Eplerenone

Eplerenone is a selective aldosterone receptor antagonist (SARA) that belongs to the class of potassium-sparing diuretics. It is structurally and pharmacologically related to spironolactone but demonstrates a higher specificity for mineralocorticoid receptors, which reduces its affinity for androgen and progesterone receptors. This selectivity significantly lowers the incidence of endocrine-related side effects such as gynecomastia, impotence, and menstrual irregularities that are commonly seen with spironolactone. Eplerenone is primarily indicated for conditions associated with aldosterone excess, including heart failure post-myocardial infarction and hypertension, particularly in patients who require potassium conservation.

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Pharmacological Classification

• Therapeutic Class: Antihypertensive, Diuretic

• Pharmacologic Class: Aldosterone Antagonist / Potassium-Sparing Diuretic

• ATC Code: C03DA04

• Drug Class: Selective mineralocorticoid receptor antagonist

• Available Forms: Oral tablets (25 mg, 50 mg)

• Brand Names: Inspra (Pfizer), Eplerex, Eplenor

• Legal Classification: Prescription only (Rx)

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Mechanism of Action

Eplerenone works by competitively inhibiting aldosterone from binding to the mineralocorticoid receptors in the distal nephron (collecting ducts) of the kidney. Aldosterone normally promotes sodium reabsorption and potassium excretion. By blocking this effect, eplerenone leads to:

• Increased excretion of sodium and water (natriuretic and diuretic effects)

• Conservation of potassium and magnesium

• Reduction of blood volume and blood pressure

• Attenuation of myocardial and vascular fibrosis, providing cardioprotective effects

Unlike spironolactone, eplerenone has minimal antiandrogenic and antiprogesterone activity, making it better tolerated in long-term therapy.

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Therapeutic Indications

Approved Uses

1. Heart Failure Post-Myocardial Infarction (MI)

   • To improve survival in patients with left ventricular systolic dysfunction (LVEF ≤40%) and clinical evidence of heart failure following MI.

   • Eplerenone reduces mortality and cardiovascular hospitalizations.

2. Hypertension

   • Treatment of essential hypertension, alone or in combination with other antihypertensives.

   • Especially beneficial in resistant hypertension and patients with elevated aldosterone levels (e.g., obesity, sleep apnea).

3. Heart Failure with Reduced Ejection Fraction (HFrEF)

   • As part of standard therapy for NYHA Class II–IV patients with LVEF ≤35%.

4. Primary Aldosteronism (Off-label)

   • For patients who are not surgical candidates or while awaiting adrenalectomy.

5. Diabetic Nephropathy (Investigational/Off-label)

   • Potential to reduce proteinuria and slow progression of nephropathy.

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Dosage and Administration

Heart Failure Post-MI

• Initial dose: 25 mg once daily

• Target dose: Increase to 50 mg once daily after 4 weeks, depending on potassium levels and renal function

Hypertension

• Initial dose: 50 mg once daily

• Maximum: 50 mg twice daily, titrated based on response and tolerability

Heart Failure (Chronic, NYHA Class II–IV)

• Initial: 25 mg once daily

• Titrate to 50 mg once daily within 4 weeks if potassium <5.0 mEq/L

Renal Impairment (adjustment required)

• If eGFR 30–50 mL/min/1.73m²: Initiate at 25 mg every other day; titrate cautiously

• Avoid in eGFR <30 mL/min/1.73m²

Hepatic Impairment

• Use with caution in moderate hepatic impairment

• Avoid in severe hepatic insufficiency

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Contraindications

• Serum potassium >5.0 mEq/L at initiation

• Severe renal impairment (eGFR <30 mL/min) or dialysis

• Concomitant use with potassium supplements or potassium-sparing diuretics

• Concomitant use with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, ritonavir, clarithromycin)

• Known hypersensitivity to eplerenone or its components

• Type 2 diabetes with microalbuminuria and elevated potassium levels

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Warnings and Precautions

Hyperkalemia

• Most significant adverse effect

• Risk is higher in elderly, patients with diabetes, renal impairment, or those using ACE inhibitors, ARBs, NSAIDs

• Monitor serum potassium and renal function at baseline, 1 week, 1 month, and periodically thereafter

Impaired Renal Function

• Dose adjustment necessary

• Risk of worsening renal function, especially in dehydrated or hypotensive patients

CYP3A4 Metabolism

• Eplerenone is metabolized by CYP3A4, so use caution with moderate CYP3A4 inhibitors (e.g., verapamil, fluconazole)

Hypotension

• Monitor blood pressure, especially in volume-depleted or elderly patients

Gynecomastia

• Rare with eplerenone compared to spironolactone

• No anti-androgenic activity at therapeutic doses

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Adverse Effects

Very Common (≥10%)

• Hyperkalemia

• Increased creatinine

Common (1–10%)

• Hypotension

• Dizziness

• Headache

• Fatigue

• Diarrhea

• Cough

• Abdominal pain

• Back pain

• Flu-like symptoms

• Elevated liver enzymes

Less Common to Rare (<1%)

• Hyponatremia

• Gynecomastia (much less than spironolactone)

• Rash

• Dyslipidemia

• Impotence (rare)

• Cardiac arrhythmias (due to electrolyte imbalance)

• Acute kidney injury in predisposed individuals

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Drug Interactions

Major Interactions

1. ACE Inhibitors / ARBs: Additive potassium retention – increased hyperkalemia risk

2. Potassium Supplements: Avoid concurrent use

3. NSAIDs: May reduce renal function and blunt diuretic effect

4. CYP3A4 Inhibitors:

   • Contraindicated with strong inhibitors (ketoconazole, clarithromycin, ritonavir)

   • Caution with moderate inhibitors (verapamil, erythromycin)

5. Lithium: Risk of lithium toxicity due to reduced renal clearance

6. Digoxin: Potential for increased serum levels – monitor closely

7. Trimethoprim: Additive hyperkalemia risk

Food Interactions

• Food does not significantly affect absorption

• Safe to take with or without meals

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Monitoring Parameters

• Serum potassium: Baseline, 3–7 days after initiation or dose increase, then monthly

• Renal function (eGFR, serum creatinine): Same schedule

• Blood pressure: Routine monitoring

• Electrolytes: Sodium, chloride, magnesium

• Liver function: Periodically in long-term use

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Use in Special Populations

Elderly

• Higher risk of hyperkalemia and renal impairment

• Start at lower doses and monitor closely

Pregnancy

• Category B (U.S.)

• Animal studies show no risk; limited human data

• Use only if potential benefit outweighs potential risk

Breastfeeding

• Unknown if excreted in human milk

• Manufacturer recommends caution or alternative drug

Pediatrics

• Not approved for pediatric use; limited data

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Clinical Trials and Efficacy

EPHESUS Trial

• Eplerenone vs. placebo in post-MI patients with LV dysfunction and HF

• Result: Significant reduction in all-cause mortality and CV deaths

EMPHASIS-HF Trial

• In patients with NYHA Class II HF and LVEF ≤35%

• Result: Eplerenone reduced hospitalizations and CV deaths by ~37%

RALES Trial (for spironolactone)

• Eplerenone used as an alternative with fewer endocrine side effects

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Comparison with Spironolactone

• Selectivity: Eplerenone is more selective for mineralocorticoid receptors, with minimal androgen or progesterone receptor affinity

• Side effects: Lower incidence of gynecomastia, menstrual irregularities, and impotence

• Cost: Eplerenone is more expensive

• Potency: Spironolactone is slightly more potent at equivalent doses

• Monitoring: Both require electrolyte and renal monitoring, especially potassium

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Patient Counseling Points

• Take at the same time daily, with or without food

• Do not use salt substitutes containing potassium

• Report symptoms of high potassium: muscle weakness, irregular heartbeat, fatigue

• Avoid NSAIDs without medical advice

• Adherence is important for blood pressure and heart failure control

• Routine blood tests are needed to monitor kidney function and potassium

• Inform your doctor if you are pregnant or planning pregnancy