Diuretics

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.

1 :Functional Anatomy of the Kidney.- A.Structural Organization of the Kidney.- I.Microanatomy of the Kidney.- 1. Nephron.- 2. Cortex.- 3. Medulla.- Kidney Size.- II.Renal Vasculature.- 1. Arteries and Arterioles.- 2. Cortical and Medullary Capillary Plexus.- 3. Venous Drainage of Cortex and Medulla.- 4. Wall Structure of Renal Vessels.- III.Interstitium, Lymphatics and Renal Nerves.- 1. Periarterial Interstitium.- 2. Peritubular Interstitium.- IV.Renal Corpuscle.- 1. Organization.- 2. Mesangium.- 3. Glomerular Capillaries.- 4. Filtration Barrier.- V. Juxtaglomerular Apparatus.- 1. Granular Cells.- 2. Extraglomerular Mesangium.- 3. Macula Densa.- B.General Organization of Renal Epithelia and Correlation with Transport.- I. Polarity of Epithelia.- 1. Transport Pathways.- II.Organization of Epithelial Surfaces.- 1. Basolateral Domain.- 2. Apical Domain.- III.Correlation of Structure with Na+ Transport Rates.- C.Nephron and Collecting Duct Structure.- I. Proximal Tubule.- II. Loop of Henle.- 1. Organization and Histotopography.- 2. Intermediate Tubule.- 3. Thick Ascending Limb (Straight Distal Tubule).- 4. Macula Densa.- III.Cortical Distal Segments.- 1. Structural and Functional Organization.- 2. Distal Convoluted Tubule.- 3. Connecting Tubule.- IV.Collecting Ducts.- 1. Organization.- 2. Cortical Collecting Duct Cells.- 3. Inner Medullary Collecting Duct Cells.- 4. Intercalated Cells.- D.Alterations of Morphology in Electrolyte Disturbances.- I. Acute Changes in Transport Rates.- 1. Mechanism.- 2. Morphological Changes Associated with Acute Changes in Transport Rates.- II. Chronic Alteration of Na+ Transport Rates.- 1. Mechanism.- 2. Time Course of Structural Changes.- III.Adaptation of Proximal Tubule.- 1. Changes in GFR.- 2. Diabetes Mellitus.- 3. Reduction of Renal Cell Mass.- IV.Adaptation of Thick Ascending Limb of Henle’s Loop.- 1. Variation of ADH Plasma Levels.- 2. Variation of Protein Intake.- V. Adaptation of Distal Segments and Collecting Duct.- 1. Role of Tubular Na+ Load.- 2. Role of Steroid Hormones.- 3. Role of Potassium Intake.- 4. Structural Changes in Intercalated Cells.- References.- 2 : Basic Concepts of Renal Physiology.- A.Introduction.- B.Renal Blood Flow and Glomerular Filtration.- I. Pressures and Resistances in Renal Vascular Segments.- II. Intrarenal Blood Flow Distribution.- III. Permeability-Selectivity of the Glomerular Filter.- IV. Determinants of Renal Glomerular Filtration Rate.- V. Autoregulation of Renal Blood Flow and Glomerular Filtration Rate.- VI. Hormonal Regulation of Renal Blood Flow and Glomerular Filtration.- C.Renal Tubular Transport.- I.Driving Forces for Epithelial Transport.- 1. Water Transport.- 2. Solvent Drag.- 3. Diffusion.- 4. Active Transport.- II. Saturability of Epithelial Transport Processes.- 1. Michealis-Menten Kinetics.- 2. Transport Kinetics of Whole Kidney.- III.Segmental Organization of Renal Epithelial Transport.- 1. Proximal Tubule.- 2. Loop of Henle.- 3. Distal Tubule and Collecting Duct.- IV.Urinary Concentrating Mechanism.- D.Regulation of Renal Water and Electrolyte Excretion.- I.Water.- II. Na+.- II. Bicarbonate and Hydrogen Ions.- IV. K+.- V. Mg2+.- VI. Calcium Phosphate.- References.- 3 : Renal Energy Metabolism.- A.Introduction.- B.Mechanisms of Renal ATP Formation.- I. Substrate-Linked ATP Formation.- 1. Glycolysis.- 2. Other Mechanisms.- II.Oxidative Phosphorylation.- 1. Coupling to Oxygen Consumption.- 2. Citric Acid Cycle.- C.Metabolic Substrates of Renal Energy Metabolism.- I. Glucose and Lactate.- II.Fatty Acids.- III. Ketone Bodies.- IV. Amino Acids.- V. Substrate Interactions.- VI. Contribution of Individual Substrates to Whole Kidney Energy Turnover.- D.Regulation of ATP in Tubule Cells.- I. Compartmentation.- II. ATP Turnover.- III. Energy-Consuming Mechanisms.- 1. Transport ATPases.- 2. Metabolic Processes.- E.Interaction of Diuretic Substances with Renal Energy Metabolism.- I. Proximal Tubule.- II. Thick Ascending Limb of Henle’s Loop.- III. Collecting Tubule.- References.- 4 : Discovery and Development of Diuretic Agents.- A.Introduction.- B.Xanthine Derivatives.- C.Osmotic Diuretics.- D.Mercurial Diuretics.- E.Carbonic Anhydrase Inhibitors.- F.Sulfonamide Diuretics.- I. Benzothiadiazines and Related Compounds.- II. Sulfamoylbenzoic Acid Derivatives.- G.Nonsulfonamide Diuretics.- I. Phenoxyacetic Acid Derivatives.- II. Potassium-Retaining Diuretics.- 1. Aldosterone Antagonists.- 2. Pteridines and Pyrazine Derivatives.- H. So-called Polyvalent Diuretics.- I. Loop Diuretics with Prolonged Duration of Action.- II. Saluretics with Eukalemic Properties.- III. Diuretics Improving Renal Function: Dopamine Agonists.- IV. Diuretics with Uricosuric Activity.- V. Avoidance of Adverse Effects on Serum Lipids and Blood Glucose.- VI. Diuretics with Predominant Cardiovascular Activity.- I. Aquaretics.- J. New Aspects: Ion Transport Modulators.- References.- 5 :Metabolism of Diuretics.- A.Introduction.- B.Biotransformation.- C.Patterns of Biotransformation.- D.Biotransformation of Diuretics.- I. Carboanhydrase Inhibitors.- 1. Acetazolamide.- II. Loop Diuretics.- 1. Furosemide.- 2. Bumetanide.- 3. Piretanide.- 4. Azosemide.- 5. Etozolin.- 6. Torasemide.- 7. Ethacrynic Acid.- III.Thiazide and Thiazide-Type Diuretics.- 1. Bendrofluazide.- 2. Chlorothiazide.- 3. Chlorthalidone.- 4. Hydrochlorothiazide.- 5. Hydroflumethiazide.- 6. Indapamide.- 7. Mefruside.- 8. Xipamide.- IV.Potassium-Sparing Diuretics.- 1. Amiloride.- 2. Triamterene.- 3. Spironolactone and Potassium Canrenoate.- References.- 6 :Interaction of Diuretics with Transport Systems in the Proximal Renal Tubule.- A.Introduction.- B.Transport System for Hydrophobic Organic Anions (pflra-Aminohippurate).- C.Transport Systems for Organic Cations.- D.Transport Systems for Sulfate.- E.Transport Systems for Dicarboxylates.- F.Interaction of Diuretics with the Different Proximal Transport Systems.- I. Sulfonamide/Thiazide Derivatives.- II. Thiazolidine, Aminopyrazol and Pyrazolidine Derivatives.- III.Arylamine-Pyridinecarboxylate and Arylamine-Pyridine Sulfonylurea Derivatives.- IV.Phenoxyacetic Acid Derivatives.- V. Pyrazinoyl-Guanidine Derivatives.- Pyrazinoyl-Aminomethylphenol Derivatives.- VI. Pteridine Derivatives.- VII. Aldosterone Antagonists.- G.How Does Metabolic Transformation Change the Interaction with the Transport Systems for Organic Anions and Cations?.- References.- 7 :Loop Diuretics.- A.Introduction.- B.The Heterogeneous Group of Loop Diuretics.- C.Organotropy of Loop Diuretics.- D.Saluretic and Diuretic Effects of Loop Diuretics and Cellular Mechanisms.- I. Luminal K+ Conductance.- II. Furosemide-Sensitive Na+2C-K+ Cotransporter.- III. Role of the Basolaterally Localized (Na+ + K+)-ATPase.- IV. Metabolic Control of NaCl Reabsorption in the TAL.- V. Cl- Channel and Its Inhibition.- VI. Loop Diuretics Related to Furosemide.- VII. Loop Diuretics Not Related to Furosemide.- E.Effects of Loop Diuretics in the Intact Kidney.- I. Macula Densa Segment.- II. Excretion of K+.- II. Excretion of NH4+.- IV. Excretion of H+ and HC03-.- V. Excretion of Ca2+ and Mg2+.- VI. Excretion of Li+.- VII. Excretion of Urate.- VIII. Phosphaturic Effect.- F.Effect of Loop Diuretics on Other Organs.- I. Ototoxic Effects.- II. Asthma.- II. Preload to the Heart.- IV. Glucose Metabolism.- G.Pharmacokinetics.- I. Ethacrynic Acid.- II. Indacrinone.- III. Furosemide.- IV. Piretanide.- V. Bumetanide.- VI. Torasemide.- VII. Azosemide.- VIII. Etozolin and Muzolimine.- H. Pharmacokinetics and Pharmacodynamics.- I. Clinical Uses.- I. Hypertension.- II. Congestive Heart Failure and Lung Edema.- III. Ascites.- IV. Edematous States in Nephrotic Syndrome.- V. Chronic Renal Failure.- VI. Other Indications.- J. Adverse Effects.- I. Hypokalemia.- II. Hyponatremia.- III. Hypocalcemia.- IV Hypomagnesemia.- V. Metabolic Alkalosis.- VI. Hyperlipidemia.- VII. Hyperglycemia and Diabetogenic Effects.- VIII. Hyperuricemia.- IX. Male Impotence.- X. Ototoxicity.- References.- 8 :Thiazide Diuretics.- A.Introduction.- B.Chemical Structures.- C.Pharmacokinetics.- I. Protein Binding.- II. Renal Excretion.- D.Pharmacodynamics.- I. Thiazide-Sensitive Systems.- 1. Na+Cl- Cotransport.- 2. Cl-/HC03- Exchange.- 3. Other Mechanisms.- II. Thiazide Binding to Transporter Proteins.- III. Cloning the Thiazide Diuretic Receptor.- IV. Renal Actions.- 1. Proximal Effects.- 2. Distal Effects.- 3. Effects on Renal Salt and Water Excretion.- 4. Effects on Renal K+ Excretion.- 5. Effects on Renal Ca2+ Excretion.- E.Pharmacokinetics in Disease States.- I. Chronic Renal Failure.- II. Liver Disease.- F.Saluretic Effects of Thiazides.- I. Effects in Healthy Controls.- II. Responses in Renal Failure.- IV. Coadministration with Loop Diuretics in Renal Failure.- V. Coadministration with Other Diuretics in Edematous States with Normal Kidney Function.- G.Diuretics in Nonedematous States.- I. Hypertension.- II. Diabetes Insipidus.- III. Nephrolithiasis.- H. Side Effects of Diuretic Therapy.- I. Hypokalemia.- II. Mg2+ Depletion.- III. Hyponatremia.- IV. Hyperuricemia.- V. Hyperglycemia.- VI. Hyperlipidemia.- VII. Allergy.- VIII. Erectile Dysfunction.- I. Drug Combinations.- References.- 9 :Potassium-Retaining Diuretics: Aldosterone Antagonists.- A. Chemical Structure and Properties, Structure-Activity Relationships of Aldosterone Antagonists.- I. Introduction.- II. Chemical Structure and Properties.- 1. Modifications of 17? Side Chain: SC compounds.- 2. Structural Modification of Ring B: RU26752 and RU28318.- 3.Structural Modification of Ring C: Mespirenone (ZK94679) and ZK91587.- 4.Recent Structural Modifications.- III. Steroidogenesis Inhibitors and Secretion Inhibitors.- B.Pharmacodynamics.- I. Renal Effects.- 1. Increase in Urinary Sodium-Potassium Ratio.- 2. Target Nephron Segments: CCT and OMCT, and Other Segments.- 3.Intracellular Mechanism of Aldosterone Antagonists.- II. Extrarenal Effects.- 1. Tissue Distribution of Type I Receptors.- 2. Cross-reactivity with the Glucocorticoid Receptors.- 3. Epithelia.- 4. Cardiovascular System.- 5. Central Nervous System.- 6. Steroidogenesis Inhibition.- 7. Antiandrogen Effects.- C.Pharmacokinetics.- I. Absorption.- II. Plasma Concentrations.- III.Metabolism.- 1. Spironolactone and Canrenoate.- 2. Spironolactone and Cytochrome P450 Destruction.- IV.Excretion.- D.Therapeutic Use (Indications, Dosage, Contraindications).- I. Indications.- 1. Congestive Heart Failure.- 2. Liver Cirrhosis.- 3. Nephrotic Syndrome.- 4. Hypertension.- 5. Endocrine Disorders.- 6. Other Disorders.- II. Dosage.- III. Contraindications.- E.Side Effects and Toxicology.- I. General Considerations.- II. Main Side Effects.- 1. Hyponatremia, Hyperkalemia and Acid-Base Disturbances.- 2. Sexual Functions and Endocrine Disorders.- 3. Carcinogenicity.- 4. Allergy.- 5. Calcium Channel Antagonism.- F. Drug Interactions.- I. Angiotensin-Converting Enzyme Inhibitors.- II. Ammonium Chloride.- II. Aspirin.- IV. Cyclosporin A.- V. Digitoxin.- VI. Digoxin.- VII. Fludrocortisone.- VIII. Mercurials.- IX. Mitotane.- X. Analgesics.- XL Warfarin.- References.- 10 :Potassium-Retaining Diuretics: Amiloride.- A.Introduction.- B.Structure-Function Relationships.- I. Guanidinium Substitutions.- II. 6-Position Ring Substitutions.- III. 5-Position Ring Substitutions.- C.Pharmacodynamics.- I. Sites of Action: Na+ Transport.- 1. General.- 2. Within the Kidney.- 3. Other Epithelia.- II. Effects on Transport of K+ and Other Ions.- III. Effects on Other Cellular Processes.- IV. Interactions with the Epithelial Na+ Channels.- 1. Stoichiometry.- 2. Rate Constants.- 3. Competition with Na+.- 4. Feedback Response to Amiloride.- 5. Divalent Cation Requirements.- 6. Model for Amiloride Block.- D.Pharmacokinetics.- E.Therapeutic Use.- F.Side Effects and Toxicity.- G. Drug Interactions.- References.- 11 :Potassium-Retaining Diuretics: Triamterene.- A.Chemical Structure and Properties.- B.Pharmacodynamics.- I. Renal Effects.- 1.Structure-Activity Relationships of Pteridine Derivatives.- 2.Triamterene.- II. Cardiac Effects.- 1. Structure-Activity Relationships.- 2. Triamterene.- III. Effects on Dihydrofolate Reductase.- C.Pharmacokinetics.- I. Metabolism in Man.- II. Pharmacokinetics in Healthy Volunteers.- II. Pharmacokinetics in Patients with Liver Disease.- IV. Pharmacokinetics in Patients with Renal Disease.- V. Pharmacokinetics in the Elderly.- D.Therapeutic Use.- I. Indications.- II. Dosage.- III. Side Effects.- IV. Contraindications.- V. Drug Interactions.- E.Toxicity.- References.- 12 :Osmotic Diuretics: Mannitol.- A.Introduction.- B.Renal Effects.- I. Renal Hemodynamic Actions.- II. Glomerular Filtration Rate.- III. Tubular Salt and Water Reabsorption.- 1. Proximal Nephron.- 2. Loop of Henle.- 3. Distal Tubule and Collecting Duct.- IV. Transport of Other Ions.- V. Urinary Concentration and Dilution.- VI. Miscellaneous Effects.- C.Beneficial Extrarenal Effects of Hypertonic Mannitol.- D.Effects on the Cardiovascular System.- E.Clinical Use.- I. Clinical Applications.- II. Pharmacokinetics.- III. Dosage.- IV. Precautions.- V. Adverse Reactions.- VI. Contraindications.- References.- 13 :Clinical Uses of Diuretics.- A.Introduction.- B.Physiological Basis of Diuretic Action and Clinical Implications of Physiological Principles.- I. Proximal Tubule.- II. Loop of Henle.- III. Early Portion of the Distal Convoluted Tubule.- IV. Late Portion of the Distal Convoluted Tubule and the Collecting Duct.- C.Diuretics in the Treatment of Edematous States and Disorders Associated with Abnormalities of Renal Function.- I. General Principles.- II. Congestive Heart Failure.- III. Nephrotic Syndrome.- IV. Liver Disease.- V. Idiopathic Edema.- VI. Premenstrual Syndrome.- VII. Acute Glomerulonephritis.- VIII. Acute Renal Failure.- IX. Chronic Renal Failure.- X. Resistant Edema.- D.Diuretics in the Treatment of Nonedematous Disorders.- I. Hypertension.- II. Toxemia of Pregnancy.- III. Hypercalcemia.- IV. Renal Stone Disease.- V. Diabetes Insipidus.- VI. Hyperkalemia.- E. Diuretic Side Effects and Adverse Reactions.- I. Volume Contraction.- II. Hyponatremia.- III. Hypokalemia.- IV. Hypomagnesemia.- V. Acid-Base Disorders.- 1. Metabolic Alkalosis.- 2. Metabolic Acidosis.- VI. Hyperglycemia.- VII. Hyperlipidemia.- VIII. Hyperuricemia.- IX. Ototoxicity.- X. Nephrotoxicity.- XI. Hyperkalemia.- References.