对药物引起QT间期延长的认识.ppt

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style,对药物所致,QT,间期延长的认识,提纲,背景介绍,QT,间期,QT,间期延长与抗抑郁药物,提纲,背景介绍,QT,间期,QT,间期延长与抗抑郁药物,FDA,陈述,-,西酞普兰,西酞普兰和艾司西酞普兰针对,QT,间期的临床研究,研究时间：,2009,年,4,月,9,日,-2009,年,9,月,24,日,研究设计：,多中心、随机化、双盲、安慰剂对照、剂量递增多次给药研究,研究中心：,2,家美国研究中心,研究时间：,2009,年,1,月,5,日,-2009,年,5,月,12,日,研究设计：,多中心、随机化、双盲、安慰剂对照、剂量递增多次给药研究,研究中心：,2,家美国研究中心,提纲,背景介绍,QT,间期,QT,间期延长与抗抑郁药物,药物所致,QT,间期延长的机制,由于心室肌细胞复极相关的离子通道以及蛋白的结构和功能异常引起,直接阻滞,I,kr,抑制,I,kr,通道表达,心室复极储备降低,I,kr,=,快激活整流钾电流,2010,获得性长,QT,间期综合征的防治建议,心肌细胞的动作电位,复极的钾离子流减弱，动作电位时限和间期延长,I,k1,=,内向整流钾电流,I,ks,=,慢激活整流钾电流,可能引起,QT,间期延长的风险因素,老年女性,严重心脏病,应用其他直接或间接延长,QT,间期的药物（如利尿剂，可以引起低钾血症）,有家族猝死病史,有复杂用药方案，其中存在抑制代谢酶高风险的药物,患者病史中的一些简单特征须引起医生的注意,Roden DM.Drug-induced prolongation of the QT interval.N Engl J Med.2004.350(10):1013-22,药物诱发,TdP,的危险因素,血药浓度增加,无论是由于大剂量药物还是由于药物相互作用、代谢器官功能障碍所致的,血药浓度升高,，均可使,QT,间期延长加重,，,易于发生,TdP,。,随剂量增加,(,血浆药浓度升高,),而出现,QT,间期延长加重，,TdP,的危险性上升。,静脉与口服用药比较,与口服给药相比，同等剂量的静脉用药通常血药浓度较高，心脏作用更强。,亚临床型先天性,QT,间期延长综合征对药物的易感性,2010,获得性长,QT,间期综合征的防治建议,常见可导致,QT,间期延长综合征的药物,抗心律失常药：奎尼丁、索他洛尔、丙吡胺、普鲁卡因胺,抗生素：大环内脂类、喹诺酮类、酮康唑,精神科药物：如氯氮平、氯丙嗪、甲硫哒嗪及舒必利,抗抑郁药,:,三环类（有阿米替林、氯米帕明）、四环类（马普替林）,胃肠动力药：西沙必利、莫沙必利、多潘立酮,抗组胺药：西替利嗪、特非那定,其他：麻醉剂、利尿剂,周云飞 刘铁榜,.,四川精神卫生，,2008,21,（,1,）：,63-65,提纲,背景介绍,QT,间期,QT,间期延长与抗抑郁药物,精神科药物导致,QTc,的原因,协同,HERG,钾通道的阻塞,药物浓度的增加,由于药物之间共享代谢通道而造成的代谢相互作用,Sala M et al.Ann Gen Psychiatry.2005 Jan 25;4(1):1.,2010,获得性长,QT,间期综合征的防治建议,HERG,钾通道,=,HERG,基因编码的钾离子通道存在于人类心室和心房肌细胞中,其,HERG,通道编码心脏快速延迟整流钾电流,Ikr,为心肌细胞动作电位三相复极期的主要外向钾电流,在心脏动作电位复极化过程中发挥着重要作用。,“精神用药导致的,QTc,延长与,TdP,风险”,文献综述,Wenzel-Seifert K et al.Dtsch Arztebl Int.2011 Oct;108(41):687-93.,背景,很多抗精神病药物及抗抑郁药物可导致,QTc,延长，并且具有剂量依赖性。,方法,在,PUBMED,上检索有关与常用精神药物可致,QTc,和,/,或,TdP,风险的文献。,结果,新型抗精神病药物对,QTc,TdP,的影响,舍吲哚及氯氮平可明显延长,QTc,，主要发生于老年患者,CYP2D6,慢代谢或同时服用,CYP2D6,抑制剂者，如氟西汀、帕罗西汀、安非他酮、度洛西汀风险显著升高,Wenzel-Seifert K et al.Dtsch Arztebl Int.2011 Oct;108(41):687-93.,结果,抗抑郁药物对,QTc,TdP,的影响,三环类和四环类抗抑郁药均可影响,QT,间期,SSRI,对,QTc,的影响多为轻中度，显著小于三环、四环抗抑郁药,Wenzel-Seifert K et al.Dtsch Arztebl Int.2011 Oct;108(41):687-93.,QTc,延长,与基线对照,QTc,延长,ms,TdP,案例报道,TdP,风险评估,*,*,*,*说明书提示,QTc,间期延长,/TdP,，出现于,药物过量,及与有,QTc,间期延长现象的其他药物的,联合应用,治疗剂量未出现；,+,轻度,(5 and 9 ms),或只出现于药物过量或中毒病例；,+,中度,9 and 16 ms);,+,重度,(17 ms),TdP,风险（,Arizona CERT,）,:,1,可接受的,TdP,风险,;,2,极少,TdP,报道,可能但不充分的,TdP,风险报道,3,与,TdP,关联小,在治疗剂量不可能，先天性,QT,综合征时,TdP,风险增加,文拉法辛*,西酞普兰*,氟西汀,帕罗西汀,舍曲林,艾司西酞普兰*,氟伏沙明,瑞波西汀,度洛西汀,美沙酮及左美沙酮具,QTc,延长及,TdP,高发生风险,美沙酮,左美沙酮,水合氯醛,哌醋甲酯,阿托莫西汀,泰必利,卡马西平,丙戊酸,拉莫三嗪,比哌立登,安定,结果,镇静及其他精神科用物对,QTc,TdP,的影响,Wenzel-Seifert K et al.Dtsch Arztebl Int.2011 Oct;108(41):687-93.,QTc,延长,与基线对照,QTc,延长,ms,TdP,案例报道,TdP,风险评估,多项报道抗抑郁药物导致,QT,间期延长,SSRIs,（氟西汀、帕罗西汀、舍曲林）、三环类抗抑郁剂（氯米帕明、丙咪嗪）以及锂盐，都可导致,QT,间期延长,1-3,；,除了抗精神病药物，抗抑郁药物也可导致,QT,间期延长，这些药物包括：去甲丙咪嗪、多赛平、氟西汀、丙咪嗪、帕罗西汀、舍曲林、文拉法辛,4,；,基础研究证实，舍曲林可阻滞心肌,K+,通道及,Na,、,Ca,通道,5,；,1.Elming H,et al,:The importance of the QT interval:a review of the literature.,Acta Psychiatr Scand 2003,107:96-101.,2.Haverkamp W,et al.,The potential for QT prolongation and pro-arrhythmia by nonanti-arrhythmic drugs:Clinical and regulatory implications Report on a Policy Conference of the European Society of Cardiology.,Cardiovasc Res 2000,47:219-33.,3.Rodriguez de la Torre B.et al.Serum Levels and cardiovascular effects of tricyclic antidepressants and selective serotonine reuptake inhibitors in depressed patients.,Ther Drug Monit 2001,23:435-440.,4.Cubeddu LX.QT prolongation and fatal arrhythmias:a review of clinical implications and effects of drugs.Am J Ther.2003.10(6):452-7,5.,Lee HA et al.Korean J Physiol Pharmacol.2012 Oct;16(5):327-32,QT,间期与尖端扭转性室速,并非线性关系,QT,间期常是预测导致晕厥或死亡的尖端扭转性室速的标记物,但如同许多其他标志一样,它与事件发生的关系是不完全的,尖端扭转性室速的发生和,QT,间期的延长并非线性关系,一些药物,(,如维拉帕米和盐酸胺碘酮,),阻断,Ikr,但很少引起尖端扭转性室速,;,Ikr,阻断剂抗组胺药物,ter fenadine,并不明显延长动作电位却因引起尖端扭转性室速，并因此而退出市场,Roden DM.Drug-induced prolongation of the QT interval.N Engl J Med.2004.350(10):1013-22,艾司西酞普兰用药剂量与,QT,间期的关系,美国,FDA,对编号,SCT-PK-21,的研究结果进行分析显示：,艾司西酞普兰,10mg,*,30mg,20mg,*,最大平均,QTcNi,延长,*,4.5 msec,10.7 msec,6.6 msec,双侧,90%,置信区间上限,6.4 msec,12.7 msec,7.9 msec,*,与基线相比的变化，安慰剂校正,*艾司西酞普兰,10 mg,，,20mg,为说明书指导治疗剂量,艾司西酞普兰在治疗剂量范围内应用安全,SCT-PK-21,FDA,陈述,-,艾司西酞普兰,小结,临床中，多种药物可引起,QT,间期延长，包括抗抑郁药物；,SSRI,对,QT,间期的影响小于三环和四环类抗抑郁药,药物治疗过程中须关注患者发生,QT,间期延长的风险因素（如既往心脏疾病史、合并用药相互作用等）,艾司西酞普兰治疗剂量范围内未发现,QT,间期延长的潜在风险增加；,FDA,并未对艾司西酞普兰治疗剂量进行任何警告和建议；,谢谢！,