ACE Inhibitors: Complete List and Key Differences

Available ACE Inhibitors

Eight ACE inhibitors are FDA-approved and clinically available in the United States: captopril, enalapril, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril, trandolapril, and benazepril 1, 2, 3. Additionally, enalaprilat is available as the only intravenous ACE inhibitor formulation 4, 3.

Critical Structural and Chemical Differences

Prodrug vs. Active Drug Status

Only captopril and lisinopril are NOT prodrugs – they are administered in their active form and do not require hepatic conversion 2, 3, 5.
All other ACE inhibitors are prodrugs requiring hepatic esterolysis to convert them to their active diacid metabolites (e.g., enalapril → enalaprilat, perindopril → perindoprilat, ramipril → ramiprilat) 6, 7, 2, 8.
Enalaprilat (IV formulation) is also not a prodrug and can be given to patients with severe hepatic dysfunction 4, 3.

Functional (Binding) Groups

ACE inhibitors are classified by their zinc-binding ligand, which influences their pharmacokinetic and safety profiles 2, 9:

Sulfhydryl-containing: Captopril (and alacepril, which converts to captopril in vivo) 2, 9.
Carboxyl-containing: Enalapril, lisinopril, benazepril, quinapril, perindopril, ramipril, cilazapril, spirapril, delapril, trandolapril 2, 9, 8.
Phosphoryl-containing: Fosinopril 2, 9.

Pharmacokinetic Differences That Matter Clinically

Elimination Routes

Predominantly renal elimination: Captopril, enalapril, lisinopril, quinapril, moexipril 2, 3, 5.
Lisinopril is the ONLY ACE inhibitor with exclusively renal elimination and no hepatic metabolism – preferred in severe liver disease 3, 5.
Dual (balanced) renal and hepatic elimination: Fosinopril, benazepril, ramipril, spirapril, trandolapril 3, 5, 8.
Fosinopril is unique with compensatory dual elimination – it does NOT require dose adjustment in renal insufficiency because hepatic excretion compensates when renal function declines 3, 5.

Bioavailability

Highest bioavailability: Captopril (60–75%), ramipril (50–60%) 2, 5.
Moderate bioavailability: Enalapril (~~40%), perindopril (~~75% for parent, but only 25% as active metabolite) 6, 2.
Lowest bioavailability: Lisinopril (~~25%), moexipril (~~13%), trandolapril (~11%) 7, 2, 5.

Food Interactions

Captopril and moexipril absorption is reduced by 30–50% when taken with food – both must be taken on an empty stomach (1 hour before meals) 7, 3.
All other ACE inhibitors can be taken without regard to meals 6, 3.

Half-Life and Dosing Frequency

Short half-life (requires 2–3 times daily dosing): Captopril (t½ ~2 hours, dosed TID) 1, 5, 8.
Intermediate half-life (once or twice daily): Enalapril, quinapril, benazepril 5, 8.
Long half-life (reliable once-daily dosing): Lisinopril, ramipril, perindopril, trandolapril, fosinopril 1, 5, 8.

Trough-to-Peak Ratios (for Once-Daily Dosing)

For true 24-hour blood pressure control with once-daily dosing, trough-to-peak ratio should be ≥50% 2:

Fosinopril, ramipril, and trandolapril have trough-to-peak ratios ≥50% – these are the most reliable for once-daily antihypertensive therapy 2.
Captopril and enalapril have lower trough-to-peak ratios and may require twice- or thrice-daily dosing for sustained effect 2, 8.

Lipophilicity and Tissue Penetration

Most lipophilic: Fosinopril, ramipril, trandolapril, perindopril 2, 8.
Least lipophilic (most hydrophilic): Lisinopril, enalaprilat 2, 8.
Lipophilic ACE inhibitors may have greater tissue ACE inhibition (cardiac, vascular, renal), though clinical significance remains debated 2, 9.

Evidence-Based Selection for Specific Indications

Heart Failure with Reduced Ejection Fraction (HFrEF)

Captopril, enalapril, and lisinopril have the strongest mortality-reduction evidence from landmark trials (CONSENSUS, SOLVD, ATLAS) and should be first-line agents 1, 10. Ramipril, perindopril, and trandolapril also have proven mortality benefits in post-MI and heart failure populations 1, 10.

Target doses from trials must be reached through titration 1, 10:

Captopril: 50 mg TID 1, 10.
Enalapril: 10–20 mg BID 1, 10.
Lisinopril: 20–40 mg once daily 1, 10.
Ramipril: 10 mg once daily 1.
Trandolapril: 4 mg once daily 1.

Hypertension with Diabetes and Chronic Kidney Disease

Any ACE inhibitor is acceptable as first-line therapy when albuminuria is present (ACR ≥30 mg/g), with dose titrated to the highest tolerated level 10, 11. Ramipril has specific evidence from the HOPE trial showing 25% reduction in MI, stroke, or death in diabetic patients 11.

Post-Myocardial Infarction with LV Dysfunction

Captopril, ramipril, trandolapril, and perindopril have proven benefits in reducing cardiovascular mortality and preventing ventricular remodeling 1, 11.

Dose Adjustments in Renal Insufficiency

All ACE inhibitors except fosinopril require dose reduction when creatinine clearance falls below 30 mL/min 1, 10, 5.
Fosinopril does NOT require dose adjustment in renal insufficiency due to compensatory hepatic elimination 3, 5.
Lisinopril and captopril (not prodrugs) are preferred in severe hepatic disease 3, 5.

Adverse Effect Profiles

Class-Wide Adverse Effects

Cough occurs in up to 20–26.9% of patients due to bradykinin accumulation; this is a class effect, not drug-specific 1, 11.
Angioedema occurs in <1% but is more frequent in Black patients and women; it is life-threatening and contraindicates all future ACE inhibitor use 1, 11.
Hypotension, hyperkalemia, and worsening renal function are common across all agents 1, 10.

Drug-Specific Considerations

Captopril's sulfhydryl group was historically associated with rash, taste disturbances, and neutropenia, though these are rare at modern doses (<150 mg/day) 1, 2.
No meaningful differences in discontinuation rates exist between ACE inhibitors and placebo in heart failure trials (12.3% vs. 17% in SOLVD) 1.

Practical Selection Algorithm

For HFrEF: Use captopril, enalapril, or lisinopril (strongest mortality evidence); titrate to trial-proven target doses 1, 10.
For once-daily dosing in hypertension: Prefer fosinopril, ramipril, or trandolapril (trough-to-peak ≥50%) 2.
For severe liver disease: Use lisinopril (no hepatic metabolism) or captopril (not a prodrug) 3, 5.
For renal insufficiency (CrCl <30 mL/min): Use fosinopril (no dose adjustment needed) or reduce doses of all others 3, 5.
For patients who cannot take medications with food: Avoid captopril and moexipril 7, 3.
For IV administration: Enalaprilat is the only option 4, 3.

Common Pitfalls to Avoid

Under-dosing is pervasive in clinical practice – many clinicians prescribe only initiation doses and fail to titrate to trial-proven targets, leading to suboptimal outcomes 10.
Do not stop ACE inhibitors for creatinine rises <30% within the first 4 weeks – this is expected and acceptable 1, 10.
Do not assume all ACE inhibitors are interchangeable for once-daily dosing – only fosinopril, ramipril, and trandolapril have trough-to-peak ratios ≥50% 2.
Do not switch to an ARB reflexively for cough – confirm the cough is truly ACE inhibitor-related first, as cough is common in heart failure itself 1, 10.

What are all angiotensin‑converting‑enzyme (ACE) inhibitors and how do they differ?

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