Biochemical pharmacology

438 Pages·2012·45.618 MB·English

by  Michael Palmer, Alice Chan, Thorsten Dieckmann, John Honek

BIOCHEMICAL PHARMACOLOGY

BIOCHEMICAL PHARMACOLOGY
MICHAEL PALMER
University of Waterloo
with chapters by
ALICE CHAN
University of Alberta
THORSTEN DIECKMANN
University of Waterloo
JOHN HONEK
University of Waterloo
©WILEY
A JOHN WILEY & SONS, INC., PUBLICATION
Copyright © 2012 by John Wiley & Sons, Inc. All rights reserved.
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Library of Congress Cataloging-in-Publication Data:
Palmer, Michael, 1961 May 4-
Biochemical pharmacology / Michael Palmer; with chapters by Alice Chan, Thorsten Dieckmann, John Honek. —
lsted.
p. ; cm.
Includes bibliographical references and index.
ISBN 978-0-470-17445-6 (hardback)
I. Title.
[DNLM: 1. Drug Interactions. 2. Pharmacokinetics. 3. Drug Delivery Systems. 4. Pharmaceutical Preparations.
QV38]
615.7045—dc23 2011041617
Printed in the United States of America.
10 9 8 7 6 5 4 3 21
CONTENTS
Preface ix
Acknowledgments xi
1 Introduction 1
1.1 Origin and preparation of drugs 3
1.2 Drugs and drug targets 4
1.3 Drug molecules may or may not resemble
the physiological ligands of their receptors 7
1.4 Strategies of drug discovery and development 11
References 14
2 Pharmacodynamics 15
2.1 Molecular features of drug-receptor interaction 15
2.2 Theory of drug-receptor binding 17
2.3 Dose-effect relationships in signaling cascades 25
2.4 Potency and efficacy 28
2.5 Beneficial and toxic drug effects 28
2.6 Appendix 30
Study questions 35
References 36
v
VI CONTENTS
3 Pharmacokinetics 37
3.1 Anatomical barriers to drug transport 38
3.2 Solute transport across cell membranes 40
3.3 Drug application 49
3.4 Drug distribution 53
3.5 Drug elimination via the kidneys 56
3.6 Quantitative experimental methods in pharmacokinetics 63
Study questions 65
References 65
4 Drug metabolism 67
4.1 Overview: Possible functional outcomes of
drug metabolism 68
4.2 Phase I and phase II reactions 70
4.3 Cytochrome P450 71
4.4 Reductive drug metabolism 74
4.5 Conjugation reactions 75
4.6 Enzyme induction 83
4.7 Metabolism-related toxicity as a therapeutic target 84
Study questions 85
References 85
5 G protein-coupled receptors 87
5.1 Overview 87
5.2 GPCR structure 89
5.3 Structural GPCR families 89
5.4 Activation of GPCRs 90
5.5 GPCR dimerization and oligomerization 96
5.6 G proteins 98
5.7 GPCR phosphorylation, endocytosis, and G protein-
independent signaling 102
5.8 Appendix 103
Study questions 107
References 108
6 Pharmacology of cell excitation 111
6.1 Ions, pumps, and channels 114
6.2 ATP-driven active ion transport 116
6.3 Voltage-gated channels and the action potential 116
6.4 Channels controlled by intracellular ligands 120
6.5 Transient receptor potential (TRP) channels 120
6.6 Voltage-gated channels of nerve cells as drug
targets 121
6.7 Synaptic transmission 127
6.8 Pharmacology of individual transmitters 136
6.9 Appendix 153
Study questions 160
References 161
CONTENTS VÜ
7 Hormones 163
7.1 Hormone receptors 164
7.2 The hypothalamus and the pituitary gland 164
7.3 Thyroid gland hormones 170
7.4 Steroid hormones 175
7.5 Endocrine control of bone mineralization 183
Study questions 188
References 189
8 Pharmacology of nitric oxide 191
8.1 Characterization of nitric oxide as a biological
signaling molecule 192
8.2 Nitric oxide synthase and its isoforms 192
8.3 Biochemical mechanisms of NO signaling 195
8.4 The biological function of iNOS 200
8.5 NO-releasing drugs 200
8.6 NOS inhibitors 204
8.7 Phosphodiesterase inhibitors 204
Study questions 205
References 205
9 Eicosanoid mediators and related drugs 207
9.1 Biosynthesis of eicosanoids 208
9.2 The cyclooxygenase reaction 211
9.3 Cyclooxygenase isoforms and inhibitors 211
9.4 Phospholipase A2 inhibitors 217
9.5 Derivatives of prostaglandin H2 and related drugs 217
9.6 Lipoxygenases, leukotrienes, and related drugs 218
9.7 Eicosanoids synthesized by cytochrome P450 219
9.8 Endocannabinoids and related drugs 219
9.9 The role of polyunsaturated fatty acids in
eicosanoid signaling 223
Study questions 224
References 224
10 Intermediate metabolism, diabetes and atherosclerosis 227
10.1 Hereditary enzyme defects 227
10.2 Gout 235
10.3 Diabetes mellitus 238
10.4 Atherosclerosis 241
Study questions 251
References 252
11 Chemotherapy of infectious diseases 255
11.1 Pathogenic microbes: Diversity and selective
toxicity 256
11.2 Pharmacokinetic considerations 257
viii CONTENTS
11.3 Resistance to antimicrobials 258
11.4 Antibacterial chemotherapy 259
11.5 Chemotherapy of fungal infections 277
11.6 Chemotherapy of parasite infections 279
11.7 Antiviral chemotherapy 284
Study questions 291
References 292
12 Tumor chemotherapy 295
12.1 Some principles of tumor biology 296
12.2 Cell-type-specific antitumor drugs 304
12.3 Drugs that target specific oncoproteins 306
12.4 Cytotoxic antitumor drugs 309
Study questions 320
References 320
13 Ribonucleic acids as drug targets and drugs 323
13.1 RNA as drug target 324
13.2 RNA as a therapeutic agent 336
Study questions 339
References 339
14 Drug delivery 343
14.1 Improving intestinal drug absorption 343
14.2 Improving drug distribution 348
14.3 Targeted drug delivery 352
14.4 Kinetically controlled drug release 358
14.5 Controlling drug toxicity 363
14.6 Delivery of nucleic acids 367
Study questions 368
References 368
15 Drug discovery 373
15.1 Target selection and validation 373
15.2 Screening of candidate compounds 375
15.3 Computational screening 381
15.4 Phenotypic screening 384
15.5 Compound acquisition 384
Study questions 389
References 389
Answers to study questions 393
References 400
Index 403