Kay Gary G, Abou-Donia Mohamed B, Messer William S, Murphy Declan G, Tsao Jack W, Ouslander Joseph G
Neuropsychology Division, Department of Neurology, Georgetown University School of Medicine, Washington, DC, USA.
J Am Geriatr Soc. 2005 Dec;53(12):2195-201. doi: 10.1111/j.1532-5415.2005.00537.x.
Antimuscarinic agents are the predominant pharmacological treatment for patients with overactive bladder (OAB). These drugs are thought to act primarily through antagonism at muscarinic M3 receptors located at neuromuscular junctions in the human bladder detrusor muscle. Several of these drugs have been shown to be efficacious in ameliorating the symptoms of OAB in older patients, but most currently available agents lack selectivity for the M3 receptor subtype, and interaction with other muscarinic receptor subtypes throughout the body may adversely affect a variety of physiological functions and result in unwanted side effects, including cognitive dysfunction. With the recent availability of antimuscarinic agents that show increased selectivity for M3 receptors relative to other muscarinic subtypes, an invitational expert panel meeting was convened to review not only the mechanisms by which antimuscarinic agents could affect cognitive function, but also the published literature on cognitive adverse events. A review of the literature shows that the cholinergic system in the central nervous system (CNS) exerts a major influence on cognitive processes, in particular memory via M1 cholinergic receptors. In addition, recent evidence suggests a role for M2 receptors in mediating cognitive function. Thus, cognitive dysfunction (including memory loss) during treatment with nonselective antimuscarinic agents for OAB is of growing concern, particularly in older patients and those with mild cognitive impairment or dementia. Increased blood-brain barrier permeability, which can occur with advanced age and certain comorbidities, may also facilitate CNS access of antimuscarinic agents (regardless of their physiochemical properties) and add to antimuscarinic burden. On the basis of available evidence, antimuscarinic agents with selectivity for M3 over M1 and M2 receptors, limited CNS penetration, or both may therefore offer a favorable balance of efficacy in treating OAB together with a reduced risk of adverse cognitive events in the older population.
抗毒蕈碱药物是治疗膀胱过度活动症（OAB）患者的主要药物疗法。这些药物被认为主要通过拮抗位于人膀胱逼尿肌神经肌肉接头处的毒蕈碱M3受体起作用。其中几种药物已被证明可有效改善老年患者的OAB症状，但目前大多数可用药物对M3受体亚型缺乏选择性，并且与全身其他毒蕈碱受体亚型的相互作用可能会对多种生理功能产生不利影响，并导致不良副作用，包括认知功能障碍。随着最近出现了相对于其他毒蕈碱亚型对M3受体具有更高选择性的抗毒蕈碱药物，召开了一次专家受邀小组会议，不仅要审查抗毒蕈碱药物影响认知功能的机制，还要审查关于认知不良事件的已发表文献。文献综述表明，中枢神经系统（CNS）中的胆碱能系统对认知过程，特别是通过M1胆碱能受体对记忆产生重大影响。此外，最近的证据表明M2受体在介导认知功能方面也发挥作用。因此，在使用非选择性抗毒蕈碱药物治疗OAB期间出现的认知功能障碍（包括记忆力丧失）越来越受到关注，尤其是在老年患者以及那些有轻度认知障碍或痴呆的患者中。随着年龄增长和某些合并症可能出现的血脑屏障通透性增加，也可能促进抗毒蕈碱药物进入中枢神经系统（无论其理化性质如何），并增加抗毒蕈碱负担。根据现有证据，相对于M1和M2受体对M3受体具有选择性、中枢神经系统穿透有限或两者兼有的抗毒蕈碱药物，可能在治疗OAB时提供良好的疗效平衡，同时降低老年人群发生不良认知事件的风险。
