What are the medication options for treating resistant hypertension?

Medication Options for Resistant Hypertension

For resistant hypertension, a mineralocorticoid receptor antagonist (MRA) such as spironolactone (12.5-25 mg daily) should be added as the preferred fourth-line agent to an optimized three-drug regimen of a RAS blocker, calcium channel blocker, and appropriate diuretic. 1

Definition and Confirmation

Resistant hypertension is defined as:

• Blood pressure remaining above goal (>140/90 mmHg) despite concurrent use of 3 antihypertensive agents of different classes at optimal doses, including a diuretic 1
• Or controlled hypertension requiring 4 or more medications 2

Before initiating additional therapy, confirm true resistant hypertension by:

• Ruling out pseudoresistance (white coat effect, poor medication adherence, improper BP measurement) 1
• Using ambulatory or home BP monitoring to confirm diagnosis 1
• Addressing lifestyle factors and interfering substances 1

Optimizing the Core Three-Drug Regimen

1. Ensure optimal diuretic therapy:

   • Replace hydrochlorothiazide with chlorthalidone (more effective) or indapamide 3, 1
   • For patients with CKD (eGFR <30 ml/min), use loop diuretics instead of thiazides 1

2. Optimize RAS blockade:

   • Use maximum tolerated dose of ACE inhibitor or ARB 1
   • For patients with albuminuria (UACR ≥300 mg/g creatinine), an ACE inhibitor or ARB is strongly recommended 3

3. Optimize calcium channel blocker:

   • Use long-acting dihydropyridine calcium channel blocker at maximum tolerated dose 1

Fourth-Line Therapy

First choice:

• Spironolactone (12.5-25 mg daily) is the preferred fourth agent 1, 4
• Particularly effective in patients with primary aldosteronism 1
• Monitor serum potassium and renal function 1-2 weeks after initiation and periodically thereafter 1
• Use with caution in patients with CKD (eGFR <45 mL/min) due to hyperkalemia risk 1

Alternatives when spironolactone is contraindicated or not tolerated:

• Eplerenone (alternative MRA with fewer anti-androgenic side effects) 1, 2
• Amiloride (potassium-sparing diuretic) 1, 5
• Alpha-blockers (e.g., doxazosin) 1, 5
• Beta-blockers 1, 5
• Centrally-acting agents (e.g., clonidine) 1, 6
• Direct vasodilators (e.g., hydralazine, up to 300 mg daily in divided doses) 7, 6

Special Considerations

• Medication adherence: Consider single-pill combinations to improve adherence 1

• Secondary causes: Screen for common secondary causes including:

  • Obstructive sleep apnea
  • Primary aldosteronism
  • Chronic kidney disease
  • Renal artery stenosis
  • Pheochromocytoma
  • Cushing's syndrome
  • Thyroid disorders 1

• Interfering medications: Avoid or minimize NSAIDs; if analgesics are necessary, acetaminophen may be preferable 3

Monitoring

• Monitor electrolytes (potassium, sodium, magnesium) 1-2 weeks after initiation and every 3-6 months 1
• Monitor kidney function (serum creatinine, eGFR) before starting treatment, 1-2 weeks after initiation, and periodically thereafter 1
• Increased monitoring frequency is needed in patients with:
  • Reduced kidney function
  • Concomitant use of ACE inhibitors or ARBs
  • Advanced age 1

Common Pitfalls

• Inadequate diuretic therapy is a frequent cause of resistant hypertension 3
• Failure to confirm true resistant hypertension before adding medications 1
• Overlooking medication adherence issues 1
• Neglecting to screen for secondary causes 1
• Inappropriate medication timing or combinations 1
• Therapeutic inertia (not intensifying treatment despite persistently elevated BP) 1

By following this structured approach to medication management for resistant hypertension, focusing on optimizing the core three-drug regimen before adding a fourth agent (preferably spironolactone), blood pressure control can be achieved in most patients with resistant hypertension.