply should be provided to new patients. • TCAs ↓ seizure threshold. • Sexual dysfunction

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Serotonin Selective Reuptake Inhibitors (SSRIs) Selective Serotonin Reuptake Inhibitors (SSRIs) Fluoxetine Paroxetine Sertraline Citalopram Escitalopram Mechanism of Action (Figure 21) The SSRIs potentiate and prolong the action of neuronally released 5-HT. Long-term treatment with SSRIs desensitizes presynaptic receptors and alters the postsynaptic transduction systems.

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Adverse Side Effects/Drug Interactions • Serotonin syndrome (especially when co-administered with MAOIs, methadone, meperidine, linezolid, triptans, ergot alkaloids and others) • Fluoxetine, fluvoxamine, and other TCAs and SSRIs inhibit cytochrome P450 isozymes and can significantly elevate levels of drugs metabolized by these hepatic enzymes. • Meperidine (an opiate with 5-HT uptake blocking properties) combined with MAOIs can cause life-threatening serotonin syndrome. • Sexual dysfunction

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Monoamine Oxidase Inhibitors (MAOIs) Monoamine Oxidase Inhibitors (MAOIs) Phenelzine Tranylcypromine Selegiline Mechanism of Action (Figure 21) Phenelzine—irreversible inhibitor of MAO-A and MAO-B Tranylcypromine—irreversible inhibitor of MAO-A and MAO-B Selegiline—MAOB inhibitor, ↑ DA in synapse (DA is metabolized by MAOB)

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Adverse Drug Effects • Serotonin syndrome (especially when co-administered with MAOIs, methadone, meperidine, linezolid, triptans, ergot alkaloids and others) • Tyramine cheese effect (MAOIs can induce hypertensive crisis if the patient ingests large quantities of products high in tyramine, including aged cheese, processed meats, avocados, dried fruits, and red wines). • CNS excitation, suppression of REM sleep • Sexual dysfunction, weight gain

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Atypical Antidepressant Agents Atypical Antidepressant Drugs Bupropion—DA uptake blocker Mirtazapine—5-HT2 and α2 (autoreceptor) antagonist Trazodone—5-HT uptake inhibitor Venlafaxine NSRI—NE and 5-HT uptake Duloxetine blockade; may be used to treat Milnacipran neuropathic pain Mechanism of Action These agents ↑ synaptic levels of 5-HT, NE, and/or DA by different mechanisms.

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Adverse Drug Reactions Bupropion—↓ seizure threshold Serotonin syndrome Trazodone—sedation and priapism Sexual dysfunction

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SECTION 3

Drug Therapy for Parkinson Disease Anti-Parkinson Drugs Levodopa (L-DOPA) and Carbidopa

Mechanism of Action Carbidopa facilitates L-DOPA transport across BBB before being converted to DA.

Dopamine agonists Bromocriptine Ropinirole Pramipexole Antimuscarinics Benztropine Trihexyphenidyl

Interact directly with DA receptors in basal ganglia

Amantadine

Antiviral agent that ↑ synaptic DA levels in the brain. It may stimulate DA release or block the DA reuptake site (DAT).

MAO inhibitors (MAOIs) Selegiline

Inhibits MAOB in the basal ganglia; used as an adjunct to L-DOPA/ carbidopa to ↑central DA activity (Figure 22)

COMT inhibitors (COMTIs) Tolcapone (CNS and PNS)* Entacapone (PNS)*

Tolcapone and entacapone block COMT and prevent the breakdown of catecholamines (e.g., L-DOPA, DA, NE, EPI). Used as adjuncts to L-DOPA/carbidopa to ↑ central DA.

Inhibit excessive cholinergic influence accompanying DA deficiency.

*Tolcapone has both central and peripheral effects, whereas entacapone acts primarily in the periphery. See dopamine metabolic pathways in Figure 22.

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Dopaminergic and Cholinergic Influence in Parkinson Disease

ACh

L-DOPA carbidopa

Benztropine trihexphenidyl

DA

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• Parkinsonism—Characterized by a ↓ in striatal dopamine levels. • The lack of striatal DA ↑ activity of striatal cholinergic (ACh) pathways. • Drug therapy for patients with Parkinson disease focuses on restoring the DA (L-DOPA/ Carbidopa) and ACh imbalance (trihexyphenidyl or benztropine) in order to improve motor function.

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Opiate Analgesics Strong Mu (μ) Opiate Receptor Agonists Morphine—prototype μ agonist Fentanyl—strong lipophilic μ agonist Meperidine—has an active metabolite (normeperidine) that is proconvulsant. Methadone—long duration; used to treat patients with opiate addiction Oxycodone—used for breakthrough pain (postsurgical pain) Sufentanil—strong lipophilic μ agonist Heroin—diacetylmorphine (Highly abused but not approved for medical use in the United States.)

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Moderate Opiate Agonists Codeine—catalyzed by P450 enzymes to morphine (P-450 inhibitors ↓ codeine’s efficacy) Hydrocodone—combined with either acetaminophen or ibuprofen

(Continued)

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Opiate Analgesics (Continued) Mechanism of Action/Indications Opiates: • are used as the mainstay of therapy for acute and chronic moderate to severe pain. • bind to μ opioid receptors in the spinal cord and inhibit the release of the nociceptive neurotransmitters substance P and glutamate. • interact with opioid receptors in the periaqueductal gray (PAG) and stimulate the descending pain inhibitory system (activating spinal 5-HT and NE). • induce euphoria by interacting with opioid receptors in the ventral tegmental area and nucleus accumbens in the brain.

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Adverse Drug Effects • High doses of opiates ↓ the responsiveness of the respiratory center to increases in CO2 tension, inducing respiratory depression. • Meperidine, methadone and fentanyl can induced a serotonin syndrome if administered with SSRIs, MAOIs or TCAs • Sedation, drowsiness, mental clouding, and coma (at toxic doses) • Miosis (pinpoint pupils)

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Opiate Receptor Antagonists Mu (μ) Opiate Blockers Naloxone—parenteral opiate antagonist Naltrexone—orally available Nalmefene—orally available Mechanism of Action • Opiate antagonists competitively block μ opioid receptors.

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Clinical Indications Opiate antagonists are used clinically to manage: • cravings of ETOH-dependent people trying to quit drinking ETOH (naltrexone). • respiratory depression caused by the overdose of opiates (heroin or oxycodone). • the compulsive use of opiates. Naltrexone blocks opiate cravings and ↓ recidivism by competitively blocking opioid receptors in the ventral tegmental area (VTA) and the nucleus accumbens (NA), areas mediating euphoria.

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Drugs of Abuse Ethanol (ETOH) Ethanol

Alcohol dehydrogenase (cytoplasm)

Acetaldehyde

Acetaldehyde dehydrogenase (mitochondria)

Acetic acid

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Mechanism of Action • ETOH interacts with the GABA ionophore to potentiate GABA-induced increases in chloride ion flux → hyperpolarization and neuronal inhibition. • ETOH also inhibits glutamate-induced NMDA receptor-mediated ion currents. • Long-term ETOH ingestion causes a persistent ↓ in glutamate function, which induces an up-regulation of NMDA receptors (EAA may mediate some ETOH withdrawal symptoms).

(Continued)

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Drugs of Abuse ETOH (Continued) Adverse Drug Reactions • Wernicke–Korsakoff syndrome • Fetal Alcohol Syndrome (FAS)—mid-facial hypoplasia, microcephaly, and marked CNS dysfunction, including mental impairment. • Cirrhosis of the liver Signs of Withdrawal: delirium tremens, seizures, ↑ heart rate, and ↑ blood pressure Treat ETOH withdrawal with oxazepam and lorazepam, benzodiazepines that are not as dependent on hepatic metabolism (remember lorazepam and oxazepam undergo Phase 2 conjugation).

(Continued)

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Drugs of Abuse Methanol and Ethylene Glycol Ethylene Glycol—metabolized to oxalic acid, which causes renal failure. Methanol—metabolized to formic acid, which can induce permanent blindness by destruction of the optic nerve. Alcohol Ethylene glycol dehydrogenase

Glycoaldehyde

Aldehyde dehydrogenase

Formaldehyde

Aldehyde dehydrogenase

Glycolic acid

Oxalic acid

1. CNS depression 2. Severe metabolic acidosis 3. Nephrotoxicity Methanol

Alcohol dehydrogenase

Formic acid

1. Respiratory failure 2. Severe anion gap metabolic acidosis 3. Ocular damage

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• Alcohol dehydrogenase can be blocked by fomepizole. • Aldehyde dehydrogenase can be blocked by disulfiram.

(Continued)

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Drugs of Abuse Amphetamine/Methamphetamine Mechanism of Action (Figure 23) • Enter through the DAT, ↑ release of DA and NE from mobile pool through DAT acting in reverse, blocks NE and DA reuptake, and act as MAO inhibitors. • ↑ DA release in various brain areas and the nucleus accumbens. • Release of NE from peripheral nerves in sympathetic nervous system (can induce myocardial infarction, cerebrovascular hemorrhage, seizures, and death).

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Amphetamine abuse causes euphoria, insomnia, psychomotor stimulation, anxiety, loss of appetite, improved concentration and ↓ fatigue. Long-term use produces a toxic psychosis that is indistinguishable from paranoid schizophrenia (treat with antipsychotic agents; haloperidol, or chlorpromazine).

(Continued)

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SECTION 3

Drugs of Abuse 3,4-Methylenedioxymethamphetamine (MDMA; Ecstasy) Mechanism of Action • MDMA has a strong affinity for the serotonin transporter (SERT) and acts by ↑ 5-HT release from central serotonergic neurons. • MDMA degenerates serotonergic neuronal terminals, causing 5-HT depletion.

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Adverse Drug Reactions • MDMA induces stimulant and psychedelic effects; withdrawal involves long-term depression and aggressiveness. • Reported to cause a long-term cognitive impairment in heavy users. • Initial excess 5HT release may induce serotonin syndrome (fatal hyperthermia and dehydration).

(Continued)

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SECTION 3

Drugs of Abuse Cocaine • Powerful psychostimulant with strong reinforcing properties • Potent local anesthetic (Na+-channel blocker) • Strong vasoconstrictor (α-adrenergic agonist) Mechanism of Action (Figure 23) • Inhibits reuptake of NE and DA in the CNS producing profound euphoria. • Inhibits reuptake of NE in the PNS—↑ HR, ↑contractility, and ↑ blood pressure. • Continual use induces psychotic episodes, paranoia, hallucinations and dyskinesias.

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Adverse Drug Reactions • The liver combines cocaine and ETOH to manufacture a substance known as cocaethylene (the euphoric effects of cocaethylene are intensified). Cocaine (and cocaethylene) produce aggression, hypertension and arrhythmias.

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SECTION 4

Antibiotics

Review of Antibiotic Pharmacology

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SECTION 4

Review of Antibiotic Pharmacology β-lactam ring

Cell Wall Synthesis Inhibitors (Figure 24) Penicillins (β-lactam structure; bactericidal) Penicillin G—Narrow-spectrum penicillins (Treponema pallidum) Penicillin V—Group A Streptococcus infection Dicloxacillin Nafcillin and Oxacillin—methicillin-sensitive Staphylococcus aureus

C

H N

H C

H C

C

N

S

H C H

O O

Site of cleavage by bacterial β-lactamases or by acid

C C

CH2

COOH

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Extended-spectrum amino penicillins (administer with β-lactamase inhibitors, clavulanate) • Amoxicillin—otitis media, community-acquired pneumonia, and sinusitis • Ampicillin—suspected Listeria meningitis • Piperacillin and Ticarcillin—used to treat methicillin-sensitive Staphylococcus aureus and some gram (−) infections such as Pseudomonas and Klebsiella Mechanism of Action The beta-lactam antibiotics (penicillins and cephalosporins) bind covalently to penicillinbinding proteins (PBPs) and inhibit the transpeptidation reaction. This halts peptidoglycan synthesis and causes death of the bacterium.

(Continued)

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SECTION 4

Review of Antibiotic Pharmacology Penicillins (continued) Adverse Drug Reactions • Penicillin G can induce a Jarisch-Herxheimer reaction in patients treated for syphilis. • The Jarisch–Herxheimer reaction is caused by the release of endotoxins from spirochetes, (cytokines, TNF, IL-6, and IL-8) as bacteria die.

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• This reaction is accompanied by headache, myalgia and fever (treat with antipyretics, acetaminophen, or NSAIDs). • Hypersensitivity reactions (true type I anaphylactic reactions are rare; < 0.05%). • Assume complete cross-allergenicity between penicillins/cephalosporins.

(Continued)

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SECTION 4

Review of Antibiotic Pharmacology Cephalosporins (β-lactam structure, bactericidal; Figure 24) First-generation cephalosporins Cephalexin—presurgical prophylaxis, urinary tract infections (UTI) Second-generation cephalosporins Cefotetan—disulfiram reaction Cefamandole—disulfiram reaction Cefaclor

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Third-generation cephalosporins—enter central nervous system after parenteral administration Ceftazidime—antipseudomonal activity; high penetration into the subarachnoid space Ceftriaxone—drug of choice for treatment of gonorrhea and meningococcal meningitis Cefoperazone—disulfiram-like reaction Fourth-generation cephalosporins Cefepime—extended spectrum of activity against gram (+) and gram (−) negative bacteria; covers pseudomonal infections

(Continued)

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SECTION 4

Review of Antibiotic Pharmacology Cephalosporins (continued) Mechanism of Action (Figure 24) The beta-lactam antibiotics (penicillins and cephalosporins) bind covalently to penicillinbinding proteins (PBPs) and inhibit the transpeptidation reaction. This halts all peptidoglycan synthesis and causes death of the bacterium.

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Adverse Drug Reactions • Hypersensitivity; partial cross-hypersensitivity with penicillins (about 5%) • Clostridium difficile colitis • Disulfiram reaction (cefoperazone, cefamandole, and cefotetan)

(Continued)

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SECTION 4

Review of Antibiotic Pharmacology Cell Wall Synthesis Inhibitors (continued) (Figure 24) Carbapenems—(plus cilastatin to inhibit metabolism by renal dehydropeptidase) gram-positive cocci, gram-negative rods, and anaerobes Imipenem—broad spectrum; used in hospitals for treatment of serious infections such as necrotizing pancreatitis Meropenem Monobactams Aztreonam—activity against gram-negative rods (parentally available), use in β-lactam allergy (virtually no cross-allergenicity to penicillins or cephalosporins). Binds to bacterial cell wall transpeptidases and inhibits cell wall synthesis.

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Bacitracin—inhibits cell wall peptidoglycan synthesis by blocking regeneration of the bactoprenol carrier. Cycloserine—prevents cross-linking of the peptidoglycan strands by inhibiting L-alanine racemase and D-alanine synthetase, enzymes are involved in the incorporation of D-alanine into the peptidoglycan structure. Fosfomycin—bactericidal; inactivates pyruvyl transferase and inhibits cell wall synthesis.

(Continued)

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SECTION 4

Review of Antibiotic Pharmacology Cell Wall Synthesis Inhibitors (continued) Vancomycin • Bactericidal; used against multi-resistant gram (+) bacteria (MRSA, enterococci, and Clostridium difficile as backup drug). • Enterococcal resistance involves change in the muramyl pentapeptide “target,” such that the terminal D-ala is replaced by D-lactate. Mechanism of Action (Figure 24) • Inhibits cell wall synthesis by binding to the D-ala-D-ala terminus of the peptidoglycan peptide and preventing chain elongation and cross-linking. • In combination with gentamycin, vancomycin is effective against enterococcal endocarditis in patients with penicillin allergy.

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Adverse Drug Reactions • Urticarial reactions, flushing (“red-man” syndrome due to histamine release), ototoxicity (can be permanent), and nephrotoxicity that can be additive with other drugs.

(Continued)

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SECTION 4

Review of Antibiotic Pharmacology Cell Wall Synthesis Inhibitors Daptomycin • Similar spectrum to vancomycin and acts as an effective alternate; more rapidly bactericidal. • Active against vancomycin-resistant strains of enterococci and Staphylococcus aureus. • Treats skin and soft tissue infections, bacteremia, and endocarditis. Mechanism of Action • Binds to the cell membrane by Ca2+-dependent insertion of its lipid tail; causes membrane depolarization, K+ efflux, and cell death.

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Adverse Drug Reactions • Myopathy • Allergic pneumonitis in patients treated >2 weeks • Daptomycin is blocked by pulmonary surfactant (do not use to treat pneumonia).

(Continued)

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SECTION 4

Review of Antibiotic Pharmacology Protein Synthesis Inhibitors Tetracyclines—broad-spectrum bacteriostatic drugs Tetracycline Doxycycline Minocycline Mechanism of Action (Figure 24) • Block tRNA from binding to the 30S ribosomal subunit; inhibit protein synthesis • Wide spectrum, effective against gram (+) and gram (−) organisms, treat Rickettsia (Rocky Mountain spotted fever), H pylori, Borrelia burgdorferi (Lyme disease), and prostatitis • The tetracycline treat infections caused by obligate intracellular organisms (Chlamydia and Mycoplasma species).

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Adverse Drug Reactions • Phototoxicity (sensitivity to the sun) • Discoloration of developing teeth • Depression of bone growth in children • Contraindicated in pregnancy and children

(Continued)

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SECTION 4

Review of Antibiotic Pharmacology Protein Synthesis Inhibitors Aminoglycosides Amikacin Gentamicin Neomycin Streptomycin Tobramycin Mechanism of Action (Figure 24) • The aminoglycosides bind to the 30S ribosomal subunit and induce an error in translation (misreading of the genetic code), causing the wrong tRNA to bind and the wrong amino acid to be inserted into the nascent peptide. • Active against aerobic gram-negative bacilli (Pseudomonas aeruginosa). • Bactericidal effects are synergistic when administered with an extended-spectrum penicillin (e.g., ticarcillin, piperacillin) or cephalosporin. • Post-antibiotic effect, which is a delay in bacterial regrowth following the removal of the agent. 105

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Adverse Drug Reactions • Nephrotoxicity • Ototoxicity • Neuromuscular blockade (↓ ACh release)

(Continued)

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SECTION 4

Review of Antibiotic Pharmacology Protein Synthesis Inhibitors Macrolides—(look for “thro” in the name) Azithromycin Erythromycin Clarithromycin Dirithromycin Mechanism of Action (Figure 24) • Broad-spectrum bacteriostatic antibiotics (can also be bactericidal) • Blocks peptidyl transferase at the 50S ribosomal subunit, preventing attachment of the nascent peptide and the new amino acid. • Inhibit ribosomal translocation, leading to inhibition of bacterial protein synthesis • Treat atypical organisms (Chlamydia, Mycoplasma, H pylori, Legionella). • Useful in treating lung and chest infections; use in patients with penicillin allergy. • Community-acquired pneumonias—where atypical pathogens such as Mycoplasma pneumoniae and Legionella pneumophila are common.

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• Chlamydial infections (Chlamydia pneumoniae pneumonia or Chlamydia trachomatis pelvic infections, especially in pregnancy.) • Bordetella pertussis Adverse Drug Reaction • Inhibit P450 3A4 (clarithromycin and erythromycin) • Prolongation of QT interval (torsades) • Pseudomembranous colitis has been reported with clarithromycin use.

(Continued)

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SECTION 4

Review of Antibiotic Pharmacology Protein Synthesis Inhibitors (continued) Streptogramins Quinupristin-Dalfopristin Mechanism of Action • Bactericidal antibiotics that inhibit protein synthesis in a manner similar to the macrolides. • Active against gram (+) cocci (multidrug-resistant strains of streptococci, penicillin-resistant strains of S pneumoniae and vancomycin-resistant E faecium) • Treats vancomycin-resistant enterococci (VRE) and Staphylococcus aureus (VRSA)

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Adverse Drug Reaction • Arthralgia/myalgia syndrome

(Continued)

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SECTION 4

Review of Antibiotic Pharmacology p-Aminobenzoic acid

Protein Synthesis Inhibitors (continued) Folic Acid Inhibitors Sulfonamides Sulfacetamide Sulfadiazine Sulfamethoxazole Sulfasalazine Sulfisoxazole

Dihydropteroate synthase

−

Sulfonamides (compete with PABA)

Dihydrofolic acid Dihydrofolate reductase

Folate Reductase Inhibitors Trimethoprim Trimethoprim-sulfamethoxazole

−

Trimethoprim

Tetrahydrofolic acid Purines DNA

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Mechanism of Action • Structural analogs of PABA and act by inhibiting dihydropteroate synthase. • The sulfonamides and trimethoprim are bactericidal and inhibit sequential steps in the synthesis of folic acid in bacteria. • Trimethoprim works by inhibiting folate reductase and produces a synergistic effect when administered with a sulfonamide (sulfamethoxazole).

(Continued)

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SECTION 4

Review of Antibiotic Pharmacology Protein Synthesis Inhibitors (continued) Fluoroquinolones—(look for “flox” in the name) Ciprofloxacin Ofloxacin Levofloxacin Norfloxacin Nalidixic Acid (there’s always one goofball) Mechanism of Action (Figure 24) • Bactericidal; act as DNA topoisomerase IV inhibitors (DNA gyrase in bacteria). These enzymes are involved in the repair and replication of DNA. • These drugs induce a post-antibiotic effect. • Fluoroquinolones chelate divalent and trivalent cations (Ca2+, Mg2+, and Fe2+).

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Adverse Drug Reactions • Damage to growing cartilage and cause reversible arthropathy. • May be used in children in some cases (treatment of pseudomonal infections in patients with cystic fibrosis). • Tendonitis in adults and risk of tendon rupture. • Contraindicated in pregnancy.

(Continued)

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SECTION 4

Review of Antibiotic Pharmacology Miscellaneous Antimicrobial Agents Metronidazole Linezolid Mechanism of Action • Metronidazole—an antiprotozoal drug with antibacterial action against anaerobes (Bacteroides and Clostridium species). Drug of choice for Clostridium difficile colitis. • Metronidazole is taken up by anaerobic cells, reduced by ferredoxin to form metabolic products that are taken up into the bacterial DNA to form unstable molecules. • Linezolid is effective against gram-positive bacteria, and treats VRSA, VRE, drug-resistant Streptococcus pneumoniae, and vancomycin-resistant E faecium infections. • Linezolid binds to the 23S ribosomal RNA on the 50S subunit to prevent formation of the ribosome complex that initiates protein synthesis.

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Adverse Drug Reactions • Linezolid can induce bone marrow suppression (platelets), and peripheral and optic neuropathy. • Metronidazole causes a metallic taste in the mouth, dark, red-brown urine, a disulfiram reaction with ETOH, and Stevens–Johnson syndrome.

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SECTION 5

Pharmacokinetic and Pharmacodynamic Principles

Routes of Administration

Cytochrome P-450 Inducers and Inhibitors

CYPInducer Case #1

CYPInducer Case #2

CYPInhibitor Case

Drugs Causing a Disulfiram-like Reaction

Properties of Charged (Ionized) and Uncharged (Unionized) Drugs

Review of Logs and Antilogs

(Continued)

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Pharmacokinetic and Pharmacodynamic Principles (Cont'd.)

HendersonHasselbalch Equation

How do Antibiotics and Oral Contraceptive Drugs Interact?

Phase I and Phase II Metabolism

Therapeutic Index

High-yield Pharmacological Equations for the USMLE

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SECTION 5

Routes of Administration Oral (PO) • Most common route • First-pass Metabolism—drugs absorbed from the gut may complex with food or be metabolized by enzymes in the liver before reaching the systemic circulation (Figure 25). This ↓’s the bioavailability of the drug (bioavailability is the fraction of unchanged drug reaching the systemic circulation). Intravenous (IV) • Drug introduced directly into the circulation (100% bioavailable) • Can be dangerous; once injected, drug cannot be recalled from the bloodstream • Potential for the introduction of infection from infected needle

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Sublingual • Fast-acting route that avoids first-pass metabolism Inhalational Route • Fastest route of absorption for aerosolized or nebulized drugs Intrathecal Route • Drug introduced in subarachnoid space • Potential for the introduction of infection

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SECTION 5

Cytochrome P-450 Inducers and Inhibitors P-450 Inhibitors • Antiulcer medication: Cimetidine and omeprazole • Antibiotics: Macrolides, chloramphenicol, erythromycin • Antifungals: Ketoconazole and itraconazole • Isoniazid (INH) • Acute ETOH • Grapefruit juice • Ritonavir • Selegiline • Clopidogrel

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P-450 Inducers • Anticonvulsants: Phenytoin, carbamazepine, barbiturates (phenobarbital) • Chronic ETOH • Glucocorticoids • Rifampin • Atorvastatin • Cigarette smoking

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SECTION 5

CYP-Inducer Case #1 A 32-year-old woman is taking carbamazepine for seizure control. She and her husband have decided not to have more children, and she comes in for a checkup and asks for birth control pills. You recommend oral ethinyl estradiol and norethindrone. Four months later, the patient becomes pregnant and comes back to see you. She is not happy and asks you what happened.

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You of course realize that despite the fact that this patient is taking oral contraceptives, she is also taking carbamazepine for seizures. Carbamazepine is a CYP-inducer and increases the metabolism of estrogen in the patient’s birth control pills. As a result, she conceived and is now pregnant. How might this situation have been prevented?

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SECTION 5

CYP-Inducer Case #2 Classic P-450 Inducer Case #2 A 67-year-old male receives a kidney transplant and is administered tacrolimus to prevent organ rejection. The patient has been taking St. John wort for 2 years to treat his depression, but was embarrassed to admit this to his physician. When he sees his doctor for an 8-week postoperative follow-up appointment, the physician informs him that his body is rejecting the transplanted kidney.

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What happened here? St. John Wort is a CYP-inducer and induces a more rapid metabolism of tacrolimus, causing organ rejection. How might this situation have been prevented?

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SECTION 5

CYP-Inhibitor Case A 57-year-old female recently received a kidney transplant and is being maintained on cyclosporine. She is also being treated with nitroglycerin, felodipine, and omeprazole, respectively, for angina, hypertension, and gastroesophageal reflux (GERD). She returns to the clinic for a postoperative follow-up appointment at 12 months and has a markedly elevated cyclosporine plasma concentration. This raises the physician’s concern for nephrotoxicity.

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Question: Which other drug was this patient taking that likely caused cyclosporine levels to become toxic? Answer: Omeprazole is a proton pump inhibitor that is being used to treat GERD in this patient. Omeprazole is a classic CYP-inhibitor that decreased the metabolism and clearance of cyclosporine in this case.

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SECTION 5

Drugs Causing a Disulfiram-like Reaction Antibiotics (Figure 26) Metronidazole Cephalosporins (cefoperazone, cefamandole, and cefotetan) First-generation Sulphonylureas (Oral Hypoglycemics) Chlorpropamide Tolbutamide Antifungal Agent Griseofulvin Symptoms of Disulfiram-like Reaction Nausea, vomiting, abdominal pain Throbbing headaches Vertigo and ataxia

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SECTION 5

Properties of Charged (Ionized) and Uncharged (Unionized) Drugs Role of pH and pKa of Drugs • Most drugs are weak acids (HA) or weak bases (HB+). • Weak acids and weak bases exist as ionized or unionized forms in the body depending upon the pH of the environment. • Charged compounds do not readily traverse biological membranes; uncharged drugs do. • Just as each person has a unique name, each drug has its own pKa (pH value where half the drug is ionized and the other half is unionized). A low pKa value indicates that the drug is acidic and will easily give up its proton to a base.

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• Weak acids (HA) donate a proton (H+) to form anions (A–). HA ↔ H+ + A– • Weak bases (B) accept a proton to form cations (HB+). B + H+ ↔ BH+

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SECTION 5

Review of Logs and Antilogs Before we review the uses of the Henderson–Hasselbalch equation, let us go over the properties of logs and antilogs. Review of Logs and Antilogs Number

Log

Antilog

0.001

–3

0.001

0.01

–2

0.01

0.1

–1

0.1

1

0

1

10

1

10

100

2

100

1,000

3

1,000

10,000

4

10,000

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SECTION 5

Henderson–Hasselbalch Equation Henderson–Hasselbalch (H–H) Equation The H–H equation can be used to describe the behavior of weak acids and weak bases in different pH environments in the body, and can be written as follows for both weak acids and weak bases: ‘Protonated’ = pka – pH ‘Unprotonated’ For a weak acid, the following equation is used: log

log

[HA] = pka – pH [A–]

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For a weak base, the following equation is used: log

[HB+] = pka – pH [B]

(Continued)

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SECTION 5

Henderson–Hasselbalch Equation Sample Problem on the USMLE A weak acid with a pKa of 3 has been orally administered. Using the Henderson–Hasselbalch equation, determine how much of this drug will be absorbed from the stomach (pH = 1) into the bloodstream. [HA] [A–] [HA] log [A–] [HA] log [A] [HA] So, [A–] log

= pka – pH =3–1 = 2 (the antilog of 2 = 100) =

100 1

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[HA] [A–]

=

100 1

This means that for every 1% of this weak acid that is charged [A–], approximately 99% of the drug is uncharged [HA]. Since the majority of this drug is in the uncharged form at a pH of 3, it will readily traverse membranes and be absorbed from the stomach into the bloodstream.

(Continued)

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SECTION 5

Henderson–Hasselbalch Equation Sample Problem on the USMLE A new antihypertensive drug, a weak base with a pKa of 5, is being tested in Phase 1 clinical trials. Determine if this drug will be more thorougly absorbed from the stomach (pH = 1) or the small intestine (pH = 7).

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Weak Base in the Stomach: [HB+] = pka – pH [B] [HB+] log =5–1 [B] [HB+] log = 4 (antilog of 4 = 10,000) [B] At a pH of 1 in the stomach, approximately 99.99% of the weak [HB+] 10,000 base is charged [HB+] and 0.01% is uncharged [B]. Since the So, = majority of the drug is charged at such a low pH, it would not [B] 1 be readily absorbed from the stomach into the bloodstream.

log

(Continued)

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SECTION 5

Henderson–Hasselbalch Equation Sample Problem on the USMLE With the same drug as was described in the previous case (weak base with a pKa of 5), determine the degree of ionization and absorbancy of the antihypertensive agent in the small intestine (pH = 7).

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[HB+] =5–7 [B] [HB+] log = –2 (antilog of –2 is 0.01) [B]

log

[HB+] 0.01 1 = = [B] 1 100

Here, we see that most of this weak base is uncharged in the small intestine and will be readily absorbed into the bloodstream.

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SECTION 5

How do Antibiotics and Oral Contraceptive Drugs Interact? • The ethinyl estradiol comprising oral contraceptives (OC) cycles through the liver where it is conjugated and excreted through the bile back to the intestines (Figure 27). Estradiol-beta-glucuronidase in the gut hydrolyzes the glucuronide moiety, freeing estrogen to be reabsorbed into the circulation. • Antibiotics reportedly destroy intestinal bacteria and interrupt enterohepatic cycling of OCs, resulting in contraceptive failure (Figure 27). The mechanisms underlying antibiotic-induced contraceptive failure remain speculative.

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• Drugs that increase the enzymatic activity of P-450 (CYP inducers) also reduce the efficacy and increase the failure rate of OCs (e.g., phenobarbital, carbamazepine, phenytoin, rifampin, and griseofulvin). • The American College of Obstetricians and Gynecologists recently concluded that tetracycline, doxycycline, ampicillin, metronidazole, fluconazole, and fluoroquinolones do not alter oral contraceptive estrogen levels in women taking combination OCs.

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SECTION 5

Phase I and Phase II Metabolism Most drugs undergo both Phase I and Phase II biotransformation. Phase I metabolism includes: • Oxidation • Hydroxylation COOH COOH • Dealkylation • Hydrolysis OCOCH3 OH • Deamination Aspirin

Salicylic acid

OH HO

COOH

OH

O O COOH

Glucuronide

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Phase II conjugation mechanisms (mnemonic is “GGAS”) include: • Glucuronidation • Glutathione • Acetylation • Sulfation

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SECTION 5

Therapeutic Index The ratio of the lethal dose and effective dose (LD50/ED50) is known as the therapeutic index (TI). A drug with a high therapeutic index is considered safer than a drug with a low or narrow therapeutic index. The word “TILE” can be used as a mnemonic to help you remember the equation for the therapeutic index. TI =

LD50 ED50

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Drugs with narrow therapeutic indices include: • Warfarin • Theophylline • Cyclosporine • Methotrexate • Digoxin

Therapeutic LD50 400 = =4 index: ED50 100 Percentage of individuals responding

100 Hypnosis

Death

80

60

40 ED50

20

ED99 LD1

LD50

0 50

200 400 100 Dose (μg/kg)

800

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SECTION 5

High-yield Pharmacological Equations for the United States Medical Licensing Examination Volume of Distribution Pharmacokinetics involves the use of mathematical equations to calculate important pharmacological parameters, such as volume of distribution (Vd) half-life (t½), clearance (CL), maintenance dose, and loading dose. The Vd is a measure of how widely a drug distributes in the body. This is a hypothetical volume representing a ratio of the amount of drug in the body to the amount of drug in the plasma.

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The apparent Vd reflects a balance between the binding of a drug to tissues and the binding to plasma proteins. dose Co Drugs with small Vd—usually tightly bound to plasma proteins and somewhat restricted to the plasma compartment. Drugs with a larger Vd—lipid-soluble drugs that do not stay in the plasma; hemodialysis is ineffective at clearing drugs with a large Vd. Vd =

(Continued)

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SECTION 5

High-yield Pharmacological Equations for the United States Medical Licensing Examination Important Equations for the USMLE Vd =

dose Co

Co = drug concentration at time zero (initial concentration of drug in the plasma)

0.693 × Vd t½ 0.693 × Vd t½ = CL Clearance =

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Maintenance dose =

Css × CL Bioavailability

Loading dose = Vd × Cp

(Css = concentration of drug at steady state)

(Cp = concentration of drug in the plasma)

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Figures and Tables Location of Muscarinic, Nicotinic, and Adrenergic (α and β) Receptors ACh

N

Medulla

Spinal cord

ACh

NN

ACh

N

ACh

Parasympathetic Cardiac and smooth muscle, gland cells, nerve terminals

ACh M

ACh M

NE α, β

Sympathetic Sweat glands

Sympathetic Cardiac and smooth muscle, gland cells, nerve terminals

N D

Sympathetic Renal vascular smooth muscle

D1 ACh N Adrenal medulla

Figure 1. (Reproduced, with permission, from Katzung BG et al [editors]: Basic & Clinical Pharmacology, 12th ed. McGraw-Hill 2012.)

Epi, NE NM

Somatic Skeletal muscle

Voluntary motor nerve

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Drugs Affecting the Cholinergic Nerve Terminal

Axon

Na+ CHT

Hemicholiniums

Choline

AcCoA + Choline ChAT Nerve terminal

ACh

H+

VAT Calcium channel

130

ACh ATP, P

Ca2+

VAMPs Botulinum toxin

SNAPs

Postsynaptic cell

Vesamicol

Heteroreceptor

Presynaptic receptors

Acetylcholine autoreceptor

ACh ATP, P

ACh

Cholinoceptors

Choline Acetate

Other receptors

Figure 2. (Reproduced, with permission, from Katzung BG et al [editors]: Basic & Clinical Pharmacology, 12th ed. McGraw-Hill 2012.) 18/07/14 10:40 AM

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Drugs Affecting the Adrenergic Pharmacology Axon

Na+ A

MAO

Tyrosine

Tyr Dopa

Tyrosine hydroxylase

Metyrosine MAO

Nerve terminal

Dopamine H+

Reserpine

VMAT Heteroreceptor

Calcium channel

NE ATP, P

131

Ca2+

VAMPs Bretylium, guanethidine

SNAPs

NE, ATP, P

Presynaptic receptors

Autoreceptor

Cocaine, tricyclic antidepressants

NET

NE Diffusion

Postsynaptic cell Adrenoceptors

Other receptors

Figure 3. (Reproduced, with permission, from Katzung BG et al [editors]: Basic & Clinical Pharmacology, 12th ed. McGraw-Hill 2012.) 18/07/14 10:40 AM

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Drugs for the Treatment of Glaucoma Muscarinic Agonists (Carbachol and Pilocarpine) and AChEIs (Demecarium, Physostigmine, and Echothiophate)—treat glaucoma by increasing the diameter of the Canal of Schlemm. β-blockers (Timolol, Betaxolol, Carteolol)—treat glaucoma by decreasing the synthesis of aqueous humor. Carbonic anhydrase inhibitors (Dorzolamide, Acetazolamide Brinzolamide)—Decrease aqueous secretion due to lack of HCO3–

Cornea Canal of Schlemm

Figure 4. Structures of the anterior chamber of the eye. Tissues with significant autonomic functions and the associated ANS receptors are shown in this schematic diagram. Aqueous humor is secreted by the epithelium of the ciliary body, flows into the space in front of the iris, flows through the trabecular meshwork, and exits via the canal of Schlemm (arrow). Blockage of the β adrenoceptors associated with the ciliary epithelium causes decreased secretion of aqueous. Blood vessels (not shown) in the sclera are also under autonomic control and influence aqueous drainage. (Reproduced, with permission, from Katzung BG et al [editors]: Basic & Clinical Pharmacology, 12th ed. McGraw-Hill 2012.)

Anterior chamber

Trabecular meshwork

Dilator (α)

Sphincter (M)

Sclera Iris

Lens

Ciliary epithelium (β) Ciliary muscle (M)

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Sites of Action of Major Antihypertensive Drugs

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

Sympathetic ganglia β-Receptors of heart

Mecamylamine

Propranolol and other β-blockers

133

Angiotensin receptors of vessels Losartan and other angiotensin receptor blockers

α-Receptors of vessels

Vascular smooth muscle

Prazosin and other α1-blockers

Hydralazine Verapamil and other Minoxidil calcium channel Nitroprusside blockers Diazoxide Fenoldopam

Kidney tubules

β-Receptors of juxtaglomerular cells that release renin

Thiazides, etc

Angiotensin II

Propranolol and other β-blockers

Angiotensinconverting enzyme

Angiotensin I

Captopril and other ACE inhibitors

Renin

Angiotensinogen

Aliskiren

Figure 5. (Reproduced, with permission, from Katzung BG et al [editors]: Basic & Clinical Pharmacology, 12th ed. McGraw-Hill 2012.) 18/07/14 10:40 AM

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Schematic Site of Antihypertensive Action of Clonidine and α-Methyldopa IC Nucleus of the tractus solitarius Brainstem

CP

α-2 adrenoreceptors

Figure 6. The antihypertensive effects of clonidine and α-methyldopa are mediated at α-2 adrenoceptors in the brainstem (1). A proposed mechanism of hypotension involves α-2-induced activation descending inhibitory fibers (2), which decreases sympathetic tone and decreases the release of circulating NE and EPI in the periphery (3). (Reproduced, with permission, from Katzung BG et al [editors]: Basic & Clinical Pharmacology, 12th ed. McGraw-Hill 2012.)

X XI

1

Inhibitory interneurons

XII Vasomotor center

Motor fibers

3

2

NE

Spinal cord

Autonomic ganglion

Sympathetic nerve ending

EPI/NE Adrenal medulla

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Direct-Acting Vasodilators Vasodilator drugs Decreased systemic vascular resistance

Figure 7. Compensatory responses to vasodilators; basis for combination therapy with β-blockers and diuretics. (Reproduced, with permission, from Katzung BG et al [editors]: Basic & Clinical Pharmacology, 12th ed. McGraw-Hill 2012.)

Decreased renal sodium excretion

Decreased arterial pressure

1

2 Increased renin release

1

Increased aldosterone

Increased angiotensin II

1 Effect blocked by diuretics. 2 Effect blocked by β-blockers.

2 Increased systemic vascular resistance

Increased arterial pressure

Sodium retention, increased plasma volume

Increased sympathetic nervous system outflow

Increased heart rate

2

Increased Decreased cardiac venous contractility capacitance

Increased cardiac output

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Direct-Acting Vasodilators Acetylcholine, bradykinin Blood

Endoplasmic reticulum Ca2+ CaM

Ca2+•CaM

Arginine eNOS

GTP Ca2+

-

Contraction

PKG

Endothelial cell

cGMP

NO

Soluble guanylyl cyclase

Vascular smooth muscle cell

Phosphodiesterase GMP

Figure 8. Regulation of vasodilation by endothelial-derived nitric oxide (NO). Endogenous vasodilators (e.g., ACh, bradykinin) activate NO synthesis in the luminal endothelial cells, leading to calcium (Ca2+) efflux from the endoplasmic reticulum into the cytoplasm. Calcium binds to calmodulin (CaM) which activates endothelial NO synthase (eNOS), resulting in NO synthesis from L-arginine. NO diffuses into smooth muscle cells, where it activates soluble guanylyl cyclase and cyclic guanosine monophosphate (cGMP) synthesis from guanosine triphosphate (GTP). cGMP binds and activates protein kinase G (PKG), resulting in an overall reduction in calcium influx, and inhibition of calcium-dependent muscle contraction. (Reproduced, with permission, from Katzung BG et al [editors]: Basic & Clinical Pharmacology, 12th ed. McGraw-Hill 2012.)

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Inhibitors of Angiotensin (ACEIs and ARBs) Angiotensinogen Renin

Kininogen Kallikrein

– Aliskiren

Bradykinin

Angiotensin I

Increased prostaglandin synthesis

Angiotensin-converting enzyme (kininase II) – Angiotensin II ACE inhibitors

Inactive metabolites

ARBs – Vasoconstriction

Figure 9. Angiotensin converting enzyme (ACE; also known as kininase II) is inhibited by ACE inhibitors (ACEIs). ACEIs prevent the synthesis of angiotensin II and the release of aldosterone from the adrenal cortex. The ARBs block the action of Angiotensin II at A-1 receptors. (Reproduced, with permission, from Katzung BG et al [editors]: Basic & Clinical Pharmacology, 12th ed. McGraw-Hill 2012.)

– Aldosterone secretion

Vasodilation

– Increased peripheral vascular resistance

Increased sodium and water retention

Increased blood pressure

Spironolactone, eplerenone Decreased peripheral vascular resistance

Decreased blood pressure

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Diuretics Proximal convoluted tubule

NaHCO3

NaCl

NaCl

1

7

Proximal straight tubule

7

K+ Ca2+ Mg2+ Na+

2 Glomerulus

H2O

Cortex

? 4

K+ 2Cl–

Outer medulla

Figure 10. (Reproduced, with permission, from Katzung BG et al [editors]: Basic & Clinical Pharmacology, 12th ed. McGraw-Hill 2012.)

1 2 3 4 5 6 7

Diuretics Acetazolamide Osmotic agents (mannitol) Loop agents (e.g., furosemide) Thiazides Aldosterone antagonists ADH antagonists Adenosine Inner medulla

Ca2+ (+PTH)

Distal convoluted tubule

4 K+ H+ Collecting tubule NaCl 5 (+aldosterone)

7 3

K+ H+

Thick ascending limb Thin descending limb 2

H2O Loop of Henle

7

H2O 6 (+ADH) 2

Collecting duct

Thin ascending limb

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Table 1.

Site and Mechanism of Action of the Diuretics

Diuretic Class

Site of Action

Mechanism of Action

Osmotic diuretics Mannitol Urea Carbonic anhydrase inhibitors Acetazolamide Dorzolamide Loop diuretics Furosemide Ethacrynic acid Bumetanide Thiazides Hydrochlorothiazide Chlorthalidone Indapamide Potassium-sparing diuretics Spironolactone Amiloride Triamterene

Proximal convoluted tubule

Inhibition of H2O reabsorption in kidney tubules.

Proximal convoluted tubule

Inhibition of NaHCO3 reabsorption and ↑ excretion of sodium bicarbonate.

Ascending limb of the loop of henle

Block the active Na+/K+/2Cl– co-transport system in ascending limb of the Loop of Henle and prevent the reabsorption of Na+, K+, Cl–, Mg2+, Ca2+ etc.

Early distal convoluted tubule

Block Na+ reabsorption in the early distal tubule by inhibition of the Na+/Cl– co-transporter on the luminal membrane (↑ NaCl excretion).

Late distal tubule and cortical collecting duct

Block Na+ reabsorption and K+ and H+ secretion in the late distal tubule and collecting duct. These drugs promote Na+ excretion and K+ retention.

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Antiarrhythmic Agents

A: SVT

B: AFL

C: AFib 140 D: VT

1 sec

E: VT-TdP

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Figure 11. Electrocardiograms typical of a variety of arrhythmias. SVT, supraventricular tachycardia; AFL, atrial flutter; AFib, atrial fibrillation; VT, ventricular tachycardia. VT-TdP, ventricular tachycardia of the torsade de pointes type. (Reproduced, with permission, from Katzung BG et al [editors]: Basic & Clinical Pharmacology, 11th ed. McGraw-Hill 2009.)

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Antiarrhythmic Agents

0 Phase 0

−20

Phase 3

−40 Phase 4

−60

r ke ma t e c n Pa urre c Na+,

−80 −100

Ca2+/

K+

Slow Ca2+ current Delayed rectifier K+ current

Cardiac action potentials in slow-response fibers Figure 12.

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Antiarrhythmic Agents Overshoot (phase 1)

−80 −100

Plateau (phase 2 )

Na+

K+

Fast Na+ current

(phase 3)

Ca2+

Repolarization

−60

tion (pha

−40

Depolariza

mV

−20

se 0)

0

K+ Resting potential (phase 4) Slow Ca2+ current Delayed rectifier K+ current

Cardiac action potentials in fast-response fibers Figure 13.

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Table 2.

Specific Antiarrhythmic Drug Contraindications

Condition

Contraindicated/Use with Caution

Heart failure

Disopyramide, Flecainide

Sinus or AV node dysfunction

Digoxin, Verapamil, Diltiazem, β-receptor antagonists, Amiodarone

Wolff–Parkinson–White syndrome (risk of extremely rapid rate if atrial fibrillation develops)

Digoxin, Verapamil, Diltiazem, β-blockers (any drug that decreases AV nodal conduction)

History of myocardial infarction

Flecainide, Encainide

Prolonged QT interval

Quinidine, Procainamide, Disopyramide, Sotalol, Ibutilide, Amiodarone

Cardiac transplant

Adenosine

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Different Conformational States of Na+ Channels During the Cardiac Action Potential Resting

Activated

Inactivated

Extracellular + + Na

m

+

Na+

m

m

+

m

m

+ h

–40 –60

Threshold

m h

+

40

Intracellular

0

Intracellular

Intracellular

h 40

Na+

0 –40 –60

40 0 –40 –60

Recovery

Figure 14. A schematic representation of Na+ channels cycling through different conformational states during the cardiac action potential. Transitions between resting, activated, and inactivated states are dependent on membrane potential and time. The activation gate is shown as m and the inactivation gate as h. Potentials typical for each state are shown under each channel schematic as a function of time. The dashed line indicates that part of the action potential during which most Na+ channels are completely or partially inactivated and unavailable for reactivation. (Reproduced, with permission, from Katzung BG et al [editors]: Basic & Clinical Pharmacology, 12th ed. McGraw-Hill 2012.)

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Compensatory Responses During Congestive Heart Failure Cardiac output

Carotid sinus firing

Renal blood flow

Sympathetic discharge

Renin release

Angiotensin II Force Figure 15. Compensatory responses that occur during congestive heart failure. Sympathetic discharge facilitates renin release, and angiotensin II ↑ NE release by sympathetic nerve endings. (Reproduced, with permission, from Katzung BG et al [editors]: Basic & Clinical Pharmacology, 12th ed. McGraw-Hill 2012.)

Rate Preload

Afterload Remodeling

Cardiac output (via compensation) 145

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Schematic of Drugs for Congestive Heart Failure Myofibril syncytium

Digoxin – Na+/K +-ATPase

Interstitium Cell membrane Cytoplasm

Cav–L – + Ca2+channel blockers

NCX

ATP K+

Na+ Ca2+

Trigger Ca2+

β agonists

SERCA

ATP CalS

CalS Ca2+

Sarcoplasmic reticulum

Ca2+

Ca2+

CalS CalS

CalS

RyR

ATP

146

Ca2+

Ca2+

Z

Actin – tropomyosintroponin

Myosin Sarcomere

Figure 16. Schematic diagram of a cardiac muscle sarcomere with sites of drug action for treating congestive heart failure.

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Na+/K+-ATPase—the sodium pump, is the site of action of cardiac glycosides. NCX is the sodium-calcium exchanger. Cav-L is the voltage-gated, L-type calcium channel. SERCA (sarcoplasmic endoplasmic reticulum Ca2+-ATPase) is a calcium transporter ATPase that pumps calcium into the sarcoplasmic reticulum (SR). RyR (ryanodine RyR2 receptor) is a calcium-activated calcium channel in the membrane of the SR that is triggered to release stored calcium. (Reproduced, with permission, from Katzung BG et al [editors]: Basic & Clinical Pharmacology, 12th ed. McGraw-Hill 2012.)

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Drugs for the Treatment of Congestive Heart Failure 100

Figure 17. Relation of left ventricular (LV) performance to filling pressure in patients with acute myocardial infarction. The upper line indicates the range for normal, healthy individuals. The heart operates at a stable point (point A) at a given level of exercise. In CHF, cardiac function is shifted down and to the right, through points 1 and 2, finally reaching point B. A “pure” positive inotropic drug (+ Ino) would move the operating point upward by increasing cardiac stroke work. A vasodilator (Vaso) would move the point leftward by reducing filling pressure. Effective therapy usually results in both effects. (Modified and reproduced with permission, from Swan HJC, Parmley WW: Congestive heart failure. In: Sodeman WA Jr, Sodeman TM [editors]: Pathologic Physiology. Saunders, 1979.)

LV stroke work (g-m/m2)

80 Normal range 60 + Ino

A

40

Depressed

1 2 Vaso

B

20 Shock 0

0

10

20

30

40

LV filling pressure (mm Hg) 147

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Drugs for the Treatment of Congestive Heart Failure Blood vessel lumen

Capillary endothelial cells Interstitium

Nitrates Nitrites

Arginine

eNOS

Nitric oxide (NO)

Ca2+

Guanylyl cyclase Ca2+ Nesiritide

148

Vascular smooth muscle cell GTP

Nitrates Nitrites

NO +

GC*

cGMP

PDE

–

Sildenafil

GMP

MLCK*

Myosin light chains (myosin-LC)

Myosin-LC-PO4

Myosin-LC

Contraction

Relaxation

Actin

Figure 18. Mechanism of action of the Nitrovasodilators (Nitroglycerin, Isosorbide Dinitrate)

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The organic nitrates ↑ release of nitric oxide (NO), which activates guanylyl cyclase and ↑ cGMP. Increased cGMP induces smooth muscle relaxation by ↑ myosin phosphatase activity, inducing dephosphorylation of myosin light chain. Relaxation of venous smooth muscle leads to venous pooling and a ↓ in preload, which will ↓ ventricular volume and wall tension, reducing cardiac work and O2 demand. (Reproduced, with permission, from Katzung BG et al [editors]: Basic & Clinical Pharmacology, 12th ed. McGraw-Hill 2012.)

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GABAA Receptor/Chloride Ionophore Complex GABA site Benzodiazepine site

Barbiturate site

Steroid site anesthetics or anxiogenics

Picrotoxin site convulsants

Cl–

Figure 19. Pharmacologic binding sites on the GABAA receptor. (Reproduced with permission from Nestler EJ et al [editors]: Molecular Basis of Neurpharmacology, McGraw-Hill 2001.)

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Table 3.

Clinical Actions of the Benzodiazepines

Benzodiazepines

Clinical Indications

Alprazolam

Anxiety, panic, and phobias

Diazepam

Anxiety, preoperative sedation, muscle relaxation, and ETOH withdrawal

Lorazepam

Anxiety, status epilepticus (drug of choice, IV), preoperative sedation, and ETOH withdrawal

Midazolam

Preoperative sedation, anesthesia (intravenous)

Temazepam

Sleep disorders

Oxazepam

Sleep disorders and anxiety

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Antipsychotic Potency 100

KD (affinity) for D2 receptors (nM)

Chlorpromazine Clozapine 10 Molindone Thiothixene

Fluphenazine

Haloperidol

1

0.1 1

10

100

1000

10000

Average daily clinical dose (mg)

Figure 20. The antipsychotic potency of the typical antipsychotic drugs is correlated with affinity for D2 receptors.

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Biogenic Amine Hypothesis of Depression Serotonergic

Noradrenergic

Tryptophan

Tyrosine

Tryptophan hydroxylase

Tyrosine hydroxylase

Serotonin

Norepinephrine Presynaptic axon

α βγ

MAO-A Metabolites

α βγ

5-HT1B

α2

γ α β

5-HT1A Serotonin receptors

S SERT

NET Adrenoceptor

152

α

βγ Gi

Postsynaptic axon

α

βγ Gs

PLC

IP3, DAG

cAMP

AC ATP

PKA

PKC

Cytoplasm CREB Nucleus

Figure 21. The Biogenic Amine Hypothesis of Depression

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Depression is associated with decreases in 5-HT and/or NE signaling in the brain with significant alterations in downstream signal transduction systems (protein kinases and ion channels). Most antidepressants are believed to alter the reuptake of 5-HT, NE and/or DA, or block the metabolism of the biogenic amines (MAO inhibitors). Long-term treatment with antidepressants desensitizes presynaptic receptors and alters the postsynaptic transduction systems of the biogenic amines. (Reproduced, with permission, from Katzung BG et al [editors]: Basic & Clinical Pharmacology, 12th ed. McGraw-Hill 2012.)

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Metabolism of Dopamine 3-O-methyldopa COMT Tolcapone AAAD Dopamine

Levodopa Carbidopa

Periphery Blood-brain barrier (BBB) CNS Levodopa Tolcapone

AAAD

MAOB Dopamine Metabolites Selegiline

COMT

3-O-methyldopa Figure 22. (Modified and reproduced, with permission, from Brunton L et al [editors]: Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 12th ed. McGraw-Hill 2011.)

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Mechanism of Action of Cocaine and Amphetamine Cocaine

Amphetamine

VMAT Amph

DA

DAT

DAT

DAT DA Cocaine

DA

DA

DA

Amph

Figure 23. Mechanism of Action of Cocaine and Amphetamine: (Left) Cocaine inhibits the DA transporter (DAT) and increases synaptic DA levels. (Right) Amphetamine acts as a substrate for the DAT (competitively inhibits the DAT). Amphetamine enters the presynaptic neuron through the DAT and once inside the cell, interferes with the VMAT and impedes DA (and NE) entrance into the presynaptic storage vesicle. Dopamine (or NE) increases in the cytosol and exits the nerve terminal via the DAT acting in the reverse (instead of exiting via normal vesicular exocitosis). Amphetamine and cocaine ↑ synaptic levels of DA or NE. (Reproduced, with permission, from Katzung BG et al [editors]: Basic & Clinical Pharmacology, 12th ed. McGraw-Hill 2012.)

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Overview of Antibiotic Mechanisms Folate synthesis inhibitors • Sulfonamides • Trimethoprim

Cell membrane inhibitors • Amphotericin • Ketoconazole • Polymyxin

RNA polymerase inhibitors • Rifampin

Protein

Ribosome

Folate synthesis

mRNA

DNA mRNA

Figure 24. Overview of Antibiotic Mechanisms.

DNA gyrase inhibitors • Fluoroquinolones

Cell wall synthesis inhibitors • Beta-lactam antibiotics: carbapenems, cephalosporins, monobactams, and penicillins • Other antibiotics: bacitracin, fosfomycin, and vancomycin

Protein synthesis

Protein synthesis inhibitors • Aminoglycosides • Chloramphenicol • Clindamycin • Macrolides • Mupirocin • Streptogramins • Tetracyclines

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First-pass Metabolism Intravenous administration Systemic circulation Oral administration

Biotransformation

Figure 25. With first-pass metabolism, drugs that are orally administered can be absorbed from the GI tract (stomach and small intestine). Some drugs are metabolized by liver enzymes before reaching the systemic circulation, thus decreasing bioavailability (i.e., the fraction of drug reaching the systemic circulation unchanged).

Liver

Hepatic portal vein

Oral drug

Intestines

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Disulfiram Reaction Ethanol

Acetaldehyde

Acetate

Aldehyde dehydrogenase

Alcohol dehydrogenase

Disulfiram (–)

Figure 26. Disulfiram and other drugs (cephalosporins, metronidazole and the sulfonylurea hypoglycemics) inhibit the action of aldehyde dehydrogenase. When these drugs are administered with ethanol, acetaldehyde builds up in the blood, causing a disulfiram reaction (nausea/vomiting, headache) within 10-30 minutes after alcohol is ingested.

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Interaction of Antibiotics with Oral Contraceptives

Excretion via bile

Liver

Intestines Estrogen glucuronide

Estrogen glucuronide Bacterial enzymes

Estrogen

Estrogen Reabsorption via circulation

Antibiotic eliminates bacteria and interrupts enterohepatic cycling

Free estrogen can be absorbed into the bloodstream.

Figure 27. Antibiotics have been shown to interrupt the enterohepatic cycling of the estrogen in estradiol-containing oral contraceptive agents. This action can decrease the efficacy of estrogen and result in contraceptive failure.

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