抗心律失常药物

Antiarrhythmicdrugs 抗心律失常药物 中南大学药学院药理学系陈小平2011 10 心律失常及病因 Arrhythmia 心跳频率 节律和传导的异常 CO life threaten 引起心律失常的因素 疾病 心肌梗死 高血压 心衰 和药物 如地高辛 麻醉药 心律失常的类型 心动过缓 bradycardia 窦性心动过缓 sinusbradycardia 房室传导阻滞 atrio ventricularblock 心动过速 tachycardia 房性早搏 atrialprematurecontraction 房性心动过速 atrialtachycardia AT 心房颤动 atrialfibrillation AF 心房扑动 atrialflutter AFL 阵发性室上性心动过速 paroxysmalsupraventriculartachycardia 室性早搏 ventricularprematurecontraction 室性心动过速 ventriculartachycardia VT 心室颤动 ventricularfibrillation VF 心律失常的电生理基础 Electrophysiologyofnormalcardiacrhythm Actionpotentialofcardiaccells 心肌缺血 缺氧时膜电位变小 快反应细胞表现出慢反应电活动 APD与ERP Electrophysiologyofarrhythmias 异位节律点自律性升高静息点位水平负值减小最大舒张点位绝对值下降4相自动除极速率加快阈点位水平下移后除极 afterdepolarization 与触发活动 1 冲动形成障碍 2 冲动传导障碍 Increasedautomaticityofectopicfocus Increasedautomaticityofectopicfocus Increasedautomaticityofectopicfocus Electrophysiologyofarrhythmias 后除极与触发活动 早后除极 earlyafterdepolarization EAD 发生于AP2相或3相 Ca2 和Na 内流所致 CCBs和利多卡因可阻断 迟后除极 delayedafterdepolarization DAD 发生于AP4相 Ca2 overload诱发Na 内流 强心苷中毒 儿茶酚胺类和心肌缺血可诱发 2 Abnormalityinimpulseconduction Singlereentry prematurestroke Repeatedreentry AF AFL VT VF ClassificationofAntiarrhythmicDrugs Class sodiumchannel blockingagentsIA InhibitNa influxmoderately e g quinidine procainamide IB InhibitNa influxslightly e glidocaine phenytoinsodium IC depressNa influxseverely e gflecainide encainide propafenone Class ARblockers e g propranolol metoprolol Class prolongingAPD e g amiodarone sotalol Class CCBs e g verapamil diltiazem Others adenosine VaughanWilliams 1971 Class Sodiumchannel blockingagents ClassIA 适度抑制Na 通道 Vmax conduction phase4slope automaticity K efflux ERPandAPD 代表药物 quinidine procainamide disopyramide 丙吡胺 与开放态或失活态Na 通道结合 频率依赖性 对正常心肌细胞无影响 Qunidine 奎尼丁 轻度抑制Na 内流 抑制K 外流和Ca2 内流 阻断 和M受体对心脏的作用 automaticity 抑制心房肌 心室肌 浦肯也氏纤维及窦房结细胞4相Na 和Ca2 内流 conduction 抑制心房肌 心室肌 浦肯也氏纤维0相Na 内流 ERP 抑制K 外流 心肌收缩力 Pharmacologicaleffects Qunidine 奎尼丁 Pharmacokinetics 口服易吸收 心肌组织中浓度为血浆中的10倍 肝脏代谢 代谢产物有活性 CHF 肝肾疾病t1 2 Therapeuticuse 广谱 broad spectrum 抗心律失常Atrialfibrillation atrialflutter Supraventricularandventriculartachycardia Supraventricularandventricularprematurebeat Toxicity 6 g mlGIsystem 恶心 呕吐 腹泻 厌食CNSsystem 金鸡纳反应 chichonicreaction CVS 心衰 低血压 室内传到阻滞 奎尼丁晕厥Druginteraction Renalclearanceofdigoxin P450inducers quinidinemetabolism P450inhibitors adjustdosages 普鲁卡因胺 作用与奎尼丁相似 阻断M受体和 受体作用较后者弱 乙酰化代谢产物具有III类抗心律失常药物的作用 为光谱抗心律失常药物丙吡胺 作用与奎尼丁相似 抗胆碱作用比奎尼丁强 抑制心肌收缩作用明显 ClassIB 轻度抑制Na 内流 降低自律性 改善传到K 外流 缩短APD ERP ERP APD 主要作用于心室肌细胞和Purkinje纤维 Representativedrugs lidocaine 利多卡因 phenytoinsodium 苯妥英钠 mexiletine 美西津 tocainide 妥卡尼 等 Lidocaine 利多卡因 Pharmacologicalactions Automaticity limitedtoP kfibers 改善传导 improveconduction Myocardialischemia phase0Na infflux conduction unidirectionalblockade bidirectionalblockadeDepolerationcausedbyhypokalemiaandstress K efflux conduction unidirectionalblockAPD or Pharmacokinetics 首关消除明显 口服生物利用度3 体内广泛分布 70 与血浆蛋白结合 心肌中浓度为血浆中的3倍 Therapeuticindex 1 5 g ml 主要经肝脏代谢 10 原型肾脏排泄 Therapeuticuse ventriculararrhythmiaVentricularprematurecontraction ventriculartachycardia andventricularfibrillationcausedbyAMI Ventriculararrhythamiascausedbyheartdisease Ventriculararrhythamiascausedbycardiacglycosidesandoperation Adversereactions CNS dizyness excitement blurredvision HR sinusstop AVblockandhypotension overdose PhenytoinSodium 与利多卡因作用相似 BindswithNa K ATPase 用于急慢性室性心律失常 强心苷类药物中毒引起房室传到阻滞或室性心律失常的首选药物 ClassIC 重度阻滞Na 内流 显著 Vmax phase4slope automaticity 抑制0相Na 内流 传到速度 QRS Representativedrugs flecainide encainide propafenone Lowtherapeuticindex Seriousadversereactions provocationoflethalarrhythmia Flecainide 心房肌 心室肌和P k纤维的传到速度 automaticity K outflow 心房肌和心室肌细胞的APD 用于室上性和室性心律失常 Causeslethalarrhythmia Propafenone 普罗帕酮 BlockNa andCa2 channelsand AR conduction automaticity ERP negativeinotropiceffects Clinicaluse Supraventricularandventriculartachycardia Supraventricularandventricularprematurebeat Atrialfibrillation Class Blockers Representativedrugs propranolol metoprolol Pharmacologicalactions ARblockingandmembrane stabilizingeffects Na in automaticityofsinoatrialnode atrialmyocardiocytesandP kfibers conductionofAVnodeandP kfibers 100ng ml AffectAPDandERP APDandERP therapeuticconcentration APDandERP highconcentration ERPofAVnode reentry Improvemyocardialischemia Pharmacologicaleffects Therapeuticuse Supraventriculararrhythamias sinustachycardiaowingtoexcessivesympatheticstimulation supraventriculartachycardiatriggeredbyreentry ventriculartachycardiatriggeredbyphysicaloremotionalstress andphaochromocytoma 嗜铬细胞瘤 congenitallongQTsyndrome ArrhythmiaowingtoAMI Class APDProlongationagents Pharmacologicaleffects inhibitK Na Ca2 channels blocks and AR APDandERP inhibitsK Automaticity inhibitsNa Ca2 channelsand AR AVnodeandP kfibersconduction inhibitsNa Ca2 channels DilatesCA myocardialO2consumption Amiodarone 胺碘酮 Pharmacokinetics F 30 40 t1 240d lastsfor4 6w Therapeuticuses 广谱抗心律失常药物Adverseeffects CVSreactions sinusbradycardia atrio ventricularblock Torsadesde Pulmonaryfibrosis Hypo orhyperthyroidism Cornealmicrodepositsandhepaticdysfunction Nonselective ARantagonistBlockIk APD ERPofatrialandventricularmyocytes AVnodeandP kfibers AutomaticityofSAnodeandP kfibers AVconduction Broad spectrumanti arrhythmia Sotalol 索他洛尔 Class Calciumchannelblockers BlockL Ca2 channelsofSAandAVnode HR AVconductionvelocity ERP Verapamil 维拉帕米 anddiltiazemareusedinsupraventriculararrhythmia Others AgonistA R activatesAChsensitiveK channels K efflux cAMP inducedCa2 influx Choiceforpromptconversionofparoxysmalsupraventriculartachycardia i v Adenosine 腺苷 Principlesinclinicaluseofantiarrhythmicdrugs Identifyandremoveprecipitatingfactors hypoxia electrolytedisturbances myocardialischemia anddru