ENALAPRIL MALEATE
Clinical safety rating: avoid
NSAIDs may diminish the antihypertensive effect Lithium levels may be increased Risk of angioedema can occur at any time discontinue immediately.
Enalapril is a prodrug that is hydrolyzed to enalaprilat, a potent competitive inhibitor of angiotensin-converting enzyme (ACE), blocking the conversion of angiotensin I to angiotensin II, reducing vasoconstriction, aldosterone secretion, and sodium/water retention.
| Metabolism | Enalapril is a prodrug hydrolyzed in the liver to the active metabolite enalaprilat. Enalaprilat is not further metabolized and is excreted primarily unchanged in urine. |
| Excretion | Primarily renal (60-80% as unchanged drug and metabolites, mainly enalaprilat); biliary/fecal excretion accounts for the remainder (approximately 20-30%). |
| Half-life | Terminal elimination half-life of enalaprilat (active metabolite) is approximately 35-38 hours. This prolonged half-life supports once-daily dosing in most patients, but may require dosage adjustment in renal impairment. |
| Protein binding | Enalapril: approximately 50-60% bound to plasma proteins; Enalaprilat: approximately 50-60% bound (primarily to albumin). |
| Volume of Distribution | Enalapril: approximately 1.2 L/kg; Enalaprilat: approximately 0.6 L/kg. These values indicate moderate distribution into tissues, with enalaprilat having lower Vd due to its polarity. |
| Bioavailability | Oral enalapril maleate: approximately 60% (following hepatic de-esterification to enalaprilat). Food does not significantly affect absorption. Intravenous enalaprilat: 100% bioavailable. |
| Onset of Action | Oral: 1 hour (peak reduction in blood pressure occurs at 4-6 hours); Intravenous: 15 minutes (enalaprilat). |
| Duration of Action | Oral: 24 hours (with consistent antihypertensive effect at steady state). |
| Molecular Weight | 376.45 |
Initial: 5 mg orally once daily; titrate to 10-40 mg/day in 1-2 divided doses. Target: 10-40 mg/day. Maximum: 40 mg/day. Route: Oral. Frequency: Once or twice daily.
| Dosage form | TABLET |
| Renal impairment | GFR 30-80 mL/min: 5 mg daily initially, titrate up to max 40 mg daily. GFR 10-29 mL/min: 2.5 mg daily initially, titrate up to max 40 mg daily. GFR <10 mL/min (dialysis): 2.5 mg on dialysis days only. |
| Liver impairment | Child-Pugh Class A: No adjustment. Child-Pugh Class B: Reduce initial dose to 2.5 mg daily. Child-Pugh Class C: Use with caution; consider 2.5 mg daily and titrate slowly. |
| Pediatric use | Weight-based: 0.08 mg/kg/day up to 5 mg/day, once daily. Titrate based on response up to 0.58 mg/kg/day (max 40 mg/day). |
| Geriatric use | Initiate at 2.5 mg daily; titrate cautiously to avoid hypotension; maximum 40 mg/day. |
| 1st trimester | Associated with increased risk of fetal renal dysfunction, oligohydramnios, and skull ossification defects. Avoid use in first trimester unless no alternative. |
| 2nd trimester | Can cause fetal hypotension, renal failure, skull hypoplasia, and death. Contraindicated. |
| 3rd trimester | Can cause neonatal hypotension, renal failure, hyperkalemia, and death. Contraindicated. |
Clinical note
NSAIDs may diminish the antihypertensive effect Lithium levels may be increased Risk of angioedema can occur at any time discontinue immediately.
| FDA category | Contraindicated |
| Placental transfer | Enalaprilat (active metabolite) crosses the placenta. Fetal levels are detectable in umbilical cord blood. Evidence suggests significant transfer. |
| Breastfeeding |
■ FDA Black Box Warning
Fetal toxicity: Drugs acting directly on the renin-angiotensin system can cause injury and death to the developing fetus. Discontinue as soon as possible once pregnancy is detected.
| Common Effects | heart failure |
| Serious Effects |
History of angioedema related to previous ACE inhibitor therapyConcomitant use with aliskiren in patients with diabetes mellitusPregnancy (especially second and third trimesters)Concomitant use with sacubitril/valsartan (due to increased risk of angioedema)
| Precautions | Angioedema (including laryngeal edema and death), Hypotension, especially in volume-depleted patients, Renal impairment, including acute renal failure, especially in bilateral renal artery stenosis, Hyperkalemia, particularly with renal dysfunction or concomitant potassium-sparing diuretics, Cough (non-productive, persistent), Hepatic failure (rare) |
| Food/Dietary |
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| Enalapril is excreted into human milk in low concentrations. In preterm infants and neonates, risk of hypotension, renal impairment, and hyperkalemia. Use with caution, especially in infants <1 month or with renal impairment. |
| Lactation Rating | L3 (Moderately Safe) |
| Teratogenic Risk | First trimester: Contains pregnancy category D data; however, the risk of major congenital malformations is considered low based on human cohort studies, though some studies suggest a small increased risk of renal and cardiovascular anomalies. Second and third trimesters: Fetal and neonatal toxicity including oligohydramnios, fetal renal impairment, skull ossification defects, hypotension, and anuria. Exposure after 12 weeks gestation is strongly associated with oligohydramnios, which can lead to fetal limb contractures, pulmonary hypoplasia, and neonatal death. ACE inhibitors are contraindicated in the second and third trimesters. |
| Fetal Monitoring | Maternal: Blood pressure, serum creatinine, blood urea nitrogen (BUN), electrolytes, and urine protein. Fetal: Serial ultrasound monitoring for amniotic fluid volume, fetal growth, and renal anomalies if exposed in utero, especially after 20 weeks gestation. Neonatal: Monitor for hypotension, oliguria, hyperkalemia, and neurologic status if exposed near term. |
| Fertility Effects | No evidence of impaired fertility in animal studies. In humans, ACE inhibitors are not associated with reduced fertility. However, untreated hypertension may contribute to infertility, so controlling blood pressure could improve fertility outcomes. |
| Avoid large amounts of potassium-rich foods (e.g., bananas, oranges, potatoes, tomatoes, avocados, spinach) and potassium-containing salt substitutes. High-fat meals may reduce absorption slightly but not clinically significant. Avoid excessive alcohol intake, which can increase hypotensive effects. |
| Clinical Pearls | Monitor serum potassium and renal function within 1-2 weeks after initiation or dose increase. ACE inhibitor cough is more common in women and may appear months after starting therapy. First-dose hypotension risk is highest in volume-depleted patients; consider starting at 2.5 mg. In heart failure, titrate to target dose of 10-20 mg twice daily as tolerated. Avoid in pregnancy; use two forms of contraception in childbearing potential. Enalaprilat, the active metabolite, is dialyzable. |
| Patient Advice | Take this medication exactly as prescribed, usually once or twice daily with or without food. · Do not use salt substitutes containing potassium without consulting your doctor. · Avoid becoming dehydrated; drink plenty of fluids unless otherwise advised. · If you experience lightheadedness, especially after the first dose, sit or lie down and avoid sudden position changes. · Contact your healthcare provider if you develop a persistent dry cough, swelling of the face or extremities, or difficulty breathing. · This medication can cause birth defects; use effective contraception and inform your doctor immediately if you become pregnant. · Do not stop taking this medication abruptly without consulting your doctor. |