What can be added to lisinopril (Angiotensin-Converting Enzyme Inhibitor) for a patient with uncontrolled hypertension (high blood pressure)?

Adding Medication to Lisinopril for Uncontrolled Hypertension

Add either a calcium channel blocker (amlodipine 5-10 mg daily) or a thiazide diuretic (hydrochlorothiazide 12.5-25 mg or chlorthalidone 12.5-25 mg daily) to lisinopril for uncontrolled hypertension. 1

Preferred Add-On Options

Calcium Channel Blocker (Amlodipine)

• Start amlodipine 5 mg once daily, which can be titrated to 10 mg if needed 1
• The ACE inhibitor + calcium channel blocker combination provides complementary mechanisms: ACE inhibition (lisinopril) plus vasodilation through calcium channel blockade (amlodipine) 1
• This combination has demonstrated superior blood pressure control compared to either agent alone and may reduce peripheral edema that occurs with amlodipine monotherapy 1
• Choose this option if the patient has coronary artery disease, angina, or diabetes 1

Thiazide Diuretic

• Start hydrochlorothiazide 12.5-25 mg once daily or chlorthalidone 12.5-25 mg once daily 1, 2
• Chlorthalidone is preferred over hydrochlorothiazide due to its longer half-life and superior cardiovascular outcomes data 3
• The combination of ACE inhibitor + thiazide diuretic targets volume reduction and renin-angiotensin system blockade 3
• Choose this option if the patient has volume-dependent hypertension, is elderly, or cost is a major concern 1
• Lisinopril attenuates the hypokalemia induced by thiazide diuretics 4

Clinical Decision Algorithm

1. First, optimize lisinopril dosing: The usual dosage range is 20-40 mg per day, with doses up to 80 mg studied (though they don't appear to give greater effect) 2

2. If blood pressure remains uncontrolled on optimized lisinopril monotherapy, add either:

   • Amlodipine 5-10 mg daily for patients with coronary disease, angina, or diabetes 1
   • Thiazide diuretic (hydrochlorothiazide 12.5-25 mg or chlorthalidone 12.5-25 mg) for volume-dependent hypertension, elderly patients, or when cost is a concern 1

3. For Black patients specifically: The combination of calcium channel blocker + thiazide diuretic may be more effective than calcium channel blocker + ACE inhibitor 3

Target Blood Pressure and Monitoring

• Target systolic BP of 120-129 mmHg if well tolerated, or at minimum <140/90 mmHg 1
• For high-risk patients (diabetes, chronic kidney disease, established cardiovascular disease), target <130/80 mmHg 5, 3
• Reassess blood pressure within 2-4 weeks after adding the second agent 1
• Goal is to achieve target blood pressure within 3 months of treatment modification 1
• Monitor serum potassium and creatinine 2-4 weeks after initiating diuretic therapy to detect potential hypokalemia or changes in renal function 1

If Blood Pressure Remains Uncontrolled on Dual Therapy

Add the third agent from the remaining class to achieve guideline-recommended triple therapy (ACE inhibitor + calcium channel blocker + thiazide diuretic) 1

• When blood pressure is not controlled with a two-drug combination, increasing to a three-drug combination is recommended, usually a RAS blocker with a dihydropyridine calcium channel blocker and a thiazide/thiazide-like diuretic, preferably in a single-pill combination 1
• The combination of ACE inhibitor + calcium channel blocker + thiazide diuretic represents guideline-recommended triple therapy with complementary mechanisms targeting volume reduction, vasodilation, and renin-angiotensin system blockade 3

Resistant Hypertension (Uncontrolled on Triple Therapy)

Add spironolactone 25-50 mg daily as the preferred fourth-line agent for resistant hypertension 5, 3, 1

• Spironolactone provides additional blood pressure reductions when added to triple therapy 3
• Monitor potassium closely when adding spironolactone to an ACE inhibitor, as hyperkalemia risk is significant 1
• Spironolactone should not be used if serum creatinine is ≥2.5 mg/dL in men or ≥2.0 mg/dL in women, or if serum potassium is ≥5.0 mEq/L 5

Critical Pitfalls to Avoid

• Do NOT combine lisinopril with an ARB, as this increases adverse events (hyperkalemia, acute kidney injury) without additional cardiovascular benefit 3, 1
• Do NOT add a beta-blocker as the third agent unless there are compelling indications (angina, post-MI, heart failure with reduced ejection fraction, or need for heart rate control) 3, 1
• Verify medication adherence first, as non-adherence is the most common cause of apparent treatment resistance 3, 1
• Do not use non-dihydropyridine calcium channel blockers (diltiazem or verapamil) if the patient has left ventricular dysfunction or heart failure 5, 3

Lifestyle Modifications (Provide Additive BP Reductions of 10-20 mmHg)

• Sodium restriction to <2 g/day 3, 1
• Weight management (target BMI 20-25 kg/m²) 1
• Regular aerobic exercise 1
• Alcohol limitation to <100 g/week 1

Special Considerations for Renal Impairment

• No dose adjustment of lisinopril is required in patients with creatinine clearance >30 mL/min 2
• In patients with creatinine clearance ≥10 mL/min and ≤30 mL/min, reduce the initial dose of lisinopril to 5 mg for hypertension 2