indication

For the palliative treatment of mild to moderate dementia of the Alzheimer's type.

pharmacology

Donepezil is a centrally acting reversible acetyl cholinesterase inhibitor. Its main therapeutic use is in the treatment of Alzheimer's disease where it is used to increase cortical acetylcholine. An early pathophysiological feature of Alzheimer's disease that is associated with memory loss and cognitive deficits is a deficiency of acetylcholine as a result of selective loss of cholinergic neurons in the cerebral cortex, nucleus basalis, and hippocampus. Donepezil is postulated to exert its therapeutic effect by enhancing cholinergic function. This is accomplished by increasing the concentration of acetylcholine through reversible inhibition of its hydrolysis by acetylcholinesterase. If this proposed mechanism of action is correct, donepezil's effect may lessen as the disease progresses and fewer cholinergic neurons remain functionally intact. There is no evidence that donepezil alters the course of the underlying dementing process.

mechanism of action

Donepezil is a piperidine derivative that is a centerally active, reversible inhibitor of acetylcholinesterase. This drug is structurally unrelated to other anticholinesterase agents. Donepezil's proposed mechanism of action involves the reversible inhibition of cholinesterases (eg. acetylcholinesterase), which prevents the hydrolysis of acetycholine, and leads to an increased concentration of acetylcholine at cholinergic synapses. Evidence suggests that the anticholinesterase activity of donepezil is relatively specific for acetylcholinesterase in the brain.

toxicity

Symptoms of overdose include severe nausea, vomiting, salivation, sweating, bradycardia, hypotension, respiratory depression, collapse and convulsions. Increasing muscle weakness is a possibility and may result in death if respiratory muscles are involved.

biotransformation

Donepezil is metabolized by CYP 450 isoenzymes 2D6 and 3A4 in the liver and also undergoes glucuronidation. The main metabolite, 6-O-desmethyl donepezil, has been reported to inhibit AChE to the same extent as donepezil in vitro.

absorption

Donepezil is well absorbed with a relative oral bioavailability of 100% and reaches peak plasma concentrations in 3 to 4 hours.

half life

70 hours

route of elimination

Donepezil is both excreted in the urine intact and extensively metabolized to four major metabolites, two of which are known to be active, and a number of minor metabolites, not all of which have been identified.

drug interactions

Acepromazine: Possible antagonism of action

Aceprometazine: Possible antagonism of action

Alverine: Possible antagonism of action

Amantadine: Possible antagonism of action

Amitriptyline: Possible antagonism of action

Amoxapine: Possible antagonism of action

Atropine: Possible antagonism of action

Azatadine: Possible antagonism of action

Benzatropine: Possible antagonism of action

Biperiden: Possible antagonism of action

Brompheniramine: Possible antagonism of action

Carbinoxamine: Possible antagonism of action

Chlorpheniramine: Possible antagonism of action

Chlorpromazine: Possible antagonism of action

Chlorprothixene: Possible antagonism of action

Cimetidine: Possible antagonism of action

Clemastine: Possible antagonism of action

Clidinium: Possible antagonism of action

Clomipramine: Possible antagonism of action

Clozapine: Possible antagonism of action

Cyclizine: Possible antagonism of action

Cyclobenzaprine: Possible antagonism of action

Cyproheptadine: Possible antagonism of action

Darifenacin: Possible antagonism of action

Desipramine: Possible antagonism of action

Dexbrompheniramine: Possible antagonism of action

Dicyclomine: Possible antagonism of action

Dimenhydrinate: Possible antagonism of action

Diphenhydramine: Possible antagonism of action

Diphenoxylate: Possible antagonism of action

Diphenylpyraline: Possible antagonism of action

Disopyramide: Possible antagonism of action

Doxepin: Possible antagonism of action

Doxylamine: Possible antagonism of action

Ethopropazine: Possible antagonism of action

Flavoxate: Possible antagonism of action

Flupenthixol: Possible antagonism of action

Glutethimide: Possible antagonism of action

Glycopyrrolate: Possible antagonism of action

Hydroxyzine: Possible antagonism of action

Hyoscyamine: Possible antagonism of action

Imipramine: Possible antagonism of action

Isocarboxazid: Possible antagonism of action

Isopropamide: Possible antagonism of action

Loxapine: Possible antagonism of action

Maprotiline: Possible antagonism of action

Meclizine: Possible antagonism of action

Meperidine: Possible antagonism of action

Mesoridazine: Possible antagonism of action

Methdilazine: Possible antagonism of action

Methotrimeprazine: Possible antagonism of action

Methylscopolamine: Possible antagonism of action

Mirtazapine: Possible antagonism of action

Moclobemide: Possible antagonism of action

Molindone: Possible antagonism of action

Nortriptyline: Possible antagonism of action

Olanzapine: Possible antagonism of action

Orphenadrine: Possible antagonism of action

Oxybutynin: Possible antagonism of action

Perphenazine: Possible antagonism of action

Phenelzine: Possible antagonism of action

Phenindamine: Possible antagonism of action

Pimozide: Possible antagonism of action

Pipotiazine: Possible antagonism of action

Procainamide: Possible antagonism of action

Prochlorperazine: Possible antagonism of action

Procyclidine: Possible antagonism of action

Promazine: Possible antagonism of action

Promethazine: Possible antagonism of action

Propantheline: Possible antagonism of action

Propericiazine: Possible antagonism of action

Protriptyline: Possible antagonism of action

Quetiapine: Possible antagonism of action

Quinidine: Possible antagonism of action

Quinidine barbiturate: Possible antagonism of action

Risperidone: Possible antagonism of action

Scopolamine: Possible antagonism of action

Sertraline: Possible antagonism of action

Solifenacin: Possible antagonism of action

Thioproperazine: Possible antagonism of action

Thioridazine: Possible antagonism of action

Thiothixene: Possible antagonism of action

Tizanidine: Possible antagonism of action

Tolterodine: Possible antagonism of action

Tranylcypromine: Possible antagonism of action

Trazodone: Possible antagonism of action

Trifluoperazine: Possible antagonism of action

Triflupromazine: Possible antagonism of action

Trihexyphenidyl: Possible antagonism of action

Trimeprazine: Possible antagonism of action

Trimethobenzamide: The therapeutic effects of the anticholinergic, Trimethobenzamide, and/or the acetylcholinesterase inhibitor (central), Donepezil, may be reduced due to antagonism. Monitor therapeutic effects of both agents.

Trimipramine: Possible antagonism of action

Tripelennamine: Possible antagonism of action

Triprolidine: Possible antagonism of action

Trospium: The therapeutic effects of the anticholinergic, Trospium, and/or the acetylcholinesterase inhibitor (central), Donepezil, may be reduced due to antagonism. Monitor therapeutic effects of both agents.

Ziprasidone: Possible antagonism of action

Zuclopenthixol: Possible antagonism of action