Diuretics PDF

DIURETICS REAGAN KABUKA (B.PHARM, MPH, MSc Pharmacology PG2) INTRODUCTION Diuretics are drugs that cause a net loss of sodium and water from the body resulting in contraction of the extracellular fluid. They include: - Loop diuretics: - Thiazide diuretics - Potassium spa...

DIURETICS REAGAN KABUKA (B.PHARM, MPH, MSc Pharmacology PG2) INTRODUCTION Diuretics are drugs that cause a net loss of sodium and water from the body resulting in contraction of the extracellular fluid. They include: - Loop diuretics: - Thiazide diuretics - Potassium sparing diuretics. - Osmotic Diuretics: - Carbonic anhydrase inhibitors.  GENERAL PRINCIPLES Diuretics act by different mechanisms and at different sites along the nephron Diuretics have to reach their sites of action in order to exert pharmacological action Diuretics inhibit excretion of K+ and Mg++ ions in distal tubules Diuretics acting at different sites or by different mechanisms of action have a synergistic effect if they are combined together Mechanisms of action LOOP DIURETICS The most effective diuretics available Referred to as high ceiling diuretics Examples are Frusemide, Bumetanide, Torsemide, Ethacrynic acid. MECHANISM OF ACTION 1) Act on the thick ascending loop of Henle blocking the 2Cl-Na-K reabsorption pump resulting in: Excretion of 20% of filtered Na+  Interference with medullary hypertonicity causing failure of water conservation by medulla causing excretion of free water in excess of Na+. Also inhibits reabsorption of Mg and Calcium 2) They release prostaglandins (PGs) that increase glomerular filtration and intensify their action at the loop of Henle by inhibiting Na+ reabsorption Indomethacin inhibits PGs synthesis and therefore interferes with action of Loop diuretics). PHARMACOLOGICAL EFFECTS ↑ urinary excretion of Na+ and K+ ↑ urine volume ↑ urinary excretion Ca++ and Mg ++ ↑ renal blood flow PHARMACOKINETICS OF LOOP DIURETICS Given orally or I. V Have fast onset of action (suitable for emergency) Have short duration of action Excreted by active tubular secretion of weak acids into urine Interfere with uric acid secretion (hyperuricemia) INDICATIONS 1- Oedema associated with CCF and nephrotic syndrome 2- Acute renal failure: -They decrease energy requirement and preserve cellular integrity by blocking active Na+ transport and increase GFR by increasing renal Prostaglandins 3- Treatment of hypercalcemia: - They interfere with Ca++ reabsorption in the loop of Henle increasing Ca++ excretion 4- Treatment of hyperkalemia: - Loop diuretics inhibit reabsorption of K+ in the loop of Henle and enhance K+ excretion in distal tubule in exchange with Na+. 5- Treatment of acidosis: - Loop diuretics increase H+ excretion in exchange of Na+ at the distal tubule hence correcting the acidosis SIDE EFFECTS 1. Hypovolemia, Hypotension, Collapse due to intensive diuresis within a short time 2. Hypokalemia, Hypomagnesemia and Alkalosis: - Increased delivery of Na+ to the distal tubules stimulates the excretion of K+ and H+ in exchange for Na+ under the effect of Aldosterone. Spironolactone, the Aldosterone antagonist prevents these effects 3. Hypocalcemia due to interference with Ca++ reabsorption in the loop of Henle 4. Ototoxicity especially with aminoglycosides 5. Interstitial nephritis with cephalosporins 6. Hypersensitivity reactions as skin rash 7. Myalgia with Bumetanide 8. Severe G.I.T upsets with Ethacrynic acid 9. Hyperglycemia 10. Hyperuricemia THIAZIDE DIURETICS They have moderately powerful diuretic effect. Mechanism of action - Inhibit active NaCl reabsorption in early distal tubule causing excretion of 5-10% of filtered Na+ - Inhibit carbonic anhydrase enzyme at high doses Examples; Chlorothiazides, Hydrochlorothiazide, Chlorthalidone, and Indapamide PHARMACOLOGICAL EFFECTS Increased urinary Na-Cl excretion Increased urinary K excretion (Hypokalemia) Increased urinary magnesium excretion Increased calcium re-absorption hypercalcemia PHARMACOKINETICS Given orally, slow of onset long duration of action are secreted by active tubular secretory system of the kidney may interfere with uric acid secretion and cause hyperuricemia INDICATIONS 1. Treatment of Hypertension:- Antihypertensive effect due to its diuretic action decreasing blood volume 2. Mild edema especially of heart failure. They are non-effective in renal insufficiency due to low excretion of Na+ 3. Hypercalcuria and calcium stones. The decreased glomerular filtration induced by chronic use of Thiazides increases Ca++ reabsorption at the proximal tubules resulting in decreased Ca++ excretion 4. Nephrogenic diabetes insipidus: - Chronic Thiazide therapy paradoxically decreases urine output in nephrogenic diabetes insipidus by decreasing glomerular filtration; Thiazides inhibit NaCl reabsorption, thus, they increase NaCl at macula densa which interferes with tubulo-glomerular balance leading to decreased glomerular filtration and urine volume SIDE EFFECTS Hypokalemia and Metabolic acidosis; Due to enhancement of K+ and H+ excretion in exchange with Na+ at more distal nephron sites Glucose intolerance: Thiazides induce hypokalemia with increased cellular outflux of K+ and causes membrane hyperpolarization. This inhibits Ca++ influx and insulin release Dyslipidemia and increases risk of coronary atherosclerosis Hyperuricemia - interfere with uric acid excretion Hypersensitivity reactions, Pancreatitis and impotence Hepatic encephalopathy in patients with liver impairment POTASSIUM SPARING DIURETICS They are weak diuretics as they excrete only 5% of filtered Na+ Mechanism: - Inhibit Na/K/H exchange at the distal tubule by two different mechanisms; a) Spironolactone and eplerenone antagonizes Aldosterone receptor- binding, reducing the synthesis of a specific protein that stimulates the Na+ pump (This mechanisms of action explains the delayed onset of action of Spironolactone- 3-4 days) b) Triamterene and Amiloride act independent of Aldosterone to block Na+ channels directly INDICATIONS 1. Oedema of Hyperaldosteronism: -(liver cirrhosis, nephrotic syndrome, C.H.F) · This oedema is usually resistant to other diuretics because the Na+ lost by these diuretics is reabsorbed again by the excess Aldosterone at the distal tubule · Spironolactone is also safer, in liver cirrhosis, than other diuretics which cause alkalosis with increased risk of hepatic encephalopathy 2. Hypokalemia and Hypomagnesaemia · The direct acting drugs; Triamterene and Amiloride, are preferable to Spironolactone due to their short action making daily dose adjustment possible · These agents are more effective in maintaining K+ and Mg++ concentrations than the exogenous supplement of these ions SIDE EFFECTS 1) Hyperkalemia and metabolic acidosis: - patients with renal insufficiency or diabetes mellitus more susceptible 2) Gynecomastia: - due to the anti-androgen effect of Spironolactone OSMOTIC DIURETICS Mechanism: - Mannitol is freely filtered at the glomerulus with limited reabsorption by the renal tubules resulting in: 1) Increase in osmotic pressure of tubular filtrate with retention of water and increased urine volume 2) The high osmotic pressure of the tubular filtrate that opposes plasma osmotic pressure inhibiting sodium reabsorption throughout the nephron INDICATIONS 1) Rapid reduction of intracranial tension in cerebral oedema caused by head injury or brain surgery 2) Rapid reduction of intraocular tension in acute congestive glaucoma 3) Prophylaxis in acute renal failure following surgery or trauma 4) Prevents concentration of toxic agents which cause renal damage by maintaining high rate of urine flow ADVERSE EFFECTS - Heart failure - Dilutional hyponatremia CARBONIC ANHYDRASE INHIBITORS MECHANISM OF ACTION - Inhibits Carbonic anhydrase enzyme responsible for H+ production - This results in inhibition of the Na/H+ exchange at the proximal tubules leading to decreased Na+ reabsorption - with subsequent inhibition of NaHCO3 reabsorption. Loss of NaHCO3 in urine leads to: a) Diuresis with alkaline urine b) Decreased blood bicarbonate with metabolic acidosis They are weak diuretics because much of the sodium lost by these diuretics is reabsorbed at more distal nephron sites Examples Dorzolamide, Methazolamide and acetazolamide Pharmacological actions of CAI ↑ Mild increase in urine volume ↑ urinary excretion of sodium, potassium , bicarbonate (alkaline urine) Metabolic acidosis ↑ Urinary phosphate excretion Promotes K+ excretion by ↑the load of Na+ delivered to the distal tubules. Acetazolamide Dose- 250mg three times daily Indications a) Oedema refractory to Loop diuretics: Acetazolamide with Loop diuretics b) Alkalosis associated with emphysema and high altitude sickness (by inducing metabolic acidosis) c) Epilepsy: suppress the irritable focus directly and by (↓PH) d) Treatment of glaucoma by decreasing formation of aqueous humor (↓IOP) e) Urinary alkalinisation to enhance renal excretion of acidic substances (uric acid, methotrexate and cysteine) Adverse reactions Drowsiness and disorientation due to metabolic acidosis Renal (Calcium and Phosphate) stones due to alkaline urine Hypersensitivity reactions as they are sulfonamide derivatives Diuretic Site of action Diuretics transporter Function segment Carbonic anhydrase Na/H transporter, Re-absorption of 66% Proximal convoluted inhibitors Carbonic anhydrase Na, K, Ca, Mg, 100% tubules enzyme glucose and amino acids; 65% NaHCO3 None Acid & base transporter Secretion and re- Proximal absorption of organic Straight Tubules acids and bases Loop diuretics Na/K/2Cl transporter Active reabsorption Thick ascending loop 25% Na, K, Cl Secondary reabsorptionCa, Mg Thiazide diuretics Na and Cl cotransporter Active tubular Distal convoluted reabsorption of 5%Na, tubules Cl, Ca K-sparing diuretics Na channels Na reabsorption Collecting tubules K & H transporter K & H secretion Classification based on efficacy QUESTIONS???