Mineralocorticoid Receptor Antagonist for Hypertension
Spironolactone is the recommended MRA for hypertension, particularly in resistant hypertension, with a typical dose of 25-50 mg daily. 1
Clinical Context and Positioning
MRAs are not first-line agents for uncomplicated hypertension. The 2024 ESC Guidelines recommend ACE inhibitors, ARBs, dihydropyridine calcium channel blockers, and thiazide/thiazide-like diuretics as first-line therapy. 1 MRAs should be reserved for specific clinical scenarios outlined below.
When to Use MRAs in Hypertension
Resistant Hypertension (Primary Indication)
Add spironolactone when blood pressure remains uncontrolled (≥130/80 mmHg) despite optimized triple therapy consisting of a RAS blocker (ACE inhibitor or ARB), calcium channel blocker, and thiazide/thiazide-like diuretic at maximal tolerated doses. 1
- Spironolactone is the most effective fourth-line agent for resistant hypertension, superior to other options including beta-blockers, alpha-blockers, or additional vasodilators. 1
- The 2024 ESC Guidelines provide a Class IIa recommendation for spironolactone in resistant hypertension (downgraded from Class I in 2018 due to lack of dedicated cardiovascular outcome trials in primary hypertension without heart failure). 1
- The 2018 AHA Scientific Statement on Resistant Hypertension specifically recommends MRAs as the preferred fourth-line agent based on the PATHWAY-2 trial demonstrating superiority. 1
Primary Hyperaldosteronism
Screen all patients with resistant hypertension for primary hyperaldosteronism using aldosterone-to-renin ratio (ARR). 1 If confirmed, spironolactone is the definitive medical therapy for bilateral disease or when surgery is not feasible for unilateral disease. 1
Choosing Between Available MRAs
Spironolactone vs. Eplerenone
Start with spironolactone 25 mg daily as the initial MRA choice for resistant hypertension. 1, 2
- Spironolactone is more potent and has longer duration of action compared to eplerenone, requiring once-daily dosing. 2
- Titrate spironolactone to 50 mg daily if blood pressure remains uncontrolled after 4-6 weeks at 25 mg. 1, 2
Switch to eplerenone only if spironolactone causes intolerable sexual side effects (gynecomastia in men, menstrual irregularities in women) due to its anti-androgenic and progestational effects. 3, 2
- Eplerenone is more selective for the mineralocorticoid receptor, resulting in fewer hormonal side effects. 2, 4
- Eplerenone requires twice-daily dosing (25 mg twice daily) for equivalent blood pressure control due to shorter half-life. 3
- Eplerenone is significantly more expensive than spironolactone. 2
Emerging Non-Steroidal MRAs
Finerenone is not currently recommended for primary hypertension management. 1 While the 2024 ESC Guidelines mention finerenone as a potential future option, it currently has proven cardiovascular and renal benefits only in type 2 diabetes with chronic kidney disease and albuminuria, not in general hypertension populations. 1
Critical Monitoring Requirements
Hyperkalemia Risk
Check serum potassium and creatinine within 1-2 weeks after initiating any MRA, then at 4 weeks, and every 3-6 months thereafter. 5, 3
- Do not initiate spironolactone if baseline potassium >5.0 mEq/L or eGFR <30 mL/min/1.73 m². 1
- Withhold MRA if potassium rises >5.5 mEq/L. 1, 3 Can restart at lower dose (10-25 mg) when potassium ≤5.0 mEq/L. 1
- Risk of hyperkalemia increases substantially when combining MRAs with ACE inhibitors or ARBs, particularly in elderly patients and those with reduced kidney function. 3
Renal Function Monitoring
Monitor creatinine and eGFR at the same intervals as potassium. 1, 3 Increases in creatinine >0.5 mg/dL occurred in 6.5% of patients on eplerenone in heart failure trials. 3
Drug Interactions to Avoid
Never combine MRAs with potassium supplements or potassium-sparing diuretics (amiloride, triamterene) due to severe hyperkalemia risk. 3
Avoid strong CYP3A4 inhibitors (ketoconazole, itraconazole, ritonavir, clarithromycin) with eplerenone as they are contraindicated. 3
Use caution with NSAIDs, which can reduce antihypertensive efficacy and increase hyperkalemia risk, particularly in patients with impaired renal function. 3
Practical Dosing Algorithm
For Resistant Hypertension
Confirm true resistance: Verify adherence, exclude white-coat effect with 24-hour ambulatory blood pressure monitoring, optimize lifestyle modifications (sodium <2400 mg/day). 1
Optimize baseline triple therapy: Ensure maximal tolerated doses of RAS blocker + calcium channel blocker + thiazide-like diuretic (chlorthalidone or indapamide preferred over hydrochlorothiazide). 1
Add spironolactone 25 mg once daily if potassium ≤5.0 mEq/L and eGFR ≥30 mL/min/1.73 m². 1, 2
Check potassium and creatinine in 1-2 weeks. 5
Increase to spironolactone 50 mg daily after 4-6 weeks if blood pressure remains uncontrolled and potassium remains ≤5.0 mEq/L. 1, 2
If sexual side effects develop, switch to eplerenone 25 mg twice daily (or 25 mg once daily if on moderate CYP3A4 inhibitor). 3, 2
For Heart Failure with Hypertension
MRAs provide additional cardiovascular mortality benefit in heart failure with reduced ejection fraction (HFrEF) beyond blood pressure lowering alone. 1, 6, 4 In this population, spironolactone or eplerenone should be added earlier in the treatment algorithm. 1
Common Pitfalls to Avoid
Do not combine ACE inhibitors with ARBs when adding an MRA - this triple combination dramatically increases hyperkalemia risk without additional cardiovascular benefit. 5, 3
Do not use MRAs as first-line therapy for uncomplicated hypertension - they lack dedicated cardiovascular outcome trials in this population and carry hyperkalemia risk. 1
Do not neglect sodium restriction - dietary sodium intake >2400 mg/day reduces MRA efficacy and increases hyperkalemia risk. 1
Do not assume beta-blockers are equivalent fourth-line agents - spironolactone provides superior blood pressure reduction in resistant hypertension compared to beta-blockers or other alternatives. 1