In a patient with resistant hypertension already taking amlodipine, hydrochlorothiazide, and lisinopril, what is the next appropriate antihypertensive medication to add?

Management of Resistant Hypertension on Triple Therapy

Add spironolactone 25 mg daily as your fourth-line agent, provided the patient's serum potassium is <4.5 mmol/L and eGFR is >45 mL/min/1.73m².

Before Adding a Fourth Agent: Critical First Steps

Confirm True Treatment Resistance

• Perform 24-hour ambulatory blood pressure monitoring to exclude white-coat hypertension and verify medication nonadherence, as approximately 50% of apparent resistant hypertension cases are actually pseudoresistance 1.
• If ambulatory monitoring is unavailable, use home blood pressure monitoring as an alternative 1.
• Ensure proper BP measurement technique with appropriate cuff size and correct patient positioning 1.

Optimize the Current Three-Drug Regimen

• Switch hydrochlorothiazide to chlorthalidone 12.5-25 mg daily or indapamide 1.25-2.5 mg daily, as thiazide-like diuretics are significantly more effective than standard thiazides in resistant hypertension 1, 2.
• Verify all three medications (ACE inhibitor, calcium channel blocker, and diuretic) are at maximal or maximally tolerated doses 1.
• Confirm the regimen includes a long-acting calcium channel blocker (amlodipine is preferred), a renin-angiotensin system blocker, and an appropriate diuretic for kidney function 1.

Intensify Lifestyle Modifications

• Restrict sodium intake to <2400 mg/day (ideally <1500 mg/day), as high sodium is a major contributor to treatment resistance and can reduce BP by 10-20 mmHg 1, 2, 3.
• Encourage weight loss if overweight or obese 1, 2.
• Limit alcohol to ≤2 drinks/day for men and ≤1 drink/day for women 2.
• Implement regular aerobic exercise ≥150 minutes/week at moderate intensity 3.

Screen for Secondary Causes

• Check serum potassium, eGFR, and TSH as basic screening 1, 2.
• Screen for primary aldosteronism even with normal potassium levels, particularly in younger patients (<30 years) 1, 2.
• Evaluate for obstructive sleep apnea using clinical screening tools, confirming with polysomnography if suspected 2.
• Assess for renal artery stenosis with kidney ultrasound if clinically indicated 2.

Fourth-Line Agent: Spironolactone

Spironolactone 25 mg daily is the preferred fourth-line agent based on superior efficacy demonstrated in the PATHWAY-2 trial and multiple meta-analyses 1, 2, 4.

Dosing and Monitoring

• Start spironolactone 25 mg daily, titrating to 50 mg daily if needed for BP control 2.
• Check serum potassium and creatinine 1-2 weeks after initiation, then regularly thereafter, as combining spironolactone with ACE inhibitors significantly increases hyperkalemia risk 1, 2, 3.
• Use caution if eGFR <45 mL/min/1.73m² due to increased hyperkalemia risk 1.

Contraindications and Precautions

• Do not use if baseline potassium ≥4.5 mmol/L or eGFR <45 mL/min/1.73m² 1.
• Monitor for gynecomastia and breast tenderness in men 4.

Alternative Fourth-Line Agents

If spironolactone is contraindicated or not tolerated, consider these alternatives in order of preference 1, 2:

• Amiloride 5-10 mg daily (alternative potassium-sparing diuretic) 2
• Doxazosin 1-8 mg daily (alpha-blocker; start low due to first-dose orthostatic hypotension) 1, 3
• Eplerenone (selective mineralocorticoid receptor antagonist with less gynecomastia) 1
• Beta-blocker (metoprolol succinate, bisoprolol, carvedilol) if heart rate >70 bpm 1
• Clonidine 0.1-0.3 mg twice daily (centrally acting agent; higher adverse effect profile) 1, 2, 3

Common Pitfalls to Avoid

• Never combine lisinopril with an ARB, as this increases hyperkalemia and acute kidney injury risk without improving outcomes 3.
• Do not add a fourth agent without first optimizing the diuretic to a thiazide-like formulation (chlorthalidone or indapamide) 1.
• Do not skip ambulatory or home BP monitoring, as white-coat hypertension accounts for roughly half of apparent resistant cases 1.
• Avoid adding spironolactone without checking baseline potassium and renal function 1, 2.

Reassessment and Follow-Up

• Reassess BP response within 2-4 weeks of any medication adjustment 2.
• Continue home BP monitoring to guide medication titration and improve adherence 2.
• Target BP <130/80 mmHg for most patients, achieving this within 3 months of treatment intensification 3.

If BP Remains Uncontrolled After Fourth Agent

If blood pressure remains elevated after optimizing spironolactone, proceed sequentially 1:

• Step 5: Add beta-blocker (if not already added) or hydralazine 25 mg three times daily, titrating upward 1.
• Step 6: Consider referral to a hypertension specialist for advanced therapies including minoxidil or device-based interventions 1.