Ramipril is an angiotensin-converting enzyme (ACE) inhibitor used in the therapy of hypertension and heart failure. Ramipril is associated with a low rate of transient serum aminotransferase elevations and has been linked to rare instances of acute liver injury.
Ramipril (ra' mi pril) is an ACE inhibitor widely used in the therapy of hypertension, heart failure and for reduction in risk of myocardial infarction and stroke. Like other ACE inhibitors, ramipril 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 ramipril and other ACE inhibitors. Ramipril was approved for use in the United States in 1991 and is available in 1.25, 2.5, 5 and 10 mg capsules or tablets in generic forms and under the trade name Altace. In adults, ramipril is usually started in a dose of 2.5 mg daily and then adjusted based upon blood pressure response and tolerance to 10 to 20 mg daily. It is typically used long term. Common side effects include dizziness, fatigue, headache, cough, gastrointestinal upset and skin rash.
Ramipril, 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 with ramipril 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 ramipril injury with a hepatocellular pattern and cases with a long latency (one or more years) have been described as well. Likelihood score:
Likelihood score: C (Probable rare cause of clinically apparent liver injury).
Mechanism of Injury
The cause of the minor serum aminotransferase elevations associated with ramipril therapy is not known. The clinically apparent acute liver injury due to ramipril is idiosyncratic and is likely due to a reaction to a minor metabolite. Ramipril is hydrolyzed in the liver to its active carboxylic metabolite ramiprilat, but undergoes little further hepatic metabolism.
Outcome and Management
Only a few cases of ramipril associated liver injury have been reported, but the rare instances that have been published have resembled typical ACE inhibitor related hepatic injury. Most instances of acute liver injury related to ACE inhibitors have been self limited, but severe cases of cholestatic hepatitis can result in prolonged jaundice and vanishing bile duct syndrome. Patients with severe ramipril induced acute liver injury or hypersensitivity 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:||Ramipril (2.5 mg daily)|
|Severity:||4+ (prolonged jaundice)|
|Other medications:||Atorvastatin, insulin, aspirin|
|4||2.5||103||957||15.5||INR=1.22, liver biopsy|
|DRUG||CAS REGISTRY NUMBER||MOLECULAR FORMULA||STRUCTURE|
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