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
Diuretics 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 DOl: 10.1007/978-3-642-79565-7
e-ISBN-13:978-3-642-79565-7
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
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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 ions 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 thiazides, the Na+2CI-K+ co-transporter, which is the target of furosemide, and the amiloride 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 hypertension, 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 mechanisms: 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 Hildesheim Frankfurt March 1995
R. GREGER
H. KNAUF
E. MUTSCHLER
List of Contributors
BEITER, O.S., 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
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 Department 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. Proximal Tubule. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 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. Distal Convoluted Tubule . . . . . . . . . . . . . . . . . . . . . . . . . . . . 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 Steroid 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. Calcium 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 Diuretic 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. Sulfonamide 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. Aldosterone 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: Ion 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. Acetazolamide...................................... 177
II. Loop Diuretics. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 177 1. Furosemide ........................................ 177 2. Bumetanide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 179 3. P~etanide .......................................... 181 4. Azosemide......................................... 181 5. Etozolin .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 182 6. Torasemide ........................................ 184 7. Ethacrynic Acid .................................... 185
III. Thiazide and Thiazide-Type Diuretics. . . . . . . . . . . . . . . . . . .. 187 1. Bendroftuazide ..................................... 187 2. Chlorothiazide...................................... 187 3. Chlorthalidone ..................................... 188 4. Hydrochlorothiazide................................. 188 5. Hydroftumethiazide ................................. 188 6. Indapamide .......... . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 189 7. Mefruside.......................................... 190 8. Xipamide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 191
IV. Potassium-Sparing Diuretics. . . . . . . . . . . . . . . . . . . . . . . . . . . .. 191 1. Amiloride.......................................... 191 2. Triamterene... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 192 3. Spironolactone and Potassium Canrenoate . . . . . . . . . . . . .. 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. Indacrinone........................................... 254 III. Furosemide ........................................... 254 IV. Piretanide ............................................ 254 V. Bumetanide ........................................... 255
VI. Torasemide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 255 VII. Azosemide............................................ 256
VIII. Etozolin and Muzolimine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 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. Antiandrogen 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. Fludrocortisone ....................................... 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: Mannitol 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