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Focus on Donepezil
Ben Green MB, ChB, MRCPsych
Halton Hospital,
Runcorn, Cheshire, UK.
- Introduction
- Indications
- Structure
- Pharmacology
- Clinical Efficacy
- Cautions and contra-indications
- Side Effects
- References
- Interactions
Introduction
Donepezil hydrochloride is a piperidine that is a cholinesterase inhibitor (ChE inhibitor). Senile dementia of the Alzheimer type (SDAT) has been linked to losses of presynaptic choliergic function in the nucleus basalis of the brain. Cholinegic agents - either agonists or enzyme inhibitors have been put forward as therapeutic agents. Donepezil is one such candidate for a thereapeutic agent in SDAT.
Dosage shown to be effective in controlled clinical trials are 5 and 10 mg administered once a day, usually in the evening.
Indications
Treatment of mild to moderate dementia of the Alzheimer's type.
Pharmacology
Donepezil hydrochloride is a selective, reversible and non-competitive acetylcholinesterase inhibitor with a relatively high central versus peripheral specificity. Acetylcholinesterase is the predominant cholinesterase in the brain. Plasma levels of donepezil and AChE inhibition are positively correlated until a plateau of inhibittion is reached at about 80% at donepezil levels of 50 ng/ml and above (Rogers et al, 1996). The loss of cholinergic neurons in the nucleus basalis of Meynert is one of the hallmarks of Alzheimer's disease. Animals with nucleus basalis lesions responded to donepezil and improved on learning and memeory tasks.
The drug is metabolised by hepatic transformation and renal excretion of the unchanged drug. It is well absorbed with a peak plasma cocnetration about three hours after administration. It is 96% plasma bound.
The elimination half life is about 70 hours.
Structure
Donepezil hydrochloride is a piperidine-based derivative.
Denepezil (E2020; (+/-)-2,3-dihydro-5,6-dimethoxy-2[[1-{phenylmethyl}-4-peridinyl]methyl]-1H-inden-1-one hydrochoride)
It has a molecular weight of 415.96.
It is a white crystalline powder.
Efficacy
A multicentre double blind study looked at the effects of donepezil in mild to moderate SDAT (Rogers et al, 1998). A placebo group (n=162}, was compared with a treatment group of 5mg donepezil / day (n=154) and a treatment group of 10mg donepezil / day (n=157).
At weeks 12, 18 and 24 cognition was significantly improved in both treatment groups (as measured by the Alzheimer's Disease Assessment Scale). Cholinergic side effects were worse at the 10 mg level.
The beneficial effect of treatment - in terms of improving cognitive and global function and reducing the slope of dementia score progression appears to be maintained over time - 98 weeks in the study by Sharon Rogers and Lawrence Friedhoff (Rogers and Friedhoff, 1997)
Cautions and contra-indications
Cholinesterase inhibitors can increase gastric acid secretion so the manufacturers advise monitoring of those at risk of developing ulcers.
Kidney or liver disease may impair metabolism.
Side Effects
Generally the drug appears well tolerated. There is no evidence of hepatotoxicity. Insomnia may occur in about 10%. 10% of patients suffer nausea and vomiting. Diarrhoea occurs in 10%. Dizziness occurs in 8%, nasal congestion and cold symptoms in 5%.
Interactions
CYP2D6 and CYP3A4 are the principal isoenzymes involved in metabolism. Ketoconazole and quinidine inhibit metabolism in vitro because they inhibit these isoenzymes.
References
- Rogers S L, et al (1996) The efficacy and safety of donepezil in patients with Alzheimer's disease: results of a US multicentre. randomised, double-blind, placebo controlled trial. Dementia;7: 293-303.
- Rogers, S L and Friedhoff L T (1997) Long term efficacy and safety of donepezil in the treatment of Alzheimer's disease: an interime analysis of the results of a US multicentre open label extension study. European Neuropsychopharmacology;8:67-75.
- Rogers S L et al (1998) A 24 week, double-blind, placebo-controlled trial of donepezil in patients with Alzheimer's disease. Neurology; 50:136-145.
Focus on Donepezil © Psychiatry On-Line
1998-99
®Priory Lodge Education Limited
Version 2.1
Last Amended:
23 March 1999
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