Diuretics.pdf

Diuretics Thiazide: Hydrochlorothiazide, Chlorothiazide, Chlorthalidone (Hygroton), Metolazone, and Indapamide. Loop diuretics: Furosemide (Lasix), Torsemide, Bumetanide (Bumex), and Ethacrynic acid. Potassium-sparing diuretics: Triamterene,...

Diuretics Thiazide: Hydrochlorothiazide, Chlorothiazide, Chlorthalidone (Hygroton), Metolazone, and Indapamide. Loop diuretics: Furosemide (Lasix), Torsemide, Bumetanide (Bumex), and Ethacrynic acid. Potassium-sparing diuretics: Triamterene, Amiloride + H (Moduretic), Spironolactone (Aldactone) and Eplerenone (Eple-renone). Note: Thiazide diuretics (They are sulfonamide derivatives) can be used as initial drug therapy for hypertension unless there are compelling (compulsory) reasons to choose another agent. Regardless of class, diuretics' initial mechanism of action is based upon decreasing blood volume, which ultimately leads to reduced blood pressure. Low-dose diuretic therapy is safe, inexpensive, and effective in preventing stroke, myocardial infarction, and heart failure. Routine serum electrolyte monitoring should be done for all patients receiving diuretics. Dietary sodium restriction has been known for many years to decrease blood pressure in hypertensive patients. Effects of Diuretics Diuretics lower blood pressure primarily by depleting body sodium stores. Initially, they reduce blood volume and cardiac output; peripheral vascular resistance (SVR) may decrease. After 6–8 weeks, cardiac output returns to normal while peripheral vascular resistance declines. Sodium is believed to contribute to vascular resistance by increasing vessel stiffness and neural reactivity, possibly related to altered sodium-calcium exchange with a resultant increase in intracellular calcium. These effects are reversed by diuretics or dietary sodium restriction. Diuretics effectively lower blood pressure by 10 - 15 Hg (Millimeter of mercury) in most patients, and diuretics alone often provide adequate treatment for mild or moderate essential hypertension (High blood pressure that is not due to another medical condition). In more severe hypertension, diuretics are used in combination with sympatholytic and vasodilator drugs to control the tendency toward sodium retention caused by these agents. In severe hypertension, when multiple drugs are used, blood pressure may be well controlled when blood volume is 95% of normal but much too high when blood volume is 105% of normal. Thiazide diuretics Thiazide diuretics, such as Hydrochlorothiazide, Chlorthalidone and Metolazone, lower blood pressure initially by increasing sodium and water excretion. This causes a decrease in extracellular volume, decreasing cardiac output and renal blood flow. With long-term treatment, plasma volume approaches a normal value, but a hypotensive effect related to decreased peripheral resistance persists. Pharmacy College / Tikrit University 1 Asst. Prof Dr. Sinan Al-Mahmood  Thiazides are useful in combination therapy with other antihypertensive agents, including β-blockers, ACE inhibitors, ARBs, and potassium-sparing diuretics. Except for Metolazone, thiazide diuretics are ineffective in patients with inadequate kidney function (estimated glomerular filtration rate less than 30 mL/min/m2). Loop diuretics may be required in these patients. Thiazide diuretics can induce hypokalemia, hyperuricemia (Thiazides directly increase urate reabsorption in the proximal tubule) and, to a lesser extent, hyperglycemia in some patients (Thiazide-induced potassium depletion is responsible for decreased insulin secretion and/or reduced insulin sensitivity, leading to impaired glucose tolerance and hyperglycemia). New-onset diabetes has been reported more often with thiazides than with other antihypertensive agents. Patients with diabetes taking thiazides should monitor glucose to assess the need for an adjustment in diabetes therapy. The efficacy of thiazide agents may be diminished with concomitant use of NSAIDs, such as indomethacin, which inhibit the production of renal prostaglandins, thereby reducing renal blood flow. The thiazides can be useful in treating idiopathic hypercalciuria because they inhibit urinary Ca2+ excretion. This particularly benefits patients with calcium oxalate stones in the urinary tract. Thiazides have the unique ability to produce hyperosmolar urine. They can substitute for ADH (act as ADH) in treating nephrogenic diabetes insipidus (The antidiuretic action of thiazides is secondary to increased renal sodium excretion. The renal sodium loss causes extracellular volume contraction, leading to lowered GFR and increased proximal tubular sodium and water reabsorption). When treated with the drug, the urine volume of such individuals may drop from 11 L/d to about 3 L/d. Loop diuretics The loop diuretics (Furosemide, Torsemide, Bumetanide, and Ethacrynic Acid) act promptly (instantly) by blocking sodium and chloride reabsorption in the kidneys, even in patients with poor renal function or those who have not responded to thiazide diuretics. Loop diuretics decrease renal vascular resistance and increase renal blood flow. Like thiazides, they can cause hypokalemia. However, unlike thiazides, loop diuretics increase the Ca2+ content of urine, whereas thiazide diuretics decrease it. These agents are rarely used alone to treat hypertension, but they are commonly used to manage symptoms of heart failure and oedema. Ototoxicity: Loop diuretics may cause reversible or permanent hearing loss, particularly when used in conjunction with other ototoxic drugs (for example, aminoglycoside antibiotics). Ethacrynic acid is the most likely to cause deafness. Hyperuricemia: Furosemide and ethacrynic acid compete with uric acid for the renal secretory systems, thus blocking its secretion and, in turn, causing or exacerbating gouty attacks. Acute hypovolemia: Loop diuretics can cause a severe and rapid reduction in blood volume, with the possibility of hypotension, shock, and cardiac arrhythmias. Hypomagnesemia: Chronic use of loop diuretics combined with low dietary intake of Mg2+ can lead to hypomagnesemia, particularly in older people. This can be corrected by oral supplementation. Pharmacy College / Tikrit University 2 Asst. Prof Dr. Sinan Al-Mahmood  Potassium-sparing diuretics Amiloride and Triamterene directly act (acts by inhibiting Na+ reabsorption in the late distal tubules & collecting ducts). They have mild diuretic effects and cause Hyperkalemia. Spironolactone and Eplerenone (Aldosterone receptor antagonists) reduce potassium loss in the urine. Aldosterone antagonists have the additional benefit of diminishing the cardiac remodelling that occurs in heart failure. They have antiandrogen activity and may cause male sexual dysfunction (Erectile dysfunction) and gynecomastia ( enlarged breast tissue in men). They are used for Hypertension, Heart failure, Severe acne, Hirsutism (Hypertrichosis), Polycystic ovary, and Hyperaldosteronism. Potassium-sparing diuretics are sometimes combined with loop diuretics and thiazides to reduce the potassium loss induced by these diuretics. Use of Diuretics Thiazide diuretics are appropriate for most patients with mild or moderate hypertension and normal renal and cardiac function. In comparison, all thiazides lower blood pressure, and chlorthalidone is preferred to others. This is supported by evidence of improved 24-hour blood pressure control and reduced cardiovascular events in large clinical trials. Chlorthalidone is likely more effective than hydrochlorothiazide because it has a longer duration of action. More powerful diuretics (e.g., those acting on the loop of Henle) such as furosemide are necessary in severe hypertension when multiple drugs with sodium-retaining properties are used; in renal insufficiency, when glomerular filtration rate is less than 30–40 mL/min; and in cardiac failure or hepatic cirrhosis, in which sodium retention is marked. Potassium-sparing diuretics help avoid excessive potassium depletion and enhance other diuretics' natriuretic effects. Although thiazide diuretics are more natriuretic at higher doses (up to 100–200 mg of hydrochlorothiazide) when used as a single agent, lower doses (25–50 mg) exert as much antihypertensive effect as higher doses. In contrast to thiazides, the blood pressure response to loop diuretics continues to increase at doses many times greater than the usual therapeutic dose. Ascites: Fluid accumulation in the abdominal cavity (ascites)is a common complication of hepatic cirrhosis. Spironolactone is effective in this condition. Polycystic ovary syndrome: Spironolactone is often used off-label to treat polycystic ovary syndrome. At high doses, it blocks androgen receptors and inhibits steroid synthesis, thereby helping to offset the increased androgen levels seen in this disorder. Toxicity of Diuretics In the treatment of hypertension, the most common adverse effect of diuretics (except for potassium-sparing diuretics) is potassium depletion. Although mild degrees of hypokalemia are tolerated well by many patients, hypokalemia may be hazardous in persons taking digitalis, those who have chronic arrhythmias, or those with acute myocardial infarction or left ventricular dysfunction. Potassium loss is coupled to sodium reabsorption, and dietary sodium intake restriction minimizes potassium loss. Pharmacy College / Tikrit University 3 Asst. Prof Dr. Sinan Al-Mahmood  Diuretics may also cause magnesium depletion, impair glucose tolerance, and increase serum lipid concentrations (The mechanism of increased lipid levels caused by diuretics remains unclear. One theory is that a reduction in insulin sensitivity may cause an increase in hepatic production of cholesterol). Diuretics increase uric acid concentrations and may precipitate gout (Diuretics can increase the risk of developing gout, a type of arthritis caused by the buildup of uric acid crystals in a joint. This may happen because diuretics increase urination, which reduces the amount of fluid in your body). The use of low doses minimizes these adverse metabolic effects without impairing the antihypertensive action. Potassium-sparing diuretics may produce hyperkalemia, particularly in patients with renal insufficiency and those taking ACE inhibitors or angiotensin receptor blockers; spironolactone (a steroid) is associated with gynecomastia. Other possible side effects of diuretics include Frequent urination, Orthostatic hypotension (Postural hypotension), Dizziness, Headaches and Dehydration. Carbonic Anhydrase Inhibitor Acetazolamide and other carbonic anhydrase inhibitors are often used for pharmacologic actions other than their diuretic effect because they are much less efficacious than thiazide or loop diuretics. Acetazolamide inhibits carbonic anhydrase located intracellularly (cytoplasm). Acetazolamide decreases aqueous humour production and reduces intraocular pressure in patients with chronic open-angle glaucoma. Topical carbonic anhydrase inhibitors, such as Dorzolamide and Brinzolamide, have the advantage of not causing systemic effects. Acetazolamide can be used to prevent acute mountain sickness. It prevents the syndrome's characteristic symptoms: weakness, breathlessness, dizziness, nausea, and cerebral and pulmonary oedema. Acetazolamide can be administered orally or intravenously. It is approximately 90% protein bound and eliminated renally by both active tubular secretion and passive reabsorption. Adverse effects: Metabolic acidosis (mild), potassium depletion, renal stone formation, drowsiness, and paresthesia may occur. The drug should be avoided in patients with hepatic cirrhosis because it could decrease the excretion of Ammonium. Osmotic Diuretics Some simple, hydrophilic chemical substances filtered through the glomerulus, such as mannitol and urea, result in diuresis. Filtered substances that undergo little or no reabsorption will cause an increase in urinary output. The presence of these substances results in a higher osmolarity of the tubular fluid and prevents further water reabsorption, resulting in osmotic diuresis. Only a small amount of additional salt may also be excreted. Osmotic diuretics increase water excretion rather than Na+ excretion, but they do not help treat conditions where Na+ retention occurs. They are used to maintain urine flow following acute toxic ingestion of substances capable of producing acute renal failure. Osmotic diuretics are a mainstay of treatment for patients with increased intracranial pressure or acute renal failure due to shock, drug toxicities, and trauma. Maintaining urine flow preserves long-term kidney function and may save the patient from dialysis. [Note: Mannitol is not absorbed when given orally and should be given intravenously.] Adverse effects include extracellular water expansion, dehydration, and hypo- or hypernatremia. The expansion of extracellular water results because the presence of mannitol in the extracellular fluid extracts water from the cells, causing hyponatremia until diuresis occurs. Pharmacy College / Tikrit University 4 Asst. Prof Dr. Sinan Al-Mahmood