What is the best antihypertensive agent to add after Norvasc (amlodipine) and losartan?

From the Guidelines

The best antihypertensive agent to add after amlodipine (Norvasc) and losartan would typically be a thiazide diuretic such as hydrochlorothiazide (HCTZ) at a dose of 12.5-25 mg daily or chlorthalidone 12.5-25 mg daily. This recommendation is based on the most recent guidelines and evidence, including the 2020 International Society of Hypertension Global Hypertension Practice Guidelines 1. The three-drug combination creates a synergistic effect by addressing different mechanisms of blood pressure control: amlodipine blocks calcium channels causing vasodilation, losartan blocks the renin-angiotensin system, and the thiazide diuretic reduces blood volume through sodium and water excretion.

When adding the thiazide, start at the lower dose and monitor electrolytes, particularly potassium, within 1-2 weeks as both the diuretic and losartan can affect potassium levels in opposite directions. The 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults also supports the use of thiazide diuretics as a primary agent for the treatment of hypertension 1.

If blood pressure remains uncontrolled after optimizing these three medications, the next step would typically be adding a fourth agent such as spironolactone 25 mg daily (particularly effective in resistant hypertension) or a beta-blocker like metoprolol, as recommended by the 2020 International Society of Hypertension Global Hypertension Practice Guidelines 1. This approach follows the principle of combining different classes of antihypertensives that work through complementary mechanisms to achieve better blood pressure control with fewer side effects than maximizing the dose of any single agent.

Key considerations include:

• Monitoring electrolytes, especially potassium, when adding a thiazide diuretic to losartan
• Starting with a low dose of the thiazide diuretic and adjusting as needed
• Considering the addition of spironolactone or a beta-blocker if blood pressure remains uncontrolled after optimizing the initial three-drug combination
• Following the guidelines for the management of resistant hypertension, including referral to specialist centers if necessary 1.

From the Research

Antihypertensive Agents

• The best antihypertensive agent to add after Norvasc (amlodipine) and losartan can be determined by considering the complementary mechanisms of action of different agents.
• Combination therapy with a calcium channel blocker and an angiotensin II-receptor blocker, such as amlodipine and losartan, is a potentially useful therapeutic option 2.
• Other options include adding a beta-blocker, such as metoprolol, or an ACE inhibitor, such as perindopril, to the existing treatment regimen.

Efficacy of Different Combinations

• The combination of amlodipine and valsartan was found to be well tolerated and efficacious in patients with stage 2 hypertension 2.
• A fixed-dose combination of metoprolol extended release and amlodipine was found to be as effective and well tolerated as losartan plus amlodipine in patients with mild-to-moderate hypertension 3.
• A low-dose combination of perindopril and indapamide was found to be more effective than a sequential monotherapy or a stepped-care approach in achieving target blood pressure 4.

Synergistic Effects

• The combination of amlodipine and losartan was found to have synergistic antihypertensive effects in spontaneously hypertensive rats, with a positive correlation between the reduction in blood pressure and the improvement in arterial endothelium-dependent relaxation 5.
• The combination therapy was also found to decrease cardiac mass and left ventricular weight, as well as collagen content in cardiac tissue, to a greater extent than either amlodipine or losartan alone 5.

Considerations for Treatment

• The choice of antihypertensive agent to add to amlodipine and losartan should be based on the individual patient's response to treatment and the presence of any comorbid conditions.
• The efficacy and tolerability of different combinations should be considered, as well as the potential for synergistic effects 2, 3, 4, 5.