Captopril is an angiotensin-converting enzyme (ACE) inhibitor used in the therapy of hypertension and heart failure. Captopril is associated with a low rate of transient serum aminotransferase elevations and has been linked to rare instances of acute liver injury.
Captopril (kap' toe pril) was the first 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, captopril 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. Captopril was approved for use in the United States in 1981 and current indications are for hypertension, congestive heart failure, left ventricular dysfunction after myocardial infarction, and treatment and prevention of diabetic nephropathy. Captopril is available in 12.5, 25, 50 and 100 mg tablets in many generic forms and formerly under the trade name Capoten. The typical dose of captopril in adults in 25 to 50 mg two or three times daily, and it is administered long term. Captopril is also available in several fixed combinations with hydrochlorothiazide (Capozide and others). Common side effects of captopril and ACE inhibitors in general include dizziness, fatigue, headache, cough, gastrointestinal upset and skin rash.
Captopril, 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. While rare, several dozen cases of clinically apparent liver injury have been reported with captopril therapy. The onset is usually within 2 to 12 weeks of starting therapy and the serum enzyme pattern is typically cholestatic (Case 1). 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. Rare instances of captopril injury with a hepatocellular pattern and cases with a long latency (one or more years) have been described as well, a distinctly unusual pattern of drug induced liver injury.
Likelihood score: B (likely but rare cause of clinically apparent liver injury).
Mechanism of Injury
The cause of the minor serum aminotransferase associated with captopril is not known. The clinically apparent acute liver injury from captopril is likely an idiosyncratic reaction to a metabolite. Captopril is hydrolyzed by the liver to its active metabolite captoprilat and has little further hepatic metabolism.
Outcome and Management
Most instances of acute liver injury reported with captopril use have been self limited, but there have been rare reports of acute liver failure due to captopril and several reports of cholestatic hepatitis leading to prolonged jaundice. Patients with severe captopril induced acute liver injury and hypersensitivity reactions 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:||Captopril (75 mg daily)|
|Severity:||3+ (jaundice, hospitalization)|
|Latency:||4 weeks to symptoms, 12 weeks to jaundice|
|Recovery:||Partial by 5 weeks|
|Other medications:||Digoxin, furosemide, isosorbide dinitrate|
|Time After Starting||Time After Stopping||ALT (U/L)||Alk P (U/L)||Bilirubin (mg/dL)||Other|
|Pre||Pre||33||338||1.3||Congestive heart failure|
|12.5 weeks||0||61||951||36.3||Captopril stopped|
|13 weeks||1 day||60||1358||31.6|
|5 days||46||683||21.8||Liver biopsy|
|14 weeks||9 days||35||536||14.3|
|18 weeks||5 weeks||60||377||3.7|
|DRUG||CAS REGISTRY NUMBER||MOLECULAR FORMULA||STRUCTURE|
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