Oakland University William Beaumont School of Medicine, and Department of Urology, William Beaumont Hospital, Royal Oak, MI 48073, USA.
Drugs Aging. 2012 Apr 1;29(4):259-73. doi: 10.2165/11597530-000000000-00000.
Overactive bladder (OAB) is a common condition, particularly in the elderly. Anticholinergic agents are the mainstay of pharmacological treatment of OAB; however, many anticholinergics can cross the blood-brain barrier (BBB) and may cause central nervous system (CNS) effects, including cognitive deficits, which can be especially detrimental in older patients. Many anticholinergics have the potential to cause adverse CNS effects due to muscarinic (M(1)) receptor binding in the brain. Of note, permeability of the BBB increases with age and can also be affected by trauma, stress, and some diseases and medications. Passive crossing of a molecule across the BBB into the brain is dependent upon its physicochemical properties. Molecular characteristics that hinder passive BBB penetration include a large molecular size, positive or negative ionic charge at physiological pH, and a hydrophilic structure. Active transport across the BBB is dependent upon protein-mediated transporter systems, such as that of permeability-glycoprotein (P-gp), which occurs only for P-gp substrates, such as trospium chloride, darifenacin and fesoterodine. Reliance on active transport can be problematic since genetic polymorphisms of P-gp exist, and many commonly used drugs and even some foods are P-gp inhibitors or are substrates themselves and, due to competition, can reduce the amount of the drug that is actively transported out of the CNS. Therefore, for drugs that are preferred not to cross into the CNS, such as potent anticholinergics intended for the bladder, it is optimal to have minimal passive crossing of the BBB, although it may also be beneficial for the drug to be a substrate for an active efflux transport system. Anticholinergics demonstrate different propensities to cross the BBB. Darifenacin, fesoterodine and trospium chloride are substrates for P-gp and, therefore, are actively transported away from the brain. In addition, trospium chloride has not been detected in cerebrospinal fluid assays and does not appear to have significant CNS penetration. This article reviews the properties of anticholinergics that affect BBB penetration and active transport out of the CNS, discusses issues of increased BBB permeability in patients with OAB, and examines the clinical implications of BBB penetration on adverse events associated with anticholinergics.
膀胱过度活动症（OAB）是一种常见的疾病，尤其在老年人中更为常见。抗胆碱能药物是治疗 OAB 的主要药物；然而，许多抗胆碱能药物可以穿过血脑屏障（BBB），并可能引起中枢神经系统（CNS）的影响，包括认知缺陷，这在老年患者中尤为不利。由于在大脑中与毒蕈碱（M(1)）受体结合，许多抗胆碱能药物都有可能引起不良的 CNS 影响。值得注意的是，BBB 的通透性会随着年龄的增长而增加，并且还会受到创伤、压力和某些疾病和药物的影响。分子被动穿过 BBB 进入大脑取决于其物理化学性质。阻碍被动 BBB 穿透的分子特征包括大的分子大小、在生理 pH 值下带正电荷或负电荷以及亲水结构。主动跨 BBB 转运取决于蛋白介导的转运系统，如多药耐药相关蛋白（P-gp），它仅适用于 P-gp 底物，如托特罗定、达非那新和非索罗定。依赖主动转运可能会出现问题，因为存在 P-gp 的遗传多态性，并且许多常用药物甚至某些食物都是 P-gp 抑制剂或本身就是底物，由于竞争，会减少主动从 CNS 转运出的药物量。因此，对于那些不希望进入 CNS 的药物，如用于膀胱的强效抗胆碱能药物，最好是最小化 BBB 的被动穿透，尽管对于药物来说，成为主动外排转运系统的底物可能也是有益的。抗胆碱能药物表现出不同的穿透 BBB 的倾向。达非那新、非索罗定和托特罗定是 P-gp 的底物，因此被主动转运出大脑。此外，托特罗定在脑脊液测定中未被检测到，并且似乎没有明显的 CNS 穿透。本文综述了影响 BBB 穿透和主动从 CNS 转运的抗胆碱能药物的特性，讨论了 OAB 患者 BBB 通透性增加的问题，并研究了 BBB 穿透对与抗胆碱能药物相关的不良事件的临床意义。
