What is the role of spironolactone in treating a patient with resistant hypertension who has failed multiple antihypertensive agents, including an angiotensin II receptor blocker, a thiazide diuretic, and a beta-blocker, and has a history of cough with lisinopril (angiotensin-converting enzyme inhibitor) and peripheral edema with amlodipine (calcium channel blocker)?

Spironolactone for Resistant Hypertension

Add spironolactone 25 mg once daily as your fourth-line agent—it is the most effective add-on therapy for resistant hypertension and is specifically indicated by the FDA for this purpose. 1, 2

Why Spironolactone is the Preferred Choice

Spironolactone is explicitly recommended as the preferred fourth-line agent for resistant hypertension by the 2017 ACC/AHA guidelines and is supported by the PATHWAY-2 trial demonstrating superior blood pressure reduction compared to alternatives. 1, 3, 4

• The average blood pressure reduction with spironolactone in resistant hypertension is 22/10 mmHg, which exceeds what is typically achieved with other fourth-line agents 5
• Approximately 70% of patients with resistant hypertension meet criteria for spironolactone use based on potassium and renal function 3
• The FDA specifically approves spironolactone as add-on therapy for hypertension not adequately controlled on other agents 2

Your Patient's Specific Context

This patient is an ideal candidate for spironolactone given the history of intolerance to ACE inhibitors (cough with lisinopril) and calcium channel blockers (edema with amlodipine), leaving limited alternative options. 1

• The patient is already on an ARB, thiazide diuretic, and beta-blocker—the standard three-drug foundation 1
• Spironolactone provides additive benefit when combined with ARBs and thiazide diuretics 4
• Cannot return to ACE inhibitor due to cough, and calcium channel blocker caused problematic edema 1

Pre-Treatment Requirements

Before initiating spironolactone, verify serum potassium is <4.5 mEq/L and eGFR is >45 mL/min/1.73m². 3, 4

• Check baseline potassium and creatinine immediately 4
• Ensure the current three-drug regimen is at maximally tolerated doses 3, 4
• Consider switching from hydrochlorothiazide to chlorthalidone (12.5-25 mg daily) if currently on HCTZ, as thiazide-like diuretics are significantly more effective 3, 4
• Confirm true resistant hypertension with home or ambulatory blood pressure monitoring to exclude white-coat effect 3, 4

Dosing and Titration

Start spironolactone at 25 mg once daily, and increase to 50 mg daily after 4-6 weeks if blood pressure remains uncontrolled and the medication is well-tolerated. 1, 4, 6

• The dose range for resistant hypertension is 25-100 mg daily, though most patients respond to 25-50 mg 1, 6
• Do not exceed 50 mg daily without specialist consultation 4

Monitoring Protocol

Check serum potassium and creatinine 5-7 days after initiation, then every 3-6 months thereafter. 4

• Discontinue spironolactone if potassium rises above 5.5-6.0 mEq/L 4
• Hyperkalemia occurs in approximately 4% of patients, with increased risk when combined with ARBs (as in this patient) 4, 7
• The combination of spironolactone with adequate doses of thiazide diuretic reduces hyperkalemia risk 6
• Monitor for gynecomastia and breast tenderness, which occurs in approximately 10% of men 6, 7

Critical Safety Considerations

Avoid spironolactone if eGFR <45 mL/min/1.73m², potassium >4.5 mEq/L, or if the patient is on potassium supplements or other potassium-sparing diuretics. 1, 4

• Risk of hyperkalemia is increased in patients with chronic kidney disease, diabetes, elderly patients, and those on ARBs or ACE inhibitors 7
• Do not combine with other potassium-sparing diuretics (amiloride, triamterene) 1
• If eGFR is 30-50 mL/min/1.73m², consider initiating at 25 mg every other day due to hyperkalemia risk 4

Alternative Agents if Spironolactone Cannot Be Used

If spironolactone is contraindicated or not tolerated due to gynecomastia, switch to eplerenone 50-100 mg daily (often requires twice-daily dosing for adequate BP control). 1, 3

• Eplerenone has less gynecomastia and sexual side effects compared to spironolactone but requires higher dosing (50-200 mg daily) for equivalent blood pressure reduction 1, 3
• If the patient cannot undergo regular laboratory monitoring, a vasodilating beta-blocker (nebivolol, carvedilol, or labetalol) is the safest option as it requires no potassium checks 3
• Other alternatives in order of preference: amiloride, doxazosin, clonidine 3, 8, 9

Common Pitfalls to Avoid

• Do not continue hydrochlorothiazide if the patient is on it—switch to chlorthalidone or indapamide for superior efficacy in resistant hypertension 3
• Do not add spironolactone without checking baseline potassium and renal function—this is the most common cause of serious adverse events 4
• Do not combine spironolactone with potassium supplements or other potassium-sparing diuretics—this dramatically increases hyperkalemia risk 1
• Do not use loop diuretics instead of thiazides unless eGFR <30 mL/min/1.73m² or clinical volume overload is present—thiazides are preferred for resistant hypertension 3, 4