Mineralocorticoid Receptor Antagonists

Mineralocorticoid receptor antagonists block aldosterone and cortisol binding at the mineralocorticoid receptor, reducing sodium retention, potassium loss, vascular stiffness and cardiac and renal fibrosis. They improve survival in heart failure with reduced ejection fraction, lower blood pressure in resistant hypertension, treat ascites and primary aldosteronism, and protect the kidney in diabetic kidney disease.

Members. Spironolactone, eplerenone, finerenone, canrenone (and potassium canrenoate where available) and esaxerenone (Japan).

Selectivity. Spironolactone is steroidal and also blocks androgen and progesterone receptors, which causes gynaecomastia and menstrual disturbance. Eplerenone is selective and has little hormonal effect. Finerenone is non-steroidal with balanced action in heart and kidney and a lower hyperkalaemia risk than spironolactone.

Mechanism. Antagonism in the late distal tubule and collecting duct reduces sodium reabsorption and potassium excretion. In the heart, vessels and kidney it reduces collagen deposition and inflammation.

Pharmacokinetics. Spironolactone is converted to active metabolites (canrenone) with a prolonged effect over 2 to 3 days. Eplerenone is metabolised by CYP3A4 with a half-life of 4 to 6 hours. Finerenone is also CYP3A4 dependent with a half-life of 2 to 3 hours.

• Spironolactone: broad evidence base: heart failure, cirrhotic ascites, resistant hypertension, primary aldosteronism, hirsutism and acne.
• Eplerenone: heart failure with reduced ejection fraction, after myocardial infarction; alternative with gynaecomastia.
• Finerenone: chronic kidney disease with type 2 diabetes; also heart failure with preserved ejection fraction in some markets.
• Canrenone and potassium canrenoate: intravenous or oral options where available.

• Heart failure with reduced ejection fraction: spironolactone 12.5 to 25 mg daily, increased to 50 mg; eplerenone 25 mg daily, increased to 50 mg. Start if eGFR is over 30 mL/min/1.73 m2 and potassium is under 5.0 mmol/L. Check potassium and creatinine at days 3 and 7, week 4, then monthly for 3 months, then every 3 months.
• After myocardial infarction with left ventricular dysfunction: eplerenone 25 mg daily, increased to 50 mg, started within 3 to 14 days.
• Resistant hypertension: spironolactone 25 to 50 mg daily, increased to 100 mg, if potassium is 4.5 mmol/L or under. Amiloride is the alternative.
• Cirrhotic ascites: spironolactone 100 mg daily, increased by 100 mg every 3 to 7 days to 400 mg, with furosemide 40 mg daily added as needed.
• Primary aldosteronism (when surgery is not possible): spironolactone 12.5 to 25 mg daily, titrated to potassium and renin response, up to 100 mg or more.
• Hirsutism and acne in women: spironolactone 50 to 200 mg daily with effective contraception.
• Diabetic chronic kidney disease with albuminuria: finerenone 20 mg daily if eGFR is 60 mL/min/1.73 m2 or more, or 10 mg daily if 25 to under 60, with the dose raised to 20 mg after 4 weeks if potassium is 4.8 mmol/L or under. Start only when potassium is 5.0 mmol/L or under.
• Selection: eplerenone or finerenone when gynaecomastia is a concern.

Contraindications. Hyperkalaemia, Addison disease, severe renal impairment (eGFR under 30 mL/min/1.73 m2 for spironolactone and eplerenone start), and hyponatraemia. Eplerenone is contraindicated with strong CYP3A4 inhibitors (itraconazole, ketoconazole, clarithromycin, ritonavir), and finerenone likewise.

Adverse effects. Hyperkalaemia, acute kidney injury, hyponatraemia, hyperchloraemic acidosis. Spironolactone: gynaecomastia and breast tenderness (dose related, up to 10% of men), menstrual irregularity, reduced libido and impotence. Eplerenone and finerenone: fewer hormonal effects.

Hyperkalaemia rules. Hold the drug when potassium exceeds 5.5 mmol/L, stop it above 6.0 mmol/L, and restart at a lower dose after correction. Warn against potassium-containing salt substitutes.

Interactions. ACE inhibitors, angiotensin receptor blockers and sacubitril-valsartan, potassium supplements, trimethoprim, NSAIDs and ciclosporin raise potassium or injure the kidney. Moderate CYP3A4 inhibitors (erythromycin, fluconazole, verapamil, diltiazem) require eplerenone at 25 mg daily at most. Spironolactone interferes with some digoxin assays and raises digoxin levels. Lithium levels rise.

Monitoring. Potassium and creatinine at days 3 and 7, week 4, then monthly for 3 months and every 3 months after that, plus blood pressure, breast symptoms and sodium.

Sick day rule. Withhold during vomiting, diarrhoea or dehydrating illness.

Special groups. Pregnancy: avoid, because spironolactone can feminise a male foetus. Breastfeeding: spironolactone is compatible in small amounts. Renal impairment: reduce dose or use alternate day dosing, and monitor potassium closely. Older adults: start low. Black patients: strong response in resistant hypertension.