What are the starting and maximum doses of Angiotensin-Converting Enzyme (ACE) inhibitors, the causes for dose adjustment, common contraindications, and side effects?

From the Guidelines

Angiotensin-converting enzyme (ACE) inhibitors are a crucial medication for treating hypertension, heart failure, and kidney disease, with common examples including lisinopril, enalapril, ramipril, and captopril, and should be started at low doses, such as lisinopril 2.5-5mg daily, enalapril 2.5mg twice daily, ramipril 1.25-2.5mg daily, or captopril 6.25mg three times daily, with maximum doses ranging from lisinopril 20-40mg daily, enalapril 10-20mg twice daily, ramipril 10mg daily, to captopril 50mg three times daily, as recommended by the 2017 ACC/AHA/HFSA focused update 1.

Key Points

• Starting doses for ACE inhibitors are typically low to minimize side effects and should be titrated upward gradually every 2-4 weeks until target blood pressure or clinical improvement is achieved.
• Dose adjustments are necessary based on blood pressure response, kidney function, electrolyte levels (particularly potassium), and symptom improvement in heart failure patients.
• Major contraindications include pregnancy (can cause fetal harm), history of angioedema, bilateral renal artery stenosis, hyperkalemia, and allergy to ACE inhibitors.
• Common side effects include dry cough (10-20% of patients), hypotension (especially first-dose), hyperkalemia, acute kidney injury, angioedema, taste disturbances, and rarely neutropenia.

Causes of Dose Adjustment

• Blood pressure response: doses should be adjusted to achieve target blood pressure.
• Kidney function: doses should be adjusted based on renal function, and ACE inhibitors should be avoided in patients with bilateral renal artery stenosis or severe renal impairment.
• Electrolyte levels: doses should be adjusted based on potassium levels, and potassium-sparing diuretics should be avoided during initiation of therapy.
• Symptom improvement: doses should be adjusted based on symptom improvement in heart failure patients.

Common Contraindications and Side Effects

• Contraindications: pregnancy, history of angioedema, bilateral renal artery stenosis, hyperkalemia, and allergy to ACE inhibitors.
• Side effects: dry cough, hypotension, hyperkalemia, acute kidney injury, angioedema, taste disturbances, and rarely neutropenia.

Recommendations

• ACE inhibitors should be started at low doses and titrated upward gradually every 2-4 weeks until target blood pressure or clinical improvement is achieved, as recommended by the 2017 ACC/AHA/HFSA focused update 1.
• The use of ACE inhibitors is beneficial for patients with prior or current symptoms of chronic heart failure to reduce morbidity and mortality, as shown in large RCTs 1.
• Although the use of an ARNI in lieu of an ACE inhibitor for HFrEF has been found to be superior, for those patients for whom ARNI is not appropriate, continued use of an ACE inhibitor for all classes of HFrEF remains strongly advised, as recommended by the 2017 ACC/AHA/HFSA focused update 1.

From the FDA Drug Label

DOSAGE & ADMINISTRATION 2. 1 Hypertension Initial Therapy in adults: The recommended initial dose is 10 mg once a day. Dosage should be adjusted according to blood pressure response. The usual dosage range is 20 mg to 40 mg per day administered in a single daily dose. 2. 2 Heart Failure The recommended starting dose for lisinopril tablets, when used with diuretics and (usually) digitalis as adjunctive therapy for systolic heart failure, is 5 mg once daily. 2. 4 Dose in Patients with Renal Impairment No dose adjustment of lisinopril tablets is required in patients with creatinine clearance > 30 mL/min. The dosage may be titrated upward until blood pressure is controlled or to a maximum of 40 mg daily.

ACE Medication Summary

• Starting Dose:
  • Lisinopril: 10 mg once daily for hypertension, 5 mg once daily for heart failure
  • Enalapril: 5 mg once daily
• Maximum Dose:
  • Lisinopril: 40 mg once daily
  • Enalapril: 40 mg daily
• Dose Adjustment:
  • Lisinopril: adjusted according to blood pressure response
  • Enalapril: titrated upward until blood pressure is controlled
• Common Contraindications:
  • Lisinopril: not recommended in pediatric patients < 6 years or in pediatric patients with glomerular filtration rate < 30 mL/min/1.73m2
  • Enalapril: not recommended in neonates and in pediatric patients with glomerular filtration rate <30 mL/min/1. 73 m 2
• Common Side Effects:
  • Lisinopril: hypotension, renal impairment
  • Enalapril: hypotension, renal impairment, hyperkalemia 2 3

From the Research

ACE Medication Overview

• ACE inhibitors are a class of drugs used to treat hypertension and heart failure by inhibiting the renin-angiotensin-aldosterone system 4.
• They exert their haemodynamic effect mainly by inhibiting the renin-angiotensin-aldosterone system, but also by modulating sympathetic nervous system activity and by increasing prostaglandin synthesis 4.

Starting Dose and Maximum Dose

• The starting dose and maximum dose of ACE inhibitors vary depending on the specific medication and the patient's condition 5.
• For example, captopril has a flat dose response curve and should be given at a dose not exceeding 150 mg/day 4.
• Lisinopril is the only ACE inhibitor that exhibits a linear dose-response curve 5.

Adjustment of Dose

• The dose of ACE inhibitors may need to be adjusted in patients with renal impairment, elderly patients, and patients with hepatic impairment 5.
• For example, trandolapril, moexipril, and imidapril require dosage reductions in patients with renal impairment 5.
• Moexipril and temocapril require dosage reductions in elderly patients, and moexipril should be given at a lower dose in patients with hepatic impairment 5.

Common Contraindications

• ACE inhibitors are contraindicated in pregnancy and in hyperkalaemic syndromes 4.
• They should be used with caution in patients with collagen disease, severe bilateral renal artery stenosis, and severe sodium depletion 4.

Common Side Effects

• Common side effects of ACE inhibitors include cough, skin rashes, fever, taste disturbances, proteinuria, and neutropenia 4.
• The side effects of ACE inhibitors are dose-dependent, and the incidence of side effects may be higher with certain medications, such as captopril and enalapril 4, 6.
• Angioedema is a rare but potentially life-threatening side effect of ACE inhibitors, and the risk is higher with certain medications, such as captopril and enalapril 7, 8.