Aldosterone receptor antagonists

Introduction

Aldosterone receptor antagonists, also known as mineralocorticoid receptor antagonists (MRAs), are a class of potassium-sparing diuretics that competitively inhibit the binding of aldosterone to mineralocorticoid receptors in the distal nephron of the kidney. By blocking aldosterone’s effects, they reduce sodium reabsorption, decrease potassium and hydrogen ion excretion, and ultimately promote natriuresis while sparing potassium.

These agents have important roles in the management of hypertension, heart failure with reduced ejection fraction (HFrEF), primary hyperaldosteronism, edema associated with liver cirrhosis, and certain endocrine disorders. In modern clinical practice, MRAs are valued not only as diuretics but also for their cardioprotective and antifibrotic effects, which significantly improve survival in patients with chronic heart failure.

The most widely used agents are spironolactone, eplerenone, and finerenone, each with specific clinical indications and pharmacological characteristics.

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Physiology of Aldosterone

Aldosterone, the principal mineralocorticoid hormone produced by the adrenal cortex, plays a critical role in fluid and electrolyte balance.

• Site of action: Collecting ducts and late distal tubules of the nephron.

• Physiological effects:

  • Increases sodium reabsorption by stimulating epithelial sodium channels (ENaCs).

  • Promotes potassium excretion by enhancing Na+/K+ exchange.

  • Causes hydrogen ion secretion in intercalated cells, affecting acid-base balance.

• Pathological role: Chronic excess of aldosterone leads to hypertension, left ventricular hypertrophy, vascular remodeling, and fibrosis, contributing to cardiovascular morbidity.

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Mechanism of Action of Aldosterone Receptor Antagonists

MRAs competitively bind to the intracellular mineralocorticoid receptor, preventing aldosterone from exerting its genomic effects. This results in:

1. Reduced expression of sodium channels and Na+/K+-ATPase → decreased sodium reabsorption.

2. Inhibition of potassium and hydrogen ion secretion → potassium-sparing effect.

3. Antifibrotic and anti-inflammatory actions in the heart and kidneys → improved survival in HFrEF and reduced progression of chronic kidney disease (CKD).

Unlike loop and thiazide diuretics, MRAs produce only mild diuresis but potent cardiovascular protection, making them unique in heart failure management.

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Classification of Aldosterone Receptor Antagonists

1. Steroidal MRAs

   • Spironolactone: Non-selective; also blocks androgen and progesterone receptors.

   • Eplerenone: More selective for mineralocorticoid receptors, fewer endocrine side effects.

2. Non-steroidal MRAs

   • Finerenone: A newer, highly selective non-steroidal MRA with potent antifibrotic effects, used primarily in diabetic kidney disease and CKD with cardiovascular risk.

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Therapeutic Uses

1. Hypertension

• Effective in resistant hypertension when added to standard therapy (ACE inhibitors, ARBs, calcium channel blockers, diuretics).

• Particularly beneficial in patients with elevated plasma aldosterone.

2. Heart Failure (HFrEF)

• Landmark trials (RALES for spironolactone, EPHESUS for eplerenone) demonstrated significant mortality reduction.

• MRAs are a standard component of guideline-directed medical therapy (GDMT) in HFrEF.

3. Primary Hyperaldosteronism (Conn’s Syndrome)

• Used to control blood pressure and correct hypokalemia before surgery, or as long-term therapy in bilateral adrenal hyperplasia.

4. Edematous States

• Cirrhosis with ascites: Spironolactone is first-line.

• Nephrotic syndrome: Used as adjunctive therapy for edema resistant to other diuretics.

5. Endocrine/Other Uses

• Spironolactone is used off-label for hirsutism, acne, and polycystic ovary syndrome (PCOS) due to its antiandrogenic effects.

• Finerenone is used in diabetic kidney disease to reduce renal and cardiovascular outcomes.

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Common Aldosterone Receptor Antagonists: Generic Names and Typical Doses

1. Spironolactone

• Indications: Hypertension, heart failure, hyperaldosteronism, cirrhotic ascites, PCOS, hirsutism.

• Typical Doses:

  • Hypertension/Heart failure: 25–50 mg orally once daily (up to 100 mg/day).

  • Primary hyperaldosteronism: 100–400 mg/day in divided doses.

  • Cirrhotic ascites: Start at 100 mg/day, titrate up to 400 mg/day as needed.

  • Hirsutism/PCOS: 50–200 mg/day orally in divided doses.

2. Eplerenone

• Indications: Hypertension, post-myocardial infarction heart failure, HFrEF.

• Typical Doses:

  • Hypertension: 50 mg orally once daily, titrated to 50 mg twice daily.

  • Heart failure (post-MI or HFrEF): Start at 25 mg once daily, increase to 50 mg once daily.

3. Finerenone (non-steroidal)

• Indications: Diabetic kidney disease with albuminuria, CKD with cardiovascular risk.

• Typical Doses:

  • Starting dose: 10–20 mg once daily depending on renal function.

  • Adjusted based on potassium levels and eGFR.

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Contraindications

• Severe renal impairment (eGFR < 30 mL/min/1.73m²).

• Hyperkalemia (baseline serum potassium > 5.0 mmol/L).

• Anuria.

• Concomitant use of potassium supplements or potassium-sparing diuretics (e.g., amiloride, triamterene).

• Concomitant strong CYP3A4 inhibitors (for eplerenone and finerenone) – risk of toxicity.

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Adverse Effects

1. Electrolyte and Renal

• Hyperkalemia (most significant and potentially fatal).

• Hyponatremia.

• Metabolic acidosis (rare).

2. Cardiovascular

• Hypotension, dizziness.

3. Endocrine/Other

• Spironolactone:

  • Gynecomastia, decreased libido, impotence (due to antiandrogenic effect).

  • Menstrual irregularities in women.

  • Breast tenderness.

• Eplerenone:

  • Lower incidence of endocrine side effects due to selectivity.

• Finerenone:

  • Better tolerability, main concern remains hyperkalemia.

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Precautions

• Serum potassium and renal function monitoring:

  • Before initiation, within 1 week of starting, monthly for 3 months, then periodically.

• Elderly patients: Higher risk of hyperkalemia due to reduced renal reserve.

• Combination therapy: Caution with ACE inhibitors, ARBs, ARNi (sacubitril/valsartan), or direct renin inhibitors (aliskiren).

• Cirrhosis: Start at low doses due to altered drug metabolism.

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Drug Interactions

1. ACE inhibitors, ARBs, ARNis → Additive risk of hyperkalemia.

2. Potassium supplements or potassium-sparing diuretics → Contraindicated due to hyperkalemia risk.

3. NSAIDs → May impair renal function and increase potassium retention.

4. Strong CYP3A4 inhibitors (ketoconazole, clarithromycin, ritonavir) → Increase levels of eplerenone and finerenone.

5. Lithium → MRAs reduce lithium clearance, increasing toxicity risk.

6. Digoxin → Spironolactone interferes with digoxin clearance, raising toxicity risk.

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Clinical Considerations

• Heart Failure Guidelines: MRAs are strongly recommended for all symptomatic patients with HFrEF (NYHA II–IV) unless contraindicated.

• Resistant Hypertension: Spironolactone is considered the most effective fourth-line agent (PATHWAY-2 trial).

• Endocrine Disorders: Spironolactone remains valuable in treating hyperandrogenism in women.

• CKD and Diabetic Nephropathy: Finerenone represents an important advance, with strong evidence from FIGARO-DKD and FIDELIO-DKD trials showing reduced cardiovascular and renal outcomes.

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Comparative Overview

• Spironolactone: Broadest use; effective but limited by endocrine side effects.

• Eplerenone: More selective; preferred when gynecomastia is problematic.

• Finerenone: Latest agent; strong evidence for renal and CV protection in CKD and diabetes; more expensive.