Eplerenone

Mechanism

Pharmacological Group

Selective non-steroidal antagonist of the mineralocorticoid receptor.

Mechanism of Action

It exerts a highly selective competitive antagonism on the Mineralocorticoid Receptor (MR). Unlike spironolactone, its chemical structure derived from 9,11-epoxyspironolactone gives it an extremely low affinity for progesterone and androgen receptors (its affinity for MR is lower than that of spironolactone, but its selectivity is substantially greater). As a consequence, it blocks the biological effects of aldosterone in TCC without inducing unwanted hormonal side effects.

Pharmacokinetics

Key Pharmacokinetics

• Bioavailability: 69%, not influenced by food.
• Protein binding: Low-moderate (~50% bound to alpha-1 acid glycoprotein).
• Metabolism: Metabolized mainly in the liver via the cytochrome CYP3A4 pathway to inactive metabolites.
• Excretion: 67% eliminated in urine (none as unchanged drug); 32% in feces.
• Half-life: 4 to 6 hours.

Indicators and dose

Clinical Indications

• Heart failure post-acute myocardial infarction (with LV dysfunction and symptomatic HF): Reduces the risk of cardiovascular mortality and hospitalization (EMPHASIS-HF and EPHESUS study).
• Treatment of essential arterial hypertension (frequently as adjuvant therapy).

Dosage and Settings

• Heart Failure: Start with 25 mg orally once daily, titrating progressively until reaching the target dose of 50 mg/day over the course of 4 weeks (as long as serum potassium remains < 5.0 mEq/L).
• Kidney adjustment:
  - CrCl 30-50 mL/min: Start with 25 mg every other day.
  - CrCl < 30 mL/min: Contraindicated.

Security

Contraindications

• Absolute: Hyperkalemia (K+ > 5.0 mEq/L); CrCl < 30 mL/min; severe liver failure (Child-Pugh Class C); concomitant use with strong CYP3A4 inhibitors (such as ketoconazole, itraconazole, ritonavir, clarithromycin).

Adverse Effects (ADR)

• Very common: Hyperkalemia (incidence rates of clinically relevant hyperkalemia around 5-10%).
• Common: Dizziness, fatigue, cough, mild diarrhea, transient elevation of serum creatinine.
• Safety differential: The incidence of gynecomastia, mastodynia and menstrual irregularities is equivalent to placebo, offering a safe alternative for patients who do not tolerate spironolactone due to hormonal effects.

Interactions

• Potent CYP3A4 inhibitors: Increase the area under the curve (AUC) of eplerenone by 5 to 6 times, critically increasing the risk of lethal hyperkalemia. Their association is strictly contraindicated.
• Potassium and ACEI/ARB supplements: Dangerous hyperkalemic synergy.

Pregnancy and Breastfeeding

Category B. There is not enough data available in pregnant women. It is preferred to avoid its prescription unless there is a clear clinical indication that cannot be treated in any other way.