Enalapril is an angiotensin-converting enzyme (ACE) inhibitor widely used in the therapy of hypertension and heart failure. Enalapril is associated with a low rate of transient serum aminotransferase elevations and has been linked to rare instances of acute liver injury.
Enalapril was the second ACE inhibitor to be approved for use in the United States and is still widely used for therapy of hypertension and heart failure. Like other ACE inhibitors, enalapril inhibits the conversion of angiotensin I, a relatively inactive molecule, to angiotensin II which is the major mediator of vasoconstriction and volume expansion induced by the renin-angiotensin system. Other enzymes besides that which converts angiotensin I to II may also be inhibited, which may account for some of the side effects of the ACE inhibitors. Like many other ACE inhibitors, enalapril is a prodrug and must be hydrolyzed in the liver to its active carboxylic metabolite, enalaprilat. Enalapril was approved for use in the United States in 1985 and current indications include hypertension, symptomatic heart failure and prevention of progression of left ventricular dysfunction. Enalapril is available in 2.5, 5, 10 and 20 mg tablets in generic forms and under the trade name Vasotec. The typical initial oral dose of enalapril in adults is 2.5 to 5 mg once or twice daily, which can be increased to a maximum of 40 mg daily. Injectable formulations of enalaprilat, the active metabolic product of enalapril, are available in 1 and 2 mL vials of 1.25 mg/mL for intravenous administration. Enalapril is also available in fixed combinations with hydrochlorothiazide (generically and as Vaseretic) and with felodipine (Lexxel). Common side effects include dizziness, fatigue, headache, cough, gastrointestinal upset and skin rash.
Enalapril, like other ACE inhibitors, has been associated with a low rate of serum aminotransferase elevations (<2%) that, in controlled trials, was no higher than with placebo therapy. These elevations were transient and rarely required dose modification. In addition, more than a dozen instances of clinically apparent acute liver injury have been reported with enalapril therapy. The onset is usually within 2 to 12 weeks of starting therapy and the serum enzyme pattern is typically cholestatic. In some instances, cholestasis has been prolonged and relapsing and associated with persistent elevations in serum alkaline phosphatase, suggestive of vanishing bile duct syndrome. Immunoallergic manifestations (rash, fever, eosinophilia) are infrequent and most patients do not develop autoantibodies. There have also been striking instances of enalapril liver injury with a hepatocellular pattern. These cases typically have a long latency (one or more years), some of which have been severe and fatal. The appearance of an acute liver injury more than a year after starting a medication is distinctly unusual, but has been described for several ACE inhibitors.
Mechanism of Injury
The cause of the minor serum aminotransferase elevations associated with enalapril is not known. The clinically apparent cases of hepatotoxicity due to enalapril are clearly idiosyncratic and likely due to a reaction to a metabolite. The instances of enalapril associated liver injury associated with a long latency may be due to a different mechanism. Enalapril is metabolized by the liver to enalaprilat, its active form, but further hepatic metabolism is minimal and enalapril has little interaction with the cytochrome P450 system.
Outcome and Management
Most instances of acute liver injury reported with enalapril use have been self limited, but severe and fatal instances have been reported as have cases of vanishing bile duct syndrome. Patients with severe enalapril induced acute liver injury should avoid use of other ACE inhibitors, although cross sensitivity to liver injury among the members of this class of agents has not always been shown.
|Medication:||Enalapril (15 mg daily)|
|Severity:||3+ (jaundice, hospitalization)|
|Latency:||6 weeks to jaundice|
|Recovery:||Partial after 2 weeks, complete after 12 weeks|
|Time After Starting||Days After Stopping||ALT* (U/L)||Alk P* (U/L)||Bilirubin* (mg/dL)||Other|
|6 weeks||0||236||437||8.9||Admission for jaundice|
|6.5 weeks||0||110||505||6.4||Enalapril stopped|
|7 weeks||3 days||65||490||3.8|
|8 weeks||10 days||25||205||0.9||Hospital discharge|
|5 months||3 months||20||75||0.6|
|Medication:||Enalapril (dose not provided)|
|Severity:||3+ (jaundice, hospitalization)|
|Recovery:||Partial after 2 weeks|
|Other medications:||Simvastatin, fenofibrate, metoprolol, synthroid|
|Time After Starting||Weeks After Stopping||ALT (U/L)||Alk P (U/L)||Bilirubin (mg/dL)||Other|
|12 months||24||82||0.5||Fenofibrate started|
|18 months||Pre||70||369||5.8||Simvastatin stopped|
|21 months||0||91||578||7.7||Enalapril stopped|
|10 days||40||423||0.7||Fenofibrate stopped|
|22 months||5 weeks||71||285||0.7|
|23 months||8 weeks||52||228||0.5|
|DRUG||CAS REGISTRY NUMBER||MOLECULAR FORMULA||STRUCTURE|
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