What's the next step for a patient with uncontrolled hypertension on chlorthalidone (thiazide-like diuretic), amlodipine (calcium channel blocker), and losartan (angiotensin II receptor antagonist)?

Add Spironolactone as the Fourth Agent

For a patient with uncontrolled hypertension on chlorthalidone, amlodipine, and losartan, add spironolactone 25-50 mg daily as the preferred fourth-line agent for resistant hypertension. 1

Confirm True Resistant Hypertension First

Before adding medication, you must exclude pseudoresistance:

• Perform 24-hour ambulatory blood pressure monitoring (or home BP monitoring if unavailable) to confirm BP remains elevated outside the clinic and to verify medication adherence 1
• Ensure adequate sodium restriction to <2400 mg/day (ideally <2000 mg/day), as inadequate dietary sodium is a common cause of apparent treatment resistance 1, 2
• Screen for secondary causes including primary aldosteronism, renal artery stenosis, obstructive sleep apnea, and thyroid disorders, particularly if BP remains >160/100 mmHg 1, 2

Why Spironolactone is the Next Step

Your patient already has the guideline-recommended three-drug foundation (RAS blocker + calcium channel blocker + thiazide-like diuretic) at appropriate doses 1:

• Spironolactone 25-50 mg daily is the preferred fourth-line agent with the strongest evidence for additional BP reduction in resistant hypertension, as demonstrated in the PATHWAY-2 trial 1, 2, 3
• This represents true resistant hypertension requiring mineralocorticoid receptor antagonist therapy 1

Critical Monitoring Requirements

Monitor serum potassium and creatinine closely 2-4 weeks after initiating spironolactone, as hyperkalemia risk is significant when combining with losartan (ARB) 1, 2:

• Hold or reduce spironolactone if potassium rises above 5.5 mEq/L 2
• Use caution if eGFR is <30 mL/min/1.73m² 1

Alternative Fourth-Line Options

If spironolactone is not tolerated or contraindicated 1, 2, 3:

• Eplerenone (alternative mineralocorticoid receptor antagonist with lower risk of gynecomastia)
• Amiloride (potassium-sparing diuretic)
• Doxazosin (alpha-blocker)
• Beta-blocker (only if compelling indication such as coronary artery disease, heart failure with reduced ejection fraction, or heart rate >70 bpm) 1

Fifth and Sixth-Line Options

If BP remains uncontrolled after optimizing spironolactone 1, 2:

• Step 5: Add hydralazine 25 mg three times daily, titrating upward to maximum dose
• Step 6: Substitute minoxidil 2.5 mg two to three times daily for hydralazine (requires concomitant beta-blocker and loop diuretic to prevent reflex tachycardia and fluid retention)

Target Blood Pressure and Timeline

• Target BP is <130/80 mmHg for most patients 1, 4
• Reassess BP within 2-4 weeks after adding spironolactone 1, 2
• Achieve target BP within 3 months of treatment modification 1

When to Refer to Specialist

Consider referral to a hypertension specialist if 1, 2:

• BP remains uncontrolled (≥160/100 mmHg) despite four-drug therapy at optimal doses
• Multiple drug intolerances occur
• Concerning features suggesting secondary hypertension are identified

Common Pitfalls to Avoid

• Do not add a beta-blocker before spironolactone unless there are compelling indications (coronary disease, heart failure, heart rate control) 1
• Do not combine losartan with an ACE inhibitor (dual RAS blockade increases adverse events without benefit) 1, 2
• Do not delay treatment intensification in patients with stage 2 hypertension, as prompt action reduces cardiovascular risk 1
• Do not assume treatment failure without confirming adherence and ruling out secondary causes 1, 2