Handbook of Experimental Pharmacology Continuation of Handbuch der experimentellen Pharmakologie
Vol. 56III
Editorial Board G. V R. Born, London· A. Farah, Rensselaer, New York H. Herken, Berlin' A. D. Welch, Memphis, Tennessee
Advisory Board S. Ebashi· E. G. Erdos' V Erspamer' U. S. von Euler' W S. Feldberg G. B. Koelle' O. Krayer· M. Rocha e Silva' J. R. Vane' P. G. Waser
Cardiac Glycosides Part II: Pharmacokinetics and Clinical Pharmacology
Contributors K.-E. Andersson· B. Bergdahl· G. Bodem· H.J. Dengler S. Dutta . 1M. Iberster· K. Greeff' F. Grosse-Brockhoff J. Krieglstein . F. Lauterbach . G. Lee· . V. Manninen D.T. Mason' L. Nyberg' H.R. Ochs' U. Peters' N. Rietbrock T.R.D. Shaw' G.A. Stewart· L. Storstein· K.E.Wirth B.G. Woodcock
Editor
K. Greeff
Springer-Verlag Berlin Heidelberg New York 1981
Professor Dr. med. KURT GREEFF
Direktor des Instituts fUr Pharmakologie der Universitat Dusseldorf, MoorenstraBe 5, D-4000 Dusseldorf
With 64 Figures
ISBN -13: 978-3-642-68168-4 e-ISBN-13 :978-3-642-68166-0 DOl: 10.1007/978-3-642-68166-0
This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned specifically those of translation, reprinting, re-use of illustrations, broadcasting, reproducing by photocopying machine or similar means, and storage in data banks. Under § 54 of the German Copyright Law where copies are made for other than private use, a fee is payable to "Verwertungsgesellschaft Wort", Munich.
© by Springer-Verlag Berlin Heidelberg 1981 Softcover reprint of the hardcover 1st edition 1981
The use of registered names, trademarks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use.
2122/3130-543210
List of Contributors
Professor K.-E. ANDERSSON, Department of Clinical Pharmacology, EA-blocket, Lund University Hospital, S-22185 Lund
Dr. B. BERGDAHL, Department of Clinical Pharmacology, EA-blocket, Lund University Hospital, S-22185 Lund
Priv.-Doz. Dr. G. BODEM, Medizinische Universitatsklinik Bonn, Venusberg, D-5300 Bonn
Professor Dr. H. J. DENGLER, Direktor der Medizinischen Universitatsklinik Bonn, Venusberg, D-5300 Bonn
Professor Dr. S. DUTrA, Dept. of Pharmacology, Wayne State University, School of Medicine, Gordon H. Scott Hall of Basic Medical Sciences, 540 East Canfield Avenue, Detroit, Michigan 48201jUSA
Professor Dr. J. M. FOERSTER, Director, Clinical Electrophysiology Section of Cardiovascular Medicine, University of California, School of Medicine, Davis, Calif. 95616jUSA
Professor Dr. med. K. GREEFF, Direktor des Instituts fur Pharmakologie der Universitat Dusseldorf, Moorenstrasse 5, D-4000 Dusseldorf
Professor Dr. med. F. GROSSE-BROCKHOFF, em. Direktor der Medizinischen KlinikA der UniversiHit Dusseldorf, Durerstrasse 7, D-4040 Neuss-Selikum
Professor Dr. Dr. J. KRIEGLSTEIN, Institut fiir Pharmakologie und Toxikologie, FB Pharmazie und Lebensmittelchemie, Deutschhausstrasse 17, D-3500 MarburgjLahn
Professor Dr. F. LAUTERBACH, Ruhr-Universitat Bochum, Institut fUr Pharmakologie und Toxikologie, 1m Lottental, D-4630 Bochum 1
Professor Dr. G. LEE, Director, Cardiac Catherization Laboratory, Section of Cardiovascular Medicine, University of California, School of Medicine, Davis, California 95616jUSA
Dr. V. MANNINEN, Associate Physician-in-Chief, Consultant in Medicine, First Department of Medicine, University of Helsinki, SF-00290 Helsinki 29
Dr. D. T. MASON, Professor of Medicine, Chief of Cardiovascular Medicine, School of Medicine, University of California, Davis, California 95616jUSA
Dr. L. NYBERG, Research and Development Department, AB Draco (Subsidiary of AB Astra), S-22101 Lund 1
VI List of Contributors
Priv.-Doz. Dr. H. R. OCHS, Medizinische Universitiitsklinik Bonn, Venusberg, D-5300 Bonn
Priv.-Doz. Dr. U. PETERS, Medizinische Klinik A der Universitiit Diisseldorf, Moorenstrasse 5, D-4000 Diisseldorf
Professor Dr. N. RIETBROCK, Klinikum der Johann-Wolfgang-Goethe-Universitiit, Zentrum fiir Pharmakologie, Abteilung II, Theodor-Stern-Kai 7, D-6000 Frankfurt/Main 70
Dr. T. R. D. SHAW, Cardiac Department, Western General Hospital, Crewe Road, GB-Edinburgh EH42XU
Dr. G. A. STEWART, Group Director of Quality Control, The Wellcome Foundation Ltd., Temple Hill, GB-Dartford, Kent DAl5AH
Dr. LIV STORSTEIN, Rikshospital, Medisinsk Avdeling B, Universitetsklinikk, Pilestredet 32, N-Oslo
Professor Dr. K. E. WIRTH, Institut fiir Pharmakologie der Universitiit Diisseldorf, Moorenstrasse 5, D-4000 Diisseldorf
Dr. B. G. WOODCOCK, Klinikum der Johann-Wolfgang-Goethe Universitiit, Zentrum fiir Pharmakologie, Abt. II, Theodor-Stern-Kai 7, D-6000 Frankfurt/Main 70
Contents
Pharmacokinetics - Distribution, Metabolism, and Elimination
CHAPTER 1
Pharmacokinetics of Digitoxin. LIV STORSTEIN
With 7 Figures
A. Introduction. . . . . . . . . . . . . 3
B. Drug Uptake and Tissue Distribution. . . . . . . 3 I. Rate of Distribution and Distribution Half-Life 3
II. Tissue Compartments and the Apparent Volume of Distribution. 3 III. Tissue Distribution. . . . . . . . 4 IV. Passage Across Biologic Membranes 4
1. Blood-Brain Barrier 4 2. Placental Transfer . . . . . . . 5
C. Metabolism . . . . . . . . . . . . . 6 I. Basic Studies with Tissue Preparations and in Animals 6
II. Single-Dose Studies in Humans . . . . . . . . . . 6 III. Digitoxin Metabolism in Humans on Maintenance Treatment 8
D. Enterohepatic Circulation . . . . . 10 E. Elimination and Excretion Pathways . . . . . . . . . . . . 10
I. Serum Elimination Half-Life. . . . . . . . . . . . . . 10 II. Serum Digitoxin Concentrations on Maintenance Treatment 12
III. Excretion Pathways. . . . . . 13 F. Modifications by Age. . . . . . . 14
I. Neonates, Infants, and Children 14 II. Old Age . . . . . . . . 15
G. Modifications by Disease States 16 I. Gastrointestinal Disease. 16
II. Thyroid Disease 16 III. Hepatic Disease . . . . 17 IV. Renal Disease . . . . . 20
1. Uremic Patients on Hemodialysis 20 2. Uremia Per Se . . . 21 3. Nephrotic Syndrome . 24
H. Concluding Remarks 25 References . . . . . . . . . . 25
VIII
CHAPTER 2
Pharmacokinetics of Digoxin and Derivatives N. RIETBROCK and B. G. WOODCOCK. With 3 Figures
A. Tissue Distribution. . . . . . B. Apparent Distribution Volume . C. Elimination . . . . . . . . .
1. 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 . . . . . . . . . . . . . . . .
CHAPTER 3
Pharmacokinetics of Strophanthus Glycosides K. GREEFF and K. E. WIRTH. With 6 Figures
A. Introduction. . . . . . B. Enteral Absorption. . .
1. 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 1. Human Investigations
1. Ouabain ..... . 2. Strophanthoside K . 3. Acetylstrophanthidin
II. Animal Experiments. 1. Ouabain ..... 2. Strophanthoside K
Contents
31 36 36 36 37 39 40 41 43 43 44 46 47 47 49 50
57 57 57 57 59 60 60 60 61 61 62 62 62 63 63 63 63 64 65 65 65 69
Contents
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. Strop han tho side K 3. Cymarin ..... 4. Acetylstrophanthidin 5. Dihydroouabain 6. Convallatoxin
F. Conclusions References . . . . . .
CHAPTER 4
Pharmacokinetics of Squill Glycosides K.-E. ANDERSSON and B. BERGDAHL. With I Figure
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
CHAPTER 5
Plasma Protein Binding of Cardiac Glycosides. J. KRIEGLSTEIN
A. Introduction. . . . . . . . . . . . . . B. Characterization of Plasma Protein Binding . . . . . .
IX
71 71 72 72 72 72 74 75 75 75 77 77 77 77 78 78 78 80 80 80 80
87 87 87 88 89 89 90 92 92 93 93
95 95
x Contents
C. Role of Albumin Binding in Pharmacokinetics D. Conclusion References . . . . . . . . . . . . . . . . .
CHAPTER 6
Intestinal Absorption and Secretion of Cardiac Glycosides F. LAUTERBACH. With 18 Figures
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 .
CHAPTER 7
Cardiac Uptake and Binding of Cardiac Glycosides. S. DUTTA. With 4 Figures
100 102 102
105 108 108 108 108 110 111 112 112 113 115 115 115 116 116 116 118 118 118 121 122 123 124 125 131 132
A. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . 141 B. Experimental Approaches . . . . . . . . . . . . . . . . . . . . 141 C. Uptake of Radiolabeled Cardiac Glycosides by Superperfused Cardiac
Preparations. . . . . . . . . . . . . . . . . . . . . . .. 143 I. General Characteristics and Kinetic Properties . . . . . .. 143
II. Characteristics of Uptake in Relation to Rate of Stimulation. 146 D. Uptake of Cardiac Glycosides by Perfused Cardiac Preparations. 148
I. Gross Cardiac Uptake of Cardiac Glycosides in Relation to their Effects . . . . . . . . . . . . . . . . . . . . . . . . . . 148
Contents XI
II. Kinetic Properties of Cardiac Glycoside Extraction by Cardiac Preparations. . . . . . . . . . . . . . . . . . . . . . . . 152
III. Translocation of Cardiac Glycosides from their Initial Site of Interaction . . . . . . . . . . . . . . . . . . . . . .. 154
IV. Characteristics of Microsomal Cardiac Glycoside-Binding Sites. 156 1. Microsomal Content in Relation to Pharmacologic Effect . 156 2. General Kinetic Considerations . . . . . . . . . . . 158 3. Species Differences ................ 159 4. Agents that Reduce the Microsomal Content of Cardiac
Glycosides . . . . . . . . . . . . . . . . . . . . 160 E. Binding of Cardiac Glycosides to Fragmented Cardiac Membranes 161 F. Summary 164 References . . . . . . . . . . . . . . . . . . . . . . . . .. 164
CHAPTER 8
Bioavailability of Cardiac Glycosides. T. R. D . SHAW
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-Aminosalicylic Acid 5. Antacids . . . . . . 6. Anion-Exchange Resins 7. Activated Charcoal .
II. Gastrointestinal Disease. G. Conclusions. References .
CHAPTER 9
Phannaceutical Quality Control Standards for Cardiac Glycosides G.A. STEWART
A. Introduction. . . . . . . . . . . . . . . . B. Cardiac Glycoside Preparations in Clinical Use C. Quality Control Standards and Test Procedures
I. Bulk Drug . . . . . . . . I. Description and Solubility . . . . . .
169 170 172 175 177 177 177 178 178 178 179 179 179 179 179 179 180 180 181 182
189 189 189 189 189
XII Contents
2. Identity Tests . . . . . . 191 3. Specific Optical Rotation. 191 4. Assay Methods . . 191
a) Biologic . . . . . . . 191 b) Chemical Assays . . . 193 c) Presence of Foreign Substances. 193 d) Loss on Drying 194 e) Ash. . . . . . . . . 194 f) Microbial Tests. . . . 194
II. Pharmaceutical Preparations. 195 1. Injections. . . . . . . . 195 2. Elixirs/Tinctures/Solutions 195
a) Elixirs. . 195 0) Tinctures . . . . 195 c) Solutions . . . . 195
3. Tablets and Capsules. 196 a) Tests for Identity and Assay 196 b) Physicochemical Test Requirements for Solid Dosage Products 196
III. General Pharmacopeial Tests Applied for Formulated Products 199 IV. Product Stability. 199 V. The Future 199
References . . . . . . . . 201
Clinical Pharmacology
CHAPTER 10
Effects of Cardiac Glycosides on the Failing and Nonfailing Heart D. T. MASON and G. LEE. With 9 Figures
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 ..... .
· 207 · 207 · 207 · 208 · 208 · 209 .211 · 212 · 212 · 212
213 213 213 214
· 214 · 214
Contents XIII
G. Unified Concept of Digitalis Cardiocirculatory Effects 215 I. Failing Versus Normal Heart . . . . . . . . . 215
II. Digitalis Effectiveness Relative to Type of Heart Disease 216 H. Conclusions 217 References . . . . . . . . . . . . . . . . . . . . . . . . 217
CHAPTER 11
The Effect of Disease on .Cardiac Glycoside Pharmacokinetics G. BODEM, H. R. OCHS, and H. J. DENGLER. With 4 Figures
Abstract/Summary. . . 219 Introduction . . . . . 220 A. Renal Insufficiency . 220
I. Strophanthin 220 II. Ouabain . 220
III. Digoxin . . 220 IV. Digitoxin. . 224
1. Absorption and Excretion 224 2. Protein Binding. . . 225 3. Nephrotic Syndrome . . 226
B. Gastrointestinal Disease. . . . . 226 I. Effect of Surgical Intervention on Digoxin Absorption and Excretion 226
II. Effect of Abdominal Radiation Therapy on Digoxin Absorption and Excretion. . . . . . . . . . . . . . . . . . . . . . . 227
III. Malabsorption Syndrome. . . . . . . . . . . . . . . . . . 227 IV. Absorption of Digoxin from the Colon in Normal Subjects and
Patients with Colitis . . . . . . . . . , . . . . . . . . . . 228 V. Kinetics of Digoxin and p-Methyldigoxin in Patients with Acute
Hepatitis and Cirrhosis. . . . . . . . . . . . . . . . . . . 229 VI. Pharmacokinetics and Metabolism of Digitoxin in Patients with
Chronic Active Hepatitis . . . . . . . . . . . . . . . . . . 229 VII. Kinetics of Digitoxin in Patients with Acute and Chronic Hepatic
Insufficiency . . 230 C. Thyroid Disease . . . 230 D. Cardiovascular Disease 233 E. Conclusion 233 References . . . . . . . 233
CHAPTER 12
Clinical Indications and Choice of Cardiac Glycosides, Clinical Conditions Influencing Glycoside Effects. F. GROSSE-BROCKHOFF and U. PETERS With 3 Figures
A. Indications for Glycoside Therapy . . . . . . . . . . . . . . . . 239 I. General Considerations . . . . . . . . . . . . . . . . . . . 239
II. The Pathogenesis and Severity of Myocardial Insufficiency as Factors Governing the Indications for the Management of Digitalis Therapy 240
XIV Contents
III. Contraindications . . . . . . . . . . . . . . . . . . . . . 241 IV. Special Factors Governing the Indications for Glycoside Therapy in
Various Heart Diseases . . 241 1. Mitral Stenosis . . . . 241 2. Chronic Cor Pulmonale 241 3. Angina Pectoris . . . 242 4. Myocardial Infarction 243 5. Myocarditis. . . . . 244 6. Hypertension . . . . 244
B. Criteria of Adequate Glycoside Treatment . 244 I. Experimental Studies Under Clinical Conditions 244
II. Clinical Criteria . . . . . . . . . . . . . . 245 III. Interpretation of Serum Glycoside Measurements. 246
C. Guidelines for the Therapeutic Use of Glycosides . 248 I. Significance of the Pharmacological Data . . . . 248
II. Misuse of the Pharmacological Data . . . . . . 249 1. Therapeutic Saturation Dose (Therapeutic Body Pool) 250 2. Absorption . . . . . 250 3. Elimination. . . . . . . 251
III. Dosage and Body Weight. . 252 IV. Choice of Digitalis Glycoside 252 V. Technique of Glycoside Administration 253
VI. Alterations in Dosage Consequent on Changes in Glycoside Requirements . . . . . . . . . . . . . . . . . . . 254 1. Dosage for Patients with Impaired Renal Function. . 254 2. Dosage for Patients with Impaired Hepatic Function . 257 3. Hormonal Factors . 257
D. Interactions . . . . . . . . . . . . . . . . . . . . 258 E. Prophylactic Digitalization? . . . . . . . . . . . . . 260 F. Do Digitalis Glycosides Differ in Their Mode of Action? 261 G. Digitalis Treatment in Infancy and Childhood . . . . . 261 H. Other Drugs Used in Conjunction with Digitalis for the Treatment of
Heart Failure . 263 J. Strophanthin . 264
K. Meproscillarin . 265 References . 266
CHAPTER 13
Side Effects and Intoxication of Cardiac Glycosides: Manifestations and Treatment. D. T. MASON and J. M. FOERSTER. With 9 Figures
A. Introduction. . . . . . . . . . . . . . . . . . 275 B. Electrophysiologic Properties . . . . . . . . . . 276
I. Automaticity, Conduction, and Responsiveness 276 II. Refractoriness. . . . . . . . . 276
III. Disorders of Impulse Formation. 276 IV. Disorders of Impulse Conduction 277
Contents
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 .
CHAPTER 14
Interactions Between Cardiac Glycosides and Other Substances in the Body V. MANNINEN and L. NYBERG
xv
277 278 278 278 279 279 279 280 280 280 280 281 281 281 282 282 284 285 288 289 290 290 291 291 292 292 292 293
A. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . 299 B. Interactions with Cardiac Glycosides Influencing the Amount of Active
Drug Available at the Site(s) of Action (Pharmacokinetic Interactions) 299 I. Interactions in the Gastrointestinal Tract 300
1. Chemical Interactions 300 a) Hydronium Ion. . 300 b) Enzyme Activity . 301
2. Physical Interactions . 301 a) Activated Charcoal 301 b) Anion-Exchange Resins 302 c) Fibers and Bulk-Forming Agents 302 d) Antacids and Antidiarrheals . . 303
3. Physiology Interactions. . . . . . 303 a) Gastric Emptying Time and Intestinal Motility 303 b) Damaged Mucosa. . . . . . . ., . . . . 304
XVI Contents
II. Interactions with Systemic Drug Disposition . 304 1. Plasma Protein Binding. 305 2. Tissue Binding . 305 3. Metabolism. . . 305
a) Hydroxylation 305 b) Conjugation . 306
4. Excretion. . . . 306 a) Renal Excretion 306 b) Biliary Excretion and Enterohepatic Circulation. 306
5. Effects on Both Distribution and Elimination 307 a) Potassium . . 307 b) Spironolactone . . . . . . . . . . . . 308 c) Quinidine . . . . . . . . . . . . . . 308 d) Thyrostatic Agents and Thyroid Hormones. 309
C. Interactions with Cardiac Glycosides at the Receptor Level (Pharmacodynamic Interactions) . . . . . . . . . . . . 310
I. Substances Associated with Electrolyte and Acis-Base Balance 310 1. Ions Influencing Cardiac Function . 311
a) Potassium . 311 b) Magnesium 311 c) Sodium . 312 d) Calcium. . 312 e) Lithium. . 312
2. Acid-Base Balance. 313 3. Diuretics. . . . . 313
a) Potassium-Depleting Diuretics 313 b) Potassium-Sparing Diuretics 314
4. Miscellaneous Agents 314 a) Insulin and Glucose. . . . 314 b) Cathartics and Liquorice. . 314
II. Drugs Known to Affect the Autonomic Nervous System. 314 1. Sympathomimetic Amines 315 2. J1-Adrenoceptor Blocking Drugs. . 316 3. IX-Adrenoceptor Blocking Drugs . . 317 4. Adrenergic-Neuron Blocking Drugs 317 5. Cholinergic and Anticholinergic Drugs 317
III. Antiarrhythmic Drugs . . . . . 318 1. Group 1 Antiarrhythmic Drugs . . . 318 2. Group 2 Antiarrhythmic Drugs . . . 319
IV. Other Drugs Used in Cardiovascular Therapy 319 1. Vasodilatating Drugs. 319 2. Calcium Antagonists. 319
V. Miscellaneous Drugs . . 320 1. Doxorubicin . . . . 320 2. Thyrostatic Agents and Thyroid Hormones 320 3. Xanthines . . . . . . . . . . . . . . 321
Contents
4. Tricyclic Antidepressive Drugs 5. Drugs Used During Anesthesia
D. Concluding Remarks References . . . . . . . . . . . . . .
Author Index
Subject Index
XVII
. 321
. 322 322 322
337
375
Erratum
Handbook of Experimental Pharmacology, Vol. 56/!
CHAPTER 11
The Positive Inotropic Action of Cardiac Glycosides on Cardiac Ventricular Muscle M.REITER
The title of the above-mentioned chapter should read as follows:
The Positive Inotropic Action of Cardioactive Steroids on Cardiac Ventricular Muscle M.REITER
Contents
Part I: Experimental Pharmacology
CHAPTER 1
Introduction and Remarks on the History of Cardiac Glycosides K. GREEFF and H. SCHADEWALDT
CHAPTER 2
Chemistry and Structure-Activity Relationships of Cardioactive Steroids T. W. GUENTERT and H. H. A. LINDE. With 4 Figures
Methods for the Determination of Cardiac Glycosides
CHAPTER 3
Chemical and Chromatographic Methods. H. FLASCH and W. DIEMBECK With 8 Figures
CHAPTER 4
Use of Radioactively Labeled Glycosides. H. FLASCH. With 3 Figures
CHAPTER 5
Radioimmunologic Methods. K. STELLNER. With 4 Figures
CHAPTER 6
ATPase for the Determination of Cardiac Glycosides URSULA GUNDERT-REMY and ELLEN WEBER. With 4 Figures
CHAPTER 7
Rubidium Uptake in Erythrocytes. G. G. BELZ. With 7 Figures
Biological Methods for the Evaluation of Cardiac Glycosides
CHAPTER 8
Evaluation of Cardiac Glycosides in the Intact Animal H. BAHRMANN und K. GREEFF. With 6 Figures
CHAPTER 9
The Use of the Isolated Papillary Muscle for the Evaluation of Positive Inotropic Effects of Cardioactive Steroids. M. REITER. With 3 Figures
xx Contents of Part I
CHAPTER 10
Evaluation of Cardiac Glycosides in Isolated Heart Preparations Other than Papillary Muscle. K. GREEFF and D. HAFNER. With 9 Figures
Mode of Action of Cardiac Glycosides
CHAPTER 11*
The Positive Inotropic Action of Cardioactive Steroids on Cardiac Ventricular Muscle. M. REITER. With 15 Figures
CHAPTER 12
Influence of Cardiac Glycosides on Electrophysiologic Processes R. WEINGART. With 11 Figures
CHAPTER 13
Influence of Cardiac Glycosides on Myocardial Energy Metabolism W. KLAUS and K. GUrrLER. With 8 Figures
CHAPTER 14
Effects of Cardiac Glycosides on Na +, K + -ATPase. T. AKERA. With 7 Figures
CHAPTER 15
Influence of Cardiac Glycosides on their Receptor. E. ERDMANN. With 18 Figures
CHAPTER 16
Stimulation and Inhibition of the Na + , K + -Pump by Cardiac Glycosides T. GODFRAIND. With 3 Figures
CHAPTER 17
Influence of Cardiac Glycosides on Cell Membrane H. LUUMANN and TH. PETERS. With 9 Figures
CHAPTER 18
Influence of Cardiac Glycosides on Electrolyte Exchange and Content in Cardiac Muscle Cells. W. G. NAYLER and E. A. NOACK. With 7 Figures
CHAPTER 19
Effects of Cardiac Glycosides on Myofibrils. P. G. WASER and M. C. SCHAUB With 7 Figures
CHAPTER 20
Substances Possessing Inotropic Properties Similar to Cardiac Glycosides T. AKERA, A. L. Fox, and K. GREEFF. With 8 Figures
* See Erratum, p. XVIII
Contents of Part I
Non-Cardiac Effects of Cardiac Glycosides
CHAPTER 21
Effects of Cardiac Glycosides on Central Nervous System. H. F. BENTHE
CHAPTER 22
Effects of Cardiac Glycosides on Vascular System. D. T. MASON
With 11 Figures
CHAPTER 23
XXI
Effects of Cardiac Glycosides on Skeletal Muscle. B. DENES and K. GREEFF
With 2 Figures
CHAPTER 24
Effects of Cardiac Glycosides on Autonomic Nervous System and Endocrine Glands P. H. JOUBERT. With 2 Figures
CHAPTER 25
Effects of Cardiac Glycosides on Kidneys. O. HEIDENREICH and H. OSSWALD
With 8 Figures
Author Index
Subject Index
