For an otherwise healthy adult with uncomplicated primary hypertension and no contraindications, what is the recommended ACE‑inhibitor choice, starting dose, titration, monitoring, common adverse effects, contraindications, and alternative therapy?

ACE Inhibitor Therapy for Uncomplicated Primary Hypertension

ACE inhibitors are a reasonable first-line choice for uncomplicated primary hypertension in non-Black adults, though thiazide diuretics have stronger evidence for reducing cardiovascular events and should be considered the preferred initial agent. 1, 2, 3

Agent Selection and Starting Doses

Choose one of these evidence-based ACE inhibitors with proven cardiovascular outcomes: 2

• Captopril: Start 6.25 mg three times daily
• Enalapril: Start 2.5 mg twice daily
• Lisinopril: Start 2.5–5 mg once daily
• Ramipril: Start 1.25–2.5 mg once daily

The once-daily formulations (lisinopril, ramipril, enalapril) improve adherence compared to captopril's three-times-daily dosing. 1

Titration Strategy

Uptitrate gradually every 2–4 weeks to target doses that demonstrated cardiovascular benefit in clinical trials: 2

• Captopril: Target 50 mg three times daily
• Enalapril: Target 10–20 mg twice daily
• Ramipril: Target 10 mg once daily

Do not stop at initial blood pressure response—push to maximum tolerated doses for optimal cardiovascular protection. 2

Blood Pressure Targets

Target <130/80 mmHg for most adults with hypertension. 1, 4

• Minimum acceptable target is <140/90 mmHg 4
• For patients ≥65 years who are ambulatory and community-dwelling, target SBP <130 mmHg if tolerated 1

Monitoring Requirements

Check serum creatinine and potassium within 1–2 weeks of initiation and after each dose increase. 1, 2

• Accept up to 30% increase in serum creatinine as expected hemodynamic effect 2
• Discontinue only if creatinine rises beyond 30%, refractory hyperkalemia develops (>5.5 mEq/L), or acute kidney injury occurs 2
• Recheck blood pressure monthly until target achieved 5
• More frequent monitoring needed in patients with baseline hypotension, hyponatremia, diabetes, azotemia, or those taking potassium supplements 2

Common Adverse Effects

Cough is the most frequent adverse effect, occurring in 5–20% of patients, though incidence is often overestimated. 6, 7

• Dry, persistent cough typically develops within weeks to months 6
• Angioedema is rare but serious (0.1–0.7% incidence) 6
• Hyperkalemia risk increases with renal impairment, diabetes, or concurrent potassium-sparing agents 2
• First-dose hypotension, particularly in volume-depleted patients 2, 8
• Headache, fatigue, dizziness, and diarrhea occur less commonly 8

If intolerable cough develops, switch to an ARB rather than discontinuing RAAS blockade entirely. 2, 6

Absolute Contraindications

Do not prescribe ACE inhibitors in these situations: 2

• Pregnancy or women planning pregnancy (teratogenic)
• History of angioedema with prior ACE inhibitor use
• Bilateral renal artery stenosis
• Current hyperkalemia >5.5 mEq/L

Relative Contraindications and Cautions

Use with extreme caution or avoid in: 2

• Systolic blood pressure <80 mmHg
• Serum creatinine >3 mg/dL (consider nephrology consultation)
• Severe aortic stenosis
• Hypertrophic cardiomyopathy with outflow obstruction

When to Add or Switch Therapy

If blood pressure remains ≥140/90 mmHg on maximum tolerated ACE inhibitor monotherapy, add a second agent from a different class. 1, 4

Preferred combination partners: 1, 4

• Thiazide diuretic (chlorthalidone preferred over hydrochlorothiazide for superior cardiovascular outcomes)
• Calcium channel blocker (amlodipine or other dihydropyridine)

For stage 2 hypertension (≥160/100 mmHg or ≥20/10 mmHg above target), initiate combination therapy immediately rather than sequential monotherapy. 1, 4

If triple therapy (ACE inhibitor + CCB + thiazide) fails to achieve target, add spironolactone and refer to hypertension specialist. 1

Critical Drug Interactions

Never combine an ACE inhibitor with an ARB or direct renin inhibitor—this dual RAAS blockade increases hyperkalemia, syncope, and acute kidney injury without cardiovascular benefit. 5, 2

Counsel patients to temporarily hold ACE inhibitor during volume depletion (vomiting, diarrhea, excessive sweating) to prevent acute kidney injury. 2

Race-Based Considerations

For Black patients without heart failure or chronic kidney disease, thiazide diuretics or calcium channel blockers are preferred over ACE inhibitors as initial monotherapy because RAAS inhibitors produce less blood pressure reduction in low-renin populations. 1, 4

However, ACE inhibitors remain appropriate as second-line agents or in combination therapy for Black patients. 1

Alternative First-Line Options

Thiazide diuretics (particularly chlorthalidone) have the strongest evidence for reducing cardiovascular events, heart failure hospitalization, and stroke compared to ACE inhibitors, ARBs, or calcium channel blockers. 4, 3

Network meta-analyses show no significant mortality difference between ACE inhibitors, ARBs, and CCBs, but thiazides demonstrate superior heart failure prevention. 4, 3

If ACE inhibitors cannot be used, ARBs provide equivalent cardiovascular outcomes with lower adverse event rates (no cough, less angioedema). 6, 7

Special Populations Favoring ACE Inhibitors

ACE inhibitors are particularly beneficial and should be strongly considered in: 2, 7

• Heart failure with reduced ejection fraction (second choice after ARNI)
• Post-myocardial infarction (start within 24 hours)
• Chronic kidney disease with albuminuria
• Diabetes mellitus with nephropathy
• Coronary artery disease

For these compelling indications, ACE inhibitors provide benefits beyond blood pressure control. 1, 2, 7