Diuretics

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.