药理学第十五章心律失常与抗心律失常药

医学院药理学教研室ArrhythmiasandAntidysrrhythmics

(AntiarrhythmicDrugs)

心律失常与抗心律失常药心音听诊节律rhythm频率rate(杂音murmur)……当节律与频率发生改变

→心律失常cardiacarrhythmia节律不齐：频率变化：期前收缩(早搏)prematurebeat……心动过缓bradycardia,bradyarrhythmias心动过速tachycardia,tachyarrhythmiasACaseStudy

《拳头的力量》-1王女士今年68岁，吃了海产品后出现腹部疼痛、腹泻2天。腹泻已有十余次，量较多，呈稀水样，伴恶心、呕吐。昨起发热，体温38.5℃。急诊医生诊断王女士为急性胃肠炎，住急诊观察室。医嘱暂禁食，并给予静脉注射庆大霉素、5%葡萄糖生理盐水1000mL、10%葡萄糖水1000mL。经过一个白天的治疗，患者吐泻逐渐减轻，体温下降，但王女士仍觉腹胀、乏力，没有胃口。晚间接班值班医师查房见患者神智清楚，平卧于病床上休息，体温37.5℃，血压110/80mmHg，心跳88次/min。王女士以往有高血压病史，平素血压控制在140/90mmHg左右。《拳头的力量》-2值班医师为患者测定血压心率之后,转身将血压计放回诊疗台，准备做病情记录，突听王女士女儿尖声呼叫：“我妈妈不好了！”医生回头见患者神智丧失，两眼上翻，四肢呈强直性痉挛状态。值班医师迅速拿起听诊器往患者胸前听诊，未闻及心音，迅即举起拳头就往患者胸部用力捶去……“为什么打我妈妈？！……”患者女儿的抗议声未落，只见患者双眼睑翻了数次，然后缓缓睁开眼睛，恢复了神智，惊异地看着身边的女儿在哭泣，不知刚才发生了什么事情。《拳头的力量》-3即刻床旁心电图检查显示：窦性心律、多发室性早搏。同时立即抽血送检验，接心电监护，并开始静脉给予连续滴注利多卡因。3分钟后患者再次发作意识丧失一次，心电监护记录显示如图1所示。

图1患者发作意识丧失前及意识丧失时的心电图经胸外捶击无效后立即开始心外按压。《拳头的力量》-4此时立即将备好的心电除颤器进行充电，接好电极立即行体外心脏电击，一次电击成功恢复窦性心律，心电图如图2所示。

图2予以电击除颤前后的心电图《拳头的力量》-5心跳骤停抢救的过程中紧急抽血化验的结果回报：血钾为2.0mmol/L，血糖5.9mg/mL。于是开始静脉输液中加入氯化钾缓慢静脉滴注。患者此时呈昏睡状，血压95/75mmHg，心跳96次/min，节律不齐。除颤成功后给予患者使用冰帽，静脉输液中继续补充氯化钾,同时补充5%碳酸氢钠40mL，连续滴注利多卡因。在接下来的治疗中，血压逐渐回升至130/85mmHg，心跳75次/min。患者的血钾逐渐恢复至正常，心律失常逐渐减少至消失。疾病的发展过程与生理基础低血钾致心肌自律性升高心室复极不一微折返→室颤胃肠炎呕吐腹泻致胃肠大量失钾补充不足不恰当心脏泵功能丧失全身供血停止(心音消失)中枢神经系统缺血缺氧意识丧失伴短暂抽搐迅速复苏抗心律失常补钾保护大脑……（>10s）最后诊断与处理Cardiacarrest心跳骤停——cardiacresuscitation心脏复苏Ventricularfibrillation室颤——defibrillation机械除颤，电除颤，药物除颤Hypokalemia低钾血症——potassiumadministration补充失钾（纠正诱发因素）AcuteGIinfection急性胃肠道感染、上吐下泻——antibacterialtherapyandmaintenanceofwaterandelectrolyteshomeostasis抗感染（病因治疗）维持水与电解质平衡其他：补充水电解质的细节问题大量葡萄糖进入细胞伴随着血钾进入细胞上吐下泻补充葡萄糖与水电解质应记住补充钾CellglucoseNa+Na+insulinNa+Na+K+K+(细胞外)低血钾易导致室性心律失常上吐下泻补充葡萄糖、水、电解质时应记住补充钾PrinciplesofCardiacElectrophysiology

心肌细胞四大电生理特性Excitability兴奋性:actionpotentialuponstimulation,whichisrelatedtothresholdpotentialandrestingpotentiallevelAutomaticity自律性:abilitytoinitiateownactivityviaspontaneousdepolarizationConductivity传导性:abilitytotransmitimpulsesfromcelltocellatappropriaterates,whichisdependentonmembrane

responsiveness(relationshipbetweenVmaxofphase0andmembranepotentiallevel)Refractoriness不应性与不应期:abilitytoresisttostimulationduringrepolarization.Thetimebetweenphase0andsufficientrecoveryofNa+channelsinphase3topermitapropagatedresponsetoexternalstimulusistherefractoryperiod.心脏的起搏传导系统与工作心肌

心电图Sino-atrialAtrial-ventricularActionpotentialofventricle

andionchannel心室肌动作电位及离子通道K+,

Cl-

ChannelscurrentPumpsExchangerK+Ca2+Na+Na+Ca2+100msOutside0mVNa+Inside-90mV01234FastresponseOutsideInside

ChannelscurrentPacemakerpotentialandionchannel

起搏心肌动作电位及离子通道K+ChannelsoutwardcurrentPumpsExchangerK+Ca2+Na+Na+Ca2+Channelsinwardcurrent100msOutside0mVInside-60mV034SlowresponseOutsideInside-45mVBackgroundinwardNa+currentsNa+Actionpotential,ionchannels

andmyocardialrefractoryperiod

动作电位与离子通道、心室肌不应期Anewactionpotentialcannotoccurinanexcitablefiberaslongasthemembraneisstilldepolarizedfromtheprecedingactionpotential.Thereasonforthisisthatshortlyaftertheactionpotentialisinitiated,thesodiumchannels(orcalciumchannels,orboth)becomeinactivated,andnoamountofexcitatorysignalappliedtothesechannelsatthispointwillopentheinactivationgates.mV0-50-100AbsoluteRefractoryPeriod绝对不应期相对不应期超常期ChannelsInactivatedPotassiumandcardiac

electrophysiology钾与心肌电生理钠钾泵的活动，是形成和维持细胞内外电位差及钠钾浓度梯度的主要因素静息膜电位主要是钾的平衡电位(神经)细胞膜对钾的通透性是钠的100倍Inside一组离子通道Relationofactionpotentialandmyocardialcontraction

动作电位与心肌收缩的时相关系Relationofactionpotentialandelectrocardiogram动作电位与心电图的关系与区别动作电位为单个心肌细胞的除极与复极电流，其基础为细胞膜离子通道电流体表心电图为所有心肌除极与复极的综合向量Sympatheticandparasympatheticcontrolsoftheheartelectricity

交感神经与副交感神经对心电活动的调节AdrenergicstimulationincreasestheheartratebyincreasingICa,LandIfactivity.CholinergicstimulationdecreasestheheartratebydecreasingICa,LandIfactivity.交感与副交感神经系统对心血管的支配Normalelectrocardiogramand

cardiacArrhythmias正常心电图与心律失常心律失常的常见原因有心肌缺血、低钾、交感兴奋、甲亢、病毒性心肌炎等房性早搏心律失常的形成机制

Mechanismsofarrhythmias--

Disturbancesinimpulseformation(冲动形成异常)Changesinautomaticityofpacemakercells自律性变化:increaseddepolarizationbecauseofenhancedβ-receptoractivityduringmentalstress,fever,exercise,etc,leadingtosinustachycardia.窦性心动过速常见于交感兴奋如心理应激、发热、运动及甲亢等

窦性心动过速(120bpm)Sinustachycardia(110bpm)Mechanismsofarrhythmias--

Disturbancesinimpulseformation(冲动形成异常)Formationofabnormalpacemaker异位起搏:increasedautomaticityinnon-pacemakercellssuchasatrialandventricularmuscle,

surpassingsinoatrialnodeandbecomingpacemakerscellsatrialorventricularprematurebeats.房性或室性早搏等

房性早搏(QRS正常，之前有P波)

室性早搏(QRS宽大畸形)与连发室早正常传导Mechanismsofarrhythmias--

Abnormalconductanceandreentry(异常传导与折返)Everycardiaccellisabletotransmit

impulsesofexcitation

ineverydirection.心肌具有向不同方向传导的特点Normally,the

actionpotential

impulsewillspreadthroughtheheartquicklyenoughthateachcellwillrespondonlyonce.单向阻滞与折返Mechanismsofarrhythmias--

Abnormalconductanceandreentry(异常传导与折返)However,ifthereissomeessentialheterogeneityof

refractoryperiod不应期不均匀orifconductionisabnormallyslowinsomeareas局部传导延缓

(asduringischemia)sothemyocardialcellsareunabletoactivatethefastsodiumchannel,partoftheimpulsewillarrivelateandpotentiallybetreatedasanewimpulse.Dependingonthetiming,thiscanproduceare-entry折返

leadingtosustainedabnormalcircuitrhythm.AVnodalreentranttachycardiaatarateof150/minMechanismsofarrhythmias--

Abnormalconductanceandreentry(折返激动)Emergenceofreentrantarrhythmias折返性心律失常requiresthreeconditionstobepresentThereexistsananatomiccircuitaroundwhichtheimpulsecancirculate解剖学环路Thecircuitshouldincludeazoneofunidirectionalblockwhereconductionisblockedinonedirectionwhileremainingpossibleconductanceintheother环路中存在单向传导阻滞Impulseconductionatsomepointinthecircuitshouldbeslowenoughtoallowtheregioninfrontoftheimpulsetorecoverfromtherefractoriness环路中部分区域脱离不应期恢复兴奋性及传导性正常传导单向阻滞与折返Mechanismsofarrhythmias--

Abnormalconductanceandreentry(异常传导与折返)Atrioventricularre-entranttachycardia.NegativePwavesareseeninleadsII,III,andaVFindicativeofretrogradeconductiontotheatriaoveraseptalaccessorypathway.Mechanismsofarrhythmias--

Abnormalconductanceandreentry(折返激动)Asasortof

re-entry折返,thevortices(vortex漩涡)ofexcitationinthemyocardium(autowavevortices)(心肌自发形成的微折返)isconsideredtobethemainmechanismoflife-threateningcardiacarrhythmias,includingatrialflutter,paroxysmal

supraventriculartachycardia,andventriculartachycardia.

目前认为折返激动是多种致命性快速型心律失常的重要电生理异常的基础

Mechanismsofarrhythmias-

ChainReactionMechanismofFibrillation

(纤维颤动的链式反应机制)Oneofthemostimportantfeaturesoffibrillationisthedivisionofimpulses,asdemonstratedinheartA.Whenadepolarizationwavereachesarefractoryareaintheheart,ittravelstobothsidesaroundtherefractoryarea.Thus,asingleimpulsebecomestwoimpulses.Then,wheneachofthesereachesanotherrefractoryarea,it,too,dividestoformtwomoreimpulses.Inthisway,manynewwavefrontsarecontinuallybeingformedintheheartbyprogressivechainreactionsuntil,finally,therearemanysmalldepolarizationwavestravelinginmanydirectionsatthesametime.Furthermore,thisirregularpatternofimpulsetravelcausesmanycircuitousroutesfortheimpulsestotravel,greatlylengtheningtheconductivepathway,whichisoneoftheconditionsthatsustainsthefibrillation.It

alsoresultsinacontinualirregularpatternofpatchyrefractoryareasintheheart.Mechanismsofarrhythmias--

Disturbancesinimpulseformation(冲动形成异常)房颤(atrialfibrillation,irregularlyirregular心律绝对不齐)+室早室性心动过速→心室颤动Hypokalemiaandcardiacelectrophysiologychanges自律性：低钾使浦氏纤维自律性升高细胞外低钾导致浦氏纤维膜Ik1通道对钾的通透性降低，膜电位变小，膜电位接近阈电位，心肌兴奋性升高传导性：低钾使心肌传导减慢膜电位减小，INa通道失活，0相除极化速度下降，传导减慢严重者发展至心室颤动心肌复极不均一，异位搏动可形成折返Mechanismsofarrhythmias-

triggeredautomaticity-afterdepolarization

(后除极)Earlyafterdepolarizations,(EADs,早后除极)，occurduringtheterminalplateauorrepolarizationphaseofactionpotential.EDAscanbetriggeredbyagentsthatprolongtheactionpotentialdurationandincreasetheinwardcurrent.Delayedafterdepolarizations,(DADs,迟后除极),occurafterrepolarizationiscompleted,andareduetoexcessiveincreasesincellular[Ca2+]i.DADscanbecausedbycatecholamines,whichincreaseCa2+influx,byglycosides,whichincrease[Ca2+]i,andinheartfailure,inwhichcalciumregulationisimpaired.Mechanismsofarrhythmias--

Abnormalimpulseconduction（冲动传导异常）Disturbanceofimpulseconduction:partialandcompleteblockadewithinanodeorbetweenatriumandventricle

sinoatrialnodeblockade窦房阻滞atrialventricularblockade房室传导阻滞房室结羊肠小道传导缓慢易受影响ThemaintypesofarrhythmiasThetachyarrhythmiasTachycardia：sinus,atrial,AVnode,ventricularEctopicbeat：atrial，AVnodal,ventricularFlatterandFibrillation:atrial,ventricularThebradyarrhythmiasBradycardia:sinusAVblock,(intra-atrial,intra-ventricle…)

Whatkindsofagentscouldstoptachy-arrhythmia用什么药物阻断快速型心律失常0FastresponseNa+╳阻止异位兴奋Antidysrrhythmicdrugs

抗心律失常药ClassI：Na+channelblockers钠通道阻断剂

Whatkindsofagentscouldstoparrhythmia用什么药物阻断快速型心律失常Slowresponse0BackgroundinwardNa+currentsNa+Ca2+╳降低自律性Antidysrrhythmicdrugs

抗心律失常药ClassI：Na+channelblockers钠通道阻断剂

ClassIV：Ca2+channelblockers钙通道阻滞药Whatkindsofagentscouldstoparrhythmia用什么药物可阻断快速型心律失常交感神经兴奋释放肾上腺素及去甲肾上腺素→β受体兴奋→L-钙通道开放→窦房结及房室交界区Pacemaker细胞舒张期自动除极加速→窦性心动过速Antidysrrhythmicdrugs

抗心律失常药ClassI：Na+channelblockers钠通道阻断剂

ClassII：β-adrenergicreceptorblockersβ肾上腺素受体阻断药ClassIV：Ca2+channelblockers钙通道阻滞药Whatkindsofagentscouldstoptachy-arrhythmia用什么药物阻断快速型心律失常3K+╳延长不应期Classificationofantidysrrhythmics

抗心律失常药物类型ClassI：Na+channelblockers钠通道阻断剂

ClassII：β-adrenergicreceptorblockersβ肾上腺素受体阻断药ClassIII：ProlongAPdurationbyinhibitingK+channel延长动作电位时程药，钾通道阻滞药ClassIV：Ca2+channelblockers钙通道阻滞药ClassV：

MiscellaneousWhatkindsofagentscouldstoparrhythmia用什么药物可阻断快速型心律失常交感神经兴奋释放肾上腺素及去甲肾上腺素→β受体兴奋→L-钙通道开放→窦房结及房室交界区Pacemaker细胞舒张期自动除极加速→窦性心动过速β受体兴奋→窦房结IrIs→复极加快→动作电位时程缩短→有利于下一心动周期开始ClassII：β-adrenergicreceptorblockersβ肾上腺素受体阻断药ClassIV：Ca2+channelblockers钙通道阻滞药心肌缺血→交感神经兴奋释放肾上腺素及去甲肾上腺素→β受体兴奋→蒲氏纤维If增加→Na+内流增加→舒张期自动除极加速自律性升高→室性心律失常ClassIaantidysrrhythmics

钠通道中度阻断药-奎尼丁quinidineBlockNa+channelmoderately：slowdownrateofaswellasreduceamplificationofdepolarizationandthusdecreaseautomaticityandconductivitysignificantly,alsoinhibitK+channelTachyarrhythmias各类快速型心律失常

Adverseeffects

心脏不良反应严重临床已基本不用金鸡钠树皮中的生物碱抗疟药奎宁与抗心律失常药quinidinenormallidocainenormalquinidineClassIbantidysrrhythmics

钠通道轻度阻断药-利多卡因lidocaineBlockNa+channelslightlyandenhanceK+channel：inhibitdepolarizationandpromotepotassiumeffluxthusdecreaseexcitation.Lidocaineshortensrefractoryperiodandthusmakeseffectiverefractoryperiodrelativelylonger.

抑制钠内流并促进钾外流，降低自律性，相对延长有效不应期，绝对不应期缩短故对传导抑制少ClassIbantidysrrhythmics

钠通道轻度阻断药-利多卡因lidocaineTherapeuticuses:Symptomaticfrequentprematureventricularcomplexes,ventriculartachycardiaandfibrillation.用于治疗有明显症状的多发室早，以及室性心动过速与室颤Lidocaineisfrequentlygivenbyintravenousinfusiontotreatandpreventventriculardysrrhythmiasintheimmediateaftermathofmyocardialinfarction.静脉注射最常用于治疗及预防急性心梗导致的室性心律失常Itisalmostcompletelyextractedfromportalcirculationbyhepaticfirst-passmetabolism.肝脏首过消除大iv，需口服维持疗效时可用美西律替代Adverseeffect：Relativelysafe,itsadverseeffectsaremainlyduetotheactiononCNSandincludedrowsiness,disorientationandconvulsion.大剂量可致中枢神经系统不良反应

ClassIIantidysrrhythmics

β肾上腺能受体阻断药-Propranolol普荼洛尔Blockβ-adrenergicreceptorsignificantly：byblockingβ-adrenergicreceptorprolongrefractoryperiodsignificantly,blockNa+channelaswellasCa2+channeliv,poTherapeuticuses：Sinustachycardia窦性心动过速(交感兴奋，甲状腺功能亢进症等)Ischemicventriculartachycardia缺血性心室快速心律失常(由于其显著的抗心肌缺血作用而用于心肌缺血所致的各类快速心律失常)Adverseeffects：Sinusbradycardia,AVblockade窦性心动过缓、房室传导阻滞Bronchialspasm诱发或加重支气管痉挛，支气管哮喘者asthma慎用Myocardialcontractiondepression抑制心肌收缩力心肌缺血所致窦速PPPamiodaronenormalClassIIIantidysrrhythmics

钾通道阻断药(延长复极药)-胺碘酮amiodaroneBlockK+channelsignificantly：prolongrefractoryperiodsignificantly,blockNa+channelaswellasCa2+channelTherapeuticuses:

各类快速型心律失常，作用强，“广谱抗心律失常药”iv,poUnwantedeffects心血管:窦性心动过缓

、传导阻滞

可致长QT综合征与尖端扭转性室颤含碘，可致甲状腺功能亢进或减退胃肠道反应光敏性皮炎角膜色素沉着肺纤维化ClassIIIantidysrrhythmics

钾通道阻断药-索他洛尔sotalolBlockK+channel：prolongrefractoryperiodandisrelativelysaferthanamiodarone变单向阻滞为双向阻滞从而取消折返单向阻滞与折返ClassIVantidysrrhythmics

钙拮抗药-维拉帕米verapamilBlockCa2+channel：blockCa2+channelinatrioventricularnode,slowingdepolarizationandconduction,thereforesuppressingAVre-entrantsupraventriculararrhythmia.ClassIVantidysrrhythmics

钙拮抗药-维拉帕米verapamilTherapeuticuse：iv,mainlyforparoxysmalsupraventriculartachycardia阵发性室上性心动过速(阵发性房性及交界区心动过速)Adverseeffects：hypotension，bradycardiaandAVblockade低血压、心动过缓、房室传导阻滞

Becareful:calciumblockernifedipine,couldnotbeusedasantidysarrhythmicssinceitincreasessympatheticactivitythroughhypotensioneffectandleadstoarrhythmias.二氢吡啶类(地平类)钙拮抗药不可用于快速性心律失常，尤其是心肌缺血及其他有交感神经系统兴奋的情况Classificationofanti-arrhythmic

drugsandtheirprototypes

抗心律失常药物的分类及其代表药ClassI：Na+channelblockers钠通道阻断剂Ia:quinidine奎尼丁Ib:lidocaine利多卡因Ic:propafenone普罗帕酮(flecanideisnolongerused)ClassII：β-adrenergicreceptorblockersβ受体阻断药Propranolol普荼洛尔，metaprolol美多洛尔，bisoprolol比索洛尔ClassIII：ProlongAPdurationbyinhibitinK+channel延长动作电位时程药，钾通道阻滞药Amiodarone胺碘酮ClassIV：Ca2+channelblockers钙通道阻滞药Verapamil维拉帕米ClassV：MiscellaneousDigitalis洋地黄类,adenosine腺苷Atropine阿托品，isoproterenol异丙肾上腺素Classificatio