color atlas of pharmacology 2nd edition

re K III

Color Atlas of Pharmacology2nd edition, revised and expanded

Heinz Lüllmann, M. D.Professor EmeritusDepartment of PharmacologyUniversity of KielGermany

Klaus Mohr, M. D.ProfessorDepartment of Pharmacologyand ToxicologyInstitute of PharmacyUniversity of BonnGermany

Albrecht Ziegler, Ph. D.ProfessorDepartment of PharmacologyUniversity of KielGermany

Detlef Bieger, M. D.ProfessorDivision of Basic Medical SciencesFaculty of MedicineMemorial University ofNewfoundlandSt. John’s, NewfoundlandCanada

164 color plates by Jürgen Wirth

ThiemeStuttgart · New York · 2000

Lüllmann, Color Atlas of Pharmacology © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.

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 1999615’.1—dc21DNLM/DLCfor Library of Congress 99-33662

CIP

IV

Illustrated by Jürgen Wirth, Darmstadt, Ger-many

This book is an authorized revised and ex-panded translation of the 3rd German editionpublished and copyrighted 1996 by GeorgThieme Verlag, Stuttgart, Germany. Title of theGerman edition:Taschenatlas der Pharmakologie

Some of the product names, patents and regis-tered designs referred to in this book are infact registered trademarks or proprietarynames even though specific reference to thisfact is not always made in the text. Therefore,the appearance of a name without designationas proprietary is not to be construed as arepresentation by the publisher that it is in thepublic domain.

This book, including all parts thereof, is legallyprotected by copyright. Any use, exploitationor commercialization outside the narrow lim-its set by copyright legislation, without thepublisher’s consent, is illegal and liable toprosecution. This applies in particular to pho-tostat reproduction, copying, mimeographingor duplication of any kind, translating, prepa-ration of microfilms, and electronic data pro-cessing and storage.

©2000 Georg Thieme Verlag, Rüdigerstrasse14,D-70469 Stuttgart, GermanyThieme New York, 333 Seventh Avenue, NewYork, NY 10001, USA

Typesetting by Gulde Druck, TübingenPrinted in Germany by Staudigl, Donauwörth

ISBN 3-13-781702-1 (GTV)ISBN 0-86577-843-4 (TNY) 1 2 3 4 5 6

Important Note: Medicine is an ever-chang-ing science undergoing continual develop-ment. Research and clinical experience arecontinually expanding our knowledge, in par-ticular our knowledge of proper treatment anddrug therapy. Insofar as this book mentionsany dosage or application, readers may rest as-sured that the authors, editors and publishershave made every effort to ensure that such ref-erences are in accordance with the state ofknowledge at the time of production of thebook.

Nevertheless this does not involve, imply, orexpress any guarantee or responsibility on thepart of the publishers in respect of any dosageinstructions and forms of application stated inthe book. Every user is requested to examinecarefully the manufacturers’ leaflets accompa-nying each drug and to check, if necessary inconsultation with a physician or specialist,whether the dosage schedules mentionedtherein or the contraindications stated by themanufacturers differ from the statementsmade in the present book. Such examination isparticularly important with drugs that areeither rarely used or have been newly releasedon the market. Every dosage schedule or ev-ery form of application used is entirely at theuser’s own risk and responsibility. The au-thors and publishers request every user to re-port to the publishers any discrepancies or in-accuracies noticed.


V

PrefaceThe present second edition of the Color Atlas of Pharmacology goes to print six yearsafter the first edition. Numerous revisions were needed, highlighting the dramaticcontinuing progress in the drug sciences. In particular, it appeared necessary to in-clude novel therapeutic principles, such as the inhibitors of platelet aggregationfrom the group of integrin GPIIB/IIIA antagonists, the inhibitors of viral protease, orthe non-nucleoside inhibitors of reverse transcriptase. Moreover, the re-evaluationand expanded use of conventional drugs, e.g., in congestive heart failure, bronchialasthma, or rheumatoid arthritis, had to be addressed. In each instance, the primaryemphasis was placed on essential sites of action and basic pharmacological princi-ples. Details and individual drug properties were deliberately omitted in the interestof making drug action more transparent and affording an overview of the pharmaco-logical basis of drug therapy.

The authors wish to reiterate that the Color Atlas of Pharmacology cannot replace atextbook of pharmacology, nor does it aim to do so. Rather, this little book is desi-gned to arouse the curiosity of the pharmacological novice; to help students of me-dicine and pharmacy gain an overview of the discipline and to review certain bits ofinformation in a concise format; and, finally, to enable the experienced therapist torecall certain factual data, with perhaps some occasional amusement.

Our cordial thanks go to the many readers of the multilingual editions of the ColorAtlas 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 stimula-ting 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 LüllmannKlaus MohrAlbrecht ZieglerDetlef BiegerJürgen Wirth

Fall 1999


Admin

Inserted Text

Admin

Inserted Text

Contents

General Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

History of Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2Drug Sources

Drug and Active Principle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4Drug Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

Drug AdministrationDosage Forms for Oral, and Nasal Applications . . . . . . . . . . . . . . . . . . . . . . . . . . . 8Dosage Forms for Parenteral Pulmonary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12Rectal or Vaginal, and Cutaneous Application . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12Drug Administration by Inhalation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14Dermatalogic Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16From Application to Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18

Cellular Sites of ActionPotential Targets of Drug Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20

Distribution in the BodyExternal Barriers of the Body . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22Blood-Tissue Barriers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24Membrane Permeation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26Possible Modes of Drug Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28Binding to Plasma Proteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30

Drug EliminationThe Liver as an Excretory Organ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32Biotransformation of Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34Enterohepatic Cycle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38The Kidney as Excretory Organ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40Elimination of Lipophilic and Hydrophilic Substances . . . . . . . . . . . . . . . . . . . . . 42

PharmacokineticsDrug Concentration in the Body as a Function of Time.First-Order (Exponential) Rate Processes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44Time Course of Drug Concentration in Plasma . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46Time Course of Drug Plasma Levels During RepeatedDosing and During Irregular Intake . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48Accumulation: Dose, Dose Interval, and Plasma Level Fluctuation . . . . . . . . . . 50Change in Elimination Characteristics During Drug Therapy . . . . . . . . . . . . . . . 50

Quantification of Drug ActionDose-Response Relationship . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52Concentration-Effect Relationship – Effect Curves . . . . . . . . . . . . . . . . . . . . . . . . 54Concentration-Binding Curves . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56

Drug-Receptor InteractionTypes of Binding Forces . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58Agonists-Antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60Enantioselectivity of Drug Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62Receptor Types . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64Mode of Operation of G-Protein-Coupled Receptors . . . . . . . . . . . . . . . . . . . . . . 66Time Course of Plasma Concentration and Effect . . . . . . . . . . . . . . . . . . . . . . . . . 68

Adverse Drug Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70

VI


Contents VII

Drug Allergy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72Drug Toxicity in Pregnancy and Lactation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74

Drug-independent EffectsPlacebo – Homeopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76

Systems Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79

Drug Acting on the Sympathetic Nervous SystemSympathetic Nervous System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80Structure of the Sympathetic Nervous System . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82Adrenoceptor Subtypes and Catecholamine Actions . . . . . . . . . . . . . . . . . . . . . . 84Structure – Activity Relationship of Sympathomimetics . . . . . . . . . . . . . . . . . . . 86Indirect Sympathomimetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88α-Sympathomimetics, α-Sympatholytics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90β-Sympatholytics (β-Blockers) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92Types of β-Blockers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94Antiadrenergics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96

Drugs Acting on the Parasympathetic Nervous SystemParasympathetic Nervous System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98Cholinergic Synapse . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100Parasympathomimetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102Parasympatholytics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104

NicotineGanglionic Transmission . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108Effects of Nicotine on Body Functions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110Consequences of Tobacco Smoking . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112

Biogenic AminesBiogenic Amines – Actions andPharmacological Implications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114Serotonin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116

VasodilatorsVasodilators – Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118Organic Nitrates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120Calcium Antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122

Inhibitors of the RAA System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124Drugs Acting on Smooth Muscle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Drugs Used to Influence Smooth Muscle Organs . . . . . . . . . . . . . . . . . . . . . . . . . . 126Cardiac Drugs

Overview of Modes of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128Cardiac Glycosides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130Antiarrhythmic Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 134Electrophysiological Actions of Antiarrhythmics ofthe Na+-Channel Blocking Type . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 136

AntianemicsDrugs for the Treatment of Anemias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138Iron Compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 140

AntithromboticsProphylaxis and Therapy of Thromboses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142Coumarin Derivatives – Heparin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144Fibrinolytic Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146Intra-arterial Thrombus Formation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148Formation, Activation, and Aggregation of Platelets . . . . . . . . . . . . . . . . . . . . . . . 148


Inhibitors of Platelet Aggregation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 150Presystemic Effect of Acetylsalicylic Acid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 150Adverse Effects of Antiplatelet Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 150

Plasma Volume Expanders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 152Drugs used in Hyperlipoproteinemias

Lipid-Lowering Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154Diuretics

Diuretics – An Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158NaCI Reabsorption in the Kidney . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160Osmotic Diuretics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160Diuretics of the Sulfonamide Type . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 162Potassium-Sparing Diuretics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 164Antidiuretic Hormone (/ADH) and Derivatives . . . . . . . . . . . . . . . . . . . . . . . . . . . 164

Drugs for the Treatment of Peptic UlcersDrugs for Gastric and Duodenal Ulcers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 166

Laxatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 170Antidiarrheals

Antidiarrheal Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 178Other Gastrointestinal Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 180Drugs Acting on Motor Systems

Drugs Affecting Motor Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 182Muscle Relaxants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 184Depolarizing Muscle Relaxants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 186Antiparkinsonian Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 188Antiepileptics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 190

Drugs for the Suppression of Pain, Analgesics,Pain Mechanisms and Pathways . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 194

Antipyretic AnalgesicsEicosanoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 196

Antipyretic Analgesics and Antiinflammatory DrugsAntipyretic Analgesics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 198

Antipyretic AnalgesicsNonsteroidal Antiinflammatory(Antirheumatic) Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 200Thermoregulation and Antipyretics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 202

Local Anesthetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 204Opioids

Opioid Analgesics – Morphine Type . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 210General Anesthetic Drugs

General Anesthesia and General Anesthetic Drugs . . . . . . . . . . . . . . . . . . . . . . . . 216Inhalational Anesthetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 218Injectable Anesthetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220

HypnoticsSoporifics, Hypnotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 222Sleep-Wake Cycle and Hypnotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 224

PsychopharmacologicalsBenzodiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 226Pharmacokinetics of Benzodiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 228Therapy of Manic-Depressive Illnes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 230Therapy of Schizophrenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 236Psychotomimetics (Psychedelics, Hallucinogens) . . . . . . . . . . . . . . . . . . . . . . . . . 240

VIII Contents


Contents IX

HormonesHypothalamic and Hypophyseal Hormones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 242Thyroid Hormone Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 244Hyperthyroidism and Antithyroid Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 246Glucocorticoid Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 248Androgens, Anabolic Steroids, Antiandrogens . . . . . . . . . . . . . . . . . . . . . . . . . . . . 252Follicular Growth and Ovulation, Estrogen andProgestin Production . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 254Oral Contraceptives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 256Insulin Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 258Treatment of Insulin-DependentDiabetes Mellitus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 260Treatment of Maturity-Onset (Type II)Diabetes Mellitus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 262Drugs for Maintaining Calcium Homeostasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 264

Antibacterial DrugsDrugs for Treating Bacterial Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 266Inhibitors of Cell Wall Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 268Inhibitors of Tetrahydrofolate Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 272Inhibitors of DNA Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 274Inhibitors of Protein Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 276Drugs for Treating Mycobacterial Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 280

Antifungal DrugsDrugs Used in the Treatment of Fungal Infection . . . . . . . . . . . . . . . . . . . . . . . . . 282

Antiviral DrugsChemotherapy of Viral Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 284Drugs for Treatment of AIDS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 288

DisinfectantsDisinfectants and Antiseptics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 290

Antiparasitic AgentsDrugs for Treating Endo- and Ectoparasitic Infestations . . . . . . . . . . . . . . . . . . . 292Antimalarials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 294

Anticancer DrugsChemotherapy of Malignant Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 296

Immune ModulatorsInhibition of Immune Responses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 300

AntidotesAntidotes and treatment of poisonings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 302

Therapy of Selected DiseasesAngina Pectoris . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 306Antianginal Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 308Acute Myocardial Infarction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 310Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 312Hypotension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 314Gout . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 316Osteoporosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 318Rheumatoid Arthritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 320Migraine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 322Common Cold . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 324Allergic Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 326Bronchial Asthma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 328Emesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 330


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

X Contents


General Pharmacology


History of Pharmacology

Since time immemorial, medicamentshave been used for treating disease inhumans and animals. The herbals of an-tiquity describe the therapeutic powersof certain plants and minerals. Belief inthe curative powers of plants and cer-tain substances rested exclusively upontraditional knowledge, that is, empiricalinformation not subjected to critical ex-amination.

The Idea

Claudius Galen (129–200 A.D.) first at-tempted to consider the theoreticalbackground of pharmacology. Both the-ory and practical experience were tocontribute equally to the rational use ofmedicines through interpretation of ob-served and experienced results.“The empiricists say that all is found byexperience. We, however, maintain that itis found in part by experience, in part bytheory. Neither experience nor theoryalone is apt to discover all.”

The Impetus

Theophrastus von Hohenheim (1493–1541 A.D.), called Paracelsus, began toquesiton doctrines handed down fromantiquity, demanding knowledge of theactive ingredient(s) in prescribed reme-dies, while rejecting the irrational con-coctions and mixtures of medieval med-

icine. He prescribed chemically definedsubstances with such success that pro-fessional enemies had him prosecutedas a poisoner. Against such accusations,he defended himself with the thesis that has become an axiom of pharma-cology:“If you want to explain any poison prop-erly, what then isn‘t a poison? All thingsare poison, nothing is without poison; thedose alone causes a thing not to be poi-son.”

Early Beginnings

Johann Jakob Wepfer (1620–1695)was the first to verify by animal experi-mentation assertions about pharmaco-logical or toxicological actions.“I pondered at length. Finally I resolved toclarify the matter by experiments.”

2 History of Pharmacology


History of Pharmacology 3

Foundation

Rudolf Buchheim (1820–1879) found-ed the first institute of pharmacology atthe University of Dorpat (Tartu, Estonia)in 1847, ushering in pharmacology as anindependent scientific discipline. In ad-dition to a description of effects, hestrove to explain the chemical proper-ties of drugs.“The science of medicines is a theoretical,i.e., explanatory, one. It is to provide uswith knowledge by which our judgementabout the utility of medicines can be vali-dated at the bedside.”

Consolidation – General Recognition

Oswald Schmiedeberg (1838–1921),together with his many disciples (12 ofwhom were appointed to chairs of phar-macology), helped to establish the high

reputation of pharmacology. Funda-mental concepts such as structure-ac-tivity relationship, drug receptor, andselective toxicity emerged from thework 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 early1920s by applying the Law of Mass Ac-tion to drug-receptor interactions. To-gether with the internist, BernhardNaunyn (1839–1925), Schmiedebergfounded the first journal of pharmacolo-gy, which has since been publishedwithout interruption. The “Father ofAmerican Pharmacology”, John J. Abel(1857–1938) was among the firstAmericans to train in Schmiedeberg‘slaboratory and was founder of the Jour-nal of Pharmacology and ExperimentalTherapeutics (published from 1909 untilthe present).

Status Quo

After 1920, pharmacological laborato-ries sprang up in the pharmaceutical in-dustry, outside established universityinstitutes. After 1960, departments ofclinical pharmacology were set up atmany universities and in industry.


Drug and Active PrincipleUntil the end of the 19th century, medi-cines were natural organic or inorganicproducts, mostly dried, but also fresh,plants or plant parts. These might con-tain substances possessing healing(therapeutic) properties or substancesexerting a toxic effect.

In order to secure a supply of medi-cally useful products not merely at thetime of harvest but year-round, plantswere preserved by drying or soakingthem in vegetable oils or alcohol. Dryingthe plant or a vegetable or animal prod-uct yielded a drug (from French “drogue” – dried herb). Colloquially, thisterm nowadays often refers to chemicalsubstances with high potential for phys-ical dependence and abuse. Used scien-tifically, this term implies nothing aboutthe quality of action, if any. In its origi-nal, wider sense, drug could refer equal-ly well to the dried leaves of pepper-mint, dried lime blossoms, dried flowersand leaves of the female cannabis plant(hashish, marijuana), or the dried milkyexudate obtained by slashing the unripeseed capsules of Papaver somniferum(raw opium). Nowadays, the term is ap-plied quite generally to a chemical sub-stance that is used for pharmacothera-py.

Soaking plants parts in alcohol(ethanol) creates a tincture. In this pro-cess, pharmacologically active constitu-ents of the plant are extracted by the al-cohol. Tinctures do not contain the com-plete spectrum of substances that existin the plant or crude drug, only thosethat are soluble in alcohol. In the case ofopium tincture, these ingredients arealkaloids (i.e., basic substances of plantorigin) including: morphine, codeine,narcotine = noscapine, papaverine, nar-ceine, and others.

Using a natural product or extractto treat a disease thus usually entails theadministration of a number of substanc-es possibly possessing very different ac-tivities. Moreover, the dose of an indi-vidual constituent contained within agiven amount of the natural product issubject to large variations, depending

upon the product‘s geographical origin(biotope), time of harvesting, or condi-tions and length of storage. For the samereasons, the relative proportion of indi-vidual constituents may vary consider-ably. Starting with the extraction ofmorphine from opium in 1804 by F. W.Sertürner (1783–1841), the active prin-ciples of many other natural productswere subsequently isolated in chemi-cally pure form by pharmaceutical la-boratories.

The aims of isolating active principlesare:1. Identification of the active ingredi-ent(s).2. Analysis of the biological effects(pharmacodynamics) of individual in-gredients and of their fate in the body(pharmacokinetics).3. Ensuring a precise and constant dos-age in the therapeutic use of chemicallypure constituents.4. The possibility of chemical synthesis,which would afford independence fromlimited natural supplies and create con-ditions for the analysis of structure-ac-tivity relationships. Finally, derivatives of the original con-stituent may be synthesized in an effortto optimize pharmacological properties.Thus, derivatives of the original constit-uent with improved therapeutic useful-ness may be developed.

4 Drug Sources


Drug Sources 5

A. From poppy to morphine

Raw opium

Preparationofopium tincture

MorphineCodeineNarcotinePapaverineetc.

Opium tincture (laudanum)


Drug Development

This process starts with the synthesis ofnovel chemical compounds. Substanceswith complex structures may be ob-tained from various sources, e.g., plants(cardiac glycosides), animal tissues(heparin), microbial cultures (penicillinG), or human cells (urokinase), or bymeans of gene technology (human insu-lin). As more insight is gained into struc-ture-activity relationships, the searchfor new agents becomes more clearlyfocused.

Preclinical testing yields informa-tion on the biological effects of new sub-stances. Initial screening may employbiochemical-pharmacological investiga-tions (e.g., receptor-binding assaysp. 56) or experiments on cell cultures,isolated cells, and isolated organs. Sincethese models invariably fall short ofreplicating complex biological process-es in the intact organism, any potentialdrug must be tested in the whole ani-mal. Only animal experiments can re-veal whether the desired effects will ac-tually occur at dosages that produce lit-tle or no toxicity. Toxicological investiga-tions serve to evaluate the potential for:(1) toxicity associated with acute orchronic administration; (2) geneticdamage (genotoxicity, mutagenicity);(3) production of tumors (onco- or car-cinogenicity); and (4) causation of birthdefects (teratogenicity). In animals,compounds under investigation alsohave to be studied with respect to theirabsorption, distribution, metabolism,and elimination (pharmacokinetics).Even at the level of preclinical testing,only a very small fraction of new com-pounds will prove potentially fit for usein humans.

Pharmaceutical technology pro-vides the methods for drug formulation.

Clinical testing starts with Phase Istudies on healthy subjects and seeks todetermine whether effects observed inanimal experiments also occur in hu-mans. Dose-response relationships aredetermined. In Phase II, potential drugsare first tested on selected patients for

therapeutic efficacy in those diseasestates for which they are intended.Should a beneficial action be evidentand the incidence of adverse effects beacceptably small, Phase III is entered,involving a larger group of patients inwhom the new drug will be comparedwith standard treatments in terms oftherapeutic outcome. As a form of hu-man experimentation, these clinicaltrials are subject to review and approvalby institutional ethics committees ac-cording to international codes of con-duct (Declarations of Helsinki, Tokyo,and Venice). During clinical testing,many drugs are revealed to be unusable.Ultimately, only one new drug remainsfrom approximately 10,000 newly syn-thesized substances.

The decision to approve a newdrug is made by a national regulatorybody (Food & Drug Administration inthe U.S.A., the Health Protection BranchDrugs Directorate in Canada, UK, Euro-pe, Australia) to which manufacturersare required to submit their applica-tions. Applicants must document bymeans of appropriate test data (frompreclinical and clinical trials) that thecriteria of efficacy and safety have beenmet and that product forms (tablet, cap-sule, etc.) satisfy general standards ofquality control.

Following approval, the new drugmay be marketed under a trade name(p. 333) and thus become available forprescription by physicians and dispens-ing by pharmacists. As the drug gainsmore widespread use, regulatory sur-veillance continues in the form of post-licensing studies (Phase IV of clinicaltrials). Only on the basis of long-termexperience will the risk: benefit ratio beproperly assessed and, thus, the thera-peutic value of the new drug be deter-mined.

6 Drug Development


Drug Development 7

ClinicaltrialPhase 4

Approval

§General useLong-term benefit-risk evaluation

Healthy subjects:effects on body functions,dose definition, pharmacokinetics

Selected patients:effects on disease;safety, efficacy, dose,pharmacokinetics

Patient groups:Comparison withstandard therapy

Substances

Cells

Animals Isolated organs

(bio)chemicalsynthesis

Tissuehomogenate

A. From drug synthesis to approval

§ §§

10

10,000Substances

Preclinicaltesting:Effects on bodyfunctions, mechanismof action, toxicity

ECG

EEG

Bloodsample

Bloodpressure

Substance

1

Phase 1 Phase 2 Phase 3Clinical trial

§


Dosage Forms for Oral, Ocular, and Nasal Applications

A medicinal agent becomes a medica-tion only after formulation suitable fortherapeutic use (i.e., in an appropriatedosage form). The dosage form takesinto account the intended mode of useand also ensures ease of handling (e.g.,stability, precision of dosing) by pa-tients and physicians. Pharmaceuticaltechnology is concerned with the designof suitable product formulations andquality control.

Liquid preparations (A) may takethe form of solutions, suspensions (asol or mixture consisting of small wa-ter-insoluble solid drug particles dis-persed in water), or emulsions (disper-sion of minute droplets of a liquid agentor a drug solution in another fluid, e.g.,oil in water). Since storage will causesedimentation of suspensions and sep-aration of emulsions, solutions are gen-erally preferred. In the case of poorlywatersoluble substances, solution is of-ten accomplished by adding ethanol (orother solvents); thus, there are bothaqueous and alcoholic solutions. Thesesolutions are made available to patientsin specially designed drop bottles, ena-bling single doses to be measured ex-actly in terms of a defined number ofdrops, the size of which depends on thearea of the drip opening at the bottlemouth and on the viscosity and surfacetension of the solution. The advantageof a drop solution is that the dose, thatis, the number of drops, can be precise-ly adjusted to the patient‘s need. Its dis-advantage lies in the difficulty thatsome patients, disabled by disease orage, will experience in measuring a pre-scribed number of drops.

When the drugs are dissolved in alarger volume — as in the case of syrupsor mixtures — the single dose is meas-ured with a measuring spoon. Dosingmay also be done with the aid of atablespoon or teaspoon (approx. 15 and5 ml, respectively). However, due to thewide variation in the size of commer-cially available spoons, dosing will not

be very precise. (Standardized medici-nal teaspoons and tablespoons areavailable.)

Eye drops and nose drops (A) aredesigned for application to the mucosalsurfaces of the eye (conjunctival sac)and nasal cavity, respectively. In orderto prolong contact time, nasal drops areformulated as solutions of increasedviscosity.

Solid dosage forms include tab-lets, coated tablets, and capsules (B).Tablets have a disk-like shape, pro-duced by mechanical compression ofactive substance, filler (e.g., lactose, cal-cium sulfate), binder, and auxiliary ma-terial (excipients). The filler providesbulk enough to make the tablet easy tohandle and swallow. It is important toconsider that the individual dose ofmany drugs lies in the range of a fewmilligrams or less. In order to conveythe idea of a 10-mg weight, two squaresare marked below, the paper mass ofeach weighing 10 mg. Disintegration ofthe tablet can be hastened by the use ofdried starch, which swells on contactwith water, or of NaHCO3, which releas-es CO2 gas on contact with gastric acid.Auxiliary materials are important withregard to tablet production, shelf life,palatability, and identifiability (color).

Effervescent tablets (compressedeffervescent powders) do not representa solid dosage form, because they aredissolved in water immediately prior toingestion and are, thus, actually, liquidpreparations.

8 Drug Administration


Drug Administration 9

C. Dosage forms controlling rate of drug dissolution

B. Solid preparations for oral application

A. Liquid preparations

Drug

Filler

Disintegratingagent

Otherexcipients

Mixing andforming bycompression

~0.5 – 500 mg

30 – 250 mg

20 – 200 mg

30 – 15 mg

min 100 – 1000 mg maxpossible tablet size

Effervescenttablet

Tablet

Coated tablet

Capsule

Eyedrops

Nosedrops

SolutionMixture

Alcoholicsolution40 drops = 1g

Aqueoussolution20 drops = 1g

Dosage:in drops

Dosage:in spoon

SterileisotonicpH-neutral

Viscoussolution

Dru

g re

leas

e

Capsule

Coatedtablet

Capsulewith coateddrug pellets

Matrixtablet

Time

5 - 50 ml

5 - 50 ml

100 - 500 ml


The coated tablet contains a drug with-in a core that is covered by a shell, e.g., awax coating, that serves to: (1) protectperishable drugs from decomposing; (2)mask a disagreeable taste or odor; (3)facilitate passage on swallowing; or (4)permit color coding.

Capsules usually consist of an ob-long casing — generally made of gelatin— that contains the drug in powder orgranulated form (See. p. 9, C).

In the case of the matrix-type tab-let, the drug is embedded in an inertmeshwork from which it is released bydiffusion upon being moistened. In con-trast to solutions, which permit directabsorption of drug (A, track 3), the useof solid dosage forms initially requirestablets to break up and capsules to open(disintegration) before the drug can bedissolved (dissolution) and passthrough the gastrointestinal mucosallining (absorption). Because disintegra-tion of the tablet and dissolution of thedrug take time, absorption will occurmainly in the intestine (A, track 2). Inthe case of a solution, absorption startsin the stomach (A, track 3).

For acid-labile drugs, a coating ofwax or of a cellulose acetate polymer isused to prevent disintegration of soliddosage forms in the stomach. Accord-ingly, disintegration and dissolutionwill take place in the duodenum at nor-mal speed (A, track 1) and drug libera-tion per se is not retarded.

The liberation of drug, hence thesite and time-course of absorption, aresubject to modification by appropriateproduction methods for matrix-typetablets, coated tablets, and capsules. Inthe case of the matrix tablet, the drug isincorporated into a lattice from which itcan be slowly leached out by gastroin-testinal fluids. As the matrix tabletundergoes enteral transit, drug libera-tion and absorption proceed en route (A,track 4). In the case of coated tablets,coat thickness can be designed such thatrelease and absorption of drug occur ei-ther in the proximal (A, track 1) or distal(A, track 5) bowel. Thus, by matchingdissolution time with small-bowel tran-

sit time, drug release can be timed to oc-cur in the colon.

Drug liberation and, hence, absorp-tion can also be spread out when thedrug is presented in the form of a granu-late consisting of pellets coated with awaxy film of graded thickness. Depend-ing on film thickness, gradual dissolu-tion occurs during enteral transit, re-leasing drug at variable rates for absorp-tion. The principle illustrated for a cap-sule can also be applied to tablets. In thiscase, either drug pellets coated withfilms of various thicknesses are com-pressed into a tablet or the drug is incor-porated into a matrix-type tablet. Con-trary to timed-release capsules (Span-sules®), slow-release tablets have the ad-vantage of being dividable ad libitum;thus, fractions of the dose containedwithin the entire tablet may be admin-istered.

This kind of retarded drug releaseis employed when a rapid rise in bloodlevel of drug is undesirable, or when ab-sorption is being slowed in order to pro-long the action of drugs that have ashort sojourn in the body.




Administration in form of

Enteric-coatedtablet

Tablet,capsule

Drops,mixture,effervescentsolution

Matrixtablet

Coatedtablet withdelayedrelease

A. Oral administration: drug release and absorption

1 2 3 4 5


Dosage Forms for Parenteral (1), Pulmonary (2), Rectal or Vaginal (3), and Cutaneous Application

Drugs need not always be administeredorally (i.e., by swallowing), but may alsobe given parenterally. This route usual-ly refers to an injection, although enter-al absorption is also bypassed whendrugs are inhaled or applied to the skin.

For intravenous, intramuscular, orsubcutaneous injections, drugs are of-ten given as solutions and, less fre-quently, in crystalline suspension forintramuscular, subcutaneous, or intra-articular injection. An injectable solu-tion must be free of infectious agents,pyrogens, or suspended matter. Itshould have the same osmotic pressureand pH as body fluids in order to avoidtissue damage at the site of injection.Solutions for injection are preserved inairtight glass or plastic sealed contain-ers. From ampules for multiple or sin-gle use, the solution is aspirated via aneedle into a syringe. The cartridge am-pule is fitted into a special injector thatenables its contents to be emptied via aneedle. An infusion refers to a solutionbeing administered over an extendedperiod of time. Solutions for infusionmust meet the same standards as solu-tions for injection.

Drugs can be sprayed in aerosolform onto mucosal surfaces of body cav-ities accessible from the outside (e.g.,the respiratory tract [p. 14]). An aerosolis a dispersion of liquid or solid particlesin a gas, such as air. An aerosol resultswhen a drug solution or micronizedpowder is reduced to a spray on beingdriven through the nozzle of a pressur-ized container.

Mucosal application of drug via therectal or vaginal route is achieved bymeans of suppositories and vaginaltablets, respectively. On rectal applica-tion, absorption into the systemic circu-lation may be intended. With vaginaltablets, the effect is generally confinedto the site of application. Usually thedrug is incorporated into a fat that solid-ifies at room temperature, but melts in

the rectum or vagina. The resulting oilyfilm spreads over the mucosa and en-ables the drug to pass into the mucosa.

Powders, ointments, and pastes(p. 16) are applied to the skin surface. Inmany cases, these do not contain drugsbut are used for skin protection or care.However, drugs may be added if a topi-cal action on the outer skin or, morerarely, a systemic effect is intended.

Transdermal drug deliverysystems are pasted to the epidermis.They contain a reservoir from whichdrugs may diffuse and be absorbedthrough the skin. They offer the advan-tage that a drug depot is attached non-invasively to the body, enabling thedrug to be administered in a mannersimilar to an infusion. Drugs amenableto this type of delivery must: (1) be ca-pable of penetrating the cutaneous bar-rier; (2) be effective in very small doses(restricted capacity of reservoir); and(3) possess a wide therapeutic margin(dosage not adjustable).



Admin

Inserted Text


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

With and withoutfracture ring

Often withpreservative

Sterile, iso-osmolar

Ampule1 – 20 ml

Cartridgeampule 2 ml

Multiple-dosevial 50 – 100 ml,always withpreservative

Infusionsolution500 – 1000 ml

Propellant gas

Drug solution

Jet nebulizer

Suppository

Vaginaltablet

Backing layer Drug reservoir

Adhesive coat

Transdermal delivery system (TDS)

Time 12 24 h

Ointment TDS

4

Paste

Ointment

Powder

1 3

2

Drug release

35 ºC Melting point

35 ºC


Drug Administration by Inhalation

Inhalation in the form of an aerosol(p. 12), a gas, or a mist permits drugs tobe applied to the bronchial mucosa and,to a lesser extent, to the alveolar mem-branes. This route is chosen for drugs in-tended to affect bronchial smooth mus-cle or the consistency of bronchial mu-cus. Furthermore, gaseous or volatileagents can be administered by inhala-tion with the goal of alveolar absorptionand systemic effects (e.g., inhalationalanesthetics, p. 218). Aerosols areformed when a drug solution or micron-ized powder is converted into a mist ordust, respectively.

In conventional sprays (e.g., nebu-lizer), the air blast required for aerosolformation is generated by the stroke of apump. Alternatively, the drug is deliv-ered from a solution or powder pack-aged in a pressurized canister equippedwith a valve through which a metereddose is discharged. During use, the in-haler (spray dispenser) is held directlyin front of the mouth and actuated atthe start of inspiration. The effective-ness of delivery depends on the positionof the device in front of the mouth, thesize of aerosol particles, and the coordi-nation between opening of the sprayvalve and inspiration. The size of aerosolparticles determines the speed at whichthey are swept along by inhaled air,hence the depth of penetration intothe respiratory tract. Particles >100 µm in diameter are trapped in theoropharyngeal cavity; those having dia-meters between 10 and 60µm will bedeposited on the epithelium of thebronchial tract. Particles < 2 µm in dia-meter can reach the alveoli, but theywill be largely exhaled because of theirlow tendency to impact on the alveolarepithelium.

Drug deposited on the mucous lin-ing of the bronchial epithelium is partlyabsorbed and partly transported withbronchial mucus towards the larynx.Bronchial mucus travels upwards due tothe orally directed undulatory beat ofthe epithelial cilia. Physiologically, this

mucociliary transport functions to re-move inspired dust particles. Thus, onlya portion of the drug aerosol (~ 10 %)gains access to the respiratory tract andjust a fraction of this amount penetratesthe mucosa, whereas the remainder ofthe aerosol undergoes mucociliarytransport to the laryngopharynx and isswallowed. The advantage of inhalation(i.e., localized application) is fully ex-ploited by using drugs that are poorlyabsorbed from the intestine (isoprotere-nol, ipratropium, cromolyn) or are sub-ject to first-pass elimination (p. 42; bec-lomethasone dipropionate, budesonide,flunisolide, fluticasone dipropionate).

Even when the swallowed portionof an inhaled drug is absorbed in un-changed form, administration by thisroute has the advantage that drug con-centrations at the bronchi will be higherthan in other organs.

The efficiency of mucociliary trans-port depends on the force of kinociliarymotion and the viscosity of bronchialmucus. Both factors can be alteredpathologically (e.g., in smoker’s cough,bronchitis) or can be adversely affectedby drugs (atropine, antihistamines).




A. Application by inhalation

Depth ofpenetrationof inhaledaerosolizeddrug solution

Nasopharynx

Trachea-bronchi

Bronchioli, alveoli

Drug swept upis swallowed

Mucociliary transport

Ciliated epithelium

Low systemic burden

As completepresystemiceliminationas possible

As littleenteralabsorptionas possible

100 µm

10 µm

1 µm 1 cm

/min

Lary

nx

10%90%


Dermatologic Agents

Pharmaceutical preparations applied tothe outer skin are intended either toprovide skin care and protection fromnoxious influences (A), or to serve as avehicle for drugs that are to be absorbedinto the skin or, if appropriate, into thegeneral circulation (B).

Skin Protection (A)Protective agents are of several kinds tomeet different requirements accordingto skin condition (dry, low in oil,chapped vs moist, oily, elastic), and thetype of noxious stimuli (prolonged ex-posure to water, regular use of alcohol-containing disinfectants [p. 290], in-tense solar irradiation).

Distinctions among protectiveagents are based upon consistency, phy-sicochemical properties (lipophilic, hy-drophilic), and the presence of addi-tives.

Dusting Powders are sprinkled on-to the intact skin and consist of talc,magnesium stearate, silicon dioxide(silica), or starch. They adhere to theskin, forming a low-friction film that at-tenuates mechanical irritation. Powdersexert a drying (evaporative) effect.

Lipophilic ointment (oil ointment)consists of a lipophilic base (paraffin oil,petroleum jelly, wool fat [lanolin]) andmay contain up to 10 % powder materi-als, such as zinc oxide, titanium oxide,starch, or a mixture of these. Emulsify-ing ointments are made of paraffins andan emulsifying wax, and are misciblewith water.

Paste (oil paste) is an ointmentcontaining more than 10 % pulverizedconstituents.

Lipophilic (oily) cream is an emul-sion of water in oil, easier to spread thanoil paste or oil ointments.

Hydrogel and water-soluble oint-ment achieve their consistency bymeans of different gel-forming agents(gelatin, methylcellulose, polyethyleneglycol). Lotions are aqueous suspen-sions of water-insoluble and solid con-stituents.

Hydrophilic (aqueous) cream is anemulsion of an oil in water formed withthe aid of an emulsifier; it may also beconsidered an oil-in-water emulsion ofan emulsifying ointment.

All dermatologic agents having alipophilic base adhere to the skin as awater-repellent coating. They do notwash off and they also prevent (oc-clude) outward passage of water fromthe skin. The skin is protected from dry-ing, and its hydration and elasticity in-crease.

Diminished evaporation of waterresults in warming of the occluded skinarea. Hydrophilic agents wash off easilyand do not impede transcutaneous out-put of water. Evaporation of water is feltas a cooling effect.

Dermatologic Agents as Vehicles (B)In order to reach its site of action, a drug(D) must leave its pharmaceutical pre-paration and enter the skin, if a local ef-fect is desired (e.g., glucocorticoid oint-ment), or be able to penetrate it, if asystemic action is intended (transder-mal delivery system, e.g., nitroglycerinpatch, p. 120). The tendency for the drugto leave the drug vehicle (V) is higherthe more the drug and vehicle differ inlipophilicity (high tendency: hydrophil-ic D and lipophilic V, and vice versa). Be-cause the skin represents a closed lipo-philic barrier (p. 22), only lipophilicdrugs are absorbed. Hydrophilic drugsfail even to penetrate the outer skinwhen applied in a lipophilic vehicle.This formulation can be meaningfulwhen high drug concentrations are re-quired at the skin surface (e.g., neomy-cin ointment for bacterial skin infec-tions).




Semi-solid

Solid Liquid

Dermatologicals

B. Dermatologicals as drug vehicles

Powder

Paste

Oily paste

Ointment

Lipophilicointment

Hydrophilicointment

Lipophiliccream

Hydrophiliccream

Cream

Solution

Aqueoussolution

Alcoholictincture

Hydrogel

Suspen-sion

Emulsion

Fat, oil Oil in waterWater in oil Gel, water

Occlusive Permeable,coolant

impossible possible

Dry, non-oily skin Oily, moist skin

Lipophilic drugin hydrophilicbase

Lipophilic drugin lipophilicbase

Hydrophilic drugin lipophilicbase

Hydrophilic drugin hydrophilicbase

Stratumcorneum

Epithelium

Subcutaneous fat tissue

Lotion

A. Dermatologicals as skin protectants

Perspiration


From Application to Distribution in the Body

As a rule, drugs reach their target organsvia the blood. Therefore, they must firstenter the blood, usually the venous limbof the circulation. There are several pos-sible sites of entry.

The drug may be injected or infusedintravenously, in which case the drug isintroduced directly into the blood-stream. In subcutaneous or intramus-cular injection, the drug has to diffusefrom its site of application into theblood. Because these procedures entailinjury to the outer skin, strict require-ments must be met concerning tech-nique. For that reason, the oral route(i.e., simple application by mouth) in-volving subsequent uptake of drugacross the gastrointestinal mucosa intothe blood is chosen much more fre-quently. The disadvantage of this routeis that the drug must pass through theliver on its way into the general circula-tion. This fact assumes practical signifi-cance with any drug that may be rapidlytransformed or possibly inactivated inthe liver (first-pass hepatic elimination;p. 42). Even with rectal administration,at least a fraction of the drug enters thegeneral circulation via the portal vein,because only veins draining the shortterminal segment of the rectum com-municate directly with the inferior venacava. Hepatic passage is circumventedwhen absorption occurs buccally orsublingually, because venous bloodfrom the oral cavity drains directly intothe superior vena cava. The same wouldapply to administration by inhalation(p. 14). However, with this route, a localeffect is usually intended; a systemic ac-tion is intended only in exceptional cas-es. Under certain conditions, drug canalso be applied percutaneously in theform of a transdermal delivery system(p. 12). In this case, drug is slowly re-leased from the reservoir, and then pen-etrates the epidermis and subepidermalconnective tissue where it enters bloodcapillaries. Only a very few drugs can beapplied transdermally. The feasibility of

this route is determined by both thephysicochemical properties of the drugand the therapeutic requirements (acute vs. long-term effect).

Speed of absorption is determinedby the route and method of application.It is fastest with intravenous injection,less fast which intramuscular injection,and slowest with subcutaneous injec-tion. When the drug is applied to theoral mucosa (buccal, sublingual route),plasma levels rise faster than with con-ventional oral administration becausethe drug preparation is deposited at itsactual site of absorption and very highconcentrations in saliva occur upon thedissolution of a single dose. Thus, up-take across the oral epithelium is accel-erated. The same does not hold true forpoorly water-soluble or poorly absorb-able drugs. Such agents should be givenorally, because both the volume of fluidfor dissolution and the absorbing sur-face are much larger in the small intes-tine than in the oral cavity.

Bioavailability is defined as thefraction of a given drug dose that reach-es the circulation in unchanged formand becomes available for systemic dis-tribution. The larger the presystemicelimination, the smaller is the bioavail-ability of an orally administered drug.




Intravenous

Sublingualbuccal

Inhalational

Transdermal

Subcutaneous

Intramuscular

Ora

l

Aor

taD

istr

ibut

ion

in b

ody

Rectal

A. From application to distribution


Potential Targets of Drug Action

Drugs are designed to exert a selectiveinfluence on vital processes in order toalleviate or eliminate symptoms of dis-ease. The smallest basic unit of an or-ganism is the cell. The outer cell mem-brane, or plasmalemma, effectively de-marcates the cell from its surroundings,thus permitting a large degree of inter-nal autonomy. Embedded in the plas-malemma are transport proteins thatserve to mediate controlled metabolicexchange with the cellular environment.These include energy-consumingpumps (e.g., Na, K-ATPase, p. 130), car-riers (e.g., for Na/glucose-cotransport, p.178), and ion channels e.g., for sodium(p. 136) or calcium (p. 122) (1).

Functional coordination betweensingle cells is a prerequisite for viabilityof the organism, hence also for the sur-vival of individual cells. Cell functionsare regulated by means of messengersubstances for the transfer of informa-tion. Included among these are “trans-mitters” released from nerves, whichthe cell is able to recognize with thehelp of specialized membrane bindingsites or receptors. Hormones secretedby endocrine glands into the blood, theninto the extracellular fluid, representanother class of chemical signals. Final-ly, signalling substances can originatefrom neighboring cells, e.g., prostaglan-dins (p. 196) and cytokines.

The effect of a drug frequently re-sults from interference with cellularfunction. Receptors for the recognitionof endogenous transmitters are obvioussites of drug action (receptor agonistsand antagonists, p. 60). Altered activityof transport systems affects cell func-tion (e.g., cardiac glycosides, p. 130;loop diuretics, p. 162; calcium-antago-nists, p. 122). Drugs may also directlyinterfere with intracellular metabolicprocesses, for instance by inhibiting(phosphodiesterase inhibitors, p. 132)or activating (organic nitrates, p. 120)an enzyme (2).

In contrast to drugs acting from theoutside on cell membrane constituents,

agents acting in the cell’s interior needto penetrate the cell membrane.

The cell membrane basically con-sists of a phospholipid bilayer (80Å =8 nm in thickness) in which are embed-ded proteins (integral membrane pro-teins, such as receptors and transportmolecules). Phospholipid moleculescontain two long-chain fatty acids in es-ter linkage with two of the three hy-droxyl groups of glycerol. Bound to thethird hydroxyl group is phosphoric acid,which, in turn, carries a further residue,e.g., choline, (phosphatidylcholine = lec-ithin), the amino acid serine (phosphat-idylserine) or the cyclic polyhydric alco-hol inositol (phosphatidylinositol). Interms of solubility, phospholipids areamphiphilic: the tail region containingthe apolar fatty acid chains is lipophilic,the remainder – the polar head – is hy-drophilic. By virtue of these properties,phospholipids aggregate spontaneouslyinto a bilayer in an aqueous medium,their polar heads directed outwards intothe aqueous medium, the fatty acidchains facing each other and projectinginto the inside of the membrane (3).

The hydrophobic interior of thephospholipid membrane constitutes adiffusion barrier virtually imperme-able for charged particles. Apolar parti-cles, however, penetrate the membraneeasily. This is of major importance withrespect to the absorption, distribution,and elimination of drugs.

20 Cellular Sites of Action


Cellular Sites of Action 21

NerveTransmitterReceptor

Enzyme

Hormonereceptors

Neuralcontrol

Hormonalcontrol

Direct actionon metabolism

Cellulartransportsystems forcontrolledtransfer ofsubstrates

Ion channel

Transportmolecule

Effect

Intracellularsite of action

Choline

Phosphoricacid

Glycerol

Fatty acid

A. Sites at which drugs act to modify cell function

1

2 3

D

Hormones

D

D

D

= DrugD

Phospholipidmatrix

D D

Protein


External Barriers of the Body

Prior to its uptake into the blood (i.e.,during absorption), a drug has to over-come barriers that demarcate the bodyfrom its surroundings, i.e., separate theinternal milieu from the external mi-lieu. These boundaries are formed bythe skin and mucous membranes.

When absorption takes place in thegut (enteral absorption), the intestinalepithelium is the barrier. This single-layered epithelium is made up of ente-rocytes and mucus-producing gobletcells. On their luminal side, these cellsare joined together by zonulae occlu-dentes (indicated by black dots in the in-set, bottom left). A zonula occludens ortight junction is a region in which thephospholipid membranes of two cellsestablish close contact and becomejoined via integral membrane proteins(semicircular inset, left center). The re-gion of fusion surrounds each cell like aring, so that neighboring cells are weld-ed together in a continuous belt. In thismanner, an unbroken phospholipidlayer is formed (yellow area in the sche-matic drawing, bottom left) and acts asa continuous barrier between the twospaces separated by the cell layer – inthe case of the gut, the intestinal lumen(dark blue) and the interstitial space(light blue). The efficiency with whichsuch a barrier restricts exchange of sub-stances can be increased by arrangingthese occluding junctions in multiplearrays, as for instance in the endotheli-um of cerebral blood vessels. The con-necting proteins (connexins) further-more serve to restrict mixing of otherfunctional membrane proteins (ionpumps, ion channels) that occupy spe-cific areas of the cell membrane.

This phospholipid bilayer repre-sents the intestinal mucosa-blood bar-rier that a drug must cross during its en-teral absorption. Eligible drugs are thosewhose physicochemical properties al-low permeation through the lipophilicmembrane interior (yellow) or that aresubject to a special carrier transportmechanism. Absorption of such drugs

proceeds rapidly, because the absorbingsurface is greatly enlarged due to theformation of the epithelial brush border(submicroscopic foldings of the plasma-lemma). The absorbability of a drug ischaracterized by the absorption quo-tient, that is, the amount absorbed di-vided by the amount in the gut availablefor absorption.

In the respiratory tract, cilia-bear-ing epithelial cells are also joined on theluminal side by zonulae occludentes, sothat the bronchial space and the inter-stitium are separated by a continuousphospholipid barrier.

With sublingual or buccal applica-tion, a drug encounters the non-kerati-nized, multilayered squamous epitheli-um of the oral mucosa. Here, the cellsestablish punctate contacts with eachother in the form of desmosomes (notshown); however, these do not seal theintercellular clefts. Instead, the cellshave the property of sequestering phos-pholipid-containing membrane frag-ments that assemble into layers withinthe extracellular space (semicircular in-set, center right). In this manner, a con-tinuous phospholipid barrier arises alsoinside squamous epithelia, although atan extracellular location, unlike that ofintestinal epithelia. A similar barrierprinciple operates in the multilayeredkeratinized squamous epithelium of theouter skin. The presence of a continu-ous phospholipid layer means thatsquamous epithelia will permit passageof lipophilic drugs only, i.e., agents ca-pable of diffusing through phospholipidmembranes, with the epithelial thick-ness determining the extent and speedof absorption. In addition, cutaneous ab-sorption is impeded by the keratinlayer, the stratum corneum, which isvery unevenly developed in various are-as of the skin.

22 Distribution in the Body


Distribution in the Body 23

A. External barriers of the body

Nonkeratinizedsquamous epitheliumCiliated epithelium

Keratinized squamousepithelium

Epithelium withbrush border


Blood-Tissue Barriers

Drugs are transported in the blood todifferent tissues of the body. In order toreach their sites of action, they mustleave the bloodstream. Drug permea-tion occurs largely in the capillary bed,where both surface area and time avail-able for exchange are maximal (exten-sive vascular branching, low velocity offlow). The capillary wall forms theblood-tissue barrier. Basically, thisconsists of an endothelial cell layer anda basement membrane enveloping thelatter (solid black line in the schematicdrawings). The endothelial cells are“riveted” to each other by tight junc-tions or occluding zonulae (labelled Z inthe electron micrograph, top left) suchthat no clefts, gaps, or pores remain thatwould permit drugs to pass unimpededfrom the blood into the interstitial fluid.

The blood-tissue barrier is devel-oped differently in the various capillarybeds. Permeability to drugs of the capil-lary wall is determined by the structuraland functional characteristics of the en-dothelial cells. In many capillary beds,e.g., those of cardiac muscle, endothe-lial cells are characterized by pro-nounced endo- and transcytotic activ-ity, as evidenced by numerous invagina-tions and vesicles (arrows in the EM mi-crograph, top right). Transcytotic activ-ity entails transport of fluid or macro-molecules from the blood into the inter-stitium and vice versa. Any solutestrapped in the fluid, including drugs,may traverse the blood-tissue barrier. Inthis form of transport, the physico-chemical properties of drugs are of littleimportance.

In some capillary beds (e.g., in thepancreas), endothelial cells exhibit fen-estrations. Although the cells are tight-ly connected by continuous junctions,they possess pores (arrows in EM mi-crograph, bottom right) that are closedonly by diaphragms. Both the dia-phragm and basement membrane canbe readily penetrated by substances oflow molecular weight — the majority ofdrugs — but less so by macromolecules,

e.g., proteins such as insulin (G: insulinstorage granules. Penetrability of mac-romolecules is determined by molecu-lar size and electrical charge. Fenestrat-ed endothelia are found in the capillar-ies of the gut and endocrine glands.

In the central nervous system(brain and spinal cord), capillary endo-thelia lack pores and there is little trans-cytotic activity. In order to cross theblood-brain barrier, drugs must diffusetranscellularly, i.e., penetrate the lumi-nal and basal membrane of endothelialcells. Drug movement along this pathrequires specific physicochemical prop-erties (p. 26) or the presence of a trans-port mechanism (e.g., L-dopa, p. 188).Thus, the blood-brain barrier is perme-able only to certain types of drugs.

Drugs exchange freely betweenblood and interstitium in the liver,where endothelial cells exhibit largefenestrations (100 nm in diameter) fac-ing Disse’s spaces (D) and where neitherdiaphragms nor basement membranesimpede drug movement. Diffusion bar-riers are also present beyond the capil-lary wall: e.g., placental barrier of fusedsyncytiotrophoblast cells; blood: testi-cle barrier — junctions interconnectingSertoli cells; brain choroid plexus: bloodbarrier — occluding junctions betweenependymal cells.

(Vertical bars in the EM micro-graphs represent 1 µm; E: cross-sec-tioned erythrocyte; AM: actomyosin; G:insulin-containing granules.)




A. Blood-tissue barriers

CNS Heart muscle

Liver

G

Pancreas

AM

D

E

Z


Membrane Permeation

An ability to penetrate lipid bilayers is aprerequisite for the absorption of drugs,their entry into cells or cellular orga-nelles, and passage across the blood-brain barrier. Due to their amphiphilicnature, phospholipids form bilayerspossessing a hydrophilic surface and ahydrophobic interior (p. 20). Substancesmay traverse this membrane in threedifferent ways.

Diffusion (A). Lipophilic substanc-es (red dots) may enter the membranefrom the extracellular space (areashown in ochre), accumulate in themembrane, and exit into the cytosol(blue area). Direction and speed of per-meation depend on the relative concen-trations in the fluid phases and themembrane. The steeper the gradient(concentration difference), the moredrug will be diffusing per unit of time(Fick’s Law). The lipid membrane repre-sents an almost insurmountable obsta-cle for hydrophilic substances (blue tri-angles).

Transport (B). Some drugs maypenetrate membrane barriers with thehelp of transport systems (carriers), ir-respective of their physicochemicalproperties, especially lipophilicity. As aprerequisite, the drug must have affin-ity for the carrier (blue triangle match-ing recess on “transport system”) and,when bound to the latter, be capable ofbeing ferried across the membrane.Membrane passage via transport mech-anisms is subject to competitive inhibi-tion by another substance possessingsimilar affinity for the carrier. Substanc-es lacking in affinity (blue circles) arenot transported. Drugs utilize carriersfor physiological substances, e.g., L-do-pa uptake by L-amino acid carrier acrossthe blood-intestine and blood-brainbarriers (p. 188), and uptake of amino-glycosides by the carrier transportingbasic polypeptides through the luminalmembrane of kidney tubular cells (p.278). Only drugs bearing sufficient re-semblance to the physiological sub-

strate of a carrier will exhibit affinity forit.

Finally, membrane penetrationmay occur in the form of small mem-brane-covered vesicles. Two differentsystems are considered.

Transcytosis (vesicular transport,C). When new vesicles are pinched off,substances dissolved in the extracellu-lar fluid are engulfed, and then ferriedthrough the cytoplasm, vesicles (phago-somes) undergo fusion with lysosomesto form phagolysosomes, and the trans-ported substance is metabolized. Alter-natively, the vesicle may fuse with theopposite cell membrane (cytopempsis).

Receptor-mediated endocytosis(C). The drug first binds to membranesurface receptors (1, 2) whose cytosolicdomains contact special proteins (adap-tins, 3). Drug-receptor complexes mi-grate laterally in the membrane and ag-gregate with other complexes by aclathrin-dependent process (4). The af-fected membrane region invaginatesand eventually pinches off to form a de-tached vesicle (5). The clathrin coat isshed immediately (6), followed by theadaptins (7). The remaining vesicle thenfuses with an “early” endosome (8),whereupon proton concentration risesinside the vesicle. The drug-receptorcomplex dissociates and the receptorreturns into the cell membrane. The“early” endosome delivers its contentsto predetermined destinations, e.g., theGolgi complex, the cell nucleus, lysoso-mes, or the opposite cell membrane(transcytosis). Unlike simple endocyto-sis, receptor-mediated endocytosis iscontingent on affinity for specific recep-tors and operates independently of con-centration gradients.




C. Membrane permeation: receptor-mediated endocytosis, vesicular uptake, andtransport

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

Vesicular transport

Lysosome Phagolysosome

Intracellular ExtracellularExtracellular

1

2

3

4

5

7

8

9

6


Possible Modes of Drug Distribution

Following its uptake into the body, thedrug is distributed in the blood (1) andthrough it to the various tissues of thebody. Distribution may be restricted tothe extracellular space (plasma volumeplus interstitial space) (2) or may alsoextend into the intracellular space (3).Certain drugs may bind strongly to tis-sue structures, so that plasma concen-trations fall significantly even beforeelimination has begun (4).

After being distributed in blood,macromolecular substances remainlargely confined to the vascular space,because their permeation through theblood-tissue barrier, or endothelium, isimpeded, even where capillaries arefenestrated. This property is exploitedtherapeutically when loss of blood ne-cessitates refilling of the vascular bed,e.g., by infusion of dextran solutions (p.152). The vascular space is, moreover,predominantly occupied by substancesbound with high affinity to plasma pro-teins (p. 30; determination of the plas-ma volume with protein-bound dyes).Unbound, free drug may leave thebloodstream, albeit with varying ease,because the blood-tissue barrier (p. 24)is differently developed in different seg-ments of the vascular tree. These re-gional differences are not illustrated inthe accompanying figures.

Distribution in the body is deter-mined by the ability to penetrate mem-branous barriers (p. 20). Hydrophilicsubstances (e.g., inulin) are neither tak-en up into cells nor bound to cell surfacestructures and can, thus, be used to de-termine the extracellular fluid volume(2). Some lipophilic substances diffusethrough the cell membrane and, as a re-sult, achieve a uniform distribution (3).

Body weight may be broken downas follows:

Further subdivisions are shown inthe table.

The volume ratio interstitial: intra-cellular water varies with age and bodyweight. On a percentage basis, intersti-tial fluid volume is large in premature ornormal neonates (up to 50 % of bodywater), and smaller in the obese and theaged.

The concentration (c) of a solutioncorresponds to the amount (D) of sub-stance dissolved in a volume (V); thus, c= D/V. If the dose of drug (D) and itsplasma concentration (c) are known, avolume of distribution (V) can be calcu-lated from V = D/c. However, this repre-sents an apparent volume of distribu-tion (Vapp), because an even distributionin the body is assumed in its calculation.Homogeneous distribution will not oc-cur if drugs are bound to cell mem-branes (5) or to membranes of intracel-lular organelles (6) or are stored withinthe latter (7). In these cases, Vapp can ex-ceed the actual size of the available fluidvolume. The significance of Vapp as apharmacokinetic parameter is dis-cussed on p. 44.

��

��

��

��

��

��

Solid substance andstructurally bound water


intracellular extracellularwater water

Potential aqueous solventspaces for drugs

Lüllmann, Color Atlas of Pharmacology ' 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.


A. Compartments for drug distribution

Distribution in tissue

Aqueous spaces of the organism

InterstitiumPlasma

ErythrocytesIntracellular space

6%

4%

25%

65%

Lysosomes

Mito-chondria

Cellmembrane

Nucleus

1 2 43

5 6 7


Binding to Plasma Proteins

Having entered the blood, drugs maybind to the protein molecules that arepresent in abundance, resulting in theformation of drug-protein complexes.Protein binding involves primarily al-bumin and, to a lesser extent, β-globu-lins and acidic glycoproteins. Otherplasma proteins (e.g., transcortin, trans-ferrin, thyroxin-binding globulin) servespecialized functions in connectionwith specific substances. The degree ofbinding is governed by the concentra-tion of the reactants and the affinity of adrug for a given protein. Albumin con-centration in plasma amounts to4.6 g/100 mL or O.6 mM, and thus pro-vides a very high binding capacity (twosites per molecule). As a rule, drugs ex-hibit much lower affinity (KD approx.10–5 –10–3 M) for plasma proteins thanfor their specific binding sites (recep-tors). In the range of therapeutically rel-evant concentrations, protein binding ofmost drugs increases linearly with con-centration (exceptions: salicylate andcertain sulfonamides).

The albumin molecule has differentbinding sites for anionic and cationic li-gands, but van der Waals’ forces alsocontribute (p. 58). The extent of bindingcorrelates with drug hydrophobicity(repulsion of drug by water).

Binding to plasma proteins is in-stantaneous and reversible, i.e., anychange in the concentration of unbounddrug is immediately followed by a cor-responding change in the concentrationof bound drug. Protein binding is ofgreat importance, because it is the con-centration of free drug that determinesthe intensity of the effect. At an identi-cal total plasma concentration (say, 100ng/mL) the effective concentration willbe 90 ng/mL for a drug 10 % bound toprotein, but 1 ng/mL for a drug 99 %bound to protein. The reduction in con-centration of free drug resulting fromprotein binding affects not only the in-tensity of the effect but also biotransfor-mation (e.g., in the liver) and elimina-tion in the kidney, because only free

drug will enter hepatic sites of metab-olism or undergo glomerular filtration.When concentrations of free drug fall,drug is resupplied from binding sites onplasma proteins. Binding to plasma pro-tein is equivalent to a depot in prolong-ing the duration of the effect by retard-ing elimination, whereas the intensityof the effect is reduced. If two substanc-es have affinity for the same binding siteon the albumin molecule, they maycompete for that site. One drug may dis-place another from its binding site andthereby elevate the free (effective) con-centration of the displaced drug (a formof drug interaction). Elevation of thefree concentration of the displaced drugmeans increased effectiveness and ac-celerated elimination.

A decrease in the concentration ofalbumin (liver disease, nephrotic syn-drome, poor general condition) leads toaltered pharmacokinetics of drugs thatare highly bound to albumin.

Plasma protein-bound drugs thatare substrates for transport carriers canbe cleared from blood at great velocity,e.g., p-aminohippurate by the renal tu-bule and sulfobromophthalein by theliver. Clearance rates of these substanc-es can be used to determine renal or he-patic blood flow.




Renal elimination

Biotransformation

Effector cellEffect

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

Drug isnot boundto plasmaproteins

Drug isstronglybound toplasmaproteins

Effector cellEffect

Biotransformation

Renal elimination

Time

Plasma concentration

Time


Bound drug

Free drug

Free drug


The Liver as an Excretory Organ

As the chief organ of drug biotransfor-mation, the liver is richly supplied withblood, of which 1100 mL is receivedeach minute from the intestinesthrough the portal vein and 350 mLthrough the hepatic artery, comprisingnearly 1/3 of cardiac output. The bloodcontent of hepatic vessels and sinusoidsamounts to 500 mL. Due to the widen-ing of the portal lumen, intrahepaticblood flow decelerates (A). Moreover,the endothelial lining of hepatic sinu-soids (p. 24) contains pores largeenough to permit rapid exit of plasmaproteins. Thus, blood and hepatic paren-chyma are able to maintain intimatecontact and intensive exchange of sub-stances, which is further facilitated bymicrovilli covering the hepatocyte sur-faces abutting Disse’s spaces.

The hepatocyte secretes biliaryfluid into the bile canaliculi (darkgreen), tubular intercellular clefts thatare sealed off from the blood spaces bytight junctions. Secretory activity in thehepatocytes results in movement offluid towards the canalicular space (A).The hepatocyte has an abundance of en-zymes carrying out metabolic functions.These are localized in part in mitochon-dria, in part on the membranes of therough (rER) or smooth (sER) endoplas-mic reticulum.

Enzymes of the sER play a most im-portant role in drug biotransformation.At this site, molecular oxygen is used inoxidative reactions. Because these en-zymes can catalyze either hydroxylationor oxidative cleavage of -N-C- or -O-C-bonds, they are referred to as “mixed-function” oxidases or hydroxylases. Theessential component of this enzymesystem is cytochrome P450, which in itsoxidized state binds drug substrates (R-H). The FeIII-P450-RH binary complex isfirst reduced by NADPH, then forms theternary complex, O2-FeII-P450-RH,which accepts a second electron and fi-nally disintegrates into FeIII-P450, oneequivalent of H2O, and hydroxylateddrug (R-OH).

Compared with hydrophilic drugsnot undergoing transport, lipophilicdrugs are more rapidly taken up fromthe blood into hepatocytes and morereadily gain access to mixed-functionoxidases embedded in sER membranes.For instance, a drug having lipophilicityby virtue of an aromatic substituent(phenyl ring) (B) can be hydroxylatedand, thus, become more hydrophilic(Phase I reaction, p. 34). Besides oxi-dases, sER also contains reductases andglucuronyl transferases. The latter con-jugate glucuronic acid with hydroxyl,carboxyl, amine, and amide groups (p.38); hence, also phenolic products ofphase I metabolism (Phase II conjuga-tion). Phase I and Phase II metabolitescan be transported back into the blood— probably via a gradient-dependentcarrier — or actively secreted into bile.

Prolonged exposure to certain sub-strates, such as phenobarbital, carbama-zepine, rifampicin results in a prolifera-tion of sER membranes (cf. C and D).This enzyme induction, a load-depen-dent hypertrophy, affects equally all en-zymes localized on sER membranes. En-zyme induction leads to acceleratedbiotransformation, not only of the in-ducing agent but also of other drugs (aform of drug interaction). With contin-ued exposure, induction develops in afew days, resulting in an increase in re-action velocity, maximally 2–3fold, thatdisappears after removal of the induc-ing agent.

32 Drug Elimination


Drug Elimination 33

D. Hepatocyte afterD. phenobarbital administration

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

C. Normal hepatocyte

Hepatocyte Disse´s space

Gall-bladder

Portal vein

sER

rER

sER

rER

Phase II-metabolite

Biliarycapillary

Glucuronide

Carrier

Phase I-metabolite

B. Fate of drugs undergoingB. hepatic hydroxylation

Biliary capillary

Intestine


Biotransformation of Drugs

Many drugs undergo chemical modifi-cation in the body (biotransformation).Most frequently, this process entails aloss of biological activity and an in-crease in hydrophilicity (water solubil-ity), thereby promoting elimination viathe renal route (p. 40). Since rapid drugelimination improves accuracy in titrat-ing the therapeutic concentration, drugsare often designed with built-in weaklinks. Ester bonds are such links, beingsubject to hydrolysis by the ubiquitousesterases. Hydrolytic cleavages, alongwith oxidations, reductions, alkylations,and dealkylations, constitute Phase I re-actions of drug metabolism. These reac-tions subsume all metabolic processesapt to alter drug molecules chemicallyand take place chiefly in the liver. InPhase II (synthetic) reactions, conju-gation products of either the drug itselfor its Phase I metabolites are formed, forinstance, with glucuronic or sulfuric ac-id (p. 38).

The special case of the endogenoustransmitter acetylcholine illustrateswell the high velocity of ester hydroly-sis. Acetylcholine is broken down at itssites of release and action by acetylchol-inesterase (pp. 100, 102) so rapidly as tonegate its therapeutic use. Hydrolysis ofother esters catalyzed by various este-rases is slower, though relatively fast incomparison with other biotransforma-tions. The local anesthetic, procaine, is acase in point; it exerts its action at thesite of application while being largelydevoid of undesirable effects at other lo-cations because it is inactivated by hy-drolysis during absorption from its siteof application.

Ester hydrolysis does not invariablylead to inactive metabolites, as exempli-fied by acetylsalicylic acid. The cleavageproduct, salicylic acid, retains phar-macological activity. In certain cases,drugs are administered in the form ofesters in order to facilitate absorption(enalapril � enalaprilate; testosteroneundecanoate � testosterone) or to re-duce irritation of the gastrointestinal

mucosa (erythromycin succinate �erythromycin). In these cases, the esteritself is not active, but the cleavageproduct is. Thus, an inactive precursoror prodrug is applied, formation of theactive molecule occurring only after hy-drolysis in the blood.

Some drugs possessing amidebonds, such as prilocaine, and of course,peptides, can be hydrolyzed by pepti-dases and inactivated in this manner.Peptidases are also of pharmacologicalinterest because they are responsiblefor the formation of highly reactivecleavage products (fibrin, p. 146) andpotent mediators (angiotensin II, p. 124;bradykinin, enkephalin, p. 210) frombiologically inactive peptides.

Peptidases exhibit some substrateselectivity and can be selectively inhib-ited, as exemplified by the formation ofangiotensin II, whose actions inter aliainclude vasoconstriction. Angiotensin IIis formed from angiotensin I by cleavageof the C-terminal dipeptide histidylleu-cine. Hydrolysis is catalyzed by “angio-tensin-converting enzyme” (ACE). Pep-tide analogues such as captopril (p. 124)block this enzyme. Angiotensin II is de-graded by angiotensinase A, which clipsoff the N-terminal asparagine residue.The product, angiotensin III, lacks vaso-constrictor activity.

34 Drug Elimination


Drug Elimination 35

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

Acetylcholine

Converting enzyme

Angiotensinase

Procaine

Acetylsalicylic acid Prilocaine

N-Propylalanine ToluidineAcetic acid Salicylic acid

Diethylaminoethanol

p-Aminobenzoic acid

Acetic acid

Choline

Angi

oten

sin

III

Angi

oten

sin

II

Angi

oten

sin

I

Esterases Ester Peptidases Amides Anilides


Oxidation reactions can be dividedinto two kinds: those in which oxygen isincorporated into the drug molecule,and those in which primary oxidationcauses part of the molecule to be lost.The former include hydroxylations,epoxidations, and sulfoxidations. Hy-droxylations may involve alkyl substitu-ents (e.g., pentobarbital) or aromaticring systems (e.g., propranolol). In bothcases, products are formed that are con-jugated to an organic acid residue, e.g.,glucuronic acid, in a subsequent Phase IIreaction.

Hydroxylation may also take placeat nitrogen atoms, resulting in hydroxyl-amines (e.g., acetaminophen). Benzene,polycyclic aromatic compounds (e.g.,benzopyrene), and unsaturated cycliccarbohydrates can be converted bymono-oxygenases to epoxides, highlyreactive electrophiles that are hepato-toxic and possibly carcinogenic.

The second type of oxidative bio-transformation comprises dealkyla-tions. In the case of primary or secon-dary amines, dealkylation of an alkylgroup starts at the carbon adjacent tothe nitrogen; in the case of tertiaryamines, with hydroxylation of the nitro-gen (e.g., lidocaine). The intermediaryproducts are labile and break up into thedealkylated amine and aldehyde of thealkyl group removed. O-dealkylation

and S-dearylation proceed via an analo-gous mechanism (e.g., phenacetin andazathioprine, respectively).

Oxidative deamination basicallyresembles the dealkylation of tertiaryamines, beginning with the formation ofa hydroxylamine that then decomposesinto ammonia and the correspondingaldehyde. The latter is partly reduced toan alcohol and partly oxidized to a car-boxylic acid.

Reduction reactions may occur atoxygen or nitrogen atoms. Keto-oxy-gens are converted into a hydroxylgroup, as in the reduction of the pro-drugs cortisone and prednisone to theactive glucocorticoids cortisol and pred-nisolone, respectively. N-reductions oc-cur in azo- or nitro-compounds (e.g., ni-trazepam). Nitro groups can be reducedto amine groups via nitroso and hydrox-ylamino intermediates. Likewise, deha-logenation is a reductive process involv-ing a carbon atom (e.g., halothane, p.218).

Methylations are catalyzed by afamily of relatively specific methyl-transferases involving the transfer ofmethyl groups to hydroxyl groups (O-methylation as in norepinephrine [nor-adrenaline]) or to amino groups (N-methylation of norepinephrine, hista-mine, or serotonin).

In thio compounds, desulfurationresults from substitution of sulfur byoxygen (e.g., parathion). This exampleagain illustrates that biotransformationis not always to be equated with bio-inactivation. Thus, paraoxon (E600)formed in the organism from parathion(E605) is the actual active agent (p. 102).

36 Drug Elimination

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Drug Elimination 37

A. Examples of chemical reactions in drug biotransformation

Pentobarbital

Hydroxylation

Propranolol

Lidocaine Phenacetin

Azathioprine

Parathion

Desulfuration

Methylation

Nitrazepam

Reduction Oxidation

Benzpyrene Chlorpromazine

Norepinephrine

Epoxidation

Sulfoxidation

Hydroxyl-amine

Dealkylation

Acetaminophen

N-Dealkylation

O-Dealkylation

S-Dealkylation

O-Methylation


Enterohepatic Cycle (A)

After an orally ingested drug has beenabsorbed from the gut, it is transportedvia the portal blood to the liver, where itcan be conjugated to glucuronic or sul-furic acid (shown in B for salicylic acidand deacetylated bisacodyl, respective-ly) or to other organic acids. At the pH ofbody fluids, these acids are predomi-nantly ionized; the negative charge con-fers high polarity upon the conjugateddrug molecule and, hence, low mem-brane penetrability. The conjugatedproducts may pass from hepatocyte intobiliary fluid and from there back intothe intestine. O-glucuronides can becleaved by bacterial β-glucuronidases inthe colon, enabling the liberated drugmolecule to be reabsorbed. The entero-hepatic cycle acts to trap drugs in thebody. However, conjugated productsenter not only the bile but also theblood. Glucuronides with a molecularweight (MW) > 300 preferentially passinto the blood, while those with MW >300 enter the bile to a larger extent.Glucuronides circulating in the bloodundergo glomerular filtration in the kid-ney and are excreted in urine becausetheir decreased lipophilicity preventstubular reabsorption.

Drugs that are subject to enterohe-patic cycling are, therefore, excretedslowly. Pertinent examples include digi-toxin and acidic nonsteroidal anti-in-flammatory agents (p. 200).

Conjugations (B)

The most important of phase II conjuga-tion reactions is glucuronidation. Thisreaction does not proceed spontaneous-ly, but requires the activated form ofglucuronic acid, namely glucuronic aciduridine diphosphate. Microsomal glucu-ronyl transferases link the activatedglucuronic acid with an acceptor mole-cule. When the latter is a phenol or alco-hol, an ether glucuronide will beformed. In the case of carboxyl-bearingmolecules, an ester glucuronide is theresult. All of these are O-glucuronides.

Amines may form N-glucuronides that,unlike O-glucuronides, are resistant tobacterial β-glucuronidases.

Soluble cytoplasmic sulfotrans-ferases conjugate activated sulfate (3’-phosphoadenine-5’-phosphosulfate)with alcohols and phenols. The conju-gates are acids, as in the case of glucuro-nides. In this respect, they differ fromconjugates formed by acetyltransfe-rases from activated acetate (acetyl-coenzyme A) and an alcohol or a phenol.

Acyltransferases are involved in theconjugation of the amino acids glycineor glutamine with carboxylic acids. Inthese cases, an amide bond is formedbetween the carboxyl groups of the ac-ceptor and the amino group of the do-nor molecule (e.g., formation of salicyl-uric acid from salicylic acid and glycine).The acidic group of glycine or glutamineremains free.

38 Drug Elimination


Drug Elimination 39

A. Enterohepatic cycle

B. Conjugation reactions

UDP-α-Glucuronic acid

Glucuronyl-transferase

Sulfo-transferase

3'-Phosphoadenine-5'-phosphosulfate

Active moiety of bisacodylSalicylic acid

Biliaryelimination

Enteralabsorption

Renalelimination

Lipophilicdrug

Sinusoid

Hepatocyte

Biliary capillaryConjugation withglucuronic acid

Portal vein

Hydrophilicconjugation product

1

3

5

7

8

4

E n t e r o h e p a t i c c i r c u l a t i on

6

2

Deconjugationby microbialβ-glucuronidase


The Kidney as Excretory Organ

Most drugs are eliminated in urine ei-ther chemically unchanged or as metab-olites. The kidney permits eliminationbecause the vascular wall structure inthe region of the glomerular capillaries(B) allows unimpeded passage of bloodsolutes having molecular weights (MW)< 5000. Filtration diminishes progres-sively as MW increases from 5000 to70000 and ceases at MW > 70000. Withfew exceptions, therapeutically useddrugs and their metabolites have muchsmaller molecular weights and can,therefore, undergo glomerular filtra-tion, i.e., pass from blood into primaryurine. Separating the capillary endothe-lium from the tubular epithelium, thebasal membrane consists of chargedglycoproteins and acts as a filtrationbarrier for high-molecular-weight sub-stances. The relative density of this bar-rier depends on the electrical charge ofmolecules that attempt to permeate it.

Apart from glomerular filtration(B), drugs present in blood may passinto urine by active secretion. Certaincations and anions are secreted by theepithelium of the proximal tubules intothe tubular fluid via special, energy-consuming transport systems. Thesetransport systems have a limited capac-ity. When several substrates are presentsimultaneously, competition for thecarrier may occur (see p. 268).

During passage down the renal tu-bule, urinary volume shrinks more than100-fold; accordingly, there is a corre-sponding concentration of filtered drugor drug metabolites (A). The resultingconcentration gradient between urineand interstitial fluid is preserved in thecase of drugs incapable of permeatingthe tubular epithelium. However, withlipophilic drugs the concentration gra-dient will favor reabsorption of the fil-tered molecules. In this case, reabsorp-tion is not based on an active processbut results instead from passive diffu-sion. Accordingly, for protonated sub-stances, the extent of reabsorption isdependent upon urinary pH or the de-

gree of dissociation. The degree of disso-ciation varies as a function of the uri-nary pH and the pKa, which representsthe pH value at which half of the sub-stance exists in protonated (or unproto-nated) form. This relationship is graphi-cally illustrated (D) with the example ofa protonated amine having a pKa of 7.0.In this case, at urinary pH 7.0, 50 % of theamine will be present in the protonated,hydrophilic, membrane-impermeantform (blue dots), whereas the other half,representing the uncharged amine(orange dots), can leave the tubular lu-men in accordance with the resultingconcentration gradient. If the pKa of anamine is higher (pKa = 7.5) or lower (pKa

= 6.5), a correspondingly smaller orlarger proportion of the amine will bepresent in the uncharged, reabsorbableform. Lowering or raising urinary pH byhalf a pH unit would result in analogouschanges for an amine having a pKa of7.0.

The same considerations hold foracidic molecules, with the importantdifference that alkalinization of theurine (increased pH) will promote thedeprotonization of -COOH groups andthus impede reabsorption. Intentionalalteration in urinary pH can be used inintoxications with proton-acceptor sub-stances in order to hasten elimination ofthe toxin (alkalinization � phenobarbi-tal; acidification � amphetamine).

40 Drug Elimination


Drug Elimination 41

C. Active secretion

180 LPrimaryurine

Glomerularfiltrationof drug

Concentrationof drugin tubule

1.2 LFinalurine

–

++

+++

+++

+ +

++

+

++

++ +

+++

+

+

--

-

-

-

-

-

-

--

-

--

-

- -

----

-

-

Tubulartransportsystem for

Cations

Anions

Blood

Plasma-protein

Endothelium

Basalmembrane

Drug

Epithelium

Primary urine

pH = 7.0

pH = 7.0 pH of urine

%6 6.5 7 7.5 8

100

50

pKa = 7.5

%6 6.5 7 7.5 8

100

50

pKa = 6.5

D. Tubular reabsorption

A. Filtration and concentration

B. Glomerular filtration

pKa of substance

%6 6.5 7 7.5 8

100

50

pKa = 7.0

+


Elimination of Lipophilic and Hydrophilic Substances

The terms lipophilic and hydrophilic(or hydro- and lipophobic) refer to thesolubility of substances in media of lowand high polarity, respectively. Bloodplasma, interstitial fluid, and cytosol arehighly polar aqueous media, whereaslipids — at least in the interior of the lip-id bilayer membrane — and fat consti-tute apolar media. Most polar substanc-es are readily dissolved in aqueous me-dia (i.e., are hydrophilic) and lipophilicones in apolar media. A hydrophilicdrug, on reaching the bloodstream,probably after a partial, slow absorption(not illustrated), passes through the liv-er unchanged, because it either cannot,or will only slowly, permeate the lipidbarrier of the hepatocyte membraneand thus will fail to gain access to hepat-ic biotransforming enzymes. The un-changed drug reaches the arterial bloodand the kidneys, where it is filtered.With hydrophilic drugs, there is littlebinding to plasma proteins (proteinbinding increases as a function of li-pophilicity), hence the entire amountpresent in plasma is available for glo-merular filtration. A hydrophilic drug isnot subject to tubular reabsorption andappears in the urine. Hydrophilic drugsundergo rapid elimination.

If a lipophilic drug, because of itschemical nature, cannot be convertedinto a polar product, despite having ac-cess to all cells, including metabolicallyactive liver cells, it is likely to be re-tained in the organism. The portion fil-tered during glomerular passage will bereabsorbed from the tubules. Reabsorp-tion will be nearly complete, becausethe free concentration of a lipophilicdrug in plasma is low (lipophilic sub-stances are usually largely protein-bound). The situation portrayed for alipophilic non-metabolizable drugwould seem undesirable because phar-macotherapeutic measures once initiat-ed would be virtually irreversible (poorcontrol over blood concentration).

Lipophilic drugs that are convert-ed in the liver to hydrophilic metab-olites permit better control, because thelipophilic agent can be eliminated inthis manner. The speed of formation ofhydrophilic metabolite determines thedrug’s length of stay in the body.

If hepatic conversion to a polar me-tabolite is rapid, only a portion of theabsorbed drug enters the systemic cir-culation in unchanged form, the re-mainder having undergone presystem-ic (first-pass) elimination. When bio-transformation is rapid, oral adminis-tration of the drug is impossible (e.g.,glyceryl trinitate, p. 120). Parenteral or,alternatively, sublingual, intranasal, ortransdermal administration is then re-quired in order to bypass the liver. Irre-spective of the route of administration,a portion of administered drug may betaken up into and transiently stored inlung tissue before entering the generalcirculation. This also constitutes pre-systemic elimination.

Presystemic elimination refers tothe fraction of drug absorbed that isexcluded from the general circulationby biotransformation or by first-passbinding.

Presystemic elimination diminish-es the bioavailability of a drug after itsoral administration. Absolute bioavail-ability = systemically available amount/dose administered; relative bioavail-ability = availability of a drug containedin a test preparation with reference to astandard preparation.

42 Drug Elimination


Drug Elimination 43

A. Elimination of hydrophilic and hydrophobic drugs

Hydrophilic drug Lipophilic drugno metabolism

Lipophilic drug Lipophilic drug

Renalexcretion

Excretionimpossible

Renal excretionof metabolite

Renal excretionof metabolite

Slow conversionin liver tohydrophilic metabolite

Rapid and completeconversion in liver tohydrophilic metabolite


Drug Concentration in the Body as a Function of Time. First-Order (Exponential) Rate Processes

Processes such as drug absorption andelimination display exponential charac-teristics. As regards the former, this fol-lows from the simple fact that theamount of drug being moved per unit oftime depends on the concentration dif-ference (gradient) between two bodycompartments (Fick’s Law). In drug ab-sorption from the alimentary tract, theintestinal contents and blood wouldrepresent the compartments containingan initially high and low concentration,respectively. In drug elimination via thekidney, excretion often depends on glo-merular filtration, i.e., the filteredamount of drug present in primaryurine. As the blood concentration falls,the amount of drug filtered per unit oftime diminishes. The resulting expo-nential decline is illustrated in (A). Theexponential time course implies con-stancy of the interval during which theconcentration decreases by one-half.This interval represents the half-life(t1/2) and is related to the eliminationrate constant k by the equation t1/2 = ln2/k. The two parameters, together withthe initial concentration co, describe afirst-order (exponential) rate process.

The constancy of the process per-mits calculation of the plasma volumethat would be cleared of drug, if the re-maining drug were not to assume a ho-mogeneous distribution in the total vol-ume (a condition not met in reality).This notional plasma volume freed ofdrug per unit of time is termed theclearance. Depending on whether plas-ma concentration falls as a result of uri-nary excretion or metabolic alteration,clearance is considered to be renal orhepatic. Renal and hepatic clearancesadd up to total clearance (Cltot) in thecase of drugs that are eliminated un-changed via the kidney and biotrans-formed in the liver. Cltot represents thesum of all processes contributing toelimination; it is related to the half-life

(t1/2) and the apparent volume of distri-bution Vapp (p. 28) by the equation:

Vappt1/2 = In 2 x ––––Cltot

The smaller the volume of distribu-tion or the larger the total clearance, theshorter is the half-life.

In the case of drugs renally elimi-nated in unchanged form, the half-life ofelimination can be calculated from thecumulative excretion in urine; the finaltotal amount eliminated corresponds tothe amount absorbed.

Hepatic elimination obeys expo-nential kinetics because metabolizingenzymes operate in the quasilinear re-gion of their concentration-activitycurve; hence the amount of drug me-tabolized per unit of time diminisheswith decreasing blood concentration.

The best-known exception to expo-nential kinetics is the elimination of al-cohol (ethanol), which obeys a lineartime course (zero-order kinetics), atleast at blood concentrations > 0.02 %. Itdoes so because the rate-limiting en-zyme, alcohol dehydrogenase, achieveshalf-saturation at very low substrateconcentrations, i.e., at about 80 mg/L(0.008 %). Thus, reaction velocity reach-es a plateau at blood ethanol concentra-tions of about 0.02 %, and the amount ofdrug eliminated per unit of time re-mains constant at concentrations abovethis level.

44 Pharmacokinetics


Pharmacokinetics 45

A. Exponential elimination of drug

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

ct = co · e-kt

ct: Drug concentration at time t

co: Initial drug concentration after administration of drug dose

e: Base of natural logarithm

k: Elimination constant

Plasma half life t12

= — co12

ct 12

t12

ln 2k

= —–

Time (t)

Totalamountof drugexcreted

(Amount administered) = Dose

Amount excreted per unit of time [amount/t]

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

Unit of time

Time

Co


Time Course of Drug Concentration inPlasma

A. Drugs are taken up into and eliminat-ed from the body by various routes. Thebody thus represents an open systemwherein the actual drug concentrationreflects the interplay of intake (inges-tion) and egress (elimination). When anorally administered drug is absorbedfrom the stomach and intestine, speedof uptake depends on many factors, in-cluding the speed of drug dissolution (inthe case of solid dosage forms) and ofgastrointestinal transit; the membranepenetrability of the drug; its concentra-tion gradient across the mucosa-bloodbarrier; and mucosal blood flow. Ab-sorption from the intestine causes thedrug concentration in blood to increase.Transport in blood conveys the drug todifferent organs (distribution), intowhich it is taken up to a degree compat-ible with its chemical properties andrate of blood flow through the organ.For instance, well-perfused organs suchas the brain receive a greater proportionthan do less well-perfused ones. Uptakeinto tissue causes the blood concentra-tion to fall. Absorption from the gut di-minishes as the mucosa-blood gradientdecreases. Plasma concentration reach-es a peak when the drug amount leavingthe blood per unit of time equals thatbeing absorbed.

Drug entry into hepatic and renaltissue constitutes movement into theorgans of elimination. The characteris-tic phasic time course of drug concen-tration in plasma represents the sum ofthe constituent processes of absorp-tion, distribution, and elimination,which overlap in time. When distribu-tion takes place significantly faster thanelimination, there is an initial rapid andthen a greatly retarded fall in the plas-ma level, the former being designatedthe α-phase (distribution phase), thelatter the β-phase (elimination phase).When the drug is distributed faster thanit is absorbed, the time course of theplasma level can be described in mathe-matically simplified form by the Bate-

man function (k1 and k2 represent therate constants for absorption and elimi-nation, respectively).

B. The velocity of absorption de-pends on the route of administration.The more rapid the administration, theshorter will be the time (tmax) requiredto reach the peak plasma level (cmax),the higher will be the cmax, and the earli-er the plasma level will begin to fallagain.

The area under the plasma level timecurve (AUC) is independent of the routeof administration, provided the dosesand bioavailability are the same (Dost’slaw of corresponding areas). The AUCcan thus be used to determine the bio-availability F of a drug. The ratio of AUCvalues determined after oral or intrave-nous administration of a given dose of aparticular drug corresponds to the pro-portion of drug entering the systemiccirculation after oral administration.The determination of plasma levels af-fords a comparison of different proprie-tary preparations containing the samedrug in the same dosage. Identical plas-ma level time-curves of differentmanufacturers’ products with referenceto a standard preparation indicate bio-equivalence of the preparation underinvestigation with the standard.

46 Pharmacokinetics


Pharmacokinetics 47

B. Mode of application and time course of drug concentration

A. Time course of drug concentration

AbsorptionUptake fromstomach andintestinesinto blood

Distributioninto bodytissues:α-phase

Eliminationfrom body bybiotransformation(chemical alteration),excretion via kidney:ß-phase

Time (t)

Dru

g co

ncen

trat

ion

in b

lood

(c)

Bateman-function

Dose˜ Vapp

k1k2 - k1

c = x x (e-k1t-e-k2t)

Dru

g co

ncen

trat

ion

in b

lood

(c)

Time (t)

Intravenous

Intramuscular

Subcutaneous

Oral


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

When a drug is administered at regularintervals over a prolonged period, therise and fall of drug concentration inblood will be determined by the rela-tionship between the half-life of elimi-nation and the time interval betweendoses. If the drug amount administeredin each dose has been eliminated beforethe next dose is applied, repeated intakeat constant intervals will result in simi-lar plasma levels. If intake occurs beforethe preceding dose has been eliminatedcompletely, the next dose will add on tothe residual amount still present in thebody, i.e., the drug accumulates. Theshorter the dosing interval relative tothe elimination half-life, the larger willbe the residual amount of drug to whichthe next dose is added and the more ex-tensively will the drug accumulate inthe body. However, at a given dosingfrequency, the drug does not accumu-late infinitely and a steady state (Css) oraccumulation equilibrium is eventual-ly reached. This is so because the activ-ity of elimination processes is concen-tration-dependent. The higher the drugconcentration rises, the greater is theamount eliminated per unit of time. Af-ter several doses, the concentration willhave climbed to a level at which theamounts eliminated and taken in perunit of time become equal, i.e., a steadystate is reached. Within this concentra-tion range, the plasma level will contin-ue to rise (peak) and fall (trough) as dos-ing is continued at a regular interval.The height of the steady state (Css) de-pends upon the amount (D) adminis-tered per dosing interval (τ) and theclearance (Cltot):

DCss = –––––––––

(τ · Cltot)

The speed at which the steady stateis reached corresponds to the speed ofelimination of the drug. The time need-ed to reach 90 % of the concentrationplateau is about 3 times the t1/2 of elimi-nation.

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

In practice, it proves difficult to achievea plasma level that undulates evenlyaround the desired effective concentra-tion. For instance, if two successive dos-es are omitted, the plasma level willdrop below the therapeutic range and alonger period will be required to regainthe desired plasma level. In everydaylife, patients will be apt to neglect drugintake at the scheduled time. Patientcompliance means strict adherence tothe prescribed regimen. Apart frompoor compliance, the same problemmay occur when the total daily dose isdivided into three individual doses (tid)and the first dose is taken at breakfast,the second at lunch, and the third atsupper. Under this condition, the noc-turnal dosing interval will be twice thediurnal one. Consequently, plasma lev-els during the early morning hours mayhave fallen far below the desired or,possibly, urgently needed range.

48 Pharmacokinetics


Pharmacokinetics 49

? ? ?

B. Time course of drug concentration with irregular intake

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

Dru

g co

ncen

trat

ion

Dru

g co

ncen

trat

ion

Accumulation:administered drug isnot completely eliminatedduring interval

Steady state:drug intake equalselimination duringdosing interval

Dosing interval

Dosing interval

Time

Time

Time

Time

Dru

g co

ncen

trat

ion

Desiredtherapeuticlevel


Accumulation: Dose, Dose Interval, andPlasma Level Fluctuation

Successful drug therapy in many illness-es is accomplished only if drug concen-tration is maintained at a steady highlevel. This requirement necessitatesregular drug intake and a dosage sched-ule that ensures that the plasma con-centration neither falls below the thera-peutically effective range nor exceedsthe minimal toxic concentration. A con-stant plasma level would, however, beundesirable if it accelerated a loss of ef-fectiveness (development of tolerance),or if the drug were required to bepresent at specified times only.

A steady plasma level can beachieved by giving the drug in a con-stant intravenous infusion, the steady-state plasma level being determined bythe infusion rate, dose D per unit of timeτ, and the clearance, according to theequation:

DCss = –––––––––

(τ · Cltot)

This procedure is routinely used inintensive care hospital settings, but isotherwise impracticable. With oral ad-ministration, dividing the total dailydose into several individual ones, e.g.,four, three, or two, offers a practicalcompromise.

When the daily dose is given in sev-eral divided doses, the mean plasmalevel shows little fluctuation. In prac-tice, it is found that a regimen of fre-quent regular drug ingestion is not welladhered to by patients. The degree offluctuation in plasma level over a givendosing interval can be reduced by use ofa dosage form permitting slow (sus-tained) release (p. 10).

The time required to reach steady-state accumulation during multipleconstant dosing depends on the rate ofelimination. As a rule of thumb, a pla-teau is reached after approximatelythree elimination half-lives (t1/2).

For slowly eliminated drugs, whichtend to accumulate extensively (phen-procoumon, digitoxin, methadone), the

optimal plasma level is attained only af-ter a long period. Here, increasing theinitial doses (loading dose) will speedup the attainment of equilibrium, whichis subsequently maintained with a low-er dose (maintenance dose).

Change in Elimination CharacteristicsDuring Drug Therapy (B)

With any drug taken regularly and accu-mulating to the desired plasma level, itis important to consider that conditionsfor biotransformation and excretion donot necessarily remain constant. Elimi-nation may be hastened due to enzymeinduction (p. 32) or to a change in uri-nary pH (p. 40). Consequently, thesteady-state plasma level declines to anew value corresponding to the newrate of elimination. The drug effect maydiminish or disappear. Conversely,when elimination is impaired (e.g., inprogressive renal insufficiency), themean plasma level of renally eliminateddrugs rises and may enter a toxic con-centration range.

50 Pharmacokinetics


Pharmacokinetics 51

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

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

Dru

g co

ncen

trat

ion

in b

lood

Des

ired

pla

sma

leve

l

12 18 24 6 12 18 24 6 12 18 24 6 126

4 x daily 50 mg2 x daily 100 mg1 x daily 200 mg

Single 50 mg

12 18 24 6 12 18 24 6 12 18 24 6 126 18

Accelerationof elimination

Inhibition of elimination

Dru

g co

ncen

trat

ion

in b

lood

Des

ired

pla

sma

leve

l


Dose–Response Relationship

The effect of a substance depends on theamount administered, i.e., the dose. Ifthe dose chosen is below the criticalthreshold (subliminal dosing), an effectwill be absent. Depending on the natureof the effect to be measured, ascendingdoses may cause the effect to increase inintensity. Thus, the effect of an antipy-retic or hypotensive drug can be quanti-fied in a graded fashion, in that the ex-tent of fall in body temperature or bloodpressure is being measured. A dose-ef-fect relationship is then encountered, asdiscussed on p. 54.

The dose-effect relationship mayvary depending on the sensitivity of theindividual person receiving the drug,i.e., for the same effect, different dosesmay be required in different individuals.Interindividual variation in sensitivity isespecially obvious with effects of the“all-or-none” kind.

To illustrate this point, we consideran experiment in which the subjects in-dividually respond in all-or-none fash-ion, as in the Straub tail phenomenon(A). Mice react to morphine with excita-tion, evident in the form of an abnormalposture of the tail and limbs. The dosedependence of this phenomenon is ob-served in groups of animals (e.g., 10mice per group) injected with increas-ing doses of morphine. At the low dose,only the most sensitive, at increasingdoses a growing proportion, at the high-est dose all of the animals are affected(B). There is a relationship between thefrequency of responding animals andthe dose given. At 2 mg/kg, one out of 10animals reacts; at 10 mg/kg, 5 out of 10respond. The dose-frequency relation-ship results from the different sensitiv-ity of individuals, which as a rule exhib-its a log-normal distribution (C, graph atright, linear scale). If the cumulative fre-quency (total number of animals re-sponding at a given dose) is plottedagainst the logarithm of the dose (ab-scissa), a sigmoidal curve results (C,graph at left, semilogarithmic scale).The inflection point of the curve lies at

the dose at which one-half of the grouphas responded. The dose range encom-passing the dose-frequency relationshipreflects the variation in individual sensi-tivity to the drug. Although similar inshape, a dose-frequency relationshiphas, thus, a different meaning than doesa dose-effect relationship. The latter canbe evaluated in one individual and re-sults from an intraindividual dependen-cy of the effect on drug concentration.

The evaluation of a dose-effect rela-tionship within a group of human sub-jects is compounded by interindividualdifferences in sensitivity. To account forthe biological variation, measurementshave to be carried out on a representa-tive sample and the results averaged.Thus, recommended therapeutic doseswill be appropriate for the majority ofpatients, but not necessarily for each in-dividual.

The variation in sensitivity may bebased on pharmacokinetic differences(same dose � different plasma levels)or on differences in target organ sensi-tivity (same plasma level � different ef-fects).

52 Quantification of Drug Action


Quantification of Drug Action 53

C. Dose-frequency relationship

A. Abnormal posture in mouse given morphine

B. Incidence of effect as a function of dose

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

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

mg/kg 2 14010010 20

20

100

40

60

80

% Cumulative frequency

mg/kg2 14010010 20

1

2

3

4

Frequency of dose needed


Concentration-Effect Relationship (A)

The relationship between the concen-tration of a drug and its effect is deter-mined in order to define the range of ac-tive drug concentrations (potency) andthe maximum possible effect (efficacy).On the basis of these parameters, differ-ences between drugs can be quantified.As a rule, the therapeutic effect or toxicaction depends critically on the re-sponse of a single organ or a limitednumber of organs, e.g., blood flow is af-fected by a change in vascular luminalwidth. By isolating critical organs or tis-sues from a larger functional system,these actions can be studied with moreaccuracy; for instance, vasoconstrictoragents can be examined in isolatedpreparations from different regions ofthe vascular tree, e.g., the portal orsaphenous vein, or the mesenteric, cor-onary, or basilar artery. In many cases,isolated organs or organ parts can bekept viable for hours in an appropriatenutrient medium sufficiently suppliedwith oxygen and held at a suitable tem-perature.

Responses of the preparation to aphysiological or pharmacological stim-ulus can be determined by a suitable re-cording apparatus. Thus, narrowing of ablood vessel is recorded with the help oftwo clamps by which the vessel is sus-pended under tension.

Experimentation on isolated organsoffers 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 compen-

satory responses that may partiallycancel the primary effect in the intactorganism — e.g., the heart rate in-creasing action of norepinephrinecannot be demonstrated in the intactorganism, because a simultaneousrise in blood pressure elicits a coun-ter-regulatory reflex that slows car-diac rate.

4. The ability to examine a drug effectover its full rage of intensities — e.g.,

it would be impossible in the intactorganism to follow negative chrono-tropic effects to the point of cardiacarrest.

Disadvantages are:1. Unavoidable tissue injury during dis-

section.2. Loss of physiological regulation of

function in the isolated tissue.3. The artificial milieu imposed on the

tissue.

Concentration-Effect Curves (B)

As the concentration is raised by a con-stant factor, the increment in effect di-minishes steadily and tends asymptoti-cally towards zero the closer one comesto the maximally effective concentra-tion.The concentration at which a maxi-mal effect occurs cannot be measuredaccurately; however, that eliciting ahalf-maximal effect (EC50) is readily de-termined. It typically corresponds to theinflection point of the concentra-tion–response curve in a semilogarith-mic plot (log concentration on abscissa).Full characterization of a concentra-tion–effect relationship requires deter-mination of the EC50, the maximallypossible effect (Emax), and the slope atthe point of inflection.




B. Concentration-effect relationship

A. Measurement of effect as a function of concentration

Portal veinMesenteric artery

Coronaryartery

Basilarartery

Saphenousvein

1005040302010521

VasoconstrictionActive tension

1 min

Drug concentration

Effect(in mm of registration unit,e.g., tension developed)

Concentration (linear)20 30 40 5010

50

40

30

20

10

Effect(% of maximum effect)

Concentration (logarithmic)10 1001

100

80

60

40

20

%


Concentration-Binding Curves

In order to elicit their effect, drug mole-cules must be bound to the cells of theeffector organ. Binding commonly oc-curs at specific cell structures, namely,the receptors. The analysis of drug bind-ing to receptors aims to determine theaffinity of ligands, the kinetics of inter-action, and the characteristics of thebinding site itself.

In studying the affinity and numberof such binding sites, use is made ofmembrane suspensions of different tis-sues. This approach is based on the ex-pectation that binding sites will retaintheir characteristic properties duringcell homogenization. Provided thatbinding sites are freely accessible in themedium in which membrane fragmentsare suspended, drug concentration atthe “site of action” would equal that inthe medium. The drug under study is ra-diolabeled (enabling low concentra-tions to be measured quantitatively),added to the membrane suspension,and allowed to bind to receptors. Mem-brane fragments and medium are thenseparated, e.g., by filtration, and theamount of bound drug is measured.Binding increases in proportion to con-centration as long as there is a negligiblereduction in the number of free bindingsites (c = 1 and B ≈ 10% of maximumbinding; c = 2 and B ≈ 20 %). As bindingapproaches saturation, the number offree sites decreases and the incrementin binding is no longer proportional tothe increase in concentration (in the ex-ample illustrated, an increase in con-centration by 1 is needed to increasebinding from 10 to 20 %; however, an in-crease by 20 is needed to raise it from 70to 80 %).

The law of mass action describesthe hyperbolic relationship betweenbinding (B) and ligand concentration (c).This relationship is characterized by thedrug’s affinity (1/KD) and the maximumbinding (Bmax), i.e., the total number ofbinding sites per unit of weight of mem-brane homogenate.

cB = Bmax · –––––––

c + KD

KD is the equilibrium dissociation con-stant and corresponds to that ligandconcentration at which 50 % of bindingsites are occupied. The values given in(A) and used for plotting the concentra-tion-binding graph (B) result when KD =10.

The differing affinity of different li-gands for a binding site can be demon-strated elegantly by binding assays. Al-though simple to perform, these bind-ing assays pose the difficulty of correlat-ing unequivocally the binding sites con-cerned with the pharmacological effect;this is particularly difficult when morethan one population of binding sites ispresent. Therefore, receptor bindingmust not be implied until it can beshown that

• binding is saturable (saturability);

• the only substances bound are thosepossessing the same pharmacologicalmechanism of action (specificity);

• binding affinity of different substanc-es is correlated with their pharmaco-logical potency.

Binding assays provide informationabout the affinity of ligands, but they donot give any clue as to whether a ligandis an agonist or antagonist (p. 60). Use ofradiolabeled drugs bound to their re-ceptors may be of help in purifying andanalyzing further the receptor protein.




B = 10% B = 20% B = 30%

B = 50% B = 70% B = 80%

B. Concentration-binding relationship

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

Binding (B)

20 30 40 5010

100

80

60

40

20

% Binding (B)

1001

100

80

60

40

20

%

10

Organs

Homogenization

Centrifugation

Membranesuspension

Mixing and incubation

Addition ofradiolabeleddrug indifferentconcentrations

Determinationof radioactivity

c = 1 c = 2 c = 5

c = 10 c = 20 c = 40

Concentration (linear) Concentration (logarithmic)


Types of Binding Forces

Unless a drug comes into contact withintrinsic structures of the body, it can-not affect body function.

Covalent bond. Two atoms enter acovalent bond if each donates an elec-tron to a shared electron pair (cloud).This state is depicted in structural for-mulas by a dash. The covalent bond is“firm”, that is, not reversible or onlypoorly so. Few drugs are covalentlybound to biological structures. Thebond, and possibly the effect, persist fora long time after intake of a drug hasbeen discontinued, making therapy dif-ficult to control. Examples include alky-lating cytostatics (p. 298) or organo-phosphates (p. 102). Conjugation reac-tions occurring in biotransformation al-so represent a covalent linkage (e.g., toglucuronic acid, p. 38).

Noncovalent bond. There is no for-mation of a shared electron pair. Thebond is reversible and typical of mostdrug-receptor interactions. Since a drugusually attaches to its site of action bymultiple contacts, several of the types ofbonds described below may participate.

Electrostatic attraction (A). A pos-itive and negative charge attract eachother.

Ionic interaction: An ion is a particlecharged either positively (cation) ornegatively (anion), i.e., the atom lacks orhas surplus electrons, respectively. At-traction between ions of oppositecharge is inversely proportional to thesquare of the distance between them; itis the initial force drawing a chargeddrug to its binding site. Ionic bonds havea relatively high stability.

Dipole-ion interaction: When bondelectrons are asymmetrically distribut-ed over both atomic nuclei, one atomwill bear a negative (δ–), and its partnera positive (δ+) partial charge. The mole-cule thus presents a positive and a nega-tive pole, i.e., has polarity or a dipole. Apartial charge can interact electrostati-cally with an ion of opposite charge.

Dipole-dipole interaction is the elec-trostatic attraction between opposite

partial charges. When a hydrogen atombearing a partial positive charge bridgestwo atoms bearing a partial negativecharge, a hydrogen bond is created.

A van der Waals’ bond (B) isformed between apolar moleculargroups that have come into close prox-imity. Spontaneous transient distortionof electron clouds (momentary faint di-pole, δδ) may induce an opposite dipolein the neighboring molecule. The vander Waals’ bond, therefore, is a form ofelectrostatic attraction, albeit of verylow strength (inversely proportional tothe seventh power of the distance).

Hydrophobic interaction (C). Theattraction between the dipoles of wateris strong enough to hinder intercalationof any apolar (uncharged) molecules. Bytending towards each other, H2O mole-cules squeeze apolar particles fromtheir midst. Accordingly, in the organ-ism, apolar particles have an increasedprobability of staying in nonaqueous,apolar surroundings, such as fatty acidchains of cell membranes or apolar re-gions of a receptor.

58 Drug-Receptor Interaction


Drug-Receptor Interaction 59

C. Hydrophobic interaction

A. Electrostatic attraction

B. van der Waals’ bond

Drug + Binding site Complex

Ionic bondIon

Dipole

Ion

Hydrogen bondDipole

Dipole (permanent)

Ion

50nm

1.5nm

0.5nm

Inducedtransientfluctuating dipoles

polar

Apolaracyl chain

"Repulsion" of apolarparticle in polar solvent (H2O)

Insertion in apolar membrane interior

apolar

Pho

spho

lipid

mem

bran

e

Adsorption toapolar surface

δ+

δ−

+ –

–

δ+

δ– δ–

δδ+

δδ–

δδ–

δδ+

δδ–

δδ+

δδ+

δδ–

= Drug

δ–δ+

+

δ–δ+

δ–δ+

δ–δ+

δ+

–

–

D

D

D

D

D

D D

D D


Agonists – Antagonists

An agonist has affinity (binding avidity)for its receptor and alters the receptorprotein in such a manner as to generatea stimulus that elicits a change in cellfunction: “intrinsic activity“. The bio-logical effect of the agonist, i.e., thechange in cell function, depends on theefficiency of signal transduction steps(p. 64, 66) initiated by the activated re-ceptor. Some agonists attain a maximaleffect even when they occupy only asmall fraction of receptors (B, agonistA). Other ligands (agonist B), possessingequal affinity for the receptor but loweractivating capacity (lower intrinsic ac-tivity), are unable to produce a full max-imal response even when all receptorsare occupied: lower efficacy. Ligand B isa partial agonist. The potency of an ago-nist can be expressed in terms of theconcentration (EC50) at which the effectreaches one-half of its respective maxi-mum.

Antagonists (A) attenuate the ef-fect of agonists, that is, their action is“anti-agonistic”.

Competitive antagonists possessaffinity for receptors, but binding to thereceptor does not lead to a change incell function (zero intrinsic activity).

When an agonist and a competitiveantagonist are present simultaneously,affinity and concentration of the two ri-vals will determine the relative amountof each that is bound. Thus, although theantagonist is present, increasing theconcentration of the agonist can restorethe full effect (C). However, in the pres-ence of the antagonist, the concentra-tion-response curve of the agonist isshifted to higher concentrations (“right-ward shift”).

Molecular Models of Agonist/AntagonistAction (A)

Agonist induces active conformation.The agonist binds to the inactive recep-tor and thereby causes a change fromthe resting conformation to the activestate. The antagonist binds to the inac-

tive receptor without causing a confor-mational change.

Agonist stabilizes spontaneouslyoccurring active conformation. Thereceptor can spontaneously “flip” intothe active conformation. However, thestatistical probability of this event isusually so small that the cells do not re-veal signs of spontaneous receptor acti-vation. Selective binding of the agonistrequires the receptor to be in the activeconformation, thus promoting its exis-tence. The “antagonist” displays affinityonly for the inactive state and stabilizesthe latter. When the system shows min-imal spontaneous activity, applicationof an antagonist will not produce a mea-surable effect. When the system hashigh spontaneous activity, the antago-nist may cause an effect that is the op-posite of that of the agonist: inverse ago-nist.

A “true” antagonist lacking intrinsicactivity (“neutral antagonist”) displaysequal affinity for both the active and in-active states of the receptor and doesnot alter basal activity of the cell.According to this model, a partial ago-nist shows lower selectivity for the ac-tive state and, to some extent, also bindsto the receptor in its inactive state.

Other Forms of Antagonism

Allosteric antagonism. The antagonistis bound outside the receptor agonistbinding site proper and induces a de-crease in affinity of the agonist. It is alsopossible that the allosteric deformationof the receptor increases affinity for anagonist, resulting in an allosteric syner-gism.

Functional antagonism. Two ago-nists affect the same parameter (e.g.,bronchial diameter) via different recep-tors in the opposite direction (epineph-rine � dilation; histamine � constric-tion).




Agonistinduces activeconformation ofreceptor protein

C. Competitive antagonism

A. Molecular mechanisms of drug-receptor interaction

B. Potency and Efficacy of agonists

AntagonistAgonist

Receptor

Antagonistoccupies receptorwithout con-formational change

Agonistselects activereceptorconformation

Antagonist Agonist

Rarespontaneoustransition

Antagonistselects inactivereceptorconformation

inactive

Effi

cacy

Potency

Concentration (log) of agonist

Receptor occupationIncrease in tension

Agonist concentration (log)

Agonist effect

Concentrationofantagonist

0 10 100 10001

Agonist A

Agonist Bsmoothmuscle cell

Receptors

EC50

EC50

active

10000


Enantioselectivity of Drug Action

Many drugs are racemates, including β-blockers, nonsteroidal anti-inflammato-ry agents, and anticholinergics (e.g.,benzetimide A). A racemate consists ofa molecule and its corresponding mirrorimage which, like the left and righthand, cannot be superimposed. Suchchiral (“handed”) pairs of molecules arereferred to as enantiomers. Usually,chirality is due to a carbon atom (C)linked to four different substituents(“asymmetric center”). Enantiomerism isa special case of stereoisomerism. Non-chiral stereoisomers are called diaster-eomers (e.g., quinidine/quinine).

Bond lengths in enantiomers, butnot in diastereomers, are the same.Therefore, enantiomers possess similarphysicochemical properties (e.g., solu-bility, melting point) and both forms areusually obtained in equal amounts bychemical synthesis. As a result of enzy-matic activity, however, only one of theenantiomers is usually found in nature.

In solution, enantiomers rotate thewave plane of linearly polarized lightin opposite directions; hence they arerefered to as “dextro”- or “levo-rotatory”,designated by the prefixes d or (+) and lor (-), respectively. The direction of ro-tation gives no clue concerning the spa-tial structure of enantiomers. The abso-lute configuration, as determined bycertain rules, is described by the prefix-es S and R. In some compounds, desig-nation as the D- and L-form is possibleby reference to the structure of D- andL-glyceraldehyde.

For drugs to exert biological ac-tions, contact with reaction partners inthe body is required. When the reactionfavors one of the enantiomers, enantio-selectivity is observed.

Enantioselectivity of affinity. If areceptor has sites for three of the sub-stituents (symbolized in B by a cone, asphere, and a cube) on the asymmetriccarbon to attach to, only one of theenantiomers will have optimal fit. Its af-finity will then be higher. Thus, dexeti-mide displays an affinity at the musca-

rinic ACh receptors almost 10000 times(p. 98) that of levetimide; and at β-adrenoceptors, S(-)-propranolol has anaffinity 100 times that of the R(+)-form.

Enantioselectivity of intrinsic ac-tivity. The mode of attachment at thereceptor also determines whether an ef-fect is elicited and whether or not a sub-stance has intrinsic activity, i.e., acts asan agonist or antagonist. For instance, (-) dobutamine is an agonist at α-adren-oceptors whereas the (+)-enantiomer isan antagonist.

Inverse enantioselectivity at an-other receptor. An enantiomer maypossess an unfavorable configuration atone receptor that may, however, be op-timal for interaction with another re-ceptor. In the case of dobutamine, the(+)-enantiomer has affinity at β-adreno-ceptors 10 times higher than that of the(-)-enantiomer, both having agonist ac-tivity. However, the α-adrenoceptorstimulant action is due to the (-)-form(see above).

As described for receptor interac-tions, enantioselectivity may also bemanifested in drug interactions withenzymes and transport proteins. Enan-tiomers may display different affinitiesand reaction velocities.

Conclusion: The enantiomers of aracemate can differ sufficiently in theirpharmacodynamic and pharmacokinet-ic properties to constitute two distinctdrugs.




Tran

spor

t p

rote

in

B. Reasons for different pharmacological properties of enantiomers

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

Physicochemical propertiesequal

Deflection of polarized light[α]20

D

Absolute configuration

Potency(rel. affinity at m-ACh-receptors

+ 125°(Dextrorotatory)

- 125°(Levorotatory

S = sinister R = rectus

ca. 10 000 1

RACEMATEBenzetimide

ENANTIOMERDexetimide

ENANTIOMERLevetimide

Ratio1 : 1

C C

Intrinsicactivity

Turnoverrate

Pharmacodynamicproperties

Pharmacokineticproperties

Affinity

Transport protein


Receptor Types

Receptors are macromolecules that bindmediator substances and transduce thisbinding into an effect, i.e., a change incell function. Receptors differ in termsof their structure and the manner inwhich they translate occupancy by a li-gand into a cellular response (signaltransduction).

G-protein-coupled receptors (A)consist of an amino acid chain thatweaves in and out of the membrane inserpentine fashion. The extramembra-nal loop regions of the molecule maypossess sugar residues at different N-glycosylation sites. The seven α-helicalmembrane-spanning domains probablyform a circle around a central pocketthat carries the attachment sites for themediator substance. Binding of the me-diator molecule or of a structurally re-lated agonist molecule induces a changein the conformation of the receptor pro-tein, enabling the latter to interact witha G-protein (= guanyl nucleotide-bind-ing protein). G-proteins lie at the innerleaf of the plasmalemma and consist ofthree subunits designated α, β, and γ.There are various G-proteins that differmainly with regard to their α-unit. As-sociation with the receptor activates theG-protein, leading in turn to activationof another protein (enzyme, ion chan-nel). A large number of mediator sub-stances act via G-protein-coupled re-ceptors (see p. 66 for more details).

An example of a ligand-gated ionchannel (B) is the nicotinic cholinocep-tor of the motor endplate. The receptorcomplex consists of five subunits, eachof which contains four transmembranedomains. Simultaneous binding of twoacetylcholine (ACh) molecules to thetwo α-subunits results in opening of theion channel, with entry of Na+ (and exitof some K+), membrane depolarization,and triggering of an action potential (p.82). The ganglionic N-cholinoceptorsapparently consist only of α and β sub-units (α2β2). Some of the receptors forthe transmitter γ-aminobutyric acid(GABA) belong to this receptor family:

the GABAA subtype is linked to a chlo-ride channel (and also to a benzodiaze-pine-binding site, see p. 227). Gluta-mate and glycine both act via ligand-gated ion channels.

The insulin receptor protein repre-sents a ligand-operated enzyme (C), acatalytic receptor. When insulin bindsto the extracellular attachment site, atyrosine kinase activity is “switched on”at the intracellular portion. Proteinphosphorylation leads to altered cellfunction via the assembly of other signalproteins. Receptors for growth hor-mones also belong to the catalytic re-ceptor class.

Protein synthesis-regulating re-ceptors (D) for steroids, thyroid hor-mone, and retinoic acid are found in thecytosol and in the cell nucleus, respec-tively.

Binding of hormone exposes a nor-mally hidden domain of the receptorprotein, thereby permitting the latter tobind to a particular nucleotide sequenceon a gene and to regulate its transcrip-tion. Transcription is usually initiated orenhanced, rarely blocked.




Amino acids

D. Protein synthesis-regulating receptor

A. G-Protein-coupled receptor

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

Nicotinicacetylcholinereceptor

Subunitconsisting offour trans-membranedomains

Na+

K+Na+

K+

α αβ

δγ

Insulin

S S S S

S S

Tyrosine kinase

ACh ACh

Phosphorylation oftyrosine-residues in proteins

-NH2

COOH

H2N

Effect

Effe

ctor

pro

tein

G-Protein

Agonist

COOH

α-HelicesTransmembrane domains

SteroidHormone Protein

NucleusCytosol

Receptor

Tran-scription

DNA mRNA

Trans-lation

765433 4 5 6 7


Mode of Operation of G-Protein-Coupled Receptors

Signal transduction at G-protein-cou-pled receptors uses essentially the samebasic mechanisms (A). Agonist bindingto the receptor leads to a change in re-ceptor protein conformation. Thischange propagates to the G-protein: theα-subunit exchanges GDP for GTP, thendissociates from the two other subunits,associates with an effector protein, andalters its functional state. The α-subunitslowly hydrolyzes bound GTP to GDP.Gα-GDP has no affinity for the effectorprotein and reassociates with the β andγ subunits (A). G-proteins can undergolateral diffusion in the membrane; theyare not assigned to individual receptorproteins. However, a relation existsbetween receptor types and G-proteintypes (B). Furthermore, the α-subunitsof individual G-proteins are distinct interms of their affinity for different effec-tor proteins, as well as the kind of influ-ence exerted on the effector protein. Gα-GTP of the GS-protein stimulates adeny-late cyclase, whereas Gα-GTP of the Gi-protein is inhibitory. The G-protein-coupled receptor family includes mus-carinic cholinoceptors, adrenoceptorsfor norepinephrine and epinephrine, re-ceptors for dopamine, histamine, serot-onin, glutamate, GABA, morphine, pros-taglandins, leukotrienes, and many oth-er mediators and hormones.

Major effector proteins for G-pro-tein-coupled receptors include adeny-late cyclase (ATP � intracellular mes-senger cAMP), phospholipase C (phos-phatidylinositol � intracellular mes-sengers inositol trisphosphate and di-acylglycerol), as well as ion channelproteins. Numerous cell functions areregulated by cellular cAMP concentra-tion, because cAMP enhances activity ofprotein kinase A, which catalyzes thetransfer of phosphate groups onto func-tional proteins. Elevation of cAMP levelsinter alia leads to relaxation of smoothmuscle tonus and enhanced contractil-ity of cardiac muscle, as well as in-creased glycogenolysis and lipolysis (p.

84). Phosphorylation of cardiac cal-cium-channel proteins increases theprobability of channel opening duringmembrane depolarization. It should benoted that cAMP is inactivated by phos-phodiesterase. Inhibitors of this enzymeelevate intracellular cAMP concentra-tion and elicit effects resembling thoseof epinephrine.

The receptor protein itself mayundergo phosphorylation, with a resul-tant loss of its ability to activate the as-sociated G-protein. This is one of themechanisms that contributes to a de-crease in sensitivity of a cell during pro-longed receptor stimulation by an ago-nist (desensitization).

Activation of phospholipase C leadsto cleavage of the membrane phospho-lipid phosphatidylinositol-4,5 bisphos-phate into inositol trisphosphate (IP3)and diacylglycerol (DAG). IP3 promotesrelease of Ca2+ from storage organelles,whereby contraction of smooth musclecells, breakdown of glycogen, or exocy-tosis may be initiated. Diacylglycerolstimulates protein kinase C, whichphosphorylates certain serine- or threo-nine-containing enzymes.

The α-subunit of some G-proteinsmay induce opening of a channel pro-tein. In this manner, K+ channels can beactivated (e.g., ACh effect on sinus node,p. 100; opioid action on neural impulsetransmission, p. 210).




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

A. G-Protein-mediated effect of an agonist

Receptor G-Protein Effectorprotein

Agonist

GDP

GTP

Gs Gi+ -

ATPcAMP

Protein kinase A

Phosphorylation offunctional proteins

Ad

enyl

ate

cycl

ase

Activation

Phosphorylation

of enzymes

Pro

tein

kina

se C

Pho

spho

lipas

e C

IP3

Ca2+

P

P P

DAG

Facilitationof ionchannelopening

Transmembraneion movements

Effect on:

e. g., GlycogenolysislipolysisCa-channelactivation

e. g., Contractionof smooth muscle,glandularsecretion

e. g., Membraneaction potential,homeostasis ofcellular ions

αβ

γ αβ

γ

βγ

ααβ

γ


Time Course of Plasma Concentrationand Effect

After the administration of a drug, itsconcentration in plasma rises, reaches apeak, and then declines gradually to thestarting level, due to the processes ofdistribution and elimination (p. 46).Plasma concentration at a given point intime depends on the dose administered.Many drugs exhibit a linear relationshipbetween plasma concentration anddose within the therapeutic range(dose-linear kinetics; (A); note differ-ent scales on ordinate). However, thesame does not apply to drugs whoseelimination processes are already suffi-ciently activated at therapeutic plasmalevels so as to preclude further propor-tional increases in the rate of elimina-tion when the concentration is in-creased further. Under these conditions,a smaller proportion of the dose admin-istered is eliminated per unit of time.

The time course of the effect and ofthe concentration in plasma are notidentical, because the concentration-effect relationships obeys a hyperbolicfunction (B; cf. also p. 54). This meansthat the time course of the effect exhib-its dose dependence also in the pres-ence of dose-linear kinetics (C).

In the lower dose range (example1), the plasma level passes through aconcentration range (0 � 0.9) in whichthe concentration effect relationship isquasi-linear. The respective time cours-es of plasma concentration and effect (Aand C, left graphs) are very similar.However, if a high dose (100) is applied,there is an extended period of time dur-ing which the plasma level will remainin a concentration range (between 90and 20) in which a change in concentra-tion does not cause a change in the sizeof the effect. Thus, at high doses (100),the time-effect curve exhibits a kind ofplateau. The effect declines only whenthe plasma level has returned (below20) into the range where a change inplasma level causes a change in the in-tensity of the effect.

The dose dependence of the timecourse of the drug effect is exploitedwhen the duration of the effect is to beprolonged by administration of a dosein excess of that required for the effect.This is done in the case of penicillin G(p. 268), when a dosing interval of 8 h isbeing recommended, although the drugis eliminated with a half-life of 30 min.This procedure is, of course, feasible on-ly if supramaximal dosing is not asso-ciated with toxic effects.

Futhermore it follows that a nearlyconstant effect can be achieved, al-though the plasma level may fluctuategreatly during the interval betweendoses.

The hyperbolic relationship between plasma concentration and effectexplains why the time course of the ef-fect, unlike that of the plasma concen-tration, cannot be described in terms ofa simple exponential function. A half-life can be given for the processes ofdrug absorption and elimination, hencefor the change in plasma levels, but ge-nerally not for the onset or decline ofthe effect.




Concentration

Dose = 10

10

5

1

Time

t12

Concentration

Dose = 100

100

50

10

Time

t12

C. Dose dependence of the time course of effect

A. Dose-linear kinetics

B. Concentration-effect relationship

Concentration

Dose = 1

1,0

0,5

0,1

Time

t12

100

50

10 20 30 40 50 60 70 80 90 1001

0

Effe

ct

Concentration

Effect

Dose = 10Time

Effect

Dose = 100

100

50

10

Time

Effect

Dose = 1Time

100

50

10

100

50

10


Adverse Drug Effects

The desired (or intended) principal ef-fect of any drug is to modify body func-tion in such a manner as to alleviatesymptoms caused by the patient’s ill-ness. In addition, a drug may also causeunwanted effects that can be groupedinto minor or “side” effects and major oradverse effects. These, in turn, may giverise to complaints or illness, or mayeven cause death.

Causes of adverse effects: over-dosage (A). The drug is administered ina higher dose than is required for theprincipal effect; this directly or indirect-ly affects other body functions. For in-stances, morphine (p. 210), given in theappropriate dose, affords excellent painrelief by influencing nociceptive path-ways in the CNS. In excessive doses, itinhibits the respiratory center andmakes apnea imminent. The dose de-pendence of both effects can be graphedin the form of dose-response curves(DRC). The distance between both DRCsindicates the difference between thetherapeutic and toxic doses. This marginof safety indicates the risk of toxicitywhen standard doses are exceeded.

“The dose alone makes the poison”(Paracelsus). This holds true for bothmedicines and environmental poisons.No substance as such is toxic! In order toassess the risk of toxicity, knowledge isrequired of: 1) the effective dose duringexposure; 2) the dose level at whichdamage is likely to occur; 3) the dura-tion of exposure.

Increased Sensitivity (B). If certainbody functions develop hyperreactivity,unwanted effects can occur even at nor-mal dose levels. Increased sensitivity ofthe respiratory center to morphine isfound in patients with chronic lung dis-ease, in neonates, or during concurrentexposure to other respiratory depress-ant agents. The DRC is shifted to the leftand a smaller dose of morphine is suffi-cient to paralyze respiration. Geneticanomalies of metabolism may also leadto hypersensitivity. Thus, several drugs(aspirin, antimalarials, etc.) can provoke

premature breakdown of red blood cells(hemolysis) in subjects with a glucose-6-phosphate dehydrogenase deficiency.The discipline of pharmacogenetics dealswith the importance of the genotype forreactions to drugs.

The above forms of hypersensitivitymust be distinguished from allergies in-volving the immune system (p. 72).

Lack of selectivity (C). Despite ap-propriate dosing and normal sensitivity,undesired effects can occur because thedrug does not specifically act on the tar-geted (diseased) tissue or organ. For in-stance, the anticholinergic, atropine, isbound only to acetylcholine receptors ofthe muscarinic type; however, these arepresent in many different organs.

Moreover, the neuroleptic, chlor-promazine, formerly used as a neuro-leptic, is able to interact with severaldifferent receptor types. Thus, its actionis neither organ-specific nor receptor-specific.

The consequences of lack of selec-tivity can often be avoided if the drugdoes not require the blood route toreach the target organ, but is, instead,applied locally, as in the administrationof parasympatholytics in the form of eyedrops or in an aerosol for inhalation.

With every drug use, unwanted ef-fects must be taken into account. Beforeprescribing a drug, the physician shouldtherefore assess the risk: benefit ratio.In this, knowledge of principal and ad-verse effects is a prerequisite.

70 Adverse Drug Effects


Adverse Drug Effects 71

A. Adverse drug effect: overdosing

B. Adverse drug effect: increased sensitivity

Effect

Dose

Decrease inpain perception(nociception)

Respiratory depression

Morphine

Morphineoverdose

Decrease inRespira-toryactivity

Nociception

Safetymargin

Effect

Dose

Normaldose

Increasedsensitivity of

respiratorycenter

Safetymargin

mACh-receptor

α-adreno-ceptor

Histaminereceptor

Dopaminereceptor

Lackingreceptorspecificity

e. g., Chlor-promazine

mACh-receptor

Atropine

Receptorspecificitybut lacking organselectivity

Atropine

C. Adverse drug effect: lacking selectivity


Drug Allergy

The immune system normally functionsto rid the organism of invading foreignparticles, such as bacteria. Immune re-sponses can occur without appropriatecause or with exaggerated intensity andmay harm the organism, for instance,when allergic reactions are caused bydrugs (active ingredient or pharmaceu-tical excipients). Only a few drugs, e.g.(heterologous) proteins, have a molecu-lar mass (>10,000) large enough to actas effective antigens or immunogens,capable by themselves of initiating animmune response. Most drugs or theirmetabolites (so-called haptens) mustfirst be converted to an antigen by link-age to a body protein. In the case of pen-icillin G, a cleavage product (penicilloylresidue) probably undergoes covalentbinding to protein. During initial con-tact with the drug, the immune systemis sensitized: antigen-specific lympho-cytes of the T-type and B-type (antibodyformation) proliferate in lymphatic tis-sue and some of them remain as so-called memory cells. Usually, these pro-cesses remain clinically silent. Duringthe second contact, antibodies are al-ready present and memory cells prolife-rate rapidly. A detectable immune re-sponse, the allergic reaction, occurs.This can be of severe intensity, even at alow dose of the antigen. Four types ofreactions can be distinguished:

Type 1, anaphylactic reaction.Drug-specific antibodies of the IgE typecombine via their Fc moiety with recep-tors on the surface of mast cells. Bindingof the drug provides the stimulus for therelease of histamine and other media-tors. In the most severe form, a life-threatening anaphylactic shock devel-ops, accompanied by hypotension,bronchospasm (asthma attack), laryn-geal edema, urticaria, stimulation of gutmusculature, and spontaneous bowelmovements (p. 326).

Type 2, cytotoxic reaction. Drug-antibody (IgG) complexes adhere to thesurface of blood cells, where either circu-lating drug molecules or complexes al-

ready formed in blood accumulate.These complexes mediate the activationof complement, a family of proteins thatcirculate in the blood in an inactiveform, but can be activated in a cascade-like succession by an appropriate stimu-lus. “Activated complement” normallydirected against microorganisms, candestroy the cell membranes and therebycause cell death; it also promotes pha-gocytosis, attracts neutrophil granulo-cytes (chemotaxis), and stimulates oth-er inflammatory responses. Activationof complement on blood cells results intheir destruction, evidenced by hemo-lytic anemia, agranulocytosis, andthrombocytopenia.

Type 3, immune complex vascu-litis (serum sickness, Arthus reaction).Drug-antibody complexes precipitate onvascular walls, complement is activated,and an inflammatory reaction is trig-gered. Attracted neutrophils, in a futileattempt to phagocytose the complexes,liberate lysosomal enzymes that dam-age the vascular walls (inflammation,vasculitis). Symptoms may include fe-ver, exanthema, swelling of lymphnodes, arthritis, nephritis, and neuropa-thy.

Type 4, contact dermatitis. A cuta-neously applied drug is bound to thesurface of T-lymphocytes directed spe-cifically against it. The lymphocytes re-lease signal molecules (lymphokines)into their vicinity that activate macro-phages and provoke an inflammatoryreaction.




Production ofantibodies(Immunoglobulins)e.g. IgE

IgG etc.

A. Adverse drug effect: allergic reaction

MacromoleculeMW > 10 000

Protein

"Non-self"

Immune system(^ lymphatictissue)recognizes:

Drug(= hapten)

Antigen

Reaction of immune system to first drug exposure

Proliferation ofantigen-specificlymphocytes

Immune reaction with repeated drug exposure

Histamine and other mediators

Receptorfor IgE

Type 1 reaction:acute anaphylactic reaction

Mast cell(tissue)basophilicgranulocyte(blood)

IgE

Urticaria, asthma, shock

IgG

Type 2 reaction:cytotoxic reaction

Celldestruc-tion

Membraneinjury

e.g., Neutrophilicgranulocyte

Complementactivation

Deposition onvessel wall

Formation ofimmune complexes

Activationof:

complement

andneutrophils

Type 3 reaction:Immune complex

Inflammatoryreaction

Contactdermatitis

Type 4 reaction:lymphocytic delayed reaction

Inflammatoryreaction

Lymphokines

Antigen-specificT-lymphocyte

Distributionin body

=


Drug Toxicity in Pregnancy and Lactation

Drugs taken by the mother can bepassed on transplacentally or via breastmilk and adversely affect the unborn orthe neonate.

Pregnancy (A)Limb malformations induced by thehypnotic, thalidomide, first focused at-tention on the potential of drugs tocause malformations (teratogenicity).Drug effects on the unborn fall into twobasic categories:1. Predictable effects that derive from

the known pharmacological drugproperties. Examples are: masculin-ization of the female fetus by andro-genic hormones; brain hemorrhagedue to oral anticoagulants; bradycar-dia due to β-blockers.

2. Effects that specifically affect the de-veloping organism and that cannotbe predicted on the basis of theknown pharmacological activity pro-file.

In assessing the risks attendingdrug use during pregnancy, the follow-ing points have to be considered:a) Time of drug use. The possible seque-

lae of exposure to a drug depend onthe stage of fetal development, asshown in A. Thus, the hazard posedby a drug with a specific action is lim-ited in time, as illustrated by the tet-racyclines, which produce effects onteeth and bones only after the thirdmonth of gestation, when mineral-ization begins.

b) Transplacental passage. Most drugscan pass in the placenta from the ma-ternal into the fetal circulation. Thefused cells of the syncytiotrophoblastform the major diffusion barrier.They possess a higher permeability todrugs than is suggested by the term“placental barrier”.

c) Teratogenicity. Statistical risk esti-mates are available for familiar, fre-quently used drugs. For many drugs,teratogenic potency cannot be dem-onstrated; however, in the case of

novel drugs it is usually not yet pos-sible to define their teratogenic haz-ard.

Drugs with established human ter-atogenicity include derivatives of vita-min A (etretinate, isotretinoin [usedinternally in skin diseases]), and oralanticoagulants. A peculiar type of dam-age results from the synthetic estrogen-ic agent, diethylstilbestrol, following itsuse during pregnancy; daughters oftreated mothers have an increased inci-dence of cervical and vaginal carcinomaat the age of approx. 20.In assessing the risk: benefit ratio, it isalso necessary to consider the benefitfor the child resulting from adequatetherapeutic treatment of its mother. Forinstance, therapy with antiepilepticdrugs is indispensable, because untreat-ed epilepsy endangers the infant at leastas much as does administration of anti-convulsants.

Lactation (B)Drugs present in the maternal organismcan be secreted in breast milk and thusbe ingested by the infant. Evaluation ofrisk should be based on factors listed inB. In case of doubt, potential danger tothe infant can be averted only by wean-ing.




Developmentstage

Nidation Embryo: organ development

Fetus: growth and maturation

Age of fetus(weeks)

B. Lactation: maternal intake of drug

A. Pregnancy: fetal damage due to drugs

Sequelaeofdamageby drug

MalformationFetal death Functional disturbances

3821 21 12

Artery VeinUterus wall

Transferofmetabolites

Capillary

Syncytio-trophoblastPlacentalbarrier

Fetu

s

M

othe

rTo umbilical cordPlacental transfer of metabolites

Therapeuticeffect inmother

Unwantedeffectin child

Drug

?

Extent oftransfer ofdrug intomilk Infant dose

Rate ofeliminationof drugfrom infant

Distributionof drugin infant

Drug concentrationin infant´s blood

Effect

Ovum 1 day

Endometrium

Blastocyst

Sensitivity ofsite of action

Sperm cells ~3 days


Placebo (A)

A placebo is a dosage form devoid of anactive ingredient, a dummy medication.Administration of a placebo may elicitthe desired effect (relief of symptoms)or undesired effects that reflect achange in the patient’s psychologicalsituation brought about by the thera-peutic setting.

Physicians may consciously or un-consciously communicate to the patientwhether or not they are concernedabout the patient’s problem, or certainabout the diagnosis and about the valueof prescribed therapeutic measures. Inthe care of a physician who projectspersonal warmth, competence, and con-fidence, the patient in turn feels com-fortable and less anxious and optimisti-cally anticipates recovery.

The physical condition determinesthe psychic disposition and vice versa.Consider gravely wounded combatantsin war, oblivious to their injuries whilefighting to survive, only to experiencesevere pain in the safety of the field hos-pital, or the patient with a peptic ulcercaused by emotional stress.

Clinical trials. In the individualcase, it may be impossible to decidewhether therapeutic success is attribu-table to the drug or to the therapeuticsituation. What is therefore required is acomparison of the effects of a drug andof a placebo in matched groups of pa-tients by means of statistical proce-dures, i.e., a placebo-controlled trial. Aprospective trial is planned in advance, aretrospective (case-control) study fol-lows patients backwards in time. Pa-tients are randomly allotted to twogroups, namely, the placebo and the ac-tive or test drug group. In a double-blindtrial, neither the patients nor the treat-ing physicians know which patient isgiven drug and which placebo. Finally, aswitch from drug to placebo and viceversa can be made in a successive phaseof treatment, the cross-over trial. In thisfashion, drug vs. placebo comparisonscan be made not only between two pa-

tient groups, but also within eithergroup itself.

Homeopathy (B) is an alternativemethod of therapy, developed in the1800s by Samuel Hahnemann. His ideawas this: when given in normal (allo-pathic) dosage, a drug (in the sense ofmedicament) will produce a constella-tion of symptoms; however, in a patientwhose disease symptoms resemble justthis mosaic of symptoms, the same drug(simile principle) would effect a curewhen given in a very low dosage (“po-tentiation”). The body’s self-healingpowers were to be properly activatedonly by minimal doses of the medicinalsubstance.

The homeopath’s task is not to di-agnose the causes of morbidity, but tofind the drug with a “symptom profile”most closely resembling that of thepatient’s illness. This drug is then ap-plied in very high dilution.

A direct action or effect on bodyfunctions cannot be demonstrated forhomeopathic medicines. Therapeuticsuccess is due to the suggestive powersof the homeopath and the expectancy ofthe patient. When an illness is stronglyinfluenced by emotional (psychic) fac-tors and cannot be treated well by allo-pathic means, a case can be made in fa-vor of exploiting suggestion as a thera-peutic tool. Homeopathy is one of sever-al possible methods of doing so.

76 Drug-independent Effects


Drug-independent Effects 77

“Similia similibus curentur”

“Drug”Normal, allopathic dosesymptom profile

Dilution“effect reversal”Very low homeopathic doseelimination of diseasesymptoms correspondingto allopathic symptom“profile”

“Potentiation”increase in efficacywith progressive dilution

B. Homeopathy: concepts and procedure

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

Well-beingcomplaints

Effect:- wanted- unwanted

Placebo

Consciousand

unconsciousexpectations

Consciousandunconscioussignals:language,facial expression,gestures

Physician

Symptom“profile”

Profile of disease symptoms

PatientHomeopath

Homeopathicremedy (“Simile”)

D9110

110

110

110

110

110

110

110

110

Stock-solution

Dilution

“Drug diagnosis”

11000 000 000

Patient

Body

Mind


Systems Pharmacology


Sympathetic Nervous System

In the course of phylogeny an efficientcontrol system evolved that enabled thefunctions of individual organs to be or-chestrated in increasingly complex lifeforms and permitted rapid adaptationto changing environmental conditions.This regulatory system consists of theCNS (brain plus spinal cord) and twoseparate pathways for two-way com-munication with peripheral organs, viz.,the somatic and the autonomic nervoussystems. The somatic nervous systemcomprising extero- and interoceptiveafferents, special sense organs, and mo-tor efferents, serves to perceive externalstates and to target appropriate bodymovement (sensory perception: threat� response: flight or attack). The auto-nomic (vegetative) nervous system(ANS), together with the endocrinesystem, controls the milieu interieur. Itadjusts internal organ functions to thechanging needs of the organism. Neuralcontrol permits very quick adaptation,whereas the endocrine system providesfor a long-term regulation of functionalstates. The ANS operates largely beyondvoluntary control; it functions autono-mously. Its central components residein the hypothalamus, brain stem, andspinal cord. The ANS also participates inthe regulation of endocrine functions.

The ANS has sympathetic andparasympathetic branches. Both aremade up of centrifugal (efferent) andcentripetal (afferent) nerves. In manyorgans innervated by both branches, re-spective activation of the sympatheticand parasympathetic input evokes op-posing responses.

In various disease states (organmalfunctions), drugs are employed withthe intention of normalizing susceptibleorgan functions. To understand the bio-logical effects of substances capable ofinhibiting or exciting sympathetic orparasympathetic nerves, one must firstenvisage the functions subserved by thesympathetic and parasympathetic divi-sions (A, Responses to sympathetic ac-tivation). In simplistic terms, activation

of the sympathetic division can be con-sidered a means by which the bodyachieves a state of maximal work capac-ity as required in fight or flight situa-tions.

In both cases, there is a need forvigorous activity of skeletal muscula-ture. To ensure adequate supply of oxy-gen and nutrients, blood flow in skeletalmuscle is increased; cardiac rate andcontractility are enhanced, resulting in alarger blood volume being pumped intothe circulation. Narrowing of splanchnicblood vessels diverts blood into vascularbeds in muscle.

Because digestion of food in the in-testinal tract is dispensable and onlycounterproductive, the propulsion of in-testinal contents is slowed to the extentthat peristalsis diminishes and sphinc-teric tonus increases. However, in orderto increase nutrient supply to heart andmusculature, glucose from the liver andfree fatty acid from adipose tissue mustbe released into the blood. The bronchiare dilated, enabling tidal volume andalveolar oxygen uptake to be increased.

Sweat glands are also innervated bysympathetic fibers (wet palms due toexcitement); however, these are excep-tional as regards their neurotransmitter(ACh, p. 106).

Although the life styles of modernhumans are different from those ofhominid ancestors, biological functionshave remained the same.

80 Drugs Acting on the Sympathetic Nervous System


Drugs Acting on the Sympathetic Nervous System 81

Eyes:pupillary dilation

CNS:drivealertness

Bronchi:dilation

Saliva:little, viscous

Heart:rateforceblood pressure

Fat tissue:lipolysisfatty acidliberation

Bladder:Sphincter tonedetrusor muscle

Skeletal muscle:blood flowglycogenolysis

A. Responses to sympathetic activation

GI-tract:peristalsissphincter toneblood flow

Liver:glycogenolysisglucose release

Skin:perspiration(cholinergic)


Structure of the Sympathetic NervousSystem

The sympathetic preganglionic neurons(first neurons) project from the inter-mediolateral column of the spinal graymatter to the paired paravertebral gan-glionic chain lying alongside the verte-bral column and to unpaired preverte-bral ganglia. These ganglia representsites of synaptic contact between pre-ganglionic axons (1st neurons) andnerve cells (2nd neurons or sympathocy-tes) that emit postganglionic axonsterminating on cells in various end or-gans. In addition, there are preganglion-ic neurons that project either to periph-eral ganglia in end organs or to the ad-renal medulla.

Sympathetic Transmitter Substances

Whereas acetylcholine (see p. 98)serves as the chemical transmitter atganglionic synapses between first andsecond neurons, norepinephrine(= noradrenaline) is the mediator atsynapses of the second neuron (B). Thissecond neuron does not synapse withonly a single cell in the effector organ;rather, it branches out, each branchmaking en passant contacts with severalcells. At these junctions the nerve axonsform enlargements (varicosities) re-sembling beads on a string. Thus, excita-tion of the neuron leads to activation ofa larger aggregate of effector cells, al-though the action of released norepi-nephrine may be confined to the regionof each junction. Excitation of pregan-glionic neurons innervating the adrenalmedulla causes a liberation of acetyl-choline. This, in turn, elicits a secretionof epinephrine (= adrenaline) into theblood, by which it is distributed to bodytissues as a hormone (A).

Adrenergic Synapse

Within the varicosities, norepinephrineis stored in small membrane-enclosedvesicles (granules, 0.05 to 0.2 µm in dia-meter). In the axoplasm, L-tyrosine is

converted via two intermediate steps todopamine, which is taken up into thevesicles and there converted to norepi-nephrine by dopamine-β-hydroxylase.When stimulated electrically, the sym-pathetic nerve discharges the contentsof part of its vesicles, including norepi-nephrine, into the extracellular space.Liberated norepinephrine reacts withadrenoceptors located postjunctionallyon the membrane of effector cells orprejunctionally on the membrane ofvaricosities. Activation of presynapticα2-receptors inhibits norepinephrinerelease. By this negative feedback, re-lease can be regulated.

The effect of released norepineph-rine wanes quickly, because approx.90 % is actively transported back intothe axoplasm, then into storage vesicles(neuronal re-uptake). Small portions ofnorepinephrine are inactivated by theenzyme catechol-O-methyltransferase(COMT, present in the cytoplasm ofpostjunctional cells, to yield normeta-nephrine), and monoamine oxidase(MAO, present in mitochondria of nervecells and postjunctional cells, to yield3,4-dihydroxymandelic acid).

The liver is richly endowed withCOMT and MAO; it therefore contrib-utes significantly to the degradation ofcirculating norepinephrine and epi-nephrine. The end product of the com-bined actions of MAO and COMT is van-illylmandelic acid.




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

A. Epinephrine as hormone, norepinephrine as transmitter

Psychicstress

or physicalstress

First neuron

SecondneuronAdrenal

medulla

NorepinephrineEpinephrine

MAO

Recep

tors

Rece

ptor

s

COMT

Norepinephrine

Presynapticα2-receptors

α

β2

β1

3.4-Dihydroxy-mandelic acid

Normeta-nephrine

First neuron


Adrenoceptor Subtypes and Catecholamine Actions

Adrenoceptors fall into three majorgroups, designated α1, α2, and β, withineach of which further subtypes can bedistinguished pharmacologically. Thedifferent adrenoceptors are differential-ly distributed according to region andtissue. Agonists at adrenoceptors (di-rect sympathomimetics) mimic the ac-tions of the naturally occurring cate-cholamines, norepinephrine and epi-nephrine, and are used for various ther-apeutic effects.

Smooth muscle effects. The op-posing effects on smooth muscle (A) ofα-and β-adrenoceptor activation aredue to differences in signal transduction(p. 66). This is exemplified by vascularsmooth muscle (A). α1-Receptor stimu-lation leads to intracellular release ofCa2+ via activation of the inositol tris-phosphate (IP3) pathway. In concertwith the protein calmodulin, Ca2+ canactivate myosin kinase, leading to a risein tonus via phosphorylation of the con-tractile protein myosin. cAMP inhibitsactivation of myosin kinase. Via the for-mer effector pathway, stimulation of α-receptors results in vasoconstriction;via the latter, β2-receptors mediate va-sodilation, particularly in skeletal mus-cle — an effect that has little therapeuticuse.Vasoconstriction. Local application ofα-sympathomimetics can be employedin infiltration anesthesia (p. 204) or fornasal decongestion (naphazoline, tetra-hydrozoline, xylometazoline; pp. 90,324). Systemically administered epi-nephrine is important in the treatmentof anaphylactic shock for combating hy-potension.

Bronchodilation. β2-Adrenocep-tor-mediated bronchodilation (e.g., withterbutaline, fenoterol, or salbutamol)plays an essential part in the treatmentof bronchial asthma (p. 328).

Tocolysis. The uterine relaxant ef-fect of β2-adrenoceptor agonists, such asterbutaline or fenoterol, can be used toprevent premature labor. Vasodilation

with a resultant drop in systemic bloodpressure results in reflex tachycardia,which is also due in part to the β1-stim-ulant action of these drugs.

Cardiostimulation. By stimulatingβ1-receptors, hence activation of ade-nylatcyclase (Ad-cyclase) and cAMPproduction, catecholamines augment allheart functions, including systolic force(positive inotropism), velocity of short-ening (p. clinotropism), sinoatrial rate(p. chronotropism), conduction velocity(p. dromotropism), and excitability (p.bathmotropism). In pacemaker fibers,diastolic depolarization is hastened, sothat the firing threshold for the actionpotential is reached sooner (positivechronotropic effect, B). The cardiostim-ulant effect of β-sympathomimeticssuch as epinephrine is exploited in thetreatment of cardiac arrest. Use of β-sympathomimetics in heart failure car-ries the risk of cardiac arrhythmias.

Metabolic effects. β-Receptors me-diate increased conversion of glycogen toglucose (glycogenolysis) in both liverand skeletal muscle. From the liver, glu-cose is released into the blood, In adi-pose tissue, triglycerides are hydrolyzedto fatty acids (lipolysis, mediated by β3-receptors), which then enter the blood(C). The metabolic effects of catechola-mines are not amenable to therapeuticuse.




Membrane potential (mV)

Time

B. Cardiac effects of catecholamines

A. Vasomotor effects of catecholamines

α1

Gi

α2

Ad

-cyc

lase

Pho

spho

lipas

e C

Ad

-cyc

lase

Ca2+

IP3

cAMP+ -

Calmod

ulin

Myosinkinase

Myosin Myosin-P

β2

β1

Gs

Ad

-cyc

lase

+cAMP

Force (mN)

Time

C. Metabolic effects of catecholamines

β

Gs

Ad

-cyc

lase

+

Glucose

Glycogenolysis

cAMP

Glucose

Lipolysis

Fatty acids

Glycogenolysis

Gi Gs


Structure – Activity Relationships ofSympathomimeticsDue to its equally high affinity for all α-and β-receptors, epinephrine does notpermit selective activation of a particu-lar receptor subtype. Like most cate-cholamines, it is also unsuitable for oraladministration (catechol is a trivialname for o-hydroxyphenol). Norepi-nephrine differs from epinephrine by itshigh affinity for α-receptors and low af-finity for β2-receptors. In contrast, iso-proterenol has high affinity for β-recep-tors, but virtually none for α-receptors(A).norepinephrine � α, β1

epinephrine � α, β1, β2

isoproterenol � β1, β2

Knowledge of structure–activityrelationships has permitted the syn-thesis of sympathomimetics that dis-play a high degree of selectivity atadrenoceptor subtypes.

Direct-acting sympathomimetics(i.e., adrenoceptor agonists) typicallyshare a phenylethylamine structure. Theside chain β-hydroxyl group confers af-finity for α- and β-receptors. Substitu-tion on the amino group reduces affinityfor α-receptors, but increases it for β-re-ceptors (exception: α-agonist phenyl-ephrine), with optimal affinity beingseen after the introduction of only oneisopropyl group. Increasing the bulk ofthe amino substituent favors affinity forβ2-receptors (e.g., fenoterol, salbuta-mol). Both hydroxyl groups on the aro-matic nucleus contribute to affinity;high activity at α-receptors is associatedwith hydroxyl groups at the 3 and 4 po-sitions. Affinity for β-receptors is pre-served in congeners bearing hydroxylgroups at positions 3 and 5 (orciprena-line, terbutaline, fenoterol).

The hydroxyl groups of catechol-amines are responsible for the very lowlipophilicity of these substances. Pola-rity is increased at physiological pH dueto protonation of the amino group. De-letion of one or all hydroxyl groups im-proves membrane penetrability at theintestinal mucosa-blood and the blood-brain barriers. Accordingly, these non-

catecholamine congeners can be givenorally and can exert CNS actions; how-ever, this structural change entails a lossin affinity.

Absence of one or both aromatichydroxyl groups is associated with anincrease in indirect sympathomimeticactivity, denoting the ability of a sub-stance to release norepinephrine fromits neuronal stores without exerting anagonist action at the adrenoceptor (p.88).

An altered position of aromatic hy-droxyl groups (e.g., in orciprenaline, fe-noterol, or terbutaline) or their substi-tution (e.g., salbutamol) protectsagainst inactivation by COMT (p. 82). In-droduction of a small alkyl residue atthe carbon atom adjacent to the aminogroup (ephedrine, methamphetamine)confers resistance to degradation byMAO (p. 80), as does replacement on theamino groups of the methyl residuewith larger substituents (e.g., ethyl inetilefrine). Accordingly, the congenersare less subject to presystemic inactiva-tion.

Since structural requirements forhigh affinity, on the one hand, and oralapplicability, on the other, do notmatch, choosing a sympathomimetic isa matter of compromise. If the high af-finity of epinephrine is to be exploited,absorbability from the intestine must beforegone (epinephrine, isoprenaline). Ifgood bioavailability with oral adminis-tration is desired, losses in receptor af-finity must be accepted (etilefrine).




B. Structure-activity relationship of epinephrine derivatives

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

EpinephrineNorepinephrine Isoproterenol

Receptor affinity

Catecholamine-O-methyltransferase

Monoamine oxidase(Enteral absorbabilityCNS permeability)

Metabolicstability

Etilefrine Ephedrine Methamphetamine

Epinephrine Orciprenaline Fenoterol

Affinity for α-receptors

Affinity for β-receptors

Resistance to degradation

Absorbability

Indirectaction

Penetrabilitythroughmembranebarriers


Indirect Sympathomimetics

Apart from receptors, adrenergic neu-rotransmission involves mechanismsfor the active re-uptake and re-storageof released amine, as well as enzymaticbreakdown by monoamine oxidase(MAO). Norepinephrine (NE) displaysaffinity for receptors, transport systems,and degradative enzymes. Chemical al-terations of the catecholamine differen-tially affect these properties and resultin substances with selective actions.

Inhibitors of MAO (A). The enzymeis located predominantly on mitochon-dria, and serves to scavenge axoplasmicfree NE. Inhibition of the enzyme causesfree NE concentrations to rise. Likewise,dopamine catabolism is impaired, mak-ing more of it available for NE synthesis.Consequently, the amount of NE storedin granular vesicles will increase, andwith it the amount of amine releasedper nerve impulse.

In the CNS, inhibition of MAO af-fects neuronal storage not only of NEbut also of dopamine and serotonin.These mediators probably play signifi-cant roles in CNS functions consistentwith the stimulant effects of MAO inhib-itors on mood and psychomotor driveand their use as antidepressants in thetreatment of depression (A). Tranylcy-promine is used to treat particular formsof depressive illness; as a covalentlybound suicide substrate, it causes long-lasting inhibition of both MAO iso-zymes, (MAOA, MAOB). Moclobemide re-versibly inhibits MAOA and is also usedas an antidepressant. The MAOB inhibi-tor selegiline (deprenyl) retards the cat-obolism of dopamine, an effect used inthe treatment of parkinsonism (p. 188).

Indirect sympathomimetics (B)are agents that elevate the concentra-tion of NE at neuroeffector junctions,because they either inhibit re-uptake(cocaine), facilitate release, or slowbreakdown by MAO, or exert all three ofthese effects (amphetamine, metham-phetamine). The effectiveness of suchindirect sympathomimetics diminishesor disappears (tachyphylaxis) when ve-

sicular stores of NE close to the axolem-ma are depleted.

Indirect sympathomimetics canpenetrate the blood-brain barrier andevoke such CNS effects as a feeling ofwell-being, enhanced physical activityand mood (euphoria), and decreasedsense of hunger or fatigue. Subsequent-ly, the user may feel tired and de-pressed. These after effects are partlyresponsible for the urge to re-adminis-ter the drug (high abuse potential). Toprevent their misuse, these substancesare subject to governmental regulations(e.g., Food and Drugs Act: Canada; Con-trolled Drugs Act: USA) restricting theirprescription and distribution.

When amphetamine-like substanc-es are misused to enhance athletic per-formance (doping), there is a risk of dan-gerous physical overexertion. Becauseof the absence of a sense of fatigue, adrugged athlete may be able to mobilizeultimate energy reserves. In extremesituations, cardiovascular failure mayresult (B).

Closely related chemically to am-phetamine are the so-called appetitesuppressants or anorexiants, such asfenfluramine, mazindole, and sibutra-mine. These may also cause dependenceand their therapeutic value and safetyare questionable.




ControlledSubstancesAct regulatesuse ofcocaine andamphetamine

MAOMAO

MAOMAO

B. Indirect sympathomimetics with central stimulant activity and abuse potential

A. Monoamine oxidase inhibitor

Nor-epinephrine

Norepinephrinetransport system

Effector organ

"Doping"

Runner-up

Pain stimulus Localanestheticeffect

Amphetamine Cocaine

§ §

Inhibitor: Moclobemide MAO-A Selegiline MAO-B


α-Sympathomimetics, α-Sympatholytics

α-Sympathomimetics can be usedsystemically in certain types of hypoten-sion (p. 314) and locally for nasal or con-junctival decongestion (pp. 324, 326) oras adjuncts in infiltration anesthesia (p.206) for the purpose of delaying the re-moval of local anesthetic. With localuse, underperfusion of the vasocon-stricted area results in a lack of oxygen(A). In the extreme case, local hypoxiacan lead to tissue necrosis. The append-ages (e.g., digits, toes, ears) are particu-larly vulnerable in this regard, thus pre-cluding vasoconstrictor adjuncts in in-filtration anesthesia at these sites.

Vasoconstriction induced by an α-sympathomimetic is followed by aphase of enhanced blood flow (reactivehyperemia, A). This reaction can be ob-served after the application of α-sympa-thomimetics (naphazoline, tetrahydro-zoline, xylometazoline) to the nasal mu-cosa. Initially, vasoconstriction reducesmucosal blood flow and, hence, capil-lary pressure. Fluid exuded into theinterstitial space is drained through theveins, thus shrinking the nasal mucosa.Due to the reduced supply of fluid, se-cretion of nasal mucus decreases. In co-ryza, nasal patency is restored. Howev-er, after vasoconstriction subsides, reac-tive hyperemia causes renewed exuda-tion of plasma fluid into the interstitialspace, the nose is “stuffy” again, and thepatient feels a need to reapply decon-gestant. In this way, a vicious cyclethreatens. Besides rebound congestion,persistent use of a decongestant entailsthe risk of atrophic damage caused byprolonged hypoxia of the nasal mucosa.

α-Sympatholytics (B). The interac-tion of norepinephrine with α-adreno-ceptors can be inhibited by α-sympath-olytics ( α-adrenoceptor antagonists, α-blockers). This inhibition can be put totherapeutic use in antihypertensivetreatment (vasodilation � peripheralresistance ↓ , blood pressure ↓ , p. 118).The first α-sympatholytics blocked theaction of norepinephrine at both post-

and prejunctional α-adrenoceptors(non-selective α-blockers, e.g., phen-oxybenzamine, phentolamine).

Presynaptic α2-adrenoceptors func-tion like sensors that enable norepi-nephrine concentration outside theaxolemma to be monitored, thus regu-lating its release via a local feedbackmechanism. When presynaptic α2-re-ceptors are stimulated, further releaseof norepinephrine is inhibited. Con-versely, their blockade leads to uncon-trolled release of norepinephrine withan overt enhancement of sympatheticeffects at β1-adrenoceptor-mediatedmyocardial neuroeffector junctions, re-sulting in tachycardia and tachyar-rhythmia.

Selective α-Sympatholytics

α-Blockers, such as prazosin, or thelonger-acting terazosin and doxazosin,lack affinity for prejunctional α2-adren-oceptors. They suppress activation ofα1-receptors without a concomitant en-hancement of norepinephrine release.

α1-Blockers may be used in hyper-tension (p. 312). Because they preventreflex vasoconstriction, they are likelyto cause postural hypotension withpooling of blood in lower limb capaci-tance veins during change from the su-pine to the erect position (orthostaticcollapse: ↓ venous return, ↓ cardiac out-put, fall in systemic pressure, ↓ bloodsupply to CNS, syncope, p. 314).

In benign hyperplasia of the pros-tate, α-blockers (terazosin, alfuzosin)may serve to lower tonus of smoothmusculature in the prostatic region andthereby facilitate micturition (p. 252).




C. Indications for α1-sympatholytics

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

B. Autoinhibition of norepinephrine release and α-sympatholytics

α-Agonist

O2 supply < O2 demand O2 supply = O2 demand

AfterBefore

O2 supply = O2 demand

NE

α2 α2 α2

nonselectiveα-blocker

α1 α1 α1β1 β1 β1

α1-blocker

α1-blockere.g., terazosin

H3CO

O

O

H3CO

NH2

N

N N

N

High blood pressureBenignprostatic hyperplasia

Inhibition ofα1-adrenergicstimulation ofsmooth muscle Neck of bladder,

prostateResistancearteries


β-Sympatholytics (β-Blockers)

β-Sympatholytics are antagonists ofnorepiphephrine and epinephrine at β-adrenoceptors; they lack affinity for α-receptors.

Therapeutic effects. β-Blockersprotect the heart from the oxygen-wasting effect of sympathetic inotrop-ism (p. 306) by blocking cardiac β-re-ceptors; thus, cardiac work can no long-er be augmented above basal levels (theheart is “coasting”). This effect is uti-lized prophylactically in angina pectoristo prevent myocardial stress that couldtrigger an ischemic attack (p. 308, 310).β-Blockers also serve to lower cardiacrate (sinus tachycardia, p. 134) and ele-vated blood pressure due to high cardiacoutput (p. 312). The mechanism under-lying their antihypertensive action viareduction of peripheral resistance is un-clear.

Applied topically to the eye, β-blockers are used in the management ofglaucoma; they lower production ofaqueous humor without affecting itsdrainage.

Undesired effects. The hazards oftreatment with β-blockers become ap-parent particularly when continuousactivation of β-receptors is needed inorder to maintain the function of an or-gan.

Congestive heart failure: In myocar-dial insufficiency, the heart depends ona tonic sympathetic drive to maintainadequate cardiac output. Sympatheticactivation gives rise to an increase inheart rate and systolic muscle tension,enabling cardiac output to be restoredto a level comparable to that in ahealthy subject. When sympatheticdrive is eliminated during β-receptorblockade, stroke volume and cardiacrate decline, a latent myocardial insuffi-ciency is unmasked, and overt insuffi-ciency is exacerbated (A).

On the other hand, clinical evidencesuggests that β-blockers produce favor-able effects in certain forms of conges-tive heart failure (idiopathic dilated car-diomyopathy).

Bradycardia, A-V block: Eliminationof sympathetic drive can lead to amarked fall in cardiac rate as well as todisorders of impulse conduction fromthe atria to the ventricles.

Bronchial asthma: Increased sym-pathetic activity prevents broncho-spasm in patients disposed to paroxys-mal constriction of the bronchial tree(bronchial asthma, bronchitis in smok-ers). In this condition, β2-receptorblockade will precipitate acute respira-tory distress (B).

Hypoglycemia in diabetes mellitus:When treatment with insulin or oral hy-poglycemics in the diabetic patient low-ers blood glucose below a critical level,epinephrine is released, which thenstimulates hepatic glucose release viaactivation of β2-receptors. β-Blockerssuppress this counter-regulation; in ad-dition, they mask other epinephrine-mediated warning signs of imminenthypoglycemia, such as tachycardia andanxiety, thereby enhancing the risk ofhypoglycemic shock.

Altered vascular responses: Whenβ2-receptors are blocked, the vasodilat-ing effect of epinephrine is abolished,leaving the α-receptor-mediated vaso-constriction unaffected: peripheralblood flow ↓ – “cold hands and feet”.

β-Blockers exert an “anxiolytic“action that may be due to the suppres-sion of somatic responses (palpitations,trembling) to epinephrine release thatis induced by emotional stress; in turn,these would exacerbate “anxiety” or“stage fright”. Because alertness is notimpaired by β-blockers, these agents areoccasionally taken by orators and musi-cians before a major performance (C).Stage fright, however, is not a diseaserequiring drug therapy.




C. “Anxiolytic” effect of β-sympatholytics

A. β-Sympatholytics: effect on cardiac function

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

Strokevolume

100 ml

β-Receptorβ-Blockerblocksreceptor

Hea

rt fa

ilure

Hea

lthy

1 sec

β1-Blockade β1-Stimulation


Hea

lthy

Ast

hmat

ic


α β2 α β2α

1 sec

β-Blockade


Types of β-Blockers

The basic structure shared by most β-sympatholytics is the side chain of β-sympathomimetics (cf. isoproterenolwith the β-blockers propranolol, pindo-lol, atenolol). As a rule, this basic struc-ture is linked to an aromatic nucleus bya methylene and oxygen bridge. Theside chain C-atom bearing the hydroxylgroup forms the chiral center. Withsome exceptions (e.g., timolol, penbuto-lol), all β-sympatholytics are brought asracemates into the market (p. 62).

Compared with the dextrorotatoryform, the levorotatory enantiomer pos-sesses a greater than 100-fold higher af-finity for the β-receptor and is, there-fore, practically alone in contributing tothe β-blocking effect of the racemate.The side chain and substituents on theamino group critically affect affinity forβ-receptors, whereas the aromatic nu-cleus determines whether the com-pound possess intrinsic sympathomi-metic activity (ISA), that is, acts as apartial agonist (p. 60) or partial antago-nist. In the presence of a partial agonist(e.g., pindolol), the ability of a full ago-nist (e.g., isoprenaline) to elicit a maxi-mal effect would be attenuated, becausebinding of the full agonist is impeded.However, the β-receptor at which suchpartial agonism can be shown appearsto be atypical (β3 or β4 subtype). Wheth-er ISA confers a therapeutic advantageon a β-blocker remains an open ques-tion.

As cationic amphiphilic drugs, β-blockers can exert a membrane-stabi-lizing effect, as evidenced by the abilityof the more lipophilic congeners to in-hibit Na+-channel function and impulseconduction in cardiac tissues. At theusual therapeutic dosage, the high con-centration required for these effects willnot be reached.

Some β-sympatholytics possesshigher affinity for cardiac β1-receptorsthan for β2-receptors and thus displaycardioselectivity (e.g., metoprolol, ace-butolol, bisoprolol). None of theseblockers is sufficiently selective to per-

mit its use in patients with bronchialasthma or diabetes mellitus (p. 92).

The chemical structure of β-block-ers also determines their pharmacoki-netic properties. Except for hydrophilicrepresentatives (atenolol), β-sympatho-lytics are completely absorbed from theintestines and subsequently undergopresystemic elimination to a major ex-tent (A).

All the above differences are of little clinical importance. The abundanceof commercially available congenerswould thus appear all the more curious(B). Propranolol was the first β-blockerto be introduced into therapy in 1965.Thirty-five years later, about 20 differentcongeners are being marketed in differ-ent countries. This questionable devel-opment unfortunately is typical of anydrug group that has major therapeuticrelevance, in addition to a relativelyfixed active structure. Variation of themolecule will create a new patentablechemical, not necessarily a drug with anovel action. Moreover, a drug no longerprotected by patent is offered as a gener-ic by different manufacturers under doz-ens of different proprietary names.Propranolol alone has been marketed by13 manufacturers under 11 differentnames.




TalinololSotalol

β1β2

B. Avalanche-like increase in commercially available β-sympatholytics

Isoproterenol Pindolol Propranolol Atenolol

Agonist partial Agonist

Antagonist

Effect No effect

selectivity

Presystemic elimination

100%

50%

A. Types of β-sympatholytics

Betaxolol

CarteololMepindolol

PenbutololCarazololNadolol

AcebutololBunitrolol

AtenololMetipranol

MetoprololTimolol

OxprenololPindolol

BupranololAlprenolol

Propranolol

1965 1970

1975 1980 1985 1990

CeliprololBisoprolol

BopindololEsmolol

Tertatolol

β1β2Cardio-

β1β2

β1β2

β1

β2

β-Receptor β-Receptor β-Receptor

Carvedilol

Befunolol

Year introduced

Antagonist


Antiadrenergics

Antiadrenergics are drugs capable oflowering transmitter output from sym-pathetic neurons, i.e., “sympathetictone”. Their action is hypotensive (indi-cation: hypertension, p. 312); however,being poorly tolerated, they enjoy onlylimited therapeutic use.

Clonidine is an α2-agonist whosehigh lipophilicity (dichlorophenyl ring)permits rapid penetration through theblood-brain barrier. The activation ofpostsynaptic α2-receptors dampens theactivity of vasomotor neurons in themedulla oblongata, resulting in a reset-ting of systemic arterial pressure at alower level. In addition, activation ofpresynaptic α2-receptors in the periph-ery (pp. 82, 90) leads to a decreased re-lease of both norepinephrine (NE) andacetylcholine.

Side effects. Lassitude, dry mouth;rebound hypertension after abrupt ces-sation of clonidine therapy.

Methyldopa (dopa = dihydroxy-phenylalanine), as an amino acid, istransported across the blood-brain bar-rier, decarboxylated in the brain to α-methyldopamine, and then hydroxylat-ed to α-methyl-NE. The decarboxylationof methyldopa competes for a portion ofthe available enzymatic activity, so thatthe rate of conversion of L-dopa to NE(via dopamine) is decreased. The falsetransmitter α-methyl-NE can be stored;however, unlike the endogenous media-tor, it has a higher affinity for α2- thanfor α1-receptors and therefore produceseffects similar to those of clonidine. Thesame events take place in peripheral ad-renergic neurons.

Adverse effects. Fatigue, orthostatichypotension, extrapyramidal Parkin-son-like symptoms (p. 88), cutaneousreactions, hepatic damage, immune-he-molytic anemia.

Reserpine, an alkaloid from theRauwolfia plant, abolishes the vesicularstorage of biogenic amines (NE, dopa-mine = DA, serotonin = 5-HT) by inhibit-ing an ATPase required for the vesicularamine pump. The amount of NE re-

leased per nerve impulse is decreased.To a lesser degree, release of epineph-rine from the adrenal medulla is alsoimpaired. At higher doses, there is irre-versible damage to storage vesicles(“pharmacological sympathectomy”),days to weeks being required for theirresynthesis. Reserpine readily entersthe brain, where it also impairs vesicu-lar storage of biogenic amines.

Adverse effects. Disorders of extra-pyramidal motor function with devel-opment of pseudo-Parkinsonism (p. 88),sedation, depression, stuffy nose, im-paired libido, and impotence; increasedappetite. These adverse effects haverendered the drug practically obsolete.

Guanethidine possesses high affin-ity for the axolemmal and vesicularamine transporters. It is stored insteadof NE, but is unable to mimic the func-tions of the latter. In addition, it stabiliz-es the axonal membrane, thereby im-peding the propagation of impulses intothe sympathetic nerve terminals. Stor-age and release of epinephrine from theadrenal medulla are not affected, owingto the absence of a re-uptake process.The drug does not cross the blood-brainbarrier.

Adverse effects. Cardiovascular cri-ses are a possible risk: emotional stressof the patient may cause sympatho-adrenal activation with epinephrine re-lease. The resulting rise in blood pres-sure can be all the more marked be-cause persistent depression of sympa-thetic nerve activity induces supersen-sitivity of effector organs to circulatingcatecholamines.




Suppression ofsympatheticimpulses invasomotorcenter

Release from adrenal medullaunaffected

CNS

A. Inhibitors of sympathetic tone

No epinephrine from adrenal medulladue to central sedative effect

Stimulation of central α2-receptors

α-Methyl-NE

False transmitter

Tyrosine

Dopa

Dopamine

NE

Clonidine

α-Methyldopa

Peripheralsympathetic activity

Inhibition ofbiogenic aminestorage

NE

DA5HT

Varicosity

Reserpine

Inhibition ofperipheralsympathetic activity

Active uptake andstorage instead ofnorepinephrine;not a transmitter

Guanethidine

Varicosity

Inhibition ofDopa-decarb-oxylase

α-Methyl-NEin brain


Parasympathetic Nervous System

Responses to activation of the para-sympathetic system. Parasympatheticnerves regulate processes connectedwith energy assimilation (food intake,digestion, absorption) and storage.These processes operate when the bodyis at rest, allowing a decreased tidal vol-ume (increased bronchomotor tone)and decreased cardiac activity. Secre-tion of saliva and intestinal fluids pro-motes the digestion of foodstuffs; trans-port of intestinal contents is speeded upbecause of enhanced peristaltic activityand lowered tone of sphincteric mus-cles. To empty the urinary bladder (mic-turition), wall tension is increased bydetrusor activation with a concurrentrelaxation of sphincter tonus.

Activation of ocular parasympa-thetic fibers (see below) results in nar-rowing of the pupil and increased curva-ture of the lens, enabling near objects tobe brought into focus (accommodation).

Anatomy of the parasympatheticsystem. The cell bodies of parasympa-thetic preganglionic neurons are locatedin the brainstem and the sacral spinal

cord. Parasympathetic outflow is chan-nelled from the brainstem (1) throughthe third cranial nerve (oculomotor n.)via the ciliary ganglion to the eye; (2)through the seventh cranial nerve (fa-cial n.) via the pterygopalatine and sub-maxillary ganglia to lacrimal glands andsalivary glands (sublingual, submandib-ular), respectively; (3) through theninth cranial nerve (glossopharyngealn.) via the otic ganglion to the parotidgland; and (4) via the tenth cranialnerve (vagus n.) to thoracic and abdom-inal viscera. Approximately 75 % of allparasympathetic fibers are containedwithin the vagus nerve. The neurons ofthe sacral division innervate the distalcolon, rectum, bladder, the distal ure-ters, and the external genitalia.

Acetylcholine (ACh) as a transmit-ter. ACh serves as mediator at terminalsof all postganglionic parasympatheticfibers, in addition to fulfilling its trans-mitter role at ganglionic synapses with-in both the sympathetic and parasym-pathetic divisions and the motor end-plates on striated muscle. However, dif-ferent types of receptors are present atthese synaptic junctions:

98 Drugs Acting on the Parasympathetic Nervous System

Localization Agonist Antagonist Receptor Type

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

receptor protein with7 transmembrane domains

Sympathetic & ACh Trimethaphan Ganglionic typeparasympathetic Nicotine (α3 β4)ganglia

Nicotinic (N)cholinoceptor ligand-gated cation channelformed by five trans-membrane subunits

Motor endplate ACh d-Tubocurarine muscular typeNicotine (α12β1γδ)

The existence of distinct cholino-ceptors at different cholinergic synap-

ses allows selective pharmacologicalinterventions.


Drugs Acting on the Parasympathetic Nervous System 99

Eyes:Accommodationfor near vision,miosis

Bronchi:constrictionsecretion

Saliva:copious, liquid

GI tract:secretionperistalsissphincter tone

Heart:rateblood pressure

Bladder:

sphincter tonedetrusor

A. Responses to parasympathetic activation


Cholinergic Synapse

Acetylcholine (ACh) is the transmitterat postganglionic synapses of parasym-pathetic nerve endings. It is highly con-centrated in synaptic storage vesiclesdensely present in the axoplasm of theterminal. ACh is formed from cholineand activated acetate (acetylcoenzymeA), a reaction catalyzed by the enzymecholine acetyltransferase. The highlypolar choline is actively transported intothe axoplasm. The specific choline trans-porter is localized exclusively to mem-branes of cholinergic axons and termi-nals. The mechanism of transmitter re-lease is not known in full detail. The vesi-cles are anchored via the protein synap-sin to the cytoskeletal network. This ar-rangement permits clustering of vesiclesnear the presynaptic membrane, whilepreventing fusion with it. During activa-tion of the nerve membrane, Ca2+ isthought to enter the axoplasm throughvoltage-gated channels and to activateprotein kinases that phosphorylate syn-apsin. As a result, vesicles close to themembrane are detached from their an-choring and allowed to fuse with thepresynaptic membrane. During fusion,vesicles discharge their contents into thesynaptic gap. ACh quickly diffusesthrough the synaptic gap (the acetylcho-line molecule is a little longer than0.5 nm; the synaptic gap is as narrow as30–40 nm). At the postsynaptic effectorcell membrane, ACh reacts with its re-ceptors. Because these receptors can al-so be activated by the alkaloid musca-rine, they are referred to as muscarinic(M-)cholinoceptors. In contrast, at gan-glionic (p. 108) and motor endplate (p.184) cholinoceptors, the action of ACh ismimicked by nicotine and they are,therefore, said to be nicotinic cholino-ceptors.

Released ACh is rapidly hydrolyzedand inactivated by a specific acetylchol-inesterase, present on pre- and post-junctional membranes, or by a less spe-cific serum cholinesterase (butyryl chol-inesterase), a soluble enzyme present inserum and interstitial fluid.

M-cholinoceptors can be classifiedinto subtypes according to their molec-ular structure, signal transduction, andligand affinity. Here, the M1, M2, and M3

subtypes are considered. M1 receptorsare present on nerve cells, e.g., in gan-glia, where they mediate a facilitation ofimpulse transmission from pregan-glionic axon terminals to ganglion cells.M2 receptors mediate acetylcholine ef-fects on the heart: opening of K+ chan-nels leads to slowing of diastolic depola-rization in sinoatrial pacemaker cellsand a decrease in heart rate. M3 recep-tors play a role in the regulation ofsmooth muscle tone, e.g., in the gut andbronchi, where their activation causesstimulation of phospholipase C, mem-brane depolarization, and increase inmuscle tone. M3 receptors are alsofound in glandular epithelia, which sim-ilarly respond with activation of phos-pholipase C and increased secretory ac-tivity. In the CNS, where all subtypes arepresent, cholinoceptors serve diversefunctions, including regulation of corti-cal excitability, memory, learning, painprocessing, and brain stem motor con-trol. The assignment of specific receptorsubtypes to these functions has yet to beachieved.

In blood vessels, the relaxant actionof ACh on muscle tone is indirect, be-cause it involves stimulation of M3-cho-linoceptors on endothelial cells that re-spond by liberating NO (= endothelium-derived relaxing factor). The latter dif-fuses into the subjacent smooth muscu-lature, where it causes a relaxation ofactive tonus (p. 121).




Acetyl coenzyme A + cholineCholine acetyltransferase

Acetylcholine

Serum-cholinesterase

Smooth muscle cellM3-receptor

Heart pacemaker cellM2-receptor

Secretory cellM3-receptor

Phospholipase C K+-channel activation Phospholipase C

Ca2+ in Cytosol

Slowing ofdiastolicdepolarization Ca2+ in Cytosol

Tone Rate Secretion

-30

-70

Time

0

-45

-90

ACheffect

Controlcondition

Time

A. Acetylcholine: release, effects, and degradation

mV

Ca2+ influx

Proteinkinase

Vesiclerelease

Exocytosis

Receptoroccupation

estericcleavage

Action potential

Ca2+

mV

mN

activereuptake ofcholine

Acetylcholineesterase:membrane-associated

Storage ofacetylcholinein vesicles


Parasympathomimetics

Acetylcholine (ACh) is too rapidly hy-drolyzed and inactivated by acetylcholi-nesterase (AChE) to be of any therapeu-tic use; however, its action can be mim-icked by other substances, namely di-rect or indirect parasympathomimetics.

Direct Parasympathomimetics.The choline ester, carbachol, activatesM-cholinoceptors, but is not hydrolyzedby AChE. Carbachol can thus be effec-tively employed for local application tothe eye (glaucoma) and systemic ad-ministration (bowel atonia, bladder ato-nia). The alkaloids, pilocarpine (from Pil-ocarpus jaborandi) and arecoline (fromAreca catechu; betel nut) also act as di-rect parasympathomimetics. As tertiaryamines, they moreover exert central ef-fects. The central effect of muscarine-like substances consists of an enliven-ing, mild stimulation that is probablythe effect desired in betel chewing, awidespread habit in South Asia. Of thisgroup, only pilocarpine enjoys thera-peutic use, which is limited to local ap-plication to the eye in glaucoma.

Indirect Parasympathomimetics.AChE can be inhibited selectively, withthe result that ACh released by nerveimpulses will accumulate at cholinergicsynapses and cause prolonged stimula-tion of cholinoceptors. Inhibitors ofAChE are, therefore, indirect parasym-pathomimetics. Their action is evidentat all cholinergic synapses. Chemically,these agents include esters of carbamicacid (carbamates such as physostig-mine, neostigmine) and of phosphoricacid (organophosphates such as para-oxon = E600 and nitrostigmine = para-thion = E605, its prodrug).

Members of both groups react likeACh with AChE and can be consideredfalse substrates. The esters are hydro-lyzed upon formation of a complex withthe enzyme. The rate-limiting step inACh hydrolysis is deacetylation of theenzyme, which takes only milliseconds,thus permitting a high turnover rateand activity of AChE. Decarbaminoyla-tion following hydrolysis of a carba-

mate takes hours to days, the enzymeremaining inhibited as long as it is car-baminoylated. Cleavage of the phos-phate residue, i.e. dephosphorylation,is practically impossible; enzyme inhi-bition is irreversible.

Uses. The quaternary carbamateneostigmine is employed as an indirectparasympathomimetic in postoperativeatonia of the bowel or bladder. Further-more, it is needed to overcome the rela-tive ACh-deficiency at the motor end-plate in myasthenia gravis or to reversethe neuromuscular blockade (p. 184)caused by nondepolarizing muscle re-laxants (decurarization before discon-tinuation of anesthesia). The tertiarycarbamate physostigmine can be usedas an antidote in poisoning with para-sympatholytic drugs, because it has ac-cess to AChE in the brain. Carbamates(neostigmine, pyridostigmine, physos-tigmine) and organophosphates (para-oxon, ecothiopate) can also be appliedlocally to the eye in the treatment ofglaucoma; however, their long-term useleads to cataract formation. Agents fromboth classes also serve as insecticides.Although they possess high acute toxic-ity in humans, they are more rapidly de-graded than is DDT following theiremission into the environment.Tacrine is not an ester and interferesonly with the choline-binding site ofAChE. It is effective in alleviating symp-toms of dementia in some subtypes ofAlzheimer’s disease.




Effe

ctor

org

an

A. Direct and indirect parasympathomimetics

Arecoline =ingredient ofbetel nut:betelchewing

AChE

Direct parasympatho-mimetics

AChE

Inhibitors ofacetylcholinesterase(AChE)

Indirectparasympathomimetics

Carbachol

Acetylcholine

Arecoline

ACh

Neostigmine Paraoxon (E 600)

Physostigmine

AChEPhosphoryl

Dephosphorylation impossible

Paraoxon +

AChECarbaminoyl

Hours to daysDecarbaminoylation

Neostigmine +

AChEAcetyl

ms

Deacetylation

Acetylcholine +

Nitrostigmine =Parathion =E 605

Choline


Parasympatholytics

Excitation of the parasympathetic divi-sion of the autonomic nervous systemcauses release of acetylcholine at neuro-effector junctions in different target or-gans. The major effects are summarizedin A (blue arrows). Some of these effectshave therapeutic applications, as indi-cated by the clinical uses of parasympa-thomimetics (p. 102).

Substances acting antagonisticallyat the M-cholinoceptor are designatedparasympatholytics (prototype: the al-kaloid atropine; actions shown in red inthe panels). Therapeutic use of theseagents is complicated by their low organselectivity. Possibilities for a targetedaction include:

• local application

• selection of drugs with either good orpoor membrane penetrability as thesituation demands

• administration of drugs possessingreceptor subtype selectivity.

Parasympatholytics are employedfor the following purposes:

1. Inhibition of exocrine glandsBronchial secretion. Premedicationwith atropine before inhalation anes-thesia prevents a possible hypersecre-tion of bronchial mucus, which cannotbe expectorated by coughing during in-tubation (anesthesia).

Gastric secretion. Stimulation ofgastric acid production by vagal impuls-es involves an M-cholinoceptor subtype(M1-receptor), probably associated withenterochromaffin cells. Pirenzepine (p.106) displays a preferential affinity forthis receptor subtype. Remarkably, theHCl-secreting parietal cells possess onlyM3-receptors. M1-receptors have alsobeen demonstrated in the brain; how-ever, these cannot be reached by piren-zepine because its lipophilicity is toolow to permit penetration of the blood-brain barrier. Pirenzepine was formerlyused in the treatment of gastric and du-odenal ulcers (p. 166).

2. Relaxation of smooth musculatureBronchodilation can be achieved by theuse of ipratropium in conditions of in-creased airway resistance (chronic ob-structive bronchitis, bronchial asth-ma). When administered by inhalation,this quaternary compound has little ef-fect on other organs because of its lowrate of systemic absorption.

Spasmolysis by N-butylscopolaminein biliary or renal colic (p. 126). Be-cause of its quaternary nitrogen, thisdrug does not enter the brain and re-quires parenteral administration. Itsspasmolytic action is especially markedbecause of additional ganglionic block-ing and direct muscle-relaxant actions.

Lowering of pupillary sphincter to-nus and pupillary dilation by local ad-ministration of homatropine or tropic-amide (mydriatics) allows observationof the ocular fundus. For diagnostic us-es, only short-term pupillary dilation isneeded. The effect of both agents sub-sides quickly in comparison with that ofatropine (duration of several days).

3. CardioaccelerationIpratropium is used in bradycardia andAV-block, respectively, to raise heartrate and to facilitate cardiac impulseconduction. As a quaternary substance,it does not penetrate into the brain,which greatly reduces the risk of CNSdisturbances (see below). Relativelyhigh oral doses are required because ofan inefficient intestinal absorption.

Atropine may be given to preventcardiac arrest resulting from vagal re-flex activation, incident to anesthetic in-duction, gastric lavage, or endoscopicprocedures.




Deadly nightshadeAtropabelladonna

Muscarinic acetylcholine receptor

Ciliary musclecontracted

PhotophobiaNear vision impossible

RateAV conduction

Sweat production

Schlemm’scanal wide

Salivary secretion

Gastric acidproduction

Pancreatic juiceproduction

Bowel peristalsis

Bladder tone

Atropine

Drainage of aqueoushumor impaired

RateAV conduction

Bronchial secretionBronchoconstriction

Bronchial secretiondecreasedBronchodilation

"Flusheddry skin"

Evaporative heatloss

Increased blood flowfor increasingheat dissipation

Pupil narrow

Pupil wide

Bladder tonedecreased

Dry mouth

Acid productiondecreased

Pancreaticsecretory activitydecreased

Bowel peristalsisdecreased

RestlessnessIrritabilityHallucinationsAntiparkinsonianeffectAntiemetic effect

Acetylcholine

+

-

+

+

+

+

+

+

+

A. Effects of parasympathetic stimulation and blockade

N. oculo-motoriusN. facialisN. glosso-pharyngeusN. vagus

Nn. sacrales

+

Sympatheticnerves


4. CNS-dampening effectsScopolamine is effective in the prophy-laxis of kinetosis (motion sickness, seasickness, see p. 330); it is well absorbedtranscutaneously. Scopolamine (pKa =7.2) penetrates the blood-brain barrierfaster than does atropine (pKa = 9), be-cause at physiologic pH a larger propor-tion is present in the neutral, mem-brane-permeant form.

In psychotic excitement (agita-tion), sedation can be achieved withscopolamine. Unlike atropine, scopol-amine exerts a calming and amnesio-genic action that can be used to advan-tage in anesthetic premedication.

Symptomatic treatment in parkin-sonism for the purpose of restoring adopaminergic-cholinergic balance inthe corpus striatum. Antiparkinsonianagents, such as benzatropine (p. 188),readily penetrate the blood-brain barri-er. At centrally equi-effective dosage,their peripheral effects are less markedthan are those of atropine.

Contraindications for parasympatholyticsGlaucoma: Since drainage of aqueoushumor is impeded during relaxation ofthe pupillary sphincter, intraocularpressure rises.

Prostatic hypertrophy with im-paired micturition: loss of parasympa-thetic control of the detrusor muscle ex-acerbates difficulties in voiding urine.

Atropine poisoningParasympatholytics have a wide thera-peutic margin. Rarely life-threatening,poisoning with atropine is character-ized by the following peripheral andcentral effects:

Peripheral: tachycardia; drymouth; hyperthermia secondary to theinhibition of sweating. Although sweatglands are innervated by sympatheticfibers, these are cholinergic in nature.When sweat secretion is inhibited, thebody loses the ability to dissipate meta-bolic heat by evaporation of sweat (p.202). There is a compensatory vasodila-tion in the skin allowing increased heat

exchange through increased cutaneousblood flow. Decreased peristaltic activ-ity of the intestines leads to constipa-tion.

Central: Motor restlessness, pro-gressing to maniacal agitation, psychicdisturbances, disorientation, and hal-lucinations. Elderly subjects are moresensitive to such central effects. In thiscontext, the diversity of drugs producingatropine-like side effects should beborne in mind: e.g., tricyclic antide-pressants, neuroleptics, antihista-mines, antiarrhythmics, antiparkinso-nian agents.

Apart from symptomatic, generalmeasures (gastric lavage, cooling withice water), therapy of severe atropineintoxication includes the administra-tion of the indirect parasympathomi-metic physostigmine (p. 102). The mostcommon instances of “atropine” intoxi-cation are observed after ingestion ofthe berry-like fruits of belladonna (chil-dren) or intentional overdosage withtricyclic antidepressants in attemptedsuicide.




Ipratropium10 mg

Atropine(0.2 – 2 mg)

N-Butyl-scopolamine10–20 mg

Benzatropine1 – 2 mg

Pirenzepine50 mg

M1M1

M1M1

M1

M1

M1

M1

M1M1

M2

M3M3M3

M3

+ ganglioplegic+ direct muscle relaxant

Homatropine0.2 mg

A. Parasympatholytics


Ganglionic Transmission

Whether sympathetic or parasympa-thetic, all efferent visceromotor nervesare made up of two serially connectedneurons. The point of contact (synapse)between the first and second neuronsoccurs mainly in ganglia; therefore, thefirst neuron is referred to as pregan-glionic and efferents of the second aspostganglionic.

Electrical excitation (action poten-tial) of the first neuron causes the re-lease of acetylcholine (ACh) within theganglia. ACh stimulates receptors locat-ed on the subsynaptic membrane of thesecond neuron. Activation of these re-ceptors causes the nonspecific cationchannel to open. The resulting influx ofNa+ leads to a membrane depolariza-tion. If a sufficient number of receptorsis activated simultaneously, a thresholdpotential is reached at which the mem-brane undergoes rapid depolarization inthe form of a propagated action poten-tial. Normally, not all preganglionic im-pulses elicit a propagated response inthe second neuron. The ganglionic syn-apse acts like a frequency filter (A). Theeffect of ACh elicited at receptors on theganglionic neuronal membrane can beimitated by nicotine; i.e., it involves nic-otinic cholinoceptors.

Ganglionic action of nicotine. If asmall dose of nicotine is given, the gan-glionic cholinoceptors are activated. Themembrane depolarizes partially, butfails to reach the firing threshold. How-ever, at this point an amount of re-leased ACh smaller than that normallyrequired will be sufficient to elicit apropagated action potential. At a lowconcentration, nicotine acts as a gan-glionic stimulant; it alters the filterfunction of the ganglionic synapse, al-lowing action potential frequency in thesecond neuron to approach that of thefirst (B). At higher concentrations, nico-tine acts to block ganglionic transmis-sion. Simultaneous activation of manynicotinic cholinoceptors depolarizes theganglionic cell membrane to such an ex-tent that generation of action potentials

is no longer possible, even in the face ofan intensive and synchronized releaseof ACh (C).

Although nicotine mimics the ac-tion of ACh at the receptors, it cannotduplicate the time course of intrasynap-tic agonist concentration required forappropriate high-frequency ganglionicactivation. The concentration of nico-tine in the synaptic cleft can neitherbuild up as rapidly as that of ACh re-leased from nerve terminals nor cannicotine be eliminated from the synap-tic cleft as quickly as ACh.

The ganglionic effects of ACh can beblocked by tetraethylammonium, hexa-methonium, and other substances (gan-glionic blockers). None of these has in-trinsic activity, that is, they fail to stim-ulate ganglia even at low concentration;some of them (e.g., hexamethonium)actually block the cholinoceptor-linkedion channel, but others (mecamyla-mine, trimethaphan) are typical recep-tor antagonists.

Certain sympathetic preganglionicneurons project without interruption tothe chromaffin cells of the adrenal me-dulla. The latter are embryologic homo-logues of ganglionic sympathocytes. Ex-citation of preganglionic fibers leads torelease of ACh in the adrenal medulla,whose chromaffin cells then respondwith a release of epinephrine into theblood (D). Small doses of nicotine, by in-ducing a partial depolarization of adre-nomedullary cells, are effective in liber-ating epinephrine (pp. 110, 112).

108 Nicotine


Nicotine 109

D. Adrenal medulla: epinephrine release by nicotine

A. Ganglionic transmission: normal state

B. Ganglionic transmission: excitation by nicotine

C. Ganglionic transmission: blockade by nicotine

-70 mV

-55 mV

-30 mV

First neuron Preganglionic Second neuron postganglionic

Acetylcholine

Impulse frequency

Persistentdepolarization

Ganglionic activation

Depolarization

Ganglionic blockade

Low concentration

High concentration

Adrenal medulla

Epinephrine

Excitation

Nicotine

Nicotine

Nicotine


Effects of Nicotine on Body Functions

At a low concentration, the tobacco al-kaloid nicotine acts as a ganglionic stim-ulant by causing a partial depolarizationvia activation of ganglionic cholinocep-tors (p. 108). A similar action is evidentat diverse other neural sites, consideredbelow in more detail.

Autonomic ganglia. Ganglionicstimulation occurs in both the sympa-thetic and parasympathetic divisions ofthe autonomic nervous system. Para-sympathetic activation results in in-creased production of gastric juice(smoking ban in peptic ulcer) and en-hanced bowel motility (“laxative” effectof the first morning cigarette: defeca-tion; diarrhea in the novice).

Although stimulation of parasym-pathetic cardioinhibitory neuronswould tend to lower heart rate, this re-sponse is overridden by the simultane-ous stimulation of sympathetic cardio-accelerant neurons and the adrenal me-dulla. Stimulation of sympatheticnerves resulting in release of norepi-nephrine gives rise to vasoconstriction;peripheral resistance rises.

Adrenal medulla. On the one hand,release of epinephrine elicits cardiovas-cular effects, such as increases in heartrate und peripheral vascular resistance.On the other, it evokes metabolic re-sponses, such as glycogenolysis and li-polysis, that generate energy-rich sub-strates. The sensation of hunger is sup-pressed. The metabolic state corre-sponds to that associated with physicalexercise – “silent stress”.

Baroreceptors. Partial depolariza-tion of baroreceptors enables activationof the reflex to occur at a relativelysmaller rise in blood pressure, leadingto decreased sympathetic vasoconstric-tor activity.

Neurohypophysis. Release of vaso-pressin (antidiuretic hormone) resultsin lowered urinary output (p. 164).Levels of vasopressin necessary for va-soconstriction will rarely be producedby nicotine.

Carotid body. Sensitivity to arterialpCO2 increases; increased afferent inputaugments respiratory rate and depth.

Receptors for pressure, tempera-ture, and pain. Sensitivity to the corre-sponding stimuli is enhanced.

Area postrema. Sensitization ofchemoceptors leads to excitation of themedullary emetic center.

At low concentration, nicotine is al-so able to augment the excitability ofthe motor endplate. This effect can bemanifested in heavy smokers in theform of muscle cramps (calf muscula-ture) and soreness.

The central nervous actions of nico-tine are thought to be mediated largelyby presynaptic receptors that facilitatetransmitter release from excitatoryaminoacidergic (glutamatergic) nerveterminals in the cerebral cortex. Nico-tine increases vigilance and the abilityto concentrate. The effect reflects an en-hanced readiness to perceive externalstimuli (attentiveness) and to respondto them.

The multiplicity of its effects makesnicotine ill-suited for therapeutic use.

110 Nicotine


Nicotine 111

A.Effects of nicotine in the body

Antidiureticeffect

Vigilance

Respiratory rate Sensitivity

Partial depolarizationof sensory nerveendings of mechano-and nociceptors

Partialdepolarization incarotid body andother ganglia

Release ofvasopressin

Partialdepolarization ofchemoreceptorsin area postrema

Partialdepolarizationof baroreceptors

Epinephrinerelease

Emetic center

EmesisPartial depolarizationof autonomic ganglia

Para-sympatheticactivity

Sympatheticactivity

DarmtätigkeitHerzfrequenzVasoconstriction

Blood pressure Defecation,diarrhea

Blood glucoseandfree fatty acids

Glycogenolysis,lipolysis,“silent stress”

Bowel motilityVasoconstriction

Nicotine


Consequences of Tobacco Smoking

The dried and cured leaves of the night-shade plant Nicotiana tabacum areknown as tobacco. Tobacco is mostlysmoked, less frequently chewed or tak-en as dry snuff. Combustion of tobaccogenerates approx. 4000 chemical com-pounds in detectable quantities. Thexenobiotic burden on the smoker de-pends on a range of parameters, includ-ing tobacco quality, presence of a filter,rate and temperature of combustion,depth of inhalation, and duration ofbreath holding.

Tobacco contains 0.2–5 % nicotine.In tobacco smoke, nicotine is present asa constituent of small tar particles. It israpidly absorbed through bronchi andlung alveoli, and is detectable in thebrain only 8 s after the first inhalation.Smoking of a single cigarette yields peakplasma levels in the range of 25–50ng/mL. The effects described on p. 110become evident. When intake stops,nicotine concentration in plasma showsan initial rapid fall, reflecting distribu-tion into tissues, and a terminal elimi-nation phase with a half-life of 2 h. Nic-otine is degraded by oxidation.

The enhanced risk of vascular dis-ease (coronary stenosis, myocardial in-farction, and central and peripheral is-chemic disorders, such as stroke andintermittent claudication) is likely to bea consequence of chronic exposure tonicotine. Endothelial impairment andhence dysfunction has been proven toresult from smoking, and nicotine isunder discussion as a factor favoringthe progression of arteriosclerosis. Byreleasing epinephrine, it elevates plas-ma levels of glucose and free fatty acidsin the absence of an immediate physio-logical need for these energy-rich me-tabolites. Furthermore, it promotesplatelet aggregability, lowers fibrinolyt-ic activity of blood, and enhances coag-ulability.

The health risks of tobacco smokingare, however, attributable not only tonicotine, but also to various other ingre-dients of tobacco smoke, some of which

possess demonstrable carcinogenicproperties.

Dust particles inhaled in tobaccosmoke, together with bronchial mucus,must be removed from the airways bythe ciliated epithelium. Ciliary activity,however, is depressed by tobaccosmoke; mucociliary transport is impair-ed. This depression favors bacterial in-fection and contributes to the chronicbronchitis associated with regularsmoking. Chronic injury to the bronchi-al mucosa could be an important causa-tive factor in increasing the risk insmokers of death from bronchial carci-noma.

Statistical surveys provide an im-pressive correlation between the num-ber of cigarettes smoked a day and therisk of death from coronary disease orlung cancer. Statistics also show that, oncessation of smoking, the increased riskof death from coronary infarction orother cardiovascular disease declinesover 5–10 years almost to the level ofnon-smokers. Similarly, the risk of de-veloping bronchial carcinoma is re-duced.

Abrupt cessation of regular smok-ing is not associated with severe physi-cal withdrawal symptoms. In general,subjects complain of increased nervous-ness, lack of concentration, and weightgain.

112 Nicotine


Nicotine 113

A. Sequelae of tobacco smoking

Nitrosamines,acrolein,polycyclichydrocarbonse. g.,benzopyreneheavy metals

Sum of noxiousstimuli

"Tar"

Nicotianatabacum

Nicotine

Number of cigarettes per day

5

4

3

2

Plateletaggregation

Epinephrine

Coronary diseaseAnnual deaths/1000 people

Bronchial carcinomaAnnual cases/1000 people

Inhibition ofmucociliarytransport

Years Months

Chronicbronchitis

BronchitisFreefatty acids

Fibrinolyticactivity

–40–20–100 >40 >4015-401–140

Ex-

smok

er

Duration ofexposure

Damage tobronchialepithelium

Damage tovascularendothelium


Biogenic Amines — Actions and Pharmacological Implications

Dopamine A. As the precursor of nore-pinephrine and epinephrine (p. 184),dopamine is found in sympathetic (adre-nergic) neurons and adrenomedullarycells. In the CNS, dopamine itself servesas a neuromediator and is implicated inneostriatal motor programming (p. 188),the elicitation of emesis at the level ofthe area postrema (p. 330), and inhibi-tion of prolactin release from the anteri-or pituitary (p. 242).Dopamine receptors are coupled to G-proteins and exist as different subtypes.D1-receptors (comprising subtypes D1

and D5) and D2-receptors (comprisingsubtypes D2, D3, and D4). The aforemen-tioned actions are mediated mainly byD2 receptors. When given by infusion,dopamine causes dilation of renal andsplanchnic arteries. This effect is mediat-ed by D1 receptors and is utilized in thetreatment of cardiovascular shock andhypertensive emergencies by infusion ofdopamine and fenoldopam, respective-ly. At higher doses, β1-adrenoceptorsand, finally, α-receptors are activated, asevidenced by cardiac stimulation andvasoconstriction, respectively.Dopamine is not to be confused with do-butamine which stimulates α- and β-ad-renoceptors but not dopamine receptors(p. 62).

Dopamine-mimetics. Administra-tion of the precursor L-dopa promotesendogenous synthesis of dopamine (in-dication: parkinsonian syndrome,p. 188). The ergolides, bromocriptine,pergolide, and lisuride, are ligands at D-receptors whose therapeutic effects areprobably due to stimulation of D2 recep-tors (indications: parkinsonism, sup-pression of lactation, infertility, acrome-galy, p. 242). Typical adverse effects ofthese substances are nausea and vomit-ing. As indirect dopamine-mimetics, (+)-amphetamine and ritaline augment do-pamine release.

Inhibition of the enzymes involvedin dopamine degradation, catechol-amine-oxygen-methyl-transferase

(COMT) and monoamineoxidase (MAO),is another means to increase actualavailable dopamine concentration(COMT-inhibitors, p. 188), MAOB-inhibi-tors, p. 88, 188).

Dopamine antagonist activity is thehallmark of classical neuroleptics. Theantihypertensive agents, reserpine (ob-solete) and α-methyldopa, deplete neu-ronal stores of the amine. A common ad-verse effect of dopamine antagonists ordepletors is parkinsonism.

Histamine (B). Histamine is storedin basophils and tissue mast cells. Itplays a role in inflammatory and allergicreactions (p. 72, 326) and producesbronchoconstriction, increased intesti-nal peristalsis, and dilation and in-creased permeability of small blood ves-sels. In the gastric mucosa, it is releasedfrom enterochromaffin-like cells andstimulates acid secretion by the parietalcells. In the CNS, it acts as a neuromod-ulator. Two receptor subtypes (G-pro-tein-coupled), H1 and H2, are of thera-peutic importance; both mediate vascu-lar responses. Prejunctional H3 recep-tors exist in brain and the periphery.

Antagonists. Most of the so-calledH1-antihistamines also block other re-ceptors, including M-cholinoceptors andD-receptors. H1-antihistamines are usedfor the symptomatic relief of allergies(e.g., bamipine, chlorpheniramine, cle-mastine, dimethindene, mebhydrolinepheniramine); as antiemetics (mecli-zine, dimenhydrinate, p. 330), as over-the-counter hypnotics (e.g., diphenhy-dramine, p. 222). Promethazine repre-sents the transition to the neurolepticphenothiazines (p. 236). Unwanted ef-fects of most H1-antihistamines are las-situde (impaired driving skills) and atro-pine-like reactions (e.g., dry mouth, con-stipation). At the usual therapeutic dos-es, astemizole, cetrizine, fexofenadine,and loratidine are practically devoid ofsedative and anticholinergic effects. H2-antihistamines (cimetidine, ranitidine,famotidine, nizatidine) inhibit gastricacid secretion, and thus are useful in thetreatment of peptic ulcers.

114 Biogenic Amines


Biogenic Amines 115

A. Dopamine actions as influenced by drugs

“H1-Antihistamines”ChlorpromazineDiphenhydramine

DopamineAcetylcholine

mACh-Receptor Dopamine receptors

Sedation,hypnotic,antiemeticaction

H2-ReceptorsH1-Receptors

H2-Antagonistse.g., ranitidine

H1-Antagonistse.g., fexofenadine

Histamine

D2-Agonistse.g., bromocriptine

Dopamin

Receptors

Dopamine

Dopaminergic neuron

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

D1

BronchoconstrictionHCl

Parietal cell

VasodilationpermeabilityBowel peristalsis

D2-Antagonistse.g., metoclopramide

D1/D2-AntagonistsNeuroleptics

D2

Inhibition of synthesis and formationof false transmitter: MethyldopaDestruction of storage vesicles: Reserpine

Increase in dopamine synthesisL-Dopa

B. Histamine actions as influenced by drugs

D1-Agonistse.g., fenoldopam

Bloodflow


Inhibitors of histamine release: Oneof the effects of the so-called mast cellstabilizers cromoglycate (cromolyn)and nedocromil is to decrease the re-lease of histamine from mast cells (p.72, 326). Both agents are applied topi-cally. Release of mast cell mediators canalso be inhibited by some H1 antihista-mines, e.g., oxatomide and ketotifen,which are used systemically.

SerotoninOccurrence. Serotonin (5-hydroxytrypt-amine, 5-HT) is synthesized from L-tryptophan in enterochromaffin cells ofthe intestinal mucosa. 5-HT-synthesiz-ing neurons occur in the enteric nerveplexus and the CNS, where the aminefulfills a neuromediator function. Bloodplatelets are unable to synthesize 5HT,but are capable of taking up, storing,and releasing it.

Serotonin receptors. Based on bio-chemical and pharmacological criteria,seven receptor classes can be distin-guished. Of major pharmacotherapeuticimportance are those designated 5-HT1,5-HT2, 5-HT4, and 5-HT7, all of which areG-protein-coupled, whereas the 5-HT3

subtype represents a ligand-gated non-selective cation channel.

Serotonin actions. The cardiovascu-lar effects of 5-HT are complex, becausemultiple, in part opposing, effects areexerted via the different receptor sub-types. Thus, 5-HT2A and 5-HT7 receptorson vascular smooth muscle cells medi-ate direct vasoconstriction and vasodi-lation, respectively. Vasodilation andlowering of blood pressure can also oc-cur by several indirect mechanisms: 5-HT1A receptors mediate sympathoinhi-bition (� decrease in neurogenic vaso-constrictor tonus) both centrally andperipherally; 5-HT2B receptors on vas-cular endothelium promote release ofvasorelaxant mediators (NO, p. 120;prostacyclin, p. 196) 5-HT released fromplatelets plays a role in thrombogenesis,hemostasis, and the pathogenesis ofpreeclamptic hypertension.

Ketanserin is an antagonist at 5-HT2A receptors and produces antihyper-tensive effects, as well as inhibition ofthrombocyte aggregation. Whether 5-HT antagonism accounts for its antihy-pertensive effect remains questionable,because ketanserin also blocks α-adren-oceptors.

Sumatriptan and other triptans areantimigraine drugs that possess agonistactivity at 5-HT1 receptors of the B, Dand F subtypes and may thereby allevi-ate this type of headache (p. 322).

Gastrointestinal tract. Serotoninreleased from myenteric neurons or en-terochromaffin cells acts on 5-HT3 and5-HT4 receptors to enhance bowel mo-tility and enteral fluid secretion. Cisa-pride is a prokinetic agent that pro-motes propulsive motor activity in thestomach and in small and large intes-tines. It is used in motility disorders. Itsmechanism of action is unclear, butstimulation of 5HT4 receptors may beimportant.

Central Nervous System. Serotoni-nergic neurons play a part in variousbrain functions, as evidenced by the ef-fects of drugs likely to interfere with se-rotonin. Fluoxetine is an antidepressantthat, by blocking re-uptake, inhibits in-activation of released serotonin. Its ac-tivity spectrum includes significant psy-chomotor stimulation, depression of ap-petite, and anxiolysis. Buspirone also hasanxiolytic properties thought to be me-diated by central presynaptic 5-HT1A re-ceptors. Ondansetron, an antagonist atthe 5-HT3 receptor, possesses strikingeffectiveness against cytotoxic drug-in-duced emesis, evident both at the startof and during cytostatic therapy. Trop-isetron and granisetron produce analo-gous effects.

Psychedelics (LSD) and other psy-chotomimetics such as mescaline andpsilocybin can induce states of alteredawareness, or induce hallucinations andanxiety, probably mediated by 5-HT2A

receptors. Overactivity of these recep-tors may also play a role in the genesisof negative symptoms in schizophrenia(p. 238) and sleep disturbances.

116 Biogenic Amines


Biogenic Amines 117

A. Serotonin receptors and actions

LSDLysergic acid diethylamide

Psychedelic

5-HT1D

5-H

T 3

5-HT1A

5-H

T 2A

Serotoninergic neuron

Ondansetron

Antiemetic

Buspirone

Anxiolytic

Fluoxetine5-HT- reuptakeinhibitor

Antidepressant

Sumatriptan

Antimigraine

Propulsivemotility

Entero-chrom-affincell

Cisapride

Prokinetic

5-HT2B

PlateletsConstriction

Endothelium-mediated Dilation

5-H

T 2

5-HT4

Hallucination

Emesis

Blood vessel Intestine

5-Hydroxy-tryptamine

Serotonin


Vasodilators–Overview

The distribution of blood within the cir-culation is a function of vascular caliber.Venous tone regulates the volume ofblood returned to the heart, hence,stroke volume and cardiac output. Theluminal diameter of the arterial vascula-ture determines peripheral resistance.Cardiac output and peripheral resis-tance are prime determinants of arterialblood pressure (p. 314).

In A, the clinically most importantvasodilators are presented in the orderof approximate frequency of therapeu-tic use. Some of these agents possessdifferent efficacy in affecting the venousand arterial limbs of the circulation(width of beam).

Possible uses. Arteriolar vasodila-tors are given to lower blood pressure inhypertension (p. 312), to reduce cardiacwork in angina pectoris (p. 308), and toreduce ventricular afterload (pressureload) in cardiac failure (p. 132). Venousvasodilators are used to reduce venousfilling pressure (preload) in angina pec-toris (p. 308) or cardiac failure (p. 132).Practical uses are indicated for eachdrug group.

Counter-regulation in acute hy-potension due to vasodilators (B). In-creased sympathetic drive raises heartrate (reflex tachycardia) and cardiacoutput and thus helps to elevate bloodpressure. Patients experience palpita-tions. Activation of the renin-angioten-sin-aldosterone (RAA) system serves toincrease blood volume, hence cardiacoutput. Fluid retention leads to an in-crease in body weight and, possibly,edemas. These counter-regulatory pro-cesses are susceptible to pharmacologi-cal inhibition (β-blockers, ACE inhibi-tors, AT1-antagonists, diuretics).

Mechanisms of action. The tonusof vascular smooth muscle can be de-creased by various means. ACE inhibi-tors, antagonists at AT1-receptors andantagonists at α-adrenoceptors protectagainst the effects of excitatory media-tors such as angiotensin II and norepi-nephrine, respectively. Prostacyclin an-

alogues such as iloprost, or prostaglan-din E1 analogues such as alprostanil,mimic the actions of relaxant mediators.Ca2+ antagonists reduce depolarizing in-ward Ca2+ currents, while K+-channel ac-tivators promote outward (hyperpolar-izing) K+ currents. Organic nitrovasodi-lators give rise to NO, an endogenousactivator of guanylate cyclase.

Individual vasodilators. Nitrates(p. 120) Ca2+-antagonists (p. 122). α1-antagonists (p. 90), ACE-inhibitors, AT1-antagonists (p. 124); and sodium nitro-prusside (p. 120) are discussed else-where.

Dihydralazine and minoxidil (viaits sulfate-conjugated metabolite) dilatearterioles and are used in antihyperten-sive therapy. They are, however, unsuit-able for monotherapy because of com-pensatory circulatory reflexes. Themechanism of action of dihydralazine isunclear. Minoxidil probably activates K+

channels, leading to hyperpolarizationof smooth muscle cells. Particular ad-verse reactions are lupus erythemato-sus with dihydralazine and hirsutismwith minoxidil—used topically for thetreatment of baldness (alopecia androg-enetica).

Diazoxide given i.v. causes promi-nent arteriolar dilation; it can be em-ployed in hypertensive crises. After itsoral administration, insulin secretion isinhibited. Accordingly, diazoxide can beused in the management of insulin-se-creting pancreatic tumors. Both effectsare probably due to opening of (ATP-gated) K+ channels.

The methylxanthine theophylline(p. 326), the phosphodiesterase inhibi-tor amrinone (p. 132), prostacyclins (p.197), and nicotinic acid derivatives (p.156) also possess vasodilating activity.

118 Vasodilators


Vasodilators 119

B. Counter-regulatory responses in hypotension due to vasodilators

A. Vasodilators

Nitroprusside sodium

α1-Antagonists

ACE-inhibitors

Nitrates

Dihydralazine

Minoxidil

Ca-antagonists

Venous bed Vasodilation Arterial bed

β-Blocker

ACE-inhibitors

Angiotensin-convertingenzyme(ACE)

Vasomotorcenter

VasodilationBloodpressure

Blood-pressure

Angiotensin II

Angiotensinogen Aldosterone

Vasoconstriction

Vasoconstriction

Angiotensin I

Cardiacoutput

Blood volume

Heart rate

Sympathetic nerves

Renin-angiotensin-aldosterone-system

Renin


Organic Nitrates

Various esters of nitric acid (HNO3) andpolyvalent alcohols relax vascularsmooth muscle, e.g., nitroglycerin (gly-ceryltrinitrate) and isosorbide dinitrate.The effect is more pronounced in venousthan in arterial beds.

These vasodilator effects producehemodynamic consequences that canbe put to therapeutic use. Due to a de-crease in both venous return (preload)and arterial afterload, cardiac work isdecreased (p. 308). As a result, the car-diac oxygen balance improves. Spas-modic constriction of larger coronaryvessels (coronary spasm) is prevented.

Uses. Organic nitrates are usedchiefly in angina pectoris (p. 308, 310),less frequently in severe forms of chron-ic and acute congestive heart failure.Continuous intake of higher doses withmaintenance of steady plasma levelsleads to loss of efficacy, inasmuch as theorganism becomes refractory (tachy-phylactic). This “nitrate tolerance” canbe avoided if a daily “nitrate-free inter-val” is maintained, e.g., overnight.

At the start of therapy, unwantedreactions occur frequently in the formof a throbbing headache, probablycaused by dilation of cephalic vessels.This effect also exhibits tolerance, evenwhen daily “nitrate pauses” are kept.Excessive dosages give rise to hypoten-sion, reflex tachycardia, and circulatorycollapse.

Mechanism of action. The reduc-tion in vascular smooth muscle tone ispresumably due to activation of guany-late cyclase and elevation of cyclic GMPlevels. The causative agent is most likelynitric oxide (NO) generated from the or-ganic nitrate. NO is a physiological mes-senger molecule that endothelial cellsrelease onto subjacent smooth musclecells (“endothelium-derived relaxingfactor,” EDRF). Organic nitrates wouldthus utilize a pre-existing pathway,hence their high efficacy. The genera-tion of NO within the smooth musclecell depends on a supply of free sulfhy-dryl (-SH) groups; “nitrate-tolerance”

has been attributed to a cellular exhaus-tion of SH-donors but this may be notthe only reason.

Nitroglycerin (NTG) is distin-guished by high membrane penetrabil-ity and very low stability. It is the drugof choice in the treatment of angina pec-toris attacks. For this purpose, it is ad-ministered as a spray, or in sublingual orbuccal tablets for transmucosal deliv-ery. The onset of action is between 1 and3 min. Due to a nearly complete pre-systemic elimination, it is poorly suitedfor oral administration. Transdermal de-livery (nitroglycerin patch) also avoidspresystemic elimination. Isosorbidedinitrate (ISDN) penetrates wellthrough membranes, is more stablethan NTG, and is partly degraded intothe weaker, but much longer acting, 5-isosorbide mononitrate (ISMN). ISDNcan also be applied sublingually; how-ever, it is mainly administered orally inorder to achieve a prolonged effect.ISMN is not suitable for sublingual usebecause of its higher polarity and slowerrate of absorption. Taken orally, it is ab-sorbed and is not subject to first-passelimination.

Molsidomine itself is inactive. Af-ter oral intake, it is slowly convertedinto an active metabolite. Apparently,there is little likelihood of "nitrate tole-rance”.

Sodium nitroprusside contains anitroso (-NO) group, but is not an ester.It dilates venous and arterial bedsequally. It is administered by infusion toachieve controlled hypotension undercontinuous close monitoring. Cyanideions liberated from nitroprusside can beinactivated with sodium thiosulfate(Na2S2O3) (p. 304).

120 Vasodilators


Vasodilators 121

5-Isosorbide mononitrate,an active metabolitet1

2~ 240 min

A. Vasodilators: Nitrates

“Nitrate-tolerance”

t12~ 30 mint1

2~ 2 min NONO

Inactivation

Route:e.g., sublingual,transdermal

Glyceryl trinitrateNitroglycerin

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

Isosorbide dinitrate

Blood pressure

Prevention ofcoronary arteryspasm

PreloadO2-supply

AfterloadO2-demand

Venous blood returnto heart

Venous bed Arterial bed

Vasodilation

“Nitrates”

Peripheralresistance

Consumption

R – O – NO2

Release ofNO

Activation ofguanylate cyclase

GTP cGMP

RelaxationSmooth muscle cell

SH-donorse.g., glutathione

Activemetabolite

Molsidomine(precursor)


Calcium Antagonists

During electrical excitation of the cellmembrane of heart or smooth muscle,different ionic currents are activated,including an inward Ca2+ current. Theterm Ca2+ antagonist is applied to drugsthat inhibit the influx of Ca2+ ions with-out affecting inward Na+ or outward K+

currents to a significant degree. Otherlabels are Ca-entry blocker or Ca-channelblocker. Therapeutically used Ca2+ an-tagonists can be divided into threegroups according to their effects onheart and vasculature.

I. Dihydropyridine derivatives.The dihydropyridines, e.g., nifedipine,are uncharged hydrophobic substances.They induce a relaxation of vascularsmooth muscle in arterial beds. An effecton cardiac function is practically absentat therapeutic dosage. (However, inpharmacological experiments on isolat-ed cardiac muscle preparations a clearnegative inotropic effect is demon-strable.) They are thus regarded as va-soselective Ca2+ antagonists. Because ofthe dilatation of resistance vessels,blood pressure falls. Cardiac afterload isdiminished (p. 306) and, therefore, alsooxygen demand. Spasms of coronary ar-teries are prevented.

Indications for nifedipine includeangina pectoris (p. 308) and, — when ap-plied as a sustained release preparation,— hypertension (p. 312). In angina pec-toris, it is effective when given eitherprophylactically or during acute attacks.Adverse effects are palpitation (reflextachycardia due to hypotension), head-ache, and pretibial edema.

Nitrendipine and felodipine are usedin the treatment of hypertension. Ni-modipine is given prophylactically aftersubarachnoidal hemorrhage to preventvasospasms due to depolarization byexcess K+ liberated from disintegratingerythrocytes or blockade of NO by freehemoglobin.

II. Verapamil and other catamphi-philic Ca2+ antagonists. Verapamil con-tains a nitrogen atom bearing a positivecharge at physiological pH and thus rep-

resents a cationic amphiphilic molecule.It exerts inhibitory effects not only onarterial smooth muscle, but also on heartmuscle. In the heart, Ca2+ inward cur-rents are important in generating depo-larization of sinoatrial node cells (im-pulse generation), in impulse propaga-tion through the AV- junction (atrioven-tricular conduction), and in electrome-chanical coupling in the ventricular car-diomyocytes. Verapamil thus producesnegative chrono-, dromo-, and inotropiceffects.

Indications. Verapamil is used asan antiarrhythmic drug in supraventric-ular tachyarrhythmias. In atrial flutteror fibrillation, it is effective in reducingventricular rate by virtue of inhibitingAV-conduction. Verapamil is also em-ployed in the prophylaxis of angina pec-toris attacks (p. 308) and the treatmentof hypertension (p. 312). Adverse ef-fects: Because of verapamil’s effects onthe sinus node, a drop in blood pressurefails to evoke a reflex tachycardia. Heartrate hardly changes; bradycardia mayeven develop. AV-block and myocardialinsufficiency can occur. Patients fre-quently complain of constipation.

Gallopamil (= methoxyverapamil) isclosely related to verapamil in bothstructure and biological activity.

Diltiazem is a catamphiphilic ben-zothiazepine derivative with an activityprofile resembling that of verapamil.

III. T-channel selective blockers.Ca2+-channel blockers, such as verapa-mil and mibefradil, may block both L-and T-type Ca2+ channels. Mibefradilshows relative selectivity for the latterand is devoid of a negative inotropic ef-fect; its therapeutic usefulness is com-promised by numerous interactionswith other drugs due to inhibition of cy-tochrome P450-dependent enzymes(CYP 1A2, 2D6 and, especially, 3A4).

122 Vasodilators


Vasodilators 123

A.Vasodilators: calcium antagonists

Smooth muscle cell

Ca2+

Arterialblood vessel

Nifedipine(dihydropyridine derivative)

Mem

bra

ne d

epol

ariz

atio

n

Na+ Ca2+10-3M

K+Ca2+10-7M

Verapamil(cationic amphiphilic)

Electro-mechanicalcoupling

Impulseconduction

Impulsegeneration

Inhibition ofcoronary spasm


Contraction

AfterloadO2-demand

Blood pressure

Vasodilation in arterial bed

Selectiveinhibition ofcalcium influx

Sinus node

Ventricularmuscle

AV-node

Contractility

AV-conduction

Heart rateReflex tachy-cardia with nifedipine

Heart muscle cell

Ca2+

Inhibition of cardiac functions


Inhibitors of the RAA System

Angiotensin-converting enzyme (ACE)is a component of the antihypotensiverenin-angiotensin-aldosterone (RAA)system. Renin is produced by special-ized cells in the wall of the afferent ar-teriole of the renal glomerulus. Thesecells belong to the juxtaglomerular ap-paratus of the nephron, the site of con-tact between afferent arteriole and dis-tal tubule, and play an important part incontrolling nephron function. Stimulieliciting release of renin are: a drop inrenal perfusion pressure, decreased rateof delivery of Na+ or Cl– to the distal tu-bules, as well as β-adrenoceptor-medi-ated sympathoactivation. The glycopro-tein renin enzymatically cleaves thedecapeptide angiotensin I from its cir-culating precursor substrate angiotensi-nogen. ACE, in turn, produces biologi-cally active angiotensin II (ANG II) fromangiotensin I (ANG I).

ACE is a rather nonspecific pepti-dase that can cleave C-terminal dipep-tides from various peptides (dipeptidylcarboxypeptidase). As “kininase II,” itcontributes to the inactivation of kinins,such as bradykinin. ACE is also present inblood plasma; however, enzyme local-ized in the luminal side of vascular endo-thelium is primarily responsible for theformation of angiotensin II. The lung isrich in ACE, but kidneys, heart, and otherorgans also contain the enzyme.

Angiotensin II can raise blood pres-sure in different ways, including (1)vasoconstriction in both the arterial andvenous limbs of the circulation; (2)stimulation of aldosterone secretion,leading to increased renal reabsorptionof NaCl and water, hence an increasedblood volume; (3) a central increase insympathotonus and, peripherally, en-hancement of the release and effects ofnorepinephrine.

ACE inhibitors, such as captopriland enalaprilat, the active metabolite ofenalapril, occupy the enzyme as falsesubstrates. Affinity significantly influ-ences efficacy and rate of elimination.Enalaprilat has a stronger and longer-

lasting effect than does captopril. Indi-cations are hypertension and cardiacfailure.

Lowering of an elevated blood pres-sure is predominantly brought about bydiminished production of angiotensin II.Impaired degradation of kinins that ex-ert vasodilating actions may contributeto the effect.

In heart failure, cardiac output risesagain because ventricular afterload di-minishes due to a fall in peripheral re-sistance. Venous congestion abates as aresult of (1) increased cardiac outputand (2) reduction in venous return (de-creased aldosterone secretion, de-creased tonus of venous capacitancevessels).

Undesired effects. The magnitudeof the antihypertensive effect of ACE in-hibitors depends on the functional stateof the RAA system. When the latter hasbeen activated by loss of electrolytesand water (resulting from treatmentwith diuretic drugs), cardiac failure, orrenal arterial stenosis, administration ofACE inhibitors may initially cause an ex-cessive fall in blood pressure. In renalarterial stenosis, the RAA system may beneeded for maintaining renal functionand ACE inhibitors may precipitate re-nal failure. Dry cough is a fairly frequentside effect, possibly caused by reducedinactivation of kinins in the bronchialmucosa. Rarely, disturbances of tastesensation, exanthema, neutropenia,proteinuria, and angioneurotic edemamay occur. In most cases, ACE inhibitorsare well tolerated and effective. Neweranalogues include lisinopril, perindo-pril, ramipril, quinapril, fosinopril, be-nazepril, cilazapril, and trandolapril.

Antagonists at angiotensin II re-ceptors. Two receptor subtypes can bedistinguished: AT1, which mediates theabove actions of AT II; and AT2, whosephysiological role is still unclear. Thesartans (candesartan, eprosartan, irbe-sartan, losartan, and valsartan) are AT1antagonists that reliably lower highblood pressure. They do not inhibitdegradation of kinins and cough is not afrequent side-effect.

124 Inhibitors of the RAA System


Inhibitors of the RAA System 125

Renin

A. Renin-angiotensin-aldosterone system and inhibitors

Kidney

Angiotensin I (Ang I)COOH

ACE inhibitors

Captopril

Enalaprilat Enalapril

Ang I Kinins

Ang II Degradationproducts

Vascularendothelium

H2N

Resistance vessels

K+

Angiotensinogen(α2-globulin)

RR

Vasoconstriction

Cardiacoutput

venouscapacitancevessels

Sympatho-activationH2O

NaCl

Arterialbloodpressure

Venoussupply


ACE

Kininase II

ACEAngiotensin I-converting-enzyme

Dipep

tidyl-

Carbo

xype

ptid

ase

Losartan

Receptors

Aldosteronesecretion

AT1-receptor antagonists

Angiotensin IIN N

Cl

HNN

N N

H3C

CH2OH

O O

O

N

HOOC

CH3CH3

HOOC

N

O

SH

CH3


Drugs Used to Influence Smooth MuscleOrgans

Bronchodilators. Narrowing of bron-chioles raises airway resistance, e.g., inbronchial or bronchitic asthma. Severalsubstances that are employed as bron-chodilators are described elsewhere inmore detail: β2-sympathomimetics (p.84, given by pulmonary, parenteral, ororal route), the methylxanthine theo-phylline (p. 326, given parenterally ororally), as well as the parasympatholyticipratropium (pp. 104, 107, given by in-halation).

Spasmolytics. N-Butylscopolamine(p. 104) is used for the relief of painfulspasms of the biliary or ureteral ducts.Its poor absorption (N.B. quaternary N;absorption rate <10%) necessitates par-enteral administration. Because thetherapeutic effect is usually weak, a po-tent analgesic is given concurrently, e.g.,the opioid meperidine. Note that somespasms of intestinal musculature can beeffectively relieved by organic nitrates(in biliary colic) or by nifedipine (esoph-ageal hypertension and achalasia).

Myometrial relaxants (Tocolyt-ics). β2-Sympathomimetics such as fe-noterol or ritodrine, given orally or par-enterally, can prevent premature laboror interrupt labor in progress when dan-gerous complications necessitate cesar-ean section. Tachycardia is a side effectproduced reflexly because of β2-mediat-ed vasodilation or direct stimulation ofcardiac β1-receptors. Magnesium sul-fate, given i.v., is a useful alternativewhen β-mimetics are contraindicated,but must be carefully titrated becauseits nonspecific calcium antagonismleads to blockade of cardiac impulseconduction and of neuromusculartransmission.

Myometrial stimulants. The neu-rohypophyseal hormone oxytocin (p.242) is given parenterally (or by the na-sal or buccal route) before, during, or af-ter labor in order to prompt uterine con-tractions or to enhance them. Certainprostaglandins or analogues of them (p.

196; F2α: dinoprost; E2: dinoprostone,misoprostol, sulprostone) are capable ofinducing rhythmic uterine contractionsand cervical relaxation at any time. Theyare mostly employed as abortifacients(oral or vaginal application of misopros-tol in combination with mifepristone [p.256]).

Ergot alkaloids are obtained fromSecale cornutum (ergot), the sclerotiumof a fungus (Claviceps purpurea) parasi-tizing rye. Consumption of flour fromcontaminated grain was once the causeof epidemic poisonings (ergotism) char-acterized by gangrene of the extremities(St. Anthony’s fire) and CNS disturbanc-es (hallucinations).

Ergot alkaloids contain lysergic acid(formula in A shows an amide). They acton uterine and vascular muscle. Ergo-metrine particularly stimulates the uter-us. It readily induces a tonic contractionof the myometrium (tetanus uteri). Thisjeopardizes placental blood flow and fe-tal O2 supply. The semisynthetic deriva-tive methylergometrine is thereforeused only after delivery for uterine con-tractions that are too weak.

Ergotamine, as well as the ergotox-ine alkaloids (ergocristine, ergocryp-tine, ergocornine), have a predominant-ly vascular action. Depending on the in-itial caliber, constriction or dilation maybe elicited. The mechanism of action isunclear; a mixed antagonism at α-adrenoceptors and agonism at 5-HT-re-ceptors may be important. Ergotamineis used in the treatment of migraine (p.322). Its congener, dihydroergotamine,is furthermore employed in orthostaticcomplaints (p. 314).

Other lysergic acid derivatives arethe 5-HT antagonist methysergide, thedopamine agonists bromocriptine, per-golide, and cabergolide (pp. 114, 188),and the hallucinogen lysergic acid di-ethylamide (LSD, p. 240).

126 Drugs Acting on Smooth Muscle


Drugs Acting on Smooth Muscle 127

A. Drugs used to alter smooth muscle function

Bronchial asthma

Bronchodilation Spasmolysis

Theophylline N-Butylscopolamine

Scopolamine

Biliary / renal colic

Inhibition of labor

Induction of labor

Oxytocin

ProstaglandinsF2α, E2

Nitratese.g., nitroglycerin

β2-Sympathomimeticse.g., fenoterol

Ipratropium

Secale cornutum(ergot)

Fungus:Claviceps purpurea

e.g., ergometrine

Contraindication:before delivery

Indication:postpartumuterine atonia

e.g., ergotamine

O2

O2

Tonic contraction of uterus

β2-Sympathomimetics

Effect onvasomotor tone

Secale alkaloids

Spasm ofsmooth muscle

Fixation of lumen at intemediate caliber


Overview of Modes of Action (A)

1. The pumping capacity of the heart isregulated by sympathetic and parasym-pathetic nerves (pp. 84, 105). Drugs ca-pable of interfering with autonomicnervous function therefore provide ameans of influencing cardiac perfor-mance. Thus, anxiolytics of the benzo-diazepine type (p. 226), such as diaze-pam, can be employed in myocardial in-farction to suppress sympathoactiva-tion due to life-threatening distress.Under the influence of antiadrenergicagents (p. 96), used to lower an elevatedblood pressure, cardiac work is de-creased. Ganglionic blockers (p. 108)are used in managing hypertensiveemergencies. Parasympatholytics (p.104) and β-blockers (p. 92) prevent thetransmission of autonomic nerve im-pulses to heart muscle cells by blockingthe respective receptors.

2. An isolated mammalian heartwhose extrinsic nervous connectionshave been severed will beat spontane-ously for hours if it is supplied with anutrient medium via the aortic trunkand coronary arteries (Langendorffpreparation). In such a preparation, onlythose drugs that act directly on cardio-myocytes will alter contractile force andbeating rate.

Parasympathomimetics and sym-pathomimetics act at membrane re-ceptors for visceromotor neurotrans-mitters. The plasmalemma also harborsthe sites of action of cardiac glycosides(the Na/K-ATPases, p. 130), of Ca2+ an-tagonists (Ca2+ channels, p. 122), and ofagents that block Na+ channels (localanesthetics; p. 134, p. 204). An intracel-lular site is the target for phosphodies-terase inhibitors (e.g., amrinone, p. 132).

3. Mention should also be made ofthe possibility of affecting cardiac func-tion in angina pectoris (p. 306) or con-gestive heart failure (p. 132) by reduc-ing venous return, peripheral resis-tance, or both, with the aid of vasodila-tors; and by reducing sympathetic driveapplying β-blockers.

Events Underlying Contraction andRelaxation (B)

The signal triggering contraction is apropagated action potential (AP) gener-ated in the sinoatrial node. Depolariza-tion of the plasmalemma leads to a rap-id rise in cytosolic Ca2+ levels, whichcauses the contractile filaments toshorten (electromechanical coupling).The level of Ca2+ concentration attaineddetermines the degree of shortening,i.e., the force of contraction. Sources ofCa2+ are: a) extracellular Ca2+ enteringthe cell through voltage-gated Ca2+

channels; b) Ca2+ stored in membranoussacs of the sarcoplasmic reticulum (SR);c) Ca2+ bound to the inside of the plas-malemma. The plasmalemma of cardio-myocytes extends into the cell interiorin the form of tubular invaginations(transverse tubuli).

The trigger signal for relaxation isthe return of the membrane potential toits resting level. During repolarization,Ca2+ levels fall below the threshold foractivation of the myofilaments (3�10–7

M), as the plasmalemmal binding sitesregain their binding capacity; the SRpumps Ca2+ into its interior; and Ca2+

that entered the cytosol during systoleis again extruded by plasmalemmalCa2+-ATPases with expenditure of ener-gy. In addition, a carrier (antiporter),utilizing the transmembrane Na+ gradi-ent as energy source, transports Ca2+ outof the cell in exchange for Na+ movingdown its transmembrane gradient(Na+/Ca2+ exchange).

128 Cardiac Drugs


Cardiac Drugs 129

Relaxation Ca2+ 10-3M

B. Processes in myocardial contraction and relaxation

A. Possible mechanisms for influencing heart function

Drugs withindirect action

Drugs with direct actionNutrient solution

Force

Rate

β-SympathomimeticsPhosphodiesterase inhibitorsCardiac

glycosides

ParasympathomimeticsCatamphiphilicCa-antagonistsLocal anesthetics

Na+

Ca-ATPase

300 ms

Para-sympathetic

Sympathetic

Epinephrine

Psychotropicdrugs

Sympatholytics

Ganglionicblockers

Force Rate

Contraction

electricalexcitation

Ca-channelSarcoplasmicreticulum

Heart muscle cell

Transversetubule

Ca2+ 10-3M

Ca2+

10-5M

Ca2+

10-7M

Ca2+Na+

Ca2+

Na+

Ca2+

Na/Ca-exchange

Plasma-lemmalbinding sites

0

-80

Membrane potential[mV]

t

Force

t

Contraction

Action potential


Cardiac Glycosides

Diverse plants (A) are sources of sugar-containing compounds (glycosides) thatalso contain a steroid ring (structuralformulas, p. 133) and augment the con-tractile force of heart muscle (B): cardio-tonic glycosides. cardiosteroids, or “digi-talis.”

If the inotropic, “therapeutic” doseis exceeded by a small increment, signsof poisoning appear: arrhythmia andcontracture (B). The narrow therapeuticmargin can be explained by the mecha-nism of action.

Cardiac glycosides (CG) bind to theextracellular side of Na+/K+-ATPases ofcardiomyocytes and inhibit enzyme ac-tivity. The Na+/K+-ATPases operate topump out Na+ leaked into the cell and toretrieve K+ leaked from the cell. In thismanner, they maintain the transmem-brane gradients for K+ and Na+, the neg-ative resting membrane potential, andthe normal electrical excitability of thecell membrane. When part of the en-zyme is occupied and inhibited by CG,the unoccupied remainder can increaseits level of activity and maintain Na+ andK+ transport. The effective stimulus is asmall elevation of intracellular Na+ con-centration (normally approx. 7 mM).Concomitantly, the amount of Ca2+ mo-bilized during systole and, thus, con-tractile force, increases. It is generallythought that the underlying cause is thedecrease in the Na+ transmembranegradient, i.e., the driving force for theNa+/Ca2+ exchange (p. 128), allowing theintracellular Ca2+ level to rise. When toomany ATPases are blocked, K+ and Na+

homeostasis is deranged; the mem-brane potential falls, arrhythmias occur.Flooding with Ca2+ prevents relaxationduring diastole, resulting in contracture.

The CNS effects of CG (C) are alsodue to binding to Na+/K+-ATPases. En-hanced vagal nerve activity causes a de-crease in sinoatrial beating rate and ve-locity of atrioventricular conduction. Inpatients with heart failure, improvedcirculation also contributes to the re-duction in heart rate. Stimulation of the

area postrema leads to nausea and vom-iting. Disturbances in color vision areevident.

Indications for CG are: (1) chroniccongestive heart failure; and (2) atrialfibrillation or flutter, where inhibition ofAV conduction protects the ventriclesfrom excessive atrial impulse activityand thereby improves cardiac perfor-mance (D). Occasionally, sinus rhythmis restored.

Signs of intoxication are: (1) car-diac arrhythmias, which under certaincircumstances are life-threatening, e.g.,sinus bradycardia, AV-block, ventricularextrasystoles, ventricular fibrillation(ECG); (2) CNS disturbances — alteredcolor vision (xanthopsia), agitation,confusion, nightmares, hallucinations;(3) gastrointestinal — anorexia, nausea,vomiting, diarrhea; (4) renal — loss ofelectrolytes and water, which must bedifferentiated from mobilization of ac-cumulated edema fluid that occurs withtherapeutic dosage.

Therapy of intoxication: adminis-tration of K+, which inter alia reducesbinding of CG, but may impair AV-con-duction; administration of antiarrhyth-mics, such as phenytoin or lidocaine (p.136); oral administration of colestyra-mine (p. 154, 156) for binding and pre-venting absorption of digitoxin presentin the intestines (enterohepatic cycle);injection of antibody (Fab) fragmentsthat bind and inactivate digitoxin anddigoxin. Compared with full antibodies,fragments have superior tissue penet-rability, more rapid renal elimination,and lower antigenicity.

130 Cardiac Drugs


Cardiac Drugs 131

C. Cardiac glycoside effects on the CNS

A. Plants containing cardiac glycosides

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

Digitalis purpureaRed foxglove

ConvallariamajalisLily of the valley

Helleborus nigerChristmas rose

Con

trac

tion

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

Na+ Na+

K+

Heart muscle cell

Ca2+

K+K+Ca2+

Na+

K+

Na+

Disturbance ofcolor vision

Area postrema:nausea, vomiting

"Re-entrant"excitation inatrialfibrillation

Cardiacglycoside

Decrease inventricularrate

D. Cardiac glycoside effects inatrial fibrillation

CouplingCa2+

CG

CG

CG

CG

CG

Na/K-ATPase

Excitation ofN. vagus:Heart rate

Arrhythmia Contracture


The pharmacokinetics of cardiacglycosides (A) are dictated by their po-larity, i.e., the number of hydroxylgroups. Membrane penetrability is vir-tually nil in ouabain, high in digoxin,and very high in digitoxin. Ouabain (g-strophanthin) does not penetrate intocells, be they intestinal epithelium, re-nal tubular, or hepatic cells. At best, it issuitable for acute intravenous inductionof glycoside therapy.

The absorption of digoxin dependson the kind of galenical preparationused and on absorptive conditions inthe intestine. Preparations are now ofsuch quality that the derivatives methyl-digoxin and acetyldigoxin no longer offerany advantage. Renal reabsorption is in-complete; approx. 30% of the totalamount present in the body (s.c. full“digitalizing” dose) is eliminated perday. When renal function is impaired,there is a risk of accumulation. Digi-toxin undergoes virtually complete re-absorption in gut and kidneys. There isactive hepatic biotransformation: cleav-age of sugar moieties, hydroxylation atC12 (yielding digoxin), and conjugationto glucuronic acid. Conjugates secretedwith bile are subject to enterohepaticcycling (p. 38); conjugates reaching theblood are renally eliminated. In renal in-sufficiency, there is no appreciable ac-cumulation. When digitoxin is with-drawn following overdosage, its effectdecays more slowly than does that of di-goxin.

Other positive inotropic drugs.The phosphodiesterase inhibitor am-rinone (cAMP elevation, p. 66) can beadministered only parenterally for amaximum of 14 d because it is poorly

tolerated. A closely related compound ismilrinone. In terms of their positive in-otropic effect, β-sympathomimetics,unlike dopamine (p. 114), are of littletherapeutic use; they are also arrhyth-mogenic and the sensitivity of the β-re-ceptor system declines during continu-ous stimulation.

Treatment Principles in Chronic HeartFailure

Myocardial insufficiency leads to a de-crease in stroke volume and venouscongestion with formation of edema.Administration of (thiazide) diuretics(p. 62) offers a therapeutic approach ofproven efficacy that is brought about bya decrease in circulating blood volume(decreased venous return) and periph-eral resistance, i.e., afterload. A similarapproach is intended with ACE-inhibi-tors, which act by preventing the syn-thesis of angiotensin II (� vasoconstric-tion) and reducing the secretion of al-dosterone (� fluid retention). In severecases of myocardial insufficiency, car-diac glycosides may be added to aug-ment cardiac force and to relieve thesymptoms of insufficiency.

In more recent times β-blocker on along term were found to improve car-diac performance — particularly in idio-pathic dilating cardiomyopathy — pro-bably by preventing sympathetic over-drive.

132 Cardiac Drugs

Substance Fraction Plasma concentr. Digitalizing Elimination Maintenanceabsorbed free total dose dose % (ng/mL) (mg) %/d (mg)

Digitoxin 100 �1 �20 �1 10 �0.1

Digoxin 50–90 �1 �1.5 �1 30 �0.3

Ouabain <1 �1 �1 0.5 no long-term use


Cardiac Drugs 133

A. Pharmacokinetics of cardiac glycosides

Plasma

Albumin

Liver-cell

Inte

stin

al e

pith

eliu

m

Ren

al t

ubul

arep

ithel

ium D

econ

juga

tion

0%35%

95%

Cleavageof sugar

Conjugation

Digitoxin Digoxin

Plasma t12

Ouabain

Digoxin

Digitoxin

9 h 2 – 3 days 5 – 7 days


Antiarrhythmic Drugs

The electrical impulse for contraction(propagated action potential; p. 136)originates in pacemaker cells of the si-noatrial node and spreads through theatria, atrioventricular (AV) node, andadjoining parts of the His-Purkinje fibersystem to the ventricles (A). Irregular-ities of heart rhythm can interfere dan-gerously with cardiac pumping func-tion.

I. Drugs for selective control of si-noatrial and AV nodes. In some formsof arrhythmia, certain drugs can be usedthat are capable of selectively facilitat-ing and inhibiting (green and red ar-rows, respectively) the pacemaker func-tion of sinoatrial or atrioventricularcells.

Sinus bradycardia. An abnormallylow sinoatrial impulse rate (<60/min)can be raised by parasympatholytics.The quaternary ipratropium is prefer-able to atropine, because it lacks CNSpenetrability (p. 107). Sympathomimet-ics also exert a positive chronotropic ac-tion; they have the disadvantage of in-creasing myocardial excitability (andautomaticity) and, thus, promoting ec-topic impulse generation (tendency toextrasystolic beats). In cardiac arrestepinephrine can be used to reinitiateheart beat.

Sinus tachycardia (resting rate>100 beats/min). β-Blockers eliminatesympathoexcitation and decrease car-diac rate.

Atrial flutter or fibrillation. An ex-cessive ventricular rate can be de-creased by verapamil (p. 122) or cardiacglycosides (p. 130). These drugs inhibitimpulse propagation through the AVnode, so that fewer impulses reach theventricles.

II. Nonspecific drug actions onimpulse generation and propagation.Impulses originating at loci outside thesinus node are seen in supraventricularor ventricular extrasystoles, tachycardia,atrial or ventricular flutter, and fibrilla-tion. In these forms of rhythm disorders,antiarrhythmics of the local anesthet-

ic, Na+-channel blocking type (B) areused for both prophylaxis and therapy.Local anesthetics inhibit electrical exci-tation of nociceptive nerve fibers (p.204); concomitant cardiac inhibition(cardiodepression) is an unwanted ef-fect. However, in certain types of ar-rhythmias (see above), this effect is use-ful. Local anesthetics are readily cleaved(arrows) and unsuitable for oral admin-istration (procaine, lidocaine). Given ju-diciously, intravenous lidocaine is an ef-fective antiarrhythmic. Procainamideand mexiletine, congeners endowedwith greater metabolic stability, are ex-amples of orally effective antiarrhyth-mics. The desired and undesired effectsare inseparable. Thus, these antiar-rhythmics not only depress electricalexcitability of cardiomyocytes (negativebathmotropism, membrane stabiliza-tion), but also lower sinoatrial rate (neg.chronotropism), AV conduction (neg.dromotropism), and force of contraction(neg. inotropism). Interference with nor-mal electrical activity can, not too para-doxically, also induce cardiac arrhyth-mias–arrhythmogenic action.

Inhibition of CNS neurons is theunderlying cause of neurological effectssuch as vertigo, confusion, sensory dis-turbances, and motor disturbances(tremor, giddiness, ataxia, convulsions).

134 Cardiac Drugs


Cardiac Drugs 135

B. Antiarrhythmics of the Na+-channel blocking type

A. Cardiac impulse generation and conduction

Main effect

Antiarrhythmiceffect

Adverse effects

CNS-disturbances

ArrhythmiaCardiodepression

Para-sympatholytics

β-Sympatho-mimetics

β-Blocker

Verapamil

Cardiacglycoside

(Vagalstimulation)

Antiarrhythmics of the local anesthetic(Na+-channel blocking) type:Inhibition of impulse generation and conduction

Atrium

Sinus node

AV-node

Bundle of His

Ventricle

Tawara´snode

Purkinjefibers

Esterases

Procainamide

Mexiletine

Procaine

Lidocaine


Electrophysiological Actions of Antiarrhythmics of the Na+-ChannelBlocking Type

Action potential and ionic currents.The transmembrane electrical potentialof cardiomyocytes can be recordedthrough an intracellular microelectrode.Upon electrical excitation, a characteris-tic change occurs in membrane poten-tial—the action potential (AP). Its under-lying cause is a sequence of transientionic currents. During rapid depolariza-tion (Phase 0), there is a short-lived in-flux of Na+ through the membrane. Asubsequent transient influx of Ca2+ (aswell as of Na+) maintains the depola-rization (Phase 2, plateau of AP). A de-layed efflux of K+ returns the membranepotential (Phase 3, repolarization) to itsresting value (Phase 4). The velocity ofdepolarization determines the speed atwhich the AP propagates through themyocardial syncytium.

Transmembrane ionic currents in-volve proteinaceous membrane pores:Na+, Ca2+, and K+ channels. In A, thephasic change in the functional state ofNa+ channels during an action potentialis illustrated.

Effects of antiarrhythmics. Antiar-rhythmics of the Na+-channel blockingtype reduce the probability that Na+

channels will open upon membrane de-polarization (“membrane stabiliza-tion”). The potential consequences are(A, bottom): 1) a reduction in the veloc-ity of depolarization and a decrease inthe speed of impulse propagation; aber-rant impulse propagation is impeded. 2)Depolarization is entirely absent; patho-logical impulse generation, e.g., in themarginal zone of an infarction, is sup-pressed. 3) The time required until anew depolarization can be elicited, i.e.,the refractory period, is increased; pro-longation of the AP (see below) contrib-utes to the increase in refractory period.Consequently, premature excitationwith risk of fibrillation is prevented.

Mechanism of action. Na+-channelblocking antiarrhythmics resemblemost local anesthetics in being cationic

amphiphilic molecules (p. 208, excep-tion: phenytoin, p. 190). Possible molec-ular mechanisms of their inhibitory ef-fects are outlined on p. 204 in more de-tail. Their low structural specificity isreflected by a low selectivity towardsdifferent cation channels. Besides theNa+ channel, Ca2+ and K+ channels are al-so likely to be blocked. Accordingly, cat-ionic amphiphilic antiarrhythmics af-fect both the depolarization and repola-rization phases. Depending on the sub-stance, AP duration can be increased(Class IA), decreased (Class IB), or re-main the same (Class IC).

Antiarrhythmics representativeof these categories include: Class IA—quinidine, procainamide, ajmaline, dis-opyramide, propafenone; Class IB—lido-caine, mexiletine, tocainide, as well asphenytoin; Class IC—flecainide.

Note: With respect to classification,β-blockers have been assigned to ClassII, and the Ca2+-channel blockers vera-pamil and diltiazem to Class IV.

Commonly listed under a separaterubric (Class III) are amiodarone and theβ-blocking agent sotalol, which both in-hibit K+-channels and which both causemarked prolongation of the AP with alesser effect on Phase 0 rate of rise.

Therapeutic uses. Because of theirnarrow therapeutic margin, these antiar-rhythmics are only employed whenrhythm disturbances are of such sever-ity as to impair the pumping action ofthe heart, or when there is a threat ofother complications. The choice of drugis empirical. If the desired effect is notachieved, another drug is tried. Combi-nations of antiarrhythmics are not cus-tomary. Amiodarone is reserved for spe-cial cases.

136 Cardiac Drugs


Cardiac Drugs 137

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

Membrane potential

Time [ms]

Actionpotential(AP)

Speed of APpropagation

Heart muscle cell

Na+ Ca2+(+Na+)

Phase 0 Phase 3 Phase 4Phases 1,2

FastNa+-entry”

Slow Ca2+-entry

Ionic currents during action potential

Na+ Na+-channels

Open (active) ClosedOpening impossible(inactivated)

ClosedOpening possible(resting, can beactivated)

States of Na+-channels during an action potential

Suppressionof AP generation

Prolongation of refractory period =duration of inexcitability

Stimulus

2500

1 2

3

4

Rate ofdepolarization

K+

Antiarrhythmics of theNa+-channel blocking type

Inhibition ofNa+-channel opening

Inexcitability

0

Rate ofdepolarization

0

-80

[mV]

Refractory period


Drugs for the Treatment of Anemias

Anemia denotes a reduction in redblood cell count, hemoglobin content,or both. Oxygen (O2) transport capacityis decreased.

Erythropoiesis (A). Blood corpus-cles develop from stem cells throughseveral cell divisions. Hemoglobin isthen synthesized and the cell nucleus isextruded. Erythropoiesis is stimulatedby the hormone erythropoietin (a gly-coprotein), which is released from thekidneys when renal O2 tension declines.

Given an adequate production oferythropoietin, a disturbance of eryth-ropoiesis is due to two principal causes:1. Cell multiplication is inhibited be-cause DNA synthesis is insufficient. Thisoccurs in deficiencies of vitamin B12 orfolic acid (macrocytic hyperchromicanemia). 2. Hemoglobin synthesis isimpaired. This situation arises in irondeficiency, since Fe2+ is a constituent ofhemoglobin (microcytic hypochromicanemia).

Vitamin B12 (B)Vitamin B12 (cyanocobalamin) is pro-duced by bacteria; B12 generated in thecolon, however, is unavailable for ab-sorption (see below). Liver, meat, fish,and milk products are rich sources ofthe vitamin. The minimal requirementis about 1 µg/d. Enteral absorption of vi-tamin B12 requires so-called “intrinsicfactor” from parietal cells of the stom-ach. The complex formed with this gly-coprotein undergoes endocytosis in theileum. Bound to its transport protein,transcobalamin, vitamin B12 is destinedfor storage in the liver or uptake into tis-sues.

A frequent cause of vitamin B12 de-ficiency is atrophic gastritis leading to alack of intrinsic factor. Besides megalo-blastic anemia, damage to mucosal lin-ings and degeneration of myelinsheaths with neurological sequelae willoccur (pernicious anemia).

Optimal therapy consists in paren-teral administration of cyanocobal-amin or hydroxycobalamin (Vitamin

B12a; exchange of -CN for -OH group).Adverse effects, in the form of hyper-sensitivity reactions, are very rare.

Folic Acid (B). Leafy vegetables andliver are rich in folic acid (FA). The min-imal requirement is approx. 50 µg/d.Polyglutamine-FA in food is hydrolyzedto monoglutamine-FA prior to being ab-sorbed. FA is heat labile. Causes of defi-ciency include: insufficient intake, mal-absorption in gastrointestinal diseases,increased requirements during preg-nancy. Antiepileptic drugs (phenytoin,primidone, phenobarbital) may de-crease FA absorption, presumably by in-hibiting the formation of monogluta-mine-FA. Inhibition of dihydro-FA re-ductase (e.g., by methotrexate, p. 298)depresses the formation of the activespecies, tetrahydro-FA. Symptoms of de-ficiency are megaloblastic anemia andmucosal damage. Therapy consists inoral administration of FA or in folinicacid (p. 298) when deficiency is causedby inhibitors of dihydro—FA—reductase.

Administration of FA can mask avitamin B12 deficiency. Vitamin B12 is re-quired for the conversion of methyltet-rahydro-FA to tetrahydro-FA, which isimportant for DNA synthesis (B). Inhibi-tion of this reaction due to B12 deficien-cy can be compensated by increased FAintake. The anemia is readily corrected;however, nerve degeneration progress-es unchecked and its cause is mademore difficult to diagnose by the ab-sence of hematological changes. Indis-criminate use of FA-containing multivi-tamin preparations can, therefore, beharmful.

138 Antianemics


Antianemics 139

B. Vitamin B12 and folate metabolism

A. Erythropoiesis in bone marrow

A very few largehemoglobin-richerythrocytes

A few smallhemoglobin-poorerythrocytes

H3C-

Trans-cobalamin II

HCl

i.m.

Parietal cell

Streptomycesgriseus

Storagesupply for3 years

Vit. B12 deficiency

Folate deficiency

Inhibition of DNAsynthesis(cell multiplication)

Inhibition ofhemoglobin synthesis

Iron deficiency

Vit. B12 Intrinsicfactor

Folic acid H4

DNAsynthesis

H3C- Folic acid H4

H3C- Vit. B12

Folic acidVit. B12

Vit. B12


Iron Compounds

Not all iron ingested in food is equallyabsorbable. Trivalent Fe3+ is virtuallynot taken up from the neutral milieu ofthe small bowel, where the divalent Fe2+

is markedly better absorbed. Uptake isparticularly efficient in the form ofheme (present in hemo- and myoglo-bin). Within the mucosal cells of the gut,iron is oxidized and either deposited asferritin (see below) or passed on to thetransport protein, transferrin, a β1-gly-coprotein. The amount absorbed doesnot exceed that needed to balance loss-es due to epithelial shedding from skinand mucosae or hemorrhage (so-called“mucosal block”). In men, this amountis approx. 1 mg/d; in women, it is ap-prox. 2 mg/d (menstrual blood loss),corresponding to about 10% of the die-tary intake. The transferrin-iron com-plex undergoes endocytotic uptakemainly into erythroblasts to be utilizedfor hemoglobin synthesis.

About 70% of the total body store ofiron (~5 g) is contained within erythro-cytes. When these are degraded by mac-rophages of the reticuloendothelial(mononuclear phagocyte) system, ironis liberated from hemoglobin. Fe3+ canbe stored as ferritin (= protein apoferri-tin + Fe3+) or returned to erythropoiesissites via transferrin.

A frequent cause of iron deficiencyis chronic blood loss due to gastric/in-testinal ulcers or tumors. One liter ofblood contains 500 mg of iron. Despite asignificant increase in absorption rate(up to 50%), absorption is unable to keepup with losses and the body store of ironfalls. Iron deficiency results in impairedsynthesis of hemoglobin and anemia (p.138).

The treatment of choice (after thecause of bleeding has been found andeliminated) consists of the oral admin-istration of Fe2+ compounds, e.g., fer-rous sulfate (daily dose 100 mg of ironequivalent to 300 mg of FeSO4, dividedinto multiple doses). Replenishing ofiron stores may take several months.Oral administration, however, is advan-

tageous in that it is impossible to over-load the body with iron through an in-tact mucosa because of its demand-reg-ulated absorption (mucosal block).

Adverse effects. The frequent gas-trointestinal complaints (epigastricpain, diarrhea, constipation) necessitateintake of iron preparations with or aftermeals, although absorption is higherfrom the empty stomach.

Interactions. Antacids inhibit ironabsorption. Combination with ascorbicacid (Vitamin C), for protecting Fe2+

from oxidation to Fe3+, is theoreticallysound, but practically is not needed.

Parenteral administration of Fe3+

salts is indicated only when adequateoral replacement is not possible. Thereis a risk of overdosage with iron deposi-tion in tissues (hemosiderosis). Thebinding capacity of transferrin is limitedand free Fe3+ is toxic. Therefore, Fe3+

complexes are employed that can do-nate Fe3+ directly to transferrin or canbe phagocytosed by macrophages, ena-bling iron to be incorporated into ferri-tin stores. Possible adverse effects are,with i.m. injection: persistent pain atthe injection site and skin discoloration;with i.v. injection: flushing, hypoten-sion, anaphylactic shock.

140 Antianemics


Antianemics 141

Fe III

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

Fe III-Salts

Fe II-Salts

Heme-FeFe III

Ferritin

Parenteraladministration

i.v. i.m.

Uptake into macrophagesspleen, liver, bone marrow

Oralintake

Fe III

Absorption

Duodenumupper jejunum

Uptake intoerythroblastbone marrow

Loss throughbleeding

Erythrocyteblood

Transportplasma

Hemoglobin

Hemosiderin= aggregatedferritin

Ferritin

Transferrin

Fe III Fe III

Fe III-complexes

Fe III


Prophylaxis and Therapy of Thromboses

Upon vascular injury, the coagulationsystem is activated: thrombocytes andfibrin molecules coalesce into a “plug”(p. 148) that seals the defect and haltsbleeding (hemostasis). Unnecessaryformation of an intravascular clot – athrombosis – can be life-threatening. Ifthe clot forms on an atheromatousplaque in a coronary artery, myocardialinfarction is imminent; a thrombus in adeep leg vein can be dislodged, carriedinto a lung artery, and cause completeor partial interruption of pulmonaryblood flow (pulmonary embolism).

Drugs that decrease the coagulabil-ity of blood, such as coumarins and hep-arin (A), are employed for the prophy-laxis of thromboses. In addition, at-tempts are directed at inhibiting the ag-gregation of blood platelets, which areprominently involved in intra-arterialthrombogenesis (p. 148). For the thera-py of thrombosis, drugs are used thatdissolve the fibrin meshwork→fibrino-lytics (p. 146).

An overview of the coagulationcascade and sites of action for coumar-ins and heparin is shown in A. There aretwo ways to initiate the cascade (B): 1)conversion of factor XII into its activeform (XIIa, intrinsic system) at intravas-cular sites denuded of endothelium; 2)conversion of factor VII into VIIa (extrin-sic system) under the influence of a tis-sue-derived lipoprotein (tissue throm-boplastin). Both mechanisms convergevia factor X into a common final path-way.

The clotting factors are proteinmolecules. “Activation” mostly meansproteolysis (cleavage of protein frag-ments) and, with the exception of fibrin,conversion into protein-hydrolyzingenzymes (proteases). Some activatedfactors require the presence of phos-pholipids (PL) and Ca2+ for their proteo-lytic activity. Conceivably, Ca2+ ionscause the adhesion of factor to a phos-pholipid surface, as depicted in C. Phos-pholipids are contained in platelet fac-tor 3 (PF3), which is released from ag-

gregated platelets, and in tissue throm-boplastin (B). The sequential activationof several enzymes allows the afore-mentioned reactions to “snowball”, cul-minating in massive production of fibrin(p. 148).

Progression of the coagulation cas-cade can be inhibited as follows:

1) coumarin derivatives decreasethe blood concentrations of inactive fac-tors II, VII, IX, and X, by inhibiting theirsynthesis; 2) the complex consisting ofheparin and antithrombin III neutraliz-es the protease activity of activated fac-tors; 3) Ca2+ chelators prevent the en-zymatic activity of Ca2+-dependent fac-tors; they contain COO-groups that bindCa2+ ions (C): citrate and EDTA (ethy-lenediaminetetraacetic acid) form solu-ble complexes with Ca2+; oxalate pre-cipitates Ca2+ as insoluble calcium oxa-late. Chelation of Ca2+ cannot be usedfor therapeutic purposes because Ca2+

concentrations would have to be low-ered to a level incompatible with life(hypocalcemic tetany). These com-pounds (sodium salts) are, therefore,used only for rendering blood incoagu-lable outside the body.

142 Antithrombotics


Antithrombotics 143

A. Inhibition of clotting cascade in vivo

XII XIIa

XI XIa

IX IXa

VIII + Ca2+ + Pl

VIIVIIa

X Xa

Prothrombin II IIa Thrombin

Fibrinogen I Ia Fibrin

B. Activation of clotting

Platelets Endothelialdefect

Tissuethrombo-kinase

Vesselrupture

Clotting factor

COO-

Phospholipidse.g., PF3

Ca2+-chelationCitrateEDTAOxalate

C. Inhibition of clotting by removal of Ca2+

Synthesis susceptible toinhibition by coumarins

Reaction susceptible toinhibition by heparin-antithrombin complex

Fibrin

XIIa

VIIa VII

XII

PF3

+Ca + –

––

––

–+

+Ca

COO–

COO–

V + Ca2+ + Pl

Ca2+ + Pl (Phospholipids)


Coumarin Derivatives (A)

Vitamin K promotes the hepatic γ-car-boxylation of glutamate residues on theprecursors of factors II, VII, IX, and X, aswell as that of other proteins, e.g., pro-tein C, protein S, or osteocalcin. Carbox-yl groups are required for Ca2+-mediat-ed binding to phospholipid surfaces (p.142). There are several vitamin K de-rivatives of different origins: K1 (phy-tomenadione) from chlorophyllousplants; K2 from gut bacteria; and K3

(menadione) synthesized chemically.All are hydrophobic and require bile ac-ids for absorption.

Oral anticoagulants. Structurallyrelated to vitamin K, 4-hydroxycouma-rins act as “false” vitamin K and preventregeneration of reduced (active) vita-min K from vitamin K epoxide, hencethe synthesis of vitamin K-dependentclotting factors.

Coumarins are well absorbed afteroral administration. Their duration ofaction varies considerably. Synthesis ofclotting factors depends on the intrahe-patocytic concentration ratio of cou-marins to vitamin K. The dose requiredfor an adequate anticoagulant effectmust be determined individually foreach patient (one-stage prothrombintime). Subsequently, the patient mustavoid changing dietary consumption ofgreen vegetables (alteration in vitaminK levels), refrain from taking additionaldrugs likely to affect absorption or elim-ination of coumarins (alteration in cou-marin levels), and not risk inhibitingplatelet function by ingesting acetylsali-cylic acid.

The most important adverse ef-fect is bleeding. With coumarins, thiscan be counteracted by giving vitaminK1. Coagulability of blood returns tonormal only after hours or days, whenthe liver has resumed synthesis and re-stored sufficient blood levels of clottingfactors. In urgent cases, deficient factorsmust be replenished directly (e.g., bytransfusion of whole blood or of pro-thrombin concentrate).

Heparin (B)A clotting factor is activated when thefactor that precedes it in the clottingcascade splits off a protein fragment andthereby exposes an enzymatic center.The latter can again be inactivated phys-iologically by complexing with anti-thrombin III (AT III), a circulating gly-coprotein. Heparin acts to inhibit clot-ting by accelerating formation of thiscomplex more than 1000-fold. Heparinis present (together with histamine) inthe vesicles of mast cells; its physiologi-cal role is unclear. Therapeutically usedheparin is obtained from porcine gut orbovine lung. Heparin molecules arechains of amino sugars bearing -COO–

and -SO4 groups; they contain approx.10 to 20 of the units depicted in (B);mean molecular weight, 20,000. Antico-agulant efficacy varies with chainlength. The potency of a preparation isstandardized in international units ofactivity (IU) by bioassay and compari-son with a reference preparation.

The numerous negative charges aresignificant in several respects: (1) theycontribute to the poor membrane pe-netrability—heparin is ineffective whenapplied by the oral route or topically on-to the skin and must be injected; (2) at-traction to positively charged lysine res-idues is involved in complex formationwith ATIII; (3) they permit binding ofheparin to its antidote, protamine(polycationic protein from salmonsperm).

If protamine is given in heparin-in-duced bleeding, the effect of heparin isimmediately reversed.

For effective thromboprophylaxis, alow dose of 5000 IU is injected s.c. twoto three times daily. With low dosage ofheparin, the risk of bleeding is suffi-ciently small to allow the first injectionto be given as early as 2 h prior to sur-gery. Higher daily i.v. doses are requiredto prevent growth of clots. Besidesbleeding, other potential adverse effectsare: allergic reactions (e.g., thrombocy-topenia) and with chronic administra-tion, reversible hair loss and osteoporo-sis.

144 Antithrombotics


Antithrombotics 145

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

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

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

Duration of action/days

Carboxylation of glutamine residues

Vit. K derivatives4-Hydroxy-Coumarin derivatives

Activatedclotting factor

Inacti-vation

Inacti-vation

Protamine

Mast cell

Vit. K1

Vit. K2

Vit. K3 Menadione

Phytomenadione Phenprocoumon

Warfarin

Acenocoumarol

II, VII, IX, X

- - - --

--

-+ +

++

++

++ +

+

+

- - - -

IIa, IXa, Xa, XIa, XIIa, XIIIa

AT III

+ + + +

AT III

+ + + +


Low-molecular-weight heparin (av-erage MW ~5000) has a longer durationof action and needs to be given onlyonce daily (e.g., certoparin, dalteparin,enoxaparin, reviparin, tinzaparin).

Frequent control of coagulability isnot necessary with low molecularweight heparin and incidence of side ef-fects (bleeding, heparin-induced throm-bocytopenia) is less frequent than withunfractionated heparin.

Fibrinolytic Therapy (A)

Fibrin is formed from fibrinogenthrough thrombin (factor IIa)-catalyzedproteolytic removal of two oligopeptidefragments. Individual fibrin moleculespolymerize into a fibrin mesh that canbe split into fragments and dissolved byplasmin. Plasmin derives by proteolysisfrom an inactive precursor, plasmino-gen. Plasminogen activators can be infu-sed for the purpose of dissolving clots(e.g., in myocardial infarction). Throm-bolysis is not likely to be successful un-less the activators can be given very so-on after thrombus formation. Urokinaseis an endogenous plasminogen activatorobtained from cultured human kidneycells. Urokinase is better tolerated thanis streptokinase. By itself, the latter isenzymatically inactive; only after bin-ding to a plasminogen molecule doesthe complex become effective in con-verting plasminogen to plasmin. Strep-tokinase is produced by streptococcalbacteria, which probably accounts forthe frequent adverse reactions. Strepto-kinase antibodies may be present as aresult of prior streptococcal infections.Binding to such antibodies would neu-tralize streptokinase molecules.

With alteplase, another endoge-nous plasminogen activator (tissueplasminogen activator, tPA) is available.With physiological concentrations thisactivator preferentially acts on plasmin-ogen bound to fibrin. In concentrationsneeded for therapeutic fibrinolysis thispreference is lost and the risk of bleed-ing does not differ with alteplase andstreptokinase. Alteplase is rather short-

lived (inactivation by complexing withplasminogen activator inhibitor, PAI)and has to be applied by infusion. Rete-plase, however, containing only theproteolytic active part of the alteplasemolecule, allows more stabile plasmalevels and can be applied in form of twoinjections at an interval of 30 min.

Inactivation of the fibrinolyticsystem can be achieved by “plasmin in-hibitors,” such as ε-aminocaproic acid,p-aminomethylbenzoic acid (PAMBA),tranexamic acid, and aprotinin, whichalso inhibits other proteases.

Lowering of blood fibrinogenconcentration. Ancrod is a constituentof the venom from a Malaysian pit viper.It enzymatically cleaves a fragmentfrom fibrinogen, resulting in the forma-tion of a degradation product that can-not undergo polymerization. Reductionin blood fibrinogen level decreases thecoagulability of the blood. Since fibrino-gen (MW ~340 000) contributes to theviscosity of blood, an improved “fluid-ity” of the blood would be expected.Both effects are felt to be of benefit inthe treatment of certain disorders ofblood flow.

146 Antithrombotics


Antithrombotics 147

A. Activators and inhibitors of fibrinolysis; ancrod

Fibrinogen

Fibrin

Thrombin Ancrod

PlasminPlasmin-inhibitors

e.g., Tranexamic acid

Urokinase

Human kidney cell culture

Streptokinase

StreptococciPlasminogen

Antibody fromprior infection

Fever,chills,and inacti-vation


Intra-arterial Thrombus Formation (A)

Activation of platelets, e.g., upon con-tact with collagen of the extracellularmatrix after injury to the vascular wall,constitutes the immediate and decisivestep in initiating the process of primaryhemostasis, i.e., cessation of bleeding.However, in the absence of vascular in-jury, platelets can be activated as a re-sult of damage to the endothelial celllining of blood vessels. Among the mul-tiple functions of the endothelium, theproduction of NO˙ and prostacyclin playsan important role. Both substances in-hibit the tendency of platelets to adhereto the endothelial surface (platelet ad-hesiveness). Impairment of endothelialfunction, e.g., due to chronic hyperten-sion, cigarette smoking, chronic eleva-tion of plasma LDL levels or of bloodglucose, increases the probability ofcontact between platelets and endothe-lium. The adhesion process involvesGPIB/IX, a glycoprotein present in theplatelet cell membrane and von Wille-brandt’s factor, an endothelial mem-brane protein. Upon endothelial con-tact, the platelet is activated with a re-sultant change in shape and affinity tofibrinogen. Platelets are linked to eachother via fibrinogen bridges: theyundergo aggregation.

Platelet aggregation increases likean avalanche because, once activated,platelets can activate other platelets. Onthe injured endothelial cell, a plateletthrombus is formed, which obstructsblood flow. Ultimately, the vascular lu-men is occluded by the thrombus as thelatter is solidified by a vasoconstrictionproduced by the release of serotoninand thromboxane A2 from the aggregat-ed platelets. When these events occur ina larger coronary artery, the conse-quence is a myocardial infarction; in-volvement of a cerebral artery leads tostroke.

The von Willebrandt’s factor plays akey role in thrombogenesis. Lack of thisfactor causes thrombasthenia, a patho-logically decreased platelet aggregation.Relative deficiency of the von Wille-

brandt’s factor can be temporarily over-come by the vasopressin anlogue des-mopressin (p. 164), which increases therelease of available factor from storagesites.

Formation, Activation, and Aggregationof Platelets (B)Platelets originate by budding off frommultinucleate precursor cells, the me-gakaryocytes. As the smallest formedelement of blood (dia. 1–4 µm), they canbe activated by various stimuli. Activa-tion entails an alteration in shape andsecretion of a series of highly active sub-stances, including serotonin, platelet ac-tivating factor (PAF), ADP, and throm-boxane A2. In turn, all of these can acti-vate other platelets, which explains theexplosive nature of the process.

The primary consequence of activa-tion is a conformational change of an in-tegrin present in the platelet mem-brane, namely, GPIIB/IIIA. In its activeconformation, GPIIB/IIIA shows high af-finity for fibrinogen; each platelet con-tains up to 50,000 copies. The high plas-ma concentration of fibrinogen and thehigh density of integrins in the plateletmembrane permit rapid cross-linking ofplatelets and formation of a plateletplug.

148 Antithrombotics


Antithrombotics 149

B. Aggregation of platelets by the integrin GPIIB/IIIA

Megakaryocyte

GlycoproteinIIB/IIIA

Fibrinogenbinding:

possible

impossible

Platelet

Adhesion

Aggregation

Platelet von Willebrandt’sfactor

FibrinogenActivatedplatelet

Contact withcollagenADPThrombinThromboxane A2Serotonin

A. Thrombogenesis

Activation

Fibrinogen

dysfunctional endothelial cell

Activatedplatelet


Inhibitors of Platelet Aggregation (A)

Platelets can be activated by mechanicaland diverse chemical stimuli, some ofwhich, e.g., thromboxane A2, thrombin,serotonin, and PAF, act via receptors onthe platelet membrane. These receptorsare coupled to Gq proteins that mediateactivation of phospholipase C and hencea rise in cytosolic Ca2+ concentration.Among other responses, this rise in Ca2+

triggers a conformational change inGPIIB/IIIA, which is thereby convertedto its fbrinogen-binding form. In con-trast, ADP activates platelets by inhibit-ing adenylyl cyclase, thus causing inter-nal cAMP levels to decrease. High cAMPlevels would stabilize the platelet in itsinactive state. Formally, the two mes-senger substances, Ca2+ and cAMP, canbe considered functional antagonists.

Platelet aggregation can be inhibit-ed by acetylsalicylic acid (ASA), whichblocks thromboxane synthase, or by re-combinant hirudin (originally harvest-ed from leech salivary gland), whichbinds and inactivates thrombin. As yet,no drugs are available for blocking ag-gregation induced by serotonin or PAF.ADP-induced aggregation can be pre-vented by ticlopidine and clopidogrel;these agents are not classic receptor an-tagonists. ADP-induced aggregation isinhibited only in vivo but not in vitro instored blood; moreover, once induced,inhibition is irreversible. A possible ex-planation is that both agents alreadyinterfere with elements of ADP receptorsignal transduction at the megakaryo-cytic stage. The ensuing functional de-fect would then be transmitted to newlyformed platelets, which would be inca-pable of reversing it.

The intra-platelet levels of cAMPcan be stabilized by prostacyclin or itsanalogues (e.g., iloprost) or by dipyrida-mole. The former activates adenyl cy-clase via a G-protein-coupled receptor;the latter inhibits a phosphodiesterasethat breaks down cAMP.

The integrin (GPIIB/IIIA)-antago-nists prevent cross-linking of platelets.Their action is independent of the ag-

gregation-inducing stimulus. Abciximabis a chimeric human-murine monoclo-nal antibody directed against GPIIb/IIIathat blocks the fibrinogen-binding siteand thus prevents attachment of fi-brinogen. The peptide derivatives, epti-fibatide and tirofiban block GPIIB/IIIAcompetitively, more selectively and ha-ve a shorter effect than does abciximab.

Presystemic Effect of Acetylsalicylic Acid(B)

Inhibition of platelet aggregation byASA is due to a selective blockade ofplatelet cyclooxygenase (B). Selectivityof this action results from acetylation ofthis enzyme during the initial passage ofthe platelets through splanchnic bloodvessels. Acetylation of the enzyme is ir-reversible. ASA present in the systemiccirculation does not play a role in plate-let inhibition. Since ASA undergoes ex-tensive presystemic elimination, cyclo-oxygenases outside platelets, e.g., in en-dothelial cells, remain largely unaffect-ed. With regular intake, selectivity is en-hanced further because the anuclearplatelets are unable to resynthesize newenzyme and the inhibitory effects ofconsecutive doses are added to eachother. However, in the endothelial cells,de novo synthesis of the enzyme per-mits restoration of prostacyclin produc-tion.

Adverse Effects of Antiplatelet Drugs

All antiplatelet drugs increase the risk ofbleeding. Even at the low ASA dosesused to inhibit platelet function (100mg/d), ulcerogenic and bronchocon-strictor (aspirin asthma) effects may oc-cur. Ticlopidine frequently causes diar-rhea and, more rarely, leukopenia, ne-cessitating cessation of treatment. Clo-pidogrel reportedly does not cause he-matological problems.

As peptides, hirudin and abciximabneed to be injected; therefore their useis restricted to intensive-care settings.

150 Antithrombotics


Antithrombotics 151

AbciximabTirofibanEptifibatide

HirudinArgatroban

A. Inhibitors of platelet aggregation

Arachidonicacid

B. Presystemic inactivation of platelet cyclooxygenase by acetylsalicylic acid

Serotonin PAF

GPIIB/IIIA[withoutaffinity forfibrinogen]

Thrombin

ATP

Phospho-diesterase

Dipyridamole

ASA

Thromb-oxane A2

Adenylate-cyclase

Inactive Active

ADP

GPIIB/IIIA[Affinity forfibrinogenhigh]

O

COOH

O CCH3

Ticlopidine, Clopidogrel

Low dose ofacetyl-salicylic acid

PlateletPlatelet withacetylated andblockedcyclooxygenase


Plasma Volume Expanders

Major blood loss entails the danger oflife-threatening circulatory failure, i.e.,hypovolemic shock. The immediatethreat results not so much from the lossof erythrocytes, i.e., oxygen carriers, asfrom the reduction in volume of circu-lating blood.

To eliminate the threat of shock, re-plenishment of the circulation is essen-tial. With moderate loss of blood, ad-ministration of a plasma volume ex-pander may be sufficient. Blood plasmaconsists basically of water, electrolytes,and plasma proteins. However, a plasmasubstitute need not contain plasmaproteins. These can be suitably re-placed with macromolecules (“col-loids”) that, like plasma proteins, (1) donot readily leave the circulation and arepoorly filtrable in the renal glomerulus;and (2) bind water along with its solutesdue to their colloid osmotic properties. Inthis manner, they will maintain circula-tory filling pressure for many hours. Onthe other hand, volume substitution isonly transiently needed and thereforecomplete elimination of these colloidsfrom the body is clearly desirable.

Compared with whole blood orplasma, plasma substitutes offer severaladvantages: they can be produced moreeasily and at lower cost, have a longershelf life, and are free of pathogens suchas hepatitis B or C or AIDS viruses.

Three colloids are currently em-ployed as plasma volume expanders—the two polysaccharides, dextran andhydroxyethyl starch, as well as the poly-peptide, gelatin.

Dextran is a glucose polymerformed by bacteria and linked by a 1→6instead of the typical 1→4 bond. Com-mercial solutions contain dextran of amean molecular weight of 70 kDa (dex-tran 70) or 40 kDa (lower-molecular-weight dextran, dextran 40). The chainlength of single molecules, however,varies widely. Smaller dextran mole-cules can be filtered at the glomerulusand slowly excreted in urine; the largerones are eventually taken up and de-

graded by cells of the reticuloendothe-lial system. Apart from restoring bloodvolume, dextran solutions are used forhemodilution in the management ofblood flow disorders.

As for microcirculatory improve-ment, it is occasionally emphasized thatlow-molecular-weight dextran, unlikedextran 70, may directly reduce the ag-gregability of erythrocytes by alteringtheir surface properties. With pro-longed use, larger molecules will accu-mulate due to the more rapid renal ex-cretion of the smaller ones. Consequent-ly, the molecular weight of dextran cir-culating in blood will tend towards ahigher mean molecular weight with thepassage of time.

The most important adverse effectresults from the antigenicity of dex-trans, which may lead to an anaphylac-tic reaction.

Hydroxyethyl starch (hetastarch) isproduced from starch. By virtue of itshydroxyethyl groups, it is metabolizedmore slowly and retained significantlylonger in blood than would be the casewith infused starch. Hydroxyethylstarch resembles dextrans in terms ofits pharmacological properties andtherapeutic applications.

Gelatin colloids consist of cross-linked peptide chains obtained fromcollagen. They are employed for bloodreplacement, but not for hemodilution,in circulatory disturbances.

152 Plasma Volume Expanders


Plasma Volume Expanders 153

Gelatin colloids= cross-linked peptide chains

MW 35, 000

Circulation

A. Plasma substitutes

Peptides MW ~ 15, 000Gelatin MW ~ 100, 000Collagen MW ~ 300, 000

Plasma

Plasma-proteins

Erythrocytes

DextranMW 70, 000MW 40, 000

Hydroxyethyl starchMW 450, 000

SucroseFructoseBacteriumLeuconostocmesenteroides

Hydroxy-ethylation

Starch

Plasma-substitutewith colloids

Blood loss danger of shock


Lipoprotein metabolism. Entero-cytes release absorbed lipids in the formof triglyceride-rich chylomicrons. By-passing the liver, these enter the circu-lation mainly via the lymph and are hy-drolyzed by extrahepatic endotheliallipoprotein lipases to liberate fatty ac-ids. The remnant particles move on intoliver cells and supply these with choles-terol of dietary origin.

The liver meets the larger part(60%) of its requirement for cholesterolby de novo synthesis from acetylcoen-zyme-A. Synthesis rate is regulated atthe step leading from hydroxymethyl-glutaryl CoA (HMG CoA) to mevalonicacid (p. 157A), with HMG CoA reductaseas the rate-limiting enzyme.

The liver requires cholesterol forsynthesizing VLDL particles and bile ac-ids. Triglyceride-rich VLDL particles arereleased into the blood and, like thechylomicrons, supply other tissues withfatty acids. Left behind are LDL particlesthat either return into the liver or sup-ply extrahepatic tissues with choleste-rol.

LDL particles carry apolipoprotein B100, by which they are bound to recep-tors that mediate uptake of LDL into the

cells, including the hepatocytes (recep-tor-mediated endocytosis, p. 27).

HDL particles are able to transfercholesterol from tissue cells to LDL par-ticles. In this way, cholesterol is trans-ported from tissues to the liver.

Hyperlipoproteinemias can becaused genetically (primary h.) or canoccur in obesity and metabolic disor-ders (secondary h). Elevated LDL-cho-lesterol serum concentrations are asso-ciated with an increased risk of athero-sclerosis, especially when there is a con-comitant decline in HDL concentration(increase in LDL:HDL quotient).

Treatment. Various drugs are avail-able that have different mechanisms ofaction and effects on LDL (cholesterol)and VLDL (triglycerides) (A). Their use isindicated in the therapy of primary hy-perlipoproteinemias. In secondary hy-perlipoproteinemias, the immediategoal should be to lower lipoprotein lev-els by dietary restriction, treatment ofthe primary disease, or both.

Drugs (B). Colestyramine and coles-tipol are nonabsorbable anion-exchangeresins. By virtue of binding bile acids,they promote consumption of choleste-rol for the synthesis of bile acids; the

154 li KT

Lipid-Lowering Agents

Triglycerides and cholesterol are essen-tial constituents of the organism.Among other things, triglycerides repre-sent a form of energy store and choles-terol is a basic building block of biologi-cal membranes. Both lipids are waterinsoluble and require appropriate trans-

port vehicles in the aqueous media oflymph and blood. To this end, smallamounts of lipid are coated with a layerof phospholipids, embedded in whichare additional proteins—the apolipopro-teins (A). According to the amount andthe composition of stored lipids, as wellas the type of apolipoprotein, one dis-tinguishes 4 transport forms:

154 Drugs used in Hyperlipoproteinemias

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


Drugs used in Hyperlipoproteinemias 155

Cell metabolism

A. Lipoprotein metabolism

LDL

Dietary fats

LDLChylomicron

Cholesterol

Live

r ce

ll

Lipoproteinsynthesis

Cholesterol

Triglycerides

Synthesis

Cholesterol-esterTriglycerides

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

Bile acids Lipoproteins

HMG-CoA-Reductase inhibitors

Live

r ce

ll

Fat tissue

HeartSkeletal muscle

OH OH OH

LDLHDL

HDL

VLDL

Chylomicronremnant

β-Sitosterol

Gut:Cholesterolabsorption

Gut::binding andexcretion ofbile acids (BA)

Liver:BA synthesis Cholesterolconsumption

Cholesterolstore

Colestyramine

CholesterolFatty acidsLipoproteinLipase

Cholesterol

Apolipo-protein


liver meets its increased cholesterol de-mand by enhancing the expression ofHMG CoA reductase and LDL receptors(negative feedback).

At the required dosage, the resinscause diverse gastrointestinal distur-bances. In addition, they interfere withthe absorption of fats and fat-soluble vi-tamins (A, D, E, K). They also adsorb anddecrease the absorption of such drugs asdigitoxin, vitamin K antagonists, anddiuretics. Their gritty texture and bulkmake ingestion an unpleasant experi-ence.

The statins, lovastatin (L), simvasta-tin (S), pravastatin (P), fluvastatin (F),cerivastatin, and atorvastatin, inhibitHMG CoA reductase. The active group ofL, S, P, and F (or their metabolites) re-sembles that of the physiological sub-strate of the enzyme (A). L and S are lac-tones that are rapidly absorbed by theenteral route, subjected to extensivefirst-pass extraction in the liver, andthere hydrolyzed into active metab-olites. P and F represent the active formand, as acids, are actively transported bya specific anion carrier that moves bileacids from blood into liver and also me-diates the selective hepatic uptake ofthe mycotoxin, amanitin (A). Atorvasta-tin has the longest duration of action.Normally viewed as presystemic elimi-nation, efficient hepatic extractionserves to confine the action of the sta-tins to the liver. Despite the inhibition ofHMG CoA reductase, hepatic cholesterolcontent does not fall, because hepato-cytes compensate any drop in choleste-rol levels by increasing the synthesis ofLDL receptor protein (along with the re-ductase). Because the newly formed re-ductase is inhibited, too, the hepatocytemust meet its cholesterol demand byuptake of LDL from the blood (B). Ac-cordingly, the concentration of circulat-ing LDL decreases, while its hepaticclearance from plasma increases. Thereis also a decreased likelihood of LDL be-ing oxidized into its proatherosleroticdegradation product. The combinationof a statin with an ion-exchange resinintensifies the decrease in LDL levels. A

rare, but dangerous, side effect of thestatins is damage to skeletal muscula-ture. This risk is increased by combineduse of fibric acid agents (see below).

Nicotinic acid and its derivatives(pyridylcarbinol, xanthinol nicotinate,acipimox) activate endothelial lipopro-tein lipase and thereby lower triglyce-ride levels. At the start of therapy, aprostaglandin-mediated vasodilationoccurs (flushing and hypotension) thatcan be prevented by low doses of acetyl-salicylic acid.

Clofibrate and derivatives (bezafi-brate, etofibrate, gemfibrozil) lower plas-ma lipids by an unknown mechanism.They may damage the liver and skeletalmuscle (myalgia, myopathy, rhabdo-myolysis).

Probucol lowers HDL more thanLDL; nonetheless, it appears effective inreducing atherogenesis, possibly by re-ducing LDL oxidation.

�3-Polyunsaturated fatty acids (ei-cosapentaenoate, docosahexaenoate)are abundant in fish oils. Dietary sup-plementation results in lowered levelsof triglycerides, decreased synthesis ofVLDL and apolipoprotein B, and im-proved clearance of remnant particles,although total and LDL cholesterol arenot decreased or are even increased.High dietary intake may correlate with areduced incidence of coronary heartdisease.

156 Drugs used in Hyperlipoproteinemias


Drugs used in Hyperlipoproteinemias 157

Low systemic availability

Fluvastatin

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

Inhibition ofHMG-CoA reductase

LDL-Receptor

Expression

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

LDLin blood

Oraladministration

Extractionof lipophiliclactone

Activeuptake ofanion

HMG-CoAreductase

Increased receptor-mediated uptake of LDL

Cholesterol

Cholesterol

Lovastatin

Mevalonate3-Hydroxy-3-methyl-glutaryl-CoA

HMG-CoAReductase

Active form

Expression Expression

Bio-activation

O

O

CH3

O

O

HO

H3C

N

OH

F

COOHHO

CH3

CH3H3CH3C


Diuretics – An Overview

Diuretics (saluretics) elicit increasedproduction of urine (diuresis). In thestrict sense, the term is applied to drugswith a direct renal action. The predomi-nant action of such agents is to augmenturine excretion by inhibiting the reab-sorption of NaCl and water.

The most important indications fordiuretics are:

Mobilization of edemas (A): In ede-ma there is swelling of tissues due to ac-cumulation of fluid, chiefly in the extra-cellular (interstitial) space. When a diu-retic is given, increased renal excretionof Na+ and H2O causes a reduction inplasma volume with hemoconcentra-tion. As a result, plasma protein concen-tration rises along with oncotic pres-sure. As the latter operates to attractwater, fluid will shift from interstitiuminto the capillary bed. The fluid contentof tissues thus falls and the edemas re-cede. The decrease in plasma volumeand interstitial volume means a dimi-nution of the extracellular fluid volume(EFV). Depending on the condition, useis made of: thiazides, loop diuretics, al-dosterone antagonists, and osmotic diu-retics.

Antihypertensive therapy. Diureticshave long been used as drugs of firstchoice for lowering elevated blood pres-sure (p. 312). Even at low dosage, theydecrease peripheral resistance (withoutsignificantly reducing EFV) and therebynormalize blood pressure.

Therapy of congestive heart failure.By lowering peripheral resistance, diu-retics aid the heart in ejecting blood (re-duction in afterload, pp. 132, 306); car-diac output and exercise tolerance areincreased. Due to the increased excre-tion of fluid, EFV and venous return de-crease (reduction in preload, p. 306).Symptoms of venous congestion, suchas ankle edema and hepatic enlarge-ment, subside. The drugs principallyused are thiazides (possibly combinedwith K+-sparing diuretics) and loop diu-retics.

Prophylaxis of renal failure. In circu-latory failure (shock), e.g., secondary tomassive hemorrhage, renal productionof urine may cease (anuria). By means ofdiuretics an attempt is made to main-tain urinary flow. Use of either osmoticor loop diuretics is indicated.

Massive use of diuretics entails ahazard of adverse effects (A): (1) thedecrease in blood volume can lead tohypotension and collapse; (2) blood vis-cosity rises due to the increase in eryth-ro- and thrombocyte concentration,bringing an increased risk of intravascu-lar coagulation or thrombosis.

When depletion of NaCl and water(EFV reduction) occurs as a result of diu-retic therapy, the body can initiatecounter-regulatory responses (B),namely, activation of the renin-angio-tensin-aldosterone system (p. 124). Be-cause of the diminished blood volume,renal blood flow is jeopardized. Thisleads to release from the kidneys of thehormone, renin, which enzymaticallycatalyzes the formation of angiotensin I.Angiotensin I is converted to angioten-sin II by the action of angiotensin-con-verting enzyme (ACE). Angiotensin IIstimulates release of aldosterone. Themineralocorticoid promotes renal reab-sorption of NaCl and water and thuscounteracts the effect of diuretics. ACEinhibitors (p. 124) augment the effec-tiveness of diuretics by preventing thiscounter-regulatory response.

158 Diuretics


Diuretics 159

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

A. Mechanism of edema fluid mobilization by diuretics

Edema

Hemoconcentration

Collapse,danger ofthrombosis

Salt andfluid retention

Mobilization ofedema fluid

Protein molecules

Colloidosmoticpressure

Diuretic

EFV:Na+, Cl-,H2O

Diuretic Diuretic

AngiotensinogenRenin

Angiotensin IACE

Angiotensin II Aldosterone


NaCl Reabsorption in the Kidney (A)

The smallest functional unit of the kid-ney is the nephron. In the glomerularcapillary loops, ultrafiltration of plasmafluid into Bowman’s capsule (BC) yieldsprimary urine. In the proximal tubules(pT), approx. 70% of the ultrafiltrate isretrieved by isoosmotic reabsorption ofNaCl and water. In the thick portion ofthe ascending limb of Henle’s loop (HL),NaCl is absorbed unaccompanied bywater. This is the prerequisite for thehairpin countercurrent mechanism thatallows build-up of a very high NaCl con-centration in the renal medulla. In thedistal tubules (dT), NaCl and water areagain jointly reabsorbed. At the end ofthe nephron, this process involves an al-dosterone-controlled exchange of Na+

against K+ or H+. In the collecting tubule(C), vasopressin (antidiuretic hormone,ADH) increases the epithelial perme-ability for water, which is drawn intothe hyperosmolar milieu of the renalmedulla and thus retained in the body.As a result, a concentrated urine entersthe renal pelvis.

Na+ transport through the tubularcells basically occurs in similar fashionin all segments of the nephron. Theintracellular concentration of Na+ is sig-nificantly below that in primary urine.This concentration gradient is the driv-ing force for entry of Na+ into the cytosolof tubular cells. A carrier mechanismmoves Na+ across the membrane. Ener-gy liberated during this influx can beutilized for the coupled outward trans-port of another particle against a gradi-ent. From the cell interior, Na+ is movedwith expenditure of energy (ATP hy-drolysis) by Na+/K+-ATPase into the ex-tracellular space. The enzyme moleculesare confined to the basolateral parts ofthe cell membrane, facing the interstiti-um; Na+ can, therefore, not escape backinto tubular fluid.

All diuretics inhibit Na+ reabsorp-tion. Basically, either the inward or theoutward transport of Na+ can be affect-ed.

Osmotic Diuretics (B)

Agents: mannitol, sorbitol. Site of action:mainly the proximal tubules. Mode ofaction: Since NaCl and H2O are reab-sorbed together in the proximal tubules,Na+ concentration in the tubular fluiddoes not change despite the extensivereabsorption of Na+ and H2O. Body cellslack transport mechanisms for polyhy-dric alcohols such as mannitol (struc-ture on p. 171) and sorbitol, which arethus prevented from penetrating cellmembranes. Therefore, they need to begiven by intravenous infusion. They alsocannot be reabsorbed from the tubularfluid after glomerular filtration. Theseagents bind water osmotically and re-tain it in the tubular lumen. When Naions are taken up into the tubule cell,water cannot follow in the usualamount. The fall in urine Na+ concentra-tion reduces Na+ reabsorption, in partbecause the reduced concentration gra-dient towards the interior of tubule cellsmeans a reduced driving force for Na+

influx. The result of osmotic diuresis is alarge volume of dilute urine.

Indications: prophylaxis of renalhypovolemic failure, mobilization ofbrain edema, and acute glaucoma.

160 Diuretics


Diuretics 161

A. Kidney: NaCl reabsorption in nephron and tubular cell

dT

BC

C

pT

Cortex

MedullaThickportionof HL

Lumen Inter-stitium

Na/K-ATPaseNa+

Na+ "carrier"

ADH

HL

Mannitol

B. NaCl reabsorption in proximal tubule and effect of mannitol

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

Na+

Na+, Cl-

Na+, Cl- + H2O

H2O

Aldosterone

K+

Diuretics


Diuretics of the Sulfonamide Type

These drugs contain the sulfonamidegroup -SO2NH2. They are suitable fororal administration. In addition to beingfiltered at the glomerulus, they are sub-ject to tubular secretion. Their concen-tration in urine is higher than in blood.They act on the luminal membrane ofthe tubule cells. Loop diuretics have thehighest efficacy. Thiazides are most fre-quently used. Their forerunners, thecarbonic anhydrase inhibitors, are nowrestricted to special indications.

Carbonic anhydrase (CAH) inhibi-tors, such as acetazolamide and sulthi-ame, act predominantly in the proximaltubules. CAH catalyzes CO2 hydra-tion/dehydration reactions:H+ + HCO3

– ↔ H2CO3 ↔ H20 + CO2.The enzyme is used in tubule cells

to generate H+, which is secreted intothe tubular fluid in exchange for Na+.There, H+ captures HCO3

–, leading to for-mation of CO2 via the unstable carbonicacid. Membrane-permeable CO2 is takenup into the tubule cell and used to re-generate H+ and HCO3

–. When the en-zyme is inhibited, these reactions areslowed, so that less Na+, HCO3

– and wa-ter are reabsorbed from the fast-flowingtubular fluid. Loss of HCO3

– leads to aci-dosis. The diuretic effectiveness of CAHinhibitors decreases with prolongeduse. CAH is also involved in the produc-tion of ocular aqueous humor. Presentindications for drugs in this class in-clude: acute glaucoma, acute mountainsickness, and epilepsy. Dorzolamide canbe applied topically to the eye to lowerintraocular pressure in glaucoma.

Loop diuretics include furosemide(frusemide), piretanide, and bumeta-nide. With oral administration, a strongdiuresis occurs within 1 h but persistsfor only about 4 h. The effect is rapid, in-tense, and brief (high-ceiling diuresis).The site of action of these agents is thethick portion of the ascending limb ofHenle’s loop, where they inhibitNa+/K+/2Cl– cotransport. As a result,these electrolytes, together with water,are excreted in larger amounts. Excre-

tion of Ca2+ and Mg2+ also increases.Special toxic effects include: (reversible)hearing loss, enhanced sensitivity torenotoxic agents. Indications: pulmo-nary edema (added advantage of i.v. in-jection in left ventricular failure: imme-diate dilation of venous capacitancevessels � preload reduction); refrac-toriness to thiazide diuretics, e.g., in re-nal hypovolemic failure with creatinineclearance reduction (<30 mL/min); pro-phylaxis of acute renal hypovolemicfailure; hypercalcemia. Ethacrynic acidis classed in this group although it is nota sulfonamide.

Thiazide diuretics (benzothiadia-zines) include hydrochlorothiazide,benzthiazide, trichlormethiazide, andcyclothiazide. A long-acting analogue ischlorthalidone. These drugs affect theintermediate segment of the distal tu-bules, where they inhibit a Na+/Cl– co-transport. Thus, reabsorption of NaCland water is inhibited. Renal excretionof Ca2+ decreases, that of Mg2+ increases.Indications are hypertension, cardiacfailure, and mobilization of edema.

Unwanted effects of sulfonamide-type diuretics: (a) hypokalemia is a con-sequence of excessive K+ loss in the ter-minal segments of the distal tubuleswhere increased amounts of Na+ areavailable for exchange with K+; (b) hy-perglycemia and glycosuria; (c) hyper-uricemia—increase in serum urate lev-els may precipitate gout in predisposedpatients. Sulfonamide diuretics com-pete with urate for the tubular organicanion secretory system.

162 Diuretics


Diuretics 163

e.g., furosemide

Loop diuretics

Na+

K+

2 Cl-

A. Diuretics of the sulfonamide type

Anionsecretorysystem

e.g., acetazolamide

Carbonic anhydrase inhibitors

Na+

H+

HCO-3

H2OCO2

CAH

HCO-3

Na+

HCO-3H+

CO2 H2O

e.g., hydrochlorothiazide

Thiazides

Na+

Cl-

Sulfonamidediuretics

Uric acid

Gout

Hypokalemia

Normalstate

Loss ofNa+, K+

H2O


Potassium-Sparing Diuretics (A)

These agents act in the distal portion ofthe distal tubule and the proximal partof the collecting ducts where Na+ is re-absorbed in exchange for K+ or H+. Theirdiuretic effectiveness is relatively mi-nor. In contrast to sulfonamide diuretics(p. 162), there is no increase in K+ secre-tion; rather, there is a risk of hyperkale-mia. These drugs are suitable for oraladministration.

a) Triamterene and amiloride, in ad-dition to glomerular filtration, undergosecretion in the proximal tubule. Theyact on the luminal membrane of tubulecells. Both inhibit the entry of Na+,hence its exchange for K+ and H+. Theyare mostly used in combination withthiazide diuretics, e.g., hydrochlorothia-zide, because the opposing effects on K+

excretion cancel each other, while theeffects on secretion of NaCl complementeach other.

b) Aldosterone antagonists. Themineralocorticoid aldosterone pro-motes the reabsorption of Na+ (Cl– andH2O follow) in exchange for K+. Its hor-monal effect on protein synthesis leadsto augmentation of the reabsorptive ca-pacity of tubule cells. Spironolactone, aswell as its metabolite canrenone, are an-tagonists at the aldosterone receptorand attenuate the effect of the hormone.The diuretic effect of spironolactone de-velops fully only with continuous ad-ministration for several days. Two pos-sible explanations are: (1) the conver-sion of spironolactone into and accumu-lation of the more slowly eliminatedmetabolite canrenone; (2) an inhibitionof aldosterone-stimulated protein syn-thesis would become noticeable only ifexisting proteins had become nonfunc-tional and needed to be replaced by denovo synthesis. A particular adverse ef-fect results from interference with gon-adal hormones, as evidenced by the de-velopment of gynecomastia (enlarge-ment of male breast). Clinical uses in-clude conditions of increased aldoste-rone secretion, e.g., liver cirrhosis withascites.

Antidiuretic Hormone (ADH) and Derivatives (B)

ADH, a nonapeptide, released from theposterior pituitary gland promotes re-absorption of water in the kidney. Thisresponse is mediated by vasopressin re-ceptors of the V2 subtype. ADH enhanc-es the permeability of collecting ductepithelium for water (but not for elec-trolytes). As a result, water is drawnfrom urine into the hyperosmolar inter-stitium of the medulla. Nicotine aug-ments (p. 110) and ethanol decreasesADH release. At concentrations abovethose required for antidiuresis, ADHstimulates smooth musculature, includ-ing that of blood vessels (“vasopres-sin”). The latter response is mediated byreceptors of the V1 subtype. Blood pres-sure rises; coronary vasoconstrictioncan precipitate angina pectoris. Lypres-sin (8-L-lysine vasopressin) acts likeADH. Other derivatives may display on-ly one of the two actions.

Desmopressin is used for the thera-py of diabetes insipidus (ADH deficien-cy), nocturnal enuresis, thrombasthe-mia (p. 148), and chronic hypotension(p. 314); it is given by injection or viathe nasal mucosa (as “snuff”).

Felypressin and ornipressin serve asadjunctive vasoconstrictors in infiltra-tion local anesthesia (p. 206).

164 Diuretics


Diuretics 165

B. Antidiuretic hormone (ADH) and derivatives

A. Potassium-sparing diuretics

Na+

Canrenone

Neuro-hypophysis

H2Opermeabilityof collectingduct

Vasoconstriction

Desmopressin Ornipressin

Felypressin

K+

Aldosteroneantagonists

K+

orH+

Na+

Protein synthesisTransport capacity

Amiloride

Triamterene

Adiuretin = Vasopressin

Ethanol

Nicotine

V2 V1

Spironolactone

Aldosterone


Drugs for Gastric and Duodenal Ulcers

In the area of a gastric or duodenal pep-tic ulcer, the mucosa has been attackedby digestive juices to such an extent asto expose the subjacent connective tis-sue layer (submucosa). This self-diges-tion occurs when the equilibriumbetween the corrosive hydrochloric acidand acid-neutralizing mucus, whichforms a protective cover on the mucosalsurface, is shifted in favor of hydro-chloric acid. Mucosal damage can bepromoted by Helicobacter pylori bacte-ria that colonize the gastric mucus.

Drugs are employed with the fol-lowing therapeutic aims: (1) to relievepain; (2) to accelerate healing; and (3)to prevent ulcer recurrence. Therapeu-tic approaches are threefold: (a) to re-duce aggressive forces by lowering H+

output; (b) to increase protective forcesby means of mucoprotectants; and (c) toeradicate Helicobacter pylori.

I. Drugs for Lowering Acid Concentration

Ia. Acid neutralization. H+-bindinggroups such as CO3

2–, HCO3– or OH–, to-

gether with their counter ions, are con-tained in antacid drugs. Neutralizationreactions occurring after intake of CaCO3 and NaHCO3, respectively, areshown in (A) at left. With nonabsorb-able antacids, the counter ion is dis-solved in the acidic gastric juice in theprocess of neutralization. Upon mixturewith the alkaline pancreatic secretion inthe duodenum, it is largely precipitatedagain by basic groups, e.g., as CaCO3 orAlPO4, and excreted in feces. Therefore,systemic absorption of counter ions orbasic residues is minor. In the presenceof renal insufficiency, however, absorp-tion of even small amounts may causean increase in plasma levels of counterions (e.g., magnesium intoxication withparalysis and cardiac disturbances). Pre-cipitation in the gut lumen is respon-sible for other side effects, such as re-duced absorption of other drugs due totheir adsorption to the surface of pre-

cipitated antacid or, phosphate deple-tion of the body with excessive intake ofAl(OH)3.

Na+ ions remain in solution even inthe presence of HCO3

–-rich pancreaticsecretions and are subject to absorption,like HCO3

–. Because of the uptake of Na+,use of NaHCO3 must be avoided in con-ditions requiring restriction of NaCl in-take, such as hypertension, cardiac fail-ure, and edema.

Since food has a buffering effect,antacids are taken between meals (e.g.,1 and 3 h after meals and at bedtime).Nonabsorbable antacids are preferred.Because Mg(OH)2 produces a laxativeeffect (cause: osmotic action, p. 170, re-lease of cholecystokinin by Mg2+, orboth) and Al(OH)3 produces constipa-tion (cause: astringent action of Al3+, p.178), these two antacids are frequentlyused in combination.

Ib. Inhibitors of acid production.Acting on their respective receptors, thetransmitter acetylcholine, the hormonegastrin, and histamine released intra-mucosally stimulate the parietal cells ofthe gastric mucosa to increase output ofHCl. Histamine comes from entero-chromaffin-like (ECL) cells; its release isstimulated by the vagus nerve (via M1

receptors) and hormonally by gastrin.The effects of acetylcholine and hista-mine can be abolished by orally appliedantagonists that reach parietal cells viathe blood.

The cholinoceptor antagonist pi-renzepine, unlike atropine, prefers cho-linoceptors of the M1 type, does notpenetrate into the CNS, and thus pro-duces fewer atropine-like side effects(p. 104). The cholinoceptors on parietalcells probably belong to the M3 subtype.Hence, pirenzepine may act by blockingM1 receptors on ECL cells or submucosalneurons.

Histamine receptors on parietalcells belong to the H2 type (p. 114) andare blocked by H2-antihistamines. Be-cause histamine plays a pivotal role inthe activation of parietal cells, H2-anti-histamines also diminish responsivityto other stimulants, e.g., gastrin (in gas-

166 Drugs for the Treatment of Peptic Ulcers


Drugs for the Treatment of Peptic Ulcers 167

Inhibition of acid production

N. vagus

M1

Pire

nzep

ine

Parietal cell

ACh

HistamineECL-cell

ATPase

H2-Antihistamines

Cimetidine

Ranitidine

Acid neutralization

Antacidsnot absorbable

absorbable

CaCO3Mg(OH)2Al(OH)3

NaHCO3

A. Drugs used to lower gastric acid concentration or production

Pancreas

K+

M3

H2

AChH+

H2CO3

H2O CO2

Ca2+Ca2+

CO32-

H2O+CO2

HCO3-

H+

Pancreas

HCO3- Na+ HCO3

-

Na+

H+

H+

CaCO3

CaCO3

Absorption

Omeprazole

Proton pump-inhibitors

Na+

N

NS

O

H

N

H3CO

OCH3

CH3H3C

Gastrin

CH2 S

(CH2)2

NH

C NHCH3

N NC

N

HN

CH3

O CH2CH2N

H3C

S

(CH2)2

NH

C NHCH3

CH NO2

H3C

CaCO3


trin-producing pancreatic tumors, Zol-linger-Ellison syndrome). Cimetidine,the first H2-antihistamine used thera-peutically, only rarely produces side ef-fects (CNS disturbances such as confu-sion; endocrine effects in the male, suchas gynecomastia, decreased libido, im-potence). Unlike cimetidine, its newerand more potent congeners, ranitidine,nizatidine, and famotidine, do not inter-fere with the hepatic biotransformationof other drugs.

Omeprazole (p. 167) can cause max-imal inhibition of HCl secretion. Givenorally in gastric juice-resistant capsules,it reaches parietal cells via the blood. Inthe acidic milieu of the mucosa, an ac-tive metabolite is formed and binds co-valently to the ATP-driven proton pump(H+/K+ ATPase) that transports H+ in ex-change for K+ into the gastric juice. Lan-soprazole and pantoprazole produceanalogous effects. The proton pump in-hibitors are first-line drugs for the treat-ment of gastroesophageal reflux dis-ease.

II. Protective Drugs

Sucralfate (A) contains numerous alu-minum hydroxide residues. However, itis not an antacid because it fails to lowerthe overall acidity of gastric juice. Afteroral intake, sucralfate molecules under-go cross-linking in gastric juice, forminga paste that adheres to mucosal defectsand exposed deeper layers. Here sucral-fate intercepts H+. Protected from acid,and also from pepsin, trypsin, and bileacids, the mucosal defect can heal morerapidly. Sucralfate is taken on an emptystomach (1 h before meals and at bed-time). It is well tolerated; however, re-leased Al3+ ions can cause constipation.

Misoprostol (B) is a semisyntheticprostaglandin derivative with greaterstability than natural prostaglandin,permitting absorption after oral admin-istration. Like locally released prosta-glandins, it promotes mucus productionand inhibits acid secretion. Additionalsystemic effects (frequent diarrhea; riskof precipitating contractions of the

gravid uterus) significantly restrict itstherapeutic utility.

Carbenoxolone (B) is a derivativeof glycyrrhetinic acid, which occurs inthe sap of licorice root (succus liquiri-tiae). Carbenoxolone stimulates mucusproduction. At the same time, it has amineralocorticoid-like action (due to in-hibition of 11-β-hydroxysteroid dehy-drogenase) that promotes renal reab-sorption of NaCl and water. It may,therefore, exacerbate hypertension,congestive heart failure, or edemas. It isobsolete.

III. Eradication of Helicobacter py-lori C. This microorganism plays an im-portant role in the pathogenesis ofchronic gastritis and peptic ulcer dis-ease. The combination of antibacterialdrugs and omeprazole has proven effec-tive. In case of intolerance to amoxicillin(p. 270) or clarithromycin (p. 276), met-ronidazole (p. 274) can be used as a sub-stitute. Colloidal bismuth compoundsare also effective; however, the problemof heavy-metal exposure compromisestheir long-term use.

168 Drugs for the Treatment of Peptic Ulcers


Drugs for the Treatment of Peptic Ulcers 169

C. Helicobacter eradication

Misoprostol

B. Chemical structure and protective effect of misoprostol

A. Chemical structure and protective effect of sucralfate

R = – SO3[Al2(OH)5]

Sucralfate

Conversionin acidic en-vironmentpH < 4

Cross-linkingand formationof paste

Coating ofmucosaldefects

R = – SO3[Al2(OH)4]+– SO3-

H+

R R

RR

R R

RR

Helicobacterpylori

Eradicatione.g., short-term triple therapy

GastritisPeptic ulcer Amoxicillin

ClarithromycinOmeprazole

(2 x 1000 mg)(2 x 500 mg)(2 x 20 mg)

7 days7 days7 days

Induction of labor

Prostaglandinreceptor

K+H+HClMucus ATPase

Parietal cell


Laxatives

Laxatives promote and facilitate bowelevacuation by acting locally to stimulateintestinal peristalsis, to soften bowelcontents, or both.

1. Bulk laxatives. Distention of theintestinal wall by bowel contents stimu-lates propulsive movements of the gutmusculature (peristalsis). Activation ofintramural mechanoreceptors induces aneurally mediated ascending reflex con-traction (red in A) and descending re-laxation (blue) whereby the intralumi-nal bolus is moved in the anal direction.

Hydrophilic colloids or bulk gels(B) comprise insoluble and nonabsorb-able carbohydrate substances that ex-pand on taking up water in the bowel.Vegetable fibers in the diet act in thismanner. They consist of the indigestibleplant cell walls containing homoglycansthat are resistant to digestive enzymes,e.g., cellulose (1�4β-linked glucose mo-lecules vs. 1�4α glucoside bond instarch, p. 153).

Bran, a grain milling waste product,and linseed (flaxseed) are both rich incellulose. Other hydrophilic colloids de-rive from the seeds of Plantago speciesor karaya gum. Ingestion of hydrophilicgels for the prophylaxis of constipationusually entails a low risk of side effects.However, with low fluid intake in com-bination with a pathological bowelstenosis, mucilaginous viscous materialcould cause bowel occlusion (ileus).

Osmotically active laxatives (C)are soluble but nonabsorbable particlesthat retain water in the bowel by virtueof their osmotic action. The osmoticpressure (particle concentration) ofbowel contents always corresponds tothat of the extracellular space. The in-testinal mucosa is unable to maintain ahigher or lower osmotic pressure of theluminal contents. Therefore, absorptionof molecules (e.g., glucose, NaCl) occursisoosmotically, i.e., solute molecules arefollowed by a corresponding amount ofwater. Conversely, water remains in thebowel when molecules cannot be ab-sorbed.

With Epsom and Glauber’s salts(MgSO4 and Na2SO4, respectively), theSO4

2– anion is nonabsorbable and re-tains cations to maintain electroneu-trality. Mg2+ ions are also believed topromote release from the duodenal mu-cosa of cholecystokinin/pancreozymin,a polypeptide that also stimulates peris-talsis. These so-called saline catharticselicit a watery bowel discharge 1–3 h af-ter administration (preferably in isoton-ic solution). They are used to purge thebowel (e.g., before bowel surgery) or tohasten the elimination of ingested poi-sons. Glauber’s salt (high Na+ content) iscontraindicated in hypertension, con-gestive heart failure, and edema. Epsomsalt is contraindicated in renal failure(risk of Mg2+ intoxication).

Osmotic laxative effects are alsoproduced by the polyhydric alcohols,mannitol and sorbitol, which unlike glu-cose cannot be transported through theintestinal mucosa, as well as by the non-hydrolyzable disaccharide, lactulose.Fermentation of lactulose by colon bac-teria results in acidification of bowelcontents and microfloral damage. Lac-tulose is used in hepatic failure in orderto prevent bacterial production of am-monia and its subsequent absorption(absorbable NH3 � nonabsorbableNH4

+), so as to forestall hepatic coma.2. Irritant laxatives—purgatives

cathartics. Laxatives in this group exertan irritant action on the enteric mucosa(A). Consequently, less fluid is absorbedthan is secreted. The increased filling ofthe bowel promotes peristalsis; excita-tion of sensory nerve endings elicits en-teral hypermotility. According to thesite of irritation, one distinguishes thesmall bowel irritant castor oil from thelarge bowel irritants anthraquinone anddiphenolmethane derivatives (for de-tails see p. 174).

Misuse of laxatives. It is a widelyheld belief that at least one bowelmovement per day is essential forhealth; yet three bowel evacuations perweek are quite normal. The desire forfrequent bowel emptying probablystems from the time-honored, albeit

170 Laxatives


Laxatives 171

C. Osmotically active laxatives

B. Bulk laxatives

A. Stimulation of peristalsis by an intraluminal bolus

Stretch receptors

Cellulose, agar-agar, bran, linseed

H2O

G = Glucose

Contraction Relaxation

H2O

H2ONa+, Cl-

H2O

H2ONa+, Cl-

H2OH2O

Na+, Cl-

H2O

H2ONa+, Cl-

H2O

H2ONa+, Cl-

H2O

H2ONa+, Cl-

H2O

H2ONa+, Cl-

H2O

H2ONa+, Cl-

H2O

H2ONa+, Cl-

H2O

H2ONa+, Cl-

H2O

H2ONa+, Cl-

H2O

H2ONa+, Cl-

H2O

H2ONa+, Cl-

H2O

H2ONa+, Cl-

H2O

Isoosmoticabsorption

GH2O

H2OG

GH2O

H2O

H2O

2 Na+ SO42- H2O H2O

MannitolH2O

GH2O

GH2O

GH2O


mistaken, notion that absorption of co-lon contents is harmful. Thus, purginghas long been part of standard thera-peutic practice. Nowadays, it is knownthat intoxication from intestinal sub-stances is impossible as long as the liverfunctions normally. Nonetheless, purga-tives continue to be sold as remedies to“cleanse the blood” or to rid the body of“corrupt humors.”

There can be no objection to the in-gestion of bulk substances for the pur-pose of supplementing low-residue“modern diets.” However, use of irritantpurgatives or cathartics is not withouthazards. Specifically, there is a risk oflaxative dependence, i.e., the inability todo without them. Chronic intake of irri-tant purgatives disrupts the water andelectrolyte balance of the body and canthus cause symptoms of illness (e.g.,cardiac arrhythmias secondary to hypo-kalemia).

Causes of purgative dependence(B). The defecation reflex is triggeredwhen the sigmoid colon and rectum arefilled. A natural defecation empties thelarge bowel up to and including the de-scending colon. The interval betweennatural stool evacuations depends onthe speed with which these colon seg-ments are refilled. A large bowel irritantpurgative clears out the entire colon.Accordingly, a longer period is neededuntil the next natural defecation can oc-cur. Fearing constipation, the user be-comes impatient and again resorts tothe laxative, which then produces thedesired effect as a result of emptyingout the upper colonic segments. There-fore, a “compensatory pause” followingcessation of laxative use must not givecause for concern (1).

In the colon, semifluid material en-tering from the small bowel is thick-ened by absorption of water and salts(from about 1000 to 150 mL/d). If, dueto the action of an irritant purgative, thecolon empties prematurely, an enteralloss of NaCl, KCl and water will be in-curred. To forestall depletion of NaCland water, the body responds with anincreased release of aldosterone (p.

124), which stimulates their reabsorp-tion in the kidney. The action of aldoste-rone is, however, associated with in-creased renal excretion of KCl. The en-teral and renal K+ loss add up to a K+ de-pletion of the body, evidenced by a fallin serum K+ concentration (hypokale-mia). This condition is accompanied bya reduction in intestinal peristalsis(bowel atonia). The affected individualinfers “constipation,” again partakes ofthe purgative, and the vicious circle isclosed (2).

Chologenic diarrhea results whenbile acids fail to be absorbed in the ile-um (e.g., after ileal resection) and enterthe colon, where they cause enhancedsecretion of electrolytes and water,leading to the discharge of fluid stools.

172 Laxatives


Laxatives 173

B. Causes of laxative habituation

A. Stimulation of peristalsis by mucosal irritation

PeristalsisIrritationof mucosa

Intervalneeded torefill colon

Normal filling defecation reflex

After normalevacuation of colon

Laxative

Longer interval neededto refill rectum

Enteralloss of K+

Na+, H2O

Renallossof K+

Aldosterone

Renal retentionof Na+, H2O

Reflex

Filling

Absorption Secretionof fluid

Bowel inertia

Hypokalemia

“Constipation”

Laxative

1

2


2.a Small Bowel Irritant Purgative, Ricinoleic AcidCastor oil comes from Ricinus commu-nis (castor plants; Fig: sprig, panicle,seed); it is obtained from the first cold-pressing of the seed (shown in naturalsize). Oral administration of 10–30 mLof castor oil is followed within 0.5 to 3 hby discharge of a watery stool. Ricinole-ic acid, but not the oil itself, is active. Itarises as a result of the regular process-es involved in fat digestion: the duoden-al mucosa releases the enterohormonecholecystokinin/pancreozymin into theblood. The hormone elicits contractionof the gallbladder and discharge of bileacids via the bile duct, as well as releaseof lipase from the pancreas (intestinalperistalsis is also stimulated). Becauseof its massive effect, castor oil is hardlysuitable for the treatment of ordinaryconstipation. It can be employed afteroral ingestion of a toxin in order to has-ten elimination and to reduce absorp-tion of toxin from the gut. Castor oil isnot indicated after the ingestion of lipo-philic toxins likely to depend on bile ac-ids for their absorption.

2.b Large Bowel Irritant Purgatives (p. 177 ff)

Anthraquinone derivatives (p. 176) areof plant origin. They occur in the leaves(folia sennae) or fruits (fructus sennae)of the senna plant, the bark of Rhamnusfrangulae and Rh. purshiana, (cortexfrangulae, cascara sagrada), the roots ofrhubarb (rhizoma rhei), or the leaf ex-tract from Aloe species (p. 176). Thestructural features of anthraquinone de-rivatives are illustrated by the proto-type structure depicted on p. 177.Among other substituents, the anthra-quinone nucleus contains hydroxylgroups, one of which is bound to a sugar(glucose, rhamnose). Following inges-tion of galenical preparations or of theanthraquinone glycosides, discharge ofsoft stool occurs after a latency of 6 to 8h. The anthraquinone glycosides them-selves are inactive but are converted by

colon bacteria to the active free agly-cones.Diphenolmethane derivatives (p. 177)were developed from phenolphthalein,an accidentally discovered laxative, useof which had been noted to result inrare but severe allergic reactions. Bisac-odyl and sodium picosulfate are convert-ed by gut bacteria into the active colon-irritant principle. Given by the enteralroute, bisacodyl is subject to hydrolysisof acetyl residues, absorption, conjuga-tion in liver to glucuronic acid (or also tosulfate, p. 38), and biliary secretion intothe duodenum. Oral administration isfollowed after approx. 6 to 8 h by dis-charge of soft formed stool. When givenby suppository, bisacodyl produces itseffect within 1 h.Indications for colon-irritant purga-tives are the prevention of straining atstool following surgery, myocardial in-farction, or stroke; and provision of re-lief in painful diseases of the anus, e.g.,fissure, hemorrhoids.

Purgatives must not be given in ab-dominal complaints of unclear origin.3. Lubricant laxatives. Liquid paraffin(paraffinum subliquidum) is almost non-absorbable and makes feces softer andmore easily passed. It interferes withthe absorption of fat-soluble vitaminsby trapping them. The few absorbedparaffin particles may induce formationof foreign-body granulomas in entericlymph nodes (paraffinomas). Aspirationinto the bronchial tract can result in li-poid pneumonia. Because of these ad-verse effects, its use is not advisable.

174 Laxatives and Purgatives


Laxatives and Purgatives 175

A. Small-bowel irritant laxative: ricinoleic acid

Ricinuscommunis

Gall-bladder

Pancreas

Per

ista

lsis

CK/PZ =Cholecystokinin/pancreozymin

CK/PZ

Castor oil

Glycerol +

3 Ricinoleic acids

Bileacids

Duodenum

Ricinoleic acid – O – CH2

Ricinoleic acid – O – CH

Ricinoleic acid – O – CH2

Lipase


176 Laxatives and Purgatives

A. Plants containing anthraquinone glycosides

Senna Frangula

Rhubarb Aloe


Laxatives and Purgatives 177

Sugar cleavage

Reduction

Anthraquinoneglycoside

Bacteria

1,8-Dihydroxy-anthrone -Anthranol

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

Glucuronide

EsteraseDiphenol

B. Large-bowel irritant laxatives: diphenylmethane derivatives

A. Large-bowel irritant laxatives: anthraquinone derivatives

Glucuronidation

Diphenol

Bacteria

Glucu-ronate

Sulfate

BisacodylSodiumpicosulfate

sugar


Antidiarrheal Agents

Causes of diarrhea (in red): Many bacte-ria (e.g., Vibrio cholerae) secrete toxinsthat inhibit the ability of mucosal ente-rocytes to absorb NaCl and water and, atthe same time, stimulate mucosal secre-tory activity. Bacteria or viruses that in-vade the gut wall cause inflammationcharacterized by increased fluid secre-tion into the lumen. The enteric muscu-lature reacts with increased peristalsis.

The aims of antidiarrheal therapyare to prevent: (1) dehydration andelectrolyte depletion; and (2) excessive-ly high stool frequency. Different ther-apeutic approaches (in green) listedare variously suited for these purposes.

Adsorbent powders are nonab-sorbable materials with a large surfacearea. These bind diverse substances, in-cluding toxins, permitting them to beinactivated and eliminated. Medicinalcharcoal possesses a particularly largesurface because of the preserved cellstructures. The recommended effectiveantidiarrheal dose is in the range of4–8 g. Other adsorbents are kaolin (hy-drated aluminum silicate) and chalk.

Oral rehydration solution (g/L ofboiled water: NaCl 3.5, glucose 20,NaHCO3 2.5, KCl 1.5). Oral administra-tion of glucose-containing salt solutionsenables fluids to be absorbed becausetoxins do not impair the cotransport ofNa+ and glucose (as well as of H2O)through the mucosal epithelium. In thismanner, although frequent discharge ofstool is not prevented, dehydration issuccessfully corrected.

Opioids. Activation of opioid recep-tors in the enteric nerve plexus resultsin inhibition of propulsive motor activ-ity and enhancement of segmentationactivity. This antidiarrheal effect wasformerly induced by application of opi-um tincture (paregoric) containing mor-phine. Because of the CNS effects (seda-tion, respiratory depression, physicaldependence), derivatives with periph-eral actions have been developed.Whereas diphenoxylate can still produceclear CNS effects, loperamide does not

affect brain functions at normal dosage.Loperamide is, therefore, the opioidantidiarrheal of first choice. The pro-longed contact time of intestinal con-tents and mucosa may also improve ab-sorption of fluid. With overdosage,there is a hazard of ileus. It is contrain-dicated in infants below age 2 y.

Antibacterial drugs. Use of theseagents (e.g., cotrimoxazole, p. 272) isonly rational when bacteria are thecause of diarrhea. This is rarely the case.It should be kept in mind that antibio-tics also damage the intestinal florawhich, in turn, can give rise to diarrhea.

Astringents such as tannic acid(home remedy: black tea) or metal saltsprecipitate surface proteins and arethought to help seal the mucosal epithe-lium. Protein denaturation must not in-clude cellular proteins, for this wouldmean cell death. Although astringentsinduce constipation (cf. Al3+ salts,p. 166), a therapeutic effect in diarrheais doubtful.

Demulcents, e.g., pectin (homeremedy: grated apples) are carbohy-drates that expand on absorbing water.They improve the consistency of bowelcontents; beyond that they are devoidof any favorable effect.

178 Antidiarrheals


Antidiarrheals 179

A. Antidiarrheals and their sites of action

Residentmicroflora

Opioid-receptors

Protein-containingmucus

Precipitation ofsurface proteins,sealing ofmucosa

Astringents:e.g., tannic acid

Viruses

Pathogenicbacteria

Fluid secretion

Cl-

Na+

Toxins

Glucose

Na+

Muc

osa

l inj

ury

Antibacterialdrugs:e.g., co-trimoxazole

Adsorptione.g., tomedicinalcharcoal

Toxins

Inhibition ofpropulsiveperistalsis

Opium tincturewith morphine

Diphenoxylate

Loperamide

CNS

Enh

ance

d p

eris

tals

is

Diarrhea

Oralrehydrationsolution:salts andglucose

Flui

dlo

ss


Drugs for Dissolving Gallstones (A)

Following its secretion from liver intobile, water-insoluble cholesterol is heldin solution in the form of micellar com-plexes with bile acids and phospholip-ids. When more cholesterol is secretedthan can be emulsified, it precipitatesand forms gallstones (cholelithiasis).Precipitated cholesterol can be reincor-porated into micelles, provided the cho-lesterol concentration in bile is belowsaturation. Thus, cholesterol-contain-ing stones can be dissolved slowly. Thiseffect can be achieved by long-term oraladministration of chenodeoxycholicacid (CDCA) or ursodeoxycholic acid(UDCA). Both are physiologically occur-ring, stereoisomeric bile acids (positionof the 7-hydroxy group being β in UCDAand α in CDCA). Normally, they repre-sent a small proportion of the totalamount of bile acid present in the body(circle diagram in A); however, this in-creases considerably with chronic ad-ministration because of enterohepaticcycling, p. 38). Bile acids undergo almostcomplete reabsorption in the ileum.Small losses via the feces are made upby de novo synthesis in the liver, keep-ing the total amount of bile acids con-stant (3–5 g). Exogenous supply re-moves the need for de novo synthesis ofbile acids. The particular acid being sup-plied gains an increasingly larger shareof the total store.

The altered composition of bile in-creases the capacity for cholesterol up-take. Thus, gallstones can be dissolvedin the course of a 1- to 2 y treatment,provided that cholesterol stones arepure and not too large (<15 mm), gallbladder function is normal, liver diseaseis absent, and patients are of normalbody weight. UCDA is more effective(daily dose, 8–10 mg) and better toler-ated than is CDCA (15 mg/d; frequentdiarrhea, elevation of liver enzymes inplasma). Stone formation may recur af-ter cessation of successful therapy.

Compared with surgical treatment,drug therapy plays a subordinate role.

UCDA may also be useful in primary bil-iary cirrhosis.

Choleretics are supposed to stimu-late production and secretion of dilutebile fluid. This principle has little thera-peutic significance.

Cholekinetics stimulate the gall-bladder to contract and empty, e.g., eggyolk, the osmotic laxative MgSO4, thecholecystokinin-related ceruletide (giv-en parenterally). Cholekinetics are em-ployed to test gallbladder function fordiagnostic purposes.

Pancreatic enzymes (B) fromslaughtered animals are used to relieveexcretory insufficiency of the pancreas(� disrupted digestion of fats; steator-rhea, inter alia). Normally, secretion ofpancreatic enzymes is activated bycholecystokinin/pancreozymin, the en-terohormone that is released into bloodfrom the duodenal mucosa upon con-tact with chyme. With oral administra-tion of pancreatic enzymes, allowancemust be made for their partial inactiva-tion by gastric acid (the lipases, particu-larly). Therefore, they are administeredin acid-resistant dosage forms.

Antiflatulents (carminatives) serveto alleviate meteorism (excessive accu-mulation of gas in the gastrointestinaltract). Aborad propulsion of intestinalcontents is impeded when the latter aremixed with gas bubbles. Defoamingagents, such as dimethicone (dimethyl-polysiloxane) and simethicone, in com-bination with charcoal, are given orallyto promote separation of gaseous andsemisolid contents.

180 Other Gastrointestinal Drugs


Other Gastrointestinal Drugs 181

CA : Cholic acidDCA : Desoxy-CA

UDCA : Ursodesoxy-CACDCA : Chenodesoxy-CA

UDCA

Gall-stoneformed bycholesterol

Ileum

Excretionin feces

Stomach

Duodenum

CK/PZ

Fat-containingchymus

Additionofdimethicone

“Defoaming”

C. Carminative effect ofdimethicone

Synthesis of bileacids to maintainstore

DAA

CDCA CA

UDCA

DCACDCA CA

UDCA

“Pancreatin” of slaughter animals:Protease, Amylase,

Lipase

Pancreaticenzyme

B. Release of pancreatic enzymes andtheir replacement

A. Gallstone dissolution

Circulation


Drugs Affecting Motor Function

The smallest structural unit of skeletalmusculature is the striated muscle fiber.It contracts in response to an impulse ofits motor nerve. In executing motor pro-grams, the brain sends impulses to thespinal cord. These converge on α-moto-neurons in the anterior horn of the spi-nal medulla. Efferent axons course, bun-dled in motor nerves, to skeletal mus-cles. Simple reflex contractions to sen-sory stimuli, conveyed via the dorsalroots to the motoneurons, occur with-out participation of the brain. Neuralcircuits that propagate afferent impuls-es into the spinal cord contain inhibit-ory interneurons. These serve to pre-vent a possible overexcitation of moto-neurons (or excessive muscle contrac-tions) due to the constant barrage ofsensory stimuli.

Neuromuscular transmission (B) ofmotor nerve impulses to the striatedmuscle fiber takes place at the motorendplate. The nerve impulse liberatesacetylcholine (ACh) from the axon ter-minal. ACh binds to nicotinic cholinocep-tors at the motor endplate. Activation ofthese receptors causes depolarization ofthe endplate, from which a propagatedaction potential (AP) is elicited in thesurrounding sarcolemma. The AP trig-gers a release of Ca2+ from its storage or-ganelles, the sarcoplasmic reticulum(SR), within the muscle fiber; the rise inCa2+ concentration induces a contrac-tion of the myofilaments (electrome-chanical coupling). Meanwhile, ACh ishydrolyzed by acetylcholinesterase(p. 100); excitation of the endplate sub-sides. If no AP follows, Ca2+ is taken upagain by the SR and the myofilamentsrelax.

Clinically important drugs (withthe exception of dantrolene) all inter-fere with neural control of the musclecell (A, B, p. 183ff.)

Centrally acting muscle relaxants(A) lower muscle tone by augmentingthe activity of intraspinal inhibitoryinterneurons. They are used in the treat-ment of painful muscle spasms, e.g., in

spinal disorders. Benzodiazepines en-hance the effectiveness of the inhibitorytransmitter GABA (p. 226) at GABAA re-ceptors. Baclofen stimulates GABAB re-ceptors. α2-Adrenoceptor agonists suchas clonidine and tizanidine probably actpresynaptically to inhibit release of ex-citatory amino acid transmitters.

The convulsant toxins, tetanus tox-in (cause of wound tetanus) and strych-nine diminish the efficacy of interneu-ronal synaptic inhibition mediated bythe amino acid glycine (A). As a conse-quence of an unrestrained spread ofnerve impulses in the spinal cord, motorconvulsions develop. The involvementof respiratory muscle groups endangerslife.

Botulinum toxin from Clostridiumbotulinum is the most potent poisonknown. The lethal dose in an adult is ap-prox. 3 � 10–6 mg. The toxin blocks exo-cytosis of ACh in motor (and also para-sympathetic) nerve endings. Death iscaused by paralysis of respiratory mus-cles. Injected intramuscularly at minus-cule dosage, botulinum toxin type A isused to treat blepharospasm, strabis-mus, achalasia of the lower esophagealsphincter, and spastic aphonia.

A pathological rise in serum Mg2+

levels also causes inhibition of ACh re-lease, hence inhibition of neuromuscu-lar transmission.

Dantrolene interferes with electro-mechanical coupling in the muscle cellby inhibiting Ca2+ release from the SR. Itis used to treat painful muscle spasmsattending spinal diseases and skeletalmuscle disorders involving excessiverelease of Ca2+ (malignant hyperther-mia).

182 Drugs Acting on Motor Systems


Drugs Acting on Motor Systems 183

Depola-rization

Attenuatedinhibition

Inhibitoryinterneuron

TetanusToxinInhibitionof release

GlycineStrychnineReceptorantagonist

ConvulsantsMyotonolytics

Increasedinhibition

Inhibitoryneuron

Benzodiazepinese.g., diazepam GABA

AgonistBaclofen

(GABA =γ-aminobutyric acid)

B. Inhibition of neuromuscular transmission and electromechanical coupling

A. Mechanisms for influencing skeletal muscle tone

Antiepileptics Antiparkinsonian drugs

Myotonolytics Dantrolene

Muscle relaxants

Mg2+

Botulinum toxininhibitACh-release

Muscle relaxantsinhibit generationof actionpotential

Sarcoplasmicreticulum

Action potential

Motorneuron

Motorendplate

ACh receptor(nicotinic)

Myofilaments

Contraction

Ca2+

Membrane potential

Muscle tone

ms 10 20

ACh

t-Tubule

DantroleneinhibitsCa2+ release


Muscle Relaxants

Muscle relaxants cause a flaccid paraly-sis of skeletal musculature by binding tomotor endplate cholinoceptors, thusblocking neuromuscular transmission (p.182). According to whether receptor oc-cupancy leads to a blockade or an exci-tation of the endplate, one distinguishesnondepolarizing from depolarizingmuscle relaxants (p. 186). As adjuncts togeneral anesthetics, muscle relaxantshelp to ensure that surgical proceduresare not disturbed by muscle contrac-tions of the patient (p. 216).

Nondepolarizing muscle relaxants

Curare is the term for plant-derived ar-row poisons of South American natives.When struck by a curare-tipped arrow,an animal suffers paralysis of skeletalmusculature within a short time afterthe poison spreads through the body;death follows because respiratory mus-cles fail (respiratory paralysis). Killedgame can be eaten without risk becauseabsorption of the poison from the gas-trointestinal tract is virtually nil. The cu-rare ingredient of greatest medicinalimportance is d-tubocurarine. Thiscompound contains a quaternary nitro-gen atom (N) and, at the opposite end ofthe molecule, a tertiary N that is proto-nated at physiological pH. These twopositively charged N atoms are commonto all other muscle relaxants. The fixedpositive charge of the quaternary N ac-counts for the poor enteral absorbabil-ity.

d-Tubocurarine is given by i.v. in-jection (average dose approx. 10 mg). Itbinds to the endplate nicotinic cholino-ceptors without exciting them, acting asa competitive antagonist towards ACh.By preventing the binding of releasedACh, it blocks neuromuscular transmis-sion. Muscular paralysis develops with-in about 4 min. d-Tubocurarine does notpenetrate into the CNS. The patientwould thus experience motor paralysisand inability to breathe, while remain-ing fully conscious but incapable of ex-

pressing anything. For this reason, caremust be taken to eliminate conscious-ness by administration of an appropri-ate drug (general anesthesia) before us-ing a muscle relaxant. The effect of a sin-gle dose lasts about 30 min.

The duration of the effect of d-tubo-curarine can be shortened by adminis-tering an acetylcholinesterase inhibitor,such as neostigmine (p. 102). Inhibitionof ACh breakdown causes the concen-tration of ACh released at the endplateto rise. Competitive “displacement” byACh of d-tubocurarine from the recep-tor allows transmission to be restored.

Unwanted effects produced by d-tu-bocurarine result from a nonimmune-mediated release of histamine frommast cells, leading to bronchospasm, ur-ticaria, and hypotension. More com-monly, a fall in blood pressure can be at-tributed to ganglionic blockade by d-tu-bocurarine.

Pancuronium is a synthetic com-pound now frequently used and notlikely to cause histamine release or gan-glionic blockade. It is approx. 5-foldmore potent than d-tubocurarine, witha somewhat longer duration of action.Increased heart rate and blood pressureare attributed to blockade of cardiac M2-cholinoceptors, an effect not shared bynewer pancuronium congeners such asvecuronium and pipecuronium.

Other nondepolarizing muscle re-laxants include: alcuronium, derivedfrom the alkaloid toxiferin; rocuroni-um, gallamine, mivacurium, and atra-curium. The latter undergoes spontane-ous cleavage and does not depend onhepatic or renal elimination.




ACh

A. Non-depolarizing muscle relaxants

Arrow poison of indigenous South Americans

Blockade of ACh receptorsNo depolarization ofendplate

Relaxation of skeletal muscles

(Respiratory paralysis)

Artificialventilationnecessary(plus generalanesthesia!)

Antidote:cholinesteraseinhibitorse.g., neostigmine

(no enteral absorption)d-Tubocurarine Pancuronium


Depolarizing Muscle Relaxants

In this drug class, only succinylcholine(succinyldicholine, suxamethonium, A)is of clinical importance. Structurally, itcan be described as a double ACh mole-cule. Like ACh, succinylcholine acts asagonist at endplate nicotinic cholino-ceptors, yet it produces muscle relaxa-tion. Unlike ACh, it is not hydrolyzed byacetylcholinesterase. However, it is asubstrate of nonspecific plasma cholin-esterase (serum cholinesterase, p. 100).Succinylcholine is degraded more slow-ly than is ACh and therefore remains inthe synaptic cleft for several minutes,causing an endplate depolarization ofcorresponding duration. This depola-rization initially triggers a propagatedaction potential (AP) in the surroundingmuscle cell membrane, leading to con-traction of the muscle fiber. After its i.v.injection, fine muscle twitches (fascicu-lations) can be observed. A new AP canbe elicited near the endplate only if themembrane has been allowed to repo-larize.

The AP is due to opening of voltage-gated Na-channel proteins, allowingNa+ ions to flow through the sarcolem-ma and to cause depolarization. After afew milliseconds, the Na channels closeautomatically (“inactivation”), themembrane potential returns to restinglevels, and the AP is terminated. As longas the membrane potential remains in-completely repolarized, renewed open-ing of Na channels, hence a new AP, isimpossible. In the case of released ACh,rapid breakdown by ACh esterase al-lows repolarization of the endplate andhence a return of Na channel excitabil-ity in the adjacent sarcolemma. Withsuccinylcholine, however, there is a per-sistent depolarization of the endplateand adjoining membrane regions. Be-cause the Na channels remain inactivat-ed, an AP cannot be triggered in the ad-jacent membrane.

Because most skeletal muscle fibersare innervated only by a single endplate,activation of such fibers, with lengthsup to 30 cm, entails propagation of the

AP through the entire cell. If the AP fails,the muscle fiber remains in a relaxedstate.

The effect of a standard dose of suc-cinylcholine lasts only about 10 min. Itis often given at the start of anesthesiato facilitate intubation of the patient. Asexpected, cholinesterase inhibitors areunable to counteract the effect of succi-nylcholine. In the few patients with agenetic deficiency in pseudocholineste-rase (= nonspecific cholinesterase), thesuccinylcholine effect is significantlyprolonged.

Since persistent depolarization ofendplates is associated with an efflux ofK+ ions, hyperkalemia can result (risk ofcardiac arrhythmias).

Only in a few muscle types (e.g.,extraocular muscle) are muscle fiberssupplied with multiple endplates. Heresuccinylcholine causes depolarizationdistributed over the entire fiber, whichresponds with a contracture. Intraocularpressure rises, which must be taken intoaccount during eye surgery.

In skeletal muscle fibers whose mo-tor nerve has been severed, ACh recep-tors spread in a few days over the entirecell membrane. In this case, succinyl-choline would evoke a persistent depo-larization with contracture and hyper-kalemia. These effects are likely to occurin polytraumatized patients undergoingfollow-up surgery.




A. Action of the depolarizing muscle relaxant succinylcholine

Depolarization Depolarization

Acetylcholine

Skeletalmusclecell

Rapid ACh cleavage byacetylcholine esterases

Propagation ofaction potential (AP)

ACh

1

Repolarization of end plate2

ACh

3

New AP and contractioncan be elicited

Succinylcholine not degradedby acetylcholine esterases

Succinylcholine

Persistent depolarization of end plate

New AP and contractioncannot be elicited

Contraction Contraction

Membrane potential

Na+-channel

Closed(opening not possible)

Repolarization

Closed(opening possible)

Open

Mem

bra

ne p

oten

tial

Persistent depolarization

No repolarization,renewed opening ofNa+-channelimpossible

Mem

bra

ne p

oten

tial

Succinylcholine


Antiparkinsonian Drugs

Parkinson’s disease (shaking palsy) andits syndromal forms are caused by a de-generation of nigrostriatal dopamineneurons. The resulting striatal dopa-mine deficiency leads to overactivity ofcholinergic interneurons and imbalanceof striopallidal output pathways, mani-fested by poverty of movement (akine-sia), muscle stiffness (rigidity), tremorat rest, postural instability, and gait dis-turbance.

Pharmacotherapeutic measures areaimed at restoring dopaminergic func-tion or suppressing cholinergic hyper-activity.

L-Dopa. Dopamine itself cannotpenetrate the blood-brain barrier; how-ever, its natural precursor, L-dihydroxy-phenylalanine (levodopa), is effective inreplenishing striatal dopamine levels,because it is transported across theblood-brain barrier via an amino acidcarrier and is subsequently decarboxy-lated by DOPA-decarboxylase, presentin striatal tissue. Decarboxylation alsotakes place in peripheral organs wheredopamine is not needed, likely causingundesirable effects (tachycardia, ar-rhythmias resulting from activation ofβ1-adrenoceptors [p. 114], hypotension,and vomiting). Extracerebral produc-tion of dopamine can be prevented byinhibitors of DOPA-decarboxylase (car-bidopa, benserazide) that do not pene-trate the blood-brain barrier, leavingintracerebral decarboxylation unaffect-ed. Excessive elevation of brain dopa-mine levels may lead to undesirable re-actions, such as involuntary movements(dyskinesias) and mental disturbances.

Dopamine receptor agonists. Defi-cient dopaminergic transmission in thestriatum can be compensated by ergotderivatives (bromocriptine [p. 114], lisu-ride, cabergoline, and pergolide) andnonergot compounds (ropinirole, prami-pexole). These agonists stimulate dopa-mine receptors (D2, D3, and D1 sub-types), have lower clinical efficacy thanlevodopa, and share its main adverse ef-fects.

Inhibitors of monoamine oxi-dase-B (MAOB). This isoenzyme breaksdown dopamine in the corpus striatumand can be selectively inhibited by se-legiline. Inactivation of norepinephrine,epinephrine, and 5-HT via MAOA is un-affected. The antiparkinsonian effects ofselegiline may result from decreaseddopamine inactivation (enhanced levo-dopa response) or from neuroprotectivemechanisms (decreased oxyradical for-mation or blocked bioactivation of anunknown neurotoxin).

Inhibitors of catechol-O-methyl-transferase (COMT). L-Dopa and dopa-mine become inactivated by methyla-tion. The responsible enzyme can beblocked by entacapone, allowing higherlevels of L-dopa and dopamine to beachieved in corpus striatum.

Anticholinergics. Antagonists atmuscarinic cholinoceptors, such asbenzatropine and biperiden (p. 106),suppress striatal cholinergic overactiv-ity and thereby relieve rigidity andtremor; however, akinesia is not re-versed or is even exacerbated. Atropine-like peripheral side effects and impair-ment of cognitive function limit the tol-erable dosage.

Amantadine. Early or mild parkin-sonian manifestations may be tempo-rarily relieved by amantadine. Theunderlying mechanism of action mayinvolve, inter alia, blockade of ligand-gated ion channels of the glutamate/NMDA subtype, ultimately leading to adiminished release of acetylcholine.

Administration of levodopa pluscarbidopa (or benserazide) remains themost effective treatment, but does notprovide benefit beyond 3–5 y and is fol-lowed by gradual loss of symptom con-trol, on-off fluctuations, and develop-ment of orobuccofacial and limb dyski-nesias. These long-term drawbacks oflevodopa therapy may be delayed byearly monotherapy with dopamine re-ceptor agonists. Treatment of advanceddisease requires the combined adminis-tration of antiparkinsonian agents.




A. Antiparkinsonian drugs

Selegiline

Inhibition ofdopamine degradationby MAO-B in CNS

Normal state

Dopamine

Acetylcholine

Dopaminedeficiency

Predominanceof acetylcholine

Parkinson´s disease

Amantadine

NMDAreceptor:Blockadeof ionophore:attenuationof cholinergicneurons

Blood-brain barrier

Dopa-decarboxylase

Carbidopa

Inhibition of dopa-decarboxylase

Dopamine substitution

Stimulation ofperipheral dop-amine receptors

Adverse effects

2000

mg

200

mg

Dopamine

BenzatropineBromocriptine

Acetylcholine antagonistDopamine-receptoragonist

Inhibition ofcatechol-O-methyltransferase

L-Dopa

Dopamine precursor

COMT

NHH

CHN

CH3

CH3

HN

H3C

COOH

NH2C2H5

N

O

CN

C2H5HO

HO

NO2

Entacapone

Br

N

H

H

N

N

H

O

ON

NO

O

OHCH3H3C

H3C CH3CH3

H

O

NH3C

N

HO

H

HHO

COOH


Antiepileptics

Epilepsy is a chronic brain disease of di-verse etiology; it is characterized by re-current paroxysmal episodes of uncon-trolled excitation of brain neurons. In-volving larger or smaller parts of thebrain, the electrical discharge is evidentin the electroencephalogram (EEG) assynchronized rhythmic activity andmanifests itself in motor, sensory, psy-chic, and vegetative (visceral) phenom-ena. Because both the affected brain re-gion and the cause of abnormal excit-ability may differ, epileptic seizures cantake many forms. From a pharmaco-therapeutic viewpoint, these may beclassified as:– general vs. focal seizures;– seizures with or without loss of con-

sciousness;– seizures with or without specific

modes of precipitation.The brief duration of a single epi-

leptic fit makes acute drug treatmentunfeasible. Instead, antiepileptics areused to prevent seizures and thereforeneed to be given chronically. Only in thecase of status epilepticus (a succession ofseveral tonic-clonic seizures) is acuteanticonvulsant therapy indicated —usually with benzodiazepines given i.v.or, if needed, rectally.

The initiation of an epileptic attackinvolves “pacemaker” cells; these differfrom other nerve cells in their unstableresting membrane potential, i.e., a de-polarizing membrane current persistsafter the action potential terminates.

Therapeutic interventions aim tostabilize neuronal resting potential and,hence, to lower excitability. In specificforms of epilepsy, initially a single drugis tried to achieve control of seizures,valproate usually being the drug of firstchoice in generalized seizures, and car-bamazepine being preferred for partial(focal), especially partial complex, sei-zures. Dosage is increased until seizuresare no longer present or adverse effectsbecome unacceptable. Only whenmonotherapy with different agentsproves inadequate can changeover to a

second-line drug or combined use (“addon”) be recommended (B), providedthat the possible risk of pharmacokinet-ic interactions is taken into account (seebelow). The precise mode of action ofantiepileptic drugs remains unknown.Some agents appear to lower neuronalexcitability by several mechanisms ofaction. In principle, responsivity can bedecreased by inhibiting excitatory or ac-tivating inhibitory neurons. Most excit-atory nerve cells utilize glutamate andmost inhibitory neurons utilize γ-ami-nobutyric acid (GABA) as their transmit-ter (p. 193A). Various drugs can lowerseizure threshold, notably certain neu-roleptics, the tuberculostatic isoniazid,and β-lactam antibiotics in high doses;they are, therefore, contraindicated inseizure disorders.

Glutamate receptors comprisethree subtypes, of which the NMDAsubtype has the greatest therapeuticimportance. (N-methyl-D-aspartate is asynthetic selective agonist.) This recep-tor is a ligand-gated ion channel that,upon stimulation with glutamate, per-mits entry of both Na+ and Ca2+ ions intothe cell. The antiepileptics lamotrigine,phenytoin, and phenobarbital inhibit,among other things, the release of glu-tamate. Felbamate is a glutamate antag-onist.

Benzodiazepines and phenobarbitalaugment activation of the GABAA recep-tor by physiologically released amountsof GABA (B) (see p. 226). Chloride influxis increased, counteracting depolariza-tion. Progabide is a direct GABA-mimet-ic. Tiagabin blocks removal of GABAfrom the synaptic cleft by decreasing itsre-uptake. Vigabatrin inhibits GABA ca-tabolism. Gabapentin may augment theavailability of glutamate as a precursorin GABA synthesis (B) and can also act asa K+-channel opener.




Focalseizures

EEG Epileptic attack

µV

150

100

50

1 sec

Valproic acid

Carbamazepine Phenytoin

TopiramateGabapentin

Phenobarbital Ethosuximide

FelbamateVigabatrin

A. Epileptic attack, EEG, and antiepileptics

Simple seizures

Complexor secondarilygeneralized

I. II. III.

Tonic-clonicattack (grand mal)

Tonic attack

Clonic attack

Myoclonic attack

Absenceseizure

Generalizedattacks

Valproic acid Carbam-azepine,Phenytoin

Ethosuximide

Lamotrigine,Primidone,Phenobarbital

B. Indications for antiepileptics

Choice

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

Drugs used in the prophylaxis of epileptic seizures

0

Waking state

µV

150

100

50

1 sec0

Carbam-azepine

Valproic acid,Phenytoin,Clobazam

Primidone,Phenobar-bital

Lamotrigine or Clonazepam

Lamotrigine or Vigabatrin or Gabapentin

alternativeaddition

+

+

+

COOHH3C

H3C

N

NH2

OCN

N

H

O

H

O

COOHH2N

N

N

N

Cl

NH2H2N

ClN C2H5

NO

OH

OH

NH

O

O

H5C2

H3C

CHCH2OCNH2

O

O

CH2OCNH2

COOHH2N

H2C

Lamotrigine or Vigabatrin or Gabapentin

Lamotrigine

OO

O

OO

OSO2NH2CH3

H3C

H3C

CH3


Carbamazepine, valproate, andphenytoin enhance inactivation of volt-age-gated sodium and calcium channelsand limit the spread of electrical excita-tion by inhibiting sustained high-fre-quency firing of neurons.

Ethosuximide blocks a neuronal T-type Ca2+ channel (A) and represents aspecial class because it is effective onlyin absence seizures.

All antiepileptics are likely, albeit todifferent degrees, to produce adverseeffects. Sedation, difficulty in concentrat-ing, and slowing of psychomotor driveencumber practically all antiepileptictherapy. Moreover, cutaneous, hemato-logical, and hepatic changes may neces-sitate a change in medication. Pheno-barbital, primidone, and phenytoin maylead to osteomalacia (vitamin D prophy-laxis) or megaloblastic anemia (folateprophylaxis). During treatment withphenytoin, gingival hyperplasia may de-velop in ca. 20% of patients.

Valproic acid (VPA) is gaining in-creasing acceptance as a first-line drug;it is less sedating than other anticonvul-sants. Tremor, gastrointestinal upset,and weight gain are frequently ob-served; reversible hair loss is a rarer oc-currence. Hepatotoxicity may be due toa toxic catabolite (4-en VPA).

Adverse reactions to carbamaze-pine include: nystagmus, ataxia, diplo-pia, particularly if the dosage is raisedtoo fast. Gastrointestinal problems andskin rashes are frequent. It exerts anantidiuretic effect (sensitization of col-lecting ducts to vasopressin � water in-toxication).

Carbamazepine is also used to treattrigeminal neuralgia and neuropathicpain.

Valproate, carbamazepine, and oth-er anticonvulsants pose teratogenicrisks. Despite this, treatment shouldcontinue during pregnancy, as the po-tential threat to the fetus by a seizure isgreater. However, it is mandatory to ad-minister the lowest dose affording safeand effective prophylaxis. Concurrenthigh-dose administration of folate may

prevent neural tube developmental de-fects.

Carbamazepine, phenytoin, pheno-barbital, and other anticonvulsants (ex-cept for gabapentin) induce hepatic en-zymes responsible for drug biotransfor-mation. Combinations between anticon-vulsants or with other drugs may resultin clinically important interactions(plasma level monitoring!).

For the often intractable childhoodepilepsies, various other agents areused, including ACTH and the glucocor-ticoid, dexamethasone. Multiple(mixed) seizures associated with theslow spike-wave (Lennox–Gastaut) syn-drome may respond to valproate, la-motrigine, and felbamate, the latter be-ing restricted to drug-resistant seizuresowing to its potentially fatal liver andbone marrow toxicity.

Benzodiazepines are the drugs ofchoice for status epilepticus (seeabove); however, development of toler-ance renders them less suitable forlong-term therapy. Clonazepam is usedfor myoclonic and atonic seizures.Clobazam, a 1,5-benzodiazepine exhib-iting an increased anticonvulsant/seda-tive activity ratio, has a similar range ofclinical uses. Personality changes andparadoxical excitement are potentialside effects.

Clomethiazole can also be effectivefor controlling status epilepticus, but isused mainly to treat agitated states, es-pecially alcoholic delirium tremens andassociated seizures.

Topiramate, derived from D-fruc-tose, has complex, long-lasting anticon-vulsant actions that cooperate to limitthe spread of seizure activity; it is effec-tive in partial seizures and as an add-onin Lennox–Gastaut syndrome.




A. Neuronal sites of action of antiepileptics

B. Sites of action of antiepileptics in GABAergic synapse

Chloridechannel

GABA

Glutamic aciddecarboxylase

Glutamicacid

Succinicsemialdehyde

Ending ofinhibitoryneuron

Succinic acid

αγ

αβ

β

Allostericenhance-ment ofGABAaction

αγ

αβ

β

VigabatrinInhibitor ofGABA-transaminase

TiagabineInhibition ofGABAreuptake

GabapentinImproved utilizationof GABA precursor:glutamate

ProgabideGABA-mimetic

Barbiturates

Benzodiazepine

GABA-transaminase

GABAA-receptor

Excitatory neuronNMDA-receptor

VoltagedependentNa+-channel

Ca2+-channel

GABA

Inhibitoryneuron

Glutamate

Na+ Ca++

CI–

GABAA-receptor

NMDA-receptor-antagonistfelbamate,valproic acid

Enhancedinactivation:

carbamazepinevalproic acidphenytoin

Inhibition ofglutamaterelease:phenytoin,lamotriginephenobarbital

Gabamimetics:benzodiazepinebarbituratesvigabatrintiagabinegabapentin

T-Type-calciumchannel blockerethosuximide,(valproic acid)


Pain Mechanisms and Pathways

Pain is a designation for a spectrum ofsensations of highly divergent characterand intensity ranging from unpleasantto intolerable. Pain stimuli are detectedby physiological receptors (sensors,nociceptors) least differentiated mor-phologically, viz., free nerve endings.The body of the bipolar afferent first-or-der neuron lies in a dorsal root ganglion.Nociceptive impulses are conducted viaunmyelinated (C-fibers, conduction ve-locity 0.2–2.0 m/s) and myelinated ax-ons (Aδ-fibers, 5–30 m/s). The free end-ings of Aδ fibers respond to intensepressure or heat, those of C-fibers re-spond to chemical stimuli (H+, K+, hista-mine, bradykinin, etc.) arising from tis-sue trauma. Irrespective of whetherchemical, mechanical, or thermal stim-uli are involved, they become signifi-cantly more effective in the presence ofprostaglandins (p. 196).

Chemical stimuli also underlie painsecondary to inflammation or ischemia(angina pectoris, myocardial infarction),or the intense pain that occurs duringoverdistention or spasmodic contrac-tion of smooth muscle abdominal or-gans, and that may be maintained by lo-cal anoxemia developing in the area ofspasm (visceral pain).

Aδ and C-fibers enter the spinalcord via the dorsal root, ascend in thedorsolateral funiculus, and then syn-apse on second-order neurons in thedorsal horn. The axons of the second-or-der neurons cross the midline and as-cend to the brain as the anterolateralpathway or spinothalamic tract. Basedon phylogenetic age, neo- and paleospi-nothalamic tracts are distinguished.Thalamic nuclei receiving neospinotha-lamic input project to circumscribed ar-eas of the postcentral gyrus. Stimuliconveyed via this path are experiencedas sharp, clearly localizable pain. Thenuclear regions receiving paleospino-thalamic input project to the postcen-tral gyrus as well as the frontal, limbiccortex and most likely represent thepathway subserving pain of a dull, ach-

ing, or burning character, i.e., pain thatcan be localized only poorly.

Impulse traffic in the neo- and pa-leospinothalamic pathways is subject tomodulation by descending projectionsthat originate from the reticular forma-tion and terminate at second-order neu-rons, at their synapses with first-orderneurons, or at spinal segmental inter-neurons (descending antinociceptivesystem). This system can inhibit im-pulse transmission from first- to sec-ond-order neurons via release of opio-peptides (enkephalins) or monoamines(norepinephrine, serotonin).

Pain sensation can be influencedor modified as follows:� elimination of the cause of pain� lowering of the sensitivity of noci-

ceptors (antipyretic analgesics, localanesthetics)

� interrupting nociceptive conductionin sensory nerves (local anesthetics)

� suppression of transmission of noci-ceptive impulses in the spinal me-dulla (opioids)

� inhibition of pain perception (opi-oids, general anesthetics)

� altering emotional responses topain, i.e., pain behavior (antidepress-ants as “co-analgesics,” p. 230).

194 Drugs for the Suppression of Pain (Analgesics)


Drugs for the Suppression of Pain (Analgesics) 195

A. Pain mechanisms and pathways

Perception:sharpquicklocalizable

Perception:dull

delayeddiffuse

Descendingantinociceptivepathway

Pal

eosp

inot

hala

mic

trac

t

Neo

spin

otha

lam

ic

trac

t

Prostaglandins

Loca

l ane

sthe

tics

ReticularformationOpioids

Opioids

Anti-depressants

Anesthetics

Gyrus postcentralis

Nociceptors

Cyclooxygenaseinhibitors

Inflammation

Cause of pain

Thalamus


Eicosanoids

Origin and metabolism. The eicosan-oids, prostaglandins, thromboxane,prostacyclin, and leukotrienes, areformed in the organism from arachi-donic acid, a C20 fatty acid with fourdouble bonds (eicosatetraenoic acid).Arachidonic acid is a regular constituentof cell membrane phospholipids; it isreleased by phospholipase A2 and formsthe substrate of cyclooxygenases andlipoxygenases.

Synthesis of prostaglandins (PG),prostacyclin, and thromboxane pro-ceeds via intermediary cyclic endoper-oxides. In the case of PG, a cyclopentanering forms in the acyl chain. The lettersfollowing PG (D, E, F, G, H, or I) indicatedifferences in substitution with hydrox-yl or keto groups; the number sub-scripts refer to the number of doublebonds, and the Greek letter designatesthe position of the hydroxyl group at C9(the substance shown is PGF2α). PG areprimarily inactivated by the enzyme 15-hydroxyprostaglandindehydrogenase.Inactivation in plasma is very rapid;during one passage through the lung,90% of PG circulating in plasma are de-graded. PG are local mediators that at-tain biologically effective concentra-tions only at their site of formation.

Biological effects. The individualPG (PGE, PGF, PGI = prostacyclin) pos-sess different biological effects.

Nociceptors. PG increase sensitiv-ity of sensory nerve fibers towards ordi-nary pain stimuli (p. 194), i.e., at a givenstimulus strength there is an increasedrate of evoked action potentials.

Thermoregulation. PG raise the setpoint of hypothalamic (preoptic) ther-moregulatory neurons; body tempera-ture increases (fever).

Vascular smooth muscle. PGE2

and PGI2 produce arteriolar vasodila-tion; PGF2α, venoconstriction.

Gastric secretion. PG promote theproduction of gastric mucus and reducethe formation of gastric acid (p. 160).

Menstruation. PGF2α is believed tobe responsible for the ischemic necrosis

of the endometrium preceding men-struation. The relative proportions of in-dividual PG are said to be altered in dys-menorrhea and excessive menstrualbleeding.

Uterine muscle. PG stimulate laborcontractions.

Bronchial muscle. PGE2 and PGI2

induce bronchodilation; PGF2α causesconstriction.

Renal blood flow. When renalblood flow is lowered, vasodilating PGare released that act to restore bloodflow.

Thromboxane A2 and prostacyclinplay a role in regulating the aggregabil-ity of platelets and vascular diameter (p.150).

Leukotrienes increase capillarypermeability and serve as chemotacticfactors for neutrophil granulocytes. As“slow-reacting substances of anaphy-laxis,” they are involved in allergic reac-tions (p. 326); together with PG, theyevoke the spectrum of characteristic in-flammatory symptoms: redness, heat,swelling, and pain.

Therapeutic applications. PG de-rivatives are used to induce labor or tointerrupt gestation (p. 126); in the ther-apy of peptic ulcer (p. 168), and in pe-ripheral arterial disease.

PG are poorly tolerated if givensystemically; in that case their effectscannot be confined to the intended siteof action.

196 Antipyretic Analgesics


Antipyretic Analgesics 197

A. Origin and effects of prostaglandins

Kidneyfunction

Labor

Fever

Thromboxane Prostacyclin

Cyclooxygenase

Arachidonic acid

Pain stimulus

e.g., PGF2α

Prostaglandins

e.g.,leukotriene A4involved inallergic reactions

Leukotrienes

Vasodilation

Phospholipase A2

Lipoxygenase

[ H+]Mucusproduction

Capillary permeabilityNociceptorsensibility

Impulsefrequency insensory fiber


Antipyretic Analgesics

Acetaminophen, the amphiphilic acidsacetylsalicylic acid (ASA), ibuprofen,and others, as well as some pyrazolonederivatives, such as aminopyrine anddipyrone, are grouped under the labelantipyretic analgesics to distinguishthem from opioid analgesics, becausethey share the ability to reduce fever.

Acetaminophen (paracetamol) hasgood analgesic efficacy in toothachesand headaches, but is of little use in in-flammatory and visceral pain. Its mech-anism of action remains unclear. It canbe administered orally or in the form ofrectal suppositories (single dose,0.5–1.0 g). The effect develops afterabout 30 min and lasts for approx. 3 h.Acetaminophen undergoes conjugationto glucuronic acid or sulfate at the phe-nolic hydroxyl group, with subsequentrenal elimination of the conjugate. Attherapeutic dosage, a small fraction isoxidized to the highly reactive N-acetyl-p-benzoquinonimine, which is detoxi-fied by coupling to glutathione. After in-gestion of high doses (approx. 10 g), theglutathione reserves of the liver are de-pleted and the quinonimine reacts withconstituents of liver cells. As a result,the cells are destroyed: liver necrosis.Liver damage can be avoided if the thiolgroup donor, N-acetylcysteine, is givenintravenously within 6–8 h after inges-tion of an excessive dose of acetamino-phen. Whether chronic regular intake ofacetaminophen leads to impaired renalfunction remains a matter of debate.

Acetylsalicylic acid (ASA) exerts anantiinflammatory effect, in addition toits analgesic and antipyretic actions.These can be attributed to inhibition ofcyclooxygenase (p. 196). ASA can be giv-en in tablet form, as effervescent pow-der, or injected systemically as lysinate(analgesic or antipyretic single dose,O.5–1.0 g). ASA undergoes rapid esterhydrolysis, first in the gut and subse-quently in the blood. The effect outlaststhe presence of ASA in plasma (t1/2 ~20 min), because cyclooxygenases areirreversibly inhibited due to covalent

binding of the acetyl residue. Hence, theduration of the effect depends on therate of enzyme resynthesis. Further-more, salicylate may contribute to theeffect. ASA irritates the gastric mucosa(direct acid effect and inhibition of cy-toprotective PG synthesis, p. 200) andcan precipitate bronchoconstriction(“aspirin asthma,” pseudoallergy) dueto inhibition of PGE2 synthesis and over-production of leukotrienes. Because ASAinhibits platelet aggregation and pro-longs bleeding time (p. 150), it shouldnot be used in patients with impairedblood coagulability. Caution is alsoneeded in children and juveniles be-cause of Reye’s syndrome. The latter hasbeen observed in association with feb-rile viral infections and ingestion ofASA; its prognosis is poor (liver andbrain damage). Administration of ASA atthe end of pregnancy may result in pro-longed labor, bleeding tendency inmother and infant, and premature clo-sure of the ductus arteriosus. Acidicnonsteroidal antiinflammatory drugs(NSAIDS; p. 200) are derived from ASA.

Among antipyretic analgesics, di-pyrone (metamizole) displays the high-est efficacy. It is also effective in visceralpain. Its mode of action is unclear, butprobably differs from that of acetamino-phen and ASA. It is rapidly absorbedwhen given via the oral or rectal route.Because of its water solubility, it is alsoavailable for injection. Its active metab-olite, 4-aminophenazone, is eliminatedfrom plasma with a t1/2 of approx. 5 h.Dipyrone is associated with a low inci-dence of fatal agranulocytosis. In sensi-tized subjects, cardiovascular collapsecan occur, especially after intravenousinjection. Therefore, the drug should berestricted to the management of painrefractory to other analgesics. Propy-phenazone presumably acts like meta-mizole both pharmacologically and tox-icologically.

198 Antipyretic Analgesics and Antiinflammatory Drugs


Antipyretic Analgesics and Antiinflammatory Drugs 199

A. Antipyretic analgesics

Tooth-ache

Head-ache Fever

Inflammatorypain

Pain of colic

Acetaminophen Acetylsalicylic acid Dipyrone

Acutemassive

over-dose

Chronicabuse

Hepato-toxicity

Nephro-toxicity

Impairedhemostasis withrisk of bleeding

Agranulo-cytosis

Broncho-constriction

Irritationofgastro-intestinalmucosa Risk of

anaphylactoidshock

>10g

?


Nonsteroidal Antiinflammatory (Antirheumatic) Agents

At relatively high dosage (> 4 g/d), ASA(p. 198) may exert antiinflammatory ef-fects in rheumatic diseases (e.g., rheu-matoid arthritis). In this dose range,central nervous signs of overdosagemay occur, such as tinnitus, vertigo,drowsiness, etc. The search for bettertolerated drugs led to the family of non-steroidal antiinflammatory drugs(NSAIDs). Today, more than 30 sub-stances are available, all of them sharingthe organic acid nature of ASA. Structu-rally, they can be grouped into carbonicacids (e.g., diclofenac, ibuprofen, na-proxene, indomethacin [p. 320]) orenolic acids (e.g., azapropazone, piroxi-cam, as well as the long-known butpoorly tolerated phenylbutazone). LikeASA, these substances have analgesic,antipyretic, and antiinflammatory ac-tivity. In contrast to ASA, they inhibit cy-clooxygenase in a reversible manner.Moreover, they are not suitable as in-hibitors of platelet aggregation. Sincetheir desired effects are similar, thechoice between NSAIDs is dictated bytheir pharmacokinetic behavior andtheir adverse effects.

Salicylates additionally inhibit thetranscription factor NFKB, hence the ex-pression of proinflammatory proteins.This effect is shared with glucocorti-coids (p. 248) and ibuprofen, but notwith some other NSAIDs.

Pharmacokinetics. NSAIDs arewell absorbed enterally. They are highlybound to plasma proteins (A). They areeliminated at different speeds: diclofe-nac (t1/2 = 1–2 h) and piroxicam (t1/2 ~ 50h); thus, dosing intervals and risk of ac-cumulation will vary. The elimination ofsalicylate, the rapidly formed metab-olite of ASA, is notable for its dose de-pendence. Salicylate is effectively reab-sorbed in the kidney, except at high uri-nary pH. A prerequisite for rapid renalelimination is a hepatic conjugation re-action (p. 38), mainly with glycine (→salicyluric acid) and glucuronic acid. Athigh dosage, the conjugation may be-

come rate limiting. Elimination now in-creasingly depends on unchanged sa-licylate, which is excreted only slowly.

Group-specific adverse effects canbe attributed to inhibition of cyclooxy-genase (B). The most frequent problem,gastric mucosal injury with risk of pepticulceration, results from reduced synthe-sis of protective prostaglandins (PG),apart from a direct irritant effect. Gas-tropathy may be prevented by co-ad-ministration of the PG derivative, mis-oprostol (p. 168). In the intestinal tract,inhibition of PG synthesis would simi-larly be expected to lead to damage ofthe blood mucosa barrier and enteropa-thy. In predisposed patients, asthma at-tacks may occur, probably because of alack of bronchodilating PG and in-creased production of leukotrienes. Be-cause this response is not immune me-diated, such “pseudoallergic” reactionsare a potential hazard with all NSAIDs.PG also regulate renal blood flow asfunctional antagonists of angiotensin IIand norepinephrine. If release of the lat-ter two is increased (e.g., in hypovole-mia), inhibition of PG production mayresult in reduced renal blood flow and re-nal impairment. Other unwanted effectsare edema and a rise in blood pressure.

Moreover, drug-specific side effectsdeserve attention. These concern theCNS (e.g., indomethacin: drowsiness,headache, disorientation), the skin (pi-roxicam: photosensitization), or theblood (phenylbutazone: agranulocyto-sis).

Outlook: Cyclooxygenase (COX)has two isozymes: COX-1, a constitutiveform present in stomach and kidney;and COX-2, which is induced in inflam-matory cells in response to appropriatestimuli. Presently available NSAIDs in-hibit both isozymes. The search forCOX-2-selective agents (Celecoxib, Ro-fecoxib) is intensifying because, in theo-ry, these ought to be tolerated better.




t1/2 =13-30h

Salicylic acid50%

90% Acetyl-salicylicacid

99%

Diclofenac

Ibuprofen

NaproxenPiroxicam

Azapropazone

t1/2 =1-2h

t1/2~50h

t1/2 =9-12h

t1/2~14h

t1/2 ~2h

t1/2~3h

Plasma protein binding

A. Nonsteroidal antiinflammatory drugs (NSAIDs)

B. NSAIDs: group-specific adverse effects

95%

99%

99%

99%

Mucus productionAcid secretionMucosal blood flow

NSAID-inducednephrotoxicity

Arachidonic acid

Prostaglandins Airway resistance

t1/2 =15min

High dose

Low dose

NSAID-inducedgastropathy

Leukotrienes

Renal bloodflow

NSAID-inducedasthma


Thermoregulation and Antipyretics

Body core temperature in the human isabout 37 °C and fluctuates within ± 1 °Cduring the 24 h cycle. In the restingstate, the metabolic activity of vital or-gans contributes 60% (liver 25%, brain20%, heart 8%, kidneys 7%) to total heatproduction. The absolute contributionto heat production from these organschanges little during physical activity,whereas muscle work, which contri-butes approx. 25% at rest, can generateup to 90% of heat production duringstrenuous exercise. The set point of thebody temperature is programmed in thehypothalamic thermoregulatory center.The actual value is adjusted to the setpoint by means of various thermoregu-latory mechanisms. Blood vessels sup-plying the skin penetrate the heat-insu-lating layer of subcutaneous adipose tis-sue and therefore permit controlledheat exchange with the environment asa function of vascular caliber and rate ofblood flow. Cutaneous blood flow canrange from ~ 0 to 30% of cardiac output,depending on requirements. Heat con-duction via the blood from interior sitesof production to the body surface pro-vides a controllable mechanism for heatloss.

Heat dissipation can also beachieved by increased production ofsweat, because evaporation of sweat onthe skin surface consumes heat (evapo-rative heat loss). Shivering is a mecha-nism to generate heat. Autonomic neu-ral regulation of cutaneous blood flowand sweat production permit homeo-static control of body temperature (A).The sympathetic system can either re-duce heat loss via vasoconstriction orpromote it by enhancing sweat produc-tion.

When sweating is inhibited due topoisoning with anticholinergics (e.g.,atropine), cutaneous blood flow in-creases. If insufficient heat is dissipatedthrough this route, overheating occurs(hyperthermia).

Thyroid hyperfunction poses aparticular challenge to the thermoregu-

latory system, because the excessive se-cretion of thyroid hormones causesmetabolic heat production to increase.In order to maintain body temperatureat its physiological level, excess heatmust be dissipated—the patients have ahot skin and are sweating.

The hypothalamic temperaturecontroller (B1) can be inactivated byneuroleptics (p. 236), without impair-ment of other centers. Thus, it is pos-sible to lower a patient’s body tempera-ture without activating counter-regula-tory mechanisms (thermogenic shiver-ing). This can be exploited in the treat-ment of severe febrile states (hyperpy-rexia) or in open-chest surgery withcardiac by-pass, during which bloodtemperature is lowered to 10 °C bymeans of a heart-lung machine.

In higher doses, ethanol and bar-biturates also depress the thermoregu-latory center (B1), thereby permittingcooling of the body to the point of death,given a sufficiently low ambient tem-perature (freezing to death in drunken-ness).

Pyrogens (e.g., bacterial matter) el-evate—probably through mediation byprostaglandins (p. 196) and interleukin-1—the set point of the hypothalamictemperature controller (B2). The bodyresponds by restricting heat loss (cuta-neous vasoconstriction → chills) and byelevating heat production (shivering), inorder to adjust to the new set point (fe-ver). Antipyretics such as acetamino-phen and ASA (p. 198) return the setpoint to its normal level (B2) and thusbring about a defervescence.




Respiration

Inhibitionof sweat

production

Parasym-patholytics(Atropine)

Hyperthermia

Heatproduction

Heat production

B. Disturbances of thermoregulation

A. Thermoregulation

37º 38º39º

36º

35º

37º 38º 39º36º

35º

37º 38º 39º36º

35º37º 38º 39º

36º

35º

Hyper-thyroidism

Increasedheatproduction

Thermoregulatorycenter

(set point)

Sympathetic system

α-Adreno-ceptors

Acetylcholinereceptors

Body temperature

Temperaturerise

Fever

e.g.,paralysis

Preferentialinhibition

Controlledhypothermia

“Artificialhibernation”

Uncontrolledheat loss

Hypothermia,freezingto death

1 2

37º 38º 39º36º

35º

Metabolicactivity

Heatloss

Hea

t co

nduc

tion

Hea

t ra

dia

tion

Eva

por

atio

n of

sw

eat

Neuroleptics EthanolBarbiturates

Set pointelevation

AntipyreticsPyrogen

Heatcenter

Cutaneousblood flow

Sweatproduction


Local Anesthetics

Local anesthetics reversibly inhibit im-pulse generation and propagation innerves. In sensory nerves, such an effectis desired when painful proceduresmust be performed, e.g., surgical or den-tal operations.

Mechanism of action. Nerve im-pulse conduction occurs in the form ofan action potential, a sudden reversal inresting transmembrane potential last-ing less than 1 ms. The change in poten-tial is triggered by an appropriate stim-ulus and involves a rapid influx of Na+

into the interior of the nerve axon (A).This inward flow proceeds through achannel, a membrane pore protein, that,upon being opened (activated), permitsrapid movement of Na+ down a chemi-cal gradient ([Na+]ext ~ 150 mM, [Na+]int

~ 7 mM). Local anesthetics are capableof inhibiting this rapid inward flux ofNa+; initiation and propagation of exci-tation are therefore blocked (A).

Most local anesthetics exist in partin the cationic amphiphilic form (cf. p.208). This physicochemical property fa-vors incorporation into membraneinterphases, boundary regions betweenpolar and apolar domains. These arefound in phospholipid membranes andalso in ion-channel proteins. Some evi-dence suggests that Na+-channel block-ade results from binding of local anes-thetics to the channel protein. It appearscertain that the site of action is reachedfrom the cytosol, implying that the drugmust first penetrate the cell membrane(p. 206).

Local anesthetic activity is alsoshown by uncharged substances, sug-gesting a binding site in apolar regionsof the channel protein or the surround-ing lipid membrane.

Mechanism-specific adverse ef-fects. Since local anesthetics block Na+

influx not only in sensory nerves but al-so in other excitable tissues, they areapplied locally and measures are taken(p. 206) to impede their distributioninto the body. Too rapid entry into the

circulation would lead to unwantedsystemic reactions such as:� blockade of inhibitory CNS neurons,

manifested by restlessness and sei-zures (countermeasure: injection of abenzodiazepine, p. 226); general par-alysis with respiratory arrest afterhigher concentrations.

� blockade of cardiac impulse conduc-tion, as evidenced by impaired AVconduction or cardiac arrest (coun-termeasure: injection of epineph-rine). Depression of excitatory pro-cesses in the heart, while undesiredduring local anesthesia, can be put totherapeutic use in cardiac arrhythmi-as (p. 134).

Forms of local anesthesia. Localanesthetics are applied via differentroutes, including infiltration of the tis-sue (infiltration anesthesia) or injec-tion next to the nerve branch carryingfibers from the region to be anesthe-tized (conduction anesthesia of thenerve, spinal anesthesia of segmentaldorsal roots), or by application to thesurface of the skin or mucosa (surfaceanesthesia). In each case, the local an-esthetic drug is required to diffuse tothe nerves concerned from a depotplaced in the tissue or on the skin.

High sensitivity of sensory nerves,low sensitivity of motor nerves. Im-pulse conduction in sensory nerves isinhibited at a concentration lower thanthat needed for motor fibers. This differ-ence may be due to the higher impulsefrequency and longer action potentialduration in nociceptive, as opposed tomotor, fibers.

Alternatively, it may be related tothe thickness of sensory and motornerves, as well as to the distancebetween nodes of Ranvier. In saltatoryimpulse conduction, only the nodalmembrane is depolarized. Because de-polarization can still occur after block-ade of three or four nodal rings, the areaexposed to a drug concentration suffi-cient to cause blockade must be largerfor motor fibers (p. 205B).

This relationship explains why sen-sory stimuli that are conducted via

204 Local Anesthetics


Local Anesthetics 205

+

A. Effects of local anesthetics

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

Local anesthetic

Na+-entry

Propagatedimpulse

Peripheral nerve

Conductionblock

Localapplication

CNS

Restlessness,convulsions,respiratoryparalysis

Heart

Impulseconductioncardiac arrest

Na+ActivatedNa+-channel

Na+BlockedNa+-channel

apolar

polar Cationicamphiphiliclocalanesthetic

Local anesthetic

Aα motor 0.8 – 1.4 mm

0.3 – 0.7 mmAδ sensory

C sensory andpostganglionic

Na+BlockedNa+-channel

Unchargedlocalanesthetic


myelinated Aδ-fibers are affected laterand to a lesser degree than are stimuliconducted via unmyelinated C-fibers.Since autonomic postganglionic fiberslack a myelin sheath, they are particu-larly susceptible to blockade by localanesthetics. As a result, vasodilation en-sues in the anesthetized region, becausesympathetically driven vasomotor tonedecreases. This local vasodilation is un-desirable (see below).

Diffusion and Effect

During diffusion from the injection site(i.e., the interstitial space of connectivetissue) to the axon of a sensory nerve,the local anesthetic must traverse theperineurium. The multilayered peri-neurium is formed by connective tissuecells linked by zonulae occludentes(p. 22) and therefore constitutes aclosed lipophilic barrier.

Local anesthetics in clinical use areusually tertiary amines; at the pH ofinterstitial fluid, these exist partly as theneutral lipophilic base (symbolized byparticles marked with two red dots) andpartly as the protonated form, i.e., am-phiphilic cation (symbolized by parti-cles marked with one blue and one reddot). The uncharged form can penetratethe perineurium and enters the endo-neural space, where a fraction of thedrug molecules regains a positivecharge in keeping with the local pH. Thesame process is repeated when the drugpenetrates the axonal membrane (axo-lemma) into the axoplasm, from whichit exerts its action on the sodium chan-nel, and again when it diffuses out of theendoneural space through the unfenes-trated endothelium of capillaries intothe blood.

The concentration of local anes-thetic at the site of action is, therefore,determined by the speed of penetrationinto the endoneurium and the speed ofdiffusion into the capillary blood. In or-der to ensure a sufficiently fast build-upof drug concentration at the site of ac-tion, there must be a correspondinglylarge concentration gradient between

drug depot in the connective tissue andthe endoneural space. Injection of solu-tions of low concentration will fail toproduce an effect; however, too highconcentrations must also be avoided be-cause of the danger of intoxication re-sulting from too rapid systemic absorp-tion into the blood.

To ensure a reasonably long-lastinglocal effect with minimal systemic ac-tion, a vasoconstrictor (epinephrine,less frequently norepinephrine (p. 84)or a vasopressin derivative; p. 164) is of-ten co-administered in an attempt toconfine the drug to its site of action. Asblood flow is diminished, diffusion fromthe endoneural space into the capillaryblood decreases because the criticalconcentration gradient between endo-neural space and blood quickly becomessmall when inflow of drug-free blood isreduced. Addition of a vasoconstrictor,moreover, helps to create a relativeischemia in the surgical field. Potentialdisadvantages of catecholamine-typevasoconstrictors include reactive hy-peremia following washout of the con-strictor agent (p. 90) and cardiostimula-tion when epinephrine enters the sys-temic circulation. In lieu of epinephrine,the vasopressin analogue felypressin(p. 164, 165) can be used as an adjunc-tive vasoconstrictor (less pronouncedreactive hyperemia, no arrhythmogenicaction, but danger of coronary constric-tion). Vasoconstrictors must not be ap-plied in local anesthesia involving theappendages (e.g., fingers, toes).




A. Disposition of local anesthetics in peripheral nerve tissue

Vasoconstrictione.g., with epinephrine

lipophilic

amphiphilic

Axolemma

Axoplasm

Axolemma

Axoplasm

Inter-stitium

Cross section through peripheralnerve (light microscope)

Peri-neurium

Endoneuralspace

Capillarywall

Axon0.1 mm

Interstitium


Characteristics of chemical struc-ture. Local anesthetics possess a uni-form structure. Generally they are sec-ondary or tertiary amines. The nitrogenis linked through an intermediary chainto a lipophilic moiety—most often anaromatic ring system.

The amine function means that lo-cal anesthetics exist either as the neu-tral amine or positively charged ammo-nium cation, depending upon their dis-sociation constant (pKa value) and theactual pH value. The pKa of typical localanesthetics lies between 7.5 and 9.0.The pka indicates the pH value at which50% of molecules carry a proton. In itsprotonated form, the molecule possess-es both a polar hydrophilic moiety (pro-tonated nitrogen) and an apolar lipo-philic moiety (ring system)—it is amphi-philic.

Graphic images of the procainemolecule reveal that the positive chargedoes not have a punctate localization atthe N atom; rather it is distributed, asshown by the potential on the van derWaals’ surface. The non-protonatedform (right) possesses a negative partialcharge in the region of the ester bondand at the amino group at the aromaticring and is neutral to slightly positivelycharged (blue) elsewhere. In the proto-nated form (left), the positive charge isprominent and concentrated at the ami-no group of the side chain (dark blue).

Depending on the pKa, 50 to 5% ofthe drug may be present at physiologi-cal pH in the uncharged lipophilic form.This fraction is important because itrepresents the lipid membrane-perme-able form of the local anesthetic (p. 26),which must take on its cationic amphi-philic form in order to exert its action(p. 204).

Clinically used local anesthetics areeither esters or amides. This structuralelement is unimportant for efficacy;even drugs containing a methylenebridge, such as chlorpromazine (p. 236)or imipramine (p. 230), would exert alocal anesthetic effect with appropriateapplication. Ester-type local anestheticsare subject to inactivation by tissue es-

terases. This is advantageous because ofthe diminished danger of systemic in-toxication. On the other hand, the highrate of bioinactivation and, therefore,shortened duration of action is a disad-vantage.

Procaine cannot be used as a surfaceanesthetic because it is inactivated fast-er than it can penetrate the dermis ormucosa.

The amide type local anestheticlidocaine is broken down primarily inthe liver by oxidative N-dealkylation.This step can occur only to a restrictedextent in prilocaine and articaine be-cause both carry a substituent on the C-atom adjacent to the nitrogen group. Ar-ticaine possesses a carboxymethylgroup on its thiophen ring. At this posi-tion, ester cleavage can occur, resultingin the formation of a polar -COO– group,loss of the amphiphilic character, andconversion to an inactive metabolite.

Benzocaine (ethoform) is a memberof the group of local anesthetics lackinga nitrogen that can be protonated atphysiological pH. It is used exclusivelyas a surface anesthetic.

Other agents employed for surfaceanesthesia include the uncharged poli-docanol and the catamphiphilic cocaine,tetracaine, and lidocaine.




A. Local anesthetics and pH value

100

80

60

40

20

0

0

20

40

60

80

1006 7 8 9 10

Procaine Lidocaine Prilocaine

Articaine Mepivacaine Benzocaine

[H+] Proton concentration

pH value

Active formcationic-amphiphilic

PoorAbility to penetratelipophilicbarriers andcell membranes

Good

Membrane-permeableform


Opioid Analgesics—Morphine Type

Source of opioids. Morphine is an opi-um alkaloid (p. 4). Besides morphine,opium contains alkaloids devoid of an-algesic activity, e.g., the spasmolytic pa-paverine, that are also classified as opi-um alkaloids. All semisynthetic deriva-tives (hydromorphone) and fully syn-thetic derivatives (pentazocine, pethi-dine = meperidine, l-methadone, andfentanyl) are collectively referred to asopioids. The high analgesic effectivenessof xenobiotic opioids derives from theiraffinity for receptors normally actedupon by endogenous opioids (enkepha-lins, β-endorphin, dynorphins; A). Opi-oid receptors occur in nerve cells. Theyare found in various brain regions andthe spinal medulla, as well as in intra-mural nerve plexuses that regulate themotility of the alimentary and urogeni-tal tracts. There are several types of opi-oid receptors, designated µ, δ, κ, thatmediate the various opioid effects; allbelong to the superfamily of G-protein-coupled receptors (p. 66).

Endogenous opioids are peptidesthat are cleaved from the precursorsproenkephalin, pro-opiomelanocortin,and prodynorphin. All contain the ami-no acid sequence of the pentapeptides[Met]- or [Leu]-enkephalin (A). The ef-fects of the opioids can be abolished byantagonists (e.g., naloxone; A), with theexception of buprenorphine.

Mode of action of opioids. Mostneurons react to opioids with hyperpo-larization, reflecting an increase in K+

conductance. Ca2+ influx into nerve ter-minals during excitation is decreased,leading to a decreased release of excita-tory transmitters and decreased synap-tic activity (A). Depending on the cellpopulation affected, this synaptic inhi-bition translates into a depressant or ex-citant effect (B).

Effects of opioids (B). The analge-sic effect results from actions at the lev-el of the spinal cord (inhibition of noci-ceptive impulse transmission) and thebrain (attenuation of impulse spread,inhibition of pain perception). Attention

and ability to concentrate are impaired.There is a mood change, the directionof which depends on the initial condi-tion. Aside from the relief associatedwith the abatement of strong pain,there is a feeling of detachment (float-ing sensation) and sense of well-being(euphoria), particularly after intrave-nous injection and, hence, rapid build-up of drug levels in the brain. The desireto re-experience this state by renewedadministration of drug may becomeoverpowering: development of psycho-logical dependence. The atttempt to quitrepeated use of the drug results in with-drawal signs of both a physical (cardio-vascular disturbances) and psychologi-cal (restlessness, anxiety, depression)nature. Opioids meet the criteria of “ad-dictive” agents, namely, psychologicaland physiological dependence as well asa compulsion to increase the dose. Forthese reasons, prescription of opioids issubject to special rules (Controlled Sub-stances Act, USA; Narcotic Control Act,Canada; etc). Regulations specify,among other things, maximum dosage(permissible single dose, daily maximaldose, maximal amount per single pre-scription). Prescriptions need to be is-sued on special forms the completion ofwhich is rigorously monitored. Certainopioid analgesics, such as codeine andtramadol, may be prescribed in the usu-al manner, because of their lesser po-tential for abuse and development ofdependence.

210 Opioids


Opioids 211

A. Action of endogenous and exogenous opioids at opioid receptors

β-Endorphin

Ureterbladderbladder sphincter

Vagal centers,Chemoreceptorsof area postremaOculomotorcenter(Edinger's nucleus)

Dampening effects

Pain sensation

Moodalertness

Respiratory centerCough center

Emetic center

Stimulant effects Mediated byopioid receptors

MorphineProopiomelanocortin

β-Lipotropin

Proenkephalin

Opioid receptors

Naloxone

K+-permeabilityExcitability

Ca2+-influxRelease oftransmitters

Antinociceptivesystem

Analgesic

Smooth musculaturestomachbowel spasticconstipation

Antidiarrheal

Analgesic

Antitussive

B. Effects of opioids

O

NCH2

HO

CH2CH

HO O

N

O OHHO

CH3

Enkephalin

6


Differences between opioids re-garding efficacy and potential for de-pendence probably reflect differing af-finity and intrinsic activity profiles forthe individual receptor subtypes. A giv-en sustance does not necessarily behaveas an agonist or antagonist at all recep-tor subtypes, but may act as an agonistat one subtype and as a partial ago-nist/antagonist or as a pure antagonist(p. 214) at another. The abuse potentialis also determined by kinetic properties,because development of dependence isfavored by rapid build-up of brain con-centrations. With any of the high-effica-cy opioid analgesics, overdosage is like-ly to result in respiratory paralysis (im-paired sensitivity of medullary chemo-receptors to CO2). The maximally pos-sible extent of respiratory depression isthought to be less in partial agonist/antagonists at opioid receptors (pentaz-ocine, nalbuphine).

The cough-suppressant (antitussive)effect produced by inhibition of thecough reflex is independent of the ef-fects on nociception or respiration(antitussives: codeine. noscapine).

Stimulation of chemoreceptors inthe area postrema (p. 330) results invomiting, particularly after first-time ad-ministration or in the ambulant patient.The emetic effect disappears with re-peated use because a direct inhibition ofthe emetic center then predominates,which overrides the stimulation of areapostrema chemoreceptors.

Opioids elicit pupillary narrowing(miosis) by stimulating the parasympa-thetic portion (Edinger-Westphal nu-cleus) of the oculomotor nucleus.

Peripheral effects concern the mo-tility and tonus of gastrointestinalsmooth muscle; segmentation is en-hanced, but propulsive peristalsis is in-hibited. The tonus of sphincter musclesis raised markedly. In this fashion, mor-phine elicits the picture of spastic con-stipation. The antidiarrheic effect isused therapeutically (loperamide, p.178). Gastric emptying is delayed (py-loric spasm) and drainage of bile andpancreatic juice is impeded, because the

sphincter of Oddi contracts. Likewise,bladder function is affected; specificallybladder emptying is impaired due to in-creased tone of the vesicular sphincter.

Uses: The endogenous opioids(metenkephalin, leuenkephalin, β-en-dorphin) cannot be used therapeuticallybecause, due to their peptide nature,they are either rapidly degraded or ex-cluded from passage through the blood-brain barrier, thus preventing access totheir sites of action even after parenter-al administration (A).

Morphine can be given orally orparenterally, as well as epidurally orintrathecally in the spinal cord. The opi-oids heroin and fentanyl are highly lipo-philic, allowing rapid entry into theCNS. Because of its high potency, fenta-nyl is suitable for transdermal delivery(A).

In opiate abuse, “smack” (“junk,”“jazz,” “stuff,” “China white;” mostlyheroin) is self administered by injection(“mainlining”) so as to avoid first-passmetabolism and to achieve a faster risein brain concentration. Evidently, psy-chic effects (“kick,” “buzz,” “rush”) areespecially intense with this route of ad-ministration. The user may also resort toother more unusual routes: opium canbe smoked, and heroin can be taken assnuff (B).

Metabolism (C). Like other opioidsbearing a hydroxyl group, morphine isconjugated to glucuronic acid and elim-inated renally. Glucuronidation of theOH-group at position 6, unlike that atposition 3, does not affect affinity. Theextent to which the 6-glucuronide con-tributes to the analgesic action remainsuncertain at present. At any rate, the ac-tivity of this polar metabolite needs tobe taken into account in renal insuffi-ciency (lower dosage or longer dosinginterval).

212 Opioids


Opioids 213

A. Bioavailability of opioids with different routes of administration

C. Metabolism of morphine

Nasalmucosa,e.g.,heroinsniffing

Intravenousapplication"Mainlining"

Oralapplication

Bronchialmucosae.g., opiumsmoking

Met-Enkephalin Morphine Fentanyl

Heroin

Opioid

Morphine

N

N

CH2 CH2

CO

CH2

CH3Tyr Gly Gly Phe Met N

CH3

O OHHO

Morphine-3-glucuronide

Morphine-6-glucuronide

B. Application and rate of disposition

N

CH3

OH3C CH3OC

O

O C

O


Tolerance. With repeated adminis-tration of opioids, their CNS effects canlose intensity (increased tolerance). Inthe course of therapy, progressivelylarger doses are needed to achieve thesame degree of pain relief. Developmentof tolerance does not involve the pe-ripheral effects, so that persistent con-stipation during prolonged use mayforce a discontinuation of analgesictherapy however urgently needed.Therefore, dietetic and pharmacologicalmeasures should be taken prophylacti-cally to prevent constipation, wheneverprolonged administration of opioiddrugs is indicated.

Morphine antagonists and partialagonists. The effects of opioids can beabolished by the antagonists naloxoneor naltrexone (A), irrespective of the re-ceptor type involved. Given by itself,neither has any effect in normal sub-jects; however, in opioid-dependentsubjects, both precipitate acute with-drawal signs. Because of its rapid pre-systemic elimination, naloxone is onlysuitable for parenteral use. Naltrexoneis metabolically more stable and is giv-en orally. Naloxone is effective as anti-dote in the treatment of opioid-inducedrespiratory paralysis. Since it is morerapidly eliminated than most opioids,repeated doses may be needed. Naltrex-one may be used as an adjunct in with-drawal therapy.

Buprenorphine behaves like a par-tial agonist/antagonist at µ-receptors.Pentazocine is an antagonist at µ-recep-tors and an agonist at κ-receptors (A).Both are classified as “low-ceiling” opi-oids (B), because neither is capable ofeliciting the maximal analgesic effectobtained with morphine or meperidine.The antagonist action of partial agonistsmay result in an initial decrease in effectof a full agonist during changeover tothe latter. Intoxication with buprenor-phine cannot be reversed with antago-nists, because the drug dissociates onlyvery slowly from the opioid receptorsand competitive occupancy of the re-ceptors cannot be achieved as fast as theclinical situation demands.

Opioids in chronic pain: In themanagement of chronic pain, opioidplasma concentration must be kept con-tinuously in the effective range, becausea fall below the critical level wouldcause the patient to experience pain.Fear of this situation would prompt in-take of higher doses than necessary.Strictly speaking, the aim is a prophy-lactic analgesia.

Like other opioids (hydromor-phone, meperidine, pentazocine, co-deine), morphine is rapidly eliminated,limiting its duration of action to approx.4 h. To maintain a steady analgesic ef-fect, these drugs need to be given every4 h. Frequent dosing, including at night-time, is a major inconvenience forchronic pain patients. Raising the indi-vidual dose would permit the dosinginterval to be lengthened; however, itwould also lead to transient peaksabove the therapeutically required plas-ma level with the attending risk of un-wanted toxic effects and tolerance de-velopment. Preferred alternatives in-clude the use of controlled-releasepreparations of morphine, a fentanyladhesive patch, or a longer-acting opi-oid such as l-methadone. The kineticproperties of the latter, however, neces-sitate adjustment of dosage in thecourse of treatment, because low dos-age during the first days of treatmentfails to provide pain relief, whereas highdosage of the drug, if continued, willlead to accumulation into a toxic con-centration range (C).

When the oral route is unavailableopioids may be administered by contin-uous infusion (pump) and when appro-priate under control by the patient – ad-vantage: constant therapeutic plasmalevel; disadvantage: indwelling cathe-ter. When constipation becomes intol-erable morphin can be applied near thespinal cord permitting strong analgesiceffect at much lower total dosage.

214 Opioids


Opioids 215

Pentazocine

A. Opioids: µ- and κ-receptor ligands B. Opioids: dose-response relationship

C. Morphine and methadone dosage regimens

Intoxication

Analgesia

Morphinet1/2 = 2 hat low doseevery 4 hDisadvantage:frequent dosingfor sustainedanalgesia

High dose

Morphine in"high dose"every 12 hDisadvantages:transient hazardof intoxication,transient lossof analgesia

Low Dose

Methadonet1/2 = 55 hDisadvantage:dose difficultto titrateDays

1 2 3 4

Dru

g co

ncen

trat

ion

in p

lasm

a

Morphine

Meperidine

Fentanyl

Nalbuphine

Naloxone

µκ

µκ

µκ

µκ

µκ

µκ

Ana

lges

ic e

ffect

Dose (mg)

0,1 1 10 100

Fent

anyl

Bup

reno

rphi

neM

orp

hine

Mep

erid

ine

Pen

tazo

cine

1 2 3 4

H3C

H3CCH

CH2

CH3

CH3

N

C

N

O

CH3

HO OH

CO

O

N

CH3

CH2

CH3

N

N

CH2

CO

CH2

CH3

CH2

HO OH

HO

CH2N

O

HO

HO

H2C CH

CH2

O

N

O

HO


General Anesthesia and General Anesthetic Drugs

General anesthesia is a state of drug-in-duced reversible inhibition of centralnervous function, during which surgicalprocedures can be carried out in the ab-sence of consciousness, responsivenessto pain, defensive or involuntary move-ments, and significant autonomic reflexresponses (A).

The required level of anesthesia de-pends on the intensity of the pain-pro-ducing stimuli, i.e., the degree of noci-ceptive stimulation. The skilful anesthe-tist, therefore, dynamically adapts theplane of anesthesia to the demands ofthe surgical situation. Originally, anes-thetization was achieved with a singleanesthetic agent (e.g., diethylether—first successfully demonstrated in 1846by W. T. G. Morton, Boston). To suppressdefensive reflexes, such a “mono-anes-thesia” necessitates a dosage in excessof that needed to cause unconscious-ness, thereby increasing the risk of par-alyzing vital functions, such as cardio-vascular homeostasis (B). Modern anes-thesia employs a combination of differ-ent drugs to achieve the goals of surgicalanesthesia (balanced anesthesia). Thisapproach reduces the hazards of anes-thesia. In C are listed examples of drugsthat are used concurrently or sequen-tially as anesthesia adjuncts. In the caseof the inhalational anesthetics, thechoice of adjuncts relates to the specificproperty to be exploited (see below).Muscle relaxants, opioid analgesics suchas fentanyl, and the parasympatholyticatropine are discussed elsewhere inmore detail.

Neuroleptanalgesia can be consid-ered a special form of combination an-esthesia, in which the short-acting opi-oid analgesics fentanyl, alfentanil, remi-fentanil is combined with the stronglysedating and affect-blunting neurolep-tic droperidol. This procedure is used inhigh-risk patients (e.g., advanced age,liver damage).

Neuroleptanesthesia refers to thecombined use of a short-acting analge-

sic, an injectable anesthetic, a short-act-ing muscle relaxant, and a low dose of aneuroleptic.

In regional anesthesia (spinal an-esthesia) with a local anesthetic (p.204), nociception is eliminated, whileconsciousness is preserved. This proce-dure, therefore, does not fall under thedefinition of general anesthesia.

According to their mode of applica-tion, general anesthetics in the restrict-ed sense are divided into inhalational(gaseous, volatile) and injectable agents.

Inhalational anesthetics are admin-istered in and, for the most part, elimi-nated via respired air. They serve tomaintain anesthesia. Pertinent sub-stances are considered on p. 218.

Injectable anesthetics (p. 220) arefrequently employed for induction.Intravenous injection and rapid onset ofaction are clearly more agreeable to thepatient than is breathing a stupefyinggas. The effect of most injectable anes-thetics is limited to a few minutes. Thisallows brief procedures to be carried outor to prepare the patient for inhalation-al anesthesia (intubation). Administra-tion of the volatile anesthetic must thenbe titrated in such a manner as to coun-terbalance the waning effect of the in-jectable agent.

Increasing use is now being madeof injectable, instead of inhalational, an-esthetics during prolonged combinedanesthesia (total intravenous anesthe-sia—TIVA).

“TIVA” has become feasible thanksto the introduction of agents with a suit-ably short duration of action, includingthe injectable anesthetics propofol andetomidate, the analgesics alfentanil undremifentanil, and the muscle relaxantmivacurium. These drugs are eliminatedwithin minutes after being adminster-ed, irrespective of the duration ofanesthesia.

216 General Anesthetic Drugs


General Anesthetic Drugs 217

Pain stimulus

C. Regimen for balanced anesthesia

A. Goals of surgical anesthesia

B. Traditional monoanesthesia vs. modern balanced anesthesia

Muscle relaxation Loss of consciousness Autonomic stabilization

Analgesia

Motorreflexes

Pain andsuffering

Autonomicreflexes

Nociception

Paralysis ofvital centers

Mono-anesthesiae.g., diethylether

Reduced painsensitivity

Muscle relaxation

Loss of consciousness

Pancuronium

N2 O

Halothane

autonomic stabilization

Atropine

Pentazocine analgesia

Neostigm

ine reversal of

neuromuscular block

Midazolam

unconsciousness

Pentazocine analgesia

Diazepam

anxiolysis

Muscle relaxation

Analgesia

Unconsciousness

muscle relaxation; intubation

Succinycholine

Pre-medication Induction Maintenance Recovery

Forunconsciousness:e.g., halothaneor propofol

Formusclerelaxatione.g., pan-curonium

Forautonomicstabilizatione.g.,atropine

Foranalgesiae.g., N2Oor fentanyl


Inhalational Anesthetics

The mechanism of action of inhala-tional anesthetics is unknown. The di-versity of chemical structures (inert gasxenon; hydrocarbons; halogenated hy-drocarbons) possessing anesthetic ac-tivity appears to rule out involvement ofspecific receptors. According to one hy-pothesis, uptake into the hydrophobicinterior of the plasmalemma of neuronsresults in inhibition of electrical excit-ability and impulse propagation in thebrain. This concept would explain thecorrelation between anesthetic potencyand lipophilicity of anesthetic drugs (A).However, an interaction with lipophilicdomains of membrane proteins is alsoconceivable. Anesthetic potency can beexpressed in terms of the minimal al-veolar concentration (MAC) at which50% of patients remain immobile fol-lowing a defined painful stimulus (skinincision). Whereas the poorly lipophilicN2O must be inhaled in high concentra-tions (>70% of inspired air has to be re-placed), much smaller concentrations(<5%) are required in the case of themore lipophilic halothane.

The rates of onset and cessation ofaction vary widely between different in-halational anesthetics and also dependon the degree of lipophilicity. In the caseof N2O, there is rapid elimination fromthe body when the patient is ventilatedwith normal air. Due to the high partialpressure in blood, the driving force fortransfer of the drug into expired air islarge and, since tissue uptake is minor,the body can be quickly cleared of N2O.In contrast, with halothane, partial pres-sure in blood is low and tissue uptake ishigh, resulting in a much slower elimi-nation.

Given alone, N2O (nitrous oxide,“laughing gas”) is incapable of produc-ing anesthesia of sufficient depth forsurgery. It has good analgesic efficacythat can be exploited when it is used inconjunction with other anesthetics. As agas, N2O can be administered directly.Although it irreversibly oxidizes vita-min B12, N2O is not metabolized appre-

ciably and is cleared entirely by exhala-tion (B).

Halothane (boiling point [BP]50 °C), enflurane (BP 56 °C), isoflurane(BP 48 °C), and the obsolete methoxyflu-rane (BP 104 °C) have to be vaporized byspecial devices. Part of the administeredhalothane is converted into hepatotoxicmetabolites (B). Liver damage may re-sult from halothane anesthesia. With asingle exposure, the risk involved is un-predictable; however, there is a correla-tion with the frequency of exposure andthe shortness of the interval betweensuccessive exposures.

Up to 70% of inhaled methoxyflu-rane is converted to metabolites thatmay cause nephrotoxicity, a problemthat has led to the withdrawal of thedrug.

Degradation products of enfluraneor isoflurane (fraction biotransformed<2%) are of no concern.

Halothane exerts a pronounced hy-potensive effect, to which a negative in-otropic effect contributes. Enfluraneand isoflurane cause less circulatory de-pression. Halothane sensitizes the myo-cardium to catecholamines (caution: se-rious tachyarrhythmias or ventricularfibrillation may accompany use of cate-cholamines as antihypotensives or toco-lytics). This effect is much less pro-nounced with enflurane and isoflurane.Unlike halothane, enflurane and isoflu-rane have a muscle-relaxant effect thatis additive with that of nondepolarizingneuromuscular blockers.

Desflurane is a close structural rela-tive of isoflurane, but has low lipophilic-ity that permits rapid induction and re-covery as well as good control of anes-thetic depth.




Low potencyhigh partial pressure neededrelatively little binding to tissue

B. Elimination routes of different volatile anesthetics

A. Lipophilicity, potency and elimination of N2O and halothane

Anesthetic potency

Lipophilicity

Nitrous oxideN2O Xenon

CyclopropaneDiethylether

Enflurane

ChloroformHalothane

Partial pressure in tissue

Time

Termination of intake

Partial pressure of anesthetic

Binding

Tissue Blood Alveolar air

High potencylow partial pressure sufficientrelatively high binding in tissue

Halothane

N2O

MetabolitesMetabolites

HalothaneMethoxy-

fluraneEtherNitrous oxideN2O

H5C2OC2H5


Injectable Anesthetics

Substances from different chemicalclasses suspend consciousness whengiven intravenously and can be used asinjectable anesthetics (B). Unlike inha-lational agents, most of these drugs af-fect consciousness only and are devoidof analgesic activity (exception: keta-mine). The effect cannot be ascribed tononselective binding to neuronal cellmembranes, although this may hold forpropofol.

Most injectable anesthetics arecharacterized by a short duration of ac-tion. The rapid cessation of action islargely due to redistribution: afterintravenous injection, brain concentra-tion climbs rapidly to anesthetic levelsbecause of the high cerebral blood flow;the drug then distributes evenly in thebody, i.e., concentration rises in the pe-riphery, but falls in the brain—redistri-bution and cessation of anesthesia (A).Thus, the effect subsides before the drughas left the body. A second injection ofthe same dose, given immediately afterrecovery from the preceding dose, cantherefore produce a more intense andlonger effect. Usually, a single injectionis administered. However, etomidateand propofol may be given by infusionover a longer time period to maintainunconsciousness.

Thiopental and methohexital belongto the barbiturates which, depending ondose, produce sedation, sleepiness, oranesthesia. Barbiturates lower the painthreshold and thereby facilitate defen-sive reflex movements; they also de-press the respiratory center. Barbitu-rates are frequently used for inductionof anesthesia.

Ketamine has analgesic activity thatpersists beyond the period of uncon-sciousness up to 1 h after injection. Onregaining consciousness, the patientmay experience a disconnectionbetween outside reality and inner men-tal state (dissociative anesthesia). Fre-quently there is memory loss for the du-ration of the recovery period; however,adults in particular complain about dis-

tressing dream-like experiences. Thesecan be counteracted by administrationof a benzodiazepine (e.g., midazolam).The CNS effects of ketamine arise, inpart, from an interference with excita-tory glutamatergic transmission via li-gand-gated cation channels of theNMDA subtype, at which ketamine actsas a channel blocker. The non-naturalexcitatory amino acid N-methyl-D-aspartate is a selective agonist at this re-ceptor. Release of catecholamines witha resultant increase in heart rate andblood pressure is another unrelated ac-tion of ketamine.

Propofol has a remarkably simplestructure. Its effect has a rapid onset anddecays quickly, being experienced bythe patient as fairly pleasant. The inten-sity of the effect can be well controlledduring prolonged administration.

Etomidate hardly affects the auto-nomic nervous system. Since it inhibitscortisol synthesis, it can be used in thetreatment of adrenocortical overactivity(Cushing’s disease).

Midazolam is a rapidly metabolizedbenzodiazepine (p. 228) that is used forinduction of anesthesia. The longer-act-ing lorazepam is preferred as adjunctanesthetic in prolonged cardiac surgerywith cardiopulmonary bypass; its am-nesiogenic effect is pronounced.




B. Intravenous anesthetics

A. Termination of drug effect by redistribution

CNS:relativelyhighblood flow

Periphery:relativelylow bloodflow

ml bloodmin x g tissue

Initial situation

i.v. injection

High concentrationin tissue

Relatively largeamount of drug

Relatively smallamount of drug

mg drugmin x g tissue

Low concentrationin tissue

Preferential accumulationof drug in brain

Decreasein tissueconcentration

Furtherincreasein tissueconcentration

Redistribution Steady-state of distribution

Sodium thiopental Ketamine Etomidate

Sodiummethohexital Propofol Midazolam


Soporifics, Hypnotics

During sleep, the brain generates a pat-terned rhythmic activity that can bemonitored by means of the electroen-cephalogram (EEG). Internal sleep cy-cles recur 4 to 5 times per night, eachcycle being interrupted by a Rapid EyeMovement (REM) sleep phase (A). TheREM stage is characterized by EEG activ-ity similar to that seen in the wakingstate, rapid eye movements, vividdreams, and occasional twitches of indi-vidual muscle groups against a back-ground of generalized atonia of skeletalmusculature. Normally, the REM stage isentered only after a preceding non-REMcycle. Frequent interruption of sleepwill, therefore, decrease the REM por-tion. Shortening of REM sleep (normallyapprox. 25% of total sleep duration) re-sults in increased irritability and rest-lessness during the daytime. With un-disturbed night rest, REM deficits arecompensated by increased REM sleepon subsequent nights (B).

Hypnotics fall into different catego-ries, including the benzodiazepines(e.g., triazolam, temazepam, clotiaze-pam, nitrazepam), barbiturates (e.g.,hexobarbital, pentobarbital), chloral hy-drate, and H1-antihistamines with seda-tive activity (p. 114). Benzodiazepinesact at specific receptors (p. 226). Thesite and mechanism of action of barbitu-rates, antihistamines, and chloral hy-drate are incompletely understood.

All hypnotics shorten the timespent in the REM stages (B). With re-peated ingestion of a hypnotic on sever-al successive days, the proportion oftime spent in REM vs. non-REM sleepreturns to normal despite continueddrug intake. Withdrawal of the hypnoticdrug results in REM rebound, which ta-pers off only over many days (B). SinceREM stages are associated with vividdreaming, sleep with excessively longREM episodes is experienced as unre-freshing. Thus, the attempt to discon-tinue use of hypnotics may result in theimpression that refreshing sleep calls

for a hypnotic, probably promotinghypnotic drug dependence.

Depending on their blood levels,both benzodiazepines and barbituratesproduce calming and sedative effects,the former group also being anxiolytic.At higher dosage, both groups promotethe onset of sleep or induce it (C).

Unlike barbiturates, benzodiaze-pine derivatives administered orallylack a general anesthetic action; cere-bral activity is not globally inhibited(respiratory paralysis is virtually impos-sible) and autonomic functions, such asblood pressure, heart rate, or body tem-perature, are unimpaired. Thus, benzo-diazepines possess a therapeutic marginconsiderably wider than that of barbitu-rates.

Zolpidem (an imidazopyridine)and zopiclone (a cyclopyrrolone) arehypnotics that, despite their differentchemical structure, possess agonist ac-tivity at the benzodiazepine receptor (p.226).

Due to their narrower margin ofsafety (risk of misuse for suicide) andtheir potential to produce physical de-pendence, barbiturates are no longer oronly rarely used as hypnotics. Depen-dence on them has all the characteris-tics of an addiction (p. 210).

Because of rapidly developing tol-erance, choral hydrate is suitable onlyfor short-term use.

Antihistamines are popular asnonprescription (over-the-counter)sleep remedies (e.g., diphenhydramine,doxylamine, p. 114), in which case theirsedative side effect is used as the princi-pal effect.

222 Hypnotics


Hypnotics 223

C. Concentration dependence of barbiturate and benzodiazepine effects

B. Effect of hypnotics on proportion of REM/NREM

A. Succession of different sleep phases during night rest

REM

Wakingstate

SleepstageI

SleepstageIV

SleepstageIII

SleepstageII

REM-sleep= Rapid Eye Movement sleep NREM = No Rapid Eye Movement sleep

Ratio

NREM

5 10 15 20 25 30Nightswithouthypnotic

Nightswithhypnotic

Nights afterwithdrawalof hypnotic

Paralyzing

Anesthetizing

Hypnogenic

Hypnagogic

Calming, anxiolytic

Triazolam

Pentobarbital

Effect

Concentration in blood

Pentobarbital

Triazolam

Barbiturates:

Benzo-diazepines:

REM


Sleep–Wake Cycle and Hypnotics

The physiological mechanisms regulat-ing the sleep-wake rhythm are not com-pletely known. There is evidence thathistaminergic, cholinergic, glutamater-gic, and adrenergic neurons are moreactive during waking than during theNREM sleep stage. Via their ascendingthalamopetal projections, these neu-rons excite thalamocortical pathwaysand inhibit GABA-ergic neurons. Duringsleep, input from the brain stem de-creases, giving rise to diminished tha-lamocortical activity and disinhibitionof the GABA neurons (A). The shift inbalance between excitatory (red) andinhibitory (green) neuron groupsunderlies a circadian change in sleeppropensity, causing it to remain low inthe morning, to increase towards earlyafternoon (midday siesta), then to de-cline again, and finally to reach its peakbefore midnight (B1).

Treatment of sleep disturbances.Pharmacotherapeutic measures are in-dicated only when causal therapy hasfailed. Causes of insomnia include emo-tional problems (grief, anxiety, “stress”),physical complaints (cough, pain), orthe ingestion of stimulant substances(caffeine-containing beverages, sympa-thomimetics, theophylline, or certainantidepressants). As illustrated for emo-tional stress (B2), these factors cause animbalance in favor of excitatory influ-ences. As a result, the interval betweengoing to bed and falling asleep becomeslonger, total sleep duration decreases,and sleep may be interrupted by severalwaking periods.

Depending on the type of insomnia,benzodiazepines (p. 226) with short orintermediate duration of action are in-dicated, e.g., triazolam and brotizolam(t1/2 ~ 4–6 h); lormetazepam or temaze-pam (t1/2 ~ 10–15 h). These drugs short-en the latency of falling asleep, lengthentotal sleep duration, and reduce the fre-quency of nocturnal awakenings. Theyact by augmenting inhibitory activity.Even with the longer-acting benzodiaz-epines, the patient awakes after about

6–8 h of sleep, because in the morningexcitatory activity exceeds the sum ofphysiological and pharmacological inhi-bition (B3). The drug effect may, howev-er, become unmasked at daytime whenother sedating substances (e.g., ethanol)are ingested and the patient shows anunusually pronounced response due toa synergistic interaction (impaired abil-ity to concentrate or react).

As the margin between excitatoryand inhibitory activity decreases withage, there is an increasing tendency to-wards shortened daytime sleep periodsand more frequent interruption of noc-turnal sleep (C).

Use of a hypnotic drug should notbe extended beyond 4 wk, because tol-erance may develop. The risk of a re-bound decrease in sleep propensity af-ter drug withdrawal may be avoided bytapering off the dose over 2 to 3 wk.

With any hypnotic, the risk of sui-cidal overdosage cannot be ignored.Since benzodiazepine intoxication maybecome life-threatening only whenother central nervous depressants (etha-nol) are taken simultaneously and can,moreover, be treated with specific ben-zodiazepine antagonists, the benzo-diazepines should be given preference as sleep remedies over the all but obso-lete barbiturates.

224 Hypnotics


Hypnotics 225

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

Waking state NREM-sleep

Neurons withtransmitters:

HistamineAcetylcholineGlutamateNorepinephrineGABA

A. Transmitters: waking state and sleep

C. Changes of the arousal reaction in the elderly

Hypnotic

Hypnotic

1

2

3

1

2

Emotional stress


Benzodiazepines

Benzodiazepines modify affective re-sponses to sensory perceptions; specifi-cally, they render a subject indifferenttowards anxiogenic stimuli, i.e., anxio-lytic action. Furthermore, benzodiaze-pines exert sedating, anticonvulsant,and muscle-relaxant (myotonolytic, p.182) effects. All these actions resultfrom augmenting the activity of inhibi-tory neurons and are mediated by spe-cific benzodiazepine receptors thatform an integral part of the GABAA re-ceptor-chloride channel complex. Theinhibitory transmitter GABA acts toopen the membrane chloride channels.Increased chloride conductance of theneuronal membrane effectively short-circuits responses to depolarizing in-puts. Benzodiazepine receptor agonistsincrease the affinity of GABA to its re-ceptor. At a given concentration ofGABA, binding to the receptors will,therefore, be increased, resulting in anaugmented response. Excitability of theneurons is diminished.

Therapeutic indications for benzo-diazepines include anxiety states asso-ciated with neurotic, phobic, and de-pressive disorders, or myocardial in-farction (decrease in cardiac stimula-tion due to anxiety); insomnia; prean-esthetic (preoperative) medication;epileptic seizures; and hypertonia ofskeletal musculature (spasticity, rigid-ity).

Since GABA-ergic synapses are con-fined to neural tissues, specific inhibi-tion of central nervous functions can beachieved; for instance, there is littlechange in blood pressure, heart rate,and body temperature. The therapeuticindex of benzodiazepines, calculatedwith reference to the toxic dose produc-ing respiratory depression, is greaterthan 100 and thus exceeds that of bar-biturates and other sedative-hypnoticsby more than tenfold. Benzodiazepineintoxication can be treated with a spe-cific antidote (see below).

Since benzodiazepines depress re-sponsivity to external stimuli, automo-

tive driving skills and other tasks re-quiring precise sensorimotor coordina-tion will be impaired.

Triazolam (t1/2 of elimination~1.5–5.5 h) is especially likely to impairmemory (anterograde amnesia) and tocause rebound anxiety or insomnia anddaytime confusion. The severity of theseand other adverse reactions (e.g., rage,violent hostility, hallucinations), andtheir increased frequency in the elderly,has led to curtailed or suspended use oftriazolam in some countries (UK).

Although benzodiazepines are welltolerated, the possibility of personalitychanges (nonchalance, paradoxical ex-citement) and the risk of physical de-pendence with chronic use must not beoverlooked. Conceivably, benzodiaze-pine dependence results from a kind ofhabituation, the functional counterpartsof which become manifest during absti-nence as restlessness and anxiety; evenseizures may occur. These symptomsreinforce chronic ingestion of benzo-diazepines.

Benzodiazepine antagonists, suchas flumazenil, possess affinity for ben-zodiazepine receptors, but they lack in-trinsic activity. Flumazenil is an effec-tive antidote in the treatment of ben-zodiazepine overdosage or can be usedpostoperatively to arouse patients se-dated with a benzodiazepine.

Whereas benzodiazepines possess-ing agonist activity indirectly augmentchloride permeability, inverse agonistsexert an opposite action. These sub-stances give rise to pronounced rest-lessness, excitement, anxiety, and con-vulsive seizures. There is, as yet, notherapeutic indication for their use.

226 Psychopharmacologicals


Psychopharmacologicals 227

A. Action of benzodiazepines

Anxiolysis

plus anticonvulsant effect,sedation, muscle relaxation

Diazepam

R1 = Cl

R2 = CH3

R3 = R4 = H

Benzodiaz

epine

R4

N

N

R1

R3

OR2

Inhibition ofexcitation

Hyper-polari-zation

GABA

GABA-gated Cl--channel

Cl-

Benzodiazepines

Unopposed excitationNormalGABA-ergic inhibition

EnhancedGABA-ergic inhibition

GA

BA

-erg

ic n

euro

n

Benzodiazepinereceptor

GABA-receptor

Chlorideionophore

GABA=γ-amino-butryc acid


Pharmacokinetics of Benzodiazepines

All benzodiazepines exert their actionsat specific receptors (p. 226). The choicebetween different agents is dictated bytheir speed, intensity, and duration ofaction. These, in turn, reflect physico-chemical and pharmacokinetic proper-ties. Individual benzodiazepines remainin the body for very different lengths oftime and are chiefly eliminated throughbiotransformation. Inactivation may en-tail a single chemical reaction or severalsteps (e.g., diazepam) before an inactivemetabolite suitable for renal elimina-tion is formed. Since the intermediaryproducts may, in part, be pharmacologi-cally active and, in part, be excretedmore slowly than the parent substance,metabolites will accumulate with con-tinued regular dosing and contributesignificantly to the final effect.

Biotransformation begins either atsubstituents on the diazepine ring (diaz-epam: N-dealkylation at position 1;midazolam: hydroxylation of the methylgroup on the imidazole ring) or at thediazepine ring itself. Hydroxylated mid-azolam is quickly eliminated followingglucuronidation (t1/2 ~ 2 h). N-de-methyldiazepam (nordazepam) is bio-logically active and undergoes hydroxy-lation at position 3 on the diazepinering. The hydroxylated product (oxaze-pam) again is pharmacologically active.By virtue of their long half-lives, diaze-pam (t1/2 ~ 32 h) and, still more so, itsmetabolite, nordazepam (t1/2 50–90 h),are eliminated slowly and accumulateduring repeated intake. Oxazepamundergoes conjugation to glucuronic ac-id via its hydroxyl group (t1/2 = 8 h) andrenal excretion (A).

The range of elimination half-livesfor different benzodiazepines or theiractive metabolites is represented by theshaded areas (B). Substances with ashort half-life that are not converted toactive metabolites can be used for in-duction or maintenance of sleep (lightblue area in B). Substances with a longhalf-life are preferable for long-termanxiolytic treatment (light green area)

because they permit maintenance ofsteady plasma levels with single dailydosing. Midazolam enjoys use by the i.v.route in preanesthetic medication andanesthetic combination regimens.

Benzodiazepine Dependence

Prolonged regular use of benzodiaze-pines can lead to physical dependence.With the long-acting substances mar-keted initially, this problem was less ob-vious in comparison with other depen-dence-producing drugs because of thedelayed appearance of withdrawalsymptoms. The severity of the absti-nence syndrome is inversely related tothe elimination t1/2, ranging from mildto moderate (restlessness, irritability,sensitivity to sound and light, insomnia,and tremulousness) to dramatic (de-pression, panic, delirium, grand mal sei-zures). Some of these symptoms posediagnostic difficulties, being indistin-guishable from the ones originally treat-ed. Administration of a benzodiazepineantagonist would abruptly provoke ab-stinence signs. There are indicationsthat substances with intermediate elim-ination half-lives are most frequentlyabused (violet area in B).




B. Rate of elimination of benzodiazepines

A. Biotransformation of benzodiazepines

Midazolam Diazepam

as glucuronide

Active metabolites

Inactive

Oxazepam

Nordazepam

Triazolam

Brotizolam

Oxazepam

Lormetazepam

Bromazepam

Flunitrazepam

Lorazepam

Camazepam

Nitrazepam

Clonazepam

Diazepam

Temazepam

Prazepam

Applied drug Active metabolitePlasma elimination half-life

Hypnagogiceffect

Abuseliability

Anxiolytic effect

0 20 30 40 50 6010 >60 h


Therapy of Manic-Depressive Illness

Manic-depressive illness connotes apsychotic disorder of affect that occursepisodically without external cause. Inendogenous depression (melancholia),mood is persistently low. Mania refersto the opposite condition (p. 234). Pa-tients may oscillate between these twoextremes with interludes of normalmood. Depending on the type of disor-der, mood swings may alternatebetween the two directions (bipolar de-pression, cyclothymia) or occur in onlyone direction (unipolar depression).

I. Endogenous Depression

In this condition, the patient experienc-es profound misery (beyond theobserver’s empathy) and feelings of se-vere guilt because of imaginary miscon-duct. The drive to act or move is inhibit-ed. In addition, there are disturbancesmostly of a somatic nature (insomnia,loss of appetite, constipation, palpita-tions, loss of libido, impotence, etc.). Al-though the patient may have suicidalthoughts, psychomotor retardation pre-vents suicidal impulses from being car-ried out. In A, endogenous depression isillustrated by the layers of somber col-ors; psychomotor drive, symbolized bya sine oscillation, is strongly reduced.

Therapeutic agents fall into twogroups:� Thymoleptics, possessing a pro-

nounced ability to re-elevate de-pressed mood e.g., the tricyclic anti-depressants;

� Thymeretics, having a predominantactivating effect on psychomotordrive, e g., monoamine oxidase inhib-itors.

It would be wrong to administerdrive-enhancing drugs, such as amphet-amines, to a patient with endogenousdepression. Because this therapy fails toelevate mood but removes psychomo-tor inhibition (A), the danger of suicideincreases.

Tricyclic antidepressants (TCA;prototype: imipramine) have had the

longest and most extensive therapeuticuse; however, in the past decade, theyhave been increasingly superseded bythe serotonin-selective reuptake inhibi-tors (SSRI; prototype: fluoxetine).

The central seven-membered ringof the TCAs imposes a 120° anglebetween the two flanking aromaticrings, in contradistinction to the flatring system present in phenothiazinetype neuroleptics (p. 237). The sidechain nitrogen is predominantly proto-nated at physiological pH.

The TCAs have affinity for both re-ceptors and transporters of monoaminetransmitters and behave as antagonistsin both respects. Thus, the neuronal re-uptake of norepinephrine (p. 82) and se-rotonin (p. 116) is inhibited, with a re-sultant increase in activity. Muscarinicacetylcholine receptors, α-adrenocep-tors, and certain 5-HT and hista-mine(H1) receptors are blocked. Inter-ference with the dopamine system isrelatively minor.

How interference with these trans-mitter/modulator substances translatesinto an antidepressant effect is still hy-pothetical. The clinical effect emergesonly after prolonged intake, i.e., 2–3 wk,as evidenced by an elevation of moodand drive. However, the alteration inmonoamine metabolism occurs as soonas therapy is started. Conceivably, adap-tive processes (such as downregulationof cortical serotonin and β-adrenocep-tors) are ultimately responsible. Inhealthy subjects, the TCAs do not im-prove mood (no euphoria).

Apart from the antidepressant ef-fect, acute effects occur that are evidentalso in healthy individuals. These varyin degree among individual substancesand thus provide a rationale for differ-entiated clinical use (p. 233), basedupon the divergent patterns of interfer-ence with amine transmitters/modula-tors. Amitriptyline exerts anxiolytic,sedative and psychomotor dampeningeffects. These are useful in depressivepatients who are anxious and agitated.

In contrast, desipramine producespsychomotor activation. Imipramine




A. Effect of antidepressants

Amphetamine Immediate

Wee

k 9

Wee

k 7

Wee

k 5

Wee

k 3

End

ogen

ous

dep

ress

ion

Imipramine

5HT orNA

Inhibition ofre-uptake

Deficient drive

Nor

mal

moo

d

Normal drive

M, H1, α1

Blockade ofreceptors

Ach

NA

Effects on synaptic transmissionby inhibition of amine re-uptakeand by receptor antagonism


occupies an intermediate position. Itshould be noted that, in the organism,biotransformation of imipramine leadsto desipramine (N-desmethylimipra-mine). Likewise, the desmethyl deriva-tive of amitriptyline (nortriptyline) isless dampening.

In nondepressive patients whosecomplaints are of predominantly psy-chogenic origin, the anxiolytic-sedativeeffect may be useful in efforts to bringabout a temporary “psychosomatic un-coupling.” In this connection, clinicaluse as “co-analgesics” (p. 194) may benoted.

The side effects of tricyclic antide-pressants are largely attributable to theability of these compounds to bind toand block receptors for endogenoustransmitter substances. These effectsdevelop acutely. Antagonism at musca-rinic cholinoceptors leads to atropine-like effects such as tachycardia, inhibi-tion of exocrine glands, constipation,impaired micturition, and blurred vi-sion.

Changes in adrenergic function arecomplex. Inhibition of neuronal cate-cholamine reuptake gives rise to super-imposed indirect sympathomimeticstimulation. Patients are supersensitiveto catecholamines (e.g., epinephrine inlocal anesthetic injections must beavoided). On the other hand, blockadeof α1-receptors may lead to orthostatichypotension.

Due to their cationic amphiphilicnature, the TCA exert membrane-stabi-lizing effects that can lead to distur-bances of cardiac impulse conductionwith arrhythmias as well as decreases inmyocardial contractility. All TCA lowerthe seizure threshold. Weight gain mayresult from a stimulant effect on appe-tite.

Maprotiline, a tetracyclic com-pound, largely resembles tricyclicagents in terms of its pharmacologicaland clinical actions. Mianserine alsopossesses a tetracyclic structure, butdiffers insofar as it increases intrasyn-aptic concentrations of norepinephrine

by blocking presynaptic α2-receptors,rather than reuptake. Moreover, it hasless pronounced atropine-like activity.

Fluoxetine, along with sertraline,fluvoxamine, and paroxetine, belongs tothe more recently developed group ofSSRI. The clinical efficacy of SSRI is con-sidered comparable to that of estab-lished antidepressants. Added advan-tages include: absence of cardiotoxicity,fewer autonomic nervous side effects,and relative safety with overdosage.Fluoxetine causes loss of appetite andweight reduction. Its main adverse ef-fects include: overarousal, insomnia,tremor, akathisia, anxiety, and distur-bances of sexual function.

Moclobemide is a new representa-tive of the group of MAO inhibitors. In-hibition of intraneuronal degradation ofserotonin and norepinephrine causes anincrease in extracellular amine levels. Apsychomotor stimulant thymeretic ac-tion is the predominant feature of MAOinhibitors. An older member of thisgroup, tranylcypromine, causes irre-versible inhibition of the two isozymesMAOA and MAOB. Therefore, presystem-ic elimination in the liver of biogenicamines, such as tyramine, which are in-gested in food (e.g., aged cheese andChianti), will be impaired. To avoid thedanger of a hypertensive crisis, therapywith tranylcypromine or other nonse-lective MAO inhibitors calls for strin-gent dietary rules. With moclobemide,this hazard is much reduced because itinactivates only MAOA and does so in areversible manner.




Serotonin

Dopamine

Anx

ioly

sis

α 1-B

lock

ade

Par

asym

pat

ho-

lytic

act

ivity

Ind

icat

ion

Amitriptyline Patient:

Depressive,anxious,agitated

50-200 mg/dt1/2 = 9-20h

Imipramine

Depressive,normaldrive

75-200 mg/dt1/2 = 15-60h

Desipramine

Depressive,lack ofdriveandenergy

20-40 mg/dt1/2 = 48-96h

Fluoxetine

300 mg/dt1/2 = 1-2h

Moclobemide

A. Antidepressants: activity profiles

5-HT-Receptor

M-Cholinoceptor

α-Adrenoceptor

D-Receptor

Norepinephrine

Acetylcholine

50-150 mg/dt1/2 = 30-40h

Patient:

Patient:

Patient:

Patient:

Driv

e, e

nerg

y




II. Mania

The manic phase is characterized by ex-aggerated elation, flight of ideas, and apathologically increased psychomotordrive. This is symbolically illustrated inA by a disjointed structure and aggres-sive color tones. The patients are over-confident, continuously active, showprogressive incoherence of thought andloosening of associations, and act irre-sponsibly (financially, sexually etc.).

Lithium ions. Lithium salts (e.g.,acetate, carbonate) are effective in con-trolling the manic phase. The effect be-comes evident approx. 10 d after thestart of therapy. The small therapeuticindex necessitates frequent monitoringof Li+ serum levels. Therapeutic levelsshould be kept between 0.8–1.0 mM infasting morning blood samples. At high-er values there is a risk of adverse effects.CNS symptoms include fine tremor,ataxia or seizures. Inhibition of the renalactions of vasopressin (p. 164) leads topolyuria and thirst. Thyroid function isimpaired (p. 244), with compensatorydevelopment of (euthyroid) goiter.

The mechanism of action of Li ionsremains to be fully elucidated. Chemi-cally, lithium is the lightest of the alkalimetals, which include such biologicallyimportant elements as sodium and po-tassium. Apart from interference withtransmembrane cation fluxes (via ionchannels and pumps), a lithium effect ofmajor significance appears to be mem-brane depletion of phosphatidylinositolbisphosphates, the principal lipid sub-strate used by various receptors intransmembrane signalling (p. 66).Blockade of this important signal trans-duction pathway leads to impaired abil-ity of neurons to respond to activationof membrane receptors for transmittersor other chemical signals. Another siteof action of lithium may be GTP-bindingproteins responsible for signal trans-duction initiated by formation of the ag-onist-receptor complex.

Rapid control of an acute attack ofmania may require the use of a neuro-leptic (see below).

Alternate treatments. Mood-sta-bilization and control of manic or hy-pomanic episodes in some subtypes ofbipolar illness may also be achievedwith the anticonvulsants valproate andcarbamazepine, as well as with calciumchannel blockers (e.g., verapamil, nifed-ipine, nimodipine). Effects are delayedand apparently unrelated to the mecha-nisms responsible for anticonvulsantand cardiovascular actions, respective-ly.

III. Prophylaxis

With continued treatment for 6 to 12months, lithium salts prevent the re-currence of either manic or depressivestates, effectively stabilizing mood at anormal level.




A. Effect of lithium salts in mania

Day

8D

ay 6

Day

4D

ay 2

Normal state

Depression Mania

H

Na

K

Rb

Cs

Be

Mg

Ca

Sr

Ba

Li+

Nor

mal

stat

eM

ania

Lithium

Day

10


Therapy of Schizophrenia

Schizophrenia is an endogenous psy-chosis of episodic character. Its chiefsymptoms reflect a thought disorder(i.e., distracted, incoherent, illogicalthinking; impoverished intellectualcontent; blockage of ideation; abruptbreaking of a train of thought: claims ofbeing subject to outside agencies thatcontrol the patient’s thoughts), and adisturbance of affect (mood inappropri-ate to the situation) and of psychomotordrive. In addition, patients exhibit delu-sional paranoia (persecution mania) orhallucinations (fearfulness hearing ofvoices). Contrasting these “positive”symptoms, the so-called “negative”symptoms, viz., poverty of thought, so-cial withdrawal, and anhedonia, assumeadded importance in determining theseverity of the disease. The disruptionand incoherence of ideation is symboli-cally represented at the top left (A) andthe normal psychic state is illustrated ason p. 237 (bottom left).

Neuroleptics

After administration of a neuroleptic,there is at first only psychomotor damp-ening. Tormenting paranoid ideas andhallucinations lose their subjective im-portance (A, dimming of flashy colors);however, the psychotic processes stillpersist. In the course of weeks, psychicprocesses gradually normalize (A); thepsychotic episode wanes, althoughcomplete normalization often cannot beachieved because of the persistence ofnegative symptoms. Nonetheless, thesechanges are significant because the pa-tient experiences relief from the tor-ment of psychotic personality changes;care of the patient is made easier andreturn to a familiar community environ-ment is accelerated.

The conventional (or classical) neu-roleptics comprise two classes of com-pounds with distinctive chemical struc-tures: 1. the phenothiazines derivedfrom the antihistamine promethazine(prototype: chlorpromazine), including

their analogues (e.g., thioxanthenes);and 2. the butyrophenones (prototype:haloperidol). According to the chemicalstructure of the side chain, phenothia-zines and thioxanthenes can be subdi-vided into aliphatic (chlorpromazine,triflupromazine, p. 239 and piperazinecongeners (trifluperazine, fluphenazine,flupentixol, p. 239).

The antipsychotic effect is probablydue to an antagonistic action at dop-amine receptors. Aside from their mainantipsychotic action, neuroleptics dis-play additional actions owing to theirantagonism at– muscarinic acetylcholine receptors �

atropine-like effects;– α-adrenoceptors for norepinephrine

� disturbances of blood pressureregulation;

– dopamine receptors in the nigrostria-tal system � extrapyramidal motordisturbances; in the area postrema �antiemetic action (p. 330), and in thepituitary gland � increased secretionof prolactin (p. 242);

– histamine receptors in the cerebralcortex � possible cause of sedation.

These ancillary effects are also elicitedin healthy subjects and vary in intensityamong individual substances.

Other indications. Acutely, there issedation with anxiolysis after neurolep-tization has been started. This effect canbe utilized for: “psychosomatic un-coupling” in disorders with a prominentpsychogenic component; neurolepta-nalgesia (p. 216) by means of the buty-rophenone droperidol in combinationwith an opioid; tranquilization of over-excited, agitated patients; treatment ofdelirium tremens with haloperidol; aswell as the control of mania (see p. 234).

It should be pointed out that neuro-leptics do not exert an anticonvulsantaction, on the contrary, they may lowerseizure thershold.




Wee

k 9

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k 7

Wee

k 5

Wee

k 3

afte

r st

art

of t

hera

py

Chlorpromazine

Butyrophenone type:Haloperidol

Sedation

Autonomic disturbancedue to atropine-likeaction

Movement disordersdue to dopamineantagonism

Antiemetic effect

A. Effects of neuroleptics in schizophrenia

Phenothiazine type:

Neuroleptics


Because they inhibit the thermoreg-ulatory center, neuroleptics can be em-ployed for controlled hypothermia(p. 202).

Adverse Effects. Clinically mostimportant and therapy-limiting are ex-trapyramidal disturbances; these resultfrom dopamine receptor blockade.Acute dystonias occur immediately af-ter neuroleptization and are manifestedby motor impairments, particularly inthe head, neck, and shoulder region. Af-ter several days to months, a parkinso-nian syndrome (pseudoparkinsonism)or akathisia (motor restlessness) maydevelop. All these disturbances can betreated by administration of antiparkin-son drugs of the anticholinergic type,such as biperiden (i.e., in acute dysto-nia). As a rule, these disturbances disap-pear after withdrawal of neurolepticmedication. Tardive dyskinesia may be-come evident after chronic neurolep-tization for several years, particularlywhen the drug is discontinued. It is dueto hypersensitivity of the dopamine re-ceptor system and can be exacerbatedby administration of anticholinergics.

Chronic use of neuroleptics can, onoccasion, give rise to hepatic damage as-sociated with cholestasis. A very rare,but dramatic, adverse effect is the ma-lignant neuroleptic syndrome (skeletalmuscle rigidity, hyperthermia, stupor)that can end fatally in the absence of in-tensive countermeasures (includingtreatment with dantrolene, p. 182).

Neuroleptic activity profiles. Themarked differences in action spectra ofthe phenothiazines, their derivativesand analogues, which may partially re-semble those of butyrophenones, areimportant in determining therapeuticuses of neuroleptics. Relevant parame-ters include: antipsychotic efficacy(symbolized by the arrow); the extentof sedation; and the ability to induce ex-trapyramidal adverse effects. The latterdepends on relative differences in an-tagonism towards dopamine and ace-tylcholine, respectively (p. 188). Thus,the butyrophenones carry an increasedrisk of adverse motor reactions because

they lack anticholinergic activity and,hence, are prone to upset the balancebetween striatal cholinergic and dop-aminergic activity.

Derivatives bearing a piperazinemoiety (e.g., trifluperazine, fluphena-zine) have greater antipsychotic poten-cy than do drugs containing an aliphaticside chain (e.g., chlorpromazine, triflu-promazine). However, their antipsy-chotic effects are qualitatively indistin-guishable.

As structural analogues of thephenothiazines, thioxanthenes (e.g.,chlorprothixene, flupentixol) possess acentral nucleus in which the N atom isreplaced by a carbon linked via a doublebond to the side chain. Unlike the phe-nothiazines, they display an added thy-moleptic activity.

Clozapine is the prototype of theso-called atypical neuroleptics, a groupthat combines a relative lack of extrapy-ramidal adverse effects with superiorefficacy in alleviating negative symp-toms. Newer members of this class in-clude risperidone, olanzapine, and ser-tindole. Two distinguishing features ofthese atypical agents are a higher affin-ity for 5-HT2 (or 5-HT6) receptors thanfor dopamine D2 receptors and relativeselectivity for mesolimbic, as opposedto nigrostriatal, dopamine neurons.Clozapine also exhibits high affinity fordopamine receptors of the D4 subtype,in addition to H1 histamine and musca-rinic acetylcholine receptors. Clozapinemay cause dose–dependent seizuresand agranulocytosis, necessitating closehematological monitoring. It is stronglysedating.

When esterified with a fatty acid,both fluphenazine and haloperidol canbe applied intramuscularly as depotpreparations.




40%

40%

20%

less

sedating

strongly

Dopamine- ≈ ACh effect

Triflupromazine30 – 150 mg/d

1

10

50

Clozapine

FlupentixolTrifluoperazine

R=H Fluphenazine2.5 – 10 mg/d

Haloperidol2 – 6 mg/dR=H

Long-actingor“depot”neuroleptics i.m. 50–150 mg every 2 weeks i.m. 50–150 mg every 4 weeks

R =

O

C C9H19 R =

O

C C9H19

25 – 200 mg/d

15 – 20 mg/d

-decanoate -decanoate

Dopamine- < ACh effect extrapyramidal disturbancesDopamine

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

R

R

ACh

2 – 10 mg/d

Relative potency


Psychotomimetics (Psychedelics, Hallucinogens)

Psychotomimetics are able to elicit psy-chic changes like those manifested inthe course of a psychosis, such as illu-sionary distortion of perception andhallucinations. This experience may beof dreamlike character; its emotional orintellectual transposition appears inad-equate to the outsider.

A psychotomimetic effect is pictori-ally recorded in the series of portraitsdrawn by an artist under the influenceof lysergic acid diethylamide (LSD). Asthe intoxicated state waxes and waneslike waves, he reports seeing the face ofthe portrayed subject turn into a gri-mace, phosphoresce bluish-purple, andfluctuate in size as if viewed through amoving zoom lens, creating the illusionof abstruse changes in proportion andgrotesque motion sequences. The dia-bolic caricature is perceived as threat-ening.

Illusions also affect the senses ofhearing and smell; sounds (tones) are“experienced” as floating beams andvisual impressions as odors (“synesthe-sia”). Intoxicated individuals see them-selves temporarily from the outside andpass judgement on themselves andtheir condition. The boundary betweenself and the environment becomesblurred. An elating sense of being onewith the other and the cosmos sets in.The sense of time is suspended; there isneither present nor past. Objects areseen that do not exist, and experiencesfelt that transcend explanation, hencethe term “psychedelic” (Greek delosis =revelation) implying expansion of con-sciousness.

The contents of such illusions andhallucinations can occasionally becomeextremely threatening (“bad” or “bumtrip”); the individual may feel provokedto turn violent or to commit suicide. In-toxication is followed by a phase of in-tense fatigue, feelings of shame, and hu-miliating emptiness.

The mechanism of the psychoto-genic effect remains unclear. Some hal-

lucinogens such as LSD, psilocin, psilocy-bin (from fungi), bufotenin (the cutane-ous gland secretion of a toad), mescaline(from the Mexican cactuses Lophophorawilliamsii and L. diffusa; peyote) bear astructural resemblance to 5-HT (p. 116),and chemically synthesized ampheta-mine-derived hallucinogens (4-methyl-2,5-dimethoxyamphetamine; 3,4-di-methoxyamphetamine; 2,5-dimethoxy-4-ethyl amphetamine) are thought tointeract with the agonist recognitionsite of the 5-HT2A receptor. Conversely,most of the psychotomimetic effects areannulled by neuroleptics having 5-HT2A

antagonist activity (e.g. clozapine, ris-peridone). The structures of otheragents such as tetrahydrocannabinol(from the hemp plant, Cannabis sativa—hashish, marihuana), muscimol (fromthe fly agaric, Amanita muscaria), orphencyclidine (formerly used as an in-jectable general anesthetic) do not re-veal a similar connection. Hallucina-tions may also occur as adverse effectsafter intake of other substances, e.g.,scopolamine and other centrally activeparasympatholytics.

The popular psychostimulant, me-thylenedioxy-methamphetamine (MD-MA, “ecstasy”) acutely increases neuro-nal dopamine and norepinephrine re-lease and causes a delayed and selectivedegeneration of forebrain 5-HT nerveterminals.

Although development of psycho-logical dependence and permanent psy-chic damage cannot be considered es-tablished sequelae of chronic use of psy-chotomimetics, the manufacture andcommercial distribution of these drugsare prohibited (Schedule I, ControlledDrugs).




A. Psychotomimetic effect of LSD in a portrait artist

Lysergic aciddiethylamide0.0001 g/70 kg HN

NCH3

C2H5

CO

NC2H5


Hypothalamic and Hypophyseal Hormones

The endocrine system is controlled bythe brain. Nerve cells of the hypothala-mus synthesize and release messengersubstances that regulate adenohy-pophyseal (AH) hormone release or arethemselves secreted into the body ashormones. The latter comprise the so-called neurohypophyseal (NH) hor-mones.

The axonal processes of hypotha-lamic neurons project to the neurohy-pophysis, where they store the nona-peptides vasopressin (= antidiuretic hor-mone, ADH) and oxytocin and releasethem on demand into the blood. Thera-peutically (ADH, p. 64, oxytocin, p. 126),these peptide hormones are given pa-renterally or via the nasal mucosa.

The hypothalamic releasing hor-mones are peptides. They reach theirtarget cells in the AH lobe by way of aportal vascular route consisting of twoserially connected capillary beds. Thefirst of these lies in the hypophysealstalk, the second corresponds to thecapillary bed of the AH lobe. Here, thehypothalamic hormones diffuse fromthe blood to their target cells, whose ac-tivity they control. Hormones releasedfrom the AH cells enter the blood, inwhich they are distributed to peripheralorgans (1).

Nomenclature of releasing hor-mones:

RH–releasing hormone; RIH—re-lease inhibiting hormone.

GnRH: gonadotropin-RH = gona-dorelin stimulates the release of FSH(follicle-stimulating hormone) and LH(luteinizing hormone).

TRH: thyrotropin-RH (protirelin)stimulates the release of TSH (thyroidstimulating hormone = thyrotropin).

CRH: corticotropin-RH stimulatesthe release of ACTH (adrenocorticotrop-ic hormone = corticotropin).

GRH: growth hormone-RH (soma-tocrinin) stimulates the release of GH(growth hormone = STH, somatotropichormone). GRIH somatostatin inhibits

release of STH (and also other peptidehormones including insulin, glucagon,and gastrin).

PRH: prolactin-RH remains to becharacterized or established. Both TRHand vasoactive intestinal peptide (VIP)are implicated.

PRIH inhibits the release of prolac-tin and could be identical with dop-amine.

Hypothalamic releasing hormonesare mostly administered (parenterally)for diagnostic reasons to test AH func-tion.

Therapeutic control of AH cells.GnRH is used in hypothalamic infertilityin women to stimulate FSH and LH se-cretion and to induce ovulation. For thispurpose, it is necessary to mimic thephysiologic intermittent “pulsatile” re-lease (approx. every 90 min) by meansof a programmed infusion pump.

Gonadorelin superagonists areGnRH analogues that bind with veryhigh avidity to GnRH receptors of AHcells. As a result of the nonphysiologicuninterrupted receptor stimulation, in-itial augmentation of FSH and LH outputis followed by a prolonged decrease. Bu-serelin, leuprorelin, goserelin, and trip-torelin are used in patients with prostat-ic carcinoma to reduce production oftestosterone, which promotes tumorgrowth. Testosterone levels fall as muchas after extirpation of the testes (2).

The dopamine D2 agonists bromo-criptine and cabergoline (pp. 114, 188)inhibit prolactin-releasing AH cells (in-dications: suppression of lactation, pro-lactin-producing tumors). Excessive,but not normal, growth hormone re-lease can also be inhibited (indication:acromegaly) (3).

Octreotide is a somatostatin ana-logue; it is used in the treatment ofsomatostatin-secreting pituitary tu-mors.

242 Hormones


Hormones 243

PRHPRIH

A. Hypothalamic and hypophyseal hormones

GnRH TRH CRH GRHGRIH

ADHOxytocin

STH(GH) ProlactinACTH ADHTSH OxytocinFSH, LH

Ovum maturation;Estradiol,Progesterone

Spermatogenesis;Testosterone

Thyroxine

Cortisol

Growth

Somatomedins

Lactation Milk ejectionLabor

H2O

Hypothalamicreleasing hormones

Synthesis andrelease ofAH hormones

AH-cells

Synthesis Synthesis

Release intoblood

Release intoblood

Neurohypophysis

Adenohypophysis (A

H)

Application

parenteral

nasal

1

90 min

Rel

ease

d a

mou

nt

Pul

satil

e re

leas

e

Rhythmic stimulation

AH-cell

FSH LH

Persistent stimulation D2-Receptors

GnRH

Leuprorelin

Dopamine agonistBromocriptine

2 3.

Cessation of hormone secretion,"chemical castration"

Inhibition of prolactin

Buserelin

Hypot

halam

us

secretion of STH


Thyroid Hormone Therapy

Thyroid hormones accelerate metab-olism. Their release (A) is regulated bythe hypophyseal glycoprotein TSH,whose release, in turn, is controlled bythe hypothalamic tripeptide TRH. Secre-tion of TSH declines as the blood level ofthyroid hormones rises; by means ofthis negative feedback mechanism, hor-mone production is “automatically” ad-justed to demand.

The thyroid releases predominantlythyroxine (T4). However, the active formappears to be triiodothyronine (T3); T4 isconverted in part to T3, receptor affinityin target organs being 10-fold higher forT3. The effect of T3 develops more rapid-ly and has a shorter duration than doesthat of T4. Plasma elimination t1/2 for T4

is about 7 d; that for T3, however, is only1.5 d. Conversion of T4 to T3 releases io-dide; 150 µg T4 contains 100 µg of io-dine.

For therapeutic purposes, T4 is cho-sen, although T3 is the active form andbetter absorbed from the gut. However,with T4 administration, more constantblood levels can be achieved becausedegradation of T4 is so slow. Since ab-sorption of T4 is maximal from an emptystomach, T4 is taken about 1/2 h beforebreakfast.

Replacement therapy of hypothy-roidism. Whether primary, i.e., causedby thyroid disease, or secondary, i.e., re-sulting from TSH deficiency, hypothy-roidism is treated by oral administra-tion of T4. Since too rapid activation ofmetabolism entails the hazard of car-diac overload (angina pectoris, myocar-dial infarction), therapy is usually start-ed with low doses and gradually in-creased. The final maintenance dose re-quired to restore a euthyroid state de-pends on individual needs (approx.150 µg/d).

Thyroid suppression therapy ofeuthyroid goiter (B). The cause of goi-ter (struma) is usually a dietary defi-ciency of iodine. Due to an increasedTSH action, the thyroid is activated toraise utilization of the little iodine avail-

able to a level at which hypothyroidismis averted. Therefore, the thyroid in-creases in size. In addition, intrathyroiddepletion of iodine stimulates growth.

Because of the negative feedbackregulation of thyroid function, thyroidactivation can be inhibited by adminis-tration of T4 doses equivalent to the en-dogenous daily output (approx.150 µg/d). Deprived of stimulation, theinactive thyroid regresses in size.

If a euthyroid goiter has not persist-ed for too long, increasing iodine supply(potassium iodide tablets) can also beeffective in reversing overgrowth of thegland.

In older patients with goiter due toiodine deficiency there is a risk of pro-voking hyperthyroidism by increasingiodine intake (p. 247): During chronicmaximal stimulation, thyroid folliclescan become independent of TSH stimu-lation (“autonomic tissue”). If the iodinesupply is increased, thyroid hormoneproduction increases while TSH secre-tion decreases due to feedback inhibi-tion. The activity of autonomic tissue,however, persists at a high level; thy-roxine is released in excess, resulting iniodine-induced hyperthyroidism.

Iodized salt prophylaxis. Goiter isendemic in regions where soils are defi-cient in iodine. Use of iodized table saltallows iodine requirements (150–300 µg/d) to be met and effectively pre-vents goiter.

244 Hormones


Hormones 245

B. Endemic goiter and its treatment with thyroxine

A. Thyroid hormones - release, effects, degradation

Thyroid

Effector cell:receptor affinity

L-Thyroxine, Levothyroxine,3,5,3´,5´-Tetraiodothyronine, T4

Liothyronine3,5,3´-Triiodothyronine, T3

T3

T4

10

1=

~ 90 µg/Day ~ 9 µg/Day

~ 25 µg/Day

I-I-

I- I-

Hypothalamus

TRH

TSH

Decrease insensivityto TRH

Hypophysis

"reverse T3"3,3´,5´-Triiodothyronine Urine Feces

Deiodinase

Thyroxine Triiodothyronine

Deiodinationcoupling

Duration

T3 T4

Day2. 9.

10 Days30 4020

TSH

Hypophysis

NormalstateI-

T4, T3 T4, T3

TSH

T4

Therap.admini-stration

Inhi

biti

on


Hyperthyroidism and Antithyroid Drugs

Thyroid overactivity in Graves’ disease(A) results from formation of IgG anti-bodies that bind to and activate TSH re-ceptors. Consequently, there is overpro-duction of hormone with cessation ofTSH secretion. Graves’ disease can abatespontaneously after 1–2 y. Therefore,initial therapy consists of reversiblesuppression of thyroid activity bymeans of antithyroid drugs. In otherforms of hyperthyroidism, such as hor-mone-producing (morphologically be-nign) thyroid adenoma, the preferredtherapeutic method is removal of tissue,either by surgery or administration of131iodine in sufficient dosage. Radioio-dine is taken up into thyroid cells anddestroys tissue within a sphere of a fewmillimeters by emitting β-(electron)particles during its radioactive decay.

Concerning iodine-induced hyper-thyroidism, see p. 244 (B).

Antithyroid drugs inhibit thyroidfunction. Release of thyroid hormone(C) is preceded by a chain of events. Amembrane transporter actively accu-mulates iodide in thyroid cells; this isfollowed by oxidation to iodine, iodina-tion of tyrosine residues in thyroglobu-lin, conjugation of two diiodotyrosinegroups, and formation of T4 and T3

moieties. These reactions are catalyzedby thyroid peroxidase, which is local-ized in the apical border of the follicularcell membrane. T4-containing thyro-globulin is stored inside the thyroid fol-licles in the form of thyrocolloid. Uponendocytotic uptake, colloid undergoeslysosomal enzymatic hydrolysis, ena-bling thyroid hormone to be released asrequired. A “thyrostatic” effect can re-sult from inhibition of synthesis or re-lease. When synthesis is arrested, theantithyroid effect develops after a delay,as stored colloid continues to be uti-lized.

Antithyroid drugs for long-termtherapy (C). Thiourea derivatives(thioureylenes, thioamides) inhibitperoxidase and, hence, hormone syn-thesis. In order to restore a euthyroid

state, two therapeutic principles can beapplied in Graves’ disease: a) monother-apy with a thioamide with gradual dosereduction as the disease abates; b) ad-ministration of high doses of a thio-amide with concurrent administrationof thyroxine to offset diminished hor-mone synthesis. Adverse effects of thi-oamides are rare; however, the possibil-ity of agranulocytosis has to be kept inmind.

Perchlorate, given orally as the so-dium salt, inhibits the iodide pump. Ad-verse reactions include aplastic anemia.Compared with thioamides, its thera-peutic importance is low but it is usedas an adjunct in scintigraphic imaging ofbone by means of technetate whenaccumulation in the thyroid gland hasto be blocked.

Short-term thyroid suppression(C). Iodine in high dosage (>6000 µg/d)exerts a transient “thyrostatic” effect inhyperthyroid, but usually not in euthyr-oid, individuals. Since release is alsoblocked, the effect develops more rapid-ly than does that of thioamides.

Clinical applications include: preop-erative suppression of thyroid secretionaccording to Plummer with Lugol’s solu-tion (5% iodine + 10% potassium iodide,50–100 mg iodine/d for a maximum of10 d). In thyrotoxic crisis, Lugol’s solu-tion is given together with thioamidesand β-blockers. Adverse effects: aller-gies; contraindications: iodine-inducedthyrotoxicosis.

Lithium ions inhibit thyroxine re-lease. Lithium salts can be used insteadof iodine for rapid thyroid suppressionin iodine-induced thyrotoxicosis. Re-garding administration of lithium inmanic-depressive illness, see p. 234.

246 Hormones


Hormones 247

C. Antithyroid drugs and their modes of action

A. Graves’ disease B. Iodine hyperthyroidosis in endemic goiter

I-

Hypophysis

T4, T3

TSH

I-TSH-likeanti-bodies T4, T3

Autonomoustissue

T4, T3

Lysosome

Storagein colloid

I-

T4-ClO4

-

Perchlorate

Iodine inhigh dose

Lithiumions

I-e

T4-Tyrosine

Tyrosine

I

I

I

TG

Synthesis

T4-T4

Peroxidase

Thioamides

Propylthiouracil

Conversionduringabsorption

CarbimazoleThiamazoleMethimazole

Release


Glucocorticoid Therapy

I. Replacement therapy. The adrenalcortex (AC) produces the glucocorticoidcortisol (hydrocortisone) and the mine-ralocorticoid aldosterone. Both steroidhormones are vitally important in adap-tation responses to stress situations,such as disease, trauma, or surgery. Cor-tisol secretion is stimulated by hypo-physeal ACTH, aldosterone secretion byangiotensin II in particular (p. 124). InAC failure (primary AC insuffiency:Addison’s disease), both cortisol and al-dosterone must be replaced; when ACTHproduction is deficient (secondary AC in-sufficiency), cortisol alone needs to be re-placed. Cortisol is effective when givenorally (30 mg/d, 2/3 a.m., 1/3 p.m.). Instress situations, the dose is raised by 5- to 10-fold. Aldosterone is poorly effective via the oral route; instead, the mineralocorticoid fludrocortisone (0.1 mg/d) is given.

II. Pharmacodynamic therapywith glucocorticoids (A). In unphysio-logically high concentrations, cortisol orother glucocorticoids suppress all phas-es (exudation, proliferation, scar forma-tion) of the inflammatory reaction, i.e.,the organism’s defensive measuresagainst foreign or noxious matter. Thiseffect is mediated by multiple compo-nents, all of which involve alterations ingene transcription (p. 64). Glucocorti-coids inhibit the expression of genes en-coding for proinflammatory proteins(phospholipase-A2, cyclooxygenase 2,IL-2-receptor). The expression of thesegenes is stimulated by the transcriptionfactor NFΚB. Binding to the glucocorti-coid receptor complex prevents translo-cation af NFΚB to the nucleus. Converse-ly, glucocorticoids augment the expres-sion of some anti-inflammatory pro-teins, e.g., lipocortin, which in turn in-hibits phospholipase A2. Consequently,release of arachidonic acid is dimin-ished, as is the formation of inflamma-tory mediators of the prostaglandin andleukotriene series (p. 196). At very highdosage, nongenomic effects may alsocontribute.

Desired effects. As anti-allergics,immunosuppressants, or anti-inflamma-tory drugs, glucocorticoids display ex-cellent efficacy against “undesired” in-flammatory reactions.

Unwanted effects. With short-termuse, glucocorticoids are practically freeof adverse effects, even at the highestdosage. Long-term use is likely to causechanges mimicking the signs ofCushing’s syndrome (endogenousoverproduction of cortisol). Sequelae ofthe anti-inflammatory action: loweredresistance to infection, delayed woundhealing, impaired healing of peptic ul-cers. Sequelae of exaggerated glucocor-ticoid action: a) increased gluconeogen-esis and release of glucose; insulin-de-pendent conversion of glucose to trigly-cerides (adiposity mainly noticeable inthe face, neck, and trunk); “steroid-dia-betes” if insulin release is insufficient;b) increased protein catabolism withatrophy of skeletal musculature (thinextremities), osteoporosis, growth re-tardation in infants, skin atrophy. Se-quelae of the intrinsically weak, butnow manifest, mineralocorticoid actionof cortisol: salt and fluid retention, hy-pertension, edema; KCl loss with dangerof hypokalemia.

Measures for Attenuating or PreventingDrug-Induced Cushing’s Syndrome

a) Use of cortisol derivatives with less(e.g., prednisolone) or negligible miner-alocorticoid activity (e.g., triamcinolone,dexamethasone). Glucocorticoid activ-ity of these congeners is more pro-nounced. Glucorticoid, anti-inflamma-tory and feedback inhibitory (p. 250) ac-tions on the hypophysis are correlated.An exclusively anti-inflammatory con-gener does not exist. The “glucocorti-coid” related Cushingoid symptomscannot be avoided. The table lists rela-tive activity (potency) with reference tocortisol, whose mineralo- and glucocor-ticoid activities are assigned a value of1.0. All listed glucocorticoids are effec-tive orally.

248 Hormones


Hormones 249

Unwanted

Wanted

A. Glucocorticoids: principal and adverse effects

Inflammation

redness,swelling heat,pain;scar

Glucocorticoidaction

Mineralocorticoidaction

HypertensionDiabetesmellitus

Cortisol

unphysiologicallyhigh concentration

Muscleweakness

Osteo-porosis

Growth inhibition

Skinatrophy

Tissue atrophy

Triamcinolone

Aldosterone

Prednisolone

Dexamethasone

Glucose

Gluconeogenesis

Amino acids

Protein catabolismK+

Na+

H2O

e.g., allergyautoimmune disease,transplant rejection

Healing oftissue injurydue to bacteria,viruses, fungi, trauma

147,5

300,3

10,800

3000

Cortisol

Prednisolone

Triamcinolone

Dexamethasone

Pot

ency


b) Local application. Typical adverseeffects, however, also occur locally, e.g.,skin atrophy or mucosal colonizationwith candidal fungi. To minimizesystemic absorption after inhalation,derivatives should be used that have ahigh rate of presystemic elimination,such as beclomethasone dipropionate,flunisolide, budesonide, or fluticasonepropionate (p. 14).

b) Lowest dosage possible. For long-term medication, a just sufficient doseshould be given. However, in attempt-ing to lower the dose to the minimal ef-fective level, it is necessary to take intoaccount that administration of exoge-nous glucocorticoids will suppress pro-duction of endogenous cortisol due toactivation of an inhibitory feedbackmechanism. In this manner, a very lowdose could be “buffered,” so that un-physiologically high glucocorticoid ac-tivity and the anti-inflammatory effectare both prevented.

Effect of glucocorticoid adminis-tration on adrenocortical cortisol pro-duction (A). Release of cortisol dependson stimulation by hypophyseal ACTH,which in turn is controlled by hypotha-lamic corticotropin-releasing hormone(CRH). In both the hypophysis and hy-pothalamus there are cortisol receptorsthrough which cortisol can exert a feed-back inhibition of ACTH or CRH release.By means of these cortisol “sensors,” theregulatory centers can monitor whetherthe actual blood level of the hormonecorresponds to the “set-point.” If theblood level exceeds the set-point, ACTHoutput is decreased and, thus, also thecortisol production. In this way cortisollevel is maintained within the requiredrange. The regulatory centers respondto synthetic glucocorticoids as they doto cortisol. Administration of exogenouscortisol or any other glucocorticoid re-duces the amount of endogenous corti-sol needed to maintain homeostasis. Re-lease of CRH and ACTH declines ("inhi-bition of higher centers by exogenousglucocorticoid”) and, thus, cortisol se-cretion (“adrenocortical suppression”).After weeks of exposure to unphysio-

logically high glucocorticoid doses, thecortisol-producing portions of the ad-renal cortex shrink (“adrenocorticalatrophy”). Aldosterone-synthesizing ca-pacity, however, remains unaffected.When glucocorticoid medication is sud-denly withheld, the atrophic cortex isunable to produce sufficient cortisol anda potentially life-threatening cortisoldeficiency may develop. Therefore, glu-cocorticoid therapy should always betapered off by gradual reduction of thedosage.

Regimens for prevention ofadrenocortical atrophy. Cortisol secre-tion is high in the early morning andlow in the late evening (circadianrhythm). This fact implies that the regu-latory centers continue to release CRHor ACTH in the face of high morningblood levels of cortisol; accordingly,sensitivity to feedback inhibition mustbe low in the morning, whereas the op-posite holds true in the late evening.

a) Circadian administration: Thedaily dose of glucocorticoid is given inthe morning. Endogenous cortisol pro-duction will have already begun, theregulatory centers being relatively in-sensitive to inhibition. In the earlymorning hours of the next day, CRF/-ACTH release and adrenocortical stimu-lation will resume.

b) Alternate-day therapy: Twice thedaily dose is given on alternate morn-ings. On the “off” day, endogenous corti-sol production is allowed to occur.

The disadvantage of either regimenis a recrudescence of disease symptomsduring the glucocorticoid-free interval.

250 Hormones


Hormones 251

Hypo-physis

Adrenalcortex

Cortisol30 mg/day

Cortisolproduction undernormalconditions

Exogenousadministration

Adreno-corticalatrophy

Decrease incortisol productionwith cortisol dose< daily production

Cortisol deficiencyafter abruptcessation ofadministration

Cortisolconcentration

normal circadian time-course

Morning dose Inhibition ofendogenouscortisolproduction

Elimination ofexogenousglucocorticoidduring daytime

Start of earlymorningcortisolproduction

A. Cortisol release and its modification by glucocorticoids

CRH

ACTH

Hypothalamus

Cessation ofcortisol productionwith cortisol dose> daily production

h0 4 8 12 16 20 24 4 8

Glucocorticoid-inducedinhibition of cortisol production

Glucocorticoidconcentration

h0 4 8 12 16 20 24 4 8


Androgens, Anabolic Steroids, Antiandrogens

Androgens are masculinizing substanc-es. The endogenous male gonadal hor-mone is the steroid testosterone fromthe interstitial Leydig cells of the testis.Testosterone secretion is stimulated byhypophyseal luteinizing hormone (LH),whose release is controlled by hypotha-lamic GnRH (gonadorelin, p. 242). Re-lease of both hormones is subject tofeedback inhibition by circulating tes-tosterone. Reduction of testosterone todihydrotestosterone occurs in most tar-get organs; the latter possesses higheraffinity for androgen receptors. Rapidintrahepatic degradation (plasma t1/2 ~15 min) yields androsterone amongother metabolites (17-ketosteroids)that are eliminated as conjugates in theurine. Because of rapid hepatic metab-olism, testosterone is unsuitable for oraluse. Although it is well absorbed, itundergoes virtually complete pre-systemic elimination.

Testosterone (T.) derivatives forclinical use. T. esters for i.m. depot injec-tion are T. propionate and T. heptanoate(or enanthate). These are given in oilysolution by deep intramuscular injec-tion. Upon diffusion of the ester fromthe depot, esterases quickly split off theacyl residue, to yield free T. With in-creasing lipophilicity, esters will tend toremain in the depot, and the duration ofaction therefore lengthens. A T. ester fororal use is the undecanoate. Owing to thefatty acid nature of undecanoic acid, thisester is absorbed into the lymph, ena-bling it to bypass the liver and enter, viathe thoracic duct, the general circula-tion. 17-a Methyltestosterone is effectiveby the oral route due to its increasedmetabolic stability, but because of thehepatotoxicity of C17-alkylated andro-gens (cholestasis, tumors) its use shouldbe avoided. Orally active mesterolone is1α-methyl-dihydrotestosterone. Trans-dermal delivery systems for T. are alsoavailable.

Indications. For hormone replace-ment in deficiency of endogenous T.

production and palliative treatment ofbreast cancer, T. esters for depot injec-tion are optimally suited. Secondary sexcharacteristics and libido are main-tained; however, fertility is not promot-ed. On the contrary, spermatogenesismay be suppressed because of feedbackinhibition of hypothalamohypophysealgonadotropin secretion.

Stimulation of spermatogenesisin gonadotropin (FSH, LH) deficiencycan be achieved by injection of HMGand HCG. HMG or human menopausalgonadotropin is obtained from the urineof postmenopausal women and is richin FSH activity. HCG, human chorionicgonadotropin, from the urine of preg-nant women, acts like LH.

Anabolics are testosterone deriva-tives (e.g., clostebol, metenolone, nan-drolone, stanozolol) that are used in de-bilitated patients, and misused by ath-letes, because of their protein anaboliceffect. They act via stimulation of andro-gen receptors and, thus, also display an-drogenic actions (e.g., virilization in fe-males, suppression of spermatogene-sis).

The antiandrogen cyproteroneacts as a competitive antagonist of T. Inaddition, it has progestin activitywhereby it inhibits gonadotropin secre-tion (p. 254). Indications: in men, inhi-bition of sex drive in hypersexuality;prostatic cancer. In women: treatmentof virilization, with potential utilizationof the gestagenic contraceptive effect.

Flutamide, an androgen receptorantagonist possessing a different chem-ical structure, lacks progestin activity.

Finasteride inhibits 5α-reductase,the enzyme converting T. into dihydro-testosterone (DHT). Thus, the androgen-ic stimulus is reduced in those tissues inwhich DHT is the active species (e.g.,prostate). T.-dependent tissues or func-tions are not or hardly affected (e.g.,skeletal muscle, negative feedback inhi-bition of gonadotropin secretion, and li-bido). Finasteride can be used in benignprostate hyperplasia to shrink the glandand, possibly, to improve micturition.

252 Hormones


Hormones 253

Target cell Dihydro-testosterone

A. Testosterone and derivatives

Testes

Inhibition

Estercleavage

R

Testosterone esterin oily solution

Skeletal muscle i. m. Depotinjection

Ester cleavage

Oral intake

Ductusthoracicus

Androsterone

Testosterone Methyl-testosterone

Testosteroneundecanoate

17-Ketosteroid

Lymph vessels

GnRH

Hypothalamus

Hypophysis

LH R =

-propionate

-heptanoate

Duration of effect 2 weeks

C – C – C – C – C – C

C – C1 2

Conjugationwith sulfate, glucuronate

Testosterone

Inactivation

AntagonistCyproterone


Follicular Growth and Ovulation, Estrogen and Progestin Production

Follicular maturation and ovulation, aswell as the associated production of fe-male gonadal hormones, are controlledby the hypophyseal gonadotropins FSH(follicle-stimulating hormone) and LH(luteinizing hormone). In the first half ofthe menstrual cycle, FSH promotesgrowth and maturation of ovarian folli-cles that respond with accelerating syn-thesis of estradiol. Estradiol stimulatesendometrial growth and increases thepermeability of cervical mucus forsperm cells. When the estradiol bloodlevel approaches a predetermined set-point, FSH release is inhibited due tofeedback action on the anterior hypoph-ysis. Since follicle growth and estrogenproduction are correlated, hypophysisand hypothalamus can “monitor” thefollicular phase of the ovarian cyclethrough their estrogen receptors. With-in hours after ovulation, the tertiary fol-licle develops into the corpus luteum,which then also releases progesteronein response to LH. The former initiatesthe secretory phase of the endometrialcycle and lowers the permeability ofcervical mucus. Nonruptured folliclescontinue to release estradiol under theinfluence of FSH. After 2 wk, productionof progesterone and estradiol subsides,causing the secretory endometrial layerto be shed (menstruation).

The natural hormones are unsuit-able for oral application because theyare subject to presystemic hepatic elim-ination. Estradiol is converted via es-trone to estriol; by conjugation, all threecan be rendered water soluble andamenable to renal excretion. The majormetabolite of progesterone is pregnan-diol, which is also conjugated and elimi-nated renally.

Estrogen preparations. Depotpreparations for i.m. injection are oilysolutions of esters of estradiol (3- or 17-OH group). The hydrophobicity of theacyl moiety determines the rate of ab-sorption, hence the duration of effect

(p. 252). Released ester is hydrolyzed toyield free estradiol.

Orally used preparations. Ethinyl-estradiol (EE) is more stable metaboli-cally, passes largely unchanged throughthe liver after oral intake and mimics es-tradiol at estrogen receptors. Mestranolitself is inactive; however, cleavage ofthe C-3 methoxy group again yields EE.In oral contraceptives, one of the twoagents forms the estrogen component(p. 256). (Sulfate-)conjugated estrogenscan be extracted from equine urine andare used for the prevention of post-menopausal osteoporosis and in thetherapy of climacteric complaints. Be-cause of their high polarity (sulfate, glu-curonide), they would hardly appearsuitable for this route of administration.For transdermal delivery, an adhesivepatch is available that releases estradioltranscutaneously into the body.

Progestin preparations. Depotformulations for i.m. injection are 17-α-hydroxyprogesterone caproate andmedroxyprogesterone acetate. Prepara-tions for oral use are derivatives of 17α-ethinyltestosterone = ethisterone (e.g.,norethisterone, dimethisterone, lynes-trenol, desogestrel, gestoden), or of17α-hydroxyprogesterone acetate (e.g.,chlormadinone acetate or cyproteroneacetate). These agents are mainly usedas the progestin component in oral con-traceptives.

Indications for estrogens and pro-gestins include: hormonal contracep-tion (p. 256), hormone replacement, asin postmenopausal women for prophy-laxis of osteoporosis; bleeding anoma-lies, menstrual complaints. Concerningadverse effects, see p. 256.

Estrogens with partial agonist ac-tivity (raloxifene, tamoxifene) are be-ing investigated as agents used to re-place estrogen in postmenopausal os-teoporosis treatment, to lower plasmalipids, and as estrogen antagonists inthe prevention of breast cancer. Raloxi-fen—in contrast to tamoxifen—is an an-tagonist at uterine estrogen receptors.

254 Hormones


Hormones 255

A. Estradiol, progesterone, and derivatives

Conjugationwith sulfate, glucuronate

GnRH

Hypothalamus

Hypophysis

FSH LH

Conjugation

Pregnanediol

Estradiol

Ethinylestradiol(EE)

Progesterone

Ethinyltestosterone,a gestagen

Mestranol =3-Methylether of EE

Conjugatedestrogens

Estriol Estrone Estradiol

Estradiol

Inactivation

Ovary

Inactivation

Progesterone

Estradiol

Duration of effect

1 week

Medroxyprogesteroneacetate

Hydroxyprogesteronecaproate

8 - 12 weeks

Duration of effect

1 2 week

3 weeks

-valerate

-benzoate


Oral Contraceptives

Inhibitors of ovulation. Negative feed-back control of gonadotropin releasecan be utilized to inhibit the ovarian cy-cle. Administration of exogenous es-trogens (ethinylestradiol or mestranol)during the first half of the cycle permitsFSH production to be suppressed (as itis by administration of progestinsalone). Due to the reduced FSH stimula-tion of tertiary follicles, maturation offollicles and, hence, ovulation are pre-vented. In effect, the regulatory braincenters are deceived, as it were, by theelevated estrogen blood level, whichsignals normal follicular growth and adecreased requirement for FSH stimula-tion. If estrogens alone are given duringthe first half of the cycle, endometrialand cervical responses, as well as otherfunctional changes, would occur in thenormal fashion. By adding a progestin(p. 254) during the second half of the cy-cle, the secretory phase of the endome-trium and associated effects can be elic-ited. Discontinuance of hormone ad-ministration would be followed bymenstruation.

The physiological time course of es-trogen-progesterone release is simulat-ed in the so-called biphasic (sequen-tial) preparations (A). In monophasicpreparations, estrogen and progestinare taken concurrently. Early adminis-tration of progestin reinforces the inhi-bition of CNS regulatory mechanisms,prevents both normal endometrialgrowth and conditions for ovum im-plantation, and decreases penetrabilityof cervical mucus for sperm cells. Thetwo latter effects also act to preventconception. According to the staging ofprogestin administration, one distin-guishes (A): one-, two-, and three-stagepreparations. In all cases, “withdrawal-bleeding” occurs when hormone intakeis discontinued (if necessary, by substi-tuting dummy tablets).

Unwanted effects: An increased in-cidence of thrombosis and embolism isattributed to the estrogen component inparticular. Hypertension, fluid reten-

tion, cholestasis, benign liver tumors,nausea, chest pain, etc. may occur. Ap-parently there is no increased overallrisk of malignant tumors.

Minipill. Continuous low-dose ad-ministration of progestin alone can pre-vent conception. Ovulations are notsuppressed regularly; the effect is thendue to progestin-induced alterations incervical and endometrial function. Be-cause of the need for constant intake atthe same time of day, a lower successrate, and relatively frequent bleedinganomalies, these preparations are nowrarely employed.

“Morning-after” pill. This refers toadministration of a high dose of estro-gen and progestin, preferably within 12to 24 h, but no later than 72 h after coi-tus. Menstrual bleeding ensues, whichprevents implantation of the fertilizedovum (normally on the 7th day after fer-tilization, p. 74). Similarly, implantationcan be inhibited by mifepristone, whichis an antagonist at both progesteroneand glucocorticoid receptors and whichalso offers a noninvasive means of in-ducing therapeutic abortion in earlypregnancy.

Stimulation of ovulation. Gona-dotropin secretion can be increased bypulsatile delivery of GnRH (p. 242). Theestrogen antagonists clomiphene and cy-clofenil block receptors mediating feed-back inhibition of central neuroendo-crine circuits and thereby disinhibitgonadotropin release. Gonadotropinscan be given in the form of HMG andHCG (p. 252).

256 Hormones


Hormones 257

A. Oral contraceptives

Hypophysis

FSH LH

Ovary

Hypophysis

7. 14. 21. 28.1.

Ovulation

Ovulation

Ovary

Penetrabilityby sperm cells

Day of cycle

Readinessfor

nidation No ovulation

Inhibition

Estradiol Progesterone

Estradiol

Progesterone

7. 14. 21. 28.1.

Intake ofestradiolderivative

Intake ofprogestin

Minipill

7. 14. 21. 28.Days of cycle

Biphasic preparation

One-stage regimen

Monophasic preparations

Two-stage regimen

Three-stage regimen


Insulin Therapy

Insulin is synthesized in the B- (or β-)cells of the pancreatic islets of Langer-hans. It is a protein (MW 5800) consist-ing of two peptide chains linked by twodisulfide bridges; the A chain has 21 andthe B chain 30 amino acids. Insulin is the“blood-sugar lowering” hormone. Uponingestion of dietary carbohydrates, it isreleased into the blood and acts to pre-vent a significant rise in blood glucoseconcentration by promoting uptake ofglucose in specific organs, viz., theheart, adipose tissue, and skeletal mus-cle, or its conversion to glycogen in theliver. It also increases lipogenesis andprotein synthesis, while inhibiting lipo-lysis and release of free fatty acids.

Insulin is used in the replacementtherapy of diabetes mellitus to supple-ment a deficient secretion of endoge-nous hormone.

Sources of therapeutic insulinpreparations (A). Insulin can be ob-tained from pancreatic tissue of slaugh-tered animals. Porcine insulin differsfrom human insulin merely by one Bchain amino acid, bovine insulin by twoamino acids in the A chain and one inthe B chain. With these slight differenc-es, animal and human hormone displaysimilar biological activity. Comparedwith human hormone, porcine insulin isbarely antigenic and bovine insulin hasa little higher antigenicity. Human insu-lin is produced by two methods: biosyn-thetically, by substituting threonine forthe C-terminal alanine in the B chain ofporcine insulin; or by gene technologyinvolving insertion of the appropriatehuman DNA into E. coli bacteria.

Types of preparations (B). As apeptide, insulin is unsuitable for oraladministration (destruction by gas-trointestinal proteases) and thus needsto be given parenterally. Usually, insulinpreparations are injected subcutane-ously. The duration of action dependson the rate of absorption from the injec-tion site.

Short-acting insulin is dispensedas a clear neutral solution known as

regular insulin. In emergencies, such ashyperglycemic coma, it can be givenintravenously (mostly by infusion be-cause i.v. injections have too brief an ac-tion; plasma t1/2 ~ 9 min). With the usu-al subcutaneous application, the effectis evident within 15 to 20 min, reaches apeak after approx. 3 h, and lasts for ap-prox. 6 h. Lispro insulin has a faster on-set and slightly shorter duration of ac-tion.

Insulin suspensions. When thehormone is injected as a suspension ofinsulin-containing particles, its dissolu-tion and release in subcutaneous tissueare retarded (rapid, intermediate, andslow insulins). Suitable particles can beobtained by precipitation of apolar,poorly water-soluble complexes con-sisting of anionic insulin and cationicpartners, e.g., the polycationic proteinprotamine or the compound aminoqui-nuride (Surfen). In the presence of zincand acetate ions, insulin crystallizes;crystal size determines the rate of disso-lution. Intermediate insulin prepara-tions (NPH or isophane, lente or zinc in-sulin) act for 18 to 26 h, slow prepara-tions (protamine zinc insulin, ultralenteor extended zinc insulin) for up to 36 h.

Combination preparations con-tain insulin mixtures in solution and insuspension (e.g., ultralente); the plasmaconcentration-time curve representsthe sum of the two components.

Unwanted effects. Hypoglycemiaresults from absolute or relative over-dosage (see p. 260). Allergic reactions arerare—locally: redness at injection site,atrophy of adipose tissue (lipodystro-phy); systemically: urticaria, skin rash,anaphylaxis. Insulin resistance can re-sult from binding to inactivating anti-bodies. A possible local lipohypertrophycan be avoided by alternating injectionsites.

258 Hormones


Hormones 259

B. Insulin: preparations and blood level-time curves

A. Insulin production

S - S

S - S

Ala Thr30Porcine insulin Human insulinInsulin

B-c

hain

A-ch

ain

Production: DNA

E. coli

Hours after injection6 12 18 24

Intermediate

Slow

Insu

linm

ixtu

res

Insu

lin s

usp

ensi

on =

pro

tam

ine

zinc

insu

linIn

sulin

sol

utio

n

=

reg

ular

insu

lin

Insu

lin c

once

ntra

tion

in b

lood

Rapid


Treatment of Insulin-Dependent Diabetes Mellitus

“Juvenile onset” (type I) diabetes mellit-us is caused by the destruction of insu-lin-producing B cells in the pancreas,necessitating replacement of insulin(daily dose approx. 40 U, equivalent to approx. 1.6 mg).

Therapeutic objectives are: (1)prevention of life-threatening hypergly-cemic (diabetic) coma; (2) prevention ofdiabetic sequelae (angiopathy withblindness, myocardial infarction, renalfailure), with precise “titration” of thepatient being essential to avoid evenshort-term spells of pathological hyper-glycemia; (3) prevention of insulinoverdosage leading to life-threateninghypoglycemic shock (CNS disturbancedue to lack of glucose).

Therapeutic principles. In healthysubjects, the amount of insulin is “auto-matically” matched to carbohydrate in-take, hence to blood glucose concentra-tion. The critical secretory stimulus isthe rise in plasma glucose level. Food in-take and physical activity (increasedglucose uptake into musculature, de-creased insulin demand) are accompa-nied by corresponding changes in insu-lin secretion (A, left track).

In the diabetic, insulin could be ad-ministered as it is normally secreted;that is, injection of short-acting insulinbefore each main meal plus bedtime ad-ministration of a Lente preparation toavoid a nocturnal shortfall of insulin.This regimen requires a well-educated,cooperative, and competent patient. Inother cases, a fixed-dosage schedulewill be needed, e.g., morning and eve-ning injections of a combination insulinin constant respective dosage (A). Toavoid hypo- or hyperglycemias withthis regimen, dietary carbohydrate (CH)intake must be synchronized with thetime course of insulin absorption fromthe s.c. depot. Caloric intake is to be dis-tributed (50% CH, 30% fat, 20% protein)in small meals over the day so as toachieve a steady CH supply—snacks, latenight meal. Rapidly absorbable CH

(sweets, cakes) must be avoided (hyper-glycemic—peaks) and replaced withslowly digestible ones.

Acarbose (an α-glucosidase inhibi-tor) delays intestinal formation of glu-cose from disaccharides.

Any change in eating and livinghabits can upset control of blood sugar:skipping a meal or unusual physicalstress leads to hypoglycemia; increasedCH intake provokes hyperglycemia.

Hypoglycemia is heralded bywarning signs: tachycardia, unrest,tremor, pallor, profuse sweating. Someof these are due to the release of glu-cose-mobilizing epinephrine. Counter-measures: glucose administration, rap-idly absorbed CH orally or 10–20 g glu-cose i.v. in case of unconsciousness; ifnecessary, injection of glucagon, thepancreatic hyperglycemic hormone.

Even with optimal control of bloodsugar, s.c. administration of insulin can-not fully replicate the physiological sit-uation. In healthy subjects, absorbedglucose and insulin released from thepancreas simultaneously reach the liverin high concentration, whereby effec-tive presystemic elimination of bothsubstances is achieved. In the diabetic,s.c. injected insulin is uniformly distrib-uted in the body. Since insulin concen-tration in blood supplying the liver can-not rise, less glucose is extracted fromportal blood. A significant amount ofglucose enters extrahepatic tissues,where it has to be utilized.

260 Hormones


Hormones 261

A. Control of blood sugar in healthy and diabetic subjects

10

12

14

16

18

20

22

24

2

4

6

8

10

12

16

18

22

24

2

4

6

8

10

12

14

16

20

22

24

Time

B

S

L

N

D

S

B

L

S

S

S

L

B

B

L

D

B

B

L

D

nolunch

Feast

Feast

Car

bohy

drat

eab

sorp

tion

Blo

od s

ugar

Insu

lin re

leas

efro

m p

ancr

eas

Car

bohy

drat

e ab

sorp

tion

Blo

od s

ugar

Insu

lin re

leas

efro

m d

epot

Glu

cose

Diabetic

HealthysubjectB = BreakfastS = SnackL = LunchD = DinnerN = Supper

L


Treatment of Maturity-Onset (Type II)Diabetes Mellitus

In overweight adults, a diabetic meta-bolic condition may develop (type II ornon-insulin-dependent diabetes) whenthere is a relative insulin deficiency—enhanced demand cannot be met by adiminishing insulin secretion. Thecause of increased insulin require-ment is a loss of insulin receptors or animpairment of the signal cascade acti-vated by the insulin receptor. Accord-ingly, insulin sensitivity of cells de-clines. This can be illustrated by com-paring concentration-binding curves incells from normal and obese individuals(A). In the obese, the maximum bindingpossible (plateau of curve) is displaceddownward, indicative of the reductionin receptor numbers. Also, at low insulinconcentrations, there is less binding ofinsulin, compared with the control con-dition. For a given metabolic effect acertain number of receptors must be oc-cupied. As shown by the binding curves(dashed lines), this can still be achievedwith a reduced receptor number, al-though only at a higher concentration ofinsulin.

Development of adult diabetes(B). Compared with a normal subject,the obese subject requires a continuallyelevated output of insulin (orangecurves) to avoid an excessive rise ofblood glucose levels (green curves) dur-ing a glucose load. When the secretorycapacity of the pancreas decreases, thisis first noted as a rise in blood glucoseduring glucose loading (latent diabetes).Subsequently, not even the fastingblood level can be maintained (mani-fest, overt diabetes). A diabetic condi-tion has developed, although insulin re-lease is not lower than that in a healthyperson (relative insulin deficiency).

Treatment. Caloric restriction torestore body weight to normal is asso-ciated with an increase in insulin recep-tor number or cellular responsiveness.The releasable amount of insulin isagain adequate to maintain a normalmetabolic rate.

Therapy of first choice is weightreduction, not administration ofdrugs! Should the diabetic condition failto resolve, consideration should first begiven to insulin replacement (p. 260).Oral antidiabetics of the sulfonylureatype increase the sensitivity of B-cellstowards glucose, enabling them to in-crease release of insulin. These drugsprobably promote depolarization of theβ-cell membrane by closing off ATP-gat-ed K+ channels. Normally, these chan-nels are closed when intracellular levelsof glucose, hence of ATP, increase. Thisdrug class includes tolbutamide (500–2000 mg/d) and glyburide (glibencla-mide) (1.75–10.5 mg/d). In some pa-tients, it is not possible to stimulate in-sulin secretion from the outset; in oth-ers, therapy fails later on. Matching dos-age of the oral antidiabetic and caloricintake follows the same principles asapply to insulin. Hypoglycemia is themost important unwanted effect. En-hancement of the hypoglycemic effectcan result from drug interactions: dis-placement of antidiabetic drug fromplasma protein-binding sites by sulfon-amides or acetylsalicylic acid.

Metformin, a biguanide deriva-tive, can lower excessive blood glucoselevels, provided that insulin is present.Metformin does not stimulate insulin re-lease. Glucose release from the liver isdecreased, while peripheral uptake isenhanced. The danger of hypoglycemiaapparently is not increased. Frequentadverse effects include: anorexia, nau-sea, and diarrhea. Overproduction of lac-tic acid (lactate acidosis, lethality 50%) isa rare, potentially fatal reaction. Metfor-min is used in combination with sulfony-lureas or by itself. It is contraindicated inrenal insufficiency and should thereforebe avoided in elderly patients.

Thiazolidinediones (Glitazones: ro-siglitazone, pioglitazone) are insulin-sensitizing agents that augment tissueresponsiveness by promoting the syn-thesis or the availability of plasmalem-mal glucose transporters via activationof a transcription factor (peroxisomeproliferator-activated receptor-γ).

262 Hormones


Hormones 263

Diagnosis:latent overtDiabetes mellitus

C. Action of oral antidiabetic drugs

A. Insulin concentration and binding in normal and overweight subjects

B. Development of maturity-onset diabetes

Insulin receptorbindingneededfor euglycemia

Insulin binding

Normal receptor number

Decreasedreceptor number

Normaldiet

Obesity

Insulin concentration

Glu

cose

in b

lood

Insu

lin r

elea

se

Time

Oralanti-diabetic

Therapy of 1st choice Therapy of 2nd choice

Membranedepolarization

ATPInsulin

B cellGlucose

BlockadeSulfonylurea derivatives

Tolbutamide

K+


Drugs for Maintaining Calcium Homeostasis

At rest, the intracellular concentrationof free calcium ions (Ca2+) is kept at0.1 µM (see p. 128 for mechanisms in-volved). During excitation, a transientrise of up to 10 µM elicits contraction inmuscle cells (electromechanical coup-ling) and secretion in glandular cells(electrosecretory coupling). The cellularcontent of Ca2+ is in equilibrium withthe extracellular Ca2+ concentration(approx. 1000 µM), as is the plasma pro-tein-bound fraction of calcium in blood.Ca2+ may crystallize with phosphate toform hydroxyapatite, the mineral ofbone. Osteoclasts are phagocytes thatmobilize Ca2+ by resorption of bone.Slight changes in extracellular Ca2+ con-centration can alter organ function:thus, excitability of skeletal muscle in-creases markedly as Ca2+ is lowered(e.g., in hyperventilation tetany). Threehormones are available to the body formaintaining a constant extracellularCa2+ concentration.

Vitamin D hormone is derivedfrom vitamin D (cholecalciferol). VitaminD can also be produced in the body; it isformed in the skin from dehydrocholes-terol during irradiation with UV light.When there is lack of solar radiation,dietary intake becomes essential, codliver oil being a rich source. Metaboli-cally active vitamin D hormone resultsfrom two successive hydroxylations: inthe liver at position 25 (� calcifediol)and in the kidney at position 1 (� calci-triol = vit. D hormone). 1-Hydroxylationdepends on the level of calcium homeo-stasis and is stimulated by parathor-mone and a fall in plasma levels of Ca2+

or phosphate. Vit. D hormone promotesenteral absorption and renal reabsorp-tion of Ca2+ and phosphate. As a result ofthe increased Ca2+ and phosphate con-centration in blood, there is an in-creased tendency for these ions to bedeposited in bone in the form of hy-droxyapatite crystals. In vit. D deficien-cy, bone mineralization is inadequate(rickets, osteomalacia). Therapeutic

use aims at replacement. Mostly, vit. D isgiven; in liver disease calcifediol may beindicated, in renal disease calcitriol. Ef-fectiveness, as well as rate of onset andcessation of action, increase in the ordervit. D. < 25-OH-vit. D < 1,25-di-OH-vit.D. Overdosage may induce hypercal-cemia with deposits of calcium salts intissues (particularly in kidney and bloodvessels): calcinosis.

The polypeptide parathormone isreleased from the parathyroid glandswhen plasma Ca2+ level falls. It stimu-lates osteoclasts to increase bone resorp-tion; in the kidneys, it promotes calciumreabsorption, while phosphate excre-tion is enhanced. As blood phosphateconcentration diminishes, the tendencyof calcium to precipitate as bone miner-al decreases. By stimulating the forma-tion of vit. D hormone, parathormonehas an indirect effect on the enteral up-take of Ca2+ and phosphate. In parathor-mone deficiency, vitamin D can be usedas a substitute that, unlike parathor-mone, is effective orally.

The polypeptide calcitonin is se-creted by thyroid C-cells during immi-nent hypercalcemia. It lowers plasmaCa2+ levels by inhibiting osteoclast activ-ity. Its uses include hypercalcemia andosteoporosis. Remarkably, calcitonin in-jection may produce a sustained analge-sic effect that is not restricted to bonepain.

Hypercalcemia can be treated by(1) administering 0.9% NaCl solutionplus furosemide (if necessary) � renalexcretion �; (2) the osteoclast inhibi-tors calcitonin, plicamycin, or clodro-nate (a bisphosphonate) � bone cal-cium mobilization �; (3) the Ca2+ chela-tors EDTA sodium or sodium citrate; aswell as (4) glucocorticoids.

264 Hormones


Hormones 265

A. Calcium homeostasis of the body

Effe

ct o

n ce

ll fu

nctio

n

Skin

7-Dehydrocholesterol

Cod liver oil

Cholecalciferol(vitamin D3)50-5000µg/day

1,25-Dihydroxychole-calciferol (calcitriol)0,5-2µg/day

25-Hydroxychole-calciferol(calcifediol)

Parafollicularcells ofthyroid

Ca2+ + PO43-

Parathyroid hormone, Ca2+ , PO43-

Parathyroidglands

Electricalexcitability

Muscle cell Gland cell

Ca2+

~1 x 10-7M

Contraction Secretion

~10-5M

Ca2+

Alb

umin

Glo

bul

in~1 x 10 -3M

Ca Ca

1 x 10-3M Ca2+ + PO43-

ParathyroidhormoneCalcitonin

Vit. D-Hormone

Ca2+

Ca10(PO4)6(OH)2

Bone trabeculaeHydroxyapatite crystals

Osteoclast

1

1

25 25

7


Antibacterial Drugs

Drugs for Treating Bacterial InfectionsWhen bacteria overcome the cutaneousor mucosal barriers and penetrate bodytissues, a bacterial infection is present.Frequently the body succeeds in remov-ing the invaders, without outward signsof disease, by mounting an immune re-sponse. If bacteria multiply faster thanthe body’s defenses can destroy them,infectious disease develops with inflam-matory signs, e.g., purulent wound in-fection or urinary tract infection. Appro-priate treatment employs substancesthat injure bacteria and thereby preventtheir further multiplication, withoutharming cells of the host organism (1).

Apropos nomenclature: antibioticsare produced by microorganisms (fungi,bacteria) and are directed “against life”at any phylogenetic level (prokaryotes,eukaryotes). Chemotherapeutic agentsoriginate from chemical synthesis. Thisdistinction has been lost in current us-age.

Specific damage to bacteria is partic-ularly practicable when a substanceinterferes with a metabolic process thatoccurs in bacterial but not in host cells.Clearly this applies to inhibitors of cellwall synthesis, because human and ani-mal cells lack a cell wall. The points ofattack of antibacterial agents are sche-matically illustrated in a grossly simpli-fied bacterial cell, as depicted in (2).

In the following sections, polymyx-ins and tyrothricin are not consideredfurther. These polypeptide antibioticsenhance cell membrane permeability.Due to their poor tolerability, they areprescribed in humans only for topicaluse.

The effect of antibacterial drugs canbe observed in vitro (3). Bacteria multi-ply in a growth medium under controlconditions. If the medium contains anantibacterial drug, two results can bediscerned: 1. bacteria are killed—bacte-ricidal effect; 2. bacteria survive, but donot multiply—bacteriostatic effect. Al-though variations may occur undertherapeutic conditions, different drugs

can be classified according to their re-spective primary mode of action (colortone in 2 and 3).

When bacterial growth remains un-affected by an antibacterial drug, bacte-rial resistance is present. This may oc-cur because of certain metabolic charac-teristics that confer a natural insensitiv-ity to the drug on a particular strain ofbacteria (natural resistance). Dependingon whether a drug affects only a few ornumerous types of bacteria, the termsnarrow-spectrum (e.g., penicillin G) orbroad-spectrum (e.g., tetracyclines)antibiotic are applied. Naturally sus-ceptible bacterial strains can be trans-formed under the influence of antibac-terial drugs into resistant ones (acquiredresistance), when a random genetic al-teration (mutation) gives rise to a resist-ant bacterium. Under the influence ofthe drug, the susceptible bacteria dieoff, whereas the mutant multiplies un-impeded. The more frequently a givendrug is applied, the more probable theemergence of resistant strains (e.g., hos-pital strains with multiple resistance)!

Resistance can also be acquiredwhen DNA responsible for nonsuscepti-bility (so-called resistance plasmid) ispassed on from other resistant bacteriaby conjugation or transduction.

266 Antibacterial Drugs


Antibacterial Drugs 267

A. Principles of antibacterial therapy

Selectiveantibacterialtoxicity

BacteriaBody cells

Cellmembrane

Cell wall

Bacterium

DNA RNA

Protein

1 day

Antibiotic

Insensitive strain

Sensitive strain withresistant mutant

Selection

3.

2.

1.

Immunedefenses

Anti-bacterialdrugsBacterial

invasion:infection

PenicillinsCephalosporins

"Gyrase-inhibitors"Nitroimidazoles

BacitracinVancomycin

PolymyxinsTyrothricin

RifampinTetracyclines

ChloramphenicolErythromycinClindamycin

AminoglycosidesSulfonamidesTrimethoprim

Tetrahydro-folatesynthesis

Resistance

Bacteriostatic

Bactericidal


Inhibitors of Cell Wall Synthesis

In most bacteria, a cell wall surroundsthe cell like a rigid shell that protectsagainst noxious outside influences andprevents rupture of the plasma mem-brane from a high internal osmoticpressure. The structural stability of thecell wall is due mainly to the murein(peptidoglycan) lattice. This consists ofbasic building blocks linked together toform a large macromolecule. Each basicunit contains the two linked aminosug-ars N-acetylglucosamine and N-acetyl-muramyl acid; the latter bears a peptidechain. The building blocks are synthe-sized in the bacterium, transported out-ward through the cell membrane, andassembled as illustrated schematically.The enzyme transpeptidase cross-linksthe peptide chains of adjacent amino-sugar chains.

Inhibitors of cell wall synthesisare suitable antibacterial agents, be-cause animal and human cells lack a cellwall. They exert a bactericidal action ongrowing or multiplying germs. Mem-bers of this class include β-lactam anti-biotics such as the penicillins and cepha-losporins, in addition to bacitracin andvancomycin.

Penicillins (A). The parent sub-stance of this group is penicillin G (ben-zylpenicillin). It is obtained from cul-tures of mold fungi, originally from Pen-icillium notatum. Penicillin G containsthe basic structure common to all peni-cillins, 6-amino-penicillanic acid (p.271, 6-APA), comprised of a thiazolidineand a 4-membered β-lactam ring. 6-APA itself lacks antibacterial activity.Penicillins disrupt cell wall synthesis byinhibiting transpeptidase. When bacte-ria are in their growth and replicationphase, penicillins are bactericidal; dueto cell wall defects, the bacteria swelland burst.

Penicillins are generally well toler-ated; with penicillin G, the daily dosecan range from approx. 0.6 g i.m. (= 106

international units, 1 Mega I.U.) to 60 gby infusion. The most important ad-verse effects are due to hypersensitivity

(incidence up to 5%), with manifesta-tions ranging from skin eruptions toanaphylactic shock (in less than 0.05% ofpatients). Known penicillin allergy is acontraindication for these drugs. Be-cause of an increased risk of sensitiza-tion, penicillins must not be used local-ly. Neurotoxic effects, mostly convul-sions due to GABA antagonism, may oc-cur if the brain is exposed to extremelyhigh concentrations, e.g., after rapid i.v.injection of a large dose or intrathecalinjection.

Penicillin G undergoes rapid renalelimination mainly in unchanged form(plasma t1/2 ~ 0.5 h). The duration ofthe effect can be prolonged by:

1. Use of higher doses, enabling plas-ma levels to remain above the minimal-ly effective antibacterial concentration;

2. Combination with probenecid. Re-nal elimination of penicillin occurschiefly via the anion (acid)-secretorysystem of the proximal tubule (-COOHof 6-APA). The acid probenecid (p. 316)competes for this route and thus retardspenicillin elimination;

3. Intramuscular administration indepot form. In its anionic form (-COO-)penicillin G forms poorly water-solublesalts with substances containing a posi-tively charged amino group (procaine,p. 208; clemizole, an antihistamine;benzathine, dicationic). Depending onthe substance, release of penicillin fromthe depot occurs over a variable inter-val.




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

Bacterium

Cell wallCell membrane

Cell wallbuilding block

Amino acidchain

Cross-linkedbytranspeptidase

Sugar

Penicillin G

FungusPenicillium notatum

Human

Penicillinallergy

Neurotoxicityat veryhigh dosage


3 x Dose

Minimalbactericidalconcentration

Time

Increasing the dose

Anionsecretorysystem

Combination with probenecid Depot preparations

~1

~7-28

~2

Inhibition ofcell wall synthesis

Probenecid

Penicillin

Proca

ine

Penici

llin

+-

Clemizo

le

Penici

llin

+-

Benza

thine

2 Pen

icillin

s+

-+

Dur

atio

n of

act

ion

(d)

Antibody


Although very well tolerated, peni-cillin G has disadvantages (A) that limitits therapeutic usefulness: (1) It is inac-tivated by gastric acid, which cleavesthe β-lactam ring, necessitating paren-teral administration. (2) The β-lactamring can also be opened by bacterial en-zymes (β-lactamases); in particular,penicillinase, which can be produced bystaphylococcal strains, renders them re-sistant to penicillin G. (3) The antibacte-rial spectrum is narrow; although it en-compasses many gram-positive bacte-ria, gram-negative cocci, and spiro-chetes, many gram-negative pathogensare unaffected.

Derivatives with a different sub-stituent on 6-APA possess advantages(B): (1) Acid resistance permits oral ad-ministration, provided that enteral ab-sorption is possible. All derivativesshown in (B) can be given orally. Penicil-lin V (phenoxymethylpenicillin) exhib-its antibacterial properties similar tothose of penicillin G. (2) Due to theirpenicillinase resistance, isoxazolylpen-icillins (oxacillin dicloxacillin, flucloxacil-lin) are suitable for the (oral) treatmentof infections caused by penicillinase-producing staphylococci. (3) Extendedactivity spectrum: The aminopenicillinamoxicillin is active against many gram-negative organisms, e.g., coli bacteria orSalmonella typhi. It can be protectedfrom destruction by penicillinase bycombination with inhibitors of penicilli-nase (clavulanic acid, sulbactam, tazo-bactam).

The structurally close congener am-picillin (no 4-hydroxy group) has a simi-lar activity spectrum. However, becauseit is poorly absorbed (<50%) and there-fore causes more extensive damage tothe gut microbial flora (side effect: diar-rhea), it should be given only by injec-tion.

A still broader spectrum (includingPseudomonas bacteria) is shown by car-boxypenicillins (carbenicillin, ticarcillin)and acylaminopenicillins (mezclocillin,azlocillin, piperacillin). These substanc-es are neither acid stable nor penicilli-nase resistant.

Cephalosporins (C). These β-lac-tam antibiotics are also fungal productsand have bactericidal activity due to in-hibition of transpeptidase. Theirshared basic structure is 7-aminocepha-losporanic acid, as exemplified bycephalexin (gray rectangle). Cephalo-sporins are acid stable, but many arepoorly absorbed. Because they must begiven parenterally, most—includingthose with high activity—are used onlyin clinical settings. A few, e.g., cepha-lexin, are suitable for oral use. Cephalo-sporins are penicillinase-resistant, butcephalosporinase-forming organismsdo exist. Some derivatives are, however,also resistant to this β-lactamase.Cephalosporins are broad-spectrumantibacterials. Newer derivatives (e.g.,cefotaxime, cefmenoxin, cefoperazone,ceftriaxone, ceftazidime, moxalactam)are also effective against pathogens re-sistant to various other antibacterials.Cephalosporins are mostly well tolerat-ed. All can cause allergic reactions, somealso renal injury, alcohol intolerance,and bleeding (vitamin K antagonism).

Other inhibitors of cell wall syn-thesis. Bacitracin and vancomycininterfere with the transport of pepti-doglycans through the cytoplasmicmembrane and are active only againstgram-positive bacteria. Bacitracin is apolypeptide mixture, markedly nephro-toxic and used only topically. Vancomy-cin is a glycopeptide and the drug ofchoice for the (oral) treatment of bowelinflammations occurring as a complica-tion of antibiotic therapy (pseudomem-branous enterocolitis caused by Clos-tridium difficile). It is not absorbed.




C. Cephalosporin

A. Disadvantages of penicillin G

B. Derivatives of penicillin G

6-Aminopenicillanic acid

Penicillin G

Penicillinase

Staphylococci

E. coli

Salmonella typhi

Gonococci

Pneumococci

Streptococci

Nar

row

-act

ion

spec

trum

Act

ive

Not

act

ive

H+Cl-

Resis-tant

Resistant,but sensitivetocephalosporinase Broad

Cefalexin

Penicillin V

Oxacillin

Amoxicillin

Resis-tant

Resis-tant

Resis-tant

Sensitive

Resistant

Resistant

Narrow

Narrow

Broad

PenicillinaseAcid Spectrum

Concentration neededto inhibit penicillin G-sensitive bacteria

Gra

m-p

ositi

ve

Gra

m-n

egat

ive

Acid sensitivity Penicillinasesensitivity


Inhibitors of Tetrahydrofolate Synthesis

Tetrahydrofolic acid (THF) is a co-en-zyme in the synthesis of purine basesand thymidine. These are constituentsof DNA and RNA and required for cellgrowth and replication. Lack of THFleads to inhibition of cell proliferation.Formation of THF from dihydrofolate(DHF) is catalyzed by the enzyme dihy-drofolate reductase. DHF is made fromfolic acid, a vitamin that cannot be syn-thesized in the body, but must be takenup from exogenous sources. Most bacte-ria do not have a requirement for folate,because they are capable of synthesiz-ing folate, more precisely DHF, fromprecursors. Selective interference withbacterial biosynthesis of THF can beachieved with sulfonamides and tri-methoprim.

Sulfonamides structurally resem-ble p-aminobenzoic acid (PABA), a pre-cursor in bacterial DHF synthesis. Asfalse substrates, sulfonamides competi-tively inhibit utilization of PABA, henceDHF synthesis. Because most bacteriacannot take up exogenous folate, theyare depleted of DHF. Sulfonamides thuspossess bacteriostatic activity against abroad spectrum of pathogens. Sulfon-amides are produced by chemical syn-thesis. The basic structure is shown in(A). Residue R determines the pharma-cokinetic properties of a given sulfon-amide. Most sulfonamides are well ab-sorbed via the enteral route. They aremetabolized to varying degrees andeliminated through the kidney. Rates ofelimination, hence duration of effect,may vary widely. Some members arepoorly absorbed from the gut and arethus suitable for the treatment of bacte-rial bowel infections. Adverse effectsmay include, among others, allergic re-actions, sometimes with severe skindamage, displacement of other plasmaprotein-bound drugs or bilirubin in neo-nates (danger of kernicterus, hence con-traindication for the last weeks of gesta-tion and in the neonate). Because of thefrequent emergence of resistant bacte-ria, sulfonamides are now rarely used.

Introduced in 1935, they were the firstbroad-spectrum chemotherapeutics.

Trimethoprim inhibits bacterialDHF reductase, the human enzyme be-ing significantly less sensitive than thebacterial one (rarely bone marrow de-pression). A 2,4-diaminopyrimidine, tri-methoprim, has bacteriostatic activityagainst a broad spectrum of pathogens.It is used mostly as a component of co-trimoxazole.

Co-trimoxazole is a combination oftrimethoprim and the sulfonamide sul-famethoxazole. Since THF synthesis isinhibited at two successive steps, theantibacterial effect of co-trimoxazole isbetter than that of the individual com-ponents. Resistant pathogens are infre-quent; a bactericidal effect may occur.Adverse effects correspond to those ofthe components.

Although initially developed as anantirheumatic agent (p. 320), sulfasala-zine (salazosulfapyridine) is used main-ly in the treatment of inflammatorybowel disease (ulcerative colitis andterminal ileitis or Crohn’s disease). Gutbacteria split this compound into thesulfonamide sulfapyridine and mesala-mine (5-aminosalicylic acid). The latteris probably the anti-inflammatory agent(inhibition of synthesis of chemotacticsignals for granulocytes, and of H2O2

formation in mucosa), but must bepresent on the gut mucosa in high con-centrations. Coupling to the sulfon-amide prevents premature absorptionin upper small bowel segments. Thecleaved-off sulfonamide can be ab-sorbed and may produce typical adverseeffects (see above).

Dapsone (p. 280) has several thera-peutic uses: besides treatment of lepro-sy, it is used for prevention/prophylaxisof malaria, toxoplasmosis, and actino-mycosis.




A. Inhibitors of tetrahydrofolate synthesis

(Vitamin)

DHF-Reductase

R determinespharmacokinetics

Duration of effect

Dosing interval

Sulfasalazine(not absorbable)

Cleavage byintestinal bacteria

Mesalamine Sulfapyridine

(absorbable)

Bacterium

Human cell

Synthesis ofpurinesThymidine

Sulfonamidesp-Aminobenzoic acid

Combination ofTrimethoprim andSulfamethoxazole

Co-trimoxazole =

Dihydro-folic acid(DHF)

Tetrahydro- folic acid

Folic acid

Trimethoprim

Sulfisoxazole6 hours

Sulfamethoxazole12 hours

Sulfalene

7 days


Inhibitors of DNA Function

Deoxyribonucleic acid (DNA) serves as atemplate for the synthesis of nucleic ac-ids. Ribonucleic acid (RNA) executesprotein synthesis and thus permits cellgrowth. Synthesis of new DNA is a pre-requisite for cell division. Substancesthat inhibit reading of genetic informa-tion at the DNA template damage theregulatory center of cell metabolism.The substances listed below are usefulas antibacterial drugs because they donot affect human cells.

Gyrase inhibitors. The enzyme gy-rase (topoisomerase II) permits the or-derly accommodation of a ~1000 µm-long bacterial chromosome in a bacteri-al cell of ~1 µm. Within the chromoso-mal strand, double-stranded DNA has adouble helical configuration. The for-mer, in turn, is arranged in loops thatare shortened by supercoiling. The gy-rase catalyzes this operation, as illus-trated, by opening, underwinding, andclosing the DNA double strand such thatthe full loop need not be rotated.

Derivatives of 4-quinolone-3-car-boxylic acid (green portion of ofloxacinformula) are inhibitors of bacterial gy-rases. They appear to prevent specifical-ly the resealing of opened strands andthereby act bactericidally. These agentsare absorbed after oral ingestion. Theolder drug, nalidixic acid, affects exclu-sively gram-negative bacteria and at-tains effective concentrations only inurine; it is used as a urinary tract anti-septic. Norfloxacin has a broader spec-trum. Ofloxacin, ciprofloxacin, andenoxacin, and others, also yield system-ically effective concentrations and areused for infections of internal organs.

Besides gastrointestinal problemsand allergy, adverse effects particularlyinvolve the CNS (confusion, hallucina-tions, seizures). Since they can damageepiphyseal chondrocytes and joint car-tilages in laboratory animals, gyrase in-hibitors should not be used during preg-nancy, lactation, and periods of growth.

Azomycin (nitroimidazole) deriv-atives, such as metronidazole, damage

DNA by complex formation or strandbreakage. This occurs in obligate an-aerobes, i.e., bacteria growing under O2

exclusion. Under these conditions, con-version to reactive metabolites that at-tack DNA takes place (e.g., the hydroxyl-amine shown). The effect is bactericidal.A similar mechanism is involved in theantiprotozoal action on Trichomonas va-ginalis (causative agent of vaginitis andurethritis) and Entamoeba histolytica(causative agent of large bowel inflam-mation, amebic dysentery, and hepaticabscesses). Metronidazole is well ab-sorbed via the enteral route; it is alsogiven i.v. or topically (vaginal insert).Because metronidazole is consideredpotentially mutagenic, carcinogenic,and teratogenic in the human, it shouldnot be used longer than 10 d, if possible,and be avoided during pregnancy andlactation. Timidazole may be consideredequivalent to metronidazole.

Rifampin inhibits the bacterial en-zyme that catalyzes DNA template-di-rected RNA transcription, i.e., DNA-de-pendent RNA polymerase. Rifampin actsbactericidally against mycobacteria (M.tuberculosis, M. leprae), as well as manygram-positive and gram-negative bac-teria. It is well absorbed after oral inges-tion. Because resistance may developwith frequent usage, it is restricted tothe treatment of tuberculosis and lepro-sy (p. 280).

Rifampin is contraindicated in thefirst trimester of gestation and duringlactation.

Rifabutin resembles rifampin butmay be effective in infections resistantto the latter.




Indication: TB

Streptomycesspecies

A. Antibacterial drugs acting on DNA

RNA

Twisting byopening, underwinding,and closureof DNA strand

1

2

3

4

Gyrase

Gyrase inhibitors

4-Quinolone-3-carboxylate-derivates, e. g.

DNA-double helix

Damageto DNA

DNA-dependentRNA polymerase

Anaerobicbacteria

Nitroimidazole

e. g., metronidazole

Trichomonas infection

Amebic infection

Rifampicin

Bacterialchromosome

ofloxacin


Inhibitors of Protein Synthesis

Protein synthesis means translationinto a peptide chain of a genetic mes-sage first copied (transcribed) into m-RNA (p. 274). Amino acid (AA) assemblyoccurs at the ribosome. Delivery of ami-no acids to m-RNA involves differenttransfer RNA molecules (t-RNA), each ofwhich binds a specific AA. Each t-RNAbears an “anticodon” nucleobase tripletthat is complementary to a particularm-RNA coding unit (codon, consisting of3 nucleobases.

Incorporation of an AA normally in-volves the following steps (A):

1. The ribosome “focuses” two co-dons on m-RNA; one (at the left) hasbound its t-RNA-AA complex, the AAhaving already been added to the pep-tide chain; the other (at the right) isready to receive the next t-RNA-AAcomplex.

2. After the latter attaches, the AAsof the two adjacent complexes arelinked by the action of the enzyme pep-tide synthetase (peptidyltransferase).Concurrently, AA and t-RNA of the leftcomplex disengage.

3. The left t-RNA dissociates fromm-RNA. The ribosome can advancealong the m-RNA strand and focus onthe next codon.

4. Consequently, the right t-RNA-AA complex shifts to the left, allowingthe next complex to be bound at theright.

These individual steps are suscepti-ble to inhibition by antibiotics of differ-ent groups. The examples shown origi-nate primarily from Streptomyces bac-teria, some of the aminoglycosides alsobeing derived from Micromonosporabacteria.

1a. Tetracyclines inhibit the bind-ing of t-RNA-AA complexes. Their actionis bacteriostatic and affects a broadspectrum of pathogens.

1b. Aminoglycosides induce thebinding of “wrong” t-RNA-AA complex-es, resulting in synthesis of false pro-teins. Aminoglycosides are bactericidal.Their activity spectrum encompasses

mainly gram-negative organisms.Streptomycin and kanamycin are usedpredominantly in the treatment of tu-berculosis.

Note on spelling: -mycin designatesorigin from Streptomyces species; -mi-cin (e.g., gentamicin) from Micromono-spora species.

2. Chloramphenicol inhibits pep-tide synthetase. It has bacteriostatic ac-tivity against a broad spectrum ofpathogens. The chemically simple mole-cule is now produced synthetically.

3. Erythromycin suppresses ad-vancement of the ribosome. Its action ispredominantly bacteriostatic and di-rected against gram-positve organisms.For oral administration, the acid-labilebase (E) is dispensed as a salt (E. stear-ate) or an ester (e.g., E. succinate).Erythromycin is well tolerated. It is asuitable substitute in penicillin allergyor resistance. Azithromycin, clarithromy-cin, and roxithromycin are derivativeswith greater acid stability and betterbioavailability. The compounds men-tioned are the most important membersof the macrolide antibiotic group, whichincludes josamycin and spiramycin. Anunrelated action of erythromycin is itsmimicry of the gastrointestinal hor-mone motiline (� interprandial bowelmotility).

Clindamycin has antibacterial ac-tivity similar to that of erythromycin. Itexerts a bacteriostatic effect mainly ongram-positive aerobic, as well as on an-aerobic pathogens. Clindamycin is asemisynthetic chloro analogue of lin-comycin, which derives from a Strepto-myces species. Taken orally, clindamy-cin is better absorbed than lincomycin,has greater antibacterial efficacy and isthus preferred. Both penetrate well intobone tissue.




A. Protein synthesis and modes of action of antibacterial drugs

Ribosome

Peptide chain

mRNA

tRNAInsertion ofincorrectamino acid

Amino acid

Streptomyces species

Tetracyclines

Aminoglycosides

Erythromycin

ChloramphenicolPeptidesynthetase

Doxycycline

Tobramycin

Chloramphenicol

Erythromycin


Tetracyclines are absorbed fromthe gastrointestinal tract to differing de-grees, depending on the substance, ab-sorption being nearly complete fordoxycycline and minocycline. Intrave-nous injection is rarely needed (rolite-tracycline is available only for i.v. ad-ministration). The most common un-wanted effect is gastrointestinal upset(nausea, vomiting, diarrhea, etc.) due to(1) a direct mucosal irritant action ofthese substances and (2) damage to thenatural bacterial gut flora (broad-spec-trum antibiotics) allowing colonizationby pathogenic organisms, includingCandida fungi. Concurrent ingestion ofantacids or milk would, however, be in-appropriate because tetracyclines forminsoluble complexes with plurivalentcations (e.g., Ca2+, Mg2+, Al3+, Fe2+/3+) re-sulting in their inactivation; that is, ab-sorbability, antibacterial activity, andlocal irritant action are abolished. Theability to chelate Ca2+ accounts for thepropensity of tetracyclines to accumu-late in growing teeth and bones. As a re-sult, there occurs an irreversible yellow-brown discoloration of teeth and a rever-sible inhibition of bone growth. Becauseof these adverse effects, tetracyclineshould not be given after the secondmonth of pregnancy and not prescribedto children aged 8 y and under. Otheradverse effects are increased photosen-sitivity of the skin and hepatic damage,mainly after i.v. administration.

The broad-spectrum antibioticchloramphenicol is completely ab-sorbed after oral ingestion. It undergoeseven distribution in the body and readi-ly crosses diffusion barriers such as theblood-brain barrier. Despite these ad-vantageous properties, use of chloram-phenicol is rarely indicated (e.g., in CNSinfections) because of the danger ofbone marrow damage. Two types of bonemarrow depression can occur: (1) adose-dependent, toxic, reversible formmanifested during therapy and, (2) afrequently fatal form that may occur af-ter a latency of weeks and is not dosedependent. Due to high tissue penet-rability, the danger of bone marrow de-

pression must also be taken into ac-count after local use (e.g., eye drops).

Aminoglycoside antibiotics con-sist of glycoside-linked amino-sugars(cf. gentamicin C1α, a constituent of thegentamicin mixture). They contain nu-merous hydroxyl groups and aminogroups that can bind protons. Hence,these compounds are highly polar,poorly membrane permeable, and notabsorbed enterally. Neomycin and paro-momycin are given orally to eradicateintestinal bacteria (prior to bowel sur-gery or for reducing NH3 formation bygut bacteria in hepatic coma). Amino-glycosides for the treatment of seriousinfections must be injected (e.g., gen-tamicin, tobramycin, amikacin, netilmi-cin, sisomycin). In addition, local inlaysof a gentamicin-releasing carrier can beused in infections of bone or soft tissues.Aminoglycosides gain access to the bac-terial interior by the use of bacterialtransport systems. In the kidney, theyenter the cells of the proximal tubulesvia an uptake system for oligopeptides.Tubular cells are susceptible to damage(nephrotoxicity, mostly reversible). Inthe inner ear, sensory cells of the vestib-ular apparatus and Corti’s organ may beinjured (ototoxicity, in part irreversible).




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

Irritation ofmucousmembranes

Absorption

Antibacterialeffect ongut flora

Disadvantage:bone marrowtoxicity

Advantage:good penetrationthrough barriers

Gentamicin C1a

Basicoligopeptides

Transport system

No absorption"bowel sterilization"

Bacterium

H+

Inactivation bychelation ofCa2+, Al3+ etc.

Chela

tion

Chloramphenicol

Cochlear andvestibularototoxicity

H+H+

Nephro-toxicity

High hydrophilicityno passive diffusionthrough membranes

e.g.,neomycin

Tetracyclines


Drugs for Treating Mycobacterial Infections

Mycobacteria are responsible for twodiseases: tuberculosis, mostly caused byM. tuberculosis, and leprosy due to M. le-prae. The therapeutic principle appli-cable to both is combined treatmentwith two or more drugs. Combinationtherapy prevents the emergence of re-sistant mycobacteria. Because the anti-bacterial effects of the individual sub-stances are additive, correspondinglysmaller doses are sufficient. Therefore,the risk of individual adverse effects islowered. Most drugs are active againstonly one of the two diseases.

Antitubercular Drugs (1)

Drugs of choice are: isoniazid, rifampin,ethambutol, along with streptomycinand pyrazinamide. Less well tolerated,second-line agents include: p-aminosal-icylic acid, cycloserine, viomycin, ka-namycin, amikacin, capreomycin, ethi-onamide.

Isoniazid is bactericidal againstgrowing M. tuberculosis. Its mechanismof action remains unclear. (In the bacte-rium it is converted to isonicotinic acid,which is membrane impermeable,hence likely to accumulate intracellu-larly.) Isoniazid is rapidly absorbed afteroral administration. In the liver, it is in-activated by acetylation, the rate ofwhich is genetically controlled andshows a characteristic distribution indifferent ethnic groups (fast vs. slowacetylators). Notable adverse effectsare: peripheral neuropathy, optic neu-ritis preventable by administration ofvitamin B6 (pyridoxine); hepatitis, jaun-dice.

Rifampin. Source, antibacterial ac-tivity, and routes of administration aredescribed on p. 274. Albeit mostly welltolerated, this drug may cause severaladverse effects including hepatic dam-age, hypersensitivity with flu-likesymptoms, disconcerting but harmlessred/orange discoloration of body fluids,and enzyme induction (failure of oral

contraceptives). Concerning rifabutinsee p. 274.

Ethambutol. The cause of its specificantitubercular action is unknown.Ethambutol is given orally. It is general-ly well tolerated, but may cause dose-dependent damage to the optic nervewith disturbances of vision (red/greenblindness, visual field defects).

Pyrazinamide exerts a bactericidalaction by an unknown mechanism. It isgiven orally. Pyrazinamide may impairliver function; hyperuricemia resultsfrom inhibition of renal urate elimina-tion.

Streptomycin must be given i.v. (pp.278ff) like other aminoglycoside antibi-otics. It damages the inner ear and thelabyrinth. Its nephrotoxicity is compar-atively minor.

Antileprotic Drugs (2)

Rifampin is frequently given in combi-nation with one or both of the followingagents:

Dapsone is a sulfone that, like sul-fonamides, inhibits dihydrofolate syn-thesis (p. 272). It is bactericidal againstsusceptible strains of M. leprae. Dapsoneis given orally. The most frequent ad-verse effect is methemoglobinemia withaccelerated erythrocyte degradation(hemolysis).

Clofazimine is a dye with bacterici-dal activity against M. leprae and anti-inflammatory properties. It is givenorally, but is incompletely absorbed. Be-cause of its high lipophilicity, it accu-mulates in adipose and other tissuesand leaves the body only rather slowly(t1/2 ~ 70 d). Red-brown skin pigmenta-tion is an unwanted effect, particularlyin fair-skinned patients.




an aminoglycosideantibiotic

Streptomycin

Vestibular andcochlearototoxicity

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

Isonicotinic acid

Nicotinic acid

Folatesynthesis

p-Aminobenzoic acidClofazimine

Skin discoloration

Pyrazinamide

Liver damage

Combination therapy

Reduced risk ofbacterial resistance

Reduction of dose and ofrisk of adverse reactions

Mycobacteriumleprae

Mycobacteriumtuberculosis

1

2

Rifampin

Liver damageand enzyme induction

Ethambutol

Optic nerve damage

Isoniazid

CNS damageand peripheralneuropathy(Vit. B6-administration)Liver damage

Dapsone

Hemolysis


Drugs Used in the Treatment of Fungal Infections

Infections due to fungi are usually con-fined to the skin or mucous membranes:local or superficial mycosis. However, inimmune deficiency states, internal or-gans may also be affected: systemic ordeep mycosis.

Mycoses are most commonly due todermatophytes, which affect the skin,hair, and nails following external infec-tion. Candida albicans, a yeast organismnormally found on body surfaces, maycause infections of mucous membranes,less frequently of the skin or internal or-gans when natural defenses are im-paired (immunosuppression, or damageof microflora by broad-spectrum antibi-otics).

Imidazole derivatives inhibit er-gosterol synthesis. This steroid forms anintegral constituent of cytoplasmicmembranes of fungal cells, analogous tocholesterol in animal plasma mem-branes. Fungi exposed to imidazole de-rivatives stop growing (fungistatic ef-fect) or die (fungicidal effect). The spec-trum of affected fungi is very broad. Be-cause they are poorly absorbed andpoorly tolerated systemically, mostimidazoles are suitable only for topicaluse (clotrimazole, econazole oxiconazole,isoconazole, bifonazole, etc.). Rarely, thisuse may result in contact dermatitis. Mi-conazole is given locally, or systemicallyby short-term infusion (despite its poortolerability). Because it is well absorbed,ketoconazole is available for oral admin-istration. Adverse effects are rare; how-ever, the possibility of fatal liver dam-age should be noted. Remarkably, keto-conazole may inhibit steroidogenesis(gonadal and adrenocortical hormones).Fluconazole and itraconazole are newer,orally effective triazole derivatives. Thetopically active allylamine naftidineand the morpholine amorolfine also in-hibit ergosterol synthesis, albeit at an-other step.

The polyene antibiotics, ampho-tericin B and nystatin, are of bacterialorigin. They insert themselves into fun-

gal cell membranes (probably next toergosterol molecules) and cause forma-tion of hydrophilic channels. The resul-tant increase in membrane permeabil-ity, e.g., to K+ ions, accounts for the fun-gicidal effect. Amphotericin B is activeagainst most organisms responsible forsystemic mycoses. Because of its poorabsorbability, it must be given by infu-sion, which is, however, poorly tolerat-ed (chills, fever, CNS disturbances, im-paired renal function, phlebitis at theinfusion site). Applied topically to skinor mucous membranes, amphotericin Bis useful in the treatment of candidalmycosis. Because of the low rate of en-teral absorption, oral administration inintestinal candidiasis can be considereda topical treatment. Nystatin is used on-ly for topical therapy.

Flucytosine is converted in candidafungi to 5-fluorouracil by the action of aspecific cytosine deaminase. As an anti-metabolite, this compound disruptsDNA and RNA synthesis (p. 298), result-ing in a fungicidal effect. Given orally,flucytosine is rapidly absorbed. It is welltolerated and often combined with am-photericin B to allow dose reduction ofthe latter.

Griseofulvin originates from moldsand has activity only against derma-tophytes. Presumably, it acts as a spin-dle poison to inhibit fungal mitosis. Al-though targeted against local mycoses,griseofulvin must be used systemically.It is incorporated into newly formedkeratin. “Impregnated” in this manner,keratin becomes unsuitable as a fungalnutrient. The time required for the erad-ication of dermatophytes correspondsto the renewal period of skin, hair, ornails. Griseofulvin may cause uncharac-teristic adverse effects. The need forprolonged administration (severalmonths), the incidence of side effects,and the availability of effective and safealternatives have rendered griseofulvintherapeutically obsolete.

282 Antifungal Drugs


Antifungal Drugs 283

Streptomyces bacteria

NystatinAmphotericin B

A. Antifungal drugs

Mitotic spindle

DNA/RNAmetabolism

Uracil

CytosineDeaminase

Fung

al c

ell

5-Fluoruracil

Ergosterol

Polyene Antibiotics

Mold fungi

Incorporation intogrowing skin, hair, nails"Impregnation effect"

25-50 weeks

2-4 weeks

Griseofulvin

Synthesis

Cell wallCytoplasmic membrane Imidazole derivatives

e.g., clotrimazole

Flucytosine


Chemotherapy of Viral Infections

Viruses essentially consist of geneticmaterial (nucleic acids, green strands in(A) and a capsular envelope made up ofproteins (blue hexagons), often with acoat (gray ring) of a phospholipid (PL)bilayer with embedded proteins (smallblue bars). They lack a metabolic systembut depend on the infected cell for theirgrowth and replication. Targeted thera-peutic suppression of viral replicationrequires selective inhibition of thosemetabolic processes that specificallyserve viral replication in infected cells.To date, this can be achieved only to alimited extent.

Viral replication as exemplifiedby Herpes simplex viruses (A): (1) Theviral particle attaches to the host cellmembrane (adsorption) by linking itscapsular glycoproteins to specific struc-tures of the cell membrane. (2) The viralcoat fuses with the plasmalemma of thehost cell and the nucleocapsid (nucleicacid plus capsule) enters the cell interi-or (penetration). (3) The capsule opens(“uncoating”) near the nuclear poresand viral DNA moves into the cell nucle-us. The genetic material of the virus cannow direct the cell’s metabolic system.(4a) Nucleic acid synthesis: The geneticmaterial (DNA in this instance) is repli-cated and RNA is produced for the pur-pose of protein synthesis. (4b) The pro-teins are used as “viral enzymes” cata-lyzing viral multiplication (e.g., DNApolymerase and thymidine kinase), ascapsomers, or as coat components, orare incorporated into the host cellmembrane. (5) Individual componentsare assembled into new virus particles(maturation). (6) Release of daughter vi-ruses results in spread of virus insideand outside the organism. With herpesviruses, replication entails host cell de-struction and development of diseasesymptoms.

Antiviral mechanisms (A). The or-ganism can disrupt viral replicationwith the aid of cytotoxic T-lymphocytesthat recognize and destroy virus-pro-ducing cells (viral surface proteins) or

by means of antibodies that bind to andinactivate extracellular virus particles.Vaccinations are designed to activatespecific immune defenses.

Interferons (IFN) are glycoproteinsthat, among other products, are re-leased from virus-infected cells. Inneighboring cells, interferon stimulatesthe production of “antiviral proteins.”These inhibit the synthesis of viral pro-teins by (preferential) destruction of vi-ral DNA or by suppressing its transla-tion. Interferons are not directed againsta specific virus, but have a broad spec-trum of antiviral action that is, however,species-specific. Thus, interferon for usein humans must be obtained from cellsof human origin, such as leukocytes(IFN-α), fibroblasts (IFN-β), or lympho-cytes (IFN-γ). Interferons are also usedto treat certain malignancies and auto-immune disorders (e.g., IFN-α for chron-ic hepatitis C and hairy cell leukemia;IFN-β for severe herpes virus infectionsand multiple sclerosis).

Virustatic antimetabolites are“false” DNA building blocks (B) or nucle-osides. A nucleoside (e.g., thymidine)consists of a nucleobase (e.g., thymine)and the sugar deoxyribose. In antime-tabolites, one of the components is de-fective. In the body, the abnormal nucle-osides undergo bioactivation by attach-ment of three phosphate residues(p. 287).

Idoxuridine and congeners are in-corporated into DNA with deleteriousresults. This also applies to the synthesisof human DNA. Therefore, idoxuridineand analogues are suitable only for topi-cal use (e.g., in herpes simplex keratitis).

Vidarabine inhibits virally inducedDNA polymerase more strongly than itdoes the endogenous enzyme. Its use isnow limited to topical treatment of se-vere herpes simplex infection. Beforethe introduction of the better toleratedacyclovir, vidarabine played a majorpart in the treatment of herpes simplexencephalitis.

Among virustatic antimetabolites,acyclovir (A) has both specificity of thehighest degree and optimal tolerability,

284 Antiviral Drugs


Antiviral Drugs 285

1. Adsorption

Virus-infected

Proteins withantigenic properties

Specific immunedefensee.g., cytotoxicT-lymphocytes

DNA

Capsule

Envelope

4a. N

ucle

ic a

cid

synt

hesi

s

5.

RNA

DNA

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

Insertion intoDNA insteadof thymidine

Correct:

Thymidine

Thymine

DesoxyriboseIncorrect:

Vidarabine Acyclovir Ganciclovir

Adenine Guanine

Arabinose

Inhibition of viral DNA polymerase

B. Chemical structure of virustatic antimetabolites

GlycoproteinInterferon

Antiviralproteins

2. Penetration

Viral DNApolymerase

6. Release

4b. P

rote

in

3.Uncoating

A. Virus multiplication and modes of action of antiviral agents

Antimetabolites = incorrect DNA building blocks


because it undergoes bioactivation onlyin infected cells, where it preferentiallyinhibits viral DNA synthesis. (1) A virallycoded thymidine kinase (specific to H.simplex and varicella-zoster virus) per-forms the initial phosphorylation step;the remaining two phosphate residuesare attached by cellular kinases. (2) Thepolar phosphate residues render acyclo-vir triphosphate membrane imperme-able and cause it to accumulate in in-fected cells. (3) Acyclovir triphosphateis a preferred substrate of viral DNApolymerase; it inhibits enzyme activityand, following its incorporation into vi-ral DNA, induces strand breakage be-cause it lacks the 3’-OH group of deoxy-ribose that is required for the attach-ment of additional nucleotides. The hightherapeutic value of acyclovir is evidentin severe infections with H. simplex vi-ruses (e.g., encephalitis, generalized in-fection) and varicella-zoster viruses(e.g., severe herpes zoster). In these cas-es, it can be given by i.v. infusion. Acy-clovir may also be given orally despiteits incomplete (15%–30%) enteral ab-sorption. In addition, it has topical uses.Because host DNA synthesis remainsunaffected, adverse effects do not in-clude bone marrow depression. Acyclo-vir is eliminated unchanged in urine(t1/2 ~ 2.5 h).

Valacyclovir, the L-valyl ester ofacyclovir, is a prodrug that can be ad-ministered orally in herpes zoster infec-tions. Its absorption rate is approx.twice that of acyclovir. During passagethrough the intestinal wall and liver, thevaline residue is cleaved by esterases,generating acyclovir.

Famcyclovir is an antiherpetic pro-drug with good bioavailability whengiven orally. It is used in genital herpesand herpes zoster. Cleavage of two ace-tate groups from the “false sugar” andoxidation of the purine ring to guanineyields penciclovir, the active form. Thelatter differs from acyclovir with respectto its “false sugar” moiety, but mimics itpharmacologically. Bioactivation ofpenciclovir, like that of acyclovir, in-volves formation of the triphosphory-

lated antimetabolite via virally inducedthymidine kinase.

Ganciclovir (structure on p. 285) isgiven by infusion in the treatment of se-vere infections with cytomegaloviruses(also belonging to the herpes group);these do not induce thymidine kinase,phosphorylation being initiated by adifferent viral enzyme. Ganciclovir isless well tolerated and, not infrequent-ly, produces leukopenia and thrombo-penia.

Foscarnet represents a diphos-phate analogue.

As shown in (A), incorporation ofnucleotide into a DNA strand entailscleavage of a diphosphate residue. Fos-carnet (B) inhibits DNA polymerase byinteracting with its binding site for thediphosphate group. Indications: system-ic therapy of severe cytomegaly infec-tion in AIDS patients; local therapy ofherpes simplex infections.

Amantadine (C) specifically affectsthe replication of influenza A (RNA) vi-ruses, the causative agent of true in-fluenza. These viruses are endocytosedinto the cell. Release of viral DNA re-quires protons from the acidic contentof endosomes to penetrate the virus.Presumably, amantadine blocks a chan-nel protein in the viral coat that permitsinflux of protons; thus, “uncoating” isprevented. Moreover, amantadine in-hibits viral maturation. The drug is alsoused prophylactically and, if possible,must be taken before the outbreak ofsymptoms. It also is an antiparkinsonian(p. 188).

286 Antiviral Drugs


Antiviral Drugs 287

ViralDNA polymerase

Infected cell:herpes simplexor varicella-zoster

Viralthymidinekinase

Cellular kinases

Acyclovir

A. Activation of acyclovir and inhibition of viral DNA synthesis

B. Inhibitor of DNA polymerase:B. Foscarnet

InfluenzaA-virus

Endosome

Viral channelprotein

H+

Inhibition ofuncoating

C. Prophylaxis for viral flu

DNAsynthesis

DNA-chaintermination

Inhibition

Base Base Base

Viral DNA template

Active metabolite

Amantadine

Base

Foscarnet

C OO

PO O

O

P OO

O

PO O

P

O

O ViralDNA polymerase


Drugs for the Treatment of AIDS

Replication of the human immuno-deficiency virus (HIV), the causativeagent of AIDS, is susceptible to targetedinterventions, because several virus-specific metabolic steps occur in infect-ed cells (A). Viral RNA must first be tran-scribed into DNA, a step catalyzed by vi-ral “reverse transcriptase.” Double-stranded DNA is incorporated into thehost genome with the help of viral inte-grase. Under control by viral DNA, viralreplication can then be initiated, withsynthesis of viral RNA and proteins (in-cluding enzymes such as reverse tran-scriptase and integrase, and structuralproteins such as the matrix protein lin-ing the inside of the viral envelope).These proteins are assembled not indi-vidually but in the form of polyproteins.These precursor proteins carry an N-ter-minal fatty acid (myristoyl) residue thatpromotes their attachment to the inter-ior face of the plasmalemma. As the vi-rus particle buds off the host cell, it car-ries with it the affected membrane areaas its envelope. During this process, aprotease contained within the polypro-tein cleaves the latter into individual,functionally active proteins.

I. Inhibitors of Reverse Transcriptase

IA. Nucleoside agentsThese substances are analogues of thy-mine (azidothymidine, stavudine),adenine (didanosine), cytosine (lami-vudine, zalcitabine), and guanine (car-bovir, a metabolite of abacavir). Theyhave in common an abnormal sugarmoiety. Like the natural nucleosides,they undergo triphosphorylation, givingrise to nucleotides that both inhibit re-verse transcriptase and cause strandbreakage following incorporation intoviral DNA.

The nucleoside inhibitors differ interms of l) their ability to decrease cir-culating HIV load; 2) their pharmacoki-netic properties (half life � dosinginterval � compliance; organ distribu-tion � passage through blood-brainbar-

rier); 3) the type of resistance-inducingmutations of the viral genome and therate at which resistance develops; and4) their adverse effects (bone marrowdepression, neuropathy, pancreatitis).

IB. Non-nucleoside inhibitorsThe non-nucleoside inhibitors of re-verse transcriptase (nevirapine, dela-virdine, efavirenz) are not phosphory-lated. They bind to the enzyme withhigh selectivity and thus prevent it fromadopting the active conformation. Inhi-bition is noncompetitive.

II. HIV protease inhibitorsViral protease cleaves precursor pro-teins into proteins required for viralreplication. The inhibitors of this pro-tease (saquinavir, ritonavir, indinavir,and nelfinavir) represent abnormalproteins that possess high antiviral effi-cacy and are generally well tolerated inthe short term. However, prolonged ad-ministration is associated with occa-sionally severe disturbances of lipid andcarbohydrate metabolism. Biotransfor-mation of these drugs involves cyto-chrome P450 (CYP 3A4) and is thereforesubject to interaction with various otherdrugs inactivated via this route.

For the dual purpose of increasingthe effectiveness of antiviral therapyand preventing the development of atherapy-limiting viral resistance, inhibi-tors of reverse transcriptase are com-bined with each other and/or with pro-tease inhibitors.

Combination regimens are de-signed in accordance with substance-specific development of resistance andpharmacokinetic parameters (CNSpenetrability, “neuroprotection,” dosingfrequency).

288 Antiviral Drugs


Antiviral Drugs 289

A. Antiretroviral drugs

Viral RNA

DNA

e.g., zidovudine

Inhibitors ofreversetranscriptase

Envelope

Matrix protein

Reversetranscriptase

Integrase

Viral RNA Polyproteins

Protease

Mature virus

Cleavage ofpolypeptideprecursor

Inhibitors ofHIV protease

CH3

N H

ON

H

N H

ON

N

O

OH2N

H3C

CH3

HO

e.g., saquinavir

O

N=N=N

HOCH2

N O

N H

O

H3C

RNA

+ -


Disinfectants and Antiseptics

Disinfection denotes the inactivation orkilling of pathogens (protozoa, bacteria,fungi, viruses) in the human environ-ment. This can be achieved by chemicalor physical means; the latter will not bediscussed here. Sterilization refers tothe killing of all germs, whether patho-genic, dormant, or nonpathogenic. Anti-sepsis refers to the reduction by chemi-cal agents of germ numbers on skin andmucosal surfaces.

Agents for chemical disinfectionideally should cause rapid, complete,and persistent inactivation of all germs,but at the same time exhibit low toxic-ity (systemic toxicity, tissue irritancy,antigenicity) and be non-deleterious toinanimate materials. These require-ments call for chemical properties thatmay exclude each other; therefore,compromises guided by the intendeduse have to be made.

Disinfectants come from variouschemical classes, including oxidants,halogens or halogen-releasing agents,alcohols, aldehydes, organic acids, phe-nols, cationic surfactants (detergents)and formerly also heavy metals. The ba-sic mechanisms of action involve de-naturation of proteins, inhibition of en-zymes, or a dehydration. Effects are de-pendent on concentration and contacttime.

Activity spectrum. Disinfectantsinactivate bacteria (gram-positive >gram-negative > mycobacteria), less ef-fectively their sporal forms, and a few(e.g., formaldehyde) are virucidal.

Applications

Skin “disinfection.” Reduction of germcounts prior to punctures or surgicalprocedures is desirable if the risk ofwound infection is to be minimized.Useful agents include: alcohols (1- and2-propanol; ethanol 60–90%; iodine-re-leasing agents like polyvinylpyrrolidone[povidone, PVP]-iodine as a depot formof the active principle iodine, instead ofiodine tincture), cationic surfactants,

and mixtures of these. Minimal contacttimes should be at least 15 s on skin are-as with few sebaceous glands and atleast 10 min on sebaceous gland-richones.

Mucosal disinfection: Germ countscan be reduced by PVP iodine or chlor-hexidine (contact time 2 min), althoughnot as effectively as on skin.

Wound disinfection can be achievedwith hydrogen peroxide (0.3%–1% solu-tion; short, foaming action on contactwith blood and thus wound cleansing)or with potassium permanganate(0.0015% solution, slightly astringent),as well as PVP iodine, chlorhexidine,and biguanidines.

Hygienic and surgical hand disinfec-tion: The former is required after a sus-pected contamination, the latter beforesurgical procedures. Alcohols, mixturesof alcohols and phenols, cationic surfac-tants, or acids are available for this pur-pose. Admixture of other agents pro-longs duration of action and reducesflammability.

Disinfection of instruments: Instru-ments that cannot be heat- or steam-sterilized can be precleaned and thendisinfected with aldehydes and deter-gents.

Surface (floor) disinfection employsaldehydes combined with cationic sur-factants and oxidants or, more rarely,acidic or alkalizing agents.

Room disinfection: room air andsurfaces can be disinfected by sprayingor vaporizing of aldehydes, providedthat germs are freely accessible.

290 Disinfectants


Disinfectants 291

Tissue

A. Disinfectants

Application sites Examples Active principles

1. Oxidants

2. Halogens

chlorinesodium hypochloriteiodine tincture

Skin

3. Alcohols

R-OH (R=C2-C6)e. g., ethanolisopropanol

Regular e.g., hands

Acute,e.g., before local procedures

4. Aldehydes

e. g., formaldehydeglutaraldehyde

5. Organic acids

e. g., lactic acid

Mucous membranes

6. Phenols

Nonhalogenated:e. g., phenylphenoleugenolthymolhalogenated:chlormethylphenol

7. CationicsurfactantsCationic soaps

e. g., benzalkoniumchlorhexidine

8. Heavy metal salts

Inanimate material: durableagainst chemical + physicalmeasures

Inanimate matter:sensitive to heat,acids, oxidation etc.

Disinfectionof instruments

Skin disinfection

Disinfection of floorsor excrement

Disinfectionof mucous membranes

Wound disinfection

Phenols NaOCl

Cationicsurfactants

Phenols

Cationic surfactants

Alcohols

Iodinetincture

Chlor-hexidine

Chlor-hexidine

Chlor-hexidine KMnO4

H2O2

STOP

Cationic surfactants

Aldehydes

Disinfectants donot afford selective

inhibition ofbacteria

viruses, or fungi

e. g., hydrogen peroxide,potassium permanganate,peroxycarbonic acids

e. g., phenylmercury borate


Drugs for Treating Endo- and Ectoparasitic Infestations

Adverse hygienic conditions favor hu-man infestation with multicellular or-ganisms (referred to here as parasites).Skin and hair are colonization sites forarthropod ectoparasites, such as insects (lice, fleas) and arachnids (mites).Against these, insecticidal or arachnici-dal agents, respectively, can be used.Endoparasites invade the intestines oreven internal organs, and are mostlymembers of the phyla of flatworms androundworms. They are combated withanthelmintics.

Anthelmintics. As shown in the ta-ble, the newer agents praziquantel andmebendazole are adequate for the treat-ment of diverse worm diseases. Theyare generally well tolerated, as are theother agents listed.

Insecticides. Whereas fleas can beeffectively dealt with by disinfection ofclothes and living quarters, lice andmites require the topical application ofinsecticides to the infested subject.

Chlorphenothane (DDT) kills in-sects after absorption of a very smallamount, e.g., via foot contact with

sprayed surfaces (contact insecticide).The cause of death is nervous systemdamage and seizures. In humans DDTcauses acute neurotoxicity only afterabsorption of very large amounts. DDTis chemically stable and degraded in theenvironment and body at extremelyslow rates. As a highly lipophilic sub-stance, it accumulates in fat tissues.Widespread use of DDT in pest controlhas led to its accumulation in foodchains to alarming levels. For this rea-son its use has now been banned inmany countries.

Lindane is the active γ-isomer ofhexachlorocyclohexane. It also exerts aneurotoxic action on insects (as well ashumans). Irritation of skin or mucousmembranes may occur after topical use.Lindane is active also against intrader-mal mites (Sarcoptes scabiei, causativeagent of scabies), besides lice and fleas.It is more readily degraded than DDT.

Permethrin, a synthetic pyreth-roid, exhibits similar anti-ectoparasiticactivity and may be the drug of choicedue to its slower cutaneous absorption,fast hydrolytic inactivation, and rapidrenal elimination.

292 Antiparasitic Agents

Worms (helminths) Anthelmintic drug of choice

Flatworms (platyhelminths)tape worms (cestodes) praziquantel*flukes (trematodes) e.g., Schistosoma praziquantelspecies (bilharziasis)

Roundworms (nematodes)pinworm (Enterobius vermicularis) mebendazole or pyrantel pamoatewhipworm (Trichuris trichiura) mebendazoleAscaris lumbricoides mebendazole or pyrantel pamoateTrichinella spiralis** mebendazole and thiabendazoleStrongyloides stercoralis thiabendazoleHookworm (Necator americanus, and mebendazole or pyrantel pamoateAncylostoma duodenale) mebendazole or pyrantel pamoate

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


Antiparasitic Agents 293

Flea

Dam

age

to n

ervo

us s

yste

m: c

onvu

lsio

ns, d

eath

A. Endo- and ectoparasites: therapeutic agents

Tapewormse.g., beeftapeworm

Louse

Round-worms,e.g.,ascaris

Pinworm

Trichinellalarvae Scabies mite

Spasm,injury ofintegument

Praziquantel

Mebendazole

Hexachlorocyclo-hexane (Lindane)

Chlor-phenothane(DDT)


Antimalarials

The causative agents of malaria are plas-modia, unicellular organisms belongingto the order hemosporidia (class proto-zoa). The infective form, the sporozoite,is inoculated into skin capillaries wheninfected female Anopheles mosquitoes(A) suck blood from humans. The sporo-zoites invade liver parenchymal cellswhere they develop into primary tissueschizonts. After multiple fission, theseschizonts produce numerous mero-zoites that enter the blood. The pre-erythrocytic stage is symptom free. Inblood, the parasite enters erythrocytes(erythrocytic stage) where it again mul-tiplies by schizogony, resulting in theformation of more merozoites. Ruptureof the infected erythrocytes releases themerozoites and pyrogens. A fever attackensues and more erythrocytes are in-fected. The generation period for thenext crop of merozoites determines theinterval between fever attacks. WithPlasmodium vivax and P. ovale, there canbe a parallel multiplication in the liver(paraerythrocytic stage). Moreover,some sporozoites may become dormantin the liver as “hypnozoites” before en-tering schizogony. When the sexualforms (gametocytes) are ingested by afeeding mosquito, they can initiate thesexual reproductive stage of the cyclethat results in a new generation oftransmittable sporozoites.

Different antimalarials selectivelykill the parasite’s different developmen-tal forms. The mechanism of action isknown for some of them: pyrimetha-mine and dapsone inhibit dihydrofolatereductase (p. 273), as does chlorguanide(proguanil) via its active metabolite. Thesulfonamide sulfadoxine inhibits syn-thesis of dihydrofolic acid (p. 272). Chlo-roquine and quinine accumulate withinthe acidic vacuoles of blood schizontsand inhibit polymerization of heme, thelatter substance being toxic for theschizonts.

Antimalarial drug choice takes intoaccount tolerability and plasmodial re-sistance.

Tolerability. The first availableantimalarial, quinine, has the smallesttherapeutic margin. All newer agentsare rather well tolerated.

Plasmodium (P.) falciparum, re-sponsible for the most dangerous formof malaria, is particularly prone to de-velop drug resistance. The incidence ofresistant strains rises with increasingfrequency of drug use. Resistance hasbeen reported for chloroquine and alsofor the combination pyrimethamine/sulfadoxine.

Drug choice for antimalarialchemoprophylaxis. In areas with a riskof malaria, continuous intake of antima-larials affords the best protectionagainst the disease, although notagainst infection. The drug of choice ischloroquine. Because of its slow excre-tion (plasma t1/2 = 3d and longer), a sin-gle weekly dose is sufficient. In areaswith resistant P. falciparum, alternativeregimens are chloroquine plus pyri-methamine/sulfadoxine (or proguanil,or doxycycline), the chloroquine ana-logue amodiaquine, as well as quinineor the better tolerated derivative meflo-quine (blood-schizonticidal). Agents ac-tive against blood schizonts do not pre-vent the (symptom-free) hepatic infec-tion, only the disease-causing infectionof erythrocytes (“suppression therapy”).On return from an endemic malaria re-gion, a 2 wk course of primaquine is ad-equate for eradication of the late hepat-ic stages (P. vivax and P. ovale).

Protection from mosquito bites(net, skin-covering clothes, etc.) is avery important prophylactic measure.

Antimalarial therapy employs thesame agents and is based on the sameprinciples. The blood-schizonticidalhalofantrine is reserved for therapy on-ly. The pyrimethamine-sulfadoxinecombination may be used for initial self-treatment.

Drug resistance is accelerating inmany endemic areas; malaria vaccinesmay hold the greatest hope for controlof infection.

294 Antiparasitic Drugs


Antiparasitic Drugs 295

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

Fever

Fever

Primaquine

Primaquine

Chloroquine

Quinine

Proguanil

Pyrimethamine

Fever

2 days : Tertian malaria Pl. vivax, Pl. ovale3 days: Quartan malaria Pl. malariaeNo feverperiodicity: Pernicious malaria: Pl. falciparum

not P. falcip.

Pl. falcip.

Hepatocyte

Primary tissue schizont

Sulfadoxine

Chloroquine

Mefloquine

Halofantrine

Quinine

Proguanil

Pyrimethamine

MerozoitesHypnozoite

Pre

eryt

hroc

ytic

cyc

le1-

4 w

eeks

Ery

thro

cytic

cyc

le

Bloodschizont

Erythrocyte

OnlyPl. vivaxPl. ovale

Gametocytes

Sporozoites


Chemotherapy of Malignant Tumors

A tumor (neoplasm) consists of cellsthat proliferate independently of thebody’s inherent “building plan.” A ma-lignant tumor (cancer) is present whenthe tumor tissue destructively invadeshealthy surrounding tissue or when dis-lodged tumor cells form secondary tu-mors (metastases) in other organs. Acure requires the elimination of all ma-lignant cells (curative therapy). Whenthis is not possible, attempts can bemade to slow tumor growth and there-by prolong the patient’s life or improvequality of life (palliative therapy).Chemotherapy is faced with the prob-lem that the malignant cells are endoge-nous and are not endowed with specialmetabolic properties.

Cytostatics (A) are cytotoxic sub-stances that particularly affect prolife-rating or dividing cells. Rapidly dividingmalignant cells are preferentially in-jured. Damage to mitotic processes notonly retards tumor growth but may alsoinitiate apoptosis (programmed celldeath). Tissues with a low mitotic rateare largely unaffected; likewise, mosthealthy tissues. This, however, also ap-plies to malignant tumors consisting ofslowly dividing differentiated cells. Tis-sues that have a physiologically highmitotic rate are bound to be affected bycytostatic therapy. Thus, typical ad-verse effects occur:

Loss of hair results from injury tohair follicles; gastrointestinal distur-bances, such as diarrhea, from inad-equate replacement of enterocyteswhose life span is limited to a few days;nausea and vomiting from stimulation ofarea postrema chemoreceptors (p. 330);and lowered resistance to infection fromweakening of the immune system (p.300). In addition, cytostatics cause bonemarrow depression. Resupply of bloodcells depends on the mitotic activity ofbone marrow stem and daughter cells.When myeloid proliferation is arrested,the short-lived granulocytes are the firstto be affected (neutropenia), then bloodplatelets (thrombopenia) and, finally,

the more long-lived erythrocytes (ane-mia). Infertility is caused by suppressionof spermatogenesis or follicle matura-tion. Most cytostatics disrupt DNA me-tabolism. This entails the risk of a po-tential genomic alteration in healthycells (mutagenic effect). Conceivably,the latter accounts for the occurrence ofleukemias several years after cytostatictherapy (carcinogenic effect). Further-more, congenital malformations are tobe expected when cytostatics must beused during pregnancy (teratogenic ef-fect).

Cytostatics possess different mech-anisms of action.

Damage to the mitotic spindle (B).The contractile proteins of the spindleapparatus must draw apart the replicat-ed chromosomes before the cell can di-vide. This process is prevented by theso-called spindle poisons (see also col-chicine, p. 316) that arrest mitosis atmetaphase by disrupting the assemblyof microtubules into spindle threads.The vinca alkaloids, vincristine and vin-blastine (from the periwinkle plant, Vin-ca rosea) exert such a cell-cycle-specificeffect. Damage to the nervous system isa predicted adverse effect arising frominjury to microtubule-operated axonaltransport mechanisms.

Paclitaxel, from the bark of the pa-cific yew (Taxus brevifolia), inhibits dis-assembly of microtubules and inducesatypical ones. Docetaxel is a semisyn-thetic derivative.

296 Anticancer Drugs


Anticancer Drugs 297

A. Chemotherapy of tumors: principal and adverse effects

B. Cytostatics: inhibition of mitosis

Malignant tissuewith numerous mitoses

Wanted effect:inhibition oftumor growth

Healthy tissuewith few mitoses

Little effect

Healthy tissue withnumerous mitoses

Lymph node

Inhibition oflymphocytemultiplication:immuneweakness

Unwantedeffects

DiarrheaGerminalcell damage

Lowered resistance toinfection

Bone marrow

Inhibition ofgranulo-,thrombocyto-,and erythropoiesis

Vincaalkaloids

Vinca rosea

Paclitaxel

Western yew tree

Damage to hair follicleHair loss

Inhibition ofephithelial renewal

Cytostatics inhibitcell division

Inhibition offormation

Microtubulesof mitotic spindle Inhibition of

degradation


Inhibition of DNA and RNA syn-thesis (A). Mitosis is preceded by repli-cation of chromosomes (DNA synthesis)and increased protein synthesis (RNAsynthesis). Existing DNA (gray) serves asa template for the synthesis of new(blue) DNA or RNA. De novo synthesismay be inhibited by:

Damage to the template (1). Alky-lating cytostatics are reactive com-pounds that transfer alkyl residues intoa covalent bond with DNA. For instance,mechlorethamine (nitrogen mustard) isable to cross-link double-stranded DNAon giving off its chlorine atoms. Correctreading of genetic information is there-by rendered impossible. Other alkylat-ing agents are chlorambucil, melphalan,thio-TEPA, cyclophosphamide (p. 300,320), ifosfamide, lomustine, and busul-fan. Specific adverse reactions includeirreversible pulmonary fibrosis due tobusulfan and hemorrhagic cystitiscaused by the cyclophosphamide me-tabolite acrolein (preventable by theuroprotectant mesna). Cisplatin binds to(but does not alkylate) DNA strands.Cystostatic antibiotics insert them-selves into the DNA double strand; thismay lead to strand breakage (e.g., withbleomycin). The anthracycline antibioticsdaunorubicin and adriamycin (doxorubi-cin) may induce cardiomyopathy. Ble-omycin can also cause pulmonary fibro-sis.

The epipodophyllotoxins, etopo-side and teniposide, interact with topo-isomerase II, which functions to split,transpose, and reseal DNA strands(p. 274); these agents cause strandbreakage by inhibiting resealing.

Inhibition of nucleobase synthe-sis (2). Tetrahydrofolic acid (THF) is re-quired for the synthesis of both purinebases and thymidine. Formation of THFfrom folic acid involves dihydrofolatereductase (p. 272). The folate analoguesaminopterin and methotrexate (ame-thopterin) inhibit enzyme activity asfalse substrates. As cellular stores of THFare depleted, synthesis of DNA and RNAbuilding blocks ceases. The effect ofthese antimetabolites can be reversed

by administration of folinic acid (5-for-myl-THF, leucovorin, citrovorum fac-tor).

Incorporation of false buildingblocks (3). Unnatural nucleobases (6-mercaptopurine; 5-fluorouracil) or nu-cleosides with incorrect sugars (cytara-bine) act as antimetabolites. They inhib-it DNA/RNA synthesis or lead to synthe-sis of missense nucleic acids.

6-Mercaptopurine results from bio-transformation of the inactive precursorazathioprine (p. 37). The uricostatic allo-purinol inhibits the degradation of 6-mercaptopurine such that co-adminis-tration of the two drugs permits dosereduction of the latter.

Frequently, the combination of cy-tostatics permits an improved thera-peutic effect with fewer adverse reac-tions. Initial success can be followed byloss of effect because of the emergenceof resistant tumor cells. Mechanisms ofresistance are multifactorial:

Diminished cellular uptake may re-sult from reduced synthesis of a trans-port protein that may be needed formembrane penetration (e.g., metho-trexate).

Augmented drug extrusion: in-creased synthesis of the P-glycoproteinthat extrudes drugs from the cell (e.g.,anthracyclines, vinca alkaloids, epipo-dophyllotoxins, and paclitaxel) is re-ponsible for multi-drug resistance(mdr-1 gene amplification).

Diminished bioactivation of a pro-drug, e.g., cytarabine, which requiresintracellular phosphorylation to be-come cytotoxic.

Change in site of action: e.g., in-creased synthesis of dihydrofolate re-ductase may occur as a compensatoryresponse to methotrexate.

Damage repair: DNA repair en-zymes may become more efficient in re-pairing defects caused by cisplatin.

298 Anticancer Drugs


Anticancer Drugs 299

A. Cytostatics: alkylating agents and cytostatic antibiotics (1),inhibitors of tetrahydrofolate synthesis (2), antimetabolites (3)

instead of

instead of

Damageto template

Alkylatione. g., bymechlor-ethamine

Insertion ofdaunorubicin,doxorubicin,bleomycin,actinomycin D, etc.

Streptomyces bacteria

Inhibition of nucleotide synthesis

Purines

ThymineNucleotide

Tetrahydro-folate

Dihydrofolate

ReductaseFolic acid

Inhibition by

Purine antimetaboliteInsertion of incorrect building blocks

Pyrimidine antimetabolite

6-Mercaptopurinefrom Azathioprine

Adenine

Uracil

Cytarabine Cytosine Cytosine

Desoxyribose

instead of

5-Fluorouracil

Arabinose

AminopterinMethotrexate

DNA

DNA DNA

3

2

1

RNA

Building blocks


Inhibition of Immune Responses

Both the prevention of transplant rejec-tion and the treatment of autoimmunedisorders call for a suppression of im-mune responses. However, immunesuppression also entails weakened de-fenses against infectious pathogens anda long-term increase in the risk of neo-plasms.

A specific immune response be-gins with the binding of antigen by lym-phocytes carrying specific receptorswith the appropriate antigen-bindingsite. B-lymphocytes “recognize” antigensurface structures by means of mem-brane receptors that resemble the anti-bodies formed subsequently. T-lympho-cytes (and naive B-cells) require theantigen to be presented on the surfaceof macrophages or other cells in con-junction with the major histocompat-ibility complex (MHC); the latter per-mits recognition of antigenic structuresby means of the T-cell receptor. T-help-er cells carry adjacent CD-3 and CD-4complexes, cytotoxic T-cells a CD-8complex. The CD proteins assist in dock-ing to the MHC. In addition to recogni-tion of antigen, activation of lympho-cytes requires stimulation by cytokines.Interleukin-1 is formed by macrophag-es, and various interleukins (IL), includ-ing IL-2, are made by T-helper cells. Asantigen-specific lymphocytes prolife-rate, immune defenses are set into mo-tion.

I. Interference with antigen re-cognition. Muromonab CD3 is a mono-clonal antibody directed against mouseCD-3 that blocks antigen recognition byT-lymphocytes (use in graft rejection).

II. Inhibition of cytokine produc-tion or action. Glucocorticoids mod-ulate the expression of numerousgenes; thus, the production of IL-1 andIL-2 is inhibited, which explains thesuppression of T-cell-dependent im-mune responses. Glucocorticoids areused in organ transplantations, autoim-mune diseases, and allergic disorders.Systemic use carries the risk of iatro-genic Cushing’s syndrome (p. 248).

Cyclosporin A is an antibiotic poly-peptide from fungi and consists of 11, inpart atypical, amino acids. Given orally,it is absorbed, albeit incompletely. Inlymphocytes, it is bound by cyclophilin,a cytosolic receptor that inhibits thephosphatase calcineurin. The latterplays a key role in T-cell signal trans-duction. It contributes to the inductionof cytokine production, including that ofIL-2. The breakthroughs of moderntransplantation medicine are largely at-tributable to the introduction of cyclo-sporin A. Prominent among its adverseeffects are renal damage, hypertension,and hyperkalemia.

Tacrolimus, a macrolide, derivesfrom a streptomyces species; pharma-cologically it resembles cyclosporin A,but is more potent and efficacious.

The monoclonal antibodies daclizu-mab and basiliximab bind to the α-chain of the II-2 receptor of T-lympho-cytes and thus prevent their activation,e.g., during transplant rejection.

III. Disruption of cell metabolismwith inhibition of proliferation. Atdosages below those needed to treatmalignancies, some cytostatics are alsoemployed for immunosuppression, e.g.,azathioprine, methotrexate, and cyclo-phosphamide (p. 298). The antipro-liferative effect is not specific for lym-phocytes and involves both T- and B-cells.

Mycophenolate mofetil has a morespecific effect on lymphocytes than onother cells. It inhibits inosine mono-phosphate dehydrogenase, which cata-lyzes purine synthesis in lymphocytes.It is used in acute tissue rejection re-sponses.

IV. Anti-T-cell immune serum isobtained from animals immunized withhuman T-lymphocytes. The antibodiesbind to and damage T-cells and can thusbe used to attenuate tissue rejection.

300 Immune Modulators


Immune Modulators 301

Antigen Macrophage

MHC II MHC I

Glucocorticoids

Inhibition oftranscriptionof cytokines,e. g.,

IL-1 IL-2

CD

4

CD

3

CD

8

CD

3 Muromonab-CD3

Monoclonalantibody

B-Lymphocyte

T-Helper-cell

T-Lymphocyte

Cyclophilin

Inhibition

Calcineurin,a phosphatase

Transcription ofcytokines e. g.,IL-2

Cytotoxic,antiproliferativedrugs

Azathioprine,Methotrexate,Cyclo-phosphamide,Mycophenolatemofetil

Proliferation

differentiationinto plasma cells

CytotoxicT-lymphocytes

Cytokines:chemotaxis

Antibody-mediatedimmune reaction

Immune reaction:delayedhypersensitivity

Elimination of“foreign” cells

A. Immune reaction and immunosuppressives

UptakeDegradationPresentation

MH

C II

Interleukins

Virus-infected cell,transplanted cell.tumor cell

Synthesis of"foreign" proteinsPresentation

PhagocytosisDegradationPresentation

IL-1

IL-2

T-cellreceptor

and

Cyclosporin A

IL-2 receptorblockade

DaclizumabBasiliximab


Antidotes and treatment of poisonings

Drugs used to counteract drug overdos-age are considered under the appropri-ate headings, e.g., physostigmine withatropine; naloxone with opioids; flu-mazenil with benzodiazepines; anti-body (Fab fragments) with digitalis; andN-acetyl-cysteine with acetaminophenintoxication.

Chelating agents (A) serve as anti-dotes in poisoning with heavy metals.They act to complex and, thus, “inactiv-ate” heavy metal ions. Chelates (fromGreek: chele = claw [of crayfish]) repre-sent complexes between a metal ionand molecules that carry several bind-ing sites for the metal ion. Because oftheir high affinity, chelating agents “at-tract” metal ions present in the organ-ism. The chelates are non-toxic, are ex-creted predominantly via the kidney,maintain a tight organometallic bondalso in the concentrated, usually acidic,milieu of tubular urine and thus pro-mote the elimination of metal ions.

Na2Ca-EDTA is used to treat leadpoisoning. This antidote cannot pene-trate cell membranes and must be givenparenterally. Because of its high bindingaffinity, the lead ion displaces Ca2+ fromits bond. The lead-containing chelate iseliminated renally. Nephrotoxicity pre-dominates among the unwanted effects.Na3Ca-Pentetate is a complex of dieth-ylenetriaminopentaacetic acid (DPTA)and serves as antidote in lead and othermetal intoxications.

Dimercaprol (BAL, British Anti-Le-wisite) was developed in World War IIas an antidote against vesicant organicarsenicals (B). It is able to chelate vari-ous metal ions. Dimercaprol forms a li-quid, rapidly decomposing substancethat is given intramuscularly in an oilyvehicle. A related compound, both interms of structure and activity, is di-mercaptopropanesulfonic acid, whosesodium salt is suitable for oral adminis-tration. Shivering, fever, and skin reac-tions are potential adverse effects.

Deferoxamine derives from thebacterium Streptomyces pilosus. The

substance possesses a very high iron-binding capacity, but does not withdrawiron from hemoglobin or cytochromes.It is poorly absorbed enterally and mustbe given parenterally to cause increasedexcretion of iron. Oral administration isindicated only if enteral absorption ofiron is to be curtailed. Unwanted effectsinclude allergic reactions. It should benoted that blood letting is the most ef-fective means of removing iron from thebody; however, this method is unsuit-able for treating conditions of iron over-load associated with anemia.

D-penicillamine can promote theelimination of copper (e.g., in Wilson’sdisease) and of lead ions. It can be givenorally. Two additional uses are cystinu-ria and rheumatoid arthritis. In the for-mer, formation of cystine stones in theurinary tract is prevented because thedrug can form a disulfide with cysteinethat is readily soluble. In the latter, pen-icillamine can be used as a basal regi-men (p. 320). The therapeutic effectmay result in part from a reaction withaldehydes, whereby polymerization ofcollagen molecules into fibrils is inhibit-ed. Unwanted effects are: cutaneousdamage (diminished resistance to me-chanical stress with a tendency to formblisters), nephrotoxicity, bone marrowdepression, and taste disturbances.

302 Antidotes


Antidotes 303

EDTA: Ethylenediaminetetra-acetate

A. Chelation of lead ions by EDTA

Dimercaprol (i.m.)

DMPS

Deferoxamine D-Penicillamine

B. Chelators

Na2Ca-EDTA

Dissolution of cystinestones:Cysteine-S-S-Cysteine

Inhibition ofcollagenpolymerization

Arsenic, mercury,gold ions

Dimercaptopropanesulfonate

β,β-Dimethylcysteinechelation withCu2+ and Pb2+

2Na+ Ca2+

Fe3+

CH2

CH2

N

N CH2

CH2

CH2

CH2

C

C

C

C

O-

O-

O-

O-

O

O

O

O


Antidotes for cyanide poisoning(A). Cyanide ions (CN-) enter the organ-ism in the form of hydrocyanic acid(HCN); the latter can be inhaled, re-leased from cyanide salts in the acidicstomach juice, or enzymatically liberat-ed from bitter almonds in the gastroin-testinal tract. The lethal dose of HCN canbe as low as 50 mg. CN- binds with highaffinity to trivalent iron and thereby ar-rests utilization of oxygen via mito-chondrial cytochrome oxidases of therespiratory chain. An internal asphyxia-tion (histotoxic hypoxia) ensues whileerythrocytes remain charged with O2

(venous blood colored bright red).In small amounts, cyanide can be

converted to the relatively nontoxicthiocyanate (SCN-) by hepatic “rhoda-nese” or sulfur transferase. As a thera-peutic measure, thiosulfate can be giveni.v. to promote formation of thiocya-nate, which is eliminated in urine. How-ever, this reaction is slow in onset. Amore effective emergency treatment isthe i.v. administration of the methe-moglobin-forming agent 4-dimethyl-aminophenol, which rapidly generatestrivalent from divalent iron in hemoglo-bin. Competition between methemoglo-bin and cytochrome oxidase for CN- ionsfavors the formation of cyanmethemo-globin. Hydroxocobalamin is an alterna-tive, very effective antidote because itscentral cobalt atom binds CN- with highaffinity to generate cyanocobalamin.

Tolonium chloride (ToluidinBlue). Brown-colored methemoglobin,containing tri- instead of divalent iron,is incapable of carrying O2. Under nor-mal conditions, methemoglobin is pro-duced continuously, but reduced againwith the help of glucose-6-phosphatedehydrogenase. Substances that pro-mote formation of methemoglobin (B)may cause a lethal deficiency of O2. To-lonium chloride is a redox dye that canbe given i.v. to reduce methemoglobin.

Obidoxime is an antidote used totreat poisoning with insecticides of theorganophosphate type (p. 102). Phos-phorylation of acetylcholinesterasecauses an irreversible inhibition of ace-

tylcholine breakdown and hence flood-ing of the organism with the transmit-ter. Possible sequelae are exaggeratedparasympathomimetic activity, block-ade of ganglionic and neuromusculartransmission, and respiratory paralysis.

Therapeutic measures include: 1.administration of atropine in high dos-age to shield muscarinic acetylcholinereceptors; and 2. reactivation of acetyl-cholinesterase by obidoxime, whichsuccessively binds to the enzyme, cap-tures the phosphate residue by a nu-cleophilic attack, and then dissociatesfrom the active center to release the en-zyme from inhibition.

Ferric Ferrocyanide (“BerlinBlue,” B) is used to treat poisoning withthallium salts (e.g., in rat poison), theinitial symptoms of which are gastroin-testinal disturbances, followed by nerveand brain damage, as well as hair loss.Thallium ions present in the organismare secreted into the gut but undergoreabsorption. The insoluble, nonabsorb-able colloidal Berlin Blue binds thalliumions. It is given orally to prevent absorp-tion of acutely ingested thallium or topromote clearance from the organismby intercepting thallium that is secretedinto the intestines.

304 Antidotes


Antidotes 305

Nitrite

Potassiumcyanide

KCN

Hydrogencyanide

HCN

Rhodanese

Sulfur donors

Na2S2O3

Sodium thiosulfate

SCN-

H+

+ CN- FeIII-Hb Methemoglobinformation

DMAP

Complex formation

HydroxocobalaminVit.B12a

Cyanocobalamin Vit.B12

Fe3+

Mitochondrialcytochrome oxidase

A. Cyanide poisoning and antidotes

Substances formingmethemoglobin

H2N Aniline

O2N

FeII-Hb

Tolonium chloride(toluidin blue)

Organophosphates

e.g., Paraoxon

Reactivated

Acetylcholineesterase

Phosphorylated,inactivated

Reactivator:obidoxime

Ferric ferrocyanide

Thalliumion

B. Poisons and antidotes

H+

K+

FeIII-Hb

Nitrobenzene

=

Tl excretion

“Prussian Blue”FeIII [FeII(CN)6] 34

Tl+

Tl+

Tl+

2 Cl-2 Cl-

Inhibition ofcellular respiration

e.g., NO2-


Angina Pectoris

An anginal pain attack signals a tran-sient hypoxia of the myocardium. As arule, the oxygen deficit results from in-adequate myocardial blood flow due tonarrowing of larger coronary arteries.The underlying causes are: most com-monly, an atherosclerotic change of thevascular wall (coronary sclerosis withexertional angina); very infrequently, aspasmodic constriction of a morpholog-ically healthy coronary artery (coronaryspasm with angina at rest; variant angi-na); or more often, a coronary spasm oc-curring in an atherosclerotic vascularsegment.

The goal of treatment is to preventmyocardial hypoxia either by raisingblood flow (oxygen supply) or by lower-ing myocardial blood demand (oxygendemand) (A).

Factors determining oxygen sup-ply. The force driving myocardial bloodflow is the pressure difference betweenthe coronary ostia (aortic pressure) andthe opening of the coronary sinus (rightatrial pressure). Blood flow is opposedby coronary flow resistance, which in-cludes three components. (1) Due totheir large caliber, the proximal coro-nary segments do not normally contrib-ute significantly to flow resistance.However, in coronary sclerosis orspasm, pathological obstruction of flowoccurs here. Whereas the more com-mon coronary sclerosis cannot be over-come pharmacologically, the less com-mon coronary spasm can be relieved byappropriate vasodilators (nitrates, ni-fedipine). (2) The caliber of arteriolar re-sistance vessels controls blood flowthrough the coronary bed. Arteriolarcaliber is determined by myocardial O2

tension and local concentrations ofmetabolic products, and is “automati-cally” adjusted to the required bloodflow (B, healthy subject). This metabolicautoregulation explains why anginal at-tacks in coronary sclerosis occur onlyduring exercise (B, patient). At rest, thepathologically elevated flow resistanceis compensated by a corresponding de-

crease in arteriolar resistance, ensuringadequate myocardial perfusion. Duringexercise, further dilation of arterioles isimpossible. As a result, there is ischemiaassociated with pain. Pharmacologicalagents that act to dilate arterioles wouldthus be inappropriate because at restthey may divert blood from underper-fused into healthy vascular regions onaccount of redundant arteriolar dilation.The resulting “steal effect” could pro-voke an anginal attack. (3) The intra-myocardial pressure, i.e., systolicsqueeze, compresses the capillary bed.Myocardial blood flow is halted duringsystole and occurs almost entirely dur-ing diastole. Diastolic wall tension (“pre-load”) depends on ventricular volumeand filling pressure. The organic nitratesreduce preload by decreasing venousreturn to the heart.

Factors determining oxygen de-mand. The heart muscle cell consumesthe most energy to generate contractileforce. O2 demand rises with an increasein (1) heart rate, (2) contraction velocity,(3) systolic wall tension (“afterload”).The latter depends on ventricular vol-ume and the systolic pressure needed toempty the ventricle. As peripheral resis-tance increases, aortic pressure rises,hence the resistance against which ven-tricular blood is ejected. O2 demand islowered by β-blockers and Ca-antago-nists, as well as by nitrates (p. 308).

306 Therapy of Selected Diseases


Therapy of Selected Diseases 307

B. Pathogenesis of exertion angina in coronary sclerosis

O2-supplyduringdiastole

O2-demandduringsystole

Flow resistance:

1. Coronary arterialcaliber

2. Arteriolarcaliber

3. Systolic wall tension = Afterload

1. Heart rate

2. Contraction velocity


Venoussupply

Healthy subject Patient with coronary sclerosis

Rest

Exercise

A. O2 supply and demand of the myocardium

Narrow Wide

Compensa-torydilation ofarterioles

Rate

Contractionvelocity

Afterload

Wide Wide

Additionaldilationnot possible

Anginapectoris

Left atrium

Coronary artery

Left ventricle

Pressure p

Vol.Vol.

Pressure p

Rightatrium

p-f

orce

Time

Aorta

3. Diastolic wall tension = Preload

Venousreservoir


Antianginal Drugs

Antianginal agents derive from threedrug groups, the pharmacological prop-erties of which have already been pre-sented in more detail, viz., the organicnitrates (p. 120), the Ca2+ antagonists(p. 122), and the β-blockers (pp. 92ff).

Organic nitrates (A) increase bloodflow, hence O2 supply, because diastolicwall tension (preload) declines as ve-nous return to the heart is diminished.Thus, the nitrates enable myocardialflow resistance to be reduced even inthe presence of coronary sclerosis withangina pectoris. In angina due to coro-nary spasm, arterial dilation overcomesthe vasospasm and restores myocardialperfusion to normal. O2 demand fallsbecause of the ensuing decrease in thetwo variables that determine systolicwall tension (afterload): ventricular fill-ing volume and aortic blood pressure.

Calcium antagonists (B) decreaseO2 demand by lowering aortic pressure,one of the components contributing toafterload. The dihydropyridine nifedi-pine is devoid of a cardiodepressant ef-fect, but may give rise to reflex tachy-cardia and an associated increase in O2

demand. The catamphiphilic drugs ve-rapamil and diltiazem are cardiode-pressant. Reduced beat frequency andcontractility contribute to a reduction inO2 demand; however, AV-block and me-chanical insufficiency can dangerouslyjeopardize heart function. In coronaryspasm, calcium antagonists can inducespasmolysis and improve blood flow(p. 122).

β-Blockers (C) protect the heartagainst the O2-wasting effect of sympa-thetic drive by inhibiting β-receptor-mediated increases in cardiac rate andspeed of contraction.

Uses of antianginal drugs (D). Forrelief of the acute anginal attack, rap-idly absorbed drugs devoid of cardiode-pressant activity are preferred. The drugof choice is nitroglycerin (NTG,0.8–2.4 mg sublingually; onset of actionwithin 1 to 2 min; duration of effect~30 min). Isosorbide dinitrate (ISDN)

can also be used (5–10 mg sublingual-ly); compared with NTG, its action issomewhat delayed in onset but of long-er duration. Finally, nifedipine may beuseful in chronic stable, or in variant an-gina (5–20 mg, capsule to be bitten andthe contents swallowed).

For sustained daytime angina pro-phylaxis, nitrates are of limited valuebecause “nitrate pauses” of about 12 hare appropriate if nitrate tolerance is tobe avoided. If attacks occur during theday, ISDN, or its metabolite isosorbidemononitrate, may be given in the morn-ing and at noon (e.g., ISDN 40 mg in ex-tended-release capsules). Because ofhepatic presystemic elimination, NTG isnot suitable for oral administration.Continuous delivery via a transdermalpatch would also not seem advisablebecause of the potential development oftolerance. With molsidomine, there isless risk of a nitrate tolerance; however,due to its potential carcinogenicity, itsclinical use is restricted.

The choice between calcium antag-onists must take into account the diffe-rential effect of nifedipine versus verap-amil or diltiazem on cardiac perfor-mance (see above). When β-blockers aregiven, the potential consequences of re-ducing cardiac contractility (withdraw-al of sympathetic drive) must be kept inmind. Since vasodilating β2-receptorsare blocked, an increased risk of va-sospasm cannot be ruled out. Therefore,monotherapy with β-blockers is recom-mended only in angina due to coronarysclerosis, but not in variant angina.




D. Clinical uses of antianginal drugs

B. Effects of Ca-antagonists

O2-supply O2-demand

Afterload

Rate

Contractionvelocity

A. Effects of nitrates

C. Effects of β-blockers

Exercise

Rest

Sympatheticsystem

β-blocker

Relaxationofresistancevessels

Relaxation ofcoronary spasm

Ca-antagonists

Afterload

O2-demand

p

Preload

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

Nitratetolerance

Relaxation ofcoronary spasm

Venouscapacitancevessels

Resistancevessels

Vasorelaxation

Angina pectorisCoronary sclerosis Coronary spasm

GTN, ISDN

Nifedipine

Long-acting nitrates

Ca-antagonistsβ-blocker

Therapy of attack

Anginal prophylaxis

p Diastole pSystole

Vol Vol


Acute Myocardial Infarction

Myocardial infarction is caused byacute thrombotic occlusion of a coronaryartery (A). Therapeutic interventionsaim to restore blood flow in the occlud-ed vessel in order to reduce infarct sizeor to rescue ischemic myocardial tissue.In the area perfused by the affected ves-sel, inadequate supply of oxygen andglucose impairs the function of heartmuscle: contractile force declines. In thegreat majority of cases, the left ventricle(anterior or posterior wall) is involved.The decreased work capacity of the in-farcted myocardium leads to a reduc-tion in stroke volume (SV) and hencecardiac output (CO). The fall in bloodpressure (RR) triggers reflex activationof the sympathetic system. The resul-tant stimulation of cardiac β-adreno-ceptors elicits an increase in both heartrate and force of systolic contraction,which, in conjunction with an α-adren-oceptor-mediated increase in peripher-al resistance, leads to a compensatoryrise in blood pressure. In ATP-depletedcells in the infarct border zone, restingmembrane potential declines with aconcomitant increase in excitabilitythat may be further exacerbated by acti-vation of β-adrenoceptors. Together,both processes promote the risk of fatalventricular arrhythmias. As a conse-quence of local ischemia, extracellularconcentrations of H+ and K+ rise in theaffected region, leading to excitation ofnociceptive nerve fibers. The resultantsensation of pain, typically experiencedby the patient as annihilating, reinforcessympathetic activation.

The success of infarct therapy criti-cally depends on the length of timebetween the onset of the attack and thestart of treatment. Whereas some thera-peutic measures are indicated only afterthe diagnosis is confirmed, others ne-cessitate prior exclusion of contraindi-cations or can be instituted only in spe-cially equipped facilities. Without ex-ception, however, prompt action is im-perative. Thus, a staggered treatmentschedule has proven useful.

The antiplatelet agent, ASA, is ad-ministered at the first suspected signs ofinfarction. Pain due to ischemia is treat-ed predominantly with antianginaldrugs (e.g., nitrates). In case this treat-ment fails (no effect within 30 min, ad-ministration of morphine, if needed incombination with an antiemetic to pre-vent morphine-induced vomiting, is in-dicated. If ECG signs of myocardial in-farction are absent, the patient is stabi-lized by antianginal therapy (nitrates, β-blockers) and given ASA and heparin.

When the diagnosis has been con-firmed by electrocardiography, at-tempts are started to dissolve thethrombus pharmacologically (thrombo-lytic therapy: alteplase or streptoki-nase) or to remove the obstruction bymechanical means (balloon dilation orangioplasty). Heparin is given to pre-vent a possible vascular reocclusion, i.e.,to safeguard the patency of the affectedvessel. Regardless of the outcome ofthrombolytic therapy or balloon dila-tion, a β-blocker is administered to sup-press imminent arrhythmias, unless it iscontraindicated. Treatment of life-threatening ventricular arrhythmiascalls for an antiarrhythmic of the classof Na+-channel blockers, e.g., lidocaine.To improve long-term prognosis, use ismade of a β-blocker (� incidence of re-infarction and acute cardiac mortality)and an ACE inhibitor (prevention ofventricular enlargement after myocar-dial infarction) (A).




no

A. Drugs for the treatment of acute myocardial infarction

A. Algorithm for the treatment of acute myocardial infarction

noyes

yes

Suspected myocardialinfarct

Acetylsalicylicacid Ischemic pain

ECG

Thrombolysiscontraindicatedyes Angioplasty

contraindicated

Glycerol trinitrate

Force

SV

RR

SV x HR = COSV x HR = CO

H+ K+PainPreload reduction:

nitrateAfterload reduction:ACE-inhibitor

Antiplateletdrugs,thrombolyticagent,heparin

If needed:antiarrhythmic:e.g., lidocaine

Persistent pain:opioids and ifneeded: antiemetics

β-blocker

Analgesic:opioids

Infarct

α

ββ β

ExcitabilityArrhythmia

Sympatheticnervous system


no

Standard therapyβ-blocker, ACE-inhibitor, optional heparin

ST-segmentelevationleft bundle block

Thrombolysissuccessful

no

Angioplastyopt. GPIIb/IIIA-blocker

yes

yes

no


Hypertension

Arterial hypertension (high blood pres-sure) generally does not impair thewell-being of the affected individual;however, in the long term it leads tovascular damage and secondary compli-cations (A). The aim of antihypertensivetherapy is to prevent the latter and,thus, to prolong life expectancy.

Hypertension infrequently resultsfrom another disease, such as a cate-cholamine-secreting tumor (pheochro-mocytoma); in most cases the causecannot be determined: essential (pri-mary) hypertension. Antihypertensivedrugs are indicated when blood pres-sure cannot be sufficiently controlled bymeans of weight reduction or a low-salt diet. In principle, lowering of eithercardiac output or peripheral resistancemay decrease blood pressure (cf. p. 306,314, blood pressure determinants). Theavailable drugs influence one or both ofthese determinants. The therapeuticutility of antihypertensives is deter-mined by their efficacy and tolerability.The choice of a specific drug is deter-mined on the basis of a benefit:risk as-sessment of the relevant drugs, in keep-ing with the patient’s individual needs.

In instituting single-drug therapy(monotherapy), the following consider-ations apply: β-blockers (p. 92) are ofvalue in the treatment of juvenile hy-pertension with tachycardia and highcardiac output; however, in patientsdisposed to bronchospasm, even β1-se-lective blockers are contraindicated.Thiazide diuretics (p. 162) are potential-ly well suited in hypertension associat-ed with congestive heart failure; how-ever, they would be unsuitable in hypo-kalemic states. When hypertension isaccompanied by angina pectoris, thepreferred choice would be a β-blockeror calcium antagonist (p. 122) ratherthan a diuretic. As for the calcium an-tagonists, it should be noted that verap-amil, unlike nifedipine, possesses car-diodepressant activity. α-Blockers maybe of particular benefit in patients withbenign prostatic hyperplasia and im-

paired micturition. At present, only β-blockers and diuretics have undergonelarge-scale clinical trials, which haveshown that reduction in blood pressureis associated with decreased morbidityand mortality due to stroke and conges-tive heart failure.

In multidrug therapy, it is neces-sary to consider which agents rationallycomplement each other. A β-blocker(bradycardia, cardiodepression due tosympathetic blockade) can be effective-ly combined with nifedipine (reflextachycardia), but obviously not with ve-rapamil (bradycardia, cardiodepres-sion). Monotherapy with ACE inhibitors(p. 124) produces an adequate reduc-tion of blood pressure in 50% of pa-tients; the response rate is increased to90% by combination with a (thiazide)diuretic. When vasodilators such as di-hydralazine or minoxidil (p. 118) aregiven, β-blockers would serve to pre-vent reflex tachycardia, and diuretics tocounteract fluid retention.

Abrupt termination of continuoustreatment can be followed by reboundhypertension (particularly with shortt1/2 β-blockers).

Drugs for the control of hyperten-sive crises include nifedipine (capsule,to be chewed and swallowed), nitrogly-cerin (sublingually), clonidine (p.o. ori.v., p. 96), dihydralazine (i.v.), diazoxide(i.v.), fenoldopam (by infusion, p. 114)and sodium nitroprusside (p. 120, by in-fusion). The nonselective α-blockerphentolamine (p. 90) is indicated onlyin pheochromocytoma.

Antihypertensives for hyperten-sion in pregnancy are β1-selectiveadrenoceptor-blockers, methyldopa(p. 96), and dihydralazine (i.v. infusion)for eclampsia (massive rise in bloodpressure with CNS symptoms).




In severe cases further combination with

A. Arterial hypertension and pharmacotherapeutic approaches

Diuretics β-

bloc

kers

Ca-antagonists

α 1-b

lock

ers

ACE inhibitors

AT1-antagonists

If therapeuticresult inadequate

change to drugfrom another group

or

combine withdrug from another group

Drug selectionaccording to conditions

and needs of theindividual patient

Initial monotherapywith one of the fivedrug groups

Antihypertensive therapy

Hypertension

Systolic: blood pressure > 160 mmHg

Diastolic: blood pressure > 96 mmHg

Secondary diseases:Heart failureCoronary atherosclerosis angina pectoris, myocardial infarction, arrhythmiaAtherosclerosis of cerebral vessels cerebral infarction strokeCerebral hemorrhageAtherosclerosis of renal vessels renal failure

Decreased life expectancy

[mm Hg]

α-blockere.g.,prazosine

Centralα2-agoniste.g., clonidine

Vasodilatione.g.,dihydralazineminoxidil

Reserpine


Hypotension

The venous side of the circulation, ex-cluding the pulmonary circulation, ac-commodates ~ 60% of the total bloodvolume; because of the low venouspressure (mean ~ 15 mmHg) it is part ofthe low-pressure system. The arterialvascular beds, representing the high-pressure system (mean pressure,~ 100 mmHg), contain ~ 15%. The arteri-al pressure generates the driving forcefor perfusion of tissues and organs.Blood draining from the latter collects inthe low-pressure system and is pumpedback by the heart into the high-pressuresystem.

The arterial blood pressure (ABP)depends on: (1) the volume of blood perunit of time that is forced by the heartinto the high-pressure system—cardiacoutput corresponding to the product ofstroke volume and heart rate (beats/min), stroke volume being determinedinter alia by venous filling pressure; (2)the counterforce opposing the flow ofblood, i.e., peripheral resistance, whichis a function of arteriolar caliber.

Chronic hypotension (systolic BP< 105 mmHg). Primary idiopathic hypo-tension generally has no clinical impor-tance. If symptoms such as lassitudeand dizziness occur, a program of physi-cal exercise instead of drugs is advis-able.

Secondary hypotension is a sign ofan underlying disease that should betreated first. If stroke volume is too low,as in heart failure, a cardiac glycosidecan be given to increase myocardialcontractility and stroke volume. Whenstroke volume is decreased due to insuf-ficient blood volume, plasma substi-tutes will be helpful in treating bloodloss, whereas aldosterone deficiency re-quires administration of a mineralocor-ticoid (e.g., fludrocortisone). The latteris the drug of choice for orthostatic hy-potension due to autonomic failure. Aparasympatholytic (or electrical pace-maker) can restore cardiac rate inbradycardia.

Acute hypotension. Failure of or-thostatic regulation. A change from therecumbent to the erect position (ortho-stasis) will cause blood within the low-pressure system to sink towards the feetbecause the veins in body parts belowthe heart will be distended, despite a re-flex venoconstriction, by the weight ofthe column of blood in the blood ves-sels. The fall in stroke volume is partlycompensated by a rise in heart rate. Theremaining reduction of cardiac outputcan be countered by elevating the pe-ripheral resistance, enabling blood pres-sure and organ perfusion to be main-tained. An orthostatic malfunction ispresent when counter-regulation failsand cerebral blood flow falls, with resul-tant symptoms, such as dizziness,“black-out,” or even loss of conscious-ness. In the sympathotonic form, sympa-thetically mediated circulatory reflexesare intensified (more pronouncedtachycardia and rise in peripheral resis-tance, i.e., diastolic pressure); however,there is failure to compensate for the re-duction in venous return. Prophylactictreatment with sympathomimeticstherefore would hold little promise. In-stead, cardiovascular fitness trainingwould appear more important. An in-crease in venous return may beachieved in two ways. Increasing NaClintake augments salt and fluid reservesand, hence, blood volume (contraindi-cations: hypertension, heart failure).Constriction of venous capacitance ves-sels might be produced by dihydroer-gotamine. Whether this effect could al-so be achieved by an α-sympathomi-metic remains debatable. In the veryrare asympathotonic form, use of sympa-thomimetics would certainly be reason-able.

In patients with hypotension due tohigh thoracic spinal cord transections(resulting in an essentially completesympathetic denervation), loss of sym-pathetic vasomotor control can be com-pensated by administration of sympa-thomimetics.




A. Treatment of hypotension

Heart

Kidney

Intestines

Skeletal muscle

Lung

Brain

Low-pressuresystem

High-pressuresystem

Venousreturn

Stroke vol. x rate= cardiac output

Blood pressure (BP)

Peripheral resistance

α-Sympatho-mimetics

Arteriolarcaliber

β-Sympathomimetics

Cardiacglycosides

Parasym-patholytics

Redistribution of blood volume

Initial condition

Constriction of venous capacitancevessels, e.g., dihydroergotamine ifappropriate, α-sympathomimetics

Increase of blood volume

BP

Salt

NaCl + H2O

0,9%NaCl

NaCl+ H2O

Mineralo-corticoid

BP

BP


Gout

Gout is an inherited metabolic diseasethat results from hyperuricemia, an el-evation in the blood of uric acid, theend-product of purine degradation. Thetypical gout attack consists of a highlypainful inflammation of the first meta-tarsophalangeal joint (“podagra”). Goutattacks are triggered by precipitation ofsodium urate crystals in the synovialfluid of joints.

During the early stage of inflamma-tion, urate crystals are phagocytosed bypolymorphonuclear leukocytes (1) thatengulf the crystals by their ameboid cy-toplasmic movements (2). The phago-cytic vacuole fuses with a lysosome (3).The lysosomal enzymes are, however,unable to degrade the sodium urate.Further ameboid movement dislodgesthe crystals and causes rupture of thephagolysosome. Lysosomal enzymesare liberated into the granulocyte, re-sulting in its destruction by self-diges-tion and damage to the adjacent tissue.Inflammatory mediators, such as pros-taglandins and chemotactic factors, arereleased (4). More granulocytes are at-tracted and suffer similar destruction;the inflammation intensifies—the goutattack flares up.

Treatment of the gout attack aimsto interrupt the inflammatory response.The drug of choice is colchicine, an alka-loid from the autumn crocus (Colchicumautumnale). It is known as a “spindlepoison” because it arrests mitosis atmetaphase by inhibiting contractilespindle proteins. Its antigout activity isdue to inhibition of contractile proteinsin the neutrophils, whereby ameboidmobility and phagocytotic activity areprevented. The most common adverseeffects of colchicine are abdominal pain,vomiting, and diarrhea, probably due toinhibition of mitoses in the rapidly di-viding gastrointestinal epithelial cells.Colchicine is usually given orally (e.g.,0.5 mg hourly until pain subsides or gas-trointestinal disturbances occur; maxi-mal daily dose, 10 mg).

Nonsteroidal anti-inflammatorydrugs, such as indomethacin and phe-nylbutazone, are also effective. In se-vere cases, glucocorticoids may be in-dicated.

Effective prophylaxis of gout at-tacks requires urate blood levels to belowered to less than 6 mg/100 mL.

Diet. Purine (cell nuclei)-rich foodsshould be avoided, e.g., organ meats.Milk, dairy products, and eggs are low inpurines and are recommended. Coffeeand tea are permitted since the meth-ylxanthine caffeine does not enter pu-rine metabolism.

Uricostatics decrease urate pro-duction. Allopurinol, as well as its accu-mulating metabolite alloxanthine (oxy-purinol), inhibit xanthine oxidase,which catalyzes urate formation fromhypoxanthine via xanthine. These pre-cursors are readily eliminated via theurine. Allopurinol is given orally(300–800 mg/d). Except for infrequentallergic reactions, it is well toleratedand is the drug of choice for gout pro-phylaxis. At the start of therapy, gout at-tacks may occur, but they can be pre-vented by concurrent administration ofcolchicine (0.5–1.5 mg/d). Uricosurics,such as probenecid, benzbromarone(100 mg/d), or sulfinpyrazone, pro-mote renal excretion of uric acid. Theysaturate the organic acid transportsystem in the proximal renal tubules,making it unavailable for urate reab-sorption. When underdosed, they inhib-it only the acid secretory system, whichhas a smaller transport capacity. Urateelimination is then inhibited and a goutattack is possible. In patients with uratestones in the urinary tract, uricosuricsare contraindicated.




A. Gout and its therapy

Alloxanthine Xanthine

Hypoxanthine

Uric acid Nucleus

Lysosome

Phagocyte

Chemotac

tic

facto

rs

1

2

3

Gout attack

Colchicine

4

Anion (urate)reabsorption

Anion secretion

Uricostatic

UricosuricProbenecid

XanthineOxidase

Allopurinol


Osteoporosis

Osteoporosis is defined as a generalizeddecrease in bone mass (osteopenia) thataffects bone matrix and mineral contentequally, giving rise to fractures of verte-bral bodies with bone pain, kyphosis,and shortening of the torso. Fractures ofthe hip and the distal radius are alsocommon. The underlying process is adisequilibrium between bone formationby osteoblasts and bone resorption byosteoclasts.

Classification: Idiopathic osteopor-osis type I, occurring in postmenopausalfemales; type II, occurring in senescentmales and females (>70 y). Secondaryosteoporosis: associated with primarydisorders such as Cushing’s disease, orinduced by drugs, e.g., chronic therapywith glucocorticoids or heparin. In theseforms, the cause can be eliminated.

Postmenopausal osteoporosisrepresents a period of accelerated lossof bone mass. The lower the preexistingbone mass, the earlier the clinical signsbecome manifest.

Risk factors are: premature meno-pause, physical inactivity, cigarettesmoking, alcohol abuse, low bodyweight, and calcium-poor diet.

Prophylaxis: Administration of es-trogen can protect against postmeno-pausal loss of bone mass. Frequently,conjugated estrogens are used (p. 254).Because estrogen monotherapy increas-es the risk of uterine cancer, a gestagenneeds to be given concurrently (exceptafter hysterectomy), as e.g., in an oralcontraceptive preparation (p. 256).Under this therapy, menses will contin-ue. The risk of thromboembolic disor-ders is increased and that of myocardialinfarction probably lowered. Hormonetreatment can be extended for 10 y orlonger. Before menopause, daily cal-cium intake should be kept at 1 g (con-tained in 1 L of milk), and 1.5 g thereaf-ter.

Therapy. Formation of new bonematrix is induced by fluoride. Adminis-tered as sodium fluoride, it stimulatesosteoblasts. Fluoride is substituted for

hydroxyl residues in hydroxyapatite toform fluorapatite, the latter being moreresistant to resorption by osteoclasts. Tosafeguard adequate mineralization ofnew bone, calcium must be supplied insufficient amounts. However, simulta-neous administration would result inprecipitation of nonabsorbable calciumfluoride in the intestines. With sodiummonofluorophosphate this problem iscircumvented. The new bone formedmay have increased resistance to com-pressive, but not torsional, strain andparadoxically bone fragility may in-crease. Because the conditions underwhich bone fragility is decreased re-main unclear, fluoride therapy is not inroutine use.

Calcitonin (p. 264) inhibits osteo-clast activity, hence bone resorption. Asa peptide it needs to be given by injec-tion (or, alternatively, as a nasal spray).Salmonid is more potent than humancalcitonin because of its slower elimina-tion.

Bisphosphonates structurallymimic endogenous pyrophosphate,which inhibits precipitation and disso-lution of bone minerals. They retardbone resorption by osteoclasts and, inpart, also decrease bone mineralization.Indications include: tumor osteolysis,hypercalcemia, and Paget’s disease.Clinical trials with etidronate, adminis-tered as an intermittent regimen, haveyielded favorable results in osteoporo-sis. With the newer drugs clodronate,pamidronate, and alendronate, inhibi-tion of osteoclasts predominates; a con-tinuous regimen would thus appear tobe feasible.

Bisphosphonates irritate esophage-al and gastric mucus membranes; tab-lets should be swallowed with a reason-able amount of water (250 mL) and thepatient should keep in an upright posi-tion for 30 min following drug intake.




Normal state Osteoporosis

Organic bone matrix, Osteoid Bone mineral: hydroxyapatite

A. Bone: normal state and osteoporosis

In postmenopauseEstrogen(+ Gestagen)

Calcium-salts1 – 1.5g Ca2+

per day

Physiologicalconstituent:

Pyrophosphoric acid

B. Osteoporosis: drugs for prophylaxis and treatment

OsteoclastsOsteoblasts

Formation Resorption

Promotion ofboneformation

Inhibition ofboneresorption

Fluoride ionsNaF:

Activation ofosteoblasts,Formation ofFluorapatite

Calcitonin

Peptideconsisting of32 aminoacids

Bisphosphonates

e. g., alendronic acid

HO P

O

C P

OOH

(CH2)3

NH2

OH

OHOH

HO P

O

O P

O

OH

OHOH


Rheumatoid Arthritis

Rheumatoid arthritis or chronic poly-arthritis is a progressive inflammatoryjoint disease that intermittently attacksmore and more joints, predominantlythose of the fingers and toes. The prob-able cause of rheumatoid arthritis is apathological reaction of the immunesystem. This malfunction can be pro-moted or triggered by various condi-tions, including genetic disposition,age–related wear and tear, hypother-mia, and infection. An initial noxiousstimulus elicits an inflammation ofsynovial membranes that, in turn,leads to release of antigens throughwhich the inflammatory process ismaintained. Inflammation of the syn-ovial membrane is associated with lib-eration of inflammatory mediator sub-stances that, among other actions,chemotactically stimulate migration(diapedesis) of phagocytic blood cells(granulocytes, macrophages) into thesynovial tissue. The phagocytes producedestructive enzymes that promote tis-sue damage. Due to the production ofprostaglandins and leukotrienes (p.196) and other factors, the inflamma-tion spreads to the entire joint. As a re-sult, joint cartilage is damaged and thejoint is ultimately immobilized or fused.

Pharmacotherapy. Acute relief ofinflammatory symptoms can beachieved by prostaglandin synthaseinhibitors; nonsteroidal anti-inflam-matory drugs, or NSAIDs, such as diclof-enac, indomethacin, piroxicam, p. 200),and glucocorticoids (p. 248). The inevi-tably chronic use of NSAIDs is likely tocause adverse effects. Neither NSAIDsnor glucocorticoids can halt the pro-gressive destruction of joints.

The use of disease-modifyingagents may reduce the requirement forNSAIDs. The use of such agents does notmean that intervention in the basic pa-thogenetic mechanisms (albeit hopedfor) is achievable. Rather, disease-modi-fying therapy permits acutely actingagents to be used as add-ons or as re-quired. The common feature of disease-

modifiers is their delayed effect, whichdevelops only after treatment for severalweeks. Among possible mechanisms ofaction, inhibition of macrophage activ-ity and inhibition of release or activityof lysosomal enzymes are being dis-cussed. Included in this category are:sulfasalazine (an inhibitor of lipoxyge-nase and cyclooxygenase, p. 272), chlo-roquine (lysosomal binding), gold com-pounds (lysosomal binding; i.m.: au-rothioglucose, aurothiomalate; p.o.: au-ranofin, less effective), as well as D-pen-icillamine (chelation of metal ions need-ed for enzyme activity, p. 302). Frequentadverse reactions are: damage to skinand mucous membranes, renal toxicity,and blood dyscrasias. In addition, use ismade of cytostatics and immune sup-pressants such as methotrexate (lowdose, once weekly) and leflumomid aswell as of cytokin antibodies (inflixi-mab) and soluble cytokin receptors(etanercept). Methotrexate exerts ananti-inflammatory effect, apart from itsanti-autoimmune action and, next tosulfasalazine, is considered to have themost favorable risk:benefit ratio. Inmost severe cases cytostatics such asazathioprin and cyclophosphamide willhave to be used.

Surgical removal of the inflamedsynovial membrane (synovectomy) fre-quently provides long-term relief. If fea-sible, this approach is preferred becauseall pharmacotherapeutic measures en-tail significant adverse effects.




A. Rheumatoid arthritis and its treatment

Genetic disposition

Environmental factors

Acute trigger

S y n o v i t i s

Immune system: reaction against articular tissue

Infectiontrauma

Chemo-tacticfactors

Inflammation

Pain

Inflammation

Cartilagedestruction

Prostaglandins

Permeability

Collagenases

Phospholipases

Peptidases

Bonedestruction

IL-1 TNFα

Non-steroidalanti-inflammatorydrugs(NSAIDs)

Glucocorticoids

Methotrexate, p.o. /s.c.weekly dosing

Sulfasalazine p.o.

Gold parenteral

Pneumonitis, nausea,vomiting, myelosuppression

allergic reaction, nephrotoxicity,gastrointestinal disturbances

Lesions of mucous membranes,kidney, skin, blood dyscrasias

Months Years1 2 3 4 5 6

Relief of symptoms“Remission”

Discontinuation because of:

side effects

or

insufficient efficacy

Side effects:


Migraine

Migraine is a syndrome characterizedby recurrent attacks of intense head-ache and nausea that occur at irregularintervals and last for several hours. Inclassic migraine, the attack is typicallyheralded by an “aura” accompanied byspreading homonymous visual field de-fects with colored sharp edges (“fortifi-cation” spectra). In addition, the patientcannot focus on certain objects, has aravenous appetite for particular foods,and is hypersensitive to odors (hyperos-mia) or light (photophobia). The exactcause of these complaints is unknown;however, a disturbance in cranial bloodflow is the likely underlying pathoge-netic mechanism. In addition to an ofteninherited predisposition, precipitatingfactors are required to provoke an at-tack, e.g., psychic stress, lack of sleep,certain foods. Pharmacotherapy of mi-graine has two aims: stopping the acuteattack and preventing subsequent ones.

Treatment of the attack. Forsymptomatic relief, headaches aretreated with analgesics (acetamino-phen, acetylsalicylic acid), and nausea istreated with metoclopramide (p. 330)or domperidone. Since there is delayedgastric emptying during the attack, drugabsorption can be markedly retarded,hence effective plasma levels are notobtained. Because metoclopramidestimulates gastric emptying, it pro-motes absorption of ingested analgesicdrugs and thus facilitates pain relief.

If acetylsalicylic acid is adminis-tered i.v. as the lysine salt, its bioavail-ability is complete. Therefore, i.v. injec-tion may be advisable in acute attacks.

Should analgesics prove insuffi-ciently effective, ergotamine or one ofthe 5-HT1, agonists may help control theacute attack in most cases or prevent animminent attack. The probable commonmechanism of action is a stimulation ofserotonin receptors of the 5-HT1D (orperhaps also the 1B and 1F) subtype.Moreover, ergotamine has affinity fordopamine receptors (� nausea, eme-

sis), as well as α-adrenoceptors and 5-HT2 receptors (� vascular tone, �platelet aggregation). With frequentuse, the vascular side effects may giverise to severe peripheral ischemia (er-gotism). Overuse (>once per week) ofergotamine may provoke “rebound”headaches, thought to result from per-sistent vasodilation. Though different incharacter (tension-type headache),these prompt further consumption ofergotamine. Thus, a vicious circle devel-ops with chronic abuse of ergotamine orother analgesics that may end with irre-versible disturbances of peripheralblood flow and impairment of renalfunction.

Administered orally, ergotamineand sumatriptan, eletriptan, naratrip-tan, rizatriptan, and zolmitriptan haveonly limited bioavailability. Dihydroer-gotamine may be given by i.m. or slowi.v. injection, sumatriptan subcutane-ously or by nasal spray.

Prophylaxis. Taken regularly over alonger period, a heterogeneous group ofdrugs comprising propranolol, nadolol,atenolol, and metoprolol (β-blockers),flunarizine (H1-histamine, dopamine,and calcium antagonist), pizotifen (pi-zotyline, 5-HT-antagonist), methyser-gide (partial 5-HTID-agonist and nonse-lective 5-HT-antagonist, p. 126), NSAIDs(p. 200), and calcitonin (p. 264) may de-crease the frequency, intensity, and du-ration of migraine attacks. Among the β-blockers (p. 90), only those lacking in-trinsic sympathomimetic activity are ef-fective.




Migraine attack:

HeadacheHypersensitivityofolfaction, gustation,audition, visionNausea, vomiting

Acetylsalicylic acid 1000 mgor acetaminophen 1000 mg

(Dihydro)-Ergotamine

Sumatriptanand other triptans

Meto-clopramide

inhibited accelerated

delayed improved

Relief ofmigraine

Psychosis

Nausea,vomiting

Plateletaggregation

α1 + α2Vaso-constriction

Ergotam

ine

α1 + α2

Sum

atrip

tan

and

oth

er t

ripta

ns

A. Migraine and its treatment

Gastric emptying

Drugabsorption

Migraine

or

6 mg 100 mg 1 mg 1-2 mg

5-HT1D

5-HT1A

D2

5-HT2

5-HT1D

5-HT1A

D2

5-HT2

When therapeutic effect inadequate

Neurogenicinflammation,local edema,vasodilation


Common Cold

The common cold—colloquially the flu,catarrh, or grippe (strictly speaking, therarer infection with influenza viruses)—is an acute infectious inflammation ofthe upper respiratory tract. Its sym-ptoms, sneezing, running nose (due torhinitis), hoarseness (laryngitis), diffi-culty in swallowing and sore throat(pharyngitis and tonsillitis), cough asso-ciated with first serous then mucoussputum (tracheitis, bronchitis), soremuscles, and general malaise can bepresent individually or concurrently invarying combination or sequence. Theterm stems from an old popular beliefthat these complaints are caused by ex-posure to chilling or dampness. Thecausative pathogens are different virus-es (rhino-, adeno-, parainfluenza v.) thatmay be transmitted by aerosol dropletsproduced by coughing and sneezing.

Therapeutic measures. First at-tempts of a causal treatment consist ofzanamavir, an inhibitor of viral neura-minidase, an enzyme necessary for virusadsorption and infection of cells. How-ever, since symptoms of common coldabate spontaneously, there is no com-pelling need to use drugs. Conventionalremedies are intended for symptomaticrelief.

Rhinitis. Nasal discharge could beprevented by parasympatholytics; how-ever, other atropine–like effects (pp.104ff) would have to be accepted.Therefore, parasympatholytics arehardly ever used, although a corre-sponding action is probably exploited inthe case of H1 antihistamines, an ingre-dient of many cold remedies. Locally ap-plied (nasal drops) vasoconstricting α-sympathomimetics (p. 90) decongestthe nasal mucosa and dry up secretions,clearing the nasal passage. Long-termuse may cause damage to nasal mucousmembranes (p. 90).

Sore throat, swallowing prob-lems. Demulcent lozenges containingsurface anesthetics such as ethylamino-benzoate (benzocaine) or tetracaine(p. 208) may provide relief; however,

the risk of allergic reactions should beborne in mind.

Cough. Since coughing serves toexpel excess tracheobronchial secre-tions, suppression of this physiologicalreflex is justified only when coughing isdangerous (after surgery) or unproduc-tive because of absent secretions. Co-deine and noscapine (p. 212) suppresscough by a central action.

Mucous airway obstruction. Mu-colytics, such as acetylcysteine, split di-sulfide bonds in mucus, hence reduce itsviscosity and promote clearing of bron-chial mucus. Other expectorants (e.g.,hot beverages, potassium iodide, andipecac) stimulate production of waterymucus. Acetylcysteine is indicated incystic fibrosis patients and inhaled as anaerosol. Whether mucolytics are indi-cated in the common cold and whetherexpectorants like bromohexine or am-broxole effectively lower viscosity ofbronchial secretions may be questioned.

Fever. Antipyretic analgesics (ace-tylsalicylic acid, acetaminophen, p. 198)are indicated only when there is high fe-ver. Fever is a natural response and use-ful in monitoring the clinical course ofan infection.

Muscle aches and pains, head-ache. Antipyretic analgesics are effectivein relieving these symptoms.




A. Drugs used in common cold

Local use ofα-sympathomimetics(nasal drops or spray)

H1-AntihistaminesCaution: sedation

Viral infection

Causal therapyimpossible

Accumulation in airwaysof mucus, inadequateexpulsion by cough

Acetylsalicylicacid

Acetaminophen

Decongestion of mucousmembranes

Soreness

Headache

Fever

Sniffles,runny nose

Common coldFlu

Sore throat

Cough

Airway congestion

Surface anestheticsCaution:risk of sensitization

Antitussive:

Mucolytics

Acetylcysteine

Givewarm fluids

Bromhexine

Codeine

Potassiumiodidesolution

Expectorants:Stimulation of bronchial secretion

Dextrometorphan


Allergic Disorders

IgE-mediated allergic reactions (p. 72)involve mast cell release of histamine(p. 114) and production of other media-tors (such as leukotrienes, p. 196). Re-sultant responses include: relaxation ofvascular smooth muscle, as evidenced lo-cally by vasodilation (e.g., conjunctivalcongestion) or systemically by hypoten-sion (as in anaphylactic shock); en-hanced capillary permeability withtransudation of fluid into tissues—swelling of conjunctiva and mucousmembranes of the upper airways (“hayfever”), cutaneous wheal formation;contraction of bronchial smooth muscle—bronchial asthma; stimulation of intesti-nal smooth muscle—diarrhea.

1. Stabilization of mast cells.Cromolyn prevents IgE-mediated re-lease of mediators, although only afterchronic treatment. Moreover, by inter-fering with the actions of mediator sub-stances on inflammatory cells, it causesa more general inhibition of allergic in-flammation. It is applied locally to: con-junctiva, nasal mucosa, bronchial tree(inhalation), intestinal mucosa (absorp-tion almost nil with oral intake). Indica-tions: prophylaxis of hay fever, allergicasthma, and food allergies.

2. Blockade of histamine recep-tors. Allergic reactions are predomi-nantly mediated by H1 receptors. H1

antihistamines (p. 114) are mostly usedorally. Their therapeutic effect is oftendisappointing. Indications: allergicrhinitis (hay fever).

3. Functional antagonists of me-diators of allergy. a) α-Sympathomi-metics, such as naphazoline, oxymeta-zoline, and tetrahydrozoline, are ap-plied topically to the conjunctival andnasal mucosa to produce local vasocon-striction, and decongestion and to dryup 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 themost important drug in the managementof anaphylactic shock: it constricts blood

vessels, reduces capillary permeability,and dilates bronchi.

c) β2-Sympathomimetics, such asterbutaline, fenoterol, and albuterol, areemployed in bronchial asthma, mostlyby inhalation, and parenterally in emer-gencies. Even after inhalation, effectiveamounts can reach the systemic circula-tion and cause side effects (e.g., palpita-tions, tremulousness, restlessness, hy-pokalemia). During chronic administra-tion, the sensitivity of bronchial muscu-lature is likely to decline.

d) Theophylline belongs to themethylxanthines. Whereas caffeine(1,3,7-trimethylxanthine) predomi-nantly stimulates the CNS and constrictscerebral blood vessels, theophylline(1,3-dimethylxanthine) possesses addi-tional marked bronchodilator, cardio-stimulant, vasorelaxant, and diuretic ac-tions. These effects are attributed toboth inhibition of phosphodiesterase(→ c AMP elevation, p. 66) and antago-nism at adenosine receptors. In bronchi-al asthma, theophylline can be givenorally for prophylaxis or parenterally tocontrol the attack. Manifestations ofoverdosage include tonic-clonic sei-zures and cardiac arrhythmias as earlysigns.

e) Ipratropium (p. 104) can be in-haled to induce bronchodilation; how-ever, it often lacks sufficient effective-ness in allergic bronchospasm.

f) Glucocorticoids (p. 248) havesignificant anti-allergic activity andprobably interfere with different stagesof the allergic response. Indications: hayfever, bronchial asthma (preferably localapplication of analogues with high pre-systemic elimination, e.g., beclometha-sone, budesonide); anaphylactic shock(i.v. in high dosage)—a probably nonge-nomic action of immediate onset.




A. Anti-allergic therapy

Antigen (e.g., pollen, penicillin G)IgE Antibodies

Inhibitors ofleukotriene synthesis:e. g., zileuton

Release ofhistamine

Histaminereceptor

Reaction of target cells

Vascular smooth muscle, permeability

Mucous membranesof nose and eye:redness swelling,secretion

Skin:wheal formation

Circulation:anaphyl. shock

Bronchial musculature

Glu

coco

rtic

oid

sVasodilation Edema

α-Sympatho-mimetics:e. g.,naphazoline

Epinephrine

Contraction

Bronchial asthma

Theophylline

β2-Sympathomimetics:e. g.,terbutaline

H1-Antihistamines

LeukotrienesLeukotriene receptorantagonist:e. g., zafirlukast

COOHS

CH3OH

NCl

CH3

Leukotrienereceptor

O

O

NH

N

CH3

H3C

N

NH

N

H

N

H

N

H

N

H

OH

OH

HO

CH3

CH3

CH3

CHO O OO

COOOOC O O

OH

CH2CH2

Mast cell stabilizationbycromolyn


Bronchial Asthma

Definition: a recurrent, episodic short-ness of breath caused by bronchocon-striction arising from airway inflamma-tion and hyperreactivity.

Asthma patients tend to underesti-mate the true severity of their disease.Therefore, self-monitoring by the use ofhome peak expiratory flow meters is anessential part of the therapeutic pro-gram. With proper education, the pa-tient can detect early signs of deteriora-tion and can adjust medication withinthe framework of a physician-directedtherapeutic regimen.

Pathophysiology. One of the mainpathogenetic factors is an allergic in-flammation of the bronchial mucosa.For instance, leukotrienes that areformed during an IgE-mediated im-mune response (p. 326) exert a chemo-tactic effect on inflammatory cells. Asthe inflammation develops, bronchi be-come hypersensitive to spasmogenicstimuli. Thus, stimuli other than theoriginal antigen(s) can act as triggers(A); e.g., breathing of cold air is an im-portant trigger in exercise-inducedasthma. Cyclooxygenase inhibitors(p. 196) exemplify drugs acting as asth-ma triggers.

Management. Avoidance of asthmatriggers is an important prophylacticmeasure, though not always feasible.Drugs that inhibit allergic inflammma-tory mechanisms or reduce bronchialhyperreactivity, viz., glucocorticoids,“mast-cell stabilizers,” and leukotrieneantagonists, attack crucial pathogeneticlinks. Bronchodilators, such as β2-sym-pathomimetics, theophylline, and ipra-tropium, provide symptomatic relief.

The step scheme (B) illustrates suc-cessive levels of pharmacotherapeuticmanagement at increasing degrees ofdisease severity.

First treatment of choice for theacute attack are short-acting, aerosolizedβ2-sympathomimetics, e.g., salbutamol,albuterol, terbutaline, fenoterol, andothers. Their action occurs within min-utes and lasts for 4 to 6 h.

If β2-mimetics have to be usedmore frequently than three times aweek, more severe disease is present. Atthis stage, management includes anti-inflammatory drugs, such as “mast-cellstabilizers” (in children or juvenile pa-tients) or else glucocorticoids. Inhala-tional treatment must be administeredregularly, improvement being evidentonly after several weeks. With properuse of glucocorticoids undergoing highpresystemic elimination, concern aboutsystemic adverse effects is unwarrant-ed. Possible local adverse effects are:oropharyngeal candidiasis and dyspho-nia. To minimize the risk of candidiasis,drug administration should occur be-fore morning or evening meals, or befollowed by rinsing of the oropharynx.Anti-inflammatory therapy is the moresuccessful the less use is made of as-needed β2-mimetic medication.

Severe cases may, however, requirean intensified bronchodilator treatmentwith systemic β2-mimetics or theophyl-line (systemic use only; low therapeuticindex; monitoring of plasma levelsneeded). Salmeterol is a long-acting in-halative β2-mimetic (duration: 12 h; on-set ~20 min) that offers the advantage ofa lower systemic exposure. It is usedprophylactically at bedtime for noctur-nal asthma.

Zafirlukast is a long-acting, selec-tive, and potent leukotriene receptor(LTD4, LTE4) antagonist with anti-in-flammatory/antiallergic activity and ef-ficacy in the maintenance therapy ofchronic asthma. It is given both orallyand by inhalation. The onset of action isslow (3 to 14 d). Protective effectsagainst inhaled LTD4 last up to 12 to24 h.

Ipratropium may be effective insome patients as an adjunct anti-asth-matic, but has greater utility in prevent-ing bronchospastic episodes in chronicbronchitis.




Antigens,infections,ozone,SO2, NO2

Bronchialspasm

Dust,cold air,drugs

A. Bronchial asthma, pathophysiology and therapeutic approach

Mild asthma Severe asthmaModerate asthma

Modified afterINTERNATIONALCONSENSUSREPORT 1992

Glucocorticoidssystemic

Glucocorticoids

B. Bronchial asthma treatment algorithm

Noxious stimuli

"or" "or/and"

Glucocorticoids

Parasympatholytics

Allergens

Avoidexposure

Treatinflammation

Dilatebronchi

Mast cell-stabilizer”orglucocorticoids

“

Antiinflammatory treatment, inhalative, chronically

Bronchodilation as needed: short-acting inhalative β2-mimetics

Maintained bronchodilation

4 x/day4 x/day4 x/day3 x /week<–

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

Inflammation

Bronchial hyperreactivity

<– <– <–

or leukotriene antagonists


Emesis

In emesis the stomach empties in a ret-rograde manner. The pyloric sphincteris closed while the cardia and esopha-gus relax to allow the gastric contents tobe propelled orad by a forceful, synchro-nous contraction of abdominal wallmuscles and diaphragm. Closure of theglottis and elevation of the soft palateprevent entry of vomitus into the tra-chea and nasopharynx. As a rule, thereis prodromal salivation or yawning. Co-ordination between these differentstages depends on the medullary cen-ter for emesis, which can be activatedby diverse stimuli. These are conveyedvia the vestibular apparatus, visual, ol-factory, and gustatory inputs, as wellas viscerosensory afferents from theupper alimentary tract. Furthermore,psychic experiences may also activatethe emetic center. The mechanismsunderlying motion sickness (kinetosis,sea sickness) and vomiting during preg-nancy are still unclear.

Polar substances cannot reach theemetic center itself because it is pro-tected by the blood-brain barrier. How-ever, they can indirectly excite the cen-ter by activating chemoreceptors in thearea postrema or receptors on periph-eral vagal nerve endings.

Antiemetic therapy. Vomiting canbe a useful reaction enabling the body toeliminate an orally ingested poison.Antiemetic drugs are used to prevent ki-netosis, pregnancy vomiting, cytotoxicdrug-induced or postoperative vomit-ing, as well as vomiting due to radiationtherapy.

Motion sickness. Effective prophy-laxis can be achieved with the parasym-patholytic scopolamine (p. 106) and H1

antihistamines (p. 114) of the diphenyl-methane type (e.g., diphenhydramine,meclizine). Antiemetic activity is not aproperty shared by all parasympatho-lytics or antihistamines. The efficacy ofthe drugs mentioned depends on the ac-tual situation of the individual (gastricfilling, ethanol consumption), environ-mental conditions (e.g., the behavior of

fellow travellers), and the type of mo-tion experienced. The drugs should betaken 30 min before the start of traveland repeated every 4 to 6 h. Scopola-mine applied transdermally through anadhesive patch can provide effectiveprotection for up to 3 d.

Pregnancy vomiting is prone tooccur in the first trimester; thus phar-macotherapy would coincide with theperiod of maximal fetal vulnerability tochemical injury. Accordingly, antiemet-ics (antihistamines, or neuroleptics ifrequired) should be used only whencontinuous vomiting threatens to dis-turb electrolyte and water balance to adegree that places the fetus at risk.

Drug-induced vomiting. To pre-vent vomiting during anticancerchemotherapy (especially with cispla-tin), effective use can be made of 5-HT3-receptor antagonists (e.g., ondansetron,granisetron, and tropisetron), alone or incombination with glucocorticoids(methylprednisolone, dexamethasone).Anticipatory nausea and vomiting, re-sulting from inadequately controllednausea and emesis in patients undergo-ing cytotoxic chemotherapy, can be at-tenuated by a benzodiazepine such aslorazepam. Dopamine agonist-inducednausea in parkinsonian patients (p. 188)can be counteracted with D2-receptorantagonists that penetrate poorly intothe CNS (e.g., domperidone, sulpiride).Metoclopramide is effective in nauseaand vomiting of gastrointestinal origin(5-HT4-receptor agonism) and at highdosage also in chemotherapy- and radi-ation-induced sickness (low potencyantagonism at 5-HT3- and D2-recep-tors). Phenothiazines (e.g., levomeprom-azine, trimeprazine, perphenazine) maysuppress nausea/emesis that followscertain types of surgery or is due to opi-oid analgesics, gastrointestinal irrita-tion, uremia, and diseases accompaniedby elevated intracranial pressure.

The synthetic cannabinoids dronab-inol and nabilone have antinau-seant/antiemetic effects that may bene-fit AIDS and cancer patients.




A. Emetic stimuli and antiemetic drugs

Pregnancyvomiting

Kinetosese.g., sea sickness

Psychogenicvomiting

Sight

Olfaction

Taste

Intramucosal sensory nerveendings in mouth, pharynx,and stomach

Vestibularsystem

Chemoreceptors(drug-inducedvomiting)

Area postrema

Emetic center

Chemo-receptors

Scopolamine

H1-Antihistamines

Diphenhydramine

Meclozine

Dopamine antagonists

Domperidone

Metoclopramide

Ondansetron

5-HT3-antagonist

N

NN

ON

H

O N H

Cl

Parasympatholytics


A. Foundations and basic principles ofpharmacology

Hardman JG, Limbird LE. Goodman &Gilman’s. The pharmacological basis oftherapeutics. 9th ed. New York:McGraw-Hill; 1996.Levine RR. Pharmacology: drug actionsand reactions. 5th ed. New York: Parthe-non Publishing Group; 1996.Munson PL, Mueller RA, Breese GR. Prin-ciples of pharmacology. London: Chap-man & Hall; 1995.Mutschler E, Derendorf H. Drug ac-tions—basic principles and therapeuticaspects. Stuttgart: Medpharm ScientificPub.; Boca Raton: CRC Press; 1995.Page CR, Curtis MJ, Sutter MC, WalkerMJA, Hoffman BB. Integrated pharma-cology. London: Mosby; 1997.Pratt WB, Taylor P. Principles of drug ac-tion—the basis of pharmacology. 3rd ed.New York: Churchill Livingstone; 1990.Rang HP, Dale MM, Ritter JM, GardinerP. Pharmacology. 4th ed. New York:Churchill Livingstone; 1999.

B. Clinical pharmacology

Dipiro JT, Talbert RL, Yee GC, Matzke GR,Wells BG, Posey LM. Pharmacothera-py–a pathophysiological approach. 3rd

ed. Norwalk, Conn: Appleton & Lange;1997.Kuemmerle H, Shibuya T, Tillement JP.Human pharmacology: the basis of clin-ical pharmacology. Amsterdam: Elsevi-er; 1991.Laurence DR, Bennett PN. Clinical phar-macology. 8th ed. Edinburgh: ChurchillLivingstone; 1998.Melmon KL, Morelli HF, Hoffman BB,Nierenberg DW. Clinical Pharmacolo-gy—basic principles in therapeutics. 3rd

ed. New York: McGraw-Hill; 1992.

The Medical Letter on Drugs and Thera-peutics. New Rochelle NY: The MedicalLetter Inc.; published bi-weekly.Clinical Pharmacology—Electronic drugreference. Tampa, Florida: Gold Stan-dard Multimedia Inc.; updated every4 months.

C. Drug interactions and adverse effects

D’Arcey PF, Griffin JP. Iatrogenic diseas-es. Oxford: Oxford University Press;1986.Davies DM. Textbook of adverse drugreactions. 4th ed. Oxford: Oxford Univer-sity Press; 1992.Hansten PD, Horn JR. Drug interactions,analysis and management. Vancouver,WA: Applied Therapeutics Inc.; 1999;updated every 4 months.

D. Drugs in pregnancy and lactation

Briggs GG, Freeman RK, Yaffe SJ. Drugsin pregnancy and lactation: a referenceguide to fetal and neonatal risk. 5th ed.Baltimore: Williams & Wilkins; 1998.Rubin PC. Prescribing in pregnancy. Lon-don: British Medical Journal; 1987

E. Pharmacokinetics

Rowland M, Tozer TN. Clinical pharma-cokinetics: concepts and applications.3rd ed. Baltimore: Williams & Wilkins;1995.

F. Toxicology

Amdur MO, Doull J, Klaassen CD. Casa-rett and Doull’s toxicology: the basicscience of poisons. 5th ed. New York:McGraw-Hill; 1995.

332

Further Reading


333

Drug Indexes

Nomenclature. The terms active agentand pharmacon designate substancesthat are capable of modifying life pro-cesses irrespective of whether the ef-fects elicited may benefit or harm theorganisms concerned. By this definition,a toxin is also a pharmacon. Taken in anarrower sense, a pharmacon means asubstance that is used for therapeuticpurposes. An unequivocal term for sucha substance is medicinal drug.

A drug can be identified by differentdesignations:– the chemical name– the generic (nonproprietary) name– a trade or brand name

The drug diazepam may serve as anillustrative example. Chemically, thiscompound is called 7-chloro-1,3-dihy-dro-1-methyl-5-phenyl-2H-1,4-benzo-diazepin-2-one, a term too unwieldy foreveryday use. A simpler name is diaze-pam. This is not a legally protectedname but a generic (nonproprietary)name. An INN (= international nonpro-prietary name) is a generic name thathas been agreed upon by an interna-tional commission.

Preparations containing diazepamwere first marketed under the tradename Valium by its manufacturer, Hoff-mann–La Roche, Inc. This name is a reg-istered trademark. After patent protec-tion for the manufacture of diazepam-containing drug preparations expired,other companies were free to producepreparations containing this drug. Eachinvented a proprietary name for its“own” preparation. As a result, therenow exists a plethora of proprietary la-bels for diazepam preparations (as of1991, more than 50). Some of these eas-ily reveal the active ingredient, becausethe company name is simply added tothe generic name, e.g., Diazepam- (com-pany’s name). Other designations arenew creations, as for example, Vivol.

Similarly, some other commerciallysuccessful drugs are sold under morethan 20 different brand labels. The num-ber of proprietary names, therefore,greatly exceeds the number of availabledrugs.

For the sake of clarity, only INNs orgeneric (nonproprietary) names areused in this atlas to designate drugs,such as the name “diazepam” in theabove example.

Use of IndexesThe indexes are meant to help the read-er:1. identify a commercial preparation fora given drug. This information is foundin the index “Generic Name → Popri-etary Name.”2. obtain information about the phar-macological properties of the active in-gredient in a commercial preparation. Inorder to find the generic (nonproprie-tary) name, the second index “Proprie-tary Name → Generic Name” can beconsulted. Page references pertaining tothe drug can then be looked up in the In-dex. The list of proprietary names givenbelow will necessarily be incompletedue to their multitude. For drugs thatare marketed under several brandnames, the trade name of the originalmanufacturer will be listed; in the caseof some frequently prescribed generics,some proprietary names of other manu-facturers will also be listed. Brandnames that clearly reveal the drug’sidentity have been omitted. Combina-tion preparations have not been includ-ed, barring a few exceptions.

Many a brand name is not listed inthe index “Proprietary Name → GenericName.” In these cases, it will be useful toconsult the packaging information,which should list the generic (nonpro-prietary) name or INN.


334

Drug Index

Drug Name Trade Name

(* denotes investigational drug status in USA)AAbacavir ZiagenAbciximab ReoProAcarbose PrecoseAcebutolol Monitan, SectralAcenocoumarin (= Nicoumalone) SintromAcetaminophen see ParacetamolAcetazolamide Diamox, GlaupaxAcetylcysteine Airbron, Fabrol, Mucomyst, ParvolexAcetyldigoxin AcylanidAcetylsalicylic acid Aspirin, Arthrisin, Asadrine, Ecotrin,

Entrophen, Pyronoval, SupasaAciclovir ZoviraxACTH Acthar, CortrophinActinomycin D CosmegenAcyclovir ZoviraxADH (= Vasopressin) Pitressin, PresynAdrenalin see epinephrineAdriamycin See doxorubicinAjmaline Cardiorhythmino; GilurytmalAlbuterol See SalbutamolAlcuronium AlloferinAldosterone AldocortenAlendronate FosamaxAlfentanil AlfentaAlfuzosin Alfoten, XatralAllopurinol Alloprin, Novopurol, Urosin, Zyloprim, ZyloricAlprazolam XanaxAlprenolol Aprobal, Aptine, GubernalAlprostadil (= PGE1) Prostin VR, MinprogAlteplase ActivaseAluminium hydroxide Aldrox, Alu-Tab, Amphojel, FluagelAmantadine Solu-Contenton, Virofral, SymmetrelAmbroxol Ambril, Bronchopront, Mucosolvan, SurfactalAmikacin Amikin, Briclin, NovaminAmiloride Arumil, Colectril, Midamor, NiluridAmiloride + Hydrochlorothiazide Moduretε-Aminocaproic acid Amicar, Afibrin, Capramolε-Aminocaproic acid + Thromboplastin Epsilon-TachostyptanAminomethylbenzoic acid Gumbix, Pamba5-Aminosalicylic acid Propasa, RezipasAmiodarone Cordarex, CordaroneAmitriptyline Amitril, Elavil, Endep, Enovil, Levate, MevarilAmodiaquine Camoquin, FlavoquineAmoxicillin Amoxil, Clamoxyl, Moxacin, Novamoxin


Drug Name → Trade Name 335

d-Amphetamine Dexedrine, SynatanAmphotericin B Amphozone, Fungilin, Fungizone, MoronalAmpicillin Amcill, Omnipen, Penbritin, Polycillin, Principen, Tota-

cillinAmrinone Inocor, WincoramAncrod* Arvin, Arwin, ViprinexAngiotensin II HypertensinAprindine Amidonal, Aspenon, FibocilArdeparin NormifloArticaine Ultracain, UbistesinAstemizole HismanalAtenolol Prenormine, TenorminAtorvastatin LipitorAtracurium TracriumAtropine Atropisol, BorotropinAuranofin RidauraAurothioglucose Aureotan, Auromyose, SolganalAzapropazone ProlixanAzathioprine Azanin, Imuran, ImurekAzidothymidine RetrovirAzithromycin ZithromaxAzlocillin Azlin, SecuropenAztreonam Azactam

B

Bacitracin Altracin, Baciguent, TopitracinBaclofen LioresalBasiliximab SimulectBeclomethasone Aldecin, Beclovent, Beconase, Becotide, Propaderm,

VancerilBenazepril LotensinBenserazide Madopar (plus Levodopa)Benzathine-Penicillin G Bicillin, Megacillin, TardocillinBenztropine CogentinBenzbromarone Desuric, Narcaricin, Normurat, UricovacBenzocaine Anaesthesin, Americaine, AnacaineBetaxolol Betoptic, KerloneBezafibrate Befizal, Bezalip, Bezatol, CedurBifonazole Amycor, Bedriol, Mycospor, MycosporanBiperiden Akineton, AkinophylBisacodyl Bicol, Broxalax, Durolax, Dulcolax, Laxanin, Laxbene,

Nigalax, Pyrilax, Telemin, UlcolaxBismuth subsalicylate Pepto-BismolBisoprolol Concor, Detensiel, Emcor, Isoten, Soprol, ZebetaBitolterol Effectin, TornalateBleomycin BlenoxaneBotulinum Toxin Type A OculinumBromazepam Durazanil, Lectopam, LexotanBromhexine Auxit, Bisolvon, OphthosolBromocriptine Parlodel, Pravidel, Serono-BagrenBrotizolam Lendorm (A), LendorminBucindolol* Bextra


Budesonide Pulmicort, SpirocortBumetanide Bumex, Burinex, Fontego, FordiuranBunitrolol Betriol, StressonBupranolol Betadran, Betadrenol, Looser, PanimitBuprenorphine Buprene, TemgesicBupropion Wellbatrin, WellbutrinBuserelin Sprecur, SuprefactBuspirone BusparBusulfan Mielucin, Mitosan, Myleran, SulfabutinButizid SaltucinN-Butyl-scopolamine Buscopan, Hyoscin-N-Butylbromid

C

Calcifediol Calderol, Dedrogyl, HidroferolCalcitonin Calcimer, Calsynar, Cibacalcin, KarilCalcitriol RocaltrolCalcium carbonate Calsan, Caltrate, Nu-CalCamazepam AlbegoCanrenone Kanrenol, Soldactone, VenactoneCandesartan AtacandCapreomycin Capastat, CaprolinCaptopril Acediur, Acepril, Alopresin, Capoten, Cesplon, Hypertil,

Lopirin, TensobonCarazolol Conducton, SuacronCarbachol Doryl, Miostat, LentinCarbamazepine Epitol, Mazepine, Sirtal, Tegretol, TimonilCarbenicillin Anabactyl (A), Carindapen, Geopen, PyopenCarbenoxolone Biogastrone, Bioplex, Neogel, SanodinCarbidopa + Levodopa Isicom, Nacom, SinemetCarbimazole Neo-Mercazole, Neo-ThyreostatCarboplatin ParaplatinCarteolol Arteoptic, Caltidren, Carteol, Endak, Ocupress, TenalinCarvedilol CoregCefalexin Keflex, KeftabCefazolin Ancef, KetzolCefixime SupraxCefmenoxime Bestcall, Cefmax, Cemix, TacefCefoperazone Cefobid, Cefobis, TomabefCefotaxime ClaforanCefoxitin MefoxinCeftazidime Fortaz, Fortum, TacicefCeftriaxone Acantex, RocephinCefuroxime axetil CeftinCellulose AvicelCephalexin Cepexin (A), Ceporex, Keflex, LosporalCerivastatin BaycolChenodeoxycholic acid ChenixChloralhydrate Lorinal, Noctec, SomnosChlorambucil Chloraminophene, LeukeranChloramphenicol Chloromycetin, Chloroptic, Leukomycin, Paraxin, Sopa-

mycetin, SpersanicolChlorhexidine Baxedin, Chlor-hex, Hibidil, Hibitane, Plak-out

336 Drug Name → Trade Name



Chlormadinone acetate GestafortinChloroquine Aralen, Avloclor, QuinachlorChlorpromazine Largactil, Hibanil, Megaphen, ThorazineChlorpropamide DiabineseChlorprothixene Taractan, Tarasan, TruxalChlorthalidone HygrotonCholecalciferol D-Tabs, Vigantol, VigorsanClorazepate Novoclopate, TranxeneCilazapril InhibaceCimetidine Peptol, TagametCiprofloxacin Ciprobay, CiproCisapride PropulsidCisplatin Platinex, PlatinolCitalopram CelexaClarithromycin BiaxinClavulanic Acid + Amoxicillin AugmentinClemastine TavistClindamycin Cleocin, Dalacin, SobelinClobazam FrisiumClodronate* Clasteon, Ossiten, OstacClofazimine LamprenClofibrate Atromid-S, Claripex, SkleromexeClomethiazole Distraneurin, HemineurinClomiphene Clomid, Dyneric, Omifin, Pergotime, SeropheneClonazepam Clonopin, Iktorivil, RivotrilClonidine Catapres, DixaritClopidogrel PlavixClostebol Macrobin, SteranabolClotiazepam Clozan, Rize, Tienor, Trecalmo, VeratranClotrimazole Canesten, Clotrimaderm, Gyne-Lotrimin, Mycelex,

TrimystenCloxacillin Clovapen, TegopenClozapine ClozarilCodeine Codicept, PaveralColestipol Cholestabyl, CholestidColestyramine Questran, CuemidCorticotropin Acthar, Cortigel, CortrophinCortisol (Hydrocortisone) Alocort, Cortate, Cortef, Cortenema, Hyderm, Hyocort,

Rectocort, UnicortCortisone Cortelan, Cortogen, CortoneCotrimoxazole Bactrim, Novotrimel, Protrin SeptraCromoglycate (Cromolyn) Intal, Nalcrom, Opticrom, Rynacrom, VistacromCyanocobalamin Anacobin, Bedoz, Rubion, RubraminCyclofenil Fertodur, Ondogyne, Ondonid, Sanocrisin, SexovidCyclopenthiazide Navidrix, SalimidCyclophosphamide Cytoxan, Endoxan, ProcytoxCyclosporine Neoral, Sandimmune, Sang-35Cyproheptadine Anarexol, Nuran, Periactin, Peritol, VimiconCyproterone-acetate AndrocurCytarabine Udicil, Cytosar


D

Daclizumab ZenapaxDactinomycin See Actinomycin DDalteparin FragminDanaparoid OrgaranDantrolene DantriumDapsone Avlosulfone, Eporal, Diphenasone, UdolacDaunorubicin Cerubidine, Daunoblastin, OndenaDeferoxamine DesferalDelavirdine RescriptorDesipramine Pertofran, NorpraminDesmopressin DDAVP, Minirin, StimateDesogestrel + Ethinylestradiol MarvelonDexamethasone Decadron, Deronil, Hexadrol, SpersadexDexetimide TremblexDextran HyskonDiazepam Apaurin, Atensine, Diastat, Dizac, Eridan, Lembrol,

Meval, Noan, Tensium, Valium, Vatran, VivolDiazoxide Eudemine, Hyperstat, Mutabase, ProglicemDiclofenac Allvoran, Diclophlogont, Rhumalgan, Voltaren, VoltarolDicloxacillin Diclocil, Dynapen, PathocilDidanosine (ddI) VidexDiethylstilbestrol HonvolDigitoxin Crystodigin, Digicor, Digimerck, Digacin, Lanicor,

Lanoxin, Lenoxin, NovodigoxinDigoxin immune FAB DigibindDihydralazine Dihyzin, Nepresol, PressunicDihydroergotamine Angionorm, D.E.H.45, Dihydergot, Divegal, Endophle-

banDiltiazem CardizemDimenhydrinate Dimetab, Dramamine, Dymenate, MarmineDinoprost Minprostin F2α, Prostarmon, Prostin F2 AlphaDinoprostone Prepidil, Prostin E2

Diphenhydramine Allerdryl, Benadryl, Insommal, NautamineDiphenoxylate Diarsed, Lomotil, RetardinDisopyramide Norpace, RythmodanDobutamine DobutrexDocetaxel TaxotereDolasetron AnzemetDomperidone* Euciton, Evoxin, Motilium, Nauzelin, PeridonDopamine Dopastat, IntropinDorzolamide TrusoptDoxacurium NuromaxDoxazosin Cardura, CarduranDoxepin Adapin, Sinequan, TriadapinDoxorubicin Adriblastin, AdriamycinDoxycycline C-Pak, Doxicin, VibramycinDoxylamine DecaprynDronabinol MarinolDroperidol Inapsine, Droleptan




E

Econazole Ecostatin, Gyno-PevarylEcothiopate Phospholine IodideEnalapril Vasotec, XanefEnflurane EthraneEnoxacin Bactidan, Comprecin, EnoramEnoxaparin LovenoxEntacapone* ComtanEpinephrine Adrenalin, Bronchaid, Epifin, Epinal, EpiPen, Epitrate,

Lyophrin, Simplene, Suprarenin, VaponefrineEphedrine Bofedrol, Efedron, Va-tro-nolEprosartan TevetenEptifibatide IntegrilineErgocalciferol DrisdolErgometrine (= Ergonovine) Ergotrate Maleate, ErmalateErgonovine ErgotrateErgotamine Ergomar, Gynergen, MigrilErythomcyin E-mycin, Eryc, ErythromidErythromycin-estolate Dowmycin, Ilosone, NovorythroErythromycin-ethylsuccinate EES, Erythrocin, WyamycinErythromycin-propionate CimetrinErythromycin-stearate Erymycin, ErythrocinErythromycin-succinate MonomycinErythropoietin (= epoetin alfa) EpogenEsmolol BreviblocEstradiol EstraceEstradiol-benzoate Progynon BEstradiol-valerate Delestrogen, Dioval, Femogex, ProgynovaEstratriol = Estriol TheelolEtanercept EnbrelEthacrynic acid Edecrin, Hydromedin, ReomaxEthambutol Etibi, MyambutolEthinylestradiol Estinyl, Feminone, LynoralEthionamide TrecatorEthopropazine Parsitan, ParsitolEthosuximide Petinimid, Suxinutin, ZarontinEtidocaine DuranestEtidronate Calcimux, Diodronel, DiphosEtilefrine Apocretin, Effontil, Effortil, Ethyl Adrianol, Circupon,

Kertasin, Pulsamin, Etodolac LodineEtomidate AmidateEtoposide Toposar, VePesidEtretinate Tegison, Tigason

F

Famotidine Pepcid, PepdulFelbamate FelbatolFelodipine PlendilFelypressin OctapressinFenfluramine Ganal, Ponderal, Pondimin


Fenofibrate Lipidyl, TricorFenoldopam CorlopamFenoprofen Nalfon, NalgesicFenoterol Berotec, PartusistenFentanyl SublimazeFentanyl + Droperidol InnovarFinasteride Propecia, ProscarFlecainide TambocorFlucloxacillin FlucloxFluconazole DiflucanFlucytosine Alcoban, AncotilFludrocortisone Alflorone, F-Cortef, FlorinefFlumazenil Anexate, RomaziconFlunarizine Dinaplex, Flugeral, SibeliumFlunisolide Aerobid, Bronalide, Nasalide, RhinalarFlunitrazepam* Hypnosedon, Narcozep, RohypnolFluoxetine Prozac5-Fluorouracil Adrucil, Effudex, EffurixFlupentixol Depixol, FluanxolFluphenazine Moditen, ProlixinFlurazepam* DalmaneFlutamide Drogenil, EulexinFluticasone Cutivate, Flixonase, Flonase, FloventFluvastatin LescolFluvoxamine Floxifral, Faverin, LuvoxFolic acid Foldine, Folvite, LeucovorinFoscarnet FoscavirFosinopril MonoprilFurosemide Fusid, Lasix, Seguril, Uritol

G

Gabapentin NeurontinGallamine FlaxedilGallopamil Algocor, Corgal, Procorum, WingomGanciclovir Cytovene, VitrasertGelatin-colloids Gelafundin, HaemaccelGemfibrozil LopidGentamicin Cidomycin, Garamycin, Refobacin, SulmycinGlibenclamide (= glyburide) Daonil, DiaBeta, Euglucon, Glynase, MicronaseGlimepiride AmarylGlipizide GlucotrolGlyceryltrinitrate (= nitroglycerin) Ang-O-Span, Nitrocap, Nitrogard, Nitroglyn,

Nitrolingual, Nitrong, NitrostatGlycopyrrolate RobinulGonadorelin Factrel, Kryptocur, RelefactGoserelin ZoladexGramicidin GramodermGranisetron KytrilGriseofulvin Fulvicin, Grisovin, LikudenGuanabenz WytensinGuanethidine Ismelin, VisutensilGuanfacine Tenex




H

Halofantrine HalfanHaloperidol Haldol, SerenaceHalothane Fluothane, NarkotanHCG (= chorionic gonadotropin) Chorex, Choron, Entromone, Follutein, Gonic,

Pregnesin, Pregnyl, ProfasiHeparin Calciparin, Hepalean, LiqueminHeparin, low molecular Fragmin, FraxiparinHetastarch (HES) HespanHexachlorophane see LindaneHexobarbital EvipalHydralazine Alazine, ApresolineHydrochlorothiazide Aprozide, Diaqua, Diuchlor, Esidrex, Hydromal, Neo-

Codema, OreticHydromorphone Dilaudid, HymorphanHydroxocobalamin Acti-B12, Alpha-redisol, SytobexHydroxychloroquine PlaquenilHydroxyethyl starch HespanHydroxyprogesterone caproate Duralutin, Gesterol L.A., Hylutin, Hyroxon, Pro-DepoHyoscyamine sulfate Cystospaz-M, Levbid, Levsin

I

Ibuprofen Actiprophen, Advil, Motrin, Nuprin, TrendarIdoxuridine Dendrid, Herplex, Kerecid, StoxilIfosfamide IfexIloprost LatanaprostImipramine Dynaprin, Impril, Janimine, Melipramin, Tofranil,

TypramineIndapamide Lozide, Lozol, NatrilixIndinavir CrixivanIndomethacin Ammuno, Indocid, Indocin, Indome, MetacenInfliximab RemicadeInsulin Humalog, Humulin, Iletin, Novolin, VelosulinInterferon-α2 Berofor alpha 2Interferon-α2b Intron AInterferon-α2a Roferon A3Interferon-β Fiblaferon 3Interferon-β-1a AvonexInterferon-β-1b BetaseronInterferon-γ ActimmuneIpratropium Atrovent, ItropIrbesartan AvaproIsoconazole Gyno-Travogen, TravogenIsoetharine Arm-a-Med, Bisorine, Bronkosol, Dey-LuteIsoflurane ForaneIsoniazid Armazid, Isotamine, Lamiazid, Nydrazid, Rimifon, Tee-

baconinIsoprenaline (= Isoproterenol) Aludrin, Isuprel, Neo Epinin, SaventrineIsosorbide dinitrate Cedocard, Coradus, Coronex, Isordil, Sorbitrate5-Isosorbide mononitrate Coleb, Elantan, IsmoIsotretinoin Acutane Roche, Roaccutan



Isoxsuprine Rolisox, Vasodilan, VasoprineIsradipine DynaCircItroconazole Sporanox

K

Kanamycin Anamid, Kantrex, KlebcilKaolin + Pectin (= attapulgite) Kaopectate, Donnagel-MB, PectokayKetamine KetalarKetoconazol NizoralKetorolac Acular, ToradolKetotifen Zaditen

L

Labetalol Normodyne, TrandateLactulose Cephulac, Chronulac, DuphalacLamivudine (3TC) EpivirLamotrigine LamictalLansoprazole PrevacidLeflunomide AravaLepirudin RefludanLeuprorelide LupronLevodopa Larodopa, Dopar, DopaidanLevodopa + Benserazide Madopar, ProlopaLevodopa + Carbidopa SinemetLevomepromazine Levoprome, NozinanLidocaine Dalcaine, Lidopen, Nulicaine, Xylocain, XylocardLincomycin Albiotic, Cillimycin, LincocinLindane Hexit, Kwell, Kildane, ScabeneLiothyronine Cytomel, TriostatLisinopril Prinivil, ZestrilLispro insulin HumalogLisuride Cuvalit, Dopergin, Eunal, LysenylLithium carbonate Carbolite, Duoralith, EskalithLithium carbonate Lithane, Lithobid, LithotabsLomustine CeeNuLoperamide Imodium, Kaopectate IILoratidine ClaritinLorazepam Alzapam, Ativan, LorazLorcainide Lopantrol, Lorivox, RemivoxLormetazepam Ergocalm, Loramet, NoctamidLosartan CozaarLovastatin Mevacor, MevinacorLypressin Diapid, Vasopressin Sandoz

M

Mannitol Isotol, OsmitrolMaprotiline LudiomilMazindol Mazonor, SanorexMebendazole VermoxMechlorethamine Mustargen



Meclizine (meclozine) Antivert, Antrizine, Bonamine, WhevertMeclofenamate MeclomenMedroxyprogesterone-acetate Amen, Depo-Provera, OragestMefloquine LariamMelphalan AlkeranMenadione SynkayvitMeperidine DemerolMepindolol Betagon, Caridian, CorindolanMepivacaine Carbocaine, Isocaine6-Mercaptopurine PurinetholMesalamine (Mesalazine) Asacol, Pentasa, RowasaMesna Mesnex, UromitexanMesterolone Androviron, ProvironMestranol Menophase, Norquen, OvastolMetamizol (= Dipyrone) Algocalmin, Bonpyrin, Divarine, Feverall, Metilon, No-

valgin, Paralgin, SulpyrinMetaproterenol Alupent, MetaprelMetformin Diabex, GlucophageMethadone Dolophine, Methadose, PhysoseptoneMethamphetamine Desoxyn, MethampexMethimazole TapazoleMethohexital BrevitalMethotrexate Folex, MexateMethoxyflurane Penthrane, MethofaneMethyl-Dopa Aldomet, Amodopa, Dopamet, Novomedopa, Presinol,

SembrinaMethylcellulose Celevac, Cellothyl, Citrucel, Cologel, Lacril, MurocelMethylergometrine (Methylergonovine) Methergine, Metenarin, Methylergobrevin, Ryegono-

vin, Partergin, Spametrin-MMethylphenidate RitalinMethylprylon NoludarMethyltestosterone Android, Metandren, Testred, VirilonMethysergide SansertMetipranolol OptipranololMetoclopramide Clopra, Emex, Maxeran, Maxolan, Reclomide, ReglanMetoprolol Betaloc, LopressorMetronidazole Clont, Femazole, Flagyl, Metronid, Protostat, SatricMexiletin MexitilMezlocillin MezlinMianserin Bolvidon, NorvalMibefradil PosicorMiconazole Micatin, MonistatMidazolam VersedMifepristone RU 486Milrinone PrimacorMinocycline Minocin, VectrinMinoxidil Loniten, RogaineMisoprostol CytotecMithramycin MithracinMitoxantrone NovantroneMivacurium MiracronMoclobemide AurorixMolsidomine Corvaton, Duracoron, Molsidolat


Montelukast SingulairMorphine hydrochloride MorphitecMorphine sulfate Astramorph, Duramorph, Epimorph, Roxanol, StatexMuromonab-CD3 Orthoclone OKT3Mycophenolate Mofetil CellCept

N

Nabilone CesametNadolol CorgardNaftifin NaftinNalbuphine NubainNalidixic acid Negram, NogramNaloxone NarcanNaltrexone Nalorex, Revia, TrexanNandrolone Anabolin, Androlone, Deca-Durabolin, Hybolin Decano-

ate, KabolinNaphazoline Albalon, Degest-2, Privine, VasoconNaproxen Aleve, Naprosyn, NaxenNarcotine (= Noscapine) Coscopin, CoscotabNadroparin* FraxiparineNedocromil TiladeNelfinavir ViraceptNeomycin Mycifradin, MyciguentNeostigmine ProstigminNetilmicin NetromycinNevirapine ViramuneNicardipine CardeneNiclosamide Niclocide, YomesanNifedipine Adalat, ProcardiaNimodipine NimotopNisoldipine SularNitrazepam Atempol, MogadonNitrendipine Bayotensin, BaypressNitroglycerin See Glyceryl trinitrateNitroprusside sodium Nipride, NitropressNizatidine AxidNor-Diazepam Tranxilium N, VegesanNoradrenalin (= Norepinephrine) Arterenol, LevophedNorethisterone Micronor= Norethindrone Norlutin, Nor-Q DNorfloxacin NoroxinNoscapine (= Narcotine) Coscopin, CoscotabNortriptyline PamelorNystatin Korostatin, Mycostatin, Mykinac, Nilstat, Nystex, O-V

Statin

O

Octreotide SandostatinOfloxacin TarividOlanzapine ZyprexaOmeprazole Losec, Prilosec




Ondansetron ZofranOpium Tincture (laudanum) ParegoricOrciprenaline (= Metaproterenol) AlupentOrnipressin POR 8Oxacillin Bactocill, ProstaphlinOxatomide TinsetOxazepam Oxpam, Serax, ZapexOxiconazole OxistatOxprenolol TrasicorOxymetazoline Afrin, Allerest, Coricidin, Dristan, Neo-Synephrine,

SinarestOxytocin Pitocin, Syntocinon

P

Paclitaxel TaxolPamidronate AminomuxPancuronium PavulonPantoprazole* PantolacPapaverine Cerebid, Cerespan, Delapav, Myobid, Papacon, Pavabid,

Pavadur, VasalParacetamol = acetaminophen Acephen, Anacin-3, Bromo-Seltzer, Datril, Tempra,

Tylenol, Valadol, ValorinParomomycin HumatinParoxetine PaxilPenbutolol LevatolPenciclovir DenavirD-Penicillamine Cuprimine, DepenPenicillin G Bicillin, Cryspen, Deltapen, Lanacillin, Megacillin, Par-

cillin, Pensorb, Pentids, Permapen, PfizerpinPencillin V Betapen-VK, Bopen-VK, Cocillin-VK, Lanacillin-VK, Le-

dercillin VK, Nadopen-V, Novopen-VK, Penapar VK,Penbec-V, Pen-Vee K, Pfizerpen VK, Robicillin-VK, Uti-cillin-VK, V-Cillin K, Veetids

Pentazocine Fortral, TalwinPentobarbital Butylone, Nembutal, Novarectal, PentancaPentoxifylline TrentalPergolide PermaxPerindopril CoversumPermethrin Elimite, Nix, PermanonePethidine = Meperidine Demerol, DolantinPhencyclidine SernylPheniramine Daneral, InhistonPhenobarbital Barbita, Gardenal, SolfotonPhenolphthalein Alophen, Correctol, Espotabs, Evac-U-gen, Evac-U-Lax,

Ex-Lax, Modane, PruletPhenoxybenzamine DibenzylinePhenprocoumon Liquamar, MarcumarPhentolamine Regitin, RogitinPhenylbutazone Algoverine, Azolid, Butagen, Butazolidin, MalgesicPhenytoin DilantinPhysostigmine AntiliriumPhytomenadione Konakion


Pilocarpine Akarpine, Almocarpine, I-Pilopine, Miocarpine, Isopto-Carpine, Pilokair

Pindolol ViskenPiperacillin PipracilPipecuronium ArduanPirenzepine GastrozepinPiroxicam FeldenPizotifen = Pizotyline Litec, Mosegor, SandomigranPlicamycin MithracinPolidocanol ThesitPranlukast* UltairPravastatin PravacholPrazepam CentraxPraziquantel BiltricidePrazosin MinipressPrednisolone Articulose, Codelsol, Cortalone, Delta-Cortef, Deltastab,

Econopred, Hydeltrasol, Inflamase, Key-Pred, Metalone,Metreton, Pediapred, Predate, Predcor, Prelone

Prednisone Meticorten, Orasone, Panasol, WinpredPrilocaine Citanest, XylonestPrimaquine PrimaquinePrimidone Myidone, Mysoline, SertanProbenecid Benemid, ProbalanProbucol LovelcoProcaine NovocaineProcainamide Procan SR, Promine, Pronestyl, RhythminProcarbazine NatulanProcyclidine KemadrinProgabide Gabren(e)Progesterone Femotrone, ProgestasertPromethazine Anergan, Ganphen, Mallergan, Pentazine, Phenazine,

Phenergan, Prometh, Prorex, Provigan, RemsedPropafenone RhythmolPropofol DiprivanPropranolol Detensol, InderalPropylthiouracil Propyl-ThyracilPyrantel Pamoate AntiminthPyrazinamide Aldinamide, TebrazidPyridostigmine Mestinon, RegonolPyridoxine Bee-six, Hexa-Betalin, PyroxinePyrimethamine DaraprimPyrimethamine + Sulfadoxine Fansidar

Q

Quazepam DoralQuinacrine AtabrineQuinapril AccuprilQuinidine Cardioqin, Cin-Quin, Quinalan, Quinidex, QuinoraQuinine Quinaminoph, Quinamm, Quine, Quinite




R

Raloxifene EvistaRamipril AltaceRanitidine ZantacRemifentanil UltivaRepaglinide Actulin, NovoNorm, PrandinReserpine Sandril, Serpalan, Serpasil, ZepineRibavirin Virazole, RebetolRifabutin MycobutinRifampin Rifadin, RimactanRitodrine YutoparRitonavir NorvirRocuronium ZemuronRolitetracyclin Reverin, Transcycline, VelacyclineRopinirole* ReQuipRoxithromycin Rulid

S

Salazosulfapyridine = sulfasalazine Azaline, Azulfidine, S.A.S.-500, SalazopyrinSalbutamol (= Albuterol) Proventil, Novosalmol, VentolinSalicylic acid Acnex, Sebcur, Soluver, Trans-Ver-SalSameterol SereventSaquinavir Fortovase, InviraseScopolamine Transderm Scop, TriptoneSelegeline Carbex, Deprenyl, EldeprylSenna Black Draught, Fletcher’s Castoria, Genna, Gentle

Nature, Nytilax, Senokot, SenolaxSertindole* SerlectSibutramine ReductilSildenafil ViagraSimethicone Gas.X, Mylicon, Phazyme, SilainSimvastatin ZocorSitosterol Sito-LandeSotalol SotacorSpectinomycin TrobicinSpiramicin Rovamycin, SelectomycinSpironolactone AldactoneStavudine (d4T) ZeritStreptokinase Kabikinase, StreptaseStreptomycin Strepolin, StreptosolStreptozocin ZanosarSuccinylcholine Anectine, Quelicin, SuccostrinSucralfate Carafate, SulcrateSufentanil SufentaSulfacetamide AK-Sulf Forte, Cetamide, Sulamyd, Sulair, Sulfex, SultenSulfacytine RenoquidSulfadiazine MicrosulfonSulfadoxine + Pyrimethamine ProklarSulfamethoxazole Gamazole, Gantanol, MethanoxanolSulfapyridine DagenanSulfisoxazole Gantrisin, Gulfasin


Sulfasalazine Azaline, Azulfidine, SalazopyrinSulfinpyrazone Anturan, AprazoneSulprostone NaladorSulthiame OspolotSumatriptan Imitrex

T

t-PA (= alteplase) ActivaseTacrine CognexTacrolimus PrografTamoxifen Nolvadex, TamofenTemazepam Euhypnos, RestorilTeniposide VumonTerazosin HytrinTerbutalin Brethine, BricanylTerfenadine SeldaneTestosterone cypionate Androcyp, Andronate, Duratest, TestojectTestosterone enantate Andro, Delatestryl, Everone, TestoneTestosterone propionate TestexTesterone undecanoate AndriolTetracaine Anethaine, PontocaineTetryzoline (= tetrahydrozoline) Collyrium, Murine, Tyzine, VisineThalidomide Contergan, SynovirTheophylline Aerolate, Bronkodyl, Constant-T, Elixophyllin, Quibron-

T, Slo-bid, Somophyllin-T, Sustaire, Theolair, UniphylThiabendazole MintezolThiamazole (= Methimazole) Tapazole, MercazolThiopental Pentothal, TrapanalThio-TEPA Thiotepa LederleThrombin Thrombinar, ThrombostatThyroxine CholoxinTiagabine GabitrilTicarcillin TicarTiclopidine TiclidTimolol Blocadren, TimopticTinidazol Fasigyn(CH), Simplotan, SorquetanTinzaparin* InnohepTirofiban AggrastatTizanidine ZanaflexTobramycin Nebcin, TobrexTocainide TonocardTolbutamide Mobenol, Oramide, OrinaseTolcapone TasmarTolmetin TolectinTolnaftate Pitrex, TinactinTolonium chloride Klot, ToazulTolterodine tartrate DetrolTopiramate TopamexTramadol TramalTrandolapril MavikTranexamic acid CyklocapronTranylcypromine Parnate




Trazodone Desyrel, TrialodineTriamcinolone Aristocort, Azmacort, Kenacort, Ledercort(CH), VolonTriamcinolone acetonide Adicort, Azmacort, Kenalog, Kenalone, Triam-ATriamterene DyreniumTriazolam HalcionTrichlormethiazide Metahydrin, Naqua, TrichlorexTrifluoperazine StelazineTrifluridine ViropticTrihexipheidyl Aparkane, Artane, Tremin, TrihexaneTriiodothyronine (= Liothyronine) CytomelTrimethaphan ArfonadTrimethoprim Proloprim, TrimpexTriptorelin DecapeptylTroglitazone RezulinTropicamide Mydriacyl, MydralTropisetron Navoband-Tubocurarine TubarineTyrothricin Hydrotricin

U

Urokinase Abbokinase, UkidanUrsodeoxycholic acid = ursodiol Actigall, Destolit, Ursofalk

V

Valacyclovir ValtrexValproic Acid DepakeneValsartan DiovanVancomycin Vancocin, Vancomycin CP LillyVasopressin PitressinVecuronium NorcuronVenlafaxine EffexorVerapamil Calan, Isoptin, VerelanVidarabine Vira-AVigabatrin* SabrilVinblastine Velban, VelbeVincamine CerebroxineVincristine OncovinViomycine Celiomycin,Vinactane, Viocin, VionactaneVit. B12 Bay-Bee, Berubigen, Betalin 12, Cabadon, Cobex,

Cyanoject, Cyomin, Pemavit, Redisol, Rubesol, Sytobex,Vibal

Vit. B6 Bee Six, Hexa-Betalin, PyroxineVit. D Calciferol, Drisdol

W

Warfarin Coumadin, Panwarfin, Sofarin


X

Xanthinol nicotinate ComplaminXylometazoline Chlorohist, Neosynephrine II, Sinutab, Sustaine

Z

Zafirlukast AccolateZalcitabine HividZidovudine RetrovirZileuton ZyfloZolpidem AmbienZopiclone Amoban, Amovane, Imovane, Zimovane

350 Drug Name → Trade NameDrug Name → Trade Name 350



A

Abbokinase UrokinaseAcantex CeftriaxoneAccolate ZafirlukastAccupril QuinaprilAcediur CaptoprilAcephen Paracetamol = acetami-

nophenAcepril CaptoprilAcnex Salicylic acidActhar ACTHActhar CorticotropinActi-B 12 HydroxocobalaminActigall Ursodeoxycholic acid =

ursodiolActimmune Interferon-γActiprophen IbuprofenActivase t-PA (= alteplase)Actulin RepaglinideAcular KetorolacAcutane Roche IsotretinoinAcylanid AcetyldigoxinAdalat NifedipineAdapin DoxepinAdicort Triamcinolone aceto-

nideAdrenalin EpinephrineAdriamycin DoxorubicinAdriblastin DoxorubicinAdrucil 5-FluorouracilAdvil IbuprofenAerobid FlunisolideAerolate TheophyllineAfibrin ε-Aminocaproic acidAfrin OxymetazolineAggrastat TirofibanAirbron AcetylcysteineAkarpine PilocarpineAkineton BiperidenAkinophyl BiperidenAK-Sulf Forte SulfacetamideAlazine HydralazineAlbalon NaphazolineAlbego Camazepam

Albiotic LincomycinAlcoban FlucytosineAldactone SpironolactoneAldecin BeclomethasoneAldinamide PyrazinamideAldocorten AldosteroneAldomet Methyl-DopaAldrox Aluminium hydroxideAlfenta AlfentanilAlflorone FludrocortisoneAlfoten AlfuzosinAlgocalmin Metamizol (= Dipyrone)Algocor GallopamilAlgoverine PhenylbutazoneAlkeran MelphalanAllerdryl DiphenhydramineAllerest OxymetazolineAlloferin AlcuroniumAlloprin AllopurinolAllvoran DiclofenacAlmocarpine PilocarpineAlocort Cortisol (Hydrocortiso-

ne)Alophen PhenolphthaleinAlopresin CaptoprilAlpha-redisol HydroxocobalaminAltace RamiprilAltracin BacitracinAlu-Tab Aluminium hydroxideAludrin Isoprenaline (= Isopro-

terenol)Alupent MetaproterenolAlzapam LorazepamAmaryl GlimepirideAmbien ZolpidemAmbril AmbroxolAmcill AmpicillinAmen Medroxyprogesterone-

acetateAmericaine BenzocaineAmicar e-Aminocaproic acidAmidate EtomidateAmidonal AprindineAmikin AmikacinAminomux Pamidronate

Drug Name Trade Name Drug Name Trade Name


Amitril AmitriptylineAmmuno IndomethacinAmoban ZopicloneAmodopa Methyl-DopaAmovane ZopicloneAmoxil AmoxicillinAmphojel Aluminium hydroxideAmphozone Amphotericin BAmycor BifonazoleAnabactyl(A) CarbenicillinAnabolin NandroloneAnacaine BenzocaineAnacin-3 Paracetamol = acetami-

nophenAnacobin CyanocobalaminAnaesthesin BenzocaineAnamid KanamycinAnarexol CyproheptadineAncef CefazolinAncotil FlucytosineAndriol Testerone undecanoateAndro Testosterone enantateAndrocur Cyproterone-acetateAndrocyp Testosterone cypionateAndroid MethyltestosteroneAndrolone NandroloneAndronate Testosterone cypionateAndroviron MesteroloneAnectine SuccinylcholineAnergan PromethazineAnethaine TetracaineAnexate FlumazenilAng-O-Span Glyceryltrinitrate (=

nitroglycerin)Angionorm DihydroergotamineAntilirium PhysostigmineAntiminth Pyrantel PamoateAntivert Meclizine (meclozine)Antrizine Meclizine (meclozine)Anturan SulfinpyrazoneAnzemet DolasetronAparkane TrihexiphenidylApaurin DiazepamApocretin EtilefrineAprazone SulfinpyrazoneApresoline HydralazineAprobal AlprenololAprozide HydrochlorothiazideAptine AlprenololAralen ChloroquineArava LeflunomideArduan PipecuroniumArfonad Trimethaphan

Aristocort TriamcinoloneArm-a-Med IsoetharineArmazid IsoniazidArtane TrihexiphenidylArteoptic CarteololArterenol Noradrenalin (= Nore-

pinephrine)Arthrisin Acetylsalicylic acidArticulose PrednisoloneArumil AmilorideArvin AncrodArwin AncrodAsacol MesalamineAsadrine Acetylsalicylic acidAspenon AprindineAspirin Acetylsalicylic acidAstramorph Moiphine sulfateAtabrine QuinacrineAtacand CandesartanAtempol NitrazepamAtensine DiazepamAtivan LorazepamAtromid-S ClofibrateAtropisol AtropineAtrovent IpratropiumAugmentin Clavulanic Acid + Amo-

xicillinAureotan AurothioglucoseAuromyose AurothioglucoseAurorix MoclobemideAuxit BromhexineAvapro IrbesartanAvicel CelluloseAvloclor ChloroquineAvlosulfone DapsoneAxid NizatidineAzactam AztreonamAzaline Salazosulfapyridine =

sulfasalazineAzanin AzathioprineAzlin AzlocillinAzmacort TriamcinoloneAzmacort Triamcinolone aceto-

nideAzolid PhenylbutazoneAzulfidine Salazosulfapyridine =

sulfasalazineAzulfdine Sulfasalazine

B

Baciguent BacitracinBactidan Enoxacin




Bactocill OxacillinBactrim CotrimoxazoleBarbita PhenobarbitalBaxedin ChlorhexidineBay-Bee Vit. B12Baycol CerivastatinBayotensin NitrendipineBaypress NitrendipineBeclovent BeclomethasoneBeconase BeclomethasoneBecotide BeclomethasoneBedoz CyanocobalamineBedriol BifonazoleBee Six Vit. B6 PyridoxineBefizal BezafbrateBenadryl DiphenhydramineBenemid ProbenecidBerofor alpha 2 Interferon-a2Berotec FenoterolBerubigen Vit. B12Bestcall CefmenoximeBetadran BupranololBetadrenol BupranololBetagon MepindololBetalin 12 Vit. B12Betaloc MetoprololBetapen-VK Pencillin VBetoptic BetaxololBextra Bucindolol*Bezalip BezafibrateBezatol BezafibrateBiaxin ClarithromycinBicillin Benzathine-Penicillin GBicol BisacodylBiltricide PraziquantelBiogastrone CarbenoxoloneBioplex CarbenoxoloneBisolvon BromhexineBisorine IsoetharineBlack Draught SennaBlenoxane BleomycinBlocadren TimololBofedrol EphedrineBolvidon MianserinBonamine Meclizine (meclozine)Bonpyrin Metamizol (= Dipyrone)Bopen-VK Pencillin VBorotropin AtropineBrethine TerbutalinBrevibloc EsmololBrevital MethohexitalBricanyl TerbutalinBriclin Amikacin

Bromo-Seltzer Paracetamol = acetami-nophen

Bronalide FlunisolideBronchaid EpinephrineBronchopront AmbroxolBronkodyl TheophyllineBronkosol IsoetharineBroxalax BisacodylBumex BumetanideBunitrolol BumetanideBuprene BuprenorphineBurinex BumetanideBuscopan N-Butyl-scopolamineBuspar BuspironeButagen PhenylbutazoneButazolidin PhenylbutazoneButylone Pentobarbital

C

C-Pak DoxycyclineCabadon Vit. B12Calan VerapamilCalciferol Vit.DCalcimer CalcitoninCalcimux EtidronateCalderol CalcifediolCalsan Calcium carbonateCalsynar CalcitoninCaltidren CarteololCaltrate Calcium carbonateCamoquin AmodiaquineCanesten ClotrimazoleCapastat CapreomycinCapoten CaptoprilCapramol ε-Aminocaproic acidCaprolin CapreomycinCarafate SucralfateCarbex SelegelineCarbocaine MepivacaineCarbolite Lithium carbonateCardene NicardipineCardioqin QuinidineCardiorhythmino AjmalineCardizem DiltiazemCardura DoxazosinCarduran DoxazosinCaridian MepindololCarindapen CarbenicillinCarteol CarteololCatapres ClonidineCedocard Isosorbide dinitrateCedur Bezafibrate


CeeNu LomustineCefmax CefmenoximeCefobis CefmenoximeCefoperazone CefmenoximeCeftin Cefuroxime axetilCelevac MethylcelluloseCeliomycin ViomycineCellCept Mycophenolate MofetilCellothyl MethylcelluloseCemix CefmenoximeCentrax PrazepamCepexin(A) CephalexinCephulac LactuloseCeporex CephalexinCerebid PapaverineCerebroxine VincamineCerespan PapaverineCerubidine DaunorubicinCesamet NabiloneCesplon CaptoprilCetamide SulfacetamideChenix Chenodeoxycholic acidChlor-hex ChlorhexidineChloraminophene ChlorambucilChlorohist XylometazolineChloromycetin ChloramphenicolChloroptic ChloramphenicolCholestabyl ColestipolCholestid ColestipolCholoxin ThyroxineChorex HCG (= chorionic gona-

dotropin)Choron HCG (= chorionic gona-

dotropin)Chronulac LactuloseCibacalcin CalcitoninCidomycin GentamicinCillimycin LincomycinCimetrin Erythromycin-propio-

nateCin-Quin QuinidineCipro CiprofloxacinCiprobay CiprofloxacinCircupon EtilefrineCitanest PrilocaineCitrucel MethylcelluloseClaforan CefotaximeClamoxyl AmoxicillinClaripex ClofibrateClaritin LoratidineClasteon Clodronate*Cleocin ClindamycinClobazam Clindamycin

Clomid ClomipheneClonopin ClonazepamClont MetronidazoleClopra MetoclopramideClotrimaderm ClotrimazoleCloxacillin ClotrimazoleClozan ClotiazepamClozaril ClozapineCobex Vit. B12Cocillin-VK Pencillin VCodelsol PrednisoloneCodicept CodeineCogentin BenztropineCognex TacrineColeb 5-Isosorbide mono-

nitrateColectril AmilorideCollyrium Tetryzoline (= tetrahy-

drozoline)Cologel MethylcelluloseComplamin Xanthinol nicotinateComprecin EnoxacinComtan Entacapone*Concor BisoprololConducton CarazololConstant-T TheophyllineContergan ThalidomideCoradus Isosorbide dinitrateCordarex AmiodaroneCordarone AmiodaroneCoreg CarvedilolCorgal GallopamilCorgard NadololCoricidin OxymetazolineCorindblan MepindololCorlopam FenoldopamCoronex Isosorbide dinitrateCorrectol PhenolphthaleinCortalone PrednisoloneCortate Cortisol (Hydrocortiso-

ne)Cortef Cortisol (Hydrocortiso-

ne)Cortelan CortisoneCortenema Cortisol (Hydrocortiso-

ne)Cortigel CorticotropinCortogen CortisoneCortone CortisoneCortrophin CorticotropinCorvaton MolsidomineCoscopin Noscapine (= Narcoti-

ne)




Coscotab Narcotine (= Noscapi-ne)

Coscotab Noscapine (= Narcoti-ne)

Cosmegen Actinomycin DCoumadin WarfarinCoversum PerindoprilCozaar LosartanCrixivan IndinavirCryspen Penicillin GCrystodigin DigitoxinCuemid ColestyramineCuprimine D-PenicillamineCutivate FluticasoneCuvalit LisurideCyanoject Vit. B 12Cyklocapron Tranexamic acidCyomin Vit. B 12Cystospaz-M Hyoscyamine sulfateCytomel Triiodothyronine (=

Liothyronine)Cytosar CytarabineCytotec MisoprostolCytovene GanciclovirCytoxan Cyclophosphamide

D

D-Tabs CholecalciferolD.E.H.45 DihydroergotamineDDAVP DesmopressinDagenan SulfapyridineDalacin ClindamycinDalcaine LidocaineDalmane FlurazepamDaneral PheniramineDantrium DantroleneDaonil Glibenclamide (= gly-

buride)Daraprim PyrimethamineDatril Paracetamol = acetami-

nophenDaunoblastin DaunorubicinDeca-Durabolin NandroloneDecadron DexamethasoneDecapeptyl TriptorelinDecapryn DoxylamineDedrogyl CalcifediolDegest-2 NaphazolineDelapav PapaverineDelatestryl Testosterone enantateDelestrogen Estradiol-valerateDelta-Cortef Prednisolone

Deltapen Penicillin GDeltastab PrednisoloneduisolmeDemerol MeperidineDemerol Pethidine = MeperidineDenavir PenciclovirDendrid IdoxuridineDepakene Valproic AcidDepen D-PenicillamineDepixol FlupentixolDepo-Provera Medroxyprogesterone-

acetateDeprenyl SelegelineDeronil DexamethasoneDesferal DeferoxamineDesoxyn MethamphetamineDestolit Ursodeoxycholic acid =

ursodiolDesuric BenzbromaroneDesyrel TrazodoneDetensiel BisoprololDetensol PropranololDetrol Tolteridine tartrateDexedrine d-AmphetamineDey-Lute IsoetharineDiaBeta Glibenclamide (= gly-

buride)Diabex MetforminDiamox AcetazolamideDiapid LypressinDiaqua HydrochlorothiazideDiarsed DiphenoxylateDiastat DiazepamDibenzyline PhenoxybenzamineDiclocil DicloxacillinDiclophlogont DiclofenacDiflucan FluconazoleDigacin DigoxinDigibind Digoxin immune FABDigicor DigitoxinDigimerck DigitoxinDigitaline DigitoxinDihydergot DihydroergotamineDihyzin DihydralazineDilantin PhenytoinDilaudid HydromorphoneDimetab DimenhydrinateDinaplex FlunarizineDiodronel EtidronateDioval Estradiol-valerateDiovan ValsartanDiphenasone DapsoneDiphos EtidronateDiprivan Propofol


Distraneurin ClomethiazoleDiuchlor HydrochlorothiazideDivarine Metamizol (= Dipyrone)Divegal DihydroergotamineDixarit ClonidineDizac DiazepamDobutrex DobutamineDolantin Pethidine = MeperidineDolophine MethadoneDonnagel-MB Kaolin + Pectin (= atta-

pulgite)Dopaidan LevodopaDopamet Methyl-DopaDopar LevodopaDopastat DopamineDopergin LisurideDoral QuazepamDoryl CarbacholDowmycin Erythromycin-estolateDoxicin DoxycyclineDoxylamine DoxycyclineDramamine DimenhydrinateDrisdol Ergocalciferol Vit. DDristan OxymetazolineDrogenil FlutamideDroleptan DroperidolDulcolax BisacodylDuoralith Lithium carbonateDuphalac LactuloseDuracoron MolsidomineDuralutin Hydroxyprogesterone

caproateDuramorph Morphine sulfateDuranest EtidocaineDuratest Testosterone cypionateDurazanil BromazepamDurolax BisacodylDymenate DimenhydrinateDynaCirc IsradipineDynapen DicloxacillinDynaprin ImipramineDyneric ClomipheneDyrenium Triamterene

E

Econopred PrednisoloneEnbrel EtanerceptE-mycin ErythomcyinEcostatin EconazoleEcotrin Acetylsalicylic acidEdecrin Ethacrynic acidEfedron Ephedrine

Effectin BitolterolEffexor VenlafaxineEffontil EtilefrineEffortil EtilefrineEffudex 5-FluorouracilEffurix 5-FluorouracilElantan 5-Isosorbide mono-

nitrateElavil AmitriptylineEldepryl SelegelineElimite PermethrinElixophyllin TheophyllineEmcor BisoprololEmex MetoclopramideEndak CarteololEndep AmitriptylineEndophleban DihydroergotamineEndoxan CyclophosphamideEnoram EnoxacinEnovil AmitriptylineEntromone HCG (= chorionic gona-

dotropin)Entrophen Acetylsalicylic acidEpiPen EpinephrineEpifin EpinephrineEpimorph Morphine sulfateEpinal EpinephrineEpitol CarbamazepineEpitrate EpinephrineEpivir Lamivudine (3TC)Epogen Erythropoietin (= epoe-

tin alfa)Eporal DapsoneErgocalm LormetazepamErgomar ErgotamineErgotrate ErgonovineErgotrate Maleate Ergometrine (= Ergono-

vine)Eridan DiazepamErmalate Ergometrine (= Ergono-

vine)Eryc ErythromcyinErymycin Erythromycin-stearateErythrocin Erythromycin-estolateErythromid ErythomcyinEsidrex HydrochlorothiazideEskalith Lithium carbonateEspotabs PhenolphthaleinEstinyl EthinylestradiolEstrace EstradiolEthrane EnfluraneEthyl Adrianol EtilefrineEtibi Ethambutol




Euciton Domperidone*Eudemine DiazoxideEuglucon Glibenclamide (= gly-

buride)Euhypnos TemazepamEulexin FlutamideEunal LisurideEvac-U-Lax PhenolphthaleinEvac-U-gen PhenolphthaleinEverone Testosterone enantateEvipal HexobarbitalEvista RaloxifeneEvoxin Domperidone*Ex-Lax Phenolphthalein

F

F-Cortef FludrocortisoneFabrol AcetylcysteineFactrel GonadorelinFansidar Pyrimethamine + Sulfa-

doxineFasigyn(CH) TinidazolFaverin FluvoxamineFelbatol FelbamateFelden PiroxicamFemazole MetronidazoleFeminone EthinylestradiolFemogex Estradiol-valerateFemotrone ProgesteroneFertodur CyclofenilFeverall Metamizol (= Dipyrone)Fiblaferon 3 Interferon-bFibocil AprindineFlagyl MetronidazoleFlavoquine AmodiaquineFlaxedil GallamineFletcher’s Castoria SennaFlixonase FluticasoneFlonase FluticasoneFlorinef FludrocortisoneFlovent FluticasoneFloxifral FluvoxamineFluagel Aluminium hydroxideFluanxol FlupentixolFluclox FlucloxacillinFlugeral FlunarizineFluothane HalothaneFoldine Folic acidFolex MethotrexateFollutein HCG (= chorionic gona-

dotropin)Folvite Folic acid

Fontego BumetanideForane IsofluraneFordiuran BumetanideFortaz CeftazidimeFortovase SaquinavirFortral PentazocineFortum CeftazidimeFosamax AlendronateFoscavir FoscarnetFragmin DalteparinFraxiparine Nadroparin*Frisium ClobazamFulvicin GriseofulvinFungilin Amphotericin BFungizone Amphotericin BFusid Furosemide

G

Gabitril TiagabineGabren(e) ProgabideGamazole SulfamethoxazoleGanal FenfluramineGanphen PromethazineGantanol SulfamethoxazoleGantrisin SulfisoxazoleGaramycin GentamicinGardenal PhenobarbitalGas. X SimethiconeGastrozepin PirenzepineGelafundin Gelatin-colloidsGenna SennaGentle Nature SennaGeopen CarbenicillinGestafortin Chlormadinone acetateGesterol L.A. Hydroxyprogesterone

caproateGilurytmal AjmalineGlaupax AcetazolamideGlucophage MetforminGlucotrol GlipizideGonic HCG (= chorionic gona-

dotropin)Gramoderm GramicidinGrisovin GriseofulvinGubernal AlprenololGulfasin SulfisoxazoleGumbix Aminomethylbenzoic

acidGyne-Lotrimin ClotrimazoleGynergen ErgotamineGyno-Pevaryl EconazoleGyno-Travogen Isoconazole


H

Haemaccel Gelatin-colloidsHalcion TriazolamHaldol HaloperidolHalfan HalofantrineHemineurin ClomethiazoleHepalean HCG (= chorionic gona-

dotropin)Heparin HCG (= chorionic gona-

dotropin)Herplex IdoxuridineHespan Hetastarch Hydroxy-

ethyl starch (HES)Hexa-Betalin Pyridoxine Vit. B6Hexadrol DexamethasoneHexit ChlorhexidineHidroferol CalcifediolHismanal AstemizoleHivid ZalcitabineHonvol DiethylstilbestrolHumalog InsulinHumatin ParomomycinHumulin InsulinHybolin Decanoate

NandroloneHydeltrasol PrednisoloneHyderm Cortisol (Hydrocortiso-

ne)Hydromal HydrochlorothiazideHydromedin Ethacrynic acidHydrotricin TyrothricinHygroton ChlorthalidoneHylutin Hydroxyprogesterone

caproateHymorphan HydromorphoneHyocort Cortisol (Hydrocortiso-

ne)Hyoscin-N-Butyl-bromid N-Butyl-scopolamineHyperstat DiazoxideHypertensin Angiotensin IIHypertil CaptoprilHypnosedon Flunitrazepam*Hyroxon Hydroxyprogesterone

caproateHyskon DextranHytrin Terazosin

I

I-Pilopine PilocarpineIfex Ifosfamide

Ifosfamide IdoxuridineIktorivil ClonazepamIletin InsulinIlosone Erythromycin-estolateImitrex SumatriptanImodium LoperamideImovane ZopicloneImpril ImipramineImuran AzathioprineImurek AzathioprineInapsine DroperidolInderal PropranololIndocid IndomethacinIndocin IndomethacinIndome IndomethacinInflamase PrednisolonechnisoloveInhibace CilazaprilInhiston PheniramineInnohep Tinzaparin*Innovar Fentanyl + DroperidolInocor AmrinoneInsommal DiphenhydramineIntal CromoglycateIntegriline EptifibatideIntron A Interferon-a2bIntropin DopamineInvirase SaquinavirIsicom Carbidopa + LevodopaIsmelin GuanethidineIsmo 5-Isosorbide mono-

nitrateIsocaine MepivacaineIsoptin VerapamilIsopto-Carpine PilocarpineIsordil Isosorbide dinitrateIsotamine IsoniazidIsoten BisoprololIsotol MannitolIsuprel Isoprenaline (= Isopro-

terenol)Itrop Ipratropium

J

Janimine Imipramine

K

Kabikinase StreptokinaseKabolin NandroloneKanrenol CanrenoneKantrex Kanamycin




Kaopectate Kaolin + Pectin (= atta-pulgite)

Kaopectate II LoperamideKaril CalcitoninKeflex CefalexinKeflex CephalexinKeftab CefalexinKemadrin ProcyclidineKenacort TriamcinoloneKenalog Triamcinolone aceto-

nideKenalone Triamcinolone aceto-

nideKerecid IdoxuridineKerlone BetaxololKertasin EtilefrineKetalar KetamineKetzol CefazolinKey-Pred PrednisoloneKildane LindaneKlebcil KanamycinKlot Tolonium chlorideKonakion PhytomenadioneKorostatin NystatinKryptocur GonadorelinKwell LindaneKytril Granisetron

L

Lacril MethylcelluloseLamiazid IsoniazidLamictal LamotrigineLampren ClofazimineLanacillin Penicillin GLanacillin-VK Penicillin VLanicor DigoxinLanoxin DigoxinLargactil ChlorpromazineLariam MefloquineLarodopa LevodopaLasix FurosemideLaxanin BisacodylLaxbene BisacodylLectopam BromazepamLedercillin VK Pencillin VLedercort(CH) TriamcinoloneLembrol DiazepamLendorm(A) BrotizolamLendormin BrotizolamLenoxin DigoxinLentin Carbachol

Lescol Noradrenalin (= Nore-pinephrine)

Levoprome LevomepromazineLevsin Hyoscyamine sulfateLexotan BromazepamLidopen LidocaineLikuden GriseofulvinLincocin LincomycinLindane HexachlorophaneLioresal BaclofenLipitor AtorvastatinLiquamar PhenprocoumonLiquemin HCG (= chorionic gona-

dotropin)Litec Pizotifen = PizotylineLithane Lithium carbonateLithobid Lithium carbonateLithotabs Lithium carbonateLodine EtodolacLomotil DiphenoxylateLoniten MinoxidilLooser BupranololLopantrol LorcainideLopid GemfibrozilLopirin CaptoprilLopressor MetoprololLoramet LormetazepamLoraz LorazepamLorinal ChloralhydrateLorivox LorcainideLosec OmeprazoleLosporal CephalexinLotensin BenazeprilLovelco ProbucolLovenox EnoxaparinLozide IndapamideLozol IndapamideLudiomil MaprotilineLupron LeuprorelideLuvox FluvoxamineLynoral EthinylestradiolLyophrin EpinephrineLysenyl Lisuride

M

Macrobin ClostebolMadopar Levodopa + Benserazi-

deMadopar (plus Levodopa)

BenserazideMalgesic PhenylbutazoneMallergan Promethazine


Marcumar PhenprocoumonMarinol DronabinolMarmine DimenhydrinateMarvelon Desogestrel + Ethinyle-

stradiolMavik TrandolaprilMaxeran MetoclopramideMaxolan MetoclopramideMazepine CarbamazepineMazonor MazindolMeclomen MeclofenamateMefoxin CefoxitinMegacillin Benzathine-Penicillin GMegaphen ChlorpromazineMelipramin ImipramineMenophase MestranolMercazol Thiamazole (= Methi-

mazole)Mesnex MesnaMestinon PyridostigmineMetacen IndomethacinMetahydrin TrichlormethiazideMetalone PrednisoloneMetandren MethyltestosteroneMetaprel MetaproterenolMetenarin MethylcelluloseMethadose MethadoneMethampex MethamphetamineMethanoxanol SulfamethoxazoleMethofane MethoxyfluraneMethylergobrevin MethylcelluloseMethylergometrine

MethylcelluloseMeticorten PrednisoneMetilon Metamizol (= Dipyrone)Metreton PrednisoloneMetronid MetronidazoleMevacor LovastatinMeval DiazepamMevaril AmitriptylineMevinacor LovastatinMexate MethotrexateMexitil MexiletinMezlin MezlocillinMicatin MiconazoleMicronase Glibenclamide (= gly-

buride)Micronor NorethisteroneMicrosulfon SulfadiazineMidamor AmilorideMielucin BusulfanMigril ErgotamineMinipress Prazosin

Minirin DesmopressinMinocin MinocyclineMinprog Alprostadil (= PGE1)Minprostin F2a DinoprostMintezol ThiabendazoleMiocarpine PilocarpineMiostat CarbacholMithracin Mithramycin, Plicamy-

cinMitosan BusulfanMobenol TolbutamideModane PhenolphthaleinModiten FluphenazineModuret Amiloride + Hydrochlo-

rothiazideMogadon NitrazepamMolsidolat MolsidomineMonistat MiconazoleMonitan AcebutololMonomycin Erythromycin-succina-

teMonopril FosinoprilMoronal Amphotericin BMorphitec Morphine hydrochlori-

deMosegor Pizotifen = PizotylineMotilium Domperidone*Motrin IbuprofenMoxacin AmoxicillinMucomyst AcetylcysteineMucosolvan AmbroxolMurine Tetryzoline (= tetrahy-

drozoline)Murocel MethylcelluloseMustargen MechlorethamineMutabase DiazoxideMyambutol EthambutolMycelex ClotrimazoleMycifradin NeomycinMyciguent NeomycinMycobutin RifabutinMycospor BifonazoleMycosporan BifonazoleMycostatin NystatinMydral TropicamideMydriacyl TropicamideMyidone PrimidoneMykinac NystatinMyleran BusulfanMylicon SimethiconeMyobid PapaverineMysoline Primidone




N

Nacom Carbidopa + LevodopaNadopen-V Pencillin VNaftin NaftifinNalador SulprostoneNalcrom CromoglycateNalfon FenoprofenNalgesic FenoprofenNalorex NaltrexoneNaprosyn NaproxenNaqua TrichlormethiazideNarcan NaloxoneNarcaricin BenzbromaroneNarcozep Flunitrazepam*Narkotan HalothaneNasalide FlunisolideNatrilix IndapamideNatulan ProcarbazineNautamine DiphenhydramineNauzelin Domperidone*Navidrix CyclopenthiazideNaxen NaproxenNebcin TobramycinNegram Nalidixic acidNembutal PentobarbitalNeo Epinin Isoprenaline (= Isopro-

terenol)Neo-Codema HydrochlorothiazideNeo-Mercazole CarbimazoleNeo-Synephrine OxymetazolineNeo-Thyreostat CarbimazoleNeogel CarbenoxoloneNeoral CyclosporineNeosynephrine II XylometazolineNepresol DihydralazineNetromycin NetilmicinNeurontin GabapentinNiclocide NiclosamideNigalax BisacodylNilstat NystatinNilurid AmilorideNimotop NimodipineNipride Nitroprusside sodiumNitrocap Glyceryltrinitrate (=

nitroglycerin)Nitrogard Glyceryltrinitrate (=

nitroglycerin)Nitroglyn Glyceryltrinitrate (=

nitroglycerin)Nitrolingual Glyceryltrinitrate (=

nitroglycerin)

Nitrong Glyceryltrinitrate (=nitroglycerin)

Nitropress Nitroprusside sodiumNitrostat Glyceryltrinitrate (=

nitroglycerin)Nix PermethrinNizoral KetoconazolNoan DiazepamNoctamid LormetazepamNoctec ChloralhydrateNogram Nalidixic acidNoludar MethylprylonNolvadex TamoxifenNor-Q D NorethindroneNorcuron VecuroniumNorlutin NorethindroneNormiflo ArdeparinNormodyne LabetalolNormurat BenzbromaroneNoroxin NorfloxacinNorpace DisopyramideNorpramin DesipramineNorquen MestranolNorval MianserinNorvir RitonavirNovalgin Metamizol (= Dipyrone)Novamin AmikacinNovamoxin AmoxicillinNovantrone MitoxantroneNovarectal PentobarbitalNovoNorm RepaglinideNovocaine ProcaineNovoclopate ClorazepateNovodigoxin DigoxinNovolin InsulinNovomedopa Methyl-DopaNovopen-VK Pencillin VNovopurol AllopurinolNovorythro Erythromycin-estolateNovosalmol Salbutamol (= Albute-

rol)Novotrimel CotrimoxazoleNozinan LevomepromazineNu-Cal Calcium carbonateNubain NalbuphineNulicaine LidocaineNuprin IbuprofenNuran CyproheptadineNuromax DoxacuriumNydrazid IsoniazidNystex NystatinNytilax Senna


O

O-V Statin NystatinOctapressin FelypressinOculinum Botulinum Toxin Type

AOcupress CarteololOmifin ClomipheneOmnipen Amphotericin BOncovin VincristineOndena DaunorubicinOndogyne CyclofenilOndonid CyclofenilOphthosol BromhexineOpticrom CromoglycateOptipranolol MetipranololOragest Medroxyprogesterone-

acetateOramide TolbutamideOrasone PrednisoneOretic HydrochlorothiazideOrgaran DanaparoidOrinase TolbutamideOrthoclone OKT3 Muromonab-CD3Osmitrol MannitolOspolot SulthiameOssiten Clodronate*Ostac Clodronate*Ovastol MestranolOxistat OxiconazoleOxpam Oxazepam

P

POR 8 OrnipressinPamba Aminomethylbenzoic

acidPamelor NortriptylinePanasol PrednisonePanimit BupranololPantolac Pantoprazole*Panwarfin WarfarinPapacon PapaverineParalgin Metamizol (= Dipyrone)Paraplatin CarboplatinParaxin ChloramphenicolParcillin Penicillin GParegoric Opium Tincture (lauda-

num)Parlodel BromocriptineParnate TranylcypromineParomomycin Paracetamol = acetami-

nophen

Parsitan EthopropazineParsitol EthopropazinePartergin MethylcellulosePartusisten FenoterolParvolex AcetylcysteinePathocil DicloxacillinPavabid PapaverinePavadur PapaverinePaveral CodeinePavulon PancuroniumPaxil ParoxetinePectokay Kaolin + Pectin (= atta-

pulgite)Pediapred PrednisolonePemavit Vit. B12Penapar VK Pencillin VPenbec-V Pencillin VPenbritin Amphotericin BPensorb Penicillin GPentanca PentobarbitalPentasa MesalaminePentazine PromethazinePenthrane MethoxyfluranePentids Penicillin GPentothal ThiopentalPepcid FamotidinePepdul FamotidinePepto-Bismol Bismuth subsalicylatePeptol CimetidinePergotime ClomiphenePeriactin CyproheptadinePeridon Domperidone*Peritol CyproheptadinePermanone PermethrinPermapen Penicillin GPermax PergolidePertofran DesipraminePetinimid EthosuximidePfizerpin Penicillin GPhazyme SimethiconePhenazine PromethazinePhenergan PromethazinePhospholine Iodide

EcothiopatePhysoseptone MethadonePilokair PilocarpinePipracil PiperacillinPitocin OxytocinPitressin ADH (= Vasopressin)Pitrex TolnaftatePlak-out ChlorhexidinePlaquenil HydroxychloroquinePlatinex Cisplatin




Platinol CisplatinPlavix ClopidogrelPlendil FelodipinePolycillin Amphotericin BPonderal FenfluraminePondimin FenfluraminePontocaine TetracainePosicor MibefradilPrandin RepaglinidePravachol PravastatinPravidel BromocriptinePredate PrednisolonePredcor PrednisolonePrecose AcarbosePregnesin HCG (= chorionic gona-

dotropin)Pregnyl HCG (= chorionic gona-

dotropin)Prelone PrednisolonePrenormine AtenololPrepidil DinoprostonePresinol Methyl-DopaPressunic DihydralazinePresyn ADH (= Vasopressin)Prevacid LansoprazolePrimacor MilrinonePrimaquine PrimaquinePrincipen Amphotericin BPrinivil LisinoprilPrivine NaphazolinePro-Depo Hydroxyprogesterone

caproateProbalan ProbenecidProcan SR ProcainamideProcardia NifedipineProcorum GallopamilProcytox CyclophosphamideProfasi HCG (= chorionic gona-

dotropin)Progestasert ProgesteroneProglicem DiazoxidePrograf TacrolimusProgynon B Estradiol-benzoateProgynova Estradiol-valerateProklar SulfamethizoleProlixan AzapropazoneProlixin FluphenazineProlopa Levodopa + Benserazi-

deProloprim TrimethoprimPrometh PromethazinePromine ProcainamidePronestyl Procainamide

Propasa 5-Aminosalicylic acidPropecia FinasteridePropulsid CisapridePropyl-Thyracil PropylthiouracilProrex PromethazineProscar FinasterideProstaphlin OxacillinProstarmon DinoprostProstigmin NeostigmineProstin E2 DinoprostoneProstin F2 DinoprostProstin VR Alprostadil (= PGE1)Protostat MetronidazoleProtrin Septra CotrimoxazoleProventil Salbutamol (= Albute-

rol)Provigan PromethazineProviron MesteroloneProzac FluoxetinePrulet PhenolphthaleinPulmicort BudesonidePulsamin EtilefrinePurinethol 6-MercaptopurinePurodigin DigitoxinPyopen CarbenicillinPyrilax BisacodylPyronoval Acetylsalicylic acidPyroxine Pyridoxine, Vit. B6

Q

Quelicin SuccinylcholineQuestran ColestyramineQuibron-T TheophyllineQuinachlor ChloroquineQuinalan QuinidineQuinaminoph QuinineQuinamm QuinineQuine QuinineQuinidex QuinidineQuinite QuinineQuinora Quinidine

R

RU 486 MifepristoneReQuip Ropinirole*Rebetol RibavirinReclomide MetoclopramideRectocort Cortisol (Hydrocortiso-

ne)Redisol Vit. B12Refludan Lepirudin


Refobacin GentamicinRegitin PhentolamineReglan MetoclopramideRegonol PyridostigmineRelefact GonadorelinRemicade InfliximabRemivox LorcainideRemsed PromethazineRenoquid SulfacytineReoPro AbciximabReomax Ethacrynic acidRescriptor DelavirdineRestoril TemazepamRetardin DiphenoxylateRetrovir Azidothymidine, Zido-

vudineReverin RolitetracyclinRevia NaltrexoneRezipas 5-Aminosalicylic acidRezulin TroglitazoneRhinalar FlunisolideRhumalgan DiclofenacRhythmin ProcainamideRhythmol PropafenoneRidaura AuranofinRifadin RifampinRimactan RifampinRimifon IsoniazidRitalin MethylphenidateRivotril ClonazepamRize ClotiazepamRoaccutan IsotretinoinRobinul GlycopyrrolateRocaltrol CalcitriolRocephin CeftriaxoneRoferon A3 Interferon-a2aRogaine MinoxidilRogitin PhentolamineRohypnol Flunitrazepam*Rolisox IsoxsuprineRomazicon FlumazenilRovamycin SpiramicinRowasa MesalamineRoxanol Moiphine sulfateRubesol Vit. B12Rubion CyanocobalaminRubramin CyanocobalaminRulid RoxithromycinRyegonovin MethylcelluloseRynacrom CromoglycateRythmodan Disopyramide

S

S.A.S.-500 Salazosulfapyridine =sulfasalazine

Sabril Vigabatrin*Salazopyrin Salazosulfapyridine =

sulfasalazineSalimid CyclopenthiazideSaltucin ButizidSandimmune CyclosporineSandomigran Pizotifen = PizotylineSandostatin OctreotideSandril ReserpineSang-35 CyclosporineSanocrisin CyclofenilSanodin CarbenoxoloneSanorex MazindolSansert MethysergideSatric MetronidazoleSaventrine Isoprenaline (= Isopro-

terenol)Scabene LindaneSebcur Salicylic acidSectral AcebutololSecuropen AzlocillinSeguril FurosemideSeldane TerfenadineSelectomycin SpiramicinSembrina Methyl-DopaSenokot SennaSenolax SennaSerax OxazepamSerenace HaloperidolSerevent SameterolSerlect Sertindole*Sernyl PhencyclidineSerono-Bagren BromocriptineSerophene ClomipheneSerpalan ReserpineSerpasil ReserpineSertan PrimidoneSexovid CyclofenilSibelium FlunarizineSilain SimethiconeSimplene EpinephrineSimplotan TinidazolSimulect BasiliximabSinarest OxymetazolineSinemet Levodopa + CarbidopaSinequan DoxepinSingulair MontelukastSintrom Acenocoumarin (= Ni-

coumalone)




Sinutab XylometazolineSirtal CarbamazepineSito-Lande SitosterolSkleromexe ClofibrateSlo-bid TheophyllineSobelin ClindamycinSofarin WarfarinSoldactone CanrenoneSolfoton PhenobarbitalSolganal AurothioglucoseSolu-Contenton AmantadineSoluver Salicylic acidSomnos ChloralhydrateSomophyllin-T TheophyllineSopamycetin ChloramphenicolSoprol BisoprololSorbitrate Isosorbide dinitrateSorquetan TinidazolSotacor SotalolSpametrin-M MethylcelluloseSpersadex DexamethasoneSpersanicol ChloramphenicolSpirocort BudesonideSporanox ItroconazoleSprecur BuserelinStatex Morphine sulfateStelazine TrifluoperazineSteranabol ClostebolStimate DesmopressinStoxil IdoxuridineStrepolin StreptomycinStreptase StreptokinaseStreptosol StreptomycinStresson BumetanideSuacron CarazololSublimaze FentanylSuccostrin SuccinylcholineSufenta SufentanilSulair SulfacetamideSulamyd SulfacetamideSular NisoldipineSulcrate SucralfateSulfabutin BusulfanSulfex SulfacetamideSulmycin GentamicinSulpyrin Metamizol (= Dipyrone)Sulten SulfacetamideSupasa Acetylsalicylic acidSuprarenin EpinephrineSuprax CefiximeSuprefact BuserelinSurfactal AmbroxolSustaine Xylometazoline

Sustaire TheophyllineSuxinutin EthosuximideSymmetrel AmantadineSynatan d-AmphetamineSynkayvit MenadioneSynovir ThalidomideSyntocinon OxytocinSytobex HydroxocobalaminSytobex Vit. B12

T

Tacef CefmenoximeTacicef CeftazidimeTagamet CimetidineTalwin PentazocineTambocor FlecainideTamofen TamoxifenTapazole MethimazoleTapazole Thiamazole (= Methi-

mazole)Taractan ChlorprothixeneTarasan ChlorprothixeneTardigal DigitoxinTardocillin Benzathine-Penicillin GTarivid OfloxacinTasmar TolcaponeTavist ClemastineTaxol PaclitaxelTaxotere DocetaxelTebrazid PyrazinamideTeebaconin IsoniazidTegison EtretinateTegopen ClotrimazoleTegretol CarbamazepineTelemin BisacodylTemgesic BuprenorphineTempra Paracetamol = acetami-

nophenTenalin CarteololTenex GuanfacineTenormin AtenololTensium DiazepamTensobon CaptoprilTestex Testosterone propiona-

teTestoject Testosterone cypionateTestone Testosterone enantateTestred MethyltestosteroneTeveten EprosartanTheelol Estratriol = EstriolTheolair TheophyllineThesit Polidocanol


Thiotepa Lederle Thio-TEPAThorazine ChlorpromazineThrombinar ThrombinThrombostat ThrombinTicar TicarcillinTiclid TiclopidineTienor ClotiazepamTigason EtretinateTilade NedocromilTimonil CarbamazepineTimoptic TimololTinactin TolnaftateTinset OxatomideToazul Tolonium chlorideTobrex TobramycinTofranil ImipramineTolectin TolmetinTomabef CefmenoximeTonocard TocainideTopamex TopiramateTopitracin BacitracinToposar EtoposideToradol KetorolacTornalate BitolterolTotacillin Amphotericin BTracrium AtracuriumTramal TramadolTrandate LabetalolTrans-Ver-Sal Salicylic acidTranscycline RolitetracyclinTransderm Scop ScopolamineTranxene ClorazepateTranxilium N Nor-DiazepamTrapanal ThiopentalTrasicor OxprenololTravogen IsoconazoleTrecalmo ClotiazepamTrecator EthionamideTremblex DexetimideTremin TrihexiphenidylTrendar IbuprofenTrental PentoxifyllineTrexan NaltrexoneTriadapin DoxepinTrialodine TrazodoneTriam-A Triamcinolone aceto-

nideTriamterene Triamcinolone aceto-

nideTrichlorex TrichlormethiazideTricor Fenofibrate*Trihexane TrihexiphenidylTrimpex Trimethoprim

Trimysten ClotrimazoleTriostat LiothyronineTriptone ScopolamineTrobicin SpectinomycinTrusopt DorzolamideTruxal ChlorprothixeneTubarine d-TubocurarineTylenol Paracetamol = acetami-

nophenTypramine ImipramineTyzine Tetryzoline (= tetrahy-

drozoline)

U

Udicil CytarabineUdolac DapsoneUkidan UrokinaseUlcolax BisacodylUltair Pranlukast*Ultiva RemifentanilUltracain ArticaineUnicort Cortisol (Hydrocortiso-

ne)Uniphyl TheophyllineUricovac BenzbromaroneUritol FurosemideUromitexan MesnaUrosin AllopurinolUrsofalk Ursodeoxycholic acid =

ursodiol

V

Va-tro-nol EphedrineValadol Paracetamol = acetami-

nophenValium DiazepamValorin Paracetamol = acetami-

nophenValtrex ValacyclovirVancocin VancomycinVancomycin VancomycinCP LillyVaponefrine EpinephrineVasal PapaverineVasocon NaphazolineVasodilan IsoxsuprineVasopressin LypressinSandozVasoprine IsoxsuprineVasotec EnalaprilVatran Diazepam




VePesid EtoposideVectrin MinocyclineVegesan Nor-DiazepamVelacycline RolitetracyclinVelban VinblastineVelbe VinblastineVelosulin InsulinVenactone CanrenoneVentolin Salbutamol (= Albute-

rol)Veratran ClotiazepamVerelan VerapamilVermox MebendazoleVersed MidazolamViagra SildenafilVibal Vit. B12Vibramycin DoxycyclineVidex Didanosine (ddI)Vigantol CholecalciferolVigorsan CholecalciferolVimicon CyproheptadineVinactane ViomycineViocin ViomycineVionactane ViomycineViprinex AncrodVira-A VidarabineViracept NelfinavirViramune NevirapineVirazole RibavirinVirilon MethyltestosteroneVirofral AmantadineViroptic TrifluridineVisine Tetryzoline (= tetrahy-

drozoline)Visken PindololVistacrom CromoglycateVisutensil GuanethidineVitrasert GanciclovirVivol DiazepamVolon TriamcinoloneVoltaren DiclofenacVoltarol DiclofenacVumon Teniposide

W

Wellbatrin BupropionWellbutrin Bupropion

Whevert Meclizine (meclozine)Wincoram AmrinoneWingom GallopamilWinpred PrednisoneWyamycin Erythromycin-estolateWytensin Guanabenz

X

Xanax AlprazolamXanef EnalaprilXatral AlfuzosinXylocain LidocaineXylocard LidocaineXylonest Prilocaine

Y

Yomesan NiclosamideYutopar Ritodrine

Z

Zaditen KetotifenZanaflex TizanidineZanosar StreptozocinZantac RanitidineZapex OxazepamZarontin EthosuximideZebeta BisoprololZemuron RocuroniumZenapax DaclizumabZepine ReserpineZerit Stavudine (d4T)Zestril LisinoprilZiagen Abacavir*Zimovane ZopicloneZithromax AzithromycinZocor SimvastatinZofran OndansetronZoladex GoserelinZovirax AciclovirZyflo ZileutonZyloprim AllopurinolZyloric AllopurinolZyprexa Olanzapine


A

abacavir, 288abciximab, 150Abel, John J., 3abortifacients, 126absorption, 10, 11, 46, 47

speed of, 18, 46accommodation, eye, 98accumulation, 48, 49, 50,

51accumulation equilibrium,

48ACE, see Angiotensin-con-

verting enzymeACE inhibitors, 118, 124

diuretics and, 158heart failure treatment,132hypertension treatment,312, 313myocardial infarctiontherapy, 310

acebutolol, 94acetaminophen, 198, 199

biotransformation, 36common cold treatment,324, 325intoxication, 302migraine treatment, 322

acetazolamide, 162N-acetyl-cysteine, 302acetylcholine (ACh), 82, 98,

166, 182binding to nicotinic re-ceptor, 64ester hydrolysis, 34, 35muscle relaxant effects,184–187release, 100, 101, 108synthesis, 100see also cholinoceptors

acetylcholinesterase(AChE), 100, 182inhibition, 102

acetylcoenzyme A, 100acetylcysteine, 324, 325acetyldigoxin, 132

N-acetylglucosamine, 268N-acetylmuramyl acid, 268acetylsalicylic acid (ASA),

198, 199, 200biotransformation, 34,35common cold treatment,324, 325migraine treatment, 322myocardial infarctiontherapy, 310platelet aggregation in-hibition, 150, 151, 310

acipimox, 156acrolein, 298acromegaly, 242, 243action potential, 136, 182,

186active principle, 4acyclovir, 284, 285, 286,

287acylaminopenicillins, 270acyltransferases, 38Addison’s disease, 248adenohypophyseal (AH)

hormones, 242, 243adenylate cyclase, 66adrenal cortex (AC), 248

insufficiency, 248adrenal medulla, nicotinic

stimulation, 108, 109,110

adrenaline, see epineph-rine

adrenergic synapse, 82adrenoceptors, 82, 230

agonists, 84, 86, 182subtypes, 84

adrenocortical atrophy,250

adrenocortical suppres-sion, 250

adrenocorticotropic hor-mone (ACTH), 242, 243,248, 250, 251

adriamycin, 298adsorbent powders, 178

adverse drug effects,70–75

aerosols, 12, 14affinity, 56

enantioselectivity, 62agitation, 106agonists, 60, 61

inverse, 60, 226partial, 60

agranulocytosis, 72AIDS treatment, 288–289ajmaline, 136akathisia, 238akinesia, 188albumin, drug binding, 30albuterol, 326, 328alcohol dehydrogenase

(ADH), 44alcohol elimination, 44alcuronium, 184aldosterone, 158, 164, 165,

248, 249antagonists, 164deficiency, 314purgative use and, 172

alendronate, 318alfuzosin, 90alkaloids, 4alkylating cytostatics, 298allergic reactions, 72–73,

196, 326–327allopurinol, 298, 316, 317allosteric antagonism, 60allosteric synergism, 60α-blockers, 90alprostanil, 118alteplase, 146, 310Alzheimer’s disease, 102amantadine, 188, 286, 287amikacin, 278, 280amiloride, 164, 1656-amino-penicillanic acid,

268γ-aminobutyric acid, see

GABAε-aminocaproic acid, 146aminoglycosides, 267,

276–279

368

Index


Index 369

p-aminomethylbenzoicacid (PAMBA), 146

aminopterin, 298aminopyrine, 198aminoquinuride, 2585-aminosalicylic acid, 272p-aminosalicylic acid, 280amiodarone, 136amitriptyline, 230, 232,

233amodiaquine, 294amorolfine, 282amoxicillin, 168, 270, 271cAMP, 66, 150amphetamines, 88, 89, 230

see also specific drugsamphotericin B, 282, 283ampicillin, 270ampules, 12amrinone, 118, 128, 132anabolic steroids, 252analgesics, 194–203

antipyretic, 4, 196–199,202–203, 324see also opioids

anaphylactic reactions, 72,73, 152treatment, 84, 326, 327

ancrod, 146, 147Ancylostoma duodenale,

292androgens, 252anemia, 138–141, 192

megaloblastic, 192pernicious, 138

anesthesiabalanced, 216, 217conduction, 204dissociative, 220infiltration, 90, 204premedication, 104, 106,226regional, 216spinal, 204, 216surface, 204total intravenous (TIVA),216see also general anes-thetics; local anesthetics

angina pectoris, 128,306–308, 311, 312prophylaxis, 308, 311

treatment, 92, 118, 120,122, 308, 311

angiotensin II, 118, 124,158, 248antagonists, 124biotransformation, 34,35formation, 34

angiotensin-convertingenzyme (ACE), 34, 124,158see also ACE inhibitors

angiotensinase, 34Anopheles mosquitoes,

294anorexiants, 88antacids, 166–168antagonists, 60, 61anthraquinone derivatives,

170, 174, 176, 177antiadrenergics, 95–96,

128antianemics, 138–141antiarrhythmics, 134–137

electrophysiological ac-tions, 136, 137

antibacterial drugs,266–282cell wall synthesis inhib-itors, 268–271DNA function inhibitors,274–275mycobacterial infections,280–281protein synthesis inhibi-tors, 276–279tetrahydrofolate synthe-sis inhibitors, 272–273

antibiotics, 178, 266broad-spectrum, 266cystostatic, 298narrow-spectrum, 266see also antibacterialdrugs; antifungal drugs;antiviral drugs

antibodies, 72, 73monoclonal, 300

anticancer drugs, 296–299anticholinergics, 188, 202anticoagulants, 144–147anticonvulsants, 190–193,

226

antidepressants, 88,230–233tricyclic, 230–232

antidiabetics, 262, 263antidiarrheals, 178–179antidiuretic hormone

(ADH), see vasopressinantidotes, 302–305antiemetics, 114, 310,

330–331antiepileptics, 190–193antiflatulents, 180antifungal drugs, 282–283antigens, 72, 73antihelmintics, 292antihistamines, 114–116

allergic disorder treat-ment, 326, 327common cold treatment,324, 325motion sickness prophy-laxis, 330peptic ulcer treatment,166–168sedative activity, 222

antimalarials, 294–295antiparasitic drugs,

292–295antiparkinsonian drugs,

188–190antipyretic analgesics, 4,

196–199, 324thermoregulation and,202–203

antiseptics, 290, 291antithrombin III, 142, 144antithrombotics, 142–143,

148–151antithyroid drugs, 246, 247antiviral drugs, 284–289

AIDS treatment,288–289interferons, 284, 285virustatic antimetab-olites, 284–287

anxiety states, 226anxiolytics, 128, 222, 226,

228, 236apolipoproteins, 154, 155apoptosis, 296aprotinin, 146appetite suppressants, 88


arachidonic acid, 196, 201,248

area postrema, 110, 130,212, 330

area under the curve(AUC), 46

arecoline, 102arthritis

chronic polyarthritis,320rheumatoid, 302,320–321

Arthus reaction, 72articaine, 208, 209Ascaris lumbricoides, 292,

293aspirin, see acetylsalicylic

acidaspirin asthma, 198astemizole, 114–116asthma, 126, 127, 326–329

β-blockers and, 92treatment, 84, 104

astringents, 178asymmetric center, 62atenolol, 94, 95, 322atherosclerosis, 154, 306atorvastatin, 156atracurium, 184atrial fibrillation, 130, 134atrial flutter, 122, 130, 131,

134atropine, 104, 107, 134,

166, 216lack of selectivity, 70, 71poisoning, 106, 202, 302

auranofin, 320aurothioglucose, 320aurothiomalate, 320autonomic nervous

system, 80AV block, 92, 104axolemma, 206axoplasm, 206azapropazone, 200azathioprine, 36, 300, 320azidothymidine, 288azithromycin, 276azlocillin, 270azomycin, 274

B

B lymphocytes, 72, 300bacitracin, 267, 268, 270baclofen, 182bacterial infections, 178,

266, 267resistance, 266, 267see also antibacterialdrugs

bactericidal effect, 266,267

bacteriostatic effect, 266,267

balanced anesthesia, 216,217

bamipine, 114barbiturates, 202, 203,

220, 222dependence, 223

baroreceptors, nicotine ef-fects, 110

barriersblood-tissue, 24–25cell membranes, 26–27external, 22–23

basiliximab, 300Bateman function, 46bathmotropism, negative,

134beclomethasone, 14, 250,

326benazepril, 124benign prostatic hyperpla-

sia, 90, 252, 312benserazide, 188benzathiazide, 162benzathine, 268benzatropine, 106, 107,

188benzbromarone, 316benzocaine, 208, 209, 324benzodiazepines, 182, 220,

226–229antagonists, 226dependence, 223, 226,228epilepsy treatment, 190,192myocardial infarctiontreatment, 128pharmacokinetics, 228,229

receptors, 226, 228sleep disturbances and,222, 224

benzopyrene, 36benzothiadiazines, see thi-

azide diureticsbenzylpenicillin, 268Berlin Blue, 304β-blockers, 92–95, 128,

136angina treatment, 308,311hypertension treatment,312–313migraine prophylaxis,322myocardial infarctiontreatment, 309, 310sinus tachycardia treat-ment, 134types of, 94, 95

bezafibrate, 156bifonazole, 282bile acids, 180bilharziasis, 292binding assays, 56binding curves, 56–57binding forces, 58–59binding sites, 56bioavailability, 18, 42

absolute, 42determination of, 46relative, 42

bioequivalence, 46biogenic amines, 114–118biotransformation, 34–39

benzodiazepines, 228,229in liver, 32, 42

biperiden, 188, 238biphosphonates, 318bisacodyl, 174bisoprolol, 94bladder atonia, 100, 102bleomycin, 298blood pressure, 314

see also hypertension;hypotension

blood sugar control, 260,261

blood-brain barrier, 24blood-tissue barriers,

24–25

370 Index


Index 371

bonds, types of, 58, 59botulinum toxin, 182bowel atonia, 100, 102bradycardia, 92, 104, 134bradykinin, 34brain, blood-brain barrier,

24bran, 170bromocriptine, 114, 126,

188, 242, 243bronchial asthma, see

asthmabronchial carcinoma, to-

bacco smoking and, 112bronchial mucus, 14bronchitis, 324, 328

chronic obstructive, 104tobacco smoking and,112

bronchoconstriction, 196,198

bronchodilation, 84, 104,127, 196, 326

bronchodilators, 126, 328brotizolam, 224buccal drug administra-

tion, 18, 19, 22Buchheim, Rudolf, 3budesonide, 14, 250, 326bufotenin, 240bulk gels, 170, 171bumetanide, 162buprenorphine, 210, 214buserelin, 242, 243buspirone, 116busulfan, 298N-butylscopolamine, 104,

126butyrophenones, 236, 238butyryl cholinesterase, 100

C

cabergolide, 126, 188, 242caffeine, 326calcifediol, 264calcineurin, 300calcitonin, 264, 265, 318,

322calcitriol, 264calcium antagonists,

122–123, 128

angina treatment, 308,311hypertension treatment,312–313

calcium channel blockers,136, 234see also calcium antago-nists

calcium chelators, 142calcium homeostasis, 264,

265calmodulin, 84cancer, 296–299

see also carcinomaCandida albicans, 282canrenone, 164capillary beds, 24capreomycin, 280capsules, 8, 9, 10captopril, 34, 124carbachol, 102, 103carbamates, 102carbamazepine, 190, 191,

192, 234carbenicillin, 270carbenoxolone, 168carbidopa, 188carbimazole, 247carbonic acids, 200carbonic anhydrase (CAH),

162inhibitors, 162, 163

carbovir, 288carboxypenicillins, 270carcinoma

bronchial, 112prostatic, 242

cardiac arrest, 104, 134cardiac drugs, 128–137

antiarrhythmics,134–137glycosides, 128, 130,131, 132, 134modes of action, 128,129

cardioacceleration, 104cardiodepression, 134cardioselectivity, 94cardiostimulation, 84, 85carminatives, 180, 181carotid body, nicotine ef-

fects, 110case-control studies, 76

castor oil, 170, 174catecholamines

actions of, 84, 85structure-activity rela-tionships, 86, 87see also epinephrine;norepinephrine

catecholmin-O-methyl-transferase (COMT), 82,86, 114inhibitors of, 188

cathartics, 170, 172cefmenoxin, 270cefoperazone, 270cefotaxime, 270ceftazidime, 270ceftriaxone, 270cell membrane, 20

membrane stabilization,94, 134, 136permeation, 26–27

cells, 20cellulose, 170cephalexin, 270, 271cephalosporinase, 270, 271cephalosporins, 267, 268,

270, 271cerivastatin, 156ceruletide, 180cestode parasites, 292cetrizine, 114–116chalk, 178charcoal, medicinal, 178chelating agents, 302, 303chemotherapeutic agents,

266chenodeoxycholic acid

(CDCA), 180chirality, 62chloral hydrate, 222chlorambucil, 298chloramphenicol, 267,

276–279chlorguanide, 294chloride channels, 226chlormadinone acetate,

254chloroquine, 294, 295, 320chlorpheniramine, 114chlorphenothane (DDT),

292, 293chlorpromazine, 208, 236,

238


lack of selectivity, 70, 71chlorprothixene, 238chlorthalidone, 162cholecalciferol, 264cholecystokinin, 180cholekinetics, 180cholelithiasis, 180choleretics, 180cholestasis, 238cholesterol, 154–157

gallstone formation, 180metabolism, 155

choline, 100choline acetyltransferase,

100cholinergic synapse, 100cholinoceptors, 98, 100,

184antacid effects, 166antagonists, 188muscarinic, 100, 188,230nicotinic, 64, 65, 100,108, 182

chronic polyarthritis, 320chronotropism, 84

negative, 134chylomicrons, 154cilazapril, 124cimetidine, 116, 168ciprofloxacin, 274cisapride, 116cisplatin, 298citrate, 142clarithromycin, 168, 276Clark, Alexander J., 3clavulanic acid, 270clearance, 44clemastine, 114clemizole, 268clindamycin, 267, 276clinical testing, 6clinical trials, 76clobazam, 192clodronate, 264, 318clofazimine, 280, 281clofibrate, 156clomethiazole, 192clomiphene, 256clonazepam, 192clonidine, 96, 182, 312clopidogrel, 150clostebol, 252

Clostridium botulinum,182

Clostridium difficile, 270clotiazepam, 222clotrimazole, 282clotting factors, 142clozapine, 238, 239, 240co-trimoxazole, 272, 273coagulation cascade, 142,

143coated tablets, 8, 9, 10cocaine, 88, 89, 208codeine, 210, 212, 214,

324, 325colchicine, 316, 317colds, 324–325colestipol, 154colestyramine, 130, 154colic, 104, 127common cold, 324–325competitive antagonists,

60, 61complement activation,

72, 73compliance, 48concentration time course,

46–47, 68, 69during irregular intake,48, 49during repeated dosing,48, 49

concentration-bindingcurves, 56–57

concentration-effectcurves, 54, 55

concentration-effect rela-tionship, 54, 55, 68, 69

conformation change, 60congestive heart failure,

92, 128, 130, 158, 312conjugation reactions, 38,

39, 58conjunctival decongestion,

90constipation, 172, 173

atropine poisoning and,106see also laxatives

contact dermatitis, 72, 73,282

controlled trials, 76coronary sclerosis, 306,

307

corpus luteum, 254corticotropin, 242corticotropin-releasing

hormone (CRH), 242,250, 251

cortisol, 36, 248, 249, 250,251receptors, 250

cortisone, biotransforma-tion, 36

coryza, 90cotrimoxazole, 178cough, 324, 325coumarins, 142, 144, 145covalent bonds, 58cranial nerves, 98creams, 16, 17cromoglycate, 116cromolyn, 14, 116, 326cross-over trials, 76curare, 184Cushing’s disease, 220,

248, 300, 318prevention of, 248

cyanide poisoning, 304,305

cyanocobalamin, 138, 304,305

cyclic endoperoxides, 196cyclofenil, 256cyclooxygenases, 196, 248

inhibition, 198, 200, 328cyclophilin, 300cyclophosphamide, 298,

300, 320cycloserine, 280cyclosporin A, 300cyclothiazide, 162cyproterone, 252cyproterone acetate, 254cystinuria, 302, 303cystostatic antibiotics, 298cytarabine, 298cytochrome P450, 32cytokines, 300cytomegaloviruses, 286cytostatics, 296, 297, 299,

300, 320cytostatics, alkylating, 298cytotoxic reactions, 72, 73

372 Index


Index 373

D

daclizumab, 300dantrolene, 182dapsone, 272, 280, 281,

294daunorubicin, 298dealkylations, 36deamination, 36decarbaminoylation, 102decongestants, 90deferoxamine, 302, 303dehalogenation, 36delavirdine, 288delirium tremens, 236dementia, 102N-demethyldiazepam, 228demulcents, 178deoxyribonucleic acid

(DNA), 274synthesis inhibition, 298,299

dependencebenzodiazepines, 223,226, 228hypnotics, 222, 223laxatives, 172, 173opioids, 210–212

dephosphorylation, 102depolarizing muscle relax-

ants, 184, 186, 187deprenyl, 88depression, 226, 230

endogenous, 230–233manic-depressive illness,230treatment, 88, 230–233

dermatologic agents, 16,17as drug vehicles, 16, 17

dermatophytes, 282descending antinocicep-

tive system, 194desensitization, 66desflurane, 218desipramine, 230, 232, 233desmopressin, 164, 165desogestrel, 254desulfuration, 36, 37dexamethasone, 192, 248,

249, 330dexazosin, 90dexetimide, 62, 63

dextran, 152diabetes mellitus

hypoglycemia, 92insulin replacementtherapy, 258insulin-dependent,260–261non-insulin-dependent,262–264

diacylglycerol, 66diarrhea, 178

antidiarrheals, 178–179chologenic, 172

diastereomers, 62diazepam, 128, 228diazoxide, 118, 312dicationic, 268diclofenac, 200, 320dicloxacillin, 270didanosine, 288diethlystilbestrol, 74diethylether, 216diffusion

barrier to, 20membrane permeation,26, 27

digitalis, 130, 131, 302digitoxin, 132

enterohepatic cycle, 38digoxin, 132dihydralazine, 118, 312dihydroergotamine, 126,

322dihydropyridines, 122, 308dihydrotestosterone, 252diltiazem, 122, 136, 308dimenhydrinate, 114dimercaprol, 302, 303dimercaptopropanesulfon-

ic acid, 302, 303dimethicone, 180, 181dimethisterone, 2542,5-dimethoxy-4-ethyl

amphetamine, 2403,4-dimethoxyampheta-

mine, 240dimetindene, 114dinoprost, 126dinoprostone, 126diphenhydramine, 114,

222, 230diphenolmethane deriva-

tives, 170, 174, 177

diphenoxylate, 178dipole-dipole interaction,

58dipole-ion interaction, 58dipyridamole, 150dipyrone, 198, 199disinfectants, 290, 291disintegration, of tablets

and capsules, 10disopyramide, 136disorientation, atropine

poisoning and, 106Disse’s spaces, 24, 32, 33dissolution, of tablets and

capsules, 9, 10distribution, 22–31, 46, 47diuretics, 158–165, 313

indications for, 158loop, 162, 163osmotic, 160, 161potassium-sparing, 164,165sulfonamide type, 162,163thiazide, 132, 162, 163,312

dobutamine, enantioselec-tivity, 62

docetaxel, 296docosahexaenoate, 156domperidone, 322, 330L-dopa, 114, 188DOPA-decarboxylase, 188dopamine, 88, 114, 115,

132agonists, 242antagonists, 114in norepinephrine syn-thesis, 82mimetics, 114Parkinson’s disease and,188

dopamine receptors, 114,322agonists, 188blockade, 236, 238

dopamine-β-hydroxylase,82

doping, 88, 89dorzolamide, 162dosage forms, 8dosage schedule, 50, 51dose-linear kinetics, 68, 69


dose-response relation-ship, 52–53

dosingirregular, 48, 49overdosing, 70, 71repeated, 48, 49subliminal, 52

double-blind trials, 76doxorubicin, 298doxycycline, 277, 278, 294doxylamine, 22dromotropism, negative,

134dronabinol, 330droperidol, 216, 236drops, 8, 9drug interactions, 30, 32

anticonvulsants, 192drug-receptor interaction,

58–69drugs

active principle, 4administration, 8–19adverse effects, 70–75approval process, 6barriers to, 22–27biotransformation, 32,34–39concentration timecourse, 46–47, 48–49,68, 69development, 6–7distribution in body,22–31, 46, 47liberation of, 10protein binding, 30–31retarded release, 10, 11sites of action, 20–21sources, 4see also elimination ofdrugs; specific types of drugs

duodenal ulcers, 104, 166dusting powders, 16dynorphins, 210dyskinesia, 238dysmenorrhea, 196dystonia, 238

E

Emax, 54E. coli, 270, 271

EC50, 54, 60econazole, 282ecothiopate, 102ecstasy, 240ectoparasites, 292edema, 158, 159EDTA, 142, 264, 302, 303efavirenz, 288effervescent tablets, 8efficacy, 54, 60, 61Ehrlich, P., 3eicosanoids, 196eicosapentaenoate, 156electromechanical

coupling, 128, 182electrostatic attraction, 58,

59elimination of drugs,

32–43, 46, 47β-blockers, 94biotransformation,34–39, 42changes during drugtherapy, 50, 51exponential rate pro-cesses, 44, 45hydrophilic drugs, 42, 43in kidney, 40–41, 44in liver, 18, 32–33, 44lipophilic drugs, 42, 43

emesis, 330–331emulsions, 8, 16enalapril, 34enalaprilat, 34, 124enantiomers, 62, 63enantioselectivity, 62endocytosis, 24

receptor-mediated, 26,27

endoneural space, 206endoparasites, 292β-endorphin, 210, 211, 212endothelium-derived re-

laxing factor (EDRF), 100,120

enflurane, 218enkephalins, 34, 210, 211enolic acids, 200enoxacin, 274entacapone, 188Entamoeba histolytica, 274Enterobius vermicularis,

292

enterohepatic cycle, 38, 39enzyme induction, 32ephedrine, 86, 87epilepsy, 190, 191, 226

antiepileptics, 190–193childhood, 192treatment, 162

epinephrine, 82, 83, 260anaphylactic shock treat-ment, 84, 326, 327β-blockers and, 92cardiac arrest treatment,134local anesthesia and, 206nicotine and, 108, 109,110structure-activity rela-tionships, 86, 87

epipodophyllotoxins, 298epoxidations, 36epoxides, 36Epsom salts, 170eptifibatide, 150ergocornine, 126ergocristine, 126ergocryptine, 126ergolides, 114ergometrine, 126, 127ergosterol, 282, 283ergot alkaloids, 126ergotamine, 126, 127, 322erythromycin, 34, 267,

276, 277erythropoiesis, 138, 139erythropoietin, 138ester hydrolysis, 34estradiol, 254, 255, 257estriol, 254, 255estrogen, 254, 318estrone, 254, 255ethacrynic acid, 162ethambutol, 280, 281ethanol, 202, 203, 224

elimination, 44ethinylestradiol (EE), 254,

255, 256ethinyltestosterone, 255ethionamide, 280ethisterone, 254ethosuximide, 191, 192ethylaminobenzoate, 324ethylenediaminetetraacet-

ic acid (EDTA), 142

374 Index


Index 375

etilefrine, 86, 87etofibrate, 156etomidate, 220, 221etoposide, 298etretinate, 74euphoria, 88, 210expectorants, 324, 325exponential rate processes,

44, 45extracellular fluid volume

(EFV), 158extracellular space, 28extrapyramidal distur-

bances, 238eye drops, 8, 9

F

factor VII, 142factor XII, 142famcyclovir, 286famotidine, 116, 168fatty acids, 20felbamate, 190, 191felodipine, 122felypressin, 164, 206fenestrations, 24fenfluramine, 88fenoldopam, 114, 312fenoterol, 86, 87

allergic disorder treat-ment, 326asthma treatment, 328tocolysis, 84, 126

fentanyl, 210, 212–216ferric ferrocyanide, 304,

305ferritin, 140fever, 202, 203, 324fexofenadine, 114–116fibrillation, 122

atrial, 130, 131, 134fibrin, 34, 142, 146fibrinogen, 146, 148, 149fibrinolytic therapy, 146Fick’s Law, 44finasteride, 252first-order rate processes,

44–45first-pass hepatic elimina-

tion, 18, 42fish oil supplementation,

156

fleas, 292, 293flecainide, 136floxacillin, 270fluconazole, 282flucytosine, 282fludrocortisone, 248, 314flukes, 292flumazenil, 226, 302flunarizine, 322flunisolide, 14, 250fluoride, 3185-fluorouracil, 298fluoxetine, 116, 230, 232,

233flupentixol, 236, 238, 239fluphenazine, 236, 238,

239flutamide, 252fluticasone dipropionate,

14, 250fluvastatin, 156, 157fluvoxamine, 232folic acid, 138, 139, 272,

273deficiency, 138

follicle-stimulating hor-mone (FSH), 242, 243,254deficiency, 252suppression, 256

follicular maturation, 254foscarnet, 286, 287fosinopril, 124Frazer, T., 3frusemide, 162functional antagonism, 60fungal infections, 282–283fungicidal effect, 282fungistatic effect, 282furosemide, 162, 264

G

G-protein-coupled recep-tors, 64, 65, 210mode of operation,66–67

G-proteins, 64, 66GABA, 190, 224, 226GABA receptors, 64, 226gabapentin, 190, 191, 192Galen, Claudius, 2gallamine, 184

gallopamil, 122gallstones, 180

dissolving of, 180, 181ganciclovir, 285, 286ganglia

nicotine action, 108, 110paravertebral, 82prevertebral, 82

ganglionic blockers, 108,128

gastric secretion, 196gastric ulcers, 104, 166gastrin, 166–168, 242gastritis, atrophic, 138gelatin, 152gels, 16gemfibrozil, 156general anesthetics,

216–221inhalational, 216,218–219injectable, 216, 220–221

generic drugs, 94gentamicin, 276, 278, 279gestoden, 254gingival hyperplasia, 192Glauber’s salts, 170glaucoma, 106

treatment, 92, 102, 162β-globulins, drug binding,

30glomerular filtration, 40glucagon, 242glucocorticoids, 200,

248–251allergic disorder treat-ment, 326asthma treatment, 328cytokine inhibition, 300gout treatment, 316hypercalcemia treat-ment, 264rheumatoid arthritistreatment, 320

glucose metabolism, 260,261see also diabetes mellit-us

glucose-6-phosphate de-hydrogenase deficiency,70

glucuronic acid, 36, 38, 39


β-glucuronidases, 38glucuronidation, 38

opioids, 212glucuronides, 38glucuronyl transferases,

32, 38glutamate, 64, 190

receptors, 190glutamine, in conjugation

reactions, 38glyburide, 262glyceraldehyde enantiom-

ers, 62glycerol, 20glycine, 64, 182, 183

in conjugation reactions,38

glycogenolysis, 66, 84glycosuria, 162cGMP, 120goiter, 244, 245, 247gold compounds, 320gonadorelin superagonists,

242gonadotropin-releasing

hormone (GnRH), 242,243,252, 256

goserelin, 242gout, 316–317GPIIB/IIIA, 148, 149, 150

antagonists, 150granisetron, 116, 330Graves’ disease, 246, 247griseofulvin, 282, 283growth hormone (GH),

242, 243growth hormone recep-

tors, 64growth hormone release

inhibiting hormone (-GRIH),242

growth hormone-releasinghormone (GRH), 242

guanethidine, 96guanylate cyclase, 120gynecomastia, 164, 168gyrase inhibitors, 274, 275

H

Hahnemann, Samuel, 76

half-life, 44hallucinations, atropine

poisoning and, 106hallucinogens, 240, 241halofantrine, 294, 295haloperidol, 236, 238, 239halothane, 218, 219haptens, 72, 73hay fever, 326HDL particles, 154heart

β-blockers and, 92cardiac arrest, 104, 134cardiac drugs, 128–137cardioacceleration, 104cardiodepression, 134cardiostimulation, 84, 85see also angina pectoris;myocardial infarction;myocardium

heart failureβ-blockers and, 92congestive, 92, 128, 130,158, 312treatment, 118, 124, 132,158

Helicobacter pylori, 166eradication of, 168, 169

hemoglobin, 138hemolysis, 70, 72hemosiderosis, 140hemostasis, 142, 148heparin, 142–146, 309,

310hepatic elimination, 18,

32–33, 44exponential kinetics, 44

hepatocytes, 32, 33, 154heroin, 212Herpes simplex viruses,

284, 286hexamethonium, 108hexobarbital, 222high blood pressure, see

hypertensionhirudin, 150histamine, 72, 114, 115,

166, 326antagonists, 114inhibitors of release, 116receptors, 114, 230, 326see also antihistamines

HMG CoA reductase, 154,156, 157

Hohenheim, Theophrastusvon, 2

homatropine, 107homeopathy, 76, 77hookworm, 292hormone replacement

therapy, 254hormones, 20

hypophyseal, 242–243hypothalamic, 242–243see also specific hor-mones

human chorionic gonado-tropin (HCG), 252, 256

human immunodeficiencyvirus (HIV), 288–289

human menopausal gona-dotropin (HMG), 252,256

hydrochlorothiazide, 162,164

hydrocortisone, 248hydrogel, 16, 17hydrolysis, 34, 35hydromorphone, 210, 214hydrophilic colloids, 170,

171hydrophilic cream, 16hydrophilic drug elimina-

tion, 42, 43hydrophobic interactions,

58, 59hydroxyapatite, 264, 3184-hydroxycoumarins, 144hydroxyethyl starch, 152hydroxylation reactions,

36, 3717-β-hydroxyprogesterone

caproate, 2545-hydroxytryptamine

(5HT), see serotoninhypercalcemia, 264hyperglycemia, 162, 258,

260hyperkalemia, 186hyperlipoproteinemia,

154–157treatment, 154

hyperpyrexia, 202hypersensitivity, 70

376 Index


Index 377

hypertension therapy,312–313α-blockers, 90ACE inhibitors, 124, 312β-blockers, 92, 312calcium antagonists, 122,312diuretics, 158, 312in pregnancy, 312vasodilators, 118, 312

hyperthermia, atropinepoisoning and, 106, 202

hyperthyroidism, 244,246–247

hypertonia, 226hyperuricemia, 162, 316hypnotics, 222–225

dependence, 222, 223hypoglycemia, 92, 260hypokalemia, 162, 163,

172, 173hypophysis, 242–243, 250hypotension, 118, 119, 314

treatment, 90, 314–315hypothalamic releasing

hormones, 242, 243hypothalamus, 242, 250,

251hypothermia, 238hypothyroidism, 244hypovolemic shock, 152

I

ibuprofen, 198, 200idiopathic dilated cardio-

myopathy, 92idoxuridine, 286ifosfamide, 298iloprost, 118imidazole derivatives, 282,

283imipramine, 208,

230–232, 233immune complex vascu-

litis, 72, 73immune modulators,

300–301immune response, 72, 73,

300immunogens, 72immunosuppression,

300–301, 320

indinavir, 288indomethacin, 200, 316,

320infertility, 242inflammation, 72, 196, 326

asthma, 328, 329glucocorticoid therapy,248, 249rheumatoid arthritis, 320

inflammatory bowel dis-ease, 272

influenza virus, 286, 287,324

infusion, 12, 50inhalation, 14, 15, 18, 19injections, 12, 18, 19inosine monophosphate

dehydrogenase, 300inositol trisphosphate, 66,

84inotropism, 92

negative, 134insecticides, 292

poisoning, 304, 305insomnia, 224, 226insulin, 242, 258–259

diabetes mellitus treat-ment, 260–261, 262preparations, 258, 259regular, 258resistance to, 258

insulin receptors, 64insulin-dependent dia-

betes mellitus, 260–261interferons (IFN), 284, 285interleukins, 300interstitial fluid, 28intestinal epithelium, 22intramuscular injection,

18, 19intravenous injection, 18,

19intrinsic activity, 60

enantioselectivity, 62intrinsic factor, 138intrinsic sympathomimetic

activity (ISA), 94intubation, 216inulin, 28inverse agonists, 60, 226inverse enantioselectivity,

62iodine, 246, 247

deficiency, 244iodized salt prophylaxis,244

ionic currents, 136ionic interaction, 58ipratropium, 14, 107

allergic disorder treat-ment, 326bronchodilation, 126,328cardiaoacceleration, 104,134

iron compounds, 140iron deficiency, 138, 140iron overload, 302isoconazole, 282isoflurane, 218isoniazid, 190, 280, 281isophane, 258isoprenaline, 94isoproterenol, 14, 94, 95

structure-activity rela-tionships, 86, 87

isosorbide dinitrate (ISDN),120, 308, 311

5-isosorbide mononitrate(ISMN), 120

isotretinoic acid, 74isoxazolylpenicillins, 270itraconazole, 282

J

josamycin, 276juvenile onset diabetes

mellitus, 260

K

K+ channels, see potassiumchannel activation

kanamycin, 276, 280kaolin, 178karaya gum, 170ketamine, 220, 221ketanserin, 116ketoconazole, 282ketotifen, 116kidney, 160, 161

drug elimination, 40–41,44

kinetosis, 106, 330, 331kyphosis, 318


L

β-lactam ring, 268, 270β-lactamases, 270lactation, drug toxicity, 74,

75lactulose, 170lamivudine, 288lamotrigine, 190, 191Langendorff preparation,

128Langley, J., 3lansoprazole, 168laryngitis, 324law of mass action, 3, 56laxatives, 170–177

bulk, 170, 171dependence, 172, 173irritant, 170, 172–174,175, 177lubricant, 174misuse of, 170–172osmotically active, 170,171

LDL particles, 154–157lead poisoning, 302, 303Lennox-Gastaut syndrome,

192leprosy, 274, 280leuenkephalin, 212leukotrienes, 196, 320,

326, 327, 328NSAIDS and, 200, 201

leuprorelin, 242, 243levetimide, 62, 63levodopa, 188levomepromazine, 330lice, 292, 293lidocaine, 134, 136, 208,

209biotransformation, 36,37digitoxin intoxicationtreatment, 130myocardial infarctiontreatment, 309, 310

ligand-gated ion channel,64, 65

ligand-operated enzymes,64, 65

lincomycin, 276lindane, 292, 293linseed, 170

lipid-lowering agents, 154lipocortin, 248lipolysis, 66, 84lipophilic cream, 16lipophilic drug elimina-

tion, 42, 43lipophilic ointment, 16lipoprotein metabolism,

154, 155lipoxygenases, 196liquid paraffin, 174liquid preparations, 8, 9lisinopril, 124lisuride, 114, 188lithium ions, 234, 235, 246,

247liver

biotransformation, 32,42blood supply, 32drug elimination, 18,32–33, 44drug exchange, 24enterohepatic cycle, 38,39lipoprotein metabolism,154–157

loading dose, 50local anesthetics, 128, 134,

204–209chemical structure,208–209diffusion and effect,206–207mechanism of action,204–206

lomustine, 298loop diuretics, 162, 163loperamide, 178, 212loratidine, 116lorazepam, 220, 330lormetazepam, 224lotions, 16, 17lovastatin, 156, 157low blood pressure, see

hypotensionLSD, see lysergic acid di-ethylamideLugol’s solution, 246luteinizing hormone (LH),

242, 243, 252, 254deficiency, 252

lymphocytes, 72

lymphokines, 72lynestrenol, 254lypressin, 164lysergic acid, 126lysergic acid diethylamide

(LSD), 126, 240, 241

M

macrophages, 300activation, 72

magnesium sulfate, 126maintenance dose, 50major histocompatibility

complex (MHC), 300malaria, 294–295malignant neuroleptic syn-

drome, 238mania, 230, 234, 235manic-depressive illness,

230mannitol, 160, 161, 170maprotiline, 232margin of safety, 70mass action, law of, 3, 56mast cells, 72

inhibitors of histaminerelease, 116stabilization, 326, 328

matrix-type tablets, 9, 10maturity-onset diabetes

mellitus, 262–264mazindole, 88mebendazole, 292, 293mebhydroline, 114mecamylamine, 108mechlorethamine, 298meclizine, 114, 330medicinal charcoal, 178medroxyprogesterone ace-

tate, 254mefloquine, 294, 295megakaryocytes, 148megaloblastic anemia, 192melphalan, 298membrane permeation,

26–27membrane stabilization,

94, 134, 136memory cells, 72menstrual cycle, 254menstruation, 196

378 Index


Index 379

meperidine, 126, 210, 214,215

mepivacaine, 2096-mercaptopurine, 298mesalamine, 272mescaline, 116, 240mesterolone, 252mestranol, 254, 256metamizole, 198metastases, 296metenkephalin, 212, 213metenolone, 252meteorism, 180metformin, 262l-methadone, 210, 214,

215methamphetamine, 86, 87,

88methemoglobin, 304, 305methimazole, 247methohexital, 220methotrexate, 298, 300,

320methoxyflurane, 218methoxyverapamil, 1224-methyl-2,5-dimethoxy-

amphetamine, 240methylation reactions, 36,

37methyldigoxin, 132methyldopa, 96, 114, 312methylenedioxy metham-

phetamine (MDMA), 240methylergometrine, 126methylprednisolone, 33017-α-methyltestosterone,

252methylxanthines, 326methysergide, 322metoclopramide, 322, 330metoprolol, 94, 322metronidazole, 168, 274mexiletine, 134, 136mezclocillin, 270mianserin, 232mibefradil, 122, 308miconazole, 282Micromonospora bacteria,

276micturition, 98midazolam, 220, 221, 228mifepristone, 126, 256

migraine treatment, 116,126, 322–323

milieu interieur, 80milrinone, 132mineralocorticoids, 248,

249minimal alveolar concen-

tration (MAC), 218minipill, 256, 257minocycline, 278minoxidil, 118, 312misoprostol, 126, 168, 169,

200mites, 292, 293mixed-function oxidases,

32mixtures, 8moclobemide, 88, 232, 233molsidomine, 120, 308monoamine oxidase

(MAO), 82, 86, 88, 114inhibitors of, 88, 89, 188,230, 232

monoclonal antibodies,300

mood change, 210morning-after pill, 256morphine, 4, 5, 178,

210–215, 310antagonists, 214increased sensitivity, 70metabolism, 212, 213overdosage, 70, 71Straub tail phenomenon,52, 53

Morton, W.T.G., 216motiline, 276motion sickness, 106, 330,

331motor endplate, 182

nicotine and, 110motor systems, drugs act-

ing on, 182–193mountain sickness, 162moxalactam, 270mucociliary transport, 14mucolytics, 324, 325mucosal administration,

12, 14, 18, 22mucosal block, 140mucosal disinfection, 290,

291murein, 268

muromonab CD3, 300muscarinic cholinoceptors,

100, 188, 230muscimol, 240muscle relaxants, 182,

184–187, 226myasthenia gravis, 102mycobacterial infections,

274, 280–281M. leprae, 280M. tuberculosis, 280

mycophenolate mofetil,300

mycoses, 282–283mydriatics, 104myocardial infarction, 128,

148, 226, 309–310myocardial insufficiency,

92, 132myocardium

contraction, 128, 129oxygen demand, 306,307oxygen supply, 306, 307relaxation, 128, 129

myometrial relaxants, 126myometrial stimulants,

126myosin kinase, 84

N

Na channel blockers, 128,134–137, 204

nabilone, 330NaCl reabsorption, kidney,

160, 161nadolol, 322naftidine, 282nalbuphine, 212, 215nalidixic acid, 274naloxone, 210, 211, 214,

215, 302naltrexone, 214nandrolone, 252naphazoline, 90, 326naproxene, 200nasal decongestion, 90Naunyn, Bernhard, 3nausea, 330–331

see also antiemetics;motion sickness

nazatidine, 116


nebulizers, 13, 14Necator americanus, 292nedocromil, 116negative bathmotropism,

134negative chronotropism,

134negative dromotropism,

134negative inotropism, 134nelfinavir, 288nematode parasites, 292neomycin, 278, 279neoplasms, see cancer;

carcinomaneostigmine, 102, 103, 184nephron, 160, 161netilmicin, 278neurohypophyseal (NH)

hormones, 242neurohypophysis, 242, 243

nicotine effects, 110neuroleptanalgesia, 216,

236neuroleptanesthesia, 216neuroleptics, 114, 216, 240

epilepsy and, 190mania treatment, 234schizophrenia treatment,236–238thermoregulation and,202, 203

neuromuscular transmis-sion, 182, 183blocking, 184

neurotic disorders, 226neutral antagonists, 60neutrophils, 72nevirapine, 288nicotine, 108–113

effects on body func-tions, 110–111ganglionic action, 108ganglionic transmission,108, 109

nicotinic acid, 118, 156nicotinic cholinoceptors,

64, 65, 100, 108, 182nifedipine, 122, 123, 126,

308hypertension treatment,312mania treatment, 234

nimodipine, 122, 234nitrate tolerance, 120nitrates, organic, 120–121nitrazepam, 222nitrendipine, 122nitric acid, 120nitric oxide (NO), 100, 116,

120, 148nitroglycerin, 120, 308,

311, 312nitroimidazole, 274, 275nitrostigmine, 102nitrous oxide (N2O), 218,

219nizatidine, 168nociceptors, 194, 196non-insulin-dependent di-

abetes mellitus,262–264

noncovalent bonds, 58nondepolarizing muscle

relaxants, 184, 185nonsteroidal antiinflam-

matory drugs (NSAIDS),38,198, 200–201gout treatment, 316pharmacokinetics, 200rheumatoid arthritistreatment, 320

noradrenaline, see norepi-nephrine

nordazepam, 228norepinephrine, 82, 83, 88,

118biotransformation, 36,37local anesthesia and, 206neuronal re-uptake, 82,230release of, 90, 91structure-activity rela-tionships, 86, 87synthesis, 82, 88

norethisterone, 254norfloxacin, 274nortriptyline, 232noscapine, 212, 324nose drops, 8, 9nucleoside inhibitors, 288,

289nystatin, 282, 283

O

obesity, diabetes mellitusand, 262, 263

obidoxime, 304, 305octreotide, 242ofloxacin, 274ointments, 12, 13, 16, 17olanzapine, 238omeprazole, 168ondansetron, 116, 330opioids, 178, 210–215, 302

effects, 210–212metabolism, 212, 213mode of action, 210tolerance, 214

opium, 4tincture, 4, 5, 178

oral administration, 8–11,18, 19, 22dosage schedule, 50

oral contraceptives, 254,256–257biphasic preparations,256, 257minipill, 256, 257monophasic prepara-tions, 256, 257morning-after pill, 256

oral rehydration solution,178

orciprenaline, 86, 87organ preparation studies,

54organophosphate insecti-

cide poisoning, 304, 305organophosphates, 102ornipressin, 164, 165osmotic diuretics, 160, 161osteomalacia, 192osteopenia, 318osteoporosis, 264,

318–319ouabain, 132overdosage, 70, 71ovulation, 254

inhibition, 256stimulation, 256

oxacillin, 270, 271oxalate, 142oxatomide, 116oxazepam, 228oxiconazole, 282

380 Index


Index 381

oxidases, mixed-function,32

oxidation reactions, 36, 37oxymetazoline, 326oxytocin, 126, 242, 243

P

p-aminobenzoic acid (PA-BA), 272, 273

paclitaxel, 296, 297pain, 194, 195

see also analgesicspalliative therapy, 296pamidronate, 318pancreatic enzymes, 180,

181pancreozymin, 180pancuronium, 184, 185pantoprazole, 168Papaver somniferum, 4papaverine, 210Paracelsus, 2paracetamol, see acetami-

nophenparaffinomas, 174paraoxon, 36, 102, 103parasitic infections,

292–295parasympathetic nervous

system, 80, 98–107anatomy, 98drugs acting on,102–107responses to activation,98, 99

parasympatholytics,104–107, 128, 134, 324contraindications for,106

parasympathomimetics,102–103, 128direct, 102, 103indirect, 102, 103

parathion, 102biotransformation, 36,37

parathormone, 264, 265paravertebral ganglia, 82parenteral administration,

12, 13Parkinsonism

antiparkinsonian drugs,188–190pseudoparkinsonism,238treatment, 88, 106, 114

paromomycin, 278paroxetine, 232partial agonists, 60pastes, 12, 13, 16, 17patient compliance, 48pectin, 178penbutolol, 94penciclovir, 286D-penicillamine, 302, 303,

320penicillinase, 270, 271penicillins, 267–270, 271

elimination, 268penicillin G, 72, 266,268–270, 271penicillin V, 270, 271

Penicillium notatum, 268pentazocine, 210, 212, 214,

215pentobarbital, 223

biotransformation, 36,37

peptic ulcers, 104, 106,166–169

peptidases, 34peptide synthetase, 276peptidoglycan, 268perchlorate, 246, 247pergolide, 114, 126, 188perindopril, 124perineurium, 206peristalsis, 170, 171, 173permethrin, 292pernicious anemia, 138perphenazine, 330pethidine, 210pharmacodynamics, 4pharmacogenetics, 70pharmacokinetics, 4, 6,

44–51accumulation, 48, 49, 50,51concentration timecourse, 46–49, 68, 69protein binding, 30see also elimination ofdrugs

pharmacology, history of,2–4

pharyngitis, 324α-phase, 46β-phase, 46phase I reactions in drug


phase II reactions in drugbiotransformation, 32,34

phenacetin, 36phencyclidine, 240pheniramine, 114phenobarbital, 138, 190,

191, 192, 222enzyme induction, 32, 33

phenolphthalein, 174phenothiazines, 236, 238,

330phenoxybenzamine, 90phenoxymethylpenicillin,

270phentolamine, 90, 312phenylbutazone, 200, 316phenylephrine, 86phenytoin, 130, 136

epilepsy treatment, 190,191, 192folic acid absorption and,138

phobic disorders, 226phosphodiesterase, 66

inhibitors, 128phospholipase A2, 248phospholipase C, 66, 100,

150phospholipid bilayer, 20,

26as barrier, 22

phospholipids, 20, 26phosphoric acid, 20physostigmine, 102, 103,

106, 302pilocarpine, 102pindolol, 94, 95pinworm, 292, 293pipecuronium, 184piperacillin, 270piperazine, 236, 238pirenzepine, 104, 107, 166piretanide, 162piroxicam, 200, 320


pizotifen, 322placebo effect, 76, 77placebo-controlled trials,

76placental barrier, 24Plantago, 170plasma volume expanders,

152–153plasmalemma, 20plasmin, 146

inhibitors, 146plasminogen, 144, 146

activators, 146Plasmodium falciparum,

294Plasmodium ovale, 294Plasmodium vivax, 294platelet activating factor

(PAF), 148, 150platelet cyclooxygenase,

150, 151platelet factor 3 (PF3), 142platelets, 148, 149, 196

inhibitors of aggregation,150, 151

plicamycin, 264poisoning

antidotes, 302–305atropine, 106, 202, 302

polidocanol, 208polyarthritis, chronic, 320polyene antibiotics, 282,

283polymyxins, 266, 267portal vein, 32, 33potassium (K+) channel ac-

tivation, 66potassium-sparing diuret-

ics, 164, 165potency, 54, 60, 61potentiation, 76powders, 12, 13, 16, 17pramipexole, 188pravastatin, 156praziquantel, 292, 293prazosin, 90preclinical testing, 6prednisolone, 36, 248, 249prednisone, biotransfor-

mation, 36pregnancy

drug toxicity, 74, 75

hypertension treatment,312vomiting, 330, 331

pregnandiol, 254, 255premedication, 104, 106,

226prevertebral ganglia, 82prilocaine, 208, 209


primaquine, 294, 295primary biliary cirrhosis,

180primidone, 138, 192pro-opiomelanocortin,

210, 211probenecid, 268, 269, 316,

317probucol, 156procainamide, 134, 136procaine, 134, 208, 209,

268biotransformation, 34,35

prodrugs, 34prodynorphin, 210proenkephalin, 210, 211progabide, 190progesterone, 254, 255,

257progestin preparations,

254oral contraceptives, 256

proguanil, 294, 295prokinetic agents, 116prolactin, 242, 243prolactin release inhibiting

hormone (PRIH), 242prolactin-releasing hor-

mone (PRH), 242promethazine, 114propafenone, 136propofol, 220, 221propranolol, 94, 95, 322

biotransformation, 36,37enantioselectivity, 62

propylthiouracil, 247propyphenazone, 198prospective trials, 76prostacyclin, 116, 118,

148, 150, 196

prostaglandin synthase in-hibitors, 320

prostaglandins, 126, 168,196, 197, 320NSAIDS and, 200, 201

prostatebenign hyperplasia, 90,252, 312carcinoma, 242hypertrophy, 106

protamine, 144protease inhibitors, 288,

289protein binding, of drugs,

30–31protein kinase A, 66protein synthesis, 276

inhibitors, 276–279protein synthesis-regulat-

ing receptors, 64, 65protirelin, 242pseudocholinesterase defi-

ciency, 186pseudoparkinsonism, 238psilocin, 240psilocybin, 116, 240psychedelic drugs,

116–118, 240, 241psychological dependence,

210–212psychomimetics, 240, 241psychopharmacologicals,

226–241psychosomatic un-

coupling, 232, 236purgatives, 170–177

dependence, 172, 173pyrazinamide, 280, 281pyridostigmine, 102pyridylcarbinol, 156pyrimethamine, 294, 295pyrogens, 202, 203

Q

quinapril, 124quinidine, 136, 295quinine, 2944-quinolone-3-carboxylic

acid, 274, 275

382 Index


Index 383

R

racemates, 62, 63raloxifen, 254ramipril, 124ranitidine, 116, 168rapid eye movement

(REM) sleep, 222, 223reactive hyperemia, 90, 91receptor-mediated endo-

cytosis, 26, 27receptors, 20

drug binding, 56types of, 64–65

rectal administration, 12,18, 19

reduction reactions, 36, 37renal failure, prophylaxis,

158renal tubular secretion, 40renin, 124, 158renin-angiotensin-aldoste-

rone (RAA) system, 118,125, 158inhibitors of, 124–125

reserpine, 96, 114resistance, 266, 267respiratory tract, 22

inhalation of drugs, 14,15, 18, 19

retarded drug release, 10,11

reteplase, 146retrospective trials, 76reverse transcriptase, 288

inhibitors, 288, 289Reye’s syndrome, 198rheumatoid arthritis, 302,

320–321rhinitis, 324ribonucleic acid (RNA),

274synthesis inhibition, 298,299

ribosomes, 276ricinoleic acid, 174, 175rifabutin, 274rifampin, 267, 274, 280,

281risk:benefit ratio, 70risperidone, 238, 240ritodrine, 126ritonavir, 288

rocuronium, 184rolitetracycline, 278ropinirole, 188rosiglitazone, 262rough endoplasmic reticu-

lum (rER), 32, 33roundworms, 292, 293

S

salazosulfapyridine, 272salbutamol, 86, 328salicylates, 200salicylic acid, 34

see also acetylsalicylicacid

salmeterol, 328Salmonella typhi, 270, 271saluretics, see diureticssaquinavir, 288, 289sarcoplasmic reticulum,

182Sarcoptes scabiei, 292sartans, 124Schistosoma, 292schizophrenia, 118, 236,

237Schmiedeberg, Oswald, 3scopolamine, 106, 107,

240, 330sea sickness, 106, 330, 331sedation, 222, 226

scopolamine, 106seizures, 190, 226selectivity, lack of, 70, 71selegiline, 88, 188senna, 174, 176sensitivity

increased, 70, 71variation, 52

sensitization, 72serotonin, 88, 116–118

actions, 116neuronal reuptake, 230platelet activation, 148,150receptors, 116, 230, 322

serotonin-selective reup-take inhibitors (SSRI),230, 232

sertindole, 238sertraline, 232Sertümer, F.W., 4

serum sickness, 72sibutramine, 88side effects, 70–75signal transduction, 64, 66

lithium ion effects, 234simethicone, 180simile principle, 76simvastatin, 156sinus bradycardia, 134sinus tachycardia, 92, 134sisomycin, 278skin

as barrier, 22disinfection, 290, 291protection, 16, 17transdermal drug deliv-ery systems, 12, 13, 18,19

sleep, 222, 223disturbances, 118, 222,224sleep-wake cycle, 224,225

slow-release tablets, 10smoking, 112–113

see also nicotinesmooth endoplasmic retic-

ulum (sER), 32, 33smooth muscle

acetylcholine effects,100, 101adrenoceptor activationeffects, 84drugs acting on,126–127relaxation of, 104, 120,122, 326vascular, 118, 120, 122,196, 326

sodium channel blockers,128, 134–137, 204

sodium chloride reabsorp-tion, kidney, 160, 161

sodium citrate, 264sodium methohexital, 221sodium monofluorophos-

phate, 318sodium nitroprusside, 120,

312sodium picosulfate, 174sodium thiopental, 221solutions, 8, 17

concentration of, 28


injectable, 12somatic nervous system,

80somatocrinin, 242somatostatin, 242somatotropic hormone

(STH), 242, 243soporifics, 222sorbitol, 160, 170sore throat, 324, 325sotalol, 136spasmolytics, 126, 127spasticity, 226spermatogenesis stimula-

tion, 252spiramycin, 276spironolactone, 164, 165stage fright, 92stanozolol, 252Staphylococcus bacteria,

270statins, 156status epilepticus, 190, 192stavudine, 288steady state, 48steal effect, 306stereoisomerism, 62sterilization, 290steroid receptors, 64steroids, anabolic, 252Straub tail phenomenon,

52, 53streptokinase, 144, 310Streptomyces bacteria,

276, 277, 300, 302streptomycin, 276, 280,

281stress, sleep disturbances

and, 224, 225stroke, 148Strongyloides stercoralis,

292strychnine, 182subcutaneous injection,

18, 19subliminal dosing, 52sublingual drug adminis-

tration, 18, 19, 22succinylcholine, 186sucralfate, 168, 169sulbactam, 270sulfadoxine, 294, 295

sulfamethoxazole, 272,273

sulfapyridine, 272sulfasalazine, 272, 320sulfinpyrazone, 316sulfonamides

antibacterial, 267, 272,273diuretics, 162, 163

sulfonylurea, 262sulfotransferases, 38sulfoxidations, 36sulprostone, 126sulthiame, 162sumatriptan, 116, 322suppositories, 12, 13suspensions, 8swallowing problems, 324sweat glands

atropine poisoning and,106sympathetic innervation,80

sympathetic nervoussystem, 80–97drugs acting on, 84–97responses to activation,80, 81structure of, 82

sympatholyticsα-sympatholytics, 90, 91β-sympatholytics, 92, 93,94, 95non-selective, 90selective, 90

sympathomimetics, 90, 91,128, 132, 314allergic disorder treat-ment, 326asthma treatment, 328bronchodilation, 126common cold treatment,324, 325direct, 84, 86indirect, 86, 88, 89intrinsic activity (IS), 94sinus bradycardia and,134structure-activity rela-tionships, 86, 87

synapseadrenergic, 82cholinergic, 100

synapsin, 100synovectomy, 320syrups, 8

T

T lymphocytes, 72, 300tablets, 8–10

vaginal, 12, 13tachycardia, 134

atropine poisoning and,106treatment, 92, 122, 134

tachyphylaxis, 88tacrine, 102tacrolimus, 300tamoxifen, 254tape worms, 292, 293tardive dyskinesia, 238tazobactam, 270temazepam, 222, 224teniposide, 298teratogenicity, 74terazosin, 90terbutaline, 84, 86, 326,

328testing

clinical, 6preclinical, 6

testosterone, 34, 242, 252,253esters, 252

testosterone heptanoate,252

testosterone propionate,252

testosterone undecanoate,34, 252

tetanus toxin, 182, 183tetracaine, 208, 324tetracyclines, 266, 267,

276–279tetrahydrocannabinol, 240tetrahydrofolic acid (THF),

272, 298, 299tetrahydrozoline, 90, 326thalidomide, 74thallium salt poisoning,

304theophylline, 118, 126,

127, 326, 328thermoregulation, 196,

202–203

384 Index


Index 385

thiamazole, 247thiazide diuretics, 132,

162, 163, 312thiazolidinediones,

262–264thio-TEPA, 298thioamides, 246, 247thiopental, 220thiourea derivatives, 246thioureylenes, 246thioxanthenes, 236, 238thrombasthenia, 148thrombin, 150thrombocytopenia, 72thromboses, 142, 148, 158

prophylaxis, 142–143,146, 148–151

thromboxane, 148, 150,196

thymeretics, 230, 232thymidine kinase, 286thymoleptics, 230, 238thyroid hormone recep-

tors, 64thyroid hormone therapy,

244–245thyroid hyperfunction, 202thyroid peroxidase, 246thyroid stimulating hor-

mone (TSH), 242, 243,244

thyrotropin, 242thyrotropin-releasing hor-

mone (TRH), 242thyroxine, 244, 245, 246tiagabin, 190ticarcillin, 270ticlopidine, 150tight junctions, 22, 24timed-release capsules, 10timidazole, 274timolol, 94tincture, 4tirofiban, 150tissue plasminogen activa-

tor (t-PA), 146tizanidine, 182tobacco smoking, 112–113

see also nicotinetobramycin, 277, 278tocainide, 136tocolysis, 84, 127tocolytics, 126

tolbutamide, 262tolonium chloride, 304,

305Toluidine Blue, 304, 305tonsillitis, 324topiramate, 191, 192topoisomerase II, 274total intravenous anesthe-

sia (TIVA), 216toxicological investiga-

tions, 6tracheitis, 324tramadol, 210trandolapril, 124tranexamic acid, 16transcytosis, 24, 26transdermal drug delivery

systems, 12, 13, 18, 19estrogen preparations,254

transferrin, 140transmitter substances, 20

cholinergic synapse, 100sympathetic, 82

transpeptidase, 268inhibition of, 268, 270

transportmembrane permeation,26, 27mucociliary, 14

transport proteins, 20tranylcypromine, 88, 232travel sickness, 106trials, clinical, 76triamcinolone, 248, 249triamterene, 164, 165triazolam, 222, 223, 224,

226triazole derivatives, 282Trichinella spiralis, 292,

293trichlormethiazide, 162Trichomonas vaginalis,

274, 275Trichuris trichiura, 292tricyclic antidepressants,

230–232trifluperazine, 236, 238,

239triflupromazine, 236, 238,

239triglycerides, 154–156,

248

triiodothyronine, 244, 245trimeprazine, 330trimethaphan, 108trimethoprim, 267, 272,

273triptorelin, 242troglitazone, 262–264trolnisetron, 330tropisetron, 116tuberculosis, 274, 276, 280d-tubocurarine, 184, 185tumours, see cancer; carci-

nomatyramine, 232L-tyrosine, 82tyrosine kinase activity, 64tyrothricin, 266, 267

U

ulcers, peptic, 104, 106,166–169

ultralente, 258uricostatics, 316, 317uricosurics, 316, 317urine, drug elimination, 40urokinase, 146ursodeoxycholic acid

(UDCA), 180

V

vaccinations, 284vaginal tablets, 12, 13vagus nerve, 98valacyclovir, 286valproate, 190, 192, 234valproic acid, 191, 192van der Waals’ bonds, 58,

59vancomycin, 267, 268, 270vanillylmandelic acid, 82varicosities, 82vasculitis, 72vasoactive intestinal pep-

tide (VIP), 242vasoconstriction, 84, 90

nicotine and, 110serotonin actions, 116

vasoconstrictors, local an-esthesia and, 206

vasodilation, 84local anesthesia and, 206


serotonin actions, 116vasodilators, 118–123, 312

calcium antagonists,122–123organic nitrates,120–121

vasopressin, 148, 160, 164,165, 242nicotine and, 110

vecuronium, 184vegetable fibers, 170verapamil, 122, 123, 136

angina treatment, 308hypertension and, 312mania treatment, 234ventricular rate modifi-cation, 134

Vibrio cholerae, 178vidarabine, 285, 386vigabatrin, 190, 191vinblastine, 296vincristine, 296viomycin, 280viral infections, 178,

284–289AIDS, 288–289common cold, 324–325

virustatic antimetabolites,284–287

vitamin A derivatives, 74vitamin B12, 138, 139

deficiency, 138vitamin D, 264vitamin D hormone, 264,

265vitamin K, 144, 145VLDL particles, 154volume of distribution, 28,

44vomiting

drug-induced, 330pregnancy, 330, 331see also antiemetics;motion sickness

Von-Willebrandt factor,148, 149

W

Wepfer, Johann Jakob, 3whipworm, 292Wilson’s disease, 302wound disinfection, 290,

291

X

xanthine oxidase, 316, 317xanthinol nicotinate, 156xenon, 218xylometazoline, 90

Z

zafirlukast, 328zalcitabine, 288zero-order kinetics, 44zidovudine, 289zinc insulin, 258Zollinger-Ellison syn-

drome, 168zolpidem, 222zonulae occludentes, 22,

24, 206zopiclone, 222

386 Index


color atlas of pharmacology 2nd edition

Education

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pharmacology atlases

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