Concepts in Biochemical Pharmacology

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.