Diuretics

Published on 07/02/2015 by admin

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Diuretics

Thomas N. Spackman, MD, MS

Drugs that increase the excretion of sodium and water through the kidneys, termed diuretics, are classified on the basis of their site (Figure 99-1) or mechanism of action in the nephron. Diuretics are the recommended drugs for initial treatment of hypertension and are used in a variety of relative fluid-overload conditions, including heart failure, renal disease, and liver cirrhosis. Despite the lack of evidence that diuretic therapy prevents acute renal injury or improves outcome following injury or that diuretics reduce morbidity or mortality risk when used in chronic heart failure, they do provide symptomatic relief from fluid-overload syndromes.

Figure 99-1 Renal tubules showing the primary sites of diuretic action. (Netter illustration from www.netterimages.com. © Elsevier Inc. All rights reserved.)

Thiazide diuretics

Thiazides inhibit Na⁺ transport in the distal convoluted tubule and also in part of the cortical ascending limb of the loop of Henle. Water follows the salt that is not reabsorbed, causing the diuresis. Because the distal convoluted tubule accounts for only 5% or less of the total Na⁺ reabsorption, the diuretic effect is much weaker than that of loop diuretics. Because the Na⁺– Cl⁻ transporter is located on the luminal side of the tubule, thiazide diuretics are not effective at glomerular filtration rates of less than 30 mL/min.

Thiazides are rapidly and effectively absorbed from the gastrointestinal tract. They reach their peak action within a few hours and exert a diuretic effect for up to 12 h. Thiazides are most commonly used as initial treatment for hypertension. The early reduction in blood pressure is due to a reduction in blood volume. Chronic treatment results in blood pressure control through reduced vascular resistance despite return of fluid volumes to pretreatment levels.

The most common adverse effects of thiazides are dehydration and hypokalemia with metabolic alkalosis. Adverse effects unique to the use of thiazides include hypercalcemia and hyperuricemia from decreased renal excretion of Ca²⁺ and uric acid. Other adverse effects include hyperglycemia, hyponatremia, hypomagnesemia, fatigue, lethargy, hypersensitivity reactions, purpura, and dermatitis with photosensitivity.

Loop diuretics

Furosemide, bumetanide, torsemide, and ethacrynic acid are classified as loop diuretics because of their action in inhibiting the reabsorption of electrolytes in the thick ascending loop of Henle. They also exert a direct effect on electrolyte transport in the proximal tubule and cause renal cortical vasodilation and increased renal blood flow. The potent diuresis results in enhanced excretion of Na⁺, Cl⁻, K⁺, H⁺, Ca²⁺, Mg²⁺, , and . Cl⁻ excretion exceeds Na⁺ excretion. Excessive losses of K⁺, H⁻, , and Cl⁻, as well as rapid contraction of extracellular fluid volume, may result in metabolic alkalosis.

A temporary but substantial decrease in glomerular filtration rate, along with decreased pulmonary vascular resistance and increased peripheral venous capacitance, occurs after intravenous administration of furosemide in patients with congestive heart failure. This decreases left ventricular filling pressures, an acute action occurring before the onset of diuresis.

All four drugs are rapidly absorbed from the gastrointestinal tract and are highly protein bound. Their effectiveness depends on active secretion into the proximal tubule and, therefore, on renal plasma flow. After intravenous administration of furosemide, diuresis usually occurs within 5 min, reaches a maximum within 20 to 60 min, and persists for approximately 2 h.

Too vigorous a diuresis may induce an acute hypotensive episode. Potassium depletion in patients receiving nondepolarizing neuromuscular blocking agents can predispose these individuals to prolonged neuromuscular blockade. Hyperuricemia is common. Gastrointestinal disturbance (including bleeding), marrow depression, hepatic dysfunction, rashes, and decreased carbohydrate tolerance (furosemide may interfere with the hypoglycemic effect of insulin) also have been reported. There is one recent study suggesting that in hypotensive patients the use of furosemide decreases O₂ levels in the kidney to a critical level—presumably because O₂ supply to the kidney is inadequate to meet the increased metabolic rate caused by the furosemide.

The use of ethacrynic acid and bumetanide has been associated with hearing loss, and the use of ethacrynic acid is associated with a higher incidence of gastrointestinal disturbance, as compared with furosemide. Patients receiving chronic anticonvulsant therapy have a reduced diuretic response, and it is postulated that renal sensitivity to furosemide is diminished by these drugs. Allergic interstitial nephritis leading to reversible renal failure has been attributed to furosemide. Competition for binding sites on albumin may lead to an increased effect of drugs such as warfarin and clofibrate.

Osmotic diuretics

Mannitol, the prototype of the osmotic diuretics, is relatively inert and draws water from tissues to the intravascular space. It is excreted unchanged in the urine and produces a greater flow rate through the lumen of the nephron, resulting in reduced efficiency of Na⁺ reabsorption and significant diuresis. The osmotic diuresis can lead to volume depletion and electrolyte imbalances, especially of Na⁺, K⁺ and Mg²⁺. Oral absorption is unreliable. The intravenous dose range is 0.25 to 1.0 g/kg infused over 15 to 30 min.

In patients with elevated intracranial pressure, mannitol can decrease intracranial pressure within 30 min, with maximum effect within 1 to 2 h and duration of effect of approximately 6 h. Despite its role as a free radical scavenger and proven effectiveness at reducing intracranial pressure, mannitol has not been shown to improve outcomes in brain-injured patients with cerebral edema. Mannitol has also not been shown to be effective in prevention of acute renal failure, and some studies have shown a greater risk of renal injury from mannitol compared with saline alone in patients with moderate renal dysfunction.

Carbonic anhydrase inhibitors

Acetazolamide acts in the proximal tubule as a potent inhibitor of carbonic anhydrase, which reduces the supply of H⁺ ions in the proximal and distal tubules. More than 90% of filtered is reabsorbed in the proximal tubule via an exchange with H⁺. Because Na⁺ is normally reabsorbed in exchange for H⁺, more Na⁺ and remain within the tubules. A diuresis is produced by the Na⁺ excretion, and the urine is alkaline from the retained . Acetazolamide is a weak diuretic because its main action is in the proximal tubule, where only a small percentage of the total filtered Na⁺ is absorbed.

Acetazolamide can be administered orally or intravenously. Peak plasma levels occur within a few hours when taken orally. There is no appreciable metabolism, and elimination is usually complete in 24 h.

Acetazolamide is used to induce an alkaline urine in certain drug overdoses (e.g., salicylates). It is also used to treat glaucoma, acute altitude sickness, and significant metabolic alkalosis.

Adverse effects common to other diuretics are infrequent because acetazolamide is a weaker diuretic. Patients on chronic therapy for glaucoma can present with a metabolic acidosis. Large doses can lead to paresthesias and drowsiness.

K⁺-sparing diuretics

Triamterene and amiloride block the exchange between Na⁺ and both K⁺ and H⁺ in the late distal tubule and collecting duct. Excessive loss of K⁺ is prevented. Both of these relatively weak diuretics are more effective when used with a thiazide or loop diuretic, which act more proximally in the nephron.

Aldosterone antagonists

Spironolactone and eplerenone act on the distal nephron to inhibit Na⁺ and K⁺ excretion. They can cause clinically significant hyperkalemia. Eplerenone has greater specificity for the aldosterone receptor and a lower incidence of gynecomastia and impotence in men and menstrual irregularities in women. Both are weak diuretics and are used in low doses more for their beneficial antagonism of aldosterone in patients with heart failure. Spironolactone is frequently used in patients with edema secondary to liver failure.

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