University of Kentucky Mental Health Research Center and Department of Psychiatry, School of Medicine, University of Kentucky, Lexington, KY, USA.
Curr Drug Metab. 2011 Sep;12(7):635-46. doi: 10.2174/138920011796504518.
Many naturalistic studies agree that adverse drug reactions (ADRs), particularly cognitive deficits, frequently occur when medications with anticholinergic activity are used in geriatric patients. However, the studies disagree on which anticholinergic drugs may have clinical relevance. The three most important methods to establish clinically relevant anticholinergic activity are: 1) the drug's affinity for muscarinic receptors, demonstrated by in vitro studies and a profile compatible with antagonist properties; 2) serum anticholinergic activity measured by radioreceptor assay; and 3) the presence of typical antimuscarinic ADRs, such as dry mouth and constipation, in patient studies or clinical trials. More recently, brain imaging of muscarinic receptors and scales for quantifying antimuscarinic activity were developed. A comprehensive approach can be crafted only by paying attention to the pharmacodynamic and pharmacokinetic mechanisms of these drugs. ADR studies on drugs with anticholinergic activity should not only consider central muscarinic receptor blockade, but also peripheral receptor blockade. The ability to cross the blood-brain barrier is important in the drug's ADR profile. Patient personal characteristics, drug-drug interactions (DDIs) and probably genetic variations may contribute to increased ADR risk through pharmacokinetic and/or pharmacodynamic mechanisms. Sophisticated clinical designs and the evidence-based medicine approach cannot succeed unless the list of drugs of anticholinergic activity is agreed upon, and the studies include a sophisticated pharmacological approach guided by our current understanding of their pharmacodynamic and pharmacokinetic mechanisms. If one agrees that antimuscarinic ADRs are probably dose-related, future studies must consider all drugs, administration routes, doses, muscarinic receptor affinity, DDIs, and brain access.
许多自然主义研究都认为，当具有抗胆碱能活性的药物在老年患者中使用时，经常会出现药物不良反应（ADR），尤其是认知功能障碍。然而，这些研究在哪些抗胆碱能药物可能具有临床相关性上存在分歧。确定具有临床相关性抗胆碱能活性的三种最重要方法是：1）通过体外研究和与拮抗剂特性相符的特征来证明药物对毒蕈碱受体的亲和力；2）通过放射受体测定法测量血清抗胆碱能活性；3）在患者研究或临床试验中存在典型的抗毒蕈碱 ADR，如口干和便秘。最近，开发了用于量化抗毒蕈碱活性的脑成像技术和量表。只有通过关注这些药物的药效学和药代动力学机制，才能制定全面的方法。具有抗胆碱能活性的药物的 ADR 研究不仅应考虑中枢毒蕈碱受体阻断，还应考虑外周受体阻断。药物穿过血脑屏障的能力在其 ADR 特征中很重要。患者的个人特征、药物-药物相互作用（DDI）以及可能的遗传变异可能通过药效学和/或药代动力学机制导致 ADR 风险增加。除非就具有抗胆碱能活性的药物清单达成一致，并且研究包括基于我们对其药效学和药代动力学机制的当前理解的复杂药理学方法，否则复杂的临床设计和循证医学方法将无法成功。如果人们认为抗毒蕈碱 ADR 可能与剂量有关，那么未来的研究必须考虑所有药物、给药途径、剂量、毒蕈碱受体亲和力、DDI 和大脑通道。
