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DiureticsContributorsO.S. Better, A. Busch, J. D0rup, H. Endou, R. GregerW.G. Guder, M. Hosoyamada, M. Hropot, B. KaisslingT.R. Kleyman, H. Knauf, F. Lang, H.-J. Lang, W. MohrkeE. Mutschler, T. Netzer, L.G. Palmer, J.B. PuschettI. Rubinstein, M. Schmolke, F. Ullrich, KJ . UllrichH. Velazquez, J. Winaver

Editors

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

Springer

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Contents

CHAPTER 1

Functional Anatomy of the KidneyB. KAISSLING and J. DORUP. With 20 Figures 1

A. Structural Organization of the Kidney 1I. Microanatomy of the Kidney 1

1. Nephron 12. Cortex 43. Medulla 44. Kidney Size 6

II. Renal Vasculature 61. Arteries and Arterioles 62. Cortical and Medullary Capillary Plexus 63. Venous Drainage of Cortex and Medulla 74. Wall Structure of Renal Vessels 8

III. Interstitium, Lymphatics and Renal Nerves 81. Periarterial Interstitium 102. Peritubular Interstitium 10

IV. Renal Corpuscle 111. Organization 112. Mesangium 123. Glomerular Capillaries 124. Filtration Barrier 15

V. Juxtaglomerular Apparatus 151. Granular Cells 162. Extraglomerular Mesangium 163. Macula Densa 16

B. General Organization of Renal Epitheliaand Correlation with Transport 17

I. Polarity of Epithelia 171. Transport Pathways 17

II. Organization of Epithelial Surfaces 191. Basolateral Domain 192. Apical Domain 20

III. Correlation of Structure with Na+ Transport Rates 21

Xv Contents

C. Nephron and Collecting Duct Structure 23I. Proximal Tubule 23

II. Loop of Henle 261. Organization and Histotopography 262. Intermediate Tubule 263. Thick Ascending Limb (Straight Distal Tubule) 284. Macula Densa 30

III. Cortical Distal Segments 321. Structural and Functional Organization 322. Distal Convoluted Tubule 353. Connecting Tubule 37

IV. Collecting Ducts 401. Organization 402. Cortical Collecting Duct Cells 403. Inner Medullary Collecting Duct Cells 424. Intercalated Cells 43

D. Alterations of Morphology in Electrolyte Disturbances 44I. Acute Changes in Transport Rates 45

1. Mechanism 452. Morphological Changes Associated

with Acute Changes in Transport Rates 45II. Chronic Alteration of Na+ Transport Rates 46

1. Mechanism 462. Time Course of Structural Changes 46

III. Adaptation of Proximal Tubule 471. Changes in.GFR 472. Diabetes Mellitus 473. Reduction of Renal Cell Mass 47

IV. Adaptation of Thick Ascending Limb of Henle's Loop 471. Variation of ADH Plasma Levels 482. Variation of Protein Intake 48

V. Adaptation of Distal Segments and Collecting Duct 481. Role of Tubular Na+ Load 492. Role of Steroid Hormones 513. Role of Potassium Intake 514. Structural Changes in Intercalated Cells 52

References 55

CHAPTER 2

Basic Concepts of Renal PhysiologyF. LANG and A. BUSCH. With 17 Figures 67

A. Introduction 67B. Renal Blood Flow and Glomerular Filtration 67

I. Pressures and Resistances in Renal Vascular Segments 68

Contents XI

II. Intrarenal Blood Flow Distribution 69III. Permeability-Selectivity of the Glomerular Filter 70IV. Determinants of Renal Glomerular Filtration Rate 71V. Autoregulation of Renal Blood Flow

and Glomerular Filtration Rate 74VI. Hormonal Regulation of Renal Blood Flow

and Glomerular Filtration 75C. Renal Tubular Transport 76

I. Driving Forces for Epithelial Transport 761. Water Transport 762. Solvent Drag 773. Diffusion 774. Active Transport 78

II. Saturability of Epithelial Transport Processes 791. Michealis-Menten Kinetics 792. Transport Kinetics of Whole Kidney 80

III. Segmental Organization of Renal Epithelial Transport 821. Proximal Tubule 842. Loop of Henle 873. Distal Tubule and Collecting Duct 89

IV. Urinary Concentrating Mechanism 91D. Regulation of Renal Water and Electrolyte Excretion 93

I. Water 93II. Na+ 95

III. Bicarbonate and Hydrogen Ions 96IV. K+ 98V. Mg2+ 100

VI. Calcium Phosphate 101References 104

CHAPTER 3

Renal Energy MetabolismW.G. GUDER and M. SCHMOLKE. With 7 Figures 115

A. Introduction 115B. Mechanisms of Renal ATP Formation 115

I. Substrate-Linked ATP Formation 1171. Glycolysis 1172. Other Mechanisms 117

II. Oxidative Phosphorylation 1191. Coupling to Oxygen Consumption 1192. Citric Acid Cycle 120

C. Metabolic Substrates of Renal Energy Metabolism 123I. Glucose and Lactate 123

II. Fatty Acids 124

XII Contents

III. Ketone Bodies 127IV. Amino Acids 129V. Substrate Interactions 130

VI. Contribution of Individual Substratesto Whole Kidney Energy Turnover 130

D. Regulation of ATP in Tubule Cells 131I. Compartmentation 131

II. ATP Turnover 131III. Energy-Consuming Mechanisms 132

1. Transport ATPases 1322. Metabolic Processes 134

E. Interaction of Diuretic Substances with RenalEnergy Metabolism 134

I. Proximal Tubule 134II. Thick Ascending Limb of Henle's Loop 135

III. Collecting Tubule 135References 135

CHAPTER 4

Discovery and Development of Diuretic AgentsH.-J. LANG and M. HROPOT. With 23 Figures 141

A. Introduction 141B. Xanthine Derivatives 141C. Osmotic Diuretics 143D. Mercurial Diuretics 144E. Carbonic Anhydrase Inhibitors 145F. Sulfonamide Diuretics 146

I. Benzothiadiazines and Related Compounds 146II. Sulfamoylbenzoic Acid Derivatives 148

G. Nonsulfonamide Diuretics 151I. Phenoxyacetic Acid Derivatives 151

II. Potassium-Retaining Diuretics 1511. Aldosterone Antagonists 1512. Pteridines and Pyrazine Derivatives 152

H. So-called Polyvalent Diuretics 153I. Loop Diuretics with Prolonged Duration of Action 153

II. Saluretics with Eukalemic Properties 155III. Diuretics Improving Renal Function: Dopamine Agonists . . . 157IV. Diuretics with Uricosuric Activity 157V. Avoidance of Adverse Effects on Serum Lipids

and Blood Glucose 159VI. Diuretics with Predominant Cardiovascular Activity 161

I. Aquaretics 163

Contents XIII

J. New Aspects: Ion Transport Modulators 166References 168

CHAPTER 5

Metabolism of DiureticsW. MOHRKE and F. ULLRICH. With 19 Figures 173

A. Introduction 173B. Biotransformation 173C. Patterns of Biotransformation 175D. Biotransformation of Diuretics 177

I. Carboanhydrase Inhibitors 1771. Acetazolamide 177

II. Loop Diuretics 1771. Furosemide 1772. Bumetanide 1793. Piretanide 1814. Azosemide 1815. Etozolin 1826. Torasemide 1847. Ethacrynic Acid 185

III. Thiazide and Thiazide-Type Diuretics 1871. Bendrofluazide 1872. Chlorothiazide 1873. Chlorthalidone 1884. Hydrochlorothiazide 1885. Hydroflumethiazide 1886. Indapamide 1897. Mefruside 1908. Xipamide 191

IV. Potassium-Sparing Diuretics 1911. Amiloride 1912. Triamterene 1923. Spironolactone and Potassium Canrenoate 193

References 196

CHAPTER 6

Interaction of Diuretics with Transport Systemsin the Proximal Renal TubuleK.J. ULLRICH. With 2 Figures 201

A. Introduction 201B. Transport System for Hydrophobic Organic Anions

(/wa-Aminohippurate) 202

XIV Contents

C. Transport Systems for Organic Cations 204D. Transport Systems for Sulfate 205E. Transport Systems for Dicarboxylates 206F. Interaction of Diuretics

with the Different Proximal Transport Systems 206I. Sulfonamide/Thiazide Derivatives 207

II. Thiazolidine, Aminopyrazoland Pyrazolidine Derivatives 212

III. Arylamine-Pyridinecarboxylate and Arylamine-PyridineSulfonylurea Derivatives 213

IV. Phenoxyacetic Acid Derivatives 213V. Pyrazinoyl-Guanidine Derivatives,

Pyrazinoyl-Aminomethylphenol Derivatives 214VI. Pteridine Derivatives 214

VII. Aldosterone Antagonists 215G. How Does Metabolic Transformation Change the Interaction

with the Transport Systems for Organic Anions and Cations? 215References 216

CHAPTER 7

Loop DiureticsR. GREGER. With 23 Figures 221

A. Introduction ; 221B. The Heterogeneous Group of Loop Diuretics 222C. Organotropy of Loop Diuretics 223D. Saluretic and Diuretic Effects of Loop Diuretics

and Cellular Mechanisms 225I. Luminal K+ Conductance 228

II. Furosemide-Sensitive Na+2C1~K+ Cotransporter 230III. Role of the Basolaterally Localized (Na+ + K+)-ATPase 232IV. Metabolic Control of NaCl Reabsorption in the TAL 234V. Cl" Channel and Its Inhibition 236

VI. Loop Diuretics Related to Furosemide 238VII. Loop Diuretics Not Related to Furosemide 241

E. Effects of Loop Diuretics in the Intact Kidney 241I. Macula Densa Segment 244

II. Excretion of K+ 246III. Excretion of NH4

+ 248IV. Excretion of H+ and HCO3~ 248V. Excretion of Ca2+ and Mg2+ 249

VI. Excretion of Li+ 249VII. Excretion of Urate 250

VIII. Phosphaturic Effect 250

Contents XV

F. Effect of Loop Diuretics on Other Organs 251I. Ototoxic Effects 251

II. Asthma 251III. Preload to the Heart 252IV. Glucose Metabolism 252

G. Pharmacokinetics 253I. Ethacrynic Acid 253

II. Indacrinone 254III. Furosemide 254IV. Piretanide 254V. Bumetanide 255

VI. Torasemide 255VII. Azosemide 256

VIII. Etozolin and Muzolimine 256H. Pharmacokinetics and Pharmacodynamics 257I. Clinical Uses 260

I. Hypertension 260II. Congestive Heart Failure and Lung Edema 261

III. Ascites 261IV. Edematous States in Nephrotic Syndrome 262V. Chronic Renal Failure 262

VI. Other Indications 263J. Adverse Effects 264

I. Hypokalemia 264II. Hyponatremia 264

III. Hypocalcemia 265IV. Hypomagnesemia 265V. Metabolic Alkalosis 265

VI. Hyperlipidemia 265VII. Hyperglycemia and Diabetogenic Effects 266

VIII. Hyperuricemia 266IX. Male Impotence 266X. Ototoxicity 267

References 267

CHAPTER 8

Thiazide DiureticsH. VELAZQUEZ, H. KNAUF, and E. MUTSCHLER. With 13 Figures 275

A. Introduction 275B. Chemical Structures 275C. Pharmacokinetics 277

I. Protein Binding 279II. Renal Excretion 279

XVI Contents

D. Pharmacodynamics 280I. Thiazide-Sensitive Systems 280

1. Na+Cl~ Cotransport 2802. Cr/HCO 3" Exchange 2833. Other Mechanisms 284

II. Thiazide Binding to Transporter Proteins 285III. Cloning the Thiazide Diuretic Receptor 287IV. Renal Actions 287

1. Proximal Effects 2882. Distal Effects 2893. Effects on Renal Salt and Water Excretion 2984. Effects on Renal K+ Excretion 3005. Effects on Renal Ca2+ Excretion 301

E. Pharmacokinetics in Disease States 301I. Chronic Renal Failure 302

II. Liver Disease 304F. Saluretic Effects of Thiazides 307

I. Effects in Healthy Controls : 307II. Responses in Renal Failure 309

III. Coadministration with Loop Diuretics in Renal Failure 309IV. Coadministration with Other Diuretics

in Edematous States with Normal Kidney Function 313G. Diuretics in Nonedematous States 314

I. Hypertension 314II. Diabetes Insipidus 317

III. Nephrolithiasis 318H. Side Effects of Diuretic Therapy 318

I. Hypokalemia 318II. Mg2+ Depletion 318

III. Hyponatremia 319IV. Hyperuricemia 319V. Hyperglycemia 319

VI. Hyperlipidemia 319VII. Allergy 320

VIII. Erectile Dysfunction 320I. Drug Combinations 320References 321

CHAPTER 9

Potassium-Retaining Diuretics: Aldosterone AntagonistsH. ENDOU and M. HOSOYAMADA. With 4 Figures 335

A. Chemical Structure and Properties, Structure-Activity Relationshipsof Aldosterone Antagonists 335

Contents XVII

I. Introduction 335II. Chemical Structure and Properties 337

1. Modifications of 17a Side Chain: SC compounds 3372. Structural Modification of Ring B: RU26752

and RU28318 3393. Structural Modification of Ring C:

Mespirenone (ZK94679) and ZK91587 3394. Recent Structural Modifications 339

III. Steroidogenesis Inhibitors and Secretion Inhibitors 339B. Pharmacodynamics 340

I. Renal Effects 3401. Increase in Urinary Sodium-Potassium Ratio 3402. Target Nephron Segments: CCT and OMCT,

and Other Segments 3403. Intracellular Mechanism of Aldosterone Antagonists 341

II. Extrarenal Effects 3421. Tissue Distribution of Type I Receptors 3422. Cross-reactivity with the Glucocorticoid Receptors 3423. Epithelia 3424. Cardiovascular System 3435. Central Nervous System 3436. Steroidogenesis Inhibition 3447. Antiandrogen Effects 344

C. Pharmacokinetics 345I. Absorption 345

II. Plasma Concentrations 345III. Metabolism 345

1. Spironolactone and Canrenoate 3452. Spironolactone and Cytochrome P450 Destruction 347

IV. Excretion 347D. Therapeutic Use (Indications, Dosage, Contraindications) 347

I. Indications 3471. Congestive Heart Failure 3482. Liver Cirrhosis 3483. Nephrotic Syndrome 3484. Hypertension 3495. Endocrine Disorders 3496. Other Disorders 349

II. Dosage 350III. Contraindications 350

E. Side Effects and Toxicology 350I. General Considerations 350

II. Main Side Effects 3511. Hyponatremia, Hyperkalemia

and Acid-Base Disturbances 351

XVIII Contents

2. Sexual Functions and Endocrine Disorders 3513. Carcinogenicity 3514. Allergy 3525. Calcium Channel Antagonism 352

F. Drug Interactions 352I. Angiotensin-Converting Enzyme Inhibitors 352

II. Ammonium Chloride 352III. Aspirin 352IV. Cyclosporin A 353V. Digitoxin 353

VI. Digoxin 353VII. Fludrocortisone 354

VIII. Mercurials 354IX. Mitotane 354X. Analgesics 355

XI. Warfarin 355References 355

CHAPTER 10

Potassium-Retaining Diuretics: AmilorideL.G. PALMER and T.R. KLEYMAN. With 7 Figures 363

A. Introduction 363B. Structure-Function Relationships 364

I. Guanidinium Substitutions 365II. 6-Position Ring Substitutions 366

III. 5-Position Ring Substitutions 367C. Pharmacodynamics 367

I. Sites of Action: Na+ Transport 3671. General 3672. Within the Kidney 3693. Other Epithelia 371

II. Effects on Transport of K+ and Other Ions 372III. Effects on Other Cellular Processes 374IV. Interactions with the Epithelial Na+ Channels 375

1. Stoichiometry 3752. Rate Constants 3763. Competition with Na+ 3784. Feedback Response to Amiloride 3805. Divalent Cation Requirements 3806. Model for Amiloride Block 381

D. Pharmacokinetics 383E. Therapeutic Use 385F. Side Effects and Toxicity 387

Contents 'XIX

G. Drug Interactions 388References 388

CHAPTER 11

Potassium-Retaining Diuretics: TriamtereneT. NETZER, F. ULLRICH, H. KNAUF, and E. MUTSCHLER.With 13 Figures 395

A. Chemical Structure and Properties 395B. Pharmacodynamics 395

I. Renal Effects 3951. Structure-Activity Relationships

of Pteridine Derivatives 3952. Triamterene 402

II. Cardiac Effects 4051. Structure-Activity Relationships 4052. Triamterene 408

III. Effects on Dihydrofolate Reductase 409C. Pharmacokinetics 409

I. Metabolism in Man 409II. Pharmacokinetics in Healthy Volunteers 409

III. Pharmacokinetics in Patients with Liver Disease 411IV. Pharmacokinetics in Patients with Renal Disease 412V. Pharmacokinetics in the Elderly 413

D. Therapeutic Use 414I. Indications 414

II. Dosage 415III. Side Effects 415IV. Contraindications 416V. Drug Interactions 416

E. Toxicity 417References 417

CHAPTER 12

Osmotic Diuretics: MannitolO.S. BETTER, I. RUBINSTEIN, and J. WINAVER. With 3 Figures 423

A. Introduction 423B. Renal Effects 424

I. Renal Hemodynamic Actions 425II. Glomerular Filtration Rate 426

III. Tubular Salt and Water Reabsorption 4281. Proximal Nephron 429

XX.. Contents

2. Loop of Henle 4293. Distal Tubule and Collecting Duct 431

IV. Transport of Other Ions 431V. Urinary Concentration and Dilution 432

VI. Miscellaneous Effects 433C. Beneficial Extrarenal Effects of Hypertonic Mannitol 434D. Effects on the Cardiovascular System 436E. Clinical Use 437

I. Clinical Applications 437II. Pharmacokinetics 437

III. Dosage 438IV. Precautions 438V. Adverse Reactions 438

VI. Contraindications 438References 439

CHAPTER 13

Clinical Uses of DiureticsJ.B. PUSCHETT. With 13 Figures 443

A. Introduction 443B. Physiological Basis of Diuretic Action and Clinical Implications

of Physiological Principles 443I. Proximal Tubule 447

II. Loop of Henle 451III. Early Portion of the Distal Convoluted Tubule 452IV. Late Portion of the Distal Convoluted Tubule and the

Collecting Duct 453C. Diuretics in the Treatment of Edematous States and Disorders

Associated with Abnormalities of Renal Function 455I. General Principles 455

II. Congestive Heart Failure 457III. Nephrotic Syndrome 467IV. Liver Disease 470V. Idiopathic Edema 471

VI. Premenstrual Syndrome 472VII. Acute Glomerulonephritis 473

VIII. Acute Renal Failure 473IX. Chronic Renal Failure 474X. Resistant Edema 475

D. Diuretics in the Treatment of Nonedematous Disorders 479I. Hypertension 479

II. Toxemia of Pregnancy 485III. Hypercalcemia 486

Contents XXI

IV. Renal Stone Disease 487V. Diabetes Insipidus 487

VI. Hyperkalemia 488E. Diuretic Side Effects and Adverse Reactions 489

I. Volume Contraction 489II. Hyponatremia 489

III. Hypokalemia 490IV. Hypomagnesemia 491V. Acid-Base Disorders 491

1. Metabolic Alkalosis 4912. Metabolic Acidosis 492

VI. Hyperglycemia 492VII. Hyperlipidemia 494

VIII. Hyperuricemia 494IX. Ototoxicity 495X. Nephrotoxicity 495

XI. Hyperkalemia 495References 496

Subject Index 507