Prescrire Int. 2006 Jun;15(83):103-6.
(1) Cholinesterase inhibitors such as donepezil, galantamine and rivastigmine, are not very effective in slowing the cognitive decline associated with Alzheimer's disease. Memantine, which is no more effective, has dopaminergic and atropinic effects but is not a cholinesterase inhibitor. (2) Cholinesterase inhibitors have mainly cholinergic adverse effects, causing gastrointestinal, neurological, cardiovascular and urinary disorders (incontinence). (3) Increased mortality, mainly due to cardiovascular events, was observed in placebo-controlled trials of galantamine. In one trial there were more deaths in patients on donepezil than on placebo. (4) Atropinic drugs tend to aggravate cognitive disorders that are treated with cholinesterase inhibitors. (5) Cholinesterase inhibitor + neuroleptic combinations are associated with an increased risk of extrapyramidal adverse effects. An increase in mortality was reported during trials of neuroleptics involving patients with dementia, and also during trials of cholinesterase inhibitors. (6) Combining cholinesterase inhibitors with drugs that reduce the heart rate, depress cardiac conduction, or induce torsades de pointes increases the risk of arrhythmias and cardiac conduction disorders. (7) Donepezil and galantamine are metabolised by cytochrome P450 isoenzymes 3A4 and 2D6, creating a strong potential for pharmacokinetic interactions with inhibitors and inducers of these isoenzymes. Rivastigmine is mainly metabolised by cholinesterases, and binds poorly to cytochrome P450 isoenzymes. (8) Cholinesterase inhibitors inhibit the metabolism of suxamethonium and thereby augment and prolong the neuromuscular blockade induced by this curare. (9) In practice, caregivers should be aware of the potential adverse effects of cholinesterase inhibitors, which often resemble symptoms of Alzheimer's disease and may be due to drug-drug interactions or to antagonist effects with other drugs, such as those with atropinic effects. Additionally, the many adverse effects associated with the use of cholinesterase inhibitors highlights the need for regular re-evaluation of the use of these medicines and of the balance of benefit versus risk in individual patients.
（1）多奈哌齐、加兰他敏和卡巴拉汀等胆碱酯酶抑制剂在减缓与阿尔茨海默病相关的认知衰退方面效果不佳。美金刚效果也不更好，它具有多巴胺能和抗胆碱能作用，但不是胆碱酯酶抑制剂。（2）胆碱酯酶抑制剂主要有胆碱能不良反应，可导致胃肠道、神经、心血管和泌尿系统紊乱（失禁）。（3）在加兰他敏的安慰剂对照试验中观察到死亡率增加，主要归因于心血管事件。在一项试验中，服用多奈哌齐的患者死亡人数比服用安慰剂的患者多。（4）抗胆碱能药物往往会加重用胆碱酯酶抑制剂治疗的认知障碍。（5）胆碱酯酶抑制剂与抗精神病药物联合使用会增加锥体外系不良反应的风险。在涉及痴呆患者的抗精神病药物试验以及胆碱酯酶抑制剂试验中均报告有死亡率增加。（6）将胆碱酯酶抑制剂与降低心率、抑制心脏传导或诱发尖端扭转型室速的药物联合使用会增加心律失常和心脏传导障碍的风险。（7）多奈哌齐和加兰他敏由细胞色素P450同工酶3A4和2D6代谢，与这些同工酶的抑制剂和诱导剂存在很强的药代动力学相互作用潜力。卡巴拉汀主要由胆碱酯酶代谢，与细胞色素P450同工酶结合不佳。（8）胆碱酯酶抑制剂抑制琥珀胆碱的代谢，从而增强并延长这种箭毒诱导的神经肌肉阻滞。（9）在实际应用中，护理人员应了解胆碱酯酶抑制剂的潜在不良反应，这些反应往往类似于阿尔茨海默病的症状，可能是由于药物相互作用或与其他药物（如具有抗胆碱能作用的药物）的拮抗作用所致。此外，与使用胆碱酯酶抑制剂相关的诸多不良反应凸显了定期重新评估这些药物的使用情况以及个体患者获益与风险平衡的必要性。
