What can be added to Amlodipine (calcium channel blocker) for uncontrolled hypertension?

Adding Medications to Amlodipine for Uncontrolled Hypertension

For patients with uncontrolled hypertension on amlodipine, adding an ACE inhibitor or ARB should be the next step, followed by a thiazide-like diuretic if needed, and spironolactone as a fourth agent if hypertension remains resistant. 1

Step 1: Add an ACE Inhibitor or ARB

• For non-black patients, add an ACE inhibitor (or ARB if ACE inhibitor is not tolerated due to cough) to amlodipine 1
• For black patients of African or Caribbean origin, an ARB is preferred over an ACE inhibitor when combined with a calcium channel blocker like amlodipine 1
• The combination of amlodipine with an ACE inhibitor or ARB provides synergistic effects and is more effective than either agent alone 2, 3
• Avoid combining an ACE inhibitor with an ARB as this dual RAAS blockade increases adverse events without improving outcomes 1

Step 2: Add a Thiazide-Like Diuretic

• If blood pressure remains uncontrolled on the combination of amlodipine plus an ACE inhibitor or ARB, add a thiazide-like diuretic as the third agent 1
• Prefer chlorthalidone (12.5-25.0 mg once daily) or indapamide (1.5 mg modified-release once daily or 2.5 mg once daily) over conventional thiazide diuretics like hydrochlorothiazide 1
• Adding a diuretic is particularly effective in patients not controlled on amlodipine and an ACE inhibitor combination 4

Step 3: Add Spironolactone for Resistant Hypertension

• If blood pressure remains uncontrolled despite optimal doses of a three-drug regimen (amlodipine, ACE inhibitor/ARB, and thiazide-like diuretic), add spironolactone 25 mg daily as the preferred fourth agent 1, 5
• Spironolactone has shown superior efficacy in resistant hypertension, with studies demonstrating additional blood pressure reductions of 25/12 mmHg when added to existing multidrug regimens 1
• Monitor serum potassium closely, especially in patients with reduced renal function, as hyperkalemia is a potential side effect 1
• If spironolactone is not tolerated (e.g., due to gynecomastia) or contraindicated, consider alternatives such as amiloride, doxazosin, eplerenone, clonidine, or a beta-blocker 1

Important Clinical Considerations

• Ensure that all medications in the current regimen are at optimal or maximum tolerated doses before adding additional agents 1, 5
• Consider once-daily dosing and single-pill combinations when possible to improve medication adherence 1, 6
• Check adherence to medication regimen before diagnosing true resistant hypertension 5
• Monitor blood pressure control regularly, aiming to achieve target within 3 months 1
• Check serum potassium and renal function within 1 month after adding or increasing the dose of diuretics, especially when adding spironolactone 1
• If blood pressure remains uncontrolled despite optimal four-drug therapy, seek specialist advice 1

Special Population Considerations

• For elderly patients (≥80 years), individualize treatment based on frailty and comorbidities, but hypertension treatment has demonstrated benefits even in this age group 1
• For patients with diabetes or chronic kidney disease, the same stepped approach is generally recommended, with particular attention to monitoring renal function and electrolytes 1