What fourth antihypertensive should be added for a patient with resistant hypertension (blood pressure 170‑190/110 mmHg) already taking losartan 100 mg, chlorthalidone 25 mg, and amlodipine 10 mg?

Add Spironolactone as Fourth-Line Agent for Resistant Hypertension

Add spironolactone 25 mg once daily as the fourth antihypertensive agent, provided serum potassium is <4.5 mEq/L and eGFR is >45 mL/min/1.73m²—this is the most effective fourth-line option supported by the PATHWAY-2 trial and multiple meta-analyses. 1, 2, 3, 4

Verify True Resistant Hypertension First

Before adding a fourth agent, confirm this is genuine resistant hypertension rather than pseudoresistance:

• Perform 24-hour ambulatory blood pressure monitoring to exclude white-coat hypertension, which accounts for approximately 50% of apparent resistant cases 2
• Verify medication adherence through direct questioning, pill counts, or pharmacy records—nonadherence is responsible for roughly half of treatment resistance 1, 2
• Ensure proper BP measurement technique using appropriate cuff size for the patient's arm circumference 2

Optimize Current Three-Drug Regimen Before Adding Fourth Agent

Your patient is already on an appropriate triple combination (ARB + calcium channel blocker + thiazide-like diuretic), which is the recommended foundation. 1 However, verify maximum tolerated dosing:

• Losartan 100 mg is at maximum dose ✓
• Amlodipine 10 mg is at maximum dose ✓
• Chlorthalidone 25 mg is at maximum dose ✓ 1

The patient is appropriately on chlorthalidone rather than hydrochlorothiazide—this is critical, as chlorthalidone provides superior 24-hour blood pressure reduction and is preferentially recommended for resistant hypertension. 1, 2

Screen for Secondary Causes and Contributing Factors

Before adding spironolactone, evaluate for reversible causes:

• Screen for primary aldosteronism with morning plasma aldosterone-to-renin ratio, even if potassium is normal 2
• Assess for obstructive sleep apnea, which is highly prevalent in resistant hypertension 2
• Review for interfering medications, particularly NSAIDs, which should be discontinued or minimized 1
• Evaluate sodium intake—restrict to <2400 mg/day, as high sodium significantly contributes to treatment resistance 2
• Check baseline eGFR and potassium before initiating spironolactone 2

Spironolactone: Dosing and Monitoring

Starting dose: 25 mg once daily, which can be increased to 50 mg daily if BP remains uncontrolled after 4-6 weeks and the medication is well-tolerated. 2, 4

Eligibility criteria (per FDA labeling):

• Serum potassium <4.5 mEq/L (contraindicated if >5.5 mEq/L) 5
• eGFR >45 mL/min/1.73m² (contraindicated if CrCl ≤30 mL/min) 5
• Not on concomitant potassium supplements or potassium-sparing diuretics 5

Monitoring requirements:

• Check serum potassium and renal function within 1 week of starting spironolactone, then at 1 month, then every 3 months 2
• Reassess BP response within 2-4 weeks of initiation 2
• Watch for gynecomastia in men (most common side effect limiting adherence) 3

Alternative Fourth-Line Agents If Spironolactone Contraindicated

If the patient has hyperkalemia (K+ ≥4.5 mEq/L) or reduced kidney function (eGFR <45 mL/min/1.73m²), consider these alternatives in order of preference:

1. Eplerenone 50-100 mg daily (less gynecomastia than spironolactone, but requires higher dosing—50-200 mg daily for equivalent BP reduction; may need twice-daily dosing due to shorter duration of action) 1, 2

   • Note: Eplerenone is contraindicated if CrCl ≤30 mL/min or K+ >5.5 mEq/L 5

2. Vasodilating beta-blocker (labetalol, carvedilol, or nebivolol)—safest option for patients who cannot undergo regular potassium monitoring, though less potent than spironolactone 1, 2

3. Doxazosin (alpha-blocker) as demonstrated in PATHWAY-2 trial 3

4. Amiloride (potassium-sparing diuretic)—one trial found it more effective than spironolactone for resistant hypertension 2

Target Blood Pressure and Referral Criteria

• Target BP: <130/80 mmHg 2, 6
• Refer to hypertension specialist if BP remains >130/80 mmHg after optimizing the four-drug regimen with lifestyle modifications, or if complications arise (severe hyperkalemia, progressive renal dysfunction, difficulty managing regimen) 2

Critical Pitfall to Avoid

Do not add a beta-blocker as the fourth agent unless the patient has a compelling indication (coronary artery disease, heart failure, or rate control need)—beta-blockers are explicitly fourth-line only and less effective than spironolactone in resistant hypertension. 1, 2