ACE Inhibitors

ACE inhibitors block angiotensin-converting enzyme, lowering angiotensin II and aldosterone and raising bradykinin. They reduce blood pressure, protect the kidney in proteinuric disease, and improve survival in heart failure with reduced ejection fraction, after myocardial infarction and in high-risk vascular disease.

Members. Captopril, enalapril, lisinopril, ramipril, perindopril, quinapril, benazepril, fosinopril, trandolapril, imidapril and moexipril.

Mechanism. The enzyme (kininase II) converts angiotensin I to angiotensin II and breaks down bradykinin. Inhibition lowers vasoconstriction and aldosterone-driven sodium retention, dilates the efferent arteriole to lower glomerular pressure, and raises bradykinin and nitric oxide, which contributes to cough and angioedema.

Prodrugs and active agents. Captopril and lisinopril are active as given. The others are prodrugs activated in the liver. Lisinopril and captopril are renally cleared, fosinopril is cleared equally by liver and kidney.

Pharmacokinetics. Captopril acts within 30 to 60 minutes and lasts 6 to 8 hours. Enalapril and ramipril act for 24 hours. Lisinopril has a long terminal half-life. Absorption of captopril falls with food.

Pregnancy risk. Use in the second and third trimester causes foetal renal failure, oligohydramnios, skull hypoplasia and death.

• Captopril: three times daily; contains a sulphydryl group; taste disturbance, rash and neutropenia are more frequent.
• Enalapril: prodrug, twice daily in heart failure.
• Lisinopril: water soluble, once daily, not metabolised.
• Ramipril: once or twice daily; best outcome data in high-risk vascular disease and after infarction.
• Perindopril: once daily; stable coronary disease, hypertension, stroke prevention with indapamide.
• Others (quinapril, benazepril, trandolapril, fosinopril): once daily; similar class effects.

• Hypertension: ramipril 2.5 mg daily, increased to 5 to 10 mg; lisinopril 10 mg daily, increased to 20 to 40 mg; enalapril 5 mg daily, increased to 10 to 40 mg; perindopril 4 mg daily, increased to 8 mg. Start with half the dose if on a diuretic, volume depleted or with renal impairment, preferably at bedtime.
• Heart failure with reduced ejection fraction: ramipril 1.25 to 2.5 mg daily increased to 10 mg daily or 5 mg twice daily; enalapril 2.5 mg twice daily increased to 10 to 20 mg twice daily; lisinopril 2.5 to 5 mg daily increased to 20 to 35 mg daily; captopril 6.25 mg 3 times daily increased to 50 mg 3 times daily.
• After myocardial infarction: ramipril 2.5 mg twice daily, increased to 5 mg twice daily.
• Vascular disease prevention: ramipril 10 mg daily.
• Diabetic and proteinuric kidney disease: titrate to the maximum tolerated dose with attention to potassium and creatinine.
• Selection: an angiotensin receptor blocker replaces an ACE inhibitor when cough is troublesome. Do not combine an ACE inhibitor with an angiotensin receptor blocker or aliskiren.

Contraindications. Pregnancy and planned pregnancy, previous angioedema (hereditary or with any ACE inhibitor), bilateral renal artery stenosis or stenosis in a single functioning kidney, potassium over 5.5 mmol/L, and use with sacubitril-valsartan within 36 hours. Caution in severe aortic stenosis, hypotension and hypovolaemia.

Adverse effects. Dry cough in about 10% to 15% of patients, more often in women and some Asian populations, hypotension (first dose), hyperkalaemia, acute kidney injury, taste disturbance, rash, and angioedema in under 1% overall, but 3 times more often in patients of African ancestry and at any time during therapy.

Angioedema. Lip, tongue or throat swelling without urticaria. It does not respond reliably to antihistamines or steroids. Give oxygen, secure the airway early, and use adrenaline 500 micrograms intramuscularly if there is airway compromise. Stop all ACE inhibitors permanently.

Acceptable laboratory change. A creatinine rise of up to 30% or an eGFR fall of up to 25% within 2 weeks of starting is expected. Larger rises mean look for renal artery stenosis, volume depletion or NSAID use. Stop for potassium over 6 mmol/L.

Interactions. NSAIDs, potassium supplements, potassium-sparing diuretics, spironolactone, trimethoprim, ciclosporin and heparin raise potassium or injure the kidney. Lithium toxicity. Allopurinol hypersensitivity. Sacubitril, mTOR inhibitors and DPP-4 inhibitors raise angioedema risk.

Monitoring. Blood pressure, potassium and creatinine before starting, 1 to 2 weeks after each dose increase, then at least yearly.

Sick day rule. Withhold during vomiting, diarrhoea or other dehydrating illness and restart after 24 to 48 hours of normal intake.

Special groups. Pregnancy: stop before conception or as soon as pregnancy is confirmed. Breastfeeding: enalapril and captopril are compatible in healthy term infants. Renal impairment: start at a quarter to half of the usual dose and reduce lisinopril and enalapril doses as eGFR falls. Black patients: lower blood pressure effect as monotherapy, with higher angioedema risk. Older adults: start low.