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DRUG RECORD

 

DONEPEZIL

OVERVIEW
Donepezil

 

Introduction

Donepezil is an oral acetylcholinesterase inhibitor used for therapy of Alzheimer’s 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.

 

Background

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’s 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’s disease.  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’s 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.

 

Hepatotoxicity

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.

Agents used specifically in therapy of Alzheimer’s disease include donepezil, galantamine, memantine and rivastigmine and tacrine.

References regarding the safety and potential hepatotoxicity of the drugs used for Alzheimer’s disease are provided together after the introductory section.

 

Drug Class:  Alzheimer's Drugs

 

 

 

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CASE REPORT
Donepezil

 

Case 1. Cholestatic hepatitis due to donepezil.
[Modified from:  Dierckx RIR, Vandewoude MFJ. Donepezil-related toxic hepatitis. Acta Clinica Belg 2008; 63: 339-42. PubMed Citation]

 

A 90 year old man developed nausea, vomiting and abdominal pain 2 weeks after starting donepezil for a new diagnosis of Alzheimer’s disease.  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.  His other medical problems included diabetes, renal insufficiency, atrial fibrillation, valvular heart disease and congestive heart failure.  Medications included aspirin, lisinopril, bisoprolol, bumetanide and insulin, all of which he had taken chronically and all of which were continued.  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).  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.  Abdominal ultrasound and magnetic resonance imaging showed no evidence of biliary obstruction.  A liver biopsy showed intrahepatic cholestasis and mild hepatitis.  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.

 

Key Points

Medication: Donepezil (dose not given)
Pattern: Cholestatic (R=1.1)
Severity: 3+ (jaundice, hospitalization)
Latency: 2 weeks
Recovery: 13 weeks
Other medications: Insulin, aspirin, lisinopril, bisoprolol, bumetanide

Laboratory Values

Tme After Starting Time After Stopping ALT (U/L) Alk P (U/L) Bilirubin (mg/dL) Other
-1 day 37 156 0.3
14 days 0 157 374 0.4 Nausea
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
Normal Values <50 <71 <1.2

 

Comment

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.  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.

 

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PRODUCT INFORMATION
Donepezil

 

REPRESENTATIVE TRADE NAMES
Donepezil – Generic, Aricept®

 

DRUG CLASS
Alzheimer’s Drugs

 

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

 

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DRUG CAS REGISTRY NUMBER MOLECULAR FORMULA STRUCTURE
Donepezil 120014-06-4 C24-H29-N-O3 Donepezil Chemical Structure

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OTHER REFERENCE LINKS
Donepezil

 

  1. PubMed logoRecent References on Donepezil

  2. Clinical Trials logoTrials on Donepezil

  3. TOXLINE logoTOXLINE Citations on Donepezil

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