What are angiotensin‑converting enzyme (ACE) inhibitors?

What Are ACE Inhibitors?

ACE inhibitors (angiotensin-converting enzyme inhibitors) are medications that block the enzyme responsible for converting angiotensin I to angiotensin II, thereby reducing vasoconstriction, lowering blood pressure, decreasing cardiac workload, and providing organ protection in cardiovascular and renal disease. 1

Mechanism of Action

ACE inhibitors work through two primary pathways that produce clinical benefit:

• Angiotensin II suppression: They block the conversion of angiotensin I to angiotensin II, a potent vasoconstrictor that also promotes sodium and water retention through aldosterone stimulation. 1, 2

• Bradykinin potentiation: They inhibit the degradation of bradykinin, a vasodilatory peptide that augments prostaglandin production and contributes to blood pressure reduction. 1

This dual mechanism results in arterial and venous vasodilation, natriuresis, decreased sympathetic activity, and reduced systemic vascular resistance without reflex tachycardia. 3, 4

Primary Clinical Indications

Heart Failure with Reduced Ejection Fraction (HFrEF)

ACE inhibitors are mandatory first-line therapy for all patients with HFrEF (ejection fraction <35-40%) unless contraindicated. 1

• More than 7,000 patients in over 30 placebo-controlled trials demonstrated that ACE inhibitors reduce mortality, decrease hospitalizations, alleviate symptoms, and improve functional status in patients with mild, moderate, or severe heart failure. 1

• The benefits occur regardless of coronary artery disease presence and are seen across diverse patient populations including women and elderly patients. 1

• ACE inhibitors must be used in conjunction with evidence-based beta blockers and aldosterone antagonists in selected patients to achieve optimal mortality reduction. 1

Post-Myocardial Infarction

• ACE inhibitors reduce cardiovascular mortality and prevent ventricular remodeling in patients with left ventricular dysfunction after myocardial infarction. 5

Diabetic Nephropathy and Chronic Kidney Disease

• ACE inhibitors slow progression of diabetic nephropathy in both type 1 and type 2 diabetes by reducing proteinuria and preserving renal function. 1, 5

• They are first-line therapy when albuminuria is present (albumin-to-creatinine ratio ≥30 mg/g), with doses titrated to the highest tolerated level. 6

Hypertension

• ACE inhibitors are first-line antihypertensive agents with efficacy comparable to thiazide diuretics, calcium channel blockers, and angiotensin receptor blockers. 7, 8

Available ACE Inhibitors and Target Dosing

The following ACE inhibitors have proven mortality and morbidity benefits in landmark trials and should be preferentially selected: 6

• Captopril: 6.25 mg three times daily initially, target 50 mg three times daily 1, 6
• Enalapril: 2.5 mg twice daily initially, target 10-20 mg twice daily 1, 6
• Lisinopril: 2.5-5 mg once daily initially, target 20-40 mg once daily 1, 6
• Ramipril: 1.25-2.5 mg once daily initially, target 10 mg once daily 1
• Perindopril: 2 mg once daily initially, target 8-16 mg once daily 1
• Trandolapril: 1 mg once daily initially, target 4 mg once daily 1

Initiation and Monitoring Protocol

Pre-Treatment Assessment

Before starting an ACE inhibitor, obtain: 6, 5

• Basic metabolic panel (serum creatinine, potassium)
• Blood pressure measurement including orthostatic readings
• Pregnancy test in women of childbearing age

Titration Strategy

Start at low doses and increase every 1-2 weeks until target doses from clinical trials are reached, unless limited by hypotension, hyperkalemia, or creatinine rise >30%. 1, 6

• Many clinicians fail to titrate beyond initiation doses, resulting in suboptimal outcomes. 6
• Target doses from landmark trials represent Class I, Level A evidence and should be the goal unless adverse effects prevent achievement. 6
• Intermediate doses are acceptable when target doses cannot be tolerated but represent suboptimal therapy. 6

Mandatory Monitoring Schedule

• 1-2 weeks after initiation: Check serum creatinine, potassium, and blood pressure. 6, 5
• 1-2 weeks after each dose increase: Repeat metabolic panel and blood pressure. 6, 5
• Acceptable creatinine rise: Up to 30% increase within the first 4 weeks is acceptable and therapy should continue. 6, 5
• Discontinuation threshold: Stop or reduce dose if creatinine rises >30% from baseline or if refractory hyperkalemia develops. 6, 5

Adverse Effects and Management

Cough

• Occurs in up to 20% of patients due to bradykinin accumulation. 1, 5
• Before switching to an ARB, confirm the cough is truly ACE inhibitor-related and not due to other causes. 6

Angioedema

• Occurs in <1% of patients but is more frequent in Black patients and women. 1
• This is a life-threatening reaction that mandates permanent discontinuation of all ACE inhibitors. 1
• ARBs may be considered as alternative therapy, but some patients develop angioedema with ARBs as well; use extreme caution. 1

Hyperkalemia

Before reducing or stopping the ACE inhibitor for hyperkalemia: 6

1. Review and discontinue concurrent medications that raise potassium (NSAIDs, potassium-sparing diuretics, potassium supplements, salt substitutes)
2. Advise moderate dietary potassium restriction
3. Correct volume depletion
4. Reduce or discontinue ACE inhibitor only if hyperkalemia remains refractory after these measures

Hypotension

• ACE inhibitors should not be prescribed without diuretics in patients with current or recent fluid retention, as diuretics maintain sodium balance and prevent edema. 1
• Hypotension with signs of fluid retention suggests worsening heart failure rather than volume depletion and requires intensification of therapy, not dose reduction. 1

Absolute Contraindications

ACE inhibitors must not be used in: 6, 5

• Prior ACE inhibitor-induced angioedema
• Pregnancy (especially second and third trimesters) or women planning to become pregnant
• Bilateral renal artery stenosis or stenosis of a solitary kidney
• Anuric renal failure

Relative Contraindications (Use With Extreme Caution)

1, 6

• Systolic blood pressure <80 mmHg
• Serum creatinine >3 mg/dL
• Serum potassium >5.0-5.5 mEq/L

Critical Drug Interactions

• Potassium-sparing diuretics, potassium supplements, salt substitutes: Markedly increase hyperkalemia risk. 6
• NSAIDs (including COX-2 inhibitors): Blunt antihypertensive effect and increase acute kidney injury risk. 6

Common Clinical Pitfall

The most frequent error in ACE inhibitor prescribing is failure to titrate beyond initiation doses. 6 Clinicians must systematically increase doses every 1-2 weeks toward trial-proven targets to achieve the mortality and morbidity benefits demonstrated in clinical trials. Stopping at initiation doses provides suboptimal disease modification and inferior outcomes.