Fosinopril is an angiotensin-converting enzyme (ACE) inhibitor used in the therapy of hypertension and heart failure. Fosinopril is associated with a low rate of transient serum aminotransferase elevations during therapy and has been linked to rare instances of acute liver injury.
Fosinopril is an ACE inhibitor approved for use alone or in combination with other agents as therapy of hypertension and heart failure. Like other ACE inhibitors, fosinopril 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 dose related side effects of the ACE inhibitors. Fosinopril was approved for use in the United States in 1991 and is available in 10, 20 and 40 mg tablets in generic forms and under the trade name Monopril. The typical dose in adults is 10 mg once daily initially, with gradual adjustment based upon blood pressure response and tolerance. The usual maintenance dosage is 20 to 40 mg daily and the maximum 80 mg in one or two divided doses administered long term. Fosinopril is also available in fixed combinations with hydrochlorothiazide (Monopril HCT). Common side effects include dizziness, fatigue, headache, cough, gastrointestinal upset and skin rash.
Fosinopril, 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. Rare instances of clinically apparent acute liver injury have been reported in association with fosinopril therapy, but they have been too few to characterize the pattern of injury reliably. The onset of symptoms was within 2 to 12 weeks of starting therapy and the serum enzyme pattern was cholestatic. In one instance, cholestasis was prolonged and relapsing and associated with persistent elevations in serum alkaline phosphatase and GGT, suggestive of vanishing bile duct syndrome (Case 1). Immunoallergic manifestations (rash, fever, eosinophilia) were infrequent and patients did not develop autoantibodies. Other ACE inhibitors have been occasionally associated with a hepatocellular pattern of liver injury and cases with a long latency (one or more years) have been described as well. These features have not been clearly linked to fosinopril hepatotoxicity.
Mechanism of Injury
The cause of the minor serum aminotransferase elevations with fosinopril therapy is not known. The cases of clinically apparent liver injury due to fosinopril were clearly idiosyncratic and likely due to a reaction to a metabolite. Fosinopril is hydrolyzed in the liver to its active metabolite fosinoprilat.
Outcome and Management
Most instances of acute liver injury reported with fosinopril use have been self limited, but there have been rare reports of acute liver failure due to other ACE inhibitors as well as reports of cholestatic hepatitis leading to prolonged jaundice. Patients with severe fosinopril 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:||Fosinopril (20 mg daily)|
|Severity:||4+ (jaundice, hospitalization, other organ failure)|
|Recovery:||Partial over 6-18 months|
|Other medications:||Metoprolol, diazepam|
|Time After Starting||Time After Stopping||GGT (U/L)||Alk P (U/L)||Bilirubin (mg/dL)||Other|
|2 months||1 month||55||260||40||Liver biopsy|
|3 months||2 month||40||230||13||Discharge|
|5 months||4 months||75||580||1||Pruritus requiring therapy|
|9 months||8 months||80||410||1|
|1.5 years||1.5 years||95||320||1||Minimal pruritus|
|DRUG||CAS REGISTRY NUMBER||MOLECULAR FORMULA||STRUCTURE|
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