What to add to lisinopril (Angiotensin-Converting Enzyme inhibitor) 40mg for uncontrolled hypertension (HTN) with blood pressure 148/105mmHg?

Add a Calcium Channel Blocker or Thiazide Diuretic to Lisinopril 40mg

For uncontrolled hypertension (148/105 mmHg) on lisinopril 40mg, add either a calcium channel blocker (amlodipine 5-10mg daily) or a thiazide diuretic (hydrochlorothiazide 12.5-25mg or chlorthalidone 12.5-25mg daily) as your second agent. 1, 2

Rationale for Adding a Second Agent

• Lisinopril 40mg represents the maximum recommended dose for hypertension, as doses up to 80mg have been studied but do not appear to give greater antihypertensive effect 2
• Your patient has stage 2 hypertension (systolic ≥140 mmHg and diastolic ≥100 mmHg), requiring immediate treatment intensification rather than waiting 1
• The FDA label explicitly states: "If blood pressure is not controlled with lisinopril tablets alone, a low dose of a diuretic may be added (e.g., hydrochlorothiazide, 12.5 mg)" 2

Preferred Add-On Options

Option 1: Calcium Channel Blocker (Amlodipine)

• Start amlodipine 5-10mg once daily to create the guideline-recommended combination of ACE inhibitor + calcium channel blocker 1
• This combination provides complementary mechanisms: vasodilation through calcium channel blockade and renin-angiotensin system inhibition 1
• The combination of an ACE inhibitor with amlodipine has demonstrated superior blood pressure control compared to either agent alone in patients with diabetes, chronic kidney disease, or heart failure 1
• Amlodipine may attenuate peripheral edema if it occurs as a side effect 1

Option 2: Thiazide Diuretic

• Start hydrochlorothiazide 12.5-25mg once daily or chlorthalidone 12.5-25mg once daily 1, 2
• The FDA label recommends starting with hydrochlorothiazide 12.5mg when adding to lisinopril 2
• Chlorthalidone is preferred over hydrochlorothiazide due to its longer duration of action 1
• This combination is particularly effective for patients with volume-dependent hypertension, elderly patients, or Black patients 1

Special Population Considerations

• For Black patients specifically, the combination of a calcium channel blocker plus thiazide diuretic may be more effective than calcium channel blocker plus ACE inhibitor 1
• If your patient is Black, consider adding both amlodipine AND a thiazide diuretic, or switching from lisinopril to this combination 1

Monitoring After Adding Second Agent

• Target blood pressure: <140/90 mmHg minimum, ideally <130/80 mmHg 1
• Reassess blood pressure within 2-4 weeks after adding the second agent 1
• With ACE inhibitor + diuretic: Monitor serum potassium and creatinine 2-4 weeks after initiating diuretic therapy to detect hypokalemia or changes in renal function 1
• With ACE inhibitor + calcium channel blocker: Monitor for peripheral edema, though this is less common when combined with an ACE inhibitor 1

If Blood Pressure Remains Uncontrolled on Dual Therapy

• Add a third agent from the remaining class to achieve guideline-recommended triple therapy (ACE inhibitor + calcium channel blocker + thiazide diuretic) 1
• The goal is to achieve target blood pressure within 3 months of initiating or modifying therapy 1
• Do not add a third drug class before optimizing doses of your current two-drug regimen 1

Fourth-Line Agent for Resistant Hypertension

• If blood pressure remains uncontrolled despite optimized triple therapy, add spironolactone 25-50mg daily as the preferred fourth-line agent 1
• Monitor potassium closely when adding spironolactone to an ACE inhibitor, as hyperkalemia risk is significant 1

Critical Pitfalls to Avoid

• Do not increase lisinopril above 40mg daily, as this provides no additional benefit and is not recommended by the FDA 2
• Do not combine lisinopril with an ARB (like valsartan or losartan), as this increases adverse events including hyperkalemia and acute kidney injury without additional cardiovascular benefit 1
• Do not add a beta-blocker as the second agent unless there are compelling indications such as angina, post-myocardial infarction, heart failure with reduced ejection fraction, or need for heart rate control 1
• Do not assume treatment failure without first confirming medication adherence and ruling out secondary causes of hypertension, as non-adherence is the most common cause of apparent treatment resistance 1

Lifestyle Modifications to Reinforce

• Sodium restriction to <2g/day can provide additive blood pressure reduction of 10-20 mmHg 1
• Weight management, regular aerobic exercise, and alcohol limitation provide additional benefit 1