Give an account of the types of drugs that can produce diuresis. Where possible, relate their efficacy or lack of efficacy, adverse effects and therapeutic use(s) to their respective mechanism(s) of action.

Outline:

·        High efficacy: loop diuretics.

·        Moderate efficacy: thiazides.

·        Low efficacy: potassium-sparing diuretics and osmotic diuretics.

Suggested answer:

Diuretics are compounds that increase the rate of urine formation, i.e. diuresis. Drugs that can produce diuresis act mostly on the renal tubules to alter the reabsorption of water and solutes. Each day the body produces 180 l of glomerular filtrate which is modified in its passage down the renal tubules to appear as 1.5 l of urine. Thus a 1% reduction in reabsorption of tubular fluid will more than double urine output. Diuresis may also be achieved by extrarenal mechanisms, by raising the cardiac output and increasing renal blood blow, e.g. with dobutamine and dopamine.

The maximum efficacy in removing salt and water that any drug can achieve is related to its site of action. The efficacy of the following drugs are ranked in ascending order in reference to their fractional excretion of filtered sodium: potassium-sparing diuretics, thiazides and loop diuretics.

The loop diuretics – frusemide, bumetanide, piretenide and ethacrynic acid act principally on the thick ascending limb of the loop of Henle by inhibiting active chloride ion transport, which thus prevents sodium ion reabsorption and lowers the osmotic gradient between cortex and medulla. The result is that large volumes of dilute urine are formed. As 25% of filtered sodium is reabsorbed at the loop of Henle, loop diuretics are the most efficacious diureics, causing 5-25% of filtered sodium to be excreted. They also have some renal vasodilator effect, reducing renal vascular resistance and increasing renal blood flow as well as decreasing peripheral vascular resistance which all leads to increased glomerular filtration rate and subsequently increased diuresis. Progressive increase in dose is matched by increasing diuresis. Indeed, they are so efficacious that overtreatment can readily dehydrate the patient. Loop diuretics remain effective at glomerular filtration rates below 10ml/min. They are readily absorbed from the gastrointestinal tract and greater than 90% bound to plasma proteins. They are rapidly secreted by the organic acid transport system at the proximal tubule.

The adverse effects of loop diuretics are a large part an extension of their therapeutic efficacy. Loop diuretics may produce profound diuresis resulting in fluid and electrolyte depletion. Fluid and electrolyte depletion are especially likely to occur when large doses are given and/or in patients with restricted sodium intake. Too vigorous diuresis, as evidenced by rapid and excessive weight loss, may induce orthostatic hypotension or acute hypotensive episodes, and the patient’s blood pressure should be closely monitored. Excessive dehydration is most likely to occur in geriatric patients and/or patients with chronic cardiac disease treated with prolonged sodium restriction or those receiving sympatholytic agents. The resultant hypovolemia may cause hemoconcentration, which could lead to circulatory collapse or thromboembolic episodes such as possibly fatal vascular thromboses and/or emboli. Pronounced reductions in plasma volume associated with rapid or excessive diuresis may also result in an abrupt fall in glomerular filtration rate and renal blood flow.

At the distal tubules, sodium is reabsorbed in exchange for potassium driven by a sodium-potassium pump at the basement membrane. Loop diuretics, by inhibiting the reabsorption of sodium at the loop of Henle cause more sodium to reach the distal tubule and so increase potassium excretion. Potassium depletion occurs frequently in patients with secondary hyperaldosteronism which may be associated with cirrhosis or nephrosis and is particularly important in cirrhotic, nephrotic, or digitalized patients. Hypokalemia and hypochloremia may result in metabolic alkalosis, especially in patients with other losses of potassium and chloride due to vomiting, diarrhea, GI drainage, excessive sweating, paracentesis, or potassium-losing renal diseases. In patients with cor pulmonale, alkalosis may cause compensatory respiratory depression. Loop diuretics may produce hyperglycemia and glycosuria, possibly as a result of hypokalemia, in patients with predisposition to diabetes. Loop diuretics also increase calcium and magnesium excretion. Hyperuricemia may result from frusemide administration and rarely gout has been precipitated; patients with a history of gout or elevated serum uric acid concentrations should be observed closely during therapy.

Other adverse effects of loop diuretics not found to have any correlation with its mechanism of action are as follows. Tinnitus, reversible or permanent hearing impairment, or reversible deafness have occurred, usually following rapid IV or IM administration of frusemide in doses greatly exceeding the usual therapeutic dose of 20—40 mg. Otic effects are most likely to occur in patients with severe impairment of renal function and/or in patients receiving other ototoxic drugs (e.g., aminoglycosides). Adverse GI effects include nausea, anorexia, oral and gastric irritation, vomiting, cramping, diarrhea, and constipation. Anemia, hemolytic anemia, leukopenia, neutropenia, and thrombocytopenia have occurred in patients receiving furosemide. Adverse dermatologic and/or hypersensitivity reactions include purpura, photosensitivity, rash, urticaria, pruritus, exfoliative dermatitis, erythema multiforme, interstitial nephritis, and necrotizing angiitis (vasculitis, cutaneous vasculitis).

Loop diuretics are used in the management of edema associated with congestive heart failure, nephrotic syndrome, and hepatic cirrhosis. IV frusemide also may be used as an adjunct in the treatment of acute pulmonary edema. Diuretics play a key role in the management of congestive heart failure because they produce symptomatic benefits more rapidly than any other drugs, relieving pulmonary and peripheral edema within hours or days compared with weeks or months for cardiac glycosides, ACE inhibitors, or beta-blockers. Loop diuretics may be used orally for the management of hypertension, especially when complicated by congestive heart failure or renal disease. Frusemide has been used as monotherapy or in combination with other classes of antihypertensive agents. Frusemide has been used IV along or with 0.9% sodium chloride injection or sodium sulfate to increase renal excretion of calcium in patients with hypercalcemia.

The thiazides – chlorothiazide, hydrochlorothiazide, benzthiazide, bendrofluazide, cyclopenthiazide and the related chlorthalidone, xipamide, clopamide and metolazone act principally at the cortical diluting segment of the ascending limb, preventing sodium reabsorption by inhibiting a sodium-chloride co-transporter. This causes 5 – 10% of filtered sodium load to be excreted. As the distal tubule is responsible for diluting the urine before it enters the collecting tubules, thiazides limit the ability of the kidneys to produce a dilute urine. Increasing the dose beyond a small range produces no added diuresis. Such drugs tend to be ineffective once the glomerular filtration rate has fallen below 20 ml/min. Therefore, thiazides have a lower efficacy than loop diuretics. Thiazides lower blood pressure due to reduction in intravascular volume and peripheral vascular resistance. In chronic use they diminish the responsiveness of vascular smooth muscle to norepinephrine. Thiazides are generally well absorbed from the gut and most begin to act within an hour.

Like loop diuretics, the most frequent adverse effects of the thiazides are a result of their diuretic action which can lead to electrolyte imbalance, hypokalaemia, hyponatraemia and hypochloraemic alkalosis. Rashes, thrombocytopenia and agranulocytosis occur. Treatment with thiazides causes an increase in total serum cholesterol. Other less common side effects are anorexia, decreased sexual function, orthostatic hypotension, allergic dermatitis, gout, stomach upset, jaundice and pancreatitis.

Thiazides are used in the management of edema associated with congestive heart failure. They are particularly useful in mild cardiac failure, where the lesser diuretic effect may be more acceptable to patients. In edema secondary to nephrotic syndrome, thiazides may be useful if the patient fails to respond to corticosteroid therapy. Edema associated with pregnancy generally responds well to thiazides except when caused by renal disease. Thiazide diuretics are used in the management of hypertension. The drugs have been used as monotherapy or in combination with other classes of antihypertensive agents. Thiazide diuretics often are used for the initial management of all degrees of hypertension, with the exception of malignant hypertension. Thiazides have been widely used in the treatment of diabetes insipidus. The drugs are effective in both the neurohypophyseal and nephrogenic forms of the disease, decreasing urine volume by up to 50%. Thiazide diuretics have been used with success in the prophylaxis of renal calculus formation associated with hypercalciuria and in the treatment of the electrolyte disturbances associated with renal tubular acidosis.

Potassium-sparing diuretics – triamterene, amiloride and spironolactone acts on the distal tubule causing 5% of filtered sodium to be excreted which is less than the excreted sodium load by the loop and thiazide diuretics and hence, these drugs are low efficacy diuretics. In the distal tubule, sodium ions are exchanged for potassium and hydrogen ions. In part the mechanism of this exchange is aldosterone-dependent and may be inhibited by the competitive minerolocorticoid receptor antagonist spironolactone; an aldosterone-independent mechanism also operates and is inhibited by triamterene and amiloride.

The most serious adverse effect of spironolactone therapy is hyperkalemia, which occurs most frequently in patients receiving potassium supplements concomitantly and in patients with renal insufficiency. Hyperkalemia can cause cardiac irregularities which may be fatal. Dehydration and hyponatremia manifested by a low serum sodium concentration, dry mouth, thirst, drowsiness, and lethargy may occur during spironolactone therapy, especially when spironolactone is used concomitantly with other diuretics. Anorexia, nausea, vomiting, diarrhea, abdominal cramping, gastritis, gastric bleeding, and ulceration have occurred during spironolactone therapy as well as headache, drowsiness, lethargy, ataxia, mental confusion, and fever. Adverse effects related to the steroid-like structure of spironolactone include painful gynecomastia, decreased libido, and relative impotence in males, and menstrual irregularities, amenorrhea, postmenopausal bleeding, and breast soreness in females. Gynecomastia appears to be related to both dosage and duration of therapy and is usually reversible following discontinuance of spironolactone.

Spironolactone is used in the management of edema associated with excessive aldosterone excretion such as idiopathic edema and edema accompanying cirrhosis of the liver, nephrotic syndrome, and congestive heart failure, usually in conjunction with other diuretics. In addition, spironolactone is a useful adjunct to thiazide therapy when diuresis is inadequate or reduction of potassium excretion is necessary. It is also employed in hypertension, congestive heart failure and hypokalaemia when oral potassium supplements or other measures are considered inappropriate or inadequate. Spironolactone has been used effectively in the treatment of hirsutism in women with polycystic ovary syndrome or idiopathic hirsutism.

Both amiloride and triamterene increases sodium loss and reduces potassium loss by a direct action on ion transport in the distal tubule. Amiloride and triamterene are used for moderate hypertension or edema. They are used for its potassium-sparing effect in the treatment or prevention of hypokalemia induced by thiazide or other kaliuretic diuretics in patients with congestive heart failure or hypertension. They are used for the management of edema including edema associated with congestive heart failure, hepatic cirrhosis, and hyperaldosteronism. In hypertensive patients, they are used concomitantly with a thiazide diuretic mainly to prevent or treat diuretic-induced hypokalemia.

Osmotic diuretics are small molecular weight substances that are filtered by the glomerulus but are not reabsorbed by the renal tubule, and thus increase the osmolarity of the tubular fluid. Their principal site of action is the proximal tubule where they prevent the reabsorption of water and sodium. The result is that urine volume increases according to the load of osmotic diuretic. Mannitol, a polyhydric alcohol, is most commonly used; it is given i.v. It is used for rapid reduction of intracranail or intraocular pressure, and to maintain urine flow to prevent renal tubular necrosis. The most severe adverse effects encountered during mannitol therapy are fluid and electrolyte imbalance. Accumulation of mannitol caused by inadequate urinary output or to rapid administration of large doses may result in overexpansion of extracellular fluid. The resulting circulatory overload may result in pulmonary edema, signs and symptoms of water intoxication, and fulminating congestive heart failure, especially in patients with diminished cardiac reserve. Other adverse effects that have occurred during mannitol therapy include acidosis, dryness of the mouth, thirst, urinary retention, headache, blurred vision, uricosuria, nausea, vomiting, rhinitis, arm pain, backache, thrombophlebitis, chills, dizziness, and urticaria.