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.Cognitive approach to learning pdf 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.Cognitive approach to learning pdf donepezil has selective activity for acetylcholinesterase in the central nervous system with little effect on the enzyme in peripheral tissue.Cognitive approach to learning pdf 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.Cognitive approach to learning pdf 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.Cognitive approach to learning pdf 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.Cognitive approach to learning pdf 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.Cognitive approach to learning pdf

In several large clinical trials, donepezil therapy was not associated with an increased rate of serum enzyme elevations compared to placebo treatment.Cognitive approach to learning pdf 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.Cognitive approach to learning pdf 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.Cognitive approach to learning pdf 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.Cognitive approach to learning pdf immunoallergic and autoimmune features were not present.

Cases of hepatotoxicity from donepezil have been too few to characterize clinically.Cognitive approach to learning pdf there have been no published reports of fatal acute liver failure, chronic hepatitis or vanishing bile duct syndrome attributed to donepezil.Cognitive approach to learning pdf there is no information on the possible cross sensitivity to liver injury among the various acetylcholinesterase inhibitors.

A 90 year old man developed nausea, vomiting and abdominal pain 2 weeks after starting donepezil for a new diagnosis of alzheimer disease.Cognitive approach to learning pdf several days later he developed jaundice, and donepezil was stopped. He had no previous history of liver disease, adverse drug reactions, alcohol abuse or risk factors for viral hepatitis.Cognitive approach to learning pdf his other medical problems included diabetes, renal insufficiency, atrial fibrillation, valvular heart disease and congestive heart failure.Cognitive approach to learning pdf medications included aspirin, lisinopril, bisoprolol, bumetanide and insulin, all of which he had taken chronically and all of which were continued.Cognitive approach to learning pdf his physical examination was normal except for jaundice. Laboratory tests showed a serum bilirubin of 5.9 mg/dl, with marked elevations in alkaline phosphatase (944 U/L) and moderate elevations in serum aminotransferase levels (ALT 329 U/L, AST 186 U/L).Cognitive approach to learning pdf liver tests results had been normal previously except for minor elevations in alkaline phosphatase (table). Tests for hepatitis A, B and C were negative as were routine autoantibodies.Cognitive approach to learning pdf abdominal ultrasound and magnetic resonance imaging showed no evidence of biliary obstruction. A liver biopsy showed intrahepatic cholestasis and mild hepatitis.Cognitive approach to learning pdf despite stopping donepezil, jaundice deepened and serum bilirubin peaked at 22.6 mg/dl two weeks later. Thereafter, the liver test abnormalities began to improve slowly, serum bilirubin falling to normal 13 weeks after donepezil was discontinued.Cognitive approach to learning pdf

The timing of onset of jaundice, cholestatic features, liver histology and absence of evidence of other forms of liver injury are quite supportive of a diagnosis of donepezil induced liver injury.Cognitive approach to learning pdf while quite rare, the cholestatic injury can be severe and protracted as in this case in which serum enzymes were still elevated 3 months after stopping donezepil.Cognitive approach to learning pdf