Basic Pharmacology. Understanding Drug Actions and Reactions

Transcription

1 Basic Pharmacology Understanding Drug Actions and Reactions MARIA A. HERNANDEZ Ph.D. Pharmaceutical and Administrative College of Pharmacy Nova Southeastern University Ft. Lauderdale, Florida, U.S.A. APPU RATHINAVELU Ph.D. Pharmaceutical and Administrative College of Pharmacy Nova Southeastern University Ft. Lauderdale, Florida, U.S.A. (fifty) Taylor & Francis \V^ J Taylor & Francis Croup Boca Raton London New York A CRC title, part of the Taylor & Francis imprint, a member of the Taylor & Francis Croup, the academic division of T&F Informa pic.

2 CONTENTS SECTION I PHYSICOCHEMICAL PROPERTIES OF DRUGS 1 Fundamental Chemical Properties of Drugs 3 Introduction 3 The Periodic Table and Properties of Drugs 3 The Periodic Table and Chemical Reactivity 10 Chemical Bonds 16 Magnitude of Ionic Charge 18 Polyatomic Ions 19 Covalent Bonds 20 Coordinate Covalent Bonds 25 Resonance Structures. 27 Shapes of Drug Molecules 28 Electronegativity 33 Polarity of Chemical Bonds 33 Molecular Polarity 34 Further Reading 35 2 Acid-Base Properties of Drugs 37 Hydrolysis of Salts, 38 Conjugate Acids and Conjugate Bases 41 Strength of Acids and Bases 43 Resonance and Inductive Effects 47 Inductive Effects 47 Resonance Effects 49 The Henderson-Hasselbach Equation 53 Further Reading 60 3 Structural Determinants of Drug Action 61 Structurally Nonspecific Drugs 6l Volatile Anesthetics 61 Structurally Specific Drugs 63 Isosterism and Isosteres 68 Structural Changes in Drug Molecules 71 Further Reading 76 xi

3 xii Basic Pharmacology: Understanding Drug Actions and Reactions 4 Chemical Approaches to the Treatment of Cancer 77 Normal vs. Malignant Cells 77 Cell Cycle and Chemotherapy 78 From Chemical Warfare to Chemotherapy 79 Anticancer Drugs 80 Alkylating Agents 81 Antimetabolites 84 DNA Intercalators 87 DNA Crosslinking Agents 89 Further Reading 90 SECTION II PRINCIPLES OF BIOPHARMACEUTICS 5 Administration and Absorption of Drugs 93 Drug Administration 93 Properties of the Drug 94 Drug Solubility 94 Polymorphism 97 Particle Size 98 PK 98 Therapeutic Objective 100 Onset of Action 100 Long-Term Administration 100 Restriction to a Local Site 101 Drug Absorption 101 Physiological and Physicochemical Factors in Drug Absorption 103 Drug Transport across Membranes 103 Passive Diffusion 103 Active Transport 104 Facilitated Transport 104 Ion Pair Transport 105 Endocytosis, Pinocytosis, Phagocytosis, and Exocytosis 105 ph of Body Compartments 105 Other Factors That Affect Absorption 107 Blood Flow to the Absorption Site 107 Surface Area Available for Absorption 108 Contact Time at the Absorption Surface 108 Drug Absorption, Bioavailability, and First-Pass Metabolism 108 Further Reading Distribution and Excretion of Drugs Ill Factors in Drug Distribution Ill Capillary Permeability 112 Blood Perfusion 114 Perfusion and Permeability 114 Drug Structure and Compartment ph 116 Plasma Protein Binding 116 Intracellular Binding 117

4 Contents xiii Patterns of Distribution 117 Determination of the Volume of Distribution 120 Clearance and Elimination Rate 122 Clearance and the Maintenance Dose Rate 122 Half-Life and the Steady State 125 Bioavailability 127 Drug Elimination 130 The Enterohepatic Cycle 130 Renal Excretion 131 Renal Processes 132 Further Reading Metabolic Changes of Drugs 135 Cytochromes P Inhibition of Drug Metabolism 138 Induction of Drug Metabolism 138 Environmental and Genetic Factors in Metabolism by CYP Clozapine and CYP1A2 Activity 142 Genetic Polymorphism and CYP2D6 142 CYP2D6 and Codeine 143 Genetic Polymorphism and CYP2C Drug Interactions via the CYP2C19 Isoform: Omeprazole-Diazepam Interaction 143 CYP3A Family 143 CYP3A4 and Grapefruit Juice 144 Redox Reactions and the CYP450 Enzyme Complex 144 NADVNADH System 145 FAD/FADH System 147 The Cytochrome P45O Cycle 147 Phase I and Phase II Reactions of Drug Metabolism 149 Phase I Reactions 149 Oxidations Using CYP450 Enzymes 149 Oxidation using Other Enzymes 163 Reduction 166 Hydrolysis Reactions 167 Phase II Reactions (Conjugation) 171 Dose-Dependent Toxicity of Acetaminophen 178 Further Reading 186 SECTION III PRINCIPLES OF DRUG-RECEPTOR AND DRUG-ENZYME INTERACTIONS 8 Drug Receptors and Pharmacodynamics 189 Mechanisms of Drug Action 189 Chemical Signaling and Receptor Function 189 Chemical Signaling 189 Autocrine, Paracrine, and Endocrine Function 192 Nature of the Signaling Molecules (Ligands) 192

5 xiv Basic Pharmacology: Understanding Drug Actions and Reactions Different Kinds of Receptors 194 Extracellular Receptors 196 Intracellular Receptors ; 196 Plasma Membrane-Bound Receptors 196 Three Types of Plasma Membrane-Bound Receptors 196 Models of Drug-Receptor Interaction 198 Drug-Receptor Interactions 198 Key Features of Binding Sites 198 Lock-and-Key Fit 198 Induced Fit 199 Affinity and Intrinsic Activity 200 Affinity 200 Intrinsic Activity 200 Agonists, Antagonists, and Partial Agonists 201 Agonists 201 Antagonists 201 Partial Agonist 201 Ligand Structure and Activity Relationship 201 Why is the Receptor Concept Important? 202 Differential Effects of Agonists 202 Differential Effects of Epinephrine 202 Selective Actions of Adrenergic Agonists and Antagonists 205 Atypical Receptors 208 Cholinergic Neurotransmission 209 Synthesis and Release of Acetylcholine 210 Differential Effects of Acetylcholine through Cholinergic Receptors Muscarinic and Nicotinic Actions of Acetylcholine 212 The Location and Function of Acetylcholine Receptors 213 Cholinomimetics 214 Cholinergic Agonists and Antagonists 215 Clinical Use of Direct-Acting Cholinomimetics 215 Antimuscarinic 221 Drug-Induced Enzyme Inhibition 223 Drug Effects Mediated through Enzyme Inhibition 223 Competitive, Uncompetitive, and Noncompetitive Inhibition 225 Competitive Inhibition 225 Uncompetitive Inhibition 226 Noncompetitive Inhibition 228 Allosteric Regulation 228 Cooperativity 229 Feedback Inhibition 229 Examples of Drug-Enzyme Interactions 230 Acetylcholinesterase 230 Butyrylcholinesterase (BuChE) 231 The Active Center of Cholinesterase 232 Anticholinesterase Drugs 234

6 Contents xv Types of Cholinesterase Inhibitors 234 Reversible Anticholinesterases 234 Irreversible Anticholinesterases 235 Effects of Anticholinesterase Drugs 236 Uses of Anticholinesterase Drugs 238 Antiocholinesterases for the Treatment of Glaucoma 238 Anticholinesterase for the Treatment of Myasthenia Gravis 239 Poisonous Effects of Irreversible Anticholinesterases 241 Cholinesterase-Regenerating Compounds 241 Transpeptidase-Penicillinase Inhibition Producing Pharmacological Effects 243 Transpeptidase 243 Bacterial Cell Wall Synthesis 243 Peptidoglycans 245 Transpeptidase 246 Transpeptidase Inhibitors 248 Penicillins 250 Penicillinases 251 Beta-Lactamase Inhibitors 251 Suicide Inhibition of Enzymes 254 Suicide Inhibition of Thymidylate Synthetase (TS) 254 Suicide Inhibition of Xanthine Oxidase (XO) 255 References Drug-Receptor Dynamics and Theories 259 Occupation Theory (Clark) 259 Modified Occupancy Theory (Ariens) 264 Rate Theory (Paton) 264 Relationship between Concentration and Response 269 Concentration-Effect Curves 269 Drug Antagonism 270 Competitive Antagonism 271 Schild's Equation 275 What Is the Importance of This Mathematical Relationship? 278 Irreversible Antagonism 280 Noncompetitive Antagonism 281 Partial Agonists 282 Various Factors That Can Regulate a Drug's Effect 285 Potency and Efficacy 286 Potency 286 Efficacy 287 Dose-Response Curves 288 Graded Dose-Response Curves 288 Quantal Dose-Response Curves 290 Statistics That Can Be Derived from the Quantal Dose-Response Curve 291 Therapeutic Index 293

7 xvi Basic Pharmacology: Understanding Drug Actions and Reactions Time-Action Curves 296 Phase I: Time to Onset of Action 297 Phase II: Time to Peak Effect 297 Phase III: Duration of Action 297 Phase IV: Residual Effects 297 Sample Problems 297 Practice Problems 303 Answers for the Problems 305 References Receptor Regulation and Signaling Mechanisms 307 Spare Receptors 307 Overshoot 308 Down Regulation 309 Other Factors That Can Affect Drug Response 312 Tolerance 312 Tachyphylaxis 312 Idiosyncratic Drug Response 313 Receptor Signaling and Second Messenger Systems 313 Four Basic Mechanisms of Receptor Signaling 313 The Four Major Types of Second Messengers 315 Hormones Acting through Intracellular Receptors 318 Mechanism of Action 318 Ligands Acting through Cell Surface Receptors 320 Protein Kinases 320 Phosphorylation and the Effects of Phosphorylation 320 Two Types of Protein Kinases 320 Examples of Receptor Signaling by Activation of Tyrosine Kinases 322 Phosphorylation-Induced Receptor Down Regulation and Receptor Desensitization 323 Receptor-Coupled (Membrane-Bound) Guanylate Cyclase (GC) 325 Soluble Guanylate Cyclase 326 Receptors Linked to G-Proteins and Second Messenger Production 327 Activation of Adenylate Cyclase and G-Protein Function 329 Downstream camp Second Messenger Pathway 331 Ca 2 7Phosphoinositide/PKC Signaling Pathway 331 What Is the Purpose of G-Proteins or Any Other Second Messenger System? 334 Ligand-Gated Ion Channels 334 Signaling through Voltage-Dependent Ion Channels 336 Voltage-Dependent Sodium (Na + ) Channel 336 Voltage-Gated Potassium (K + ) Channel 337 Ligand-Gated Sodium Channel 337 Calcium Channels 338 Location(s) of the Voltage-Sensitive Ca 2+ Channels (VSCC) 339

8 Contents xvii How Does Calcium Contract the Skeletal Muscles and the Vascular Smooth Muscles? 342 Chloride Channel 344 GABA Receptors 344 Structure of GABA A Receptors 344 GABA Binding Site 346 Benzodiazepine Binding Site 348 Barbiturates Binding Site 348 Picrotoxin Binding Site 349 GABA Antagonists 349 References 350 Index 353