ALDOSTERONE RECEPTOR ANTAGONISTS
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Aldosterone receptor antagonists (ARA)s, also called mineralocorticoid receptor antagonists, competitively inhibit aldosterone at the mineralocorticoid receptor, thus reducing the adverse effects of elevated plasma aldosterone concentrations, including the cardiovascular effects of elevated blood pressure, left ventricular hypertrophy, and myocardial fibrosis in heart failure. The mechanism of action of ARAs in heart failure and other indications is complex and appears to be independent of diuretic and potassium-sparing effects. 
Spironolactone, a nonselective ARA with similar structure to progesterone, is associated with dose-dependent progestogenic and antiandrogenic adverse effects, including gynecomastia, impotence, and menstrual irregularities. Eplerenone was developed to avoid these adverse effects, possessing a 100- to 1000-fold lower affinity for androgen, progesterone, and glucocorticoid receptors than spironolactone. While in vitro studies show that spironolactone has greater affinity than eplerenone at the aldosterone receptor, eplerenone inhibits aldosterone binding in vivo at a lower dosage than spironolactone.
Spironolactone has a shorter half-life than eplerenone and has active metabolites (including canrenone) that prolong its activity. Eplerenone undergoes rapid metabolism by the liver to inactive metabolites. Elimination of both agents occurs predominately via the kidneys; however, a higher percentage of spironolactone than eplerenone is eliminated through the feces. Elimination properties of spironolactone and eplerenone have an important role in determining appropriate doses in patients with renal and/or hepatic dysfunction.
Comparative Dosage of Aldosterone Receptor Antagonists
Daily Dose (mg)
Daily dose (mg)
Aldosterone Receptor Antagonist Comparative Efficacy Trials
Randomized, double-blind, placebo-controlled. Mean follow-up 24 months
1663 patients with NYHA Class III/IV (ischemic 54-55%)
Spironolactone 25 mg daily versus placebo
Baseline ACE inhibitor or angiotensin receptor blocker: 94-95%, beta-blocker: 10-11%
35% spironolactone vs
RR 0.70 (95% CI 0.60-0.82), p<0.001
CV death or CV hospitalization:
RR 0.68 (95% CI, 0.59-0.78), p<0.001
Serious hyperkalemia (=6 mmol/L):
2% spironolactone vs
1% placebo (p=0 .42)
Blockade of aldosterone receptors by spironolactone, in addition to standard therapy, substantially reduces the risk of both morbidity and death among patients with severe HF
Randomized, double-blind, placebo-controlled. Mean follow-up 16 months
6632 patients with recent (3-14 days) AMI, LVEF = 40, and HF symptoms
Eplerenone 25 mg daily initially, titrated to maximum of 50 mg per day, versus placebo
Baseline ACE inhibitor or angiotensin receptor blocker: 86-87%, beta-blocker: 75
14.4% eplerenone vs
RR 0.85 (95% CI, 0.75-0.96), p=0.008
26.7% eplerenone vs
RR 0.87 (95% CI 0.79-0.95), p=0.002
5.5% eplerenone vs
3.9% placebo (p=0 .02)
Randomized, double-blind, placebo-controlled. Median follow-up 21 months
2737 patients with NYHA Class II (ischemic 68-70%)
Baseline ACE inhibitor or angiotensin receptor blocker: 93-94%, beta-blocker: 87%
12.5% eplerenone vs
RR 0.76 (95% CI 0.62-0.93), p=0.008
CV death or HF hospitalization:
18.3% eplerenone vs
HR 0.63 (95% CI, 0.54-0.74), p<0.001
Serious hyperkalemia (>6 mmol/L):
2.5% eplerenone vs
1.9% placebo (p=0 .29)
Adjusted mean change in baseline to final visit for seated
and standing diastolic blood pressure (DBP) measured at trough
-4.1 mmHg eplerenone 50 mg daily vs -1.5 mmHg placebo
-5.9 mmHg eplerenone 100 mg daily vs -1.5 mmHg placebo
-8.4 mmHg eplerenone 400 mg daily vs -1.5 mmHg placebo (p< 0.05)
-4.8 mmHg eplerenone 25 mg twice daily vs -1.5 mmHg placebo
-7 mmHg eplerenone 50 mg twice daily vs -1.5 mmHg placebo (p< 0.05)
-12.1 mmHg eplerenone 200 mg twice daily vs -1.5 mmHg placebo (p< 0.05)
-9.6 mmHg spironolactone 50 mg twice daily vs -1.5 mmHg placebo (p< 0.05)
Spironolactone and eplerenone are associated with dose-related increases in serum potassium concentrations by blocking potassium excretion in the renal distal tubule and collecting ducts. Serious hyperkalemia (> 5.5 or 6 mmol/L) has been reported and can cause life-threatening cardiac arrhythmias. If hyperkalemia occurs, ARAs should be discontinued immediately and specific measures taken to reduce serum potassium concentrations. Subsequently, a reduction in the dose of the ARA may be warranted.
Spironolactone may cause gynecomastia, libido decrease, and impotence (erectile dysfunction) in men. Women taking spironolactone may experience menstrual irregularity, postmenopausal bleeding, breast tenderness or mastalgia, hirsutism, deepened voice, and amenorrhea. These effects are usually reversible following discontinuation of therapy. Endocrine-related effects may also be seen with eplerenone, but they occur at a much lower incidence.
Hepatic enzymes (i.e. ALT, GGT) increased in a dose-related manner with eplerenone. In clinical trials at 50 mg/day, on average the serum alanine aminotransferase (ALT) increased 0.8 Units/L and gamma glutamyl transpeptidase (GGT) increased 3.1 Units/L.
Eplerenone appears to decrease the serum sodium concentration in a dose-dependent manner. Spironolactone alone does not usually cause hyponatremia, but it can develop in patients taking spironolactone with other diuretic therapy.
Use of ARAs with other drugs that block potassium excretion or raise serum potassium concentrations should be avoided with the exception of ACE inhibitors or angiotensin receptor blockers, which should be used with caution. Any substance containing potassium salts should also be avoided because of increased risk of hyperkalemia, especially in the presence of renal impairment. In patients with hypertension, administration of eplerenone with potassium supplements or potassium-sparing diuretics (e.g., amiloride, spironolactone, or triamterene) is contraindicated due to the risk of hyperkalemia.
Eplerenone is a substrate of the cytochrome P450 3A4 isoenzyme and is contraindicated for use by patients taking strong 3A4 inhibitors. In patients taking eplerenone for hypertension who are taking a moderate to weak inhibitor of CYP3A4, reduce the starting dose to 25 mg once daily. For all patients, check serum potassium and serum creatinine in 3-7 days after starting a moderate 3A4 inhibitor.
Spironolactone increases the half-life of digoxin. A reduction in the dose of digoxin may be needed.
Spironolactone and eplerenone can have additive hypotensive effects when administered with other antihypertensive agents.
Both spironolactone and eplerenone can cause hyperkalemia and are contraindicated for use in patients with hyperkalemia. Caution is advised in those patients at risk for hyperkalemia, including those with underlying renal dysfunction, heart failure or diabetes. Additionally, elderly patients are also at increased risk.
Aldosterone receptor antagonists are contraindicated for use by patients with various degrees of renal impairment as renal impairment increases the risk of hyperkalemia. Specifically, spironolactone is contraindicated in patients with anuria, acute renal insufficiency, or significant impairment of renal excretory function. Eplerenone is contraindicated in patients with a CrCl 30 mL/minute or less, except when used for hypertension. In hypertension, eplerenone is contraindicated in patients with a CrCl less than 50 mL/minute, a serum creatinine greater than 2 mg/dL (males) or greater than 1.8 mg/dL (females), if the patient has type 2 diabetes mellitus with microalbuminuria, or if the patient is taking potassium supplements or potassium-sparing diuretics.
Spironolactone has been shown to be a tumorigen in chronic toxicity studies in rats, and breast cancer has been reported in patients taking spironolactone, although a cause and effect relationship has not been established. Avoid unnecessary spironolactone use, and only use it for FDA-approved indications.
The Endocrine Society guidelines on the diagnosis and treatment of primary adrenal insufficiency state that use of aldosterone antagonists are contraindicated in patients with adrenal insufficiency (Addison's disease). Hyperkalemia stimulates aldosterone production and aldosterone, in turn, enhances sodium and water reabsorption in exchange for potassium excretion in the distal tubule and collecting duct of the kidney. In Addison's disease, aldosterone deficiency results in hyponatremia, hypovolemia, hypotension and hyperkalemia. Thus, spironolactone therapy will exacerbate the hyponatremia, hypovolemia, hypotension and hyperkalemia seen in patients with adrenal insufficiency and will worsen the signs and symptoms of the disease.
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