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Handbook of Experimental Pharmacology Volume 117

Editorial Board G.V.R. Born, London P. Cuatrecasas, Ann Arbor, MI D. Ganten, Berlin H. Herken, Berlin K.L. Melmon, Stanford, CA Springer Berlin Heidelberg New York Barcelona Budapest Hong Kong London Milan Paris Tokyo

Contributors o.s. Better, A. Busch, J. D(ljrup, H. Endou, R. Greger W.G. Guder, M. Hosoyamada, M. Hropot, B. Kaissling T.R. Kleyman, H. Knauf, F. Lang, H.-J. Lang, W. Mohrke E. Mutschler, T. Netzer, L.G. Palmer, J.B. Puschett I. Rubinstein, M. Schmolke, F. Ullrich, K.J. Ullrich H. Velazquez, J. Winaver

Editors R.F. Greger, H. Knauf and E. Mutschler

, Springer Professor Dr. med. RAINER F. GREGER Physiologisches Institut der Albert-Ludwigs-UniversiHit Freiburg Hermann-Herder-Str. 7 D-79104 Freiburg, Germany

Professor Dr. med. H. KNAUF St. Bernward Krankenhaus Hildesheim Medizinische Klinik I Gastroenterologie-Kardiologie-N ephrologie Treibestr. 9 D-31134 Hildesheim, Germany

Professor Dr.rer.nat. Dr. med. E. MUTSCHLER Pharmakologisches Institut fUr Naturwissenschaftler Biozentrum Niederursel Gebiiude N 260, Marie-Curie-Str. 9 D-64271 Frankfurt, Germany

With 164 Figures and 32 Tables

ISBN-13:978-3-642-79567-1 e-ISBN-13:978-3-642-79565-7 DOl: 10.1007/978-3-642-79565-7

Library of Congress Cataloging·in-Publication Data. Diuretics/contributors, O.S. Better ... let al.]; editors, R.F. Greger, H. Knauf, and E. Mutschler. p. cm. - (Handbook of experimental pharmacology; v. 117) Includes bibliographical references and index. ISBN-13:978-3-642-79567-I 1. Diuretics. I. Better, O.S. II. Greger, Rainer. III. Knauf, H. IV. Mutschler, Ernst. V. Series. [DNLM: 1. Diuretics. WI HA51L v. 117 1995/QV 160 D6171 1995] QP905.H3 vol. 117 [RM377] 615'.1 s - dc20 [615'.761] DNLMIDLC for Library of Congress 95-3116

This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilm or in any other ways, and storage in data banks. Duplication of this publication or parts thereof is permitted only under the provisions of the German Copyright Law of September 9, 1965, in its current version, and permission for use must always be obtained from Springer-Verlag. Violations are liable for prosecution under the German Copyright Law. © Springer-Verlag Berlin Heidelberg 1995 Sof tcover reprint of the hardcover I st edition 1995

The use of general descriptive names, 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. Product liability: The publisher cannot guarantee the accuracy of any information about dosage and applica• tion contained in this book. In every individual case the user must check such information by consulting the relevant literature. Typesetting: Best-set Typesetter Ltd., Hong Kong SPIN: 10478734 27/3136/SPS - 5 4 3 2 1 0 - Printed on acid-free paper Preface

The first edition of this handbook appeared exactly twenty-five years ago. Due to enormous changes in the area of diuretics, the second edition has had to be completely revised. Substantial progress has been made in the functional anatomy of the kidney and in the concepts of how substances and are specifically transported across the various nephron segments. No one could have foreseen twenty-five years ago that the late 1980s and the early 1990s have provided us with methodologies to study transport events not only at the single cell level, but even at the level of the single transporter molecule. Many of the transporters for ions and organic substances have been cloned meanwhile by the new methods of molecular biology, and their function can be described more precisely by new transport studies such as the patch-clamp technique. These new insights have also led to a new understanding of how the currently used diuretics act. Just a few months ago, the Na+Cl- co-transporter, which is the target of , the Na+2CI-K+ co-transporter, which is the target of , and the sensitive Na+ channel were cloned. Hence, the targets of diuretics have now been identified at the molecular level. In addition, during the past twenty-five years extensive studies have been performed on the pharmacokinetics of diuretics. We have learned how changes in liver metabolism and altered renal excretion influence the pharmacology of this class of compounds. Most recent studies have also focused on the transport of diuretics in the proximal nephron and tell us more about the kidney selectivity of these substances and this specific aspect of pharmacokinetics. Enormous clinical experience, together with our new understanding of the mode of action, has had a major impact on the usage of diuretics. For instance, high dosages of thiazides, which previously were used in the treatment of , are now regarded as unacceptable and much lower doses have been shown to be equally effective but do not induce comparable side effects. Intentionally, a major focus of the second editon is on basic mech• anisms: functional anatomy, the physiological and biochemical processes involved in kidney function, metabolism, and the transport of diuretics. Furthermore, the specific chapters dealing with the most frequently used VI Preface groups of diuretics provide a comprehensive update, and the final chapter discusses the clinical use of diuretics as from this year's prospective. We would like to thank Prof. H. Herken, the editor of the first edition, who helped us with the concept of this second edition, and we are very grateful to all the authors for their expert contributions. Finally, we would also like to thank the publisher for its most competent co-operation.

Freiburg R. GREGER Hildesheim H. KNAUF Frankfurt E. MUTSCHLER March 1995 List of Contributors

BEITER, O.S., Dr. Rebecca Chutick Crush Syndrome Center and Depart• ment of Physiology and Biophysics, Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, POB 9649, Haifa 31096, Israel BUSCH, A., Physiologisches Institut, UniversiHit Tiibingen, GmelinstraBe 5, 0-72076 Tiibingen, Germany D0RUP, J., Department of Cell Biology, Institute of Anatomy, University of Aarhus, DK-8000 Aarhus, Denmark ENDou, H., Department of Pharmacology and Toxicology, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo 181, Japan

GREGER, R., Physiologisches Institut der Albert-Ludwigs-Universitat, Hermann-Herder-Str. 7,0-79104 Freiburg, Germany GUDER, W.G., Institut fUr Klinische Chemie, Stadtisches Krankenhaus Miinchen-Bogenhausen, Englschalkinger StraBe 77, 0-81925 Miinchen, Germany HOSOYAMADA, M., Department of Pharmacology and Toxicology, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo 181, Japan HROPOT, M., Hoechst AG, Herz/KreislaufTherapeutika, FB Pharmakologie, H 821, 0-65926 Frankfurt, Germany KAISSLING, B., Anatomisches Institut der Universitat, Winterthurerstr. 190, CH-8057 Ziirich, Switzerland

KLEYMAN, T.R., Department of Medicine, Renal-Electrolyte Division, University of Pennsylvania School of Medicine, 700 Clinical Research Building, 422 Curie Boulevard, Philadelphia, PA 19104, USA KNAUF, H., St. Bernward Krankenhaus Hildesheim, Medizinische Klinik I, Gastroenterologie-Kardiologie-Nephrologie, Treibestr. 9, 0-31134 Hildesheim, Germany VIII List of Contributors

LANG, F., Physiologisches Institut, UniversiHit Tiibingen, GmelinstraBe 5, D-72076 Tiibingen, Germany LANG, H.-J., Hoechst AG, Herz/Kreislauf Therapeutika, FB Pharmakologie, H 821, D-65926 Frankfurt, Germany MOHRKE, W., Procter & Gamble Pharmaceuticals, Dr. Otto-Rohm-Str. 2-4, D-64331 Weiterstadt, Germany MUTSCHLER, E., Pharmakologisches Institut fUr Naturwissenschaftler, Biozentrum Niederursel, Gebaude N260, Marie-Curie-Str. 9, D-60439 Frankfurt, Germany NETZER, T., E. Merck, Klinische Forschung und Entwicklung Deutschland 1, D-64271 Darmstadt, Germany PALMER, L.G., Department of Physiology and Biophysics, Cornell University Medical College, 1300 York Avenue, New York, NY 10021, USA PUSCHETT, J.B., Department of Medicine SL 12, Tulane University Medical Center, 1430 Tulane Avenue, New Orleans, LA 70112-2699, USA RUBINSTEIN, I., Dr. Rebecca Chutick Crush Syndrome Center and Depart• ment of Physiology and Biophysics, Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, POB 9649, Haifa 31096, Israel SCHMOLKE, M. Institut fUr Klinische Chemie, Stadtisches Krankenhaus Miinchen-Bogenhausen, Englschalkinger StraBe 77, D-81925 Miinchen, Germany ULLRICH, F., Du Pont Pharma GmbH, Du Pont StraBe 1, D-61352 Bad Homburg, Germany ULLRICH, K.J., Max-Planck-Institut fUr Biophysik, Kennedyallee 70, D-60596 Frankfurt, Germany VELAZQUEZ, H., Research Office (151), Department of Veterans Affairs Medical Center, 950 Campbell Avenue, West Haven, CT 06516, USA WINAVER, J., Dr. Rebecca Chutick Crush Syndrome Center and Department of Physiology and Biophysics, Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, POB 9649, Haifa 31096, Israel Contents

CHAPTER 1 Functional Anatomy of the Kidney B. KAISSLING and J. D0RUP. With 20 Figures...... 1 A. Structural Organization ofthe Kidney...... 1 I. Microanatomy of the Kidney ...... 1 1. Nephron...... 1 2. Cortex...... 4 3. Medulla ...... 4 4. Kidney Size ...... 6 II. Renal Vasculature...... 6 1. Arteries and Arterioles ...... 6 2. Cortical and Medullary Capillary Plexus...... 6 3. Venous Drainage of Cortex and Medulla...... 7 4. Wall Structure of Renal Vessels...... 8 III. Interstitium, Lymphatics and Renal Nerves...... 8 1. Periarterial Interstitium ...... 10 2. Peritubular Interstitium...... 10 IV. Renal Corpuscle...... 11 1. Organization ...... 11 2. Mesangium...... 12 3. Glomerular Capillaries...... 12 4. Filtration Barrier...... 15 V. Juxtaglomerular Apparatus...... 15 1. Granular Cells...... 16 2. Extraglomerular Mesangium ...... 16 3. Macula Densa ...... 16 B. General Organization of Renal Epithelia and Correlation with Transport...... 17 I. Polarity of Epithelia...... 17 1. Transport Pathways ...... 17 II. Organization of Epithelial Surfaces...... 19 1. Basolateral Domain ...... 19 2. Apical Domain ...... 20 III. Correlation of Structure with Na+ Transport Rates...... 21 x Contents

C. Nephron and Collecting Duct Structure ...... 23 I. ...... 23 II. Loop of Henle ...... 26 1. Organization and Histotopography ...... 26 2. Intermediate Tubule...... 26 3. Thick Ascending Limb (Straight Distal Tubule) ...... 28 4. Macula Densa ...... 30 III. Cortical Distal Segments...... 32 1. Structural and Functional Organization ...... 32 2. ...... 35 3. Connecting Tubule...... 37 IV. Collecting Ducts...... 40 1. Organization ...... 40 2. Cortical Collecting Duct Cells...... 40 3. Inner Medullary Collecting Duct Cells...... 42 4. Intercalated Cells ...... 43 D. Alterations of Morphology in Electrolyte Disturbances ...... 44 I. Acute Changes in Transport Rates ...... 45 1. Mechanism...... 45 2. Morphological Changes Associated with Acute Changes in Transport Rates ...... 45 II. Chronic Alteration of Na+ Transport Rates...... 46 1. Mechanism...... 46 2. Time Course of Structural Changes...... 46 III. Adaptation of Proximal Tubule...... 47 1. Changes in GFR ...... 47 2. Diabetes Mellitus ...... 47 3. Reduction of Renal Cell Mass ...... 47 IV. Adaptation of Thick Ascending Limb of Henle's Loop...... 47 1. Variation of ADH Plasma Levels...... 48 2. Variation of Protein Intake...... 48 V. Adaptation of Distal Segments and Collecting Duct ...... 48 1. Role of Tubular N a + Load ...... 49 2. Role of Hormones...... 51 3. Role of Potassium Intake...... 51 4. Structural Changes in Intercalated Cells...... 52 References ...... 55

CHAPTER 2 Basic Concepts of Renal Physiology F. LANG and A. BUSCH. With 17 Figures...... 67 A. Introduction...... 67 B. Renal Blood Flow and Glomerular Filtration...... 67 I. Pressures and Resistances in Renal Vascular Segments...... 68 Contents XI

II. Intrarenal Blood Flow Distribution...... 69 III. Permeability-Selectivity of the Glomerular Filter...... 70 IV. Determinants of Renal Glomerular Filtration Rate...... 71 V. Autoregulation of Renal Blood Flow and Glomerular Filtration Rate...... 74 VI. Hormonal Regulation of Renal Blood Flow and Glomerular Filtration...... 75 C. Renal Tubular Transport...... 76 I. Driving Forces for Epithelial Transport ...... 76 1. Water Transport...... 76 2. Solvent Drag ...... 77 3. Diffusion ...... 77 4. Active Transport...... 78 II. Saturability of Epithelial Transport Processes ...... 79 1. Michealis-Menten Kinetics ...... 79 2. Transport Kinetics of Whole Kidney...... 80 III. Segmental Organization of Renal Epithelial Transport...... 82 1. Proximal Tubule ...... 84 2. Loop of Henle...... 87 3. Distal Tubule and Collecting Duct...... 89 IV. Urinary Concentrating Mechanism...... 91 D. Regulation of Renal Water and Electrolyte Excretion...... 93 I. Water...... 93 II. Na+ ...... 95 III. Bicarbonate and Hydrogen Ions ...... 96 IV. K+ ...... 98 V. Mg2+ ...... 100 VI. Phosphate ...... 101 References ...... 104

CHAPTER 3 Renal Energy Metabolism W.G. GUDER and M. SCHMOLKE. With 7 Figures 115 A. Introduction...... 115 B. Mechanisms of Renal ATP Formation ...... 115 I. Substrate-Linked A TP Formation...... 117 1. Glycolysis...... 117 2. Other Mechanisms ...... 117 II. Oxidative Phosphorylation...... 119 1. Coupling to Oxygen Consumption ...... 119 2. Citric Acid Cycle...... 120 C. Metabolic Substrates of Renal Energy Metabolism ...... 123 I. Glucose and Lactate ...... 123 II. Fatty Acids ...... 124 XII Contents

III. Ketone Bodies...... 127 IV. Amino Acids...... 129 V. Substrate Interactions...... 130 VI. Contribution of Individual Substrates to Whole Kidney Energy Turnover...... 130 D. Regulation of ATP in Tubule Cells ...... 131 I. Compartmentation...... 131 II. ATP Turnover ...... 131 III. Energy-Consuming Mechanisms...... 132 1. Transport A TPases ...... 132 2. Metabolic Processes ...... 134 E. Interaction of Substances with Renal Energy Metabolism...... 134 I. Proximal Tubule...... 134 II. Thick Ascending Limb of Henle's Loop...... 135 III. Collecting Tubule...... 135 References ...... 135

CHAPTER 4 Discovery and Development of Diuretic Agents H.-J. LANG and M. HRoPoT. With 23 Figures ...... 141 A. Introduction...... 141 B. Xanthine Derivatives...... 141 C. Osmotic Diuretics...... 143 D. Mercurial Diuretics...... 144 E. Carbonic Anhydrase Inhibitors...... 145 F. Diuretics ...... 146 I. Benzothiadiazines and Related Compounds ...... 146 II. Suifamoylbenzoic Acid Derivatives...... 148 G. Nonsulfonamide Diuretics ...... 151 I. Phenoxy acetic Acid Derivatives...... 151 II. Potassium-Retaining Diuretics...... 151 1. Antagonists...... 151 2. Pteridines and Pyrazine Derivatives...... 152 H. So-called Polyvalent Diuretics...... 153 I. Loop Diuretics with Prolonged Duration of Action ...... 153 II. Saluretics with Eukalemic Properties ...... 155 III. Diuretics Improving Renal Function: Dopamine Agonists . .. 157 IV. Diuretics with Uricosuric Activity...... 157 V. A voidance of Adverse Effects on Serum Lipids and Blood Glucose...... 159 VI. Diuretics with Predominant Cardiovascular Activity ...... 161 I. Aquaretics...... 163 Contents XIII

1. New Aspects: Transport Modulators ...... 166 References...... 168

CHAPTER 5 Metabolism of Diuretics W. MOHRKE and F. ULLRICH. With 19 Figures 173 A. Introduction...... 173 B. Biotransformation...... 173 C. Patterns of Biotransformation...... 175 D. Biotransformation of Diuretics...... 177 I. Carbo anhydrase Inhibitors ...... 177 1. ...... 177 II. Loop Diuretics...... 177 1. Furosemide ...... 177 2. ...... 179 3. P~etanide ...... 181 4. ...... 181 5. ...... 182 6. ...... 184 7. Ethacrynic Acid ...... 185 III. and Thiazide-Type Diuretics...... 187 1. Bendroftuazide ...... 187 2. ...... 187 3. Chlorthalidone ...... 188 4. ...... 188 5. Hydroftumethiazide ...... 188 6. ...... 189 7. ...... 190 8. ...... 191 IV. Potassium-Sparing Diuretics...... 191 1. Amiloride...... 191 2. ...... 192 3. and ...... 193 References ...... 196

CHAPTER 6 Interaction of Diuretics with Transport Systems in the Proximal Renal Tubule K.l. ULLRICH. With 2 Figures ...... 201 A. Introduction...... 201 B. Transport System for Hydrophobic Organic Anions (para-Aminohippurate) ...... 202 XIV Contents

C. Transport Systems for Organic Cations...... 204 D. Transport Systems for Sulfate ...... 205 E. Transport Systems for Dicarboxylates ...... 206 F. Interaction of Diuretics with the Different Proximal Transport Systems ...... 206 I. SulfonamidelThiazide Derivatives...... 207 II. Thiazolidine, Aminopyrazol and Pyrazolidine Derivatives ...... 212 III. Arylamine-Pyridinecarboxylate and Arylamine-Pyridine Sulfonylurea Derivatives...... 213 IV. Phenoxyacetic Acid Derivatives...... 213 V. Pyrazinoyl-Guanidine Derivatives, Pyrazinoyl-Aminomethylphenol Derivatives ...... 214 VI. Pteridine Derivatives...... 214 VII. Aldosterone Antagonists ...... 215 G. How Does Metabolic Transformation Change the Interaction with the Transport Systems for Organic Anions and Cations? ...... 215 References ...... 216

CHAPTER 7 Loop Diuretics R. GREGER. With 23 Figures...... 221 A. Introduction...... 221 B. The Heterogeneous Group of Loop Diuretics ...... 222 C. Organotropy of Loop Diuretics ...... 223 D. Saluretic and Diuretic Effects of Loop Diuretics and Cellular Mechanisms...... 225 I. Luminal K + Conductance ..... '...... 228 II. Furosemide-Sensitive Na+2Cl-K+ Co transporter ...... 230 III. Role of the Basolaterally Localized (Na+ + K+)-ATPase .... 232 IV. Metabolic Control of NaCl Reabsorption in the TAL ...... 234 V. Cl- Channel and Its Inhibition...... 236 VI. Loop Diuretics Related to Furosemide...... 238 VII. Loop Diuretics Not Related to Furosemide ...... 241 E. Effects of Loop Diuretics in the Intact Kidney...... 241 I. Macula Densa Segment...... 244 II. Excretion of K+ ...... 246 III. Excretion of NH4 + ...... 248 IV. Excretion of H+ and HC03 - ...... 248 V. Excretion of Ca2+ and Mg2+ ...... 249 VI. Excretion of Li+ ...... 249 VII. Excretion of Urate ...... 250 VIII. Phosphaturic Effect ...... 250 Contents XV

F. Effect of Loop Diuretics on Other Organs ...... 251 I. Ototoxic Effects...... 251 II. Asthma ...... 251 III. Preload to the Heart ...... 252 IV. Glucose Metabolism ...... 252 G. Pharmacokinetics ...... 253 I. Ethacrynic Acid ...... 253 II. ...... 254 III. Furosemide ...... 254 IV. ...... 254 V. Bumetanide ...... 255 VI. Torasemide ...... 255 VII. Azosemide...... 256 VIII. Etozolin and ...... 256 H. Pharmacokinetics and Pharmacodynamics ...... 257 I. Clinical Uses ...... 260 I. Hypertension ...... 260 II. Congestive Heart Failure and Lung Edema...... 261 III. Ascites...... 261 IV. Edematous States in Nephrotic Syndrome ...... 262 V. Chronic Renal Failure ...... 262 VI. Other Indications ...... 263 J. Adverse Effects ...... 264 I. Hypokalemia...... 264 II. Hyponatremia...... 264 III. Hypocalcemia ...... 265 IV. Hypomagnesemia ...... 265 V. Metabolic Alkalosis ...... 265 VI. Hyperlipidemia...... 265 VII. Hyperglycemia and Diabetogenic Effects...... 266 VIII. Hyperuricemia ...... 266 IX. Male Impotence ...... 266 X. Ototoxicity ...... 267 References ...... 267

CHAPTER 8 Thiazide Diuretics H. VELAZQUEZ, H. KNAUF, and E. MUTSCHLER. With 13 Figures 275 A. Introduction...... 275 B. Chemical Structures ...... 275 C. Pharmacokinetics ...... 277 I. Protein Binding ...... 279 II. Renal Excretion ...... 279 XVI Contents

D. Pharmacodynamics ...... , ...... 280 I. Thiazide-Sensitive Systems ...... 280 1. Na+Cl- Cotransport...... , 280 2. Cl-IHC03 - Exchange...... 283 3. Other Mechanisms ...... 284 II. Thiazide Binding to Transporter Proteins ...... 285 III. Cloning the Thiazide Diuretic Receptor ...... , 287 IV. Renal Actions...... 287 1. Proximal Effects ...... , 288 2. Distal Effects...... 289 3. Effects on Renal Salt and Water Excretion ...... 298 4. Effects on Renal K+ Excretion ...... 300 5. Effects on Renal Ca2+ Excretion ...... 301 E. Pharmacokinetics in Disease States ...... , 301 I. Chronic Renal Failure ...... , 302 II. Liver Disease ...... 304 F. Saluretic Effects of Thiazides ...... 307 I. Effects in Healthy Controls ...... 307 II. Responses in Renal Failure ...... 309 III. Coadministration with Loop Diuretics in Renal Failure ..... 309 IV. Coadministration with Other Diuretics in Edematous States with Normal Kidney Function ...... 313 G. Diuretics in Nonedematous States ...... 314 I. Hypertension ...... 314 II. Diabetes Insipidus ...... 317 III. Nephrolithiasis ...... , 318 H. Side Effects of Diuretic Therapy...... 318 I. Hypokalemia ...... 318 II. Mg2+ Depletion ...... 318 III. Hyponatremia...... 319 IV. Hyperuricemia ...... 319 V. Hyperglycemia ...... 319 VI. Hyperlipidemia ...... 319 VII. Allergy...... 320 VIII. Erectile Dysfunction ...... 320 I. Drug Combinations...... 320 References ...... 321

CHAPTER 9 Potassium-Retaining Diuretics: Aldosterone Antagonists H. ENDou and M. HOSOYAMADA. With 4 Figures ...... 335 A. Chemical Structure and Properties, Structure-Activity Relationships of Aldosterone Antagonists...... 335 Contents XVII

I. Introduction ...... 335 II. Chemical Structure and Properties ...... 337 1. Modifications of 17a Side Chain: SC compounds...... 337 2. Structural Modification of Ring B: RU26752 and RU28318 ...... 339 3. Structural Modification of Ring C: Mespirenone (ZK94679) and ZK91587 ...... 339 4. Recent Structural Modifications...... 339 III. Steroidogenesis Inhibitors and Secretion Inhibitors ...... 339 B. Pharmacodynamics ...... 340 I. Renal Effects ...... 340 1. Increase in Urinary Sodium-Potassium Ratio...... 340 2. Target Nephron Segments: CCT and OMCT, and Other Segments...... 340 3. Intracellular Mechanism of Aldosterone Antagonists. . . .. 341 II. Extrarenal Effects ...... 342 1. Tissue Distribution of Type I Receptors...... 342 2. Cross-reactivity with the Glucocorticoid Receptors...... 342 3. Epithelia...... 342 4. Cardiovascular System...... 343 5. Central Nervous System ...... 343 6. Steroidogenesis Inhibition...... 344 7. Effects ...... 344 C. Pharmacokinetics ...... 345 I. Absorption ...... 345 II. Plasma Concentrations ...... 345 III. Metabolism ...... 345 1. Spironolactone and Canrenoate ...... 345 2. Spironolactone and Cytochrome P450 Destruction...... 347 IV. Excretion ...... 347 D. Therapeutic Use (Indications, Dosage, Contraindications) ...... 347 I. Indications...... 347 1. Congestive Heart Failure...... 348 2. Liver Cirrhosis...... 348 3. Nephrotic Syndrome ...... 348 4. Hypertension...... 349 5. Endocrine Disorders ...... 349 6. Other Disorders ...... 349 II. Dosage...... 350 III. Contraindications...... 350 E. Side Effects and Toxicology ...... 350 I. General Considerations...... 350 II. Main Side Effects...... 351 1. Hyponatremia, Hyperkalemia and Acid-Base Disturbances ...... 351 XVIII Contents

2. Sexual Functions and Endocrine Disorders ...... 351 3. Carcinogenicity...... 351 4. Allergy ...... 352 5. Calcium Channel Antagonism ...... 352 F. Drug Interactions ...... 352 I. Angiotensin-Converting Enzyme Inhibitors...... 352 II. Ammonium Chloride...... 352 III. Aspirin...... 352 IV. Cyclosporin A ...... 353 V. Digitoxin ...... 353 VI. Digoxin ...... 353 VII. ...... 354 VIII. Mercurials ...... 354 IX. Mitotane ...... 354 X. Analgesics ...... 355 XI. Warfarin ...... 355 References ...... 355

CHAPTER 10 Potassium-Retaining Diuretics: Amiloride L.G. PALMER and T.R. KLEYMAN. With 7 Figures 363 A. Introduction...... 363 B. Structure-Function Relationships...... 364 I. Guanidinium Substitutions ...... 365 II. 6-Position Ring Substitutions...... 366 III. 5-Position Ring Substitutions...... 367 C. Pharmacodynamics...... 367 I. Sites of Action: Na+ Transport' ...... 367 1. General...... 367 2. Within the Kidney ...... 369 3. Other Epithelia...... 371 II. Effects on Transport of K+ and Other Ions ...... 372 III. Effects on Other Cellular Processes ...... 374 IV. Interactions with the Epithelial Na+ Channels ...... 375 1. Stoichiometry ...... 375 2. Rate Constants ...... 376 3. Competition with Na+ ...... 378 4. Feedback Response to Amiloride ...... 380 5. Divalent Cation Requirements ...... 380 6. Model for Amiloride Block...... 381 D. Pharmacokinetics ...... 383 E. Therapeutic Use ...... 385 F. Side Effects and Toxicity ...... 387 Contents XIX

G. Drug Interactions ...... 388 References ...... 388

CHAPTER 11 Potassium-Retaining Diuretics: Triamterene T. NETZER, F. ULLRICH, H. KNAUF, and E. MUTSCHLER. With 13 Figures ...... 395 A. Chemical Structure and Properties...... 395 B. Pharmacodynamics ...... 395 I. Renal Effects ...... 395 1. Structure-Activity Relationships of Pteridine Derivatives ...... 395 2. Triamterene...... 402 II. Cardiac Effects ...... 405 1. Structure-Activity Relationships...... 405 2. Triamterene...... 408 III. Effects on Dihydrofolate Reductase ...... 409 C. Pharmacokinetics ...... 409 I. Metabolism in Man ...... 409 II. Pharmacokinetics in Healthy Volunteers ...... 409 III. Pharmacokinetics in Patients with Liver Disease ...... 411 IV. Pharmacokinetics in Patients with Renal Disease ...... 412 V. Pharmacokinetics in the Elderly ...... 413 D. Therapeutic Use ...... 414 I. Indications...... 414 II. Dosage...... 415 III. Side Effects...... 415 IV. Contraindications ...... 416 V. Drug Interactions ...... 416 E. Toxicity...... 417 References ...... 417

CHAPTER 12 Osmotic Diuretics: O.S. BETTER, I. RUBINSTEIN, and J. WINAVER. With 3 Figures ...... 423 A. Introduction ...... 423 B. Renal Effects ...... 424 I. Renal Hemodynamic Actions...... 425 II. Glomerular Filtration Rate...... 426 III. Tubular Salt and Water Reabsorption ...... 428 1. Proximal Nephron ...... 429 xx Contents

2. Loop of Henle...... 429 3. Distal Tubule and Collecting Duct...... 431 IV. Transport of Other Ions ...... 431 V. Urinary Concentration and Dilution ...... 432 VI. Miscellaneous Effects ...... 433 C. Beneficial Extrarenal Effects of Hypertonic Mannitol...... 434 D. Effects on the Cardiovascular System ...... 436 E. Clinical Use ...... 437 I. Clinical Applications ...... 437 II. Pharmacokinetics...... 437 III. Dosage...... 438 IV. Precautions ...... 438 V. Adverse Reactions...... 438 VI. Contraindications...... 438 References ...... 439

CHAPTER 13 Clinical Uses of Diuretics J.B. PUSCHETI. With 13 Figures ...... 443 A. Introduction...... 443 B. Physiological Basis of Diuretic Action and Clinical Implications of Physiological Principles ...... 443 I. Proximal Tubule...... 447 II. Loop of Henle ...... 451 III. Early Portion of the Distal Convoluted Tubule...... 452 IV. Late Portion of the Distal Convoluted Tubule and the Collecting Duct...... 453 C. Diuretics in the Treatment of Edematous States and Disorders Associated with Abnormalities of Renal Function...... 455 I. General Principles ...... 455 II. Congestive Heart Failure ...... 457 III. Nephrotic Syndrome ...... 467 IV. Liver Disease ...... 470 V. Idiopathic Edema ...... 471 VI. Premenstrual Syndrome ...... 472 VII. Acute Glomerulonephritis ...... 473 VIII. Acute Renal Failure ...... 473 IX. Chronic Renal Failure ...... 474 X. Resistant Edema ...... 475 D. Diuretics in the Treatment of Nonedematous Disorders...... 479 I. Hypertension ...... 479 II. Toxemia of Pregnancy...... 485 III. Hypercalcemia ...... 486 Contents XXI

IV. Renal Stone Disease ...... 487 V. Diabetes Insipidus ...... 487 VI. Hyperkalemia...... 488 E. Diuretic Side Effects and Adverse Reactions ...... 489 I. Volume Contraction ...... 489 II. Hyponatremia ...... 489 III. Hypokalemia ...... 490 IV. Hypomagnesemia ...... 491 V. Acid-Base Disorders ...... 491 1. Metabolic Alkalosis ...... 491 2. Metabolic Acidosis...... 492 VI. Hyperglycemia ...... 492 VII. Hyperlipidemia ...... 494 VIII. Hyperuricemia ...... 494 IX. Ototoxicity ...... 495 X. Nephrotoxicity ...... 495 XI. Hyperkalemia...... 495 References ...... 496

Subject Index ...... 507