Illustrated by Jürgen Wirth, Darmstadt, Germany
This book is an authorized revised and expanded translation of the 3rd German edition published and copyrighted 1996 by Georg Thieme Verlag, Stuttgart, Germany. Title of the German edition: Taschenatlas der Pharmakologie
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 or duplication of any kind, translating, preparation of microfilms, and electronic data processing and storage.
©2000 Georg Thieme Verlag, Rüdigerstrasse 14, D-70469 Stuttgart, Germany Thieme New York, 333 Seventh Avenue, New York, NY 10001, USA
Typesetting by Gulde Druck, Tübingen Printed in Germany by Staudigl, Donauwörth
ISBN 3-13-781702-1 (GTV)
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 of any dosage instructions and forms of application 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.
The present second edition of the Color Atlas of Pharmacology goes to print six years after the first edition. Numerous revisions were needed, highlighting the dramatic continuing progress in the drug sciences. In particular, it appeared necessary to include novel therapeutic principles, such as the inhibitors of platelet aggregation from the group of integrin GPIIB/IIIA antagonists, the inhibitors of viral protease, or the non-nucleoside inhibitors of reverse transcriptase. Moreover, the re-evaluation and expanded use of conventional drugs, e.g., in congestive heart failure, bronchial asthma, or rheumatoid arthritis, had to be addressed. In each instance, the primary emphasis was placed on essential sites of action and basic pharmacological principles. Details and individual drug properties were deliberately omitted in the interest of making drug action more transparent and affording an overview of the pharmacological basis of drug therapy.
The authors wish to reiterate that the Color Atlas of Pharmacology cannot replace a textbook of pharmacology, nor does it aim to do so. Rather, this little book is designed to arouse the curiosity of the pharmacological novice; to help students of medicine and pharmacy gain an overview of the discipline and to review certain bits of information in a concise format; and, finally, to enable the experienced therapist to recall certain factual data, with perhaps some occasional amusement.
Our cordial thanks go to the many readers of the multilingual editions of the Color Atlas for their suggestions. We are indebted to Prof. Ulrike Holzgrabe, Würzburg, Doc. Achim Meißner, Kiel, Prof. Gert-Hinrich Reil, Oldenburg, Prof. Reza Tabrizchi, St. John's, Mr Christian Klein, Bonn, and Mr Christian Riedel, Kiel, for providing stimulating and helpful discussions and technical support, as well as to Dr. Liane Platt-Rohloff, Stuttgart, and Dr. David Frost, New York, for their editorial and stylistic guidance.
Heinz Lüllmann Klaus Mohr Albrecht Ziegler Detlef Bieger Jürgen Wirth
General Pharmacology 1
History of Pharmacology 2
Drug and Active Principle 4
Drug Development 6
Dosage Forms for Oral, and Nasal Applications 8
Dosage Forms for Parenteral Pulmonary 12
Rectal or Vaginal, and Cutaneous Application 12
Drug Administration by Inhalation 14
Dermatalogic Agents 16
From Application to Distribution 18
Cellular Sites of Action
Potential Targets of Drug Action 20
Distribution in the Body
External Barriers of the Body 22
Blood-Tissue Barriers 24
Membrane Permeation 26
Possible Modes of Drug Distribution 28
Binding to Plasma Proteins 30
The Liver as an Excretory Organ 32
Biotransformation of Drugs 34
Enterohepatic Cycle 38
The Kidney as Excretory Organ 40
Elimination of Lipophilic and Hydrophilic Substances 42
Pharmacokinetics Drug Concentration in the Body as a Function of Time.
First-Order (Exponential) Rate Processes 44
Time Course of Drug Concentration in Plasma 46
Time Course of Drug Plasma Levels During Repeated
Dosing and During Irregular Intake 48
Accumulation: Dose, Dose Interval, and Plasma Level Fluctuation 50
Change in Elimination Characteristics During Drug Therapy 50
Quantification of Drug Action
Dose-Response Relationship 52
Concentration-Effect Relationship - Effect Curves 54
Concentration-Binding Curves 56
Types of Binding Forces 58
Enantioselectivity of Drug Action 62
Receptor Types 64
Mode of Operation of G-Protein-Coupled Receptors 66
Time Course of Plasma Concentration and Effect 68
Adverse Drug Effects 70
Drug Allergy 72
Drug Toxicity in Pregnancy and Lactation 74
Placebo - Homeopathy 76
Systems Pharmacology 79
Drug Acting on the Sympathetic Nervous System
Sympathetic Nervous System 80
Structure of the Sympathetic Nervous System 82
Adrenoceptor Subtypes and Catecholamine Actions 84
Structure - Activity Relationship of Sympathomimetics 86
Indirect Sympathomimetics 88
a-Sympathomimetics, a-Sympatholytics 90
P-Sympatholytics (P-Blockers) 92
Types of P-Blockers 94
Drugs Acting on the Parasympathetic Nervous System
Parasympathetic Nervous System 98
Cholinergic Synapse 100
Ganglionic Transmission 108
Effects of Nicotine on Body Functions 110
Consequences of Tobacco Smoking 112
Biogenic Amines Biogenic Amines - Actions and
Pharmacological Implications 114
Vasodilators - Overview 118
Organic Nitrates 120
Calcium Antagonists 122
Inhibitors of the RAA System 124
Drugs Acting on Smooth Muscle
Drugs Used to Influence Smooth Muscle Organs 126
Overview of Modes of Action 128
Cardiac Glycosides 130
Antiarrhythmic Drugs 134
Electrophysiological Actions of Antiarrhythmics of the Na+-Channel Blocking Type 136
Drugs for the Treatment of Anemias 138
Iron Compounds 140
Prophylaxis and Therapy of Thromboses 142
Coumarin Derivatives - Heparin 144
Fibrinolytic Therapy 146
Intra-arterial Thrombus Formation 148
Formation, Activation, and Aggregation of Platelets 148
Inhibitors of Platelet Aggregation 150
Presystemic Effect of Acetylsalicylic Acid 150
Adverse Effects of Antiplatelet Drugs 150
Plasma Volume Expanders 152
Drugs used in Hyperlipoproteinemias
Lipid-Lowering Agents 154
Diuretics - An Overview 158
NaCI Reabsorption in the Kidney 160
Osmotic Diuretics 160
Diuretics of the Sulfonamide Type 162
Potassium-Sparing Diuretics 164
Antidiuretic Hormone (/ADH) and Derivatives 164
Drugs for the Treatment of Peptic Ulcers
Drugs for Gastric and Duodenal Ulcers 166
Antidiarrheal Agents 178
Other Gastrointestinal Drugs 180
Drugs Acting on Motor Systems
Drugs Affecting Motor Function 182
Muscle Relaxants 184
Depolarizing Muscle Relaxants 186
Antiparkinsonian Drugs 188
Drugs for the Suppression of Pain, Analgesics,
Pain Mechanisms and Pathways 194
Antipyretic Analgesics and Antiinflammatory Drugs
Antipyretic Analgesics 198
Antipyretic Analgesics Nonsteroidal Antiinflammatory
(Antirheumatic) Agents 200
Thermoregulation and Antipyretics 202
Local Anesthetics 204
Opioid Analgesics - Morphine Type 210
General Anesthetic Drugs
General Anesthesia and General Anesthetic Drugs 216
Inhalational Anesthetics 218
Injectable Anesthetics 220
Soporifics, Hypnotics 222
Sleep-Wake Cycle and Hypnotics 224
Pharmacokinetics of Benzodiazepines 228
Therapy of Manic-Depressive Illnes 230
Therapy of Schizophrenia 236
Psychotomimetics (Psychedelics, Hallucinogens) 240
Hypothalamic and Hypophyseal Hormones 242
Thyroid Hormone Therapy 244
Hyperthyroidism and Antithyroid Drugs 246
Glucocorticoid Therapy 248
Androgens, Anabolic Steroids, Antiandrogens 252
Follicular Growth and Ovulation, Estrogen and
Progestin Production 254
Oral Contraceptives 256
Insulin Therapy 258
Treatment of Insulin-Dependent
Diabetes Mellitus 260
Treatment of Maturity-Onset (Type II)
Diabetes Mellitus 262
Drugs for Maintaining Calcium Homeostasis 264
Drugs for Treating Bacterial Infections 266
Inhibitors of Cell Wall Synthesis 268
Inhibitors of Tetrahydrofolate Synthesis 272
Inhibitors of DNA Function 274
Inhibitors of Protein Synthesis 276
Drugs for Treating Mycobacterial Infections 280
Drugs Used in the Treatment of Fungal Infection 282
Chemotherapy of Viral Infections 284
Drugs for Treatment of AIDS 288
Disinfectants and Antiseptics 290
Drugs for Treating Endo- and Ectoparasitic Infestations 292
Chemotherapy of Malignant Tumors 296
Inhibition of Immune Responses 300
Antidotes and treatment of poisonings 302
Therapy of Selected Diseases
Angina Pectoris 306
Antianginal Drugs 308
Acute Myocardial Infarction 310
Rheumatoid Arthritis 320
Common Cold 324
Allergic Disorders 326
Bronchial Asthma 328
Further Reading 332
Drug Index 334
Since time immemorial, medicaments have been used for treating disease in humans and animals. The herbals of antiquity describe the therapeutic powers of certain plants and minerals. Belief in the curative powers of plants and certain substances rested exclusively upon traditional knowledge, that is, empirical information not subjected to critical examination.
icine. He prescribed chemically defined substances with such success that professional enemies had him prosecuted as a poisoner. Against such accusations, he defended himself with the thesis that has become an axiom of pharmacology:
"If you want to explain any poison properly, what then isn't a poison? All things are poison, nothing is without poison; the dose alone causes a thing not to be poison."
Claudius Galen (129-200 A.D.) first attempted to consider the theoretical background of pharmacology. Both theory and practical experience were to contribute equally to the rational use of medicines through interpretation of observed and experienced results. "The empiricists say that all is found by experience. We, however, maintain that it is found in part by experience, in part by theory. Neither experience nor theory alone is apt to discover all."
Theophrastus von Hohenheim (14931541 A.D.), called Paracelsus, began to quesiton doctrines handed down from antiquity, demanding knowledge of the active ingredient(s) in prescribed remedies, while rejecting the irrational concoctions and mixtures of medieval med-Lullmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license
Johann Jakob Wepfer (1620-1695) was the first to verify by animal experimentation assertions about pharmacological or toxicological actions. "Ipondered at length. Finally I resolved to clarify the matter by experiments."
Rudolf Buchheim (1820-1879) founded the first institute of pharmacology at the University of Dorpat (Tartu, Estonia) in 1847, ushering in pharmacology as an independent scientific discipline. In addition to a description of effects, he strove to explain the chemical properties of drugs.
"The science of medicines is a theoretical, i.e., explanatory, one. ¡t is to provide us with knowledge by which our judgement about the utility of medicines can be validated at the bedside."
Consolidation - General Recognition
Consolidation - General Recognition
Oswald Schmiedeberg (1838-1921), together with his many disciples (12 of whom were appointed to chairs of pharmacology), helped to establish the high reputation of pharmacology. Fundamental concepts such as structure-activity relationship, drug receptor, and selective toxicity emerged from the work of, respectively, T. Frazer (18411921) in Scotland, J. Langley (18521925) in England, and P. Ehrlich (1854-1915) in Germany. Alexander J. Clark (1885-1941) in England first formalized receptor theory in the early 1920s by applying the Law of Mass Action to drug-receptor interactions. Together with the internist, Bernhard Naunyn (1839-1925), Schmiedeberg founded the first journal of pharmacology, which has since been published without interruption. The "Father of American Pharmacology", John J. Abel (1857-1938) was among the first Americans to train in Schmiedeberg's laboratory and was founder of the Journal of Pharmacology and Experimental Therapeutics (published from 1909 until the present).
After 1920, pharmacological laboratories sprang up in the pharmaceutical industry, outside established university institutes. After 1960, departments of clinical pharmacology were set up at many universities and in industry.
Until the end of the 19th century, medicines were natural organic or inorganic products, mostly dried, but also fresh, plants or plant parts. These might contain substances possessing healing (therapeutic) properties or substances exerting a toxic effect.
In order to secure a supply of medically useful products not merely at the time of harvest but year-round, plants were preserved by drying or soaking them in vegetable oils or alcohol. Drying the plant or a vegetable or animal product yielded a drug (from French "drogue" - dried herb). Colloquially, this term nowadays often refers to chemical substances with high potential for physical dependence and abuse. Used scientifically, this term implies nothing about the quality of action, if any. In its original, wider sense, drug could refer equally well to the dried leaves of peppermint, dried lime blossoms, dried flowers and leaves of the female cannabis plant (hashish, marijuana), or the dried milky exudate obtained by slashing the unripe seed capsules of Papaver somniferum (raw opium). Nowadays, the term is applied quite generally to a chemical substance that is used for pharmacothera-py.
Soaking plants parts in alcohol (ethanol) creates a tincture. In this process, pharmacologically active constituents of the plant are extracted by the alcohol. Tinctures do not contain the complete spectrum of substances that exist in the plant or crude drug, only those that are soluble in alcohol. In the case of opium tincture, these ingredients are alkaloids (i.e., basic substances of plant origin) including: morphine, codeine, narcotine = noscapine, papaverine, nar-ceine, and others.
Using a natural product or extract to treat a disease thus usually entails the administration of a number of substances possibly possessing very different activities. Moreover, the dose of an individual constituent contained within a given amount of the natural product is subject to large variations, depending upon the product's geographical origin (biotope), time of harvesting, or conditions and length of storage. For the same reasons, the relative proportion of individual constituents may vary considerably. Starting with the extraction of morphine from opium in 1804 by F. W. Sertürner (1783-1841), the active principles of many other natural products were subsequently isolated in chemically pure form by pharmaceutical laboratories.
The aims of isolating active principles are:
1. Identification of the active ingredi-ent(s).
2. Analysis of the biological effects (pharmacodynamics) of individual ingredients and of their fate in the body (pharmacokinetics).
3. Ensuring a precise and constant dosage in the therapeutic use of chemically pure constituents.
4. The possibility of chemical synthesis, which would afford independence from limited natural supplies and create conditions for the analysis of structure-activity relationships.
Finally, derivatives of the original constituent may be synthesized in an effort to optimize pharmacological properties. Thus, derivatives of the original constituent with improved therapeutic usefulness may be developed.
This process starts with the synthesis of novel chemical compounds. Substances with complex structures may be obtained from various sources, e.g., plants (cardiac glycosides), animal tissues (heparin), microbial cultures (penicillin G), or human cells (urokinase), or by means of gene technology (human insulin). As more insight is gained into structure-activity relationships, the search for new agents becomes more clearly focused.
Preclinical testing yields information on the biological effects of new substances. Initial screening may employ biochemical-pharmacological investigations (e.g., receptor-binding assays p. 56) or experiments on cell cultures, isolated cells, and isolated organs. Since these models invariably fall short of replicating complex biological processes in the intact organism, any potential drug must be tested in the whole animal. Only animal experiments can reveal whether the desired effects will actually occur at dosages that produce little or no toxicity. Toxicological investigations serve to evaluate the potential for: (1) toxicity associated with acute or chronic administration; (2) genetic damage (genotoxicity, mutagenicity); (3) production of tumors (onco- or carcinogenicity); and (4) causation of birth defects (teratogenicity). In animals, compounds under investigation also have to be studied with respect to their absorption, distribution, metabolism, and elimination (pharmacokinetics). Even at the level of preclinical testing, only a very small fraction of new compounds will prove potentially fit for use in humans.
Pharmaceutical technology provides the methods for drug formulation.
Clinical testing starts with Phase I studies on healthy subjects and seeks to determine whether effects observed in animal experiments also occur in humans. Dose-response relationships are determined. In Phase II, potential drugs are first tested on selected patients for therapeutic efficacy in those disease states for which they are intended. Should a beneficial action be evident and the incidence of adverse effects be acceptably small, Phase III is entered, involving a larger group of patients in whom the new drug will be compared with standard treatments in terms of therapeutic outcome. As a form of human experimentation, these clinical trials are subject to review and approval by institutional ethics committees according to international codes of conduct (Declarations of Helsinki, Tokyo, and Venice). During clinical testing, many drugs are revealed to be unusable. Ultimately, only one new drug remains from approximately 10,000 newly synthesized substances.
The decision to approve a new drug is made by a national regulatory body (Food & Drug Administration in the U.S.A., the Health Protection Branch Drugs Directorate in Canada, UK, Europe, Australia) to which manufacturers are required to submit their applications. Applicants must document by means of appropriate test data (from preclinical and clinical trials) that the criteria of efficacy and safety have been met and that product forms (tablet, capsule, etc.) satisfy general standards of quality control.
Following approval, the new drug may be marketed under a trade name (p. 333) and thus become available for prescription by physicians and dispensing by pharmacists. As the drug gains more widespread use, regulatory surveillance continues in the form of post-licensing studies (Phase IV of clinical trials). Only on the basis of long-term experience will the risk: benefit ratio be properly assessed and, thus, the therapeutic value of the new drug be determined.
Dosage Forms for Oral, Ocular, and Nasal Applications
A medicinal agent becomes a medication only after formulation suitable for therapeutic use (i.e., in an appropriate dosage form). The dosage form takes into account the intended mode of use and also ensures ease of handling (e.g., stability, precision of dosing) by patients and physicians. Pharmaceutical technology is concerned with the design of suitable product formulations and quality control.
Liquid preparations (A) may take the form of solutions, suspensions (a sol or mixture consisting of small water-insoluble solid drug particles dispersed in water), or emulsions (dispersion of minute droplets of a liquid agent or a drug solution in another fluid, e.g., oil in water). Since storage will cause sedimentation of suspensions and separation of emulsions, solutions are generally preferred. In the case of poorly watersoluble substances, solution is often accomplished by adding ethanol (or other solvents); thus, there are both aqueous and alcoholic solutions. These solutions are made available to patients in specially designed drop bottles, enabling single doses to be measured exactly in terms of a defined number of drops, the size of which depends on the area of the drip opening at the bottle mouth and on the viscosity and surface tension of the solution. The advantage of a drop solution is that the dose, that is, the number of drops, can be precisely adjusted to the patient's need. Its disadvantage lies in the difficulty that some patients, disabled by disease or age, will experience in measuring a prescribed number of drops.
When the drugs are dissolved in a larger volume — as in the case of syrups or mixtures — the single dose is measured with a measuring spoon. Dosing may also be done with the aid of a tablespoon or teaspoon (approx. 15 and 5 ml, respectively). However, due to the wide variation in the size of commer-daily available spoons, dosing will not Lullmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
be very precise. (Standardized medicinal teaspoons and tablespoons are available.)
Eye drops and nose drops (A) are designed for application to the mucosal surfaces of the eye (conjunctival sac) and nasal cavity, respectively. In order to prolong contact time, nasal drops are formulated as solutions of increased viscosity.
Solid dosage forms include tablets, coated tablets, and capsules (B). Tablets have a disk-like shape, produced by mechanical compression of active substance, filler (e.g., lactose, calcium sulfate), binder, and auxiliary material (excipients). The filler provides bulk enough to make the tablet easy to handle and swallow. It is important to consider that the individual dose of many drugs lies in the range of a few milligrams or less. In order to convey the idea of a 10-mg weight, two squares are marked below, the paper mass of each weighing 10 mg. Disintegration of the tablet can be hastened by the use of dried starch, which swells on contact with water, or of NaHCO3, which releases CO2 gas on contact with gastric acid. Auxiliary materials are important with regard to tablet production, shelf life, palatability, and identifiability (color).
Effervescent tablets (compressed effervescent powders) do not represent a solid dosage form, because they are dissolved in water immediately prior to ingestion and are, thus, actually, liquid preparations.
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