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Thursday, August 21, 2025

ACE inhibitors with calcium channel blocking agents


Introduction

ACE inhibitor + calcium channel blocker (CCB) combinations are fixed-dose antihypertensive therapies that pair two complementary mechanisms:

  1. ACE inhibitors – inhibit conversion of angiotensin I to angiotensin II, reducing vasoconstriction, sodium retention, and aldosterone secretion, while improving vascular compliance.

  2. Calcium channel blockers (CCBs) – block L-type calcium channels in vascular smooth muscle and/or cardiac tissue, causing vasodilation (dihydropyridines) or negative inotropy/chronotropy (non-dihydropyridines).

This combination is frequently recommended in hypertension guidelines because it produces additive blood pressure reduction while minimizing individual drug-related adverse effects.

Rationale for Combination

  • ACE inhibitors can reduce CCB-induced peripheral edema by lowering hydrostatic pressure in capillaries.

  • CCBs can counterbalance the RAAS activation sometimes seen with ACE inhibitors.

  • Together they lower blood pressure more effectively than either alone and reduce cardiovascular risk.

Common ACE Inhibitor + CCB Combinations

1. Benazepril + Amlodipine

  • Doses: 5/5 mg, 10/5 mg, 20/5 mg, 10/10 mg, 20/10 mg, 40/10 mg (once daily).

  • Indication: Hypertension not controlled on monotherapy.

  • Notes: Well-studied; effective in diverse populations.

2. Perindopril + Amlodipine

  • Doses: 3.5/2.5 mg, 7/5 mg, 14/10 mg once daily.

  • Indication: Hypertension and high cardiovascular risk patients.

  • Notes: Combination studied in ASCOT-BPLA trial, showing significant reduction in cardiovascular outcomes compared to other regimens.

3. Ramipril + Felodipine

  • Doses: 2.5/5 mg, 5/5 mg, 5/10 mg, 10/5 mg, 10/10 mg once daily.

  • Indication: Moderate to severe hypertension.

4. Trandolapril + Verapamil (unique: non-dihydropyridine CCB)

  • Doses: 1/180 mg, 2/240 mg, 4/240 mg once daily.

  • Indication: Hypertension, especially when HR control may be beneficial.

  • Notes: Caution in bradycardia, AV block, or heart failure with reduced ejection fraction.

5. Other available combinations

  • Enalapril + Felodipine.

  • Quinapril + Amlodipine.

Clinical Uses

  • Essential hypertension: Especially when monotherapy fails to achieve targets.

  • Resistant hypertension: Effective step-up therapy.

  • High cardiovascular risk: Certain combinations (e.g., perindopril + amlodipine) have outcome data showing reduced risk of stroke, myocardial infarction, and mortality.

  • Elderly or African ancestry patients: Combination therapy more effective due to reduced RAAS responsiveness in these groups.

Adverse Effects

From ACE inhibitors

  • Dry cough.

  • Angioedema (rare but serious).

  • Hyperkalemia.

  • Renal impairment (especially in bilateral renal artery stenosis).

From CCBs

  • Peripheral edema.

  • Flushing, headache, palpitations (more with dihydropyridines).

  • Bradycardia, constipation, AV block (non-dihydropyridines).

Combination benefit

  • ACE inhibitors reduce CCB-induced peripheral edema, improving tolerability.

Contraindications

  • Pregnancy (ACE inhibitors are teratogenic).

  • History of ACE inhibitor–induced angioedema.

  • Severe renal artery stenosis.

  • Hyperkalemia.

  • For trandolapril/verapamil: contraindicated in severe heart failure, significant bradycardia, or AV block.

Drug Interactions

  • Potassium supplements, potassium-sparing diuretics: Increase risk of hyperkalemia.

  • NSAIDs: May reduce antihypertensive effect, increase renal risk.

  • Beta-blockers (with verapamil or diltiazem combinations): Risk of bradycardia or AV block.

  • CYP3A4 inhibitors/inducers: Alter CCB metabolism (especially amlodipine, felodipine, verapamil).

Clinical Considerations

  • Efficacy: ACE inhibitor + CCB combination is superior in lowering BP compared with ACE inhibitor + thiazide in some populations, and has proven cardiovascular protection (e.g., ASCOT trial).

  • Tolerability: Better than CCB monotherapy (less edema) and avoids some metabolic effects of ACE inhibitor + thiazide (e.g., dyslipidemia, hyperglycemia).

  • Patient selection:

    • Useful in patients with metabolic syndrome, diabetes, or gout (avoids thiazide side effects).

    • Appropriate in patients who develop edema on CCB monotherapy.

    • Not first-line in pregnancy or bilateral renal artery stenosis.



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