抗结核药物所致QTc间期延长临床监测和管理专家共识

doi:10.19982/j.issn.1000-6621.20230271

摘要/Abstract

摘要：

贝达喹啉、德拉马尼、氯法齐明及氟喹诺酮类药物(如左氧氟沙星、莫西沙星)对于提高耐多药和广泛耐药结核病的治疗成功率至关重要。然而,这些药物可能导致心电图的QTc间期延长,若不及时发现和处理,严重者可危及患者生命。因此,临床医师需要采取积极措施进行预防、监测和妥善处理。本共识旨在解决抗结核药物引发的QTc间期延长的临床监测和管理问题。依托公开发表的研究数据,以及参与专家的应用经验,经过深入的讨论,形成了关于抗结核药物导致的QTc间期延长的临床监测和管理的专业建议。希望本共识能够指导医生及时和规范地预防、发现、处理抗结核治疗过程中可能出现的QTc间期延长的不良反应。

关键词: 抗结核药, 心电描记术, QT延长综合征, 药物毒性, 病人医护管理

Abstract:

Bedaquiline, delamanid, clofazimine and fluoroquinolones such as levofloxacin and moxifloxacin are essential to improve the global cure rate of multidrug resistant and extensively drug-resistant tuberculosis. However, these drugs may lead to the prolongation of QTc interval corrected by electrocardiograph, which may cause serious adverse effects. Clinicians need to timely find, properly deal with and prevent adverse effects. This article aims at the common problems in clinical monitoring and management of QTc interval prolongation caused by anti-tuberculous drugs. According to the published research data and the application experience of participating experts, it was formed through discussion among many experts. Professional advice was given on the discovery, treatment and prevention of QTc interval prolongation caused by anti-tuberculous drugs, aiming at timely and standardized prevention and treatment of adverse reactions in the process of anti-tuberculous treatment.

Key words: Antitubercular agents, Electrocardiography, Long QT syndrome, Drug toxicity, Patient care management

中图分类号:

R521
R540

中国防痨协会, 《中国防痨杂志》编辑委员会, 首都医科大学附属北京胸科医院. 抗结核药物所致QTc间期延长临床监测和管理专家共识[J]. 中国防痨杂志, 2024, 46(1): 8-17. doi: 10.19982/j.issn.1000-6621.20230271

Chinese Antituberculosis Association, Editorial Board of Chinese Journal of Antituberculosis, Beijing Chest Hospital, Capital Medical University. Expert consensus on clinical monitoring and management of QTc interval prolongation caused by anti-tuberculous drugs[J]. Chinese Journal of Antituberculosis, 2024, 46(1): 8-17. doi: 10.19982/j.issn.1000-6621.20230271

图/表 5

图1

表1

表2

可能导致QTc间期延长的药物[18?????????????-32]

类别	代表药物	对QTc间期的影响
抗结核药
氟喹诺酮类	莫西沙星	被认为是氟喹诺酮类药物中导致QTc间期延长最常见的药物,估计QTc间期延长10~20ms
	左氧氟沙星	有导致QTc间期延长的风险,认为比莫西沙星更安全
	加替沙星	有导致QTc间期延长的风险,认为比莫西沙星更安全
吩嗪类	氯法齐明	研究较少,估计QTc间期延长10~20ms
二芳基喹啉类	贝达喹啉	QTc间期延长峰值发生在贝达喹啉开始治疗8周后,估计QTc间期延长10~15ms
硝基二氢咪唑并噁唑类衍生物	德拉马尼	QTc间期延长峰值发生在德拉马尼开始治疗8周后,估计QTc间期延长5~15ms
氨基糖苷类	卷曲霉素	由于低钾血症或肾功能损伤导致QTc间期延长
	阿米卡星、卡那霉素	由于肾功能损伤导致QTc间期延长
抗心律失常药
抗心律失常药	索他洛尔、胺碘酮、洋地黄和其他药物	能够延长QTc间期并诱发尖端扭转型室性心动过速的最常见药物,需检查患者使用的所有可引起QTc间期延长的抗心律失常药物
抗精神病药
吩噻嗪类	氯丙嗪	有发生尖端扭转型室性心动过速的报道,考虑替换为其他抗精神病药物
丁酰苯类	氟哌啶醇	在气管插管后或精神病需使用较高剂量氟哌啶醇时,通常发生QTc间期延长,但在较低剂量时也可能发生
	硫利达嗪	秘鲁用于广泛耐药结核病患者的抗精神病药物,相关数据很少,不良反应相对少见,但也可产生心脏毒性,使QTc间期延长,可考虑替代其他精神安定药
抗抑郁药
三环类抗抑郁药	阿米替林、麦普替林	仅在高剂量使用时观察到QTc间期延长,在低剂量或无其他引起QTc间期延长的风险因素下未观察到
选择性5-羟色胺再摄取抑制剂	西酞普兰、艾司西酞普兰	被认为是抗抑郁药中QTc间期延长风险较高的药物,建议使用替代药物治疗
消化系统药
促胃肠动力药物	多潘立酮	QTc间期延长的风险高,不建议使用
止吐药	昂丹司琼	高剂量使用或静脉使用时观察到QTc间期延长
	甲氧氯普胺	导致QTc间期延长的不同机制,当存在相关危险因素时会发生
抗感染药
大环内酯类	克拉霉素、阿奇霉素	长期使用常有发生尖端扭转型室性心动过速的报道
氨基糖苷类	阿米卡星、卡那霉素	可能因肾功能损伤导致QTc间期延长
唑类	氟康唑、伏立康唑、伊曲康唑、酮康唑	存在其他伴随的危险因素时,使用的唑类有潜在的QTc间期延长风险
磺胺类	甲氧苄氨嘧啶、磺胺甲恶唑、乙胺嘧啶	可导致QTc间期延长,甚至诱发尖端扭转型室性心动过速
抗疟药	卤泛群、氯喹、奎宁	特别是静脉使用药物时QTc间期延长更明显
	喷他脒	用于治疗或预防肺孢子菌感染,仅在静脉给药时发生QTc间期延长
利尿剂
泮利尿剂	呋塞米、托拉塞米	因血钾丢失导致QTc间期延长
噻嗪类利尿剂	氢氯噻嗪、甲氯噻嗪	因血钾丢失导致QTc间期延长
抗逆转录病毒药物
非核苷类抗逆转录酶抑制剂	依法韦仑	在其他危险因素存在的情况下,可发生QTc间期延长
核苷类抗逆转录酶抑制剂	替诺福韦	由于Fanconi综合征引起的肾毒性,导致低钾血症
蛋白酶抑制剂	沙奎那韦	PR间期和QTc间期延长,呈剂量依赖性
蛋白酶抑制剂	阿扎那韦	在其他危险因素存在的情况下,可发生QTc间期延长
蛋白酶抑制剂	利托那韦	可能通过抑制CYP3A4酶,减慢通过CYP3A4酶介导的药物代谢,增加这些药物浓度,从而发生QTc间期延长,如多潘立酮
镇痛药
阿片受体激动剂	美沙酮	降低危害的阿片类替代品,长期使用可导致QTc间期延长

表2

图2

表3

参考文献 42

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分类	危险因素
先天性危险因素	女性
	高龄(60岁以后风险增加)
	遗传倾向
	先天性长QT间期综合征
	猝死家族史
	药物诱导QTc间期延长的既往史
	结构性心脏病/左心室功能障碍
	肝功能或肾功能损伤
获得性危险因素	电解质紊乱
	低钾血症
	严重低镁血症
	低钙血症
	甲状腺功能减退
	结构性和功能性心脏问题
	近期心房纤颤复律
	缺血性和充血性心脏病
	缺血性心肌病
	扩张或肥厚充血性心脏病
	充血性心力衰竭
	药物相互作用
	超过1种引起QTc间期延长的药物
	抑制其他可引起QTc间期延长药物代谢的药物
	结核病患者的常见情况
	HIV感染(潜在的附加临床风险因素,特别是疾病晚期和使用多种药物)
	低体质量指数:营养不良、饥饿、消瘦综合征
	严重呕吐、腹泻导致低钾血症
	肝功能损伤
	肾功能损伤
	由于超剂量用药或静脉注射速度过快导致药物浓度增高

QTc间期水平	指标定义	管理措施^a
正常	QTc间期≤450ms(男性)、≤470ms(女性)	继续原方案治疗,每月监测ECG
轻度延长	男性患者≤470ms或较基线增幅<30ms	继续原方案治疗,每月监测ECG
中度延长	470~499ms或30ms<较基线增幅<60ms	若无心脏临床症状(胸痛、心悸、眩晕、晕厥),则继续采用原方案治疗,1周后重复监测ECG;若出现上述临床症状,则中止潜在可引起QTc间期延长的药物治疗,1周内重复监测ECG;同时排除其他延长QTc间期的影响因素(药物、电解质紊乱、甲状腺功能降低),并给予适当的处理措施
重度延长	QTc间期≥500ms或较基线增幅≥60ms	30min后重复ECG检查,如果持续延长,则中止贝达喹啉、左氧氟沙星(莫西沙星)、氯法齐明治疗。排除其他延长QTc间期的影响因素(药物、电解质紊乱、甲状腺功能降低),并给予适当的处理措施,咨询心内科专家。48h后重复监测ECG,若QTc间期下降,则改为每周监测ECG;当QTc间期>470ms,如使用莫西沙星,则停用,采用左氧氟沙星替代莫西沙星(如果药物敏感性试验结果提示对左氧氟沙星敏感)治疗,依次重启左氧氟沙星、氯法齐明,永久停用贝达喹啉治疗,期间监测ECG;若2周内QTc间期依然>470ms,则应再次咨询心内科专家,并请专家组评估患者获益及风险,酌情调整抗结核治疗方案