In a patient with resistant hypertension on maximally dosed amlodipine 10 mg and losartan 100 mg, blood pressure >140/90 mm Hg, and thiazide diuretics contraindicated due to gout, what is the next best medication to add?

Management of Resistant Hypertension When Thiazides Are Contraindicated Due to Gout

Add spironolactone 25 mg daily as the fourth-line agent for this patient with resistant hypertension on maximally dosed amlodipine and losartan, given that thiazide diuretics are contraindicated due to gout. 1

Defining Resistant Hypertension in This Case

• This patient meets criteria for resistant hypertension: BP >140/90 mmHg despite treatment with three medications at optimal doses including a diuretic (or when a diuretic cannot be used) 1
• Before adding a fourth agent, you must exclude pseudoresistance by confirming medication adherence, ruling out white-coat hypertension with home BP monitoring (≥135/85 mmHg) or 24-hour ambulatory monitoring (≥130/80 mmHg), and screening for interfering substances (NSAIDs, decongestants, oral contraceptives, systemic corticosteroids) 1

Why Thiazides Are Problematic in Gout

• Thiazide and thiazide-like diuretics (hydrochlorothiazide, chlorthalidone, indapamide) significantly increase serum uric acid levels by reducing renal uric acid excretion through volume depletion and direct effects on uric acid transporters 2, 3
• The 2016 EULAR gout guidelines explicitly recommend substituting thiazide diuretics when gout occurs in a patient receiving them, suggesting losartan or calcium channel blockers for hypertension management instead 1
• Multiple studies confirm that diuretics raise serum uric acid levels and increase gout risk, with beta-blockers and alpha-1 blockers also implicated, while calcium channel blockers, ACE inhibitors, and ARBs (especially losartan) do not increase uric acid 2, 3

Spironolactone as the Preferred Fourth-Line Agent

• The 2020 International Society of Hypertension and 2024 ESC guidelines both recommend spironolactone 25-50 mg daily as the preferred fourth-line agent for resistant hypertension when BP remains >140/90 mmHg despite triple therapy 1
• Spironolactone provides additional BP reductions of approximately 20-25 mmHg systolic and 10-12 mmHg diastolic when added to triple therapy, addressing occult volume expansion and aldosterone excess that commonly underlie treatment resistance 1
• Start spironolactone 25 mg daily if serum potassium is <4.5 mmol/L and eGFR is >45 mL/min/1.73m² 1
• Check serum potassium and creatinine 2-4 weeks after initiating spironolactone because hyperkalemia risk increases when combined with losartan 1

Alternative Fourth-Line Agents When Spironolactone Is Contraindicated

If spironolactone cannot be used (hyperkalemia, eGFR <45 mL/min/1.73m², or intolerance), the guidelines recommend these alternatives in order of preference:

• Amiloride 5-10 mg daily – A 2025 JAMA trial demonstrated that amiloride was noninferior to spironolactone for lowering home systolic BP in resistant hypertension (mean reduction -13.6 mmHg vs -14.7 mmHg), with only one case of hyperkalemia and no gynecomastia 1, 4
• Eplerenone 50-100 mg daily – Selective mineralocorticoid receptor antagonist with lower gynecomastia risk than spironolactone 1
• Doxazosin 4-8 mg daily – Alpha-1 blocker, though it may increase serum uric acid levels 1, 2
• Beta-blockers (if not already prescribed and if compelling indication exists such as coronary disease, heart failure, or atrial fibrillation) – Note that beta-blockers can increase serum uric acid 1, 2
• Clonidine 0.1-0.3 mg twice daily – Centrally acting agent 1

Why Not Loop Diuretics?

• Loop diuretics (furosemide, torsemide, bumetanide) are reserved for patients with eGFR <30 mL/min/1.73m² or symptomatic heart failure 1
• Loop diuretics also increase serum uric acid and precipitate gout, making them unsuitable for this patient 3
• This patient does not have the clinical indications (severe CKD or volume overload) that would justify a loop diuretic 1

Losartan's Unique Uricosuric Properties

• Losartan is the only antihypertensive with mild uricosuric properties, making it particularly appropriate for hypertensive patients with gout 1, 3
• The patient is already on losartan 100 mg (maximum dose), which is optimal 1, 2
• Other ARBs, ACE inhibitors, and calcium channel blockers are uric acid-neutral but lack losartan's active uricosuric effect 2, 3

Blood Pressure Targets and Monitoring

• Target BP is <140/90 mmHg minimum, ideally <130/80 mmHg if well tolerated 1
• Reassess BP within 2-4 weeks after adding spironolactone, with the goal of achieving target BP within 3 months 1
• If BP remains ≥140/90 mmHg after optimized four-drug therapy, refer to a hypertension specialist for evaluation of secondary causes (primary aldosteronism, renal artery stenosis, obstructive sleep apnea, pheochromocytoma) 1

Critical Pitfalls to Avoid

• Do not add a thiazide or loop diuretic in a patient with active gout – both classes significantly increase serum uric acid and precipitate gout attacks 1, 2, 3
• Do not add a beta-blocker as the fourth agent unless there is a compelling indication (coronary disease, heart failure, atrial fibrillation), as beta-blockers are less effective than spironolactone for resistant hypertension and may increase uric acid 1, 2
• Do not combine losartan with an ACE inhibitor (dual RAS blockade) – this increases hyperkalemia and acute kidney injury risk without additional cardiovascular benefit 1
• Do not delay treatment intensification – resistant hypertension requires prompt action within 2-4 weeks to reduce cardiovascular risk 1

Lifestyle Modifications to Reinforce

• Sodium restriction to <2 g/day provides 5-10 mmHg systolic reduction and enhances the efficacy of all antihypertensive classes 1
• Weight loss if BMI ≥25 kg/m² (10 kg loss reduces BP by ~6/4.6 mmHg) 1
• DASH dietary pattern (high in fruits, vegetables, whole grains, low-fat dairy) reduces BP by ~11.4/5.5 mmHg 1
• Regular aerobic exercise (≥150 min/week moderate intensity) lowers BP by ~4/3 mmHg 1
• Alcohol limitation to <100 g/week 1