Grossberg George T
Department of Psychiatry, St. Louis University School of Medicine, St. Louis, Missouri, MO, USA.
Curr Ther Res Clin Exp. 2003 Apr;64(4):216-35. doi: 10.1016/S0011-393X(03)00059-6.
Cholinesterase (ChE) inhibitors currently used in the treatment of Alzheimer's disease (AD) are the acetylcholinesterase (AChE)-selective inhibitors, donepezil and galantamine, and the dual AChE and butyrylcholinesterase (BuChE) inhibitor, rivastigmine. In addition to differences in selectivity for AChE and BuChE, ChE inhibitors also differ in pharmacokinetic and pharmacodynamic properties, and these differences could significantly impact on safety, tolerability, and efficacy.
The aim of this article was to provide an overview of the ChE inhibitors widely used in AD, focusing on key pharmacologic differences among agents and how these may translate into important differences in safety, tolerability, and efficacy in clinical practice.
Using published literature collected over time by the author, a review was conducted, focusing on the pharmacology and clinical data of donepezil, galantamine, and rivastigmine.
All ChE inhibitors have the potential to induce centrally mediated cholinergic adverse events (AEs), such as nausea and vomiting, if the dose is increased too rapidly or in increments that are too large. These AEs, which are most likely to occur during the "getting on," or dose-escalation, phase of treatment, may result in patients discontinuing treatment early without achieving optimum therapeutic benefit. To reduce the incidence of these AEs, a slow dose-escalation schedule has been established in clinical practice, consisting of a "start low, go slow" procedure with a minimum of 4 weeks between dose increases. After "getting on" treatment, maintaining treatment in the long term, or "staying on," may be achieved with good safety, tolerability, and sustained symptomatic efficacy across the key symptom domains (activities of daily living, behavior, and cognition).
ChE inhibitors provide symptomatic benefit in AD across key symptom domains. Factors influencing the safety, tolerability, and efficacy of these agents in clinical practice include ChE enzymes inhibited, brain and brain-region ChE selectivity, and metabolism route. Class-specific cholinergic AEs can be minimized using slow, flexible dose escalation.
目前用于治疗阿尔茨海默病（AD）的胆碱酯酶（ChE）抑制剂包括乙酰胆碱酯酶（AChE）选择性抑制剂多奈哌齐和加兰他敏，以及AChE和丁酰胆碱酯酶（BuChE）双重抑制剂卡巴拉汀。除了对AChE和BuChE的选择性不同外，ChE抑制剂在药代动力学和药效学特性方面也存在差异，而这些差异可能会对安全性、耐受性和疗效产生重大影响。
本文旨在概述AD中广泛使用的ChE抑制剂，重点关注各药物之间的关键药理学差异，以及这些差异如何在临床实践中转化为安全性、耐受性和疗效方面的重要差异。
利用作者长期收集的已发表文献进行综述，重点关注多奈哌齐、加兰他敏和卡巴拉汀的药理学和临床数据。
如果剂量增加过快或增量过大，所有ChE抑制剂都有可能诱发中枢介导的胆碱能不良事件（AE），如恶心和呕吐。这些AE最有可能在治疗的“起始”或剂量递增阶段出现，可能导致患者在未获得最佳治疗益处的情况下提前停药。为了降低这些AE的发生率，临床实践中已制定了缓慢的剂量递增方案，即采用“低起始、慢增加”程序，每次增加剂量之间至少间隔4周。在“起始”治疗后，长期维持治疗，即“持续治疗”，可以在关键症状领域（日常生活活动、行为和认知）实现良好的安全性、耐受性和持续的症状缓解疗效。
ChE抑制剂在AD的关键症状领域提供症状缓解益处。影响这些药物在临床实践中安全性、耐受性和疗效的因素包括被抑制的ChE酶、脑和脑区ChE选择性以及代谢途径。使用缓慢、灵活的剂量递增可以将特定类别的胆碱能AE降至最低。
