re K III

Color Atlas of

Pharmacology

edition, revised and expanded

Heinz Lüllmann, M.D.

Professor Emeritus

Department of Pharmacology

University of Kiel

Germany

Klaus Mohr, M.D.

Professor

Department of Pharmacology

and Toxicology

Institute of Pharmacy

University of Bonn

Germany

Albrecht Ziegler, Ph.D.

Professor

Department of Pharmacology

University of Kiel

Germany

Detlef Bieger, M.D.

Professor

Division of Basic Medical Sciences

Faculty of Medicine

Memorial University of

Newfoundland

St. John’s, Newfoundland

Canada

164 color plates by Jürgen Wirth

Thieme

Stuttgart · New York · 2000

Library of Congress Cataloging-in-Publication

Data

Taschenatlas der Pharmakologie. English.

Color atlas of pharmacology / Heinz Lullmann … [et al.] ; color

plates by Jurgen Wirth. — 2nd ed., rev. and expanded.

p. cm.

Rev. and expanded translation of: Taschenatlas der Pharmakologie.

3rd ed. 1996.

Includes bibliographical references and indexes.

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

1. Pharmacology Atlases. 2. Pharmacology Handbooks, manuals, etc.

I. Lullmann, Heinz. II. Title.

[DNLM: 1. Pharmacology Atlases. 2. Pharmacology Handbooks. QV

17 T197c 1999a]

RM301.12.T3813 1999

615’.1—dc21

DNLM/DLC

for Library of Congress 99-33662

CIP

Illustrated by Jürgen Wirth, Darmstadt, Ger-

many

This book is an authorized revised and ex-

panded translation of the 3rd German edition

published and copyrighted 1996 by Georg

Thieme Verlag, Stuttgart, Germany. Title of the

German edition:

Taschenatlas der Pharmakologie

Some of the product names, patents and regis-

tered designs referred to in this book are in

fact registered trademarks or proprietary

names even though specific reference to this

fact is not always made in the text. Therefore,

the appearance of a name without designation

as proprietary is not to be construed as a

representation by the publisher that it is in the

public domain.

This book, including all parts thereof, is legally

protected by copyright. Any use, exploitation

or commercialization outside the narrow lim-

its set by copyright legislation, without the

publisher’s consent, is illegal and liable to

prosecution. This applies in particular to pho-

tostat reproduction, copying, mimeographing

or duplication of any kind, translating, prepa-

ration of microfilms, and electronic data pro-

cessing and storage.

D-70469 Stuttgart, Germany

Thieme New York, 333 Seventh Avenue, New

York, NY 10001, USA

Typesetting by Gulde Druck, Tübingen

Printed in Germany by Staudigl, Donauwörth

ISBN 3-13-781702-1 (GTV)

ISBN 0-86577-843-4 (TNY) 123456

Important Note: Medicine is an ever-chang-

ing science undergoing continual develop-

ment. Research and clinical experience are

continually expanding our knowledge, in par-

ticular our knowledge of proper treatment and

drug therapy. Insofar as this book mentions

any dosage or application, readers may rest as-

sured that the authors, editors and publishers

have made every effort to ensure that such ref-

erences are in accordance with the state of

knowledge at the time of production of the

book.

Nevertheless this does not involve, imply, or

express any guarantee or responsibility on the

part of the publishers in respect of any dosage

instructions and forms of application stated in

the book. Every user is requested toexamine

carefully the manufacturers’ leaflets accompa-

nying each drug and to check, if necessary in

consultation with a physician or specialist,

whether the dosage schedules mentioned

therein or the contraindications stated by the

manufacturers differ from the statements

made in the present book. Such examination is

particularly important with drugs that are

either rarely used or have been newly released

on the market. Every dosage schedule or ev-

ery form of application used is entirely at the

user’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.

Preface

The present second edition of the Color Atlas of Pharmacology goes to print six years

after the first edition. Numerous revisions were needed, highlighting the dramatic

continuing progress in the drug sciences. In particular, it appeared necessary to in-

clude novel therapeutic principles, such as the inhibitors of platelet aggregation

from the group of integrin GPIIB/IIIA antagonists, the inhibitors of viral protease, or

the non-nucleoside inhibitors of reverse transcriptase. Moreover, the re-evaluation

and expanded use of conventional drugs, e.g., in congestive heart failure, bronchial

asthma, or rheumatoid arthritis, had to be addressed. In each instance, the primary

emphasis was placed on essential sites of action and basic pharmacological princi-

ples. Details and individual drug properties were deliberately omitted in the interest

of 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 a

textbook 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 of

information in a concise format; and, finally, to enable the experienced therapist to

recall certain factual data, with perhaps some occasional amusement.

Our cordial thanks go to the many readers of the multilingual editions of the Color

Atlas for their suggestions. We are indebted to Prof. Ulrike Holzgrabe, Würzburg,

Doc. Achim Meißner, Kiel, Prof. Gert-Hinrich Reil, Oldenburg, Prof. Reza Tabrizchi, St.

John’s, Mr Christian Klein, Bonn, and Mr Christian Riedel, Kiel, for providing 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 Lüllmann

Klaus Mohr

Albrecht Ziegler

Detlef Bieger

Jürgen Wirth

Fall 1999

Contents

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

History of Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2

Drug Sources

Drug and Active Principle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4

Drug Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

Drug Administration

Dosage Forms for Oral, and Nasal Applications . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

Dosage Forms for Parenteral Pulmonary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

Rectal or Vaginal, and Cutaneous Application . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

Drug Administration by Inhalation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14

Dermatalogic Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16

From Application to Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18

Cellular Sites of Action

Potential Targets of Drug Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20

Distribution in the Body

External Barriers of the Body . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22

Blood-Tissue Barriers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24

Membrane Permeation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26

Possible Modes of Drug Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28

Binding to Plasma Proteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30

Drug Elimination

The Liver as an Excretory Organ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32

Biotransformation of Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34

Enterohepatic Cycle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38

The Kidney as Excretory Organ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40

Elimination of Lipophilic and Hydrophilic Substances . . . . . . . . . . . . . . . . . . . . . 42

Pharmacokinetics

Drug Concentration in the Body as a Function of Time.

First-Order (Exponential)Rate Processes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44

Time Course of Drug Concentration in Plasma . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46

Time Course of Drug Plasma Levels During Repeated

Dosing and During Irregular Intake . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48

Accumulation: Dose, Dose Interval, and Plasma Level Fluctuation . . . . . . . . . . 50

Change in Elimination Characteristics During Drug Therapy . . . . . . . . . . . . . . . 50

Quantification of Drug Action

Dose-Response Relationship . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52

Concentration-Effect Relationship – Effect Curves . . . . . . . . . . . . . . . . . . . . . . . . 54

Concentration-Binding Curves . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56

Drug-Receptor Interaction

Types of Binding Forces . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58

Agonists-Antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60

Enantioselectivity of Drug Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62

Receptor Types . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64

Mode of Operation of G-Protein-Coupled Receptors . . . . . . . . . . . . . . . . . . . . . . 66

Time Course of Plasma Concentration and Effect . . . . . . . . . . . . . . . . . . . . . . . . . 68

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

Contents VII

Drug Allergy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72

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

Drug-independent Effects

Placebo – Homeopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76

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

Drug Acting on the Sympathetic Nervous System

Sympathetic Nervous System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80

Structure of the Sympathetic Nervous System . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82

Adrenoceptor Subtypes and Catecholamine Actions . . . . . . . . . . . . . . . . . . . . . . 84

Structure – Activity Relationship of Sympathomimetics . . . . . . . . . . . . . . . . . . . 86

Indirect Sympathomimetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88

α-Sympathomimetics, α-Sympatholytics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90

β-Sympatholytics (β-Blockers) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92

Types of β-Blockers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94

Antiadrenergics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96

Drugs Acting on the Parasympathetic Nervous System

Parasympathetic Nervous System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98

Cholinergic Synapse . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100

Parasympathomimetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102

Parasympatholytics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104

Nicotine

Ganglionic Transmission . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108

Effects of Nicotine on Body Functions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110

Consequences of Tobacco Smoking . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112

Biogenic Amines

Biogenic Amines – Actions and

Pharmacological Implications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114

Serotonin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116

Vasodilators

Vasodilators – Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118

Organic Nitrates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120

Calcium Antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122

Inhibitors of the RAA System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124

Drugs Acting on Smooth Muscle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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

Cardiac Drugs

Overview of Modes of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128

Cardiac Glycosides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130

Antiarrhythmic Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 134

Electrophysiological Actions of Antiarrhythmics of

the Na

-Channel Blocking Type . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 136

Antianemics

Drugs for the Treatment of Anemias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138

Iron Compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 140

Antithrombotics

Prophylaxis and Therapy of Thromboses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142

Coumarin Derivatives – Heparin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144

Fibrinolytic Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146

Intra-arterial Thrombus Formation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148

Formation, Activation, and Aggregation of Platelets . . . . . . . . . . . . . . . . . . . . . . . 148

Inhibitors of Platelet Aggregation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 150

Presystemic Effect of Acetylsalicylic Acid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 150

Adverse Effects of Antiplatelet Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 150

Plasma Volume Expanders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 152

Drugs used in Hyperlipoproteinemias

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

Diuretics

Diuretics – An Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158

NaCI Reabsorption in the Kidney . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160

Osmotic Diuretics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160

Diuretics of the Sulfonamide Type . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 162

Potassium-Sparing Diuretics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 164

Antidiuretic Hormone (/ADH) and Derivatives . . . . . . . . . . . . . . . . . . . . . . . . . . . 164

Drugs for the Treatment of Peptic Ulcers

Drugs for Gastric and Duodenal Ulcers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 166

Laxatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 170

Antidiarrheals

Antidiarrheal Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 178

Other Gastrointestinal Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 180

Drugs Acting on Motor Systems

Drugs Affecting Motor Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 182

Muscle Relaxants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 184

Depolarizing Muscle Relaxants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 186

Antiparkinsonian Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 188

Antiepileptics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 190

Drugs for the Suppression of Pain, Analgesics,

Pain Mechanisms and Pathways . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 194

Antipyretic Analgesics

Eicosanoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 196

Antipyretic Analgesics and Antiinflammatory Drugs

Antipyretic Analgesics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 198

Antipyretic Analgesics

Nonsteroidal Antiinflammatory

(Antirheumatic) Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 200

Thermoregulation and Antipyretics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 202

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

Opioids

Opioid Analgesics – Morphine Type . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 210

General Anesthetic Drugs

General Anesthesia and General Anesthetic Drugs . . . . . . . . . . . . . . . . . . . . . . . . 216

Inhalational Anesthetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 218

Injectable Anesthetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220

Hypnotics

Soporifics, Hypnotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 222

Sleep-Wake Cycle and Hypnotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 224

Psychopharmacologicals

Benzodiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 226

Pharmacokinetics of Benzodiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 228

Therapy of Manic-Depressive Illnes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 230

Therapy of Schizophrenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 236

Psychotomimetics (Psychedelics, Hallucinogens) . . . . . . . . . . . . . . . . . . . . . . . . . 240

VIII Contents

Contents IX

Hormones

Hypothalamic and Hypophyseal Hormones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 242

Thyroid Hormone Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 244

Hyperthyroidism and Antithyroid Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 246

Glucocorticoid Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 248

Androgens, Anabolic Steroids, Antiandrogens . . . . . . . . . . . . . . . . . . . . . . . . . . . . 252

Follicular Growth and Ovulation, Estrogen and

Progestin Production . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 254

Oral Contraceptives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 256

Insulin Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 258

Treatment of Insulin-Dependent

Diabetes Mellitus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 260

Treatment of Maturity-Onset (Type II)

Diabetes Mellitus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 262

Drugs for Maintaining Calcium Homeostasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 264

Antibacterial Drugs

Drugs for Treating Bacterial Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 266

Inhibitors of Cell Wall Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 268

Inhibitors of Tetrahydrofolate Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 272

Inhibitors of DNA Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 274

Inhibitors of Protein Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 276

Drugs for Treating Mycobacterial Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 280

Antifungal Drugs

Drugs Used in the Treatment of Fungal Infection . . . . . . . . . . . . . . . . . . . . . . . . . 282

Antiviral Drugs

Chemotherapy of Viral Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 284

Drugs for Treatment of AIDS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 288

Disinfectants

Disinfectants and Antiseptics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 290

Antiparasitic Agents

Drugs for Treating Endo- and Ectoparasitic Infestations . . . . . . . . . . . . . . . . . . . 292

Antimalarials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 294

Anticancer Drugs

Chemotherapy of Malignant Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 296

Immune Modulators

Inhibition of Immune Responses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 300

Antidotes

Antidotes and treatment of poisonings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 302

Therapy of Selected Diseases

Angina Pectoris . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 306

Antianginal Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 308

Acute Myocardial Infarction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 310

Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 312

Hypotension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 314

Gout . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 316

Osteoporosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 318

Rheumatoid Arthritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 320

Migraine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 322

Common Cold . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 324

Allergic Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 326

Bronchial Asthma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 328

Emesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 330

Further Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 332

Drug Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 334

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 368

X Contents

General Pharmacology

History of Pharmacology

Since time immemorial, medicaments

have been used for treating disease in

humans and animals. The herbals of an-

tiquity describe the therapeutic powers

of certain plants and minerals. Belief in

the curative powers of plants and cer-

tain substances rested exclusively upon

traditional knowledge, that is, empirical

information not subjected to critical ex-

amination.

The Idea

Claudius Galen(129 –200 A.D.) first at-

tempted to consider the theoretical

background of pharmacology. Both the-

ory and practical experience were to

contribute equally to the rational use of

medicines through interpretation of ob-

served and experienced results.

“The empiricists say that all is found by

experience. We, however, maintain that it

isfound in part by experience, in part by

theory. Neither experience nor theory

alone is apt todiscover all.”

The Impetus

Theophrastus von Hohenheim(1493 –

1541 A.D.), called Paracelsus, began to

quesiton doctrines handed down from

antiquity, demanding knowledge of the

active ingredient(s) in prescribed reme-

dies, while rejecting the irrational con-

coctions and mixtures of medieval med-

icine. He prescribed chemically defined

substances with such success that pro-

fessional enemies had him prosecuted

as a poisoner. Against such accusations,

he defended himself with the thesis

that has become an axiom of pharma-

cology:

“If you want to explain any poison prop-

erly,what then isn‘t a poison? All things

are poison,nothing is without poison; the

dose 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 to

clarify the matter by experiments.”

2 History of Pharmacology

History of Pharmacology 3

Foundation

Rudolf Buchheim(1820 –1879) found-

ed the first institute of pharmacology at

the University of Dorpat (Tartu, Estonia)

in 1847, ushering in pharmacology as an

independent scientific discipline. In ad-

dition to a description of effects, he

strove to explain the chemical proper-

ties of drugs.

“The science of medicines is a theoretical,

i.e., explanatory, one. It is to provide us

withknowledge by which our judgement

about theutility of medicines can be vali-

dated at thebedside.”

Consolidation – General Recognition

Oswald Schmiedeberg (1838–1921),

together with his many disciples (12 of

whom 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, and

selective toxicity emerged from the

work of, respectively, T. Frazer (1841–

1921) in Scotland, J. Langley (1852–

1925) in England, and P. Ehrlich

(1854–1915) in Germany. Alexander J.

Clark (1885–1941) in England first for-

malized receptor theory in the early

1920s by applying the Law of Mass Ac-

tion to drug-receptor interactions. To-

gether with the internist, Bernhard

Naunyn (1839–1925), Schmiedeberg

founded the first journal of pharmacolo-

gy, which has since been published

without interruption. The “Father of

American Pharmacology”, John J. Abel

(1857–1938) was among the first

Americans to train in Schmiedeberg‘s

laboratory and was founder of the Jour-

nal of Pharmacology and Experimental

Therapeutics (published from 1909 until

the present).

Status Quo

After 1920, pharmacological laborato-

ries sprang up in the pharmaceutical in-

dustry, outside established university

institutes. After 1960, departments of

clinical pharmacology were set up at

many universities and in industry.

Drug and Active Principle

Until the end of the 19

century, medi-

cines were natural organic or inorganic

products, mostly dried, but also fresh,

plants or plant parts. These might con-

tain substances possessing healing

(therapeutic) properties or substances

exerting a toxic effect.

In order to secure a supply of medi-

cally useful products not merely at the

time of harvest but year-round, plants

were preserved by drying or soaking

them in vegetable oils or alcohol. Drying

the plant or a vegetable or animal prod-

uct yielded a drug (from French

“drogue” – dried herb). Colloquially, this

term nowadays often refers to chemical

substances with high potential for phys-

ical dependence and abuse. Used scien-

tifically, this term implies nothing about

the 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 flowers

and leaves of the female cannabis plant

(hashish, marijuana), or the dried milky

exudate obtained by slashing the unripe

seed capsules of Papaver somniferum

(raw opium). Nowadays, the term is 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 exist

in the plant or crude drug, only those

that are soluble in alcohol. In the case of

opium tincture, these ingredients are

alkaloids(i.e., basic substances of plant

origin) including: morphine, codeine,

narcotine = noscapine, papaverine, nar-

ceine, and others.

Using a natural product or extract

to treat a disease thus usually entails the

administration of a number of substanc-

es possibly possessing very different ac-

tivities. Moreover, the dose of an indi-

vidual constituent contained within a

given amount of the natural product is

subject to large variations, depending

upon the product‘s geographical origin

(biotope), time of harvesting, or condi-

tions and length of storage. For the same

reasons, the relative proportion of indi-

vidual constituents may vary consider-

ably. Starting with the extraction of

morphine from opium in 1804 by F. W.

Sertürner (1783–1841), the active prin-

ciples of many other natural products

were subsequently isolated in chemi-

cally pure form by pharmaceutical la-

boratories.

The aims of isolating active principles

are:

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 chemically

pure constituents.

4. The possibility of chemical synthesis,

which would afford independence from

limited 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 effort

to 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

Preparation

opium tincture

Morphine

Codeine

Narcotine

Papaverine

etc.

Opium tincture (laudanum)

Drug Development

This process starts with the synthesisof

novel chemical compounds. Substances

with complex structures may be ob-

tained from various sources, e.g., plants

(cardiac glycosides), animal tissues

(heparin), microbial cultures (penicillin

G), or human cells (urokinase), or by

means of gene technology (human insu-

lin). As more insight is gained into struc-

ture-activity relationships, the search

for new agents becomes more clearly

focused.

Preclinical testingyields informa-

tion on the biological effects of new sub-

stances. Initial screening may employ

biochemical-pharmacological investiga-

tions (e.g., receptor-binding assays

p.56) or experiments on cell cultures,

isolated cells, and isolated organs. Since

these models invariably fall short of

replicating complex biological process-

es in the intact organism, any potential

drug 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-

tionsserve to evaluate the potential for:

(1) toxicity associated with acute or

chronic administration; (2) genetic

damage (genotoxicity, mutagenicity);

(3) production of tumors (onco- or car-

cinogenicity); and (4) causation of birth

defects (teratogenicity). In animals,

compounds under investigation also

have to be studied with respect to their

absorption, distribution, metabolism,

and elimination (pharmacokinetics).

Even at the level of preclinical testing,

only a very small fraction of new com-

pounds will prove potentially fit for use

in humans.

Pharmaceutical technology pro-

vides the methods for drug formulation.

Clinical testingstarts with Phase I

studies on healthy subjects and seeks to

determine whether effects observed in

animal experiments also occur in hu-

mans. Dose-response relationships are

determined. In Phase II, potential drugs

are first tested on selected patients for

therapeutic efficacy in those disease

states for which they are intended.

Should a beneficial action be evident

and the incidence of adverse effects be

acceptably small, Phase III is entered,

involving a larger group of patients in

whom the new drug will be compared

with standard treatments in terms of

therapeutic outcome. As a form of hu-

man experimentation, these clinical

trials are subject to review and approval

by 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 remains

from approximately 10,000 newly syn-

thesized substances.

The decision to approve a new

drug is made by a national regulatory

body (Food & Drug Administration in

the U.S.A., the Health Protection Branch

Drugs Directorate in Canada, UK, Euro-

pe, Australia) to which manufacturers

are required to submit their applica-

tions. Applicants must document by

means of appropriate test data (from

preclinical and clinical trials) that the

criteria of efficacy and safety have been

met and that product forms (tablet, cap-

sule, etc.) satisfy general standards of

quality control.

Following approval, the new drug

may be marketed under a trade name

(p. 333) and thus become available for

prescription by physicians and dispens-

ing by pharmacists. As the drug gains

more widespread use, regulatory sur-

veillance continues in the form of post-

licensing studies (Phase IV of clinical

trials). Only on the basis of long-term

experience will the risk: benefit ratio be

properly assessed and, thus, the thera-

peutic value of the new drug be deter-

mined.

6 Drug Development

Drug Development 7

Clinical

trial

Phase 4

Approval

General use

Long-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 with

standard therapy

Substances

Cells

Animals Isolated organs

(bio)chemical

synthesis

Tissue

homogenate

A. From drug synthesis to approval

10,000

Substances

Preclinical

testing:

Effects on body

functions, mechanism

of action, toxicity

ECG

EEG

Blood

sample

Blood

pressure

Substance

Phase 1 Phase 2 Phase 3

Clinical trial

Dosage Forms for Oral, Ocular, and

Nasal Applications

A medicinal agent becomes a medica-

tion only after formulation suitable for

therapeutic use (i.e., in an appropriate

dosage form). The dosage form takes

into account the intended mode of use

and also ensures ease of handling (e.g.,

stability, precision of dosing) by pa-

tients and physicians. Pharmaceutical

technologyis concerned with the design

of suitable product formulations and

quality control.

Liquid preparations (A) may take

the form of solutions, suspensions (a

sol or mixture consisting of small wa-

ter-insoluble solid drug particles dis-

persed in water), or emulsions(disper-

sion of minute droplets of a liquid agent

or a drug solution in another fluid, e.g.,

oil in water). Since storage will cause

sedimentation of suspensions and sep-

aration of emulsions, solutions are gen-

erally preferred. In the case of poorly

watersoluble substances, solution is of-

ten accomplished by adding ethanol (or

other solvents); thus, there are both

aqueous and alcoholic solutions. These

solutions are made available to patients

in specially designed drop bottles, ena-

bling single doses to be measured ex-

actly in terms of a defined number of

drops, the size of which depends on the

area of the drip opening at the bottle

mouth and on the viscosity and surface

tension of the solution. The advantage

of a drop solution is that the dose, that

is, the number of drops, can be precise-

ly adjusted to the patient‘s need. Its dis-

advantage lies in the difficulty that

some patients, disabled by disease or

age, will experience in measuring a pre-

scribed number of drops.

When the drugs are dissolved in a

larger volume — as in the case of syrups

or mixtures — the single dose is meas-

ured with a measuring spoon. Dosing

may also be done with the aid of a

tablespoon or teaspoon (approx. 15 and

5 ml, respectively). However, due to the

wide variation in the size of commer-

cially available spoons, dosing will not

be very precise. (Standardized medici-

nal teaspoons and tablespoons are

available.)

Eye dropsand nose drops (A) are

designed for application to the mucosal

surfaces of the eye (conjunctival sac)

and nasal cavity, respectively. In order

to prolong contact time, nasal drops are

formulated as solutions of increased

viscosity.

Solid dosage forms include tab-

lets, coated tablets, and capsules (B).

Tablets have a disk-like shape, pro-

duced by mechanical compression of

active substance, filler (e.g., lactose, cal-

cium sulfate), binder, and auxiliary ma-

terial (excipients). The filler provides

bulk enough to make the tablet easy to

handle and swallow. It is important to

consider that the individual dose of

many drugs lies in the range of a few

milligrams or less. In order to convey

the idea of a 10-mg weight, two squares

are marked below, the paper mass of

each weighing 10 mg. Disintegration of

the tablet can be hastened by the use of

dried starch, which swells on contact

with water, or of NaHCO

, which releas-

es CO

gas on contact with gastric acid.

Auxiliary materials are important with

regard to tablet production, shelf life,

palatability, and identifiability (color).

Effervescent tablets (compressed

effervescent powders) do not represent

a solid dosage form, because they are

dissolved in water immediately prior to

ingestion and are, thus, actually, liquid

preparations.

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

Disintegrating

agent

Other

excipients

Mixing and

forming by

compression

~0.5 – 500 mg

30 – 250 mg

20 – 200 mg

30 – 15 mg

min 100 – 1000 mg max

possible tablet size

Effervescent

tablet

Tablet

Coated tablet

Capsule

Eye

drops

Nose

drops

Solution

Mixture

Alcoholic

solution

40 drops = 1g

Aqueous

solution

20 drops = 1g

Dosage:

in drops

Dosage:

in spoon

Sterile

isotonic

pH-neutral

Viscous

solution

Drug release

Capsule

Coated

tablet

Capsule

with coated

drug pellets

Matrix

tablet

Time

5 - 50 ml

The coated tabletcontains a drug with-

in a core that is covered by a shell, e.g., a

wax coating, that serves to: (1) protect

perishable 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 or

granulated form (See. p. 9, C).

In the case of the matrix-typetab-

let, the drug is embedded in an inert

meshwork from which it is released by

diffusion upon being moistened. In con-

trast to solutions, which permit direct

absorption of drug (A, track 3), the use

of solid dosage forms initially requires

tabletsto break up and capsules to open

(disintegration) before the drug can be

dissolved (dissolution) and pass

through the gastrointestinal mucosal

lining (absorption). Because disintegra-

tion of the tablet and dissolution of the

drug take time, absorption will occur

mainly in the intestine (A, track 2). In

the case of a solution, absorption starts

in the stomach (A, track 3).

For acid-labile drugs, a coating of

wax or of a cellulose acetate polymer is

used to prevent disintegration of solid

dosage forms in the stomach. Accord-

ingly, disintegration and dissolution

will take place in the duodenum at nor-

mal speed (A, track 1) and drug libera-

tion per se is not retarded.

The liberation of drug, hence the

site and time-course of absorption, are

subject to modification by appropriate

production methods for matrix-type

tablets, coated tablets, and capsules. In

the case of the matrix tablet, the drug is

incorporated into a lattice from which it

can be slowly leached out by gastroin-

testinal fluids. As the matrix tablet

undergoes 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 that

release and absorption of drug occur ei-

ther in the proximal (A, track 1) or distal

(A, track 5) bowel. Thus, by matching

dissolution 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 the

drug is presented in the form of a granu-

late consisting of pellets coated with a

waxy 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-

sulecan also be applied to tablets. In this

case, either drug pellets coated with

films 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 tabletshave the ad-

vantage of being dividable ad libitum;

thus, fractions of the dose contained

within the entire tablet may be admin-

istered.

This kind of retarded drug release

is employed when a rapid rise in blood

level of drug is undesirable, or when ab-

sorption is being slowed in order to pro-

long the action of drugs that have a

short sojourn in the body.

10 Drug Administration

Drug Administration 11

Administration in form of

Enteric-

coated

tablet

Tablet,

capsule

Drops,

mixture,

effervescent

solution

Matrix

tablet

Coated

tablet with

delayed

release

A. Oral administration: drug release and absorption

12345

Dosage Forms for Parenteral (1),

Pulmonary (2), Rectal or Vaginal (3),

and Cutaneous Application

Drugs need not always be administered

orally(i.e., by swallowing), but may also

be given parenterally. This route usual-

ly refers to an injection, although enter-

al absorption is also bypassed when

drugs are inhaled or applied to the skin.

For intravenous, intramuscular, or

subcutaneous injections, drugs are of-

ten given as solutions and, less fre-

quently, in crystalline suspension for

intramuscular, subcutaneous, or intra-

articular injection. An injectable solu-

tion must be free of infectious agents,

pyrogens, or suspended matter. It

should have the same osmotic pressure

and pH as body fluids in order to avoid

tissue damage at the site of injection.

Solutions for injection are preserved in

airtight glass or plastic sealed contain-

ers. From ampules for multiple or sin-

gle use, the solution is aspirated via a

needle into a syringe. The cartridge am-

pule isfitted into a special injector that

enables its contents to be emptied via a

needle. An infusion refers to a solution

being administered over an extended

period of time. Solutions for infusion

must meet the same standards as solu-

tions for injection.

Drugs can be sprayed in aerosol

form onto mucosal surfaces of body cav-

ities accessible from the outside (e.g.,

the respiratory tract [p. 14]). An aerosol

is a dispersion of liquid or solid particles

in a gas, such as air. An aerosol results

when a drug solution or micronized

powder is reduced to a spray on being

driven through the nozzle of a pressur-

ized container.

Mucosal application of drug via the

rectal or vaginal route is achieved by

means of suppositories and vaginal

tablets,respectively. On rectal applica-

tion, absorption into the systemic circu-

lation may be intended. With vaginal

tablets, the effect is generally confined

to the site of application. Usually the

drug is incorporated into a fat that solid-

ifies at room temperature, but melts in

the rectum or vagina. The resulting oily

film 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. In

many cases, these do not contain drugs

but are used for skin protection or care.

However, drugs may be added if a topi-

cal action on the outer skin or, more

rarely, a systemic effect is intended.

Transdermal drug delivery

systems are pasted to the epidermis.

They contain a reservoir from which

drugs may diffuse and be absorbed

through the skin. They offer the advan-

tage that a drug depot is attached non-

invasively to the body, enabling the

drug to be administered in a manner

similar to an infusion. Drugs amenable

to 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).

12 Drug Administration

Drug Administration 13

A. Preparations for parenteral (1), inhalational (2), rectal or vaginal (3),

and percutaneous (4) application

With and without

fracture ring

Often with

preservative

Sterile, iso-osmolar

Ampule

1 – 20 ml

Cartridge

ampule 2 ml

Multiple-dose

vial 50 – 100 ml,

always with

preservative

Infusion

solution

500 – 1000 ml

Propellant gas

Drug solution

Jet nebulizer

Suppository

Vaginal

tablet

Backing layer Drug reservoir

Adhesive coat

Transdermal delivery system (TDS)

Time 12 24 h

Ointment TDS

Paste

Ointment

Powder

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 to

be 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 volatile

agents can be administered by inhala-

tion with the goal of alveolar absorption

and systemic effects (e.g., inhalational

anesthetics, p. 218). Aerosols are

formed when a drug solution or micron-

ized powder is converted into a mist or

dust, respectively.

In conventional sprays (e.g., nebu-

lizer), the air blast required for aerosol

formation is generated by the stroke of a

pump. Alternatively, the drug is deliv-

ered from a solution or powder pack-

aged in a pressurized canister equipped

with a valve through which a metered

dose is discharged. During use, the in-

haler (spray dispenser) is held directly

in front of the mouth and actuated at

the start of inspiration. The effective-

ness of delivery depends on the position

of the device in front of the mouth, the

size of aerosol particles, and the coordi-

nation between opening of the spray

valve and inspiration. The size of aerosol

particles determines the speed at which

they are swept along by inhaled air,

hence the depth of penetration into

the respiratory tract. Particles >

100µm in diameter are trapped in the

oropharyngeal cavity; those having dia-

meters between 10 and 60µm will be

deposited on the epithelium of the

bronchial tract. Particles < 2 µm in dia-

meter can reach the alveoli, but they

will be largely exhaled because of their

low tendency to impact on the alveolar

epithelium.

Drug deposited on the mucous lin-

ing of the bronchial epithelium is partly

absorbed and partly transported with

bronchial mucus towards the larynx.

Bronchial mucus travels upwards due to

the orally directed undulatory beat of

the epithelial cilia. Physiologically, this

mucociliary transport functions to re-

move inspired dust particles. Thus, only

a portion of the drug aerosol (~ 10%)

gains access to the respiratory tract and

just a fraction of this amount penetrates

the mucosa, whereas the remainder of

the aerosol undergoes mucociliary

transport to the laryngopharynx and is

swallowed. The advantage of inhalation

(i.e., localized application) is fully ex-

ploited by using drugs that are poorly

absorbed 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 portion

of an inhaled drug is absorbed in un-

changed form, administration by this

route has the advantage that drug con-

centrations at the bronchi will be higher

than in other organs.

The efficiency of mucociliary trans-

port depends on the force of kinociliary

motion and the viscosity of bronchial

mucus. Both factors can be altered

pathologically (e.g., in smoker’s cough,

bronchitis) or can be adversely affected

by drugs (atropine, antihistamines).

14 Drug Administration

Drug Administration 15

A. Application by inhalation

Depth of

penetration

of inhaled

aerosolized

drug solution

Nasopharynx

Trachea-bronchi

Bronchioli, alveoli

Drug swept up

is swallowed

Mucociliary transport

Ciliated epithelium

Low systemic burden

As complete

presystemic

elimination

as possible

As little

enteral

absorption

as possible

100 µm

10 µm

1 µm

1 cm/min

Larynx

10%

90%

Dermatologic Agents

Pharmaceutical preparations applied to

the outer skin are intended either to

provide skin care and protection from

noxious influences (A), or to serve as a

vehicle for drugs that are to be absorbed

into the skin or, if appropriate, into the

general circulation (B).

Skin Protection (A)

Protective agents are of several kinds to

meet different requirements according

to skin condition (dry, low in oil,

chapped vs moist, oily, elastic), and the

type of noxious stimuli (prolonged ex-

posure to water, regular use of alcohol-

containing disinfectants [p. 290], in-

tense solar irradiation).

Distinctions among protective

agents are based upon consistency, phy-

sicochemical properties (lipophilic, hy-

drophilic), and the presence of addi-

tives.

Dusting Powdersare sprinkled on-

to the intact skin and consist of talc,

magnesium stearate, silicon dioxide

(silica), or starch. They adhere to the

skin, forming a low-friction film that at-

tenuates mechanical irritation. Powders

exert a drying (evaporative) effect.

Lipophilic ointment(oil ointment)

consists of a lipophilic base (paraffin oil,

petroleum jelly, wool fat [lanolin]) and

may 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 and

an emulsifying wax, and are miscible

with water.

Paste (oil paste) is an ointment

containing more than 10% pulverized

constituents.

Lipophilic (oily) creamis an emul-

sion of water in oil, easier to spread than

oil paste or oil ointments.

Hydrogel and water-soluble oint-

ment achieve their consistency by

means of different gel-forming agents

(gelatin, methylcellulose, polyethylene

glycol). Lotions are aqueous suspen-

sions of water-insoluble and solid con-

stituents.

Hydrophilic (aqueous) creamis an

emulsion of an oil in water formed with

the aid of an emulsifier; it may also be

considered an oil-in-water emulsion of

an emulsifying ointment.

All dermatologic agents having a

lipophilic base adhere to the skin as a

water-repellent coating. They do not

wash off and they also prevent (oc-

clude) outward passage of water from

the skin. The skin is protected from dry-

ing, and its hydration and elasticity in-

crease.

Diminished evaporation of water

results in warming of the occluded skin

area. Hydrophilic agents wash off easily

and do not impede transcutaneous out-

put of water. Evaporation of water is felt

as 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 a

systemic action is intended (transder-

mal delivery system, e.g., nitroglycerin

patch, p. 120). The tendency for the drug

to leave the drug vehicle (V) is higher

the more the drug and vehicle differ in

lipophilicity (high tendency: hydrophil-

ic D and lipophilic V, and vice versa). Be-

cause the skin represents a closed lipo-

philic barrier (p. 22), only lipophilic

drugs are absorbed. Hydrophilic drugs

fail even to penetrate the outer skin

when applied in a lipophilic vehicle.

This formulation can be meaningful

when high drug concentrations are re-

quired at the skin surface (e.g., neomy-

cin ointment for bacterial skin infec-

tions).

16 Drug Administration

Drug Administration 17

Semi-solid

Solid Liquid

Dermatologicals

B. Dermatologicals as drug vehicles

Powder

Paste

Oily paste

Ointment

Lipophilic

ointment

Hydrophilic

ointment

Lipophilic

cream

Hydrophilic

cream

Cream

Solution

Aqueous

solution

Alcoholic

tincture

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 drug

in hydrophilic

base

Lipophilic drug

in lipophilic

base

Hydrophilic drug

in lipophilic

base

Hydrophilic drug

in hydrophilic

base

Stratum

corneum

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 organs

via the blood. Therefore, they must first

enter the blood, usually the venous limb

of the circulation. There are several pos-

sible sites of entry.

The drug may be injected or infused

intravenously,in which case the drug is

introduced directly into the blood-

stream. In subcutaneous or intramus-

cular injection, the drug has to diffuse

from its site of application into the

blood. Because these procedures entail

injury 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 drug

across the gastrointestinal mucosa into

the blood is chosen much more fre-

quently. The disadvantage of this route

is that the drug must pass through the

liver on its way into the general circula-

tion. This fact assumes practical signifi-

cance with any drug that may be rapidly

transformed or possibly inactivated in

the liver (first-pass hepatic elimination;

p. 42). Even with rectaladministration,

at least a fraction of the drug enters the

general circulation via the portal vein,

because only veins draining the short

terminal segment of the rectum com-

municate directly with the inferior vena

cava. Hepatic passage is circumvented

when absorption occurs buccally or

sublingually, because venous blood

from the oral cavity drains directly into

the superior vena cava. The same would

apply to administration by inhalation

(p. 14). However, with this route, a local

effect is usually intended; a systemic ac-

tion is intended only in exceptional cas-

es. Under certain conditions, drug can

also be applied percutaneously in the

form of a transdermaldelivery system

(p. 12). In this case, drug is slowly re-

leased from the reservoir, and then pen-

etrates the epidermis and subepidermal

connective tissue where it enters blood

capillaries. Only a very few drugs can be

applied transdermally. The feasibility of

this route is determined by both the

physicochemical properties of the drug

and the therapeutic requirements

(acute vs. long-term effect).

Speed of absorption is determined

by the route and method of application.

It is fastest with intravenousinjection,

less fast which intramuscularinjection,

and slowest with subcutaneous injec-

tion. When the drug is applied to the

oral mucosa (buccal, sublingualroute),

plasma levels rise faster than with con-

ventional oral administration because

the drug preparation is deposited at its

actual site of absorption and very high

concentrations in saliva occur upon the

dissolution of a single dose. Thus, up-

take across the oral epithelium is accel-

erated. The same does not hold true for

poorly water-soluble or poorly absorb-

able drugs. Such agents should be given

orally, because both the volume of fluid

for dissolution and the absorbing sur-

face are much larger in the small intes-

tine than in the oral cavity.

Bioavailability is defined as the

fraction of a given drug dose that reach-

es the circulation in unchanged form

and becomes available for systemic dis-

tribution. The larger the presystemic

elimination, the smaller is the bioavail-

ability of an orally administered drug.

18 Drug Administration

Drug Administration 19

Intravenous

Sublingual

buccal

Inhalational

Transdermal

Subcutaneous

Intramuscular

Oral

AortaDistribution in body

Rectal

A. From application to distribution

Potential Targets of Drug Action

Drugs are designed to exert a selective

influence on vital processes in order to

alleviate 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 that

serve to mediate controlled metabolic

exchange with the cellular environment.

These include energy-consuming

pumps (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 between

single cellsis a prerequisite for viability

of the organism, hence also for the sur-

vival of individual cells. Cell functions

are regulated by means of messenger

substances for the transfer of informa-

tion. Included among these are “trans-

mitters” released from nerves, which

the cell is able to recognize with the

help of specialized membrane binding

sites or receptors. Hormones secreted

by endocrine glands into the blood, then

into the extracellular fluid, represent

another class of chemical signals. Final-

ly, signalling substances can originate

from neighboring cells, e.g., prostaglan-

dins (p. 196) and cytokines.

The effect of a drug frequently re-

sults from interference with cellular

function. Receptors for the recognition

of endogenous transmitters are obvious

sites of drug action (receptor agonists

and antagonists, p. 60). Altered activity

of transport systems affects cell func-

tion (e.g., cardiac glycosides, p. 130;

loop diuretics, p. 162; calcium-antago-

nists, p. 122). Drugs may also directly

interfere with intracellular metabolic

processes, for instance by inhibiting

(phosphodiesterase inhibitors, p. 132)

or activating (organic nitrates, p. 120)

an enzyme (2).

In contrast to drugs acting from the

outside on cell membrane constituents,

agents acting in the cell’s interior need

to penetrate the cell membrane.

The cell membrane basically con-

sists of a phospholipid bilayer (80Å =

8nm in thickness) in which are embed-

ded proteins (integral membrane pro-

teins, such as receptors and transport

molecules). Phospholipid molecules

contain two long-chain fatty acidsin es-

ter linkage with two of the three hy-

droxyl groups of glycerol. Bound to the

third 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). In

terms of solubility, phospholipids are

amphiphilic: the tail region containing

the apolar fatty acid chains is lipophilic,

the remainder – the polar head – is hy-

drophilic. By virtue of these properties,

phospholipids aggregate spontaneously

into a bilayer in an aqueous medium,

their polar heads directed outwards into

the aqueous medium, the fatty acid

chains facing each other and projecting

into the inside of the membrane (3).

The hydrophobic interior of the

phospholipid membrane constitutes a

diffusion barrier virtually imperme-

able for charged particles. Apolar parti-

cles, however, penetrate the membrane

easily. This is of major importance with

respect to the absorption, distribution,

and elimination of drugs.

20 Cellular Sites of Action

Cellular Sites of Action 21

Nerve

Transmitter

Receptor

Enzyme

Hormone

receptors

Neural

control

Hormonal

control

Direct action

on metabolism

Cellular

transport

systems for

controlled

transfer of

substrates

Ion channel

Transport

molecule

Effect

Intracellular

site of action

Choline

Phosphoric

acid

Glycerol

Fatty acid

A. Sites at which drugs act to modify cell function

2 3

Hormones

= Drug

Phospholipid

matrix

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 body

from its surroundings, i.e., separate the

internal milieu from the external mi-

lieu. These boundaries are formed by

the skin and mucous membranes.

When absorption takes place in the

gut (enteral absorption), the intestinal

epithelium is the barrier. This single-

layered epithelium is made up of ente-

rocytes and mucus-producing goblet

cells. On their luminal side, these cells

are joined together by zonulae occlu-

dentes(indicated by black dots in the in-

set, bottom left). A zonula occludens or

tight junction is a region in which the

phospholipid membranes of two cells

establish close contact and become

joined via integral membrane proteins

(semicircular inset, left center). The re-

gion of fusion surrounds each cell like a

ring, so that neighboring cells are weld-

ed together in a continuous belt. In this

manner, an unbroken phospholipid

layer is formed (yellow area in the sche-

matic drawing, bottom left) and acts as

a continuous barrier between the two

spaces separated by the cell layer – in

the case of the gut, the intestinal lumen

(dark blue) and the interstitial space

(light blue). The efficiency with which

such a barrier restricts exchange of sub-

stances can be increased by arranging

these occluding junctions in multiple

arrays, as for instance in the endotheli-

um of cerebral blood vessels. The con-

necting proteins (connexins) further-

more serve to restrict mixing of other

functional membrane proteins (ion

pumps, 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 those

whose physicochemical properties al-

low permeation through the lipophilic

membrane interior (yellow) or that are

subject to a special carrier transport

mechanism. Absorption of such drugs

proceeds rapidly, because the absorbing

surface is greatly enlarged due to the

formation of the epithelial brush border

(submicroscopic foldings of the plasma-

lemma). The absorbability of a drug is

characterized by the absorption quo-

tient, that is, the amount absorbed di-

vided by the amount in the gut available

for absorption.

In the respiratory tract, cilia-bear-

ing epithelial cells are also joined on the

luminal side by zonulae occludentes, so

that the bronchial space and the inter-

stitium are separated by a continuous

phospholipid barrier.

With sublingual or buccal applica-

tion, a drug encounters the non-kerati-

nized, multilayered squamous epitheli-

um of the oral mucosa. Here, the cells

establish punctate contacts with each

other in the form of desmosomes (not

shown); however, these do not seal the

intercellular clefts. Instead, the cells

have the property of sequestering phos-

pholipid-containing membrane frag-

ments that assemble into layers within

the extracellular space (semicircular in-

set, center right). In this manner, a con-

tinuous phospholipid barrier arises also

inside squamous epithelia, although at

an extracellular location, unlike that of

intestinal epithelia. A similar barrier

principle operates in the multilayered

keratinized squamous epithelium of the

outer skin. The presence of a continu-

ous phospholipid layer means that

squamous epithelia will permit passage

of lipophilic drugs only, i.e., agents ca-

pable of diffusing through phospholipid

membranes, with the epithelial thick-

ness determining the extent and speed

of absorption. In addition, cutaneous ab-

sorption is impeded by the keratin

layer, the stratum corneum, which is

very 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

Nonkeratinized

squamous epithelium

Ciliated epithelium

Keratinized squamous

epithelium

Epithelium with

brush border

Blood-Tissue Barriers

Drugs are transported in the blood to

different tissues of the body. In order to

reach their sites of action, they must

leave 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 of

flow). The capillary wall forms the

blood-tissue barrier. Basically, this

consists of an endothelial cell layer and

a basement membrane enveloping the

latter (solid black line in the schematic

drawings). The endothelial cells are

“riveted” to each other by tight junc-

tions or occluding zonulae (labelled Z in

the electron micrograph, top left) such

that no clefts, gaps, or pores remain that

would permit drugs to pass unimpeded

from the blood into the interstitial fluid.

The blood-tissue barrier is devel-

oped differently in the various capillary

beds. Permeability to drugs of the capil-

lary wall is determined by the structural

and 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 solutes

trapped in the fluid, including drugs,

may traverse the blood-tissue barrier. In

this form of transport, the physico-

chemical properties of drugs are of little

importance.

In some capillary beds (e.g., in the

pancreas), 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 closed

only by diaphragms. Both the dia-

phragm and basement membrane can

be readily penetrated by substances of

low molecular weight — the majority of

drugs — but less so by macromolecules,

e.g., proteins such as insulin (G: insulin

storage 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 gutand 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 the

blood-brain barrier, drugs must diffuse

transcellularly, i.e., penetrate the lumi-

nal and basal membrane of endothelial

cells. Drug movement along this path

requires 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 between

blood and interstitium in the liver,

where endothelial cells exhibit large

fenestrations (100nm in diameter) fac-

ing Disse’s spaces (D) and where neither

diaphragms nor basement membranes

impede drug movement. Diffusion bar-

riers are also present beyond the capil-

lary wall: e.g., placental barrierof fused

syncytiotrophoblast cells; blood: testi-

cle barrier — junctions interconnecting

Sertoli cells; brain choroid plexus: blood

barrier — occluding junctions between

ependymal cells.

(Vertical bars in the EM micro-

graphs represent 1 µm; E: cross-sec-

tioned erythrocyte; AM: actomyosin; G:

insulin-containing granules.)

24 Distribution in the Body

Distribution in the Body 25

A. Blood-tissue barriers

CNS Heart muscle

Liver

Pancreas

Membrane Permeation

An ability to penetrate lipid bilayers is a

prerequisite for the absorption of drugs,

their entry into cells or cellular orga-

nelles, and passage across the blood-

brain barrier. Due to their amphiphilic

nature, phospholipids form bilayers

possessing a hydrophilic surface and a

hydrophobic interior (p. 20). Substances

may traverse this membrane in three

different ways.

Diffusion (A). Lipophilic substanc-

es (red dots) may enter the membrane

from the extracellular space (area

shown in ochre), accumulate in the

membrane, and exit into the cytosol

(blue area). Direction and speed of per-

meation depend on the relative concen-

trations in the fluid phases and the

membrane. The steeper the gradient

(concentration difference), the more

drug 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 may

penetrate membrane barriers with the

help of transport systems (carriers), ir-

respective of their physicochemical

properties, especially lipophilicity. As a

prerequisite, 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 of

being ferried across the membrane.

Membrane passage via transport mech-

anisms is subject to competitive inhibi-

tion by another substance possessing

similar affinity for the carrier. Substanc-

es lacking in affinity (blue circles) are

not transported. Drugs utilize carriers

for physiological substances, e.g., L-do-

pa uptake by L-amino acid carrier across

the blood-intestine and blood-brain

barriers (p. 188), and uptake of amino-

glycosides by the carrier transporting

basic polypeptides through the luminal

membrane of kidney tubular cells (p.

278). Only drugs bearing sufficient re-

semblance to the physiological sub-

strate of a carrier will exhibit affinity for

it.

Finally, membrane penetration

may occur in the form of small mem-

brane-covered vesicles. Two different

systems are considered.

Transcytosis (vesicular transport,

C).When new vesicles are pinched off,

substances dissolved in the extracellu-

lar fluid are engulfed, and then ferried

through the cytoplasm, vesicles (phago-

somes) undergo fusion with lysosomes

to form phagolysosomes, and the trans-

ported substance is metabolized. Alter-

natively, the vesicle may fuse with the

opposite cell membrane (cytopempsis).

Receptor-mediated endocytosis

(C). The drug first binds to membrane

surface receptors (1, 2) whose cytosolic

domains contact special proteins (adap-

tins, 3). Drug-receptor complexes mi-

grate laterally in the membrane and ag-

gregate with other complexes by a

clathrin-dependent process (4). The af-

fected membrane region invaginates

and eventually pinches off to form a de-

tached vesicle (5). The clathrin coat is

shed immediately (6), followed by the

adaptins (7). The remaining vesicle then

fuses with an “early” endosome (8),

whereupon proton concentration rises

inside the vesicle. The drug-receptor

complex dissociates and the receptor

returns into the cell membrane. The

“early” endosome delivers its contents

to predetermined destinations, e.g., the

Golgi complex, the cell nucleus, lysoso-

mes, or the opposite cell membrane

(transcytosis). Unlike simple endocyto-

sis, receptor-mediated endocytosis is

contingent on affinity for specific recep-

tors and operates independently of con-

centration gradients.

26 Distribution in the Body

Distribution in the Body 27

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

transport

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

Vesicular transport

Lysosome Phagolysosome

Intracellular ExtracellularExtracellular

Possible Modes of Drug Distribution

Following its uptake into the body, the

drug is distributed in the blood (1) and

through it to the various tissues of the

body. Distribution may be restricted to

the extracellular space (plasma volume

plus interstitial space) (2) or may also

extend into the intracellular space (3).

Certain drugs may bind strongly to tis-

sue structures, so that plasma concen-

trations fall significantly even before

elimination has begun (4).

After being distributed in blood,

macromolecular substances remain

largely confined to the vascular space,

because their permeation through the

blood-tissue barrier, or endothelium, is

impeded, even where capillaries are

fenestrated. This property is exploited

therapeutically 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 substances

bound with high affinity to plasma pro-

teins (p. 30; determination of the plas-

ma volume with protein-bound dyes).

Unbound, free drug may leave the

bloodstream, 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 in

the accompanying figures.

Distribution in the body is deter-

mined by the ability to penetrate mem-

branous barriers (p. 20). Hydrophilic

substances (e.g., inulin) are neither tak-

en up into cells nor bound to cell surface

structures and can, thus, be used to de-

termine the extracellular fluid volume

(2). Some lipophilic substances diffuse

through the cell membrane and, as a re-

sult, achieve a uniform distribution (3).

Body weight may be broken down

as follows:

Further subdivisions are shown in

the table.

The volume ratio interstitial: intra-

cellular water varies with age and body

weight. On a percentage basis, intersti-

tial fluid volume is large in premature or

normal neonates (up to 50% of body

water), and smaller in the obese and the

aged.

The concentration (c) of a solution

corresponds to the amount (D) of sub-

stance dissolved in a volume (V); thus, c

= D/V. If the dose of drug (D) and its

plasma concentration (c) are known, a

volume of distribution (V) can be calcu-

lated from V = D/c. However, this repre-

sents an apparent volume of distribu-

tion (V

app

), because an even distribution

in 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 within

the latter (7). In these cases, V

app

can ex-

ceed the actual size of the available fluid

volume. The significance of V

app

as a

pharmacokinetic parameter is dis-

cussed on p. 44.

Potential aqueous solvent

spaces for drugs

40%

20%

40%

Solid substance and

structurally bound

water

intracellular

water

extra-cellular

water

Solid substance and

structurally bound water

28 Distribution in the Body

intracellular extracellular

water water

Potential aqueous solvent

spaces for drugs

Lllmann, Color Atlas of Pharmacology ' 2000 Thieme

Distribution in the Body 29

A. Compartments for drug distribution

Distribution in tissue

Aqueous spaces of the organism

InterstitiumPlasma

Erythrocytes

Intracellular space

25%

65%

Lysosomes

Mito-

chondria

Cell

membrane

Nucleus

12 43

56 7

Binding to Plasma Proteins

Having entered the blood, drugs may

bind to the protein molecules that are

present in abundance, resulting in the

formation of drug-protein complexes.

Protein binding involves primarily al-

bumin and, to a lesser extent, β-globu-

lins and acidic glycoproteins. Other

plasma proteins (e.g., transcortin, trans-

ferrin, thyroxin-binding globulin) serve

specialized functions in connection

with specific substances. The degree of

binding is governed by the concentra-

tion of the reactants and the affinity of a

drug for a given protein. Albumin con-

centration in plasma amounts to

4.6g/100 mL or O.6 mM, and thus pro-

vides a very high binding capacity (two

sites per molecule). As a rule, drugs ex-

hibit much lower affinity (K

approx.

–5

–10

–3

M) for plasma proteins than

for their specific binding sites (recep-

tors). In the range of therapeutically rel-

evant concentrations, protein binding of

most drugs increases linearly with con-

centration (exceptions: salicylate and

certain sulfonamides).

The albumin molecule has different

binding sites for anionic and cationic li-

gands, but van der Waals’ forces also

contribute (p. 58). The extent of binding

correlates with drug hydrophobicity

(repulsion of drug by water).

Binding to plasma proteins is in-

stantaneous and reversible, i.e., any

change in the concentration of unbound

drug is immediately followed by a cor-

responding change in the concentration

of bound drug. Protein binding is of

great importance, because it is the con-

centration of free drug that determines

the intensity of the effect. At an identi-

cal total plasma concentration (say, 100

ng/mL) the effective concentration will

be 90 ng/mL for a drug 10% bound to

protein, but 1 ng/mL for a drug 99%

bound to protein. The reduction in con-

centration of free drug resulting from

protein 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 on

plasma 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 intensity

of the effect is reduced. If two substanc-

es have affinity for the same binding site

on the albumin molecule, they may

compete for that site. One drug may dis-

place another from its binding site and

thereby elevate the free (effective) con-

centration of the displaced drug (a form

of drug interaction). Elevation of the

free concentration of the displaced drug

means increased effectiveness and ac-

celerated elimination.

A decrease in the concentration of

albumin (liver disease, nephrotic syn-

drome, poor general condition) leads to

altered pharmacokinetics of drugs that

are highly bound to albumin.

Plasma protein-bound drugs that

are substrates for transport carriers can

be cleared from blood at great velocity,

e.g., p-aminohippurate by the renal tu-

bule and sulfobromophthalein by the

liver. Clearance rates of these substanc-

es can be used to determine renal or he-

patic blood flow.

30 Distribution in the Body

Distribution in the Body 31

Renal elimination

Biotransformation

Effector cell

Effect

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

Drug is

not bound

to plasma

proteins

Drug is

strongly

bound to

plasma

proteins

Effector cell

Effect

Biotransformation

Renal elimination

Time

Plasma concentration

Time

Plasma concentration

Bound drug

Free drug

The Liver as an Excretory Organ

As the chief organ of drug biotransfor-

mation, the liver is richly supplied with

blood, of which 1100 mL is received

each minute from the intestines

through the portal vein and 350 mL

through the hepatic artery, comprising

nearly

of cardiac output. The blood

content of hepatic vessels and sinusoids

amounts to 500 mL. Due to the widen-

ing of the portal lumen, intrahepatic

blood flow decelerates (A). Moreover,

the endothelial lining of hepatic sinu-

soids (p. 24) contains pores large

enough to permit rapid exit of plasma

proteins. Thus, blood and hepatic paren-

chyma are able to maintain intimate

contact and intensive exchange of sub-

stances, which is further facilitated by

microvilli covering the hepatocyte sur-

faces abutting Disse’s spaces.

The hepatocyte secretes biliary

fluid into the bile canaliculi (dark

green), tubular intercellular clefts that

are sealed off from the blood spaces by

tight junctions. Secretory activity in the

hepatocytes results in movement of

fluid 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 the

rough (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 in

oxidative reactions. Because these en-

zymes can catalyze either hydroxylation

or oxidative cleavage of -N-C- or -O-C-

bonds, they are referred to as “mixed-

function” oxidases or hydroxylases. The

essential component of this enzyme

system is cytochrome P450, which in its

oxidized state binds drug substrates (R-

H). The Fe

III

-P450-RH binary complex is

first reduced by NADPH, then forms the

ternary complex, O

-Fe

-P450-RH,

which accepts a second electron and fi-

nally disintegrates into Fe

III

-P450, one

equivalent of H

O, and hydroxylated

drug (R-OH).

Compared with hydrophilic drugs

not undergoing transport, lipophilic

drugs are more rapidly taken up from

the blood into hepatocytes and more

readily gain access to mixed-function

oxidases embedded in sER membranes.

For instance, a drug having lipophilicity

by virtue of an aromatic substituent

(phenyl ring) (B) can be hydroxylated

and, thus, become more hydrophilic

(Phase I reaction, p. 34). Besides oxi-

dases, sER also contains reductases and

glucuronyl transferases. The latter con-

jugate glucuronic acid with hydroxyl,

carboxyl, amine, and amide groups (p.

38); hence, also phenolic products of

phase I metabolism (Phase II conjuga-

tion). Phase I and Phase II metabolites

can be transported back into the blood

— probably via a gradient-dependent

carrier — 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 sERmembranes. En-

zyme induction leads to accelerated

biotransformation, not only of the in-

ducing agent but also of other drugs (a

form of drug interaction). With contin-

ued exposure, induction develops in a

few days, resulting in an increase in re-

action velocity, maximally 2–3fold, that

disappears after removal of the induc-

ing agent.

32 Drug Elimination

Drug Elimination 33

D. Hepatocyte after

D. 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

Biliary

capillary

Glucuronide

Carrier

Phase I-

metabolite

B. Fate of drugs undergoing

B. hepatic hydroxylation

Biliary capillary

Intestine

Biotransformation of Drugs

Many drugs undergo chemical modifi-

cation in the body (biotransformation).

Most frequently, this process entails a

loss of biological activity and an in-

crease in hydrophilicity (water solubil-

ity), thereby promoting elimination via

the renal route (p. 40). Since rapid drug

elimination improves accuracy in titrat-

ing the therapeutic concentration, drugs

are often designed with built-in weak

links. Ester bonds are such links, being

subject to hydrolysis by the ubiquitous

esterases. Hydrolytic cleavages, along

with oxidations, reductions, alkylations,

and dealkylations,constitute Phase I re-

actionsof drug metabolism. These reac-

tions subsume all metabolic processes

apt to alter drug molecules chemically

and take place chiefly in the liver. In

Phase II (synthetic) reactions, conju-

gation productsof either the drug itself

or its Phase I metabolites are formed, for

instance, with glucuronic or sulfuric ac-

id (p. 38).

The special case of the endogenous

transmitter acetylcholine illustrates

well the high velocity of ester hydroly-

sis. Acetylcholine is broken down at its

sites of release and action by acetylchol-

inesterase (pp. 100, 102) so rapidly as to

negate its therapeutic use. Hydrolysis of

other esters catalyzed by various este-

rases is slower, though relatively fast in

comparison with other biotransforma-

tions. The local anesthetic, procaine, is a

case in point; it exerts its action at the

site of application while being largely

devoid of undesirable effects at other lo-

cations because it is inactivated by hy-

drolysis during absorption from its site

of application.

Ester hydrolysis does not invariably

lead to inactive metabolites, as exempli-

fied by acetylsalicylic acid. The cleavage

product, salicylic acid, retains phar-

macological activity. In certain cases,

drugs are administered in the form of

esters in order to facilitate absorption

(enalapril  enalaprilate; testosterone

undecanoate  testosterone) or to re-

duce irritation of the gastrointestinal

mucosa (erythromycin succinate 

erythromycin). In these cases, the ester

itself is not active, but the cleavage

product is. Thus, an inactive precursor

or prodrug is applied, formation of the

active molecule occurring only after hy-

drolysis in the blood.

Some drugs possessing amide

bonds, such as prilocaine, and of course,

peptides, can be hydrolyzed by pepti-

dases and inactivated in this manner.

Peptidases are also of pharmacological

interest because they are responsible

for the formation of highly reactive

cleavage products (fibrin, p. 146) and

potent mediators (angiotensin II, p. 124;

bradykinin, enkephalin, p. 210) from

biologically inactive peptides.

Peptidases exhibit some substrate

selectivity and can be selectively inhib-

ited, as exemplified by the formation of

angiotensin II, whose actions inter alia

include vasoconstriction. Angiotensin II

is formed from angiotensin I by cleavage

of 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 clips

off 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

Angiotensin III

Angiotensin II

Angiotensin I

Esterases Ester Peptidases Amides Anilides

Oxidation reactionscan be divided

into two kinds: those in which oxygen is

incorporated into the drug molecule,

and those in which primary oxidation

causes 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 aromatic

ring systems (e.g., propranolol). In both

cases, products are formed that are con-

jugated to an organic acid residue, e.g.,

glucuronic acid, in a subsequent Phase II

reaction.

Hydroxylation may also take place

at nitrogen atoms, resulting in hydroxyl-

amines (e.g., acetaminophen). Benzene,

polycyclic aromatic compounds (e.g.,

benzopyrene), and unsaturated cyclic

carbohydrates can be converted by

mono-oxygenases to epoxides, highly

reactive 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 alkyl

group starts at the carbon adjacent to

the nitrogen; in the case of tertiary

amines, with hydroxylation of the nitro-

gen (e.g., lidocaine). The intermediary

products are labile and break up into the

dealkylated amine and aldehyde of the

alkyl group removed. O-dealkylation

and S-dearylation proceed via an analo-

gous mechanism (e.g., phenacetin and

azathioprine, respectively).

Oxidative deamination basically

resembles the dealkylation of tertiary

amines, beginning with the formation of

a hydroxylamine that then decomposes

into ammonia and the corresponding

aldehyde. The latter is partly reduced to

an alcohol and partly oxidized to a car-

boxylic acid.

Reduction reactions may occur at

oxygen or nitrogen atoms. Keto-oxy-

gens are converted into a hydroxyl

group, as in the reduction of the pro-

drugs cortisone and prednisone to the

active glucocorticoids cortisol and pred-

nisolone, respectively. N-reductions oc-

cur in azo- or nitro-compounds (e.g., ni-

trazepam). Nitro groups can be reduced

to 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 a

family of relatively specific methyl-

transferases involving the transfer of

methyl 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, desulfuration

results from substitution of sulfur by

oxygen (e.g., parathion). This example

again illustrates that biotransformation

is 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

Desalkylierung

Lllmann, Color Atlas of Pharmacology ' 2000 Thieme

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 been

absorbed from the gut, it is transported

via the portal blood to the liver, where it

can be conjugated to glucuronic or sul-

furic acid (shown in Bfor salicylic acid

and deacetylated bisacodyl, respective-

ly) or to other organic acids. At the pH of

body fluids, these acids are predomi-

nantly ionized; the negative charge con-

fers high polarity upon the conjugated

drug molecule and, hence, low mem-

brane penetrability. The conjugated

products may pass from hepatocyte into

biliary fluid and from there back into

the intestine. O-glucuronides can be

cleaved by bacterial β-glucuronidases in

the colon, enabling the liberated drug

molecule to be reabsorbed. The entero-

hepatic cycle acts to trap drugs in the

body. However, conjugated products

enter not only the bile but also the

blood. Glucuronides with a molecular

weight (MW) > 300 preferentially pass

into the blood, while those with MW >

300 enter the bile to a larger extent.

Glucuronides circulating in the blood

undergo glomerular filtration in the kid-

ney and are excreted in urine because

their decreased lipophilicity prevents

tubular reabsorption.

Drugs that are subject to enterohe-

patic cycling are, therefore, excreted

slowly. 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. This

reaction does not proceed spontaneous-

ly, but requires the activated form of

glucuronic acid, namely glucuronic acid

uridine diphosphate. Microsomal glucu-

ronyl transferases link the activated

glucuronic acid with an acceptor mole-

cule. When the latter is a phenol or alco-

hol, an ether glucuronide will be

formed. In the case of carboxyl-bearing

molecules, an ester glucuronide is the

result. All of these are O-glucuronides.

Amines may form N-glucuronides that,

unlike O-glucuronides, are resistant to

bacterial 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 from

conjugates formed by acetyltransfe-

rases from activated acetate (acetyl-

coenzyme A) and an alcohol or a phenol.

Acyltransferases are involved in the

conjugation of the amino acids glycine

or glutamine with carboxylic acids. In

these cases, an amide bond is formed

between 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 glutamine

remains 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

Biliary

elimination

Enteral

absorption

Renal

elimination

Lipophilic

drug

Sinusoid

Hepatocyte

Biliary capillary

Conjugation with

glucuronic acid

Portal vein

Hydrophilic

conjugation product

Deconjugation

by microbial

β-glucuronidase

The Kidney as Excretory Organ

Most drugs are eliminated in urine ei-

ther chemically unchanged or as metab-

olites. The kidney permits elimination

because the vascular wall structure in

the region of the glomerular capillaries

(B) allows unimpeded passage of blood

solutes having molecular weights (MW)

< 5000. Filtration diminishes progres-

sively as MW increases from 5000 to

70000 and ceases at MW >70000. With

few exceptions, therapeutically used

drugs and their metabolites have much

smaller molecular weights and can,

therefore, undergo glomerular filtra-

tion, i.e., pass from blood into primary

urine. Separating the capillary endothe-

lium from the tubular epithelium, the

basal membrane consists of charged

glycoproteins and acts as a filtration

barrier for high-molecular-weight sub-

stances. The relative density of this bar-

rier depends on the electrical charge of

molecules that attempt to permeate it.

Apart from glomerular filtration

(B), drugs present in blood may pass

into urine by active secretion. Certain

cations and anions are secreted by the

epithelium of the proximal tubules into

the tubular fluid via special, energy-

consuming transport systems. These

transport systems have a limited capac-

ity. When several substrates are present

simultaneously, competition for the

carrier may occur (see p. 268).

During passage down the renal tu-

bule, urinary volume shrinks more than

100-fold; accordingly, there is a corre-

sponding concentration of filtered drug

or drug metabolites (A). The resulting

concentration gradient between urine

and interstitial fluid is preserved in the

case of drugs incapable of permeating

the tubular epithelium. However, with

lipophilic drugs the concentration gra-

dient will favor reabsorptionof the fil-

tered molecules. In this case, reabsorp-

tion is not based on an active process

but results instead from passive diffu-

sion. Accordingly, for protonated sub-

stances, the extent of reabsorption is

dependent 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 pK

, which represents

the 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 of

a protonated amine having a pK

of 7.0.

In this case, at urinary pH 7.0, 50% of the

amine will be present in the protonated,

hydrophilic, membrane-impermeant

form (blue dots), whereas the other half,

representing the uncharged amine

(orange dots), can leave the tubular lu-

men in accordance with the resulting

concentration gradient. If the pK

of an

amine is higher (pK

= 7.5) or lower (pK

= 6.5), a correspondingly smaller or

larger proportion of the amine will be

present in the uncharged, reabsorbable

form. Lowering or raising urinary pH by

half a pH unit would result in analogous

changes for an amine having a pK

7.0.

The same considerations hold for

acidic molecules, with the important

difference that alkalinization of the

urine (increased pH) will promote the

deprotonization of -COOH groups and

thus impede reabsorption. Intentional

alteration in urinary pH can be used in

intoxications with proton-acceptor sub-

stances in order to hasten elimination of

the toxin (alkalinization phenobarbi-

tal; acidification amphetamine).

40 Drug Elimination

Drug Elimination 41

C. Active secretion

180 L

Primary

urine

Glomerular

filtration

of drug

Concentration

of drug

in tubule

1.2 L

Final

urine

–

Tubular

transport

system for

Cations

Anions

Blood

Plasma-

protein

Endothelium

Basal

membrane

Drug

Epithelium

Primary urine

pH = 7.0

pH = 7.0 pH of urine

6 6.5 7 7.5 8

100

= 7.5

6 6.5 7 7.5 8

100

= 6.5

D. Tubular reabsorption

A. Filtration and concentration

B. Glomerular filtration

of substance

6 6.5 7 7.5 8

100

= 7.0

Elimination of Lipophilic and

Hydrophilic Substances

The terms lipophilic and hydrophilic

(or hydro- and lipophobic) refer to the

solubility of substances in media of low

and high polarity, respectively. Blood

plasma, interstitial fluid, and cytosol are

highly polar aqueous media, whereas

lipids — 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 lipophilic

ones in apolar media. A hydrophilic

drug, 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 lipid

barrier of the hepatocyte membrane

and thus will fail to gain access to hepat-

ic biotransforming enzymes. The un-

changed drug reaches the arterial blood

and the kidneys, where it is filtered.

With hydrophilic drugs, there is little

binding to plasma proteins (protein

binding increases as a function of li-

pophilicity), hence the entire amount

present in plasma is available for glo-

merular filtration. A hydrophilic drug is

not subject to tubular reabsorption and

appears in the urine. Hydrophilic drugs

undergo rapid elimination.

If a lipophilic drug, because of its

chemical nature, cannot be converted

into a polar product, despite having ac-

cess to all cells, including metabolically

active liver cells, it is likely to be re-

tained in the organism. The portion fil-

tered during glomerular passage will be

reabsorbed from the tubules. Reabsorp-

tion will be nearly complete, because

the free concentration of a lipophilic

drug in plasma is low (lipophilic sub-

stances are usually largely protein-

bound). The situation portrayed for a

lipophilic non-metabolizable drug

would seem undesirable because phar-

macotherapeutic measures once initiat-

ed would be virtually irreversible (poor

control over blood concentration).

Lipophilic drugs that are convert-

ed in the liver to hydrophilic metab-

olitespermit better control, because the

lipophilic agent can be eliminated in

this manner. The speed of formation of

hydrophilic metabolite determines the

drug’s length of stay in the body.

If hepatic conversion to a polar me-

tabolite is rapid, only a portion of the

absorbed 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, or

transdermal administration is then re-

quired in order to bypass the liver. Irre-

spective of the route of administration,

a portion of administered drug may be

taken up into and transiently stored in

lung tissue before entering the general

circulation. This also constitutes pre-

systemic elimination.

Presystemic elimination refers to

the fraction of drug absorbed that is

excluded from the general circulation

by biotransformation or by first-pass

binding.

Presystemic elimination diminish-

es the bioavailability of a drug after its

oral administration. Absolute bioavail-

ability= systemically available amount/

dose administered; relative bioavail-

ability = availability of a drug contained

in a test preparation with reference to a

standard preparation.

42 Drug Elimination

Drug Elimination 43

A. Elimination of hydrophilic and hydrophobic drugs

Hydrophilic drug Lipophilic drug

no metabolism

Lipophilic drug Lipophilic drug

Renal

excretion

Excretion

impossible

Renal excretion

of metabolite

Renal excretion

of metabolite

Slow conversion

in liver to

hydrophilic metabolite

Rapid and complete

conversion in liver to

hydrophilic metabolite

Drug Concentration in the Body

as a Function of Time. First-Order

(Exponential) Rate Processes

Processes such as drug absorption and

elimination display exponential charac-

teristics. As regards the former, this fol-

lows from the simple fact that the

amount of drug being moved per unit of

time depends on the concentration dif-

ference (gradient) between two body

compartments (Fick’s Law). In drug ab-

sorption from the alimentary tract, the

intestinal contents and blood would

represent the compartments containing

an initially high and low concentration,

respectively. In drug elimination via the

kidney, excretion often depends on glo-

merular filtration, i.e., the filtered

amount of drug present in primary

urine. As the blood concentration falls,

the amount of drug filtered per unit of

time diminishes. The resulting expo-

nential decline is illustrated in (A). The

exponential time course implies con-

stancy of the interval during which the

concentration decreases by one-half.

This interval represents the half-life

1/2

) and is related to the elimination

rate constant k by the equation t

1/2

= ln

2/k. The two parameters, together with

the initial concentration c

, describe a

first-order (exponential) rate process.

The constancy of the process per-

mits calculation of the plasma volume

that 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 of

drug per unit of time is termed the

clearance. Depending on whether plas-

ma concentration falls as a result of uri-

nary excretion or metabolic alteration,

clearance is considered to be renal or

hepatic. Renal and hepatic clearances

add up to total clearance (Cl

tot

) in the

case of drugs that are eliminated un-

changed via the kidney and biotrans-

formed in the liver. Cl

tot

represents the

sum of all processes contributing to

elimination; it is related to the half-life

1/2

) and the apparent volume of distri-

bution V

app

(p. 28) by the equation:

app

1/2

= In 2 x ––––

tot

The smaller the volume of distribu-

tion or the larger the total clearance, the

shorter is the half-life.

In the case of drugs renally elimi-

nated in unchanged form, the half-life of

elimination can be calculated from the

cumulative excretion in urine; the final

total amount eliminated corresponds to

the amount absorbed.

Hepatic elimination obeys expo-

nential kinetics because metabolizing

enzymes operate in the quasilinear re-

gion of their concentration-activity

curve; hence the amount of drug me-

tabolized per unit of time diminishes

with decreasing blood concentration.

The best-known exception to expo-

nential kinetics is the elimination of al-

cohol (ethanol), which obeys a linear

time course (zero-order kinetics), at

least at blood concentrations > 0.02%. It

does so because the rate-limiting en-

zyme, alcohol dehydrogenase, achieves

half-saturation at very low substrate

concentrations, 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 of

drug eliminated per unit of time re-

mains constant at concentrations above

this level.

44 Pharmacokinetics

Lllmann, Color Atlas of Pharmacology ' 2000 Thieme

Pharmacokinetics 45

A. Exponential elimination of drug

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

= c

· e

-kt

: Drug concentration at time t

: Initial drug concentration after

administration of drug dose

e: Base of natural logarithm

k: Elimination constant

Plasma half life

= — c

ln 2

—–

Time (t)

Total

amount

of drug

excreted

(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

Time Course of Drug Concentration in

Plasma

A.Drugs are taken up into and eliminat-

ed from the body by various routes. The

body thus represents an open system

wherein the actual drug concentration

reflects the interplay of intake (inges-

tion) and egress (elimination). When an

orally administered drug is absorbed

from the stomach and intestine, speed

of uptake depends on many factors, in-

cluding the speed of drug dissolution (in

the case of solid dosage forms) and of

gastrointestinal transit; the membrane

penetrability of the drug; its concentra-

tion gradient across the mucosa-blood

barrier; and mucosal blood flow. Ab-

sorption from the intestine causes the

drug concentration in blood to increase.

Transport in blood conveys the drug to

different organs (distribution), into

which it is taken up to a degree compat-

ible with its chemical properties and

rate of blood flow through the organ.

For instance, well-perfused organs such

as the brain receive a greater proportion

than do less well-perfused ones. Uptake

into tissue causes the blood concentra-

tion to fall. Absorption from the gut di-

minishes as the mucosa-blood gradient

decreases. Plasma concentration reach-

es a peak when the drug amount leaving

the blood per unit of time equals that

being absorbed.

Drug entry into hepatic and renal

tissue constitutes movement into the

organs of elimination. The characteris-

tic phasic time course of drug concen-

tration in plasma represents the sum of

the constituent processes of absorp-

tion, distribution, and elimination,

which overlap in time. When distribu-

tion takes place significantly faster than

elimination, there is an initial rapid and

then a greatly retarded fall in the plas-

ma level, the former being designated

the α-phase (distribution phase), the

latter the β-phase (elimination phase).

When the drug is distributed faster than

it is absorbed, the time course of the

plasma level can be described in mathe-

matically simplified form by the Bate-

man function (k

and k

represent the

rate constants for absorption and elimi-

nation, respectively).

B. The velocity of absorption de-

pends on the route of administration.

The more rapid the administration, the

shorter will be the time (t

max

) required

to reach the peak plasma level (c

max

the higher will be the c

max

, and the earli-

er the plasma level will begin to fall

again.

The area under the plasma level time

curve(AUC) is independent of the route

of administration, provided the doses

and bioavailability are the same (Dost’s

law of corresponding areas). The AUC

can thus be used to determine the bio-

availabilityF of a drug. The ratio of AUC

values determined after oral or intrave-

nous administration of a given dose of a

particular drug corresponds to the pro-

portion of drug entering the systemic

circulation after oral administration.

The determination of plasma levels af-

fords a comparison of different proprie-

tary preparations containing the same

drug in the same dosage. Identical plas-

ma level time-curves of different

manufacturers’ products with reference

to a standard preparation indicate bio-

equivalence of the preparation under

investigation with the standard.

46 Pharmacokinetics

Pharmacokinetics 47

B. Mode of application and time course of drug concentration

A. Time course of drug concentration

Absorption

Uptake from

stomach and

intestines

into blood

Distribution

into body

tissues:

α-phase

Elimination

from body by

biotransformation

(chemical alteration),

excretion via kidney:

ß-phase

Time (t)

Drug concentration in blood (c)

Bateman-function

Dose

˜ V

app

- k

c = x x (e

-k

-e

-k

)

Drug concentration in blood (c)

Time (t)

Intravenous

Intramuscular

Subcutaneous

Oral

Time Course of Drug Plasma Levels

During Repeated Dosing (A)

When a drug is administered at regular

intervals over a prolonged period, the

rise and fall of drug concentration in

blood will be determined by the rela-

tionship between the half-life of elimi-

nation and the time interval between

doses. If the drug amount administered

in each dose has been eliminated before

the next dose is applied, repeated intake

at constant intervals will result in simi-

lar plasma levels. If intake occurs before

the preceding dose has been eliminated

completely, the next dose will add on to

the residual amount still present in the

body, i.e., the drug accumulates. The

shorter the dosing interval relative to

the elimination half-life, the larger will

be the residual amount of drug to which

the next dose is added and the more ex-

tensively will the drug accumulate in

the body. However, at a given dosing

frequency, the drug does not accumu-

late infinitely and a steady state(C

) or

accumulation equilibriumis eventual-

ly reached. This is so because the activ-

ity of elimination processes is concen-

tration-dependent. The higher the drug

concentration rises, the greater is the

amount eliminated per unit of time. Af-

ter several doses, the concentration will

have climbed to a level at which the

amounts eliminated and taken in per

unit of time become equal, i.e., a steady

state is reached. Within this 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 (C

) de-

pends upon the amount (D) adminis-

tered per dosing interval (τ) and the

clearance (Cl

tot

= –––––––––

(τ· Cl

tot

)

The speed at which the steady state

is reached corresponds to the speed of

elimination of the drug. The time need-

ed to reach 90% of the concentration

plateau is about 3 times the t

1/2

of elimi-

nation.

Time Course of Drug Plasma Levels

During Irregular Intake (B)

In practice, it proves difficult to achieve

a plasma level that undulates evenly

around the desired effective concentra-

tion. For instance, if two successive dos-

es are omitted, the plasma level will

drop below the therapeutic range and a

longer period will be required to regain

the desired plasma level. In everyday

life, patients will be apt to neglect drug

intake at the scheduled time. Patient

compliance means strict adherence to

the prescribed regimen. Apart from

poor compliance, the same problem

may occur when the total daily dose is

divided into three individual doses (tid)

and the first dose is taken at breakfast,

the second at lunch, and the third at

supper. Under this condition, the noc-

turnal dosing interval will be twice the

diurnal one. Consequently, plasma lev-

els during the early morning hours may

have 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

Drug concentrationDrug concentration

Accumulation:

administered drug is

not completely eliminated

during interval

Steady state:

drug intake equals

elimination during

dosing interval

Dosing interval

Time

Drug concentration

Desired

therapeutic

level

Accumulation: Dose, Dose Interval, and

Plasma Level Fluctuation

Successful drug therapy in many illness-

es is accomplished only if drug concen-

tration is maintained at a steady high

level. This requirement necessitates

regular drug intake and a dosage sched-

ule that ensures that the plasma con-

centration neither falls below the thera-

peutically effective range nor exceeds

the minimal toxic concentration. A con-

stant plasma level would, however, be

undesirable if it accelerated a loss of ef-

fectiveness (development of tolerance),

or if the drug were required to be

present at specified times only.

A steady plasma level can be

achieved by giving the drug in a con-

stant intravenous infusion, the steady-

state plasma level being determined by

the infusion rate, dose D per unit of time

τ, and the clearance, according to the

equation:

= –––––––––

(τ· Cl

tot

)

This procedure is routinely used in

intensive care hospital settings, but is

otherwise impracticable. With oral ad-

ministration, dividing the total daily

dose into several individual ones, e.g.,

four, three, or two, offers a practical

compromise.

When the daily dose is given in sev-

eral divided doses, the mean plasma

level shows little fluctuation. In prac-

tice, it is found that a regimen of fre-

quent regular drug ingestion is not well

adhered to by patients. The degree of

fluctuation in plasma level over a given

dosing interval can be reduced by use of

a dosage form permitting slow (sus-

tained) release (p. 10).

The time required to reach steady-

state accumulation during multiple

constant dosing depends on the rate of

elimination. As a rule of thumb, a pla-

teau is reached after approximately

three elimination half-lives (t

1/2

For slowly eliminated drugs, which

tend to accumulate extensively (phen-

procoumon, digitoxin, methadone), the

optimal plasma level is attained only af-

ter a long period. Here, increasing the

initial doses (loading dose) will speed

up the attainment of equilibrium, which

is subsequently maintained with a low-

er dose (maintenance dose).

Change in Elimination Characteristics

During Drug Therapy (B)

With any drug taken regularly and accu-

mulating to the desired plasma level, it

is important to consider that conditions

for biotransformation and excretion do

not necessarily remain constant. Elimi-

nation may be hastened due to enzyme

induction (p. 32) or to a change in uri-

nary pH (p. 40). Consequently, the

steady-state plasma level declines to a

new value corresponding to the new

rate of elimination. The drug effect may

diminish or disappear. Conversely,

when elimination is impaired (e.g., in

progressive renal insufficiency), the

mean plasma level of renally eliminated

drugs 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

Drug concentration in blood

Desired plasma level

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

4 x daily 50 mg

2 x daily 100 mg

1 x daily 200 mg

Single 50 mg

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

Acceleration

of elimination

Inhibition of elimination

Drug concentration in blood

Desired plasma level