1. Introduction
Aldosterone receptor antagonists (ARAs), also known as mineralocorticoid receptor antagonists, are drugs that block the action of aldosterone at the mineralocorticoid receptor (MR) in the kidney and other tissues.
By antagonizing aldosterone, ARAs:
- Promote sodium excretion (natriuresis)
- Retain potassium (potassium-sparing)
- Reduce fibrosis and cardiac remodeling in the heart and vasculature
They are used in heart failure, hypertension, primary hyperaldosteronism, and certain renal disorders.
2. Mechanism of Action
- Aldosterone normally:
- Binds MR in distal tubules and collecting ducts
- Upregulates Na+/K+ ATPase and epithelial sodium channels (ENaC)
- Leads to sodium retention, potassium excretion, and water retention
- ARAs:
- Compete with aldosterone at MR → inhibit Na+ reabsorption and K+ excretion
- Reduce aldosterone-mediated cardiac fibrosis and vascular remodeling
- Provide neurohormonal blockade beneficial in heart failure
3. Common Agents
| Drug | Type | Notes |
|---|---|---|
| Spironolactone | Non-selective MR antagonist | Blocks MR, also weak androgen/progesterone receptor antagonist; may cause gynecomastia |
| Eplerenone | Selective MR antagonist | More selective → lower endocrine side effects; used in heart failure post-MI and resistant hypertension |
| Finerenone | Non-steroidal selective MR antagonist | Used in chronic kidney disease with type 2 diabetes; less hyperkalemia risk than spironolactone |
4. Clinical Uses
- Heart Failure
- HFrEF (heart failure with reduced ejection fraction): Reduces morbidity and mortality
- In combination with ACE inhibitors/ARBs
- Eplerenone recommended post-MI with left ventricular dysfunction
- Hypertension
- Resistant hypertension (especially with elevated aldosterone)
- Can be combined with other antihypertensives
- Primary Hyperaldosteronism (Conn’s Syndrome)
- Spironolactone or eplerenone to control BP and hypokalemia
- Chronic Kidney Disease
- Finerenone reduces renal and cardiovascular events in patients with type 2 diabetes
5. Pharmacokinetics
| Drug | Absorption | Metabolism | Half-life | Excretion |
|---|---|---|---|---|
| Spironolactone | Oral; bioavailability 60–70% | Hepatic (CYP3A4) → active metabolites | 1–2 h (parent), 14–16 h (active metabolites) | Urine and feces |
| Eplerenone | Oral; 69% | Hepatic (CYP3A4) | 4–6 h | Urine and feces |
| Finerenone | Oral; 80% | Hepatic (CYP3A4, CYP2C8) | 2–3 h | Urine and feces |
Note: Hepatic metabolism → caution in liver impairment; dose adjustment in renal dysfunction recommended.
6. Adverse Effects
| Drug | Common Adverse Effects | Special Considerations |
|---|---|---|
| Spironolactone | Hyperkalemia, gynecomastia, menstrual irregularities, impotence | Due to non-selective steroid receptor binding |
| Eplerenone | Hyperkalemia, hypotension, dizziness | Lower risk of endocrine side effects than spironolactone |
| Finerenone | Hyperkalemia, hypotension | Less gynecomastia; used in CKD with diabetes |
Key risk: Hyperkalemia (can be life-threatening, especially in CKD or when combined with ACEIs/ARBs)
7. Drug Interactions
- ACE inhibitors / ARBs / Direct renin inhibitors: Increase hyperkalemia risk
- Potassium supplements / salt substitutes: Increase hyperkalemia risk
- CYP3A4 inhibitors (ketoconazole, itraconazole): Increase spironolactone/eplerenone levels
- Diuretics: Thiazides may counteract hyperkalemia but increase risk of hypotension
8. Monitoring Parameters
- Serum potassium: Baseline, 3–7 days after initiation, then periodically
- Renal function (serum creatinine, eGFR): Baseline and periodically
- Blood pressure: At baseline and follow-up
- Liver function: Especially with spironolactone
9. Special Populations
- Pregnancy: Spironolactone not recommended; eplerenone data limited
- Renal impairment: Hyperkalemia risk higher; dose adjustment required
- Elderly: Monitor for hypotension, renal function, and potassium
10. Summary
Aldosterone receptor antagonists are essential in:
- Reducing morbidity and mortality in heart failure
- Managing resistant hypertension
- Treating primary hyperaldosteronism
- Preventing renal and cardiovascular complications in CKD with diabetes
Key considerations: Monitor serum potassium and renal function, choose selective agents when endocrine side effects are problematic, and adjust dosing in renal or hepatic impairment.
11. References
- Pitt B, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure (RALES). N Engl J Med. 1999;341:709–717.
- Pitt B, et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med. 2003;348:1309–1321.
- Bakris GL, et al. Finerenone and cardiovascular and kidney outcomes in type 2 diabetes with chronic kidney disease. N Engl J Med. 2020;383:2219–2229.
- Funder JW, et al. Mineralocorticoid receptor antagonists: pharmacology and clinical use. Endocr Rev. 2010;31:520–563.
- Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 14th Edition, 2021.
