How should I start and manage an ACE inhibitor for hypertension, including dose, titration, monitoring, contraindications, and alternatives?

ACE Inhibitor Management for Hypertension

Initial Drug Selection

For hypertension, start with lisinopril 10 mg once daily or enalapril 5 mg twice daily, as these agents have proven mortality benefits in cardiovascular disease and offer convenient dosing. 1

• All ACE inhibitors provide comparable blood pressure reduction, but agents with landmark trial evidence (captopril, enalapril, lisinopril, perindopril, ramipril, trandolapril) are preferred because they have clearly defined target doses that modify disease progression 1
• Lisinopril offers once-daily dosing convenience and is effective at 20-80 mg daily for all grades of essential hypertension 2
• Enalapril 10-20 mg twice daily has strong mortality-reduction evidence from the SOLVD trial 1

Pre-Treatment Requirements

Obtain a basic metabolic panel (creatinine, potassium) within 1-2 weeks before starting therapy. 3

• Baseline laboratory values identify patients at higher risk for adverse effects, particularly those with elevated creatinine or potassium 3
• Measure baseline blood pressure to establish starting point 3

Absolute Contraindications

Do not prescribe ACE inhibitors in patients with prior ACE inhibitor-induced angioedema, pregnancy (especially second/third trimester), bilateral renal artery stenosis, or anuric renal failure. 1

• Angioedema occurs in <1% of patients but is life-threatening; prior angioedema justifies lifetime avoidance of all ACE inhibitors 4
• ACE inhibitors cause fetal injury and death; counsel all women of childbearing age about pregnancy risks 1

Relative Contraindications (Use With Extreme Caution)

• Systolic blood pressure <80 mmHg 1
• Serum creatinine >3 mg/dL 1
• Serum potassium >5.0-5.5 mEq/L 1

Starting Doses and Titration Protocol

Start low and titrate every 1-2 weeks to target doses proven in clinical trials. 1

Recommended Starting and Target Doses:

• Lisinopril: Start 2.5-5 mg once daily → Target 20-40 mg once daily 1
• Enalapril: Start 2.5 mg twice daily → Target 10-20 mg twice daily 1
• Ramipril: Start 2.5 mg once daily → Target 5 mg twice daily or 10 mg once daily 5
• Captopril: Start 6.25 mg three times daily → Target 50 mg three times daily 1

Titration Rules:

• Increase doses every 1-2 weeks if the lower dose has been well tolerated 1
• Do not adjust more frequently than every 2 weeks to allow adequate assessment of tolerance 1
• Aim for target doses from landmark trials; intermediate doses are acceptable when target doses cannot be tolerated but represent suboptimal therapy 1

Mandatory Monitoring Schedule

Check creatinine and potassium 1-2 weeks after initiation and after each dose increase. 1, 3

Acceptable Changes:

• Creatinine increase up to 30% within the first 4 weeks is acceptable; continue therapy 1, 3
• Creatinine increase up to 50% above baseline or to 3 mg/dL (266 μmol/L), whichever is greater, is acceptable 5
• Potassium up to 5.5 mEq/L is generally acceptable 5

When to Stop or Reduce Dose:

• Creatinine rises >30% and persists beyond 4 weeks 1
• Potassium >6.0 mEq/L requires intervention 5
• Symptomatic hypotension despite dose adjustment 3

Managing Hyperkalemia

Before reducing or stopping the ACE inhibitor, eliminate other causes of hyperkalemia. 1

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

Special Populations

Hypertension with Diabetes or Chronic Kidney Disease:

ACE inhibitors are first-line therapy when albuminuria is present (ACR ≥30 mg/g); titrate to the highest tolerated dose. 1

• ACE inhibitors slow progression of diabetic nephropathy in both type 1 and type 2 diabetes 1
• The fall in glomerular filtration rate at onset of therapy is the trade-off for long-term renal protection 6

African American Patients:

• May not have as robust a response to ACE inhibitors; consider higher initial doses or start with a thiazide diuretic or long-acting calcium channel blocker instead 4

Heart Failure with Reduced Ejection Fraction:

• ACE inhibitors should be started in all patients with HFrEF unless contraindicated 4
• Combine with beta-blockers (bisoprolol, carvedilol, or sustained-release metoprolol succinate) 4
• Target doses: captopril 50 mg TID, enalapril 10-20 mg BID, lisinopril 20-40 mg daily 1

Post-Myocardial Infarction:

• Start ACE inhibitors within the first 24 hours after MI if no contraindications are present 4
• Continue indefinitely in patients with LVEF ≤40%, hypertension, diabetes, or chronic kidney disease 4

Managing ACE Inhibitor-Induced Cough

If persistent cough develops, confirm it is ACE inhibitor-related before switching to an ARB. 1

• Cough occurs in up to 20% of patients and is related to kinin potentiation 4
• ARBs (angiotensin receptor blockers) are alternatives for patients with ACE inhibitor-induced cough 4
• Caution: some patients who developed angioedema with ACE inhibitors have also developed angioedema with ARBs 4

Critical Drug Interactions

Avoid concomitant use of potassium-sparing diuretics, potassium supplements, or salt substitutes—these markedly increase hyperkalemia risk. 1

• NSAIDs (including COX-2 inhibitors) blunt the antihypertensive effect and raise the risk of acute kidney injury 1
• Never combine two ACE inhibitors—this significantly increases risk of hypotension, hyperkalemia, and renal dysfunction without additional benefit 5
• Never combine ACE inhibitor with ARB and aldosterone antagonist—this triple combination is potentially harmful 4

Common Pitfalls to Avoid

Under-Dosing:

Many clinicians prescribe only the initiation dose and fail to titrate to trial-proven target doses; this leads to suboptimal outcomes. 1

• Aim to reach target doses from landmark trials (Class I, Level A evidence) unless limited by adverse effects 1

Premature Discontinuation for Creatinine Rise:

• Do not stop ACE inhibitor for creatinine increases <30% within the first 4 weeks 1, 3
• This initial rise is expected and correlates with better long-term renal protection 6

Failure to Monitor:

• Not checking electrolytes and renal function after initiation is a common error 3
• Recheck creatinine and potassium 1-2 weeks after each dose change 1, 3

Starting Too High in High-Risk Patients:

• Patients with systolic BP <80 mmHg, low serum sodium, diabetes mellitus, or impaired renal function merit close surveillance 4
• Start with the lowest recommended dose in these patients 1

When to Consider Alternatives

Switch to an ARB if the patient develops persistent cough or has a contraindication to ACE inhibitors. 4

• ARBs (e.g., losartan, valsartan) provide similar mortality and morbidity benefits in hypertension and heart failure 4
• ARBs are associated with much lower incidence of cough and angioedema compared to ACE inhibitors 4
• For patients intolerant to both ACE inhibitors and ARBs, consider long-acting calcium channel blockers or thiazide diuretics 4