What is the first-line treatment with a mineralocorticoid receptor antagonist (MRA) for hypertension?

First-Line Mineralocorticoid Receptor Antagonist for Hypertension

Spironolactone is the first-line mineralocorticoid receptor antagonist (MRA) for the treatment of resistant hypertension, typically initiated at 25 mg daily. 1

Definition and Placement in Hypertension Treatment Algorithm

Mineralocorticoid receptor antagonists are not first-line agents for uncomplicated hypertension but are specifically indicated as third-line or fourth-line therapy for resistant hypertension.

• Resistant hypertension is defined as blood pressure ≥140/90 mmHg despite a therapeutic strategy that includes appropriate lifestyle management plus a diuretic and two other antihypertensive drugs belonging to different classes at adequate doses 1
• Before diagnosing resistant hypertension, clinicians should exclude pseudoresistance, medication nonadherence, white coat effect, and secondary hypertension 1

Treatment Algorithm for Hypertension

1. First-line agents for initial hypertension treatment should include:

   • ACE inhibitors or ARBs
   • Thiazide-like diuretics
   • Dihydropyridine calcium channel blockers 1

2. Second-line approach: Optimize the three-drug regimen of different classes (RAS blocker, calcium channel blocker, diuretic) at maximum or maximally tolerated doses 1

3. Third-line approach: Substitute optimally dosed thiazide-like diuretic (chlorthalidone or indapamide) for the prior diuretic 1

4. Fourth-line approach: Add mineralocorticoid receptor antagonist (MRA) - spironolactone or eplerenone 1

Spironolactone as First-Line MRA

• Spironolactone (25-50 mg daily) is the preferred first-line MRA for resistant hypertension 1, 2
• Spironolactone provides significant antihypertensive benefit when added to existing multidrug regimens, with studies showing blood pressure reductions of 25/12 mmHg when added to regimens that included a diuretic and ACE inhibitor or ARB 1
• The antihypertensive response to spironolactone is not predicted by baseline plasma aldosterone, plasma renin activity, or aldosterone/renin ratio 1

Eplerenone as Alternative MRA

• Eplerenone is an appropriate alternative if spironolactone is not tolerated due to sexual side effects 2
• Eplerenone is more selective for mineralocorticoid receptors with fewer progestational and antiandrogenic effects than spironolactone, enhancing tolerability 2, 3
• Eplerenone has been shown to be effective in heart failure but has less extensive data specifically for resistant hypertension compared to spironolactone 4

Monitoring and Safety Considerations

• For patients treated with MRAs, serum creatinine/estimated glomerular filtration rate and serum potassium levels should be monitored at least annually 1
• Adding an MRA to a regimen including an ACE inhibitor or ARB may increase the risk for hyperkalemia, requiring regular monitoring 1
• The combined use of spironolactone with adequate doses of a thiazide diuretic or chlorthalidone maximizes efficacy and reduces the risk of hyperkalemia 2

Special Populations

• In patients with diabetes and resistant hypertension, MRAs are effective when added to existing treatment with an ACE inhibitor or ARB, thiazide-like diuretic, and dihydropyridine calcium channel blocker 1
• MRAs also reduce albuminuria and have additional cardiovascular benefits in diabetic patients 1
• In patients with heart failure, MRAs (spironolactone or eplerenone) should be started as soon as possible, renal function and potassium permitting 1

Common Pitfalls and Caveats

• Avoid using MRAs in patients with severe renal impairment (eGFR <30 mL/min/1.73m²) due to increased risk of hyperkalemia 5
• Monitor for hyperkalemia (potassium >5.5 mEq/L), especially when combining MRAs with ACE inhibitors or ARBs 1
• Consider the potential for sexual side effects with spironolactone (gynecomastia, decreased libido); eplerenone may be preferred if these occur 2, 6
• Recognize that approximately 10% of hypertension cases may be due to primary aldosteronism, where MRAs are particularly effective 3