How to treat resistant hypertension with medications?

Treatment of Resistant Hypertension with Medications

Spironolactone is the preferred fourth agent for resistant hypertension, with a dose of 25-50 mg daily, added to an optimal three-drug regimen of an ACE inhibitor/ARB, a long-acting calcium channel blocker, and a thiazide-like diuretic (preferably chlorthalidone or indapamide). 1

Diagnosis Confirmation

Before initiating treatment for resistant hypertension, confirm the diagnosis by:

• Ensuring accurate BP measurements (proper cuff size)
• Excluding white-coat effect with 24-hour ambulatory or home BP monitoring
• Assessing medication adherence
• Identifying contributing lifestyle factors
• Discontinuing interfering substances
• Excluding secondary causes (primary aldosteronism, sleep apnea, CKD, renal artery stenosis) 1

Stepwise Medication Approach

1. Optimize first-line triple therapy:

   • ACE inhibitor or ARB
   • Long-acting calcium channel blocker (CCB)
   • Thiazide-like diuretic (chlorthalidone or indapamide preferred over hydrochlorothiazide) 1
   • Ensure all medications are at optimal doses

2. Add spironolactone as fourth agent:

   • Start at 25 mg daily, may increase to 50 mg daily
   • Monitor serum potassium and renal function within 1-2 weeks of initiation
   • Use with caution when adding to ARB therapy due to increased hyperkalemia risk 1, 2

3. Alternative fourth-line agents (if spironolactone contraindicated or not tolerated):

   • Eplerenone
   • Amiloride
   • Doxazosin
   • Beta-blockers (especially if heart rate >70 bpm) 1, 3

4. Fifth-line therapy:

   • Add hydralazine (starting at 25 mg three times daily and titrating upward) 1

5. Sixth-line therapy:

   • Substitute minoxidil for hydralazine (starting at 2.5 mg two to three times daily) 1

Special Considerations

For Chronic Kidney Disease

• Consider loop diuretics instead of thiazide diuretics
• Monitor renal function and electrolytes closely, especially with RAS blockers 1

For Elderly Patients (≥65 years)

• Treatment goal remains <130 mmHg systolic
• Careful titration and close monitoring essential, especially with high comorbidity burden 1

Monitoring

• Check BP within 1 month of medication changes
• Monitor electrolytes and renal function 1-2 weeks after initiation of RAS blockers or diuretics
• Schedule follow-up at least every 3-6 months once BP is controlled 1

Essential Lifestyle Modifications

• 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) 1

Common Pitfalls to Avoid

• Failing to confirm true resistant hypertension (vs. pseudoresistance)
• Using hydrochlorothiazide instead of more effective thiazide-like diuretics (chlorthalidone, indapamide)
• Inadequate diuretic dosing
• Not considering spironolactone as fourth agent despite strong evidence
• Overlooking secondary causes, particularly primary aldosteronism (present in 10-20% of resistant hypertension cases) 1, 4
• Not monitoring electrolytes after adding mineralocorticoid receptor antagonists 1

If BP remains uncontrolled after adding spironolactone and optimizing therapy, consider referral to a hypertension specialist for further evaluation 1.