Aldosterone Receptor Antagonists

• Spironolactone is indicated for patients who cannot be treated adequately with other antihypertensive drugs or for whom other agents are considered inappropriate; spironolactone is usually used in combination with other drugs.
• Eplerenone is FDA approved as monotherapy or combination therapy with efficacy reported as equivalent to that of an ACE inhibitor.[50362][50363]

• Three large randomized, controlled trials of ARAs in patients with heart failure and reduced LVEF – ie, RALES, EPHESUS, EMPHASIS-HF – have demonstrated significant reductions in mortality and morbidity.
• A comparison of the efficacy of spironolactone and eplerenone in heart failure based on RALES, EPHESUS, and EMPHASIS-HF is limited by differences in patient populations, baseline medications, and achieved dose.
• Based on these landmark trials, the American College of Cardiology Foundation/American Heart Association guidelines and the Heart Failure of Society guidelines recommend the use of ARAs in the following 3 situations:[46155][50360]
  • low-dose spironolactone or eplerenone in patients with LVEF <= 35% and New York Heart Association (NYHA) Class III-IV symptoms in absence of significant renal dysfunction or hyperkalemia
  • eplerenone in patients after acute myocardial infarction (AMI) with clinical heart failure signs and symptoms and LVEF < 40%.
  • eplerenone in patients with LVEF <= 30% (or if LVEF > 30 to 35, QRS > 130 ms), NYHA Class II symptoms and another high risk feature [eg, age > 55 years, heart failure hospitalization within the previous 6 months, or brain natriuretic peptide > 250 pg/mL, N-terminal prohormone of brain natriuretic peptide > 500 pg/mL (men) or >750 pg/mL (women)].

• Indications, renal function, and drug interactions are the main determinants of which agent will be selected for a particular patient.

Comparative Dosage of Aldosterone Receptor Antagonists

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.[50357][50358] Serious hyperkalemia (> 5.5 or 6 mmol/L) has been reported and can cause life-threatening cardiac arrhythmias.[46156] 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.[46156] 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.[50365] 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.[50359]

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.[66494][66495][66496]