在老年患者中常见的血清浓度下，艾司西酞普兰和西酞普兰的致心律失常作用 - 基于 19742 名患者队列的研究。
Pro-arrhythmic effect of escitalopram and citalopram at serum concentrations commonly observed in older patients - a study based on a cohort of 19,742 patients.
机构信息
Center for Psychopharmacology, Diakonhjemmet Hospital, Oslo, Norway.
Center for Psychopharmacology, Diakonhjemmet Hospital, Oslo, Norway; Department of Life Sciences and Health, Oslo Metropolitan University, Oslo, Norway.
出版信息
EBioMedicine. 2023 Sep;95:104779. doi: 10.1016/j.ebiom.2023.104779. Epub 2023 Aug 26.
BACKGROUND
For a decade, patients have been advised against using high citalopram- and escitalopram-doses due to risk for ventricular arrhythmia and cardiac arrest. Still, these drugs are widely used to treat depression and anxiety especially in older patients. It is unclear why they are cardiotoxic and at what serum concentrations patients are at risk for arrhythmias. Thus, how many patients that are at risk for iatrogenic cardiac arrest is unknown.
METHODS
We studied the arrhythmogenic effects of citalopram, escitalopram and their metabolites on human cardiomyocytes. Concentrations showing pro-arrhythmic activity were compared with observed drug and metabolite serum concentrations in a cohort of 19,742 patients (age 12-105 years) using escitalopram or citalopram in Norway (2010-2019). As arrhythmia-risk is related to maximum serum concentration, this was simulated for different age-groups from the escitalopram patient material.
FINDINGS
Therapeutic concentrations of both citalopram and escitalopram but not their metabolites showed pro-arrhythmic changes in the human cardiac action potential. Due to age-dependent reduction of drug clearance, the proportion of patients above threshold for arrhythmia-risk increased with age. 20% of patients >65 years were predicted to reach potentially pro-arrhythmic concentrations, following intake of 10 mg escitalopram.
INTERPRETATION
All patients that are using escitalopram or citalopram and have genetic disposition for acquired long-QT syndrome, are >65 years, are using additional pro-arrhythmic drugs or have predisposition for arrhythmias, should be monitored with therapeutic drug monitoring (TDM) to avoid exposure to potentially cardiotoxic concentrations. Serum concentrations should be kept below 100 nM, to reduce arrhythmia-risk.
FUNDING
This study was funded by The Research Council of Norway (project number: 324062).
背景
十年来，由于存在室性心律失常和心脏骤停的风险，患者一直被建议避免使用高剂量西酞普兰和艾司西酞普兰。尽管如此，这些药物仍被广泛用于治疗抑郁症和焦虑症，尤其是在老年患者中。目前尚不清楚它们为何具有心脏毒性，以及患者在何种血清浓度下会有发生心律失常的风险。因此，有多少患者存在医源性心脏骤停的风险尚不清楚。
方法
我们研究了西酞普兰、艾司西酞普兰及其代谢物对人心肌细胞的致心律失常作用。将显示致心律失常活性的浓度与挪威 19742 名（年龄 12-105 岁）使用艾司西酞普兰或西酞普兰的患者队列中的药物和代谢物血清浓度进行比较（2010-2019 年）。由于心律失常风险与最大血清浓度有关，因此根据艾司西酞普兰患者资料中的不同年龄组对其进行了模拟。
结果
治疗浓度的西酞普兰和艾司西酞普兰，而不是它们的代谢物，会导致人心律失常的动作电位发生致心律失常变化。由于药物清除率随年龄的依赖性降低，随着年龄的增长，超过心律失常风险阈值的患者比例增加。预计 20%的>65 岁患者在服用 10mg 艾司西酞普兰后，可能会达到潜在的致心律失常浓度。
结论
所有正在使用艾司西酞普兰或西酞普兰且具有获得性长 QT 综合征遗传易感性、年龄>65 岁、正在使用其他致心律失常药物或存在心律失常易感性的患者，都应进行治疗药物监测（TDM）以避免暴露于潜在的心脏毒性浓度。为降低心律失常风险，应将血清浓度保持在 100nm 以下。
这项研究由挪威研究理事会（项目编号：324062）资助。
Zotero 插件