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Luellmann, Color Atlas of Pharmacology © 2005 Thieme All rights reserved. Usage subject to terms and conditions of license. Color Atlas of Pharmacology 3rd edition, revised and expanded Heinz Lüllmann, M.D. Lutz Hein, M.D. Former Professor and Chairman Department of Pharmacology University of Kiel Germany Professor Department of Pharmacology University of Freiburg Germany Klaus Mohr, M.D. Detlef Bieger, M.D. Professor Department of Pharmacology and Toxicology University of Bonn Germany Professor Emeritus Division of Medical Sciences Faculty of Medicine Memorial University of Newfoundland St. John’s, Newfoundland Canada With 170 color plates by Jürgen Wirth Thieme Stuttgart · New York Luellmann, Color Atlas of Pharmacology © 2005 Thieme All rights reserved. Usage subject to terms and conditions of license. IV Library of Congress Cataloging-in-Publication Data Taschenatlas der Pharmakologie. Englisch. Color atlas of pharmacology/Heinz Luellmann ... [et al.]; 172 color plates by Juergen Wirth.— 3rd ed., rev. and expanded p. ; cm. Rev. and expanded translation of: Taschenatlas der Pharmakologie. 5th ed. c2004. Includes bibliographical references and index. ISBN 3- 13- 781703-X (GTV: alk. paper)— ISBN 1- 58890- 332-X (alk. paper) 1. Pharmacology—Atlases. 2. Pharmacology— Handbooks, manuals, etc. [DNLM: 1. Pharmacology—Atlases. 2. Pharmacology—Handbooks. 3. Drug Therapy—Atlases. 4. Drug Therapy— Handbooks. 5. Pharmaceutical Preparations— Atlases. 6. Pharmaceutical Preparations—Handbooks. QV 17 T197c 2005a] I. Lüllmann, Heinz. II. Title. RM301.12.T3813 2005 615’.1—dc22 2005012554 Translator: Detlef Bieger, M.D. Illustrator: Jürgen Wirth, Professor of Visual Communication, University of Applied Sciences, Darmstadt, Germany © 2005 Georg Thieme Verlag, Rüdigerstrasse 14, 70469 Stuttgart, Germany http://www.thieme.de Thieme New York, 333 Seventh Avenue, New York, NY 10001 USA http://www.thieme.com Cover design: Cyclus, Stuttgart Typesetting by primustype Hurler GmbH, Notzingen Printed in Germany by Appl, Wemding ISBN 3- 13- 781703- X (GTV) ISBN 1- 58890- 332-X (TNY) Important note: Medicine is an ever- changing science undergoing continual development. Research and clinical experience are continually expanding our knowledge, in particular our knowledge of proper treatment and drug therapy. Insofar as this book mentions any dosage or application, readers may rest assured that the authors, editors, and publishers have made every effort to ensure that such references are in accordance with the state of knowledge at the time of production of the book. Nevertheless, this does not involve, imply, or express any guarantee or responsibility on the part of the publishers in respect to any dosage instructions and forms of applications stated in the book. Every user is requested to examine carefully the manufacturers’ leaflets accompanying each drug and to check, if necessary in consultation with a physician or specialist, whether the dosage schedules mentioned therein or the contraindications stated by the manufacturers differ from the statements made in the present book. Such examination is particularly important with drugs that are either rarely used or have been newly released on the market. Every dosage schedule or every form of application used is entirely at the user’s own risk and responsibility. The authors and publishers request every user to report to the publishers any discrepancies or inaccuracies noticed. Some of the product names, patents, and registered designs referred to in this book are in fact registered trademarks or proprietary names even though specific reference to this fact is not always made in the text. Therefore, the appearance of a name without designation as proprietary is not to be construed as a representation by the publisher that it is in the public domain. This book, including all parts thereof, is legally protected by copyright. Any use, exploitation, or commercialization outside the narrow limits set by copyright legislation, without the publisher’s consent, is illegal and liable to prosecution. This applies in particular to photostat reproduction, copying, mimeographing, preparation of microfilms, and electronic data processing and storage. Luellmann, Color Atlas of Pharmacology © 2005 Thieme All rights reserved. Usage subject to terms and conditions of license. V Preface to the 3rd edition In many countries, medicine is at present facing urgent political and economic calls for reform. These socioeconomic pressures notwithstanding, pharmacotherapy has always been an integral part of the health care system and will remain so in the future. Well-founded knowledge of the preventive and therapeutic value of drugs is a sine qua non for the successful treatment of patients entrusting themselves to a physician or pharmacist. As the new edition was nearing completion, several high-profile drugs experienced withdrawal from the market, substantive change in labeling, or class action litigation against their manufacturers. Amid growing concern over effectiveness of drug safety regulations, “pharmacovigilance” has become a new priority. It is hoped that this compendium may aid in promoting the critical awareness and rational attitude required to meet that demand. Because of the plethora of proprietary medicines and the continuous influx of new pharmaceuticals, the drug market is dif cult to survey and hard to understand. This is true not only for the student in search of a logical system for dealing with the wealth of available drugs, but also for the practicing clinician in immediate need of independent information. We are grateful for comments and suggestions from colleagues, and from students, both doctoral and undergraduate. Thanks are due to Professor R. Lüllmann-Rauch for histological and cell-biological advice. We are indebted to Ms. M. Mauch and Ms. K. Jürgens, Thieme Verlag, for their care and assistance and to Ms. Gabriele Kuhn for harmonious editorial guidance. Clearly, a pocket atlas can provide only a basic framework. Comprehensive knowledge has to be gained from major textbooks. As is evident from the drug lists included in the Appendix, some 600 drugs are covered in the present Atlas. This number should be suf cient for everyday medical practice and could be interpreted as a Model List. The advances in pharmacotherapy made in recent years have required us to incorporate new plates and text passages, and to expunge obsolete approaches. Several plates needed to be brought in line with new knowledge. Heinz Lüllmann, Kiel Klaus Mohr, Bonn Lutz Hein, Freiburg Detlef Bieger, St. John’s, Canada Jürgen Wirth, Darmstadt Disclosure: The authors of the Color Atlas of Pharmacology have no financial interests or other relationships that would influence the content of this book. Luellmann, Color Atlas of Pharmacology © 2005 Thieme All rights reserved. Usage subject to terms and conditions of license. VI Contents Contents General Pharmacology 1 History of Pharmacology. . . . . . . . The Idea . . . . . . . . The Impetus . . . . . . Early Beginnings . . . . Foundation . . . . . . . Consolidation—General Status Quo . . . . . . . 2 Drug Metabolism by Cytochrome P450 . . . . . . . . . . . . . . . . . . . . The Kidney as an Excretory Organ . . . Presystemic Elimination . . . . . . . . . 38 40 42 Pharmacokinetics . . . . . . . . . . . . 44 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Recognition . . . . . . . . . 2 2 3 3 3 3 Drug Sources . . . . . . . . . . . . . . 4 Drug and Active Principle . . . . . . . . The Aims of Isolating Active Principles . . . . . . . . . . . . . . . . . European Plants as Sources of Effective Medicines . . . . . . . . . . . 4 4 Drug Development . . . . . . . . . . . 8 Congeneric Drugs and Name Diversity . . . . . . . . . . . . . . . . . 10 Drug Concentration in the Body as a Function of Time—First Order (Exponential) Rate Processes . . . . . Time Course of Drug Concentration in Plasma . . . . . . . . . . . . . . . . Time Course of Drug Plasma Levels during Repeated Dosing (A) . . . . . . Time Course of Drug Plasma Levels during Irregular Intake (B) . . . . . . . Accumulation: Dose, Dose Interval, and Plasma Level Fluctuation (A) . . . Change in Elimination Characteristics during Drug Therapy (B) . . . . . . . . Drug Administration . . . . . . . . . . 12 Quantification of Drug Action . . . . . 52 Oral Dosage Forms. . . . . . . . . . . . Drug Administration by Inhalation . . . Dermatological Agents . . . . . . . . . Skin Protection (A). . . . . . . . . . . . Dermatological Agents as Vehicles (B). From Application to Distribution in the Body . . . . . . . . . . . . . . . . . 12 14 16 16 16 Dose–Response Relationship . . . . . . Concentration–Effect Relationship (A) . Concentration–Effect Curves (B) . . . . 52 54 54 Drug–Receptor Interaction . . . . . . . 56 Cellular Sites of Action . . . . . . . . . 20 Potential Targets of Drug Action . . . . 20 56 58 58 58 60 Distribution in the Body . . . . . . . . 22 External Barriers of the Body . . . . . Blood–Tissue Barriers . . . . . . . . . Membrane Permeation . . . . . . . . Possible Modes of Drug Distribution . Binding to Plasma Proteins . . . . . . . . . . . 22 24 26 28 30 Drug Elimination . . . . . . . . . . . . 32 Concentration–Binding Curves . . . . . Types of Binding Forces . . . . . . . . . Covalent Bonding . . . . . . . . . . . Noncovalent Bonding . . . . . . . . . Agonists—Antagonists . . . . . . . . . . Models of the Molecular Mechanism of Agonist/Antagonist Action (A) . . . . Other Forms of Antagonism. . . . . . . Enantioselectivity of Drug Action . . . . Receptor Types . . . . . . . . . . . . . . Mode of Operation of G-Proteincoupled Receptors . . . . . . . . . . . . Time Course of Plasma Concentration and Effect . . . . . . . . . . . . . . . . . The Liver as an Excretory Organ . . . . Biotransformation of Drugs . . . . . . . 32 34 6 18 . 44 . 46 . 48 . 48 . 50 . 50 60 60 62 64 66 68 Adverse Drug Effects . . . . . . . . . . 70 Undesirable Drug Effects, Side Effects . . . . . . . . . . . . . . . . . . . 70 Luellmann, Color Atlas of Pharmacology © 2005 Thieme All rights reserved. Usage subject to terms and conditions of license. Contents Causes of Adverse Effects . . . . Drug Allergy . . . . . . . . . . . Cutaneous Reactions . . . . . . Drug Toxicity in Pregnancy and Lactation . . . . . . . . . . . . . . . . . . . . . . . . . 70 72 74 . . . . 76 VII Genetic Variation of Drug Effects . . . 78 Pharmacogenetics . . . . . . . . . . . . 78 Drug- independent Effects . . . . . . . 80 Placebo (A) . . . . . . . . . . . . . . . . 80 Systems Pharmacology 83 Drugs Acting on the Sympathetic Nervous System . . . . . . . . . . . . . Sympathetic Nervous System. . Structure of the Sympathetic Nervous System . . . . . . . . . Adrenergic Synapse . . . . . . . Adrenoceptor Subtypes and Catecholamine Actions . . . . . Smooth Muscle Effects . . . . . Cardiostimulation . . . . . . . . Metabolic Effects. . . . . . . . . Structure–Activity Relationships of Sympathomimetics . . . . . . Indirect Sympathomimetics. . . α- Sympathomimetics, α- Sympatholytics . . . . . . . . β-Sympatholytics (β- Blockers) . Types of β-Blockers . . . . . . . Antiadrenergics . . . . . . . . . Vasodilators . . . . . . . . . . . . . . . 122 84 Vasodilators—Overview . . . . . . . . . Organic Nitrates . . . . . . . . . . . . . Calcium Antagonists . . . . . . . . . . . I. Dihydropyridine Derivatives . . . . . . II. Verapamil and Other Catamphiphilic Ca2+ Antagonists . . . . . . . . . . . . . 122 124 126 126 . . . . 84 . . . . . . . . 86 86 . . . . . . . . 88 88 88 88 Inhibitors of the Renin–Angiotensin– Aldosterone System . . . . . . . . . . . 128 . . . . . . . . 90 92 Drugs Acting on Smooth Muscle . . . 130 . . . . . . . . . . . . . . . . . . . . . 94 . 96 . 98 . 100 Drugs Acting on the Parasympathetic Nervous System . . . . . . . . . . . . . 102 Parasympathetic Nervous System Cholinergic Synapse . . . . . . . . Parasympathomimetics . . . . . . Parasympatholytics . . . . . . . . . . . . . . . . . . . . 102 104 106 108 126 ACE Inhibitors . . . . . . . . . . . . . . . 128 Drugs Used to Influence Smooth Muscle Organs . . . . . . . . . . . . . . 130 Cardiac Drugs . . . . . . . . . . . . . . 132 Cardiac Glycosides . . . . . . . . . . . . Antiarrhythmic Drugs . . . . . . . . . . I. Drugs for Selective Control of Sinoatrial and AV Nodes. . . . . . . . II. Nonspecific Drug Actions on Impulse Generation and Propagation Electrophysiological Actions of Antiarrhythmics of the Na+- Channel Blocking Type . . . . . . . . . . . . . . . 134 136 136 136 138 Nicotine. . . . . . . . . . . . . . . . . . 112 Actions of Nicotine . . . . . . . . . . Localization of Nicotinic ACh Receptors . . . . . . . . . . . . . . . . Effects of Nicotine on Body Function Aids for Smoking Cessation . . . . . . Consequences of Tobacco Smoking . . 112 . . . . 112 112 112 114 Antianemics . . . . . . . . . . . . . . . 140 Drugs for the Treatment of Anemias . Erythropoiesis (A) . . . . . . . . . . Vitamin B12 (B) . . . . . . . . . . . Folic Acid (B) . . . . . . . . . . . . . Iron Compounds . . . . . . . . . . . . . . . . . 140 140 140 140 142 Biogenic Amines. . . . . . . . . . . . . 116 Antithrombotics . . . . . . . . . . . . . 144 Dopamine. . . . . . . . . . . . . . . . . 116 Histamine Effects and Their Pharmacological Properties . . . . . . . 118 Serotonin . . . . . . . . . . . . . . . . . 120 Prophylaxis and Therapy of Thromboses Vitamin K Antagonists and Vitamin K . Possibilities for Interference (B) . . . . . Heparin (A) . . . . . . . . . . . . . . . . Luellmann, Color Atlas of Pharmacology © 2005 Thieme All rights reserved. Usage subject to terms and conditions of license. 144 146 146 148 VIII Contents Hirudin and Derivatives (B) . Fibrinolytics. . . . . . . . . . Intra- arterial Thrombus Formation (A) . . . . . . . . Formation, Activation, and Aggregation of Platelets (B). Inhibitors of Platelet Aggregation (A) . . . . . . . Presystemic Effect of ASA . . . . . . . . 148 . . . . . . 150 Depolarizing Muscle Relaxants . . . . . 186 Antiparkinsonian Drugs . . . . . . . . . 188 Antiepileptics . . . . . . . . . . . . . . . 190 . . . . . . 152 . . . . . . 152 . . . . . . 154 . . . . . . 154 Plasma Volume Expanders . . . . . . . 156 Drugs Used in Hyperlipoproteinemias 158 Drugs for the Suppression of Pain . . 194 Pain Mechanisms and Pathways . . . . 194 Antipyretic Analgesics . . . . . . . . . 196 Eicosanoids . . . . . . . . . . . . . . . . 196 Antipyretic Analgesics vs. NSAIDs. . . . 198 Nonsteroidal Anti- inflammatory Drugs (NSAIDs) . . . . . . . . . . . . . . 198 Lipid- lowering Agents . . . . . . . . . . 158 Diuretics . . . . . . . . . . . . . . . . . 162 Diuretics—An Overview . . . . . . . . NaCl Reabsorption in the Kidney (A) . Aquaporins (AQP) . . . . . . . . . . . Osmotic Diuretics (B) . . . . . . . . . Diuretics of the Sulfonamide Type . . Potassium- sparing Diuretics and Vasopressin . . . . . . . . . . . . . . . Potassium- sparing Diuretics (A) . . . Vasopressin and Derivatives (B) . . . 162 164 164 164 166 Cyclooxygenase (COX) Inhibitors . . . . 200 . 168 . 168 . 168 Opioid Analgesics—Morphine Type . . . 208 . . . . . Drugs for the Treatment of Peptic Ulcers . . . . . . . . . . . . . . . . . . . 170 Drugs for Gastric and Duodenal Ulcers . . . . . . . . . . . . . . . . . . I. Lowering of Acid Concentration . II. Protective Drugs . . . . . . . . . III. Eradication of Helicobacter pylori (C) . . . . . . . . . . . . . . . . 170 . 170 . 172 . 172 Laxatives . . . . . . . . . . . . . . . . . 174 1. Bulk Laxatives . . . . . . . . . . . 2. Irritant Laxatives . . . . . . . . . 2a. Small- Bowel Irritant Purgative . 2b. Large-Bowel Irritant Purgatives 3. Lubricant laxatives . . . . . . . . Nonsteroidal Anti- inflammatory Drugs . . . . . . . . . . . . . . . . . . . 200 . . . . . 174 176 178 178 178 Local Anesthetics . . . . . . . . . . . . 202 Opioids . . . . . . . . . . . . . . . . . . 208 General Anesthetics . . . . . . . . . . . 214 General Anesthesia and General Anesthetic Drugs . . . . . . . . . . . . . 214 Inhalational Anesthetics . . . . . . . . . 216 Injectable Anesthetics . . . . . . . . . . 218 Psychopharmacologicals . . . . . . . . 220 Sedatives, Hypnotics . . . . . . . . . . Benzodiazepines . . . . . . . . . . . . Benzodiazepine Antagonist . . . . . Pharmacokinetics of Benzodiazepines Therapy of Depressive Illness . . . . . Mania . . . . . . . . . . . . . . . . . . Therapy of Schizophrenia . . . . . . . Neuroleptics . . . . . . . . . . . . . Psychotomimetics (Psychedelics, Hallucinogens) . . . . . . . . . . . . . . . . . . . . . 220 222 222 224 226 230 232 232 . 236 Antidiarrheals . . . . . . . . . . . . . . 180 Hormones. . . . . . . . . . . . . . . . . 238 Antidiarrheal Agents . . . . . . . . . . . 180 Hypothalamic and Hypophyseal Hormones . . . . . . . . . . . . . . Thyroid Hormone Therapy. . . . . Hyperthyroidism and Antithyroid Drugs . . . . . . . . . . . . . . . . Glucocorticoid Therapy . . . . . . I. Replacement Therapy . . . . . . Drugs Acting on the Motor System . 182 Drugs Affecting Motor Function . . . . 182 Muscle Relaxants. . . . . . . . . . . . . 184 Nondepolarizing Muscle Relaxants . . . 184 Luellmann, Color Atlas of Pharmacology © 2005 Thieme All rights reserved. Usage subject to terms and conditions of license. . . . 238 . . . 240 . . . 242 . . . 244 . . . 244 Contents II. Pharmacodynamic Therapy with Glucocorticoids (A) . . . . . . . . . . Androgens, Anabolic Steroids, Antiandrogens . . . . . . . . . . . . . Inhibitory Principles . . . . . . . . . Follicular Growth and Ovulation, Estrogen and Progestin Production . Oral Contraceptives . . . . . . . . . . Antiestrogen and Antiprogestin Active Principles . . . . . . . . . . . . Aromatase Inhibitors . . . . . . . . . Insulin Formulations . . . . . . . . . . Variations in Dosage Form . . . . . Variation in Amino Acid Sequence. Treatment of Insulin-dependent Diabetes Mellitus. . . . . . . . . . . . Undesirable Effects . . . . . . . . . Treatment of Maturity- Onset (Type II) Diabetes Mellitus. . . . . . . Oral Antidiabetics . . . . . . . . . . . Drugs for Maintaining Calcium Homeostasis . . . . . . . . . . . . . . Antifungal Drugs . . . . . . . . . . . . 284 . 244 . 248 . 248 . 250 . 252 . . . . . 254 256 258 258 258 Drugs Used in the Treatment of Fungal Infections . . . . . . . . . . . . . 284 Antiviral Drugs . . . . . . . . . . . . . . 286 Chemotherapy of Viral Infections . . Drugs for the Treatment of AIDS . . I. Inhibitors of Reverse Transcriptase—Nucleoside Agents Nonnucleoside Inhibitors . . . . . II. HIV protease Inhibitors . . . . . III. Fusion Inhibitors . . . . . . . . . . 286 . . 290 . . . . . . . . 290 290 290 290 Antiparasitic Drugs . . . . . . . . . . . 292 . 260 . 260 . 262 . 264 . 266 Antibacterial Drugs . . . . . . . . . . . 268 Drugs for Treating Bacterial Infections . . . . . . . . . . . . . . Inhibitors of Cell Wall Synthesis . Inhibitors of Tetrahydrofolate Synthesis . . . . . . . . . . . . . . Inhibitors of DNA Function . . . . Inhibitors of Protein Synthesis . . Drugs for Treating Mycobacterial Infections . . . . . . . . . . . . . . Antitubercular drugs (1) . . . . Antileprotic drugs (2) . . . . . . IX . . . 268 . . . 270 . . . 274 . . . 276 . . . 278 Drugs for Treating Endoparasitic and Ectoparasitic Infestations . . . . . . 292 Antimalarials . . . . . . . . . . . . . . . 294 Other Tropical Diseases . . . . . . . . . 296 Anticancer Drugs . . . . . . . . . . . . 298 Chemotherapy of Malignant Tumors . . . . . . . . . . . . . . . . . . 298 Targeting of Antineoplastic Drug Action (A) . . . . . . . . . . . . . . . . . 302 Mechanisms of Resistance to Cytostatics (B) . . . . . . . . . . . . . . 302 Immune Modulators . . . . . . . . . . 304 Inhibition of Immune Responses . . . . 304 . . . 282 . . . 282 . . . 282 Antidotes . . . . . . . . . . . . . . . . . 308 Therapy of Selected Diseases 313 Hypertension . . . . . . . . . Angina Pectoris . . . . . . . Antianginal Drugs . . . . . . Acute Coronary Syndrome— Myocardial Infarction . . . . Congestive Heart Failure . . Hypotension . . . . . . . . . Gout . . . . . . . . . . . . . . Obesity—Sequelae and Therapeutic Approaches. . . . . . . . . 314 . . . . . . 316 . . . . . . 318 . . . . . . . . . . . . . . . . . . . . . . . . 320 322 324 326 Antidotes and Treatment of Poisonings. . . . . . . . . . . . . . . . . 308 Osteoporosis . . . . . . . . . . . Rheumatoid Arthritis . . . . . . . Migraine . . . . . . . . . . . . . . Common Cold . . . . . . . . . . Atopy and Antiallergic Therapy . Bronchial Asthma. . . . . . . . . Emesis . . . . . . . . . . . . . . . Alcohol Abuse. . . . . . . . . . . Local Treatment of Glaucoma . . . . . . . . 328 Luellmann, Color Atlas of Pharmacology © 2005 Thieme All rights reserved. Usage subject to terms and conditions of license. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 330 332 334 336 338 340 342 344 346 X Contents Further Reading 349 Drug Indexes 351 Trade Name – Drug Name . . . . . . . 352 Drug Name – Trade Name. . . . . . . . 369 Subject Index Luellmann, Color Atlas of Pharmacology © 2005 Thieme All rights reserved. Usage subject to terms and conditions of license. 381