Diuretics

Pharmacology: Renal Pharmacology, Diuretics

1. DIURETICS Dr. Ankita Bist Assistant Professor Department of Pharmacology

2. 76 years old lady, has a history of cardiovascular disease including hypertension and heart failure. She had been receiving furosemide and developed mild hypokalemia for which a potassium supplement was prescribed. 2 weeks later she arrives at the hospital and during the assessment, she reveals she has been experiencing nausea, abdominal cramping, and diarrhea along with some muscle cramps, weakness, and a feeling that “her heart was going to jump out of her chest.” What might be occurring now?

3. D iure t i cs Drugs which cause a net loss of Na+ and water in urine. E x c ep t o s mo t i c diu r e t i c s whi ch d o n o t cause na t r i ure s i s but produce diuresis Causes increase in urine volume . Causes concomitant decrease in extra-cellular volume (blood volume)

4. Classification of Diuretics Thiazides: Hydrochlorothiazide, Chlorthalidone, Indapamide , Metolazone High ceiling: Furosemide , Bumetanide, Torsemide, K+ sparing: Spironolactone, Eplerenone , Triamterene, Amiloride Others: Carbonic Anhydrase Inhibitors: Acetazolamide, Methazolamide, Dorzolamide Osmotic Diuretics: Mannitol, Glycerin, Isosorbide

5. Thiazide Diuretics Mechanism of action: Inhibit Na + -Cl - symporter Increase excretion of Na and H2O causing decrease in blood volume hypotensive action Na exchanges with K + in the DT causing K + loss: hypokalemia Additional Carbonic anhydrase inhibitory action Reduce Ca ++ excretion: hypercalcemia Hyperglycemia Hyperuricemia

6. U s e s Hypertension (hydrochlorothiazide, indapamide) Edema Hypercalciuria and renal ca stones Diabetes insipidus (DI) (nephrogenic responds better)

7. Loop Diuretics Mechanism of action: Thick ascending limb of loop of Henle Inhibit Na + K + -2Cl - cotransporter Increase excretion of Na, Cl and H2O causing decrease in blood volume Na exchanges with K + in the DT causing K + loss: hypokalemia Increases Ca ++ and Mg ++ excretion Hyperuricemia and hypokalemia

8. Uses Edema: cardiac, hepatic, renal Acute pulmonary edema Cerebral edema – (osmotic diuretics more preferred) Hypertension (only in presence of CHF, renal insufficiency etc ) Hypercalcemia

9. Loop & Thiazide drugs: Complications Hypokalemia Acute saline depletion Dilutional hyponatremia Hearing loss Hyperuricemia Hyperglycemia Hypocalcemia with loop and hypercalcemia with thiazides Magnesium loss

10. K+ sparing diuretics MOA: competitive antagonists, either compete with aldosterone or directly block Na channels. Aldosterone competitive antagonists: spironolactone, eplerenone Reduce reabsorption of Na+ and water K+ loss in urine is decreased Conserve K+ indirectly, produces mild natriuresis No effect in the absence of aldosterone Useful in states related to high aldosterone activity

11. Adverse effects Drowsiness, mental confusion, ataxia, epigastric discomfort, loose motions Spironolactone has hormonal side effects : gynecomastia, erectile dysfunction, menstrual irregularities Eplerenone is safer in this regard Hyperkaliemia in renal impaired patients, and those taking ACE I/ ARB’s Acidosis in cirrhotic Contraindicated in ulcer patients

12. Renal epithelial Na+ Channel inhibitors Triamterene, amiloride Mechanism of action: blocks luminal renal epithelial Na+ channels, decrease reabsorption of Na+. Decreases K+ excretion, accompanied with small increase in Na+ loss, reduces Ca2+ and Mg2+ excretion Uses: hypertension, as adjuvant, prevents hypokalemia Adverse effects: nausea, diarrhea, headache, impaired glucose tolerance, photosensitivity, rise in blood urea. HYPERKALEMIA

13. Carbonic Anhydrase Inhibitors Acetazolamide, methazolamide, dorzolamide Reversible, non-competitive inhibitor of carbonic anhydrase. Acts at PT, DT and CD Less H+ available for exchange with Na+, induces natriuresis USES: Glaucoma, Alkalinize urine, epilepsy, mountain sickness ADR: Acidosis, hypokalemia, drowsiness, hypersensitivity, Hepatic coma

14. Osmotic Diuretics Mannitol, isosorbide Non-electrolyte, low molecular weight, pharmacologically inert Acts by: raising osmolarity of plasma and tubular fluid gets freely filtered at glomerulus limits tubular water and electrolyte reabsorption (cations as well as anions) USES: Increased ICT, dialysis disequilibrium

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