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治疗心律失常药物Antiarrhythmicagents一、BasicConcept正常心率（窦性心律）：Theelectricalimpulsethattriggersanormalcardiaccontractionoriginatesatregularintervalsinthesinoatrialnode,usuallyatafrequencyof60-100beatsperminute.Thisimpulsespreadsrapidlythroughtheatriaandenterstheatrioventricularnode,thenpropagatesovertheHis-Purkinjesystemandinvadesallpartsoftheventricles.心律失常：Arrhythmiasconsistofcardiacdepolarizationsthatdeviatefromtheabovedescriptioninoneormoreaspects—ie,thereisanabnormalityinthesiteoforiginoftheimpulse,itsrateorregularity,oritsconduction。心律失常分类总的可分快速型和过缓型（然后根据发生部位和性质再分）快速型：房早，房速，房颤；室早，室速，室颤过缓型（缓慢型）：房室传导阻滞，束支传导阻滞，窦性心动过缓等，阿托品，拟肾上腺素药物等有一定作用。心律失常的治疗学分类就临床治疗的观点，心律失常可分为三类：1.良性（无器质性病变）benignarrhythmias:VPBs,sinustachycardiausingAnxiolyticsandSedatives2.可能恶性（轻中度器质性病变）potentialmalignantarrhythmias：ParoxysmalSupraventricularTachycardia,monomorphicventriculartachycardia,atrialfibrillation3.恶性（重度器质性病变）malignantarrhythmias(life-threateningarrhythmias)：sustainedventriculartachycardia,polymorphicventriculartachycardia,ventricularfibrillation二、Pathophysiology•Arrhythmiasdevelopbecauseofabnormalimpulsegeneration,abnormalpropagationorboth•Bradyarrhythmias•Whicharisethroughabnormalitiesofintrinsicautomaticbehaviororconduction,principallywithintheatrioventricularnodeandtheHis-Purkinje'snetwork.•Tachyarrhythmias•Threemechanismshavebeenassociatedwithmanytachyarrhythmias1.Alteredautomaticity:Factorsthatincreaseautomaticityincludemechanicalstretchbeta-adrenergicstimulationhypokalemia2.Triggeredautomaticity:–EarlyAfterdepolarization(EAD)早后除极whichisassociatedwithsignificantprolongationoftheactionpotentialduration.FactorsthatpredisposetoEAD:bradycardialowextracellularK+certaindrugs,includingsomeantiarrhythmics–Torsadesdepointes,apolymorphicventriculararrhythmia-associatedwithProlongationofcardiacrepolarization(prolongedQ-Tinterval)Possiblyinducedbyearlyafterdepolarizations–Delayedafterdepolarization(DAD)迟后除极.FactorsthatpredisposetoDADinclude:excessiveadrenergicactivitydigitalistoxicityhighintracellularCa2+3.reentry:Mostclinicallysignificanttachyarrhythmiasareprobablyduetoreentry.Afterdepolarizationsandtriggeredactivity•SymptomsandSigns•Palpitations(awarenessoftheheartbeat)areoftendisagreeableandmayariseequallyfromincreasedforceofcontractionandfromrhythmdisturbance.Theyshouldbeinvestigatedtodefinethecauseandtoallayanxiety.•Arrhythmiasthatcausehemodynamicupsetareusuallysustainedbradycardiasortachycardiasandmaybelifethreatening.Resultingdizzinessandsyncopearecommon.Thesearrhythmiasrequireurgentattentionand,often,hospitalization.•Somearrhythmiascausefewornosymptomsbutareassociatedwithanadverseprognosis.Muchevidencesuggeststhatprognosisisnotnecessarilyimprovedbytheirsuppression.Otherarrhythmias,althoughsymptomatic,arebenign.•Thenatureandseverityofunderlyingheartdiseaseareoftenofgreaterprognosticsignificancethanisthearrhythmiaitself.•Treatment•Mostcardiacarrhythmiascausenosymptoms,havenohemodynamicimportance,andhavenoprognosticsignificancebutmaycauseanxietyinapatientwhobecomesawareofthem.Somepatientswithbenignarrhythmiasremaindisableddespitereassurance.Behaviormodificationtherapyoftenhelpswhenreassurancehasfailed.Inrarecases,aprecipitatingfactormaybeidentifiedandmodified(eg,excessiveintakeofcaffeineoralcohol).•Drugtreatment:•Antiarrhythmicdrugtherapyisthemainstayofmanagementformostimportantarrhythmias.•Thereisnouniversallyeffectivedrug;allhaveimportantsafetylimitationsandcanaggravateorpromotearrhythmias(arrhythmogenesis,proarrhythmia).•Drugselectionisdifficultandofteninvolvestrialanderror.抗心律失常药物分类•Willams分类法分为四类：•Ⅰ类：钠通道阻断剂，又再分为a,b,c三亚类•Ⅱ类：beta-受体阻断剂•Ⅲ类：钾通道阻断剂（动作电位时程延长药）•Ⅳ类：钙通道阻断剂•其它类：强心苷、腺苷、镁，等分类阻断钠通道抑制0相Vmax延长APD阻钾外流Ⅰa类++++++Ⅰb类++--Ⅰc类++++++--•ClassIdrugsareNachannelblockers,includingolderantiarrhythmicdrugs(eg,quinidine).Allreducethemaximalrateofdepolarizationoftheactionpotentialandtherebyslowconduction.•Theyaresubclassifiedbasedonthekineticsoftheirreceptoreffects:–classIa--drugswithintermediateonsetandoffset;–classIb--drugswithshorteffects;–classIc--drugswithprolongedeffects.•第Ⅰ类药钠通道阻滞药Ⅰa类代表药主要有奎尼丁（quinidine）、普鲁卡因胺(procainamide)Ⅰb类代表药主要有利多卡因（lidocaine）、苯妥英钠(phenytoinsodium)、美西律（mexiletine）Ⅰc类代表药主要有心律平（普罗帕酮，propafenone），氟卡尼(flecainide，氟卡胺)，恩卡尼(encainide，恩卡胺)奎尼丁（quinidine）Ⅰa类代表药药理作用：阻钠内流，阻钾外流，A传导：抑制0相，减慢传导，P-R延长。B自律性：抑制4相钠内流除极，降低自律性，抑制异位节律C时程：延长APD，ERP，QRS增宽另外，通过钠钙交换降低细胞内钙，抑制心肌收缩，阻断α受体降血压应用：为广谱抗心律失常药，对房性，室性，早搏、心动过速均有效。不良反应：较严重的为心律失常：多相性室性心动过速（尖端扭转性室速，torsadedepoints）,可演变成室颤。低血压——扩张血管，抑制心肌金鸡钠反应：头痛，头晕，耳鸣，视听力减退。利多卡因（lidocaine）Ⅰb类代表药阻钠内流，促钾外流？自律性：4相除极减慢，提高兴奋阈，降低自律性，时程：缩短APD，相对延长ERP传导：增加病变区心肌的舒张电位，改善浦氏纤维传导，消除折返主要用于室性心动过速。首过效应大，多iv给药。副作用：嗜睡，共济失调，惊厥等中枢神经反应，心脏毒性较低，过量也可导致心律失常，传导阻滞心律平（普罗帕酮，propafenone），氟卡胺，英卡胺等，Ⅰc类强阻钠内流，抑制0相，减慢传导，P-R显著延长，QRS增宽，降低室性早搏作用强，但无抗室颤作用，甚至可能加重（CAST结果）。但只要不用于患严重器质性心脏病的病人，还是很安全的。心律平兼有慢通道及β受体阻断作用。•ClassIIdrugsmaybetheleasttoxicandmostpowerfuldrugsavailable,yettheirantiarrhythmiceffectsareoftenoverlooked.Whereasrelativelyfewarrhythmiasareprimarilycausedbysympatheticoveractivity,mostaremodulatedbyautonomictone.β-Blockershavepoorefficacy