Color Atlas of Pharmacology, 2Nd Edition, Revised and Expanded

re K III Color Atlas of Pharmacology

2nd edition, revised and expanded

Heinz Lüllmann, M. D. Albrecht Ziegler, Ph. D. Professor Emeritus Professor Department of Pharmacology Department of Pharmacology University of Kiel University of Kiel Germany Germany

Klaus Mohr, M. D. Detlef Bieger, M. D. Professor Professor Department of Pharmacology Division of Basic Medical Sciences and Toxicology Faculty of Medicine Institute of Pharmacy Memorial University of University of Bonn Newfoundland Germany St. John’s, Newfoundland Canada

164 color plates by Jürgen Wirth

Thieme Stuttgart · New York · 2000

Library of Congress Cataloging-in-Publication Data

Taschenatlas der Pharmakologie. English. Color atlas of pharmacology / Heinz Lullmann … [et al.] ; color plates by Jurgen Wirth. — 2nd ed., rev. and expanded. p. cm. Rev. and expanded translation of: Taschenatlas der Pharmakologie. 3rd ed. 1996. Includes bibliographical references and indexes. ISBN 3-13-781702-1 (GTV). — ISBN 0-86577-843-4 (TNY) 1. Pharmacology Atlases. 2. Pharmacology Handbooks, manuals, etc. I. Lullmann, Heinz. II. Title. [DNLM: 1. Pharmacology Atlases. 2. Pharmacology Handbooks. QV 17 T197c 1999a] RM301.12.T3813 1999 615’.1—dc21 DNLM/DLC for Library of Congress 99-33662 CIP

Illustrated by Jürgen Wirth, Darmstadt, Ger- Important Note: Medicine is an ever-chang- many ing science undergoing continual development. Research and clinical experience are This book is an authorized revised and ex- continually expanding our knowledge, in par- panded translation of the 3rd German edition ticular our knowledge of proper treatment and published and copyrighted 1996 by Georg drug therapy. Insofar as this book mentions Thieme Verlag, Stuttgart, Germany. Title of the any dosage or application, readers may rest as- German edition: sured that the authors, editors and publishers Taschenatlas der Pharmakologie have made every effort to ensure that such references are in accordance with the state of Some of the product names, patents and regis- knowledge at the time of production of the tered designs referred to in this book are in book. fact registered trademarks or proprietary names even though specific reference to this Nevertheless this does not involve, imply, or fact is not always made in the text. Therefore, express any guarantee or responsibility on the the appearance of a name without designation part of the publishers in respect of any dosage as proprietary is not to be construed as a instructions and forms of application stated in representation by the publisher that it is in the the book. Every user is requested to examine public domain. carefully the manufacturers’ leaflets accompanying each drug and to check, if necessary in This book, including all parts thereof, is legally consultation with a physician or specialist, protected by copyright. Any use, exploitation whether the dosage schedules mentioned or commercialization outside the narrow lim- therein or the contraindications stated by the its set by copyright legislation, without the manufacturers differ from the statements publisher’s consent, is illegal and liable to made in the present book. Such examination is prosecution. This applies in particular to pho- particularly important with drugs that are tostat reproduction, copying, mimeographing either rarely used or have been newly released or duplication of any kind, translating, prepa- on the market. Every dosage schedule or ev- ration of microfilms, and electronic data pro- ery form of application used is entirely at the cessing and storage. user’s own risk and responsibility. The au- ©2000 Georg Thieme Verlag, Rüdigerstrasse14, thors and publishers request every user to re- D-70469 Stuttgart, Germany port to the publishers any discrepancies or in- Thieme New York, 333 Seventh Avenue, New accuracies noticed. York, NY 10001, USA

Typesetting by Gulde Druck, Tübingen Printed in Germany by Staudigl, Donauwörth

ISBN 3-13-781702-1 (GTV) ISBN 0-86577-843-4 (TNY) 123456

Preface

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 gui- dance.

Heinz Lüllmann Klaus Mohr Albrecht Ziegler Detlef Bieger Jürgen Wirth

Fall 1999

Contents

General Pharmacology ...... 1

History of Pharmacology ...... 2 Drug Sources Drug and Active Principle ...... 4 Drug Development ...... 6 Drug Administration 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 Drug Elimination 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 Drug-Receptor Interaction Types of Binding Forces ...... 58 Agonists-Antagonists ...... 60 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

Contents VII

Drug Allergy ...... 72 Drug Toxicity in Pregnancy and Lactation ...... 74 Drug-independent Effects 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 α-Sympathomimetics, α-Sympatholytics ...... 90 β-Sympatholytics (β-Blockers) ...... 92 Types of β-Blockers ...... 94 Antiadrenergics ...... 96 Drugs Acting on the Parasympathetic Nervous System Parasympathetic Nervous System ...... 98 Cholinergic Synapse ...... 100 Parasympathomimetics ...... 102 Parasympatholytics ...... 104 Nicotine Ganglionic Transmission ...... 108 Effects of Nicotine on Body Functions ...... 110 Consequences of Tobacco Smoking ...... 112 Biogenic Amines Biogenic Amines – Actions and Pharmacological Implications ...... 114 Serotonin ...... 116 Vasodilators 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 Cardiac Drugs Overview of Modes of Action ...... 128 Cardiac Glycosides ...... 130 Antiarrhythmic Drugs ...... 134 Electrophysiological Actions of Antiarrhythmics of the Na+-Channel Blocking Type ...... 136 Antianemics Drugs for the Treatment of Anemias ...... 138 Iron Compounds ...... 140 Antithrombotics 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

VIII Contents

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 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 Laxatives ...... 170 Antidiarrheals 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 Antiepileptics ...... 190 Drugs for the Suppression of Pain, Analgesics, Pain Mechanisms and Pathways ...... 194 Antipyretic Analgesics Eicosanoids ...... 196 Antipyretic Analgesics and Antiinflammatory Drugs Antipyretic Analgesics ...... 198 Antipyretic Analgesics Nonsteroidal Antiinflammatory (Antirheumatic) Agents ...... 200 Thermoregulation and Antipyretics ...... 202 Local Anesthetics ...... 204 Opioids Opioid Analgesics – Morphine Type ...... 210 General Anesthetic Drugs General Anesthesia and General Anesthetic Drugs ...... 216 Inhalational Anesthetics ...... 218 Injectable Anesthetics ...... 220 Hypnotics Soporifics, Hypnotics ...... 222 Sleep-Wake Cycle and Hypnotics ...... 224 Psychopharmacologicals Benzodiazepines ...... 226 Pharmacokinetics of Benzodiazepines ...... 228 Therapy of Manic-Depressive Illnes ...... 230 Therapy of Schizophrenia ...... 236 Psychotomimetics (Psychedelics, Hallucinogens) ...... 240

Contents IX

Hormones 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 Antibacterial Drugs 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 Antifungal Drugs Drugs Used in the Treatment of Fungal Infection ...... 282 Antiviral Drugs Chemotherapy of Viral Infections ...... 284 Drugs for Treatment of AIDS ...... 288 Disinfectants Disinfectants and Antiseptics ...... 290 Antiparasitic Agents Drugs for Treating Endo- and Ectoparasitic Infestations ...... 292 Antimalarials ...... 294 Anticancer Drugs Chemotherapy of Malignant Tumors ...... 296 Immune Modulators Inhibition of Immune Responses ...... 300 Antidotes Antidotes and treatment of poisonings ...... 302 Therapy of Selected Diseases Angina Pectoris ...... 306 Antianginal Drugs ...... 308 Acute Myocardial Infarction ...... 310 Hypertension ...... 312 Hypotension ...... 314 Gout ...... 316 Osteoporosis ...... 318 Rheumatoid Arthritis ...... 320 Migraine ...... 322 Common Cold ...... 324 Allergic Disorders ...... 326 Bronchial Asthma ...... 328 Emesis ...... 330

X Contents

Further Reading ...... 332 Drug Index ...... 334 Index ...... 368

General Pharmacology

2 History of Pharmacology

History of Pharmacology

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.

The Idea

icine. He prescribed chemically defined substances with such success that pro- fessional 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.”

Early Beginnings

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.”

The Impetus Theophrastus von Hohenheim (1493– Johann Jakob Wepfer (1620–1695) 1541 A.D.), called Paracelsus, began to was the first to verify by animal experi- quesiton doctrines handed down from mentation assertions about pharmaco- antiquity, demanding knowledge of the logical or toxicological actions. active ingredient(s) in prescribed reme- “I pondered at length. Finally I resolved to dies, while rejecting the irrational con- clarify the matter by experiments.” coctions and mixtures of medieval med-

History of Pharmacology 3

Foundation reputation of pharmacology. Funda- mental concepts such as structure-activity relationship, drug receptor, and selective toxicity emerged from the work of, respectively, T. Frazer (1841– 1921) in Scotland, J. Langley (1852– 1925) in England, and P. Ehrlich (1854–1915) in Germany. Alexander J. Clark (1885–1941) in England first for- malized receptor theory in the early 1920s by applying the Law of Mass Ac- tion to drug-receptor interactions. To- gether 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 Rudolf Buchheim (1820–1879) found- (1857–1938) was among the first ed the first institute of pharmacology at Americans to train in Schmiedeberg‘s the University of Dorpat (Tartu, Estonia) laboratory and was founder of the Jour- in 1847, ushering in pharmacology as an nal of Pharmacology and Experimental independent scientific discipline. In ad- Therapeutics (published from 1909 until dition to a description of effects, he the present). strove to explain the chemical properties of drugs. “The science of medicines is a theoretical, Status Quo i.e., explanatory, one. It is to provide us with knowledge by which our judgement After 1920, pharmacological laborato- about the utility of medicines can be vali- ries sprang up in the pharmaceutical in- dated at the bedside.” dustry, outside established university institutes. After 1960, departments of Consolidation – General Recognition clinical pharmacology were set up at many universities and in industry.

Oswald Schmiedeberg (1838–1921), together with his many disciples (12 of whom were appointed to chairs of pharmacology), helped to establish the high

4 Drug Sources

Drug and Active Principle upon the product‘s geographical origin Until the end of the 19th century, medi- (biotope), time of harvesting, or condi- cines were natural organic or inorganic tions and length of storage. For the same products, mostly dried, but also fresh, reasons, the relative proportion of indi- plants or plant parts. These might con- vidual constituents may vary consider- tain substances possessing healing ably. Starting with the extraction of (therapeutic) properties or substances morphine from opium in 1804 by F. W. exerting a toxic effect. Sertürner (1783–1841), the active prin- In order to secure a supply of medi- ciples of many other natural products cally useful products not merely at the were subsequently isolated in chemi- time of harvest but year-round, plants cally pure form by pharmaceutical la- were preserved by drying or soaking boratories. them in vegetable oils or alcohol. Drying the plant or a vegetable or animal prod- The aims of isolating active principles uct yielded a drug (from French are: “drogue” – dried herb). Colloquially, this 1. Identification of the active ingredi- term nowadays often refers to chemical ent(s). substances with high potential for phys- 2. Analysis of the biological effects ical dependence and abuse. Used scien- (pharmacodynamics) of individual in- tifically, this term implies nothing about gredients and of their fate in the body the quality of action, if any. In its origi- (pharmacokinetics). nal, wider sense, drug could refer equal- 3. Ensuring a precise and constant dos- ly well to the dried leaves of pepper- age in the therapeutic use of chemically mint, dried lime blossoms, dried flowers pure constituents. and leaves of the female cannabis plant 4. The possibility of chemical synthesis, (hashish, marijuana), or the dried milky which would afford independence from exudate obtained by slashing the unripe limited natural supplies and create con- seed capsules of Papaver somniferum ditions for the analysis of structure-ac- (raw opium). Nowadays, the term is ap- tivity relationships. plied quite generally to a chemical sub- Finally, derivatives of the original con- stance that is used for pharmacothera- stituent may be synthesized in an effort py. to optimize pharmacological properties. Soaking plants parts in alcohol Thus, derivatives of the original constit- (ethanol) creates a tincture. In this pro- uent with improved therapeutic useful- cess, pharmacologically active constitu- ness may be developed. ents 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

Drug Sources 5

Raw opium

Preparation of opium tincture

Morphine Codeine Narcotine Papaverine etc.

Opium tincture (laudanum)

A. From poppy to morphine

6 Drug Development

Drug Development therapeutic efficacy in those disease states for which they are intended. This process starts with the synthesis of Should a beneficial action be evident novel chemical compounds. Substances and the incidence of adverse effects be with complex structures may be ob- acceptably small, Phase III is entered, tained from various sources, e.g., plants involving a larger group of patients in (cardiac glycosides), animal tissues whom the new drug will be compared (heparin), microbial cultures (penicillin with standard treatments in terms of G), or human cells (urokinase), or by therapeutic outcome. As a form of hu- means of gene technology (human insu- man experimentation, these clinical lin). As more insight is gained into struc- trials are subject to review and approval ture-activity relationships, the search by institutional ethics committees ac- for new agents becomes more clearly cording to international codes of con- focused. duct (Declarations of Helsinki, Tokyo, Preclinical testing yields informa- and Venice). During clinical testing, tion on the biological effects of new sub- many drugs are revealed to be unusable. stances. Initial screening may employ Ultimately, only one new drug remains biochemical-pharmacological investiga- from approximately 10,000 newly syn- tions (e.g., receptor-binding assays thesized substances. p. 56) or experiments on cell cultures, The decision to approve a new isolated cells, and isolated organs. Since drug is made by a national regulatory these models invariably fall short of body (Food & Drug Administration in replicating complex biological process- the U.S.A., the Health Protection Branch es in the intact organism, any potential Drugs Directorate in Canada, UK, Euro- drug must be tested in the whole ani- pe, Australia) to which manufacturers mal. Only animal experiments can re- are required to submit their applica- veal whether the desired effects will actions. Applicants must document by tually occur at dosages that produce lit- means of appropriate test data (from tle or no toxicity. Toxicological investiga- preclinical and clinical trials) that the tions serve to evaluate the potential for: criteria of efficacy and safety have been (1) toxicity associated with acute or met and that product forms (tablet, cap- chronic administration; (2) genetic sule, etc.) satisfy general standards of damage (genotoxicity, mutagenicity); quality control. (3) production of tumors (onco- or car- Following approval, the new drug cinogenicity); and (4) causation of birth may be marketed under a trade name defects (teratogenicity). In animals, (p. 333) and thus become available for compounds under investigation also prescription by physicians and dispens- have to be studied with respect to their ing by pharmacists. As the drug gains absorption, distribution, metabolism, more widespread use, regulatory sur- and elimination (pharmacokinetics). veillance continues in the form of post- Even at the level of preclinical testing, licensing studies (Phase IV of clinical only a very small fraction of new com- trials). Only on the basis of long-term pounds will prove potentially fit for use experience will the risk: benefit ratio be in humans. properly assessed and, thus, the thera- Pharmaceutical technology pro- peutic value of the new drug be deter- vides the methods for drug formulation. mined. 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

Drug Development 7

Clinical Approval trial Phase 4 § § §

§ § General use 1 Long-term benefit-risk evaluation Substance

Clinical trial Phase 1 Phase 2 Phase 3 Healthy subjects: Selected patients: Patient groups: effects on body functions, effects on disease; Comparison with dose definition, pharmacokinetics safety, efficacy, dose, standard therapy pharmacokinetics EEG Blood pressure

ECG Blood sample

10 Substances

Cells

Animals Isolated organs Preclinical testing: (bio)chemical Effects on body synthesis functions, mechanism of action, toxicity

10,000 Substances

Tissue homogenate

A. From drug synthesis to approval

8 Drug Administration

Dosage Forms for Oral, Ocular, and be very precise. (Standardized medici- Nasal Applications nal teaspoons and tablespoons are available.) A medicinal agent becomes a medica- Eye drops and nose drops (A) are tion only after formulation suitable for designed for application to the mucosal therapeutic use (i.e., in an appropriate surfaces of the eye (conjunctival sac) dosage form). The dosage form takes and nasal cavity, respectively. In order into account the intended mode of use to prolong contact time, nasal drops are and also ensures ease of handling (e.g., formulated as solutions of increased stability, precision of dosing) by pa- viscosity. tients and physicians. Pharmaceutical Solid dosage forms include tab- technology is concerned with the design lets, coated tablets, and capsules (B). of suitable product formulations and Tablets have a disk-like shape, pro- quality control. duced by mechanical compression of Liquid preparations (A) may take active substance, filler (e.g., lactose, cal- the form of solutions, suspensions (a cium sulfate), binder, and auxiliary ma- sol or mixture consisting of small wa- terial (excipients). The filler provides ter-insoluble solid drug particles dis- bulk enough to make the tablet easy to persed in water), or emulsions (disper- handle and swallow. It is important to sion of minute droplets of a liquid agent consider that the individual dose of or a drug solution in another fluid, e.g., many drugs lies in the range of a few oil in water). Since storage will cause milligrams or less. In order to convey sedimentation of suspensions and sep- the idea of a 10-mg weight, two squares aration of emulsions, solutions are gen- are marked below, the paper mass of erally preferred. In the case of poorly each weighing 10 mg. Disintegration of watersoluble substances, solution is of- the tablet can be hastened by the use of ten accomplished by adding ethanol (or dried starch, which swells on contact other solvents); thus, there are both with water, or of NaHCO3, which releas- aqueous and alcoholic solutions. These es CO2 gas on contact with gastric acid. solutions are made available to patients Auxiliary materials are important with in specially designed drop bottles, ena- regard to tablet production, shelf life, bling single doses to be measured ex- palatability, and identifiability (color). actly in terms of a defined number of Effervescent tablets (compressed drops, the size of which depends on the effervescent powders) do not represent area of the drip opening at the bottle a solid dosage form, because they are mouth and on the viscosity and surface dissolved in water immediately prior to tension of the solution. The advantage ingestion and are, thus, actually, liquid of a drop solution is that the dose, that preparations. 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 commercially available spoons, dosing will not

Drug Administration 9

5 - 50 ml Aqueous Eye solution drops 20 drops = 1g Sterile isotonic Dosage: pH-neutral in drops

5 - 50 ml Alcoholic solution 40 drops = 1g Viscous solution

1 Nose 00 - 5 0 drops 0 m l

Dosage: Solution in spoon Mixture

A. Liquid preparations

Mixing and forming by compression Drug ~0.5 – 500 mg Effervescent tablet

Filler 30 – 250 mg

Disintegrating 20 – 200 mg agent Tablet Capsule Other 30 – 15 mg excipients min 100 – 1000 mg max possible tablet size Coated tablet

B. Solid preparations for oral application

Capsule

Time

Coated tablet

Capsule

with coated Drug release drug pellets

Matrix tablet

C. Dosage forms controlling rate of drug dissolution

10 Drug Administration

The coated tablet contains a drug with- sit time, drug release can be timed to oc- in a core that is covered by a shell, e.g., a cur in the colon. wax coating, that serves to: (1) protect Drug liberation and, hence, absorp- perishable drugs from decomposing; (2) tion can also be spread out when the mask a disagreeable taste or odor; (3) drug is presented in the form of a granu- facilitate passage on swallowing; or (4) late consisting of pellets coated with a permit color coding. waxy film of graded thickness. Depend- Capsules usually consist of an ob- ing on film thickness, gradual dissolu- long casing — generally made of gelatin tion occurs during enteral transit, re- — that contains the drug in powder or leasing drug at variable rates for absorp- granulated form (See. p. 9, C). tion. The principle illustrated for a cap- In the case of the matrix-type tab- sule can also be applied to tablets. In this let, the drug is embedded in an inert case, either drug pellets coated with meshwork from which it is released by films of various thicknesses are com- diffusion upon being moistened. In con- pressed into a tablet or the drug is incor- trast to solutions, which permit direct porated into a matrix-type tablet. Con- absorption of drug (A, track 3), the use trary to timed-release capsules (Span- of solid dosage forms initially requires sules®), slow-release tablets have the ad- tablets to break up and capsules to open vantage of being dividable ad libitum; (disintegration) before the drug can be thus, fractions of the dose contained dissolved (dissolution) and pass within the entire tablet may be admin- through the gastrointestinal mucosal istered. lining (absorption). Because disintegra- This kind of retarded drug release tion of the tablet and dissolution of the is employed when a rapid rise in blood drug take time, absorption will occur level of drug is undesirable, or when ab- mainly in the intestine (A, track 2). In sorption is being slowed in order to pro- the case of a solution, absorption starts long the action of drugs that have a in the stomach (A, track 3). short sojourn in the body. For acid-labile drugs, a coating of wax or of a cellulose acetate polymer is used to prevent disintegration of solid dosage forms in the stomach. Accord- ingly, disintegration and dissolution will take place in the duodenum at normal speed (A, track 1) and drug liberation per se is not retarded. The liberation of drug, hence the site and time-course of absorption, are subject to modification by appropriate production methods for matrix-type tablets, coated tablets, and capsules. In the case of the matrix tablet, the drug is incorporated into a lattice from which it can be slowly leached out by gastrointestinal fluids. As the matrix tablet undergoes enteral transit, drug liberation and absorption proceed en route (A, track 4). In the case of coated tablets, coat thickness can be designed such that release and absorption of drug occur either in the proximal (A, track 1) or distal (A, track 5) bowel. Thus, by matching dissolution time with small-bowel tran-

Drug Administration 11

Administration in form of

Enteric- Tablet, Drops, Matrix Coated coated capsule mixture, tablet tablet with tablet effervescent delayed solution release

12345

A. Oral administration: drug release and absorption

12 Drug Administration

Dosage Forms for Parenteral (1), the rectum or vagina. The resulting oily Pulmonary (2), Rectal or Vaginal (3), film spreads over the mucosa and en- and Cutaneous Application ables the drug to pass into the mucosa. Powders, ointments, and pastes Drugs need not always be administered (p. 16) are applied to the skin surface. In orally (i.e., by swallowing), but may also many cases, these do not contain drugs be given parenterally. This route usual- but are used for skin protection or care. ly refers to an injection, although enter- However, drugs may be added if a topi- al absorption is also bypassed when cal action on the outer skin or, more drugs are inhaled or applied to the skin. rarely, a systemic effect is intended. For intravenous, intramuscular, or Transdermal drug delivery subcutaneous injections, drugs are of- systems are pasted to the epidermis. ten given as solutions and, less fre- They contain a reservoir from which quently, in crystalline suspension for drugs may diffuse and be absorbed intramuscular, subcutaneous, or intra- through the skin. They offer the advan- articular injection. An injectable solu- tage that a drug depot is attached non- tion must be free of infectious agents, invasively to the body, enabling the pyrogens, or suspended matter. It drug to be administered in a manner should have the same osmotic pressure similar to an infusion. Drugs amenable and pH as body fluids in order to avoid to this type of delivery must: (1) be ca- tissue damage at the site of injection. pable of penetrating the cutaneous bar- Solutions for injection are preserved in rier; (2) be effective in very small doses airtight glass or plastic sealed contain- (restricted capacity of reservoir); and ers. From ampules for multiple or sin- (3) possess a wide therapeutic margin gle use, the solution is aspirated via a (dosage not adjustable). needle into a syringe. The cartridge ampule is fitted into a special injector that enables its contents to be emptied via a needle. An infusion refers to a solution being administered over an extended period of time. Solutions for infusion must meet the same standards as solutions for injection. Drugs can be sprayed in aerosol form onto mucosal surfaces of body cav- ities accessible from the outside (e.g., the respiratory tract [p. 14]). An aerosol is a dispersion of liquid or solid particles in a gas, such as air. An aerosol results when a drug solution or micronized powder is reduced to a spray on being driven through the nozzle of a pressurized container. Mucosal application of drug via the rectal or vaginal route is achieved by means of suppositories and vaginal tablets, respectively. On rectal application, absorption into the systemic circulation may be intended. With vaginal tablets, the effect is generally confined to the site of application. Usually the drug is incorporated into a fat that solid- ifies at room temperature, but melts in

Drug Administration 13

Sterile, iso-osmolar Ampule Cartridge Propellant gas 1 – 20 ml ampule 2 ml Drug solution

With and without Often with fracture ring preservative Jet nebulizer 2

35 ºC

Vaginal tablet Suppository

Multiple-dose Infusion vial 50 – 100 ml, solution always with 500 – 1000 ml preservative 1335 ºC Melting point

Backing layer Drug reservoir Adhesive coat

Paste

Ointment

Transdermal delivery system (TDS)

Drug release Powder Ointment TDS

Time 12 24 h 4 A. Preparations for parenteral (1), inhalational (2), rectal or vaginal (3), and percutaneous (4) application

14 Drug Administration

Drug Administration by Inhalation mucociliary transport functions to remove inspired dust particles. Thus, only Inhalation in the form of an aerosol a portion of the drug aerosol (~ 10 %) (p. 12), a gas, or a mist permits drugs to gains access to the respiratory tract and be applied to the bronchial mucosa and, just a fraction of this amount penetrates to a lesser extent, to the alveolar mem- the mucosa, whereas the remainder of branes. This route is chosen for drugs in- the aerosol undergoes mucociliary tended to affect bronchial smooth mus- transport to the laryngopharynx and is cle or the consistency of bronchial mu- swallowed. The advantage of inhalation cus. Furthermore, gaseous or volatile (i.e., localized application) is fully ex- agents can be administered by inhala- ploited by using drugs that are poorly tion with the goal of alveolar absorption absorbed from the intestine (isoprotere- and systemic effects (e.g., inhalational nol, ipratropium, cromolyn) or are sub- anesthetics, p. 218). Aerosols are ject to first-pass elimination (p. 42; bec- formed when a drug solution or micron- lomethasone dipropionate, budesonide, ized powder is converted into a mist or flunisolide, fluticasone dipropionate). dust, respectively. Even when the swallowed portion In conventional sprays (e.g., nebu- of an inhaled drug is absorbed in un- lizer), the air blast required for aerosol changed form, administration by this formation is generated by the stroke of a route has the advantage that drug con- pump. Alternatively, the drug is deliv- centrations at the bronchi will be higher ered from a solution or powder pack- than in other organs. aged in a pressurized canister equipped The efficiency of mucociliary trans- with a valve through which a metered port depends on the force of kinociliary dose is discharged. During use, the in- motion and the viscosity of bronchial haler (spray dispenser) is held directly mucus. Both factors can be altered in front of the mouth and actuated at pathologically (e.g., in smoker’s cough, the start of inspiration. The effective- bronchitis) or can be adversely affected ness of delivery depends on the position by drugs (atropine, antihistamines). of the device in front of the mouth, the size of aerosol particles, and the coordination between opening of the spray valve and inspiration. The size of aerosol particles determines the speed at which they are swept along by inhaled air, hence the depth of penetration into the respiratory tract. Particles > 100 µm in diameter are trapped in the oropharyngeal cavity; those having dia- meters between 10 and 60µm will be deposited on the epithelium of the bronchial tract. Particles < 2 µm in diameter can reach the alveoli, but they will be largely exhaled because of their low tendency to impact on the alveolar epithelium. Drug deposited on the mucous lining of the bronchial epithelium is partly absorbed and partly transported with bronchial mucus towards the larynx. Bronchial mucus travels upwards due to the orally directed undulatory beat of the epithelial cilia. Physiologically, this

Drug Administration 15

Depth of penetration of inhaled aerosolized drug solution 10% 90%

Drug swept up 100 µm is swallowed Nasopharynx Larynx

10 µm Trachea-bronchi

1 µm 1 cm/min Bronchioli, alveoli

Mucociliary transport

As complete As little presystemic enteral elimination absorption as possible as possible

Low systemic burden Ciliated epithelium

A. Application by inhalation

16 Drug Administration

Dermatologic Agents Hydrophilic (aqueous) cream is an emulsion of an oil in water formed with Pharmaceutical preparations applied to the aid of an emulsifier; it may also be the outer skin are intended either to considered an oil-in-water emulsion of provide skin care and protection from an emulsifying ointment. noxious influences (A), or to serve as a All dermatologic agents having a vehicle for drugs that are to be absorbed lipophilic base adhere to the skin as a into the skin or, if appropriate, into the water-repellent coating. They do not general circulation (B). wash off and they also prevent (oc- clude) outward passage of water from Skin Protection (A) the skin. The skin is protected from dry- Protective agents are of several kinds to ing, and its hydration and elasticity in- meet different requirements according crease. to skin condition (dry, low in oil, Diminished evaporation of water chapped vs moist, oily, elastic), and the results in warming of the occluded skin type of noxious stimuli (prolonged ex- area. Hydrophilic agents wash off easily posure to water, regular use of alcohol- and do not impede transcutaneous out- containing disinfectants [p. 290], input of water. Evaporation of water is felt tense solar irradiation). as a cooling effect. Distinctions among protective agents are based upon consistency, phy- Dermatologic Agents as Vehicles (B) sicochemical properties (lipophilic, hy- In order to reach its site of action, a drug drophilic), and the presence of addi- (D) must leave its pharmaceutical pre- tives. paration and enter the skin, if a local ef- Dusting Powders are sprinkled on- fect is desired (e.g., glucocorticoid oint- to the intact skin and consist of talc, ment), or be able to penetrate it, if a magnesium stearate, silicon dioxide systemic action is intended (transder- (silica), or starch. They adhere to the mal delivery system, e.g., nitroglycerin skin, forming a low-friction film that at- patch, p. 120). The tendency for the drug tenuates mechanical irritation. Powders to leave the drug vehicle (V) is higher exert a drying (evaporative) effect. the more the drug and vehicle differ in Lipophilic ointment (oil ointment) lipophilicity (high tendency: hydrophil- consists of a lipophilic base (paraffin oil, ic D and lipophilic V, and vice versa). Be- petroleum jelly, wool fat [lanolin]) and cause the skin represents a closed lipo- may contain up to 10 % powder materi- philic barrier (p. 22), only lipophilic als, such as zinc oxide, titanium oxide, drugs are absorbed. Hydrophilic drugs starch, or a mixture of these. Emulsify- fail even to penetrate the outer skin ing ointments are made of paraffins and when applied in a lipophilic vehicle. an emulsifying wax, and are miscible This formulation can be meaningful with water. when high drug concentrations are re- Paste (oil paste) is an ointment quired at the skin surface (e.g., neomy- containing more than 10 % pulverized cin ointment for bacterial skin infec- constituents. tions). Lipophilic (oily) cream is an emulsion of water in oil, easier to spread than oil paste or oil ointments. Hydrogel and water-soluble ointment achieve their consistency by means of different gel-forming agents (gelatin, methylcellulose, polyethylene glycol). Lotions are aqueous suspensions of water-insoluble and solid constituents.

Drug Administration 17

Solid Liquid Powder Solution

Aqueous Alcoholic Paste Dermatologicals solution tincture

Oily paste Semi-solid Hydrogel

Ointment Lotion Cream Lipophilic Hydrophilic Suspen- Emulsion ointment ointment sion Lipophilic Hydrophilic cream cream

Fat, oilWater in oil Oil in water Gel, water

Occlusive Permeable, coolant

Perspiration impossible possible

Dry, non-oily skin Oily, moist skin

A. Dermatologicals as skin protectants

Lipophilic drug Lipophilic drug Hydrophilic drug Hydrophilic drug in lipophilic in hydrophilic in lipophilic in hydrophilic base base base base

Epithelium

Stratum corneum

Subcutaneous fat tissue

B. Dermatologicals as drug vehicles

18 Drug Administration

From Application to Distribution this route is determined by both the in the Body physicochemical properties of the drug and the therapeutic requirements As a rule, drugs reach their target organs (acute vs. long-term effect). via the blood. Therefore, they must first Speed of absorption is determined enter the blood, usually the venous limb by the route and method of application. of the circulation. There are several pos- It is fastest with intravenous injection, sible sites of entry. less fast which intramuscular injection, The drug may be injected or infused and slowest with subcutaneous injec- intravenously, in which case the drug is tion. When the drug is applied to the introduced directly into the blood- oral mucosa (buccal, sublingual route), stream. In subcutaneous or intramus- plasma levels rise faster than with con- cular injection, the drug has to diffuse ventional oral administration because from its site of application into the the drug preparation is deposited at its blood. Because these procedures entail actual site of absorption and very high injury to the outer skin, strict require- concentrations in saliva occur upon the ments must be met concerning tech- dissolution of a single dose. Thus, up- nique. For that reason, the oral route take across the oral epithelium is accel- (i.e., simple application by mouth) in- erated. The same does not hold true for volving subsequent uptake of drug poorly water-soluble or poorly absorb- across the gastrointestinal mucosa into able drugs. Such agents should be given the blood is chosen much more fre- orally, because both the volume of fluid quently. The disadvantage of this route for dissolution and the absorbing sur- is that the drug must pass through the face are much larger in the small intes- liver on its way into the general circula- tine than in the oral cavity. tion. This fact assumes practical signifi- Bioavailability is defined as the cance with any drug that may be rapidly fraction of a given drug dose that reach- transformed or possibly inactivated in es the circulation in unchanged form the liver (first-pass hepatic elimination; and becomes available for systemic dis- p. 42). Even with rectal administration, tribution. The larger the presystemic at least a fraction of the drug enters the elimination, the smaller is the bioavail- general circulation via the portal vein, ability of an orally administered drug. because only veins draining the short terminal segment of the rectum communicate directly with the inferior vena cava. Hepatic passage is circumvented when absorption occurs buccally or sublingually, because venous blood from the oral cavity drains directly into the superior vena cava. The same would apply to administration by inhalation (p. 14). However, with this route, a local effect is usually intended; a systemic action is intended only in exceptional cases. Under certain conditions, drug can also be applied percutaneously in the form of a transdermal delivery system (p. 12). In this case, drug is slowly released from the reservoir, and then penetrates the epidermis and subepidermal connective tissue where it enters blood capillaries. Only a very few drugs can be applied transdermally. The feasibility of

Drug Administration 19

Inhalational Sublingual buccal

Intravenous Oral

Transdermal Aorta

Subcutaneous Distribution in body

Intramuscular Rectal

A. From application to distribution

20 Cellular Sites of Action

Potential Targets of Drug Action agents acting in the cell’s interior need to penetrate the cell membrane. Drugs are designed to exert a selective The cell membrane basically con- influence on vital processes in order to sists of a phospholipid bilayer (80Å = alleviate or eliminate symptoms of dis- 8 nm in thickness) in which are embed- ease. The smallest basic unit of an or- ded proteins (integral membrane pro- ganism is the cell. The outer cell mem- teins, such as receptors and transport brane, or plasmalemma, effectively de- molecules). Phospholipid molecules marcates the cell from its surroundings, contain two long-chain fatty acids in es- thus permitting a large degree of inter- ter linkage with two of the three hy- nal autonomy. Embedded in the plas- droxyl groups of glycerol. Bound to the malemma are transport proteins that third hydroxyl group is phosphoric acid, serve to mediate controlled metabolic which, in turn, carries a further residue, exchange with the cellular environment. e.g., choline, (phosphatidylcholine = lec- These include energy-consuming ithin), the amino acid serine (phosphat- pumps (e.g., Na, K-ATPase, p. 130), car- idylserine) or the cyclic polyhydric alco- riers (e.g., for Na/glucose-cotransport, p. hol inositol (phosphatidylinositol). In 178), and ion channels e.g., for sodium terms of solubility, phospholipids are (p. 136) or calcium (p. 122) (1). amphiphilic: the tail region containing Functional coordination between the apolar fatty acid chains is lipophilic, single cells is a prerequisite for viability the remainder – the polar head – is hy- of the organism, hence also for the sur- drophilic. By virtue of these properties, vival of individual cells. Cell functions phospholipids aggregate spontaneously are regulated by means of messenger into a bilayer in an aqueous medium, substances for the transfer of informa- their polar heads directed outwards into tion. Included among these are “trans- the aqueous medium, the fatty acid mitters” released from nerves, which chains facing each other and projecting the cell is able to recognize with the into the inside of the membrane (3). help of specialized membrane binding The hydrophobic interior of the sites or receptors. Hormones secreted phospholipid membrane constitutes a by endocrine glands into the blood, then diffusion barrier virtually imperme- into the extracellular fluid, represent able for charged particles. Apolar parti- another class of chemical signals. Final- cles, however, penetrate the membrane ly, signalling substances can originate easily. This is of major importance with from neighboring cells, e.g., prostaglan- respect to the absorption, distribution, dins (p. 196) and cytokines. and elimination of drugs. The effect of a drug frequently results from interference with cellular function. Receptors for the recognition of endogenous transmitters are obvious sites of drug action (receptor agonists and antagonists, p. 60). Altered activity of transport systems affects cell function (e.g., cardiac glycosides, p. 130; loop diuretics, p. 162; calcium-antagonists, p. 122). Drugs may also directly interfere with intracellular metabolic processes, for instance by inhibiting (phosphodiesterase inhibitors, p. 132) or activating (organic nitrates, p. 120) an enzyme (2). In contrast to drugs acting from the outside on cell membrane constituents,

Cellular Sites of Action 21

Neural control

D Nerve Transmitter Receptor

Ion channel

Cellular Hormonal transport control systems for Hormones controlled transfer of D substrates

Hormone D receptors

Transport molecule Enzyme D Direct action D = Drug on metabolism

2 3 Choline D D Phosphoric acid Phospholipid matrix Glycerol

Protein Fatty acid

Effect

Intracellular site of action

A. Sites at which drugs act to modify cell function

22 Distribution in the Body

External Barriers of the Body proceeds rapidly, because the absorbing surface is greatly enlarged due to the Prior to its uptake into the blood (i.e., formation of the epithelial brush border during absorption), a drug has to over- (submicroscopic foldings of the plasma- come barriers that demarcate the body lemma). The absorbability of a drug is from its surroundings, i.e., separate the characterized by the absorption quo- internal milieu from the external mi- tient, that is, the amount absorbed di- lieu. These boundaries are formed by vided by the amount in the gut available the skin and mucous membranes. for absorption. When absorption takes place in the In the respiratory tract, cilia-bear- gut (enteral absorption), the intestinal ing epithelial cells are also joined on the epithelium is the barrier. This single- luminal side by zonulae occludentes, so layered epithelium is made up of ente- that the bronchial space and the inter- rocytes and mucus-producing goblet stitium are separated by a continuous cells. On their luminal side, these cells phospholipid barrier. are joined together by zonulae occlu- With sublingual or buccal applica- dentes (indicated by black dots in the in- tion, a drug encounters the non-kerati- set, bottom left). A zonula occludens or nized, multilayered squamous epitheli- tight junction is a region in which the um of the oral mucosa. Here, the cells phospholipid membranes of two cells establish punctate contacts with each establish close contact and become other in the form of desmosomes (not joined via integral membrane proteins shown); however, these do not seal the (semicircular inset, left center). The re- intercellular clefts. Instead, the cells gion of fusion surrounds each cell like a have the property of sequestering phos- ring, so that neighboring cells are weld- pholipid-containing membrane frag- ed together in a continuous belt. In this ments that assemble into layers within manner, an unbroken phospholipid the extracellular space (semicircular in- layer is formed (yellow area in the sche- set, center right). In this manner, a con- matic drawing, bottom left) and acts as tinuous phospholipid barrier arises also a continuous barrier between the two inside squamous epithelia, although at spaces separated by the cell layer – in an extracellular location, unlike that of the case of the gut, the intestinal lumen intestinal epithelia. A similar barrier (dark blue) and the interstitial space principle operates in the multilayered (light blue). The efficiency with which keratinized squamous epithelium of the such a barrier restricts exchange of sub- outer skin. The presence of a continu- stances can be increased by arranging ous phospholipid layer means that these occluding junctions in multiple squamous epithelia will permit passage arrays, as for instance in the endotheli- of lipophilic drugs only, i.e., agents ca- um of cerebral blood vessels. The con- pable of diffusing through phospholipid necting proteins (connexins) further- membranes, with the epithelial thick- more serve to restrict mixing of other ness determining the extent and speed functional membrane proteins (ion of absorption. In addition, cutaneous ab- pumps, ion channels) that occupy spe- sorption is impeded by the keratin cific areas of the cell membrane. layer, the stratum corneum, which is This phospholipid bilayer repre- very unevenly developed in various are- sents the intestinal mucosa-blood bar- as of the skin. rier that a drug must cross during its enteral absorption. Eligible drugs are those whose physicochemical properties allow permeation through the lipophilic membrane interior (yellow) or that are subject to a special carrier transport mechanism. Absorption of such drugs

Distribution in the Body 23

Nonkeratinized Ciliated epithelium squamous epithelium

Epithelium with Keratinized squamous brush border epithelium

A. External barriers of the body

24 Distribution in the Body

Blood-Tissue Barriers e.g., proteins such as insulin (G: insulin storage granules. Penetrability of mac- Drugs are transported in the blood to romolecules is determined by molecu- different tissues of the body. In order to lar size and electrical charge. Fenestrat- reach their sites of action, they must ed endothelia are found in the capillar- leave the bloodstream. Drug permea- ies of the gut and endocrine glands. tion occurs largely in the capillary bed, In the central nervous system where both surface area and time avail- (brain and spinal cord), capillary endo- able for exchange are maximal (exten- thelia lack pores and there is little trans- sive vascular branching, low velocity of cytotic activity. In order to cross the flow). The capillary wall forms the blood-brain barrier, drugs must diffuse blood-tissue barrier. Basically, this transcellularly, i.e., penetrate the lumi- consists of an endothelial cell layer and nal and basal membrane of endothelial a basement membrane enveloping the cells. Drug movement along this path latter (solid black line in the schematic requires specific physicochemical prop- drawings). The endothelial cells are erties (p. 26) or the presence of a trans- “riveted” to each other by tight junc- port mechanism (e.g., L-dopa, p. 188). tions or occluding zonulae (labelled Z in Thus, the blood-brain barrier is perme- the electron micrograph, top left) such able only to certain types of drugs. that no clefts, gaps, or pores remain that Drugs exchange freely between would permit drugs to pass unimpeded blood and interstitium in the liver, from the blood into the interstitial fluid. where endothelial cells exhibit large The blood-tissue barrier is devel- fenestrations (100 nm in diameter) fac- oped differently in the various capillary ing Disse’s spaces (D) and where neither beds. Permeability to drugs of the capil- diaphragms nor basement membranes lary wall is determined by the structural impede drug movement. Diffusion bar- and functional characteristics of the en- riers are also present beyond the capil- dothelial cells. In many capillary beds, lary wall: e.g., placental barrier of fused e.g., those of cardiac muscle, endothe- syncytiotrophoblast cells; blood: testi- lial cells are characterized by pro- cle barrier — junctions interconnecting nounced endo- and transcytotic activ- Sertoli cells; brain choroid plexus: blood ity, as evidenced by numerous invagina- barrier — occluding junctions between tions and vesicles (arrows in the EM mi- ependymal cells. crograph, top right). Transcytotic activ- (Vertical bars in the EM micro- ity entails transport of fluid or macro- graphs represent 1 µm; E: cross-sec- molecules from the blood into the inter- tioned erythrocyte; AM: actomyosin; G: stitium and vice versa. Any solutes insulin-containing granules.) trapped in the fluid, including drugs, may traverse the blood-tissue barrier. In this form of transport, the physicochemical properties of drugs are of little importance. In some capillary beds (e.g., in the pancreas), endothelial cells exhibit fenestrations. Although the cells are tight- ly connected by continuous junctions, they possess pores (arrows in EM micrograph, bottom right) that are closed only by diaphragms. Both the diaphragm and basement membrane can be readily penetrated by substances of low molecular weight — the majority of drugs — but less so by macromolecules,

Distribution in the Body 25

CNS Heart muscle

E AM

G D

Liver Pancreas

A. Blood-tissue barriers

26 Distribution in the Body

Membrane Permeation strate of a carrier will exhibit affinity for it. An ability to penetrate lipid bilayers is a Finally, membrane penetration prerequisite for the absorption of drugs, may occur in the form of small mem- their entry into cells or cellular orga- brane-covered vesicles. Two different nelles, and passage across the blood- systems are considered. brain barrier. Due to their amphiphilic Transcytosis (vesicular transport, nature, phospholipids form bilayers C). When new vesicles are pinched off, possessing a hydrophilic surface and a substances dissolved in the extracellu- hydrophobic interior (p. 20). Substances lar fluid are engulfed, and then ferried may traverse this membrane in three through the cytoplasm, vesicles (phago- different ways. somes) undergo fusion with lysosomes Diffusion (A). Lipophilic substanc- to form phagolysosomes, and the trans- es (red dots) may enter the membrane ported substance is metabolized. Alter- from the extracellular space (area natively, the vesicle may fuse with the shown in ochre), accumulate in the opposite cell membrane (cytopempsis). membrane, and exit into the cytosol Receptor-mediated endocytosis (blue area). Direction and speed of per- (C). The drug first binds to membrane meation depend on the relative concen- surface receptors (1, 2) whose cytosolic trations in the fluid phases and the domains contact special proteins (adap- membrane. The steeper the gradient tins, 3). Drug-receptor complexes mi- (concentration difference), the more grate laterally in the membrane and ag- drug will be diffusing per unit of time gregate with other complexes by a (Fick’s Law). The lipid membrane repre- clathrin-dependent process (4). The af- sents an almost insurmountable obsta- fected membrane region invaginates cle for hydrophilic substances (blue tri- and eventually pinches off to form a de- angles). tached vesicle (5). The clathrin coat is Transport (B). Some drugs may shed immediately (6), followed by the penetrate membrane barriers with the adaptins (7). The remaining vesicle then help of transport systems (carriers), ir- fuses with an “early” endosome (8), respective of their physicochemical whereupon proton concentration rises properties, especially lipophilicity. As a inside the vesicle. The drug-receptor prerequisite, the drug must have affin- complex dissociates and the receptor ity for the carrier (blue triangle match- returns into the cell membrane. The ing recess on “transport system”) and, “early” endosome delivers its contents when bound to the latter, be capable of to predetermined destinations, e.g., the being ferried across the membrane. Golgi complex, the cell nucleus, lysoso- Membrane passage via transport mech- mes, or the opposite cell membrane anisms is subject to competitive inhibi- (transcytosis). Unlike simple endocyto- tion by another substance possessing sis, receptor-mediated endocytosis is similar affinity for the carrier. Substanc- contingent on affinity for specific recep- es lacking in affinity (blue circles) are tors and operates independently of con- not transported. Drugs utilize carriers centration gradients. for physiological substances, e.g., L-dopa uptake by L-amino acid carrier across the blood-intestine and blood-brain barriers (p. 188), and uptake of aminoglycosides by the carrier transporting basic polypeptides through the luminal membrane of kidney tubular cells (p. 278). Only drugs bearing sufficient resemblance to the physiological sub-

Distribution in the Body 27

A. Membrane permeation: diffusion B. Membrane permeation: transport

1 2

4 8 9

6 5

Vesicular transport

Lysosome Phagolysosome

Extracellular Intracellular Extracellular C. Membrane permeation: receptor-mediated endocytosis, vesicular uptake, and transport

28 Distribution in the Body

Possible Modes of Drug Distribution Solid substance substance and and structurally bound bound water Following its uptake into the body, the water drug is distributed in the blood (1) and through it to the various tissues of the 40% body. Distribution may be restricted to 20% the extracellular space (plasma volume plus interstitial space) (2) or may also 40% extend into the intracellular space (3). Certain drugs may bind strongly to tissue structures, so that plasma concen- intracellularintracellularextra-cellular extracellular trations fall significantly even before water water elimination has begun (4). water water After being distributed in blood, PotentialPotential aqueous aqueous solvent solvent macromolecular substances remain spaces for drugs largely confined to the vascular space, spaces for drugs because their permeation through the blood-tissue barrier, or endothelium, is impeded, even where capillaries are Further subdivisions are shown in fenestrated. This property is exploited the table. therapeutically when loss of blood ne- The volume ratio interstitial: intra- cessitates refilling of the vascular bed, cellular water varies with age and body e.g., by infusion of dextran solutions (p. weight. On a percentage basis, intersti- 152). The vascular space is, moreover, tial fluid volume is large in premature or predominantly occupied by substances normal neonates (up to 50 % of body bound with high affinity to plasma pro- water), and smaller in the obese and the teins (p. 30; determination of the plas- aged. ma volume with protein-bound dyes). The concentration (c) of a solution Unbound, free drug may leave the corresponds to the amount (D) of sub- bloodstream, albeit with varying ease, stance dissolved in a volume (V); thus, c because the blood-tissue barrier (p. 24) = D/V. If the dose of drug (D) and its is differently developed in different seg- plasma concentration (c) are known, a ments of the vascular tree. These re- volume of distribution (V) can be calcu- gional differences are not illustrated in lated from V = D/c. However, this repre- the accompanying figures. sents an apparent volume of distribu- Distribution in the body is deter- tion (Vapp), because an even distribution mined by the ability to penetrate mem- in the body is assumed in its calculation. branous barriers (p. 20). Hydrophilic Homogeneous distribution will not oc- substances (e.g., inulin) are neither tak- cur if drugs are bound to cell mem- en up into cells nor bound to cell surface branes (5) or to membranes of intracel- structures and can, thus, be used to de- lular organelles (6) or are stored within termine the extracellular fluid volume the latter (7). In these cases, Vapp can ex- (2). Some lipophilic substances diffuse ceed the actual size of the available fluid through the cell membrane and, as a re- volume. The significance of Vapp as a sult, achieve a uniform distribution (3). pharmacokinetic parameter is dis- Body weight may be broken down cussed on p. 44. as follows:

Distribution in the Body 29

123 4

Distribution in tissue

Plasma Interstitium 6% 25% 4% 65%

Erythrocytes Aqueous spaces of the organism Intracellular space

Lysosomes

Mito- chondria

Nucleus

Cell membrane 56 7 A. Compartments for drug distribution

30 Distribution in the Body

Binding to Plasma Proteins drug will enter hepatic sites of metabolism or undergo glomerular filtration. Having entered the blood, drugs may When concentrations of free drug fall, bind to the protein molecules that are drug is resupplied from binding sites on present in abundance, resulting in the plasma proteins. Binding to plasma pro- formation of drug-protein complexes. tein is equivalent to a depot in prolong- Protein binding involves primarily al- ing the duration of the effect by retard- bumin and, to a lesser extent, β-globu- ing elimination, whereas the intensity lins and acidic glycoproteins. Other of the effect is reduced. If two substanc- plasma proteins (e.g., transcortin, trans- es have affinity for the same binding site ferrin, thyroxin-binding globulin) serve on the albumin molecule, they may specialized functions in connection compete for that site. One drug may dis- with specific substances. The degree of place another from its binding site and binding is governed by the concentra- thereby elevate the free (effective) con- tion of the reactants and the affinity of a centration of the displaced drug (a form drug for a given protein. Albumin con- of drug interaction). Elevation of the centration in plasma amounts to free concentration of the displaced drug 4.6 g/100 mL or O.6 mM, and thus pro- means increased effectiveness and ac- vides a very high binding capacity (two celerated elimination. sites per molecule). As a rule, drugs ex- A decrease in the concentration of hibit much lower affinity (KD approx. albumin (liver disease, nephrotic syn- 10–5 –10–3 M) for plasma proteins than drome, poor general condition) leads to for their specific binding sites (recep- altered pharmacokinetics of drugs that tors). In the range of therapeutically rel- are highly bound to albumin. evant concentrations, protein binding of Plasma protein-bound drugs that most drugs increases linearly with con- are substrates for transport carriers can centration (exceptions: salicylate and be cleared from blood at great velocity, certain sulfonamides). e.g., p-aminohippurate by the renal tu- The albumin molecule has different bule and sulfobromophthalein by the binding sites for anionic and cationic li- liver. Clearance rates of these substanc- gands, but van der Waals’ forces also es can be used to determine renal or he- contribute (p. 58). The extent of binding patic blood flow. correlates with drug hydrophobicity (repulsion of drug by water). Binding to plasma proteins is in- stantaneous and reversible, i.e., any change in the concentration of unbound drug is immediately followed by a corresponding change in the concentration of bound drug. Protein binding is of great importance, because it is the concentration of free drug that determines the intensity of the effect. At an identical total plasma concentration (say, 100 ng/mL) the effective concentration will be 90 ng/mL for a drug 10 % bound to protein, but 1 ng/mL for a drug 99 % bound to protein. The reduction in concentration of free drug resulting from protein binding affects not only the intensity of the effect but also biotransformation (e.g., in the liver) and elimination in the kidney, because only free

Distribution in the Body 31

Drug is Drug is not bound strongly to plasma bound to proteins plasma proteins

Effect Effect Effector cell Effector cell

Biotransformation Biotransformation

Renal elimination Renal elimination

Plasma concentration Plasma concentration

Free drug Bound drug

Free drug

Time Time

A. Importance of protein binding for intensity and duration of drug effect

32 Drug Elimination

The Liver as an Excretory Organ Compared with hydrophilic drugs not undergoing transport, lipophilic As the chief organ of drug biotransfor- drugs are more rapidly taken up from mation, the liver is richly supplied with the blood into hepatocytes and more blood, of which 1100 mL is received readily gain access to mixed-function each minute from the intestines oxidases embedded in sER membranes. through the portal vein and 350 mL For instance, a drug having lipophilicity through the hepatic artery, comprising by virtue of an aromatic substituent 1 nearly /3 of cardiac output. The blood (phenyl ring) (B) can be hydroxylated content of hepatic vessels and sinusoids and, thus, become more hydrophilic amounts to 500 mL. Due to the widen- (Phase I reaction, p. 34). Besides oxi- ing of the portal lumen, intrahepatic dases, sER also contains reductases and blood flow decelerates (A). Moreover, glucuronyl transferases. The latter con- the endothelial lining of hepatic sinu- jugate glucuronic acid with hydroxyl, soids (p. 24) contains pores large carboxyl, amine, and amide groups (p. enough to permit rapid exit of plasma 38); hence, also phenolic products of proteins. Thus, blood and hepatic paren- phase I metabolism (Phase II conjuga- chyma are able to maintain intimate tion). Phase I and Phase II metabolites contact and intensive exchange of sub- can be transported back into the blood stances, which is further facilitated by — probably via a gradient-dependent microvilli covering the hepatocyte sur- carrier — or actively secreted into bile. faces abutting Disse’s spaces. Prolonged exposure to certain sub- The hepatocyte secretes biliary strates, such as phenobarbital, carbama- fluid into the bile canaliculi (dark zepine, rifampicin results in a prolifera- green), tubular intercellular clefts that tion of sER membranes (cf. C and D). are sealed off from the blood spaces by This enzyme induction, a load-depen- tight junctions. Secretory activity in the dent hypertrophy, affects equally all en- hepatocytes results in movement of zymes localized on sER membranes. En- fluid towards the canalicular space (A). zyme induction leads to accelerated The hepatocyte has an abundance of en- biotransformation, not only of the in- zymes carrying out metabolic functions. ducing agent but also of other drugs (a These are localized in part in mitochon- form of drug interaction). With contin- dria, in part on the membranes of the ued exposure, induction develops in a rough (rER) or smooth (sER) endoplas- few days, resulting in an increase in re- mic reticulum. action velocity, maximally 2–3fold, that Enzymes of the sER play a most im- disappears after removal of the induc- portant role in drug biotransformation. ing agent. At this site, molecular oxygen is used in oxidative reactions. Because these enzymes can catalyze either hydroxylation or oxidative cleavage of -N-C- or -O-C- bonds, they are referred to as “mixed- function” oxidases or hydroxylases. The essential component of this enzyme system is cytochrome P450, which in its oxidized state binds drug substrates (R- H). The FeIII-P450-RH binary complex is first reduced by NADPH, then forms the II ternary complex, O2-Fe -P450-RH, which accepts a second electron and finally disintegrates into FeIII-P450, one equivalent of H2O, and hydroxylated drug (R-OH).

Drug Elimination 33

HepatocyteBiliary capillary Disse´s space

Intestine Portal vein

Gall-bladder

A. Flow patterns in portal vein, Disse’s space, and hepatocyte

Phase I- metabolite sER rER Biliary capillary

C. Normal hepatocyte

Phase II- metabolite Glucuronide rER Carrier

sER

B. Fate of drugs undergoing D. Hepatocyte after B. hepatic hydroxylation D. phenobarbital administration

34 Drug Elimination

Biotransformation of Drugs mucosa (erythromycin succinate erythromycin). In these cases, the ester Many drugs undergo chemical modifi- itself is not active, but the cleavage cation in the body (biotransformation). product is. Thus, an inactive precursor Most frequently, this process entails a or prodrug is applied, formation of the loss of biological activity and an inactive molecule occurring only after hy- crease in hydrophilicity (water solubil- drolysis in the blood. ity), thereby promoting elimination via Some drugs possessing amide the renal route (p. 40). Since rapid drug bonds, such as prilocaine, and of course, elimination improves accuracy in titrat- peptides, can be hydrolyzed by pepti- ing the therapeutic concentration, drugs dases and inactivated in this manner. are often designed with built-in weak Peptidases are also of pharmacological links. Ester bonds are such links, being interest because they are responsible subject to hydrolysis by the ubiquitous for the formation of highly reactive esterases. Hydrolytic cleavages, along cleavage products (fibrin, p. 146) and with oxidations, reductions, alkylations, potent mediators (angiotensin II, p. 124; and dealkylations, constitute Phase I re- bradykinin, enkephalin, p. 210) from actions of drug metabolism. These reac- biologically inactive peptides. tions subsume all metabolic processes Peptidases exhibit some substrate apt to alter drug molecules chemically selectivity and can be selectively inhib- and take place chiefly in the liver. In ited, as exemplified by the formation of Phase II (synthetic) reactions, conju- angiotensin II, whose actions inter alia gation products of either the drug itself include vasoconstriction. Angiotensin II or its Phase I metabolites are formed, for is formed from angiotensin I by cleavage instance, with glucuronic or sulfuric ac- of the C-terminal dipeptide histidylleu- id (p. 38). cine. Hydrolysis is catalyzed by “angio- The special case of the endogenous tensin-converting enzyme” (ACE). Pep- transmitter acetylcholine illustrates tide analogues such as captopril (p. 124) well the high velocity of ester hydroly- block this enzyme. Angiotensin II is de- sis. Acetylcholine is broken down at its graded by angiotensinase A, which clips sites of release and action by acetylchol- off the N-terminal asparagine residue. inesterase (pp. 100, 102) so rapidly as to The product, angiotensin III, lacks vaso- negate its therapeutic use. Hydrolysis of constrictor activity. other esters catalyzed by various esterases is slower, though relatively fast in comparison with other biotransforma- tions. The local anesthetic, procaine, is a case in point; it exerts its action at the site of application while being largely devoid of undesirable effects at other lo- cations because it is inactivated by hydrolysis during absorption from its site of application. Ester hydrolysis does not invariably lead to inactive metabolites, as exemplified by acetylsalicylic acid. The cleavage product, salicylic acid, retains pharmacological activity. In certain cases, drugs are administered in the form of esters in order to facilitate absorption (enalapril enalaprilate; testosterone undecanoate testosterone) or to reduce irritation of the gastrointestinal

Drug Elimination 35

Esterases Ester Peptidases Amides Anilides

Acetylcholine

Converting enzyme

Acetic acid

Angiotensin I

Choline

Angiotensin II Procaine Angiotensin III

Angiotensinase

p-Aminobenzoic acid

Diethylaminoethanol

Acetylsalicylic acid Prilocaine

Acetic acid Salicylic acid N-Propylalanine Toluidine

A. Examples of chemical reactions in drug biotransformation (hydrolysis)

36 Drug Elimination

Oxidation reactions can be divided and S-dearylation proceed via an analo- into two kinds: those in which oxygen is gous mechanism (e.g., phenacetin and incorporated into the drug molecule, azathioprine, respectively). and those in which primary oxidation Oxidative deamination basically causes part of the molecule to be lost. resembles the dealkylation of tertiary The former include hydroxylations, amines, beginning with the formation of epoxidations, and sulfoxidations. Hy- a hydroxylamine that then decomposes droxylations may involve alkyl substitu- into ammonia and the corresponding ents (e.g., pentobarbital) or aromatic aldehyde. The latter is partly reduced to ring systems (e.g., propranolol). In both an alcohol and partly oxidized to a car- cases, products are formed that are con- boxylic acid. jugated to an organic acid residue, e.g., Reduction reactions may occur at glucuronic acid, in a subsequent Phase II oxygen or nitrogen atoms. Keto-oxy- reaction. gens are converted into a hydroxyl Hydroxylation may also take place group, as in the reduction of the pro- at nitrogen atoms, resulting in hydroxyl- drugs cortisone and prednisone to the amines (e.g., acetaminophen). Benzene, active glucocorticoids cortisol and pred- polycyclic aromatic compounds (e.g., nisolone, respectively. N-reductions oc- benzopyrene), and unsaturated cyclic cur in azo- or nitro-compounds (e.g., ni- carbohydrates can be converted by trazepam). Nitro groups can be reduced mono-oxygenases to epoxides, highly to amine groups via nitroso and hydrox- reactive electrophiles that are hepato- ylamino intermediates. Likewise, deha- toxic and possibly carcinogenic. logenation is a reductive process involv- The second type of oxidative bio- ing a carbon atom (e.g., halothane, p. transformation comprises dealkyla- 218). tions. In the case of primary or secon- Methylations are catalyzed by a dary amines, dealkylation of an alkyl family of relatively specific methyl- group starts at the carbon adjacent to transferases involving the transfer of the nitrogen; in the case of tertiary methyl groups to hydroxyl groups (O- amines, with hydroxylation of the nitro- methylation as in norepinephrine [nor- gen (e.g., lidocaine). The intermediary adrenaline]) or to amino groups (N- products are labile and break up into the methylation of norepinephrine, hista- dealkylated amine and aldehyde of the mine, or serotonin). alkyl group removed. O-dealkylation In thio compounds, desulfuration results from substitution of sulfur by oxygen (e.g., parathion). This example O2 again illustrates that biotransformation is not always to be equated with bio- R1 inactivation. Thus, paraoxon (E600) formed in the organism from parathion N (E605) is the actual active agent (p. 102). R2 R1 CH3 N OH R2

CH3 Desalkylierung Desalkylierung R1 O + HC N CH3 R2 H

Drug Elimination 37

Propranolol

Pentobarbital

Hydroxylation

Lidocaine Phenacetin Parathion

N-Dealkylation Desulfuration O-Dealkylation

Norepinephrine Dealkylation

S-Dealkylation

O-Methylation Azathioprine Methylation

Nitrazepam Benzpyrene Chlorpromazine

Acetaminophen Sulfoxidation

Epoxidation

Hydroxyl- amine Reduction Oxidation

A. Examples of chemical reactions in drug biotransformation

38 Drug Elimination

Enterohepatic Cycle (A) Amines may form N-glucuronides that, unlike O-glucuronides, are resistant to After an orally ingested drug has been bacterial β-glucuronidases. absorbed from the gut, it is transported Soluble cytoplasmic sulfotrans- via the portal blood to the liver, where it ferases conjugate activated sulfate (3’- can be conjugated to glucuronic or sul- phosphoadenine-5’-phosphosulfate) furic acid (shown in B for salicylic acid with alcohols and phenols. The conju- and deacetylated bisacodyl, respective- gates are acids, as in the case of glucuro- ly) or to other organic acids. At the pH of nides. In this respect, they differ from body fluids, these acids are predomi- conjugates formed by acetyltransfe- nantly ionized; the negative charge con- rases from activated acetate (acetyl- fers high polarity upon the conjugated coenzyme A) and an alcohol or a phenol. drug molecule and, hence, low mem- Acyltransferases are involved in the brane penetrability. The conjugated conjugation of the amino acids glycine products may pass from hepatocyte into or glutamine with carboxylic acids. In biliary fluid and from there back into these cases, an amide bond is formed the intestine. O-glucuronides can be between the carboxyl groups of the ac- cleaved by bacterial β-glucuronidases in ceptor and the amino group of the do- the colon, enabling the liberated drug nor molecule (e.g., formation of salicyl- molecule to be reabsorbed. The entero- uric acid from salicylic acid and glycine). hepatic cycle acts to trap drugs in the The acidic group of glycine or glutamine body. However, conjugated products remains free. enter not only the bile but also the blood. Glucuronides with a molecular weight (MW) > 300 preferentially pass into the blood, while those with MW > 300 enter the bile to a larger extent. Glucuronides circulating in the blood undergo glomerular filtration in the kidney and are excreted in urine because their decreased lipophilicity prevents tubular reabsorption. Drugs that are subject to enterohepatic cycling are, therefore, excreted slowly. Pertinent examples include digitoxin and acidic nonsteroidal anti-inflammatory agents (p. 200).

Conjugations (B)

The most important of phase II conjugation reactions is glucuronidation. This reaction does not proceed spontaneously, but requires the activated form of glucuronic acid, namely glucuronic acid uridine diphosphate. Microsomal glucuronyl transferases link the activated glucuronic acid with an acceptor molecule. When the latter is a phenol or alcohol, an ether glucuronide will be formed. In the case of carboxyl-bearing molecules, an ester glucuronide is the result. All of these are O-glucuronides.

Drug Elimination 39

Hepatocyte

Sinusoid

4 Biliary capillary Biliary 5 elimination 3 Conjugation with 7 glucuronic acid 2

Portal vein

E n t e n r i o Deconjugation o a t 6 h e p c u l by microbial a t i c c i r β-glucuronidase

Renal Lipophilic Enteral 8 elimination drug absorption Hydrophilic conjugation product

A. Enterohepatic cycle

UDP-α-Glucuronic acid 3'-Phosphoadenine-5'-phosphosulfate

Glucuronyl- Sulfo- transferase transferase

Salicylic acid Active moiety of bisacodyl

B. Conjugation reactions

40 Drug Elimination

The Kidney as Excretory Organ gree of dissociation. The degree of dissociation varies as a function of the uri- Most drugs are eliminated in urine ei- nary pH and the pKa, which represents ther chemically unchanged or as metab- the pH value at which half of the sub- olites. The kidney permits elimination stance exists in protonated (or unproto- because the vascular wall structure in nated) form. This relationship is graphi- the region of the glomerular capillaries cally illustrated (D) with the example of (B) allows unimpeded passage of blood a protonated amine having a pKa of 7.0. solutes having molecular weights (MW) In this case, at urinary pH 7.0, 50 % of the < 5000. Filtration diminishes progres- amine will be present in the protonated, sively as MW increases from 5000 to hydrophilic, membrane-impermeant 70000 and ceases at MW > 70000. With form (blue dots), whereas the other half, few exceptions, therapeutically used representing the uncharged amine drugs and their metabolites have much (orange dots), can leave the tubular lu- smaller molecular weights and can, men in accordance with the resulting therefore, undergo glomerular filtra- concentration gradient. If the pKa of an tion, i.e., pass from blood into primary amine is higher (pKa = 7.5) or lower (pKa urine. Separating the capillary endothe- = 6.5), a correspondingly smaller or lium from the tubular epithelium, the larger proportion of the amine will be basal membrane consists of charged present in the uncharged, reabsorbable glycoproteins and acts as a filtration form. Lowering or raising urinary pH by barrier for high-molecular-weight sub- half a pH unit would result in analogous stances. The relative density of this bar- changes for an amine having a pKa of rier depends on the electrical charge of 7.0. molecules that attempt to permeate it. The same considerations hold for Apart from glomerular filtration acidic molecules, with the important (B), drugs present in blood may pass difference that alkalinization of the into urine by active secretion. Certain urine (increased pH) will promote the cations and anions are secreted by the deprotonization of -COOH groups and epithelium of the proximal tubules into thus impede reabsorption. Intentional the tubular fluid via special, energy- alteration in urinary pH can be used in consuming transport systems. These intoxications with proton-acceptor sub- transport systems have a limited capac- stances in order to hasten elimination of ity. When several substrates are present the toxin (alkalinization phenobarbi- simultaneously, competition for the tal; acidification amphetamine). carrier may occur (see p. 268). During passage down the renal tubule, urinary volume shrinks more than 100-fold; accordingly, there is a corresponding concentration of filtered drug or drug metabolites (A). The resulting concentration gradient between urine and interstitial fluid is preserved in the case of drugs incapable of permeating the tubular epithelium. However, with lipophilic drugs the concentration gradient will favor reabsorption of the filtered molecules. In this case, reabsorption is not based on an active process but results instead from passive diffusion. Accordingly, for protonated substances, the extent of reabsorption is dependent upon urinary pH or the de-

Drug Elimination 41

Blood Plasma- protein Endothelium Basal membrane Drug

180 L Glomerular Primary filtration Epithelium urine of drug

Primary urine

B. Glomerular filtration

pH = 7.0 pKa of substance

pKa = 7.0 100

Concentration 1.2 L of drug % Final in tubule 6 6.5 7 7.5 8 urine pKa = 7.5 100

A. Filtration and concentration 50

+ + + % + + 6 6.5 7 7.5 8 + + + + + + + + + pK = 6.5 + + a + 100 + + + + +

Tubular - - transport 50 system for - - - + - - - Cations - - - - - % – Anions - - - - 6 6.5 7 7.5 8 - - - - - pH = 7.0 pH of urine

C. Active secretion D. Tubular reabsorption

42 Drug Elimination

Elimination of Lipophilic and Lipophilic drugs that are convert- Hydrophilic Substances ed in the liver to hydrophilic metabolites permit better control, because the The terms lipophilic and hydrophilic lipophilic agent can be eliminated in (or hydro- and lipophobic) refer to the this manner. The speed of formation of solubility of substances in media of low hydrophilic metabolite determines the and high polarity, respectively. Blood drug’s length of stay in the body. plasma, interstitial fluid, and cytosol are If hepatic conversion to a polar me- highly polar aqueous media, whereas tabolite is rapid, only a portion of the lipids — at least in the interior of the lip- absorbed drug enters the systemic cir- id bilayer membrane — and fat consti- culation in unchanged form, the re- tute apolar media. Most polar substanc- mainder having undergone presystem- es are readily dissolved in aqueous me- ic (first-pass) elimination. When bio- dia (i.e., are hydrophilic) and lipophilic transformation is rapid, oral adminis- ones in apolar media. A hydrophilic tration of the drug is impossible (e.g., drug, on reaching the bloodstream, glyceryl trinitate, p. 120). Parenteral or, probably after a partial, slow absorption alternatively, sublingual, intranasal, or (not illustrated), passes through the liv- transdermal administration is then re- er unchanged, because it either cannot, quired in order to bypass the liver. Irre- or will only slowly, permeate the lipid spective of the route of administration, barrier of the hepatocyte membrane a portion of administered drug may be and thus will fail to gain access to hepat- taken up into and transiently stored in ic biotransforming enzymes. The un- lung tissue before entering the general changed drug reaches the arterial blood circulation. This also constitutes pre- and the kidneys, where it is filtered. systemic elimination. With hydrophilic drugs, there is little Presystemic elimination refers to binding to plasma proteins (protein the fraction of drug absorbed that is binding increases as a function of li- excluded from the general circulation pophilicity), hence the entire amount by biotransformation or by first-pass present in plasma is available for glo- binding. merular filtration. A hydrophilic drug is Presystemic elimination diminish- not subject to tubular reabsorption and es the bioavailability of a drug after its appears in the urine. Hydrophilic drugs oral administration. Absolute bioavail- undergo rapid elimination. ability = systemically available amount/ If a lipophilic drug, because of its dose administered; relative bioavail- chemical nature, cannot be converted ability = availability of a drug contained into a polar product, despite having ac- in a test preparation with reference to a cess to all cells, including metabolically standard preparation. active liver cells, it is likely to be retained in the organism. The portion filtered during glomerular passage will be reabsorbed from the tubules. Reabsorp- tion will be nearly complete, because the free concentration of a lipophilic drug in plasma is low (lipophilic substances are usually largely protein- bound). The situation portrayed for a lipophilic non-metabolizable drug would seem undesirable because pharmacotherapeutic measures once initiated would be virtually irreversible (poor control over blood concentration).

Drug Elimination 43

Hydrophilic drug Lipophilic drug no metabolism

Renal Excretion excretion impossible

Lipophilic drug Lipophilic drug

Slow conversion Rapid and complete in liver to conversion in liver to hydrophilic metabolite hydrophilic metabolite

Renal excretion Renal excretion of metabolite of metabolite

A. Elimination of hydrophilic and hydrophobic drugs

44 Pharmacokinetics

Drug Concentration in the Body (t1/2) and the apparent volume of distri- as a Function of Time. First-Order bution Vapp (p. 28) by the equation: (Exponential) Rate Processes Vapp t = In 2 x –––– 1/2 Cl Processes such as drug absorption and tot elimination display exponential charac- The smaller the volume of distribu- teristics. As regards the former, this fol- tion or the larger the total clearance, the lows from the simple fact that the shorter is the half-life. amount of drug being moved per unit of In the case of drugs renally elimi- time depends on the concentration dif- nated in unchanged form, the half-life of ference (gradient) between two body elimination can be calculated from the compartments (Fick’s Law). In drug ab- cumulative excretion in urine; the final sorption from the alimentary tract, the total amount eliminated corresponds to intestinal contents and blood would the amount absorbed. represent the compartments containing Hepatic elimination obeys expo- an initially high and low concentration, nential kinetics because metabolizing respectively. In drug elimination via the enzymes operate in the quasilinear re- kidney, excretion often depends on glo- gion of their concentration-activity merular filtration, i.e., the filtered curve; hence the amount of drug me- amount of drug present in primary tabolized per unit of time diminishes urine. As the blood concentration falls, with decreasing blood concentration. the amount of drug filtered per unit of The best-known exception to expo- time diminishes. The resulting exponential kinetics is the elimination of al- nential decline is illustrated in (A). The cohol (ethanol), which obeys a linear exponential time course implies con- time course (zero-order kinetics), at stancy of the interval during which the least at blood concentrations > 0.02 %. It concentration decreases by one-half. does so because the rate-limiting en- This interval represents the half-life zyme, alcohol dehydrogenase, achieves (t1/2) and is related to the elimination half-saturation at very low substrate rate constant k by the equation t1/2 = ln concentrations, i.e., at about 80 mg/L 2/k. The two parameters, together with (0.008 %). Thus, reaction velocity reach- the initial concentration co, describe a es a plateau at blood ethanol concentra- first-order (exponential) rate process. tions of about 0.02 %, and the amount of The constancy of the process per- drug eliminated per unit of time re- mits calculation of the plasma volume mains constant at concentrations above that would be cleared of drug, if the re- this level. maining drug were not to assume a homogeneous distribution in the total volume (a condition not met in reality). This notional plasma volume freed of drug per unit of time is termed the clearance. Depending on whether plasma concentration falls as a result of urinary excretion or metabolic alteration, clearance is considered to be renal or hepatic. Renal and hepatic clearances add up to total clearance (Cltot) in the case of drugs that are eliminated unchanged via the kidney and biotransformed in the liver. Cltot represents the sum of all processes contributing to elimination; it is related to the half-life

Pharmacokinetics 45

Concentration (c) of drug in plasma [amount/vol] Co

-kt Plasma half life t1 c = c · e 2 t o 1 c 1 = — c ct: Drug concentration at time t t 2 2 o ln 2 co: Initial drug concentration after t1 = —– administration of drug dose 2 k e: Base of natural logarithm k: Elimination constant

Unit of time Time (t)

Notional plasma volume per unit of time freed of drug = clearance [vol/t]

Amount excreted per unit of time [amount/t]

Total amount of drug (Amount administered) = Dose excreted

Time

A. Exponential elimination of drug

46 Pharmacokinetics

Time Course of Drug Concentration in man function (k1 and k2 represent the Plasma rate constants for absorption and elimination, respectively). A. Drugs are taken up into and eliminat- B. The velocity of absorption de- ed from the body by various routes. The pends on the route of administration. body thus represents an open system The more rapid the administration, the wherein the actual drug concentration shorter will be the time (tmax) required reflects the interplay of intake (inges- to reach the peak plasma level (cmax), tion) and egress (elimination). When an the higher will be the cmax, and the earli- orally administered drug is absorbed er the plasma level will begin to fall from the stomach and intestine, speed again. of uptake depends on many factors, in- The area under the plasma level time cluding the speed of drug dissolution (in curve (AUC) is independent of the route the case of solid dosage forms) and of of administration, provided the doses gastrointestinal transit; the membrane and bioavailability are the same (Dost’s penetrability of the drug; its concentra- law of corresponding areas). The AUC tion gradient across the mucosa-blood can thus be used to determine the bio- barrier; and mucosal blood flow. Ab- availability F of a drug. The ratio of AUC sorption from the intestine causes the values determined after oral or intrave- drug concentration in blood to increase. nous administration of a given dose of a Transport in blood conveys the drug to particular drug corresponds to the pro- different organs (distribution), into portion of drug entering the systemic which it is taken up to a degree compat- circulation after oral administration. ible with its chemical properties and The determination of plasma levels af- rate of blood flow through the organ. fords a comparison of different proprie- For instance, well-perfused organs such tary preparations containing the same as the brain receive a greater proportion drug in the same dosage. Identical plas- than do less well-perfused ones. Uptake ma level time-curves of different into tissue causes the blood concentra- manufacturers’ products with reference tion to fall. Absorption from the gut di- to a standard preparation indicate bio- minishes as the mucosa-blood gradient equivalence of the preparation under decreases. Plasma concentration reach- investigation with the standard. es a peak when the drug amount leaving the blood per unit of time equals that being absorbed. Drug entry into hepatic and renal tissue constitutes movement into the organs of elimination. The characteristic phasic time course of drug concentration in plasma represents the sum of the constituent processes of absorption, distribution, and elimination, which overlap in time. When distribution takes place significantly faster than elimination, there is an initial rapid and then a greatly retarded fall in the plasma level, the former being designated the α-phase (distribution phase), the latter the β-phase (elimination phase). When the drug is distributed faster than it is absorbed, the time course of the plasma level can be described in mathe- matically simplified form by the Bate-

Pharmacokinetics 47

Absorption Distribution Elimination Uptake from into body from body by stomach and tissues: biotransformation intestines α-phase (chemical alteration), into blood excretion via kidney: ß-phase

Bateman-function Dose k c = x 1 x (e-k1t-e-k2t) ˜ Vapp k2 - k1 Drug concentration in blood (c) Time (t)

A. Time course of drug concentration

Intravenous

Intramuscular

Subcutaneous

Oral Drug concentration in blood (c) Time (t)

B. Mode of application and time course of drug concentration

48 Pharmacokinetics

Time Course of Drug Plasma Levels Time Course of Drug Plasma Levels During Repeated Dosing (A) During Irregular Intake (B)

When a drug is administered at regular In practice, it proves difficult to achieve intervals over a prolonged period, the a plasma level that undulates evenly rise and fall of drug concentration in around the desired effective concentra- blood will be determined by the relation. For instance, if two successive dos- tionship between the half-life of elimi- es are omitted, the plasma level will nation and the time interval between drop below the therapeutic range and a doses. If the drug amount administered longer period will be required to regain in each dose has been eliminated before the desired plasma level. In everyday the next dose is applied, repeated intake life, patients will be apt to neglect drug at constant intervals will result in simi- intake at the scheduled time. Patient lar plasma levels. If intake occurs before compliance means strict adherence to the preceding dose has been eliminated the prescribed regimen. Apart from completely, the next dose will add on to poor compliance, the same problem the residual amount still present in the may occur when the total daily dose is body, i.e., the drug accumulates. The divided into three individual doses (tid) shorter the dosing interval relative to and the first dose is taken at breakfast, the elimination half-life, the larger will the second at lunch, and the third at be the residual amount of drug to which supper. Under this condition, the noc- the next dose is added and the more ex- turnal dosing interval will be twice the tensively will the drug accumulate in diurnal one. Consequently, plasma lev- the body. However, at a given dosing els during the early morning hours may frequency, the drug does not accumu- have fallen far below the desired or, late infinitely and a steady state (Css) or possibly, urgently needed range. accumulation equilibrium is eventually reached. This is so because the activity of elimination processes is concentration-dependent. The higher the drug concentration rises, the greater is the amount eliminated per unit of time. Af- ter several doses, the concentration will have climbed to a level at which the amounts eliminated and taken in per unit of time become equal, i.e., a steady state is reached. Within this concentration range, the plasma level will continue to rise (peak) and fall (trough) as dosing is continued at a regular interval. The height of the steady state (Css) depends upon the amount (D) administered per dosing interval (τ) and the clearance (Cltot): D Css = ––––––––– (τ · Cltot) The speed at which the steady state is reached corresponds to the speed of elimination of the drug. The time needed to reach 90 % of the concentration plateau is about 3 times the t1/2 of elimination.

Pharmacokinetics 49

Dosing interval

Time

Dosing interval Drug concentration

Time

Accumulation: Steady state: administered drug is drug intake equals not completely eliminated elimination during during interval dosing interval Drug concentration

Time

A. Time course of drug concentration in blood during regular intake

Desired therapeutic level Drug concentration

?? ? Time

B. Time course of drug concentration with irregular intake

50 Pharmacokinetics

Accumulation: Dose, Dose Interval, and optimal plasma level is attained only af- Plasma Level Fluctuation ter a long period. Here, increasing the initial doses (loading dose) will speed Successful drug therapy in many illness- up the attainment of equilibrium, which es is accomplished only if drug concen- is subsequently maintained with a low- tration is maintained at a steady high er dose (maintenance dose). level. This requirement necessitates regular drug intake and a dosage sched- Change in Elimination Characteristics ule that ensures that the plasma con- During Drug Therapy (B) centration neither falls below the therapeutically effective range nor exceeds With any drug taken regularly and accu- the minimal toxic concentration. A con- mulating to the desired plasma level, it stant plasma level would, however, be is important to consider that conditions undesirable if it accelerated a loss of ef- for biotransformation and excretion do fectiveness (development of tolerance), not necessarily remain constant. Elimi- or if the drug were required to be nation may be hastened due to enzyme present at specified times only. induction (p. 32) or to a change in uri- A steady plasma level can be nary pH (p. 40). Consequently, the achieved by giving the drug in a con- steady-state plasma level declines to a stant intravenous infusion, the steady- new value corresponding to the new state plasma level being determined by rate of elimination. The drug effect may the infusion rate, dose D per unit of time diminish or disappear. Conversely, τ, and the clearance, according to the when elimination is impaired (e.g., in equation: progressive renal insufficiency), the mean plasma level of renally eliminated D Css = ––––––––– drugs rises and may enter a toxic con- (τ · Cl ) tot centration range. This procedure is routinely used in intensive care hospital settings, but is otherwise impracticable. With oral administration, dividing the total daily dose into several individual ones, e.g., four, three, or two, offers a practical compromise. When the daily dose is given in several divided doses, the mean plasma level shows little fluctuation. In practice, it is found that a regimen of frequent regular drug ingestion is not well adhered to by patients. The degree of fluctuation in plasma level over a given dosing interval can be reduced by use of a dosage form permitting slow (sustained) release (p. 10). The time required to reach steady- state accumulation during multiple constant dosing depends on the rate of elimination. As a rule of thumb, a plateau is reached after approximately three elimination half-lives (t1/2). For slowly eliminated drugs, which tend to accumulate extensively (phenprocoumon, digitoxin, methadone), the

Pharmacokinetics 51

4 x daily 50 mg

2 x daily 100 mg plasma level Desired 1 x daily 200 mg Drug concentration in blood Single 50 mg

6 12 18 24 6 12 18 24 6 12 18 24 6 12

A. Accumulation: dose, dose interval, and fluctuation of plasma level

Inhibition of elimination

Acceleration plasma level Desired

Drug concentration in blood of elimination

6 12 18 24 6 12 18 24 6 12 18 24 6 12 18

B. Changes in elimination kinetics in the course of drug therapy

52 Quantification of Drug Action

Dose–Response Relationship the dose at which one-half of the group has responded. The dose range encom- The effect of a substance depends on the passing the dose-frequency relationship amount administered, i.e., the dose. If reflects the variation in individual sensi- the dose chosen is below the critical tivity to the drug. Although similar in threshold (subliminal dosing), an effect shape, a dose-frequency relationship will be absent. Depending on the nature has, thus, a different meaning than does of the effect to be measured, ascending a dose-effect relationship. The latter can doses may cause the effect to increase in be evaluated in one individual and re- intensity. Thus, the effect of an antipy- sults from an intraindividual dependen- retic or hypotensive drug can be quanti- cy of the effect on drug concentration. fied in a graded fashion, in that the ex- The evaluation of a dose-effect rela- tent of fall in body temperature or blood tionship within a group of human sub- pressure is being measured. A dose-ef- jects is compounded by interindividual fect relationship is then encountered, as differences in sensitivity. To account for discussed on p. 54. the biological variation, measurements The dose-effect relationship may have to be carried out on a representa- vary depending on the sensitivity of the tive sample and the results averaged. individual person receiving the drug, Thus, recommended therapeutic doses i.e., for the same effect, different doses will be appropriate for the majority of may be required in different individuals. patients, but not necessarily for each in- Interindividual variation in sensitivity is dividual. especially obvious with effects of the The variation in sensitivity may be “all-or-none” kind. based on pharmacokinetic differences To illustrate this point, we consider (same dose different plasma levels) an experiment in which the subjects in- or on differences in target organ sensi- dividually respond in all-or-none fash- tivity (same plasma level different ef- ion, as in the Straub tail phenomenon fects). (A). Mice react to morphine with excitation, evident in the form of an abnormal posture of the tail and limbs. The dose dependence of this phenomenon is observed in groups of animals (e.g., 10 mice per group) injected with increasing doses of morphine. At the low dose, only the most sensitive, at increasing doses a growing proportion, at the highest dose all of the animals are affected (B). There is a relationship between the frequency of responding animals and the dose given. At 2 mg/kg, one out of 10 animals reacts; at 10 mg/kg, 5 out of 10 respond. The dose-frequency relationship results from the different sensitivity of individuals, which as a rule exhibits a log-normal distribution (C, graph at right, linear scale). If the cumulative frequency (total number of animals responding at a given dose) is plotted against the logarithm of the dose (abscissa), a sigmoidal curve results (C, graph at left, semilogarithmic scale). The inflection point of the curve lies at

Quantification of Drug Action 53

A. Abnormal posture in mouse given morphine

Dose = 0 = 2 mg/kg = 10 mg/kg

= 20 mg/kg= 100 mg/kg = 140 mg/kg

B. Incidence of effect as a function of dose

% Cumulative frequency Frequency of dose needed 100

80 4

60 3

40 2

20 1

mg/kg 210 20 100 140 210 20 100 140 mg/kg

C. Dose-frequency relationship

54 Quantification of Drug Action

Concentration-Effect Relationship (A) it would be impossible in the intact organism to follow negative chrono- The relationship between the concen- tropic effects to the point of cardiac tration of a drug and its effect is deter- arrest. mined in order to define the range of active drug concentrations (potency) and Disadvantages are: the maximum possible effect (efficacy). 1. Unavoidable tissue injury during dis- On the basis of these parameters, differ- section. ences between drugs can be quantified. 2. Loss of physiological regulation of As a rule, the therapeutic effect or toxic function in the isolated tissue. action depends critically on the re- 3. The artificial milieu imposed on the sponse of a single organ or a limited tissue. number of organs, e.g., blood flow is affected by a change in vascular luminal Concentration-Effect Curves (B) width. By isolating critical organs or tissues from a larger functional system, As the concentration is raised by a con- these actions can be studied with more stant factor, the increment in effect di- accuracy; for instance, vasoconstrictor minishes steadily and tends asymptoti- agents can be examined in isolated cally towards zero the closer one comes preparations from different regions of to the maximally effective concentra- the vascular tree, e.g., the portal or tion.The concentration at which a maxi- saphenous vein, or the mesenteric, cor- mal effect occurs cannot be measured onary, or basilar artery. In many cases, accurately; however, that eliciting a isolated organs or organ parts can be half-maximal effect (EC50) is readily de- kept viable for hours in an appropriate termined. It typically corresponds to the nutrient medium sufficiently supplied inflection point of the concentra- with oxygen and held at a suitable tem- tion–response curve in a semilogarith- perature. mic plot (log concentration on abscissa). Responses of the preparation to a Full characterization of a concentra- physiological or pharmacological stim- tion–effect relationship requires deter- ulus can be determined by a suitable re- mination of the EC50, the maximally cording apparatus. Thus, narrowing of a possible effect (Emax), and the slope at blood vessel is recorded with the help of the point of inflection. two clamps by which the vessel is suspended under tension. Experimentation on isolated organs offers several advantages: 1. The drug concentration in the tissue is usually known. 2. Reduced complexity and ease of re- lating stimulus and effect. 3. It is possible to circumvent compensatory responses that may partially cancel the primary effect in the intact organism — e.g., the heart rate increasing action of norepinephrine cannot be demonstrated in the intact organism, because a simultaneous rise in blood pressure elicits a counter-regulatory reflex that slows cardiac rate. 4. The ability to examine a drug effect over its full rage of intensities — e.g.,

Quantification of Drug Action 55

Portal vein Coronary Basilar Saphenous Mesenteric artery artery artery vein

Vasoconstriction 1 min Active tension

1 2 5 10 20 30 40 50 100 Drug concentration

A. Measurement of effect as a function of concentration

Effect % Effect 50 (in mm of registration unit, 100 (% of maximum effect) e.g., tension developed) 40 80

30 60

20 40

10 20

10 20 30 40 50 1 10 100 Concentration (linear) Concentration (logarithmic)

B. Concentration-effect relationship

56 Quantification of Drug Action

Concentration-Binding Curves c B = Bmax · ––––––– c + KD In order to elicit their effect, drug molecules must be bound to the cells of the KD is the equilibrium dissociation con- effector organ. Binding commonly oc- stant and corresponds to that ligand curs at specific cell structures, namely, concentration at which 50 % of binding the receptors. The analysis of drug bind- sites are occupied. The values given in ing to receptors aims to determine the (A) and used for plotting the concentra- affinity of ligands, the kinetics of inter- tion-binding graph (B) result when KD = action, and the characteristics of the 10. binding site itself. The differing affinity of different li- In studying the affinity and number gands for a binding site can be demon- of such binding sites, use is made of strated elegantly by binding assays. Al- membrane suspensions of different tis- though simple to perform, these bind- sues. This approach is based on the ex- ing assays pose the difficulty of correlat- pectation that binding sites will retain ing unequivocally the binding sites con- their characteristic properties during cerned with the pharmacological effect; cell homogenization. Provided that this is particularly difficult when more binding sites are freely accessible in the than one population of binding sites is medium in which membrane fragments present. Therefore, receptor binding are suspended, drug concentration at must not be implied until it can be the “site of action” would equal that in shown that the medium. The drug under study is ra- • binding is saturable (saturability); diolabeled (enabling low concentra- • the only substances bound are those tions to be measured quantitatively), possessing the same pharmacological added to the membrane suspension, mechanism of action (specificity); and allowed to bind to receptors. Mem- • binding affinity of different substanc- brane fragments and medium are then es is correlated with their pharmaco- separated, e.g., by filtration, and the logical potency. amount of bound drug is measured. Binding assays provide information Binding increases in proportion to con- about the affinity of ligands, but they do centration as long as there is a negligible not give any clue as to whether a ligand reduction in the number of free binding is an agonist or antagonist (p. 60). Use of sites (c = 1 and B ≈ 10% of maximum radiolabeled drugs bound to their re- binding; c = 2 and B ≈ 20 %). As binding ceptors may be of help in purifying and approaches saturation, the number of analyzing further the receptor protein. free sites decreases and the increment in binding is no longer proportional to the increase in concentration (in the example illustrated, an increase in concentration by 1 is needed to increase binding from 10 to 20 %; however, an increase by 20 is needed to raise it from 70 to 80 %). The law of mass action describes the hyperbolic relationship between binding (B) and ligand concentration (c). This relationship is characterized by the drug’s affinity (1/KD) and the maximum binding (Bmax), i.e., the total number of binding sites per unit of weight of membrane homogenate.

Quantification of Drug Action 57

Addition of radiolabeled drug in different Organs concentrations

Homogenization Membrane Mixing and incubation suspension

Determination of radioactivity Centrifugation

c = 1 c = 2 c = 5 B = 10% B = 20% B = 30%

c = 10 c = 20 c = 40 B = 50% B = 70% B = 80%

A. Measurement of binding (B) as a function of concentration (c)

% Binding (B) % Binding (B) 100 100

80 80

60 60

40 40

20 20

10 20 30 40 50 1 10 100 Concentration (linear) Concentration (logarithmic) B. Concentration-binding relationship

58 Drug-Receptor Interaction

Types of Binding Forces partial charges. When a hydrogen atom bearing a partial positive charge bridges Unless a drug comes into contact with two atoms bearing a partial negative intrinsic structures of the body, it can- charge, a hydrogen bond is created. not affect body function. A van der Waals’ bond (B) is Covalent bond. Two atoms enter a formed between apolar molecular covalent bond if each donates an elec- groups that have come into close prox- tron to a shared electron pair (cloud). imity. Spontaneous transient distortion This state is depicted in structural for- of electron clouds (momentary faint di- mulas by a dash. The covalent bond is pole, δδ) may induce an opposite dipole “firm”, that is, not reversible or only in the neighboring molecule. The van poorly so. Few drugs are covalently der Waals’ bond, therefore, is a form of bound to biological structures. The electrostatic attraction, albeit of very bond, and possibly the effect, persist for low strength (inversely proportional to a long time after intake of a drug has the seventh power of the distance). been discontinued, making therapy dif- Hydrophobic interaction (C). The ficult to control. Examples include alky- attraction between the dipoles of water lating cytostatics (p. 298) or organo- is strong enough to hinder intercalation phosphates (p. 102). Conjugation reac- of any apolar (uncharged) molecules. By tions occurring in biotransformation al- tending towards each other, H2O mole- so represent a covalent linkage (e.g., to cules squeeze apolar particles from glucuronic acid, p. 38). their midst. Accordingly, in the organ- Noncovalent bond. There is no for- ism, apolar particles have an increased mation of a shared electron pair. The probability of staying in nonaqueous, bond is reversible and typical of most apolar surroundings, such as fatty acid drug-receptor interactions. Since a drug chains of cell membranes or apolar re- usually attaches to its site of action by gions of a receptor. multiple contacts, several of the types of bonds described below may participate. Electrostatic attraction (A). A positive and negative charge attract each other. Ionic interaction: An ion is a particle charged either positively (cation) or negatively (anion), i.e., the atom lacks or has surplus electrons, respectively. At- traction between ions of opposite charge is inversely proportional to the square of the distance between them; it is the initial force drawing a charged drug to its binding site. Ionic bonds have a relatively high stability. Dipole-ion interaction: When bond electrons are asymmetrically distributed over both atomic nuclei, one atom will bear a negative (δ–), and its partner a positive (δ+) partial charge. The molecule thus presents a positive and a negative pole, i.e., has polarity or a dipole. A partial charge can interact electrostati- cally with an ion of opposite charge. Dipole-dipole interaction is the electrostatic attraction between opposite

Drug-Receptor Interaction 59

Drug + Binding site Complex

+ – + – D 50nm D

Ion Ion Ionic bond

δ+ δ– δ+ δ– – – D 1.5nm D

Dipole (permanent) Ion

δ+ δ– δ– δ+ δ– δ– D 0.5nm D δ+ δ+

D = Drug Dipole Dipole Hydrogen bond

A. Electrostatic attraction

δδ+ δδ– δδ– δδ+ D D δδ– δδ+ δδ+ δδ–

Induced transient fluctuating dipoles B. van der Waals’ bond δ+ "Repulsion" of apolar particle in polar solvent (H O) δ− apolar 2 polar

Apolar acyl chain

Insertion in apolar membrane interior Adsorption to Phospholipid membrane apolar surface

C. Hydrophobic interaction

60 Drug-Receptor Interaction

Agonists – Antagonists tive receptor without causing a conformational change. An agonist has affinity (binding avidity) Agonist stabilizes spontaneously for its receptor and alters the receptor occurring active conformation. The protein in such a manner as to generate receptor can spontaneously “flip” into a stimulus that elicits a change in cell the active conformation. However, the function: “intrinsic activity“. The bio- statistical probability of this event is logical effect of the agonist, i.e., the usually so small that the cells do not re- change in cell function, depends on the veal signs of spontaneous receptor acti- efficiency of signal transduction steps vation. Selective binding of the agonist (p. 64, 66) initiated by the activated re- requires the receptor to be in the active ceptor. Some agonists attain a maximal conformation, thus promoting its exis- effect even when they occupy only a tence. The “antagonist” displays affinity small fraction of receptors (B, agonist only for the inactive state and stabilizes A). Other ligands (agonist B), possessing the latter. When the system shows min- equal affinity for the receptor but lower imal spontaneous activity, application activating capacity (lower intrinsic ac- of an antagonist will not produce a mea- tivity), are unable to produce a full max- surable effect. When the system has imal response even when all receptors high spontaneous activity, the antago- are occupied: lower efficacy. Ligand B is nist may cause an effect that is the op- a partial agonist. The potency of an ago- posite of that of the agonist: inverse agonist can be expressed in terms of the nist. concentration (EC50) at which the effect A “true” antagonist lacking intrinsic reaches one-half of its respective maxi- activity (“neutral antagonist”) displays mum. equal affinity for both the active and in- Antagonists (A) attenuate the ef- active states of the receptor and does fect of agonists, that is, their action is not alter basal activity of the cell. “anti-agonistic”. According to this model, a partial ago- Competitive antagonists possess nist shows lower selectivity for the ac- affinity for receptors, but binding to the tive state and, to some extent, also binds receptor does not lead to a change in to the receptor in its inactive state. cell function (zero intrinsic activity). When an agonist and a competitive Other Forms of Antagonism antagonist are present simultaneously, affinity and concentration of the two ri- Allosteric antagonism. The antagonist vals will determine the relative amount is bound outside the receptor agonist of each that is bound. Thus, although the binding site proper and induces a de- antagonist is present, increasing the crease in affinity of the agonist. It is also concentration of the agonist can restore possible that the allosteric deformation the full effect (C). However, in the pres- of the receptor increases affinity for an ence of the antagonist, the concentra- agonist, resulting in an allosteric syner- tion-response curve of the agonist is gism. shifted to higher concentrations (“right- Functional antagonism. Two ago- ward shift”). nists affect the same parameter (e.g., bronchial diameter) via different recep- Molecular Models of Agonist/Antagonist tors in the opposite direction (epineph- Action (A) rine dilation; histamine constriction). Agonist induces active conformation. The agonist binds to the inactive receptor and thereby causes a change from the resting conformation to the active state. The antagonist binds to the inac-

Drug-Receptor Interaction 61

Agonist Antagonist Antagonist Agonist Rare spontaneous transition Receptor inactive active

Agonist Antagonist Antagonist Agonist induces active occupies receptor selects inactive selects active conformation of without con- receptor receptor receptor protein formational change conformation conformation

A. Molecular mechanisms of drug-receptor interaction

Receptors Increase in tension Agonist A Receptor occupation Efficacy EC50 EC50

Concentration (log) of agonist

smooth muscle cell Agonist B Potency

B. Potency and Efficacy of agonists

Agonist effect

01 10 100 1000 10000 Concentration of antagonist

Agonist concentration (log) C. Competitive antagonism

62 Drug-Receptor Interaction

Enantioselectivity of Drug Action rinic ACh receptors almost 10000 times (p. 98) that of levetimide; and at β- Many drugs are racemates, including β- adrenoceptors, S(-)-propranolol has an blockers, nonsteroidal anti-inflammato- affinity 100 times that of the R(+)-form. ry agents, and anticholinergics (e.g., Enantioselectivity of intrinsic ac- benzetimide A). A racemate consists of tivity. The mode of attachment at the a molecule and its corresponding mirror receptor also determines whether an ef- image which, like the left and right fect is elicited and whether or not a sub- hand, cannot be superimposed. Such stance has intrinsic activity, i.e., acts as chiral (“handed”) pairs of molecules are an agonist or antagonist. For instance, referred to as enantiomers. Usually, (-) dobutamine is an agonist at α-adren- chirality is due to a carbon atom (C) oceptors whereas the (+)-enantiomer is linked to four different substituents an antagonist. (“asymmetric center”). Enantiomerism is Inverse enantioselectivity at an- a special case of stereoisomerism. Non- other receptor. An enantiomer may chiral stereoisomers are called diaster- possess an unfavorable configuration at eomers (e.g., quinidine/quinine). one receptor that may, however, be op- Bond lengths in enantiomers, but timal for interaction with another re- not in diastereomers, are the same. ceptor. In the case of dobutamine, the Therefore, enantiomers possess similar (+)-enantiomer has affinity at β-adreno- physicochemical properties (e.g., solu- ceptors 10 times higher than that of the bility, melting point) and both forms are (-)-enantiomer, both having agonist ac- usually obtained in equal amounts by tivity. However, the α-adrenoceptor chemical synthesis. As a result of enzy- stimulant action is due to the (-)-form matic activity, however, only one of the (see above). enantiomers is usually found in nature. As described for receptor interac- In solution, enantiomers rotate the tions, enantioselectivity may also be wave plane of linearly polarized light manifested in drug interactions with in opposite directions; hence they are enzymes and transport proteins. Enan- refered to as “dextro”- or “levo-rotatory”, tiomers may display different affinities designated by the prefixes d or (+) and l and reaction velocities. or (-), respectively. The direction of ro- Conclusion: The enantiomers of a tation gives no clue concerning the spa- racemate can differ sufficiently in their tial structure of enantiomers. The abso- pharmacodynamic and pharmacokinet- lute configuration, as determined by ic properties to constitute two distinct certain rules, is described by the prefix- drugs. es S and R. In some compounds, designation as the D- and L-form is possible by reference to the structure of D- and L-glyceraldehyde. For drugs to exert biological actions, contact with reaction partners in the body is required. When the reaction favors one of the enantiomers, enantioselectivity is observed. Enantioselectivity of affinity. If a receptor has sites for three of the substituents (symbolized in B by a cone, a sphere, and a cube) on the asymmetric carbon to attach to, only one of the enantiomers will have optimal fit. Its affinity will then be higher. Thus, dexetimide displays an affinity at the musca-

Drug-Receptor Interaction 63

RACEMATE Benzetimide

ENANTIOMER Ratio ENANTIOMER Dexetimide 1 : 1 Levetimide

Physicochemical properties equal

+ 125° Deflection of polarized light - 125° (Dextrorotatory) α 20 (Levorotatory [ ] D

S = sinisterAbsolute configuration R = rectus

ca. 10 000Potency 1 (rel. affinity at m-ACh-receptors

A. Example of an enantiomeric pair with different affinity for A. a stereoselective receptor

C C Transport protein Transport Affinity

Transport protein

Pharmacodynamic Intrinsic Turnover Pharmacokinetic properties activity rate properties

B. Reasons for different pharmacological properties of enantiomers

64 Drug-Receptor Interaction

Receptor Types the GABAA subtype is linked to a chloride channel (and also to a benzodiaze- Receptors are macromolecules that bind pine-binding site, see p. 227). Gluta- mediator substances and transduce this mate and glycine both act via ligand- binding into an effect, i.e., a change in gated ion channels. cell function. Receptors differ in terms The insulin receptor protein repre- of their structure and the manner in sents a ligand-operated enzyme (C), a which they translate occupancy by a li- catalytic receptor. When insulin binds gand into a cellular response (signal to the extracellular attachment site, a transduction). tyrosine kinase activity is “switched on” G-protein-coupled receptors (A) at the intracellular portion. Protein consist of an amino acid chain that phosphorylation leads to altered cell weaves in and out of the membrane in function via the assembly of other signal serpentine fashion. The extramembra- proteins. Receptors for growth hor- nal loop regions of the molecule may mones also belong to the catalytic re- possess sugar residues at different N- ceptor class. glycosylation sites. The seven α-helical Protein synthesis-regulating re- membrane-spanning domains probably ceptors (D) for steroids, thyroid hor- form a circle around a central pocket mone, and retinoic acid are found in the that carries the attachment sites for the cytosol and in the cell nucleus, respec- mediator substance. Binding of the me- tively. diator molecule or of a structurally re- Binding of hormone exposes a nor- lated agonist molecule induces a change mally hidden domain of the receptor in the conformation of the receptor pro- protein, thereby permitting the latter to tein, enabling the latter to interact with bind to a particular nucleotide sequence a G-protein (= guanyl nucleotide-bind- on a gene and to regulate its transcrip- ing protein). G-proteins lie at the inner tion. Transcription is usually initiated or leaf of the plasmalemma and consist of enhanced, rarely blocked. three subunits designated α, β, and γ. There are various G-proteins that differ mainly with regard to their α-unit. As- sociation with the receptor activates the G-protein, leading in turn to activation of another protein (enzyme, ion channel). A large number of mediator substances act via G-protein-coupled receptors (see p. 66 for more details). An example of a ligand-gated ion channel (B) is the nicotinic cholinoceptor of the motor endplate. The receptor complex consists of five subunits, each of which contains four transmembrane domains. Simultaneous binding of two acetylcholine (ACh) molecules to the two α-subunits results in opening of the ion channel, with entry of Na+ (and exit of some K+), membrane depolarization, and triggering of an action potential (p. 82). The ganglionic N-cholinoceptors apparently consist only of α and β subunits (α2β2). Some of the receptors for the transmitter γ-aminobutyric acid (GABA) belong to this receptor family:

Drug-Receptor Interaction 65

Amino acids Agonist -NH2 H2N

3 7 4 6 34567 5 G- Protein COOH COOH Effector protein Effector α-Helices Transmembrane domains Effect

A. G-Protein-coupled receptor

+ Na K+ Insulin ACh ACh

S S γ δ αα S S S S β Nicotinic acetylcholine receptor

Subunit Tyrosine kinase consisting of four transmembrane + Phosphorylation of Na+ K domains tyrosine-residues in proteins

B. Ligand-gated ion channel C. Ligand-regulated enzyme

Cytosol Nucleus

Tran- scription Steroid Trans- Hormone lation Protein DNA mRNA

Receptor

D. Protein synthesis-regulating receptor

66 Drug-Receptor Interaction

Mode of Operation of G-Protein- 84). Phosphorylation of cardiac cal- Coupled Receptors cium-channel proteins increases the probability of channel opening during Signal transduction at G-protein-cou- membrane depolarization. It should be pled receptors uses essentially the same noted that cAMP is inactivated by phos- basic mechanisms (A). Agonist binding phodiesterase. Inhibitors of this enzyme to the receptor leads to a change in re- elevate intracellular cAMP concentra- ceptor protein conformation. This tion and elicit effects resembling those change propagates to the G-protein: the of epinephrine. α-subunit exchanges GDP for GTP, then The receptor protein itself may dissociates from the two other subunits, undergo phosphorylation, with a resul- associates with an effector protein, and tant loss of its ability to activate the as- alters its functional state. The α-subunit sociated G-protein. This is one of the slowly hydrolyzes bound GTP to GDP. mechanisms that contributes to a de- Gα-GDP has no affinity for the effector crease in sensitivity of a cell during pro- protein and reassociates with the β and longed receptor stimulation by an ago- γ subunits (A). G-proteins can undergo nist (desensitization). lateral diffusion in the membrane; they Activation of phospholipase C leads are not assigned to individual receptor to cleavage of the membrane phospho- proteins. However, a relation exists lipid phosphatidylinositol-4,5 bisphos- between receptor types and G-protein phate into inositol trisphosphate (IP3) types (B). Furthermore, the α-subunits and diacylglycerol (DAG). IP3 promotes of individual G-proteins are distinct in release of Ca2+ from storage organelles, terms of their affinity for different effec- whereby contraction of smooth muscle tor proteins, as well as the kind of influ- cells, breakdown of glycogen, or exocy- ence exerted on the effector protein. Gα- tosis may be initiated. Diacylglycerol GTP of the GS-protein stimulates adeny- stimulates protein kinase C, which late cyclase, whereas Gα-GTP of the Gi- phosphorylates certain serine- or threo- protein is inhibitory. The G-protein- nine-containing enzymes. coupled receptor family includes mus- The α-subunit of some G-proteins carinic cholinoceptors, adrenoceptors may induce opening of a channel pro- for norepinephrine and epinephrine, re- tein. In this manner, K+ channels can be ceptors for dopamine, histamine, serot- activated (e.g., ACh effect on sinus node, onin, glutamate, GABA, morphine, pros- p. 100; opioid action on neural impulse taglandins, leukotrienes, and many oth- transmission, p. 210). er mediators and hormones. Major effector proteins for G-protein-coupled receptors include adenylate cyclase (ATP intracellular messenger cAMP), phospholipase C (phosphatidylinositol intracellular mes- sengers inositol trisphosphate and diacylglycerol), as well as ion channel proteins. Numerous cell functions are regulated by cellular cAMP concentration, because cAMP enhances activity of protein kinase A, which catalyzes the transfer of phosphate groups onto functional proteins. Elevation of cAMP levels inter alia leads to relaxation of smooth muscle tonus and enhanced contractility of cardiac muscle, as well as increased glycogenolysis and lipolysis (p.

Drug-Receptor Interaction 67

Receptor G-Protein Effector Agonist protein

β β α γ α γ

GDP GTP

β β γ α γ α

A. G-Protein-mediated effect of an agonist

DAG Adenylate cyclase Gs + - Gi Facilitation P of ion ATP P channel

Phospholipase C P C Proteinkinase cAMP opening IP3 Ca2+ Protein kinase A Transmembrane Activation ion movements Phosphorylation Phosphorylation of functional proteins of enzymes Effect on:

e. g., Glycogenolysis e. g., Contraction e. g., Membrane lipolysis of smooth muscle, action potential, Ca-channel glandular homeostasis of activation secretion cellular ions

B. G-Proteins, cellular messenger substances, and effects

68 Drug-Receptor Interaction

Time Course of Plasma Concentration The dose dependence of the time and Effect course of the drug effect is exploited when the duration of the effect is to be After the administration of a drug, its prolonged by administration of a dose concentration in plasma rises, reaches a in excess of that required for the effect. peak, and then declines gradually to the This is done in the case of penicillin G starting level, due to the processes of (p. 268), when a dosing interval of 8 h is distribution and elimination (p. 46). being recommended, although the drug Plasma concentration at a given point in is eliminated with a half-life of 30 min. time depends on the dose administered. This procedure is, of course, feasible on- Many drugs exhibit a linear relationship ly if supramaximal dosing is not asso- between plasma concentration and ciated with toxic effects. dose within the therapeutic range Futhermore it follows that a nearly (dose-linear kinetics; (A); note differ- constant effect can be achieved, al- ent scales on ordinate). However, the though the plasma level may fluctuate same does not apply to drugs whose greatly during the interval between elimination processes are already suffi- doses. ciently activated at therapeutic plasma The hyperbolic relationship be levels so as to preclude further propor- tween plasma concentration and effect tional increases in the rate of elimina- explains why the time course of the ef- tion when the concentration is infect, unlike that of the plasma concen- creased further. Under these conditions, tration, cannot be described in terms of a smaller proportion of the dose admin- a simple exponential function. A half- istered is eliminated per unit of time. life can be given for the processes of The time course of the effect and of drug absorption and elimination, hence the concentration in plasma are not for the change in plasma levels, but ge- identical, because the concentration- nerally not for the onset or decline of effect relationships obeys a hyperbolic the effect. function (B; cf. also p. 54). This means that the time course of the effect exhibits dose dependence also in the presence of dose-linear kinetics (C). In the lower dose range (example 1), the plasma level passes through a concentration range (0 0.9) in which the concentration effect relationship is quasi-linear. The respective time cours- es of plasma concentration and effect (A and C, left graphs) are very similar. However, if a high dose (100) is applied, there is an extended period of time during which the plasma level will remain in a concentration range (between 90 and 20) in which a change in concentration does not cause a change in the size of the effect. Thus, at high doses (100), the time-effect curve exhibits a kind of plateau. The effect declines only when the plasma level has returned (below 20) into the range where a change in plasma level causes a change in the intensity of the effect.

Drug-Receptor Interaction 69

Concentration Concentration Concentration 1,0 10 100

0,5 5 50 t1 t1 t1 2 2 2

0,1 1 10

Time Time Time Dose = 1 Dose = 10 Dose = 100

A. Dose-linear kinetics

100 Effect

0 Concentration

1 10 20 30 40 50 60 70 80 90 100

B. Concentration-effect relationship

Effect Effect Effect 100 100 100

50 50 50

10 10 10

Time Time Time Dose = 1 Dose = 10 Dose = 100

C. Dose dependence of the time course of effect

70 Adverse Drug Effects

Adverse Drug Effects premature breakdown of red blood cells (hemolysis) in subjects with a glucose- The desired (or intended) principal ef- 6-phosphate dehydrogenase deficiency. fect of any drug is to modify body func- The discipline of pharmacogenetics deals tion in such a manner as to alleviate with the importance of the genotype for symptoms caused by the patient’s ill- reactions to drugs. ness. In addition, a drug may also cause The above forms of hypersensitivity unwanted effects that can be grouped must be distinguished from allergies in- into minor or “side” effects and major or volving the immune system (p. 72). adverse effects. These, in turn, may give Lack of selectivity (C). Despite ap- rise to complaints or illness, or may propriate dosing and normal sensitivity, even cause death. undesired effects can occur because the Causes of adverse effects: over- drug does not specifically act on the tar- dosage (A). The drug is administered in geted (diseased) tissue or organ. For in- a higher dose than is required for the stance, the anticholinergic, atropine, is principal effect; this directly or indirect- bound only to acetylcholine receptors of ly affects other body functions. For in- the muscarinic type; however, these are stances, morphine (p. 210), given in the present in many different organs. appropriate dose, affords excellent pain Moreover, the neuroleptic, chlor- relief by influencing nociceptive path- promazine, formerly used as a neuro- ways in the CNS. In excessive doses, it leptic, is able to interact with several inhibits the respiratory center and different receptor types. Thus, its action makes apnea imminent. The dose de- is neither organ-specific nor receptor- pendence of both effects can be graphed specific. in the form of dose-response curves The consequences of lack of selec- (DRC). The distance between both DRCs tivity can often be avoided if the drug indicates the difference between the does not require the blood route to therapeutic and toxic doses. This margin reach the target organ, but is, instead, of safety indicates the risk of toxicity applied locally, as in the administration when standard doses are exceeded. of parasympatholytics in the form of eye “The dose alone makes the poison” drops or in an aerosol for inhalation. (Paracelsus). This holds true for both With every drug use, unwanted ef- medicines and environmental poisons. fects must be taken into account. Before No substance as such is toxic! In order to prescribing a drug, the physician should assess the risk of toxicity, knowledge is therefore assess the risk: benefit ratio. required of: 1) the effective dose during In this, knowledge of principal and ad- exposure; 2) the dose level at which verse effects is a prerequisite. damage is likely to occur; 3) the duration of exposure. Increased Sensitivity (B). If certain body functions develop hyperreactivity, unwanted effects can occur even at normal dose levels. Increased sensitivity of the respiratory center to morphine is found in patients with chronic lung disease, in neonates, or during concurrent exposure to other respiratory depressant agents. The DRC is shifted to the left and a smaller dose of morphine is sufficient to paralyze respiration. Genetic anomalies of metabolism may also lead to hypersensitivity. Thus, several drugs (aspirin, antimalarials, etc.) can provoke

Adverse Drug Effects 71

Decrease in Effect Respiratory depression pain perception Decrease in (nociception) Nociception Respira- Morphine tory overdose activity Morphine Safety margin

Dose

A. Adverse drug effect: overdosing

Increased Effect sensitivity of respiratory Safety center margin

Normal dose

Dose

B. Adverse drug effect: increased sensitivity

e. g., Chlor- Atropine promazine

mACh- mACh- receptor receptor Receptor specificity but lacking organ α-adreno- selectivity ceptor

Atropine Dopamine receptor

Histamine receptor Lacking receptor specificity

C. Adverse drug effect: lacking selectivity

72 Adverse Drug Effects

Drug Allergy ready formed in blood accumulate. These complexes mediate the activation The immune system normally functions of complement, a family of proteins that to rid the organism of invading foreign circulate in the blood in an inactive particles, such as bacteria. Immune re- form, but can be activated in a cascade- sponses can occur without appropriate like succession by an appropriate stimu- cause or with exaggerated intensity and lus. “Activated complement” normally may harm the organism, for instance, directed against microorganisms, can when allergic reactions are caused by destroy the cell membranes and thereby drugs (active ingredient or pharmaceu- cause cell death; it also promotes pha- tical excipients). Only a few drugs, e.g. gocytosis, attracts neutrophil granulo- (heterologous) proteins, have a molecu- cytes (chemotaxis), and stimulates oth- lar mass (> 10,000) large enough to act er inflammatory responses. Activation as effective antigens or immunogens, of complement on blood cells results in capable by themselves of initiating an their destruction, evidenced by hemo- immune response. Most drugs or their lytic anemia, agranulocytosis, and metabolites (so-called haptens) must thrombocytopenia. first be converted to an antigen by link- Type 3, immune complex vascu- age to a body protein. In the case of pen- litis (serum sickness, Arthus reaction). icillin G, a cleavage product (penicilloyl Drug-antibody complexes precipitate on residue) probably undergoes covalent vascular walls, complement is activated, binding to protein. During initial con- and an inflammatory reaction is trig- tact with the drug, the immune system gered. Attracted neutrophils, in a futile is sensitized: antigen-specific lympho- attempt to phagocytose the complexes, cytes of the T-type and B-type (antibody liberate lysosomal enzymes that dam- formation) proliferate in lymphatic tis- age the vascular walls (inflammation, sue and some of them remain as so- vasculitis). Symptoms may include fe- called memory cells. Usually, these pro- ver, exanthema, swelling of lymph cesses remain clinically silent. During nodes, arthritis, nephritis, and neuropa- the second contact, antibodies are al- thy. ready present and memory cells prolife- Type 4, contact dermatitis. A cuta- rate rapidly. A detectable immune re- neously applied drug is bound to the sponse, the allergic reaction, occurs. surface of T-lymphocytes directed spe- This can be of severe intensity, even at a cifically against it. The lymphocytes re- low dose of the antigen. Four types of lease signal molecules (lymphokines) reactions can be distinguished: into their vicinity that activate macro- Type 1, anaphylactic reaction. phages and provoke an inflammatory Drug-specific antibodies of the IgE type reaction. combine via their Fc moiety with receptors on the surface of mast cells. Binding of the drug provides the stimulus for the release of histamine and other mediators. In the most severe form, a life- threatening anaphylactic shock develops, accompanied by hypotension, bronchospasm (asthma attack), laryn- geal edema, urticaria, stimulation of gut musculature, and spontaneous bowel movements (p. 326). Type 2, cytotoxic reaction. Drug- antibody (IgG) complexes adhere to the surface of blood cells, where either circulating drug molecules or complexes al-

Adverse Drug Effects 73

Reaction of immune system to first drug exposure Production of antibodies Drug (Immunoglobulins) (= hapten) Immune system e.g. IgE (^= lymphatic IgG etc. tissue) recognizes: Protein Proliferation of antigen-specific "Non-self" lymphocytes

Macromolecule MW > 10 000

Distribution Antigen in body

Immune reaction with repeated drug exposure e.g., Neutrophilic IgE granulocyte

IgG Mast cell (tissue) Receptor basophilic for IgE granulocyte (blood) Complement activation Cell Histamine and other mediators destruction Urticaria, asthma, shock Membrane injury Type 1 reaction: Type 2 reaction: acute anaphylactic reaction cytotoxic reaction

Formation of Contact immune complexes dermatitis Antigen- specific Deposition on Activation T-lymphocyte vessel wall of:

complement Inflammatory reaction and neutrophils Lymphokines Inflammatory reaction Type 3 reaction: Type 4 reaction: Immune complex lymphocytic delayed reaction

A. Adverse drug effect: allergic reaction

74 Adverse Drug Effects

Drug Toxicity in Pregnancy and novel drugs it is usually not yet pos- Lactation sible to define their teratogenic hazard. Drugs taken by the mother can be Drugs with established human ter- passed on transplacentally or via breast atogenicity include derivatives of vita- milk and adversely affect the unborn or min A (etretinate, isotretinoin [used the neonate. internally in skin diseases]), and oral anticoagulants. A peculiar type of dam- Pregnancy (A) age results from the synthetic estrogen- Limb malformations induced by the ic agent, diethylstilbestrol, following its hypnotic, thalidomide, first focused at- use during pregnancy; daughters of tention on the potential of drugs to treated mothers have an increased inci- cause malformations (teratogenicity). dence of cervical and vaginal carcinoma Drug effects on the unborn fall into two at the age of approx. 20. basic categories: In assessing the risk: benefit ratio, it is 1. Predictable effects that derive from also necessary to consider the benefit the known pharmacological drug for the child resulting from adequate properties. Examples are: masculin- therapeutic treatment of its mother. For ization of the female fetus by andro- instance, therapy with antiepileptic genic hormones; brain hemorrhage drugs is indispensable, because untreat- due to oral anticoagulants; bradycar- ed epilepsy endangers the infant at least dia due to β-blockers. as much as does administration of anti- 2. Effects that specifically affect the de- convulsants. veloping organism and that cannot be predicted on the basis of the Lactation (B) known pharmacological activity pro- Drugs present in the maternal organism file. can be secreted in breast milk and thus In assessing the risks attending be ingested by the infant. Evaluation of drug use during pregnancy, the follow- risk should be based on factors listed in ing points have to be considered: B. In case of doubt, potential danger to a) Time of drug use. The possible seque- the infant can be averted only by wean- lae of exposure to a drug depend on ing. the stage of fetal development, as shown in A. Thus, the hazard posed by a drug with a specific action is limited in time, as illustrated by the tetracyclines, which produce effects on teeth and bones only after the third month of gestation, when mineralization begins. b) Transplacental passage. Most drugs can pass in the placenta from the maternal into the fetal circulation. The fused cells of the syncytiotrophoblast form the major diffusion barrier. They possess a higher permeability to drugs than is suggested by the term “placental barrier”. c) Teratogenicity. Statistical risk esti- mates are available for familiar, frequently used drugs. For many drugs, teratogenic potency cannot be demonstrated; however, in the case of

Adverse Drug Effects 75

Ovum 1 day

Sperm cells ~3 days

Endometrium Blastocyst

Age of fetus 1 21 2 12 38 (weeks) Development Nidation Embryo: organ Fetus: growth stage develop- and ment maturation

Fetal death Malformation Functional disturbances

ArteryUterus wall Vein

Sequelae of Transfer damage of metabolites Syncytio- by drug trophoblast Capillary Placental barrier Fetus Mother Placental transfer of metabolites To umbilical cord

A. Pregnancy: fetal damage due to drugs

Drug

Extent of Distribution transfer of of drug drug into in infant milk Infant dose Therapeutic effect in Rate of mother elimination of drug from infant ? Drug concentration in infant´s blood Unwanted effect in child Sensitivity of Effect site of action

B. Lactation: maternal intake of drug

76 Drug-independent Effects

Placebo (A) tient groups, but also within either group itself. A placebo is a dosage form devoid of an Homeopathy (B) is an alternative active ingredient, a dummy medication. method of therapy, developed in the Administration of a placebo may elicit 1800s by Samuel Hahnemann. His idea the desired effect (relief of symptoms) was this: when given in normal (allo- or undesired effects that reflect a pathic) dosage, a drug (in the sense of change in the patient’s psychological medicament) will produce a constella- situation brought about by the thera- tion of symptoms; however, in a patient peutic setting. whose disease symptoms resemble just Physicians may consciously or un- this mosaic of symptoms, the same drug consciously communicate to the patient (simile principle) would effect a cure whether or not they are concerned when given in a very low dosage (“po- about the patient’s problem, or certain tentiation”). The body’s self-healing about the diagnosis and about the value powers were to be properly activated of prescribed therapeutic measures. In only by minimal doses of the medicinal the care of a physician who projects substance. personal warmth, competence, and con- The homeopath’s task is not to di- fidence, the patient in turn feels com- agnose the causes of morbidity, but to fortable and less anxious and optimisti- find the drug with a “symptom profile” cally anticipates recovery. most closely resembling that of the The physical condition determines patient’s illness. This drug is then ap- the psychic disposition and vice versa. plied in very high dilution. Consider gravely wounded combatants A direct action or effect on body in war, oblivious to their injuries while functions cannot be demonstrated for fighting to survive, only to experience homeopathic medicines. Therapeutic severe pain in the safety of the field hos- success is due to the suggestive powers pital, or the patient with a peptic ulcer of the homeopath and the expectancy of caused by emotional stress. the patient. When an illness is strongly Clinical trials. In the individual influenced by emotional (psychic) fac- case, it may be impossible to decide tors and cannot be treated well by allo- whether therapeutic success is attribu- pathic means, a case can be made in fa- table to the drug or to the therapeutic vor of exploiting suggestion as a thera- situation. What is therefore required is a peutic tool. Homeopathy is one of sever- comparison of the effects of a drug and al possible methods of doing so. of a placebo in matched groups of patients by means of statistical procedures, i.e., a placebo-controlled trial. A prospective trial is planned in advance, a retrospective (case-control) study follows patients backwards in time. Pa- tients are randomly allotted to two groups, namely, the placebo and the active or test drug group. In a double-blind trial, neither the patients nor the treating physicians know which patient is given drug and which placebo. Finally, a switch from drug to placebo and vice versa can be made in a successive phase of treatment, the cross-over trial. In this fashion, drug vs. placebo comparisons can be made not only between two pa-

Drug-independent Effects 77

Conscious Conscious and and unconscious unconscious signals: expectations Mind language, facial expression, gestures

Well-being complaints

Placebo Effect: - wanted - unwanted Body

Physician Patient

A. Therapeutic effects resulting from physician´s power of suggestion

Homeopath Patient “Similia similibus curentur” “Drug” Normal, allopathic dose symptom profile Dilution “effect reversal” Very low homeopathic dose elimination of disease symptoms corresponding to allopathic symptom “profile” “Potentiation” increase in efficacy with progressive dilution Profile of disease symptoms

Symptom “profile”

“Drug diagnosis” Homeopathic Stock- remedy (“Simile”) solution

Dilution 1 1 1 1 1 1 1 1 1 D9 10 10 10 10 10 10 10 10 10 1 1000 000 000

B. Homeopathy: concepts and procedure

Systems Pharmacology

80 Drugs Acting on the Sympathetic Nervous System

Sympathetic Nervous System of the sympathetic division can be considered a means by which the body In the course of phylogeny an efficient achieves a state of maximal work capac- control system evolved that enabled the ity as required in fight or flight situa- functions of individual organs to be or- tions. chestrated in increasingly complex life In both cases, there is a need for forms and permitted rapid adaptation vigorous activity of skeletal muscula- to changing environmental conditions. ture. To ensure adequate supply of oxy- This regulatory system consists of the gen and nutrients, blood flow in skeletal CNS (brain plus spinal cord) and two muscle is increased; cardiac rate and separate pathways for two-way com- contractility are enhanced, resulting in a munication with peripheral organs, viz., larger blood volume being pumped into the somatic and the autonomic nervous the circulation. Narrowing of splanchnic systems. The somatic nervous system blood vessels diverts blood into vascular comprising extero- and interoceptive beds in muscle. afferents, special sense organs, and mo- Because digestion of food in the in- tor efferents, serves to perceive external testinal tract is dispensable and only states and to target appropriate body counterproductive, the propulsion of in- movement (sensory perception: threat testinal contents is slowed to the extent response: flight or attack). The auto- that peristalsis diminishes and sphinc- nomic (vegetative) nervous system teric tonus increases. However, in order (ANS), together with the endocrine to increase nutrient supply to heart and system, controls the milieu interieur. It musculature, glucose from the liver and adjusts internal organ functions to the free fatty acid from adipose tissue must changing needs of the organism. Neural be released into the blood. The bronchi control permits very quick adaptation, are dilated, enabling tidal volume and whereas the endocrine system provides alveolar oxygen uptake to be increased. for a long-term regulation of functional Sweat glands are also innervated by states. The ANS operates largely beyond sympathetic fibers (wet palms due to voluntary control; it functions autono- excitement); however, these are excep- mously. Its central components reside tional as regards their neurotransmitter in the hypothalamus, brain stem, and (ACh, p. 106). spinal cord. The ANS also participates in Although the life styles of modern the regulation of endocrine functions. humans are different from those of The ANS has sympathetic and hominid ancestors, biological functions parasympathetic branches. Both are have remained the same. made up of centrifugal (efferent) and centripetal (afferent) nerves. In many organs innervated by both branches, respective activation of the sympathetic and parasympathetic input evokes opposing responses. In various disease states (organ malfunctions), drugs are employed with the intention of normalizing susceptible organ functions. To understand the biological effects of substances capable of inhibiting or exciting sympathetic or parasympathetic nerves, one must first envisage the functions subserved by the sympathetic and parasympathetic divisions (A, Responses to sympathetic activation). In simplistic terms, activation

Drugs Acting on the Sympathetic Nervous System 81

CNS: drive Eyes: alertness pupillary dilation

Saliva: little, viscous

Bronchi: dilation

Heart: Skin: rate perspiration force (cholinergic) blood pressure

Fat tissue: lipolysis fatty acid liberation

Liver: glycogenolysis Bladder: glucose release Sphincter tone detrusor muscle

GI-tract: peristalsis sphincter tone blood flow

Skeletal muscle: blood flow glycogenolysis

A. Responses to sympathetic activation

82 Drugs Acting on the Sympathetic Nervous System

Structure of the Sympathetic Nervous converted via two intermediate steps to System dopamine, which is taken up into the vesicles and there converted to norepi- The sympathetic preganglionic neurons nephrine by dopamine-β-hydroxylase. (first neurons) project from the inter- When stimulated electrically, the sym- mediolateral column of the spinal gray pathetic nerve discharges the contents matter to the paired paravertebral gan- of part of its vesicles, including norepi- glionic chain lying alongside the verte- nephrine, into the extracellular space. bral column and to unpaired preverte- Liberated norepinephrine reacts with bral ganglia. These ganglia represent adrenoceptors located postjunctionally sites of synaptic contact between pre- on the membrane of effector cells or ganglionic axons (1st neurons) and prejunctionally on the membrane of nerve cells (2nd neurons or sympathocy- varicosities. Activation of presynaptic tes) that emit postganglionic axons α2-receptors inhibits norepinephrine terminating on cells in various end or- release. By this negative feedback, re- gans. In addition, there are preganglion- lease can be regulated. ic neurons that project either to periph- The effect of released norepineph- eral ganglia in end organs or to the ad- rine wanes quickly, because approx. renal medulla. 90 % is actively transported back into the axoplasm, then into storage vesicles Sympathetic Transmitter Substances (neuronal re-uptake). Small portions of norepinephrine are inactivated by the Whereas acetylcholine (see p. 98) enzyme catechol-O-methyltransferase serves as the chemical transmitter at (COMT, present in the cytoplasm of ganglionic synapses between first and postjunctional cells, to yield normeta- second neurons, norepinephrine nephrine), and monoamine oxidase (= noradrenaline) is the mediator at (MAO, present in mitochondria of nerve synapses of the second neuron (B). This cells and postjunctional cells, to yield second neuron does not synapse with 3,4-dihydroxymandelic acid). only a single cell in the effector organ; The liver is richly endowed with rather, it branches out, each branch COMT and MAO; it therefore contrib- making en passant contacts with several utes significantly to the degradation of cells. At these junctions the nerve axons circulating norepinephrine and epi- form enlargements (varicosities) re- nephrine. The end product of the com- sembling beads on a string. Thus, excita- bined actions of MAO and COMT is van- tion of the neuron leads to activation of illylmandelic acid. a larger aggregate of effector cells, although the action of released norepinephrine may be confined to the region of each junction. Excitation of preganglionic neurons innervating the adrenal medulla causes a liberation of acetylcholine. This, in turn, elicits a secretion of epinephrine (= adrenaline) into the blood, by which it is distributed to body tissues as a hormone (A).

Adrenergic Synapse

Within the varicosities, norepinephrine is stored in small membrane-enclosed vesicles (granules, 0.05 to 0.2 µm in diameter). In the axoplasm, L-tyrosine is

Drugs Acting on the Sympathetic Nervous System 83

Psychic or physical stress stress

First neuron First neuron

Second Adrenal neuron medulla

Epinephrine Norepinephrine

A. Epinephrine as hormone, norepinephrine as transmitter

Presynaptic α 2-receptors

Receptors

3.4-Dihydroxy- mandelic acid α O MA

β 1 Receptors β 2

Normeta- nephrine COMT Norepinephrine

B. Second neuron of sympathetic system, varicosity, norepinephrine release

84 Drugs Acting on the Sympathetic Nervous System

Adrenoceptor Subtypes and with a resultant drop in systemic blood Catecholamine Actions pressure results in reflex tachycardia, which is also due in part to the β1-stim- Adrenoceptors fall into three major ulant action of these drugs. groups, designated α1, α2, and β, within Cardiostimulation. By stimulating each of which further subtypes can be β1-receptors, hence activation of ade- distinguished pharmacologically. The nylatcyclase (Ad-cyclase) and cAMP different adrenoceptors are differential- production, catecholamines augment all ly distributed according to region and heart functions, including systolic force tissue. Agonists at adrenoceptors (di- (positive inotropism), velocity of short- rect sympathomimetics) mimic the ac- ening (p. clinotropism), sinoatrial rate tions of the naturally occurring cate- (p. chronotropism), conduction velocity cholamines, norepinephrine and epi- (p. dromotropism), and excitability (p. nephrine, and are used for various ther- bathmotropism). In pacemaker fibers, apeutic effects. diastolic depolarization is hastened, so Smooth muscle effects. The op- that the firing threshold for the action posing effects on smooth muscle (A) of potential is reached sooner (positive α-and β-adrenoceptor activation are chronotropic effect, B). The cardiostim- due to differences in signal transduction ulant effect of β-sympathomimetics (p. 66). This is exemplified by vascular such as epinephrine is exploited in the smooth muscle (A). α1-Receptor stimu- treatment of cardiac arrest. Use of β- lation leads to intracellular release of sympathomimetics in heart failure car- Ca2+ via activation of the inositol tris- ries the risk of cardiac arrhythmias. phosphate (IP3) pathway. In concert Metabolic effects. β-Receptors me- with the protein calmodulin, Ca2+ can diate increased conversion of glycogen to activate myosin kinase, leading to a rise glucose (glycogenolysis) in both liver in tonus via phosphorylation of the con- and skeletal muscle. From the liver, glu- tractile protein myosin. cAMP inhibits cose is released into the blood, In adi- activation of myosin kinase. Via the for- pose tissue, triglycerides are hydrolyzed mer effector pathway, stimulation of α- to fatty acids (lipolysis, mediated by β3- receptors results in vasoconstriction; receptors), which then enter the blood via the latter, β2-receptors mediate va- (C). The metabolic effects of catechola- sodilation, particularly in skeletal mus- mines are not amenable to therapeutic cle — an effect that has little therapeutic use. use. Vasoconstriction. Local application of α-sympathomimetics can be employed in infiltration anesthesia (p. 204) or for nasal decongestion (naphazoline, tetrahydrozoline, xylometazoline; pp. 90, 324). Systemically administered epinephrine is important in the treatment of anaphylactic shock for combating hypotension. Bronchodilation. β2-Adrenocep- tor-mediated bronchodilation (e.g., with terbutaline, fenoterol, or salbutamol) plays an essential part in the treatment of bronchial asthma (p. 328). Tocolysis. The uterine relaxant effect of β2-adrenoceptor agonists, such as terbutaline or fenoterol, can be used to prevent premature labor. Vasodilation

Drugs Acting on the Sympathetic Nervous System 85

α β α 1 2 2 Gi Gs Gi

IP3 Ad-cyclase Ad-cyclase Ca2+

Phospholipase C + cAMP -

Calmodulin

Myosin kinase

Myosin Myosin-P

A. Vasomotor effects of catecholamines

β β 1 Gs Gs Ad-cyclase Ad-cyclase

cAMP + cAMP +

Force (mN) Glycogenolysis Lipolysis

Glucose

Time Glycogenolysis Membrane potential (mV) Fatty acids

Glucose

Time

B. Cardiac effects of catecholamines C. Metabolic effects of catecholamines

86 Drugs Acting on the Sympathetic Nervous System

Structure – Activity Relationships of catecholamine congeners can be given Sympathomimetics orally and can exert CNS actions; how- Due to its equally high affinity for all α- ever, this structural change entails a loss and β-receptors, epinephrine does not in affinity. permit selective activation of a particu- Absence of one or both aromatic lar receptor subtype. Like most cate- hydroxyl groups is associated with an cholamines, it is also unsuitable for oral increase in indirect sympathomimetic administration (catechol is a trivial activity, denoting the ability of a sub- name for o-hydroxyphenol). Norepi- stance to release norepinephrine from nephrine differs from epinephrine by its its neuronal stores without exerting an high affinity for α-receptors and low af- agonist action at the adrenoceptor (p. finity for β2-receptors. In contrast, iso- 88). proterenol has high affinity for β-recep- An altered position of aromatic hy- tors, but virtually none for α-receptors droxyl groups (e.g., in orciprenaline, fe- (A). noterol, or terbutaline) or their substi- norepinephrine α, β1 tution (e.g., salbutamol) protects epinephrine α, β1, β2 against inactivation by COMT (p. 82). In- isoproterenol β1, β2 droduction of a small alkyl residue at Knowledge of structure–activity the carbon atom adjacent to the amino relationships has permitted the syn- group (ephedrine, methamphetamine) thesis of sympathomimetics that dis- confers resistance to degradation by play a high degree of selectivity at MAO (p. 80), as does replacement on the adrenoceptor subtypes. amino groups of the methyl residue Direct-acting sympathomimetics with larger substituents (e.g., ethyl in (i.e., adrenoceptor agonists) typically etilefrine). Accordingly, the congeners share a phenylethylamine structure. The are less subject to presystemic inactiva- side chain β-hydroxyl group confers af- tion. finity for α- and β-receptors. Substitu- Since structural requirements for tion on the amino group reduces affinity high affinity, on the one hand, and oral for α-receptors, but increases it for β-re- applicability, on the other, do not ceptors (exception: α-agonist phenyl- match, choosing a sympathomimetic is ephrine), with optimal affinity being a matter of compromise. If the high af- seen after the introduction of only one finity of epinephrine is to be exploited, isopropyl group. Increasing the bulk of absorbability from the intestine must be the amino substituent favors affinity for foregone (epinephrine, isoprenaline). If β2-receptors (e.g., fenoterol, salbuta- good bioavailability with oral adminis- mol). Both hydroxyl groups on the aro- tration is desired, losses in receptor af- matic nucleus contribute to affinity; finity must be accepted (etilefrine). high activity at α-receptors is associated with hydroxyl groups at the 3 and 4 positions. Affinity for β-receptors is preserved in congeners bearing hydroxyl groups at positions 3 and 5 (orciprenaline, terbutaline, fenoterol). The hydroxyl groups of catecholamines are responsible for the very low lipophilicity of these substances. Pola- rity is increased at physiological pH due to protonation of the amino group. De- letion of one or all hydroxyl groups improves membrane penetrability at the intestinal mucosa-blood and the blood- brain barriers. Accordingly, these non-

Drugs Acting on the Sympathetic Nervous System 87

NorepinephrineEpinephrine Isoproterenol

A. Chemical structure of catecholamines and affinity for α- and β-receptors

Receptor affinity

Catecholamine- O-methyltransferase

Penetrability through Metabolic membrane stability barriers

(Enteral absorbability CNS permeability) Monoamine oxidase

Epinephrine Orciprenaline Fenoterol

Etilefrine Ephedrine Methamphetamine

Affinity for α-receptors Indirect Resistance to degradation action Affinity for β-receptors Absorbability

B. Structure-activity relationship of epinephrine derivatives

88 Drugs Acting on the Sympathetic Nervous System

Indirect Sympathomimetics sicular stores of NE close to the axolemma are depleted. Apart from receptors, adrenergic neu- Indirect sympathomimetics can rotransmission involves mechanisms penetrate the blood-brain barrier and for the active re-uptake and re-storage evoke such CNS effects as a feeling of of released amine, as well as enzymatic well-being, enhanced physical activity breakdown by monoamine oxidase and mood (euphoria), and decreased (MAO). Norepinephrine (NE) displays sense of hunger or fatigue. Subsequent- affinity for receptors, transport systems, ly, the user may feel tired and de- and degradative enzymes. Chemical al- pressed. These after effects are partly terations of the catecholamine differen- responsible for the urge to re-adminis- tially affect these properties and result ter the drug (high abuse potential). To in substances with selective actions. prevent their misuse, these substances Inhibitors of MAO (A). The enzyme are subject to governmental regulations is located predominantly on mitochon- (e.g., Food and Drugs Act: Canada; Con- dria, and serves to scavenge axoplasmic trolled Drugs Act: USA) restricting their free NE. Inhibition of the enzyme causes prescription and distribution. free NE concentrations to rise. Likewise, When amphetamine-like substanc- dopamine catabolism is impaired, makes are misused to enhance athletic per- ing more of it available for NE synthesis. formance (doping), there is a risk of dan- Consequently, the amount of NE stored gerous physical overexertion. Because in granular vesicles will increase, and of the absence of a sense of fatigue, a with it the amount of amine released drugged athlete may be able to mobilize per nerve impulse. ultimate energy reserves. In extreme In the CNS, inhibition of MAO af- situations, cardiovascular failure may fects neuronal storage not only of NE result (B). but also of dopamine and serotonin. Closely related chemically to am- These mediators probably play signifi- phetamine are the so-called appetite cant roles in CNS functions consistent suppressants or anorexiants, such as with the stimulant effects of MAO inhib- fenfluramine, mazindole, and sibutra- itors on mood and psychomotor drive mine. These may also cause dependence and their use as antidepressants in the and their therapeutic value and safety treatment of depression (A). Tranylcy- are questionable. promine is used to treat particular forms of depressive illness; as a covalently bound suicide substrate, it causes long- lasting inhibition of both MAO isozymes, (MAOA, MAOB). Moclobemide reversibly inhibits MAOA and is also used as an antidepressant. The MAOB inhibitor selegiline (deprenyl) retards the cat- obolism of dopamine, an effect used in the treatment of parkinsonism (p. 188). Indirect sympathomimetics (B) are agents that elevate the concentration of NE at neuroeffector junctions, because they either inhibit re-uptake (cocaine), facilitate release, or slow breakdown by MAO, or exert all three of these effects (amphetamine, methamphetamine). The effectiveness of such indirect sympathomimetics diminishes or disappears (tachyphylaxis) when ve-

Drugs Acting on the Sympathetic Nervous System 89

Inhibitor: Moclobemide MAO-A Selegiline MAO-B

MAO MAO Nor- epinephrine

Norepinephrine transport system Effector organ

A. Monoamine oxidase inhibitor

§ § Pain stimulus Local anesthetic effect

Controlled Substances Act regulates use of Amphetaminecocaine and Cocaine amphetamine

MAO MAO

"Doping"

Runner-up

B. Indirect sympathomimetics with central stimulant activity and abuse potential

90 Drugs Acting on the Sympathetic Nervous System

α-Sympathomimetics, and prejunctional α-adrenoceptors α-Sympatholytics (non-selective α-blockers, e.g., phen- oxybenzamine, phentolamine). α-Sympathomimetics can be used Presynaptic α2-adrenoceptors func- systemically in certain types of hypoten- tion like sensors that enable norepi- sion (p. 314) and locally for nasal or con- nephrine concentration outside the junctival decongestion (pp. 324, 326) or axolemma to be monitored, thus regu- as adjuncts in infiltration anesthesia (p. lating its release via a local feedback 206) for the purpose of delaying the re- mechanism. When presynaptic α2-removal of local anesthetic. With local ceptors are stimulated, further release use, underperfusion of the vasocon- of norepinephrine is inhibited. Con- stricted area results in a lack of oxygen versely, their blockade leads to uncon- (A). In the extreme case, local hypoxia trolled release of norepinephrine with can lead to tissue necrosis. The append- an overt enhancement of sympathetic ages (e.g., digits, toes, ears) are particu- effects at β1-adrenoceptor-mediated larly vulnerable in this regard, thus pre- myocardial neuroeffector junctions, re- cluding vasoconstrictor adjuncts in in- sulting in tachycardia and tachyar- filtration anesthesia at these sites. rhythmia. Vasoconstriction induced by an α- sympathomimetic is followed by a Selective α-Sympatholytics phase of enhanced blood flow (reactive hyperemia, A). This reaction can be ob- α-Blockers, such as prazosin, or the served after the application of α-sympa- longer-acting terazosin and doxazosin, thomimetics (naphazoline, tetrahydro- lack affinity for prejunctional α2-adren- zoline, xylometazoline) to the nasal mu- oceptors. They suppress activation of cosa. Initially, vasoconstriction reduces α1-receptors without a concomitant en- mucosal blood flow and, hence, capil- hancement of norepinephrine release. lary pressure. Fluid exuded into the α1-Blockers may be used in hyper- interstitial space is drained through the tension (p. 312). Because they prevent veins, thus shrinking the nasal mucosa. reflex vasoconstriction, they are likely Due to the reduced supply of fluid, se- to cause postural hypotension with cretion of nasal mucus decreases. In co- pooling of blood in lower limb capaci- ryza, nasal patency is restored. Howev- tance veins during change from the su- er, after vasoconstriction subsides, reac- pine to the erect position (orthostatic tive hyperemia causes renewed exuda- collapse: ↓ venous return, ↓ cardiac out- tion of plasma fluid into the interstitial put, fall in systemic pressure, ↓ blood space, the nose is “stuffy” again, and the supply to CNS, syncope, p. 314). patient feels a need to reapply decon- In benign hyperplasia of the pros- gestant. In this way, a vicious cycle tate, α-blockers (terazosin, alfuzosin) threatens. Besides rebound congestion, may serve to lower tonus of smooth persistent use of a decongestant entails musculature in the prostatic region and the risk of atrophic damage caused by thereby facilitate micturition (p. 252). prolonged hypoxia of the nasal mucosa. α-Sympatholytics (B). The interaction of norepinephrine with α-adrenoceptors can be inhibited by α-sympatholytics ( α-adrenoceptor antagonists, α- blockers). This inhibition can be put to therapeutic use in antihypertensive treatment (vasodilation peripheral resistance ↓, blood pressure ↓, p. 118). The first α-sympatholytics blocked the action of norepinephrine at both post-

Drugs Acting on the Sympathetic Nervous System 91

Before α-Agonist After

O supply = O demand O2 supply = O2 demand O2 supply < O2 demand 2 2

A. Reactive hyperemia due to α-sympathomimetics, e.g., following decongestion of nasal mucosa

α2 α2 α2

nonselective NE α-blocker α1-blocker

α1 β1 α1 β1 α1 β1

B. Autoinhibition of norepinephrine release and α-sympatholytics

α1-blocker Benign High blood pressure e.g., terazosin prostatic hyperplasia

O N N N O H3CO N H3CO

NH2

Inhibition of α1-adrenergic stimulation of Resistance smooth muscle Neck of bladder, arteries prostate

C. Indications for α1-sympatholytics

92 Drugs Acting on the Sympathetic Nervous System

β-Sympatholytics (β-Blockers) Bradycardia, A-V block: Elimination of sympathetic drive can lead to a β-Sympatholytics are antagonists of marked fall in cardiac rate as well as to norepiphephrine and epinephrine at β- disorders of impulse conduction from adrenoceptors; they lack affinity for α- the atria to the ventricles. receptors. Bronchial asthma: Increased sym- Therapeutic effects. β-Blockers pathetic activity prevents broncho- protect the heart from the oxygen- spasm in patients disposed to paroxys- wasting effect of sympathetic inotrop- mal constriction of the bronchial tree ism (p. 306) by blocking cardiac β-re- (bronchial asthma, bronchitis in smok- ceptors; thus, cardiac work can no long- ers). In this condition, β2-receptor er be augmented above basal levels (the blockade will precipitate acute respira- heart is “coasting”). This effect is uti- tory distress (B). lized prophylactically in angina pectoris Hypoglycemia in diabetes mellitus: to prevent myocardial stress that could When treatment with insulin or oral hy- trigger an ischemic attack (p. 308, 310). poglycemics in the diabetic patient low- β-Blockers also serve to lower cardiac ers blood glucose below a critical level, rate (sinus tachycardia, p. 134) and ele- epinephrine is released, which then vated blood pressure due to high cardiac stimulates hepatic glucose release via output (p. 312). The mechanism under- activation of β2-receptors. β-Blockers lying their antihypertensive action via suppress this counter-regulation; in ad- reduction of peripheral resistance is un- dition, they mask other epinephrine- clear. mediated warning signs of imminent Applied topically to the eye, β- hypoglycemia, such as tachycardia and blockers are used in the management of anxiety, thereby enhancing the risk of glaucoma; they lower production of hypoglycemic shock. aqueous humor without affecting its Altered vascular responses: When drainage. β2-receptors are blocked, the vasodilat- Undesired effects. The hazards of ing effect of epinephrine is abolished, treatment with β-blockers become ap- leaving the α-receptor-mediated vaso- parent particularly when continuous constriction unaffected: peripheral activation of β-receptors is needed in blood flow ↓ – “cold hands and feet”. order to maintain the function of an or- β-Blockers exert an “anxiolytic“ gan. action that may be due to the suppres- Congestive heart failure: In myocar- sion of somatic responses (palpitations, dial insufficiency, the heart depends on trembling) to epinephrine release that a tonic sympathetic drive to maintain is induced by emotional stress; in turn, adequate cardiac output. Sympathetic these would exacerbate “anxiety” or activation gives rise to an increase in “stage fright”. Because alertness is not heart rate and systolic muscle tension, impaired by β-blockers, these agents are enabling cardiac output to be restored occasionally taken by orators and musi- to a level comparable to that in a cians before a major performance (C). healthy subject. When sympathetic Stage fright, however, is not a disease drive is eliminated during β-receptor requiring drug therapy. blockade, stroke volume and cardiac rate decline, a latent myocardial insufficiency is unmasked, and overt insufficiency is exacerbated (A). On the other hand, clinical evidence suggests that β-blockers produce favorable effects in certain forms of congestive heart failure (idiopathic dilated cardiomyopathy).

Drugs Acting on the Sympathetic Nervous System 93

β-Blocker β-Receptor blocks receptor

100 ml

Stroke

volume Healthy

1 sec β β 1-Blockade 1-Stimulation

1 sec Heart failure

A. β-Sympatholytics: effect on cardiac function Healthy

α α β α β

Asthmatic 2 2

β β β β 2-Blockade 2-Stimulation 2-Blockade 2-Stimulation

B. β-Sympatholytics: effect on bronchial and vascular tone

β-Blockade

C. “Anxiolytic” effect of β-sympatholytics

94 Drugs Acting on the Sympathetic Nervous System

Types of β-Blockers mit its use in patients with bronchial asthma or diabetes mellitus (p. 92). The basic structure shared by most β- The chemical structure of β-block- sympatholytics is the side chain of β- ers also determines their pharmacoki- sympathomimetics (cf. isoproterenol netic properties. Except for hydrophilic with the β-blockers propranolol, pindo- representatives (atenolol), β-sympatho- lol, atenolol). As a rule, this basic struc- lytics are completely absorbed from the ture is linked to an aromatic nucleus by intestines and subsequently undergo a methylene and oxygen bridge. The presystemic elimination to a major ex- side chain C-atom bearing the hydroxyl tent (A). group forms the chiral center. With All the above differences are of some exceptions (e.g., timolol, penbuto- little clinical importance. The abundance lol), all β-sympatholytics are brought as of commercially available congeners racemates into the market (p. 62). would thus appear all the more curious Compared with the dextrorotatory (B). Propranolol was the first β-blocker form, the levorotatory enantiomer pos- to be introduced into therapy in 1965. sesses a greater than 100-fold higher af- Thirty-five years later, about 20 different finity for the β-receptor and is, there- congeners are being marketed in differ- fore, practically alone in contributing to ent countries. This questionable devel- the β-blocking effect of the racemate. opment unfortunately is typical of any The side chain and substituents on the drug group that has major therapeutic amino group critically affect affinity for relevance, in addition to a relatively β-receptors, whereas the aromatic nu- fixed active structure. Variation of the cleus determines whether the com- molecule will create a new patentable pound possess intrinsic sympathomi- chemical, not necessarily a drug with a metic activity (ISA), that is, acts as a novel action. Moreover, a drug no longer partial agonist (p. 60) or partial antago- protected by patent is offered as a gener- nist. In the presence of a partial agonist ic by different manufacturers under doz- (e.g., pindolol), the ability of a full ago- ens of different proprietary names. nist (e.g., isoprenaline) to elicit a maxi- Propranolol alone has been marketed by mal effect would be attenuated, because 13 manufacturers under 11 different binding of the full agonist is impeded. names. However, the β-receptor at which such partial agonism can be shown appears to be atypical (β3 or β4 subtype). Wheth- er ISA confers a therapeutic advantage on a β-blocker remains an open ques- tion. As cationic amphiphilic drugs, β- blockers can exert a membrane-stabilizing effect, as evidenced by the ability of the more lipophilic congeners to inhibit Na+-channel function and impulse conduction in cardiac tissues. At the usual therapeutic dosage, the high concentration required for these effects will not be reached. Some β-sympatholytics possess higher affinity for cardiac β1-receptors than for β2-receptors and thus display cardioselectivity (e.g., metoprolol, acebutolol, bisoprolol). None of these blockers is sufficiently selective to per-

Drugs Acting on the Sympathetic Nervous System 95

Isoproterenol Pindolol Propranolol Atenolol

β-Receptor β-Receptor β-Receptor Agonist partial Antagonist Antagonist Agonist Effect No effect

β1 β1 β1 β1 β β1 2 β β β Cardio- 2 2 2 β2 selectivity 100% Presystemic 50% elimination

A. Types of β-sympatholytics 1965 1970 Year introduced Tertatolol Carvedilol Esmolol Bopindolol Bisoprolol Celiprolol Betaxolol Befunolol Carteolol Mepindolol Penbutolol Carazolol Nadolol Acebutolol Bunitrolol Atenolol Metipranol Metoprolol Timolol Sotalol Talinolol Oxprenolol Pindolol Bupranolol Alprenolol Propranolol 1975 1980 1985 1990 B. Avalanche-like increase in commercially available β-sympatholytics

96 Drugs Acting on the Sympathetic Nervous System

Antiadrenergics leased per nerve impulse is decreased. To a lesser degree, release of epineph- Antiadrenergics are drugs capable of rine from the adrenal medulla is also lowering transmitter output from sym- impaired. At higher doses, there is irre- pathetic neurons, i.e., “sympathetic versible damage to storage vesicles tone”. Their action is hypotensive (indi- (“pharmacological sympathectomy”), cation: hypertension, p. 312); however, days to weeks being required for their being poorly tolerated, they enjoy only resynthesis. Reserpine readily enters limited therapeutic use. the brain, where it also impairs vesicu- Clonidine is an α2-agonist whose lar storage of biogenic amines. high lipophilicity (dichlorophenyl ring) Adverse effects. Disorders of extra- permits rapid penetration through the pyramidal motor function with devel- blood-brain barrier. The activation of opment of pseudo-Parkinsonism (p. 88), postsynaptic α2-receptors dampens the sedation, depression, stuffy nose, im- activity of vasomotor neurons in the paired libido, and impotence; increased medulla oblongata, resulting in a reset- appetite. These adverse effects have ting of systemic arterial pressure at a rendered the drug practically obsolete. lower level. In addition, activation of Guanethidine possesses high affin- presynaptic α2-receptors in the periph- ity for the axolemmal and vesicular ery (pp. 82, 90) leads to a decreased re- amine transporters. It is stored instead lease of both norepinephrine (NE) and of NE, but is unable to mimic the func- acetylcholine. tions of the latter. In addition, it stabiliz- Side effects. Lassitude, dry mouth; es the axonal membrane, thereby im- rebound hypertension after abrupt ces- peding the propagation of impulses into sation of clonidine therapy. the sympathetic nerve terminals. Stor- Methyldopa (dopa = dihydroxy- age and release of epinephrine from the phenylalanine), as an amino acid, is adrenal medulla are not affected, owing transported across the blood-brain bar- to the absence of a re-uptake process. rier, decarboxylated in the brain to α- The drug does not cross the blood-brain methyldopamine, and then hydroxylat- barrier. ed to α-methyl-NE. The decarboxylation Adverse effects. Cardiovascular cri- of methyldopa competes for a portion of ses are a possible risk: emotional stress the available enzymatic activity, so that of the patient may cause sympatho- the rate of conversion of L-dopa to NE adrenal activation with epinephrine re- (via dopamine) is decreased. The false lease. The resulting rise in blood pres- transmitter α-methyl-NE can be stored; sure can be all the more marked be- however, unlike the endogenous media- cause persistent depression of sympa- tor, it has a higher affinity for α2- than thetic nerve activity induces supersen- for α1-receptors and therefore produces sitivity of effector organs to circulating effects similar to those of clonidine. The catecholamines. same events take place in peripheral adrenergic neurons. Adverse effects. Fatigue, orthostatic hypotension, extrapyramidal Parkin- son-like symptoms (p. 88), cutaneous reactions, hepatic damage, immune-he- molytic anemia. Reserpine, an alkaloid from the Rauwolfia plant, abolishes the vesicular storage of biogenic amines (NE, dopamine = DA, serotonin = 5-HT) by inhibiting an ATPase required for the vesicular amine pump. The amount of NE re-

Drugs Acting on the Sympathetic Nervous System 97

α Stimulation of central 2-receptors

Suppression of sympathetic α-Methyl-NE impulses in in brain vasomotor center Clonidine Tyrosine Inhibition of Dopa Dopa-decarboxylase Dopamine NE α-Methyl-NE α-Methyldopa

False transmitter

CNS NE 5HT DA Inhibition of biogenic amine storage

Peripheral sympathetic activity

Reserpine

No epinephrine from adrenal medulla Varicosity due to central sedative effect

Inhibition of peripheral sympathetic activity

Guanethidine Active uptake and storage instead of norepinephrine; not a transmitter

Release from adrenal medulla Varicosity unaffected

A. Inhibitors of sympathetic tone

98 Drugs Acting on the Parasympathetic Nervous System

Parasympathetic Nervous System cord. Parasympathetic outflow is chan- nelled from the brainstem (1) through Responses to activation of the para- the third cranial nerve (oculomotor n.) sympathetic system. Parasympathetic via the ciliary ganglion to the eye; (2) nerves regulate processes connected through the seventh cranial nerve (fa- with energy assimilation (food intake, cial n.) via the pterygopalatine and sub- digestion, absorption) and storage. maxillary ganglia to lacrimal glands and These processes operate when the body salivary glands (sublingual, submandib- is at rest, allowing a decreased tidal vol- ular), respectively; (3) through the ume (increased bronchomotor tone) ninth cranial nerve (glossopharyngeal and decreased cardiac activity. Secre- n.) via the otic ganglion to the parotid tion of saliva and intestinal fluids pro- gland; and (4) via the tenth cranial motes the digestion of foodstuffs; trans- nerve (vagus n.) to thoracic and abdom- port of intestinal contents is speeded up inal viscera. Approximately 75 % of all because of enhanced peristaltic activity parasympathetic fibers are contained and lowered tone of sphincteric mus- within the vagus nerve. The neurons of cles. To empty the urinary bladder (mic- the sacral division innervate the distal turition), wall tension is increased by colon, rectum, bladder, the distal ure- detrusor activation with a concurrent ters, and the external genitalia. relaxation of sphincter tonus. Acetylcholine (ACh) as a transmit- Activation of ocular parasympa- ter. ACh serves as mediator at terminals thetic fibers (see below) results in nar- of all postganglionic parasympathetic rowing of the pupil and increased curva- fibers, in addition to fulfilling its trans- ture of the lens, enabling near objects to mitter role at ganglionic synapses with- be brought into focus (accommodation). in both the sympathetic and parasym- Anatomy of the parasympathetic pathetic divisions and the motor end- system. The cell bodies of parasympa- plates on striated muscle. However, dif- thetic preganglionic neurons are located ferent types of receptors are present at in the brainstem and the sacral spinal these synaptic junctions:

Localization Agonist Antagonist Receptor Type

Target tissues of 2nd ACh Atropine Muscarinic (M) parasympathetic Muscarine cholinoceptor; neurons G-protein-coupled- receptor protein with 7 transmembrane domains

Sympathetic & ACh Trimethaphan Ganglionic type parasympathetic Nicotine (α3 β4) ganglia Nicotinic (N) cholinoceptor ligand- gated cation channel formed by five transmembrane subunits

Motor endplate ACh d-Tubocurarine muscular type Nicotine (α12β1γδ)

The existence of distinct cholino- ses allows selective pharmacological ceptors at different cholinergic synap- interventions.

Drugs Acting on the Parasympathetic Nervous System 99

Eyes: Accommodation for near vision, miosis

Saliva: copious, liquid

Bronchi: constriction secretion Heart: rate blood pressure

GI tract: secretion peristalsis sphincter tone

Bladder:

sphincter tone detrusor

A. Responses to parasympathetic activation

100 Drugs Acting on the Parasympathetic Nervous System

Cholinergic Synapse M-cholinoceptors can be classified into subtypes according to their molec- Acetylcholine (ACh) is the transmitter ular structure, signal transduction, and at postganglionic synapses of parasym- ligand affinity. Here, the M1, M2, and M3 pathetic nerve endings. It is highly con- subtypes are considered. M1 receptors centrated in synaptic storage vesicles are present on nerve cells, e.g., in gan- densely present in the axoplasm of the glia, where they mediate a facilitation of terminal. ACh is formed from choline impulse transmission from pregan- and activated acetate (acetylcoenzyme glionic axon terminals to ganglion cells. A), a reaction catalyzed by the enzyme M2 receptors mediate acetylcholine ef- choline acetyltransferase. The highly fects on the heart: opening of K+ chan- polar choline is actively transported into nels leads to slowing of diastolic depola- the axoplasm. The specific choline trans- rization in sinoatrial pacemaker cells porter is localized exclusively to mem- and a decrease in heart rate. M3 recep- branes of cholinergic axons and termi- tors play a role in the regulation of nals. The mechanism of transmitter re- smooth muscle tone, e.g., in the gut and lease is not known in full detail. The vesi- bronchi, where their activation causes cles are anchored via the protein synap- stimulation of phospholipase C, mem- sin to the cytoskeletal network. This ar- brane depolarization, and increase in rangement permits clustering of vesicles muscle tone. M3 receptors are also near the presynaptic membrane, while found in glandular epithelia, which sim- preventing fusion with it. During activa- ilarly respond with activation of phos- tion of the nerve membrane, Ca2+ is pholipase C and increased secretory ac- thought to enter the axoplasm through tivity. In the CNS, where all subtypes are voltage-gated channels and to activate present, cholinoceptors serve diverse protein kinases that phosphorylate syn- functions, including regulation of corti- apsin. As a result, vesicles close to the cal excitability, memory, learning, pain membrane are detached from their an- processing, and brain stem motor con- choring and allowed to fuse with the trol. The assignment of specific receptor presynaptic membrane. During fusion, subtypes to these functions has yet to be vesicles discharge their contents into the achieved. synaptic gap. ACh quickly diffuses In blood vessels, the relaxant action through the synaptic gap (the acetylcho- of ACh on muscle tone is indirect, be- line molecule is a little longer than cause it involves stimulation of M3-cho- 0.5 nm; the synaptic gap is as narrow as linoceptors on endothelial cells that re- 30–40 nm). At the postsynaptic effector spond by liberating NO (= endothelium- cell membrane, ACh reacts with its re- derived relaxing factor). The latter dif- ceptors. Because these receptors can al- fuses into the subjacent smooth muscu- so be activated by the alkaloid musca- lature, where it causes a relaxation of rine, they are referred to as muscarinic active tonus (p. 121). (M-)cholinoceptors. In contrast, at ganglionic (p. 108) and motor endplate (p. 184) cholinoceptors, the action of ACh is mimicked by nicotine and they are, therefore, said to be nicotinic cholinoceptors. Released ACh is rapidly hydrolyzed and inactivated by a specific acetylcholinesterase, present on pre- and postjunctional membranes, or by a less specific serum cholinesterase (butyryl cholinesterase), a soluble enzyme present in serum and interstitial fluid.

Drugs Acting on the Parasympathetic Nervous System 101

Acetyl coenzyme A + choline Action potential Choline acetyltransferase

Ca2+ influx

Acetylcholine

Protein Ca2+ kinase Storage of acetylcholine in vesicles

active Vesicle reuptake of release choline

Exocytosis esteric Receptor cleavage occupation Serum- cholinesterase Acetylcholine esterase: membrane- associated

Smooth muscle cell Heart pacemaker cell Secretory cell M3-receptor M2-receptor M3-receptor

Phospholipase C K+-channel activation Phospholipase C

Slowing of diastolic Ca2+ in Cytosol depolarization Ca2+ in Cytosol

Tone Rate Secretion

mV 0

-30 ACh effect -45 mV mN -90 -70 Control condition Time Time

A. Acetylcholine: release, effects, and degradation

102 Drugs Acting on the Parasympathetic Nervous System

Parasympathomimetics mate takes hours to days, the enzyme remaining inhibited as long as it is car- Acetylcholine (ACh) is too rapidly hy- baminoylated. Cleavage of the phos- drolyzed and inactivated by acetylcholi- phate residue, i.e. dephosphorylation, nesterase (AChE) to be of any therapeu- is practically impossible; enzyme inhi- tic use; however, its action can be mim- bition is irreversible. icked by other substances, namely di- Uses. The quaternary carbamate rect or indirect parasympathomimetics. neostigmine is employed as an indirect Direct Parasympathomimetics. parasympathomimetic in postoperative The choline ester, carbachol, activates atonia of the bowel or bladder. Further- M-cholinoceptors, but is not hydrolyzed more, it is needed to overcome the rela- by AChE. Carbachol can thus be effective ACh-deficiency at the motor end- tively employed for local application to plate in myasthenia gravis or to reverse the eye (glaucoma) and systemic ad- the neuromuscular blockade (p. 184) ministration (bowel atonia, bladder ato- caused by nondepolarizing muscle re- nia). The alkaloids, pilocarpine (from Pil- laxants (decurarization before discon- ocarpus jaborandi) and arecoline (from tinuation of anesthesia). The tertiary Areca catechu; betel nut) also act as di- carbamate physostigmine can be used rect parasympathomimetics. As tertiary as an antidote in poisoning with para- amines, they moreover exert central ef- sympatholytic drugs, because it has ac- fects. The central effect of muscarine- cess to AChE in the brain. Carbamates like substances consists of an enliven- (neostigmine, pyridostigmine, physos- ing, mild stimulation that is probably tigmine) and organophosphates (para- the effect desired in betel chewing, a oxon, ecothiopate) can also be applied widespread habit in South Asia. Of this locally to the eye in the treatment of group, only pilocarpine enjoys thera- glaucoma; however, their long-term use peutic use, which is limited to local ap- leads to cataract formation. Agents from plication to the eye in glaucoma. both classes also serve as insecticides. Indirect Parasympathomimetics. Although they possess high acute toxic- AChE can be inhibited selectively, with ity in humans, they are more rapidly de- the result that ACh released by nerve graded than is DDT following their impulses will accumulate at cholinergic emission into the environment. synapses and cause prolonged stimula- Tacrine is not an ester and interferes tion of cholinoceptors. Inhibitors of only with the choline-binding site of AChE are, therefore, indirect parasym- AChE. It is effective in alleviating symp- pathomimetics. Their action is evident toms of dementia in some subtypes of at all cholinergic synapses. Chemically, Alzheimer’s disease. these agents include esters of carbamic acid (carbamates such as physostigmine, neostigmine) and of phosphoric acid (organophosphates such as paraoxon = E600 and nitrostigmine = parathion = E605, its prodrug). Members of both groups react like ACh with AChE and can be considered false substrates. The esters are hydrolyzed upon formation of a complex with the enzyme. The rate-limiting step in ACh hydrolysis is deacetylation of the enzyme, which takes only milliseconds, thus permitting a high turnover rate and activity of AChE. Decarbaminoyla- tion following hydrolysis of a carba-

Drugs Acting on the Parasympathetic Nervous System 103

Arecoline Carbachol Direct parasympathomimetics Arecoline = ingredient of betel nut: betel Acetylcholine chewing

AChE

ACh Effector organ Effector

AChE Physostigmine

Inhibitors of acetylcholinesterase (AChE)

Indirect Neostigmine parasympathomimetics Paraoxon (E 600)

Acetylcholine Nitrostigmine = + Acetyl Parathion = E 605 AChE ms Choline Deacetylation

Neostigmine + Carbaminoyl AChE Hours to days Decarbaminoylation

Paraoxon + Phosphoryl AChE

Dephosphorylation impossible

A. Direct and indirect parasympathomimetics

104 Drugs Acting on the Parasympathetic Nervous System

Parasympatholytics 2. Relaxation of smooth musculature Bronchodilation can be achieved by the Excitation of the parasympathetic divi- use of ipratropium in conditions of in- sion of the autonomic nervous system creased airway resistance (chronic ob- causes release of acetylcholine at neuro- structive bronchitis, bronchial asth- effector junctions in different target or- ma). When administered by inhalation, gans. The major effects are summarized this quaternary compound has little ef- in A (blue arrows). Some of these effects fect on other organs because of its low have therapeutic applications, as indi- rate of systemic absorption. cated by the clinical uses of parasympa- Spasmolysis by N-butylscopolamine thomimetics (p. 102). in biliary or renal colic (p. 126). Be- Substances acting antagonistically cause of its quaternary nitrogen, this at the M-cholinoceptor are designated drug does not enter the brain and re- parasympatholytics (prototype: the al- quires parenteral administration. Its kaloid atropine; actions shown in red in spasmolytic action is especially marked the panels). Therapeutic use of these because of additional ganglionic block- agents is complicated by their low organ ing and direct muscle-relaxant actions. selectivity. Possibilities for a targeted Lowering of pupillary sphincter to- action include: nus and pupillary dilation by local ad- • local application ministration of homatropine or tropic- • selection of drugs with either good or amide (mydriatics) allows observation poor membrane penetrability as the of the ocular fundus. For diagnostic us- situation demands es, only short-term pupillary dilation is • administration of drugs possessing needed. The effect of both agents sub- receptor subtype selectivity. sides quickly in comparison with that of atropine (duration of several days). Parasympatholytics are employed for the following purposes: 3. Cardioacceleration Ipratropium is used in bradycardia and 1. Inhibition of exocrine glands AV-block, respectively, to raise heart Bronchial secretion. Premedication rate and to facilitate cardiac impulse with atropine before inhalation anes- conduction. As a quaternary substance, thesia prevents a possible hypersecre- it does not penetrate into the brain, tion of bronchial mucus, which cannot which greatly reduces the risk of CNS be expectorated by coughing during in- disturbances (see below). Relatively tubation (anesthesia). high oral doses are required because of Gastric secretion. Stimulation of an inefficient intestinal absorption. gastric acid production by vagal impuls- Atropine may be given to prevent es involves an M-cholinoceptor subtype cardiac arrest resulting from vagal re- (M1-receptor), probably associated with flex activation, incident to anesthetic in- enterochromaffin cells. Pirenzepine (p. duction, gastric lavage, or endoscopic 106) displays a preferential affinity for procedures. this receptor subtype. Remarkably, the HCl-secreting parietal cells possess only M3-receptors. M1-receptors have also been demonstrated in the brain; however, these cannot be reached by pirenzepine because its lipophilicity is too low to permit penetration of the blood- brain barrier. Pirenzepine was formerly used in the treatment of gastric and duodenal ulcers (p. 166).

Drugs Acting on the Parasympathetic Nervous System 105

N. oculo- motorius Deadly nightshade N. facialis Atropa N. glosso- belladonna pharyngeus N. vagus

Atropine

Acetylcholine Nn. sacrales Muscarinic acetylcholine receptor

Schlemm’s canal wide + Ciliary muscle + contracted Salivary secretion + + Gastric acid Pupil narrow production Pupil wide + Pancreatic juice production + Photophobia Bowel peristalsis Near vision impossible + Drainage of aqueous Bladder tone humor impaired - Rate AV conduction Restlessness Irritability Hallucinations + Antiparkinsonian Rate effect AV conduction Antiemetic effect

Sweat production Dry mouth Bronchial secretion Bronchoconstriction Acid production decreased Pancreatic secretory activity decreased "Flushed dry skin" Bowel peristalsis decreased Bronchial secretion decreased Bladder tone Evaporative heat Bronchodilation decreased loss + Increased blood flow for increasing Sympathetic heat dissipation nerves

A. Effects of parasympathetic stimulation and blockade

106 Drugs Acting on the Parasympathetic Nervous System

4. CNS-dampening effects exchange through increased cutaneous Scopolamine is effective in the prophy- blood flow. Decreased peristaltic activ- laxis of kinetosis (motion sickness, sea ity of the intestines leads to constipa- sickness, see p. 330); it is well absorbed tion. transcutaneously. Scopolamine (pKa = Central: Motor restlessness, pro- 7.2) penetrates the blood-brain barrier gressing to maniacal agitation, psychic faster than does atropine (pKa = 9), be- disturbances, disorientation, and hal- cause at physiologic pH a larger propor- lucinations. Elderly subjects are more tion is present in the neutral, mem- sensitive to such central effects. In this brane-permeant form. context, the diversity of drugs producing In psychotic excitement (agita- atropine-like side effects should be tion), sedation can be achieved with borne in mind: e.g., tricyclic antide- scopolamine. Unlike atropine, scopol- pressants, neuroleptics, antihista- amine exerts a calming and amnesio- mines, antiarrhythmics, antiparkinso- genic action that can be used to advan- nian agents. tage in anesthetic premedication. Apart from symptomatic, general Symptomatic treatment in parkin- measures (gastric lavage, cooling with sonism for the purpose of restoring a ice water), therapy of severe atropine dopaminergic-cholinergic balance in intoxication includes the administra- the corpus striatum. Antiparkinsonian tion of the indirect parasympathomi- agents, such as benzatropine (p. 188), metic physostigmine (p. 102). The most readily penetrate the blood-brain barri- common instances of “atropine” intoxi- er. At centrally equi-effective dosage, cation are observed after ingestion of their peripheral effects are less marked the berry-like fruits of belladonna (chil- than are those of atropine. dren) or intentional overdosage with tricyclic antidepressants in attempted Contraindications for suicide. parasympatholytics Glaucoma: Since drainage of aqueous humor is impeded during relaxation of the pupillary sphincter, intraocular pressure rises. Prostatic hypertrophy with impaired micturition: loss of parasympathetic control of the detrusor muscle ex- acerbates difficulties in voiding urine.

Atropine poisoning Parasympatholytics have a wide therapeutic margin. Rarely life-threatening, poisoning with atropine is characterized by the following peripheral and central effects: Peripheral: tachycardia; dry mouth; hyperthermia secondary to the inhibition of sweating. Although sweat glands are innervated by sympathetic fibers, these are cholinergic in nature. When sweat secretion is inhibited, the body loses the ability to dissipate metabolic heat by evaporation of sweat (p. 202). There is a compensatory vasodilation in the skin allowing increased heat

Drugs Acting on the Parasympathetic Nervous System 107

Homatropine 0.2 mg

M1 M1 M M1 1 M3 M3 M3

M Benzatropine 2 Pirenzepine 1 – 2 mg 50 mg

M1 M 1 M1 M1 M1 M1

N-Butyl- scopolamine 10–20 mg

Atropine (0.2 – 2 mg)

Ipratropium 10 mg + ganglioplegic + direct muscle relaxant

A. Parasympatholytics

108 Nicotine

Ganglionic Transmission is no longer possible, even in the face of an intensive and synchronized release Whether sympathetic or parasympa- of ACh (C). thetic, all efferent visceromotor nerves Although nicotine mimics the ac- are made up of two serially connected tion of ACh at the receptors, it cannot neurons. The point of contact (synapse) duplicate the time course of intrasynap- between the first and second neurons tic agonist concentration required for occurs mainly in ganglia; therefore, the appropriate high-frequency ganglionic first neuron is referred to as pregan- activation. The concentration of nico- glionic and efferents of the second as tine in the synaptic cleft can neither postganglionic. build up as rapidly as that of ACh re- Electrical excitation (action poten- leased from nerve terminals nor can tial) of the first neuron causes the re- nicotine be eliminated from the synap- lease of acetylcholine (ACh) within the tic cleft as quickly as ACh. ganglia. ACh stimulates receptors locat- The ganglionic effects of ACh can be ed on the subsynaptic membrane of the blocked by tetraethylammonium, hexa- second neuron. Activation of these re- methonium, and other substances (gan- ceptors causes the nonspecific cation glionic blockers). None of these has in- channel to open. The resulting influx of trinsic activity, that is, they fail to stim- Na+ leads to a membrane depolariza- ulate ganglia even at low concentration; tion. If a sufficient number of receptors some of them (e.g., hexamethonium) is activated simultaneously, a threshold actually block the cholinoceptor-linked potential is reached at which the mem- ion channel, but others (mecamyla- brane undergoes rapid depolarization in mine, trimethaphan) are typical recep- the form of a propagated action poten- tor antagonists. tial. Normally, not all preganglionic im- Certain sympathetic preganglionic pulses elicit a propagated response in neurons project without interruption to the second neuron. The ganglionic syn- the chromaffin cells of the adrenal me- apse acts like a frequency filter (A). The dulla. The latter are embryologic homo- effect of ACh elicited at receptors on the logues of ganglionic sympathocytes. Ex- ganglionic neuronal membrane can be citation of preganglionic fibers leads to imitated by nicotine; i.e., it involves nic- release of ACh in the adrenal medulla, otinic cholinoceptors. whose chromaffin cells then respond Ganglionic action of nicotine. If a with a release of epinephrine into the small dose of nicotine is given, the gan- blood (D). Small doses of nicotine, by in- glionic cholinoceptors are activated. The ducing a partial depolarization of adre- membrane depolarizes partially, but nomedullary cells, are effective in liber- fails to reach the firing threshold. How- ating epinephrine (pp. 110, 112). ever, at this point an amount of released ACh smaller than that normally required will be sufficient to elicit a propagated action potential. At a low concentration, nicotine acts as a ganglionic stimulant; it alters the filter function of the ganglionic synapse, allowing action potential frequency in the second neuron to approach that of the first (B). At higher concentrations, nicotine acts to block ganglionic transmission. Simultaneous activation of many nicotinic cholinoceptors depolarizes the ganglionic cell membrane to such an extent that generation of action potentials

Nicotine 109

First neuron Preganglionic Second neuron postganglionic

-70 mV

Acetylcholine

Impulse frequency

A. Ganglionic transmission: normal state

-55 mV Persistent depolarization Low concentration Ganglionic activation Nicotine

B. Ganglionic transmission: excitation by nicotine

-30 mV Depolarization High concentration Ganglionic blockade Nicotine

C. Ganglionic transmission: blockade by nicotine

Adrenal medulla

Nicotine

Excitation Epinephrine

D. Adrenal medulla: epinephrine release by nicotine

110 Nicotine

Effects of Nicotine on Body Functions Carotid body. Sensitivity to arterial pCO2 increases; increased afferent input At a low concentration, the tobacco al- augments respiratory rate and depth. kaloid nicotine acts as a ganglionic stim- Receptors for pressure, tempera- ulant by causing a partial depolarization ture, and pain. Sensitivity to the corre- via activation of ganglionic cholinocep- sponding stimuli is enhanced. tors (p. 108). A similar action is evident Area postrema. Sensitization of at diverse other neural sites, considered chemoceptors leads to excitation of the below in more detail. medullary emetic center. Autonomic ganglia. Ganglionic At low concentration, nicotine is al- stimulation occurs in both the sympa- so able to augment the excitability of thetic and parasympathetic divisions of the motor endplate. This effect can be the autonomic nervous system. Para- manifested in heavy smokers in the sympathetic activation results in in- form of muscle cramps (calf muscula- creased production of gastric juice ture) and soreness. (smoking ban in peptic ulcer) and en- The central nervous actions of nico- hanced bowel motility (“laxative” effect tine are thought to be mediated largely of the first morning cigarette: defeca- by presynaptic receptors that facilitate tion; diarrhea in the novice). transmitter release from excitatory Although stimulation of parasym- aminoacidergic (glutamatergic) nerve pathetic cardioinhibitory neurons terminals in the cerebral cortex. Nico- would tend to lower heart rate, this re- tine increases vigilance and the ability sponse is overridden by the simultane- to concentrate. The effect reflects an en- ous stimulation of sympathetic cardio- hanced readiness to perceive external accelerant neurons and the adrenal me- stimuli (attentiveness) and to respond dulla. Stimulation of sympathetic to them. nerves resulting in release of norepi- The multiplicity of its effects makes nephrine gives rise to vasoconstriction; nicotine ill-suited for therapeutic use. peripheral resistance rises. Adrenal medulla. On the one hand, release of epinephrine elicits cardiovascular effects, such as increases in heart rate und peripheral vascular resistance. On the other, it evokes metabolic responses, such as glycogenolysis and lipolysis, that generate energy-rich substrates. The sensation of hunger is suppressed. The metabolic state corresponds to that associated with physical exercise – “silent stress”. Baroreceptors. Partial depolarization of baroreceptors enables activation of the reflex to occur at a relatively smaller rise in blood pressure, leading to decreased sympathetic vasoconstrictor activity. Neurohypophysis. Release of vasopressin (antidiuretic hormone) results in lowered urinary output (p. 164). Levels of vasopressin necessary for vasoconstriction will rarely be produced by nicotine.

Nicotine 111

Vigilance

Antidiuretic Respiratory rate Sensitivity effect

Partial Partial depolarization Release of depolarization in vasopressin of sensory nerve carotid body and endings of mechano- other ganglia and nociceptors

Nicotine Partial depolarization of Partial chemoreceptors depolarization in area postrema of baroreceptors

Epinephrine Emetic center release

Partial depolarization Emesis of autonomic ganglia

Sympathetic Para- activity sympathetic activity

Vasoconstriction VasoconstrictionHerzfrequenz BowelDarmtätigkeit motility

Blood pressure Defecation, diarrhea

Glycogenolysis, Blood glucose lipolysis, and “silent stress” free fatty acids

A.Effects of nicotine in the body

112 Nicotine

Consequences of Tobacco Smoking possess demonstrable carcinogenic properties. The dried and cured leaves of the night- Dust particles inhaled in tobacco shade plant Nicotiana tabacum are smoke, together with bronchial mucus, known as tobacco. Tobacco is mostly must be removed from the airways by smoked, less frequently chewed or tak- the ciliated epithelium. Ciliary activity, en as dry snuff. Combustion of tobacco however, is depressed by tobacco generates approx. 4000 chemical com- smoke; mucociliary transport is impair- pounds in detectable quantities. The ed. This depression favors bacterial in- xenobiotic burden on the smoker de- fection and contributes to the chronic pends on a range of parameters, includ- bronchitis associated with regular ing tobacco quality, presence of a filter, smoking. Chronic injury to the bronchi- rate and temperature of combustion, al mucosa could be an important causa- depth of inhalation, and duration of tive factor in increasing the risk in breath holding. smokers of death from bronchial carci- Tobacco contains 0.2–5 % nicotine. noma. In tobacco smoke, nicotine is present as Statistical surveys provide an im- a constituent of small tar particles. It is pressive correlation between the num- rapidly absorbed through bronchi and ber of cigarettes smoked a day and the lung alveoli, and is detectable in the risk of death from coronary disease or brain only 8 s after the first inhalation. lung cancer. Statistics also show that, on Smoking of a single cigarette yields peak cessation of smoking, the increased risk plasma levels in the range of 25–50 of death from coronary infarction or ng/mL. The effects described on p. 110 other cardiovascular disease declines become evident. When intake stops, over 5–10 years almost to the level of nicotine concentration in plasma shows non-smokers. Similarly, the risk of de- an initial rapid fall, reflecting distribu- veloping bronchial carcinoma is re- tion into tissues, and a terminal elimi- duced. nation phase with a half-life of 2 h. Nic- Abrupt cessation of regular smok- otine is degraded by oxidation. ing is not associated with severe physi- The enhanced risk of vascular dis- cal withdrawal symptoms. In general, ease (coronary stenosis, myocardial in- subjects complain of increased nervous- farction, and central and peripheral is- ness, lack of concentration, and weight chemic disorders, such as stroke and gain. intermittent claudication) is likely to be a consequence of chronic exposure to nicotine. Endothelial impairment and hence dysfunction has been proven to result from smoking, and nicotine is under discussion as a factor favoring the progression of arteriosclerosis. By releasing epinephrine, it elevates plasma levels of glucose and free fatty acids in the absence of an immediate physiological need for these energy-rich metabolites. Furthermore, it promotes platelet aggregability, lowers fibrinolytic activity of blood, and enhances coagulability. The health risks of tobacco smoking are, however, attributable not only to nicotine, but also to various other ingredients of tobacco smoke, some of which

Nicotine 113

Nicotine

Nicotiana tabacum

"Tar"

Nitrosamines, acrolein, polycyclic hydrocarbons e. g., benzopyrene heavy metals Sum of noxious stimuli

Platelet Damage to Damage to Inhibition of aggregation vascular bronchial mucociliary endothelium epithelium transport Duration of Fibrinolytic Epinephrine Yearsexposure Months activity

Free Chronic Bronchitis fatty acids bronchitis

Coronary disease Bronchial carcinoma Annual deaths/1000 people Annual cases/1000 people

2 Ex-smoker 0–10 –20 –40 >400 1–14 15-40 >40

Number of cigarettes per day

A. Sequelae of tobacco smoking

114 Biogenic Amines

Biogenic Amines — Actions and (COMT) and monoamineoxidase (MAO), Pharmacological Implications is another means to increase actual available dopamine concentration Dopamine A. As the precursor of nore- (COMT-inhibitors, p. 188), MAOB-inhibi- pinephrine and epinephrine (p. 184), tors, p. 88, 188). dopamine is found in sympathetic (adre- Dopamine antagonist activity is the nergic) neurons and adrenomedullary hallmark of classical neuroleptics. The cells. In the CNS, dopamine itself serves antihypertensive agents, reserpine (ob- as a neuromediator and is implicated in solete) and α-methyldopa, deplete neu- neostriatal motor programming (p. 188), ronal stores of the amine. A common ad- the elicitation of emesis at the level of verse effect of dopamine antagonists or the area postrema (p. 330), and inhibi- depletors is parkinsonism. tion of prolactin release from the anteri- Histamine (B). Histamine is stored or pituitary (p. 242). in basophils and tissue mast cells. It Dopamine receptors are coupled to G- plays a role in inflammatory and allergic proteins and exist as different subtypes. reactions (p. 72, 326) and produces D1-receptors (comprising subtypes D1 bronchoconstriction, increased intesti- and D5) and D2-receptors (comprising nal peristalsis, and dilation and in- subtypes D2, D3, and D4). The aforemen- creased permeability of small blood ves- tioned actions are mediated mainly by sels. In the gastric mucosa, it is released D2 receptors. When given by infusion, from enterochromaffin-like cells and dopamine causes dilation of renal and stimulates acid secretion by the parietal splanchnic arteries. This effect is mediat- cells. In the CNS, it acts as a neuromod- ed by D1 receptors and is utilized in the ulator. Two receptor subtypes (G-pro- treatment of cardiovascular shock and tein-coupled), H1 and H2, are of thera- hypertensive emergencies by infusion of peutic importance; both mediate vascu- dopamine and fenoldopam, respective- lar responses. Prejunctional H3 recep- ly. At higher doses, β1-adrenoceptors tors exist in brain and the periphery. and, finally, α-receptors are activated, as Antagonists. Most of the so-called evidenced by cardiac stimulation and H1-antihistamines also block other re- vasoconstriction, respectively. ceptors, including M-cholinoceptors and Dopamine is not to be confused with do- D-receptors. H1-antihistamines are used butamine which stimulates α- and β-ad- for the symptomatic relief of allergies renoceptors but not dopamine receptors (e.g., bamipine, chlorpheniramine, cle- (p. 62). mastine, dimethindene, mebhydroline Dopamine-mimetics. Administra- pheniramine); as antiemetics (mecli- tion of the precursor L-dopa promotes zine, dimenhydrinate, p. 330), as over- endogenous synthesis of dopamine (in- the-counter hypnotics (e.g., diphenhy- dication: parkinsonian syndrome, dramine, p. 222). Promethazine repre- p. 188). The ergolides, bromocriptine, sents the transition to the neuroleptic pergolide, and lisuride, are ligands at D- phenothiazines (p. 236). Unwanted ef- receptors whose therapeutic effects are fects of most H1-antihistamines are las- probably due to stimulation of D2 recep- situde (impaired driving skills) and atro- tors (indications: parkinsonism, sup- pine-like reactions (e.g., dry mouth, con- pression of lactation, infertility, acrome- stipation). At the usual therapeutic dos- galy, p. 242). Typical adverse effects of es, astemizole, cetrizine, fexofenadine, these substances are nausea and vomit- and loratidine are practically devoid of ing. As indirect dopamine-mimetics, (+)- sedative and anticholinergic effects. H2- amphetamine and ritaline augment do- antihistamines (cimetidine, ranitidine, pamine release. famotidine, nizatidine) inhibit gastric Inhibition of the enzymes involved acid secretion, and thus are useful in the in dopamine degradation, catechol- treatment of peptic ulcers. amine-oxygen-methyl-transferase

Biogenic Amines 115

Increase in dopamine synthesis Dopaminergic neuron L-Dopa

Inhibition of synthesis and formation of false transmitter: Methyldopa Destruction of storage vesicles: Reserpine

Dopamin D2-Agonists e.g., bromocriptine

D1/D2-Antagonists D2-Antagonists Neuroleptics e.g., metoclopramide D1 D2 Receptors

Striatum (extrapyramidal motor function) Area postrema (emesis) Dopamine Adenohypophysis (prolactin secretion )

D1-Agonists Blood e.g., fenoldopam flow

A. Dopamine actions as influenced by drugs

H1-Antagonists H2-Antagonists e.g., fexofenadine e.g., ranitidine Histamine

H1-Receptors H2-Receptors

Vasodilation HCl Bronchoconstriction Bowel peristalsis permeability

“H1-Antihistamines” Diphenhydramine Chlorpromazine Parietal cell

Acetylcholine Dopamine Sedation, hypnotic, antiemetic action mACh-Receptor Dopamine receptors

B. Histamine actions as influenced by drugs

116 Biogenic Amines

Inhibitors of histamine release: One Ketanserin is an antagonist at 5- of the effects of the so-called mast cell HT2A receptors and produces antihyper- stabilizers cromoglycate (cromolyn) tensive effects, as well as inhibition of and nedocromil is to decrease the re- thrombocyte aggregation. Whether 5- lease of histamine from mast cells (p. HT antagonism accounts for its antihy- 72, 326). Both agents are applied topi- pertensive effect remains questionable, cally. Release of mast cell mediators can because ketanserin also blocks α-adren- also be inhibited by some H1 antihista- oceptors. mines, e.g., oxatomide and ketotifen, Sumatriptan and other triptans are which are used systemically. antimigraine drugs that possess agonist activity at 5-HT1 receptors of the B, D Serotonin and F subtypes and may thereby allevi- Occurrence. Serotonin (5-hydroxytrypt- ate this type of headache (p. 322). amine, 5-HT) is synthesized from L- Gastrointestinal tract. Serotonin tryptophan in enterochromaffin cells of released from myenteric neurons or en- the intestinal mucosa. 5-HT-synthesiz- terochromaffin cells acts on 5-HT3 and ing neurons occur in the enteric nerve 5-HT4 receptors to enhance bowel mo- plexus and the CNS, where the amine tility and enteral fluid secretion. Cisa- fulfills a neuromediator function. Blood pride is a prokinetic agent that pro- platelets are unable to synthesize 5HT, motes propulsive motor activity in the but are capable of taking up, storing, stomach and in small and large intes- and releasing it. tines. It is used in motility disorders. Its Serotonin receptors. Based on bio- mechanism of action is unclear, but chemical and pharmacological criteria, stimulation of 5HT4 receptors may be seven receptor classes can be distin- important. guished. Of major pharmacotherapeutic Central Nervous System. Serotoni- importance are those designated 5-HT1, nergic neurons play a part in various 5-HT2, 5-HT4, and 5-HT7, all of which are brain functions, as evidenced by the ef- G-protein-coupled, whereas the 5-HT3 fects of drugs likely to interfere with se- subtype represents a ligand-gated non- rotonin. Fluoxetine is an antidepressant selective cation channel. that, by blocking re-uptake, inhibits in- Serotonin actions. The cardiovascu- activation of released serotonin. Its ac- lar effects of 5-HT are complex, because tivity spectrum includes significant psy- multiple, in part opposing, effects are chomotor stimulation, depression of ap- exerted via the different receptor sub- petite, and anxiolysis. Buspirone also has types. Thus, 5-HT2A and 5-HT7 receptors anxiolytic properties thought to be me- on vascular smooth muscle cells medi- diated by central presynaptic 5-HT1A re- ate direct vasoconstriction and vasodi- ceptors. Ondansetron, an antagonist at lation, respectively. Vasodilation and the 5-HT3 receptor, possesses striking lowering of blood pressure can also oc- effectiveness against cytotoxic drug-in- cur by several indirect mechanisms: 5- duced emesis, evident both at the start HT1A receptors mediate sympathoinhi- of and during cytostatic therapy. Trop- bition ( decrease in neurogenic vaso- isetron and granisetron produce analo- constrictor tonus) both centrally and gous effects. peripherally; 5-HT2B receptors on vas- Psychedelics (LSD) and other psy- cular endothelium promote release of chotomimetics such as mescaline and vasorelaxant mediators (NO, p. 120; psilocybin can induce states of altered prostacyclin, p. 196) 5-HT released from awareness, or induce hallucinations and platelets plays a role in thrombogenesis, anxiety, probably mediated by 5-HT2A hemostasis, and the pathogenesis of receptors. Overactivity of these recep- preeclamptic hypertension. tors may also play a role in the genesis of negative symptoms in schizophrenia (p. 238) and sleep disturbances.

Biogenic Amines 117

Serotoninergic neuron

LSD Buspirone Lysergic acid diethylamide Anxiolytic Psychedelic 5-HT1A

Hallucination 2A Ondansetron

5-HT Antiemetic 3 Fluoxetine

5-HT- reuptake 5-HT inhibitor Antidepressant Emesis

5-HT1D Sumatriptan Antimigraine

5-Hydroxy-tryptamine

Cisapride Prokinetic Serotonin

Blood vessel Intestine

Endothelium- mediated Dilation

5-HT2B

5-HT4 Constriction Platelets Propulsive motility 2 Entero- 5-HT chromaffin cell

A. Serotonin receptors and actions

118 Vasodilators

Vasodilators–Overview alogues such as iloprost, or prostaglandin E1 analogues such as alprostanil, The distribution of blood within the cir- mimic the actions of relaxant mediators. culation is a function of vascular caliber. Ca2+ antagonists reduce depolarizing in- Venous tone regulates the volume of ward Ca2+ currents, while K+-channel ac- blood returned to the heart, hence, tivators promote outward (hyperpolar- stroke volume and cardiac output. The izing) K+ currents. Organic nitrovasodi- luminal diameter of the arterial vascula- lators give rise to NO, an endogenous ture determines peripheral resistance. activator of guanylate cyclase. Cardiac output and peripheral resis- Individual vasodilators. Nitrates 2+ tance are prime determinants of arterial (p. 120) Ca -antagonists (p. 122). α1- blood pressure (p. 314). antagonists (p. 90), ACE-inhibitors, AT1- In A, the clinically most important antagonists (p. 124); and sodium nitro- vasodilators are presented in the order prusside (p. 120) are discussed else- of approximate frequency of therapeu- where. tic use. Some of these agents possess Dihydralazine and minoxidil (via different efficacy in affecting the venous its sulfate-conjugated metabolite) dilate and arterial limbs of the circulation arterioles and are used in antihyperten- (width of beam). sive therapy. They are, however, unsuit- Possible uses. Arteriolar vasodila- able for monotherapy because of com- tors are given to lower blood pressure in pensatory circulatory reflexes. The hypertension (p. 312), to reduce cardiac mechanism of action of dihydralazine is work in angina pectoris (p. 308), and to unclear. Minoxidil probably activates K+ reduce ventricular afterload (pressure channels, leading to hyperpolarization load) in cardiac failure (p. 132). Venous of smooth muscle cells. Particular ad- vasodilators are used to reduce venous verse reactions are lupus erythemato- filling pressure (preload) in angina pec- sus with dihydralazine and hirsutism toris (p. 308) or cardiac failure (p. 132). with minoxidil—used topically for the Practical uses are indicated for each treatment of baldness (alopecia androg- drug group. enetica). Counter-regulation in acute hy- Diazoxide given i.v. causes promi- potension due to vasodilators (B). In- nent arteriolar dilation; it can be em- creased sympathetic drive raises heart ployed in hypertensive crises. After its rate (reflex tachycardia) and cardiac oral administration, insulin secretion is output and thus helps to elevate blood inhibited. Accordingly, diazoxide can be pressure. Patients experience palpita- used in the management of insulin-se- tions. Activation of the renin-angioten- creting pancreatic tumors. Both effects sin-aldosterone (RAA) system serves to are probably due to opening of (ATP- increase blood volume, hence cardiac gated) K+ channels. output. Fluid retention leads to an in- The methylxanthine theophylline crease in body weight and, possibly, (p. 326), the phosphodiesterase inhibi- edemas. These counter-regulatory pro- tor amrinone (p. 132), prostacyclins (p. cesses are susceptible to pharmacologi- 197), and nicotinic acid derivatives (p. cal inhibition (β-blockers, ACE inhibi- 156) also possess vasodilating activity. tors, AT1-antagonists, diuretics). Mechanisms of action. The tonus of vascular smooth muscle can be decreased by various means. ACE inhibitors, antagonists at AT1-receptors and antagonists at α-adrenoceptors protect against the effects of excitatory mediators such as angiotensin II and norepinephrine, respectively. Prostacyclin an-

Vasodilators 119

Venous bed Vasodilation Arterial bed Nitrates

Ca-antagonists

ACE-inhibitors

Dihydralazine

Minoxidil

α 1-Antagonists

Nitroprusside sodium

A. Vasodilators

Sympathetic nerves Vasoconstriction

β-Blocker Blood Vasodilation pressure Vasomotor Heart rate center Blood- Cardiac output pressure Blood volume

Angiotensinogen Aldosterone Renin Angiotensin- Angiotensin I converting enzyme (ACE) Angiotensin II Vasoconstriction ACE-inhibitors Renin-angiotensin-aldosterone-system

B. Counter-regulatory responses in hypotension due to vasodilators

120 Vasodilators

Organic Nitrates has been attributed to a cellular exhaus- tion of SH-donors but this may be not Various esters of nitric acid (HNO3) and the only reason. polyvalent alcohols relax vascular Nitroglycerin (NTG) is distin- smooth muscle, e.g., nitroglycerin (gly- guished by high membrane penetrabil- ceryltrinitrate) and isosorbide dinitrate. ity and very low stability. It is the drug The effect is more pronounced in venous of choice in the treatment of angina pec- than in arterial beds. toris attacks. For this purpose, it is ad- These vasodilator effects produce ministered as a spray, or in sublingual or hemodynamic consequences that can buccal tablets for transmucosal deliv- be put to therapeutic use. Due to a de- ery. The onset of action is between 1 and crease in both venous return (preload) 3 min. Due to a nearly complete pre- and arterial afterload, cardiac work is systemic elimination, it is poorly suited decreased (p. 308). As a result, the car- for oral administration. Transdermal de- diac oxygen balance improves. Spas- livery (nitroglycerin patch) also avoids modic constriction of larger coronary presystemic elimination. Isosorbide vessels (coronary spasm) is prevented. dinitrate (ISDN) penetrates well Uses. Organic nitrates are used through membranes, is more stable chiefly in angina pectoris (p. 308, 310), than NTG, and is partly degraded into less frequently in severe forms of chron- the weaker, but much longer acting, 5- ic and acute congestive heart failure. isosorbide mononitrate (ISMN). ISDN Continuous intake of higher doses with can also be applied sublingually; how- maintenance of steady plasma levels ever, it is mainly administered orally in leads to loss of efficacy, inasmuch as the order to achieve a prolonged effect. organism becomes refractory (tachy- ISMN is not suitable for sublingual use phylactic). This “nitrate tolerance” can because of its higher polarity and slower be avoided if a daily “nitrate-free inter- rate of absorption. Taken orally, it is ab- val” is maintained, e.g., overnight. sorbed and is not subject to first-pass At the start of therapy, unwanted elimination. reactions occur frequently in the form Molsidomine itself is inactive. Af- of a throbbing headache, probably ter oral intake, it is slowly converted caused by dilation of cephalic vessels. into an active metabolite. Apparently, This effect also exhibits tolerance, even there is little likelihood of "nitrate tole- when daily “nitrate pauses” are kept. rance”. Excessive dosages give rise to hypoten- Sodium nitroprusside contains a sion, reflex tachycardia, and circulatory nitroso (-NO) group, but is not an ester. collapse. It dilates venous and arterial beds Mechanism of action. The reduc- equally. It is administered by infusion to tion in vascular smooth muscle tone is achieve controlled hypotension under presumably due to activation of guany- continuous close monitoring. Cyanide late cyclase and elevation of cyclic GMP ions liberated from nitroprusside can be levels. The causative agent is most likely inactivated with sodium thiosulfate nitric oxide (NO) generated from the or- (Na2S2O3) (p. 304). ganic nitrate. NO is a physiological messenger molecule that endothelial cells release onto subjacent smooth muscle cells (“endothelium-derived relaxing factor,” EDRF). Organic nitrates would thus utilize a pre-existing pathway, hence their high efficacy. The generation of NO within the smooth muscle cell depends on a supply of free sulfhy- dryl (-SH) groups; “nitrate-tolerance”

Vasodilators 121

Preload Afterload O2-supply O2-demand

Blood pressure

Prevention of Venous blood return coronary artery Peripheral to heart spasm resistance

Venous bed “Nitrate- Arterial bed tolerance”

Route: Route: e.g., sublingual, e.g., sublingual, transdermal oral, transdermal

Vasodilation

“Nitrates”

Glyceryl trinitrate Nitroglycerin Isosorbide dinitrate

NO t1 ~ 2 mint1 ~ 30 min NO 2 2 Inactivation 5-Isosorbide mononitrate, an active metabolite t1 ~ 240 min 2

R – O – NO2

SH-donors e.g., glutathione Release of NO

Consumption Activation of Active guanylate cyclase metabolite

GTP cGMP

Molsidomine Smooth muscle cell Relaxation (precursor)

A. Vasodilators: Nitrates

122 Vasodilators

Calcium Antagonists resents a cationic amphiphilic molecule. It exerts inhibitory effects not only on During electrical excitation of the cell arterial smooth muscle, but also on heart membrane of heart or smooth muscle, muscle. In the heart, Ca2+ inward cur- different ionic currents are activated, rents are important in generating depo- including an inward Ca2+ current. The larization of sinoatrial node cells (im- term Ca2+ antagonist is applied to drugs pulse generation), in impulse propaga- that inhibit the influx of Ca2+ ions with- tion through the AV- junction (atrioven- out affecting inward Na+ or outward K+ tricular conduction), and in electrome- currents to a significant degree. Other chanical coupling in the ventricular car- labels are Ca-entry blocker or Ca-channel diomyocytes. Verapamil thus produces blocker. Therapeutically used Ca2+ an- negative chrono-, dromo-, and inotropic tagonists can be divided into three effects. groups according to their effects on Indications. Verapamil is used as heart and vasculature. an antiarrhythmic drug in supraventric- I. Dihydropyridine derivatives. ular tachyarrhythmias. In atrial flutter The dihydropyridines, e.g., nifedipine, or fibrillation, it is effective in reducing are uncharged hydrophobic substances. ventricular rate by virtue of inhibiting They induce a relaxation of vascular AV-conduction. Verapamil is also em- smooth muscle in arterial beds. An effect ployed in the prophylaxis of angina pec- on cardiac function is practically absent toris attacks (p. 308) and the treatment at therapeutic dosage. (However, in of hypertension (p. 312). Adverse ef- pharmacological experiments on isolat- fects: Because of verapamil’s effects on ed cardiac muscle preparations a clear the sinus node, a drop in blood pressure negative inotropic effect is demon- fails to evoke a reflex tachycardia. Heart strable.) They are thus regarded as va- rate hardly changes; bradycardia may soselective Ca2+ antagonists. Because of even develop. AV-block and myocardial the dilatation of resistance vessels, insufficiency can occur. Patients fre- blood pressure falls. Cardiac afterload is quently complain of constipation. diminished (p. 306) and, therefore, also Gallopamil (= methoxyverapamil) is oxygen demand. Spasms of coronary ar- closely related to verapamil in both teries are prevented. structure and biological activity. Indications for nifedipine include Diltiazem is a catamphiphilic ben- angina pectoris (p. 308) and, — when ap- zothiazepine derivative with an activity plied as a sustained release preparation, profile resembling that of verapamil. — hypertension (p. 312). In angina pec- III. T-channel selective blockers. toris, it is effective when given either Ca2+-channel blockers, such as verapa- prophylactically or during acute attacks. mil and mibefradil, may block both L- Adverse effects are palpitation (reflex and T-type Ca2+ channels. Mibefradil tachycardia due to hypotension), head- shows relative selectivity for the latter ache, and pretibial edema. and is devoid of a negative inotropic ef- Nitrendipine and felodipine are used fect; its therapeutic usefulness is com- in the treatment of hypertension. Ni- promised by numerous interactions modipine is given prophylactically after with other drugs due to inhibition of cy- subarachnoidal hemorrhage to prevent tochrome P450-dependent enzymes vasospasms due to depolarization by (CYP 1A2, 2D6 and, especially, 3A4). excess K+ liberated from disintegrating erythrocytes or blockade of NO by free hemoglobin. II. Verapamil and other catamphiphilic Ca2+ antagonists. Verapamil contains a nitrogen atom bearing a positive charge at physiological pH and thus rep-

Vasodilators 123

Smooth muscle cell

Afterload O2-demand

Blood pressure Contraction

Inhibition of Peripheral coronary spasm resistance

Ca2+

Arterial blood vessel

Vasodilation in arterial bed

+ 2+ Na Ca10-3M

2+ + Ca10-7M K

Selective inhibition of calcium influx Membrane depolarization Nifedipine Verapamil (dihydropyridine derivative) (cationic amphiphilic)

Inhibition of cardiac functions

Impulse Heart rate Sinus node generation Reflex tachy- Ca2+ cardia with nifedipine

Impulse AV- AV-node conduction conduction

Electro- Ventricular mechanical Contractility muscle coupling

Heart muscle cell

A.Vasodilators: calcium antagonists

124 Inhibitors of the RAA System

Inhibitors of the RAA System lasting effect than does captopril. Indi- cations are hypertension and cardiac Angiotensin-converting enzyme (ACE) failure. is a component of the antihypotensive Lowering of an elevated blood pres- renin-angiotensin-aldosterone (RAA) sure is predominantly brought about by system. Renin is produced by special- diminished production of angiotensin II. ized cells in the wall of the afferent ar- Impaired degradation of kinins that ex- teriole of the renal glomerulus. These ert vasodilating actions may contribute cells belong to the juxtaglomerular ap- to the effect. paratus of the nephron, the site of con- In heart failure, cardiac output rises tact between afferent arteriole and dis- again because ventricular afterload di- tal tubule, and play an important part in minishes due to a fall in peripheral re- controlling nephron function. Stimuli sistance. Venous congestion abates as a eliciting release of renin are: a drop in result of (1) increased cardiac output renal perfusion pressure, decreased rate and (2) reduction in venous return (de- of delivery of Na+ or Cl– to the distal tu- creased aldosterone secretion, de- bules, as well as β-adrenoceptor-medi- creased tonus of venous capacitance ated sympathoactivation. The glycopro- vessels). tein renin enzymatically cleaves the Undesired effects. The magnitude decapeptide angiotensin I from its cir- of the antihypertensive effect of ACE in- culating precursor substrate angiotensi- hibitors depends on the functional state nogen. ACE, in turn, produces biologi- of the RAA system. When the latter has cally active angiotensin II (ANG II) from been activated by loss of electrolytes angiotensin I (ANG I). and water (resulting from treatment ACE is a rather nonspecific pepti- with diuretic drugs), cardiac failure, or dase that can cleave C-terminal dipep- renal arterial stenosis, administration of tides from various peptides (dipeptidyl ACE inhibitors may initially cause an ex- carboxypeptidase). As “kininase II,” it cessive fall in blood pressure. In renal contributes to the inactivation of kinins, arterial stenosis, the RAA system may be such as bradykinin. ACE is also present in needed for maintaining renal function blood plasma; however, enzyme local- and ACE inhibitors may precipitate re- ized in the luminal side of vascular endo- nal failure. Dry cough is a fairly frequent thelium is primarily responsible for the side effect, possibly caused by reduced formation of angiotensin II. The lung is inactivation of kinins in the bronchial rich in ACE, but kidneys, heart, and other mucosa. Rarely, disturbances of taste organs also contain the enzyme. sensation, exanthema, neutropenia, Angiotensin II can raise blood pres- proteinuria, and angioneurotic edema sure in different ways, including (1) may occur. In most cases, ACE inhibitors vasoconstriction in both the arterial and are well tolerated and effective. Newer venous limbs of the circulation; (2) analogues include lisinopril, perindo- stimulation of aldosterone secretion, pril, ramipril, quinapril, fosinopril, be- leading to increased renal reabsorption nazepril, cilazapril, and trandolapril. of NaCl and water, hence an increased Antagonists at angiotensin II re- blood volume; (3) a central increase in ceptors. Two receptor subtypes can be sympathotonus and, peripherally, en- distinguished: AT1, which mediates the hancement of the release and effects of above actions of AT II; and AT2, whose norepinephrine. physiological role is still unclear. The ACE inhibitors, such as captopril sartans (candesartan, eprosartan, irbe- and enalaprilat, the active metabolite of sartan, losartan, and valsartan) are AT1 enalapril, occupy the enzyme as false antagonists that reliably lower high substrates. Affinity significantly influ- blood pressure. They do not inhibit ences efficacy and rate of elimination. degradation of kinins and cough is not a Enalaprilat has a stronger and longer- frequent side-effect.

Inhibitors of the RAA System 125

Kidney ACE inhibitors RR HOOC O

N SH Captopril CH3

O HOOC

CH3 O O CH3 Renin Enalaprilat Enalapril

Angiotensinogen ACE (α -globulin) Angiotensin I- 2 converting- Ang Ienzyme Kinins

Angiotensin I (Ang I) Kininase II COOH Dipeptidyl-Carboxypeptidase

Ang II Degradation products ACE Vascular endothelium Losartan CH OH Angiotensin II Cl 2 NN H H2N N N NN Receptors AT -receptor antagonists H3C 1

Venous Cardiac Arterial supply output blood pressure

Peripheral resistance venous capacitance vessels Resistance vessels Vasoconstriction

NaCl Aldosterone Sympatho- secretion activation H2O

K+

A. Renin-angiotensin-aldosterone system and inhibitors

126 Drugs Acting on Smooth Muscle

Drugs Used to Influence Smooth Muscle 196; F2α: dinoprost; E2: dinoprostone, Organs misoprostol, sulprostone) are capable of inducing rhythmic uterine contractions Bronchodilators. Narrowing of bron- and cervical relaxation at any time. They chioles raises airway resistance, e.g., in are mostly employed as abortifacients bronchial or bronchitic asthma. Several (oral or vaginal application of misopros- substances that are employed as bron- tol in combination with mifepristone [p. chodilators are described elsewhere in 256]). more detail: β2-sympathomimetics (p. Ergot alkaloids are obtained from 84, given by pulmonary, parenteral, or Secale cornutum (ergot), the sclerotium oral route), the methylxanthine theo- of a fungus (Claviceps purpurea) parasi- phylline (p. 326, given parenterally or tizing rye. Consumption of flour from orally), as well as the parasympatholytic contaminated grain was once the cause ipratropium (pp. 104, 107, given by in- of epidemic poisonings (ergotism) char- halation). acterized by gangrene of the extremities Spasmolytics. N-Butylscopolamine (St. Anthony’s fire) and CNS disturbanc- (p. 104) is used for the relief of painful es (hallucinations). spasms of the biliary or ureteral ducts. Ergot alkaloids contain lysergic acid Its poor absorption (N.B. quaternary N; (formula in A shows an amide). They act absorption rate <10%) necessitates par- on uterine and vascular muscle. Ergo- enteral administration. Because the metrine particularly stimulates the uter- therapeutic effect is usually weak, a po- us. It readily induces a tonic contraction tent analgesic is given concurrently, e.g., of the myometrium (tetanus uteri). This the opioid meperidine. Note that some jeopardizes placental blood flow and fe- spasms of intestinal musculature can be tal O2 supply. The semisynthetic deriva- effectively relieved by organic nitrates tive methylergometrine is therefore (in biliary colic) or by nifedipine (esoph- used only after delivery for uterine con- ageal hypertension and achalasia). tractions that are too weak. Myometrial relaxants (Tocolyt- Ergotamine, as well as the ergotox- ics). β2-Sympathomimetics such as fe- ine alkaloids (ergocristine, ergocryp- noterol or ritodrine, given orally or par- tine, ergocornine), have a predominant- enterally, can prevent premature labor ly vascular action. Depending on the in- or interrupt labor in progress when dan- itial caliber, constriction or dilation may gerous complications necessitate cesar- be elicited. The mechanism of action is ean section. Tachycardia is a side effect unclear; a mixed antagonism at α- produced reflexly because of β2-mediat- adrenoceptors and agonism at 5-HT-re- ed vasodilation or direct stimulation of ceptors may be important. Ergotamine cardiac β1-receptors. Magnesium sul- is used in the treatment of migraine (p. fate, given i.v., is a useful alternative 322). Its congener, dihydroergotamine, when β-mimetics are contraindicated, is furthermore employed in orthostatic but must be carefully titrated because complaints (p. 314). its nonspecific calcium antagonism Other lysergic acid derivatives are leads to blockade of cardiac impulse the 5-HT antagonist methysergide, the conduction and of neuromuscular dopamine agonists bromocriptine, per- transmission. golide, and cabergolide (pp. 114, 188), Myometrial stimulants. The neu- and the hallucinogen lysergic acid di- rohypophyseal hormone oxytocin (p. ethylamide (LSD, p. 240). 242) is given parenterally (or by the nasal or buccal route) before, during, or after labor in order to prompt uterine contractions or to enhance them. Certain prostaglandins or analogues of them (p.

Drugs Acting on Smooth Muscle 127

Bronchial asthma Biliary / renal colic O2

Spasm of smooth muscle

Bronchodilation Spasmolysis Inhibition of labor

Theophylline N-Butylscopolamine β2- Sympathomimetics

Induction of labor

Scopolamine Oxytocin

β2-Sympathomimetics Nitrates Prostaglandins e.g., fenoterol e.g., nitroglycerin F2α, E2 Ipratropium

Secale cornutum (ergot) Tonic contraction of uterus e.g., ergometrine O 2 Contraindication: before delivery

Fungus: Claviceps purpurea Indication: postpartum uterine atonia Secale alkaloids

Effect on vasomotor tone e.g., ergotamine

Fixation of lumen at intemediate caliber

A. Drugs used to alter smooth muscle function

128 Cardiac Drugs

Overview of Modes of Action (A) Events Underlying Contraction and Relaxation (B) 1. The pumping capacity of the heart is regulated by sympathetic and parasym- The signal triggering contraction is a pathetic nerves (pp. 84, 105). Drugs ca- propagated action potential (AP) gener- pable of interfering with autonomic ated in the sinoatrial node. Depolariza- nervous function therefore provide a tion of the plasmalemma leads to a rap- means of influencing cardiac perfor- id rise in cytosolic Ca2+ levels, which mance. Thus, anxiolytics of the benzo- causes the contractile filaments to diazepine type (p. 226), such as diaze- shorten (electromechanical coupling). pam, can be employed in myocardial in- The level of Ca2+ concentration attained farction to suppress sympathoactiva- determines the degree of shortening, tion due to life-threatening distress. i.e., the force of contraction. Sources of Under the influence of antiadrenergic Ca2+ are: a) extracellular Ca2+ entering agents (p. 96), used to lower an elevated the cell through voltage-gated Ca2+ blood pressure, cardiac work is de- channels; b) Ca2+ stored in membranous creased. Ganglionic blockers (p. 108) sacs of the sarcoplasmic reticulum (SR); are used in managing hypertensive c) Ca2+ bound to the inside of the plas- emergencies. Parasympatholytics (p. malemma. The plasmalemma of cardio- 104) and β-blockers (p. 92) prevent the myocytes extends into the cell interior transmission of autonomic nerve im- in the form of tubular invaginations pulses to heart muscle cells by blocking (transverse tubuli). the respective receptors. The trigger signal for relaxation is 2. An isolated mammalian heart the return of the membrane potential to whose extrinsic nervous connections its resting level. During repolarization, have been severed will beat spontane- Ca2+ levels fall below the threshold for ously for hours if it is supplied with a activation of the myofilaments (310–7 nutrient medium via the aortic trunk M), as the plasmalemmal binding sites and coronary arteries (Langendorff regain their binding capacity; the SR preparation). In such a preparation, only pumps Ca2+ into its interior; and Ca2+ those drugs that act directly on cardio- that entered the cytosol during systole myocytes will alter contractile force and is again extruded by plasmalemmal beating rate. Ca2+-ATPases with expenditure of ener- Parasympathomimetics and sym- gy. In addition, a carrier (antiporter), pathomimetics act at membrane re- utilizing the transmembrane Na+ gradi- ceptors for visceromotor neurotrans- ent as energy source, transports Ca2+ out mitters. The plasmalemma also harbors of the cell in exchange for Na+ moving the sites of action of cardiac glycosides down its transmembrane gradient (the Na/K-ATPases, p. 130), of Ca2+ an- (Na+/Ca2+ exchange). tagonists (Ca2+ channels, p. 122), and of agents that block Na+ channels (local anesthetics; p. 134, p. 204). An intracellular site is the target for phosphodiesterase inhibitors (e.g., amrinone, p. 132). 3. Mention should also be made of the possibility of affecting cardiac function in angina pectoris (p. 306) or congestive heart failure (p. 132) by reducing venous return, peripheral resistance, or both, with the aid of vasodilators; and by reducing sympathetic drive applying β-blockers.

Cardiac Drugs 129

Drugs with Drugs with direct action indirect action Nutrient solution

Psychotropic drugs Force

Sympatholytics Rate Ganglionic blockers β-Sympathomimetics Para- Cardiac Phosphodiesterase inhibitors sympathetic glycosides Force Rate Sympathetic Parasympathomimetics Catamphiphilic Epinephrine Ca-antagonists Local anesthetics A. Possible mechanisms for influencing heart function

Contraction 2+ -3 Membrane potential Ca 10 M [mV] electrical excitation 0 Ca-channel Sarcoplasmic reticulum Action potential Heart muscle cell Ca2+ -5 10 M -80 Transverse tubule

Force Relaxation Ca2+ 10-3M Na+

Ca2+ Ca-ATPase Contraction Na/Ca- exchange Ca2+ Ca2+ Na+ Na+ Ca2+ Plasma- 10-7M lemmal binding sites 300 ms t B. Processes in myocardial contraction and relaxation

130 Cardiac Drugs

Cardiac Glycosides area postrema leads to nausea and vomiting. Disturbances in color vision are Diverse plants (A) are sources of sugar- evident. containing compounds (glycosides) that Indications for CG are: (1) chronic also contain a steroid ring (structural congestive heart failure; and (2) atrial formulas, p. 133) and augment the con- fibrillation or flutter, where inhibition of tractile force of heart muscle (B): cardio- AV conduction protects the ventricles tonic glycosides. cardiosteroids, or “digi- from excessive atrial impulse activity talis.” and thereby improves cardiac perfor- If the inotropic, “therapeutic” dose mance (D). Occasionally, sinus rhythm is exceeded by a small increment, signs is restored. of poisoning appear: arrhythmia and Signs of intoxication are: (1) car- contracture (B). The narrow therapeutic diac arrhythmias, which under certain margin can be explained by the mecha- circumstances are life-threatening, e.g., nism of action. sinus bradycardia, AV-block, ventricular Cardiac glycosides (CG) bind to the extrasystoles, ventricular fibrillation extracellular side of Na+/K+-ATPases of (ECG); (2) CNS disturbances — altered cardiomyocytes and inhibit enzyme ac- color vision (xanthopsia), agitation, tivity. The Na+/K+-ATPases operate to confusion, nightmares, hallucinations; pump out Na+ leaked into the cell and to (3) gastrointestinal — anorexia, nausea, retrieve K+ leaked from the cell. In this vomiting, diarrhea; (4) renal — loss of manner, they maintain the transmem- electrolytes and water, which must be brane gradients for K+ and Na+, the neg- differentiated from mobilization of ac- ative resting membrane potential, and cumulated edema fluid that occurs with the normal electrical excitability of the therapeutic dosage. cell membrane. When part of the en- Therapy of intoxication: adminis- zyme is occupied and inhibited by CG, tration of K+, which inter alia reduces the unoccupied remainder can increase binding of CG, but may impair AV-con- its level of activity and maintain Na+ and duction; administration of antiarrhyth- K+ transport. The effective stimulus is a mics, such as phenytoin or lidocaine (p. small elevation of intracellular Na+ con- 136); oral administration of colestyra- centration (normally approx. 7 mM). mine (p. 154, 156) for binding and pre- Concomitantly, the amount of Ca2+ mo- venting absorption of digitoxin present bilized during systole and, thus, con- in the intestines (enterohepatic cycle); tractile force, increases. It is generally injection of antibody (Fab) fragments thought that the underlying cause is the that bind and inactivate digitoxin and decrease in the Na+ transmembrane digoxin. Compared with full antibodies, gradient, i.e., the driving force for the fragments have superior tissue penet- Na+/Ca2+ exchange (p. 128), allowing the rability, more rapid renal elimination, intracellular Ca2+ level to rise. When too and lower antigenicity. many ATPases are blocked, K+ and Na+ homeostasis is deranged; the membrane potential falls, arrhythmias occur. Flooding with Ca2+ prevents relaxation during diastole, resulting in contracture. The CNS effects of CG (C) are also due to binding to Na+/K+-ATPases. En- hanced vagal nerve activity causes a decrease in sinoatrial beating rate and velocity of atrioventricular conduction. In patients with heart failure, improved circulation also contributes to the reduction in heart rate. Stimulation of the

Cardiac Drugs 131

Helleborus niger Christmas rose

Convallaria Digitalis purpurea majalis Red foxglove Lily of the valley

A. Plants containing cardiac glycosides

Arrhythmia Contracture Contraction

Time ´therapeutic´ ´toxic´ Dose of cardiac glycoside (CG)

+ Na/K-ATPase Na CG CG

Na+ Na+ Na+ Coupling 2+ 2+ 2+ Ca Ca Ca CG K+ K+ K+ K+

Heart muscle cell CG CG B. Therapeutic and toxic effects of cardiac glycosides (CG)

Disturbance of "Re-entrant" color vision excitation in atrial fibrillation

Cardiac glycoside Excitation of N. vagus: Decrease in Heart rate ventricular rate

Area postrema: nausea, vomiting

C. Cardiac glycoside effects on the CNS D. Cardiac glycoside effects in atrial fibrillation

132 Cardiac Drugs

Substance Fraction Plasma concentr. Digitalizing Elimination Maintenance absorbed free total dose dose % (ng/mL) (mg) %/d (mg) Digitoxin 100 1 20 110 0.1

Digoxin 50–90 1 1.5 130 0.3

Ouabain <1 1 1 0.5 no long-term use

The pharmacokinetics of cardiac tolerated. A closely related compound is glycosides (A) are dictated by their po- milrinone. In terms of their positive in- larity, i.e., the number of hydroxyl otropic effect, β-sympathomimetics, groups. Membrane penetrability is vir- unlike dopamine (p. 114), are of little tually nil in ouabain, high in digoxin, therapeutic use; they are also arrhyth- and very high in digitoxin. Ouabain (g- mogenic and the sensitivity of the β-re- strophanthin) does not penetrate into ceptor system declines during continu- cells, be they intestinal epithelium, re- ous stimulation. nal tubular, or hepatic cells. At best, it is suitable for acute intravenous induction Treatment Principles in Chronic Heart of glycoside therapy. Failure The absorption of digoxin depends on the kind of galenical preparation Myocardial insufficiency leads to a de- used and on absorptive conditions in crease in stroke volume and venous the intestine. Preparations are now of congestion with formation of edema. such quality that the derivatives methyl- Administration of (thiazide) diuretics digoxin and acetyldigoxin no longer offer (p. 62) offers a therapeutic approach of any advantage. Renal reabsorption is in- proven efficacy that is brought about by complete; approx. 30% of the total a decrease in circulating blood volume amount present in the body (s.c. full (decreased venous return) and periph- “digitalizing” dose) is eliminated per eral resistance, i.e., afterload. A similar day. When renal function is impaired, approach is intended with ACE-inhibi- there is a risk of accumulation. Digi- tors, which act by preventing the syn- toxin undergoes virtually complete re- thesis of angiotensin II ( vasoconstric- absorption in gut and kidneys. There is tion) and reducing the secretion of al- active hepatic biotransformation: cleav- dosterone ( fluid retention). In severe age of sugar moieties, hydroxylation at cases of myocardial insufficiency, car- C12 (yielding digoxin), and conjugation diac glycosides may be added to aug- to glucuronic acid. Conjugates secreted ment cardiac force and to relieve the with bile are subject to enterohepatic symptoms of insufficiency. cycling (p. 38); conjugates reaching the In more recent times β-blocker on a blood are renally eliminated. In renal in- long term were found to improve car- sufficiency, there is no appreciable ac- diac performance — particularly in idio- cumulation. When digitoxin is with- pathic dilating cardiomyopathy — pro- drawn following overdosage, its effect bably by preventing sympathetic over- decays more slowly than does that of di- drive. goxin. Other positive inotropic drugs. The phosphodiesterase inhibitor amrinone (cAMP elevation, p. 66) can be administered only parenterally for a maximum of 14 d because it is poorly

Cardiac Drugs 133

Ouabain

Plasma

Digoxin

95%

Digitoxin 35% 0% Albumin

Liver- cell

Digitoxin Digoxin

Cleavage of sugar Conjugation Deconjugation Intestinal epithelium Renal tubular epithelium

Plasma t1 9 h 2 – 3 days 5 – 7 days 2

A. Pharmacokinetics of cardiac glycosides

134 Cardiac Drugs

Antiarrhythmic Drugs ic, Na+-channel blocking type (B) are used for both prophylaxis and therapy. The electrical impulse for contraction Local anesthetics inhibit electrical exci- (propagated action potential; p. 136) tation of nociceptive nerve fibers (p. originates in pacemaker cells of the si- 204); concomitant cardiac inhibition noatrial node and spreads through the (cardiodepression) is an unwanted ef- atria, atrioventricular (AV) node, and fect. However, in certain types of ar- adjoining parts of the His-Purkinje fiber rhythmias (see above), this effect is use- system to the ventricles (A). Irregular- ful. Local anesthetics are readily cleaved ities of heart rhythm can interfere dan- (arrows) and unsuitable for oral admin- gerously with cardiac pumping func- istration (procaine, lidocaine). Given ju- tion. diciously, intravenous lidocaine is an ef- I. Drugs for selective control of si- fective antiarrhythmic. Procainamide noatrial and AV nodes. In some forms and mexiletine, congeners endowed of arrhythmia, certain drugs can be used with greater metabolic stability, are ex- that are capable of selectively facilitat- amples of orally effective antiarrhyth- ing and inhibiting (green and red ar- mics. The desired and undesired effects rows, respectively) the pacemaker func- are inseparable. Thus, these antiar- tion of sinoatrial or atrioventricular rhythmics not only depress electrical cells. excitability of cardiomyocytes (negative Sinus bradycardia. An abnormally bathmotropism, membrane stabiliza- low sinoatrial impulse rate (<60/min) tion), but also lower sinoatrial rate (neg. can be raised by parasympatholytics. chronotropism), AV conduction (neg. The quaternary ipratropium is prefer- dromotropism), and force of contraction able to atropine, because it lacks CNS (neg. inotropism). Interference with nor- penetrability (p. 107). Sympathomimet- mal electrical activity can, not too para- ics also exert a positive chronotropic ac- doxically, also induce cardiac arrhyth- tion; they have the disadvantage of in- mias–arrhythmogenic action. creasing myocardial excitability (and Inhibition of CNS neurons is the automaticity) and, thus, promoting ec- underlying cause of neurological effects topic impulse generation (tendency to such as vertigo, confusion, sensory dis- extrasystolic beats). In cardiac arrest turbances, and motor disturbances epinephrine can be used to reinitiate (tremor, giddiness, ataxia, convulsions). heart beat. Sinus tachycardia (resting rate >100 beats/min). β-Blockers eliminate sympathoexcitation and decrease cardiac rate. Atrial flutter or fibrillation. An excessive ventricular rate can be decreased by verapamil (p. 122) or cardiac glycosides (p. 130). These drugs inhibit impulse propagation through the AV node, so that fewer impulses reach the ventricles. II. Nonspecific drug actions on impulse generation and propagation. Impulses originating at loci outside the sinus node are seen in supraventricular or ventricular extrasystoles, tachycardia, atrial or ventricular flutter, and fibrillation. In these forms of rhythm disorders, antiarrhythmics of the local anesthet-

Cardiac Drugs 135

Sinus node Para- sympatholytics Atrium β-Sympatho- mimetics AV-node

Bundle of His β-Blocker Tawara´s node Verapamil

Purkinje Cardiac fibers glycoside (Vagal Ventricle stimulation)

A. Cardiac impulse generation and conduction

Antiarrhythmics of the local anesthetic Main effect (Na+-channel blocking) type: Inhibition of impulse generation and conduction Antiarrhythmic effect Esterases Procaine

Procainamide Adverse effects

Lidocaine

CNS-disturbances

Mexiletine

Arrhythmia Cardiodepression

B. Antiarrhythmics of the Na+-channel blocking type

136 Cardiac Drugs

Electrophysiological Actions of amphiphilic molecules (p. 208, excep- Antiarrhythmics of the Na+-Channel tion: phenytoin, p. 190). Possible molec- Blocking Type ular mechanisms of their inhibitory effects are outlined on p. 204 in more de- Action potential and ionic currents. tail. Their low structural specificity is The transmembrane electrical potential reflected by a low selectivity towards of cardiomyocytes can be recorded different cation channels. Besides the through an intracellular microelectrode. Na+ channel, Ca2+ and K+ channels are al- Upon electrical excitation, a characteris- so likely to be blocked. Accordingly, cat- tic change occurs in membrane poten- ionic amphiphilic antiarrhythmics af- tial—the action potential (AP). Its under- fect both the depolarization and repola- lying cause is a sequence of transient rization phases. Depending on the sub- ionic currents. During rapid depolariza- stance, AP duration can be increased tion (Phase 0), there is a short-lived in- (Class IA), decreased (Class IB), or reflux of Na+ through the membrane. A main the same (Class IC). subsequent transient influx of Ca2+ (as Antiarrhythmics representative well as of Na+) maintains the depola- of these categories include: Class IA— rization (Phase 2, plateau of AP). A de- quinidine, procainamide, ajmaline, dis- layed efflux of K+ returns the membrane opyramide, propafenone; Class IB—lido- potential (Phase 3, repolarization) to its caine, mexiletine, tocainide, as well as resting value (Phase 4). The velocity of phenytoin; Class IC—flecainide. depolarization determines the speed at Note: With respect to classification, which the AP propagates through the β-blockers have been assigned to Class myocardial syncytium. II, and the Ca2+-channel blockers vera- Transmembrane ionic currents in- pamil and diltiazem to Class IV. volve proteinaceous membrane pores: Commonly listed under a separate Na+, Ca2+, and K+ channels. In A, the rubric (Class III) are amiodarone and the phasic change in the functional state of β-blocking agent sotalol, which both in- Na+ channels during an action potential hibit K+-channels and which both cause is illustrated. marked prolongation of the AP with a Effects of antiarrhythmics. Antiar- lesser effect on Phase 0 rate of rise. rhythmics of the Na+-channel blocking Therapeutic uses. Because of their type reduce the probability that Na+ narrow therapeutic margin, these antiar- channels will open upon membrane de- rhythmics are only employed when polarization (“membrane stabiliza- rhythm disturbances are of such sever- tion”). The potential consequences are ity as to impair the pumping action of (A, bottom): 1) a reduction in the veloc- the heart, or when there is a threat of ity of depolarization and a decrease in other complications. The choice of drug the speed of impulse propagation; aber- is empirical. If the desired effect is not rant impulse propagation is impeded. 2) achieved, another drug is tried. Combi- Depolarization is entirely absent; patho- nations of antiarrhythmics are not cus- logical impulse generation, e.g., in the tomary. Amiodarone is reserved for spe- marginal zone of an infarction, is sup- cial cases. pressed. 3) The time required until a new depolarization can be elicited, i.e., the refractory period, is increased; prolongation of the AP (see below) contributes to the increase in refractory period. Consequently, premature excitation with risk of fibrillation is prevented. Mechanism of action. Na+-channel blocking antiarrhythmics resemble most local anesthetics in being cationic

Cardiac Drugs 137

[mV] Membrane potential 1 2 0 Rate of Action 0 depolarization potential (AP) Speed of AP 3 propagation

4 -80 Refractory period 0 250 Time [ms]

Heart muscle cell

Na+ Ca2+(+Na+)

K+ Phase 0Phases 1,2 Phase 3 Phase 4

Fast Slow Ca2+-entry Na+-entry” Ionic currents during action potential

Na+ Na+-channels

Open (active) Closed Closed Opening impossible Opening possible (inactivated) (resting, can be activated) States of Na+-channels during an action potential

Inhibition of Antiarrhythmics of the Na+-channel opening Na+-channel blocking type

Inexcitability

Stimulus

Rate of Suppression Prolongation of refractory period = depolarization of AP generation duration of inexcitability

A. Effects of antiarrhythmics of the Na+-channel blocking type

138 Antianemics

Drugs for the Treatment of Anemias B12a; exchange of -CN for -OH group). Adverse effects, in the form of hyper- Anemia denotes a reduction in red sensitivity reactions, are very rare. blood cell count, hemoglobin content, Folic Acid (B). Leafy vegetables and or both. Oxygen (O2) transport capacity liver are rich in folic acid (FA). The min- is decreased. imal requirement is approx. 50 µg/d. Erythropoiesis (A). Blood corpus- Polyglutamine-FA in food is hydrolyzed cles develop from stem cells through to monoglutamine-FA prior to being ab- several cell divisions. Hemoglobin is sorbed. FA is heat labile. Causes of defi- then synthesized and the cell nucleus is ciency include: insufficient intake, mal- extruded. Erythropoiesis is stimulated absorption in gastrointestinal diseases, by the hormone erythropoietin (a gly- increased requirements during preg- coprotein), which is released from the nancy. Antiepileptic drugs (phenytoin, kidneys when renal O2 tension declines. primidone, phenobarbital) may de- Given an adequate production of crease FA absorption, presumably by in- erythropoietin, a disturbance of eryth- hibiting the formation of monogluta- ropoiesis is due to two principal causes: mine-FA. Inhibition of dihydro-FA re- 1. Cell multiplication is inhibited be- ductase (e.g., by methotrexate, p. 298) cause DNA synthesis is insufficient. This depresses the formation of the active occurs in deficiencies of vitamin B12 or species, tetrahydro-FA. Symptoms of de- folic acid (macrocytic hyperchromic ficiency are megaloblastic anemia and anemia). 2. Hemoglobin synthesis is mucosal damage. Therapy consists in impaired. This situation arises in iron oral administration of FA or in folinic deficiency, since Fe2+ is a constituent of acid (p. 298) when deficiency is caused hemoglobin (microcytic hypochromic by inhibitors of dihydro—FA—reductase. anemia). Administration of FA can mask a vitamin B12 deficiency. Vitamin B12 is re- Vitamin B12 (B) quired for the conversion of methyltet- Vitamin B12 (cyanocobalamin) is pro- rahydro-FA to tetrahydro-FA, which is duced by bacteria; B12 generated in the important for DNA synthesis (B). Inhibi- colon, however, is unavailable for ab- tion of this reaction due to B12 deficien- sorption (see below). Liver, meat, fish, cy can be compensated by increased FA and milk products are rich sources of intake. The anemia is readily corrected; the vitamin. The minimal requirement however, nerve degeneration progress- is about 1 µg/d. Enteral absorption of vi- es unchecked and its cause is made tamin B12 requires so-called “intrinsic more difficult to diagnose by the ab- factor” from parietal cells of the stom- sence of hematological changes. Indis- ach. The complex formed with this gly- criminate use of FA-containing multivi- coprotein undergoes endocytosis in the tamin preparations can, therefore, be ileum. Bound to its transport protein, harmful. transcobalamin, vitamin B12 is destined for storage in the liver or uptake into tissues. A frequent cause of vitamin B12 deficiency is atrophic gastritis leading to a lack of intrinsic factor. Besides megaloblastic anemia, damage to mucosal lin- ings and degeneration of myelin sheaths with neurological sequelae will occur (pernicious anemia). Optimal therapy consists in parenteral administration of cyanocobalamin or hydroxycobalamin (Vitamin

Antianemics 139

Inhibition of DNA Inhibition of synthesis hemoglobin synthesis (cell multiplication)

Vit. B deficiency 12 Iron deficiency

Folate deficiency

A very few large A few small hemoglobin-rich hemoglobin-poor erythrocytes erythrocytes

A. Erythropoiesis in bone marrow

Folic acid H4 DNA synthesis Vit. B12 Folic acid H3C- Folic acid H4

H3C- Vit. B12

Vit. B12 H3C- HCl Trans- cobalamin II Storage supply for Vit. B Intrinsic 3 years 12 factor

Parietal cell

i.m.

Streptomyces griseus

B. Vitamin B12 and folate metabolism

140 Antianemics

Iron Compounds tageous in that it is impossible to overload the body with iron through an in- Not all iron ingested in food is equally tact mucosa because of its demand-reg- absorbable. Trivalent Fe3+ is virtually ulated absorption (mucosal block). not taken up from the neutral milieu of Adverse effects. The frequent gas- the small bowel, where the divalent Fe2+ trointestinal complaints (epigastric is markedly better absorbed. Uptake is pain, diarrhea, constipation) necessitate particularly efficient in the form of intake of iron preparations with or after heme (present in hemo- and myoglo- meals, although absorption is higher bin). Within the mucosal cells of the gut, from the empty stomach. iron is oxidized and either deposited as Interactions. Antacids inhibit iron ferritin (see below) or passed on to the absorption. Combination with ascorbic 2+ transport protein, transferrin, a β1-gly- acid (Vitamin C), for protecting Fe coprotein. The amount absorbed does from oxidation to Fe3+, is theoretically not exceed that needed to balance loss- sound, but practically is not needed. es due to epithelial shedding from skin Parenteral administration of Fe3+ and mucosae or hemorrhage (so-called salts is indicated only when adequate “mucosal block”). In men, this amount oral replacement is not possible. There is approx. 1 mg/d; in women, it is ap- is a risk of overdosage with iron deposi- prox. 2 mg/d (menstrual blood loss), tion in tissues (hemosiderosis). The corresponding to about 10% of the die- binding capacity of transferrin is limited tary intake. The transferrin-iron com- and free Fe3+ is toxic. Therefore, Fe3+ plex undergoes endocytotic uptake complexes are employed that can do- mainly into erythroblasts to be utilized nate Fe3+ directly to transferrin or can for hemoglobin synthesis. be phagocytosed by macrophages, ena- About 70% of the total body store of bling iron to be incorporated into ferri- iron (~5 g) is contained within erythro- tin stores. Possible adverse effects are, cytes. When these are degraded by mac- with i.m. injection: persistent pain at rophages of the reticuloendothelial the injection site and skin discoloration; (mononuclear phagocyte) system, iron with i.v. injection: flushing, hypoten- is liberated from hemoglobin. Fe3+ can sion, anaphylactic shock. be stored as ferritin (= protein apoferri- tin + Fe3+) or returned to erythropoiesis sites via transferrin. A frequent cause of iron deficiency is chronic blood loss due to gastric/intestinal ulcers or tumors. One liter of blood contains 500 mg of iron. Despite a significant increase in absorption rate (up to 50%), absorption is unable to keep up with losses and the body store of iron falls. Iron deficiency results in impaired synthesis of hemoglobin and anemia (p. 138). The treatment of choice (after the cause of bleeding has been found and eliminated) consists of the oral administration of Fe2+ compounds, e.g., fer- rous sulfate (daily dose 100 mg of iron equivalent to 300 mg of FeSO4, divided into multiple doses). Replenishing of iron stores may take several months. Oral administration, however, is advan-

Antianemics 141

Fe III-Salts

Oral intake Fe II-Salts

Heme-Fe Fe III

Fe III

Absorption Fe III Duodenum upper jejunum Ferritin

Parenteral administration Transport Fe III Fe III plasma Transferrin

i.v. i.m.

Hemoglobin Uptake into Fe III-complexes erythroblast bone marrow

Fe III

Erythrocyte Ferritin blood Hemosiderin = aggregated ferritin

Loss through Uptake into macrophages bleeding spleen, liver, bone marrow

A. Iron: possible routes of administration and fate in the organism

142 Antithrombotics

Prophylaxis and Therapy of Thromboses gregated platelets, and in tissue throm- boplastin (B). The sequential activation Upon vascular injury, the coagulation of several enzymes allows the afore- system is activated: thrombocytes and mentioned reactions to “snowball”, cul- fibrin molecules coalesce into a “plug” minating in massive production of fibrin (p. 148) that seals the defect and halts (p. 148). bleeding (hemostasis). Unnecessary Progression of the coagulation cas- formation of an intravascular clot – a cade can be inhibited as follows: thrombosis – can be life-threatening. If 1) coumarin derivatives decrease the clot forms on an atheromatous the blood concentrations of inactive fac- plaque in a coronary artery, myocardial tors II, VII, IX, and X, by inhibiting their infarction is imminent; a thrombus in a synthesis; 2) the complex consisting of deep leg vein can be dislodged, carried heparin and antithrombin III neutraliz- into a lung artery, and cause complete es the protease activity of activated fac- or partial interruption of pulmonary tors; 3) Ca2+ chelators prevent the en- blood flow (pulmonary embolism). zymatic activity of Ca2+-dependent fac- Drugs that decrease the coagulabil- tors; they contain COO-groups that bind ity of blood, such as coumarins and hep- Ca2+ ions (C): citrate and EDTA (ethy- arin (A), are employed for the prophy- lenediaminetetraacetic acid) form solu- laxis of thromboses. In addition, at- ble complexes with Ca2+; oxalate pre- tempts are directed at inhibiting the ag- cipitates Ca2+ as insoluble calcium oxa- gregation of blood platelets, which are late. Chelation of Ca2+ cannot be used prominently involved in intra-arterial for therapeutic purposes because Ca2+ thrombogenesis (p. 148). For the thera- concentrations would have to be low- py of thrombosis, drugs are used that ered to a level incompatible with life dissolve the fibrin meshwork→fibrino- (hypocalcemic tetany). These com- lytics (p. 146). pounds (sodium salts) are, therefore, An overview of the coagulation used only for rendering blood incoagu- cascade and sites of action for coumar- lable outside the body. ins and heparin is shown in A. There are two ways to initiate the cascade (B): 1) conversion of factor XII into its active form (XIIa, intrinsic system) at intravascular sites denuded of endothelium; 2) conversion of factor VII into VIIa (extrinsic system) under the influence of a tissue-derived lipoprotein (tissue throm- boplastin). Both mechanisms converge via factor X into a common final pathway. The clotting factors are protein molecules. “Activation” mostly means proteolysis (cleavage of protein fragments) and, with the exception of fibrin, conversion into protein-hydrolyzing enzymes (proteases). Some activated factors require the presence of phospholipids (PL) and Ca2+ for their proteolytic activity. Conceivably, Ca2+ ions cause the adhesion of factor to a phospholipid surface, as depicted in C. Phos- pholipids are contained in platelet factor 3 (PF3), which is released from ag-

Antithrombotics 143

XII XIIa Synthesis susceptible to inhibition by coumarins XI XIa Reaction susceptible to inhibition by heparin- antithrombin complex IX IXa VIIa VII VIII + Ca2+ + Pl Ca2+ + Pl (Phospholipids)

XXa

V + Ca2+ + Pl

Prothrombin II IIa Thrombin

Fibrinogen IIa Fibrin

A. Inhibition of clotting cascade in vivo

Platelets Endothelial Clotting factor defect COO– COO- XII COO– + Tissue thrombo- Ca kinase + – – XIIa – – – PF3 VIIa VII – Phospholipids e.g., PF Vessel 3 rupture Ca2+-chelation Citrate Fibrin EDTA Oxalate

B. Activation of clotting C. Inhibition of clotting by removal of Ca2+

144 Antithrombotics

Coumarin Derivatives (A) Heparin (B) A clotting factor is activated when the Vitamin K promotes the hepatic γ-car- factor that precedes it in the clotting boxylation of glutamate residues on the cascade splits off a protein fragment and precursors of factors II, VII, IX, and X, as thereby exposes an enzymatic center. well as that of other proteins, e.g., pro- The latter can again be inactivated phys- tein C, protein S, or osteocalcin. Carbox- iologically by complexing with anti- yl groups are required for Ca2+-mediat- thrombin III (AT III), a circulating gly- ed binding to phospholipid surfaces (p. coprotein. Heparin acts to inhibit clot- 142). There are several vitamin K de- ting by accelerating formation of this rivatives of different origins: K1 (phy- complex more than 1000-fold. Heparin tomenadione) from chlorophyllous is present (together with histamine) in plants; K2 from gut bacteria; and K3 the vesicles of mast cells; its physiologi- (menadione) synthesized chemically. cal role is unclear. Therapeutically used All are hydrophobic and require bile ac- heparin is obtained from porcine gut or ids for absorption. bovine lung. Heparin molecules are Oral anticoagulants. Structurally chains of amino sugars bearing -COO– related to vitamin K, 4-hydroxycouma- and -SO4 groups; they contain approx. rins act as “false” vitamin K and prevent 10 to 20 of the units depicted in (B); regeneration of reduced (active) vita- mean molecular weight, 20,000. Antico- min K from vitamin K epoxide, hence agulant efficacy varies with chain the synthesis of vitamin K-dependent length. The potency of a preparation is clotting factors. standardized in international units of Coumarins are well absorbed after activity (IU) by bioassay and compari- oral administration. Their duration of son with a reference preparation. action varies considerably. Synthesis of The numerous negative charges are clotting factors depends on the intrahe- significant in several respects: (1) they patocytic concentration ratio of cou- contribute to the poor membrane pe- marins to vitamin K. The dose required netrability—heparin is ineffective when for an adequate anticoagulant effect applied by the oral route or topically on- must be determined individually for to the skin and must be injected; (2) at- each patient (one-stage prothrombin traction to positively charged lysine res- time). Subsequently, the patient must idues is involved in complex formation avoid changing dietary consumption of with ATIII; (3) they permit binding of green vegetables (alteration in vitamin heparin to its antidote, protamine K levels), refrain from taking additional (polycationic protein from salmon drugs likely to affect absorption or elim- sperm). ination of coumarins (alteration in cou- If protamine is given in heparin-in- marin levels), and not risk inhibiting duced bleeding, the effect of heparin is platelet function by ingesting acetylsali- immediately reversed. cylic acid. For effective thromboprophylaxis, a The most important adverse ef- low dose of 5000 IU is injected s.c. two fect is bleeding. With coumarins, this to three times daily. With low dosage of can be counteracted by giving vitamin heparin, the risk of bleeding is suffi- K1. Coagulability of blood returns to ciently small to allow the first injection normal only after hours or days, when to be given as early as 2 h prior to sur- the liver has resumed synthesis and re- gery. Higher daily i.v. doses are required stored sufficient blood levels of clotting to prevent growth of clots. Besides factors. In urgent cases, deficient factors bleeding, other potential adverse effects must be replenished directly (e.g., by are: allergic reactions (e.g., thrombocy- transfusion of whole blood or of pro- topenia) and with chronic administra- thrombin concentrate). tion, reversible hair loss and osteoporosis.

Antithrombotics 145

Duration of action/days

Vit. K1 Phytomenadione Phenprocoumon

Vit. K2 Warfarin

Vit. K3 Menadione Acenocoumarol

Carboxylation of glutamine residues

II, VII, IX, X

4-Hydroxy- Vit. K derivatives Coumarin derivatives

A. Vitamin K-antagonists of the coumarin type and vitamin K

Activated clotting factor Ia a, Xa, X , XIIa, IX XI a, IIa II

Inacti- Inacti- vation vation Mast cell

AT III AT III ++++ ++++

---- Heparin 3 x 5000 IU s.c. + ------30 000 IU i.v. + ++++ +++ + + Protamine

B. Heparin: origin, structure, and mechanism of action

146 Antithrombotics

Low-molecular-weight heparin (av- lived (inactivation by complexing with erage MW ~5000) has a longer duration plasminogen activator inhibitor, PAI) of action and needs to be given only and has to be applied by infusion. Rete- once daily (e.g., certoparin, dalteparin, plase, however, containing only the enoxaparin, reviparin, tinzaparin). proteolytic active part of the alteplase Frequent control of coagulability is molecule, allows more stabile plasma not necessary with low molecular levels and can be applied in form of two weight heparin and incidence of side ef- injections at an interval of 30 min. fects (bleeding, heparin-induced throm- Inactivation of the fibrinolytic bocytopenia) is less frequent than with system can be achieved by “plasmin in- unfractionated heparin. hibitors,” such as ε-aminocaproic acid, p-aminomethylbenzoic acid (PAMBA), Fibrinolytic Therapy (A) tranexamic acid, and aprotinin, which also inhibits other proteases. Fibrin is formed from fibrinogen Lowering of blood fibrinogen through thrombin (factor IIa)-catalyzed concentration. Ancrod is a constituent proteolytic removal of two oligopeptide of the venom from a Malaysian pit viper. fragments. Individual fibrin molecules It enzymatically cleaves a fragment polymerize into a fibrin mesh that can from fibrinogen, resulting in the forma- be split into fragments and dissolved by tion of a degradation product that can- plasmin. Plasmin derives by proteolysis not undergo polymerization. Reduction from an inactive precursor, plasmino- in blood fibrinogen level decreases the gen. Plasminogen activators can be infu- coagulability of the blood. Since fibrino- sed for the purpose of dissolving clots gen (MW ~340 000) contributes to the (e.g., in myocardial infarction). Throm- viscosity of blood, an improved “fluid- bolysis is not likely to be successful un- ity” of the blood would be expected. less the activators can be given very so- Both effects are felt to be of benefit in on after thrombus formation. Urokinase the treatment of certain disorders of is an endogenous plasminogen activator blood flow. obtained from cultured human kidney cells. Urokinase is better tolerated than is streptokinase. By itself, the latter is enzymatically inactive; only after binding to a plasminogen molecule does the complex become effective in converting plasminogen to plasmin. Strep- tokinase is produced by streptococcal bacteria, which probably accounts for the frequent adverse reactions. Strepto- kinase antibodies may be present as a result of prior streptococcal infections. Binding to such antibodies would neu- tralize streptokinase molecules. With alteplase, another endogenous plasminogen activator (tissue plasminogen activator, tPA) is available. With physiological concentrations this activator preferentially acts on plasminogen bound to fibrin. In concentrations needed for therapeutic fibrinolysis this preference is lost and the risk of bleeding does not differ with alteplase and streptokinase. Alteplase is rather short-

Antithrombotics 147

Fibrinogen

Thrombin Ancrod

Fibrin

Plasmin-inhibitors Plasmin

Antibody from prior infection

e.g., Tranexamic acid

Fever, chills, and inactivation

Urokinase Streptokinase

Human kidney cell culture Plasminogen Streptococci

A. Activators and inhibitors of fibrinolysis; ancrod

148 Antithrombotics

Intra-arterial Thrombus Formation (A) brandt’s factor can be temporarily overcome by the vasopressin anlogue des- Activation of platelets, e.g., upon con- mopressin (p. 164), which increases the tact with collagen of the extracellular release of available factor from storage matrix after injury to the vascular wall, sites. constitutes the immediate and decisive step in initiating the process of primary Formation, Activation, and Aggregation hemostasis, i.e., cessation of bleeding. of Platelets (B) However, in the absence of vascular in- Platelets originate by budding off from jury, platelets can be activated as a re- multinucleate precursor cells, the me- sult of damage to the endothelial cell gakaryocytes. As the smallest formed lining of blood vessels. Among the mul- element of blood (dia. 1–4 µm), they can tiple functions of the endothelium, the be activated by various stimuli. Activa- production of NO˙ and prostacyclin plays tion entails an alteration in shape and an important role. Both substances in- secretion of a series of highly active sub- hibit the tendency of platelets to adhere stances, including serotonin, platelet ac- to the endothelial surface (platelet ad- tivating factor (PAF), ADP, and throm- hesiveness). Impairment of endothelial boxane A2. In turn, all of these can acti- function, e.g., due to chronic hyperten- vate other platelets, which explains the sion, cigarette smoking, chronic eleva- explosive nature of the process. tion of plasma LDL levels or of blood The primary consequence of activa- glucose, increases the probability of tion is a conformational change of an in- contact between platelets and endothe- tegrin present in the platelet mem- lium. The adhesion process involves brane, namely, GPIIB/IIIA. In its active GPIB/IX, a glycoprotein present in the conformation, GPIIB/IIIA shows high af- platelet cell membrane and von Wille- finity for fibrinogen; each platelet con- brandt’s factor, an endothelial mem- tains up to 50,000 copies. The high plas- brane protein. Upon endothelial con- ma concentration of fibrinogen and the tact, the platelet is activated with a re- high density of integrins in the platelet sultant change in shape and affinity to membrane permit rapid cross-linking of fibrinogen. Platelets are linked to each platelets and formation of a platelet other via fibrinogen bridges: they plug. undergo aggregation. Platelet aggregation increases like an avalanche because, once activated, platelets can activate other platelets. On the injured endothelial cell, a platelet thrombus is formed, which obstructs blood flow. Ultimately, the vascular lumen is occluded by the thrombus as the latter is solidified by a vasoconstriction produced by the release of serotonin and thromboxane A2 from the aggregated platelets. When these events occur in a larger coronary artery, the consequence is a myocardial infarction; involvement of a cerebral artery leads to stroke. The von Willebrandt’s factor plays a key role in thrombogenesis. Lack of this factor causes thrombasthenia, a pathologically decreased platelet aggregation. Relative deficiency of the von Wille-

Antithrombotics 149

Aggregation

Adhesion

dysfunctional endothelial cell

PlateletActivated von Willebrandt’s Fibrinogen platelet factor

A. Thrombogenesis

Megakaryocyte Contact with collagen Activation ADP Thrombin Thromboxane A2 Serotonin

Platelet

Activated platelet

Glycoprotein Fibrinogen IIB/IIIA Fibrinogen binding: impossible possible

B. Aggregation of platelets by the integrin GPIIB/IIIA

150 Antithrombotics

Inhibitors of Platelet Aggregation (A) gregation-inducing stimulus. Abciximab is a chimeric human-murine monoclo- Platelets can be activated by mechanical nal antibody directed against GPIIb/IIIa and diverse chemical stimuli, some of that blocks the fibrinogen-binding site which, e.g., thromboxane A2, thrombin, and thus prevents attachment of fi- serotonin, and PAF, act via receptors on brinogen. The peptide derivatives, epti- the platelet membrane. These receptors fibatide and tirofiban block GPIIB/IIIA are coupled to Gq proteins that mediate competitively, more selectively and ha- activation of phospholipase C and hence ve a shorter effect than does abciximab. a rise in cytosolic Ca2+ concentration. Among other responses, this rise in Ca2+ Presystemic Effect of Acetylsalicylic Acid triggers a conformational change in (B) GPIIB/IIIA, which is thereby converted to its fbrinogen-binding form. In con- Inhibition of platelet aggregation by trast, ADP activates platelets by inhibit- ASA is due to a selective blockade of ing adenylyl cyclase, thus causing inter- platelet cyclooxygenase (B). Selectivity nal cAMP levels to decrease. High cAMP of this action results from acetylation of levels would stabilize the platelet in its this enzyme during the initial passage of inactive state. Formally, the two mes- the platelets through splanchnic blood senger substances, Ca2+ and cAMP, can vessels. Acetylation of the enzyme is irbe considered functional antagonists. reversible. ASA present in the systemic Platelet aggregation can be inhibit- circulation does not play a role in plate- ed by acetylsalicylic acid (ASA), which let inhibition. Since ASA undergoes ex- blocks thromboxane synthase, or by re- tensive presystemic elimination, cyclo- combinant hirudin (originally harvest- oxygenases outside platelets, e.g., in ened from leech salivary gland), which dothelial cells, remain largely unaffect- binds and inactivates thrombin. As yet, ed. With regular intake, selectivity is en- no drugs are available for blocking ag- hanced further because the anuclear gregation induced by serotonin or PAF. platelets are unable to resynthesize new ADP-induced aggregation can be pre- enzyme and the inhibitory effects of vented by ticlopidine and clopidogrel; consecutive doses are added to each these agents are not classic receptor another. However, in the endothelial cells, tagonists. ADP-induced aggregation is de novo synthesis of the enzyme per- inhibited only in vivo but not in vitro in mits restoration of prostacyclin produc- stored blood; moreover, once induced, tion. inhibition is irreversible. A possible explanation is that both agents already Adverse Effects of Antiplatelet Drugs interfere with elements of ADP receptor signal transduction at the megakaryo- All antiplatelet drugs increase the risk of cytic stage. The ensuing functional de- bleeding. Even at the low ASA doses fect would then be transmitted to newly used to inhibit platelet function (100 formed platelets, which would be inca- mg/d), ulcerogenic and bronchocon- pable of reversing it. strictor (aspirin asthma) effects may oc- The intra-platelet levels of cAMP cur. Ticlopidine frequently causes diar- can be stabilized by prostacyclin or its rhea and, more rarely, leukopenia, ne- analogues (e.g., iloprost) or by dipyrida- cessitating cessation of treatment. Clo- mole. The former activates adenyl cy- pidogrel reportedly does not cause he- clase via a G-protein-coupled receptor; matological problems. the latter inhibits a phosphodiesterase As peptides, hirudin and abciximab that breaks down cAMP. need to be injected; therefore their use The integrin (GPIIB/IIIA)-antago- is restricted to intensive-care settings. nists prevent cross-linking of platelets. Their action is independent of the ag-

Antithrombotics 151

Arachidonic Thrombin acid Hirudin Serotonin PAF Argatroban

Thromb- Abciximab Tirofiban oxane A2 ASA Eptifibatide

GPIIB/IIIA GPIIB/IIIA [without ATP [Affinity for affinity for fibrinogen fibrinogen] Phospho- high] diesterase Adenylate- cyclase

Dipyridamole ADP

Ticlopidine, Clopidogrel Inactive Active

A. Inhibitors of platelet aggregation

Platelet with Platelet acetylated and blocked cyclooxygenase

Low dose of acetylsalicylic acid

COOH

O CCH3 O

B. Presystemic inactivation of platelet cyclooxygenase by acetylsalicylic acid

152 Plasma Volume Expanders

Plasma Volume Expanders graded by cells of the reticuloendothelial system. Apart from restoring blood Major blood loss entails the danger of volume, dextran solutions are used for life-threatening circulatory failure, i.e., hemodilution in the management of hypovolemic shock. The immediate blood flow disorders. threat results not so much from the loss As for microcirculatory improve- of erythrocytes, i.e., oxygen carriers, as ment, it is occasionally emphasized that from the reduction in volume of circu- low-molecular-weight dextran, unlike lating blood. dextran 70, may directly reduce the ag- To eliminate the threat of shock, re- gregability of erythrocytes by altering plenishment of the circulation is essen- their surface properties. With pro- tial. With moderate loss of blood, ad- longed use, larger molecules will accu- ministration of a plasma volume ex- mulate due to the more rapid renal ex- pander may be sufficient. Blood plasma cretion of the smaller ones. Consequent- consists basically of water, electrolytes, ly, the molecular weight of dextran cir- and plasma proteins. However, a plasma culating in blood will tend towards a substitute need not contain plasma higher mean molecular weight with the proteins. These can be suitably re- passage of time. placed with macromolecules (“col- The most important adverse effect loids”) that, like plasma proteins, (1) do results from the antigenicity of dex- not readily leave the circulation and are trans, which may lead to an anaphylac- poorly filtrable in the renal glomerulus; tic reaction. and (2) bind water along with its solutes Hydroxyethyl starch (hetastarch) is due to their colloid osmotic properties. In produced from starch. By virtue of its this manner, they will maintain circula- hydroxyethyl groups, it is metabolized tory filling pressure for many hours. On more slowly and retained significantly the other hand, volume substitution is longer in blood than would be the case only transiently needed and therefore with infused starch. Hydroxyethyl complete elimination of these colloids starch resembles dextrans in terms of from the body is clearly desirable. its pharmacological properties and Compared with whole blood or therapeutic applications. plasma, plasma substitutes offer several Gelatin colloids consist of cross- advantages: they can be produced more linked peptide chains obtained from easily and at lower cost, have a longer collagen. They are employed for blood shelf life, and are free of pathogens such replacement, but not for hemodilution, as hepatitis B or C or AIDS viruses. in circulatory disturbances. Three colloids are currently employed as plasma volume expanders— the two polysaccharides, dextran and hydroxyethyl starch, as well as the polypeptide, gelatin. Dextran is a glucose polymer formed by bacteria and linked by a 1→6 instead of the typical 1→4 bond. Com- mercial solutions contain dextran of a mean molecular weight of 70 kDa (dextran 70) or 40 kDa (lower-molecular- weight dextran, dextran 40). The chain length of single molecules, however, varies widely. Smaller dextran molecules can be filtered at the glomerulus and slowly excreted in urine; the larger ones are eventually taken up and de-

Plasma Volume Expanders 153

Circulation

Blood loss danger of shock Gelatin colloids = cross-linked peptide chains MW 35, 000 Plasma Plasma- proteins Peptides MW ~ 15, 000 Gelatin MW ~ 100, 000 Collagen MW ~ 300, 000

Dextran MW 70, 000 Plasma- MW 40, 000 substitute Erythrocytes with colloids

Hydroxyethyl starch MW 450, 000

Sucrose Fructose Bacterium Leuconostoc Hydroxy- mesenteroides ethylation

Starch

A. Plasma substitutes

154 liDrugs KT used in Hyperlipoproteinemias

Lipid-Lowering Agents port vehicles in the aqueous media of lymph and blood. To this end, small Triglycerides and cholesterol are essen- amounts of lipid are coated with a layer tial constituents of the organism. of phospholipids, embedded in which Among other things, triglycerides repre- are additional proteins—the apolipopro- sent a form of energy store and choles- teins (A). According to the amount and terol is a basic building block of biologi- the composition of stored lipids, as well cal membranes. Both lipids are water as the type of apolipoprotein, one dis- insoluble and require appropriate trans- tinguishes 4 transport forms:

Origin Density Mean sojourn Diameter in blood (nm) plasma (h)

Chylomicron Gut epithelium <1.006 0.2 500

VLDL particle liver 0.95 –1.006 3 100–200

LDL particle (blood) 1.006–1.063 50 25

HDL particle liver 1.063–1.210 – 5–10

Lipoprotein metabolism. Entero- cells, including the hepatocytes (recep- cytes release absorbed lipids in the form tor-mediated endocytosis, p. 27). of triglyceride-rich chylomicrons. By- HDL particles are able to transfer passing the liver, these enter the circu- cholesterol from tissue cells to LDL par- lation mainly via the lymph and are hy- ticles. In this way, cholesterol is trans- drolyzed by extrahepatic endothelial ported from tissues to the liver. lipoprotein lipases to liberate fatty ac- Hyperlipoproteinemias can be ids. The remnant particles move on into caused genetically (primary h.) or can liver cells and supply these with choles- occur in obesity and metabolic disor- terol of dietary origin. ders (secondary h). Elevated LDL-cho- The liver meets the larger part lesterol serum concentrations are asso- (60%) of its requirement for cholesterol ciated with an increased risk of athero- by de novo synthesis from acetylcoen- sclerosis, especially when there is a con- zyme-A. Synthesis rate is regulated at comitant decline in HDL concentration the step leading from hydroxymethyl- (increase in LDL:HDL quotient). glutaryl CoA (HMG CoA) to mevalonic Treatment. Various drugs are avail- acid (p. 157A), with HMG CoA reductase able that have different mechanisms of as the rate-limiting enzyme. action and effects on LDL (cholesterol) The liver requires cholesterol for and VLDL (triglycerides) (A). Their use is synthesizing VLDL particles and bile ac- indicated in the therapy of primary hy- ids. Triglyceride-rich VLDL particles are perlipoproteinemias. In secondary hy- released into the blood and, like the perlipoproteinemias, the immediate chylomicrons, supply other tissues with goal should be to lower lipoprotein lev- fatty acids. Left behind are LDL particles els by dietary restriction, treatment of that either return into the liver or sup- the primary disease, or both. ply extrahepatic tissues with choleste- Drugs (B). Colestyramine and coles- rol. tipol are nonabsorbable anion-exchange LDL particles carry apolipoprotein B resins. By virtue of binding bile acids, 100, by which they are bound to recep- they promote consumption of choleste- tors that mediate uptake of LDL into the rol for the synthesis of bile acids; the

Drugs used in Hyperlipoproteinemias 155

Dietary fats Cell metabolism Cholesterol

LDL Chylomicron Fat tissue

HDL Heart Skeletal muscle VLDL HDL LDL

Chylomicron Lipoprotein Cholesterol remnant synthesis Triglycerides

Cholesterol- ester Triglycerides Cholesterol Cholesterol Fatty acids

Liver cell Apolipo- Lipoprotein protein OH OH Lipase OH

A. Lipoprotein metabolism

Colestyramine Gut:: Bile acids Lipoproteins binding and excretion of bile acids (BA) Liver: BA synthesis Liver cell Cholesterol Cholesterol consumption store

β-Sitosterol LDL Gut: Cholesterol absorption Synthesis

HMG-CoA-Reductase inhibitors

B. Cholesterol metabolism in liver cell and cholesterol-lowering drugs

156 Drugs used in Hyperlipoproteinemias liver meets its increased cholesterol de- rare, but dangerous, side effect of the mand by enhancing the expression of statins is damage to skeletal muscula- HMG CoA reductase and LDL receptors ture. This risk is increased by combined (negative feedback). use of fibric acid agents (see below). At the required dosage, the resins Nicotinic acid and its derivatives cause diverse gastrointestinal distur- (pyridylcarbinol, xanthinol nicotinate, bances. In addition, they interfere with acipimox) activate endothelial lipopro- the absorption of fats and fat-soluble vi- tein lipase and thereby lower triglyce- tamins (A, D, E, K). They also adsorb and ride levels. At the start of therapy, a decrease the absorption of such drugs as prostaglandin-mediated vasodilation digitoxin, vitamin K antagonists, and occurs (flushing and hypotension) that diuretics. Their gritty texture and bulk can be prevented by low doses of acetyl- make ingestion an unpleasant experi- salicylic acid. ence. Clofibrate and derivatives (bezafi- The statins, lovastatin (L), simvasta- brate, etofibrate, gemfibrozil) lower plas- tin (S), pravastatin (P), fluvastatin (F), ma lipids by an unknown mechanism. cerivastatin, and atorvastatin, inhibit They may damage the liver and skeletal HMG CoA reductase. The active group of muscle (myalgia, myopathy, rhabdo- L, S, P, and F (or their metabolites) re- myolysis). sembles that of the physiological sub- Probucol lowers HDL more than strate of the enzyme (A). L and S are lac- LDL; nonetheless, it appears effective in tones that are rapidly absorbed by the reducing atherogenesis, possibly by re- enteral route, subjected to extensive ducing LDL oxidation. first-pass extraction in the liver, and 3-Polyunsaturated fatty acids (ei- there hydrolyzed into active metab- cosapentaenoate, docosahexaenoate) olites. P and F represent the active form are abundant in fish oils. Dietary sup- and, as acids, are actively transported by plementation results in lowered levels a specific anion carrier that moves bile of triglycerides, decreased synthesis of acids from blood into liver and also me- VLDL and apolipoprotein B, and im- diates the selective hepatic uptake of proved clearance of remnant particles, the mycotoxin, amanitin (A). Atorvasta- although total and LDL cholesterol are tin has the longest duration of action. not decreased or are even increased. Normally viewed as presystemic elimi- High dietary intake may correlate with a nation, efficient hepatic extraction reduced incidence of coronary heart serves to confine the action of the sta- disease. tins to the liver. Despite the inhibition of HMG CoA reductase, hepatic cholesterol content does not fall, because hepatocytes compensate any drop in cholesterol levels by increasing the synthesis of LDL receptor protein (along with the reductase). Because the newly formed reductase is inhibited, too, the hepatocyte must meet its cholesterol demand by uptake of LDL from the blood (B). Ac- cordingly, the concentration of circulating LDL decreases, while its hepatic clearance from plasma increases. There is also a decreased likelihood of LDL being oxidized into its proatheroslerotic degradation product. The combination of a statin with an ion-exchange resin intensifies the decrease in LDL levels. A

Drugs used in Hyperlipoproteinemias 157

Low systemic availability

3-Hydroxy-3-methyl- Mevalonate glutaryl-CoA

HMG-CoA Reductase Cholesterol

Bio- activation Active form

Extraction Active of lipophilic uptake of lactone anion HO HO O COOH OH O O F CH3 H3C O Oral CH administration H3C 3 N CH3

H3C Lovastatin Fluvastatin A. Accumulation and effect of HMG-CoA reductase inhibitors in liver

Inhibition of HMG-CoA reductase

LDL- Receptor

HMG-CoA Expression Expression reductase

Cholesterol

Increased receptor- LDL mediated uptake of LDL in blood

B. Regulation by cellular cholesterol concentration of HMG-CoA reductase and LDL-receptors

158 Diuretics

Diuretics – An Overview Prophylaxis of renal failure. In circulatory failure (shock), e.g., secondary to Diuretics (saluretics) elicit increased massive hemorrhage, renal production production of urine (diuresis). In the of urine may cease (anuria). By means of strict sense, the term is applied to drugs diuretics an attempt is made to main- with a direct renal action. The predomi- tain urinary flow. Use of either osmotic nant action of such agents is to augment or loop diuretics is indicated. urine excretion by inhibiting the reab- Massive use of diuretics entails a sorption of NaCl and water. hazard of adverse effects (A): (1) the The most important indications for decrease in blood volume can lead to diuretics are: hypotension and collapse; (2) blood vis- Mobilization of edemas (A): In ede- cosity rises due to the increase in eryth- ma there is swelling of tissues due to ac- ro- and thrombocyte concentration, cumulation of fluid, chiefly in the extra- bringing an increased risk of intravascu- cellular (interstitial) space. When a diu- lar coagulation or thrombosis. retic is given, increased renal excretion When depletion of NaCl and water + of Na and H2O causes a reduction in (EFV reduction) occurs as a result of diu- plasma volume with hemoconcentra- retic therapy, the body can initiate tion. As a result, plasma protein concen- counter-regulatory responses (B), tration rises along with oncotic pres- namely, activation of the renin-angio- sure. As the latter operates to attract tensin-aldosterone system (p. 124). Be- water, fluid will shift from interstitium cause of the diminished blood volume, into the capillary bed. The fluid content renal blood flow is jeopardized. This of tissues thus falls and the edemas re- leads to release from the kidneys of the cede. The decrease in plasma volume hormone, renin, which enzymatically and interstitial volume means a dimi- catalyzes the formation of angiotensin I. nution of the extracellular fluid volume Angiotensin I is converted to angioten- (EFV). Depending on the condition, use sin II by the action of angiotensin-con- is made of: thiazides, loop diuretics, al- verting enzyme (ACE). Angiotensin II dosterone antagonists, and osmotic diu- stimulates release of aldosterone. The retics. mineralocorticoid promotes renal reab- Antihypertensive therapy. Diuretics sorption of NaCl and water and thus have long been used as drugs of first counteracts the effect of diuretics. ACE choice for lowering elevated blood pres- inhibitors (p. 124) augment the effec- sure (p. 312). Even at low dosage, they tiveness of diuretics by preventing this decrease peripheral resistance (without counter-regulatory response. significantly reducing EFV) and thereby normalize blood pressure. Therapy of congestive heart failure. By lowering peripheral resistance, diuretics aid the heart in ejecting blood (reduction in afterload, pp. 132, 306); cardiac output and exercise tolerance are increased. Due to the increased excretion of fluid, EFV and venous return decrease (reduction in preload, p. 306). Symptoms of venous congestion, such as ankle edema and hepatic enlargement, subside. The drugs principally used are thiazides (possibly combined with K+-sparing diuretics) and loop diuretics.

Diuretics 159

Protein molecules

Edema

Hemoconcentration

Colloid osmotic pressure

Collapse, Mobilization of danger of edema fluid thrombosis Diuretic

A. Mechanism of edema fluid mobilization by diuretics

Salt and Diuretic Diuretic fluid retention

EFV: Na+, Cl-, H2O

Angiotensinogen Renin Angiotensin I ACE Angiotensin II Aldosterone

B. Possible counter-regulatory responses during long-term diuretic therapy

160 Diuretics

NaCl Reabsorption in the Kidney (A) Osmotic Diuretics (B)

The smallest functional unit of the kid- Agents: mannitol, sorbitol. Site of action: ney is the nephron. In the glomerular mainly the proximal tubules. Mode of capillary loops, ultrafiltration of plasma action: Since NaCl and H2O are reab- fluid into Bowman’s capsule (BC) yields sorbed together in the proximal tubules, primary urine. In the proximal tubules Na+ concentration in the tubular fluid (pT), approx. 70% of the ultrafiltrate is does not change despite the extensive + retrieved by isoosmotic reabsorption of reabsorption of Na and H2O. Body cells NaCl and water. In the thick portion of lack transport mechanisms for polyhy- the ascending limb of Henle’s loop (HL), dric alcohols such as mannitol (struc- NaCl is absorbed unaccompanied by ture on p. 171) and sorbitol, which are water. This is the prerequisite for the thus prevented from penetrating cell hairpin countercurrent mechanism that membranes. Therefore, they need to be allows build-up of a very high NaCl con- given by intravenous infusion. They also centration in the renal medulla. In the cannot be reabsorbed from the tubular distal tubules (dT), NaCl and water are fluid after glomerular filtration. These again jointly reabsorbed. At the end of agents bind water osmotically and re- the nephron, this process involves an al- tain it in the tubular lumen. When Na dosterone-controlled exchange of Na+ ions are taken up into the tubule cell, against K+ or H+. In the collecting tubule water cannot follow in the usual (C), vasopressin (antidiuretic hormone, amount. The fall in urine Na+ concentra- ADH) increases the epithelial perme- tion reduces Na+ reabsorption, in part ability for water, which is drawn into because the reduced concentration gra- the hyperosmolar milieu of the renal dient towards the interior of tubule cells medulla and thus retained in the body. means a reduced driving force for Na+ As a result, a concentrated urine enters influx. The result of osmotic diuresis is a the renal pelvis. large volume of dilute urine. Na+ transport through the tubular Indications: prophylaxis of renal cells basically occurs in similar fashion hypovolemic failure, mobilization of in all segments of the nephron. The brain edema, and acute glaucoma. intracellular concentration of Na+ is significantly below that in primary urine. This concentration gradient is the driving force for entry of Na+ into the cytosol of tubular cells. A carrier mechanism moves Na+ across the membrane. Ener- gy liberated during this influx can be utilized for the coupled outward transport of another particle against a gradient. From the cell interior, Na+ is moved with expenditure of energy (ATP hydrolysis) by Na+/K+-ATPase into the extracellular space. The enzyme molecules are confined to the basolateral parts of the cell membrane, facing the interstitium; Na+ can, therefore, not escape back into tubular fluid. All diuretics inhibit Na+ reabsorption. Basically, either the inward or the outward transport of Na+ can be affected.

Diuretics 161

Aldosterone Na+, Cl-

+ - Na , Cl + H2O H O dT K+ 2

C Lumen Inter- stitium BC

pT Na+ "carrier" Na+

Cortex Na/K- Na+ ATPase Thick Medulla portion of HL

Diuretics

ADH

A. Kidney: NaCl reabsorption in nephron and tubular cell

Mannitol

+ + + + [Na ]inside = [Na ]outside [Na ]inside < [Na ]outside

B. NaCl reabsorption in proximal tubule and effect of mannitol

162 Diuretics

Diuretics of the Sulfonamide Type tion of Ca2+ and Mg2+ also increases. Special toxic effects include: (reversible) These drugs contain the sulfonamide hearing loss, enhanced sensitivity to group -SO2NH2. They are suitable for renotoxic agents. Indications: pulmo- oral administration. In addition to being nary edema (added advantage of i.v. in- filtered at the glomerulus, they are sub- jection in left ventricular failure: imme- ject to tubular secretion. Their concen- diate dilation of venous capacitance tration in urine is higher than in blood. vessels preload reduction); refrac- They act on the luminal membrane of toriness to thiazide diuretics, e.g., in re- the tubule cells. Loop diuretics have the nal hypovolemic failure with creatinine highest efficacy. Thiazides are most fre- clearance reduction (<30 mL/min); pro- quently used. Their forerunners, the phylaxis of acute renal hypovolemic carbonic anhydrase inhibitors, are now failure; hypercalcemia. Ethacrynic acid restricted to special indications. is classed in this group although it is not Carbonic anhydrase (CAH) inhibi- a sulfonamide. tors, such as acetazolamide and sulthi- Thiazide diuretics (benzothiadia- ame, act predominantly in the proximal zines) include hydrochlorothiazide, tubules. CAH catalyzes CO2 hydra- benzthiazide, trichlormethiazide, and tion/dehydration reactions: cyclothiazide. A long-acting analogue is + – H + HCO3 ↔ H2CO3 ↔ H20 + CO2. chlorthalidone. These drugs affect the The enzyme is used in tubule cells intermediate segment of the distal tu- to generate H+, which is secreted into bules, where they inhibit a Na+/Cl– co- the tubular fluid in exchange for Na+. transport. Thus, reabsorption of NaCl + – There, H captures HCO3 , leading to for- and water is inhibited. Renal excretion 2+ 2+ mation of CO2 via the unstable carbonic of Ca decreases, that of Mg increases. acid. Membrane-permeable CO2 is taken Indications are hypertension, cardiac up into the tubule cell and used to re- failure, and mobilization of edema. + – generate H and HCO3 . When the en- Unwanted effects of sulfonamide- zyme is inhibited, these reactions are type diuretics: (a) hypokalemia is a con- + – + slowed, so that less Na , HCO3 and wa- sequence of excessive K loss in the ter- ter are reabsorbed from the fast-flowing minal segments of the distal tubules – + tubular fluid. Loss of HCO3 leads to aci- where increased amounts of Na are dosis. The diuretic effectiveness of CAH available for exchange with K+; (b) hy- inhibitors decreases with prolonged perglycemia and glycosuria; (c) hyper- use. CAH is also involved in the produc- uricemia—increase in serum urate lev- tion of ocular aqueous humor. Present els may precipitate gout in predisposed indications for drugs in this class in- patients. Sulfonamide diuretics com- clude: acute glaucoma, acute mountain pete with urate for the tubular organic sickness, and epilepsy. Dorzolamide can anion secretory system. be applied topically to the eye to lower intraocular pressure in glaucoma. Loop diuretics include furosemide (frusemide), piretanide, and bumeta- nide. With oral administration, a strong diuresis occurs within 1 h but persists for only about 4 h. The effect is rapid, intense, and brief (high-ceiling diuresis). The site of action of these agents is the thick portion of the ascending limb of Henle’s loop, where they inhibit Na+/K+/2Cl– cotransport. As a result, these electrolytes, together with water, are excreted in larger amounts. Excre-

Diuretics 163

Normal Sulfonamide state diuretics

Anion secretory Hypokalemia system

Loss of + + Uric acid Na , K H2O

Thiazides

Gout Na+ Cl-

e.g., hydrochlorothiazide

Carbonic anhydrase inhibitors Loop diuretics

+ Na Na+ + H + - - + H HCO3 HCO3 Na HCO- + 3 CAH K 2 Cl- H2O CO2 H2O CO2

e.g., acetazolamide e.g., furosemide

A. Diuretics of the sulfonamide type

164 Diuretics

Potassium-Sparing Diuretics (A) Antidiuretic Hormone (ADH) and Derivatives (B) These agents act in the distal portion of the distal tubule and the proximal part ADH, a nonapeptide, released from the of the collecting ducts where Na+ is re- posterior pituitary gland promotes reabsorbed in exchange for K+ or H+. Their absorption of water in the kidney. This diuretic effectiveness is relatively mi- response is mediated by vasopressin re- nor. In contrast to sulfonamide diuretics ceptors of the V2 subtype. ADH enhanc- (p. 162), there is no increase in K+ secre- es the permeability of collecting duct tion; rather, there is a risk of hyperkale- epithelium for water (but not for elec- mia. These drugs are suitable for oral trolytes). As a result, water is drawn administration. from urine into the hyperosmolar inter- a) Triamterene and amiloride, in ad- stitium of the medulla. Nicotine aug- dition to glomerular filtration, undergo ments (p. 110) and ethanol decreases secretion in the proximal tubule. They ADH release. At concentrations above act on the luminal membrane of tubule those required for antidiuresis, ADH cells. Both inhibit the entry of Na+, stimulates smooth musculature, includ- hence its exchange for K+ and H+. They ing that of blood vessels (“vasopres- are mostly used in combination with sin”). The latter response is mediated by thiazide diuretics, e.g., hydrochlorothia- receptors of the V1 subtype. Blood pres- zide, because the opposing effects on K+ sure rises; coronary vasoconstriction excretion cancel each other, while the can precipitate angina pectoris. Lypres- effects on secretion of NaCl complement sin (8-L-lysine vasopressin) acts like each other. ADH. Other derivatives may display on- b) Aldosterone antagonists. The ly one of the two actions. mineralocorticoid aldosterone pro- Desmopressin is used for the thera- motes the reabsorption of Na+ (Cl– and py of diabetes insipidus (ADH deficien- + H2O follow) in exchange for K . Its hor- cy), nocturnal enuresis, thrombasthe- monal effect on protein synthesis leads mia (p. 148), and chronic hypotension to augmentation of the reabsorptive ca- (p. 314); it is given by injection or via pacity of tubule cells. Spironolactone, as the nasal mucosa (as “snuff”). well as its metabolite canrenone, are an- Felypressin and ornipressin serve as tagonists at the aldosterone receptor adjunctive vasoconstrictors in infiltra- and attenuate the effect of the hormone. tion local anesthesia (p. 206). The diuretic effect of spironolactone develops fully only with continuous administration for several days. Two possible explanations are: (1) the conversion of spironolactone into and accumulation of the more slowly eliminated metabolite canrenone; (2) an inhibition of aldosterone-stimulated protein synthesis would become noticeable only if existing proteins had become nonfunc- tional and needed to be replaced by de novo synthesis. A particular adverse effect results from interference with gonadal hormones, as evidenced by the development of gynecomastia (enlargement of male breast). Clinical uses include conditions of increased aldosterone secretion, e.g., liver cirrhosis with ascites.

Diuretics 165

Na+

K+

Triamterene Aldosterone

Na+ Aldosterone antagonists K+ or H+ Canrenone Protein synthesis Transport capacity

Amiloride Spironolactone

A. Potassium-sparing diuretics

Nicotine

Neuro- hypophysis Ethanol Vasoconstriction

V2 Adiuretin = Vasopressin V1

H2O permeability of collecting duct

Desmopressin Ornipressin

Felypressin

B. Antidiuretic hormone (ADH) and derivatives

166 Drugs for the Treatment of Peptic Ulcers

Drugs for Gastric and Duodenal Ulcers cipitated antacid or, phosphate depletion of the body with excessive intake of In the area of a gastric or duodenal pep- Al(OH)3. tic ulcer, the mucosa has been attacked Na+ ions remain in solution even in – by digestive juices to such an extent as the presence of HCO3 -rich pancreatic to expose the subjacent connective tis- secretions and are subject to absorption, – + sue layer (submucosa). This self-diges- like HCO3 . Because of the uptake of Na , tion occurs when the equilibrium use of NaHCO3 must be avoided in con- between the corrosive hydrochloric acid ditions requiring restriction of NaCl in- and acid-neutralizing mucus, which take, such as hypertension, cardiac fail- forms a protective cover on the mucosal ure, and edema. surface, is shifted in favor of hydro- Since food has a buffering effect, chloric acid. Mucosal damage can be antacids are taken between meals (e.g., promoted by Helicobacter pylori bacte- 1 and 3 h after meals and at bedtime). ria that colonize the gastric mucus. Nonabsorbable antacids are preferred. Drugs are employed with the fol- Because Mg(OH)2 produces a laxative lowing therapeutic aims: (1) to relieve effect (cause: osmotic action, p. 170, re- pain; (2) to accelerate healing; and (3) lease of cholecystokinin by Mg2+, or to prevent ulcer recurrence. Therapeu- both) and Al(OH)3 produces constipa- tic approaches are threefold: (a) to re- tion (cause: astringent action of Al3+, p. duce aggressive forces by lowering H+ 178), these two antacids are frequently output; (b) to increase protective forces used in combination. by means of mucoprotectants; and (c) to Ib. Inhibitors of acid production. eradicate Helicobacter pylori. Acting on their respective receptors, the transmitter acetylcholine, the hormone I. Drugs for Lowering Acid gastrin, and histamine released intra- Concentration mucosally stimulate the parietal cells of the gastric mucosa to increase output of Ia. Acid neutralization. H+-binding HCl. Histamine comes from entero- 2– – – groups such as CO3 , HCO3 or OH , to- chromaffin-like (ECL) cells; its release is gether with their counter ions, are con- stimulated by the vagus nerve (via M1 tained in antacid drugs. Neutralization receptors) and hormonally by gastrin. reactions occurring after intake of The effects of acetylcholine and hista- CaCO3 and NaHCO3, respectively, are mine can be abolished by orally applied shown in (A) at left. With nonabsorb- antagonists that reach parietal cells via able antacids, the counter ion is dis- the blood. solved in the acidic gastric juice in the The cholinoceptor antagonist pi- process of neutralization. Upon mixture renzepine, unlike atropine, prefers cho- with the alkaline pancreatic secretion in linoceptors of the M1 type, does not the duodenum, it is largely precipitated penetrate into the CNS, and thus pro- again by basic groups, e.g., as CaCO3 or duces fewer atropine-like side effects AlPO4, and excreted in feces. Therefore, (p. 104). The cholinoceptors on parietal systemic absorption of counter ions or cells probably belong to the M3 subtype. basic residues is minor. In the presence Hence, pirenzepine may act by blocking of renal insufficiency, however, absorp- M1 receptors on ECL cells or submucosal tion of even small amounts may cause neurons. an increase in plasma levels of counter Histamine receptors on parietal ions (e.g., magnesium intoxication with cells belong to the H2 type (p. 114) and paralysis and cardiac disturbances). Pre- are blocked by H2-antihistamines. Be- cipitation in the gut lumen is respon- cause histamine plays a pivotal role in sible for other side effects, such as re- the activation of parietal cells, H2-anti- duced absorption of other drugs due to histamines also diminish responsivity their adsorption to the surface of pre- to other stimulants, e.g., gastrin (in gas-

Drugs for the Treatment of Peptic Ulcers 167

Acid neutralization Inhibition of acid production

N. vagus

CaCO3 CaCO3 Pirenzepine

H+ Parietal cell + ACh H2CO3 H M3 ACh M1 H2O CO2 H+ ATPase ECL- Histamine K+ H2 cell Ca2+ Ca2+

Pancreas Gastrin

2- CO3 CaCO3 Proton pump- inhibitors H

N O S Antacids absorbable N not absorbable H3CO N CaCO NaHCO 3 3 H C 3 CH3 Mg(OH)2 Omeprazole OCH3 Al(OH)3

H2-Antihistamines N H O+CO HN 2 2 CH2 S

Cimetidine CH3 (CH2)2 - NH Na+ HCO3

C NHCH3 H+ N C N H3C N CH OCHS Na+ 2 2 H C (CH ) Pancreas 3 2 2 NH Absorption C NHCH3

- + - Ranitidine CH NO2 HCO3 Na HCO3

A. Drugs used to lower gastric acid concentration or production

168 Drugs for the Treatment of Peptic Ulcers trin-producing pancreatic tumors, Zol- gravid uterus) significantly restrict its linger-Ellison syndrome). Cimetidine, therapeutic utility. the first H2-antihistamine used thera- Carbenoxolone (B) is a derivative peutically, only rarely produces side ef- of glycyrrhetinic acid, which occurs in fects (CNS disturbances such as confu- the sap of licorice root (succus liquiri- sion; endocrine effects in the male, such tiae). Carbenoxolone stimulates mucus as gynecomastia, decreased libido, im- production. At the same time, it has a potence). Unlike cimetidine, its newer mineralocorticoid-like action (due to in- and more potent congeners, ranitidine, hibition of 11-β-hydroxysteroid dehy- nizatidine, and famotidine, do not inter- drogenase) that promotes renal reab- fere with the hepatic biotransformation sorption of NaCl and water. It may, of other drugs. therefore, exacerbate hypertension, Omeprazole (p. 167) can cause max- congestive heart failure, or edemas. It is imal inhibition of HCl secretion. Given obsolete. orally in gastric juice-resistant capsules, it reaches parietal cells via the blood. In III. Eradication of Helicobacter py- the acidic milieu of the mucosa, an ac- lori C. This microorganism plays an im- tive metabolite is formed and binds co- portant role in the pathogenesis of valently to the ATP-driven proton pump chronic gastritis and peptic ulcer dis- (H+/K+ ATPase) that transports H+ in ex- ease. The combination of antibacterial change for K+ into the gastric juice. Lan- drugs and omeprazole has proven effec- soprazole and pantoprazole produce tive. In case of intolerance to amoxicillin analogous effects. The proton pump in- (p. 270) or clarithromycin (p. 276), met- hibitors are first-line drugs for the treat- ronidazole (p. 274) can be used as a sub- ment of gastroesophageal reflux dis- stitute. Colloidal bismuth compounds ease. are also effective; however, the problem of heavy-metal exposure compromises II. Protective Drugs their long-term use.

Sucralfate (A) contains numerous aluminum hydroxide residues. However, it is not an antacid because it fails to lower the overall acidity of gastric juice. After oral intake, sucralfate molecules undergo cross-linking in gastric juice, forming a paste that adheres to mucosal defects and exposed deeper layers. Here sucralfate intercepts H+. Protected from acid, and also from pepsin, trypsin, and bile acids, the mucosal defect can heal more rapidly. Sucralfate is taken on an empty stomach (1 h before meals and at bedtime). It is well tolerated; however, released Al3+ ions can cause constipation. Misoprostol (B) is a semisynthetic prostaglandin derivative with greater stability than natural prostaglandin, permitting absorption after oral administration. Like locally released prostaglandins, it promotes mucus production and inhibits acid secretion. Additional systemic effects (frequent diarrhea; risk of precipitating contractions of the

Drugs for the Treatment of Peptic Ulcers 169

R R Sucralfate

R R R R R R

R = – SO3[Al2(OH)5] Conversion H+ in acidic environment - + pH < 4 – SO3 R = – SO3[Al2(OH)4] Cross-linking and formation of paste

Coating of mucosal defects

A. Chemical structure and protective effect of sucralfate

Mucus HCl ATPase H+ K+

Parietal cell Prostaglandin receptor

Induction of labor Misoprostol B. Chemical structure and protective effect of misoprostol

Helicobacter Eradication pylori e.g., short-term triple therapy

Gastritis Peptic ulcer Amoxicillin (2 x 1000 mg) 7 days Clarithromycin (2 x 500 mg) 7 days Omeprazole (2 x 20 mg) 7 days

C. Helicobacter eradication

170 Laxatives

Laxatives With Epsom and Glauber’s salts (MgSO4 and Na2SO4, respectively), the 2– Laxatives promote and facilitate bowel SO4 anion is nonabsorbable and re- evacuation by acting locally to stimulate tains cations to maintain electroneu- intestinal peristalsis, to soften bowel trality. Mg2+ ions are also believed to contents, or both. promote release from the duodenal mu- 1. Bulk laxatives. Distention of the cosa of cholecystokinin/pancreozymin, intestinal wall by bowel contents stimu- a polypeptide that also stimulates peris- lates propulsive movements of the gut talsis. These so-called saline cathartics musculature (peristalsis). Activation of elicit a watery bowel discharge 1–3 h af- intramural mechanoreceptors induces a ter administration (preferably in isoton- neurally mediated ascending reflex con- ic solution). They are used to purge the traction (red in A) and descending re- bowel (e.g., before bowel surgery) or to laxation (blue) whereby the intralumi- hasten the elimination of ingested poi- nal bolus is moved in the anal direction. sons. Glauber’s salt (high Na+ content) is Hydrophilic colloids or bulk gels contraindicated in hypertension, con- (B) comprise insoluble and nonabsorb- gestive heart failure, and edema. Epsom able carbohydrate substances that ex- salt is contraindicated in renal failure pand on taking up water in the bowel. (risk of Mg2+ intoxication). Vegetable fibers in the diet act in this Osmotic laxative effects are also manner. They consist of the indigestible produced by the polyhydric alcohols, plant cell walls containing homoglycans mannitol and sorbitol, which unlike glu- that are resistant to digestive enzymes, cose cannot be transported through the e.g., cellulose (14β-linked glucose mo- intestinal mucosa, as well as by the non- lecules vs. 14α glucoside bond in hydrolyzable disaccharide, lactulose. starch, p. 153). Fermentation of lactulose by colon bac- Bran, a grain milling waste product, teria results in acidification of bowel and linseed (flaxseed) are both rich in contents and microfloral damage. Lac- cellulose. Other hydrophilic colloids de- tulose is used in hepatic failure in order rive from the seeds of Plantago species to prevent bacterial production of am- or karaya gum. Ingestion of hydrophilic monia and its subsequent absorption gels for the prophylaxis of constipation (absorbable NH3 nonabsorbable + usually entails a low risk of side effects. NH4 ), so as to forestall hepatic coma. However, with low fluid intake in com- 2. Irritant laxatives—purgatives bination with a pathological bowel cathartics. Laxatives in this group exert stenosis, mucilaginous viscous material an irritant action on the enteric mucosa could cause bowel occlusion (ileus). (A). Consequently, less fluid is absorbed Osmotically active laxatives (C) than is secreted. The increased filling of are soluble but nonabsorbable particles the bowel promotes peristalsis; excita- that retain water in the bowel by virtue tion of sensory nerve endings elicits en- of their osmotic action. The osmotic teral hypermotility. According to the pressure (particle concentration) of site of irritation, one distinguishes the bowel contents always corresponds to small bowel irritant castor oil from the that of the extracellular space. The in- large bowel irritants anthraquinone and testinal mucosa is unable to maintain a diphenolmethane derivatives (for de- higher or lower osmotic pressure of the tails see p. 174). luminal contents. Therefore, absorption Misuse of laxatives. It is a widely of molecules (e.g., glucose, NaCl) occurs held belief that at least one bowel isoosmotically, i.e., solute molecules are movement per day is essential for followed by a corresponding amount of health; yet three bowel evacuations per water. Conversely, water remains in the week are quite normal. The desire for bowel when molecules cannot be ab- frequent bowel emptying probably sorbed. stems from the time-honored, albeit

Laxatives 171

Stretch receptors

Contraction Relaxation

A. Stimulation of peristalsis by an intraluminal bolus

H2O H2O

Cellulose, agar-agar, bran, linseed

B. Bulk laxatives

H2O Na+, Cl- H2O H2O H2O + - + - Na , Cl Na , Cl H O H2O G 2 H2O + - H2O Na , Cl H2O G H2O H2O H2O Na+, Cl- Na+, Cl- H2O G H2O H2O H2O Na+, Cl- Isoosmotic H2O absorption G = Glucose

H2O H2O Na+, Cl- H2O Na+, Cl- Na+, Cl- H2O H2O H2O

H2O + - Na , Cl H2O H2O G

H2O H2O G G Na+, Cl- H2O Na+, Cl- H O H O Na+, Cl- 2 2 H2O H2O H2O

H O 2 Mannitol + 2- 2 Na SO4 H2OH2O H2O H2O

C. Osmotically active laxatives

172 Laxatives mistaken, notion that absorption of co- 124), which stimulates their reabsorp- lon contents is harmful. Thus, purging tion in the kidney. The action of aldoste- has long been part of standard thera- rone is, however, associated with in- peutic practice. Nowadays, it is known creased renal excretion of KCl. The en- that intoxication from intestinal sub- teral and renal K+ loss add up to a K+ de- stances is impossible as long as the liver pletion of the body, evidenced by a fall functions normally. Nonetheless, purga- in serum K+ concentration (hypokale- tives continue to be sold as remedies to mia). This condition is accompanied by “cleanse the blood” or to rid the body of a reduction in intestinal peristalsis “corrupt humors.” (bowel atonia). The affected individual There can be no objection to the in- infers “constipation,” again partakes of gestion of bulk substances for the pur- the purgative, and the vicious circle is pose of supplementing low-residue closed (2). “modern diets.” However, use of irritant Chologenic diarrhea results when purgatives or cathartics is not without bile acids fail to be absorbed in the ile- hazards. Specifically, there is a risk of um (e.g., after ileal resection) and enter laxative dependence, i.e., the inability to the colon, where they cause enhanced do without them. Chronic intake of irri- secretion of electrolytes and water, tant purgatives disrupts the water and leading to the discharge of fluid stools. electrolyte balance of the body and can thus cause symptoms of illness (e.g., cardiac arrhythmias secondary to hypokalemia). Causes of purgative dependence (B). The defecation reflex is triggered when the sigmoid colon and rectum are filled. A natural defecation empties the large bowel up to and including the descending colon. The interval between natural stool evacuations depends on the speed with which these colon segments are refilled. A large bowel irritant purgative clears out the entire colon. Accordingly, a longer period is needed until the next natural defecation can occur. Fearing constipation, the user becomes impatient and again resorts to the laxative, which then produces the desired effect as a result of emptying out the upper colonic segments. There- fore, a “compensatory pause” following cessation of laxative use must not give cause for concern (1). In the colon, semifluid material entering from the small bowel is thick- ened by absorption of water and salts (from about 1000 to 150 mL/d). If, due to the action of an irritant purgative, the colon empties prematurely, an enteral loss of NaCl, KCl and water will be in- curred. To forestall depletion of NaCl and water, the body responds with an increased release of aldosterone (p.

Laxatives 173

Reflex

Irritation Peristalsis of mucosa Filling

Absorption Secretion of fluid

A. Stimulation of peristalsis by mucosal irritation

Interval needed to refill colon

Normal filling After normal defecation reflex evacuation of colon

Longer interval needed to refill rectum 1 Laxative

“Constipation” Renal retention + of Na , H2O

Laxative

Bowel inertia Aldosterone

Hypokalemia Renal Enteral loss loss of K+ of K+

+ 2 Na , H2O

B. Causes of laxative habituation

174 Laxatives and Purgatives

2.a Small Bowel Irritant Purgative, colon bacteria to the active free agly- Ricinoleic Acid cones. Castor oil comes from Ricinus commu- Diphenolmethane derivatives (p. 177) nis (castor plants; Fig: sprig, panicle, were developed from phenolphthalein, seed); it is obtained from the first cold- an accidentally discovered laxative, use pressing of the seed (shown in natural of which had been noted to result in size). Oral administration of 10–30 mL rare but severe allergic reactions. Bisac- of castor oil is followed within 0.5 to 3 h odyl and sodium picosulfate are convert- by discharge of a watery stool. Ricinole- ed by gut bacteria into the active colonic acid, but not the oil itself, is active. It irritant principle. Given by the enteral arises as a result of the regular process- route, bisacodyl is subject to hydrolysis es involved in fat digestion: the duoden- of acetyl residues, absorption, conjuga- al mucosa releases the enterohormone tion in liver to glucuronic acid (or also to cholecystokinin/pancreozymin into the sulfate, p. 38), and biliary secretion into blood. The hormone elicits contraction the duodenum. Oral administration is of the gallbladder and discharge of bile followed after approx. 6 to 8 h by dis- acids via the bile duct, as well as release charge of soft formed stool. When given of lipase from the pancreas (intestinal by suppository, bisacodyl produces its peristalsis is also stimulated). Because effect within 1 h. of its massive effect, castor oil is hardly Indications for colon-irritant purga- suitable for the treatment of ordinary tives are the prevention of straining at constipation. It can be employed after stool following surgery, myocardial in- oral ingestion of a toxin in order to has- farction, or stroke; and provision of reten elimination and to reduce absorp- lief in painful diseases of the anus, e.g., tion of toxin from the gut. Castor oil is fissure, hemorrhoids. not indicated after the ingestion of lipo- Purgatives must not be given in ab- philic toxins likely to depend on bile ac- dominal complaints of unclear origin. ids for their absorption. 3. Lubricant laxatives. Liquid paraffin (paraffinum subliquidum) is almost non- 2.b Large Bowel Irritant Purgatives absorbable and makes feces softer and (p. 177 ff) more easily passed. It interferes with the absorption of fat-soluble vitamins Anthraquinone derivatives (p. 176) are by trapping them. The few absorbed of plant origin. They occur in the leaves paraffin particles may induce formation (folia sennae) or fruits (fructus sennae) of foreign-body granulomas in enteric of the senna plant, the bark of Rhamnus lymph nodes (paraffinomas). Aspiration frangulae and Rh. purshiana, (cortex into the bronchial tract can result in li- frangulae, cascara sagrada), the roots of poid pneumonia. Because of these ad- rhubarb (rhizoma rhei), or the leaf ex- verse effects, its use is not advisable. tract from Aloe species (p. 176). The structural features of anthraquinone derivatives are illustrated by the prototype structure depicted on p. 177. Among other substituents, the anthraquinone nucleus contains hydroxyl groups, one of which is bound to a sugar (glucose, rhamnose). Following ingestion of galenical preparations or of the anthraquinone glycosides, discharge of soft stool occurs after a latency of 6 to 8 h. The anthraquinone glycosides themselves are inactive but are converted by

Laxatives and Purgatives 175

Ricinus communis

Gall- bladder CK/PZ

Ricinoleic acid – O – CH2 Castor oil Ricinoleic acid – O – CH

Ricinoleic acid – O – CH2

Bile acids

Peristalsis Lipase

Pancreas Glycerol +

3 Ricinoleic acids Duodenum

CK/PZ = Cholecystokinin/pancreozymin

A. Small-bowel irritant laxative: ricinoleic acid

176 Laxatives and Purgatives

Senna Frangula

Rhubarb Aloe

A. Plants containing anthraquinone glycosides

Laxatives and Purgatives 177

sugar e.g., 1,8-Dihydroxy- anthraquinone glycoside

1,8-Dihydroxy- anthrone -Anthranol

Reduction

Sugar cleavage

Bacteria

Anthraquinone glycoside

A. Large-bowel irritant laxatives: anthraquinone derivatives

Glucuronidation

Sodium Bisacodyl picosulfate

Diphenol Esterase

Diphenol Sulfate Glucuronide

Glucu- ronate

Bacteria

B. Large-bowel irritant laxatives: diphenylmethane derivatives

178 Antidiarrheals

Antidiarrheal Agents affect brain functions at normal dosage. Loperamide is, therefore, the opioid Causes of diarrhea (in red): Many bacte- antidiarrheal of first choice. The pro- ria (e.g., Vibrio cholerae) secrete toxins longed contact time of intestinal con- that inhibit the ability of mucosal ente- tents and mucosa may also improve ab- rocytes to absorb NaCl and water and, at sorption of fluid. With overdosage, the same time, stimulate mucosal secre- there is a hazard of ileus. It is contrain- tory activity. Bacteria or viruses that indicated in infants below age 2 y. vade the gut wall cause inflammation Antibacterial drugs. Use of these characterized by increased fluid secre- agents (e.g., cotrimoxazole, p. 272) is tion into the lumen. The enteric muscu- only rational when bacteria are the lature reacts with increased peristalsis. cause of diarrhea. This is rarely the case. The aims of antidiarrheal therapy It should be kept in mind that antibio- are to prevent: (1) dehydration and tics also damage the intestinal flora electrolyte depletion; and (2) excessive- which, in turn, can give rise to diarrhea. ly high stool frequency. Different ther- Astringents such as tannic acid apeutic approaches (in green) listed (home remedy: black tea) or metal salts are variously suited for these purposes. precipitate surface proteins and are Adsorbent powders are nonab- thought to help seal the mucosal epithe- sorbable materials with a large surface lium. Protein denaturation must not in- area. These bind diverse substances, include cellular proteins, for this would cluding toxins, permitting them to be mean cell death. Although astringents inactivated and eliminated. Medicinal induce constipation (cf. Al3+ salts, charcoal possesses a particularly large p. 166), a therapeutic effect in diarrhea surface because of the preserved cell is doubtful. structures. The recommended effective Demulcents, e.g., pectin (home antidiarrheal dose is in the range of remedy: grated apples) are carbohy- 4–8 g. Other adsorbents are kaolin (hy- drates that expand on absorbing water. drated aluminum silicate) and chalk. They improve the consistency of bowel Oral rehydration solution (g/L of contents; beyond that they are devoid boiled water: NaCl 3.5, glucose 20, of any favorable effect. NaHCO3 2.5, KCl 1.5). Oral administration of glucose-containing salt solutions enables fluids to be absorbed because toxins do not impair the cotransport of + Na and glucose (as well as of H2O) through the mucosal epithelium. In this manner, although frequent discharge of stool is not prevented, dehydration is successfully corrected. Opioids. Activation of opioid receptors in the enteric nerve plexus results in inhibition of propulsive motor activity and enhancement of segmentation activity. This antidiarrheal effect was formerly induced by application of opium tincture (paregoric) containing morphine. Because of the CNS effects (sedation, respiratory depression, physical dependence), derivatives with peripheral actions have been developed. Whereas diphenoxylate can still produce clear CNS effects, loperamide does not

Antidiarrheals 179

Adsorption e.g., to medicinal charcoal Toxins Toxins Na+

Cl-

Oral Fluid secretion rehydration solution: Na+ salts and glucose Glucose Antibacterial Resident drugs: e.g., co-trimoxazole microflora

Pathogenic bacteria

Opium tincture with morphine CNS Viruses Diphenoxylate Mucosal injury Loperamide

Inhibition of propulsive peristalsis

Opioid- receptors

Protein- containing mucus

Enhanced peristalsis Astringents: e.g., tannic acid

Precipitation of surface proteins, sealing of mucosa Fluid loss

Diarrhea

A. Antidiarrheals and their sites of action

180 Other Gastrointestinal Drugs

Drugs for Dissolving Gallstones (A) UCDA may also be useful in primary biliary cirrhosis. Following its secretion from liver into Choleretics are supposed to stimu- bile, water-insoluble cholesterol is held late production and secretion of dilute in solution in the form of micellar com- bile fluid. This principle has little thera- plexes with bile acids and phospholip- peutic significance. ids. When more cholesterol is secreted Cholekinetics stimulate the gall- than can be emulsified, it precipitates bladder to contract and empty, e.g., egg and forms gallstones (cholelithiasis). yolk, the osmotic laxative MgSO4, the Precipitated cholesterol can be reincor- cholecystokinin-related ceruletide (giv- porated into micelles, provided the cho- en parenterally). Cholekinetics are em- lesterol concentration in bile is below ployed to test gallbladder function for saturation. Thus, cholesterol-contain- diagnostic purposes. ing stones can be dissolved slowly. This Pancreatic enzymes (B) from effect can be achieved by long-term oral slaughtered animals are used to relieve administration of chenodeoxycholic excretory insufficiency of the pancreas acid (CDCA) or ursodeoxycholic acid ( disrupted digestion of fats; steator- (UDCA). Both are physiologically occur- rhea, inter alia). Normally, secretion of ring, stereoisomeric bile acids (position pancreatic enzymes is activated by of the 7-hydroxy group being β in UCDA cholecystokinin/pancreozymin, the en- and α in CDCA). Normally, they repre- terohormone that is released into blood sent a small proportion of the total from the duodenal mucosa upon con- amount of bile acid present in the body tact with chyme. With oral administra- (circle diagram in A); however, this in- tion of pancreatic enzymes, allowance creases considerably with chronic ad- must be made for their partial inactiva- ministration because of enterohepatic tion by gastric acid (the lipases, particu- cycling, p. 38). Bile acids undergo almost larly). Therefore, they are administered complete reabsorption in the ileum. in acid-resistant dosage forms. Small losses via the feces are made up Antiflatulents (carminatives) serve by de novo synthesis in the liver, keep- to alleviate meteorism (excessive accu- ing the total amount of bile acids con- mulation of gas in the gastrointestinal stant (3–5 g). Exogenous supply re- tract). Aborad propulsion of intestinal moves the need for de novo synthesis of contents is impeded when the latter are bile acids. The particular acid being sup- mixed with gas bubbles. Defoaming plied gains an increasingly larger share agents, such as dimethicone (dimethyl- of the total store. polysiloxane) and simethicone, in com- The altered composition of bile in- bination with charcoal, are given orally creases the capacity for cholesterol up- to promote separation of gaseous and take. Thus, gallstones can be dissolved semisolid contents. in the course of a 1- to 2 y treatment, provided that cholesterol stones are pure and not too large (<15 mm), gall bladder function is normal, liver disease is absent, and patients are of normal body weight. UCDA is more effective (daily dose, 8–10 mg) and better tolerated than is CDCA (15 mg/d; frequent diarrhea, elevation of liver enzymes in plasma). Stone formation may recur after cessation of successful therapy. Compared with surgical treatment, drug therapy plays a subordinate role.

Other Gastrointestinal Drugs 181

CA : Cholic acid DCA : Desoxy-CA UDCA UDCA : Ursodesoxy-CA CDCA : Chenodesoxy-CA

Synthesis of bile acids to maintain store

Gall-stone formed by cholesterol DAA DCA CDCA CA CA CDCA UDCA UDCA

Ileum

Excretion in feces

A. Gallstone dissolution

“Pancreatin” of slaughter animals: Protease, Amylase, Lipase Stomach

Duodenum

CK/PZ Addition Fat- of containing Circulation dimethicone chymus

Pancreatic enzyme “Defoaming”

B. Release of pancreatic enzymes and C. Carminative effect of their replacement dimethicone

182 Drugs Acting on Motor Systems

Drugs Affecting Motor Function spinal disorders. Benzodiazepines enhance the effectiveness of the inhibitory The smallest structural unit of skeletal transmitter GABA (p. 226) at GABAA re- musculature is the striated muscle fiber. ceptors. Baclofen stimulates GABAB re- It contracts in response to an impulse of ceptors. α2-Adrenoceptor agonists such its motor nerve. In executing motor pro- as clonidine and tizanidine probably act grams, the brain sends impulses to the presynaptically to inhibit release of ex- spinal cord. These converge on α-moto- citatory amino acid transmitters. neurons in the anterior horn of the spi- The convulsant toxins, tetanus tox- nal medulla. Efferent axons course, bun- in (cause of wound tetanus) and strych- dled in motor nerves, to skeletal mus- nine diminish the efficacy of interneu- cles. Simple reflex contractions to sen- ronal synaptic inhibition mediated by sory stimuli, conveyed via the dorsal the amino acid glycine (A). As a conse- roots to the motoneurons, occur with- quence of an unrestrained spread of out participation of the brain. Neural nerve impulses in the spinal cord, motor circuits that propagate afferent impuls- convulsions develop. The involvement es into the spinal cord contain inhibit- of respiratory muscle groups endangers ory interneurons. These serve to pre- life. vent a possible overexcitation of moto- Botulinum toxin from Clostridium neurons (or excessive muscle contrac- botulinum is the most potent poison tions) due to the constant barrage of known. The lethal dose in an adult is ap- sensory stimuli. prox. 3 10–6 mg. The toxin blocks exo- Neuromuscular transmission (B) of cytosis of ACh in motor (and also para- motor nerve impulses to the striated sympathetic) nerve endings. Death is muscle fiber takes place at the motor caused by paralysis of respiratory mus- endplate. The nerve impulse liberates cles. Injected intramuscularly at minus- acetylcholine (ACh) from the axon ter- cule dosage, botulinum toxin type A is minal. ACh binds to nicotinic cholinocep- used to treat blepharospasm, strabis- tors at the motor endplate. Activation of mus, achalasia of the lower esophageal these receptors causes depolarization of sphincter, and spastic aphonia. the endplate, from which a propagated A pathological rise in serum Mg2+ action potential (AP) is elicited in the levels also causes inhibition of ACh re- surrounding sarcolemma. The AP trig- lease, hence inhibition of neuromuscu- gers a release of Ca2+ from its storage or- lar transmission. ganelles, the sarcoplasmic reticulum Dantrolene interferes with electro- (SR), within the muscle fiber; the rise in mechanical coupling in the muscle cell Ca2+ concentration induces a contrac- by inhibiting Ca2+ release from the SR. It tion of the myofilaments (electrome- is used to treat painful muscle spasms chanical coupling). Meanwhile, ACh is attending spinal diseases and skeletal hydrolyzed by acetylcholinesterase muscle disorders involving excessive (p. 100); excitation of the endplate sub- release of Ca2+ (malignant hyperther- sides. If no AP follows, Ca2+ is taken up mia). again by the SR and the myofilaments relax. Clinically important drugs (with the exception of dantrolene) all interfere with neural control of the muscle cell (A, B, p. 183ff.) Centrally acting muscle relaxants (A) lower muscle tone by augmenting the activity of intraspinal inhibitory interneurons. They are used in the treatment of painful muscle spasms, e.g., in

Drugs Acting on Motor Systems 183

Antiepileptics Antiparkinsonian drugs Myotonolytics Dantrolene

Muscle relaxants

Myotonolytics Convulsants

Increased Attenuated inhibition inhibition

Inhibitory Inhibitory neuron interneuron

Benzodiazepines Tetanus e.g., diazepam GABA Glycine Toxin Strychnine Inhibition of release Agonist Receptor Baclofen antagonist

(GABA = γ-aminobutyric acid)

A. Mechanisms for influencing skeletal muscle tone

Motor Mg2+ Muscle relaxants neuron Botulinum toxin inhibit generation inhibit of action ACh-release potential

Sarcoplasmic reticulum Action potential t-Tubule

ACh Depola- Dantrolene rization inhibits Ca2+ release Membrane potential Motor endplate Myofilaments

Muscle tone 2+ ACh receptor Ca (nicotinic) Contraction ms 10 20

B. Inhibition of neuromuscular transmission and electromechanical coupling

184 Drugs Acting on Motor Systems

Muscle Relaxants pressing anything. For this reason, care must be taken to eliminate conscious- Muscle relaxants cause a flaccid paraly- ness by administration of an appropri- sis of skeletal musculature by binding to ate drug (general anesthesia) before us- motor endplate cholinoceptors, thus ing a muscle relaxant. The effect of a sin- blocking neuromuscular transmission (p. gle dose lasts about 30 min. 182). According to whether receptor oc- The duration of the effect of d-tubo- cupancy leads to a blockade or an exci- curarine can be shortened by adminis- tation of the endplate, one distinguishes tering an acetylcholinesterase inhibitor, nondepolarizing from depolarizing such as neostigmine (p. 102). Inhibition muscle relaxants (p. 186). As adjuncts to of ACh breakdown causes the concen- general anesthetics, muscle relaxants tration of ACh released at the endplate help to ensure that surgical procedures to rise. Competitive “displacement” by are not disturbed by muscle contrac- ACh of d-tubocurarine from the recep- tions of the patient (p. 216). tor allows transmission to be restored. Unwanted effects produced by d-tu- Nondepolarizing muscle relaxants bocurarine result from a nonimmune- mediated release of histamine from Curare is the term for plant-derived ar- mast cells, leading to bronchospasm, ur- row poisons of South American natives. ticaria, and hypotension. More com- When struck by a curare-tipped arrow, monly, a fall in blood pressure can be at- an animal suffers paralysis of skeletal tributed to ganglionic blockade by d-tu- musculature within a short time after bocurarine. the poison spreads through the body; Pancuronium is a synthetic com- death follows because respiratory mus- pound now frequently used and not cles fail (respiratory paralysis). Killed likely to cause histamine release or gan- game can be eaten without risk because glionic blockade. It is approx. 5-fold absorption of the poison from the gas- more potent than d-tubocurarine, with trointestinal tract is virtually nil. The cu- a somewhat longer duration of action. rare ingredient of greatest medicinal Increased heart rate and blood pressure importance is d-tubocurarine. This are attributed to blockade of cardiac M2- compound contains a quaternary nitro- cholinoceptors, an effect not shared by gen atom (N) and, at the opposite end of newer pancuronium congeners such as the molecule, a tertiary N that is proto- vecuronium and pipecuronium. nated at physiological pH. These two Other nondepolarizing muscle re- positively charged N atoms are common laxants include: alcuronium, derived to all other muscle relaxants. The fixed from the alkaloid toxiferin; rocuroni- positive charge of the quaternary N ac- um, gallamine, mivacurium, and atra- counts for the poor enteral absorbabil- curium. The latter undergoes spontane- ity. ous cleavage and does not depend on d-Tubocurarine is given by i.v. in- hepatic or renal elimination. jection (average dose approx. 10 mg). It binds to the endplate nicotinic cholinoceptors without exciting them, acting as a competitive antagonist towards ACh. By preventing the binding of released ACh, it blocks neuromuscular transmission. Muscular paralysis develops within about 4 min. d-Tubocurarine does not penetrate into the CNS. The patient would thus experience motor paralysis and inability to breathe, while remaining fully conscious but incapable of ex-

Drugs Acting on Motor Systems 185

Arrow poison of indigenous South Americans

d-Tubocurarine Pancuronium (no enteral absorption)

ACh

Blockade of ACh receptors No depolarization of endplate

Artificial Antidote: Relaxation of skeletal muscles ventilation cholinesterase necessary inhibitors (Respiratory paralysis) (plus general e.g., neostigmine anesthesia!)

A. Non-depolarizing muscle relaxants

186 Drugs Acting on Motor Systems

Depolarizing Muscle Relaxants AP through the entire cell. If the AP fails, the muscle fiber remains in a relaxed In this drug class, only succinylcholine state. (succinyldicholine, suxamethonium, A) The effect of a standard dose of suc- is of clinical importance. Structurally, it cinylcholine lasts only about 10 min. It can be described as a double ACh mole- is often given at the start of anesthesia cule. Like ACh, succinylcholine acts as to facilitate intubation of the patient. As agonist at endplate nicotinic cholino- expected, cholinesterase inhibitors are ceptors, yet it produces muscle relaxa- unable to counteract the effect of succi- tion. Unlike ACh, it is not hydrolyzed by nylcholine. In the few patients with a acetylcholinesterase. However, it is a genetic deficiency in pseudocholineste- substrate of nonspecific plasma cholin- rase (= nonspecific cholinesterase), the esterase (serum cholinesterase, p. 100). succinylcholine effect is significantly Succinylcholine is degraded more slow- prolonged. ly than is ACh and therefore remains in Since persistent depolarization of the synaptic cleft for several minutes, endplates is associated with an efflux of causing an endplate depolarization of K+ ions, hyperkalemia can result (risk of corresponding duration. This depola- cardiac arrhythmias). rization initially triggers a propagated Only in a few muscle types (e.g., action potential (AP) in the surrounding extraocular muscle) are muscle fibers muscle cell membrane, leading to con- supplied with multiple endplates. Here traction of the muscle fiber. After its i.v. succinylcholine causes depolarization injection, fine muscle twitches (fascicu- distributed over the entire fiber, which lations) can be observed. A new AP can responds with a contracture. Intraocular be elicited near the endplate only if the pressure rises, which must be taken into membrane has been allowed to repo- account during eye surgery. larize. In skeletal muscle fibers whose mo- The AP is due to opening of voltage- tor nerve has been severed, ACh recep- gated Na-channel proteins, allowing tors spread in a few days over the entire Na+ ions to flow through the sarcolem- cell membrane. In this case, succinyl- ma and to cause depolarization. After a choline would evoke a persistent depo- few milliseconds, the Na channels close larization with contracture and hyper- automatically (“inactivation”), the kalemia. These effects are likely to occur membrane potential returns to resting in polytraumatized patients undergoing levels, and the AP is terminated. As long follow-up surgery. as the membrane potential remains incompletely repolarized, renewed opening of Na channels, hence a new AP, is impossible. In the case of released ACh, rapid breakdown by ACh esterase allows repolarization of the endplate and hence a return of Na channel excitability in the adjacent sarcolemma. With succinylcholine, however, there is a persistent depolarization of the endplate and adjoining membrane regions. Be- cause the Na channels remain inactivated, an AP cannot be triggered in the adjacent membrane. Because most skeletal muscle fibers are innervated only by a single endplate, activation of such fibers, with lengths up to 30 cm, entails propagation of the

Drugs Acting on Motor Systems 187

Acetylcholine Succinylcholine

Depolarization Depolarization

ACh Propagation of Succinylcholine action potential (AP)

Skeletal Contractionmuscle Contraction cell

1 Rapid ACh cleavage by Succinylcholine not degraded acetylcholine esterases by acetylcholine esterases

2 Repolarization of end plate Persistent depolarization of end plate

ACh

New AP and contraction New AP and contraction can be elicited cannot be elicited 3

Membrane potential

Na+-channel Open Closed (opening not possible) Persistent depolarization

Repolarization No repolarization, renewed opening of Closed Na+-channel (opening possible) impossible Membrane potential Membrane potential

A. Action of the depolarizing muscle relaxant succinylcholine

188 Drugs Acting on Motor Systems

Antiparkinsonian Drugs Inhibitors of monoamine oxidase-B (MAOB). This isoenzyme breaks Parkinson’s disease (shaking palsy) and down dopamine in the corpus striatum its syndromal forms are caused by a de- and can be selectively inhibited by se- generation of nigrostriatal dopamine legiline. Inactivation of norepinephrine, neurons. The resulting striatal dopa- epinephrine, and 5-HT via MAOA is un- mine deficiency leads to overactivity of affected. The antiparkinsonian effects of cholinergic interneurons and imbalance selegiline may result from decreased of striopallidal output pathways, mani- dopamine inactivation (enhanced levo- fested by poverty of movement (akine- dopa response) or from neuroprotective sia), muscle stiffness (rigidity), tremor mechanisms (decreased oxyradical for- at rest, postural instability, and gait dis- mation or blocked bioactivation of an turbance. unknown neurotoxin). Pharmacotherapeutic measures are Inhibitors of catechol-O-methyl- aimed at restoring dopaminergic func- transferase (COMT). L-Dopa and dopa- tion or suppressing cholinergic hyper- mine become inactivated by methyla- activity. tion. The responsible enzyme can be L-Dopa. Dopamine itself cannot blocked by entacapone, allowing higher penetrate the blood-brain barrier; how- levels of L-dopa and dopamine to be ever, its natural precursor, L-dihydroxy- achieved in corpus striatum. phenylalanine (levodopa), is effective in Anticholinergics. Antagonists at replenishing striatal dopamine levels, muscarinic cholinoceptors, such as because it is transported across the benzatropine and biperiden (p. 106), blood-brain barrier via an amino acid suppress striatal cholinergic overactiv- carrier and is subsequently decarboxy- ity and thereby relieve rigidity and lated by DOPA-decarboxylase, present tremor; however, akinesia is not re- in striatal tissue. Decarboxylation also versed or is even exacerbated. Atropine- takes place in peripheral organs where like peripheral side effects and impair- dopamine is not needed, likely causing ment of cognitive function limit the tol- undesirable effects (tachycardia, ar- erable dosage. rhythmias resulting from activation of Amantadine. Early or mild parkin- β1-adrenoceptors [p. 114], hypotension, sonian manifestations may be tempo- and vomiting). Extracerebral produc- rarily relieved by amantadine. The tion of dopamine can be prevented by underlying mechanism of action may inhibitors of DOPA-decarboxylase (car- involve, inter alia, blockade of ligand- bidopa, benserazide) that do not pene- gated ion channels of the glutamate/ trate the blood-brain barrier, leaving NMDA subtype, ultimately leading to a intracerebral decarboxylation unaffect- diminished release of acetylcholine. ed. Excessive elevation of brain dopa- Administration of levodopa plus mine levels may lead to undesirable re- carbidopa (or benserazide) remains the actions, such as involuntary movements most effective treatment, but does not (dyskinesias) and mental disturbances. provide benefit beyond 3–5 y and is fol- Dopamine receptor agonists. Defi- lowed by gradual loss of symptom con- cient dopaminergic transmission in the trol, on-off fluctuations, and develop- striatum can be compensated by ergot ment of orobuccofacial and limb dyski- derivatives (bromocriptine [p. 114], lisu- nesias. These long-term drawbacks of ride, cabergoline, and pergolide) and levodopa therapy may be delayed by nonergot compounds (ropinirole, prami- early monotherapy with dopamine re- pexole). These agonists stimulate dopa- ceptor agonists. Treatment of advanced mine receptors (D2, D3, and D1 sub- disease requires the combined adminis- types), have lower clinical efficacy than tration of antiparkinsonian agents. levodopa, and share its main adverse effects.

Drugs Acting on Motor Systems 189

Normal state

Selegiline Amantadine H H Dopamine Acetylcholine N N CH CH 3 NMDA CH3 Dopamine receptor: deficiency Blockade of ionophore: Inhibition of attenuation dopamine degradation of cholinergic neurons by MAO-B in CNS Predominance of acetylcholine Parkinson´s disease

Blood-brain barrier

Dopa- COMT decarboxylase 200 mg

Carbidopa Dopamine Entacapone O

H3C NH HO C2H5 N 2 N C H H Stimulation of CN 2 5 HO COOH peripheral dopamine receptors NO2 2000 mg Inhibition of dopa- Inhibition of decarboxylase catechol- Adverse effects O-methyltransferase Dopamine substitution

Bromocriptine L-Dopa H C Benzatropine 3 N CH3 H3C OH O O N H H N HO N N H O H O O N COOH H CH3 H3C CH3 HO

N Dopamine-receptor H Br agonist Dopamine precursor Acetylcholine antagonist

A. Antiparkinsonian drugs

190 Drugs Acting on Motor Systems

Antiepileptics second-line drug or combined use (“add on”) be recommended (B), provided Epilepsy is a chronic brain disease of di- that the possible risk of pharmacokinet- verse etiology; it is characterized by re- ic interactions is taken into account (see current paroxysmal episodes of uncon- below). The precise mode of action of trolled excitation of brain neurons. In- antiepileptic drugs remains unknown. volving larger or smaller parts of the Some agents appear to lower neuronal brain, the electrical discharge is evident excitability by several mechanisms of in the electroencephalogram (EEG) as action. In principle, responsivity can be synchronized rhythmic activity and decreased by inhibiting excitatory or ac- manifests itself in motor, sensory, psy- tivating inhibitory neurons. Most excit- chic, and vegetative (visceral) phenom- atory nerve cells utilize glutamate and ena. Because both the affected brain re- most inhibitory neurons utilize γ-ami- gion and the cause of abnormal excit- nobutyric acid (GABA) as their transmit- ability may differ, epileptic seizures can ter (p. 193A). Various drugs can lower take many forms. From a pharmaco- seizure threshold, notably certain neu- therapeutic viewpoint, these may be roleptics, the tuberculostatic isoniazid, classified as: and β-lactam antibiotics in high doses; – general vs. focal seizures; they are, therefore, contraindicated in – seizures with or without loss of con- seizure disorders. sciousness; Glutamate receptors comprise – seizures with or without specific three subtypes, of which the NMDA modes of precipitation. subtype has the greatest therapeutic The brief duration of a single epi- importance. (N-methyl-D-aspartate is a leptic fit makes acute drug treatment synthetic selective agonist.) This recep- unfeasible. Instead, antiepileptics are tor is a ligand-gated ion channel that, used to prevent seizures and therefore upon stimulation with glutamate, per- need to be given chronically. Only in the mits entry of both Na+ and Ca2+ ions into case of status epilepticus (a succession of the cell. The antiepileptics lamotrigine, several tonic-clonic seizures) is acute phenytoin, and phenobarbital inhibit, anticonvulsant therapy indicated — among other things, the release of glu- usually with benzodiazepines given i.v. tamate. Felbamate is a glutamate antag- or, if needed, rectally. onist. The initiation of an epileptic attack Benzodiazepines and phenobarbital involves “pacemaker” cells; these differ augment activation of the GABAA recep- from other nerve cells in their unstable tor by physiologically released amounts resting membrane potential, i.e., a de- of GABA (B) (see p. 226). Chloride influx polarizing membrane current persists is increased, counteracting depolariza- after the action potential terminates. tion. Progabide is a direct GABA-mimet- Therapeutic interventions aim to ic. Tiagabin blocks removal of GABA stabilize neuronal resting potential and, from the synaptic cleft by decreasing its hence, to lower excitability. In specific re-uptake. Vigabatrin inhibits GABA ca- forms of epilepsy, initially a single drug tabolism. Gabapentin may augment the is tried to achieve control of seizures, availability of glutamate as a precursor valproate usually being the drug of first in GABA synthesis (B) and can also act as choice in generalized seizures, and car- a K+-channel opener. bamazepine being preferred for partial (focal), especially partial complex, seizures. Dosage is increased until seizures are no longer present or adverse effects become unacceptable. Only when monotherapy with different agents proves inadequate can changeover to a

Drugs Acting on Motor Systems 191

Drugs used in the treatment of status epilepticus: Benzodiazepines, e.g., diazepam

Waking state EEG Epileptic attack µV µV 150 150

100 100

50 50

0 0 1 sec 1 sec

Drugs used in the prophylaxis of epileptic seizures

Cl H H O H C O Cl NC2H5 3 N O O N N N N N H5C2 H N O C O H O O H H2N N NH2 NH2 Carbamazepine Phenytoin Phenobarbital Ethosuximide Lamotrigine

CH3 H3C O COOH H3C O O H2N COOH CH2OCNH2 H3C H C 2 CH O CH2OCNH2 O H2N COOH O O H3C OSO2NH2 CH3 Valproic acid Vigabatrin Gabapentin Felbamate Topiramate

A. Epileptic attack, EEG, and antiepileptics

Focal I. II. III. Choice seizures Simple seizures Carbam- Valproic acid, Primidone, azepine Phenytoin, Phenobar- Clobazam bital Complex + Lamotrigine or Vigabatrin or Gabapentin or secondarily generalized

Generalized Tonic-clonic Valproic acid Carbam- Lamotrigine, attacks attack (grand mal) azepine, Primidone, Phenytoin Phenobarbital Tonic attack Clonic attack + Lamotrigine or Vigabatrin or Gabapentin Myoclonic attack

Ethosuximide alternative Absence addition seizure + Lamotrigine or Clonazepam

B. Indications for antiepileptics

192 Drugs Acting on Motor Systems

Carbamazepine, valproate, and prevent neural tube developmental de- phenytoin enhance inactivation of volt- fects. age-gated sodium and calcium channels Carbamazepine, phenytoin, pheno- and limit the spread of electrical excita- barbital, and other anticonvulsants (ex- tion by inhibiting sustained high-fre- cept for gabapentin) induce hepatic en- quency firing of neurons. zymes responsible for drug biotransfor- Ethosuximide blocks a neuronal T- mation. Combinations between anticon- type Ca2+ channel (A) and represents a vulsants or with other drugs may result special class because it is effective only in clinically important interactions in absence seizures. (plasma level monitoring!). All antiepileptics are likely, albeit to For the often intractable childhood different degrees, to produce adverse epilepsies, various other agents are effects. Sedation, difficulty in concentrat- used, including ACTH and the glucocor- ing, and slowing of psychomotor drive ticoid, dexamethasone. Multiple encumber practically all antiepileptic (mixed) seizures associated with the therapy. Moreover, cutaneous, hemato- slow spike-wave (Lennox–Gastaut) syn- logical, and hepatic changes may neces- drome may respond to valproate, la- sitate a change in medication. Pheno- motrigine, and felbamate, the latter be- barbital, primidone, and phenytoin may ing restricted to drug-resistant seizures lead to osteomalacia (vitamin D prophy- owing to its potentially fatal liver and laxis) or megaloblastic anemia (folate bone marrow toxicity. prophylaxis). During treatment with Benzodiazepines are the drugs of phenytoin, gingival hyperplasia may de- choice for status epilepticus (see velop in ca. 20% of patients. above); however, development of toler- Valproic acid (VPA) is gaining in- ance renders them less suitable for creasing acceptance as a first-line drug; long-term therapy. Clonazepam is used it is less sedating than other anticonvul- for myoclonic and atonic seizures. sants. Tremor, gastrointestinal upset, Clobazam, a 1,5-benzodiazepine exhib- and weight gain are frequently ob- iting an increased anticonvulsant/seda- served; reversible hair loss is a rarer oc- tive activity ratio, has a similar range of currence. Hepatotoxicity may be due to clinical uses. Personality changes and a toxic catabolite (4-en VPA). paradoxical excitement are potential Adverse reactions to carbamaze- side effects. pine include: nystagmus, ataxia, diplo- Clomethiazole can also be effective pia, particularly if the dosage is raised for controlling status epilepticus, but is too fast. Gastrointestinal problems and used mainly to treat agitated states, es- skin rashes are frequent. It exerts an pecially alcoholic delirium tremens and antidiuretic effect (sensitization of col- associated seizures. lecting ducts to vasopressin water in- Topiramate, derived from D-fruc- toxication). tose, has complex, long-lasting anticon- Carbamazepine is also used to treat vulsant actions that cooperate to limit trigeminal neuralgia and neuropathic the spread of seizure activity; it is effec- pain. tive in partial seizures and as an add-on Valproate, carbamazepine, and oth- in Lennox–Gastaut syndrome. er anticonvulsants pose teratogenic risks. Despite this, treatment should continue during pregnancy, as the potential threat to the fetus by a seizure is greater. However, it is mandatory to administer the lowest dose affording safe and effective prophylaxis. Concurrent high-dose administration of folate may

Drugs Acting on Motor Systems 193

Na+ Ca++ Excitatory neuron NMDA- receptor Inhibition of Glutamate glutamate NMDA-receptor- release: antagonist phenytoin, felbamate, lamotrigine valproic acid phenobarbital Ca2+-channel

T-Type- calcium channel blocker Voltage ethosuximide, dependent (valproic acid) Na+-channel Enhanced inactivation:

GABAA- receptor carbamazepine GABA valproic acid phenytoin – CI Gabamimetics: benzodiazepine barbiturates vigabatrin Inhibitory tiagabine neuron gabapentin

A. Neuronal sites of action of antiepileptics

Benzodiazepine GABAA- receptor Tiagabine Allosteric β α Inhibition of enhance- α GABA γ β ment of β α α Chloride reuptake GABA γ β channel action

Barbiturates

Progabide GABA- GABA- transaminase mimetic GABA Vigabatrin Glutamic acid Inhibitor of decarboxylase Succinic GABA- semialdehyde transaminase Succinic acid Glutamic acid Gabapentin Improved utilization Ending of of GABA precursor: inhibitory glutamate neuron

B. Sites of action of antiepileptics in GABAergic synapse

194 Drugs for the Suppression of Pain (Analgesics)

Pain Mechanisms and Pathways ing, or burning character, i.e., pain that can be localized only poorly. Pain is a designation for a spectrum of Impulse traffic in the neo- and pa- sensations of highly divergent character leospinothalamic pathways is subject to and intensity ranging from unpleasant modulation by descending projections to intolerable. Pain stimuli are detected that originate from the reticular forma- by physiological receptors (sensors, tion and terminate at second-order neu- nociceptors) least differentiated mor- rons, at their synapses with first-order phologically, viz., free nerve endings. neurons, or at spinal segmental inter- The body of the bipolar afferent first-or- neurons (descending antinociceptive der neuron lies in a dorsal root ganglion. system). This system can inhibit im- Nociceptive impulses are conducted via pulse transmission from first- to sec- unmyelinated (C-fibers, conduction ve- ond-order neurons via release of opio- locity 0.2–2.0 m/s) and myelinated ax- peptides (enkephalins) or monoamines ons (Aδ-fibers, 5–30 m/s). The free end- (norepinephrine, serotonin). ings of Aδ fibers respond to intense Pain sensation can be influenced pressure or heat, those of C-fibers re- or modified as follows: spond to chemical stimuli (H+, K+, hista- elimination of the cause of pain mine, bradykinin, etc.) arising from tis- lowering of the sensitivity of noci- sue trauma. Irrespective of whether ceptors (antipyretic analgesics, local chemical, mechanical, or thermal stim- anesthetics) uli are involved, they become signifi- interrupting nociceptive conduction cantly more effective in the presence of in sensory nerves (local anesthetics) prostaglandins (p. 196). suppression of transmission of noci- Chemical stimuli also underlie pain ceptive impulses in the spinal me- secondary to inflammation or ischemia dulla (opioids) (angina pectoris, myocardial infarction), inhibition of pain perception (opi- or the intense pain that occurs during oids, general anesthetics) overdistention or spasmodic contrac- altering emotional responses to tion of smooth muscle abdominal or- pain, i.e., pain behavior (antidepress- gans, and that may be maintained by lo- ants as “co-analgesics,” p. 230). cal anoxemia developing in the area of spasm (visceral pain). Aδ and C-fibers enter the spinal cord via the dorsal root, ascend in the dorsolateral funiculus, and then synapse on second-order neurons in the dorsal horn. The axons of the second-order neurons cross the midline and ascend to the brain as the anterolateral pathway or spinothalamic tract. Based on phylogenetic age, neo- and paleospinothalamic tracts are distinguished. Thalamic nuclei receiving neospinothalamic input project to circumscribed areas of the postcentral gyrus. Stimuli conveyed via this path are experienced as sharp, clearly localizable pain. The nuclear regions receiving paleospinothalamic input project to the postcentral gyrus as well as the frontal, limbic cortex and most likely represent the pathway subserving pain of a dull, ach-

Drugs for the Suppression of Pain (Analgesics) 195

Gyrus postcentralis

Perception: Perception: sharp dull quick delayed localizable diffuse

Thalamus Anesthetics Anti- depressants

Reticular Opioids formation Descending antinociceptive pathway Opioids tract tract Neospinothalamic Paleospinothalamic Local anesthetics

Nociceptors

Cyclooxygenase Prostaglandins inhibitors

Inflammation

Cause of pain

A. Pain mechanisms and pathways

196 Antipyretic Analgesics

Eicosanoids of the endometrium preceding menstruation. The relative proportions of in- Origin and metabolism. The eicosan- dividual PG are said to be altered in dys- oids, prostaglandins, thromboxane, menorrhea and excessive menstrual prostacyclin, and leukotrienes, are bleeding. formed in the organism from arachi- Uterine muscle. PG stimulate labor donic acid, a C20 fatty acid with four contractions. double bonds (eicosatetraenoic acid). Bronchial muscle. PGE2 and PGI2 Arachidonic acid is a regular constituent induce bronchodilation; PGF2α causes of cell membrane phospholipids; it is constriction. released by phospholipase A2 and forms Renal blood flow. When renal the substrate of cyclooxygenases and blood flow is lowered, vasodilating PG lipoxygenases. are released that act to restore blood Synthesis of prostaglandins (PG), flow. prostacyclin, and thromboxane pro- Thromboxane A2 and prostacyclin ceeds via intermediary cyclic endoper- play a role in regulating the aggregabil- oxides. In the case of PG, a cyclopentane ity of platelets and vascular diameter (p. ring forms in the acyl chain. The letters 150). following PG (D, E, F, G, H, or I) indicate Leukotrienes increase capillary differences in substitution with hydrox- permeability and serve as chemotactic yl or keto groups; the number sub- factors for neutrophil granulocytes. As scripts refer to the number of double “slow-reacting substances of anaphy- bonds, and the Greek letter designates laxis,” they are involved in allergic reac- the position of the hydroxyl group at C9 tions (p. 326); together with PG, they (the substance shown is PGF2α). PG are evoke the spectrum of characteristic in- primarily inactivated by the enzyme 15- flammatory symptoms: redness, heat, hydroxyprostaglandindehydrogenase. swelling, and pain. Inactivation in plasma is very rapid; Therapeutic applications. PG de- during one passage through the lung, rivatives are used to induce labor or to 90% of PG circulating in plasma are de- interrupt gestation (p. 126); in the ther- graded. PG are local mediators that at- apy of peptic ulcer (p. 168), and in pe- tain biologically effective concentra- ripheral arterial disease. tions only at their site of formation. PG are poorly tolerated if given Biological effects. The individual systemically; in that case their effects PG (PGE, PGF, PGI = prostacyclin) pos- cannot be confined to the intended site sess different biological effects. of action. Nociceptors. PG increase sensitivity of sensory nerve fibers towards ordinary pain stimuli (p. 194), i.e., at a given stimulus strength there is an increased rate of evoked action potentials. Thermoregulation. PG raise the set point of hypothalamic (preoptic) thermoregulatory neurons; body temperature increases (fever). Vascular smooth muscle. PGE2 and PGI2 produce arteriolar vasodilation; PGF2α, venoconstriction. Gastric secretion. PG promote the production of gastric mucus and reduce the formation of gastric acid (p. 160). Menstruation. PGF2α is believed to be responsible for the ischemic necrosis

Antipyretic Analgesics 197

Phospholipase A2

Thromboxane Prostacyclin

Cyclooxygenase

Lipoxygenase

Arachidonic acid

Prostaglandins Leukotrienes

e.g., PGF2α e.g., leukotriene A4 involved in allergic reactions

[ H+] Mucus production

Fever

Kidney function Vasodilation

Labor Impulse frequency in sensory fiber

Nociceptor Capillary permeability sensibility

Pain stimulus

A. Origin and effects of prostaglandins

198 Antipyretic Analgesics and Antiinflammatory Drugs

Antipyretic Analgesics binding of the acetyl residue. Hence, the duration of the effect depends on the Acetaminophen, the amphiphilic acids rate of enzyme resynthesis. Further- acetylsalicylic acid (ASA), ibuprofen, more, salicylate may contribute to the and others, as well as some pyrazolone effect. ASA irritates the gastric mucosa derivatives, such as aminopyrine and (direct acid effect and inhibition of cy- dipyrone, are grouped under the label toprotective PG synthesis, p. 200) and antipyretic analgesics to distinguish can precipitate bronchoconstriction them from opioid analgesics, because (“aspirin asthma,” pseudoallergy) due they share the ability to reduce fever. to inhibition of PGE2 synthesis and over- Acetaminophen (paracetamol) has production of leukotrienes. Because ASA good analgesic efficacy in toothaches inhibits platelet aggregation and pro- and headaches, but is of little use in in- longs bleeding time (p. 150), it should flammatory and visceral pain. Its mech- not be used in patients with impaired anism of action remains unclear. It can blood coagulability. Caution is also be administered orally or in the form of needed in children and juveniles be- rectal suppositories (single dose, cause of Reye’s syndrome. The latter has 0.5–1.0 g). The effect develops after been observed in association with feb- about 30 min and lasts for approx. 3 h. rile viral infections and ingestion of Acetaminophen undergoes conjugation ASA; its prognosis is poor (liver and to glucuronic acid or sulfate at the phe- brain damage). Administration of ASA at nolic hydroxyl group, with subsequent the end of pregnancy may result in pro- renal elimination of the conjugate. At longed labor, bleeding tendency in therapeutic dosage, a small fraction is mother and infant, and premature clo- oxidized to the highly reactive N-acetyl- sure of the ductus arteriosus. Acidic p-benzoquinonimine, which is detoxi- nonsteroidal antiinflammatory drugs fied by coupling to glutathione. After in- (NSAIDS; p. 200) are derived from ASA. gestion of high doses (approx. 10 g), the Among antipyretic analgesics, di- glutathione reserves of the liver are de- pyrone (metamizole) displays the high- pleted and the quinonimine reacts with est efficacy. It is also effective in visceral constituents of liver cells. As a result, pain. Its mode of action is unclear, but the cells are destroyed: liver necrosis. probably differs from that of acetamino- Liver damage can be avoided if the thiol phen and ASA. It is rapidly absorbed group donor, N-acetylcysteine, is given when given via the oral or rectal route. intravenously within 6–8 h after inges- Because of its water solubility, it is also tion of an excessive dose of acetamino- available for injection. Its active metab- phen. Whether chronic regular intake of olite, 4-aminophenazone, is eliminated acetaminophen leads to impaired renal from plasma with a t1/2 of approx. 5 h. function remains a matter of debate. Dipyrone is associated with a low inci- Acetylsalicylic acid (ASA) exerts an dence of fatal agranulocytosis. In sensi- antiinflammatory effect, in addition to tized subjects, cardiovascular collapse its analgesic and antipyretic actions. can occur, especially after intravenous These can be attributed to inhibition of injection. Therefore, the drug should be cyclooxygenase (p. 196). ASA can be giv- restricted to the management of pain en in tablet form, as effervescent pow- refractory to other analgesics. Propy- der, or injected systemically as lysinate phenazone presumably acts like meta- (analgesic or antipyretic single dose, mizole both pharmacologically and tox- O.5–1.0 g). ASA undergoes rapid ester icologically. hydrolysis, first in the gut and subsequently in the blood. The effect outlasts the presence of ASA in plasma (t1/2 ~ 20 min), because cyclooxygenases are irreversibly inhibited due to covalent

Antipyretic Analgesics and Antiinflammatory Drugs 199

Tooth- Head- ache ache Fever

Inflammatory pain

Pain of colic Acetaminophen Acetylsalicylic acid Dipyrone

Acute Chronic massive abuse overdose >10g

Irritation ? Broncho- of constriction gastrointestinal mucosa Risk of anaphylactoid Impaired shock Hepato- Nephro- hemostasis with Agranulo- toxicity toxicity risk of bleeding cytosis

A. Antipyretic analgesics

200 Antipyretic Analgesics

Nonsteroidal Antiinflammatory come rate limiting. Elimination now in- (Antirheumatic) Agents creasingly depends on unchanged salicylate, which is excreted only slowly. At relatively high dosage (> 4 g/d), ASA Group-specific adverse effects can (p. 198) may exert antiinflammatory ef- be attributed to inhibition of cyclooxy- fects in rheumatic diseases (e.g., rheu- genase (B). The most frequent problem, matoid arthritis). In this dose range, gastric mucosal injury with risk of peptic central nervous signs of overdosage ulceration, results from reduced synthe- may occur, such as tinnitus, vertigo, sis of protective prostaglandins (PG), drowsiness, etc. The search for better apart from a direct irritant effect. Gas- tolerated drugs led to the family of non- tropathy may be prevented by co-ad- steroidal antiinflammatory drugs ministration of the PG derivative, mis- (NSAIDs). Today, more than 30 sub- oprostol (p. 168). In the intestinal tract, stances are available, all of them sharing inhibition of PG synthesis would simi- the organic acid nature of ASA. Structu- larly be expected to lead to damage of rally, they can be grouped into carbonic the blood mucosa barrier and enteropa- acids (e.g., diclofenac, ibuprofen, na- thy. In predisposed patients, asthma at- proxene, indomethacin [p. 320]) or tacks may occur, probably because of a enolic acids (e.g., azapropazone, piroxi- lack of bronchodilating PG and in- cam, as well as the long-known but creased production of leukotrienes. Be- poorly tolerated phenylbutazone). Like cause this response is not immune me- ASA, these substances have analgesic, diated, such “pseudoallergic” reactions antipyretic, and antiinflammatory ac- are a potential hazard with all NSAIDs. tivity. In contrast to ASA, they inhibit cy- PG also regulate renal blood flow as clooxygenase in a reversible manner. functional antagonists of angiotensin II Moreover, they are not suitable as in- and norepinephrine. If release of the lat- hibitors of platelet aggregation. Since ter two is increased (e.g., in hypovole- their desired effects are similar, the mia), inhibition of PG production may choice between NSAIDs is dictated by result in reduced renal blood flow and re- their pharmacokinetic behavior and nal impairment. Other unwanted effects their adverse effects. are edema and a rise in blood pressure. Salicylates additionally inhibit the Moreover, drug-specific side effects transcription factor NFKB, hence the ex- deserve attention. These concern the pression of proinflammatory proteins. CNS (e.g., indomethacin: drowsiness, This effect is shared with glucocorti- headache, disorientation), the skin (pi- coids (p. 248) and ibuprofen, but not roxicam: photosensitization), or the with some other NSAIDs. blood (phenylbutazone: agranulocyto- Pharmacokinetics. NSAIDs are sis). well absorbed enterally. They are highly Outlook: Cyclooxygenase (COX) bound to plasma proteins (A). They are has two isozymes: COX-1, a constitutive eliminated at different speeds: diclofe- form present in stomach and kidney; nac (t1/2 = 1–2 h) and piroxicam (t1/2 ~ 50 and COX-2, which is induced in inflam- h); thus, dosing intervals and risk of ac- matory cells in response to appropriate cumulation will vary. The elimination of stimuli. Presently available NSAIDs in- salicylate, the rapidly formed metab- hibit both isozymes. The search for olite of ASA, is notable for its dose de- COX-2-selective agents (Celecoxib, Ro- pendence. Salicylate is effectively reab- fecoxib) is intensifying because, in theo- sorbed in the kidney, except at high uri- ry, these ought to be tolerated better. nary pH. A prerequisite for rapid renal elimination is a hepatic conjugation reaction (p. 38), mainly with glycine (→ salicyluric acid) and glucuronic acid. At high dosage, the conjugation may be-

Antipyretic Analgesics 201

High dose t =13-30h 1/2 50% Salicylic acid Low dose t1/2~3h t1/2 =1-2h

90% Acetyl- t1/2 =15min salicylic 99% acid 95% 99% Diclofenac

Ibuprofen Azapropazone

t1/2 ~2h

t1/2 =9-12h

Piroxicam Naproxen t1/2~50h 99% 99% t1/2~14h

Plasma protein binding A. Nonsteroidal antiinflammatory drugs (NSAIDs)

Arachidonic acid Leukotrienes NSAID-induced nephrotoxicity

Renal blood Prostaglandins Airway resistance flow

NSAID-induced Mucus production NSAID-induced gastropathy Acid secretion asthma Mucosal blood flow

B. NSAIDs: group-specific adverse effects

202 Antipyretic Analgesics

Thermoregulation and Antipyretics latory system, because the excessive secretion of thyroid hormones causes Body core temperature in the human is metabolic heat production to increase. about 37 °C and fluctuates within ± 1 °C In order to maintain body temperature during the 24 h cycle. In the resting at its physiological level, excess heat state, the metabolic activity of vital or- must be dissipated—the patients have a gans contributes 60% (liver 25%, brain hot skin and are sweating. 20%, heart 8%, kidneys 7%) to total heat The hypothalamic temperature production. The absolute contribution controller (B1) can be inactivated by to heat production from these organs neuroleptics (p. 236), without impair- changes little during physical activity, ment of other centers. Thus, it is pos- whereas muscle work, which contri- sible to lower a patient’s body tempera- butes approx. 25% at rest, can generate ture without activating counter-regula- up to 90% of heat production during tory mechanisms (thermogenic shiver- strenuous exercise. The set point of the ing). This can be exploited in the treat- body temperature is programmed in the ment of severe febrile states (hyperpy- hypothalamic thermoregulatory center. rexia) or in open-chest surgery with The actual value is adjusted to the set cardiac by-pass, during which blood point by means of various thermoregu- temperature is lowered to 10 °C by latory mechanisms. Blood vessels sup- means of a heart-lung machine. plying the skin penetrate the heat-insu- In higher doses, ethanol and bar- lating layer of subcutaneous adipose tis- biturates also depress the thermoregu- sue and therefore permit controlled latory center (B1), thereby permitting heat exchange with the environment as cooling of the body to the point of death, a function of vascular caliber and rate of given a sufficiently low ambient tem- blood flow. Cutaneous blood flow can perature (freezing to death in drunken- range from ~ 0 to 30% of cardiac output, ness). depending on requirements. Heat con- Pyrogens (e.g., bacterial matter) el- duction via the blood from interior sites evate—probably through mediation by of production to the body surface pro- prostaglandins (p. 196) and interleukin- vides a controllable mechanism for heat 1—the set point of the hypothalamic loss. temperature controller (B2). The body Heat dissipation can also be responds by restricting heat loss (cuta- achieved by increased production of neous vasoconstriction → chills) and by sweat, because evaporation of sweat on elevating heat production (shivering), in the skin surface consumes heat (evapo- order to adjust to the new set point (fe- rative heat loss). Shivering is a mecha- ver). Antipyretics such as acetamino- nism to generate heat. Autonomic neu- phen and ASA (p. 198) return the set ral regulation of cutaneous blood flow point to its normal level (B2) and thus and sweat production permit homeo- bring about a defervescence. static control of body temperature (A). The sympathetic system can either reduce heat loss via vasoconstriction or promote it by enhancing sweat production. When sweating is inhibited due to poisoning with anticholinergics (e.g., atropine), cutaneous blood flow increases. If insufficient heat is dissipated through this route, overheating occurs (hyperthermia). Thyroid hyperfunction poses a particular challenge to the thermoregu-

Antipyretic Analgesics 203

Sympathetic system Thermoregulatory center α-Adreno- Acetylcholine (set point) ceptors receptors

Hyper- thyroidism 35º 36º 39º 37º 38º Cutaneous Sweat Increased blood flow production heat production

Respiration

Heat production

Parasym- patholytics (Atropine) Heat conduction Heat radiation Evaporation of sweat

Heat Heat production loss Inhibition of sweat production Metabolic activity Hyperthermia

35º 39º 36º 37º 38º Body temperature

A. Thermoregulation

Neuroleptics Ethanol Pyrogen Antipyretics Barbiturates Preferential e.g., Heat 35º inhibition center paralysis 36º 39º 37º 38º

Controlled Uncontrolled Set point hypothermia heat loss elevation

“Artificial Hypothermia, hibernation” freezing to death Temperature rise

35º 35º 36º 39º Fever 36º 39º 37º 38º 37º 38º 1 2

B. Disturbances of thermoregulation

204 Local Anesthetics

Local Anesthetics circulation would lead to unwanted systemic reactions such as: Local anesthetics reversibly inhibit im- blockade of inhibitory CNS neurons, pulse generation and propagation in manifested by restlessness and sei- nerves. In sensory nerves, such an effect zures (countermeasure: injection of a is desired when painful procedures benzodiazepine, p. 226); general par- must be performed, e.g., surgical or den- alysis with respiratory arrest after tal operations. higher concentrations. Mechanism of action. Nerve im- blockade of cardiac impulse conduc- pulse conduction occurs in the form of tion, as evidenced by impaired AV an action potential, a sudden reversal in conduction or cardiac arrest (coun- resting transmembrane potential last- termeasure: injection of epineph- ing less than 1 ms. The change in poten- rine). Depression of excitatory pro- tial is triggered by an appropriate stim- cesses in the heart, while undesired ulus and involves a rapid influx of Na+ during local anesthesia, can be put to into the interior of the nerve axon (A). therapeutic use in cardiac arrhythmi- This inward flow proceeds through a as (p. 134). channel, a membrane pore protein, that, Forms of local anesthesia. Local upon being opened (activated), permits anesthetics are applied via different rapid movement of Na+ down a chemi- routes, including infiltration of the tis- + + cal gradient ([Na ]ext ~ 150 mM, [Na ]int sue (infiltration anesthesia) or injec- ~ 7 mM). Local anesthetics are capable tion next to the nerve branch carrying of inhibiting this rapid inward flux of fibers from the region to be anesthe- Na+; initiation and propagation of exci- tized (conduction anesthesia of the tation are therefore blocked (A). nerve, spinal anesthesia of segmental Most local anesthetics exist in part dorsal roots), or by application to the in the cationic amphiphilic form (cf. p. surface of the skin or mucosa (surface 208). This physicochemical property fa- anesthesia). In each case, the local an- vors incorporation into membrane esthetic drug is required to diffuse to interphases, boundary regions between the nerves concerned from a depot polar and apolar domains. These are placed in the tissue or on the skin. found in phospholipid membranes and High sensitivity of sensory nerves, also in ion-channel proteins. Some evi- low sensitivity of motor nerves. Im- dence suggests that Na+-channel block- pulse conduction in sensory nerves is ade results from binding of local anes- inhibited at a concentration lower than thetics to the channel protein. It appears that needed for motor fibers. This differ- certain that the site of action is reached ence may be due to the higher impulse from the cytosol, implying that the drug frequency and longer action potential must first penetrate the cell membrane duration in nociceptive, as opposed to (p. 206). motor, fibers. Local anesthetic activity is also Alternatively, it may be related to shown by uncharged substances, sug- the thickness of sensory and motor gesting a binding site in apolar regions nerves, as well as to the distance of the channel protein or the surround- between nodes of Ranvier. In saltatory ing lipid membrane. impulse conduction, only the nodal Mechanism-specific adverse ef- membrane is depolarized. Because defects. Since local anesthetics block Na+ polarization can still occur after block- influx not only in sensory nerves but al- ade of three or four nodal rings, the area so in other excitable tissues, they are exposed to a drug concentration suffi- applied locally and measures are taken cient to cause blockade must be larger (p. 206) to impede their distribution for motor fibers (p. 205B). into the body. Too rapid entry into the This relationship explains why sensory stimuli that are conducted via

Local Anesthetics 205

Local anesthetic Propagated Na+ impulse + Activated Na -entry Na+-channel

Na+ Peripheral nerve CNS Blocked Na+-channel

Conduction Restlessness, block convulsions, Na+ respiratory Blocked paralysis Na+-channel Heart

polar Cationic Uncharged amphiphilic local Impulse + Local conduction local anesthetic application cardiac arrest apolar anesthetic A. Effects of local anesthetics

Local anesthetic

Aα motor 0.8 – 1.4 mm

Aδ sensory 0.3 – 0.7 mm

C sensory and postganglionic

B. Inhibition of impulse conduction in different types of nerve fibers

206 Local Anesthetics myelinated Aδ-fibers are affected later drug depot in the connective tissue and and to a lesser degree than are stimuli the endoneural space. Injection of solu- conducted via unmyelinated C-fibers. tions of low concentration will fail to Since autonomic postganglionic fibers produce an effect; however, too high lack a myelin sheath, they are particu- concentrations must also be avoided be- larly susceptible to blockade by local cause of the danger of intoxication re- anesthetics. As a result, vasodilation en- sulting from too rapid systemic absorp- sues in the anesthetized region, because tion into the blood. sympathetically driven vasomotor tone To ensure a reasonably long-lasting decreases. This local vasodilation is un- local effect with minimal systemic ac- desirable (see below). tion, a vasoconstrictor (epinephrine, less frequently norepinephrine (p. 84) Diffusion and Effect or a vasopressin derivative; p. 164) is often co-administered in an attempt to During diffusion from the injection site confine the drug to its site of action. As (i.e., the interstitial space of connective blood flow is diminished, diffusion from tissue) to the axon of a sensory nerve, the endoneural space into the capillary the local anesthetic must traverse the blood decreases because the critical perineurium. The multilayered peri- concentration gradient between endoneurium is formed by connective tissue neural space and blood quickly becomes cells linked by zonulae occludentes small when inflow of drug-free blood is (p. 22) and therefore constitutes a reduced. Addition of a vasoconstrictor, closed lipophilic barrier. moreover, helps to create a relative Local anesthetics in clinical use are ischemia in the surgical field. Potential usually tertiary amines; at the pH of disadvantages of catecholamine-type interstitial fluid, these exist partly as the vasoconstrictors include reactive hy- neutral lipophilic base (symbolized by peremia following washout of the con- particles marked with two red dots) and strictor agent (p. 90) and cardiostimula- partly as the protonated form, i.e., am- tion when epinephrine enters the sys- phiphilic cation (symbolized by parti- temic circulation. In lieu of epinephrine, cles marked with one blue and one red the vasopressin analogue felypressin dot). The uncharged form can penetrate (p. 164, 165) can be used as an adjunc- the perineurium and enters the endo- tive vasoconstrictor (less pronounced neural space, where a fraction of the reactive hyperemia, no arrhythmogenic drug molecules regains a positive action, but danger of coronary constric- charge in keeping with the local pH. The tion). Vasoconstrictors must not be ap- same process is repeated when the drug plied in local anesthesia involving the penetrates the axonal membrane (axo- appendages (e.g., fingers, toes). lemma) into the axoplasm, from which it exerts its action on the sodium channel, and again when it diffuses out of the endoneural space through the unfenes- trated endothelium of capillaries into the blood. The concentration of local anesthetic at the site of action is, therefore, determined by the speed of penetration into the endoneurium and the speed of diffusion into the capillary blood. In order to ensure a sufficiently fast build-up of drug concentration at the site of action, there must be a correspondingly large concentration gradient between

Local Anesthetics 207

Interstitium

Axon 0.1 mm Cross section through peripheral Peri- Endoneural Capillary nerve (light microscope) neurium space wall

Inter- Axolemma stitium Axoplasm

Vasoconstriction e.g., with epinephrine

Axolemma

lipophilic Axoplasm amphiphilic

A. Disposition of local anesthetics in peripheral nerve tissue

208 Local Anesthetics

Characteristics of chemical struc- terases. This is advantageous because of ture. Local anesthetics possess a uni- the diminished danger of systemic in- form structure. Generally they are sec- toxication. On the other hand, the high ondary or tertiary amines. The nitrogen rate of bioinactivation and, therefore, is linked through an intermediary chain shortened duration of action is a disad- to a lipophilic moiety—most often an vantage. aromatic ring system. Procaine cannot be used as a surface The amine function means that lo- anesthetic because it is inactivated fast- cal anesthetics exist either as the neu- er than it can penetrate the dermis or tral amine or positively charged ammo- mucosa. nium cation, depending upon their dis- The amide type local anesthetic sociation constant (pKa value) and the lidocaine is broken down primarily in actual pH value. The pKa of typical local the liver by oxidative N-dealkylation. anesthetics lies between 7.5 and 9.0. This step can occur only to a restricted The pka indicates the pH value at which extent in prilocaine and articaine be- 50% of molecules carry a proton. In its cause both carry a substituent on the C- protonated form, the molecule possess- atom adjacent to the nitrogen group. Ar- es both a polar hydrophilic moiety (pro- ticaine possesses a carboxymethyl tonated nitrogen) and an apolar lipo- group on its thiophen ring. At this posi- philic moiety (ring system)—it is amphi- tion, ester cleavage can occur, resulting philic. in the formation of a polar -COO– group, Graphic images of the procaine loss of the amphiphilic character, and molecule reveal that the positive charge conversion to an inactive metabolite. does not have a punctate localization at Benzocaine (ethoform) is a member the N atom; rather it is distributed, as of the group of local anesthetics lacking shown by the potential on the van der a nitrogen that can be protonated at Waals’ surface. The non-protonated physiological pH. It is used exclusively form (right) possesses a negative partial as a surface anesthetic. charge in the region of the ester bond Other agents employed for surface and at the amino group at the aromatic anesthesia include the uncharged poli- ring and is neutral to slightly positively docanol and the catamphiphilic cocaine, charged (blue) elsewhere. In the proto- tetracaine, and lidocaine. nated form (left), the positive charge is prominent and concentrated at the amino group of the side chain (dark blue). Depending on the pKa, 50 to 5% of the drug may be present at physiological pH in the uncharged lipophilic form. This fraction is important because it represents the lipid membrane-permeable form of the local anesthetic (p. 26), which must take on its cationic amphiphilic form in order to exert its action (p. 204). Clinically used local anesthetics are either esters or amides. This structural element is unimportant for efficacy; even drugs containing a methylene bridge, such as chlorpromazine (p. 236) or imipramine (p. 230), would exert a local anesthetic effect with appropriate application. Ester-type local anesthetics are subject to inactivation by tissue es-

Local Anesthetics 209

Procaine Lidocaine Prilocaine

Articaine Mepivacaine Benzocaine

[H+] Proton concentration 100 0

80 20

60 40

40 60

20 80

0 100 67 8 910 pH value Active form Membrane- cationic- permeable amphiphilic form

Ability to penetrate Poor lipophilic Good barriers and cell membranes

A. Local anesthetics and pH value

210 Opioids

Opioid Analgesics—Morphine Type and ability to concentrate are impaired. There is a mood change, the direction Source of opioids. Morphine is an opi- of which depends on the initial condi- um alkaloid (p. 4). Besides morphine, tion. Aside from the relief associated opium contains alkaloids devoid of an- with the abatement of strong pain, algesic activity, e.g., the spasmolytic pa- there is a feeling of detachment (float- paverine, that are also classified as opi- ing sensation) and sense of well-being um alkaloids. All semisynthetic deriva- (euphoria), particularly after intrave- tives (hydromorphone) and fully syn- nous injection and, hence, rapid build- thetic derivatives (pentazocine, pethi- up of drug levels in the brain. The desire dine = meperidine, l-methadone, and to re-experience this state by renewed fentanyl) are collectively referred to as administration of drug may become opioids. The high analgesic effectiveness overpowering: development of psycho- of xenobiotic opioids derives from their logical dependence. The atttempt to quit affinity for receptors normally acted repeated use of the drug results in with- upon by endogenous opioids (enkepha- drawal signs of both a physical (cardio- lins, β-endorphin, dynorphins; A). Opi- vascular disturbances) and psychologi- oid receptors occur in nerve cells. They cal (restlessness, anxiety, depression) are found in various brain regions and nature. Opioids meet the criteria of “ad- the spinal medulla, as well as in intra- dictive” agents, namely, psychological mural nerve plexuses that regulate the and physiological dependence as well as motility of the alimentary and urogeni- a compulsion to increase the dose. For tal tracts. There are several types of opi- these reasons, prescription of opioids is oid receptors, designated µ, δ, κ, that subject to special rules (Controlled Sub- mediate the various opioid effects; all stances Act, USA; Narcotic Control Act, belong to the superfamily of G-protein- Canada; etc). Regulations specify, coupled receptors (p. 66). among other things, maximum dosage Endogenous opioids are peptides (permissible single dose, daily maximal that are cleaved from the precursors dose, maximal amount per single pre- proenkephalin, pro-opiomelanocortin, scription). Prescriptions need to be is- and prodynorphin. All contain the ami- sued on special forms the completion of no acid sequence of the pentapeptides which is rigorously monitored. Certain [Met]- or [Leu]-enkephalin (A). The ef- opioid analgesics, such as codeine and fects of the opioids can be abolished by tramadol, may be prescribed in the usu- antagonists (e.g., naloxone; A), with the al manner, because of their lesser po- exception of buprenorphine. tential for abuse and development of Mode of action of opioids. Most dependence. neurons react to opioids with hyperpolarization, reflecting an increase in K+ conductance. Ca2+ influx into nerve terminals during excitation is decreased, leading to a decreased release of excitatory transmitters and decreased synaptic activity (A). Depending on the cell population affected, this synaptic inhibition translates into a depressant or ex- citant effect (B). Effects of opioids (B). The analgesic effect results from actions at the level of the spinal cord (inhibition of nociceptive impulse transmission) and the brain (attenuation of impulse spread, inhibition of pain perception). Attention

Opioids 211

Proopiomelanocortin Proenkephalin Morphine

CH3 N

β-Lipotropin 6 HO O OH

Enkephalin β-Endorphin

Opioid receptors

K+-permeability Ca2+-influx CH2 CH CH2 N Excitability Release of transmitters HO

O HO O Naloxone

A. Action of endogenous and exogenous opioids at opioid receptors

Stimulant effects Mediated by Dampening effects opioid receptors Vagal centers, Pain sensation Chemoreceptors Analgesic of area postrema Oculomotor center Mood (Edinger's nucleus) alertness Antinociceptive system Analgesic Respiratory center Cough center Smooth musculature Antitussive stomach bowel Emetic center spastic constipation Antidiarrheal

Ureter bladder bladder sphincter

B. Effects of opioids

212 Opioids

Differences between opioids re- sphincter of Oddi contracts. Likewise, garding efficacy and potential for de- bladder function is affected; specifically pendence probably reflect differing af- bladder emptying is impaired due to in- finity and intrinsic activity profiles for creased tone of the vesicular sphincter. the individual receptor subtypes. A giv- Uses: The endogenous opioids en sustance does not necessarily behave (metenkephalin, leuenkephalin, β-en- as an agonist or antagonist at all recep- dorphin) cannot be used therapeutically tor subtypes, but may act as an agonist because, due to their peptide nature, at one subtype and as a partial ago- they are either rapidly degraded or ex- nist/antagonist or as a pure antagonist cluded from passage through the blood- (p. 214) at another. The abuse potential brain barrier, thus preventing access to is also determined by kinetic properties, their sites of action even after parenter- because development of dependence is al administration (A). favored by rapid build-up of brain con- Morphine can be given orally or centrations. With any of the high-effica- parenterally, as well as epidurally or cy opioid analgesics, overdosage is like- intrathecally in the spinal cord. The opi- ly to result in respiratory paralysis (im- oids heroin and fentanyl are highly lipo- paired sensitivity of medullary chemo- philic, allowing rapid entry into the receptors to CO2). The maximally pos- CNS. Because of its high potency, fenta- sible extent of respiratory depression is nyl is suitable for transdermal delivery thought to be less in partial agonist/ (A). antagonists at opioid receptors (pentaz- In opiate abuse, “smack” (“junk,” ocine, nalbuphine). “jazz,” “stuff,” “China white;” mostly The cough-suppressant (antitussive) heroin) is self administered by injection effect produced by inhibition of the (“mainlining”) so as to avoid first-pass cough reflex is independent of the ef- metabolism and to achieve a faster rise fects on nociception or respiration in brain concentration. Evidently, psy- (antitussives: codeine. noscapine). chic effects (“kick,” “buzz,” “rush”) are Stimulation of chemoreceptors in especially intense with this route of ad- the area postrema (p. 330) results in ministration. The user may also resort to vomiting, particularly after first-time ad- other more unusual routes: opium can ministration or in the ambulant patient. be smoked, and heroin can be taken as The emetic effect disappears with re- snuff (B). peated use because a direct inhibition of Metabolism (C). Like other opioids the emetic center then predominates, bearing a hydroxyl group, morphine is which overrides the stimulation of area conjugated to glucuronic acid and elim- postrema chemoreceptors. inated renally. Glucuronidation of the Opioids elicit pupillary narrowing OH-group at position 6, unlike that at (miosis) by stimulating the parasympa- position 3, does not affect affinity. The thetic portion (Edinger-Westphal nu- extent to which the 6-glucuronide con- cleus) of the oculomotor nucleus. tributes to the analgesic action remains Peripheral effects concern the mo- uncertain at present. At any rate, the ac- tility and tonus of gastrointestinal tivity of this polar metabolite needs to smooth muscle; segmentation is en- be taken into account in renal insuffi- hanced, but propulsive peristalsis is in- ciency (lower dosage or longer dosing hibited. The tonus of sphincter muscles interval). is raised markedly. In this fashion, morphine elicits the picture of spastic constipation. The antidiarrheic effect is used therapeutically (loperamide, p. 178). Gastric emptying is delayed (pyloric spasm) and drainage of bile and pancreatic juice is impeded, because the

Opioids 213

Met-Enkephalin Morphine Fentanyl CH2 CH2 N CH3 Tyr Gly Gly Phe Met N CH N 3 CH3 C CH 2 N O

HO O OH

O H3C C O OCCH3 O O Heroin

A. Bioavailability of opioids with different routes of administration

Opioid Oral Nasal application mucosa, e.g., Morphine heroin sniffing

Intravenous application "Mainlining" Morphine-6- glucuronide

Morphine-3- glucuronide

Bronchial mucosa e.g., opium smoking

B. Application and rate of disposition C. Metabolism of morphine

214 Opioids

Tolerance. With repeated adminis- Opioids in chronic pain: In the tration of opioids, their CNS effects can management of chronic pain, opioid lose intensity (increased tolerance). In plasma concentration must be kept con- the course of therapy, progressively tinuously in the effective range, because larger doses are needed to achieve the a fall below the critical level would same degree of pain relief. Development cause the patient to experience pain. of tolerance does not involve the pe- Fear of this situation would prompt in- ripheral effects, so that persistent con- take of higher doses than necessary. stipation during prolonged use may Strictly speaking, the aim is a prophy- force a discontinuation of analgesic lactic analgesia. therapy however urgently needed. Like other opioids (hydromor- Therefore, dietetic and pharmacological phone, meperidine, pentazocine, co- measures should be taken prophylacti- deine), morphine is rapidly eliminated, cally to prevent constipation, whenever limiting its duration of action to approx. prolonged administration of opioid 4 h. To maintain a steady analgesic ef- drugs is indicated. fect, these drugs need to be given every Morphine antagonists and partial 4 h. Frequent dosing, including at night- agonists. The effects of opioids can be time, is a major inconvenience for abolished by the antagonists naloxone chronic pain patients. Raising the indi- or naltrexone (A), irrespective of the re- vidual dose would permit the dosing ceptor type involved. Given by itself, interval to be lengthened; however, it neither has any effect in normal sub- would also lead to transient peaks jects; however, in opioid-dependent above the therapeutically required plas- subjects, both precipitate acute with- ma level with the attending risk of un- drawal signs. Because of its rapid pre- wanted toxic effects and tolerance de- systemic elimination, naloxone is only velopment. Preferred alternatives in- suitable for parenteral use. Naltrexone clude the use of controlled-release is metabolically more stable and is giv- preparations of morphine, a fentanyl en orally. Naloxone is effective as anti- adhesive patch, or a longer-acting opi- dote in the treatment of opioid-induced oid such as l-methadone. The kinetic respiratory paralysis. Since it is more properties of the latter, however, neces- rapidly eliminated than most opioids, sitate adjustment of dosage in the repeated doses may be needed. Naltrex- course of treatment, because low dos- one may be used as an adjunct in with- age during the first days of treatment drawal therapy. fails to provide pain relief, whereas high Buprenorphine behaves like a par- dosage of the drug, if continued, will tial agonist/antagonist at µ-receptors. lead to accumulation into a toxic con- Pentazocine is an antagonist at µ-recep- centration range (C). tors and an agonist at κ-receptors (A). When the oral route is unavailable Both are classified as “low-ceiling” opi- opioids may be administered by contin- oids (B), because neither is capable of uous infusion (pump) and when appro- eliciting the maximal analgesic effect priate under control by the patient – ad- obtained with morphine or meperidine. vantage: constant therapeutic plasma The antagonist action of partial agonists level; disadvantage: indwelling cathe- may result in an initial decrease in effect ter. When constipation becomes intol- of a full agonist during changeover to erable morphin can be applied near the the latter. Intoxication with buprenor- spinal cord permitting strong analgesic phine cannot be reversed with antago- effect at much lower total dosage. nists, because the drug dissociates only very slowly from the opioid receptors and competitive occupancy of the receptors cannot be achieved as fast as the clinical situation demands.

Opioids 215

CH3 µ N κ Morphine

CH3 HOO OH µ N κ CH3 Fentanyl Morphine Meperidine CH2 C O CH CH 2 2 O N µ Meperidine κ CH N 3 Fentanyl C CH H3C 2 C CH O H3C µ CH2 N κ Buprenorphine Analgesic effect Pentazocine CH3 CH CH 3 2 µ HO N κ Pentazocine H2C CH HO Nalbuphine CH2 N O HO OH µ HO κ 0,1 1 10 100 Dose (mg) Naloxone HO O O A. Opioids: µ- and κ-receptor ligands B. Opioids: dose-response relationship

Intoxication Morphine t1/2 = 2 h at low dose every 4 h Analgesia Disadvantage: frequent dosing for sustained analgesia

Morphine in "high dose" every 12 h Disadvantages: transient hazard of intoxication, transient loss of analgesia

Drug concentration in plasma High dose

Low Dose 12 3 4 Methadone t1/2 = 55 h Disadvantage: dose difficult to titrate 1234Days C. Morphine and methadone dosage regimens

216 General Anesthetic Drugs

General Anesthesia and General sic, an injectable anesthetic, a short-act- Anesthetic Drugs ing muscle relaxant, and a low dose of a neuroleptic. General anesthesia is a state of drug-in- In regional anesthesia (spinal an- duced reversible inhibition of central esthesia) with a local anesthetic (p. nervous function, during which surgical 204), nociception is eliminated, while procedures can be carried out in the ab- consciousness is preserved. This proce- sence of consciousness, responsiveness dure, therefore, does not fall under the to pain, defensive or involuntary move- definition of general anesthesia. ments, and significant autonomic reflex According to their mode of applica- responses (A). tion, general anesthetics in the restrict- The required level of anesthesia de- ed sense are divided into inhalational pends on the intensity of the pain-pro- (gaseous, volatile) and injectable agents. ducing stimuli, i.e., the degree of noci- Inhalational anesthetics are admin- ceptive stimulation. The skilful anesthe- istered in and, for the most part, elimi- tist, therefore, dynamically adapts the nated via respired air. They serve to plane of anesthesia to the demands of maintain anesthesia. Pertinent sub- the surgical situation. Originally, anes- stances are considered on p. 218. thetization was achieved with a single Injectable anesthetics (p. 220) are anesthetic agent (e.g., diethylether— frequently employed for induction. first successfully demonstrated in 1846 Intravenous injection and rapid onset of by W. T. G. Morton, Boston). To suppress action are clearly more agreeable to the defensive reflexes, such a “mono-anes- patient than is breathing a stupefying thesia” necessitates a dosage in excess gas. The effect of most injectable anes- of that needed to cause unconscious- thetics is limited to a few minutes. This ness, thereby increasing the risk of par- allows brief procedures to be carried out alyzing vital functions, such as cardio- or to prepare the patient for inhalation- vascular homeostasis (B). Modern anes- al anesthesia (intubation). Administra- thesia employs a combination of differ- tion of the volatile anesthetic must then ent drugs to achieve the goals of surgical be titrated in such a manner as to coun- anesthesia (balanced anesthesia). This terbalance the waning effect of the in- approach reduces the hazards of anes- jectable agent. thesia. In C are listed examples of drugs Increasing use is now being made that are used concurrently or sequen- of injectable, instead of inhalational, an- tially as anesthesia adjuncts. In the case esthetics during prolonged combined of the inhalational anesthetics, the anesthesia (total intravenous anesthe- choice of adjuncts relates to the specific sia—TIVA). property to be exploited (see below). “TIVA” has become feasible thanks Muscle relaxants, opioid analgesics such to the introduction of agents with a suit- as fentanyl, and the parasympatholytic ably short duration of action, including atropine are discussed elsewhere in the injectable anesthetics propofol and more detail. etomidate, the analgesics alfentanil und Neuroleptanalgesia can be consid- remifentanil, and the muscle relaxant ered a special form of combination an- mivacurium. These drugs are eliminated esthesia, in which the short-acting opi- within minutes after being adminster- oid analgesics fentanyl, alfentanil, remi- ed, irrespective of the duration of fentanil is combined with the strongly anesthesia. sedating and affect-blunting neuroleptic droperidol. This procedure is used in high-risk patients (e.g., advanced age, liver damage). Neuroleptanesthesia refers to the combined use of a short-acting analge-

General Anesthetic Drugs 217

Muscle relaxation Loss of consciousness Autonomic stabilization

Motor Pain and Autonomic reflexes suffering reflexes

Nociception

Analgesia

Pain stimulus A. Goals of surgical anesthesia

Mono-anesthesia e.g., diethylether For unconsciousness: Reduced pain e.g., halothane sensitivity or propofol For For Loss of consciousness muscle autonomic relaxation stabilization e.g., pan- e.g., Muscle relaxation curonium atropine For analgesia Paralysis of e.g., N2O vital centers or fentanyl

B. Traditional monoanesthesia vs. modern balanced anesthesia

Pre- medication Induction Maintenance Recovery

Pentazocineautonom Atropineanalgesia M m SuccinycholineHalothane N Pancuronium Neostigm Pentazocine analgesia neurom idazolam uscle relaxation; intubation 2 O

ic stabilization uscular block ine reversal of unconsciousness Diazepam

anxiolysis Muscle relaxation

Analgesia

Unconsciousness

C. Regimen for balanced anesthesia

218 General Anesthetic Drugs

Inhalational Anesthetics ciably and is cleared entirely by exhala- tion (B). The mechanism of action of inhala- Halothane (boiling point [BP] tional anesthetics is unknown. The di- 50 °C), enflurane (BP 56 °C), isoflurane versity of chemical structures (inert gas (BP 48 °C), and the obsolete methoxyflu- xenon; hydrocarbons; halogenated hy- rane (BP 104 °C) have to be vaporized by drocarbons) possessing anesthetic ac- special devices. Part of the administered tivity appears to rule out involvement of halothane is converted into hepatotoxic specific receptors. According to one hy- metabolites (B). Liver damage may re- pothesis, uptake into the hydrophobic sult from halothane anesthesia. With a interior of the plasmalemma of neurons single exposure, the risk involved is un- results in inhibition of electrical excit- predictable; however, there is a correla- ability and impulse propagation in the tion with the frequency of exposure and brain. This concept would explain the the shortness of the interval between correlation between anesthetic potency successive exposures. and lipophilicity of anesthetic drugs (A). Up to 70% of inhaled methoxyflu- However, an interaction with lipophilic rane is converted to metabolites that domains of membrane proteins is also may cause nephrotoxicity, a problem conceivable. Anesthetic potency can be that has led to the withdrawal of the expressed in terms of the minimal al- drug. veolar concentration (MAC) at which Degradation products of enflurane 50% of patients remain immobile fol- or isoflurane (fraction biotransformed lowing a defined painful stimulus (skin <2%) are of no concern. incision). Whereas the poorly lipophilic Halothane exerts a pronounced hy- N2O must be inhaled in high concentra- potensive effect, to which a negative in- tions (>70% of inspired air has to be re- otropic effect contributes. Enflurane placed), much smaller concentrations and isoflurane cause less circulatory de- (<5%) are required in the case of the pression. Halothane sensitizes the myo- more lipophilic halothane. cardium to catecholamines (caution: se- The rates of onset and cessation of rious tachyarrhythmias or ventricular action vary widely between different in- fibrillation may accompany use of cate- halational anesthetics and also depend cholamines as antihypotensives or toco- on the degree of lipophilicity. In the case lytics). This effect is much less pro- of N2O, there is rapid elimination from nounced with enflurane and isoflurane. the body when the patient is ventilated Unlike halothane, enflurane and isoflu- with normal air. Due to the high partial rane have a muscle-relaxant effect that pressure in blood, the driving force for is additive with that of nondepolarizing transfer of the drug into expired air is neuromuscular blockers. large and, since tissue uptake is minor, Desflurane is a close structural rela- the body can be quickly cleared of N2O. tive of isoflurane, but has low lipophilic- In contrast, with halothane, partial pres- ity that permits rapid induction and re- sure in blood is low and tissue uptake is covery as well as good control of anes- high, resulting in a much slower elimi- thetic depth. nation. Given alone, N2O (nitrous oxide, “laughing gas”) is incapable of producing anesthesia of sufficient depth for surgery. It has good analgesic efficacy that can be exploited when it is used in conjunction with other anesthetics. As a gas, N2O can be administered directly. Although it irreversibly oxidizes vitamin B12, N2O is not metabolized appre-

General Anesthetic Drugs 219

Anesthetic potency

Low potency Halothane high partial pressure needed relatively little binding to tissue Chloroform Enflurane Diethylether Nitrous oxide Cyclopropane N2O Xenon

Lipophilicity

N2O Partial pressure of anesthetic Tissue Blood Alveolar air

Binding

Partial pressure in tissue Halothane Termination of intake

High potency low partial pressure sufficient relatively high binding in tissue Time

A. Lipophilicity, potency and elimination of N2O and halothane

Metabolites Metabolites

N2O Nitrous oxide Methoxy- H5C2OC2H5 Ether Halothane flurane

B. Elimination routes of different volatile anesthetics

220 General Anesthetic Drugs

Injectable Anesthetics tressing dream-like experiences. These can be counteracted by administration Substances from different chemical of a benzodiazepine (e.g., midazolam). classes suspend consciousness when The CNS effects of ketamine arise, in given intravenously and can be used as part, from an interference with excita- injectable anesthetics (B). Unlike inha- tory glutamatergic transmission via li- lational agents, most of these drugs af- gand-gated cation channels of the fect consciousness only and are devoid NMDA subtype, at which ketamine acts of analgesic activity (exception: keta- as a channel blocker. The non-natural mine). The effect cannot be ascribed to excitatory amino acid N-methyl-D- nonselective binding to neuronal cell aspartate is a selective agonist at this re- membranes, although this may hold for ceptor. Release of catecholamines with propofol. a resultant increase in heart rate and Most injectable anesthetics are blood pressure is another unrelated ac- characterized by a short duration of action of ketamine. tion. The rapid cessation of action is Propofol has a remarkably simple largely due to redistribution: after structure. Its effect has a rapid onset and intravenous injection, brain concentra- decays quickly, being experienced by tion climbs rapidly to anesthetic levels the patient as fairly pleasant. The inten- because of the high cerebral blood flow; sity of the effect can be well controlled the drug then distributes evenly in the during prolonged administration. body, i.e., concentration rises in the pe- Etomidate hardly affects the auto- riphery, but falls in the brain—redistri- nomic nervous system. Since it inhibits bution and cessation of anesthesia (A). cortisol synthesis, it can be used in the Thus, the effect subsides before the drug treatment of adrenocortical overactivity has left the body. A second injection of (Cushing’s disease). the same dose, given immediately after Midazolam is a rapidly metabolized recovery from the preceding dose, can benzodiazepine (p. 228) that is used for therefore produce a more intense and induction of anesthesia. The longer-act- longer effect. Usually, a single injection ing lorazepam is preferred as adjunct is administered. However, etomidate anesthetic in prolonged cardiac surgery and propofol may be given by infusion with cardiopulmonary bypass; its am- over a longer time period to maintain nesiogenic effect is pronounced. unconsciousness. Thiopental and methohexital belong to the barbiturates which, depending on dose, produce sedation, sleepiness, or anesthesia. Barbiturates lower the pain threshold and thereby facilitate defensive reflex movements; they also depress the respiratory center. Barbitu- rates are frequently used for induction of anesthesia. Ketamine has analgesic activity that persists beyond the period of unconsciousness up to 1 h after injection. On regaining consciousness, the patient may experience a disconnection between outside reality and inner mental state (dissociative anesthesia). Fre- quently there is memory loss for the duration of the recovery period; however, adults in particular complain about dis-

General Anesthetic Drugs 221

CNS: High concentration relatively in tissue high blood flow Relatively large amount of drug

i.v. injection

Periphery: relatively low blood Relatively small flow amount of drug

ml blood mg drug min x g tissue min x g tissue

Low concentration in tissue Initial situation Preferential accumulation of drug in brain

Decrease in tissue concentration

Further increase in tissue concentration

Redistribution Steady-state of distribution A. Termination of drug effect by redistribution

Sodium thiopental Ketamine Etomidate

Sodium methohexital Propofol Midazolam

B. Intravenous anesthetics

222 Hypnotics

Soporifics, Hypnotics for a hypnotic, probably promoting hypnotic drug dependence. During sleep, the brain generates a pat- Depending on their blood levels, terned rhythmic activity that can be both benzodiazepines and barbiturates monitored by means of the electroen- produce calming and sedative effects, cephalogram (EEG). Internal sleep cy- the former group also being anxiolytic. cles recur 4 to 5 times per night, each At higher dosage, both groups promote cycle being interrupted by a Rapid Eye the onset of sleep or induce it (C). Movement (REM) sleep phase (A). The Unlike barbiturates, benzodiaze- REM stage is characterized by EEG activ- pine derivatives administered orally ity similar to that seen in the waking lack a general anesthetic action; cere- state, rapid eye movements, vivid bral activity is not globally inhibited dreams, and occasional twitches of indi- (respiratory paralysis is virtually impos- vidual muscle groups against a back- sible) and autonomic functions, such as ground of generalized atonia of skeletal blood pressure, heart rate, or body tem- musculature. Normally, the REM stage is perature, are unimpaired. Thus, benzo- entered only after a preceding non-REM diazepines possess a therapeutic margin cycle. Frequent interruption of sleep considerably wider than that of barbitu- will, therefore, decrease the REM por- rates. tion. Shortening of REM sleep (normally Zolpidem (an imidazopyridine) approx. 25% of total sleep duration) re- and zopiclone (a cyclopyrrolone) are sults in increased irritability and rest- hypnotics that, despite their different lessness during the daytime. With un- chemical structure, possess agonist ac- disturbed night rest, REM deficits are tivity at the benzodiazepine receptor (p. compensated by increased REM sleep 226). on subsequent nights (B). Due to their narrower margin of Hypnotics fall into different catego- safety (risk of misuse for suicide) and ries, including the benzodiazepines their potential to produce physical de- (e.g., triazolam, temazepam, clotiaze- pendence, barbiturates are no longer or pam, nitrazepam), barbiturates (e.g., only rarely used as hypnotics. Depen- hexobarbital, pentobarbital), chloral hy- dence on them has all the characteris- drate, and H1-antihistamines with seda- tics of an addiction (p. 210). tive activity (p. 114). Benzodiazepines Because of rapidly developing tol- act at specific receptors (p. 226). The erance, choral hydrate is suitable only site and mechanism of action of barbitu- for short-term use. rates, antihistamines, and chloral hy- Antihistamines are popular as drate are incompletely understood. nonprescription (over-the-counter) All hypnotics shorten the time sleep remedies (e.g., diphenhydramine, spent in the REM stages (B). With re- doxylamine, p. 114), in which case their peated ingestion of a hypnotic on sever- sedative side effect is used as the princi- al successive days, the proportion of pal effect. time spent in REM vs. non-REM sleep returns to normal despite continued drug intake. Withdrawal of the hypnotic drug results in REM rebound, which ta- pers off only over many days (B). Since REM stages are associated with vivid dreaming, sleep with excessively long REM episodes is experienced as unre- freshing. Thus, the attempt to discon- tinue use of hypnotics may result in the impression that refreshing sleep calls

Hypnotics 223

Waking state

Sleep REM stage I Sleep stage II Sleep stage III Sleep stage IV REM-sleep= Rapid Eye Movement sleep NREM = No Rapid Eye Movement sleep

A. Succession of different sleep phases during night rest

Ratio REM

NREM

5 1015202530 Nights Nights Nights after without with withdrawal hypnotic hypnotic of hypnotic

B. Effect of hypnotics on proportion of REM/NREM

Barbiturates: Effect Paralyzing

Pentobarbital Anesthetizing Pentobarbital

Benzo- Hypnogenic diazepines: Hypnagogic

Calming, anxiolytic

Triazolam Triazolam Concentration in blood

C. Concentration dependence of barbiturate and benzodiazepine effects

224 Hypnotics

Sleep–Wake Cycle and Hypnotics 6–8 h of sleep, because in the morning excitatory activity exceeds the sum of The physiological mechanisms regulat- physiological and pharmacological inhi- ing the sleep-wake rhythm are not com- bition (B3). The drug effect may, howev- pletely known. There is evidence that er, become unmasked at daytime when histaminergic, cholinergic, glutamater- other sedating substances (e.g., ethanol) gic, and adrenergic neurons are more are ingested and the patient shows an active during waking than during the unusually pronounced response due to NREM sleep stage. Via their ascending a synergistic interaction (impaired abil- thalamopetal projections, these neu- ity to concentrate or react). rons excite thalamocortical pathways As the margin between excitatory and inhibit GABA-ergic neurons. During and inhibitory activity decreases with sleep, input from the brain stem de- age, there is an increasing tendency to- creases, giving rise to diminished tha- wards shortened daytime sleep periods lamocortical activity and disinhibition and more frequent interruption of noc- of the GABA neurons (A). The shift in turnal sleep (C). balance between excitatory (red) and Use of a hypnotic drug should not inhibitory (green) neuron groups be extended beyond 4 wk, because tol- underlies a circadian change in sleep erance may develop. The risk of a re- propensity, causing it to remain low in bound decrease in sleep propensity af- the morning, to increase towards early ter drug withdrawal may be avoided by afternoon (midday siesta), then to de- tapering off the dose over 2 to 3 wk. cline again, and finally to reach its peak With any hypnotic, the risk of sui- before midnight (B1). cidal overdosage cannot be ignored. Treatment of sleep disturbances. Since benzodiazepine intoxication may Pharmacotherapeutic measures are in- become life-threatening only when dicated only when causal therapy has other central nervous depressants (etha- failed. Causes of insomnia include emo- nol) are taken simultaneously and can, tional problems (grief, anxiety, “stress”), moreover, be treated with specific ben- physical complaints (cough, pain), or zodiazepine antagonists, the benzo- the ingestion of stimulant substances diazepines should be given preference (caffeine-containing beverages, sympa- as sleep remedies over the all but obso- thomimetics, theophylline, or certain lete barbiturates. antidepressants). As illustrated for emotional stress (B2), these factors cause an imbalance in favor of excitatory influences. As a result, the interval between going to bed and falling asleep becomes longer, total sleep duration decreases, and sleep may be interrupted by several waking periods. Depending on the type of insomnia, benzodiazepines (p. 226) with short or intermediate duration of action are indicated, e.g., triazolam and brotizolam (t1/2 ~ 4–6 h); lormetazepam or temazepam (t1/2 ~ 10–15 h). These drugs shorten the latency of falling asleep, lengthen total sleep duration, and reduce the frequency of nocturnal awakenings. They act by augmenting inhibitory activity. Even with the longer-acting benzodiazepines, the patient awakes after about

Hypnotics 225

Neurons with transmitters:

Histamine Acetylcholine Glutamate Norepinephrine GABA Waking state NREM-sleep

A. Transmitters: waking state and sleep

Emotional stress 2

Hypnotic 3

B. Wake-sleep pattern, stress, and hypnotic drug action

Hypnotic 2 C. Changes of the arousal reaction in the elderly

226 Psychopharmacologicals

Benzodiazepines tive driving skills and other tasks requiring precise sensorimotor coordina- Benzodiazepines modify affective re- tion will be impaired. sponses to sensory perceptions; specifi- Triazolam (t1/2 of elimination cally, they render a subject indifferent ~1.5–5.5 h) is especially likely to impair towards anxiogenic stimuli, i.e., anxio- memory (anterograde amnesia) and to lytic action. Furthermore, benzodiaze- cause rebound anxiety or insomnia and pines exert sedating, anticonvulsant, daytime confusion. The severity of these and muscle-relaxant (myotonolytic, p. and other adverse reactions (e.g., rage, 182) effects. All these actions result violent hostility, hallucinations), and from augmenting the activity of inhibi- their increased frequency in the elderly, tory neurons and are mediated by spe- has led to curtailed or suspended use of cific benzodiazepine receptors that triazolam in some countries (UK). form an integral part of the GABAA re- Although benzodiazepines are well ceptor-chloride channel complex. The tolerated, the possibility of personality inhibitory transmitter GABA acts to changes (nonchalance, paradoxical ex- open the membrane chloride channels. citement) and the risk of physical de- Increased chloride conductance of the pendence with chronic use must not be neuronal membrane effectively short- overlooked. Conceivably, benzodiaze- circuits responses to depolarizing in- pine dependence results from a kind of puts. Benzodiazepine receptor agonists habituation, the functional counterparts increase the affinity of GABA to its re- of which become manifest during absti- ceptor. At a given concentration of nence as restlessness and anxiety; even GABA, binding to the receptors will, seizures may occur. These symptoms therefore, be increased, resulting in an reinforce chronic ingestion of benzo- augmented response. Excitability of the diazepines. neurons is diminished. Benzodiazepine antagonists, such Therapeutic indications for benzo- as flumazenil, possess affinity for ben- diazepines include anxiety states asso- zodiazepine receptors, but they lack in- ciated with neurotic, phobic, and de- trinsic activity. Flumazenil is an effec- pressive disorders, or myocardial in- tive antidote in the treatment of ben- farction (decrease in cardiac stimula- zodiazepine overdosage or can be used tion due to anxiety); insomnia; prean- postoperatively to arouse patients se- esthetic (preoperative) medication; dated with a benzodiazepine. epileptic seizures; and hypertonia of Whereas benzodiazepines possess- skeletal musculature (spasticity, rigid- ing agonist activity indirectly augment ity). chloride permeability, inverse agonists Since GABA-ergic synapses are con- exert an opposite action. These sub- fined to neural tissues, specific inhibi- stances give rise to pronounced rest- tion of central nervous functions can be lessness, excitement, anxiety, and con- achieved; for instance, there is little vulsive seizures. There is, as yet, no change in blood pressure, heart rate, therapeutic indication for their use. and body temperature. The therapeutic index of benzodiazepines, calculated with reference to the toxic dose producing respiratory depression, is greater than 100 and thus exceeds that of barbiturates and other sedative-hypnotics by more than tenfold. Benzodiazepine intoxication can be treated with a specific antidote (see below). Since benzodiazepines depress responsivity to external stimuli, automo-

Psychopharmacologicals 227

R2 O N diaz Benzo R3 epine R1 N 4 R1 = Cl R 2 R = CH3 R3 = R4 = H Diazepam

GABA= Inhibition of γ-amino- excitation butryc acid Anxiolysis

Hyper- Benzodiazepine polari- receptor zation

Chloride GABA Cl- ionophore

GABA-receptor plus anticonvulsant effect, sedation, muscle relaxation GABA-gated Cl--channel

Benzodiazepines GABA-ergic neuron GABA-ergic

Normal Enhanced Unopposed excitation GABA-ergic inhibition GABA-ergic inhibition

A. Action of benzodiazepines

228 Psychopharmacologicals

Pharmacokinetics of Benzodiazepines because they permit maintenance of steady plasma levels with single daily All benzodiazepines exert their actions dosing. Midazolam enjoys use by the i.v. at specific receptors (p. 226). The choice route in preanesthetic medication and between different agents is dictated by anesthetic combination regimens. their speed, intensity, and duration of action. These, in turn, reflect physico- Benzodiazepine Dependence chemical and pharmacokinetic properties. Individual benzodiazepines remain Prolonged regular use of benzodiaze- in the body for very different lengths of pines can lead to physical dependence. time and are chiefly eliminated through With the long-acting substances mar- biotransformation. Inactivation may en- keted initially, this problem was less ob- tail a single chemical reaction or several vious in comparison with other depen- steps (e.g., diazepam) before an inactive dence-producing drugs because of the metabolite suitable for renal elimina- delayed appearance of withdrawal tion is formed. Since the intermediary symptoms. The severity of the absti- products may, in part, be pharmacologi- nence syndrome is inversely related to cally active and, in part, be excreted the elimination t1/2, ranging from mild more slowly than the parent substance, to moderate (restlessness, irritability, metabolites will accumulate with con- sensitivity to sound and light, insomnia, tinued regular dosing and contribute and tremulousness) to dramatic (de- significantly to the final effect. pression, panic, delirium, grand mal sei- Biotransformation begins either at zures). Some of these symptoms pose substituents on the diazepine ring (diaz- diagnostic difficulties, being indistin- epam: N-dealkylation at position 1; guishable from the ones originally treat- midazolam: hydroxylation of the methyl ed. Administration of a benzodiazepine group on the imidazole ring) or at the antagonist would abruptly provoke ab- diazepine ring itself. Hydroxylated mid- stinence signs. There are indications azolam is quickly eliminated following that substances with intermediate elim- glucuronidation (t1/2 ~ 2 h). N-de- ination half-lives are most frequently methyldiazepam (nordazepam) is bio- abused (violet area in B). logically active and undergoes hydroxylation at position 3 on the diazepine ring. The hydroxylated product (oxazepam) again is pharmacologically active. By virtue of their long half-lives, diazepam (t1/2 ~ 32 h) and, still more so, its metabolite, nordazepam (t1/2 50–90 h), are eliminated slowly and accumulate during repeated intake. Oxazepam undergoes conjugation to glucuronic acid via its hydroxyl group (t1/2 = 8 h) and renal excretion (A). The range of elimination half-lives for different benzodiazepines or their active metabolites is represented by the shaded areas (B). Substances with a short half-life that are not converted to active metabolites can be used for induction or maintenance of sleep (light blue area in B). Substances with a long half-life are preferable for long-term anxiolytic treatment (light green area)

Psychopharmacologicals 229

Midazolam Diazepam

as glucuronide

Inactive Nordazepam

Oxazepam Active metabolites

A. Biotransformation of benzodiazepines

Hypnagogic Abuse Triazolam effect liability Brotizolam Oxazepam Lormetazepam Bromazepam Flunitrazepam Lorazepam Camazepam Nitrazepam Clonazepam Diazepam Temazepam Anxiolytic effect Prazepam 0203040506010 >60 h Plasma elimination half-life Applied drug Active metabolite

B. Rate of elimination of benzodiazepines

230 Psychopharmacologicals

Therapy of Manic-Depressive Illness longest and most extensive therapeutic use; however, in the past decade, they Manic-depressive illness connotes a have been increasingly superseded by psychotic disorder of affect that occurs the serotonin-selective reuptake inhibi- episodically without external cause. In tors (SSRI; prototype: fluoxetine). endogenous depression (melancholia), The central seven-membered ring mood is persistently low. Mania refers of the TCAs imposes a 120° angle to the opposite condition (p. 234). Pa- between the two flanking aromatic tients may oscillate between these two rings, in contradistinction to the flat extremes with interludes of normal ring system present in phenothiazine mood. Depending on the type of disor- type neuroleptics (p. 237). The side der, mood swings may alternate chain nitrogen is predominantly proto- between the two directions (bipolar de- nated at physiological pH. pression, cyclothymia) or occur in only The TCAs have affinity for both re- one direction (unipolar depression). ceptors and transporters of monoamine transmitters and behave as antagonists I. Endogenous Depression in both respects. Thus, the neuronal re- uptake of norepinephrine (p. 82) and se- In this condition, the patient experienc- rotonin (p. 116) is inhibited, with a re- es profound misery (beyond the sultant increase in activity. Muscarinic observer’s empathy) and feelings of se- acetylcholine receptors, α-adrenocep- vere guilt because of imaginary miscon- tors, and certain 5-HT and hista- duct. The drive to act or move is inhibit- mine(H1) receptors are blocked. Inter- ed. In addition, there are disturbances ference with the dopamine system is mostly of a somatic nature (insomnia, relatively minor. loss of appetite, constipation, palpita- How interference with these trans- tions, loss of libido, impotence, etc.). Al- mitter/modulator substances translates though the patient may have suicidal into an antidepressant effect is still hy- thoughts, psychomotor retardation pre- pothetical. The clinical effect emerges vents suicidal impulses from being car- only after prolonged intake, i.e., 2–3 wk, ried out. In A, endogenous depression is as evidenced by an elevation of mood illustrated by the layers of somber col- and drive. However, the alteration in ors; psychomotor drive, symbolized by monoamine metabolism occurs as soon a sine oscillation, is strongly reduced. as therapy is started. Conceivably, adap- Therapeutic agents fall into two tive processes (such as downregulation groups: of cortical serotonin and β-adrenocep- Thymoleptics, possessing a pro- tors) are ultimately responsible. In nounced ability to re-elevate de- healthy subjects, the TCAs do not im- pressed mood e.g., the tricyclic anti- prove mood (no euphoria). depressants; Apart from the antidepressant ef- Thymeretics, having a predominant fect, acute effects occur that are evident activating effect on psychomotor also in healthy individuals. These vary drive, e g., monoamine oxidase inhib- in degree among individual substances itors. and thus provide a rationale for differ- It would be wrong to administer entiated clinical use (p. 233), based drive-enhancing drugs, such as amphet- upon the divergent patterns of interfer- amines, to a patient with endogenous ence with amine transmitters/modula- depression. Because this therapy fails to tors. Amitriptyline exerts anxiolytic, elevate mood but removes psychomo- sedative and psychomotor dampening tor inhibition (A), the danger of suicide effects. These are useful in depressive increases. patients who are anxious and agitated. Tricyclic antidepressants (TCA; In contrast, desipramine produces prototype: imipramine) have had the psychomotor activation. Imipramine

Psychopharmacologicals 231

Imipramine Endogenous depression Week 3 Week

Deficient drive

5HT or Ach NA NA Week 5 Week

M, H1, α1 Inhibition of Blockade of re-uptake receptors Effects on synaptic transmission by inhibition of amine re-uptake and by receptor antagonism Week 7 Week Week 9 Week Amphetamine Immediate Normal mood

Normal drive

A. Effect of antidepressants

232 Psychopharmacologicals

occupies an intermediate position. It by blocking presynaptic α2-receptors, should be noted that, in the organism, rather than reuptake. Moreover, it has biotransformation of imipramine leads less pronounced atropine-like activity. to desipramine (N-desmethylimipra- Fluoxetine, along with sertraline, mine). Likewise, the desmethyl deriva- fluvoxamine, and paroxetine, belongs to tive of amitriptyline (nortriptyline) is the more recently developed group of less dampening. SSRI. The clinical efficacy of SSRI is con- In nondepressive patients whose sidered comparable to that of estab- complaints are of predominantly psy- lished antidepressants. Added advan- chogenic origin, the anxiolytic-sedative tages include: absence of cardiotoxicity, effect may be useful in efforts to bring fewer autonomic nervous side effects, about a temporary “psychosomatic un- and relative safety with overdosage. coupling.” In this connection, clinical Fluoxetine causes loss of appetite and use as “co-analgesics” (p. 194) may be weight reduction. Its main adverse ef- noted. fects include: overarousal, insomnia, The side effects of tricyclic antide- tremor, akathisia, anxiety, and distur- pressants are largely attributable to the bances of sexual function. ability of these compounds to bind to Moclobemide is a new representa- and block receptors for endogenous tive of the group of MAO inhibitors. In- transmitter substances. These effects hibition of intraneuronal degradation of develop acutely. Antagonism at musca- serotonin and norepinephrine causes an rinic cholinoceptors leads to atropine- increase in extracellular amine levels. A like effects such as tachycardia, inhibi- psychomotor stimulant thymeretic action of exocrine glands, constipation, tion is the predominant feature of MAO impaired micturition, and blurred vi- inhibitors. An older member of this sion. group, tranylcypromine, causes irre- Changes in adrenergic function are versible inhibition of the two isozymes complex. Inhibition of neuronal cate- MAOA and MAOB. Therefore, presystem- cholamine reuptake gives rise to super- ic elimination in the liver of biogenic imposed indirect sympathomimetic amines, such as tyramine, which are in- stimulation. Patients are supersensitive gested in food (e.g., aged cheese and to catecholamines (e.g., epinephrine in Chianti), will be impaired. To avoid the local anesthetic injections must be danger of a hypertensive crisis, therapy avoided). On the other hand, blockade with tranylcypromine or other nonse- of α1-receptors may lead to orthostatic lective MAO inhibitors calls for strin- hypotension. gent dietary rules. With moclobemide, Due to their cationic amphiphilic this hazard is much reduced because it nature, the TCA exert membrane-stabi- inactivates only MAOA and does so in a lizing effects that can lead to distur- reversible manner. bances of cardiac impulse conduction with arrhythmias as well as decreases in myocardial contractility. All TCA lower the seizure threshold. Weight gain may result from a stimulant effect on appetite. Maprotiline, a tetracyclic compound, largely resembles tricyclic agents in terms of its pharmacological and clinical actions. Mianserine also possesses a tetracyclic structure, but differs insofar as it increases intrasyn- aptic concentrations of norepinephrine

Psychopharmacologicals 233

Serotonin 5-HT-Receptor Dopamine D-Receptor α Norepinephrine -Adrenoceptor -Blockade 1 Parasympatho- lytic activity Indication Acetylcholine M-Cholinoceptor Anxiolysis Drive, energy α

Amitriptyline Patient:

Depressive, 50-150 mg/d anxious, t1/2 = 30-40h agitated

Imipramine Patient:

Depressive, 50-200 mg/d normal t1/2 = 9-20h drive

Desipramine Patient:

Depressive, lack of drive 75-200 mg/d and t1/2 = 15-60h energy

Fluoxetine Patient:

Depressive, lack of drive 20-40 mg/d and t1/2 = 48-96h energy

Moclobemide Patient:

Depressive, lack of drive 300 mg/d and t1/2 = 1-2h energy A. Antidepressants: activity profiles

234 Psychopharmacologicals

II. Mania Alternate treatments. Mood-stabilization and control of manic or hy- The manic phase is characterized by ex- pomanic episodes in some subtypes of aggerated elation, flight of ideas, and a bipolar illness may also be achieved pathologically increased psychomotor with the anticonvulsants valproate and drive. This is symbolically illustrated in carbamazepine, as well as with calcium A by a disjointed structure and aggres- channel blockers (e.g., verapamil, nifed- sive color tones. The patients are over- ipine, nimodipine). Effects are delayed confident, continuously active, show and apparently unrelated to the mecha- progressive incoherence of thought and nisms responsible for anticonvulsant loosening of associations, and act irre- and cardiovascular actions, respective- sponsibly (financially, sexually etc.). ly. Lithium ions. Lithium salts (e.g., acetate, carbonate) are effective in con- III. Prophylaxis trolling the manic phase. The effect becomes evident approx. 10 d after the With continued treatment for 6 to 12 start of therapy. The small therapeutic months, lithium salts prevent the re- index necessitates frequent monitoring currence of either manic or depressive of Li+ serum levels. Therapeutic levels states, effectively stabilizing mood at a should be kept between 0.8–1.0 mM in normal level. fasting morning blood samples. At higher values there is a risk of adverse effects. CNS symptoms include fine tremor, ataxia or seizures. Inhibition of the renal actions of vasopressin (p. 164) leads to polyuria and thirst. Thyroid function is impaired (p. 244), with compensatory development of (euthyroid) goiter. The mechanism of action of Li ions remains to be fully elucidated. Chemi- cally, lithium is the lightest of the alkali metals, which include such biologically important elements as sodium and potassium. Apart from interference with transmembrane cation fluxes (via ion channels and pumps), a lithium effect of major significance appears to be membrane depletion of phosphatidylinositol bisphosphates, the principal lipid substrate used by various receptors in transmembrane signalling (p. 66). Blockade of this important signal transduction pathway leads to impaired ability of neurons to respond to activation of membrane receptors for transmitters or other chemical signals. Another site of action of lithium may be GTP-binding proteins responsible for signal transduction initiated by formation of the agonist-receptor complex. Rapid control of an acute attack of mania may require the use of a neuroleptic (see below).

Psychopharmacologicals 235

Mania H

Day 2 Li+ Be Lithium

Na Mg

K Ca Day 4

Rb Sr

Cs Ba Day 6

Depression Mania Day 8

Normal state Normal state Day 10

A. Effect of lithium salts in mania

236 Psychopharmacologicals

Therapy of Schizophrenia their analogues (e.g., thioxanthenes); and 2. the butyrophenones (prototype: Schizophrenia is an endogenous psy- haloperidol). According to the chemical chosis of episodic character. Its chief structure of the side chain, phenothia- symptoms reflect a thought disorder zines and thioxanthenes can be subdi- (i.e., distracted, incoherent, illogical vided into aliphatic (chlorpromazine, thinking; impoverished intellectual triflupromazine, p. 239 and piperazine content; blockage of ideation; abrupt congeners (trifluperazine, fluphenazine, breaking of a train of thought: claims of flupentixol, p. 239). being subject to outside agencies that The antipsychotic effect is probably control the patient’s thoughts), and a due to an antagonistic action at dop- disturbance of affect (mood inappropri- amine receptors. Aside from their main ate to the situation) and of psychomotor antipsychotic action, neuroleptics dis- drive. In addition, patients exhibit delu- play additional actions owing to their sional paranoia (persecution mania) or antagonism at hallucinations (fearfulness hearing of – muscarinic acetylcholine receptors voices). Contrasting these “positive” atropine-like effects; symptoms, the so-called “negative” – α-adrenoceptors for norepinephrine symptoms, viz., poverty of thought, so- disturbances of blood pressure cial withdrawal, and anhedonia, assume regulation; added importance in determining the – dopamine receptors in the nigrostria- severity of the disease. The disruption tal system extrapyramidal motor and incoherence of ideation is symboli- disturbances; in the area postrema cally represented at the top left (A) and antiemetic action (p. 330), and in the the normal psychic state is illustrated as pituitary gland increased secretion on p. 237 (bottom left). of prolactin (p. 242); – histamine receptors in the cerebral Neuroleptics cortex possible cause of sedation. These ancillary effects are also elicited After administration of a neuroleptic, in healthy subjects and vary in intensity there is at first only psychomotor damp- among individual substances. ening. Tormenting paranoid ideas and Other indications. Acutely, there is hallucinations lose their subjective im- sedation with anxiolysis after neurolep- portance (A, dimming of flashy colors); tization has been started. This effect can however, the psychotic processes still be utilized for: “psychosomatic un- persist. In the course of weeks, psychic coupling” in disorders with a prominent processes gradually normalize (A); the psychogenic component; neurolepta- psychotic episode wanes, although nalgesia (p. 216) by means of the buty- complete normalization often cannot be rophenone droperidol in combination achieved because of the persistence of with an opioid; tranquilization of over- negative symptoms. Nonetheless, these excited, agitated patients; treatment of changes are significant because the pa- delirium tremens with haloperidol; as tient experiences relief from the tor- well as the control of mania (see p. 234). ment of psychotic personality changes; It should be pointed out that neuro- care of the patient is made easier and leptics do not exert an anticonvulsant return to a familiar community environ- action, on the contrary, they may lower ment is accelerated. seizure thershold. The conventional (or classical) neuroleptics comprise two classes of compounds with distinctive chemical structures: 1. the phenothiazines derived from the antihistamine promethazine (prototype: chlorpromazine), including

Psychopharmacologicals 237

Neuroleptics

Phenothiazine type: Chlorpromazine

Butyrophenone type: Week 3 Week after start of therapy Haloperidol Week 5 Week

Sedation Week 7 Week

Autonomic disturbance due to atropine-like action Week 9 Week Movement disorders due to dopamine antagonism

Antiemetic effect

A. Effects of neuroleptics in schizophrenia

238 Psychopharmacologicals

Because they inhibit the thermoreg- they lack anticholinergic activity and, ulatory center, neuroleptics can be em- hence, are prone to upset the balance ployed for controlled hypothermia between striatal cholinergic and dop- (p. 202). aminergic activity. Adverse Effects. Clinically most Derivatives bearing a piperazine important and therapy-limiting are ex- moiety (e.g., trifluperazine, fluphena- trapyramidal disturbances; these result zine) have greater antipsychotic poten- from dopamine receptor blockade. cy than do drugs containing an aliphatic Acute dystonias occur immediately af- side chain (e.g., chlorpromazine, triflu- ter neuroleptization and are manifested promazine). However, their antipsy- by motor impairments, particularly in chotic effects are qualitatively indistin- the head, neck, and shoulder region. Af- guishable. ter several days to months, a parkinso- As structural analogues of the nian syndrome (pseudoparkinsonism) phenothiazines, thioxanthenes (e.g., or akathisia (motor restlessness) may chlorprothixene, flupentixol) possess a develop. All these disturbances can be central nucleus in which the N atom is treated by administration of antiparkin- replaced by a carbon linked via a double son drugs of the anticholinergic type, bond to the side chain. Unlike the phe- such as biperiden (i.e., in acute dysto- nothiazines, they display an added thy- nia). As a rule, these disturbances disap- moleptic activity. pear after withdrawal of neuroleptic Clozapine is the prototype of the medication. Tardive dyskinesia may be- so-called atypical neuroleptics, a group come evident after chronic neurolep- that combines a relative lack of extrapy- tization for several years, particularly ramidal adverse effects with superior when the drug is discontinued. It is due efficacy in alleviating negative symp- to hypersensitivity of the dopamine re- toms. Newer members of this class in- ceptor system and can be exacerbated clude risperidone, olanzapine, and ser- by administration of anticholinergics. tindole. Two distinguishing features of Chronic use of neuroleptics can, on these atypical agents are a higher affin- occasion, give rise to hepatic damage as- ity for 5-HT2 (or 5-HT6) receptors than sociated with cholestasis. A very rare, for dopamine D2 receptors and relative but dramatic, adverse effect is the ma- selectivity for mesolimbic, as opposed lignant neuroleptic syndrome (skeletal to nigrostriatal, dopamine neurons. muscle rigidity, hyperthermia, stupor) Clozapine also exhibits high affinity for that can end fatally in the absence of in- dopamine receptors of the D4 subtype, tensive countermeasures (including in addition to H1 histamine and musca- treatment with dantrolene, p. 182). rinic acetylcholine receptors. Clozapine Neuroleptic activity profiles. The may cause dose–dependent seizures marked differences in action spectra of and agranulocytosis, necessitating close the phenothiazines, their derivatives hematological monitoring. It is strongly and analogues, which may partially re- sedating. semble those of butyrophenones, are When esterified with a fatty acid, important in determining therapeutic both fluphenazine and haloperidol can uses of neuroleptics. Relevant parame- be applied intramuscularly as depot ters include: antipsychotic efficacy preparations. (symbolized by the arrow); the extent of sedation; and the ability to induce extrapyramidal adverse effects. The latter depends on relative differences in antagonism towards dopamine and acetylcholine, respectively (p. 188). Thus, the butyrophenones carry an increased risk of adverse motor reactions because

Psychopharmacologicals 239

Triflupromazine Clozapine 30 – 150 mg/d 25 – 200 mg/d

Trifluoperazine Flupentixol 15 – 20 mg/d 2 – 10 mg/d

40%

R 20% 40%

R=H Fluphenazine R=H Haloperidol Relative potency 2.5 – 10 mg/d 2 – 6 mg/d

O O Long-acting R = C C H R = C C H or 9 19 9 19 “depot” -decanoate -decanoate neuroleptics i.m. 50–150 mg every 2 weeks i.m. 50–150 mg every 4 weeks

less Dopamine- ≈ ACh effect sedating Dopamine- < ACh effect strongly Dopamine ACh extrapyramidal disturbances

A. Neuroleptics: Antipsychotic potency, sedative, and extrapyramidal motor effects

240 Psychopharmacologicals

Psychotomimetics lucinogens such as LSD, psilocin, psilocy- (Psychedelics, Hallucinogens) bin (from fungi), bufotenin (the cutaneous gland secretion of a toad), mescaline Psychotomimetics are able to elicit psy- (from the Mexican cactuses Lophophora chic changes like those manifested in williamsii and L. diffusa; peyote) bear a the course of a psychosis, such as illu- structural resemblance to 5-HT (p. 116), sionary distortion of perception and and chemically synthesized ampheta- hallucinations. This experience may be mine-derived hallucinogens (4-methyl- of dreamlike character; its emotional or 2,5-dimethoxyamphetamine; 3,4-di- intellectual transposition appears inad- methoxyamphetamine; 2,5-dimethoxy- equate to the outsider. 4-ethyl amphetamine) are thought to A psychotomimetic effect is pictori- interact with the agonist recognition ally recorded in the series of portraits site of the 5-HT2A receptor. Conversely, drawn by an artist under the influence most of the psychotomimetic effects are of lysergic acid diethylamide (LSD). As annulled by neuroleptics having 5-HT2A the intoxicated state waxes and wanes antagonist activity (e.g. clozapine, ris- like waves, he reports seeing the face of peridone). The structures of other the portrayed subject turn into a gri- agents such as tetrahydrocannabinol mace, phosphoresce bluish-purple, and (from the hemp plant, Cannabis sativa— fluctuate in size as if viewed through a hashish, marihuana), muscimol (from moving zoom lens, creating the illusion the fly agaric, Amanita muscaria), or of abstruse changes in proportion and phencyclidine (formerly used as an in- grotesque motion sequences. The dia- jectable general anesthetic) do not re- bolic caricature is perceived as threat- veal a similar connection. Hallucina- ening. tions may also occur as adverse effects Illusions also affect the senses of after intake of other substances, e.g., hearing and smell; sounds (tones) are scopolamine and other centrally active “experienced” as floating beams and parasympatholytics. visual impressions as odors (“synesthe- The popular psychostimulant, me- sia”). Intoxicated individuals see them- thylenedioxy-methamphetamine (MD- selves temporarily from the outside and MA, “ecstasy”) acutely increases neuro- pass judgement on themselves and nal dopamine and norepinephrine re- their condition. The boundary between lease and causes a delayed and selective self and the environment becomes degeneration of forebrain 5-HT nerve blurred. An elating sense of being one terminals. with the other and the cosmos sets in. Although development of psycho- The sense of time is suspended; there is logical dependence and permanent psy- neither present nor past. Objects are chic damage cannot be considered es- seen that do not exist, and experiences tablished sequelae of chronic use of psy- felt that transcend explanation, hence chotomimetics, the manufacture and the term “psychedelic” (Greek delosis = commercial distribution of these drugs revelation) implying expansion of con- are prohibited (Schedule I, Controlled sciousness. Drugs). The contents of such illusions and hallucinations can occasionally become extremely threatening (“bad” or “bum trip”); the individual may feel provoked to turn violent or to commit suicide. In- toxication is followed by a phase of intense fatigue, feelings of shame, and hu- miliating emptiness. The mechanism of the psychoto- genic effect remains unclear. Some hal-

Psychopharmacologicals 241

O C2H5 C N C2H5

N CH3

Lysergic acid diethylamide 0.0001 g/70 kg HN

A. Psychotomimetic effect of LSD in a portrait artist

242 Hormones

Hypothalamic and Hypophyseal release of STH (and also other peptide Hormones hormones including insulin, glucagon, and gastrin). The endocrine system is controlled by PRH: prolactin-RH remains to be the brain. Nerve cells of the hypothala- characterized or established. Both TRH mus synthesize and release messenger and vasoactive intestinal peptide (VIP) substances that regulate adenohy- are implicated. pophyseal (AH) hormone release or are PRIH inhibits the release of prolac- themselves secreted into the body as tin and could be identical with dop- hormones. The latter comprise the so- amine. called neurohypophyseal (NH) hor- Hypothalamic releasing hormones mones. are mostly administered (parenterally) The axonal processes of hypotha- for diagnostic reasons to test AH func- lamic neurons project to the neurohy- tion. pophysis, where they store the nona- Therapeutic control of AH cells. peptides vasopressin (= antidiuretic hor- GnRH is used in hypothalamic infertility mone, ADH) and oxytocin and release in women to stimulate FSH and LH se- them on demand into the blood. Thera- cretion and to induce ovulation. For this peutically (ADH, p. 64, oxytocin, p. 126), purpose, it is necessary to mimic the these peptide hormones are given pa- physiologic intermittent “pulsatile” re- renterally or via the nasal mucosa. lease (approx. every 90 min) by means The hypothalamic releasing hor- of a programmed infusion pump. mones are peptides. They reach their Gonadorelin superagonists are target cells in the AH lobe by way of a GnRH analogues that bind with very portal vascular route consisting of two high avidity to GnRH receptors of AH serially connected capillary beds. The cells. As a result of the nonphysiologic first of these lies in the hypophyseal uninterrupted receptor stimulation, in- stalk, the second corresponds to the itial augmentation of FSH and LH output capillary bed of the AH lobe. Here, the is followed by a prolonged decrease. Bu- hypothalamic hormones diffuse from serelin, leuprorelin, goserelin, and trip- the blood to their target cells, whose ac- torelin are used in patients with prostat- tivity they control. Hormones released ic carcinoma to reduce production of from the AH cells enter the blood, in testosterone, which promotes tumor which they are distributed to peripheral growth. Testosterone levels fall as much organs (1). as after extirpation of the testes (2). Nomenclature of releasing hor- The dopamine D2 agonists bromo- mones: criptine and cabergoline (pp. 114, 188) RH–releasing hormone; RIH—re- inhibit prolactin-releasing AH cells (in- lease inhibiting hormone. dications: suppression of lactation, pro- GnRH: gonadotropin-RH = gona- lactin-producing tumors). Excessive, dorelin stimulates the release of FSH but not normal, growth hormone re- (follicle-stimulating hormone) and LH lease can also be inhibited (indication: (luteinizing hormone). acromegaly) (3). TRH: thyrotropin-RH (protirelin) Octreotide is a somatostatin ana- stimulates the release of TSH (thyroid logue; it is used in the treatment of stimulating hormone = thyrotropin). somatostatin-secreting pituitary tu- CRH: corticotropin-RH stimulates mors. the release of ACTH (adrenocorticotrop- ic hormone = corticotropin). GRH: growth hormone-RH (soma- tocrinin) stimulates the release of GH (growth hormone = STH, somatotropic hormone). GRIH somatostatin inhibits

Hormones 243

Hypothalamic ADH releasing hormones Oxytocin

SynthesisHypothalamus Synthesis

Release into Release into blood blood

GnRH TRH CRH GRH PRH

GRIH PRIH Neurohypophysis Synthesis and Adenohypophysis (AH) release of AH hormones Application parenteral

AH-cells

nasal

FSH, LH TSH ACTH STH(GH) Prolactin ADH Oxytocin

Ovum maturation; Somatomedins H2O Estradiol, Progesterone Thyroxine Growth Spermatogenesis; Labor Testosterone Cortisol Lactation Milk ejection 1

GnRH Buserelin

Leuprorelin

Dopamine agonist

Released amount Pulsatile release Bromocriptine 90 min

Persistent stimulation D2-Receptors Rhythmic stimulation AH- cell

Cessation of hormone secretion, Inhibition of secretion of FSH LH "chemical castration" prolactin STH 23. A. Hypothalamic and hypophyseal hormones

244 Hormones

Thyroid Hormone Therapy able to a level at which hypothyroidism is averted. Therefore, the thyroid in- Thyroid hormones accelerate metab- creases in size. In addition, intrathyroid olism. Their release (A) is regulated by depletion of iodine stimulates growth. the hypophyseal glycoprotein TSH, Because of the negative feedback whose release, in turn, is controlled by regulation of thyroid function, thyroid the hypothalamic tripeptide TRH. Secre- activation can be inhibited by adminis- tion of TSH declines as the blood level of tration of T4 doses equivalent to the en- thyroid hormones rises; by means of dogenous daily output (approx. this negative feedback mechanism, hor- 150 µg/d). Deprived of stimulation, the mone production is “automatically” ad- inactive thyroid regresses in size. justed to demand. If a euthyroid goiter has not persist- The thyroid releases predominantly ed for too long, increasing iodine supply thyroxine (T4). However, the active form (potassium iodide tablets) can also be appears to be triiodothyronine (T3); T4 is effective in reversing overgrowth of the converted in part to T3, receptor affinity gland. in target organs being 10-fold higher for In older patients with goiter due to T3. The effect of T3 develops more rapid- iodine deficiency there is a risk of pro- ly and has a shorter duration than does voking hyperthyroidism by increasing that of T4. Plasma elimination t1/2 for T4 iodine intake (p. 247): During chronic is about 7 d; that for T3, however, is only maximal stimulation, thyroid follicles 1.5 d. Conversion of T4 to T3 releases io- can become independent of TSH stimu- dide; 150 µg T4 contains 100 µg of io- lation (“autonomic tissue”). If the iodine dine. supply is increased, thyroid hormone For therapeutic purposes, T4 is cho- production increases while TSH secre- sen, although T3 is the active form and tion decreases due to feedback inhibi- better absorbed from the gut. However, tion. The activity of autonomic tissue, with T4 administration, more constant however, persists at a high level; thy- blood levels can be achieved because roxine is released in excess, resulting in degradation of T4 is so slow. Since ab- iodine-induced hyperthyroidism. sorption of T4 is maximal from an empty Iodized salt prophylaxis. Goiter is 1 stomach, T4 is taken about /2 h before endemic in regions where soils are defi- breakfast. cient in iodine. Use of iodized table salt Replacement therapy of hypothy- allows iodine requirements (150– roidism. Whether primary, i.e., caused 300 µg/d) to be met and effectively pre- by thyroid disease, or secondary, i.e., re- vents goiter. sulting from TSH deficiency, hypothyroidism is treated by oral administration of T4. Since too rapid activation of metabolism entails the hazard of cardiac overload (angina pectoris, myocardial infarction), therapy is usually started with low doses and gradually increased. The final maintenance dose required to restore a euthyroid state depends on individual needs (approx. 150 µg/d). Thyroid suppression therapy of euthyroid goiter (B). The cause of goiter (struma) is usually a dietary deficiency of iodine. Due to an increased TSH action, the thyroid is activated to raise utilization of the little iodine avail-

Hormones 245

Hypothalamus

TRH

Decrease in L-Thyroxine, Levothyroxine, sensivity 3,5,3´,5´-Tetraiodothyronine, T to TRH 4 Hypophysis

TSH

Thyroid Liothyronine 3,5,3´-Triiodothyronine, T3

Effector cell: ~ 90 µg/Day ~ 9 µg/Day receptor affinity T 10 3 = T4 1 Thyroxine Triiodothyronine

Duration ~ 25 µg/Day Deiodinase 2. 9. Day I- - Deiodination I coupling T3 T4 "reverse T3" 3,3´,5´-Triiodothyronine Urine Feces 1020 30 40 Days A. Thyroid hormones - release, effects, degradation

Hypophysis

TSH TSH Inhibition

Normal Therap. - state - - admini- I I I stration

T4, T3 T4, T3 T4

B. Endemic goiter and its treatment with thyroxine

246 Hormones

Hyperthyroidism and Antithyroid Drugs state, two therapeutic principles can be applied in Graves’ disease: a) monother- Thyroid overactivity in Graves’ disease apy with a thioamide with gradual dose (A) results from formation of IgG anti- reduction as the disease abates; b) ad- bodies that bind to and activate TSH re- ministration of high doses of a thio- ceptors. Consequently, there is overpro- amide with concurrent administration duction of hormone with cessation of of thyroxine to offset diminished hor- TSH secretion. Graves’ disease can abate mone synthesis. Adverse effects of thi- spontaneously after 1–2 y. Therefore, oamides are rare; however, the possibil- initial therapy consists of reversible ity of agranulocytosis has to be kept in suppression of thyroid activity by mind. means of antithyroid drugs. In other Perchlorate, given orally as the so- forms of hyperthyroidism, such as hor- dium salt, inhibits the iodide pump. Ad- mone-producing (morphologically be- verse reactions include aplastic anemia. nign) thyroid adenoma, the preferred Compared with thioamides, its thera- therapeutic method is removal of tissue, peutic importance is low but it is used either by surgery or administration of as an adjunct in scintigraphic imaging of 131iodine in sufficient dosage. Radioio- bone by means of technetate when dine is taken up into thyroid cells and accumulation in the thyroid gland has destroys tissue within a sphere of a few to be blocked. millimeters by emitting β-(electron) Short-term thyroid suppression particles during its radioactive decay. (C). Iodine in high dosage (>6000 µg/d) Concerning iodine-induced hyper- exerts a transient “thyrostatic” effect in thyroidism, see p. 244 (B). hyperthyroid, but usually not in euthyr- Antithyroid drugs inhibit thyroid oid, individuals. Since release is also function. Release of thyroid hormone blocked, the effect develops more rapid- (C) is preceded by a chain of events. A ly than does that of thioamides. membrane transporter actively accu- Clinical applications include: preop- mulates iodide in thyroid cells; this is erative suppression of thyroid secretion followed by oxidation to iodine, iodina- according to Plummer with Lugol’s solution of tyrosine residues in thyroglobu- tion (5% iodine + 10% potassium iodide, lin, conjugation of two diiodotyrosine 50–100 mg iodine/d for a maximum of groups, and formation of T4 and T3 10 d). In thyrotoxic crisis, Lugol’s solu- moieties. These reactions are catalyzed tion is given together with thioamides by thyroid peroxidase, which is local- and β-blockers. Adverse effects: aller- ized in the apical border of the follicular gies; contraindications: iodine-induced cell membrane. T4-containing thyro- thyrotoxicosis. globulin is stored inside the thyroid fol- Lithium ions inhibit thyroxine re- licles in the form of thyrocolloid. Upon lease. Lithium salts can be used instead endocytotic uptake, colloid undergoes of iodine for rapid thyroid suppression lysosomal enzymatic hydrolysis, ena- in iodine-induced thyrotoxicosis. Re- bling thyroid hormone to be released as garding administration of lithium in required. A “thyrostatic” effect can re- manic-depressive illness, see p. 234. sult from inhibition of synthesis or release. When synthesis is arrested, the antithyroid effect develops after a delay, as stored colloid continues to be utilized. Antithyroid drugs for long-term therapy (C). Thiourea derivatives (thioureylenes, thioamides) inhibit peroxidase and, hence, hormone synthesis. In order to restore a euthyroid

Hormones 247

Hypophysis

TSH Autonomous tissue

I- I- TSH- like antibodies T4, T3 T4, T3 T4, T3 A. Graves’ disease B. Iodine hyperthyroidosis in endemic goiter

Thioamides Conversion during absorption

Thiamazole Propylthiouracil Methimazole Carbimazole

Peroxidase

I - e I Tyrosine I- I TG T4- - Tyrosine ClO4 I T - Perchlorate Synthesis 4

Iodine in high dose Storage Release in colloid T4- T4

Lithium Lysosome ions

C. Antithyroid drugs and their modes of action

248 Hormones

Glucocorticoid Therapy Desired effects. As anti-allergics, immunosuppressants, or anti-inflamma- I. Replacement therapy. The adrenal tory drugs, glucocorticoids display ex- cortex (AC) produces the glucocorticoid cellent efficacy against “undesired” in- cortisol (hydrocortisone) and the mine- flammatory reactions. ralocorticoid aldosterone. Both steroid Unwanted effects. With short-term hormones are vitally important in adap- use, glucocorticoids are practically free tation responses to stress situations, of adverse effects, even at the highest such as disease, trauma, or surgery. Cor- dosage. Long-term use is likely to cause tisol secretion is stimulated by hypo- changes mimicking the signs of physeal ACTH, aldosterone secretion by Cushing’s syndrome (endogenous angiotensin II in particular (p. 124). In overproduction of cortisol). Sequelae of AC failure (primary AC insuffiency: the anti-inflammatory action: lowered Addison’s disease), both cortisol and al- resistance to infection, delayed wound dosterone must be replaced; when ACTH healing, impaired healing of peptic ul- production is deficient (secondary AC in- cers. Sequelae of exaggerated glucocor- sufficiency), cortisol alone needs to be re- ticoid action: a) increased gluconeogen- placed. Cortisol is effective when given esis and release of glucose; insulin-de- orally (30 mg/d, 2/3 a.m., 1/3 p.m.). In pendent conversion of glucose to trigly- stress situations, the dose is raised by cerides (adiposity mainly noticeable in 5- to 10-fold. Aldosterone is poorly the face, neck, and trunk); “steroid-dia- effective via the oral route; instead, betes” if insulin release is insufficient; the mineralocorticoid fludrocortisone b) increased protein catabolism with (0.1 mg/d) is given. atrophy of skeletal musculature (thin II. Pharmacodynamic therapy extremities), osteoporosis, growth re- with glucocorticoids (A). In unphysio- tardation in infants, skin atrophy. Se- logically high concentrations, cortisol or quelae of the intrinsically weak, but other glucocorticoids suppress all phas- now manifest, mineralocorticoid action es (exudation, proliferation, scar forma- of cortisol: salt and fluid retention, hy- tion) of the inflammatory reaction, i.e., pertension, edema; KCl loss with danger the organism’s defensive measures of hypokalemia. against foreign or noxious matter. This effect is mediated by multiple compo- Measures for Attenuating or Preventing nents, all of which involve alterations in Drug-Induced Cushing’s Syndrome gene transcription (p. 64). Glucocorti- coids inhibit the expression of genes en- a) Use of cortisol derivatives with less coding for proinflammatory proteins (e.g., prednisolone) or negligible miner- (phospholipase-A2, cyclooxygenase 2, alocorticoid activity (e.g., triamcinolone, IL-2-receptor). The expression of these dexamethasone). Glucocorticoid activ- genes is stimulated by the transcription ity of these congeners is more pro- factor NFΚB. Binding to the glucocorti- nounced. Glucorticoid, anti-inflamma- coid receptor complex prevents translo- tory and feedback inhibitory (p. 250) ac- cation af NFΚB to the nucleus. Converse- tions on the hypophysis are correlated. ly, glucocorticoids augment the expres- An exclusively anti-inflammatory con- sion of some anti-inflammatory pro- gener does not exist. The “glucocorti- teins, e.g., lipocortin, which in turn in- coid” related Cushingoid symptoms hibits phospholipase A2. Consequently, cannot be avoided. The table lists rela- release of arachidonic acid is dimin- tive activity (potency) with reference to ished, as is the formation of inflamma- cortisol, whose mineralo- and glucocor- tory mediators of the prostaglandin and ticoid activities are assigned a value of leukotriene series (p. 196). At very high 1.0. All listed glucocorticoids are effec- dosage, nongenomic effects may also tive orally. contribute.

Hormones 249

e.g., allergy Inflammation Unwanted autoimmune disease, transplant rejection redness, swelling heat, pain; Healing of scar tissue injury Wanted due to bacteria, viruses, fungi, trauma

Mineralocorticoid Glucocorticoid action unphysiologically action high concentration Diabetes Hypertension mellitus Cortisol

Na+ Glucose H2O Gluconeogenesis

Amino acids

Protein catabolism K+

1 Cortisol 1 Muscle Tissue atrophy 0,8 Prednisolone 4 weakness 0 Triamcinolone 7,5 Osteo- Skin 0 Dexamethasone 30 porosis atrophy 3000 0,3 Growth inhibition Potency

Prednisolone Triamcinolone

Dexamethasone Aldosterone

A. Glucocorticoids: principal and adverse effects

250 Hormones

b) Local application. Typical adverse logically high glucocorticoid doses, the effects, however, also occur locally, e.g., cortisol-producing portions of the ad- skin atrophy or mucosal colonization renal cortex shrink (“adrenocortical with candidal fungi. To minimize atrophy”). Aldosterone-synthesizing ca- systemic absorption after inhalation, pacity, however, remains unaffected. derivatives should be used that have a When glucocorticoid medication is sud- high rate of presystemic elimination, denly withheld, the atrophic cortex is such as beclomethasone dipropionate, unable to produce sufficient cortisol and flunisolide, budesonide, or fluticasone a potentially life-threatening cortisol propionate (p. 14). deficiency may develop. Therefore, glu- b) Lowest dosage possible. For long- cocorticoid therapy should always be term medication, a just sufficient dose tapered off by gradual reduction of the should be given. However, in attempt- dosage. ing to lower the dose to the minimal ef- Regimens for prevention of fective level, it is necessary to take into adrenocortical atrophy. Cortisol secre- account that administration of exoge- tion is high in the early morning and nous glucocorticoids will suppress pro- low in the late evening (circadian duction of endogenous cortisol due to rhythm). This fact implies that the regu- activation of an inhibitory feedback latory centers continue to release CRH mechanism. In this manner, a very low or ACTH in the face of high morning dose could be “buffered,” so that un- blood levels of cortisol; accordingly, physiologically high glucocorticoid ac- sensitivity to feedback inhibition must tivity and the anti-inflammatory effect be low in the morning, whereas the op- are both prevented. posite holds true in the late evening. Effect of glucocorticoid adminis- a) Circadian administration: The tration on adrenocortical cortisol pro- daily dose of glucocorticoid is given in duction (A). Release of cortisol depends the morning. Endogenous cortisol pro- on stimulation by hypophyseal ACTH, duction will have already begun, the which in turn is controlled by hypotha- regulatory centers being relatively in- lamic corticotropin-releasing hormone sensitive to inhibition. In the early (CRH). In both the hypophysis and hy- morning hours of the next day, CRF/- pothalamus there are cortisol receptors ACTH release and adrenocortical stimu- through which cortisol can exert a feed- lation will resume. back inhibition of ACTH or CRH release. b) Alternate-day therapy: Twice the By means of these cortisol “sensors,” the daily dose is given on alternate morn- regulatory centers can monitor whether ings. On the “off” day, endogenous corti- the actual blood level of the hormone sol production is allowed to occur. corresponds to the “set-point.” If the The disadvantage of either regimen blood level exceeds the set-point, ACTH is a recrudescence of disease symptoms output is decreased and, thus, also the during the glucocorticoid-free interval. cortisol production. In this way cortisol level is maintained within the required range. The regulatory centers respond to synthetic glucocorticoids as they do to cortisol. Administration of exogenous cortisol or any other glucocorticoid reduces the amount of endogenous cortisol needed to maintain homeostasis. Re- lease of CRH and ACTH declines ("inhibition of higher centers by exogenous glucocorticoid”) and, thus, cortisol secretion (“adrenocortical suppression”). After weeks of exposure to unphysio-

Hormones 251

Hypothalamus

CRH

Hypo- physis ACTH Adreno- cortical atrophy

Adrenal cortex

Cortisol Exogenous 30 mg/day administration

Cortisol Decrease in Cessation of Cortisol deficiency production under cortisol production cortisol production after abrupt normal with cortisol dose with cortisol dose cessation of conditions < daily production > daily production administration

Cortisol Glucocorticoid-induced concentration inhibition of cortisol production normal circadian time-course

04 81216202448h

Morning dose Inhibition of Elimination of Start of early endogenous exogenous morning cortisol glucocorticoid cortisol production during daytime production

Glucocorticoid concentration

04 81216202448h

A. Cortisol release and its modification by glucocorticoids

252 Hormones

Androgens, Anabolic Steroids, production and palliative treatment of Antiandrogens breast cancer, T. esters for depot injection are optimally suited. Secondary sex Androgens are masculinizing substanc- characteristics and libido are main- es. The endogenous male gonadal hor- tained; however, fertility is not promot- mone is the steroid testosterone from ed. On the contrary, spermatogenesis the interstitial Leydig cells of the testis. may be suppressed because of feedback Testosterone secretion is stimulated by inhibition of hypothalamohypophyseal hypophyseal luteinizing hormone (LH), gonadotropin secretion. whose release is controlled by hypotha- Stimulation of spermatogenesis lamic GnRH (gonadorelin, p. 242). Re- in gonadotropin (FSH, LH) deficiency lease of both hormones is subject to can be achieved by injection of HMG feedback inhibition by circulating tes- and HCG. HMG or human menopausal tosterone. Reduction of testosterone to gonadotropin is obtained from the urine dihydrotestosterone occurs in most tar- of postmenopausal women and is rich get organs; the latter possesses higher in FSH activity. HCG, human chorionic affinity for androgen receptors. Rapid gonadotropin, from the urine of preg- intrahepatic degradation (plasma t1/2 ~ nant women, acts like LH. 15 min) yields androsterone among Anabolics are testosterone deriva- other metabolites (17-ketosteroids) tives (e.g., clostebol, metenolone, nan- that are eliminated as conjugates in the drolone, stanozolol) that are used in de- urine. Because of rapid hepatic metab- bilitated patients, and misused by ath- olism, testosterone is unsuitable for oral letes, because of their protein anabolic use. Although it is well absorbed, it effect. They act via stimulation of andro- undergoes virtually complete pre- gen receptors and, thus, also display an- systemic elimination. drogenic actions (e.g., virilization in fe- Testosterone (T.) derivatives for males, suppression of spermatogene- clinical use. T. esters for i.m. depot injec- sis). tion are T. propionate and T. heptanoate The antiandrogen cyproterone (or enanthate). These are given in oily acts as a competitive antagonist of T. In solution by deep intramuscular injec- addition, it has progestin activity tion. Upon diffusion of the ester from whereby it inhibits gonadotropin secre- the depot, esterases quickly split off the tion (p. 254). Indications: in men, inhi- acyl residue, to yield free T. With in- bition of sex drive in hypersexuality; creasing lipophilicity, esters will tend to prostatic cancer. In women: treatment remain in the depot, and the duration of of virilization, with potential utilization action therefore lengthens. A T. ester for of the gestagenic contraceptive effect. oral use is the undecanoate. Owing to the Flutamide, an androgen receptor fatty acid nature of undecanoic acid, this antagonist possessing a different chem- ester is absorbed into the lymph, ena- ical structure, lacks progestin activity. bling it to bypass the liver and enter, via Finasteride inhibits 5α-reductase, the thoracic duct, the general circula- the enzyme converting T. into dihydro- tion. 17-a Methyltestosterone is effective testosterone (DHT). Thus, the androgen- by the oral route due to its increased ic stimulus is reduced in those tissues in metabolic stability, but because of the which DHT is the active species (e.g., hepatotoxicity of C17-alkylated andro- prostate). T.-dependent tissues or func- gens (cholestasis, tumors) its use should tions are not or hardly affected (e.g., be avoided. Orally active mesterolone is skeletal muscle, negative feedback inhi- 1α-methyl-dihydrotestosterone. Trans- bition of gonadotropin secretion, and li- dermal delivery systems for T. are also bido). Finasteride can be used in benign available. prostate hyperplasia to shrink the gland Indications. For hormone replace- and, possibly, to improve micturition. ment in deficiency of endogenous T.

Hormones 253

Hypothalamus Skeletal muscle i. m. Depot Inhibition injection GnRH Testosterone ester in oily solution Testes R Hypophysis

R = LH Ester cleavage -propionate C – C 1 -heptanoate 2 C – C – C – C – C – C Duration of effect 2 weeks Testosterone

Ester cleavage Target cell Dihydro- testosterone Ductus thoracicus

Antagonist Cyproterone Oral intake

Androsterone

Inactivation

Conjugation with sulfate, glucuronate

Testosterone Methyl- testosterone

Testosterone Lymph vessels undecanoate 17-Ketosteroid A. Testosterone and derivatives

254 Hormones

Follicular Growth and Ovulation, (p. 252). Released ester is hydrolyzed to Estrogen and Progestin Production yield free estradiol. Orally used preparations. Ethinyl- Follicular maturation and ovulation, as estradiol (EE) is more stable metaboli- well as the associated production of fe- cally, passes largely unchanged through male gonadal hormones, are controlled the liver after oral intake and mimics es- by the hypophyseal gonadotropins FSH tradiol at estrogen receptors. Mestranol (follicle-stimulating hormone) and LH itself is inactive; however, cleavage of (luteinizing hormone). In the first half of the C-3 methoxy group again yields EE. the menstrual cycle, FSH promotes In oral contraceptives, one of the two growth and maturation of ovarian folli- agents forms the estrogen component cles that respond with accelerating syn- (p. 256). (Sulfate-)conjugated estrogens thesis of estradiol. Estradiol stimulates can be extracted from equine urine and endometrial growth and increases the are used for the prevention of post- permeability of cervical mucus for menopausal osteoporosis and in the sperm cells. When the estradiol blood therapy of climacteric complaints. Be- level approaches a predetermined set- cause of their high polarity (sulfate, glu- point, FSH release is inhibited due to curonide), they would hardly appear feedback action on the anterior hypoph- suitable for this route of administration. ysis. Since follicle growth and estrogen For transdermal delivery, an adhesive production are correlated, hypophysis patch is available that releases estradiol and hypothalamus can “monitor” the transcutaneously into the body. follicular phase of the ovarian cycle Progestin preparations. Depot through their estrogen receptors. With- formulations for i.m. injection are 17- in hours after ovulation, the tertiary fol- α-hydroxyprogesterone caproate and licle develops into the corpus luteum, medroxyprogesterone acetate. Prepara- which then also releases progesterone tions for oral use are derivatives of 17α- in response to LH. The former initiates ethinyltestosterone = ethisterone (e.g., the secretory phase of the endometrial norethisterone, dimethisterone, lynes- cycle and lowers the permeability of trenol, desogestrel, gestoden), or of cervical mucus. Nonruptured follicles 17α-hydroxyprogesterone acetate (e.g., continue to release estradiol under the chlormadinone acetate or cyproterone influence of FSH. After 2 wk, production acetate). These agents are mainly used of progesterone and estradiol subsides, as the progestin component in oral con- causing the secretory endometrial layer traceptives. to be shed (menstruation). Indications for estrogens and pro- The natural hormones are unsuit- gestins include: hormonal contracep- able for oral application because they tion (p. 256), hormone replacement, as are subject to presystemic hepatic elim- in postmenopausal women for prophy- ination. Estradiol is converted via es- laxis of osteoporosis; bleeding anoma- trone to estriol; by conjugation, all three lies, menstrual complaints. Concerning can be rendered water soluble and adverse effects, see p. 256. amenable to renal excretion. The major Estrogens with partial agonist ac- metabolite of progesterone is pregnan- tivity (raloxifene, tamoxifene) are be- diol, which is also conjugated and elimi- ing investigated as agents used to re- nated renally. place estrogen in postmenopausal os- Estrogen preparations. Depot teoporosis treatment, to lower plasma preparations for i.m. injection are oily lipids, and as estrogen antagonists in solutions of esters of estradiol (3- or 17- the prevention of breast cancer. Raloxi- OH group). The hydrophobicity of the fen—in contrast to tamoxifen—is an an- acyl moiety determines the rate of ab- tagonist at uterine estrogen receptors. sorption, hence the duration of effect

Hormones 255

Hypothalamus Hydroxyprogesterone Estradiol caproate GnRH -valerate

3 weeks Hypophysis 1 week

FSH LH Medroxyprogesterone acetate -benzoate 1 2 week 8 - 12 weeks Duration of effect Ovary Duration of effect

Estradiol

Progesterone

Estriol Estrone Estradiol Pregnanediol

Conjugation Conjugation with sulfate, glucuronate

Inactivation Inactivation

Estradiol Progesterone

Ethinylestradiol Ethinyltestosterone, (EE) a gestagen

Mestranol = 3-Methylether of EE Conjugated estrogens

A. Estradiol, progesterone, and derivatives

256 Hormones

Oral Contraceptives tion, cholestasis, benign liver tumors, nausea, chest pain, etc. may occur. Ap- Inhibitors of ovulation. Negative feed- parently there is no increased overall back control of gonadotropin release risk of malignant tumors. can be utilized to inhibit the ovarian cy- Minipill. Continuous low-dose ad- cle. Administration of exogenous es- ministration of progestin alone can pre- trogens (ethinylestradiol or mestranol) vent conception. Ovulations are not during the first half of the cycle permits suppressed regularly; the effect is then FSH production to be suppressed (as it due to progestin-induced alterations in is by administration of progestins cervical and endometrial function. Be- alone). Due to the reduced FSH stimula- cause of the need for constant intake at tion of tertiary follicles, maturation of the same time of day, a lower success follicles and, hence, ovulation are pre- rate, and relatively frequent bleeding vented. In effect, the regulatory brain anomalies, these preparations are now centers are deceived, as it were, by the rarely employed. elevated estrogen blood level, which “Morning-after” pill. This refers to signals normal follicular growth and a administration of a high dose of estro- decreased requirement for FSH stimula- gen and progestin, preferably within 12 tion. If estrogens alone are given during to 24 h, but no later than 72 h after coi- the first half of the cycle, endometrial tus. Menstrual bleeding ensues, which and cervical responses, as well as other prevents implantation of the fertilized functional changes, would occur in the ovum (normally on the 7th day after fer- normal fashion. By adding a progestin tilization, p. 74). Similarly, implantation (p. 254) during the second half of the cy- can be inhibited by mifepristone, which cle, the secretory phase of the endome- is an antagonist at both progesterone trium and associated effects can be elic- and glucocorticoid receptors and which ited. Discontinuance of hormone ad- also offers a noninvasive means of in- ministration would be followed by ducing therapeutic abortion in early menstruation. pregnancy. The physiological time course of es- Stimulation of ovulation. Gona- trogen-progesterone release is simulat- dotropin secretion can be increased by ed in the so-called biphasic (sequen- pulsatile delivery of GnRH (p. 242). The tial) preparations (A). In monophasic estrogen antagonists clomiphene and cy- preparations, estrogen and progestin clofenil block receptors mediating feed- are taken concurrently. Early adminis- back inhibition of central neuroendo- tration of progestin reinforces the inhi- crine circuits and thereby disinhibit bition of CNS regulatory mechanisms, gonadotropin release. Gonadotropins prevents both normal endometrial can be given in the form of HMG and growth and conditions for ovum im- HCG (p. 252). plantation, and decreases penetrability of cervical mucus for sperm cells. The two latter effects also act to prevent conception. According to the staging of progestin administration, one distinguishes (A): one-, two-, and three-stage preparations. In all cases, “withdrawal- bleeding” occurs when hormone intake is discontinued (if necessary, by substituting dummy tablets). Unwanted effects: An increased incidence of thrombosis and embolism is attributed to the estrogen component in particular. Hypertension, fluid reten-

Hormones 257

Hypophysis Hypophysis

1. 7. 14. 21. 28. FSH LH Inhibition Minipill Ovulation

Ovary Ovary Ovulation

Estradiol Progesterone Intake of Intake of estradiol progestin Estradiol derivative

Penetrability by sperm cells Progesterone

1. 7. 14. 21. 28. Readiness for Day of cycle nidation No ovulation

Biphasic preparation

Days of cycle 7. 14. 21. 28.

Monophasic preparations

One-stage regimen

Two-stage regimen

Three-stage regimen

A. Oral contraceptives

258 Hormones

Insulin Therapy regular insulin. In emergencies, such as hyperglycemic coma, it can be given Insulin is synthesized in the B- (or β-) intravenously (mostly by infusion be- cells of the pancreatic islets of Langer- cause i.v. injections have too brief an ac- hans. It is a protein (MW 5800) consist- tion; plasma t1/2 ~ 9 min). With the usu- ing of two peptide chains linked by two al subcutaneous application, the effect disulfide bridges; the A chain has 21 and is evident within 15 to 20 min, reaches a the B chain 30 amino acids. Insulin is the peak after approx. 3 h, and lasts for ap- “blood-sugar lowering” hormone. Upon prox. 6 h. Lispro insulin has a faster on- ingestion of dietary carbohydrates, it is set and slightly shorter duration of ac- released into the blood and acts to pre- tion. vent a significant rise in blood glucose Insulin suspensions. When the concentration by promoting uptake of hormone is injected as a suspension of glucose in specific organs, viz., the insulin-containing particles, its dissolu- heart, adipose tissue, and skeletal mus- tion and release in subcutaneous tissue cle, or its conversion to glycogen in the are retarded (rapid, intermediate, and liver. It also increases lipogenesis and slow insulins). Suitable particles can be protein synthesis, while inhibiting lipo- obtained by precipitation of apolar, lysis and release of free fatty acids. poorly water-soluble complexes con- Insulin is used in the replacement sisting of anionic insulin and cationic therapy of diabetes mellitus to supple- partners, e.g., the polycationic protein ment a deficient secretion of endoge- protamine or the compound aminoqui- nous hormone. nuride (Surfen). In the presence of zinc Sources of therapeutic insulin and acetate ions, insulin crystallizes; preparations (A). Insulin can be ob- crystal size determines the rate of disso- tained from pancreatic tissue of slaugh- lution. Intermediate insulin prepara- tered animals. Porcine insulin differs tions (NPH or isophane, lente or zinc in- from human insulin merely by one B sulin) act for 18 to 26 h, slow prepara- chain amino acid, bovine insulin by two tions (protamine zinc insulin, ultralente amino acids in the A chain and one in or extended zinc insulin) for up to 36 h. the B chain. With these slight differenc- Combination preparations cones, animal and human hormone display tain insulin mixtures in solution and in similar biological activity. Compared suspension (e.g., ultralente); the plasma with human hormone, porcine insulin is concentration-time curve represents barely antigenic and bovine insulin has the sum of the two components. a little higher antigenicity. Human insu- Unwanted effects. Hypoglycemia lin is produced by two methods: biosyn- results from absolute or relative over- thetically, by substituting threonine for dosage (see p. 260). Allergic reactions are the C-terminal alanine in the B chain of rare—locally: redness at injection site, porcine insulin; or by gene technology atrophy of adipose tissue (lipodystro- involving insertion of the appropriate phy); systemically: urticaria, skin rash, human DNA into E. coli bacteria. anaphylaxis. Insulin resistance can re- Types of preparations (B). As a sult from binding to inactivating anti- peptide, insulin is unsuitable for oral bodies. A possible local lipohypertrophy administration (destruction by gas- can be avoided by alternating injection trointestinal proteases) and thus needs sites. to be given parenterally. Usually, insulin preparations are injected subcutane- ously. The duration of action depends on the rate of absorption from the injection site. Short-acting insulin is dispensed as a clear neutral solution known as

Hormones 259

Porcine insulinAla Insulin 30 Thr Human insulin

Production: DNA S - S B-chain E. coli

S - S A-chain

A. Insulin production

Hours after injection 6121824

Rapid

Intermediate

Slow Insulin suspension = protamine zinc insulinInsulin suspension = protamine insulin Insulin solution = regular Insulin mixtures Insulin concentration in blood

B. Insulin: preparations and blood level-time curves

260 Hormones

Treatment of Insulin-Dependent (sweets, cakes) must be avoided (hyper- Diabetes Mellitus glycemic—peaks) and replaced with slowly digestible ones. “Juvenile onset” (type I) diabetes mellit- Acarbose (an α-glucosidase inhibi- us is caused by the destruction of insu- tor) delays intestinal formation of glu- lin-producing B cells in the pancreas, cose from disaccharides. necessitating replacement of insulin Any change in eating and living (daily dose approx. 40 U, equivalent to habits can upset control of blood sugar: approx. 1.6 mg). skipping a meal or unusual physical Therapeutic objectives are: (1) stress leads to hypoglycemia; increased prevention of life-threatening hypergly- CH intake provokes hyperglycemia. cemic (diabetic) coma; (2) prevention of Hypoglycemia is heralded by diabetic sequelae (angiopathy with warning signs: tachycardia, unrest, blindness, myocardial infarction, renal tremor, pallor, profuse sweating. Some failure), with precise “titration” of the of these are due to the release of glu- patient being essential to avoid even cose-mobilizing epinephrine. Counter- short-term spells of pathological hyper- measures: glucose administration, rap- glycemia; (3) prevention of insulin idly absorbed CH orally or 10–20 g glu- overdosage leading to life-threatening cose i.v. in case of unconsciousness; if hypoglycemic shock (CNS disturbance necessary, injection of glucagon, the due to lack of glucose). pancreatic hyperglycemic hormone. Therapeutic principles. In healthy Even with optimal control of blood subjects, the amount of insulin is “auto- sugar, s.c. administration of insulin can- matically” matched to carbohydrate in- not fully replicate the physiological sit- take, hence to blood glucose concentra- uation. In healthy subjects, absorbed tion. The critical secretory stimulus is glucose and insulin released from the the rise in plasma glucose level. Food in- pancreas simultaneously reach the liver take and physical activity (increased in high concentration, whereby effec- glucose uptake into musculature, de- tive presystemic elimination of both creased insulin demand) are accompa- substances is achieved. In the diabetic, nied by corresponding changes in insu- s.c. injected insulin is uniformly distrib- lin secretion (A, left track). uted in the body. Since insulin concen- In the diabetic, insulin could be ad- tration in blood supplying the liver can- ministered as it is normally secreted; not rise, less glucose is extracted from that is, injection of short-acting insulin portal blood. A significant amount of before each main meal plus bedtime ad- glucose enters extrahepatic tissues, ministration of a Lente preparation to where it has to be utilized. avoid a nocturnal shortfall of insulin. This regimen requires a well-educated, cooperative, and competent patient. In other cases, a fixed-dosage schedule will be needed, e.g., morning and evening injections of a combination insulin in constant respective dosage (A). To avoid hypo- or hyperglycemias with this regimen, dietary carbohydrate (CH) intake must be synchronized with the time course of insulin absorption from the s.c. depot. Caloric intake is to be distributed (50% CH, 30% fat, 20% protein) in small meals over the day so as to achieve a steady CH supply—snacks, late night meal. Rapidly absorbable CH

Hormones 261

Time

L 10 12 B D 14 S 16 L 18 Healthy subject 20 S B = Breakfast 22 S = Snack L = Lunch 24 D = Dinner D

N = Supper Carbohydrate 2 B absorption Blood sugar 4 N Insulin release from pancreas L 6 Carbohydrate absorption 8 Blood sugar 10 Insulin release from depot 12 Feast B S 16 L 18 no lunch Glucose S 22 24 Feast 2 B 4 6 L 8 10 12 B Diabetic D 14 16 S L

20 22 24

A. Control of blood sugar in healthy and diabetic subjects

262 Hormones

Treatment of Maturity-Onset (Type II) Therapy of first choice is weight Diabetes Mellitus reduction, not administration of drugs! Should the diabetic condition fail In overweight adults, a diabetic meta- to resolve, consideration should first be bolic condition may develop (type II or given to insulin replacement (p. 260). non-insulin-dependent diabetes) when Oral antidiabetics of the sulfonylurea there is a relative insulin deficiency— type increase the sensitivity of B-cells enhanced demand cannot be met by a towards glucose, enabling them to in- diminishing insulin secretion. The crease release of insulin. These drugs cause of increased insulin require- probably promote depolarization of the ment is a loss of insulin receptors or an β-cell membrane by closing off ATP-gat- impairment of the signal cascade acti- ed K+ channels. Normally, these chan- vated by the insulin receptor. Accord- nels are closed when intracellular levels ingly, insulin sensitivity of cells de- of glucose, hence of ATP, increase. This clines. This can be illustrated by com- drug class includes tolbutamide (500– paring concentration-binding curves in 2000 mg/d) and glyburide (glibencla- cells from normal and obese individuals mide) (1.75–10.5 mg/d). In some pa- (A). In the obese, the maximum binding tients, it is not possible to stimulate in- possible (plateau of curve) is displaced sulin secretion from the outset; in oth- downward, indicative of the reduction ers, therapy fails later on. Matching dos- in receptor numbers. Also, at low insulin age of the oral antidiabetic and caloric concentrations, there is less binding of intake follows the same principles as insulin, compared with the control con- apply to insulin. Hypoglycemia is the dition. For a given metabolic effect a most important unwanted effect. En- certain number of receptors must be oc- hancement of the hypoglycemic effect cupied. As shown by the binding curves can result from drug interactions: dis- (dashed lines), this can still be achieved placement of antidiabetic drug from with a reduced receptor number, al- plasma protein-binding sites by sulfon- though only at a higher concentration of amides or acetylsalicylic acid. insulin. Metformin, a biguanide deriva- Development of adult diabetes tive, can lower excessive blood glucose (B). Compared with a normal subject, levels, provided that insulin is present. the obese subject requires a continually Metformin does not stimulate insulin re- elevated output of insulin (orange lease. Glucose release from the liver is curves) to avoid an excessive rise of decreased, while peripheral uptake is blood glucose levels (green curves) dur- enhanced. The danger of hypoglycemia ing a glucose load. When the secretory apparently is not increased. Frequent capacity of the pancreas decreases, this adverse effects include: anorexia, nau- is first noted as a rise in blood glucose sea, and diarrhea. Overproduction of lac- during glucose loading (latent diabetes). tic acid (lactate acidosis, lethality 50%) is Subsequently, not even the fasting a rare, potentially fatal reaction. Metfor- blood level can be maintained (mani- min is used in combination with sulfony- fest, overt diabetes). A diabetic condi- lureas or by itself. It is contraindicated in tion has developed, although insulin re- renal insufficiency and should therefore lease is not lower than that in a healthy be avoided in elderly patients. person (relative insulin deficiency). Thiazolidinediones (Glitazones: ro- Treatment. Caloric restriction to siglitazone, pioglitazone) are insulin- restore body weight to normal is asso- sensitizing agents that augment tissue ciated with an increase in insulin recep- responsiveness by promoting the syn- tor number or cellular responsiveness. thesis or the availability of plasmalem- The releasable amount of insulin is mal glucose transporters via activation again adequate to maintain a normal of a transcription factor (peroxisome metabolic rate. proliferator-activated receptor-γ).

Hormones 263

Insulin binding Normal receptor number

Insulin receptor Normal binding diet needed for euglycemia Decreased receptor number

Obesity Insulin concentration A. Insulin concentration and binding in normal and overweight subjects Oral antidiabetic

Time Glucose in blood Insulin release

Diagnosis: latent overt Diabetes mellitus Therapy of 1st choice Therapy of 2nd choice

B. Development of maturity-onset diabetes

Membrane K+ Sulfonylurea derivatives depolarization Blockade

Insulin ATP Glucose B cell Tolbutamide C. Action of oral antidiabetic drugs

264 Hormones

Drugs for Maintaining Calcium use aims at replacement. Mostly, vit. D is Homeostasis given; in liver disease calcifediol may be indicated, in renal disease calcitriol. Ef- At rest, the intracellular concentration fectiveness, as well as rate of onset and of free calcium ions (Ca2+) is kept at cessation of action, increase in the order 0.1 µM (see p. 128 for mechanisms in- vit. D. < 25-OH-vit. D < 1,25-di-OH-vit. volved). During excitation, a transient D. Overdosage may induce hypercal- rise of up to 10 µM elicits contraction in cemia with deposits of calcium salts in muscle cells (electromechanical coup- tissues (particularly in kidney and blood ling) and secretion in glandular cells vessels): calcinosis. (electrosecretory coupling). The cellular The polypeptide parathormone is content of Ca2+ is in equilibrium with released from the parathyroid glands the extracellular Ca2+ concentration when plasma Ca2+ level falls. It stimu- (approx. 1000 µM), as is the plasma pro- lates osteoclasts to increase bone resorp- tein-bound fraction of calcium in blood. tion; in the kidneys, it promotes calcium Ca2+ may crystallize with phosphate to reabsorption, while phosphate excre- form hydroxyapatite, the mineral of tion is enhanced. As blood phosphate bone. Osteoclasts are phagocytes that concentration diminishes, the tendency mobilize Ca2+ by resorption of bone. of calcium to precipitate as bone miner- Slight changes in extracellular Ca2+ con- al decreases. By stimulating the forma- centration can alter organ function: tion of vit. D hormone, parathormone thus, excitability of skeletal muscle in- has an indirect effect on the enteral up- creases markedly as Ca2+ is lowered take of Ca2+ and phosphate. In parathor- (e.g., in hyperventilation tetany). Three mone deficiency, vitamin D can be used hormones are available to the body for as a substitute that, unlike parathor- maintaining a constant extracellular mone, is effective orally. Ca2+ concentration. The polypeptide calcitonin is se- Vitamin D hormone is derived creted by thyroid C-cells during immi- from vitamin D (cholecalciferol). Vitamin nent hypercalcemia. It lowers plasma D can also be produced in the body; it is Ca2+ levels by inhibiting osteoclast activ- formed in the skin from dehydrocholes- ity. Its uses include hypercalcemia and terol during irradiation with UV light. osteoporosis. Remarkably, calcitonin in- When there is lack of solar radiation, jection may produce a sustained analge- dietary intake becomes essential, cod sic effect that is not restricted to bone liver oil being a rich source. Metaboli- pain. cally active vitamin D hormone results Hypercalcemia can be treated by from two successive hydroxylations: in (1) administering 0.9% NaCl solution the liver at position 25 ( calcifediol) plus furosemide (if necessary) renal and in the kidney at position 1 ( calci- excretion ; (2) the osteoclast inhibi- triol = vit. D hormone). 1-Hydroxylation tors calcitonin, plicamycin, or clodro- depends on the level of calcium homeo- nate (a bisphosphonate) bone cal- stasis and is stimulated by parathor- cium mobilization ; (3) the Ca2+ chela- mone and a fall in plasma levels of Ca2+ tors EDTA sodium or sodium citrate; as or phosphate. Vit. D hormone promotes well as (4) glucocorticoids. enteral absorption and renal reabsorption of Ca2+ and phosphate. As a result of the increased Ca2+ and phosphate concentration in blood, there is an increased tendency for these ions to be deposited in bone in the form of hydroxyapatite crystals. In vit. D deficiency, bone mineralization is inadequate (rickets, osteomalacia). Therapeutic

Hormones 265

Electrical excitability Bone trabeculae Hydroxyapatite crystals ~1 x 10-7M Ca (PO ) (OH) 2+ -3 2+ 3- 10 4 6 2 Ca 1 x 10 M Ca + PO4

Muscle cell Gland cell Ca Ca ~1 x 10 Osteoclast -5 ~10 M -3

Effect on cell function Effect M Ca2+

Contraction Secretion Albumin Globulin

Skin 2+ , 3- Parathyroid hormone, Ca PO4

25 25

7 7-Dehydrocholesterol

Cholecalciferol 25-Hydroxychole- 1,25-Dihydroxychole- (vitamin D3) calciferol calciferol (calcitriol) 50-5000µg/day (calcifediol) 0,5-2µg/day

Cod liver oil Vit. D-Hormone Parafollicular Parathyroid cells of Ca2+ glands thyroid

Calcitonin Parathyroid hormone

2+ 3- Ca + PO4

A. Calcium homeostasis of the body

266 Antibacterial Drugs

Antibacterial Drugs can be classified according to their respective primary mode of action (color Drugs for Treating Bacterial Infections tone in 2 and 3). When bacteria overcome the cutaneous When bacterial growth remains un- or mucosal barriers and penetrate body affected by an antibacterial drug, bacte- tissues, a bacterial infection is present. rial resistance is present. This may oc- Frequently the body succeeds in remov- cur because of certain metabolic charac- ing the invaders, without outward signs teristics that confer a natural insensitiv- of disease, by mounting an immune re- ity to the drug on a particular strain of sponse. If bacteria multiply faster than bacteria (natural resistance). Depending the body’s defenses can destroy them, on whether a drug affects only a few or infectious disease develops with inflam- numerous types of bacteria, the terms matory signs, e.g., purulent wound in- narrow-spectrum (e.g., penicillin G) or fection or urinary tract infection. Appro- broad-spectrum (e.g., tetracyclines) priate treatment employs substances antibiotic are applied. Naturally sus- that injure bacteria and thereby prevent ceptible bacterial strains can be trans- their further multiplication, without formed under the influence of antibac- harming cells of the host organism (1). terial drugs into resistant ones (acquired Apropos nomenclature: antibiotics resistance), when a random genetic al- are produced by microorganisms (fungi, teration (mutation) gives rise to a resist- bacteria) and are directed “against life” ant bacterium. Under the influence of at any phylogenetic level (prokaryotes, the drug, the susceptible bacteria die eukaryotes). Chemotherapeutic agents off, whereas the mutant multiplies un- originate from chemical synthesis. This impeded. The more frequently a given distinction has been lost in current us- drug is applied, the more probable the age. emergence of resistant strains (e.g., hos- Specific damage to bacteria is partic- pital strains with multiple resistance)! ularly practicable when a substance Resistance can also be acquired interferes with a metabolic process that when DNA responsible for nonsuscepti- occurs in bacterial but not in host cells. bility (so-called resistance plasmid) is Clearly this applies to inhibitors of cell passed on from other resistant bacteria wall synthesis, because human and ani- by conjugation or transduction. mal cells lack a cell wall. The points of attack of antibacterial agents are schematically illustrated in a grossly simplified bacterial cell, as depicted in (2). In the following sections, polymyxins and tyrothricin are not considered further. These polypeptide antibiotics enhance cell membrane permeability. Due to their poor tolerability, they are prescribed in humans only for topical use. The effect of antibacterial drugs can be observed in vitro (3). Bacteria multiply in a growth medium under control conditions. If the medium contains an antibacterial drug, two results can be discerned: 1. bacteria are killed—bactericidal effect; 2. bacteria survive, but do not multiply—bacteriostatic effect. Al- though variations may occur under therapeutic conditions, different drugs

Antibacterial Drugs 267

Anti- bacterial Bacterial drugs invasion: infection

Selective antibacterial toxicity Immune defenses Body cells Bacteria 1.

Penicillins Bacitracin Polymyxins Cephalosporins Vancomycin Tyrothricin

Cell wall DNA RNA Cell membrane Tetrahydro- folate Protein synthesis

Sulfonamides Tetracyclines Rifampin Bacterium Trimethoprim Aminoglycosides Chloramphenicol "Gyrase-inhibitors" Erythromycin Nitroimidazoles Clindamycin 2.

1 day Resistance

Antibiotic

Insensitive strain

Bactericidal

Sensitive strain with Selection Bacteriostatic resistant mutant 3. A. Principles of antibacterial therapy

268 Antibacterial Drugs

Inhibitors of Cell Wall Synthesis (incidence up to 5%), with manifestations ranging from skin eruptions to In most bacteria, a cell wall surrounds anaphylactic shock (in less than 0.05% of the cell like a rigid shell that protects patients). Known penicillin allergy is a against noxious outside influences and contraindication for these drugs. Be- prevents rupture of the plasma mem- cause of an increased risk of sensitiza- brane from a high internal osmotic tion, penicillins must not be used local- pressure. The structural stability of the ly. Neurotoxic effects, mostly convul- cell wall is due mainly to the murein sions due to GABA antagonism, may oc- (peptidoglycan) lattice. This consists of cur if the brain is exposed to extremely basic building blocks linked together to high concentrations, e.g., after rapid i.v. form a large macromolecule. Each basic injection of a large dose or intrathecal unit contains the two linked aminosug- injection. ars N-acetylglucosamine and N-acetyl- Penicillin G undergoes rapid renal muramyl acid; the latter bears a peptide elimination mainly in unchanged form chain. The building blocks are synthe- (plasma t1/2 ~ 0.5 h). The duration of sized in the bacterium, transported out- the effect can be prolonged by: ward through the cell membrane, and 1. Use of higher doses, enabling plas- assembled as illustrated schematically. ma levels to remain above the minimal- The enzyme transpeptidase cross-links ly effective antibacterial concentration; the peptide chains of adjacent amino- 2. Combination with probenecid. Re- sugar chains. nal elimination of penicillin occurs Inhibitors of cell wall synthesis chiefly via the anion (acid)-secretory are suitable antibacterial agents, be- system of the proximal tubule (-COOH cause animal and human cells lack a cell of 6-APA). The acid probenecid (p. 316) wall. They exert a bactericidal action on competes for this route and thus retards growing or multiplying germs. Mem- penicillin elimination; bers of this class include β-lactam anti- 3. Intramuscular administration in biotics such as the penicillins and cepha- depot form. In its anionic form (-COO-) losporins, in addition to bacitracin and penicillin G forms poorly water-soluble vancomycin. salts with substances containing a posi- Penicillins (A). The parent sub- tively charged amino group (procaine, stance of this group is penicillin G (ben- p. 208; clemizole, an antihistamine; zylpenicillin). It is obtained from cul- benzathine, dicationic). Depending on tures of mold fungi, originally from Pen- the substance, release of penicillin from icillium notatum. Penicillin G contains the depot occurs over a variable inter- the basic structure common to all peni- val. cillins, 6-amino-penicillanic acid (p. 271, 6-APA), comprised of a thiazolidine and a 4-membered β-lactam ring. 6- APA itself lacks antibacterial activity. Penicillins disrupt cell wall synthesis by inhibiting transpeptidase. When bacteria are in their growth and replication phase, penicillins are bactericidal; due to cell wall defects, the bacteria swell and burst. Penicillins are generally well tolerated; with penicillin G, the daily dose can range from approx. 0.6 g i.m. (= 106 international units, 1 Mega I.U.) to 60 g by infusion. The most important adverse effects are due to hypersensitivity

Antibacterial Drugs 269

Cell wall Cell membrane

Bacterium Cross-linked by transpeptidase

Amino acid Inhibition of chain cell wall synthesis Cell wall Sugar building block

Human Antibody

Penicillin Penicillin G allergy

Neurotoxicity at very high dosage Fungus Penicillium notatum

Plasma concentration + Penicillin -

Procaine Penicillin 3 x Dose ~1 Minimal + bactericidal - concentration Clemizole Penicillin Probenecid + + ~2 - Anion secretory Benzathine system 2 Penicillins Time ~7-28 Duration of action (d) Increasing the dose Combination with probenecid Depot preparations

A. Penicillin G: structure and origin; mode of action of penicillins; methods for prolonging duration of action

270 Antibacterial Drugs

Although very well tolerated, peni- Cephalosporins (C). These β-lac- cillin G has disadvantages (A) that limit tam antibiotics are also fungal products its therapeutic usefulness: (1) It is inac- and have bactericidal activity due to in- tivated by gastric acid, which cleaves hibition of transpeptidase. Their the β-lactam ring, necessitating paren- shared basic structure is 7-aminocepha- teral administration. (2) The β-lactam losporanic acid, as exemplified by ring can also be opened by bacterial en- cephalexin (gray rectangle). Cephalo- zymes (β-lactamases); in particular, sporins are acid stable, but many are penicillinase, which can be produced by poorly absorbed. Because they must be staphylococcal strains, renders them re- given parenterally, most—including sistant to penicillin G. (3) The antibacte- those with high activity—are used only rial spectrum is narrow; although it en- in clinical settings. A few, e.g., cepha- compasses many gram-positive bacte- lexin, are suitable for oral use. Cephalo- ria, gram-negative cocci, and spiro- sporins are penicillinase-resistant, but chetes, many gram-negative pathogens cephalosporinase-forming organisms are unaffected. do exist. Some derivatives are, however, Derivatives with a different sub- also resistant to this β-lactamase. stituent on 6-APA possess advantages Cephalosporins are broad-spectrum (B): (1) Acid resistance permits oral ad- antibacterials. Newer derivatives (e.g., ministration, provided that enteral ab- cefotaxime, cefmenoxin, cefoperazone, sorption is possible. All derivatives ceftriaxone, ceftazidime, moxalactam) shown in (B) can be given orally. Penicil- are also effective against pathogens re- lin V (phenoxymethylpenicillin) exhib- sistant to various other antibacterials. its antibacterial properties similar to Cephalosporins are mostly well tolerat- those of penicillin G. (2) Due to their ed. All can cause allergic reactions, some penicillinase resistance, isoxazolylpen- also renal injury, alcohol intolerance, icillins (oxacillin dicloxacillin, flucloxacil- and bleeding (vitamin K antagonism). lin) are suitable for the (oral) treatment Other inhibitors of cell wall syn- of infections caused by penicillinase- thesis. Bacitracin and vancomycin producing staphylococci. (3) Extended interfere with the transport of pepti- activity spectrum: The aminopenicillin doglycans through the cytoplasmic amoxicillin is active against many gram- membrane and are active only against negative organisms, e.g., coli bacteria or gram-positive bacteria. Bacitracin is a Salmonella typhi. It can be protected polypeptide mixture, markedly nephro- from destruction by penicillinase by toxic and used only topically. Vancomy- combination with inhibitors of penicilli- cin is a glycopeptide and the drug of nase (clavulanic acid, sulbactam, tazo- choice for the (oral) treatment of bowel bactam). inflammations occurring as a complica- The structurally close congener am- tion of antibiotic therapy (pseudomem- picillin (no 4-hydroxy group) has a simi- branous enterocolitis caused by Clos- lar activity spectrum. However, because tridium difficile). It is not absorbed. it is poorly absorbed (<50%) and therefore causes more extensive damage to the gut microbial flora (side effect: diarrhea), it should be given only by injection. A still broader spectrum (including Pseudomonas bacteria) is shown by car- boxypenicillins (carbenicillin, ticarcillin) and acylaminopenicillins (mezclocillin, azlocillin, piperacillin). These substances are neither acid stable nor penicillinase resistant.

Antibacterial Drugs 271

6-Aminopenicillanic acid

Salmonella typhi Not active Penicillin G E. coli

Acid sensitivity Penicillinase sensitivity

Gonococci

H+Cl-

Penicillinase Active Pneumococci

Gram-positive Gram-negative Narrow-action spectrum Narrow-action Staphylococci Streptococci

A. Disadvantages of penicillin G

Concentration needed to inhibit penicillin G- AcidPenicillinase Spectrum sensitive bacteria

Penicillin V Resis- Sensitive tant Narrow

Resis- Resistant tant Oxacillin Narrow

Resis- Resistant tant Amoxicillin Broad B. Derivatives of penicillin G

Cefalexin Resistant, but sensitive Resis- to tant cephalosporinase Broad

C. Cephalosporin

272 Antibacterial Drugs

Inhibitors of Tetrahydrofolate Synthesis Introduced in 1935, they were the first broad-spectrum chemotherapeutics. Tetrahydrofolic acid (THF) is a co-en- Trimethoprim inhibits bacterial zyme in the synthesis of purine bases DHF reductase, the human enzyme be- and thymidine. These are constituents ing significantly less sensitive than the of DNA and RNA and required for cell bacterial one (rarely bone marrow de- growth and replication. Lack of THF pression). A 2,4-diaminopyrimidine, tri- leads to inhibition of cell proliferation. methoprim, has bacteriostatic activity Formation of THF from dihydrofolate against a broad spectrum of pathogens. (DHF) is catalyzed by the enzyme dihy- It is used mostly as a component of co- drofolate reductase. DHF is made from trimoxazole. folic acid, a vitamin that cannot be syn- Co-trimoxazole is a combination of thesized in the body, but must be taken trimethoprim and the sulfonamide sul- up from exogenous sources. Most bacte- famethoxazole. Since THF synthesis is ria do not have a requirement for folate, inhibited at two successive steps, the because they are capable of synthesiz- antibacterial effect of co-trimoxazole is ing folate, more precisely DHF, from better than that of the individual com- precursors. Selective interference with ponents. Resistant pathogens are infre- bacterial biosynthesis of THF can be quent; a bactericidal effect may occur. achieved with sulfonamides and tri- Adverse effects correspond to those of methoprim. the components. Sulfonamides structurally resem- Although initially developed as an ble p-aminobenzoic acid (PABA), a pre- antirheumatic agent (p. 320), sulfasala- cursor in bacterial DHF synthesis. As zine (salazosulfapyridine) is used main- false substrates, sulfonamides competi- ly in the treatment of inflammatory tively inhibit utilization of PABA, hence bowel disease (ulcerative colitis and DHF synthesis. Because most bacteria terminal ileitis or Crohn’s disease). Gut cannot take up exogenous folate, they bacteria split this compound into the are depleted of DHF. Sulfonamides thus sulfonamide sulfapyridine and mesala- possess bacteriostatic activity against a mine (5-aminosalicylic acid). The latter broad spectrum of pathogens. Sulfon- is probably the anti-inflammatory agent amides are produced by chemical syn- (inhibition of synthesis of chemotactic thesis. The basic structure is shown in signals for granulocytes, and of H2O2 (A). Residue R determines the pharma- formation in mucosa), but must be cokinetic properties of a given sulfon- present on the gut mucosa in high con- amide. Most sulfonamides are well ab- centrations. Coupling to the sulfon- sorbed via the enteral route. They are amide prevents premature absorption metabolized to varying degrees and in upper small bowel segments. The eliminated through the kidney. Rates of cleaved-off sulfonamide can be ab- elimination, hence duration of effect, sorbed and may produce typical adverse may vary widely. Some members are effects (see above). poorly absorbed from the gut and are Dapsone (p. 280) has several thera- thus suitable for the treatment of bacte- peutic uses: besides treatment of lepro- rial bowel infections. Adverse effects sy, it is used for prevention/prophylaxis may include, among others, allergic re- of malaria, toxoplasmosis, and actino- actions, sometimes with severe skin mycosis. damage, displacement of other plasma protein-bound drugs or bilirubin in neonates (danger of kernicterus, hence contraindication for the last weeks of gestation and in the neonate). Because of the frequent emergence of resistant bacteria, sulfonamides are now rarely used.

Antibacterial Drugs 273

p-Aminobenzoic acid Sulfonamides

R determines Folic acid pharmacokinetics

(Vitamin) Duration of effect

Sulfisoxazole 6 hours Dihydro- folic acid Sulfamethoxazole (DHF) 12 hours

Sulfalene 7 days Dosing interval

DHF-Reductase Co-trimoxazole =

Tetrahydro- folic acid Combination of Trimethoprim and Sulfamethoxazole Trimethoprim

Sulfasalazine (not absorbable)

Synthesis of purines Cleavage by Thymidine intestinal bacteria Bacterium

Mesalamine Sulfapyridine Human cell (absorbable)

A. Inhibitors of tetrahydrofolate synthesis

274 Antibacterial Drugs

Inhibitors of DNA Function DNA by complex formation or strand breakage. This occurs in obligate an- Deoxyribonucleic acid (DNA) serves as a aerobes, i.e., bacteria growing under O2 template for the synthesis of nucleic ac- exclusion. Under these conditions, con- ids. Ribonucleic acid (RNA) executes version to reactive metabolites that at- protein synthesis and thus permits cell tack DNA takes place (e.g., the hydroxyl- growth. Synthesis of new DNA is a pre- amine shown). The effect is bactericidal. requisite for cell division. Substances A similar mechanism is involved in the that inhibit reading of genetic informa- antiprotozoal action on Trichomonas vation at the DNA template damage the ginalis (causative agent of vaginitis and regulatory center of cell metabolism. urethritis) and Entamoeba histolytica The substances listed below are useful (causative agent of large bowel inflam- as antibacterial drugs because they do mation, amebic dysentery, and hepatic not affect human cells. abscesses). Metronidazole is well ab- Gyrase inhibitors. The enzyme gy- sorbed via the enteral route; it is also rase (topoisomerase II) permits the or- given i.v. or topically (vaginal insert). derly accommodation of a ~1000 µm- Because metronidazole is considered long bacterial chromosome in a bacteri- potentially mutagenic, carcinogenic, al cell of ~1 µm. Within the chromoso- and teratogenic in the human, it should mal strand, double-stranded DNA has a not be used longer than 10 d, if possible, double helical configuration. The for- and be avoided during pregnancy and mer, in turn, is arranged in loops that lactation. Timidazole may be considered are shortened by supercoiling. The gy- equivalent to metronidazole. rase catalyzes this operation, as illus- Rifampin inhibits the bacterial en- trated, by opening, underwinding, and zyme that catalyzes DNA template-di- closing the DNA double strand such that rected RNA transcription, i.e., DNA-de- the full loop need not be rotated. pendent RNA polymerase. Rifampin acts Derivatives of 4-quinolone-3-car- bactericidally against mycobacteria (M. boxylic acid (green portion of ofloxacin tuberculosis, M. leprae), as well as many formula) are inhibitors of bacterial gy- gram-positive and gram-negative bac- rases. They appear to prevent specifical- teria. It is well absorbed after oral inges- ly the resealing of opened strands and tion. Because resistance may develop thereby act bactericidally. These agents with frequent usage, it is restricted to are absorbed after oral ingestion. The the treatment of tuberculosis and lepro- older drug, nalidixic acid, affects exclu- sy (p. 280). sively gram-negative bacteria and at- Rifampin is contraindicated in the tains effective concentrations only in first trimester of gestation and during urine; it is used as a urinary tract anti- lactation. septic. Norfloxacin has a broader spec- Rifabutin resembles rifampin but trum. Ofloxacin, ciprofloxacin, and may be effective in infections resistant enoxacin, and others, also yield system- to the latter. ically effective concentrations and are used for infections of internal organs. Besides gastrointestinal problems and allergy, adverse effects particularly involve the CNS (confusion, hallucinations, seizures). Since they can damage epiphyseal chondrocytes and joint car- tilages in laboratory animals, gyrase inhibitors should not be used during pregnancy, lactation, and periods of growth. Azomycin (nitroimidazole) derivatives, such as metronidazole, damage

Antibacterial Drugs 275

1 Gyrase inhibitors 4-Quinolone- 2 3-carboxylate- derivates, e. g.

3 ofloxacin

4 Twisting by opening, underwinding, and closure of DNA strand

Gyrase DNA-double helix

Indication: TB

Bacterial chromosome

Rifampicin DNA-dependent RNA polymerase

Streptomyces species

Damage RNA to DNA

Trichomonas infection

Nitroimidazole

Amebic infection

Anaerobic bacteria e. g., metronidazole

A. Antibacterial drugs acting on DNA

276 Antibacterial Drugs

Inhibitors of Protein Synthesis mainly gram-negative organisms. Streptomycin and kanamycin are used Protein synthesis means translation predominantly in the treatment of tu- into a peptide chain of a genetic mes- berculosis. sage first copied (transcribed) into m- Note on spelling: -mycin designates RNA (p. 274). Amino acid (AA) assembly origin from Streptomyces species; -mi- occurs at the ribosome. Delivery of ami- cin (e.g., gentamicin) from Micromono- no acids to m-RNA involves different spora species. transfer RNA molecules (t-RNA), each of 2. Chloramphenicol inhibits pep- which binds a specific AA. Each t-RNA tide synthetase. It has bacteriostatic ac- bears an “anticodon” nucleobase triplet tivity against a broad spectrum of that is complementary to a particular pathogens. The chemically simple mole- m-RNA coding unit (codon, consisting of cule is now produced synthetically. 3 nucleobases. 3. Erythromycin suppresses ad- Incorporation of an AA normally in- vancement of the ribosome. Its action is volves the following steps (A): predominantly bacteriostatic and di- 1. The ribosome “focuses” two co- rected against gram-positve organisms. dons on m-RNA; one (at the left) has For oral administration, the acid-labile bound its t-RNA-AA complex, the AA base (E) is dispensed as a salt (E. stear- having already been added to the pep- ate) or an ester (e.g., E. succinate). tide chain; the other (at the right) is Erythromycin is well tolerated. It is a ready to receive the next t-RNA-AA suitable substitute in penicillin allergy complex. or resistance. Azithromycin, clarithromy- 2. After the latter attaches, the AAs cin, and roxithromycin are derivatives of the two adjacent complexes are with greater acid stability and better linked by the action of the enzyme pep- bioavailability. The compounds men- tide synthetase (peptidyltransferase). tioned are the most important members Concurrently, AA and t-RNA of the left of the macrolide antibiotic group, which complex disengage. includes josamycin and spiramycin. An 3. The left t-RNA dissociates from unrelated action of erythromycin is its m-RNA. The ribosome can advance mimicry of the gastrointestinal hor- along the m-RNA strand and focus on mone motiline ( interprandial bowel the next codon. motility). 4. Consequently, the right t-RNA- Clindamycin has antibacterial ac- AA complex shifts to the left, allowing tivity similar to that of erythromycin. It the next complex to be bound at the exerts a bacteriostatic effect mainly on right. gram-positive aerobic, as well as on an- These individual steps are suscepti- aerobic pathogens. Clindamycin is a ble to inhibition by antibiotics of differ- semisynthetic chloro analogue of lin- ent groups. The examples shown origi- comycin, which derives from a Strepto- nate primarily from Streptomyces bac- myces species. Taken orally, clindamy- teria, some of the aminoglycosides also cin is better absorbed than lincomycin, being derived from Micromonospora has greater antibacterial efficacy and is bacteria. thus preferred. Both penetrate well into 1a. Tetracyclines inhibit the bind- bone tissue. ing of t-RNA-AA complexes. Their action is bacteriostatic and affects a broad spectrum of pathogens. 1b. Aminoglycosides induce the binding of “wrong” t-RNA-AA complexes, resulting in synthesis of false proteins. Aminoglycosides are bactericidal. Their activity spectrum encompasses

Antibacterial Drugs 277

mRNA

Ribosome Tetracyclines Doxycycline

Amino acid tRNA Insertion of incorrect amino acid Peptide chain Aminoglycosides Tobramycin

Chloramphenicol

Chloramphenicol Peptide synthetase

Erythromycin

Streptomyces species

A. Protein synthesis and modes of action of antibacterial drugs

278 Antibacterial Drugs

Tetracyclines are absorbed from pression must also be taken into ac- the gastrointestinal tract to differing de- count after local use (e.g., eye drops). grees, depending on the substance, ab- Aminoglycoside antibiotics con- sorption being nearly complete for sist of glycoside-linked amino-sugars doxycycline and minocycline. Intrave- (cf. gentamicin C1α, a constituent of the nous injection is rarely needed (rolite- gentamicin mixture). They contain nu- tracycline is available only for i.v. ad- merous hydroxyl groups and amino ministration). The most common un- groups that can bind protons. Hence, wanted effect is gastrointestinal upset these compounds are highly polar, (nausea, vomiting, diarrhea, etc.) due to poorly membrane permeable, and not (1) a direct mucosal irritant action of absorbed enterally. Neomycin and paro- these substances and (2) damage to the momycin are given orally to eradicate natural bacterial gut flora (broad-spec- intestinal bacteria (prior to bowel sur- trum antibiotics) allowing colonization gery or for reducing NH3 formation by by pathogenic organisms, including gut bacteria in hepatic coma). Amino- Candida fungi. Concurrent ingestion of glycosides for the treatment of serious antacids or milk would, however, be in- infections must be injected (e.g., gen- appropriate because tetracyclines form tamicin, tobramycin, amikacin, netilmi- insoluble complexes with plurivalent cin, sisomycin). In addition, local inlays cations (e.g., Ca2+, Mg2+, Al3+, Fe2+/3+) re- of a gentamicin-releasing carrier can be sulting in their inactivation; that is, abused in infections of bone or soft tissues. sorbability, antibacterial activity, and Aminoglycosides gain access to the bac- local irritant action are abolished. The terial interior by the use of bacterial ability to chelate Ca2+ accounts for the transport systems. In the kidney, they propensity of tetracyclines to accumu- enter the cells of the proximal tubules late in growing teeth and bones. As a re- via an uptake system for oligopeptides. sult, there occurs an irreversible yellow- Tubular cells are susceptible to damage brown discoloration of teeth and a rever- (nephrotoxicity, mostly reversible). In sible inhibition of bone growth. Because the inner ear, sensory cells of the vestib- of these adverse effects, tetracycline ular apparatus and Corti’s organ may be should not be given after the second injured (ototoxicity, in part irreversible). month of pregnancy and not prescribed to children aged 8 y and under. Other adverse effects are increased photosen- sitivity of the skin and hepatic damage, mainly after i.v. administration. The broad-spectrum antibiotic chloramphenicol is completely absorbed after oral ingestion. It undergoes even distribution in the body and readily crosses diffusion barriers such as the blood-brain barrier. Despite these advantageous properties, use of chloramphenicol is rarely indicated (e.g., in CNS infections) because of the danger of bone marrow damage. Two types of bone marrow depression can occur: (1) a dose-dependent, toxic, reversible form manifested during therapy and, (2) a frequently fatal form that may occur after a latency of weeks and is not dose dependent. Due to high tissue penetrability, the danger of bone marrow de-

Antibacterial Drugs 279

Tetracyclines Chloramphenicol

Inactivation by chelation of Ca2+, Al3+ etc. Advantage: good penetration through barriers

Irritation of mucous membranes

Absorption

Antibacterial Chelation effect on Disadvantage: gut flora bone marrow toxicity

e.g., neomycin

Gentamicin C1a Cochlear and vestibular High hydrophilicity ototoxicity no passive diffusion H+ through membranes + H+ H Basic oligopeptides Transport system

Nephro- Bacterium toxicity

No absorption "bowel sterilization"

A. Aspects of the therapeutic use of tetracyclines, chloramphenicol, and aminoglycosides

280 Antibacterial Drugs

Drugs for Treating Mycobacterial contraceptives). Concerning rifabutin Infections see p. 274. Ethambutol. The cause of its specific Mycobacteria are responsible for two antitubercular action is unknown. diseases: tuberculosis, mostly caused by Ethambutol is given orally. It is general- M. tuberculosis, and leprosy due to M. le- ly well tolerated, but may cause dose- prae. The therapeutic principle appli- dependent damage to the optic nerve cable to both is combined treatment with disturbances of vision (red/green with two or more drugs. Combination blindness, visual field defects). therapy prevents the emergence of re- Pyrazinamide exerts a bactericidal sistant mycobacteria. Because the anti- action by an unknown mechanism. It is bacterial effects of the individual sub- given orally. Pyrazinamide may impair stances are additive, correspondingly liver function; hyperuricemia results smaller doses are sufficient. Therefore, from inhibition of renal urate elimina- the risk of individual adverse effects is tion. lowered. Most drugs are active against Streptomycin must be given i.v. (pp. only one of the two diseases. 278ff) like other aminoglycoside antibiotics. It damages the inner ear and the Antitubercular Drugs (1) labyrinth. Its nephrotoxicity is compar- atively minor. Drugs of choice are: isoniazid, rifampin, ethambutol, along with streptomycin Antileprotic Drugs (2) and pyrazinamide. Less well tolerated, second-line agents include: p-aminosal- Rifampin is frequently given in combi- icylic acid, cycloserine, viomycin, ka- nation with one or both of the following namycin, amikacin, capreomycin, ethi- agents: onamide. Dapsone is a sulfone that, like sul- Isoniazid is bactericidal against fonamides, inhibits dihydrofolate syn- growing M. tuberculosis. Its mechanism thesis (p. 272). It is bactericidal against of action remains unclear. (In the bacte- susceptible strains of M. leprae. Dapsone rium it is converted to isonicotinic acid, is given orally. The most frequent ad- which is membrane impermeable, verse effect is methemoglobinemia with hence likely to accumulate intracellu- accelerated erythrocyte degradation larly.) Isoniazid is rapidly absorbed after (hemolysis). oral administration. In the liver, it is in- Clofazimine is a dye with bacterici- activated by acetylation, the rate of dal activity against M. leprae and anti- which is genetically controlled and inflammatory properties. It is given shows a characteristic distribution in orally, but is incompletely absorbed. Be- different ethnic groups (fast vs. slow cause of its high lipophilicity, it accu- acetylators). Notable adverse effects mulates in adipose and other tissues are: peripheral neuropathy, optic neu- and leaves the body only rather slowly ritis preventable by administration of (t1/2 ~ 70 d). Red-brown skin pigmenta- vitamin B6 (pyridoxine); hepatitis, jaun- tion is an unwanted effect, particularly dice. in fair-skinned patients. Rifampin. Source, antibacterial activity, and routes of administration are described on p. 274. Albeit mostly well tolerated, this drug may cause several adverse effects including hepatic damage, hypersensitivity with flu-like symptoms, disconcerting but harmless red/orange discoloration of body fluids, and enzyme induction (failure of oral

Antibacterial Drugs 281

Combination therapy Reduced risk of Reduction of dose and of bacterial resistance risk of adverse reactions

Isoniazid Pyrazinamide

Mycobacterium CNS damage tuberculosis and peripheral neuropathy Liver damage (Vit. B6-administration) Liver damage Streptomycin Ethambutol Isonicotinic acid an aminoglycoside antibiotic

Nicotinic acid Optic nerve damage

Rifampin

Vestibular and 1 cochlear ototoxicity

Liver damage and enzyme induction

Clofazimine p-Aminobenzoic acid

Folate Dapsone synthesis

Mycobacterium Hemolysis leprae Skin discoloration

A. Drugs used to treat infections with mycobacteria (1. tuberculosis, 2. leprosy)

282 Antifungal Drugs

Drugs Used in the Treatment of gal cell membranes (probably next to Fungal Infections ergosterol molecules) and cause formation of hydrophilic channels. The resul- Infections due to fungi are usually con- tant increase in membrane permeabil- fined to the skin or mucous membranes: ity, e.g., to K+ ions, accounts for the fun- local or superficial mycosis. However, in gicidal effect. Amphotericin B is active immune deficiency states, internal or- against most organisms responsible for gans may also be affected: systemic or systemic mycoses. Because of its poor deep mycosis. absorbability, it must be given by infu- Mycoses are most commonly due to sion, which is, however, poorly tolerat- dermatophytes, which affect the skin, ed (chills, fever, CNS disturbances, im- hair, and nails following external infec- paired renal function, phlebitis at the tion. Candida albicans, a yeast organism infusion site). Applied topically to skin normally found on body surfaces, may or mucous membranes, amphotericin B cause infections of mucous membranes, is useful in the treatment of candidal less frequently of the skin or internal or- mycosis. Because of the low rate of en- gans when natural defenses are im- teral absorption, oral administration in paired (immunosuppression, or damage intestinal candidiasis can be considered of microflora by broad-spectrum antibi- a topical treatment. Nystatin is used on- otics). ly for topical therapy. Imidazole derivatives inhibit er- Flucytosine is converted in candida gosterol synthesis. This steroid forms an fungi to 5-fluorouracil by the action of a integral constituent of cytoplasmic specific cytosine deaminase. As an anti- membranes of fungal cells, analogous to metabolite, this compound disrupts cholesterol in animal plasma mem- DNA and RNA synthesis (p. 298), result- branes. Fungi exposed to imidazole de- ing in a fungicidal effect. Given orally, rivatives stop growing (fungistatic ef- flucytosine is rapidly absorbed. It is well fect) or die (fungicidal effect). The spec- tolerated and often combined with am- trum of affected fungi is very broad. Be- photericin B to allow dose reduction of cause they are poorly absorbed and the latter. poorly tolerated systemically, most Griseofulvin originates from molds imidazoles are suitable only for topical and has activity only against derma- use (clotrimazole, econazole oxiconazole, tophytes. Presumably, it acts as a spin- isoconazole, bifonazole, etc.). Rarely, this dle poison to inhibit fungal mitosis. Al- use may result in contact dermatitis. Mi- though targeted against local mycoses, conazole is given locally, or systemically griseofulvin must be used systemically. by short-term infusion (despite its poor It is incorporated into newly formed tolerability). Because it is well absorbed, keratin. “Impregnated” in this manner, ketoconazole is available for oral admin- keratin becomes unsuitable as a fungal istration. Adverse effects are rare; how- nutrient. The time required for the erad- ever, the possibility of fatal liver dam- ication of dermatophytes corresponds age should be noted. Remarkably, keto- to the renewal period of skin, hair, or conazole may inhibit steroidogenesis nails. Griseofulvin may cause uncharac- (gonadal and adrenocortical hormones). teristic adverse effects. The need for Fluconazole and itraconazole are newer, prolonged administration (several orally effective triazole derivatives. The months), the incidence of side effects, topically active allylamine naftidine and the availability of effective and safe and the morpholine amorolfine also in- alternatives have rendered griseofulvin hibit ergosterol synthesis, albeit at an- therapeutically obsolete. other step. The polyene antibiotics, amphotericin B and nystatin, are of bacterial origin. They insert themselves into fun-

Antifungal Drugs 283

Cell wall Cytoplasmic membrane Imidazole derivatives e.g., clotrimazole

Ergosterol

Synthesis

Griseofulvin

Mitotic spindle Mold fungi DNA/RNA metabolism Incorporation into growing skin, hair, nails "Impregnation effect" 25-50 weeks

2-4 weeks 5-Fluoruracil Uracil

Cytosine Deaminase Fungal cell Polyene Antibiotics

Streptomyces bacteria Amphotericin B Nystatin

Flucytosine

A. Antifungal drugs

284 Antiviral Drugs

Chemotherapy of Viral Infections by means of antibodies that bind to and inactivate extracellular virus particles. Viruses essentially consist of genetic Vaccinations are designed to activate material (nucleic acids, green strands in specific immune defenses. (A) and a capsular envelope made up of Interferons (IFN) are glycoproteins proteins (blue hexagons), often with a that, among other products, are re- coat (gray ring) of a phospholipid (PL) leased from virus-infected cells. In bilayer with embedded proteins (small neighboring cells, interferon stimulates blue bars). They lack a metabolic system the production of “antiviral proteins.” but depend on the infected cell for their These inhibit the synthesis of viral pro- growth and replication. Targeted thera- teins by (preferential) destruction of vi- peutic suppression of viral replication ral DNA or by suppressing its transla- requires selective inhibition of those tion. Interferons are not directed against metabolic processes that specifically a specific virus, but have a broad spec- serve viral replication in infected cells. trum of antiviral action that is, however, To date, this can be achieved only to a species-specific. Thus, interferon for use limited extent. in humans must be obtained from cells Viral replication as exemplified of human origin, such as leukocytes by Herpes simplex viruses (A): (1) The (IFN-α), fibroblasts (IFN-β), or lympho- viral particle attaches to the host cell cytes (IFN-γ). Interferons are also used membrane (adsorption) by linking its to treat certain malignancies and auto- capsular glycoproteins to specific struc- immune disorders (e.g., IFN-α for chron- tures of the cell membrane. (2) The viral ic hepatitis C and hairy cell leukemia; coat fuses with the plasmalemma of the IFN-β for severe herpes virus infections host cell and the nucleocapsid (nucleic and multiple sclerosis). acid plus capsule) enters the cell interi- Virustatic antimetabolites are or (penetration). (3) The capsule opens “false” DNA building blocks (B) or nucle- (“uncoating”) near the nuclear pores osides. A nucleoside (e.g., thymidine) and viral DNA moves into the cell nucle- consists of a nucleobase (e.g., thymine) us. The genetic material of the virus can and the sugar deoxyribose. In antime- now direct the cell’s metabolic system. tabolites, one of the components is de- (4a) Nucleic acid synthesis: The genetic fective. In the body, the abnormal nucle- material (DNA in this instance) is repli- osides undergo bioactivation by attach- cated and RNA is produced for the pur- ment of three phosphate residues pose of protein synthesis. (4b) The pro- (p. 287). teins are used as “viral enzymes” cata- Idoxuridine and congeners are in- lyzing viral multiplication (e.g., DNA corporated into DNA with deleterious polymerase and thymidine kinase), as results. This also applies to the synthesis capsomers, or as coat components, or of human DNA. Therefore, idoxuridine are incorporated into the host cell and analogues are suitable only for topi- membrane. (5) Individual components cal use (e.g., in herpes simplex keratitis). are assembled into new virus particles Vidarabine inhibits virally induced (maturation). (6) Release of daughter vi- DNA polymerase more strongly than it ruses results in spread of virus inside does the endogenous enzyme. Its use is and outside the organism. With herpes now limited to topical treatment of se- viruses, replication entails host cell de- vere herpes simplex infection. Before struction and development of disease the introduction of the better tolerated symptoms. acyclovir, vidarabine played a major Antiviral mechanisms (A). The or- part in the treatment of herpes simplex ganism can disrupt viral replication encephalitis. with the aid of cytotoxic T-lymphocytes Among virustatic antimetabolites, that recognize and destroy virus-pro- acyclovir (A) has both specificity of the ducing cells (viral surface proteins) or highest degree and optimal tolerability,

Antiviral Drugs 285

Virus- Specific immune infected defense e.g., cytotoxic Glycoprotein T-lymphocytes Interferon Proteins with 1. Adsorption antigenic properties

Antiviral proteins

6. Release RNA 2. Penetration Protein 4b.

3.Uncoating Viral DNA synthesis

Nucleic acid polymerase

DNA 4a. Capsule DNA Envelope 5.

A. Virus multiplication and modes of action of antiviral agents

Antimetabolites = incorrect DNA building blocks Correct:

Thymidine Incorrect: R: - I Idoxuridine - CF3 Trifluridine Thymine - C2H2 Edoxudine

Desoxyribose Insertion into Incorrect: DNA instead of thymidine

Vidarabine Acyclovir Ganciclovir

Adenine Guanine

Arabinose

Inhibition of viral DNA polymerase B. Chemical structure of virustatic antimetabolites

286 Antiviral Drugs because it undergoes bioactivation only lated antimetabolite via virally induced in infected cells, where it preferentially thymidine kinase. inhibits viral DNA synthesis. (1) A virally Ganciclovir (structure on p. 285) is coded thymidine kinase (specific to H. given by infusion in the treatment of se- simplex and varicella-zoster virus) per- vere infections with cytomegaloviruses forms the initial phosphorylation step; (also belonging to the herpes group); the remaining two phosphate residues these do not induce thymidine kinase, are attached by cellular kinases. (2) The phosphorylation being initiated by a polar phosphate residues render acyclo- different viral enzyme. Ganciclovir is vir triphosphate membrane imperme- less well tolerated and, not infrequent- able and cause it to accumulate in in- ly, produces leukopenia and thrombo- fected cells. (3) Acyclovir triphosphate penia. is a preferred substrate of viral DNA Foscarnet represents a diphos- polymerase; it inhibits enzyme activity phate analogue. and, following its incorporation into vi- As shown in (A), incorporation of ral DNA, induces strand breakage be- nucleotide into a DNA strand entails cause it lacks the 3’-OH group of deoxy- cleavage of a diphosphate residue. Fos- ribose that is required for the attach- carnet (B) inhibits DNA polymerase by ment of additional nucleotides. The high interacting with its binding site for the therapeutic value of acyclovir is evident diphosphate group. Indications: system- in severe infections with H. simplex vi- ic therapy of severe cytomegaly infec- ruses (e.g., encephalitis, generalized in- tion in AIDS patients; local therapy of fection) and varicella-zoster viruses herpes simplex infections. (e.g., severe herpes zoster). In these cas- Amantadine (C) specifically affects es, it can be given by i.v. infusion. Acy- the replication of influenza A (RNA) vi- clovir may also be given orally despite ruses, the causative agent of true in- its incomplete (15%–30%) enteral ab- fluenza. These viruses are endocytosed sorption. In addition, it has topical uses. into the cell. Release of viral DNA re- Because host DNA synthesis remains quires protons from the acidic content unaffected, adverse effects do not in- of endosomes to penetrate the virus. clude bone marrow depression. Acyclo- Presumably, amantadine blocks a chan- vir is eliminated unchanged in urine nel protein in the viral coat that permits (t1/2 ~ 2.5 h). influx of protons; thus, “uncoating” is Valacyclovir, the L-valyl ester of prevented. Moreover, amantadine in- acyclovir, is a prodrug that can be ad- hibits viral maturation. The drug is also ministered orally in herpes zoster infec- used prophylactically and, if possible, tions. Its absorption rate is approx. must be taken before the outbreak of twice that of acyclovir. During passage symptoms. It also is an antiparkinsonian through the intestinal wall and liver, the (p. 188). valine residue is cleaved by esterases, generating acyclovir. Famcyclovir is an antiherpetic prodrug with good bioavailability when given orally. It is used in genital herpes and herpes zoster. Cleavage of two acetate groups from the “false sugar” and oxidation of the purine ring to guanine yields penciclovir, the active form. The latter differs from acyclovir with respect to its “false sugar” moiety, but mimics it pharmacologically. Bioactivation of penciclovir, like that of acyclovir, involves formation of the triphosphory-

Antiviral Drugs 287

Acyclovir

Infected cell: Viral herpes simplex thymidine or varicella-zoster kinase

Cellular kinases

Active metabolite Viral DNA template

Base Base Base DNA-chain termination

DNA synthesis Viral Inhibition DNA polymerase

A. Activation of acyclovir and inhibition of viral DNA synthesis

Influenza A-virus Base

O Endosome O P O

O Viral channel protein O P O H+ O Viral DNA polymerase

O Inhibition of C O uncoating

Foscarnet Amantadine O P O O

B. Inhibitor of DNA polymerase: C. Prophylaxis for viral flu B. Foscarnet

288 Antiviral Drugs

Drugs for the Treatment of AIDS rier); 3) the type of resistance-inducing mutations of the viral genome and the Replication of the human immuno- rate at which resistance develops; and deficiency virus (HIV), the causative 4) their adverse effects (bone marrow agent of AIDS, is susceptible to targeted depression, neuropathy, pancreatitis). interventions, because several virus- specific metabolic steps occur in infect- IB. Non-nucleoside inhibitors ed cells (A). Viral RNA must first be tran- The non-nucleoside inhibitors of re- scribed into DNA, a step catalyzed by vi- verse transcriptase (nevirapine, dela- ral “reverse transcriptase.” Double- virdine, efavirenz) are not phosphory- stranded DNA is incorporated into the lated. They bind to the enzyme with host genome with the help of viral inte- high selectivity and thus prevent it from grase. Under control by viral DNA, viral adopting the active conformation. Inhi- replication can then be initiated, with bition is noncompetitive. synthesis of viral RNA and proteins (including enzymes such as reverse tran- II. HIV protease inhibitors scriptase and integrase, and structural Viral protease cleaves precursor pro- proteins such as the matrix protein lin- teins into proteins required for viral ing the inside of the viral envelope). replication. The inhibitors of this pro- These proteins are assembled not indi- tease (saquinavir, ritonavir, indinavir, vidually but in the form of polyproteins. and nelfinavir) represent abnormal These precursor proteins carry an N-ter- proteins that possess high antiviral effi- minal fatty acid (myristoyl) residue that cacy and are generally well tolerated in promotes their attachment to the inter- the short term. However, prolonged ad- ior face of the plasmalemma. As the vi- ministration is associated with occa- rus particle buds off the host cell, it car- sionally severe disturbances of lipid and ries with it the affected membrane area carbohydrate metabolism. Biotransfor- as its envelope. During this process, a mation of these drugs involves cyto- protease contained within the polypro- chrome P450 (CYP 3A4) and is therefore tein cleaves the latter into individual, subject to interaction with various other functionally active proteins. drugs inactivated via this route. For the dual purpose of increasing I. Inhibitors of Reverse Transcriptase the effectiveness of antiviral therapy and preventing the development of a IA. Nucleoside agents therapy-limiting viral resistance, inhibi- These substances are analogues of thy- tors of reverse transcriptase are com- mine (azidothymidine, stavudine), bined with each other and/or with pro- adenine (didanosine), cytosine (lami- tease inhibitors. vudine, zalcitabine), and guanine (car- Combination regimens are de- bovir, a metabolite of abacavir). They signed in accordance with substance- have in common an abnormal sugar specific development of resistance and moiety. Like the natural nucleosides, pharmacokinetic parameters (CNS they undergo triphosphorylation, giving penetrability, “neuroprotection,” dosing rise to nucleotides that both inhibit re- frequency). verse transcriptase and cause strand breakage following incorporation into viral DNA. The nucleoside inhibitors differ in terms of l) their ability to decrease circulating HIV load; 2) their pharmacokinetic properties (half life dosing interval compliance; organ distribution passage through blood-brainbar-

Antiviral Drugs 289

Envelope

Matrix protein

RNA Reverse transcriptase

Integrase

Viral RNA Inhibitors of reverse transcriptase O H C H 3 N DNA N O HOCH 2 O

- N=N=N+

e.g., zidovudine

Inhibitors of Viral RNA Polyproteins HIV protease

N O NH

H2N O O H N

HO Protease

N Cleavage of O polypeptide precursor N H H3C CH3

CH3 Mature virus e.g., saquinavir

A. Antiretroviral drugs

290 Disinfectants

Disinfectants and Antiseptics and mixtures of these. Minimal contact times should be at least 15 s on skin are- Disinfection denotes the inactivation or as with few sebaceous glands and at killing of pathogens (protozoa, bacteria, least 10 min on sebaceous gland-rich fungi, viruses) in the human environ- ones. ment. This can be achieved by chemical Mucosal disinfection: Germ counts or physical means; the latter will not be can be reduced by PVP iodine or chlor- discussed here. Sterilization refers to hexidine (contact time 2 min), although the killing of all germs, whether patho- not as effectively as on skin. genic, dormant, or nonpathogenic. Anti- Wound disinfection can be achieved sepsis refers to the reduction by chemi- with hydrogen peroxide (0.3%–1% solu- cal agents of germ numbers on skin and tion; short, foaming action on contact mucosal surfaces. with blood and thus wound cleansing) Agents for chemical disinfection or with potassium permanganate ideally should cause rapid, complete, (0.0015% solution, slightly astringent), and persistent inactivation of all germs, as well as PVP iodine, chlorhexidine, but at the same time exhibit low toxic- and biguanidines. ity (systemic toxicity, tissue irritancy, Hygienic and surgical hand disinfec- antigenicity) and be non-deleterious to tion: The former is required after a sus- inanimate materials. These require- pected contamination, the latter before ments call for chemical properties that surgical procedures. Alcohols, mixtures may exclude each other; therefore, of alcohols and phenols, cationic surfac- compromises guided by the intended tants, or acids are available for this pur- use have to be made. pose. Admixture of other agents pro- Disinfectants come from various longs duration of action and reduces chemical classes, including oxidants, flammability. halogens or halogen-releasing agents, Disinfection of instruments: Instru- alcohols, aldehydes, organic acids, phe- ments that cannot be heat- or steam- nols, cationic surfactants (detergents) sterilized can be precleaned and then and formerly also heavy metals. The ba- disinfected with aldehydes and deter- sic mechanisms of action involve de- gents. naturation of proteins, inhibition of en- Surface (floor) disinfection employs zymes, or a dehydration. Effects are de- aldehydes combined with cationic sur- pendent on concentration and contact factants and oxidants or, more rarely, time. acidic or alkalizing agents. Activity spectrum. Disinfectants Room disinfection: room air and inactivate bacteria (gram-positive > surfaces can be disinfected by spraying gram-negative > mycobacteria), less ef- or vaporizing of aldehydes, provided fectively their sporal forms, and a few that germs are freely accessible. (e.g., formaldehyde) are virucidal.

Applications

Skin “disinfection.” Reduction of germ counts prior to punctures or surgical procedures is desirable if the risk of wound infection is to be minimized. Useful agents include: alcohols (1- and 2-propanol; ethanol 60–90%; iodine-releasing agents like polyvinylpyrrolidone [povidone, PVP]-iodine as a depot form of the active principle iodine, instead of iodine tincture), cationic surfactants,

Disinfectants 291

Application sites Examples Active principles 1. Oxidants Disinfection of floors e. g., hydrogen peroxide, or excrement potassium permanganate, peroxycarbonic acids Inanimate material: durable Phenols NaOCl against chemical + physical measures Cationic surfactants Disinfection 2. Halogens of instruments

Cationic surfactants chlorine sodium hypochlorite Inanimate matter: Aldehydes iodine tincture sensitive to heat, acids, oxidation etc. 3. Alcohols Skin disinfection Regular e.g., hands R-OH (R=C2-C6) e. g., ethanol Alcohols Phenols isopropanol Skin Cationic surfactants 4. Aldehydes

Acute, e. g., formaldehyde e.g., before local procedures glutaraldehyde

Iodine Chlor- 5. Organic acids tincture hexidine e. g., lactic acid Disinfection 6. Phenols of mucous membranes Chlor- hexidine Mucous membranes Wound disinfection

Chlor- Nonhalogenated: hexidine KMnO4 e. g., phenylphenol eugenol thymol H2O2 halogenated: chlormethylphenol

Tissue 7. Cationic surfactants STOP Cationic soaps

Disinfectants do e. g., benzalkonium not afford selective chlorhexidine inhibition of bacteria 8. Heavy metal salts viruses, or fungi e. g., phenylmercury borate

A. Disinfectants

292 Antiparasitic Agents

Drugs for Treating Endo- and sprayed surfaces (contact insecticide). Ectoparasitic Infestations The cause of death is nervous system damage and seizures. In humans DDT Adverse hygienic conditions favor hu- causes acute neurotoxicity only after man infestation with multicellular or- absorption of very large amounts. DDT ganisms (referred to here as parasites). is chemically stable and degraded in the Skin and hair are colonization sites for environment and body at extremely arthropod ectoparasites, such as insects slow rates. As a highly lipophilic sub- (lice, fleas) and arachnids (mites). stance, it accumulates in fat tissues. Against these, insecticidal or arachnici- Widespread use of DDT in pest control dal agents, respectively, can be used. has led to its accumulation in food Endoparasites invade the intestines or chains to alarming levels. For this rea- even internal organs, and are mostly son its use has now been banned in members of the phyla of flatworms and many countries. roundworms. They are combated with Lindane is the active γ-isomer of anthelmintics. hexachlorocyclohexane. It also exerts a Anthelmintics. As shown in the ta- neurotoxic action on insects (as well as ble, the newer agents praziquantel and humans). Irritation of skin or mucous mebendazole are adequate for the treat- membranes may occur after topical use. ment of diverse worm diseases. They Lindane is active also against intrader- are generally well tolerated, as are the mal mites (Sarcoptes scabiei, causative other agents listed. agent of scabies), besides lice and fleas. Insecticides. Whereas fleas can be It is more readily degraded than DDT. effectively dealt with by disinfection of Permethrin, a synthetic pyreth- clothes and living quarters, lice and roid, exhibits similar anti-ectoparasitic mites require the topical application of activity and may be the drug of choice insecticides to the infested subject. due to its slower cutaneous absorption, Chlorphenothane (DDT) kills in- fast hydrolytic inactivation, and rapid sects after absorption of a very small renal elimination. amount, e.g., via foot contact with

Worms (helminths) Anthelmintic drug of choice Flatworms (platyhelminths) tape worms (cestodes) praziquantel* flukes (trematodes) e.g., Schistosoma praziquantel species (bilharziasis) Roundworms (nematodes) pinworm (Enterobius vermicularis) mebendazole or pyrantel pamoate whipworm (Trichuris trichiura) mebendazole Ascaris lumbricoides mebendazole or pyrantel pamoate Trichinella spiralis** mebendazole and thiabendazole Strongyloides stercoralis thiabendazole Hookworm (Necator americanus, and mebendazole or pyrantel pamoate Ancylostoma duodenale) mebendazole or pyrantel pamoate

* not for ocular or spinal cord cysticercosis ** [thiabendazole: intestinal phase; mebendazole: tissue phase]

Antiparasitic Agents 293

Tapeworms Louse e.g., beef tapeworm

Spasm, injury of integument Chlor- phenothane (DDT)

Praziquantel

Round- worms, e.g., ascaris

Pinworm Flea Damage to nervous system: convulsions, death

Hexachlorocyclo- hexane (Lindane) Mebendazole

Trichinella larvae Scabies mite

A. Endo- and ectoparasites: therapeutic agents

294 Antiparasitic Drugs

Antimalarials Tolerability. The first available antimalarial, quinine, has the smallest The causative agents of malaria are plas- therapeutic margin. All newer agents modia, unicellular organisms belonging are rather well tolerated. to the order hemosporidia (class proto- Plasmodium (P.) falciparum, re- zoa). The infective form, the sporozoite, sponsible for the most dangerous form is inoculated into skin capillaries when of malaria, is particularly prone to de- infected female Anopheles mosquitoes velop drug resistance. The incidence of (A) suck blood from humans. The sporo- resistant strains rises with increasing zoites invade liver parenchymal cells frequency of drug use. Resistance has where they develop into primary tissue been reported for chloroquine and also schizonts. After multiple fission, these for the combination pyrimethamine/ schizonts produce numerous mero- sulfadoxine. zoites that enter the blood. The pre- Drug choice for antimalarial erythrocytic stage is symptom free. In chemoprophylaxis. In areas with a risk blood, the parasite enters erythrocytes of malaria, continuous intake of antima- (erythrocytic stage) where it again mul- larials affords the best protection tiplies by schizogony, resulting in the against the disease, although not formation of more merozoites. Rupture against infection. The drug of choice is of the infected erythrocytes releases the chloroquine. Because of its slow excre- merozoites and pyrogens. A fever attack tion (plasma t1/2 = 3d and longer), a sin- ensues and more erythrocytes are in- gle weekly dose is sufficient. In areas fected. The generation period for the with resistant P. falciparum, alternative next crop of merozoites determines the regimens are chloroquine plus pyri- interval between fever attacks. With methamine/sulfadoxine (or proguanil, Plasmodium vivax and P. ovale, there can or doxycycline), the chloroquine ana- be a parallel multiplication in the liver logue amodiaquine, as well as quinine (paraerythrocytic stage). Moreover, or the better tolerated derivative meflo- some sporozoites may become dormant quine (blood-schizonticidal). Agents ac- in the liver as “hypnozoites” before en- tive against blood schizonts do not pre- tering schizogony. When the sexual vent the (symptom-free) hepatic infec- forms (gametocytes) are ingested by a tion, only the disease-causing infection feeding mosquito, they can initiate the of erythrocytes (“suppression therapy”). sexual reproductive stage of the cycle On return from an endemic malaria re- that results in a new generation of gion, a 2 wk course of primaquine is ad- transmittable sporozoites. equate for eradication of the late hepat- Different antimalarials selectively ic stages (P. vivax and P. ovale). kill the parasite’s different developmen- Protection from mosquito bites tal forms. The mechanism of action is (net, skin-covering clothes, etc.) is a known for some of them: pyrimetha- very important prophylactic measure. mine and dapsone inhibit dihydrofolate Antimalarial therapy employs the reductase (p. 273), as does chlorguanide same agents and is based on the same (proguanil) via its active metabolite. The principles. The blood-schizonticidal sulfonamide sulfadoxine inhibits syn- halofantrine is reserved for therapy on- thesis of dihydrofolic acid (p. 272). Chlo- ly. The pyrimethamine-sulfadoxine roquine and quinine accumulate within combination may be used for initial self- the acidic vacuoles of blood schizonts treatment. and inhibit polymerization of heme, the Drug resistance is accelerating in latter substance being toxic for the many endemic areas; malaria vaccines schizonts. may hold the greatest hope for control Antimalarial drug choice takes into of infection. account tolerability and plasmodial resistance.

Antiparasitic Drugs 295

Sporozoites

Hepatocyte

Primary tissue schizont

Proguanil Primaquine Pl. falcip. Pyrimethamine

Hypnozoite Merozoites Preerythrocytic cycle Preerythrocytic 1-4 weeks

Only Pl. vivax Pl. ovale Erythrocyte Blood Chloroquine schizont Mefloquine Halofantrine Quinine

Proguanil Erythrocytic cycle Erythrocytic Pyrimethamine Sulfadoxine

Fever

Fever 2 days : Tertian malaria Pl. vivax, Pl. ovale 3 days: Primaquine Quartan malaria Pl. malariae No fever periodicity: Pernicious malaria: Pl. falciparum not P. falcip. Chloroquine Gametocytes Quinine

Fever

A. Malaria: stages of the plasmodial life cycle in the human; hi h

296 Anticancer Drugs

Chemotherapy of Malignant Tumors the more long-lived erythrocytes (anemia). Infertility is caused by suppression A tumor (neoplasm) consists of cells of spermatogenesis or follicle matura- that proliferate independently of the tion. Most cytostatics disrupt DNA me- body’s inherent “building plan.” A ma- tabolism. This entails the risk of a po- lignant tumor (cancer) is present when tential genomic alteration in healthy the tumor tissue destructively invades cells (mutagenic effect). Conceivably, healthy surrounding tissue or when dis- the latter accounts for the occurrence of lodged tumor cells form secondary tu- leukemias several years after cytostatic mors (metastases) in other organs. A therapy (carcinogenic effect). Further- cure requires the elimination of all ma- more, congenital malformations are to lignant cells (curative therapy). When be expected when cytostatics must be this is not possible, attempts can be used during pregnancy (teratogenic ef- made to slow tumor growth and there- fect). by prolong the patient’s life or improve Cytostatics possess different mech- quality of life (palliative therapy). anisms of action. Chemotherapy is faced with the prob- Damage to the mitotic spindle (B). lem that the malignant cells are endoge- The contractile proteins of the spindle nous and are not endowed with special apparatus must draw apart the replicat- metabolic properties. ed chromosomes before the cell can di- Cytostatics (A) are cytotoxic sub- vide. This process is prevented by the stances that particularly affect prolife- so-called spindle poisons (see also col- rating or dividing cells. Rapidly dividing chicine, p. 316) that arrest mitosis at malignant cells are preferentially in- metaphase by disrupting the assembly jured. Damage to mitotic processes not of microtubules into spindle threads. only retards tumor growth but may also The vinca alkaloids, vincristine and vin- initiate apoptosis (programmed cell blastine (from the periwinkle plant, Vin- death). Tissues with a low mitotic rate ca rosea) exert such a cell-cycle-specific are largely unaffected; likewise, most effect. Damage to the nervous system is healthy tissues. This, however, also ap- a predicted adverse effect arising from plies to malignant tumors consisting of injury to microtubule-operated axonal slowly dividing differentiated cells. Tis- transport mechanisms. sues that have a physiologically high Paclitaxel, from the bark of the pa- mitotic rate are bound to be affected by cific yew (Taxus brevifolia), inhibits dis- cytostatic therapy. Thus, typical ad- assembly of microtubules and induces verse effects occur: atypical ones. Docetaxel is a semisyn- Loss of hair results from injury to thetic derivative. hair follicles; gastrointestinal disturbances, such as diarrhea, from inadequate replacement of enterocytes whose life span is limited to a few days; nausea and vomiting from stimulation of area postrema chemoreceptors (p. 330); and lowered resistance to infection from weakening of the immune system (p. 300). In addition, cytostatics cause bone marrow depression. Resupply of blood cells depends on the mitotic activity of bone marrow stem and daughter cells. When myeloid proliferation is arrested, the short-lived granulocytes are the first to be affected (neutropenia), then blood platelets (thrombopenia) and, finally,

Anticancer Drugs 297

Malignant tissue Cytostatics inhibit Healthy tissue with numerous mitoses cell division with few mitoses

Wanted effect: Little effect inhibition of tumor growth

Healthy tissue with Lymph node numerous mitoses

Inhibition of lymphocyte multiplication: Damage to hair follicle immune Hair loss weakness Lowered resistance to infection Unwanted Bone marrow effects Inhibition of granulo-, thrombocyto-, Inhibition of and erythropoiesis ephithelial renewal

Germinal Diarrhea cell damage

A. Chemotherapy of tumors: principal and adverse effects

Microtubules Inhibition of of mitotic spindle Inhibition of formation degradation Vinca alkaloids Paclitaxel

Vinca rosea Western yew tree

B. Cytostatics: inhibition of mitosis

298 Anticancer Drugs

Inhibition of DNA and RNA syn- by administration of folinic acid (5-for- thesis (A). Mitosis is preceded by repli- myl-THF, leucovorin, citrovorum fac- cation of chromosomes (DNA synthesis) tor). and increased protein synthesis (RNA Incorporation of false building synthesis). Existing DNA (gray) serves as blocks (3). Unnatural nucleobases (6- a template for the synthesis of new mercaptopurine; 5-fluorouracil) or nu- (blue) DNA or RNA. De novo synthesis cleosides with incorrect sugars (cytara- may be inhibited by: bine) act as antimetabolites. They inhib- Damage to the template (1). Alky- it DNA/RNA synthesis or lead to synthe- lating cytostatics are reactive com- sis of missense nucleic acids. pounds that transfer alkyl residues into 6-Mercaptopurine results from bio- a covalent bond with DNA. For instance, transformation of the inactive precursor mechlorethamine (nitrogen mustard) is azathioprine (p. 37). The uricostatic allo- able to cross-link double-stranded DNA purinol inhibits the degradation of 6- on giving off its chlorine atoms. Correct mercaptopurine such that co-adminis- reading of genetic information is there- tration of the two drugs permits dose by rendered impossible. Other alkylat- reduction of the latter. ing agents are chlorambucil, melphalan, Frequently, the combination of cy- thio-TEPA, cyclophosphamide (p. 300, tostatics permits an improved thera- 320), ifosfamide, lomustine, and busul- peutic effect with fewer adverse reac- fan. Specific adverse reactions include tions. Initial success can be followed by irreversible pulmonary fibrosis due to loss of effect because of the emergence busulfan and hemorrhagic cystitis of resistant tumor cells. Mechanisms of caused by the cyclophosphamide me- resistance are multifactorial: tabolite acrolein (preventable by the Diminished cellular uptake may re- uroprotectant mesna). Cisplatin binds to sult from reduced synthesis of a trans- (but does not alkylate) DNA strands. port protein that may be needed for Cystostatic antibiotics insert them- membrane penetration (e.g., metho- selves into the DNA double strand; this trexate). may lead to strand breakage (e.g., with Augmented drug extrusion: in- bleomycin). The anthracycline antibiotics creased synthesis of the P-glycoprotein daunorubicin and adriamycin (doxorubi- that extrudes drugs from the cell (e.g., cin) may induce cardiomyopathy. Ble- anthracyclines, vinca alkaloids, epipo- omycin can also cause pulmonary fibro- dophyllotoxins, and paclitaxel) is resis. ponsible for multi-drug resistance The epipodophyllotoxins, etopo- (mdr-1 gene amplification). side and teniposide, interact with topo- Diminished bioactivation of a pro- isomerase II, which functions to split, drug, e.g., cytarabine, which requires transpose, and reseal DNA strands intracellular phosphorylation to be- (p. 274); these agents cause strand come cytotoxic. breakage by inhibiting resealing. Change in site of action: e.g., in- Inhibition of nucleobase synthe- creased synthesis of dihydrofolate resis (2). Tetrahydrofolic acid (THF) is reductase may occur as a compensatory quired for the synthesis of both purine response to methotrexate. bases and thymidine. Formation of THF Damage repair: DNA repair en- from folic acid involves dihydrofolate zymes may become more efficient in re- reductase (p. 272). The folate analogues pairing defects caused by cisplatin. aminopterin and methotrexate (ame- thopterin) inhibit enzyme activity as false substrates. As cellular stores of THF are depleted, synthesis of DNA and RNA building blocks ceases. The effect of these antimetabolites can be reversed

Anticancer Drugs 299

DNA Damage to template

Alkylation e. g., by mechlorethamine

Insertion of daunorubicin, doxorubicin, bleomycin, actinomycin D, etc. 1 Streptomyces bacteria

Inhibition of nucleotide synthesis Building blocks

Purines Tetrahydro- Dihydrofolate folate Thymine Reductase Nucleotide Folic acid

RNA Inhibition by

Aminopterin Methotrexate 2

DNA DNA Insertion of incorrect building blocks Purine antimetabolite

6-Mercaptopurine instead of Adenine from Azathioprine

Pyrimidine antimetabolite 5-Fluorouracil instead of Uracil Cytarabine Cytosine Cytosine Arabinose instead of Desoxyribose 3 A. Cytostatics: alkylating agents and cytostatic antibiotics (1), inhibitors of tetrahydrofolate synthesis (2), antimetabolites (3)

300 Immune Modulators

Inhibition of Immune Responses Cyclosporin A is an antibiotic polypeptide from fungi and consists of 11, in Both the prevention of transplant rejec- part atypical, amino acids. Given orally, tion and the treatment of autoimmune it is absorbed, albeit incompletely. In disorders call for a suppression of im- lymphocytes, it is bound by cyclophilin, mune responses. However, immune a cytosolic receptor that inhibits the suppression also entails weakened de- phosphatase calcineurin. The latter fenses against infectious pathogens and plays a key role in T-cell signal trans- a long-term increase in the risk of neo- duction. It contributes to the induction plasms. of cytokine production, including that of A specific immune response be- IL-2. The breakthroughs of modern gins with the binding of antigen by lym- transplantation medicine are largely at- phocytes carrying specific receptors tributable to the introduction of cyclo- with the appropriate antigen-binding sporin A. Prominent among its adverse site. B-lymphocytes “recognize” antigen effects are renal damage, hypertension, surface structures by means of mem- and hyperkalemia. brane receptors that resemble the anti- Tacrolimus, a macrolide, derives bodies formed subsequently. T-lympho- from a streptomyces species; pharma- cytes (and naive B-cells) require the cologically it resembles cyclosporin A, antigen to be presented on the surface but is more potent and efficacious. of macrophages or other cells in con- The monoclonal antibodies daclizu- junction with the major histocompat- mab and basiliximab bind to the α- ibility complex (MHC); the latter per- chain of the II-2 receptor of T-lympho- mits recognition of antigenic structures cytes and thus prevent their activation, by means of the T-cell receptor. T-help- e.g., during transplant rejection. er cells carry adjacent CD-3 and CD-4 III. Disruption of cell metabolism complexes, cytotoxic T-cells a CD-8 with inhibition of proliferation. At complex. The CD proteins assist in dock- dosages below those needed to treat ing to the MHC. In addition to recogni- malignancies, some cytostatics are also tion of antigen, activation of lympho- employed for immunosuppression, e.g., cytes requires stimulation by cytokines. azathioprine, methotrexate, and cyclo- Interleukin-1 is formed by macrophag- phosphamide (p. 298). The antipro- es, and various interleukins (IL), includ- liferative effect is not specific for lym- ing IL-2, are made by T-helper cells. As phocytes and involves both T- and B- antigen-specific lymphocytes prolife- cells. rate, immune defenses are set into mo- Mycophenolate mofetil has a more tion. specific effect on lymphocytes than on I. Interference with antigen re- other cells. It inhibits inosine mono- cognition. Muromonab CD3 is a mono- phosphate dehydrogenase, which cata- clonal antibody directed against mouse lyzes purine synthesis in lymphocytes. CD-3 that blocks antigen recognition by It is used in acute tissue rejection re- T-lymphocytes (use in graft rejection). sponses. II. Inhibition of cytokine produc- IV. Anti-T-cell immune serum is tion or action. Glucocorticoids mod- obtained from animals immunized with ulate the expression of numerous human T-lymphocytes. The antibodies genes; thus, the production of IL-1 and bind to and damage T-cells and can thus IL-2 is inhibited, which explains the be used to attenuate tissue rejection. suppression of T-cell-dependent immune responses. Glucocorticoids are used in organ transplantations, autoimmune diseases, and allergic disorders. Systemic use carries the risk of iatro- genic Cushing’s syndrome (p. 248).

Immune Modulators 301

Antigen Macrophage Virus-infected cell, Glucocorticoids transplanted cell. tumor cell Inhibition of transcription Phagocytosis Synthesis of of cytokines, Degradation "foreign" proteins e. g., Presentation Presentation IL-1 IL-2

MHC II MHC I IL-1

T-cell receptor Muromonab- CD4 CD3 CD8 CD3 CD3 MHC II Uptake Monoclonal Degradation T-Helper- antibody Presentation cell Cyclosporin A

B-Lymphocyte Interleukins IL-2 T-Lymphocyte IL-2 receptor Cyclophilin blockade Inhibition Daclizumab Basiliximab Calcineurin, a phosphatase

Transcription of cytokines e. g., Proliferation IL-2 and differentiation into plasma cells Cytotoxic, antiproliferative drugs

Azathioprine, Methotrexate, Cyclo- Cytotoxic phosphamide, T-lymphocytes Mycophenolate mofetil

Cytokines: chemotaxis

Immune reaction: Antibody-mediated delayed Elimination of immune reaction hypersensitivity “foreign” cells

A. Immune reaction and immunosuppressives

302 Antidotes

Antidotes and treatment of poisonings substance possesses a very high iron- binding capacity, but does not withdraw Drugs used to counteract drug overdos- iron from hemoglobin or cytochromes. age are considered under the appropri- It is poorly absorbed enterally and must ate headings, e.g., physostigmine with be given parenterally to cause increased atropine; naloxone with opioids; flu- excretion of iron. Oral administration is mazenil with benzodiazepines; anti- indicated only if enteral absorption of body (Fab fragments) with digitalis; and iron is to be curtailed. Unwanted effects N-acetyl-cysteine with acetaminophen include allergic reactions. It should be intoxication. noted that blood letting is the most ef- Chelating agents (A) serve as anti- fective means of removing iron from the dotes in poisoning with heavy metals. body; however, this method is unsuit- They act to complex and, thus, “inactiv- able for treating conditions of iron over- ate” heavy metal ions. Chelates (from load associated with anemia. Greek: chele = claw [of crayfish]) repre- D-penicillamine can promote the sent complexes between a metal ion elimination of copper (e.g., in Wilson’s and molecules that carry several bind- disease) and of lead ions. It can be given ing sites for the metal ion. Because of orally. Two additional uses are cystinu- their high affinity, chelating agents “atria and rheumatoid arthritis. In the for- tract” metal ions present in the organ- mer, formation of cystine stones in the ism. The chelates are non-toxic, are ex- urinary tract is prevented because the creted predominantly via the kidney, drug can form a disulfide with cysteine maintain a tight organometallic bond that is readily soluble. In the latter, pen- also in the concentrated, usually acidic, icillamine can be used as a basal regi- milieu of tubular urine and thus pro- men (p. 320). The therapeutic effect mote the elimination of metal ions. may result in part from a reaction with Na2Ca-EDTA is used to treat lead aldehydes, whereby polymerization of poisoning. This antidote cannot pene- collagen molecules into fibrils is inhibit- trate cell membranes and must be given ed. Unwanted effects are: cutaneous parenterally. Because of its high binding damage (diminished resistance to me- affinity, the lead ion displaces Ca2+ from chanical stress with a tendency to form its bond. The lead-containing chelate is blisters), nephrotoxicity, bone marrow eliminated renally. Nephrotoxicity pre- depression, and taste disturbances. dominates among the unwanted effects. Na3Ca-Pentetate is a complex of dieth- ylenetriaminopentaacetic acid (DPTA) and serves as antidote in lead and other metal intoxications. Dimercaprol (BAL, British Anti-Le- wisite) was developed in World War II as an antidote against vesicant organic arsenicals (B). It is able to chelate various metal ions. Dimercaprol forms a liquid, rapidly decomposing substance that is given intramuscularly in an oily vehicle. A related compound, both in terms of structure and activity, is di- mercaptopropanesulfonic acid, whose sodium salt is suitable for oral administration. Shivering, fever, and skin reactions are potential adverse effects. Deferoxamine derives from the bacterium Streptomyces pilosus. The

Antidotes 303

2Na+ Ca2+ Na2Ca- EDTA

CH2 N CH2 C CH 2 O- O - O CH2 N CH2 C C O O- O O- CH2 C O EDTA: Ethylenediaminetetra-acetate

A. Chelation of lead ions by EDTA

Dimercaprol (i.m.) Deferoxamine D-Penicillamine

+ Arsenic, mercury, Fe3 gold ions β,β-Dimethylcysteine chelation with Cu2+ and Pb2+ DMPS

Dissolution of cystine stones: Dimercaptopropane Cysteine-S-S-Cysteine sulfonate

Inhibition of collagen polymerization

B. Chelators

304 Antidotes

Antidotes for cyanide poisoning tylcholine breakdown and hence flood- (A). Cyanide ions (CN-) enter the organ- ing of the organism with the transmit- ism in the form of hydrocyanic acid ter. Possible sequelae are exaggerated (HCN); the latter can be inhaled, re- parasympathomimetic activity, block- leased from cyanide salts in the acidic ade of ganglionic and neuromuscular stomach juice, or enzymatically liberat- transmission, and respiratory paralysis. ed from bitter almonds in the gastroin- Therapeutic measures include: 1. testinal tract. The lethal dose of HCN can administration of atropine in high dos- be as low as 50 mg. CN- binds with high age to shield muscarinic acetylcholine affinity to trivalent iron and thereby ar- receptors; and 2. reactivation of acetyl- rests utilization of oxygen via mito- cholinesterase by obidoxime, which chondrial cytochrome oxidases of the successively binds to the enzyme, cap- respiratory chain. An internal asphyxia- tures the phosphate residue by a nution (histotoxic hypoxia) ensues while cleophilic attack, and then dissociates erythrocytes remain charged with O2 from the active center to release the en- (venous blood colored bright red). zyme from inhibition. In small amounts, cyanide can be Ferric Ferrocyanide (“Berlin converted to the relatively nontoxic Blue,” B) is used to treat poisoning with thiocyanate (SCN-) by hepatic “rhoda- thallium salts (e.g., in rat poison), the nese” or sulfur transferase. As a thera- initial symptoms of which are gastroin- peutic measure, thiosulfate can be given testinal disturbances, followed by nerve i.v. to promote formation of thiocya- and brain damage, as well as hair loss. nate, which is eliminated in urine. How- Thallium ions present in the organism ever, this reaction is slow in onset. A are secreted into the gut but undergo more effective emergency treatment is reabsorption. The insoluble, nonabsorb- the i.v. administration of the methe- able colloidal Berlin Blue binds thallium moglobin-forming agent 4-dimethyl- ions. It is given orally to prevent absorp- aminophenol, which rapidly generates tion of acutely ingested thallium or to trivalent from divalent iron in hemoglo- promote clearance from the organism bin. Competition between methemoglo- by intercepting thallium that is secreted bin and cytochrome oxidase for CN- ions into the intestines. favors the formation of cyanmethemo- globin. Hydroxocobalamin is an alternative, very effective antidote because its central cobalt atom binds CN- with high affinity to generate cyanocobalamin. Tolonium chloride (Toluidin Blue). Brown-colored methemoglobin, containing tri- instead of divalent iron, is incapable of carrying O2. Under normal conditions, methemoglobin is produced continuously, but reduced again with the help of glucose-6-phosphate dehydrogenase. Substances that promote formation of methemoglobin (B) may cause a lethal deficiency of O2. To- lonium chloride is a redox dye that can be given i.v. to reduce methemoglobin. Obidoxime is an antidote used to treat poisoning with insecticides of the organophosphate type (p. 102). Phos- phorylation of acetylcholinesterase causes an irreversible inhibition of ace-

Antidotes 305

Potassium KCN Sulfur donors cyanide - SCN Na2S2O3 H+ Rhodanese Sodium thiosulfate

Hydrogen H+ + CN- FeIII-Hb Methemoglobin HCN formation cyanide K+

DMAP

Fe3+ Complex formation Mitochondrial cytochrome oxidase Hydroxocobalamin Vit.B12a Inhibition of cellular respiration Cyanocobalamin Vit.B12

A. Cyanide poisoning and antidotes

Substances forming Organophosphates Ferric ferrocyanide methemoglobin FeIII [FeII(CN) ] - 4 6 3 e.g., NO2 Nitrite e.g., Paraoxon “Prussian Blue”

+ H2N Aniline Tl = Thallium O2N Nitrobenzene Reactivated ion

Acetylcholine FeII-Hb esterase + Phosphorylated, Tl inactivated Tl+ FeIII-Hb

2 Cl- 2 Cl-

Tolonium chloride Reactivator: (toluidin blue) obidoxime Tl excretion

B. Poisons and antidotes

306 Therapy of Selected Diseases

Angina Pectoris crease in arteriolar resistance, ensuring adequate myocardial perfusion. During An anginal pain attack signals a tran- exercise, further dilation of arterioles is sient hypoxia of the myocardium. As a impossible. As a result, there is ischemia rule, the oxygen deficit results from in- associated with pain. Pharmacological adequate myocardial blood flow due to agents that act to dilate arterioles would narrowing of larger coronary arteries. thus be inappropriate because at rest The underlying causes are: most com- they may divert blood from underper- monly, an atherosclerotic change of the fused into healthy vascular regions on vascular wall (coronary sclerosis with account of redundant arteriolar dilation. exertional angina); very infrequently, a The resulting “steal effect” could pro- spasmodic constriction of a morpholog- voke an anginal attack. (3) The intra- ically healthy coronary artery (coronary myocardial pressure, i.e., systolic spasm with angina at rest; variant angi- squeeze, compresses the capillary bed. na); or more often, a coronary spasm oc- Myocardial blood flow is halted during curring in an atherosclerotic vascular systole and occurs almost entirely dur- segment. ing diastole. Diastolic wall tension (“pre- The goal of treatment is to prevent load”) depends on ventricular volume myocardial hypoxia either by raising and filling pressure. The organic nitrates blood flow (oxygen supply) or by lower- reduce preload by decreasing venous ing myocardial blood demand (oxygen return to the heart. demand) (A). Factors determining oxygen de- Factors determining oxygen sup- mand. The heart muscle cell consumes ply. The force driving myocardial blood the most energy to generate contractile flow is the pressure difference between force. O2 demand rises with an increase the coronary ostia (aortic pressure) and in (1) heart rate, (2) contraction velocity, the opening of the coronary sinus (right (3) systolic wall tension (“afterload”). atrial pressure). Blood flow is opposed The latter depends on ventricular vol- by coronary flow resistance, which in- ume and the systolic pressure needed to cludes three components. (1) Due to empty the ventricle. As peripheral resis- their large caliber, the proximal coro- tance increases, aortic pressure rises, nary segments do not normally contrib- hence the resistance against which ven- ute significantly to flow resistance. tricular blood is ejected. O2 demand is However, in coronary sclerosis or lowered by β-blockers and Ca-antago- spasm, pathological obstruction of flow nists, as well as by nitrates (p. 308). occurs here. Whereas the more common coronary sclerosis cannot be overcome pharmacologically, the less common coronary spasm can be relieved by appropriate vasodilators (nitrates, nifedipine). (2) The caliber of arteriolar resistance vessels controls blood flow through the coronary bed. Arteriolar caliber is determined by myocardial O2 tension and local concentrations of metabolic products, and is “automatically” adjusted to the required blood flow (B, healthy subject). This metabolic autoregulation explains why anginal attacks in coronary sclerosis occur only during exercise (B, patient). At rest, the pathologically elevated flow resistance is compensated by a corresponding de-

Therapy of Selected Diseases 307

O -supply 2 O2-demand during during diastole systole

Flow resistance: Left atrium 1. Heart rate 1. Coronary arterial 2. Contraction caliber Coronary artery velocity 2. Arteriolar caliber

Right Left ventricle p-force atrium Time 3. Diastolic 3. Systolic wall wall tension tension = Preload = Afterload Pressure p Pressure p Aorta Venous supply Vol. Vol. Peripheral resistance

Venous reservoir

A. O2 supply and demand of the myocardium

Healthy subject Patient with coronary sclerosis

Rest Compensa- tory dilation of arterioles Narrow Wide

Rate Contraction velocity

Afterload

Exercise

Additional dilation not possible

Wide Wide

Angina pectoris

B. Pathogenesis of exertion angina in coronary sclerosis

308 Therapy of Selected Diseases

Antianginal Drugs can also be used (5–10 mg sublingually); compared with NTG, its action is Antianginal agents derive from three somewhat delayed in onset but of long- drug groups, the pharmacological proper duration. Finally, nifedipine may be erties of which have already been pre- useful in chronic stable, or in variant an- sented in more detail, viz., the organic gina (5–20 mg, capsule to be bitten and nitrates (p. 120), the Ca2+ antagonists the contents swallowed). (p. 122), and the β-blockers (pp. 92ff). For sustained daytime angina pro- Organic nitrates (A) increase blood phylaxis, nitrates are of limited value flow, hence O2 supply, because diastolic because “nitrate pauses” of about 12 h wall tension (preload) declines as ve- are appropriate if nitrate tolerance is to nous return to the heart is diminished. be avoided. If attacks occur during the Thus, the nitrates enable myocardial day, ISDN, or its metabolite isosorbide flow resistance to be reduced even in mononitrate, may be given in the morn- the presence of coronary sclerosis with ing and at noon (e.g., ISDN 40 mg in ex- angina pectoris. In angina due to coro- tended-release capsules). Because of nary spasm, arterial dilation overcomes hepatic presystemic elimination, NTG is the vasospasm and restores myocardial not suitable for oral administration. perfusion to normal. O2 demand falls Continuous delivery via a transdermal because of the ensuing decrease in the patch would also not seem advisable two variables that determine systolic because of the potential development of wall tension (afterload): ventricular fill- tolerance. With molsidomine, there is ing volume and aortic blood pressure. less risk of a nitrate tolerance; however, Calcium antagonists (B) decrease due to its potential carcinogenicity, its O2 demand by lowering aortic pressure, clinical use is restricted. one of the components contributing to The choice between calcium antag- afterload. The dihydropyridine nifedi- onists must take into account the diffe- pine is devoid of a cardiodepressant ef- rential effect of nifedipine versus verap- fect, but may give rise to reflex tachy- amil or diltiazem on cardiac perfor- cardia and an associated increase in O2 mance (see above). When β-blockers are demand. The catamphiphilic drugs ve- given, the potential consequences of re- rapamil and diltiazem are cardiode- ducing cardiac contractility (withdraw- pressant. Reduced beat frequency and al of sympathetic drive) must be kept in contractility contribute to a reduction in mind. Since vasodilating β2-receptors O2 demand; however, AV-block and me- are blocked, an increased risk of va- chanical insufficiency can dangerously sospasm cannot be ruled out. Therefore, jeopardize heart function. In coronary monotherapy with β-blockers is recom- spasm, calcium antagonists can induce mended only in angina due to coronary spasmolysis and improve blood flow sclerosis, but not in variant angina. (p. 122). β-Blockers (C) protect the heart against the O2-wasting effect of sympathetic drive by inhibiting β-receptor- mediated increases in cardiac rate and speed of contraction. Uses of antianginal drugs (D). For relief of the acute anginal attack, rapidly absorbed drugs devoid of cardiodepressant activity are preferred. The drug of choice is nitroglycerin (NTG, 0.8–2.4 mg sublingually; onset of action within 1 to 2 min; duration of effect ~30 min). Isosorbide dinitrate (ISDN)

Therapy of Selected Diseases 309

p Diastole Systole p

Vol Vol

Resistance vessels Venous capacitance Preload Afterload vessels Nitrate tolerance O2-supply O2-demand Relaxation of Vasorelaxation coronary spasm

Nitrates e.g., Nitroglycerin (GTN), Isosorbide dinitrate (ISDN)

A. Effects of nitrates

p Rest Ca- antagonists Sympathetic system Relaxation of resistance vessels β-blocker

Afterload Rate Contraction velocity

Relaxation of coronary spasm O2-demand Exercise B. Effects of Ca-antagonists C. Effects of β-blockers

Angina pectoris Coronary sclerosis Coronary spasm

Therapy of attack GTN, ISDN

Nifedipine

Anginal prophylaxis Long-acting nitrates

β-blocker Ca-antagonists

D. Clinical uses of antianginal drugs

310 Therapy of Selected Diseases

Acute Myocardial Infarction The antiplatelet agent, ASA, is administered at the first suspected signs of Myocardial infarction is caused by infarction. Pain due to ischemia is treat- acute thrombotic occlusion of a coronary ed predominantly with antianginal artery (A). Therapeutic interventions drugs (e.g., nitrates). In case this treat- aim to restore blood flow in the occlud- ment fails (no effect within 30 min, ad- ed vessel in order to reduce infarct size ministration of morphine, if needed in or to rescue ischemic myocardial tissue. combination with an antiemetic to pre- In the area perfused by the affected ves- vent morphine-induced vomiting, is in- sel, inadequate supply of oxygen and dicated. If ECG signs of myocardial in- glucose impairs the function of heart farction are absent, the patient is stabi- muscle: contractile force declines. In the lized by antianginal therapy (nitrates, β- great majority of cases, the left ventricle blockers) and given ASA and heparin. (anterior or posterior wall) is involved. When the diagnosis has been con- The decreased work capacity of the in- firmed by electrocardiography, at- farcted myocardium leads to a reduc- tempts are started to dissolve the tion in stroke volume (SV) and hence thrombus pharmacologically (thrombo- cardiac output (CO). The fall in blood lytic therapy: alteplase or streptoki- pressure (RR) triggers reflex activation nase) or to remove the obstruction by of the sympathetic system. The resul- mechanical means (balloon dilation or tant stimulation of cardiac β-adreno- angioplasty). Heparin is given to pre- ceptors elicits an increase in both heart vent a possible vascular reocclusion, i.e., rate and force of systolic contraction, to safeguard the patency of the affected which, in conjunction with an α-adren- vessel. Regardless of the outcome of oceptor-mediated increase in peripher- thrombolytic therapy or balloon dila- al resistance, leads to a compensatory tion, a β-blocker is administered to sup- rise in blood pressure. In ATP-depleted press imminent arrhythmias, unless it is cells in the infarct border zone, resting contraindicated. Treatment of life- membrane potential declines with a threatening ventricular arrhythmias concomitant increase in excitability calls for an antiarrhythmic of the class that may be further exacerbated by acti- of Na+-channel blockers, e.g., lidocaine. vation of β-adrenoceptors. Together, To improve long-term prognosis, use is both processes promote the risk of fatal made of a β-blocker ( incidence of re- ventricular arrhythmias. As a conse- infarction and acute cardiac mortality) quence of local ischemia, extracellular and an ACE inhibitor (prevention of concentrations of H+ and K+ rise in the ventricular enlargement after myocar- affected region, leading to excitation of dial infarction) (A). nociceptive nerve fibers. The resultant sensation of pain, typically experienced by the patient as annihilating, reinforces sympathetic activation. The success of infarct therapy critically depends on the length of time between the onset of the attack and the start of treatment. Whereas some therapeutic measures are indicated only after the diagnosis is confirmed, others necessitate prior exclusion of contraindications or can be instituted only in specially equipped facilities. Without exception, however, prompt action is im- perative. Thus, a staggered treatment schedule has proven useful.

Therapy of Selected Diseases 311

Sympathetic nervous system β-blocker βββ SV x HR = CO SV x HR = CO

SV If needed: antiarrhythmic: RR Force e.g., lidocaine Excitability Arrhythmia Antiplatelet drugs, α thrombolytic agent, Peripheral heparin Infarct resistance

Analgesic: opioids H+ K+ Preload reduction: Pain Afterload reduction: nitrate ACE-inhibitor

A. Drugs for the treatment of acute myocardial infarction

Suspected myocardial Acetylsalicylic Ischemic pain infarct acid yes no

Persistent pain: Glycerol trinitrate opioids and if needed: antiemetics ECG

ST-segment yes Thrombolysis yes Angioplasty elevation contraindicated contraindicated left bundle block no no yes no

Angioplasty Thrombolysis no successful opt. GPIIb/IIIA- blocker yes

Standard therapy β-blocker, ACE-inhibitor, optional heparin

A. Algorithm for the treatment of acute myocardial infarction

312 Therapy of Selected Diseases

Hypertension paired micturition. At present, only β- blockers and diuretics have undergone Arterial hypertension (high blood pres- large-scale clinical trials, which have sure) generally does not impair the shown that reduction in blood pressure well-being of the affected individual; is associated with decreased morbidity however, in the long term it leads to and mortality due to stroke and conges- vascular damage and secondary compli- tive heart failure. cations (A). The aim of antihypertensive In multidrug therapy, it is neces- therapy is to prevent the latter and, sary to consider which agents rationally thus, to prolong life expectancy. complement each other. A β-blocker Hypertension infrequently results (bradycardia, cardiodepression due to from another disease, such as a cate- sympathetic blockade) can be effective- cholamine-secreting tumor (pheochro- ly combined with nifedipine (reflex mocytoma); in most cases the cause tachycardia), but obviously not with ve- cannot be determined: essential (pri- rapamil (bradycardia, cardiodepres- mary) hypertension. Antihypertensive sion). Monotherapy with ACE inhibitors drugs are indicated when blood pres- (p. 124) produces an adequate reduc- sure cannot be sufficiently controlled by tion of blood pressure in 50% of pa- means of weight reduction or a low- tients; the response rate is increased to salt diet. In principle, lowering of either 90% by combination with a (thiazide) cardiac output or peripheral resistance diuretic. When vasodilators such as di- may decrease blood pressure (cf. p. 306, hydralazine or minoxidil (p. 118) are 314, blood pressure determinants). The given, β-blockers would serve to pre- available drugs influence one or both of vent reflex tachycardia, and diuretics to these determinants. The therapeutic counteract fluid retention. utility of antihypertensives is deter- Abrupt termination of continuous mined by their efficacy and tolerability. treatment can be followed by rebound The choice of a specific drug is deter- hypertension (particularly with short mined on the basis of a benefit:risk as- t1/2 β-blockers). sessment of the relevant drugs, in keep- Drugs for the control of hyperten- ing with the patient’s individual needs. sive crises include nifedipine (capsule, In instituting single-drug therapy to be chewed and swallowed), nitrogly- (monotherapy), the following consider- cerin (sublingually), clonidine (p.o. or ations apply: β-blockers (p. 92) are of i.v., p. 96), dihydralazine (i.v.), diazoxide value in the treatment of juvenile hy- (i.v.), fenoldopam (by infusion, p. 114) pertension with tachycardia and high and sodium nitroprusside (p. 120, by in- cardiac output; however, in patients fusion). The nonselective α-blocker disposed to bronchospasm, even β1-se- phentolamine (p. 90) is indicated only lective blockers are contraindicated. in pheochromocytoma. Thiazide diuretics (p. 162) are potential- Antihypertensives for hyperten- ly well suited in hypertension associat- sion in pregnancy are β1-selective ed with congestive heart failure; how- adrenoceptor-blockers, methyldopa ever, they would be unsuitable in hypo- (p. 96), and dihydralazine (i.v. infusion) kalemic states. When hypertension is for eclampsia (massive rise in blood accompanied by angina pectoris, the pressure with CNS symptoms). preferred choice would be a β-blocker or calcium antagonist (p. 122) rather than a diuretic. As for the calcium antagonists, it should be noted that verapamil, unlike nifedipine, possesses cardiodepressant activity. α-Blockers may be of particular benefit in patients with benign prostatic hyperplasia and im-

Therapy of Selected Diseases 313

Hypertension Systolic: blood pressure > 160 mmHg Diastolic: blood pressure > 96 mmHg

[mm Hg] Secondary diseases: Heart failure Coronary atherosclerosis angina pectoris, myocardial infarction, arrhythmia Atherosclerosis of cerebral vessels cerebral infarction stroke Cerebral hemorrhage Atherosclerosis of renal vessels renal failure

Decreased life expectancy

Antihypertensive therapy

Initial monotherapy Drug selection with one of the five according to conditions drug groups and needs of the individual patient

Diuretics

-blockers β

Ca- antagonists ACE-antagonists inhibitors AT 1 -blockers 1 If therapeutic α or result inadequate

change to drug combine with from another group drug from another group

In severe cases further combination with α-blocker Central Vasodilation α Reserpine e.g., 2-agonist e.g., prazosine e.g., clonidine dihydralazine minoxidil

A. Arterial hypertension and pharmacotherapeutic approaches

314 Therapy of Selected Diseases

Hypotension Acute hypotension. Failure of orthostatic regulation. A change from the The venous side of the circulation, ex- recumbent to the erect position (ortho- cluding the pulmonary circulation, ac- stasis) will cause blood within the low- commodates ~ 60% of the total blood pressure system to sink towards the feet volume; because of the low venous because the veins in body parts below pressure (mean ~ 15 mmHg) it is part of the heart will be distended, despite a re- the low-pressure system. The arterial flex venoconstriction, by the weight of vascular beds, representing the high- the column of blood in the blood ves- pressure system (mean pressure, sels. The fall in stroke volume is partly ~ 100 mmHg), contain ~ 15%. The arteri- compensated by a rise in heart rate. The al pressure generates the driving force remaining reduction of cardiac output for perfusion of tissues and organs. can be countered by elevating the pe- Blood draining from the latter collects in ripheral resistance, enabling blood pres- the low-pressure system and is pumped sure and organ perfusion to be main- back by the heart into the high-pressure tained. An orthostatic malfunction is system. present when counter-regulation fails The arterial blood pressure (ABP) and cerebral blood flow falls, with resul- depends on: (1) the volume of blood per tant symptoms, such as dizziness, unit of time that is forced by the heart “black-out,” or even loss of conscious- into the high-pressure system—cardiac ness. In the sympathotonic form, sympa- output corresponding to the product of thetically mediated circulatory reflexes stroke volume and heart rate (beats/ are intensified (more pronounced min), stroke volume being determined tachycardia and rise in peripheral resis- inter alia by venous filling pressure; (2) tance, i.e., diastolic pressure); however, the counterforce opposing the flow of there is failure to compensate for the re- blood, i.e., peripheral resistance, which duction in venous return. Prophylactic is a function of arteriolar caliber. treatment with sympathomimetics Chronic hypotension (systolic BP therefore would hold little promise. In- < 105 mmHg). Primary idiopathic hypo- stead, cardiovascular fitness training tension generally has no clinical impor- would appear more important. An in- tance. If symptoms such as lassitude crease in venous return may be and dizziness occur, a program of physi- achieved in two ways. Increasing NaCl cal exercise instead of drugs is advis- intake augments salt and fluid reserves able. and, hence, blood volume (contraindi- Secondary hypotension is a sign of cations: hypertension, heart failure). an underlying disease that should be Constriction of venous capacitance ves- treated first. If stroke volume is too low, sels might be produced by dihydroer- as in heart failure, a cardiac glycoside gotamine. Whether this effect could al- can be given to increase myocardial so be achieved by an α-sympathomi- contractility and stroke volume. When metic remains debatable. In the very stroke volume is decreased due to insuf- rare asympathotonic form, use of sympa- ficient blood volume, plasma substi- thomimetics would certainly be reason- tutes will be helpful in treating blood able. loss, whereas aldosterone deficiency re- In patients with hypotension due to quires administration of a mineralocor- high thoracic spinal cord transections ticoid (e.g., fludrocortisone). The latter (resulting in an essentially complete is the drug of choice for orthostatic hy- sympathetic denervation), loss of sym- potension due to autonomic failure. A pathetic vasomotor control can be com- parasympatholytic (or electrical pace- pensated by administration of sympa- maker) can restore cardiac rate in thomimetics. bradycardia.

Therapy of Selected Diseases 315

Low-pressure High-pressure system system

Brain

Lung

β-Sympathomimetics Cardiac Parasym- glycosides patholytics

Venous return Stroke vol. x rate Heart = cardiac output

Blood pressure (BP) Kidney

Peripheral resistance

Intestines

Arteriolar α-Sympatho- caliber mimetics Skeletal muscle Initial condition Increase of blood volume

0,9% Sa NaCl lt

NaCl + H2O BP

Redistribution of blood volume NaCl + H2O BP

Constriction of venous capacitance vessels, e.g., dihydroergotamine if Mineralo- appropriate, α-sympathomimetics corticoid

A. Treatment of hypotension

316 Therapy of Selected Diseases

Gout Nonsteroidal anti-inflammatory drugs, such as indomethacin and phe- Gout is an inherited metabolic disease nylbutazone, are also effective. In se- that results from hyperuricemia, an el- vere cases, glucocorticoids may be in- evation in the blood of uric acid, the dicated. end-product of purine degradation. The Effective prophylaxis of gout at- typical gout attack consists of a highly tacks requires urate blood levels to be painful inflammation of the first meta- lowered to less than 6 mg/100 mL. tarsophalangeal joint (“podagra”). Gout Diet. Purine (cell nuclei)-rich foods attacks are triggered by precipitation of should be avoided, e.g., organ meats. sodium urate crystals in the synovial Milk, dairy products, and eggs are low in fluid of joints. purines and are recommended. Coffee During the early stage of inflamma- and tea are permitted since the meth- tion, urate crystals are phagocytosed by ylxanthine caffeine does not enter pu- polymorphonuclear leukocytes (1) that rine metabolism. engulf the crystals by their ameboid cy- Uricostatics decrease urate pro- toplasmic movements (2). The phago- duction. Allopurinol, as well as its accu- cytic vacuole fuses with a lysosome (3). mulating metabolite alloxanthine (oxy- The lysosomal enzymes are, however, purinol), inhibit xanthine oxidase, unable to degrade the sodium urate. which catalyzes urate formation from Further ameboid movement dislodges hypoxanthine via xanthine. These pre- the crystals and causes rupture of the cursors are readily eliminated via the phagolysosome. Lysosomal enzymes urine. Allopurinol is given orally are liberated into the granulocyte, re- (300–800 mg/d). Except for infrequent sulting in its destruction by self-diges- allergic reactions, it is well tolerated tion and damage to the adjacent tissue. and is the drug of choice for gout pro- Inflammatory mediators, such as pros- phylaxis. At the start of therapy, gout at- taglandins and chemotactic factors, are tacks may occur, but they can be pre- released (4). More granulocytes are at- vented by concurrent administration of tracted and suffer similar destruction; colchicine (0.5–1.5 mg/d). Uricosurics, the inflammation intensifies—the gout such as probenecid, benzbromarone attack flares up. (100 mg/d), or sulfinpyrazone, pro- Treatment of the gout attack aims mote renal excretion of uric acid. They to interrupt the inflammatory response. saturate the organic acid transport The drug of choice is colchicine, an alka- system in the proximal renal tubules, loid from the autumn crocus (Colchicum making it unavailable for urate reab- autumnale). It is known as a “spindle sorption. When underdosed, they inhib- poison” because it arrests mitosis at it only the acid secretory system, which metaphase by inhibiting contractile has a smaller transport capacity. Urate spindle proteins. Its antigout activity is elimination is then inhibited and a gout due to inhibition of contractile proteins attack is possible. In patients with urate in the neutrophils, whereby ameboid stones in the urinary tract, uricosurics mobility and phagocytotic activity are are contraindicated. prevented. The most common adverse effects of colchicine are abdominal pain, vomiting, and diarrhea, probably due to inhibition of mitoses in the rapidly dividing gastrointestinal epithelial cells. Colchicine is usually given orally (e.g., 0.5 mg hourly until pain subsides or gastrointestinal disturbances occur; maximal daily dose, 10 mg).

Therapy of Selected Diseases 317

Allopurinol Hypoxanthine

Xanthine Alloxanthine Oxidase Xanthine

Colchicine

Uricostatic Uric acid Nucleus

Uricosuric Probenecid Lysosome 1

Phagocyte

2 factors Chemotactic

Anion (urate) reabsorption

Anion secretion

Gout attack

A. Gout and its therapy

318 Therapy of Selected Diseases

Osteoporosis hydroxyl residues in hydroxyapatite to form fluorapatite, the latter being more Osteoporosis is defined as a generalized resistant to resorption by osteoclasts. To decrease in bone mass (osteopenia) that safeguard adequate mineralization of affects bone matrix and mineral content new bone, calcium must be supplied in equally, giving rise to fractures of verte- sufficient amounts. However, simulta- bral bodies with bone pain, kyphosis, neous administration would result in and shortening of the torso. Fractures of precipitation of nonabsorbable calcium the hip and the distal radius are also fluoride in the intestines. With sodium common. The underlying process is a monofluorophosphate this problem is disequilibrium between bone formation circumvented. The new bone formed by osteoblasts and bone resorption by may have increased resistance to com- osteoclasts. pressive, but not torsional, strain and Classification: Idiopathic osteopor- paradoxically bone fragility may in- osis type I, occurring in postmenopausal crease. Because the conditions under females; type II, occurring in senescent which bone fragility is decreased re- males and females (>70 y). Secondary main unclear, fluoride therapy is not in osteoporosis: associated with primary routine use. disorders such as Cushing’s disease, or Calcitonin (p. 264) inhibits osteo- induced by drugs, e.g., chronic therapy clast activity, hence bone resorption. As with glucocorticoids or heparin. In these a peptide it needs to be given by injec- forms, the cause can be eliminated. tion (or, alternatively, as a nasal spray). Postmenopausal osteoporosis Salmonid is more potent than human represents a period of accelerated loss calcitonin because of its slower elimina- of bone mass. The lower the preexisting tion. bone mass, the earlier the clinical signs Bisphosphonates structurally become manifest. mimic endogenous pyrophosphate, Risk factors are: premature meno- which inhibits precipitation and disso- pause, physical inactivity, cigarette lution of bone minerals. They retard smoking, alcohol abuse, low body bone resorption by osteoclasts and, in weight, and calcium-poor diet. part, also decrease bone mineralization. Prophylaxis: Administration of es- Indications include: tumor osteolysis, trogen can protect against postmeno- hypercalcemia, and Paget’s disease. pausal loss of bone mass. Frequently, Clinical trials with etidronate, adminis- conjugated estrogens are used (p. 254). tered as an intermittent regimen, have Because estrogen monotherapy increas- yielded favorable results in osteoporo- es the risk of uterine cancer, a gestagen sis. With the newer drugs clodronate, needs to be given concurrently (except pamidronate, and alendronate, inhibi- after hysterectomy), as e.g., in an oral tion of osteoclasts predominates; a con- contraceptive preparation (p. 256). tinuous regimen would thus appear to Under this therapy, menses will contin- be feasible. ue. The risk of thromboembolic disor- Bisphosphonates irritate esophage- ders is increased and that of myocardial al and gastric mucus membranes; tab- infarction probably lowered. Hormone lets should be swallowed with a reason- treatment can be extended for 10 y or able amount of water (250 mL) and the longer. Before menopause, daily cal- patient should keep in an upright posi- cium intake should be kept at 1 g (con- tion for 30 min following drug intake. tained in 1 L of milk), and 1.5 g thereaf- ter. Therapy. Formation of new bone matrix is induced by fluoride. Adminis- tered as sodium fluoride, it stimulates osteoblasts. Fluoride is substituted for

Therapy of Selected Diseases 319

Normal state Osteoporosis

Organic bone matrix, Osteoid Bone mineral: hydroxyapatite

A. Bone: normal state and osteoporosis

In postmenopause Calcium-salts Estrogen 1 – 1.5g Ca2+ (+ Gestagen) per day

Promotion of Inhibition of bone bone formation resorption

Fluoride ions Calcitonin NaF: Formation Resorption Activation of Peptide osteoblasts, consisting of Formation of 32 amino Fluorapatite Osteoblasts Osteoclasts acids

Physiological Bisphosphonates

constituent: NH2

(CH2)3 OH OH OH OH HO P O P OH HO P C P OH O O O OH O Pyrophosphoric acid e. g., alendronic acid

B. Osteoporosis: drugs for prophylaxis and treatment

320 Therapy of Selected Diseases

Rheumatoid Arthritis modifiers is their delayed effect, which develops only after treatment for several Rheumatoid arthritis or chronic poly- weeks. Among possible mechanisms of arthritis is a progressive inflammatory action, inhibition of macrophage activ- joint disease that intermittently attacks ity and inhibition of release or activity more and more joints, predominantly of lysosomal enzymes are being dis- those of the fingers and toes. The prob- cussed. Included in this category are: able cause of rheumatoid arthritis is a sulfasalazine (an inhibitor of lipoxyge- pathological reaction of the immune nase and cyclooxygenase, p. 272), chlo- system. This malfunction can be pro- roquine (lysosomal binding), gold com- moted or triggered by various condi- pounds (lysosomal binding; i.m.: au- tions, including genetic disposition, rothioglucose, aurothiomalate; p.o.: au- age–related wear and tear, hypother- ranofin, less effective), as well as D-pen- mia, and infection. An initial noxious icillamine (chelation of metal ions need- stimulus elicits an inflammation of ed for enzyme activity, p. 302). Frequent synovial membranes that, in turn, adverse reactions are: damage to skin leads to release of antigens through and mucous membranes, renal toxicity, which the inflammatory process is and blood dyscrasias. In addition, use is maintained. Inflammation of the syn- made of cytostatics and immune sup- ovial membrane is associated with lib- pressants such as methotrexate (low eration of inflammatory mediator sub- dose, once weekly) and leflumomid as stances that, among other actions, well as of cytokin antibodies (inflixi- chemotactically stimulate migration mab) and soluble cytokin receptors (diapedesis) of phagocytic blood cells (etanercept). Methotrexate exerts an (granulocytes, macrophages) into the anti-inflammatory effect, apart from its synovial tissue. The phagocytes produce anti-autoimmune action and, next to destructive enzymes that promote tis- sulfasalazine, is considered to have the sue damage. Due to the production of most favorable risk:benefit ratio. In prostaglandins and leukotrienes (p. most severe cases cytostatics such as 196) and other factors, the inflamma- azathioprin and cyclophosphamide will tion spreads to the entire joint. As a re- have to be used. sult, joint cartilage is damaged and the Surgical removal of the inflamed joint is ultimately immobilized or fused. synovial membrane (synovectomy) fre- Pharmacotherapy. Acute relief of quently provides long-term relief. If fea- inflammatory symptoms can be sible, this approach is preferred because achieved by prostaglandin synthase all pharmacotherapeutic measures en- inhibitors; nonsteroidal anti-inflam- tail significant adverse effects. matory drugs, or NSAIDs, such as diclofenac, indomethacin, piroxicam, p. 200), and glucocorticoids (p. 248). The inevi- tably chronic use of NSAIDs is likely to cause adverse effects. Neither NSAIDs nor glucocorticoids can halt the progressive destruction of joints. The use of disease-modifying agents may reduce the requirement for NSAIDs. The use of such agents does not mean that intervention in the basic pathogenetic mechanisms (albeit hoped for) is achievable. Rather, disease-modifying therapy permits acutely acting agents to be used as add-ons or as required. The common feature of disease-

Therapy of Selected Diseases 321

Genetic disposition Environmental factors Acute trigger Infection trauma

Immune system: reaction against articular tissue

Synovitis

Pain

Chemo- Prostaglandins Inflammation tactic factors Permeability

Bone Cartilage destruction destruction Collagenases

Phospholipases

Peptidases Inflammation IL-1 TNFα

Side effects: Non-steroidal Methotrexate, p.o. /s.c. Pneumonitis, nausea, anti-inflammatory weekly dosing vomiting, myelosuppression drugs Sulfasalazine p.o. allergic reaction, nephrotoxicity, (NSAIDs) gastrointestinal disturbances Glucocorticoids Gold parenteral Lesions of mucous membranes, kidney, skin, blood dyscrasias

Relief of symptoms “Remission” Discontinuation because of:

side effects or insufficient efficacy

123456 Months Years

A. Rheumatoid arthritis and its treatment

322 Therapy of Selected Diseases

Migraine sis), as well as α-adrenoceptors and 5- HT2 receptors ( vascular tone, Migraine is a syndrome characterized platelet aggregation). With frequent by recurrent attacks of intense head- use, the vascular side effects may give ache and nausea that occur at irregular rise to severe peripheral ischemia (er- intervals and last for several hours. In gotism). Overuse (>once per week) of classic migraine, the attack is typically ergotamine may provoke “rebound” heralded by an “aura” accompanied by headaches, thought to result from per- spreading homonymous visual field de- sistent vasodilation. Though different in fects with colored sharp edges (“fortifi- character (tension-type headache), cation” spectra). In addition, the patient these prompt further consumption of cannot focus on certain objects, has a ergotamine. Thus, a vicious circle devel- ravenous appetite for particular foods, ops with chronic abuse of ergotamine or and is hypersensitive to odors (hyperos- other analgesics that may end with irre- mia) or light (photophobia). The exact versible disturbances of peripheral cause of these complaints is unknown; blood flow and impairment of renal however, a disturbance in cranial blood function. flow is the likely underlying pathoge- Administered orally, ergotamine netic mechanism. In addition to an often and sumatriptan, eletriptan, naratrip- inherited predisposition, precipitating tan, rizatriptan, and zolmitriptan have factors are required to provoke an at- only limited bioavailability. Dihydroer- tack, e.g., psychic stress, lack of sleep, gotamine may be given by i.m. or slow certain foods. Pharmacotherapy of mi- i.v. injection, sumatriptan subcutane- graine has two aims: stopping the acute ously or by nasal spray. attack and preventing subsequent ones. Prophylaxis. Taken regularly over a Treatment of the attack. For longer period, a heterogeneous group of symptomatic relief, headaches are drugs comprising propranolol, nadolol, treated with analgesics (acetamino- atenolol, and metoprolol (β-blockers), phen, acetylsalicylic acid), and nausea is flunarizine (H1-histamine, dopamine, treated with metoclopramide (p. 330) and calcium antagonist), pizotifen (pi- or domperidone. Since there is delayed zotyline, 5-HT-antagonist), methyser- gastric emptying during the attack, drug gide (partial 5-HTID-agonist and nonse- absorption can be markedly retarded, lective 5-HT-antagonist, p. 126), NSAIDs hence effective plasma levels are not (p. 200), and calcitonin (p. 264) may de- obtained. Because metoclopramide crease the frequency, intensity, and du- stimulates gastric emptying, it pro- ration of migraine attacks. Among the β- motes absorption of ingested analgesic blockers (p. 90), only those lacking in- drugs and thus facilitates pain relief. trinsic sympathomimetic activity are ef- If acetylsalicylic acid is adminis- fective. tered i.v. as the lysine salt, its bioavailability is complete. Therefore, i.v. injection may be advisable in acute attacks. Should analgesics prove insuffi- ciently effective, ergotamine or one of the 5-HT1, agonists may help control the acute attack in most cases or prevent an imminent attack. The probable common mechanism of action is a stimulation of serotonin receptors of the 5-HT1D (or perhaps also the 1B and 1F) subtype. Moreover, ergotamine has affinity for dopamine receptors ( nausea, eme-

Therapy of Selected Diseases 323

Acetylsalicylic acid 1000 mg or acetaminophen 1000 mg

When therapeutic effect inadequate Sumatriptan or (Dihydro)- and other triptans Ergotamine

6 mg 100 mg 1 mg 1-2 mg

Migraine Meto- clopramide

Migraine attack: Gastric emptying Headache inhibited accelerated Hypersensitivity of olfaction, gustation, audition, vision Drug Nausea, vomiting Neurogenic absorption inflammation, local edema, delayed improved vasodilation

Relief of 5-HT1D migraine 5-HT1D Ergotamine 5-HT1A Psychosis 5-HT1A

D2 D2 Sumatriptan and other triptans Nausea, vomiting

5-HT2 Platelet 5-HT2 aggregation

α1 + α2 Vaso- α1 + α2 constriction

A. Migraine and its treatment

324 Therapy of Selected Diseases

Common Cold the risk of allergic reactions should be borne in mind. The common cold—colloquially the flu, Cough. Since coughing serves to catarrh, or grippe (strictly speaking, the expel excess tracheobronchial secre- rarer infection with influenza viruses)— tions, suppression of this physiological is an acute infectious inflammation of reflex is justified only when coughing is the upper respiratory tract. Its sym- dangerous (after surgery) or unproduc- ptoms, sneezing, running nose (due to tive because of absent secretions. Co- rhinitis), hoarseness (laryngitis), diffi- deine and noscapine (p. 212) suppress culty in swallowing and sore throat cough by a central action. (pharyngitis and tonsillitis), cough asso- Mucous airway obstruction. Mu- ciated with first serous then mucous colytics, such as acetylcysteine, split di- sputum (tracheitis, bronchitis), sore sulfide bonds in mucus, hence reduce its muscles, and general malaise can be viscosity and promote clearing of bron- present individually or concurrently in chial mucus. Other expectorants (e.g., varying combination or sequence. The hot beverages, potassium iodide, and term stems from an old popular belief ipecac) stimulate production of watery that these complaints are caused by ex- mucus. Acetylcysteine is indicated in posure to chilling or dampness. The cystic fibrosis patients and inhaled as an causative pathogens are different virus- aerosol. Whether mucolytics are indi- es (rhino-, adeno-, parainfluenza v.) that cated in the common cold and whether may be transmitted by aerosol droplets expectorants like bromohexine or am- produced by coughing and sneezing. broxole effectively lower viscosity of Therapeutic measures. First at- bronchial secretions may be questioned. tempts of a causal treatment consist of Fever. Antipyretic analgesics (ace- zanamavir, an inhibitor of viral neura- tylsalicylic acid, acetaminophen, p. 198) minidase, an enzyme necessary for virus are indicated only when there is high fe- adsorption and infection of cells. How- ver. Fever is a natural response and use- ever, since symptoms of common cold ful in monitoring the clinical course of abate spontaneously, there is no com- an infection. pelling need to use drugs. Conventional Muscle aches and pains, head- remedies are intended for symptomatic ache. Antipyretic analgesics are effective relief. in relieving these symptoms. Rhinitis. Nasal discharge could be prevented by parasympatholytics; however, other atropine–like effects (pp. 104ff) would have to be accepted. Therefore, parasympatholytics are hardly ever used, although a corresponding action is probably exploited in the case of H1 antihistamines, an ingredient of many cold remedies. Locally applied (nasal drops) vasoconstricting α- sympathomimetics (p. 90) decongest the nasal mucosa and dry up secretions, clearing the nasal passage. Long-term use may cause damage to nasal mucous membranes (p. 90). Sore throat, swallowing problems. Demulcent lozenges containing surface anesthetics such as ethylamino- benzoate (benzocaine) or tetracaine (p. 208) may provide relief; however,

Therapy of Selected Diseases 325

Soreness Local use of Acetylsalicylic α acid -sympathomimetics Headache (nasal drops or spray) Acetaminophen Fever

Decongestion of mucous membranes Sniffles, runny nose H1-Antihistamines Caution: sedation Common cold Flu Viral infection

Causal therapy impossible

Surface anesthetics Caution: Sore throat risk of sensitization

Antitussive: Dextrometorphan

Codeine Cough

Mucolytics

Airway congestion Acetylcysteine

Expectorants: Stimulation of bronchial secretion Accumulation in airways of mucus, inadequate Give expulsion by cough warm fluids Potassium iodide solution Bromhexine

A. Drugs used in common cold

326 Therapy of Selected Diseases

Allergic Disorders vessels, reduces capillary permeability, and dilates bronchi. IgE-mediated allergic reactions (p. 72) c) β2-Sympathomimetics, such as involve mast cell release of histamine terbutaline, fenoterol, and albuterol, are (p. 114) and production of other media- employed in bronchial asthma, mostly tors (such as leukotrienes, p. 196). Re- by inhalation, and parenterally in emer- sultant responses include: relaxation of gencies. Even after inhalation, effective vascular smooth muscle, as evidenced lo- amounts can reach the systemic circula- cally by vasodilation (e.g., conjunctival tion and cause side effects (e.g., palpita- congestion) or systemically by hypoten- tions, tremulousness, restlessness, hy- sion (as in anaphylactic shock); en- pokalemia). During chronic administra- hanced capillary permeability with tion, the sensitivity of bronchial muscu- transudation of fluid into tissues— lature is likely to decline. swelling of conjunctiva and mucous d) Theophylline belongs to the membranes of the upper airways (“hay methylxanthines. Whereas caffeine fever”), cutaneous wheal formation; (1,3,7-trimethylxanthine) predomi- contraction of bronchial smooth muscle— nantly stimulates the CNS and constricts bronchial asthma; stimulation of intesti- cerebral blood vessels, theophylline nal smooth muscle—diarrhea. (1,3-dimethylxanthine) possesses addi- 1. Stabilization of mast cells. tional marked bronchodilator, cardio- Cromolyn prevents IgE-mediated re- stimulant, vasorelaxant, and diuretic ac- lease of mediators, although only after tions. These effects are attributed to chronic treatment. Moreover, by inter- both inhibition of phosphodiesterase fering with the actions of mediator sub- (→ c AMP elevation, p. 66) and antago- stances on inflammatory cells, it causes nism at adenosine receptors. In bronchi- a more general inhibition of allergic inal asthma, theophylline can be given flammation. It is applied locally to: con- orally for prophylaxis or parenterally to junctiva, nasal mucosa, bronchial tree control the attack. Manifestations of (inhalation), intestinal mucosa (absorp- overdosage include tonic-clonic sei- tion almost nil with oral intake). Indica- zures and cardiac arrhythmias as early tions: prophylaxis of hay fever, allergic signs. asthma, and food allergies. e) Ipratropium (p. 104) can be in- 2. Blockade of histamine recep- haled to induce bronchodilation; how- tors. Allergic reactions are predomi- ever, it often lacks sufficient effective- nantly mediated by H1 receptors. H1 ness in allergic bronchospasm. antihistamines (p. 114) are mostly used f) Glucocorticoids (p. 248) have orally. Their therapeutic effect is often significant anti-allergic activity and disappointing. Indications: allergic probably interfere with different stages rhinitis (hay fever). of the allergic response. Indications: hay 3. Functional antagonists of me- fever, bronchial asthma (preferably local diators of allergy. a) α-Sympathomi- application of analogues with high pre- metics, such as naphazoline, oxymeta- systemic elimination, e.g., beclometha- zoline, and tetrahydrozoline, are ap- sone, budesonide); anaphylactic shock plied topically to the conjunctival and (i.v. in high dosage)—a probably nonge- nasal mucosa to produce local vasocon- nomic action of immediate onset. striction, and decongestion and to dry up secretions (p. 90), e.g., in hay fever. Since they may cause mucosal damage, their use should be short-term. b) Epinephrine, given i.v., is the most important drug in the management of anaphylactic shock: it constricts blood

Therapy of Selected Diseases 327

Antigen (e.g., pollen, penicillin G) IgE Antibodies Mast cell stabilization by cromolyn OH O O CH2 CH CH2 OO

OOC O O COO Inhibitors of leukotriene synthesis: e. g., zileuton Cl N S COOH

OH CH3 Release of CH3

histamine Leukotrienes Glucocorticoids Leukotriene receptor antagonist: e. g., zafirlukast H1-Antihistamines

Histamine Leukotriene receptor receptor

Reaction of target cells

Vascular smooth muscle, permeability Bronchial musculature Vasodilation Edema Contraction

Bronchial asthma α -Sympatho- Mucous membranes β mimetics: of nose and eye: 2-Sympathomimetics: e. g., redness swelling, e. g., naphazoline secretion terbutaline H N OH N CH3 N HO H CH3 CH Skin: 3 wheal formation OH

Theophylline

O H

Epinephrine Circulation: H3C N anaphyl. shock O N

CH3

A. Anti-allergic therapy

328 Therapy of Selected Diseases

Bronchial Asthma If β2-mimetics have to be used more frequently than three times a Definition: a recurrent, episodic short- week, more severe disease is present. At ness of breath caused by bronchocon- this stage, management includes anti- striction arising from airway inflamma- inflammatory drugs, such as “mast-cell tion and hyperreactivity. stabilizers” (in children or juvenile pa- Asthma patients tend to underesti- tients) or else glucocorticoids. Inhala- mate the true severity of their disease. tional treatment must be administered Therefore, self-monitoring by the use of regularly, improvement being evident home peak expiratory flow meters is an only after several weeks. With proper essential part of the therapeutic pro- use of glucocorticoids undergoing high gram. With proper education, the pa- presystemic elimination, concern about tient can detect early signs of deteriora- systemic adverse effects is unwarrant- tion and can adjust medication within ed. Possible local adverse effects are: the framework of a physician-directed oropharyngeal candidiasis and dyspho- therapeutic regimen. nia. To minimize the risk of candidiasis, Pathophysiology. One of the main drug administration should occur be- pathogenetic factors is an allergic in- fore morning or evening meals, or be flammation of the bronchial mucosa. followed by rinsing of the oropharynx. For instance, leukotrienes that are Anti-inflammatory therapy is the more formed during an IgE-mediated im- successful the less use is made of as- mune response (p. 326) exert a chemo- needed β2-mimetic medication. tactic effect on inflammatory cells. As Severe cases may, however, require the inflammation develops, bronchi be- an intensified bronchodilator treatment come hypersensitive to spasmogenic with systemic β2-mimetics or theophyl- stimuli. Thus, stimuli other than the line (systemic use only; low therapeutic original antigen(s) can act as triggers index; monitoring of plasma levels (A); e.g., breathing of cold air is an im- needed). Salmeterol is a long-acting in- portant trigger in exercise-induced halative β2-mimetic (duration: 12 h; on- asthma. Cyclooxygenase inhibitors set ~20 min) that offers the advantage of (p. 196) exemplify drugs acting as asth- a lower systemic exposure. It is used ma triggers. prophylactically at bedtime for noctur- Management. Avoidance of asthma nal asthma. triggers is an important prophylactic Zafirlukast is a long-acting, selec- measure, though not always feasible. tive, and potent leukotriene receptor Drugs that inhibit allergic inflammma- (LTD4, LTE4) antagonist with anti-in- tory mechanisms or reduce bronchial flammatory/antiallergic activity and ef- hyperreactivity, viz., glucocorticoids, ficacy in the maintenance therapy of “mast-cell stabilizers,” and leukotriene chronic asthma. It is given both orally antagonists, attack crucial pathogenetic and by inhalation. The onset of action is links. Bronchodilators, such as β2-sym- slow (3 to 14 d). Protective effects pathomimetics, theophylline, and ipra- against inhaled LTD4 last up to 12 to tropium, provide symptomatic relief. 24 h. The step scheme (B) illustrates suc- Ipratropium may be effective in cessive levels of pharmacotherapeutic some patients as an adjunct anti-asth- management at increasing degrees of matic, but has greater utility in prevent- disease severity. ing bronchospastic episodes in chronic First treatment of choice for the bronchitis. acute attack are short-acting, aerosolized β2-sympathomimetics, e.g., salbutamol, albuterol, terbutaline, fenoterol, and others. Their action occurs within minutes and lasts for 4 to 6 h.

Therapy of Selected Diseases 329

Allergens

Inflammation

Antigens, Bronchial hyperreactivity infections, ozone, SO2, NO2 Bronchial Noxious stimuli spasm Dust, cold air, drugs

Avoid Treat Dilate exposure inflammation bronchi

A. Bronchial asthma, pathophysiology and therapeutic approach

Modified after INTERNATIONAL CONSENSUS REPORT 1992

Glucocorticoids systemic

Maintained bronchodilation

Theophylline p.o./ß2-mimetics p.o. or long-acting ß2-mimetics inhalative "or" "or/and" Parasympatholytics

Antiinflammatory treatment, inhalative, chronically “Mast cell- stabilizer” Glucocorticoids Glucocorticoids or glucocorticoids or leukotriene antagonists

Bronchodilation as needed: short-acting inhalative β2-mimetics

<– 3 x /week <– 4 x/day <– 4 x/day <– 4 x/day Mild asthmaModerate asthma Severe asthma

B. Bronchial asthma treatment algorithm

330 Therapy of Selected Diseases

Emesis fellow travellers), and the type of motion experienced. The drugs should be In emesis the stomach empties in a ret- taken 30 min before the start of travel rograde manner. The pyloric sphincter and repeated every 4 to 6 h. Scopola- is closed while the cardia and esopha- mine applied transdermally through an gus relax to allow the gastric contents to adhesive patch can provide effective be propelled orad by a forceful, synchro- protection for up to 3 d. nous contraction of abdominal wall Pregnancy vomiting is prone to muscles and diaphragm. Closure of the occur in the first trimester; thus phar- glottis and elevation of the soft palate macotherapy would coincide with the prevent entry of vomitus into the tra- period of maximal fetal vulnerability to chea and nasopharynx. As a rule, there chemical injury. Accordingly, antiemet- is prodromal salivation or yawning. Co- ics (antihistamines, or neuroleptics if ordination between these different required) should be used only when stages depends on the medullary cen- continuous vomiting threatens to dis- ter for emesis, which can be activated turb electrolyte and water balance to a by diverse stimuli. These are conveyed degree that places the fetus at risk. via the vestibular apparatus, visual, ol- Drug-induced vomiting. To pre- factory, and gustatory inputs, as well vent vomiting during anticancer as viscerosensory afferents from the chemotherapy (especially with cispla- upper alimentary tract. Furthermore, tin), effective use can be made of 5-HT3- psychic experiences may also activate receptor antagonists (e.g., ondansetron, the emetic center. The mechanisms granisetron, and tropisetron), alone or in underlying motion sickness (kinetosis, combination with glucocorticoids sea sickness) and vomiting during preg- (methylprednisolone, dexamethasone). nancy are still unclear. Anticipatory nausea and vomiting, re- Polar substances cannot reach the sulting from inadequately controlled emetic center itself because it is pro- nausea and emesis in patients undergo- tected by the blood-brain barrier. How- ing cytotoxic chemotherapy, can be at- ever, they can indirectly excite the cen- tenuated by a benzodiazepine such as ter by activating chemoreceptors in the lorazepam. Dopamine agonist-induced area postrema or receptors on periph- nausea in parkinsonian patients (p. 188) eral vagal nerve endings. can be counteracted with D2-receptor Antiemetic therapy. Vomiting can antagonists that penetrate poorly into be a useful reaction enabling the body to the CNS (e.g., domperidone, sulpiride). eliminate an orally ingested poison. Metoclopramide is effective in nausea Antiemetic drugs are used to prevent ki- and vomiting of gastrointestinal origin netosis, pregnancy vomiting, cytotoxic (5-HT4-receptor agonism) and at high drug-induced or postoperative vomit- dosage also in chemotherapy- and radi- ing, as well as vomiting due to radiation ation-induced sickness (low potency therapy. antagonism at 5-HT3- and D2-recep- Motion sickness. Effective prophy- tors). Phenothiazines (e.g., levomeprom- laxis can be achieved with the parasym- azine, trimeprazine, perphenazine) may patholytic scopolamine (p. 106) and H1 suppress nausea/emesis that follows antihistamines (p. 114) of the diphenyl- certain types of surgery or is due to opi- methane type (e.g., diphenhydramine, oid analgesics, gastrointestinal irrita- meclizine). Antiemetic activity is not a tion, uremia, and diseases accompanied property shared by all parasympatho- by elevated intracranial pressure. lytics or antihistamines. The efficacy of The synthetic cannabinoids dronab- the drugs mentioned depends on the ac- inol and nabilone have antinau- tual situation of the individual (gastric seant/antiemetic effects that may bene- filling, ethanol consumption), environ- fit AIDS and cancer patients. mental conditions (e.g., the behavior of

Therapy of Selected Diseases 331

Kinetoses e.g., sea sickness Pregnancy vomiting Chemo- receptors

Emetic center Psychogenic vomiting

Sight

Vestibular Area postrema Olfaction system

Taste Chemoreceptors (drug-induced vomiting) Intramucosal sensory nerve endings in mouth, pharynx, and stomach

Parasympatholytics Dopamine antagonists O N H H O N N N N Cl Scopolamine Domperidone H1-Antihistamines

Diphenhydramine Metoclopramide

Meclozine

Ondansetron

5-HT3-antagonist A. Emetic stimuli and antiemetic drugs

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