Medications for Resistant Hypertension
For resistant hypertension, mineralocorticoid receptor antagonists (particularly spironolactone) should be added as fourth-line therapy to an existing regimen of ACE inhibitor/ARB, thiazide-like diuretic, and dihydropyridine calcium channel blocker. 1, 2, 3
Definition and Diagnosis
Resistant hypertension is defined as:
- Blood pressure ≥140/90 mmHg despite appropriate lifestyle management and concurrent use of 3 antihypertensive medications from different classes at optimal doses, including a diuretic 1, 3
- Or blood pressure controlled only with 4+ medications 4
Before diagnosing true resistant hypertension, exclude:
- Medication nonadherence
- White coat hypertension
- Secondary hypertension
- Improper BP measurement technique
- Interfering substances (especially NSAIDs)
First-Line Treatment Approach
Ensure optimization of the foundational three-drug regimen:
- ACE inhibitor or ARB (at maximum tolerated dose)
- Thiazide-like diuretic (chlorthalidone or indapamide preferred over hydrochlorothiazide)
- Dihydropyridine calcium channel blocker
Important considerations:
- For patients with eGFR <30 mL/min, switch from thiazide to loop diuretics 2, 5
- Chlorthalidone provides 7-8 mmHg greater SBP reduction than hydrochlorothiazide 2
- For patients with albuminuria (UACR ≥30 mg/g), ACE inhibitor or ARB is mandatory 1
- Avoid combining ACE inhibitors with ARBs or direct renin inhibitors 1, 2
Fourth-Line Therapy
Add a mineralocorticoid receptor antagonist (MRA):
- Spironolactone is the preferred agent with strongest evidence 1, 2, 3, 4
- Starting dose: 25 mg daily 6
- Alternative MRA: eplerenone (has fewer endocrine side effects) 2
When adding an MRA:
- Monitor serum potassium and kidney function within 1-2 weeks of initiation
- Continue monitoring every 3-6 months
- Use with caution when combined with ACE inhibitors or ARBs due to hyperkalemia risk
Alternative Fourth-Line Options
If MRAs are contraindicated or not tolerated:
- Amiloride (potassium-sparing diuretic) 3, 4
- Alpha blockers (doxazosin) 3, 7
- Beta-blockers (especially if coronary artery disease or heart failure present) 3
- Centrally-acting agents (clonidine) 3, 7
- Vasodilators (hydralazine) - can be titrated up to 300 mg daily in resistant cases 8
Lifestyle Modifications
Essential adjuncts to pharmacotherapy:
- Dietary sodium restriction (<2,300 mg/day)
- DASH diet implementation
- Weight loss if overweight/obese
- Regular physical activity
- Alcohol limitation
- Adequate sleep (≥6 hours uninterrupted)
- Discontinuation of interfering substances
Monitoring and Follow-up
- Monitor serum creatinine/eGFR and potassium levels within 2-4 weeks after medication changes
- Discontinue ACE inhibitor/ARB if creatinine rises >30% 2
- Consider home BP monitoring to improve adherence and detect white coat effect
- Simplify regimen when possible (once-daily dosing, combination pills)
Common Pitfalls to Avoid
- Failing to confirm true resistant hypertension (vs. pseudoresistance)
- Inadequate diuretic therapy (inappropriate type or dose)
- Overlooking medication adherence issues
- Neglecting to screen for secondary causes
- Inappropriate medication timing
- Not addressing interfering substances
By following this structured approach to resistant hypertension management, focusing on optimizing the three-drug regimen and adding spironolactone as fourth-line therapy, blood pressure control can be achieved in the majority of patients with resistant hypertension.