What are the next steps for a patient with uncontrolled hypertension on lisinopril (Angiotensin-Converting Enzyme Inhibitor) 20 mg, hydrochlorothiazide (HCTZ, Diuretic) 12.5 mg, and amlodipine (Calcium Channel Blocker) 10 mg?

Management of Uncontrolled Hypertension on Triple Therapy

For a patient with uncontrolled hypertension on lisinopril 20 mg, hydrochlorothiazide 12.5 mg, and amlodipine 10 mg, the next step should be to switch from hydrochlorothiazide to chlorthalidone (12.5-25 mg daily) due to its superior efficacy in resistant hypertension. 1

Assessment of Current Regimen

• The patient is currently on a three-drug regimen that includes an ACE inhibitor (lisinopril), a thiazide diuretic (hydrochlorothiazide), and a calcium channel blocker (amlodipine) at maximum dose, which represents a good foundation for hypertension management 1
• This triple regimen of different drug classes (ACE inhibitor/ARB, calcium channel blocker, and thiazide diuretic) is recommended as an effective combination for hypertension management 1
• Uncontrolled hypertension despite this regimen meets the definition of resistant hypertension, requiring optimization of the current medications before adding a fourth agent 1

Optimization of Current Regimen

• Maximize the ACE inhibitor dose: Increase lisinopril from 20 mg to 40 mg daily, as the recommended dosage range for hypertension is 20-40 mg per day (doses up to 80 mg have been used but provide minimal additional benefit) 2
• Optimize the diuretic therapy: Replace hydrochlorothiazide 12.5 mg with chlorthalidone 25 mg daily 1
  • Chlorthalidone has been shown to provide greater 24-hour ambulatory blood pressure reduction than hydrochlorothiazide, with the largest difference occurring overnight 1
  • Given the outcome benefit demonstrated with chlorthalidone and its superior efficacy compared with hydrochlorothiazide, chlorthalidone should be preferentially used in patients with resistant hypertension 1

Addition of a Fourth Agent

• If blood pressure remains uncontrolled after optimizing the current regimen, add a mineralocorticoid receptor antagonist (spironolactone 25 mg daily) as the fourth agent 1
• Studies have demonstrated that spironolactone provides significant antihypertensive benefit when added to existing multidrug regimens, lowering blood pressure on average by an additional 25 mm Hg systolic and 12 mm Hg diastolic 1
• The antihypertensive benefit of spironolactone was similar in both African American and white patients 1
• Alternatively, amiloride (5-10 mg daily) can be considered if spironolactone is not tolerated 1

Monitoring Recommendations

• Check serum electrolytes (particularly potassium) and renal function within 1 month of adding or increasing the dose of diuretics or ACE inhibitors 3, 4
• Monitor for potential adverse effects of thiazide-like diuretics, including hyponatremia, hypokalemia, elevated uric acid, and elevated calcium levels 3, 4
• Risk of hyperkalemia is increased in older patients, patients with diabetes and/or chronic kidney disease, or when mineralocorticoid receptor antagonists are added to ongoing treatment with ACE inhibitors 1

Important Caveats

• Avoid combining an ACE inhibitor (lisinopril) with an ARB due to increased risk of hyperkalemia and renal dysfunction without additional blood pressure lowering benefit 3, 4
• Consider the timing of medication administration - taking at least one antihypertensive medication at bedtime may improve 24-hour blood pressure control, particularly nighttime blood pressure values 1
• If blood pressure remains uncontrolled despite optimization of the current regimen and addition of a fourth agent, consider referral to a hypertension specialist to evaluate for secondary causes of hypertension 4