Donepezil is an oral acetylcholinesterase inhibitor used for therapy of Alzheimer disease. Donepezil is associated with a minimal rate of serum enzyme elevations during therapy and has only rarely been implicated as a cause of clinically apparent liver injury.
Donepezil (doe nep' e zil) is an acetylcholinesterase inhibitor which acts by inhibition of the metabolism of acetylcholine in the postsynaptic clefts, thus enhancing cholinergic neurotransmission. Alzheimer disease is associated with a cholinergic deficiency in the cerebral cortex, and the increase in concentration of acetylcholine with acetylcholinesterase inhibition is associated with improvement in cognitive function in patients with Alzheimer dementia. Donepezil has selective activity for acetylcholinesterase in the central nervous system with little effect on the enzyme in peripheral tissue. Donepezil was approved for use in the United States in 1996 and is currently the most commonly used acetylcholinesterase inhibitor used for management of Alzheimer disease. Donepezil is available as regular tablets of 5 and 10 (and recently 23 mg) and as orally disintegrating tablets of 5 and 10 mg in generic forms and under the brand name Aricept. Donepezil is also available as an solution of 1 mg/mL for oral administration. The usual maintenance dosage is 5 to 10 mg once daily. Patients who tolerate the 10 mg daily dose may benefit from a higher dose of 23 mg daily. Common side effects include diarrhea, nausea, vomiting, dizziness, fatigue, insomnia, vivid dreams, anxiety, restlessness, blurred vision, dry mouth and pruritus, symptoms common to cholinergic stimulation.
In several large clinical trials, donepezil therapy was not associated with an increased rate of serum enzyme elevations compared to placebo treatment. Furthermore, escalation of the dose from 10 to 23 mg daily was not followed by an increased rate of ALT elevations compared to patients maintained on the lower dose. Nevertheless, since its introduction into clinical use, donepezil has been implicated in at least one report of clinically apparent hepatotoxicity, although the patient was also taking other potentially hepatotoxic drugs. The time to onset was 10 days and the pattern of serum enzyme elevations was cholestatic. The course of illness was severe with prolonged jaundice and itching, but it ultimately resolved. Immunoallergic and autoimmune features were not present.
Mechanism of Injury
Donepezil is extensively metabolized by the hepatic cytochrome P450 system (CYP 2D6 and 3A4) followed by glucuronidation. Hepatotoxicity is likely due to idiosyncratic metabolism to a toxic or immunogenic intermediate.
Outcome and Management
Cases of hepatotoxicity from donepezil have been too few to characterize clinically. There have been no published reports of fatal acute liver failure, chronic hepatitis or vanishing bile duct syndrome attributed to donepezil. There is no information on the possible cross sensitivity to liver injury among the various acetylcholinesterase inhibitors.
|Medication:||Donepezil (dose not given)|
|Severity:||3+ (jaundice, hospitalization)|
|Other medications:||Insulin, aspirin, lisinopril, bisoprolol, bumetanide|
|Tme After Starting||Time After Stopping||ALT (U/L)||Alk P (U/L)||Bilirubin (mg/dL)||Other|
|22 days||0||329||944||5.9||Donepezil stopped|
|24 days||2 days||354||897||8.3||Liver biopsy|
|6 weeks||2 weeks||363||1343||22.6||INR=1.2|
|7 weeks||4 weeks||180||1243||13.6|
|10 weeks||7 weeks||93||1152||3.4|
|13 weeks||10 weeks||81||839||1.9|
|16 weeks||13 weeks||60||620||1.0||Symptoms resolved|
|DRUG||CAS REGISTRY NUMBER||MOLECULAR FORMULA||STRUCTURE|