Concepts in Biochemical Pharmacology: Part 3 by P.S. RandallConcepts in Biochemical Pharmacology: Part 3 by P.S. Randall

Concepts in Biochemical Pharmacology: Part 3

byP.S. RandallEditorJames R. Gillette, J.R. Mitchell

Paperback | March 15, 2012

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Part 3 of the Handbook of Experimental Pharmacology (Concepts in Biochem­ ical Pharmacology) applies the principles enunciated in Parts 1 and 2 to clinical pharmacology and toxicology. The major objective is to elucidate the many factors that determine the relationships between pharmacokinetic aspects of the disposition and metabolism of drugs and their therapeutic or toxic actions in man. Because of the more restricted information obtainable in human studies, this volume reflects the editors' bias that an understanding of pharmacokinetics is fundamental for assessing pharmacologic or toxicologic effects of drugs in humans. The first chapter is a unique primer on when to apply and how to use pharmaco­ kinetic tools in human pharmacology. The second chapter explains the general assumptions underlying pharmacokinetic approaches both in simple terms for the novice and in mathematical form for the more sophisticated reader. Several chapters on determinants of drug concentration and activity discuss drug absorption, drug latentiation, drugs acting through metabolites, entero­ hepatic drug circulation, influence of route of drug administration on response, genetic variations in drug disposition and response, age differences in absorption, distribution and excretion of drugs, and pathologic and physiologic factors affecting absorption, distribution and excretion of drugs and drug response. The focus of these chapters is data obtained in human, rather than animal, studies. Most of the chapters contain new material never summarized previously.
Title:Concepts in Biochemical Pharmacology: Part 3Format:PaperbackDimensions:482 pages, 24.4 × 17 × 1.73 inPublished:March 15, 2012Publisher:Springer NatureLanguage:English

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ISBN - 10:3642463169

ISBN - 13:9783642463167

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Table of Contents

Section Six: Determinants of Drug Concentration and Activity.- 59: Pharmacokinetics.- I. Introduction.- II. Absorption and Elimination; Linear, One-Compartment Systems.- A. Elimination of Single Intravenous Doses.- B. Apparent Volume of Distribution.- C. Urinary Excretion of Drug and Metabolites.- D. Drug Metabolite Levels in the Body.- E. Bioavailability and Absorption Kinetics.- F. Intravenous Infusions.- G. Repetitive Drug Administration.- III. Absorption, Distribution, and Elimination; Linear, Multicompartment Systems.- A. Distribution and Elimination of Single Intravenous Doses.- B. Apparent Volume of Distribution.- C. The Meaning of ?.- D. Bioavailability and Absorption Kinetics.- E. Intravenous Infusion.- F. Repetitive Drug Administration.- G. The "First-Pass" Effect.- H. Other Multicompartment Models.- IV. Pharmacokinetics of Non-Linear Systems.- A. Elimination of Single Intravenous Doses.- B. Various Processes Resulting in Non-Linear Elimination Kinetics.- C. Non-Linear Absorption Kinetics.- D. Repetitive Drug Administration.- V. Kinetics of Reversible Pharmacologic Effects.- A. One-Compartment Systems.- B. Multicompartment Systems.- VI. Some Useful Suggestions for the Experimentalist.- References.- 60: Other Aspects of Pharmacokinetics.- I. Introduction.- II. Factors that Affect the Rate of Distribution of Drugs in Tissues.- A. Permeability of Capillaries and Cells.- B. Lipid Solubility and Ionization of Drugs.- C. Differences in pH between Cells and Blood.- D. Reversible Binding of Drugs to Proteins and Other Components.- 1. General Considerations.- 2. Dissociation Rate Constants and Transit Times.- 3. Diffusion into Extracellular Spaces.- 4. Effect of Reversible Binding on the Clearance of Drugs by Liver.- E. Diffusion Barriers in the Extracellular Space.- F. Active Transport of Drugs.- G. Time-Delay Factors.- III. Some Problems in the Development of Pharmacokinetic Models for Tissues and Organs.- A. General Aspects.- B. Closed Model for a Tissue.- C. Perfusion Systems (Nonrecirculatory).- 1. General.- 2. Model 1.- 3. Model 2.- 4. Model 3.- 5. Model 4.- 6. Emptying of Tissue Compartments.- D. Pharmacokinetics of Drug Disposition and Metabolism after Intravenous Administration of Drugs.- 1. General.- 2. In vivo Kinetic Models.- a) Model I - Caternary 3-Pool System.- b) Model Ia fa Mammillary, Degenerate Diffusion Limited System).- c) Model II (a Mammillary, Caternary System).- d) Model III (2-Pool System).- e) Model IV (Mammillary, 3-Pool Flow-Limited System).- 3. General Comments on the Central Compartment.- 4. Concepts of Volume of Distribution.- a) Equations for Vd(eq), and Vd (?) in 2 and 3 Compartment Systems.- b) Volume of Distribution by the Extrapolation Method.- c) The Partition of Areas Method.- 5. Area under the Curve Method Applied to Metabolites.- 6. Effects of Reversible Binding of Drugs to Macromolecules on Pharmacokinetic Parameters.- a) General.- b) Effects of Reversible Binding on the Clearance of Drugs by a Single Organ.- c) Effects of Reversible Binding on the Volume of Distribution of Drugs.- d) Effects of Reversible Binding on Rate Constants of Elimination in Linear, First Order Models.- e) Non-Linear Binding.- f) Area Under the Curves (AUC) of Total Drug Concentration in Plasma.- Appendix 1.- References.- 61: Drug Latentiation.- I. Introduction.- II. Chemical and Structural Consideration.- III. Prodrug Design.- IV. Carboxylic Acid Drugs.- V. Alcohol Drugs.- VI. Amine Drugs.- References.- 62: Biotransformation of Drugs to Pharmacologically Active Metabolites.- I. Introduction.- II. Drugs Acting on the Central Nervous System.- A. Hypnotics and Sedatives.- a) Chloralhydrate.- B. Anticonvulsants.- a) Mephobarbital.- b) Primidone.- c) Trimethadione.- d) Methsuximide.- C. Centrally Acting Muscle Relaxant.- a) Zoxazolamine.- D. Narcotic Analgesics.- a) Codeine.- b) Meperidine.- c) Acetylmethadol.- d) Diphenoxylate.- E. Analgesic-Antipyretics, Anti-Inflammatory Agents, and Inhibitors of Uric Acid Synthesis.- a) Salicylates.- b) Phenacetin.- c) Aminopyrine.- d) Phenylbutazone.- e) Allopurinol.- f) (4-phenylthioethyl).- F. Drugs Used in the Treatment of Psychiatric Disorders.- 1. Drugs for Treatment of Psychoses.- a) Tetrabenazine.- 2. Drugs for Anxiety.- a) Chlordiazepoxide.- b) Diazepam.- c) Medazepam.- d) Prazepam.- 3. Psychotropic Drugs for Affective Disorders.- a) Tricyclic Compounds.- b) Monoaminoxidase (MAO) Inhibitors.- III. Drugs Acting at Synaptic and Neuroeffector Functional Sites.- A. Anticholinesterase Agents.- a) Parathion.- B. Drugs Acting on Postganglionic Adrenergic Nerve Endings and Structures Innervated by them (Sympathomimetic Drugs).- a) N-isopropylmethoxamine.- b) Fenfluramine.- c) Fenproporex.- C. Drugs Inhibiting Adrenergic Nerves and Structures Innervated by them.- 1. Adrenergic Neuron Blocking Agents.- a) ?-methyldopa.- b) ?-methyl-wt-tyrosine.- IV. Cardiovascular Drugs.- A. Antiarrhythmic Drugs.- a) Lidocaine.- b) Propranolol.- B. Vasodilator Drugs.- a) Diallylmelamine.- b) Prenylamine.- C. Drugs Lowering Blood Lipids or Glucose.- a) Nicotinic Acid.- b) Clofibrate.- c) 3,5-dimethylpyrazole.- d) 3,5-dimethylisoxazole.- e) Acetohexamide.- V. Chemotherapy of Parasitic Diseases.- A. Drugs Used in the Chemotherapy of Helminthiasis.- a) Lucanthone.- VI. Chemotherapy of Neoplastic Diseases.- A. Alkylating Agents.- a) Cyclophosphamide.- VII. Conclusions.- References.- 63: The Enterohepatic Circulation.- I. Introduction.- II. Methods for Studying the Enterohepatic Circulation.- III. The Enterohepatic Circulation of Bile Salts.- A. Excretion of Bile Salts.- B. Absorption of Bile Salts.- IV. Enterohepatic Circulation of Drugs.- A. Morphine.- B. Methadone.- C. Etorphine.- D. Digitoxin.- E. Diethylstilbestrol.- F. Steroids.- G. Indomethacin.- H. Glutethimide.- I. Amphetamine.- J. Butylated Hydroxytoluene.- K. Pentaerythritol Trinitrate.- L. Fenamates.- M. Phenothiazines.- N. Antibiotics.- V. Enhanced Biliary Excretion of Drugs.- A. Enhanced Biliary Plow.- B. Enhanced Formation of Metabolites.- C. Formation of Complexes.- References.- 64: Routes of Administration and Drug Response.- I. Introduction.- II. Enteral Administration of Drugs.- A. The Oral Route.- 1. Advantages of Oral Dosing.- 2. Disadvantages of Oral Dosing.- a) Slow Onset of Action.- b) Nonavailability of Oral Route.- c) Poor Drug Availability.- d) Selective Local Action.- B. Sublingual and Rectal Administration.- III. Parenteral Administration.- A. Intravascular Injection.- B. Intramuscular Injection.- C. Subcutaneous and Percutaneous Administration.- D. Inhalation of Drugs.- IV. Influence of Route of Administration on Drug Response.- A. Isoproterenol.- B. Chlorpromazine.- C. Lidocaine.- D. Propranolol.- V. Conclusions.- References.- 65: Genetically Determined Variations in Drug Disposition and Response in Man.- I. Introduction.- II. Hereditary Conditions Affecting Drug Response Transmitted as Simple Single Factors.- A. Genetic Conditions Transmitted as Single Factors Affecting the Manner in which the Body Acts on Drugs.- 1. Acatalasia.- 2. Slow Inactivation of Isoniazid.- 3. Succinylcholine Sensitivity or Atypical PseudoCholinesterase.- 4. Deficient Parahydroxylation of Diphenylhydantoin.- 5. Bishydroxycoumarin Sensitivity.- 6. Acetophenetidin-Induced Methemoglobinemia.- B. Genetic Conditions Probably Transmitted as Single Factors Altering the Way Drugs Act on the Body.- 1. Warfarin Resistance.- 2. G6PD Deficiency, Primaquine Sensitivity or Favism.- 3. Drug-Sensitive Hemoglobins.- 4. Taste of Phenylthiourea or Phenylthiocarbamide (PTC).- 5. Responses of Intraocular Pressure to Steroids: Relationship to Glaucoma...- 6. Malignant Hyperthermia with Muscular Rigidity.- III. Atypical Liver Alcohol Dehydrogenase.- IV. Ethanol Metabolism in Various Racial Groups.- V. Correlation of Certain Genetic Factors with Adverse Reactions to Various Drugs.- VI. Reduced Drug Binding Capacity in Fetal and Newborn Blood.- VII. Variation Among Individuals in Kate of Drug Elimination.- A. Genetic Control of Variations in Drug Clearance.- B. Environmental Effects on Drug Action and Genetic Control of their Expression.- References.- 66: Aging Effects and Drugs in Man.- I. Introduction.- II. Absorption.- III. Distribution and Elimination.- A. Body Water Compartments.- B. Binding.- 1. Serum Proteins.- 2. Plasma Lipids.- 3. Other Binding Components.- C. Renal Excretion.- D. Relations Affecting Distribution and Elimination.- IV. Concluding Remarks.- References.- 67: Pathological and Physiological Factors Affecting Drug Absorption, Distribution, Elimination, and Response in Man.- I. Introduction.- II. Drug Absorption.- A. Parenteral Administration.- B. Oral Administration.- 1. Effects of Food.- 2. Gastrointestinal pH.- 3. Gastric Emptying Rate.- 4. Malabsorption Syndromes.- 5. Gastrointestinal Surgery.- 6. Mesenteric Blood Flow and Biliary Tract Disease.- III. Drug Distribution.- A. Regional Tissue Distribution.- B. Volume of Drug Distribution.- C. Plasma Protein Binding.- IV. Drug Metabolism.- A. Liver Disease.- B. Acetaminophen-Induced Acute Hepatic Necrosis.- C. Drug Metabolism in Other Pathological Conditions.- D. Extrahepatic Drug Metabolism.- V. Renal Excretion of Drugs.- A. Renal Failure and Drug Excretion.- B. Urine Flow and pH.- C. Increased Hepatic Drug Metabolism in Renal Failure.- VI. Receptor Sensitivity.- A. Diminished Response to Drugs.- B. Enhanced Response to Drugs.- C. Acid-Base and Electrolyte Balance.- VII. Conclusions.- Acknowledgement.- References.- 68: Absorption, Distribution, Excretion, and Response to the Drug in the Presence of Chronic Renal Failure.- I. Introduction.- II. Absorption.- III. Distribution: Protein Binding.- IV. Metabolism.- V. Renal Elimination of Drugs in Patients with CRF.- VI. Response to Drugs.- VII. Conclusions.- References.- Section Seven: Drug Interactions and Adverse Drug Reactions.- 69: Pharmacokinetic Drug Interactions.- I. Introduction.- II. Biological Determinants of Kinetic Parameters.- A. Drug Half-Life.- B. Drug Clearance.- C. Volume of Distribution.- D. Drug Concentration.- E. Summary.- III. Mechanisms of Drug Interactions.- A. Altered Absorption.- 1. Alterations in Gastrointestinal pH.- 2. Gut Motility.- 3. Sequestration or Metabolism in the Gut Lumen.- 4. Alteration in the Absorptive Process.- 5. Summary.- B. Altered Elimination.- 1. Drug Metabolism.- a) Stimulation of Drug Metabolism.- b) Inhibition of Metabolism.- c) Altered Formation of Active Drug Metabolites.- 2. Renal Excretion.- a) Altered Tubular Reabsorption.- b) Tubular Secretion.- 3. Hemodynamic Drug Interactions.- C. Redistribution.- 1. Drug Binding in the Blood.- a) Restrictive Elimination.- b) Non-Restrictive Elimination.- 2. Tissue Binding or Uptake.- D. Multiple Mechanisms.- IV. Investigation of Drug Interactions.- V. Clinical Relevance.- A. Factors Determining the Clinical Significance of Pharmacokinetic Drug Interactions.- 1. Inherent Properties of the Drug or Disease State.- 2. Pharmacokinetic Factors.- 3. Pharmacogenetic Factors.- 4. Disease-Induced Pharmacokinetic Factors.- B. Summary.- References.- 70: Interactions of Cardiovascular Drugs at the Receptor Level.- I. Introduction.- II. Drugs that Increase Myocardial Contractility.- A. Cardiac Glycosides.- 1. Influence of Cations.- a) Potassium.- b) Calcium.- c) Magnesium.- 2. Specific Digitalis Blocking Agents.- 3. Relationship of Digitalis Blood Levels to Cardiac Activity.- B. Sympathomimetic Amines.- C. Methylxanthines.- D. Glucagon.- E. Interaction: Therapeutic and Adverse.- III. Drugs Acting on Blood Vessels.- A. Vasoconstricting Agents.- 1. Sympathomimetic Amines.- 2. Angiotensin.- 3. Ergot Derivatives.- B. Vasodilating Agents.- 1. Sympathomimetic Amines.- 2. Dopamine.- 3. Cholinergic Drugs.- 4. Histamine.- IV. Summary.- References.- 71: Drug Interactions in Cancer Chemotherapy.- I. Introduction.- II. Use of Drug Combinations for Enhanced Antitumor Effect.- A. Definition of Terms.- B. Experimental Assessment of Drug Interaction.- C. Biochemical Rationale for Combination Chemotherapy.- III. Clinical Experience with Combination Chemotherapy.- A. Acute Leukemia.- B. Lymphomas.- C. Therapy of Solid Tumors.- IV. Antagonistic Drug Interactions.- References.- 72: Combined Actions of Antimicrobial Drugs.- I. Introduction.- II. Possible Clinical Indications for Combined Antimicrobial Drug Treatment.- a) Overwhelming, Life-Threatening Infections.- b) Rapid Emergence of Drug-Resistant Microbial Mutants.- c) Microbial Infections that May Require Drug Synergism for Eradication of an Infectious Process.- d) Mixed Infections.- e) Possible Reduction in Toxicity.- III. Clinical Disadvantages of Combined Antimicrobial Drug Treatment.- IV. Problems in Defining and Measuring Effects of Antimicrobial Drugs in Combination.- V. Dynamics of Combined Antimicrobial Action.- A. Antagonism.- 1. Mechanism of Antimicrobial Antagonism.- 2. Antimicrobial Antagonism in the Treatment of Clinical Disease.- B. Synergism.- 1. Mechanism of Antimicrobial Synergism.- a) Blocking Successive Steps in a Metabolic Sequence.- b) Inhibition by one Drug of an Enzyme Capable of Destroying the Second Drug.- c) Antimicrobial Synergism Manifested by Marked Enhancement of Early Bactericidal Rate.- 2. Antimicrobial Synergism in Clinical Disease.- VI. Conclusion.- Acknowledgements.- References.- Section Eight: Perspectives on the Importance of Drug Disposition in Drug Therapy and Toxicology.- 73: Drug Actions and Interactions: Theoretical Considerations.- I. Pharmacologic and Toxicologic Effects are Mediated Solely by the Parent Drug.- A. What Proportion of the Drug is Excreted Unchanged ?.- B. Does Increasing the Dose of a Drug Affect its Total Body Clearance ?.- C. What is the Relative Importance of Drug Metabolizing Enzymes in Different Tissues?.- D. Is the Rate of Drug Metabolism Limited Mainly by the Blood Flow Rate through the Tissues?.- E. What is the Relative Importance of the Pathways of Drug Metabolism in the Tissues?.- F. Do Substances that Deplete the Body of Cosubstrates for Conjugation Limit the Rate of Metabolism of the Drug ?.- G. Are Changes in the Plasma Level of a Drug Therapeutically or Toxicologically Significant?.- II. Pharmacologic and Toxicologic Effects are Mediated Solely by Reversibly Acting Metabolites of the Drug.- A. Do Inducers or Inhibitors Alter the Proportion of the Dose that is Converted to the Active Metabolite ?.- B. Do Inducers or Inhibitors Alter the Rate of Formation of the Active Metabolite without Significantly Changing the Proportion of the Dose that is Converted to the Active Metabolite?.- C. Do Inducers or Inhibitors Alter the Rate of Elimination of the Active Metabolite?.- D. Do Substances Change the Tissue Levels of Cosubstrates Used in the Conjugation Reactions of the Active Metabolite ?.- E. Do High Doses of the Drug Alter the Pattern of Metabolites Derived from the Active Metabolite by Depleting the Cosubstrate?.- F. Do Inducers or Inhibitors Alter the Rates of Both the Formation and Inactivation of the Active Metabolite?.- G. Is the Clearance of the Active Metabolite Greater than the Clearance of the ParentDrug?.- III. Pharmacologic and Toxicologic Effects are Mediated Solely by Chemically Reactive Metabolites.- A. Do Inducers or Inhibitors Alter the Relative Proportion of the Dose that is Converted to the Reactive Metabolite?.- B. Do Inducers or Inhibitors Alter the Relative Proportion of the Reactive Metabolite that Becomes Covalently Bound?.- C. Do Substances Change the Tissue Levels of Cosubstrates Used in Conjugation Reactions?.- D. Do High Doses of the Drug Lead to Depletion of Cosubstrates Used in Conjugation Reactions?.- E. Are Chemically Reactive Metabolites Formed in Different Tissues?.- F. Do Reactive Metabolites Leave the Tissues in which They are Formed?.- G. Examples of the Effects of Inducers, Inhibitors and Depleting Substances on Covalent Binding and Drug Toxicity.- Acknowledgement.- References.- 74: Toxic Drug Reactions.- I. Exaggerated or Unwanted Drug Actions.- 1. Pharmacokinetic Drug Reactions.- 2. Pharmacodynamic Drug Reactions.- II. Toxic Drug Reactions.- A. Cell Necrosis.- 1. Acetaminophen (Paracetamol).- 2. Phenacetin.- 3. Furosemide (Frusemide).- 4. Cephaloridine.- 5. Isoniazid and Iproniazid.- 6. Fluroxene.- 7. Acetanilide.- 8. Halobenzenes.- 9. Spironolactone.- 10. Porphyria.- B. Drug-Induced Neoplasia.- 1. Antineoplastic Drugs.- 2. Estrogens.- 3. Phenacetin.- 4. Drugs Used Clinically Not Known to be Carcinogenic in Humans but Known to Induce Cancer in Animals.- a) Isoniazid.- b) Nitrofuran Derivatives.- c) Miscellaneous Drugs.- C. Drug Allergy.- III. Drug Reactions of Unknown Etiology.- IV. Perspective.- References.- Authors Index.