Eplerenone - Drug Monograph

Introduction

Eplerenone is a selective aldosterone receptor antagonist (SARA) belonging to the class of medications known as mineralocorticoid receptor antagonists. It is structurally similar to spironolactone but demonstrates greater selectivity for the aldosterone receptor with reduced affinity for progesterone and androgen receptors. Eplerenone is primarily used in cardiovascular medicine for its protective effects on the heart and blood vessels.

Mechanism of Action

Eplerenone competitively binds to mineralocorticoid receptors in the kidneys, heart, blood vessels, and brain. By blocking aldosterone binding, it prevents aldosterone-mediated sodium reabsorption in the distal tubules and collecting ducts of the nephron. This action promotes natriuresis and diuresis while conserving potassium. Additionally, eplerenone reduces aldosterone-mediated cardiac and vascular fibrosis, inflammation, and endothelial dysfunction, providing cardioprotective and vasculoprotective effects beyond its diuretic properties.

Indications

• Post-myocardial infarction heart failure: To improve survival following acute MI in clinically stable patients with left ventricular dysfunction (LVEF ≤40%) and clinical evidence of heart failure
• Hypertension: Management of essential hypertension, typically as add-on therapy
• Chronic heart failure with reduced ejection fraction (NYHA Class II-IV): To reduce morbidity and mortality (off-label but evidence-supported use)

Dosage and Administration

• Heart failure post-MI: Initial dose 25 mg once daily; titrate to target dose of 50 mg once daily within 4 weeks as tolerated
• Hypertension: Initial dose 50 mg once daily; may increase to 50 mg twice daily if inadequate response after 4 weeks

• Renal impairment: Contraindicated when serum creatinine >2.0 mg/dL in men or >1.8 mg/dL in women, or eGFR <50 mL/min
• Hepatic impairment: No dosage adjustment necessary for mild to moderate impairment; use with caution in severe impairment
• Geriatric patients: Consider lower starting doses due to potential decreased renal function
• Pediatric patients: Safety and effectiveness not established

• May be taken with or without food
• Consistent daily timing recommended

Pharmacokinetics

• Absorption: Oral bioavailability approximately 69%; peak plasma concentrations reached in 1.5-2 hours
• Distribution: Volume of distribution ~43-90 L; plasma protein binding approximately 50%
• Metabolism: Primarily hepatic via CYP3A4; no active metabolites identified
• Elimination: Half-life 4-6 hours; excreted equally in urine (67%) and feces (32%) as metabolites

Contraindications

• Serum potassium >5.5 mEq/L at initiation
• Severe renal impairment (serum creatinine >2.0 mg/dL in men, >1.8 mg/dL in women or eGFR <50 mL/min)
• Concomitant use with strong CYP3A4 inhibitors (ketoconazole, itraconazole, clarithromycin, etc.)
• Known hypersensitivity to eplerenone or any component of the formulation

Warnings and Precautions

• Hyperkalemia: Risk increased in patients with renal impairment, diabetes, elderly patients, and those taking other potassium-raising drugs
• Renal function deterioration: Monitor renal function periodically, especially in susceptible populations
• Hypotension: May occur, particularly in volume-depleted patients
• Hormonal effects: Unlike spironolactone, minimal antiandrogenic effects, but monitor for possible endocrine abnormalities
• Pregnancy: Category B - use only if potential benefit justifies potential risk
• Lactation: Not recommended due to unknown excretion in human milk

Drug Interactions

• CYP3A4 inhibitors: Strong inhibitors (ketoconazole, itraconazole) significantly increase eplerenone exposure - contraindicated
• Potassium-sparing diuretics: Increased hyperkalemia risk (avoid combination)
• Potassium supplements/salt substitutes: Increased hyperkalemia risk (use with caution)
• ACE inhibitors/ARBs: Increased hyperkalemia risk (requires close monitoring)
• NSAIDs: May reduce antihypertensive effect and increase renal impairment risk
• Lithium: Increased lithium toxicity risk (monitor lithium levels)

Adverse Effects

• Hyperkalemia (3.4-5.5%)
• Dizziness (3.4%)
• Fatigue (2.4%)
• Diarrhea (2.1%)
• Cough (2.1%)

• Severe hyperkalemia (potentially life-threatening)
• Acute renal failure
• Hypotension
• Hypertriglyceridemia
• Elevated liver enzymes

Monitoring Parameters

• Serum potassium: Baseline, within first week, at 1 month, and periodically thereafter (more frequently with dose changes or in high-risk patients)
• Renal function: Serum creatinine and eGFR at baseline and periodically
• Blood pressure: Regular monitoring, especially during initiation and titration
• Electrolytes: Periodic assessment of sodium, magnesium
• Clinical status: Signs/symptoms of heart failure, fluid status, hypotension

Patient Education

• Take medication exactly as prescribed; do not double doses
• Regular blood tests are essential to monitor potassium levels and kidney function
• Report signs of hyperkalemia: muscle weakness, irregular heartbeat, nausea, numbness/tingling
• Avoid potassium supplements and salt substitutes unless specifically instructed by healthcare provider
• Inform all healthcare providers about eplerenone use, especially before new prescriptions
• Maintain consistent intake of potassium-rich foods (consult provider about dietary recommendations)
• Rise slowly from sitting/lying position to prevent dizziness
• Report any unusual side effects, including excessive fatigue, dizziness, or gastrointestinal symptoms

References

1. Pitt B, Remme W, Zannad F, et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med. 2003;348(14):1309-1321. 2. FDA Prescribing Information: Inspra (eplerenone). Pfizer Laboratories. 3. Williams B, MacDonald TM, Morant S, et al. Spironolactone versus placebo, bisoprolol, and doxazosin to determine the optimal treatment for drug-resistant hypertension (PATHWAY-2): a randomised, double-blind, crossover trial. Lancet. 2015;386(10008):2059-2068. 4. Zannad F, McMurray JJ, Krum H, et al. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med. 2011;364(1):11-21. 5. Kolkhof P, Nowack C, Eitner F. Nonsteroidal antagonists of the mineralocorticoid receptor. Curr Opin Nephrol Hypertens. 2015;24(5):417-424. 6. American College of Cardiology/American Heart Association Heart Failure Guidelines. Circulation. 2017;136(6):e137-e161.