Bentué-Ferrer Danièle, Tribut Olivier, Polard Elisabeth, Allain Hervé
Laboratoire de Pharmacologie, Faculté de Médecine, Rennes, France.
CNS Drugs. 2003;17(13):947-63. doi: 10.2165/00023210-200317130-00002.
Cholinesterase inhibitors are the only pharmacological class indicated for the treatment of mild to moderate Alzheimer's disease. These drugs are also being used off label to treat severe cases of Alzheimer's disease or vascular dementia and other disorders. The widespread use of cholinesterase inhibitors raises the possibility of their use in combination regimens, with the subsequent risk of deleterious drug-drug interactions in high-risk populations. The purpose of this review is to present the possible sources of pharmacokinetic or pharmacodynamic drug-drug interactions involving cholinesterase inhibitors. The four cholinesterase inhibitors (tacrine, donepezil, rivastigmine and galantamine) that are currently available have different pharmacological properties that expose patients to the risk of several types of drug interactions of nonequivalent clinical relevance. The principal proven clinically relevant drug interactions involve tacrine and drugs metabolised by the cytochrome P450 (CYP) 1A2 enzyme, as well as tacrine or donepezil and antipsychotics (which results in the appearance of parkinsonian symptoms). The bioavailability of galantamine is increased by coadministration with paroxetine, ketoconazole and erythromycin. It is of interest to note that because rivastigmine is metabolised by esterases rather than CYP enzymes, unlike the other cholinesterase inhibitors, it is unlikely to be involved in pharmacokinetic drug-drug interactions. Care must be taken to reduce the risk of inducing central (excitation, agitation) or peripheral (e.g. bradycardia, loss of consciousness, digestive disorders) hypercholinergic effects via drug interactions with cholinesterase inhibitors. A review of the literature does not reveal any alarming data but does highlight the need for prudent prescription, particularly when cholinesterase inhibitors are given in combination with psychotropics or antiarrhythmics. Possible interactions involving other often coprescribed antidementia agents (e.g. memantine, antioxidants, cognitive enhancers) remain an open area requiring particularly prudent use.
胆碱酯酶抑制剂是唯一被指明用于治疗轻至中度阿尔茨海默病的一类药物。这些药物也被用于治疗重度阿尔茨海默病或血管性痴呆及其他病症，但属于超适应证用药。胆碱酯酶抑制剂的广泛使用增加了其用于联合治疗方案的可能性，随之而来的是高危人群中有害药物相互作用的风险。本综述的目的是介绍涉及胆碱酯酶抑制剂的药代动力学或药效学药物相互作用的可能来源。目前可用的四种胆碱酯酶抑制剂（他克林、多奈哌齐、卡巴拉汀和加兰他敏）具有不同的药理特性，这使患者面临几种临床相关性不等的药物相互作用风险。临床上已证实的主要相关药物相互作用涉及他克林与细胞色素P450（CYP）1A2酶代谢的药物，以及他克林或多奈哌齐与抗精神病药物（会导致帕金森症状出现）。加兰他敏与帕罗西汀、酮康唑和红霉素合用会增加其生物利用度。值得注意的是，与其他胆碱酯酶抑制剂不同，卡巴拉汀是由酯酶而非CYP酶代谢，因此不太可能参与药代动力学药物相互作用。必须注意降低通过与胆碱酯酶抑制剂发生药物相互作用而诱发中枢（兴奋、激动）或外周（如心动过缓、意识丧失、消化系统紊乱）胆碱能亢进效应的风险。文献综述未发现任何警示性数据，但确实强调了谨慎处方的必要性，尤其是在胆碱酯酶抑制剂与精神药物或抗心律失常药物联合使用时。涉及其他常同时开具的抗痴呆药物（如美金刚、抗氧化剂、认知增强剂）的可能相互作用仍是一个需要特别谨慎使用的开放领域。
