Can chlorthalidone, ramipril (Angiotensin-Converting Enzyme Inhibitor, ACEI), and amlodipine (Calcium Channel Blocker, CCB) be combined?

From the Guidelines

Yes, chlorthalidone, ramipril, and amlodipine can be combined for blood pressure management, as recommended by the 2024 ESC guidelines for the management of elevated blood pressure and hypertension 1. This combination includes three different classes of antihypertensive medications that work through complementary mechanisms: chlorthalidone is a thiazide-like diuretic that reduces blood volume, ramipril is an ACE inhibitor that blocks the renin-angiotensin system, and amlodipine is a calcium channel blocker that relaxes blood vessels. The key points to consider when combining these medications include:

• Monitoring for potential side effects such as electrolyte imbalances (particularly potassium levels), dizziness from blood pressure dropping too low, and peripheral edema.
• Dosing typically starts lower when medications are combined, with gradual adjustments based on blood pressure response and tolerance.
• Regular monitoring of kidney function is also necessary, especially when using an ACE inhibitor like ramipril in combination with a diuretic. The 2024 ESC guidelines recommend a RAS blocker (either an ACE inhibitor or an ARB) with a dihydropyridine CCB or diuretic as preferred combinations for most patients with confirmed hypertension 1. In patients receiving combination BP-lowering treatment, fixed-dose single-pill combination treatment is recommended, and if BP is not controlled with a two-drug combination, increasing to a three-drug combination is recommended, usually a RAS blocker with a dihydropyridine CCB and a thiazide/thiazide-like diuretic, and preferably in a single-pill combination 1.

From the FDA Drug Label

DRUG INTERACTIONS 7. 1 Diuretics Patients on diuretics, especially those in whom diuretic therapy was recently instituted, may occasionally experience an excessive reduction of blood pressure after initiation of therapy with ramipril 7. 2 Other Antihypertensive Agents Limited experience in controlled and uncontrolled trials combining ramipril with a calcium channel blocker, a loop diuretic, or triple therapy (beta-blocker, vasodilator, and a diuretic) indicate no unusual drug-drug interactions

The combination of chlorthalidone (a diuretic), ramipril (an ACEI), and amlodipine (a CCB) may be used with caution, as there is limited experience with this specific combination, but the label indicates no unusual interactions with diuretics or calcium channel blockers in general. However, patients should be monitored for excessive reduction of blood pressure and hyperkalemia.

• Monitor the patient’s serum potassium frequently.
• Monitor renal function periodically.
• Monitor blood pressure closely to avoid excessive reduction. 2

From the Research

Combination Therapy

• The combination of chlorthalidone, ramipril (Angiotensin-Converting Enzyme Inhibitor, ACEI), and amlodipine (Calcium Channel Blocker, CCB) can be considered based on the available evidence 3, 4, 5, 6, 7.
• Studies have shown that combining different classes of antihypertensive drugs, such as ACEIs, CCBs, and thiazide diuretics, can have an additive effect on lowering blood pressure without increasing adverse events 5.
• The use of low-dose combination therapy, including amlodipine, telmisartan, and chlorthalidone, has been shown to be effective and safe in patients with essential hypertension 3, 6.
• Ramipril has been found to decrease chlorthalidone-induced loss of magnesium and potassium in hypertensive patients, suggesting a potential benefit of combining these two medications 7.

Pharmacokinetics and Safety

• The pharmacokinetic profiles of a fixed-dose combination of amlodipine, losartan, and chlorthalidone have been found to be equivalent to those of individual tablets in a loose combination, with no clinically significant changes in safety assessments 4.
• The safety and efficacy of a single-pill, low-dose combination of amlodipine, telmisartan, and chlorthalidone have been evaluated in randomized controlled trials, with results showing significant reductions in mean sitting systolic and diastolic blood pressure and a generally safe profile 3.
• The combination of ramipril and chlorthalidone has been found to be effective in reducing blood pressure, with ramipril decreasing chlorthalidone-induced loss of magnesium and potassium 7.

Efficacy

• The efficacy of low-dose triple combinations of amlodipine, telmisartan, and chlorthalidone has been assessed in a randomized, double-blind, parallel, phase II trial, with results showing significant BP-lowering effects and similar control rates of hypertension and response rates compared to higher-dose combinations 6.
• The combination of an ACEI or ARB with a CCB and/or thiazide diuretic has been found to be effective in lowering blood pressure, with data from a large number of trials supporting the efficacy of this combination 5.