Enalapril

Enalapril is an angiotensin converting enzyme inhibitor prodrug converted in the liver to enalaprilat. It is used in hypertension, heart failure with reduced ejection fraction, asymptomatic left ventricular dysfunction and diabetic kidney disease. It is widely available and low cost in East Africa.

Classification. Angiotensin converting enzyme inhibitor; carboxyl containing prodrug.

Mechanism. Blocks conversion of angiotensin I to angiotensin II, lowering vasoconstriction and aldosterone secretion, and prevents breakdown of bradykinin (the likely cause of cough and angioedema).

Pharmacodynamics. Oral onset 1 hour, peak 4 to 6 hours, duration 12 to 24 hours. Efferent arteriolar dilation reduces glomerular pressure and proteinuria. Plasma potassium rises slightly.

Pharmacokinetics. Oral bioavailability about 60%; enalaprilat half life about 11 hours; excreted unchanged in urine, so accumulates in kidney impairment.

Hypertension, adult.

• Start 5 mg once daily (2.5 mg if on a diuretic, volume depleted, older, or creatinine clearance 30 mL/min or less).

• Increase after 1 to 2 weeks to the usual range 10 to 20 mg daily in one or two doses.

• Maximum 40 mg daily.

Heart failure with reduced ejection fraction, adult.

• Start 2.5 mg once or twice daily under observation.

• Increase every 2 weeks as tolerated to the target 10 to 20 mg twice daily.

• Maximum 40 mg daily.

• Add a beta blocker, a mineralocorticoid antagonist, and a diuretic as needed.

Asymptomatic left ventricular dysfunction, adult. 2.5 mg twice daily, titrated to 10 mg twice daily.

Hypertensive emergency, enalaprilat IV (where available). 1.25 mg IV over 5 minutes every 6 hours; maximum 5 mg every 6 hours. Use is limited by unpredictable response; avoid in acute myocardial infarction.

Children, hypertension. 0.08 mg/kg daily (maximum 5 mg) initially, increased as needed to a maximum 0.58 mg/kg or 40 mg daily. Specialist.

Contraindications. Pregnancy; history of angioedema (hereditary, idiopathic or from an angiotensin converting enzyme inhibitor); bilateral renal artery stenosis or stenosis in a single kidney; hyperkalaemia; hypotension; concurrent sacubitril with valsartan (36 hour gap required); aliskiren in diabetes or kidney impairment.

Warnings. Angioedema occurs more often in patients of African ancestry and can affect the airway; stop permanently. Dry cough in 5 to 15%. First dose hypotension. Hyperkalaemia and kidney function decline. Sick day rule: hold during vomiting, diarrhoea or dehydration and restart when eating and drinking. Neutropenia (rare).

Adverse effects. Cough, dizziness, hypotension, hyperkalaemia, creatinine rise, rash, taste disturbance, angioedema.

Interactions. Potassium supplements, potassium sparing diuretics, trimethoprim, ciclosporin: hyperkalaemia. Non steroidal anti-inflammatory drugs: kidney injury and reduced effect. Diuretics: first dose hypotension. Lithium: raised lithium. Allopurinol: hypersensitivity. Gold salts: flushing. Sacubitril: angioedema.

Special groups.

• Pregnancy: contraindicated; foetal kidney injury, oligohydramnios and skull defects; stop when pregnancy is confirmed.

• Breastfeeding: acceptable for term infants; small amounts in milk.

• Patients of African ancestry: reduced blood pressure response as monotherapy; add a calcium channel blocker or thiazide like diuretic; higher angioedema risk.

• Older adults: start at 2.5 mg.

• Kidney impairment: creatinine clearance 30 mL/min or less: start 2.5 mg daily; titrate to effect.

• Liver impairment: conversion to the active form may be reduced; titrate by response.

Formulations. Tablets 2.5, 5, 10, 20 mg; injection (enalaprilat) 1.25 mg/mL; oral solution in some markets.

Administration. Oral once or twice daily, with or without food. First dose at bedtime or with supervision in at risk patients.

Baseline. Blood pressure, creatinine and eGFR, potassium, pregnancy status, history of angioedema.

Monitoring. Creatinine and potassium 1 to 2 weeks after starting or each dose increase, then every 6 to 12 months. Accept a rise in creatinine up to 30% from baseline. Reduce or stop if creatinine rises over 30% or potassium is over 6.0 mmol/L; review other contributors if potassium is over 5.5 mmol/L. Blood pressure, cough, swelling.

Stopping. Stop for angioedema, pregnancy, intractable cough (switch to an angiotensin receptor blocker), or creatinine rise over 30% or potassium over 6.0 mmol/L.

Common prescribing errors. Starting at full dose with a diuretic; using it in pregnancy; ignoring the 36 hour gap with sacubitril; failing to check potassium and creatinine; continuing during dehydrating illness.