What additional antihypertensive medication can be safely added to a patient's regimen who is already taking 20 mg of lisinopril (angiotensin-converting enzyme inhibitor) and has uncontrolled hypertension with blood pressures ranging in the 140s/90s?

Adding a Second Antihypertensive to Lisinopril 20mg for Uncontrolled Hypertension

Add either a calcium channel blocker (amlodipine 5-10mg daily) or a thiazide-like diuretic (chlorthalidone 12.5-25mg daily or hydrochlorothiazide 25mg daily) to achieve guideline-recommended dual therapy for your patient with persistently elevated blood pressure in the 140s/90s. 1

Recommended Add-On Options

First Choice: Calcium Channel Blocker (Amlodipine)

• Adding amlodipine 5-10mg once daily provides complementary vasodilation through calcium channel blockade alongside the ACE inhibitor's renin-angiotensin system inhibition, which has demonstrated superior blood pressure control compared to either agent alone 1
• This combination is particularly beneficial for patients with diabetes, chronic kidney disease, or heart failure 1
• Amlodipine can be taken with or without food, once daily, and is generally well tolerated 2
• A notable benefit: adding an ACE inhibitor like lisinopril to amlodipine may attenuate the peripheral edema that sometimes occurs with calcium channel blockers alone 1

Alternative First Choice: Thiazide-Like Diuretic

• Adding chlorthalidone 12.5-25mg daily or hydrochlorothiazide 25mg daily is equally effective as initial dual therapy, particularly for patients with volume-dependent hypertension, elderly patients, or Black patients 1
• Chlorthalidone is preferred over hydrochlorothiazide due to its longer duration of action and superior cardiovascular outcomes data 1, 3
• The combination of ACE inhibitor plus thiazide diuretic represents guideline-recommended dual therapy with complementary mechanisms 1

Treatment Algorithm

Step 1: Choose Your Add-On Agent

• For non-Black patients: Either amlodipine OR a thiazide diuretic are equally appropriate first additions 1
• For Black patients specifically: The combination of ACE inhibitor plus thiazide diuretic may be more effective than ACE inhibitor plus calcium channel blocker 1

Step 2: Monitoring After Addition

• Reassess blood pressure within 2-4 weeks after adding the second agent 1
• Target blood pressure: <140/90 mmHg minimum for most patients, ideally <130/80 mmHg for higher-risk patients 1
• If adding a thiazide diuretic: Check serum potassium and creatinine 2-4 weeks after initiation to detect potential hypokalemia or changes in renal function 1
• If adding amlodipine: Monitor for peripheral edema, though this is less common when combined with an ACE inhibitor 1

Step 3: If Blood Pressure Remains Uncontrolled on Dual Therapy

• Add the third agent from the remaining class (if started with amlodipine, add thiazide; if started with thiazide, add amlodipine) to achieve guideline-recommended triple therapy 1
• The goal is to achieve target blood pressure within 3 months of initiating or modifying therapy 1

Critical Monitoring Parameters

With Calcium Channel Blocker Addition:

• Watch for peripheral edema (though attenuated by concurrent ACE inhibitor use) 1
• Monitor for headache, flushing, or dizziness 2

With Thiazide Diuretic Addition:

• Monitor for hypokalemia, hyperuricemia, and glucose intolerance 1
• Check serum potassium and creatinine 2-4 weeks after starting 1
• Lisinopril helps attenuate the hypokalemia induced by thiazide diuretics 4

Important Caveats to Avoid

• Do not combine lisinopril with an ARB (like losartan or valsartan)—this dual RAS blockade increases adverse events including hyperkalemia and acute kidney injury without additional cardiovascular benefit 1
• Do not add a third drug class before optimizing doses of your current two-drug regimen—this violates guideline-recommended stepwise approaches and may expose patients to unnecessary polypharmacy 1
• Do not assume treatment failure without first confirming medication adherence—non-adherence is the most common cause of apparent treatment resistance 1, 5
• Before adding medication, verify the patient is actually taking the lisinopril 20mg daily and reinforce lifestyle modifications including sodium restriction to <2g/day 1

Dosing Considerations

If Choosing Amlodipine:

• Start with amlodipine 5mg once daily 1
• Can increase to 10mg once daily if blood pressure remains uncontrolled after 2-4 weeks 1

If Choosing a Thiazide Diuretic:

• Chlorthalidone 12.5-25mg once daily (preferred) 1, 3
• OR Hydrochlorothiazide 25mg once daily if chlorthalidone unavailable 1
• According to the FDA label, when lisinopril is used with diuretics, a low dose of diuretic should be added (e.g., hydrochlorothiazide 12.5mg) 6

If Triple Therapy Becomes Necessary

• Add spironolactone 25-50mg daily as the preferred fourth-line agent if blood pressure remains uncontrolled despite optimized triple therapy (ACE inhibitor + calcium channel blocker + thiazide diuretic) 1, 5, 3
• Monitor potassium closely when adding spironolactone to lisinopril, as hyperkalemia risk is significant 1