What medication can be added to a regimen of amlodipine, losartan (Angiotensin II Receptor Blocker), and metoprolol for a patient with uncontrolled hypertension?

Adding a Thiazide Diuretic for Uncontrolled Hypertension

For patients with uncontrolled hypertension already on amlodipine, losartan, and metoprolol, a thiazide or thiazide-like diuretic should be added as the fourth agent. 1, 2

Rationale for Adding a Thiazide Diuretic

• The International Society of Hypertension guidelines recommend adding a thiazide/thiazide-like diuretic for patients with uncontrolled hypertension who are already on an ARB (losartan) and calcium channel blocker (amlodipine) 1
• Thiazide diuretics have demonstrated efficacy in reducing cardiovascular morbidity and mortality in major clinical trials 3
• For patients already on beta-blockers (metoprolol), ARBs (losartan), and calcium channel blockers (amlodipine), a thiazide diuretic represents a complementary mechanism of action 2

Specific Diuretic Recommendations

• Chlorthalidone (12.5-25 mg daily) is preferred over hydrochlorothiazide due to its longer duration of action and better evidence for cardiovascular outcomes 2
• Indapamide (1.25-2.5 mg daily) is another thiazide-like diuretic option with good efficacy and tolerability 2
• Lower doses of thiazides (equivalent to 12.5-25 mg of chlorthalidone) should be used initially, as higher doses add little additional antihypertensive efficacy but increase adverse effects 3

Monitoring After Adding a Thiazide Diuretic

• Check electrolytes and renal function 1-2 weeks after initiating the diuretic 2
• Monitor for potential adverse effects including hypokalemia, hyperuricemia, and glucose intolerance 2
• Assess blood pressure response within 4-6 weeks of adding the thiazide diuretic 2
• Target blood pressure control should be achieved within 3 months 1

If Blood Pressure Remains Uncontrolled

• If blood pressure remains uncontrolled after adding a thiazide diuretic, consider adding spironolactone 25-50 mg daily as a fifth agent 1, 4
• The PATHWAY-2 trial and meta-analyses have demonstrated that spironolactone is the most effective fourth-line agent for resistant hypertension 4
• Alternative options to spironolactone include eplerenone, amiloride, or doxazosin (alpha-blocker) 1, 4

Important Considerations

• Fixed-dose combinations improve adherence and should be considered when available (e.g., losartan-hydrochlorothiazide) 3
• Verify medication adherence before adding new medications 1
• Reinforce lifestyle modifications, especially sodium restriction, regular physical activity, and weight management 1, 2
• Potassium levels should be maintained above 3.5 mmol/L to preserve the benefits of diuretic therapy 3

Cautions with Thiazide Diuretics

• Monitor for metabolic effects including potential increases in blood glucose (diabetes incidence was higher with diuretics compared to other agents in some trials) 3
• Uric acid levels may increase with thiazide diuretics, though gout is uncommon at recommended doses 3
• Sexual dysfunction has been reported with higher doses of thiazide diuretics 3