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DIURETICS Prof. Hanan Hagar Pharmacology Department Classification of diuretics Carbonic Anhydrase Inhibitors Loop Diuretics Thiazides Potassium-Sparing Diuretics Osmotic Diuretics SITES OF ACTION OF DIURETICS Thiazide diuretics Mechanism of action: acts via inhibition of Na/Cl co-transporter on the luminal membrane of distal convoluted tubules Efficacy: Moderate 5% natriuresis Drugs as: hydrochlorothiazide -metolazone Distal convoluted tubules Mechanism of action of thiazide diuretics Pharmacokinetics: Given orally, slow of onset long duration of action (40 h) are secreted by active tubular secretory system of the kidney may interfere with uric acid secretion and cause hyperuricemia Pharmacological effects: urinary NaCl excretion urinary K excretion (Hypokalemia) urinary magnesium excretion urinary calcium excretion calcium re-absorption (hypercalcemia) uric acid in blood (hyperuricemia). glucose in blood (hyperglycemia) Thiazide diuretics Uses: Treatment of essential hypertension (cheap-well tolerated) Treatment of mild heart failure (to reduce extracellular volume). Uses: Nephrolithiasis due to hypercalciuria (to increase calcium re-absorption and decrease renal calcium stones) Nephrogenic diabetes insipidus (decrease blood volume and GFR) Adverse effects: Fluid and electrolyte imbalance Hyponatremia Hypovolemia (volume depletion) Hypokalemia Metabolic alkalosis. Hyperuricaemia (gout) Hypercalcemia Hyperglycaemia Potassium sparing diuretics Drugs: Spironolactone. Triamterene. Amiloride. given by oral administration Mechanism of action Act in collecting tubules and ducts by inhibiting Na reabsorption and K & H secretion (K-sparing effect) by either: Inhibition of Na influx through Na channels in the luminal membrane (triamterene – amiloride). Mechanism of action Or by antagonizing cytoplasmic aldosterone receptors (mineralocorticoid receptors Spironolactone). Spironolactone : is a synthetic steroid that acts as a competitive antagonist for aldosterone. COLLECTED TUBULES (CT) Pharmacodynamics: urinary Na excretion urinary K excretion (hyperkalemia) H secretion (acidosis) Therapeutic uses: Drug of choice for patients with hepatic cirrhosis In mineralocorticoid hypersecretion e.g. Conn’s syndrome Therapeutic uses: Secondary hyperaldosteronism: (CHF, hepatic cirrhosis, nephrotic syndrome). Treatment of hypertension (combined with thiazide or loop diuretics to correct for hypokalemia). Adverse Effects Hyperkalaemia. Metabolic acidosis. Gynaecomastia GIT upset and peptic ulcer Contraindications: Hyperkalaemia: as in chronic renal failure, K+ supplementation, -blockers or ACE inhibitors. liver disease (dose adjustment is needed). Osmotic diuretics Mannitol Poorly absorbed Given intravenously. Not metabolized Excreted by glomerular filtration without being re-absorbed or secreted within 30-60 min. Mannitol Acts in proximal tubules & descending loop of Henle by osmotic effect. Retains water within the tubules (water diuresis). Has a secondary effect on reducing sodium re-absorption. Therapeutic Uses: Cerebral edema (increased intracranial pressure). Glaucoma. Acute renal failure due to shock, trauma, drug toxicities (maintain urine flow- preserve kidney function). Adverse Effects: Extracellular water expansion (extracts water from cells) Dehydration Hypernatremia Headache, Adequate required. nausea, vomiting water replacement is Therapeutic applications of diuretics of hypertension: Treatment Thiazide diuretics o used alone or in combination with betablockers at low-dose (fewer side effects) o In presence of renal failure, loop diuretic is used Edema States Thiazide diuretic is used in mild edema with normal renal function o Loop diuretics are used in cases with impaired renal function o Congestive Heart failure Thiazides may be used in only mild cases with well-preserved renal function Loop diuretics are much preferred in severe cases especially when GF is lowered In life-threatening acute pulmonary edema, furosemide is given IV Renal failure Thiazides are used till GFR ≥ 40-50 ml/min Loop diuretic are used below given values, with increasing the dose with as GFR goes down. Diabetes inspidus Large volume(>10 L/day) of dilute urine thiazide diuretics reduces urine volume Hepatic cirrhosis with ascites Spironolactone is of choice. Diuretics CA inhibitors Acetohexamide Dorzolamide Osmotic diuretic Mannitol Loop diuretics Furosemide Thiazide diuretics hydrochlorothiazide K-sparing diuretic Spironolactone. Mechanism of action Effects Inhibition of NaHCO3 reabsorption in PCT Urinary Na HCO3, K Urinary alkalosis Metabolic acidosis Osmotic effect in PCT & DLH Urine excretion Little Na Na/K/2Cl Urinary Na, K, Ca, Mg transporter in TAL the most effective Na and Cl cotransporter in DCT Urinary Na, K, Mg BUT↓ urinary Ca (hypercalcemia) Metabolic alkalosis ↑ Urinary Na competitive ↓ K, H secretion antagonist of aldosterone in CCT Metabolic acidosis Diuretics CA inhibitors Acetohexamide Dorzolamide (topically) for glaucoma Osmotic diuretic Mannitol Loop diuretics Furosemide Thiazide diuretics hydrochlorothiazide K-sparing diuretic Spironolactone. Uses Glaucoma, epilepsy Mountain sickness • Cerebral edema • Acute renal failure Acute pulmonary edema (Drug of choice) Heart failure Hyperkalemia, Hypercalcemia Commonly used Hypertension, heart failure, hypercalciuria, kidney stones, diabetes inspidus Hepatic cirrhosis (Drug of choice) Diuretics CA inhibitors Acetohexamide Dorzolamide Osmotic diuretic Mannitol Loop diuretics Furosemide Thiazide diuretics hydrochlorothiazide K-sparing diuretic Spironolactone. Side effects Metabolic acidosis , Urinary alkalosis Hypokalemia Extracellular water expansion Dehydration Hypernatremia Hypokalemia, hypovolemia, hyponatremia, hypomagnesemia, hypocalcemia Precipitate gout, alkalosis Hypokalemia, hyponatremia, hypovolemia, hypomagnesemia, hypercalcemia Alkalosis, precipitate gout Hyperlipidemia, hyperglycemia Gynaecomastia Hyperkalaemia, Metabolic acidosis. GIT upset and peptic ulcer