Pharmacology Primer (eBook)

Front cover 1
A PHARMACOLOGY PRIMER THEORY, APPLICATION, AND METHODS 4
Copyright page 5
Foreword to Second Edition 12
Foreword to First Edition 14
Table of contents 16
Chapter 1. What Is Pharmacology? 20
1.1 About This Book 20
1.2 What Is Pharmacology? 20
1.3 The Receptor Concept 21
1.4 Pharmacological Test Systems 23
1.5 The Nature of Drug Receptors 25
1.6 Pharmacological Intervention and the Therapeutic Landscape 25
1.7 System-independent Drug Parameters: Affinity and Efficacy 28
1.8 What Is Affinity? 29
1.9 The Langmuir Adsorption Isotherm 29
1.10 What Is Efficacy? 32
1.11 Dose-response Curves 33
1.12 Chapter Summary and Conclusions 37
1.13 Derivations: Conformational Selections as a Mechanism of Efficacy 37
References 38
Chapter 2. How Different Tissues Process Drug Response 40
2.1 Drug Response as Seen Through the ‘‘Cellular Veil’’ 40
2.2 The Biochemical Nature of Stimulus-response Cascades 42
2.3 The Mathematical Approximation of Stimulus-response Mechanisms 44
2.4 System Effects on Agonist Response: Full and Partial Agonists 46
2.5 Differential Cellular Response to Receptor Stimulus 49
2.6 Receptor Desensitization and Tachyphylaxis 53
2.7 The Measurement of Drug Activity 53
2.8 Advantages and Disadvantages of Different Assay Formats 54
2.9 Drug Concentration as an Independent Variable 54
2.10 Chapter Summary and Conclusions 56
2.11 Derivations 57
References 58
Chapter 3. Drug-Receptor Theory 60
3.1 About This Chapter 60
3.2 Drug-Receptor Theory 61
3.3 The Use of Mathematical Models in Pharmacology 61
3.4 Some Specific Uses of Models in Pharmacology 62
3.5 Classical Model of Receptor Function 63
3.6 The Operational Model of Receptor Function 64
3.7 Two-state Theory 66
3.8 The Ternary Complex Model 67
3.9 The Extended Ternary Model 67
3.10 Constitutive Receptor Activity 68
3.11 The Cubic Ternary Complex Model 69
3.12 Chapter Summary and Conclusions 71
3.13 Derivations 71
References 76
Chapter 4. Pharmacological Assay Formats: Binding 78
4.1 The Structure of This Chapter 78
4.2 Binding Theory and Experiment 78
4.3 Complex Binding Phenomena: Agonist Affinity from Binding Curves 86
4.4 Experimental Prerequisites for Correct Application of Binding Techniques 90
4.5 Chapter Summary and Conclusions 92
4.6 Derivations 93
References 96
Chapter 5. Agonists: The Measurement of Affinity and Efficacy in Functional Assays 98
5.1 Functional Pharmacological Experiments 98
5.2 The Choice of Functional Assays 99
5.3 Recombinant Functional Systems 103
5.4 Functional Experiments: Dissimulation in Time 106
5.5 Experiments in Real Time Versus Stop Time 107
5.6 The Measurement of Agonist Affinity in Functional Experiments 108
5.7 Estimates of Relative Efficacy of Agonists in Functional Experiments 114
5.8 Chapter Summary and Conclusions 115
5.9 Derivations 115
References 117
Chapter 6. Orthosteric Drug Antagonism 118
6.1 Introduction 118
6.2 Kinetics of Drug-Receptor Interaction 118
6.3 Surmountable Competitive Antagonism 121
6.4 Noncompetitive Antagonism 133
6.5 Agonist-Antagonist Hemi-equilibria 136
6.6 Resultant Analysis 138
6.7 Chapter Summary and Conclusions 139
6.8 Derivations 140
References 145
Chapter 7. Allosteric Drug Antagonism 146
7.1 Introduction 146
7.2 The Nature of Receptor Allosterism 146
7.3 Properties of Allosteric Modulators 148
7.4 Functional Study of Allosteric Modulators 153
7.5 Measurement of the Potency of Allosteric Insurmountable Antagonists 157
7.6 Methods for Detecting Allosterism 159
7.7 Chapter Summary and Conclusions 161
7.8 Derivations 162
References 164
Chapter 8. The Process of Drug Discovery 166
8.1 Pharmacology in Drug Discovery 166
8.2 Chemical Sources for Potential Drugs 166
8.3 Pharmacodynamics and High-throughput Screening 171
8.4 Pharmacokinetics 181
8.5 Pharmaceutical Development 188
8.6 Adverse Drug Effects 188
8.7 Chapter Summary and Conclusions 191
References 191
Chapter 9. Target- and System-based Strategies for Drug Discovery 194
9.1 Some Challenges for Modern Drug Discovery 194
9.2 Target-based Drug Discovery 194
9.3 Systems-based Drug Discovery 203
9.4 In Vivo Systems, Biomarkers, and Clinical Feedback 208
9.5 Types of Therapeutically Active Ligands 209
9.6 Summary and Conclusions 212
References 215
Chapter 10. ‘‘Hit’’ to Drug: Lead Optimization 218
10.1 Tracking SARs and Determining Mechanism of Action: Data-driven Drug-based Pharmacology 218
10.2 Drug Initiation of Response: Agonism 218
10.3 Inhibition of Agonist Response: Antagonism 225
10.4 ‘‘Short-form’’ Measures of Antagonism for Following Structure-activity Relationship 228
10.5 Summary and Conclusions 237
10.6 Derivations 237
References 242
Chapter 11. Statistics and Experimental Design 244
11.1 Structure of This Chapter 244
11.2 Introduction 244
11.3 Descriptive Statistics: Comparing Sample Data 244
11.4 How Consistent Is Experimental Data with Models? 251
11.5 Comparison of Samples to ‘‘Standard Values’’ 268
11.6 Experimental Design and Quality Control 270
11.7 Chapter Summary and Conclusions 273
References 273
Chapter 12. Selected Pharmacological Methods 274
12.1 Binding Experiments 274
12.2 Functional Experiments 276
Glossary of Pharmacological Terms 296
Appendices 302
A.1 Statistical Tables of Use for Assessing Significant Difference 302
A.2 Mathematical Fitting Functions 306
Index 312