Donepezil for Alzheimer's Disease: Pharmacodynamic, Pharmacokinetic, and Clinical Profiles

Abstract

Donepezil was developed in order to overcome the disadvantages of physostigmine and tacrine. Its use is based on the cholinergic hypothesis. Donepezil is a piperidine-based, reversible acetylcholinesterase inhibitor, that is chemically unrelated to other cholinesterase inhibitors. It was developed for the symptomatic treatment of Alzheimer's disease (AD). Donepezil is highly selective for acetylcholinesterase with a significantly lower affinity for butyrylcholinesterase, which is present predominantly in the periphery. Phase I and II clinical trials demonstrated donepezil's favorable pharmacokinetic, pharmacodynamic and safety profile. There is no need to modify the dose of donepezil in the elderly or in patients with renal and hepatic failure. Pivotal phase-III trials in the US, European countries, and Japan showed that donepezil significantly improved cognition and global function in patients with mild to moderate AD. In long-term trials, donepezil maintained cognitive and global function for up to 1 year prior to the resumption of gradual deterioration. Donepezil is generally well tolerated; most of its adverse events are mild, transient and cholinergic in nature. Donepezil produces no clinically significant changes in laboratory parameters, including liver function.The drug is approved for the treatment of mild to moderate Alzheimer's disease, but donepezil therapy does not have to be discontinued if a patient continues to deteriorate. Possible new indications for donepezil in psychiatric and neurologic diseases, other than 353

Acetylcholinesterase inhibitors ameliorate behavioral deficits in the Tg2576 mouse model of Alzheimer’s disease

“…While physostigmine is not used clinically, donepezil has been shown to ameliorate impaired memory as well as a variety of other cognitive functions in patients with mild to moderate dementia of the Alzheimer type (Rogers, et al, 1998;Shigeta and Homma, 2001). Notably, the pharmacological features of physostigmine donepezil are slightly different, and could form a basis for differences in behavioral effects.…”

“…In fact, reduced cholinergic activity in the brains of individuals with AD formed the rationale for the development of acetylcholinesterse inhibitors as drugs to ameliorate the dementia associated with AD (Davis et al 1992, Rogers et al 1998, Tariot et al 2000, Csernansky, et al, 2002. Commonly prescribed cholinesterase inhibitors include donepezil, rivastigmine and galantamine (Moghul andWilkinson, 2001, Shigeta andHomma, 2001). …”

The Seed Extract of Cassia obtusifolia Ameliorates Learning and Memory Impairments Induced by Scopolamine or Transient Cerebral Hypoperfusion in Mice

“…In fact, reduced cholinergic activity in the brains of individuals with AD provides the rationale for the development of acetylcholinesterase (AChE) inhibitors to treat the dementia associated with AD (7 -9). The commonly prescribed AChE inhibitors, such as donepezil, rivastigmine, and galantamine were developed on this basis (10,11). Nevertheless, new drugs without adverse effects are urgently required (12).…”

Bioequivalence study of Donepezil hydrochloride in healthy Korean volunteers

“…Previous pharmacokinetic studies have shown that the elimination half-life of donepezil in elderly patients is almost twice as long as that in young healthy volunteers. [8,9] However, the exposure of the drug including C max , CL/F and AUC measured during therapeutic drug monitoring of elderly patients with Alzheimer's disease are comparable to those observed in young healthy volunteers. The difference of the half-life between the two age groups is probably due to a large distribution volume in the elderly.…”