What blood pressure medication to add to a patient taking losartan (angiotensin II receptor antagonist) and amlodipine (calcium channel blocker) with uncontrolled hypertension, history of hyponatremia, and alcohol use?

Add a Thiazide or Thiazide-Like Diuretic as the Third Agent

For this patient already on losartan (ARB) and amlodipine (CCB) with uncontrolled hypertension, add a thiazide or thiazide-like diuretic as the third medication, specifically preferring chlorthalidone over hydrochlorothiazide for superior 24-hour blood pressure control. 1

Rationale for Thiazide Diuretic Addition

The current regimen represents the standard two-drug combination (ARB + CCB), and guideline-directed therapy clearly indicates a thiazide diuretic as the third agent:

• The 2024 ESC Guidelines explicitly recommend that when blood pressure is not controlled with a three-drug combination of ACE inhibitor/ARB, calcium channel blocker, and diuretic, treatment should be increased by adding spironolactone as the fourth agent 1
• This confirms the standard three-drug regimen is ARB + CCB + thiazide diuretic before considering additional agents 1
• The triple regimen of ARB, CCB, and thiazide diuretic is effective, generally well-tolerated, and can be accomplished with two pills using fixed-dose combinations 1

Specific Diuretic Selection: Chlorthalidone Over Hydrochlorothiazide

Choose chlorthalidone 12.5-25 mg daily rather than hydrochlorothiazide:

• Chlorthalidone provides greater 24-hour ambulatory blood pressure reduction compared to hydrochlorothiazide 50 mg, with the largest difference occurring overnight 1
• Chlorthalidone demonstrated outcome benefits in major trials and has superior efficacy in resistant hypertension 1
• Given the patient's alcohol use (which may contribute to volume expansion), the longer-acting chlorthalidone is particularly advantageous 1

Critical Consideration: History of Hyponatremia

The history of hyponatremia requires careful monitoring but does not contraindicate thiazide use:

• Start with a lower dose (chlorthalidone 12.5 mg) and monitor serum sodium closely within 1-2 weeks of initiation
• Check baseline electrolytes including sodium and potassium before starting therapy
• Alcohol use itself can contribute to hyponatremia, making blood pressure control even more important 1
• The combination of thiazide with potassium-sparing properties (if needed later) may attenuate hypokalemia and its metabolic effects 1

Alternative if Thiazide Contraindicated: Loop Diuretic

If the patient has chronic kidney disease with creatinine clearance <30 mL/min, substitute a loop diuretic:

• Use torsemide (longer-acting) rather than furosemide to avoid twice-daily dosing 1
• Loop diuretics may be necessary for effective volume and blood pressure control in advanced CKD 1

Fourth-Line Agent if Blood Pressure Remains Uncontrolled

If blood pressure remains elevated on ARB + CCB + thiazide diuretic, add spironolactone:

• The 2024 ESC Guidelines recommend spironolactone as the fourth agent for resistant hypertension 1
• If spironolactone is not tolerated, consider eplerenone, or alternatively a beta-blocker, centrally acting agent, or alpha-blocker 1
• Recent studies demonstrate significant add-on benefit of aldosterone antagonists in patients uncontrolled on multidrug regimens 1

Monitoring Strategy

• Recheck blood pressure within 2-4 weeks of adding the diuretic
• Monitor serum sodium and potassium within 1-2 weeks given hyponatremia history
• Target blood pressure <130/80 mmHg if tolerated, with first objective <140/90 mmHg 1
• Counsel on alcohol reduction to <14 units/week for men or <8 units/week for women 1

Common Pitfalls to Avoid

• Do not combine two RAS blockers (e.g., adding an ACE inhibitor to the existing ARB), as this increases adverse effects without additional benefit 2
• Do not add a beta-blocker as the third agent unless there is a specific indication (coronary disease, heart failure), as beta-blockers combined with diuretics increase diabetes risk in susceptible patients 1
• Do not skip the diuretic and jump to spironolactone—patients with resistant hypertension frequently have inappropriate volume expansion that requires diuretic therapy 1