What is the next antihypertensive medication if lisinopril (Angiotensin-Converting Enzyme Inhibitor) and amlodipine (Calcium Channel Blocker) are not effective?

Next Antihypertensive After Lisinopril and Amlodipine Fail

Add a thiazide diuretic—specifically chlorthalidone 12.5-25 mg daily—as your third agent to the existing ACE inhibitor and calcium channel blocker regimen. 1, 2

Why a Thiazide Diuretic is the Correct Choice

The combination of an ACE inhibitor (lisinopril), calcium channel blocker (amlodipine), and thiazide diuretic represents the most effective and evidence-based triple therapy regimen for resistant hypertension 1. This approach is both intuitive and empirically validated because:

• Thiazide diuretics address volume expansion, which is frequently the underlying mechanism of treatment resistance in patients failing dual therapy 1
• Thiazides potentiate other antihypertensive classes through complementary mechanisms—the Veterans Affairs Single Drug Therapy Cooperative Study demonstrated that combinations including a thiazide diuretic were consistently more effective than combinations without one 1
• This triple regimen is specifically endorsed as effective and generally well tolerated by the American Heart Association 1

Chlorthalidone vs. Hydrochlorothiazide

Preferentially use chlorthalidone over hydrochlorothiazide for superior efficacy 1:

• In head-to-head comparison, chlorthalidone 25 mg provided greater 24-hour ambulatory blood pressure reduction than hydrochlorothiazide 50 mg, with the largest difference occurring overnight 1
• Chlorthalidone demonstrated outcome benefit in major trials (ALLHAT) and should be the preferred thiazide in resistant hypertension 1
• The typical dose range is 12.5-25 mg daily 1, 3

Direct Evidence Supporting This Approach

A randomized controlled trial specifically addressed your clinical scenario 4:

• In 18 patients uncontrolled on amlodipine 5 mg plus lisinopril (5 mg twice daily), adding bendrofluazide 5 mg daily caused significantly greater blood pressure reduction compared to adding atenolol 100 mg daily or placebo 4
• This demonstrates that a diuretic is more effective than a beta-blocker as the third agent in patients failing ACE inhibitor plus calcium channel blocker therapy 4

Practical Implementation

Start with chlorthalidone 12.5 mg daily and titrate to 25 mg if needed after 2-4 weeks 1, 3. This can often be accomplished with a two-pill regimen using fixed-dose combinations to improve adherence 2.

Essential Monitoring

• Check serum potassium and creatinine within 2-4 weeks of initiating thiazide therapy, as chlorthalidone can cause hypokalemia 3
• Monitor for hyperglycemia and hyperlipidemia, particularly in patients at risk for diabetes 3
• Ensure adequate dosing—many fixed-dose triple combinations contain suboptimal diuretic doses (often only 12.5 mg hydrochlorothiazide), which may be insufficient 5

Alternative Considerations for Specific Scenarios

If the patient has chronic kidney disease with creatinine clearance <30 mL/min 1:

• Switch to a loop diuretic (furosemide or torsemide) instead of a thiazide, as thiazides lose efficacy at this level of renal function 1
• Torsemide has longer duration of action than furosemide and may require less frequent dosing 1

If volume overload is not the primary issue, consider 1:

• Aldosterone antagonists (spironolactone 25-50 mg daily) have demonstrated add-on benefit in patients uncontrolled on multidrug regimens 1
• This is particularly useful if the patient has resistant hypertension with evidence of primary aldosteronism

Common Pitfalls to Avoid

• Don't add a beta-blocker as the third agent unless there's a compelling indication (coronary disease, heart failure), as diuretics are more effective in this scenario 1, 4
• Don't use subtherapeutic diuretic doses—ensure chlorthalidone is dosed at least 12.5-25 mg or hydrochlorothiazide at 25-50 mg if used 1
• Don't combine two RAS blockers (e.g., adding an ARB to lisinopril), as this increases cardiovascular and renal risk without additional benefit 5