Cardiac Glycosides

Pharmacokinetics — Distribution, Metabolism, and Elimination.- 1 Pharmacokinetics of Digitoxin.- A. Introduction.- B. Drug Uptake and Tissue Distribution.- I. Rate of Distribution and Distribution Half-Life.- II. Tissue Compartments and the Apparent Volume of Distribution.- III. Tissue Distribution.- IV. Passage Across Biologic Membranes.- 1. Blood-Brain Barrier.- 2. Placental Transfer.- C. Metabolism.- I. Basic Studies with Tissue Preparations and in Animals.- II. Single-Dose Studies in Humans.- III. Digitoxin Metabolism in Humans on Maintenance Treatment.- D. Enterohepatic Circulation.- E. Elimination and Excretion Pathways.- I. Serum Elimination Half-Life.- II. Serum Digitoxin Concentrations on Maintenance Treatment.- III. Excretion Pathways.- F. Modifications by Age.- I. Neonates, Infants, and Children.- II. Old Age.- G. Modifications by Disease States.- I. Gastrointestinal Disease.- II. Thyroid Disease.- III. Hepatic Disease.- IV. Renal Disease.- 1. Uremic Patients on Hemodialysis.- 2. Uremia Per Se.- 3. Nephrotic Syndrome.- H. Concluding Remarks.- References.- 2 Pharmacokinetics of Digoxin and Derivatives.- A. Tissue Distribution.- B. Apparent Distribution Volume.- C. Elimination.- I. Metabolism.- 1. Cleavage of Digitoxose Residues.- 2. Conjugation Reactions.- 3. Hydrogenation.- II. Excretion.- 1. Renal Excretion.- 2. Renal Excretion of Metabolites.- 3. Factors Influencing Renal Elimination.- 4. Extrarenal Excretion.- 5. Effect of Extrarenal Excretion on Bioavailability.- 6. Prediction of Digoxin Elimination.- 7. Acceleration of Digoxin Elimination.- References.- 3 Pharmacokinetics of Strophanthus Glycosides.- A. Introduction.- B. Enteral Absorption.- I. Human Investigations.- 1. Ouabain.- 2. Strophanthoside K.- 3. Cymarin.- 4. Cymarol.- 5. Helveticoside Derivatives.- II Animal Experiments.- 1. Ouabain.- 2. Strophanthoside K.- 3. Cymarin.- 4. Convallatoxin.- 5. Other Derivatives of Strophanthidin K.- C. Blood Level and Tissue Distribution.- I. Human Investigations.- 1. Ouabain.- 2. Strophanthoside K.- 3. Acetylstrophanthidin.- II. Animal Experiments.- 1. Ouabain.- 2. Strophanthoside K.- 3. Cymarin.- 4. Convallatoxin.- D. Metabolism.- I. Human Investigations and Animal Experiments.- 1. Ouabain.- 2. Strophanthidin K Derivatives.- E. Excretion.- I. Human Investigations.- 1. Ouabain.- 2. Strophanthoside K.- 3. Cymarin.- 4. Acetylstrophanthidin.- II Animal Experiments.- 1. Ouabain.- 2. Strophanthoside K.- 3. Cymarin.- 4. Acetylstrophanthidin.- 5. Dihydroouabain.- 6. Convallatoxin.- F. Conclusions.- References.- 4 Pharmacokinetics of Squill Glycosides.- A. Introduction.- B. Distribution After Intravenous and Oral Administration.- I. Proscillaridin A.- II. Meproscillarin.- C. Metabolism and Excretion Pathways.- I. Proscillaridin A.- II. Meproscillarin.- D. Elimination Rate.- I. Proscillaridin A.- II. Meproscillarin.- References.- Pharmacokinetics — Additional Pharmacokinetic Parameters of Cardiac Glycosides.- 5 Plasma Protein Binding of Cardiac Glycosides.- A. Introduction.- B. Characterization of Plasma Protein Binding.- C. Role of Albumin Binding in Pharmacokinetics.- D. Conclusion.- References.- 6 Intestinal Absorption and Secretion of Cardiac Glycosides.- A. Introduction.- B. Intestinal Absorption of Cardiac Glycosides.- I. Dependence on Polarity.- 1. Results Compatible with Diffusion.- a) Natural Glycosides.- b) Semisynthetic Glycosides.- 2. Results Incompatible with Diffusion.- II. Dependence on Dose.- 1. Results Compatible with Diffusion.- 2. Results Incompatible with Diffusion.- III. Dependence on Inhibitors.- 1. Results Compatible with Diffusion.- 2. Results Incompatible with Diffusion.- IV. Dependence on Time.- 1. Results Compatible with Diffusion.- 2. Results Incompatible with Diffusion.- V. Dependence on Blood Flow and Lymph Drainage.- C. Intestinal Secretion of Cardiac Glycosides.- I. Secretion by the Isolated Mucosa of Guinea Pig Jejunum.- II. Secretion by the Isolated Mucosa of Guinea Pig Ileum and Colon.- III. Secretion by the Isolated Mucosa of Human Intestine.- IV. Intestinal Secretion of Glycosides in Vivo.- V. Comparative Aspects of Intestinal Glycoside Secretion.- D. A Concept for the Intestinal Permeation of Cardiac Glycosides.- E. Conclusions.- References.- 7 Cardiac Uptake and Binding of Cardiac Glycosides.- A. Introduction.- B. Experimental Approaches.- C. Uptake of Radiolabeled Cardiac Glycosides by Superperfused Cardiac Preparations.- I. General Characteristics and Kinetic Properties.- II. Characteristics of Uptake in Relation to Rate of Stimulation.- D. Uptake of Cardiac Glycosides by Perfused Cardiac Preparations.- I. Gross Cardiac Uptake of Cardiac Glycosides in Relation to their Effects.- II. Kinetic Properties of Cardiac Glycoside Extraction by Cardiac Preparations.- III. Translocation of Cardiac Glycosides from their Initial Site of Interaction.- IV. Characteristics of Microsomal Cardiac Glycoside-Binding Sites.- 1. Microsomal Content in Relation to Pharmacologic Effect.- 2. General Kinetic Considerations.- 3. Species Differences.- 4. Agents that Reduce the Microsomal Content of Cardiac Glycosides.- E. Binding of Cardiac Glycosides to Fragmented Cardiac Membranes.- F. Summary.- References.- 8 Bioavailability of Cardiac Glycosides.- A. General Aspects.- B. Methods of Measurement.- C. Digoxin Tablets.- D. Other Digoxin Formulations.- E. Other Cardiac Glycosides.- I. Digitoxin.- II. Lanatoside C.- III. Methyldigoxin and Acetyldigoxin.- F. Effect of Nonbiopharmaceutical Factors.- I. Impairment by Drug Interaction.- 1. Neomycin.- 2. Sulphasalazine.- 3. Diphenylhydantoin.- 4. p-Amino salicylic Acid.- 5. Antacids.- 6. Anion-Exchange Resins.- 7. Activated Charcoal.- II. Gastrointestinal Disease.- G. Conclusions.- References.- 9 Pharmaceutical Quality Control Standards for Cardiac Glycosides.- A. Introduction.- B. Cardiac Glycoside Preparations in Clinical Use.- C. Quality Control Standards and Test Procedures.- I. Bulk Drug.- 1. Description and Solubility.- 2. Identity Tests.- 3. Specific Optical Rotation.- 4. Assay Methods.- a) Biologic.- b) Chemical Assays.- c) Presence of Foreign Substances.- d) Loss on Drying.- e) Ash.- f) Microbial Tests.- II. Pharmaceutical Preparations.- 1. Injections.- 2. Elixirs/Tinctures/Solutions.- a) Elixirs.- b) Tinctures.- c) Solutions.- 3. Tablets and Capsules.- a) Tests for Identity and Assay.- b) Physicochemical Test Requirements for Solid Dosage Products.- III. General Pharmacopeial Tests Applied for Formulated Products.- IV. Product Stability.- V. The Future.- References.- Clinical Pharmacology.- 10 Effects of Cardiac Glycosides on the Failing and Nonfailing Heart.- A. Introduction.- B. Fundamental Positive Inotropic Action.- I. Failing Ventricle.- II. Normal Ventricle.- III. Diseased Nonfailing Ventricle.- IV. Atrial Myocardium.- C. Cardiac Energetics.- I. Normal Ventricle.- II. Failing Ventricle.- III. Coronary Artery Disease.- D. Acute Myocardial Infarction.- I. Failing Ventricle.- II. Diuretics and Nitrates.- III. Digitalis Mechanisms in Infarcted Ventricle.- E. Dose-Contractile Response Relationship.- F. Time Course of Contractile Action.- G. Unified Concept of Digitalis Cardiocirculatory Effects.- I. Failing Versus Normal Heart.- II. Digitalis Effectiveness Relative to Type of Heart Disease.- H. Conclusions.- References.- 11 The Effect of Disease on Cardiac Glycoside Pharmacokinetics.- Abstract/Summary.- A. Renal Insufficiency.- I. Strophanthin.- II. Ouabain.- III. Digoxin.- IV. Digitoxin.- 1. Absorption and Excretion.- 2. Protein Binding.- 3. Nephrotic Syndrome.- B. Gastrointestinal Disease.- I. Effect of Surgical Intervention on Digoxin Absorption and Excretion.- II. Effect of Abdominal Radiation Therapy on Digoxin Absorption and Excretion.- III. Malabsorption Syndrome.- IV. Absorption of Digoxin from the Colon in Normal Subjects and Patients with Colitis.- V. Kinetics of Digoxin and ?-Methyldigoxin in Patients with Acute Hepatitis and Cirrhosis.- VI. Pharmacokinetics and Metabolism of Digitoxin in Patients with Chronic Active Hepatitis.- VII. Kinetics of Digitoxin in Patients with Acute and Chronic Hepatic Insufficiency.- C. Thyroid Disease.- D. Cardiovascular Disease.- E. Conclusion.- References.- 12 Clinical Indications and Choice of Cardiac Glycosides, Clinical Conditions Influencing Glycoside Effects.- A. Indications for Glycoside Therapy.- I. General Considerations.- II. The Pathogenesis and Severity of Myocardial Insufficiency as Factors Governing the Indications for the Management of Digitalis Therapy.- III. Contraindications.- IV. Special Factors Governing the Indications for Glycoside Therapy in Various Heart Diseases.- 1. Mitral Stenosis.- 2. Chronic Cor Pulmonale.- 3. Angina Pectoris.- 4. Myocardial Infarction.- 5. Myocarditis.- 6. Hypertension.- B. Criteria of Adequate Glycoside Treatment.- I. Experimental Studies Under Clinical Conditions.- II. Clinical Criteria.- III. Interpretation of Serum Glycoside Measurements.- C. Guidelines for the Therapeutic Use of Glycosides.- I. Significance of the Pharmacological Data.- II. Misuse of the Pharmacological Data.- 1. Therapeutic Saturation Dose (Therapeutic Body Pool).- 2. Absorption.- 3. Elimination.- III. Dosage and Body Weight.- IV. Choice of Digitalis Glycoside.- V. Technique of Glycoside Administration.- VI. Alterations in Dosage Consequent on Changes in Glycoside Requirements.- 1. Dosage for Patients with Impaired Renal Function.- 2. Dosage for Patients with Impaired Hepatic Function.- 3. Hormonal. Factors.- D. Interactions.- E. Prophylactic Digitalization?.- F. Do Digitalis Glycosides Differ in Their Mode of Action?.- G. Digitalis Treatment in Infancy and Childhood.- H. Other Drugs Used in Conjunction with Digitalis for the Treatment of Heart Failure.- J. Strophanthin.- K. Meproscillarin.- References.- 13 Side Effects and Intoxication of Cardiac Glycosides: Manifestations and Treatment.- A. Introduction.- B. Electrophysiologic Properties.- I. Automaticity, Conduction, and Responsiveness.- II. Refractoriness.- III. Disorders of Impulse Formation.- IV. Disorders of Impulse Conduction.- V. Subcellular Basis of Toxicity.- C. Recognition of Toxicity.- I. Digoxin Pharmacodynamics.- II. Digitoxin Pharmacodynamics.- III. Digitalis Radioimmunoassay.- IV. Acetylstrophanthidin Tolerance Test.- V. Electrical and Vagal Stimulation Tests.- D. Conditions Affecting Toxicity.- I. Hypokalemia, Hypomagnesemia, and Alkalosis.- II. Hypercalcemia.- III. Hypoxemia, Stroke, and Renal Disease.- IV. Hormone and Related Influences.- V. Heart Disease.- VI. Patient Age.- VII. Atrial Fibrillation.- E. Potassium-Digitalis Interactions.- F. Quinidine-Digoxin Interactions.- G. Digitalis-Induced Arrhythmias.- H. Treatment of Toxicity.- I. Quinidine and Procainamide.- II. Lidocaine and Phenytoin.- III. Propranolol.- IV. Bretylium and Colestyramine.- V. Ventricular Pacemaker Overdrive.- VI. Rapid Right Atrial Pacing.- VII. Atrioventricular Block.- J. Conclusions.- References.- 14 Interactions Between Cardiac Glycosides and Other Substances in the Body.- A. Introduction.- B. Interactions with Cardiac Glycosides Influencing the Amount of Active Drug Available at the Site(s) of Action (Pharmacokinetic Interactions).- I. Interactions in the Gastrointestinal Tract.- 1. Chemical Interactions.- a) Hydronium Ion.- b) Enzyme Activity.- 2. Physical Interactions.- a) Activated Charcoal.- b) Anion-Exchange Resins.- c) Fibers and Bulk-Forming Agents.- d) Antacids and Antidiarrheals.- 3. Physiology Interactions.- a) Gastric Emptying Time and Intestinal Motility.- b) Damaged Mucosa.- II. Interactions with Systemic Drug Disposition.- 1. Plasma Protein Binding.- 2. Tissue Binding.- 3. Metabolism.- a) Hydroxylation.- b) Conjugation.- 4. Excretion.- a) Renal Excretion.- b) Biliary Excretion and Enterohepatic Circulation.- 5. Effects on Both Distribution and Elimination.- a) Potassium.- b) Spironolactone.- c) Quinidine.- d) Thyrostatic Agents and Thyroid Hormones.- C. Interactions with Cardiac Glycosides at the Receptor Level (Pharmacodynamic Interactions).- I. Substances Associated with Electrolyte and Acis-Base Balance.- 1. Ions Influencing Cardiac Function.- a) Potassium.- b) Magnesium.- c) Sodium.- d) Calcium.- e) Lithium.- 2. Acid-Base Balance.- 3. Diuretics.- a) Potassium-Depleting Diuretics.- b) Potassium-Sparing Diuretics.- 4. Miscellaneous Agents.- a) Insulin and Glucose.- b) Cathartics and Liquorice.- II. Drugs Known to Affect the Autonomic Nervous System.- 1. Sympathomimetic Amines.- 2. ?-Adrenoceptor Blocking Drugs.- 3. ?-Adrenoceptor Blocking Drugs.- 4. Adrenergic-Neuron Blocking Drugs.- 5. Cholinergie and Anticholinergic Drugs.- III. Antiarrhythmic Drugs.- 1. Group 1 Antiarrhythmic Drugs.- 2. Group 2 Antiarrhythmic Drugs.- IV. Other Drugs Used in Cardiovascular Therapy.- 1. Vasodilatating Drugs.- 2. Calcium Antagonists.- V. Miscellaneous Drugs.- 1. Doxorubicin.- 2. Thyrostatic Agents and Thyroid Hormones.- 3. Xanthines.- 4. Tricyclic Antidepressive Drugs.- 5. Drugs Used During Anesthesia.- D. Concluding Remarks.- References.- Author Index.