How does Eplerenone (generic name) work?

Mechanism of Action of Eplerenone

Eplerenone works by selectively binding to mineralocorticoid receptors and blocking the binding of aldosterone, thereby inhibiting the harmful effects of aldosterone on the cardiovascular system. 1

Primary Mechanism

Eplerenone is a selective aldosterone receptor antagonist (also known as mineralocorticoid receptor antagonist or MRA) with the following mechanism:

• Receptor Binding: Selectively binds to mineralocorticoid receptors in both epithelial tissues (e.g., kidney) and non-epithelial tissues (e.g., heart, blood vessels, and brain) 1
• Aldosterone Blockade: Prevents aldosterone from binding to these receptors, blocking its physiological effects 1
• Selectivity: Unlike spironolactone, eplerenone selectively binds to human mineralocorticoid receptors with minimal binding to glucocorticoid, progesterone, and androgen receptors 1

Physiological Effects

When eplerenone blocks aldosterone receptors, it produces several important physiological effects:

• Reduced Sodium Reabsorption: Blocks aldosterone-induced sodium reabsorption in the kidney 1
• Increased Renin and Aldosterone Levels: Produces sustained increases in plasma renin and serum aldosterone due to inhibition of the negative feedback loop, but these increased levels cannot overcome eplerenone's receptor blockade 1
• Reduced Myocardial Fibrosis: Prevents aldosterone-mediated myocardial fibrosis, which is important in heart failure 2
• Blood Pressure Reduction: Lowers systolic blood pressure by approximately 9.21 mmHg and diastolic blood pressure by 4.18 mmHg compared to placebo 3

Clinical Applications

Eplerenone has demonstrated efficacy in several clinical conditions:

• Heart Failure: In the EPHESUS trial, eplerenone significantly improved mortality by approximately 15% in patients with left ventricular ejection fraction <40% after myocardial infarction 2
• Chronic Heart Failure: In the EMPHASIS trial, eplerenone reduced the primary endpoint of cardiovascular death or heart failure hospitalization by 37% in patients with mild symptoms (NYHA class II) 2
• Hypertension: Effectively lowers blood pressure in patients with essential hypertension 3
• Resistant Hypertension: Particularly effective in patients with resistant hypertension, especially those with low renin status or salt sensitivity 2

Pharmacokinetics

• Absorption: Reaches peak plasma concentrations in 1.5-2 hours; not affected by food; absolute bioavailability of 69% 1
• Metabolism: Primarily metabolized via CYP3A4 with no active metabolites identified 1
• Elimination: Half-life of 3-6 hours; steady state reached within 2 days 1
• Excretion: Less than 5% recovered as unchanged drug in urine and feces 1

Advantages Over Spironolactone

• Reduced Hormonal Side Effects: Due to its selectivity for mineralocorticoid receptors, eplerenone causes fewer hormonal side effects such as gynecomastia, breast pain, and menstrual irregularities compared to spironolactone 4, 5
• Better Tolerated: Particularly beneficial for male patients who may develop gynecomastia with spironolactone 4

Important Considerations and Monitoring

• Hyperkalemia Risk: Like other aldosterone antagonists, eplerenone can cause hyperkalemia, requiring monitoring of serum potassium and renal function 2
• Dosing: Typically started at 25-50 mg daily with maintenance doses of 50-100 mg daily 4
• Contraindications: Should be avoided in patients with severe renal impairment or high baseline potassium levels 1
• Drug Interactions: Inhibitors of CYP3A4 (e.g., ketoconazole, saquinavir) increase blood levels of eplerenone and should be avoided 1

Eplerenone represents an important therapeutic option for patients with heart failure and hypertension, offering the benefits of aldosterone blockade with fewer hormonal side effects than spironolactone.