General and Molecular Pharmacology: Principles of Drug Action

785 Pages·2015·64.17 MB·English

by  Francesco Clementi

General and Molecular PharMacoloGy

General and Molecular
PharMacoloGy
Principles of drug action
Edited By
Francesco cleMenti and Guido FuMaGalli
Co‐editors
christiano chiaMulera, eMilio cleMenti,
riccardo Fesce, dieGo Fornasari, and cecilia Gotti
Translated and modified by Francesco Clementi and Guido Fumagalli. Originally published in Italian under the title “Farmacologia Generale e Molecolare.
Il meccanismo d’azione dei farmaci”, 4th edition, by Francesco Clementi and Guido Fumagalli, © UTET SpA – Unione Tipografico-Editrice Torinese,
Torino, Italy (2012).
Copyright © 2015 by John Wiley & Sons, Inc. All rights reserved
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Published simultaneously in Canada
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Library of Congress Cataloging-in-Publication Data
General and molecular pharmacology : principles of drug action / Francesco Clementi, Guido Fumagalli, editors ; Christiano Chiamulera,
Emilio Clementi, Riccardo Fesce, Diego Fornasari, Cecilia Gotti, co-editors.
1 online resource.
Includes bibliographical references and index.
Description based on print version record and CIP data provided by publisher; resource not viewed.
ISBN 978-1-118-76859-4 (pdf) – ISBN 978-1-118-76868-6 (epub) – ISBN 978-1-118-76857-0 (cloth : alk. paper)
I. Clementi, Francesco, editor. II. Fumagalli, Guido, editor.
[DNLM: 1. Chemistry, Pharmaceutical. 2. Molecular Biology. 3. Pharmacological Phenomena. QV 744]
RS403
615.1′9–dc23
2015008591
Printed in the United States of America
10 9 8 7 6 5 4 3 2 1
1 2015
CONTeNTS
LIST OF CONTRIBUTORS xlvi
PReFaCe xlix
SeCTION 1 INTRODUCTION TO PHaRMaCOLOGY 1
1 essential Lexicon of Pharmacology 3
Francesco Clementi and Guido Fumagalli
The Social Impact of Pharmacology, 3
Essential Lexicon, 4
Active Substances, 4
Pharmacological Disciplines, 5
Drug–Receptor Interactions, 6
Measure of the Clinical Response, 7
Take‐Home Message, 7
2 a Short History of Pharmacology 8
Vittorio A. Sironi
Birth and Historical Developments of Pharmacology, 8
From Magical and Natural Remedies of Ancient Medicine to Arabic Alchemy, 8
From Monastic Medicine to Botanical Gardens, 9
From Anatomical Renaissance to the “Experienz”: Paracelsus’ Spagyric, 10
From Iatrochemistry to the Age of Enlightenment, 11
From the Search of the Active Principle to the Discovery of Alkaloids
and Glucosides, 12
The Drug Synthesis Revolution: From Handmade to Industrial Production, 12
Modern Pharmacology, 13
Ehrlich and Chemotherapy: The Concept of Receptor, 13
The Birth of Modern Pharmacology, 14
The Biotechnology Era and the Pharmacology in the Third Millennium, 15
The Impact of New Biotechnologies: Molecular Biology, Bioinformatics,
and Combinatorial Chemistry, 15
Biological Drugs and Pharmacology Perspectives, 16
vi CoNTENTS
Personalized Therapies and New Sceneries in Pharmaceutical Industry, 17
Take‐Home Message, 18
Further Reading, 18
SeCTION 2 GeTTING THe DRUG TO ITS SITe OF aCTION 19
3 Cellular Basis of Pharmacokinetics 21
Riccardo Fesce and Guido Fumagalli
A Quick Journey with the Drug in the Body, 21
Absorption, 21
Distribution, 21
Drug Elimination, 22
Crossing Cell Membranes, 23
Passive Diffusion across Cell Membranes, 24
Drug Transport across Cell Membranes, 25
Endocytosis, 25
Drug Diffusion to organs and Tissues, 27
Properties of the Most Important Cell Barriers, 27
Take‐Home Message, 30
Further Reading, 30
4 Drug absorption and administration Routes 31
Riccardo Fesce and Guido Fumagalli
General Rules About Drug Absorption Rate, 32
Partition Coefficient, 32
Drug Dispersion, 32
Extension of the Absorbing Surface, 32
Permeability of the Absorbing Surface, 32
Vascularization, 33
Enteral Routes of Administration, 33
oral Route, 33
Sublingual and Rectal Routes, 35
Systemic Parenteral Routes of Administration, 35
The Intravascular Route, 35
i.m. Injection, 36
Subcutaneous and Intradermal Injections, 36
other Routes of Drug Administration, 36
Inhalation Route, 36
Topical/Regional Routes, 37
Intracavity Routes, 37
Dermal or Transcutaneous Route, 37
Mucosal Routes, 38
Absorption Kinetics, 38
General Rules, 38
Interrelation between Gene Therapy and Drug Delivery Techniques, 43
Take‐Home Message, 44
Further Reading, 44
5 Drug Distribution and elimination 45
Riccardo Fesce and Guido Fumagalli
Distribution, 46
Tissues and Avidity for Drugs, 46
The Apparent Distribution Volume, 48
CoNTENTS vii
Drug Binding to Plasma Proteins, 50
Factors That Determine the Distribution Rate of Drugs to the Various
Compartments, 51
Elimination, 53
The Concept of Half‐Life, 53
The Concept of Clearance, 54
Renal Excretion of Drugs, 55
Glomerular Filtration, 56
Tubular Functions and Pharmacokinetics, 56
Active Transport of organic Anions and Cations, 56
Factors Determining Renal Clearance of Drugs, 57
Hepatic Excretion and Enterohepatic Cycle, 58
Perfusion, Binding to Plasma Proteins, Enzymatic Activity,
and Hepatic Clearance, 59
Take‐Home Message, 59
Further Reading, 60
6 Drug Metabolism 61
Enzo Chiesara, Laura Marabini, and Sonia Radice
Metabolic Modification of Drug Activity, 61
Two Phases of Drug Metabolism, 62
Phase I Reactions, 62
Phase II Enzymatic Reactions, 66
Extrahepatic Biotransformations, 68
Biotransformation by the Intestinal Flora, 69
Pharmacometabolic Induction and Inhibition, 69
Induction of Drug Metabolism, 69
Inhibition of Drug Metabolism, 71
Take‐Home Message, 72
Further Reading, 72
7 Control of Drug Plasma Concentration 73
Riccardo Fesce and Guido Fumagalli
Time Course of Drug Plasma Concentration Following a Single
Administration, 73
Drugs Distribute to organs and Tissues and then are Eliminated, 74
Description of Drug Plasma Concentration Time Course Following a Single
Administration, 74
Area under the Plasma Concentration Curve (AUC), 74
The Plasma Concentration Peak, 75
Drug Plasma Concentration Time Course During Repetitive Administrations, 75
During Repetitive Administrations, the Drug Plasma Concentration Time
Course Is Given by the Sum of the Time Courses of the Single Doses, 75
In a Chronic Therapy at Steady State, Each New Dose Replaces the Drug
Amount that has been Eliminated Since the Last Administration, 77
The Time to Reach the Steady State Depends on the Drug Half‐Life, 77
Plasma Concentration at Steady State, 78
The Single Dose to Administer is Computed as a Function of the Interval
between Successive Administrations, 78
Fluctuations of Drug Plasma Concentration at Steady State, 79
Absorption Kinetics Influence the Amplitude of oscillations in Plasma
Concentration at Steady State, 80
Loading (Attack) Doses to Rapidly Attain Steady‐State Concentration, 80
Multicompartmental Kinetics, 81
Drug Binding to Plasma Proteins and Tissue Equilibration with Plasma, 81
viii CoNTENTS
The Particular Case of the Nephron, 82
Drugs Redistribution among Compartments, 83
Corrections of the Therapeutic Regimen, 83
Normally Available Pharmacokinetic Data Are Average Values, 84
Varying Dosage as a Function of Body Weight and Physical
Constitution, 84
Varying Dosage as a Function of Age, 84
Dosage Correction in the Presence of Hepatic Pathologies, 86
Dosage Correction in the Presence of Renal Pathologies, 86
Take‐Home Message, 87
Further Reading, 89
SeCTION 3 ReCePTORS aND SIGNaL TRaNSDUCTION 91
8 Drug–Receptor Interactions: Quantitative and Qualitative aspects 93
Gian Enrico Rovati and Valérie Capra
General Properties of Drug Receptors, 93
Drug Receptors Are Molecules Relevant for Cellular Functions, 93
Not All Drugs Interact with a Receptor, 94
Drug Activity Follows to Drug–Receptor Complex Formation, 94
Drug–Receptor Interaction Is Mostly Mediated by Weak Chemical Bonds, 94
Reversible or Irreversible Drug–Receptor Interactions, 95
Characteristics of Drug–Receptor Interaction, 95
The Relationship between Drug Concentration and Drug–Receptor Complex
Is Similar to the Michaelis–Menten Equation, 97
The Binding Isotherm and Its Linear Transformations Allow to obtain
the Parameters of the Drug–Receptor Interaction, 97
Receptors Can Be Heterogeneous, 99
Drug Competition for a Same Receptor Binding Site, 99
Quantitative Aspects of Drug Effects: Dose–Response Curves, 99
Potency and Efficacy, 100
From Drug–Receptor Interaction to Drug Response, 101
occupancy Theory, 101
Modifications to the occupancy Assumption, 102
Efficacy Theory, 104
Nonlinear Function between Receptor occupancy and Tissue Response:
EC Different from K, 106
50 d
Constitutively Active Receptors and Inverse Agonists, 107
Two‐State Receptor Model and Beyond: Multiple Receptor States
and “Biased” Signaling, 108
Take‐Home Message, 108
Further Reading, 108
9 Receptors and Modulation of Their Response 109
Francesco Clementi and Guido Fumagalli
Classes of Receptors and Strategies of Signal Transduction, 109
Intracellular/Intranuclear Receptors, 110
Membrane Receptors, 110
Control of Receptor Localization in the Cell Membrane, 116
Intracellular Traffic of Cell Receptors, 117
How Receptors Reach the Cell Membrane and how Their Number
is Regulated, 117
Modulation of Receptor Responses, 117
Receptor Modulation By Drugs, 118