Lect_Diuretics(2).pdf
- 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