Switching cholinesterase inhibitors in patients with Alzheimer's disease.

Despite recognition that cholinesterase inhibitors can provide clinical benefits for patients with Alzheimer's disease (AD), the average durations of treatment and beneficial effects are not optimal in all cases. This may be due to disappointing efficacy or poor tolerability of the initial treatment, as well as secondary efficacy failure or adverse effects emerging during the maintenance phase. In such cases, pharmacological differences between available cholinesterase inhibitors provide a good rationale to switch to another drug in the same class. The pharmacological properties of rivastigmine, a dual inhibitor of acetylcholinesterase (AChE) and butyrylcholinesterase, and donepezil and galantamine, two AChE-selective inhibitors, are reviewed. Rivastigmine is reported to show brain- and brain region-selectivity. Donepezil appeared to be more selective for central than peripheral enzymes in rats. Galantamine and donepezil have also been shown to exert nicotinic receptor allosteric modulation in vitro, while rivastigmine has been shown to increase binding of acetylcholine to nicotinic receptors in the AD brain. Donepezil and galantamine are metabolised by the hepatic CYP450 system, whereas rivastigmine is metabolised by its target enzymes. Several switching studies indicated that a substantial proportion of patients who fail to benefit from treatment with donepezil could draw benefits after being switched to rivastigmine. An immediate switch from donepezil to rivastigmine was reported to be well tolerated and was not associated with cholinergic side effects. A post hoc analysis of a 5-month trial with galantamine showed that patients had similar efficacy outcomes, whether or not they had received prior anticholinesterase therapy, suggesting that a previous failure to respond to another cholinesterase inhibitor did not predict response to galantamine. On the basis of available data it is suggested that patients not tolerating or not responding to one particular cholinesterase inhibitor may still draw benefits upon switching to another.