What medications are used to treat resistant hypertension?

Medication Management for Resistant Hypertension

Definition and Confirmation

Add spironolactone 25 mg daily as the fourth-line agent to your existing three-drug regimen (ACE inhibitor/ARB, long-acting calcium channel blocker, and thiazide-like diuretic) if potassium is <4.5 mmol/L and eGFR >45 mL/min/1.73m²—this is the most effective medication for resistant hypertension. 1, 2

Before adding medications, confirm true resistant hypertension exists by:

• Performing 24-hour ambulatory blood pressure monitoring to exclude white-coat effect, which accounts for approximately 50% of apparent resistant cases 1, 2
• Verifying medication adherence through direct questioning, pill counts, or pharmacy records 1, 2
• Ensuring proper BP measurement technique with appropriate cuff size and correct patient positioning 1, 2

Optimize Your Current Three-Drug Regimen First

Before adding a fourth agent, maximize your existing regimen 1, 2:

• Verify the regimen includes: A renin-angiotensin system blocker (ACE inhibitor or ARB), a long-acting dihydropyridine calcium channel blocker, and a diuretic at maximal or maximally tolerated doses 1

• Switch to thiazide-like diuretics: Replace standard thiazides with chlorthalidone or indapamide, as these long-acting agents are more effective in resistant hypertension 1, 2

• Adjust diuretic based on kidney function: Switch to loop diuretics if eGFR <30 mL/min/1.73m² or clinical volume overload is present, as unrecognized volume overload is a common cause of treatment failure 1, 2

Fourth-Line Medication: Mineralocorticoid Receptor Antagonists

Spironolactone is the preferred fourth-line agent based on superior efficacy demonstrated in resistant hypertension 1, 2:

• Dosing: Start spironolactone at 25 mg daily (can start at 12.5 mg if concerned about side effects) 1, 3
• Eligibility criteria: Serum potassium <4.5 mmol/L and eGFR >45 mL/min/1.73m² 1
• Monitoring: Check serum potassium and renal function 1-2 weeks after initiation, then regularly, especially when combining with RAS blockade 1, 2
• Mechanism: Aldosterone excess is common in resistant hypertension, and spironolactone reduces albuminuria while providing additional cardiovascular benefits 1, 4

The American College of Cardiology and American Diabetes Association both strongly recommend mineralocorticoid receptor antagonists for patients not meeting BP targets on three classes of antihypertensives 1.

Alternative Fourth-Line Agents

If spironolactone is contraindicated (hyperkalemia risk, eGFR <45 mL/min/1.73m²) or not tolerated, consider these alternatives in order 1, 2:

1. Amiloride (alternative potassium-sparing diuretic with less hyperkalemia risk) 1, 4
2. Eplerenone (selective mineralocorticoid receptor antagonist with fewer side effects) 1, 5
3. Doxazosin (alpha-1 blocker; FDA-approved for hypertension and can be used alone or in combination) 1, 6
4. Beta-blockers (particularly if prior MI, active angina, or heart failure with reduced ejection fraction) 1
5. Clonidine (centrally acting agent) 1, 3

Fifth-Line and Beyond (Refractory Hypertension)

If BP remains uncontrolled on four optimized medications including a mineralocorticoid receptor antagonist, consider 1, 4:

• Hydralazine: Direct vasodilator; start 10 mg four times daily, increase gradually to 25 mg four times daily, then 50 mg four times daily; up to 300 mg daily may be required in resistant cases 7
• Additional alpha-blockers or centrally acting agents if not already prescribed 1, 3
• Referral to specialist hypertension center for further evaluation and management 1, 2, 8

Critical Lifestyle and Secondary Cause Management

Address these factors that significantly contribute to treatment resistance 1, 2, 8:

Lifestyle modifications:

• Restrict sodium intake to <2400 mg/day (ideally <1500 mg/day) 2, 8
• Encourage weight loss if overweight/obese 2, 8
• Limit alcohol to ≤2 drinks/day for men, ≤1 drink/day for women 2, 8
• Implement structured regular exercise program 2, 8

Screen for secondary causes:

• Primary aldosteronism (even with normal potassium, particularly in patients <30 years) 2, 8
• Obstructive sleep apnea using Berlin Questionnaire or Epworth Sleepiness Score, confirm with polysomnography 1, 2, 8
• Renal artery stenosis with kidney ultrasound followed by renal artery imaging if indicated 2, 8
• Thyroid dysfunction by checking TSH 2, 8

Monitoring Strategy

• Reassess BP response within 2-4 weeks of any medication adjustment 2, 8
• Check serum potassium and renal function at least annually for patients on ACE inhibitors, ARBs, or diuretics 1
• Monitor more frequently (1-2 weeks) after adding spironolactone or other potassium-sparing agents 2, 8
• Use home BP monitoring to guide medication titration and improve adherence 2, 8

Common Pitfalls to Avoid

• Don't combine ACE inhibitors with ARBs—this combination does not reduce cardiovascular events and increases adverse effects 1
• Don't use standard thiazides when thiazide-like diuretics are available—chlorthalidone and indapamide are superior for resistant hypertension 1, 2
• Don't add spironolactone without checking potassium and renal function—hyperkalemia risk is significant, especially with concurrent RAS blockade 1
• Don't overlook medication nonadherence—this accounts for roughly half of apparent treatment resistance 1, 2, 4