What is the next line of treatment for hypertension after using a thiazide, Angiotensin-Converting Enzyme (ACE) inhibitor, and a calcium channel blocker?

Next Drug for Hypertension After Thiazide, ACE Inhibitor, and Calcium Channel Blocker

For patients with resistant hypertension who have already used a thiazide diuretic, ACE inhibitor, and calcium channel blocker, a mineralocorticoid receptor antagonist (such as spironolactone) should be added as the fourth-line agent. 1

Understanding Resistant Hypertension

Resistant hypertension is defined as blood pressure ≥140/90 mmHg despite a therapeutic strategy that includes:

• Appropriate lifestyle management
• A diuretic
• Two other antihypertensive drugs belonging to different classes at adequate doses

Before adding a fourth medication, it's important to exclude:

• Medication nonadherence
• White coat hypertension
• Secondary hypertension

Evidence-Based Fourth-Line Therapy

The 2018 Diabetes Care guidelines clearly recommend mineralocorticoid receptor antagonists (MRAs) as the most effective option for managing resistant hypertension when added to existing treatment with an ACE inhibitor or ARB, thiazide-like diuretic, and dihydropyridine calcium channel blocker 1. This recommendation is based on strong evidence showing that MRAs:

• Effectively reduce blood pressure when added to triple therapy
• Provide additional cardiovascular benefits
• Can reduce albuminuria in patients with kidney disease

Specific Medication Options

1. Spironolactone - First-choice MRA for resistant hypertension

   • Starting dose: 25 mg daily
   • May titrate up to 50 mg daily if needed and tolerated

2. Eplerenone - Alternative MRA with fewer anti-androgenic side effects

   • May be preferred in men experiencing gynecomastia with spironolactone

Important Monitoring Considerations

When adding an MRA to a regimen that includes an ACE inhibitor or ARB:

• Monitor serum potassium and creatinine levels:
  • Check within 1 week of initiation
  • Recheck at 4 weeks
  • Continue regular monitoring (at least annually) 1
• Risk of hyperkalemia is increased, especially in patients with reduced kidney function

Alternative Fourth-Line Options

If MRAs are contraindicated or not tolerated, consider:

1. Beta-blockers - Such as metoprolol 2

   • Particularly useful in patients with coronary artery disease or heart failure
   • Less effective in Black patients

2. Alpha-blockers - Such as doxazosin 3

   • Effective for blood pressure reduction (10/8 mmHg compared to placebo)
   • Useful in men with benign prostatic hyperplasia

3. Direct renin inhibitors - Such as aliskiren 4

   • Note: Should NOT be combined with ACE inhibitors or ARBs due to increased risk of adverse effects without additional benefit 1, 5

Special Population Considerations

• Elderly patients: Start with lower doses of MRAs and monitor more closely for adverse effects 1
• Patients with diabetes: The same approach applies, with MRAs as fourth-line therapy 1
• Patients with kidney disease: Use MRAs with caution; monitor renal function and potassium more frequently 1

Common Pitfalls to Avoid

1. Inappropriate combinations: Never combine ACE inhibitors with ARBs or direct renin inhibitors, as this increases adverse effects without additional benefit 1, 5

2. Inadequate monitoring: Failure to monitor potassium and renal function when using MRAs with ACE inhibitors or ARBs can lead to dangerous hyperkalemia 1

3. Overlooking medication adherence: Always assess adherence before adding another medication, as non-adherence is a common cause of apparent treatment resistance 1

4. Neglecting lifestyle modifications: Continue to emphasize sodium restriction, weight reduction, physical activity, and alcohol limitation even when adding a fourth medication 5

By following this evidence-based approach and carefully monitoring for adverse effects, blood pressure control can be achieved in the majority of patients with resistant hypertension.