Lecture 7 Diuretics-3 PDF

DIURETICS REAGAN KABUKA (PHARMACIST) 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: - Thiazides. - Potassium retaining diuretics. - Osmotic...

DIURETICS REAGAN KABUKA (PHARMACIST) 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: - Thiazides. - Potassium retaining 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 act All diuretics (except Spironolactone) must reach the lumen of the nephron to inhibit sodium reabsorption Osmotic diuretics reach their site of action by glomerular filtration. The other diuretics depend on upon renal secretion to reach the nephron. Therefore, any impairment of delivery of diuretics to their site of action will result in diminished diuretic response (e.g. in renal impairment). Diuretics act only if sodium reaches their site of action. Thus, more distally acting diuretics lose their effectiveness if proximal sodium reabsorption is increased as occurs in edematous states due to the associated renal hypotension. This explains why loop diuretics are usually effective in cases resistant to distally acting diuretics e.g. Thiazides. Diuretics interfering with reabsorption of Na+ at any site lead to enhanced Na+ reabsorption in exchange with K+ or H+ at more distal tubular sites e.g. Loop and Thiazides diuretics are associated with increased excretion of K+ and H+ in exchange with Na+ at distal tubule resulting in hypokalemia and alkalosis. Diuretics by inhibiting Na+ reabsorption at a certain site interfere with other renal functions related to sodium reabsorption at that site e.g. Loop diuretics inhibit calcium reabsorption at thick ascending loop of Henle and Potassium retaining 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. LOOP DIURETICS The most effective diuretics available. Mechanism: - 1) Act on the thick ascending loop of Henle blocking the 2Cl-Na-K reabsorption pump resulting in: Ø Excretion of 20% of filtered Na+. Ø Interference with medullary hypertonicity with failure of water conservation by medulla causing excretion of free water in excess of Na+. 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). Examples are Frusemide, Bumetanide INDICATIONS 1- Pulmonary oedema and hypertensive encephalopathy. 2- Acute renal failure: -They decrease energy requirement and preserve cellular integrity by blocking active Na+ transport and increase GFR by increasing renal PGs. 3- Treatment of hypercalcemia: - They interfere with Na+ and 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 hyponatremia: - Loop diuretics by increasing free water loss, will increase blood level of Na+ in dilutional hyponatremic states. 6- 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. Hemoconcentration with thrombosis. These effects are 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- Refractoriness to Loop diuretics. THIAZIDE DIURETICS They have moderately powerful diuretic effect. Mechanism: - 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 INDICATIONS 1- Mild oedema especially of heart failure. They are non-effective in renal insufficiency due to low excretion of Na+ and the diuretic. 2- Nephrogenic diabetes insipidus: - Chronic Thiazide therapy paradoxically decreases urine output in nephrogenic diabetes insipidus by decreasing glomerular filtration by the following mechanism: 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. 3- Treatment of idiopathic Hypercalcuria and prevention of calcium stones. They decreased glomerular filtration induced by chronic use of Thiazides increases Ca++ reabsorption at the proximal tubules resulting in decreased Ca++ excretion. 4- Treatment of Hypertension:- Initial hypotensive effect due to its diuretic action decreasing blood volume. - Persistent hypotensive effect due to direct vasodilatation. SIDE EFFECTS 1- Hypokalemia and Metabolic acidosis; Due to enhancement of K+ and H+ excretion in exchange with Na+ at more distal nephron sites. 2- Glucose intolerance: Thiazides induce hypokalemia with increased cellular outflux of K+ and causes membrane hyperpolarization. This inhibits Ca++ influx and insulin release. 3- Dyslipidemia and increases risk of coronary atherosclerosis. 4- Hyperuricemia: - interfere with uric acid excretion. 5- Hyponatremia. 6- Hypersensitivity reactions, Pancreatitis and impotence. 7- Hepatic encephalopathy in patients with liver impairment: Alkalosis induced by Thiazides increases lipid soluble NH3 rather than water soluble NH4. Accumulation of NH3, due to failure of the liver to convert it to urea, leads to its diffusion into the brain depleting the excitatory neurotransmitter Glutamic acid and inducing coma. 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 antagonizes Aldosterone receptor-binding, reducing the synthesis of a specific protein that stimulates the Na+ pump. b) Triamterene and Amiloride act independent of Aldosterone to block Na+ channels directly. These mechanisms of action explain the delayed onset of action of Spironolactone (3-4 days) in contrast to that of Triamterene and Amiloride. INDICATIONS 1- Oedema of Hyperaldosteronism: - Spironolactone is the drug of choice in oedema associated with secondary hyperaldosteronism (liver cirrhosis, nephrotic syndrome, C.H.F). · This oedema is usually resistant to other diuretics including the potent Loop diuretics because the Na+ lost by these diuretics is reabsorbed again by the excess Aldosterone at the distal tubule. · The other Potassium-retaining diuretics are less effective in hyperaldosteronism. · Spironolactone is also safer, in liver cirrhosis, than other diuretics which cause alkalosis with increased risk of hepatic encephalopathy. 2- Hypokalemia and Hypomagnesemia: · 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 (hyporeninemia) are more susceptible to these complications. 2) Gynecomastia: - due to the anti-androgen effect of Spironolactone. OSMOTIC DIURETICS · Mannitol has a powerful diuretic action. · Mechanism: - Mannitol is freely filtered at the glomerulus with limited reabsorption by the renal tubules resulting in: - Increase in osmotic pressure of tubular filtrate with retention of water and increased urine volume. - The high osmotic pressure of the tubular filtrate that opposes plasma osmotic pressure inhibits 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. Mannitol by maintaining high rate of urine flow prevents concentration of toxic agents which cause renal damage. · Adverse effects: - Heart failure. - Dilutional hyponatremia. CARBONIC ANHYDRASE INHIBITORS · They are weak diuretics because much of the sodium lost by these diuretics is reabsorbed at more distal nephron sites. · Mechanism of action: - Inhibits Carbonic anhydrase enzyme responsible for H+ production. - This results in inhibition of the Na/H+ exchange at the proximal tubules 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.  Dose and Preparations: · Acetazolamide 250mg three times daily. Indications of Carbonic anhydrase inhibitors a) Oedema refractory to Loop diuretics: Co-administration of Acetazolamide with Loop diuretics improves diuresis in severe Oedema of heart failure. b) Alkalosis associated with emphysema and high altitude sickness (by inducing metabolic acidosis). c) Epilepsy: suppress the irritable focus directly or by acidosis. d) Treatment of glaucoma by decreasing formation of aqueous humor. v Methazolamide is preferred to Acetazolamide because it has less renal and systemic effects. Adverse reactions: · Drowsiness and disorientation due to metabolic acidosis. · Calcium and Phosphate stones due to alkaline urine. · Hypersensitivity reactions as they are sulfonamide derivatives.