Donepezil

Abstract

Donepezil (E-2020) is a reversible, noncompetitive, piperidine-type cholinesterase inhibitor. It is selective for acetylcholinesterase rather than butyrylcholinesterase. Donepezil 5 and 10 mg/day significantly improved cognition and global clinical function compared with placebo in well designed short term trials (14 to 30 weeks) in 161 to 818 patients with mild to moderate Alzheimer’s disease. Beneficial effects on cognition were observed from week 3 of treatment. Donepezil 10 mg/day significantly delayed the deterioration in activities of daily living (ADL) [by 55 weeks] compared with placebo in a retrospective analysis of 1 trial, and in the largest trial significantly improved patients’ abilities to perform complex tasks. However, no significant improvement in function was observed with donepezil 5 mg/day in another trial. In the 2 trials of longest duration donepezil (5 and 10mg) significantly delayed symptomatic progression of the disease. While there was no evidence for a positive effect of donepezil on patients’ quality of life, there are no validated measures of this parameter specific to patients with Alzheimer’s disease. Donepezil (5 and 10mg) significantly reduced caregiver burden. Long term efficacy data suggest that improvements in cognition, global function or ADL are maintained for about 21 to 81 weeks with donepezil (10 mg/day in most patients). Donepezil is generally well tolerated with the majority of adverse events being mild and transient. Predictably, most events were cholinergic in nature and generally related to the gastrointestinal and nervous systems. The incidence of these events was significantly higher with donepezil 10mg than with placebo in short term clinical trials; however, this may have been due to the 7-day dose increase schedule used in these studies and can be minimised by increasing the dose after a longer (6-week) period. The incidence of serious adverse events was generally similar between donepezil 5 and 10mg (4 to 10%) and placebo (5 to 9%) in short term trials. 26% of patients receiving donepezil (5 and 10mg) reported serious events over a 98-week period in a long term trial. Importantly, there was no evidence of hepatotoxicity with this drug. Conclusions. Donepezil (5 and 10mg) is an agent with a simple once-daily dosage schedule which improves cognition and global clinical function in the short (up to 24 weeks) and long term (up to about 1 year) in patients with mild to moderate Alzheimer’s disease. Improvements in ADL were also observed with donepezil 10 mg/day. Adverse events associated with donepezil are mainly cho- linergic. Donepezil has been extensively studied and should be considered as a first-line treatment in patients with mild to moderate Alzheimer’s disease. Donepezil is defined as a mixed inhibitor of acetylcholinesterase exhibiting primarily noncompetitive, but also some competitive, inhibition of this enzyme. Donepezil inhibited acetylcholinesterase (from the electric eel and human erythrocyte) more potently than tacrine in in vitro studies. As with other cholinesterase inhibitors, donepezil less potently inhibited acetylcholinesterase from senile plaques in the cortex of patients with moderate to severe Alzheimer’s disease than that from other fractions of diseased brain or from the cortex of individuals with no neurological disease in an in vitro study. Donepezil selectively inhibits acetylcholinesterase rather than butyrylcholin-esterase and was more selective for this enzyme than tacrine and physostigmine in in vitro and ex vivo (rat) studies. The ratio of the concentrations of donepezil needed to produce a 50% inhibition (IC50) of human butyrylcholinesterase to the IC50 of acetylcholinesterase was 405: 1. Acetylcholinesterase in skeletal muscle (rodent) was inhibited to a greater extent by donepezil than that from the brain (rodent) or erythrocytes (human). A similar effect was observed with tacrine, rivastigmine and physostigmine, although donepezil inhibited all 3 isoenzymes more potently than these agents. However, in another study donepezil more potently inhibited cholinesterase from rodent brain than that from the plasma, heart or pectoral muscle. In contrast, tacrine less potently inhibited brain cholinesterase than that in other tissues. The inhibitory effects of donepezil on erythrocyte acetylcholinesterase appears to correspond closely to that in the rodent cortex. Donepezil dose-relatedly inhibits erythrocyte acetylcholinesterase, as shown in studies in patients with Alzheimer’s disease receiving dosages of 1 to 10 mg/day for 12 to 98 weeks. Mean percentage inhibition was 64% with donepezil 5mg and 75 to 77% with donepezil 10mg at 6 or 12 weeks. Donepezil significantly increased extracellular acetylcholine levels in rat hippocampus and cortex and was more potent than tacrine in producing this effect. Extracellular noradrenaline (norepinephrine) and dopamine, but not serotonin (5-hydroxytryptamine; 5-HT), levels in the cortex were increased by donepezil in rats. Donepezil produced centrally-mediated cholinergic effects in rodent models. No peripherally-mediated effects were observed in 1 study but were apparent in another study. However, some peripheral effects were more prominent, and both types of effects persisted for longer, with tacrine. Induced deficits in working and reference memory and attention are significantly reversed by donepezil, as shown in various animal models of cognitive impairment. Similarly, donepezil attenuated naturally occurring memory deficits in young rats. In general, donepezil is more potent than tacrine at enhancing cognition and attention according to animal studies. The maximum plasma concentration (C_max), area under the plasma concentration-time curve (AUC) and the mean donepezil concentration at steady state are linearly proportional to dosage but clearance is independent of dose, as seen...