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 heart failure, usually in conjunction with other diuretics. Careful etiologic diagnosis should precede the use of any diuretic. Although thiazides and chlorthalidone are more rapidly acting and more effective diuretics, spironolactone does not cause potassium depletion or affect glucose metabolism or uric acid excretion as may result from thiazide or chlorthalidone therapy. In addition, spironolactone is a useful adjunct to thiazide therapy when diuresis is inadequate or reduction of potassium excretion is necessary. When used in conjunction with a thiazide diuretic in the treatment of edema associated with cirrhosis of the liver, spironolactone should be given for 2-3 days prior to administration of the thiazide diuretic in order to prevent potassium depletion and precipitation of hepatic coma.
Spironolactone is used in the management of hypertension, usually in conjunction with other diuretics or hypotensive agents. Used alone, spironolactone produces a modest lowering of blood pressure in most patients with hypertension, and blood pressure returns to within normal limits in about 20% of patients. Because of established clinical benefits (e.g., reductions in overall mortality and in adverse cardiovascular, cerebrovascular, and renal outcomes), angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, calcium-channel blockers, and thiazide diuretics generally are considered the preferred drugs for the initial management of hypertension in adults; however, aldosterone antagonists (e.g., spironolactone, eplerenone) may be considered as add-on therapy if goal blood pressure cannot be achieved with the recommended drugs. Aldosterone antagonists may be particularly useful in selected patients with heart failure or following myocardial infarction; the American College of Cardiology Foundation (ACCF) and American Heart Association (AHA) recommend the addition of an aldosterone antagonist (i.e., spironolactone or eplerenone) in selected patients with heart failure or following myocardial infarction when left ventricular ejection fraction (LVEF) is reduced and the patient is already receiving an agent to inhibit the renin-angiotensin system (e.g., ACE inhibitor, angiotensin II receptor antagonist) and a β-adrenergic blocking agent (β-blocker). For information on antihypertensive therapy for patients with heart failure or following myocardial infarction, see and also
Spironolactone may be useful to decrease the potassium loss caused by other diuretics and potentiate the hypotensive effects of those agents or other more potent hypotensive agents. In addition, the drug may be useful in hypertensive patients with gout or diabetes mellitus that may be aggravated by thiazide diuretics. Potassium-sparing diuretics should be avoided in patients with renal insufficiency and in those with hyperkalemia who have serum potassium concentrations exceeding 5 mEq/L while not receiving drug therapy.
For additional information on the role of aldosterone antagonists in the management of hypertension in patients with underlying cardiovascular risk factors and information on overall principles and expert recommendations for treatment of hypertension,
Spironolactone is used in the management of severe heart failure (New York Heart Association [NYHA] functional class III-IV) in conjunction with standard therapy for heart failure to increase survival and reduce heart failure-related hospitalizations.
Current guidelines for the management of heart failure in adults generally recommend a combination of drug therapies to reduce morbidity and mortality, including neurohormonal antagonists (e.g., ACE inhibitors, angiotensin II receptor antagonists, angiotensin receptor-neprilysin inhibitors [ARNIs], β-blockers, aldosterone receptor antagonists) that inhibit the detrimental compensatory mechanisms in heart failure. Additional agents (e.g., cardiac glycosides, diuretics, sinoatrial modulators [i.e., ivabradine]) added to a heart failure treatment regimen in selected patients have been associated with symptomatic improvement and/or reduction in heart failure-related hospitalizations. For additional information on the management of heart failure, , , and . ACCF and AHA recommend the addition of an aldosterone antagonist (i.e., spironolactone or eplerenone) in selected patients with heart failure and reduced LVEF who are already receiving a β-blocker and an agent to inhibit the renin-angiotensin-aldosterone (RAA) system (e.g., ACE inhibitor, angiotensin II receptor antagonist, ARNI); careful patient selection is required to minimize the risk of hyperkalemia and renal insufficiency.
(See Cautions: Electrolyte and Metabolic Effects.)
Aldosterone receptor antagonists are also recommended, unless contraindicated, in conjunction with other heart failure therapy to reduce morbidity and mortality following acute myocardial infarction in patients with reduced LVEF who develop symptoms of heart failure or who have a history of diabetes mellitus. ACCF and AHA state that there are limited data to support or refute whether spironolactone and eplerenone are interchangeable. The perceived difference between eplerenone and spironolactone is attributed to the selectivity of aldosterone receptor antagonism and not the effectiveness of mineralocorticoid-blocking activity.
The concomitant use of spironolactone and an ACE inhibitor had been considered relatively contraindicated because of the potential for developing severe hyperkalemia. In addition, it was believed that ACE inhibitors would inhibit formation of aldosterone, a hormone associated with the pathophysiology of heart failure, by suppressing the RAA system. However, results of several studies have indicated that ACE inhibitors only transiently inhibit the production of aldosterone, and the addition of spironolactone to ACE inhibitor therapy may augment the suppressive effect of ACE inhibitors on aldosterone.
(See Pharmacology: Cardiovascular Effects.)
Results of a randomized, multicenter, controlled study (Randomized Aldactone Evaluation Study [RALES]) in 1663 patients with moderate or severe heart failure (NYHA functional class III or IV) and LVEF of 35% or less indicate that addition of low-dose (25-50 mg daily) spironolactone to standard therapy (e.g., an ACE inhibitor and a loop diuretic with or without a cardiac glycoside was associated with decreases in overall mortality and hospitalization (for worsening heart failure) rates of approximately 30 and 35%, respectively, compared with standard therapy and placebo. The reduction in mortality and hospitalization rates was observed within 2-3 months of initiation of combined therapy and continued throughout the study (mean follow-up: 24 months). The combined therapy also was associated with an improvement in NYHA functional class in about 41% of patients. Because interim analysis of this study after a mean follow-up of 24 months revealed that morbidity and death were reduced significantly in patients receiving spironolactone concomitantly with standard therapy compared with those receiving standard therapy and placebo, the study was discontinued.
Spironolactone also is used for the management of edema and sodium retention in patients with heart failure who do not respond adequately to or are intolerant of other therapeutic measures.
(See Uses: Edema.)
Spironolactone is used in the diagnosis of primary hyperaldosteronism; however, test results may be equivocal and more complete diagnostic studies are often required.
Spironolactone is also used for the short-term preoperative treatment of primary hyperaldosteronism and for long-term maintenance therapy in patients with discrete aldosterone-producing adrenal adenomas who cannot undergo adrenalectomy or who decline surgery. The drug is also used for long-term maintenance therapy for patients with bilateral micronodular or macronodular adrenal hyperplasia (idiopathic hyperaldosteronism).
Spironolactone is used in the treatment of hypokalemia when oral potassium supplements or other measures are considered inappropriate or inadequate. The drug is also used for the prophylaxis of hypokalemia in patients taking cardiac glycosides when other measures are considered inappropriate or inadequate.
Spironolactone is used for its antiandrogenic effects in combination with testolactone in the management of certain forms of gonadotropin releasing hormone (GnRH)-independent (peripheral) precocious puberty (e.g., familial male precocious puberty [ testotoxicosis]). Such therapy has effectively controlled acne, spontaneous erections, and aggressive behavior and slowed accelerated growth and skeletal maturation, at least in the short term (e.g., 2 years), in boys with familial precocious puberty. Neither drug alone effectively controls pubertal characteristics nor the rate of growth and skeletal maturation in boys with this condition, although some benefit (e.g., on height velocity) with testolactone alone may be apparent. Testolactone generally prevents the gynecomastia that may be associated with spironolactone. Testolactone also has been used in combination with other antiandrogens (e.g., flutamide) in the management of this condition, but experience is less extensive. While spironolactone currently is the most widely used antiandrogenic drug in familial male precocious puberty, alternative antiandrogenic drugs (e.g., flutamide) that avoid some of the potentially serious adverse effects of spironolactone therapy (e.g., mineralocorticoid-antagonist effects) are being studied for this condition and congenital adrenal hyperplasia. However, concerns about potential hepatotoxic effects of flutamide may limit the use of this drug in such precocious puberty. A gradual escape from the beneficial effects of combined therapy with spironolactone and testolactone may occur during long-term therapy because of the development of secondary GnRH-dependent precocity or pubertal increases in gonadotropins. In such cases, a GnRH analog has been added to the regimen to restore effective control of puberty progression. Additional study and experience are needed to elucidate further the optimum regimens for the management of these forms of precocious puberty and the long-term effects of such therapy, and such patients should be managed in consultation with experts in the diagnosis and treatment of these conditions. Combinations of testolactone with flutamide or with spironolactone also have been studied as a component in the complex regimen of therapy for boys and girls with congenital adrenal hyperplasia caused by steroid 21-hydroxylase or 11-hydroxylase deficiency; the rationale for the addition of such therapy to the therapeutic regimen was similar to that for familial male precocious puberty (i.e., to control androgenic effects and accelerated growth and skeletal maturation).
Spironolactone has been used effectively in the treatment of hirsutism in women with polycystic ovary syndrome or idiopathic hirsutism. In the treatment of hirsutism, spironolactone appears to exert its therapeutic effects by interfering with ovarian androgen secretion and peripheral androgen activity.
Spironolactone has also been used as an adjunct in the treatment of myasthenia gravis and familial periodic paralysis.