Eplerenone

Eplerenone is a potassium-sparing diuretic that selectively blocks the mineralocorticoid (aldosterone) receptor in the distal nephron (cortical collecting duct), preventing aldosterone-mediated sodium reabsorption and potassium/hydrogen secretion. This results in natriuresis with potassium retention, making it useful in conditions of hyperaldosteronism and fluid overload.

Clinical uses include: post-myocardial infarction heart failure with reduced ejection fraction (reduces mortality per EPHESUS trial), chronic heart failure (EMPHASIS-HF trial showed benefit in NYHA class II patients), resistant hypertension, and primary hyperaldosteronism (Conn syndrome) as an alternative to spironolactone.

Key pharmacologic distinction from spironolactone: eplerenone is more selective for the mineralocorticoid receptor and has much lower affinity for androgen and progesterone receptors, significantly reducing the incidence of gynecomastia, breast tenderness, and menstrual irregularities seen with spironolactone. However, eplerenone is generally more expensive and has a shorter half-life, often requiring twice-daily dosing.

Major adverse effect: hyperkalemia, especially when combined with ACE inhibitors, ARBs, or other potassium-sparing agents, or in patients with renal impairment. Regular monitoring of serum potassium and renal function is essential. Contraindicated in severe renal impairment (CrCl <30 mL/min), hyperkalemia, and concurrent strong CYP3A4 inhibitors (eplerenone is metabolized by CYP3A4, so drugs like ketoconazole, ritonavir can increase its levels).

Mechanistically important for boards: understanding the aldosterone-sensitive principal cells, the renin-angiotensin-aldosterone system (RAAS), and the distinction between mineralocorticoid receptor antagonists (K+-sparing diuretics) versus other diuretic classes (loop, thiazide) is high-yield.