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  1. Renal Pharmacology
  2. I. Diuretics 1. CA inhibitors 2. Loop diuretics 3. Thiazide diuretics 4. Potassium sparing diuretics 5. Osmotic diuretics II. Agents affecting renal conservation of water 1. ADH, analogs and antagonists
  3. Overview Table: Major segments of the nephron and their functions
  4. I. Diuretics 1. Carbonic anhydrase (CA) inhibitors Acetazolamide: is a prototypical CA inhibitor Pharmacokinetics • Well absorbed after oral administration • Onset of action: 30 min → ↑urine pH (HCO3 – diuresis ) is apparent within 30 minutes • Duration of action: 12 hrs after a single dose • Excretion: secretion by the proximal tubule – Dose reduction in renal insufficiency
  5. CA inhibitors…Cont’d Pharmacodynamics • Inhibition of CA activity → ↓HCO3– reabsorption in the PCT • The efficacy of acetazolamide decreases significantly with use over several days. – reduced HCO3– in the glomerular filtrate – enhanced NaCl reabsorption (with HCO3– depletion) • Present major clinical applications are at sites other than the kidney – The ciliary body of the eye secretes HCO3– from the blood into the aqueous humor. – Formation of CSF by the choroid plexus involves HCO3– secretion
  6. Proximal tubule…cont’d Figure 1: Apical membrane Na+/H+ exchange (via NHE3) & bicarbonate reabsorption in the proximal convoluted tubule cell.
  7. CA inhibitors…Cont’d Clinical Indications i. Glaucoma • Inhibition of CA →↓aqueous humor →↓IOP • Topically active ones: dorzolamide, brinzolamide ii. Urinary Alkalinization • To enhance renal excretion of weak acids ( CA inhibitors ↑urine pH) iii. Acute Mountain Sickness • Rapidly progressing pulmonary or cerebral edema can be life-threatening. • Acetazolamide: ↓CSF formation and pH of CSF & brain
  8. CA inhibitors…Cont’d Toxicity A. Hyperchloremic Metabolic Acidosis • Acidosis resulting from chronic reduction of body HCO3– stores by CA inhibitors B. Renal Stones • Phosphaturia and hypercalciuria • Calcium salts are insoluble at alkaline pH → ↑renal stone formation C. Renal Potassium Wasting • Potassium wasting: Na+ reabsorption →↑lumen-negative electrical potential →↑K+ secretion
  9. CA inhibitors…Cont’d Contraindications: cirrhosis • CA inhibitor → alkalinization of the urine →↓excretion of NH4+ (converted to NH3 & reabsorbed) → hyperammonemia → hepatic encephalopathy
  10. 2. Loop diuretics • Are the most efficacious diuretic agents currently available • Prototypical drugs: furosemide & ethacrynic acid • Other loop diuretics: bumetanide and torsemide • Loop diuretics selectively inhibit NaCl reabsorption in the thick ascending LH
  11. Loop diuretics…cont’d 2.1. Furosemide  Mechanism of action: inhibition of reabsorption of sodium chloride by blocking Na+/K+/2Cl- symport in the thick ascending limb of the LH. Figure 2: Ion transport pathways across the luminal and basolateral membranes of the thick ascending limb cell.
  12.  They also diminishes the luminal-positive potential due to recycling of K+ →↑excretion of divalent ions (Mg2+, Ca2+)  Uses: – Hypertension, heart failure, ascites, pulmonary edema  Adverse effects: – Dehydration, hyperglycemia, hypokalemia, hypomagnisemia, hyperuricemia, metabolic alkalosis – Generally no hypocalcaemia (intestinal absorption of Ca2+ & reabsorption at the DCT)
  13. Loop diuretics…cont’d 2. 2. Ethacrynic acid  MOA: inhibition of sulfhydryl-catalyzed enzyme system, which is responsible for reabsorption of sodium and chloride in the proximal and distal tubules.  Uses: – In patients who are hypersensitive to sulfonamide drugs such as thiazides and furosemide – Edema related to heart failure or cirrhosis  Adverse effects: – Ototoxicity
  14. 3. Thiazides • Differ from each other in potency & duration of action • Prototype: hydrochlorothiazide • Other thiazides: bendroflumethiazide, chlorothiazide, hydroflumethiazide, etc. • Thiazide-like diuretics: chlorthalidone, indapamide, metolazone Pharmacokinetics • Administered orally (exception is chlorothiazide → parenteral) • Secretion: All thiazides compete for the same secretory system with uric acid → hyperuricemia
  15. Thiazides…cont’d MOA: • Thiazides block Na+/Cl– transporter in the DCT → inhibition of NaCl reabsorption from the tubular lumine • Thiazides enhance Ca2+ reabsorption • ↓IC Na+ by thiazide →↑Na+/Ca2+ exchange in the basolateral membrane → reabsorption of Ca2+
  16. Thiazides…cont’d Figure 3: Ion transport across the luminal and basolateral membranes of the DCT cell.
  17. Thiazides…cont’d Indications 1) Hypertension 2) Heart failure 3) Nephrolithiasis (kidney stones) → hypercalciuria 4) Nephrogenic diabetes insipidus Toxicity  Hypokalemic Metabolic Alkalosis  Hyperuricemia  Hyponatremia Contraindications • Cirrhosis • Borderline renal failure • Heart failure
  18. 4. Potassium sparing diuretics • Inhibit Na+ reabsorption (and K+ secretion) at the late distal and cortical collecting tubules • MOA: – Inhibition of aldosterone receptors (spironolactone, eplerenone) or – inhibition of Na+ influx through ion channels in the luminal membrane (amiloride, triamterene) → spare also K+ (as K+ secretion is coupled with Na+ reabsorption)
  19. Cont’d… Figure 4: Mechanisms of ions transport and sites of diuretics action in the cells of the late distal tubule and CCT
  20. Cont’d… • Spironolactone and eplerenone: – Are competitive antagonist of aldosterone – eplerenone has greater selectivity for the mineralocorticoid /aldosterone receptor than spironolactone → has considerably fewer adverse effects. • Amiloride and triamterene: – are direct inhibitors of Na+ influx – Triamterene is extensively metabolized in the liver → has a shorter half-life → warranting more frequent dosing – Amiloride is not metabolized → less frequent dosing
  21. Cont’d… Clinical Indications • As adjunct therapy with thiazides or loop diuretics (wastage of K+) • Ascitis • Heart failure Toxicity • Hyperkalemia • Hyperchloremic metabolic acidosis • Gynecomastia • Kidney Stones
  22. Cont’d… Contraindications • Oral K+ administration • Chronic renal insufficiency • Concomitant use with agents blunting the RAAS (ARB/ACEI) – Exacerbates hyperkalemia • Liver disease → carefully dose adjustment
  23. 5. Osmotic diuretics • Prototype: mannitol Pharmacokinetics • Absorption: poorly absorbed by the GI tract – Must be given parenterally for systemic effect • Metabolism: not metabolized • Excretion:filtration→no reabsorption nor secretion MOA: • Filtered by the glomerulus but not reabsorbed → ↑osmotic pressure → ↑water retention & diuresis • Site of action of osmotic diuretics – The PCT and descending limb of LH → freely permeable to water
  24. Osmotic…cont’d Clinical Indications  Maintain urine flow in acute renal failure  Treat acute oligouria  Reduce intracranial pressure and cerebral edema  Treat acute glaucoma (↓IOP) Toxicity • Extracellular Volume Expansion • Dehydration • Hyperkalemia