藥理學(xué)第十五章心律失常與抗心律失常藥

醫(yī)學(xué)院藥理學(xué)教研室ArrhythmiasandAntidysrrhythmics

(AntiarrhythmicDrugs)

心律失常與抗心律失常藥心音聽診節(jié)律rhythm頻率rate(雜音murmur)……當(dāng)節(jié)律與頻率發(fā)生改變

→心律失常cardiacarrhythmia節(jié)律不齊：頻率變化：期前收縮(早搏)prematurebeat……心動過緩bradycardia,bradyarrhythmias心動過速tachycardia,tachyarrhythmiasACaseStudy

《拳頭的力量》-1王女士今年68歲，吃了海產(chǎn)品后出現(xiàn)腹部疼痛、腹瀉2天。腹瀉已有十余次，量較多，呈稀水樣，伴惡心、嘔吐。昨起發(fā)熱，體溫38.5℃。急診醫(yī)生診斷王女士為急性胃腸炎，住急診觀察室。醫(yī)囑暫禁食，并給予靜脈注射慶大霉素、5%葡萄糖生理鹽水1000mL、10%葡萄糖水1000mL。經(jīng)過一個白天的治療，患者吐瀉逐漸減輕，體溫下降，但王女士仍覺腹脹、乏力，沒有胃口。晚間接班值班醫(yī)師查房見患者神智清楚，平臥于病床上休息，體溫37.5℃，血壓110/80mmHg，心跳88次/min。王女士以往有高血壓病史，平素血壓控制在140/90mmHg左右?！度^的力量》-2值班醫(yī)師為患者測定血壓心率之后,轉(zhuǎn)身將血壓計放回診療臺，準(zhǔn)備做病情記錄，突聽王女士女兒尖聲呼叫：“我媽媽不好了！”醫(yī)生回頭見患者神智喪失，兩眼上翻，四肢呈強(qiáng)直性痙攣狀態(tài)。值班醫(yī)師迅速拿起聽診器往患者胸前聽診，未聞及心音，迅即舉起拳頭就往患者胸部用力捶去……“為什么打我媽媽？！……”患者女兒的抗議聲未落，只見患者雙眼瞼翻了數(shù)次，然后緩緩睜開眼睛，恢復(fù)了神智，驚異地看著身邊的女兒在哭泣，不知剛才發(fā)生了什么事情?！度^的力量》-3即刻床旁心電圖檢查顯示：竇性心律、多發(fā)室性早搏。同時立即抽血送檢驗，接心電監(jiān)護(hù)，并開始靜脈給予連續(xù)滴注利多卡因。3分鐘后患者再次發(fā)作意識喪失一次，心電監(jiān)護(hù)記錄顯示如圖1所示。

圖1患者發(fā)作意識喪失前及意識喪失時的心電圖經(jīng)胸外捶擊無效后立即開始心外按壓?！度^的力量》-4此時立即將備好的心電除顫器進(jìn)行充電，接好電極立即行體外心臟電擊，一次電擊成功恢復(fù)竇性心律，心電圖如圖2所示。

圖2予以電擊除顫前后的心電圖《拳頭的力量》-5心跳驟停搶救的過程中緊急抽血化驗的結(jié)果回報：血鉀為2.0mmol/L，血糖5.9mg/mL。于是開始靜脈輸液中加入氯化鉀緩慢靜脈滴注。患者此時呈昏睡狀，血壓95/75mmHg，心跳96次/min，節(jié)律不齊。除顫成功后給予患者使用冰帽，靜脈輸液中繼續(xù)補(bǔ)充氯化鉀,同時補(bǔ)充5%碳酸氫鈉40mL，連續(xù)滴注利多卡因。在接下來的治療中，血壓逐漸回升至130/85mmHg，心跳75次/min。患者的血鉀逐漸恢復(fù)至正常，心律失常逐漸減少至消失。疾病的發(fā)展過程與生理基礎(chǔ)低血鉀致心肌自律性升高心室復(fù)極不一微折返→室顫胃腸炎嘔吐腹瀉致胃腸大量失鉀補(bǔ)充不足不恰當(dāng)心臟泵功能喪失全身供血停止(心音消失)中樞神經(jīng)系統(tǒng)缺血缺氧意識喪失伴短暫抽搐迅速復(fù)蘇抗心律失常補(bǔ)鉀保護(hù)大腦……（>10s）最后診斷與處理Cardiacarrest心跳驟?！猚ardiacresuscitation心臟復(fù)蘇Ventricularfibrillation室顫——defibrillation機(jī)械除顫，電除顫，藥物除顫Hypokalemia低鉀血癥——potassiumadministration補(bǔ)充失鉀（糾正誘發(fā)因素）AcuteGIinfection急性胃腸道感染、上吐下瀉——antibacterialtherapyandmaintenanceofwaterandelectrolyteshomeostasis抗感染（病因治療）維持水與電解質(zhì)平衡其他：補(bǔ)充水電解質(zhì)的細(xì)節(jié)問題大量葡萄糖進(jìn)入細(xì)胞伴隨著血鉀進(jìn)入細(xì)胞上吐下瀉補(bǔ)充葡萄糖與水電解質(zhì)應(yīng)記住補(bǔ)充鉀CellglucoseNa+Na+insulinNa+Na+K+K+(細(xì)胞外)低血鉀易導(dǎo)致室性心律失常上吐下瀉補(bǔ)充葡萄糖、水、電解質(zhì)時應(yīng)記住補(bǔ)充鉀PrinciplesofCardiacElectrophysiology

心肌細(xì)胞四大電生理特性Excitability興奮性:actionpotentialuponstimulation,whichisrelatedtothresholdpotentialandrestingpotentiallevelAutomaticity自律性:abilitytoinitiateownactivityviaspontaneousdepolarizationConductivity傳導(dǎo)性:abilitytotransmitimpulsesfromcelltocellatappropriaterates,whichisdependentonmembrane

responsiveness(relationshipbetweenVmaxofphase0andmembranepotentiallevel)Refractoriness不應(yīng)性與不應(yīng)期:abilitytoresisttostimulationduringrepolarization.Thetimebetweenphase0andsufficientrecoveryofNa+channelsinphase3topermitapropagatedresponsetoexternalstimulusistherefractoryperiod.心臟的起搏傳導(dǎo)系統(tǒng)與工作心肌

心電圖Sino-atrialAtrial-ventricularActionpotentialofventricle

andionchannel心室肌動作電位及離子通道K+,

Cl-

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

ChannelscurrentPacemakerpotentialandionchannel

起搏心肌動作電位及離子通道K+ChannelsoutwardcurrentPumpsExchangerK+Ca2+Na+Na+Ca2+Channelsinwardcurrent100msOutside0mVInside-60mV034SlowresponseOutsideInside-45mVBackgroundinwardNa+currentsNa+Actionpotential,ionchannels

andmyocardialrefractoryperiod

動作電位與離子通道、心室肌不應(yīng)期Anewactionpotentialcannotoccurinanexcitablefiberaslongasthemembraneisstilldepolarizedfromtheprecedingactionpotential.Thereasonforthisisthatshortlyaftertheactionpotentialisinitiated,thesodiumchannels(orcalciumchannels,orboth)becomeinactivated,andnoamountofexcitatorysignalappliedtothesechannelsatthispointwillopentheinactivationgates.mV0-50-100AbsoluteRefractoryPeriod絕對不應(yīng)期相對不應(yīng)期超常期ChannelsInactivatedPotassiumandcardiac

electrophysiology鉀與心肌電生理鈉鉀泵的活動，是形成和維持細(xì)胞內(nèi)外電位差及鈉鉀濃度梯度的主要因素靜息膜電位主要是鉀的平衡電位(神經(jīng))細(xì)胞膜對鉀的通透性是鈉的100倍Inside一組離子通道Relationofactionpotentialandmyocardialcontraction

動作電位與心肌收縮的時相關(guān)系Relationofactionpotentialandelectrocardiogram動作電位與心電圖的關(guān)系與區(qū)別動作電位為單個心肌細(xì)胞的除極與復(fù)極電流，其基礎(chǔ)為細(xì)胞膜離子通道電流體表心電圖為所有心肌除極與復(fù)極的綜合向量Sympatheticandparasympatheticcontrolsoftheheartelectricity

交感神經(jīng)與副交感神經(jīng)對心電活動的調(diào)節(jié)AdrenergicstimulationincreasestheheartratebyincreasingICa,LandIfactivity.CholinergicstimulationdecreasestheheartratebydecreasingICa,LandIfactivity.交感與副交感神經(jīng)系統(tǒng)對心血管的支配Normalelectrocardiogramand

cardiacArrhythmias正常心電圖與心律失常心律失常的常見原因有心肌缺血、低鉀、交感興奮、甲亢、病毒性心肌炎等房性早搏心律失常的形成機(jī)制

Mechanismsofarrhythmias--

Disturbancesinimpulseformation(沖動形成異常)Changesinautomaticityofpacemakercells自律性變化:increaseddepolarizationbecauseofenhancedβ-receptoractivityduringmentalstress,fever,exercise,etc,leadingtosinustachycardia.竇性心動過速常見于交感興奮如心理應(yīng)激、發(fā)熱、運(yùn)動及甲亢等

竇性心動過速(120bpm)Sinustachycardia(110bpm)Mechanismsofarrhythmias--

Disturbancesinimpulseformation(沖動形成異常)Formationofabnormalpacemaker異位起搏: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寬大畸形)與連發(fā)室早正常傳導(dǎo)Mechanismsofarrhythmias--

Abnormalconductanceandreentry(異常傳導(dǎo)與折返)Everycardiaccellisabletotransmit

impulsesofexcitation

ineverydirection.心肌具有向不同方向傳導(dǎo)的特點(diǎn)Normally,the

actionpotential

impulsewillspreadthroughtheheartquicklyenoughthateachcellwillrespondonlyonce.單向阻滯與折返Mechanismsofarrhythmias--

Abnormalconductanceandreentry(異常傳導(dǎo)與折返)However,ifthereissomeessentialheterogeneityof

refractoryperiod不應(yīng)期不均勻orifconductionisabnormallyslowinsomeareas局部傳導(dǎo)延緩

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

leadingtosustainedabnormalcircuitrhythm.AVnodalreentranttachycardiaatarateof150/minMechanismsofarrhythmias--

Abnormalconductanceandreentry(折返激動)Emergenceofreentrantarrhythmias折返性心律失常requiresthreeconditionstobepresentThereexistsananatomiccircuitaroundwhichtheimpulsecancirculate解剖學(xué)環(huán)路Thecircuitshouldincludeazoneofunidirectionalblockwhereconductionisblockedinonedirectionwhileremainingpossibleconductanceintheother環(huán)路中存在單向傳導(dǎo)阻滯Impulseconductionatsomepointinthecircuitshouldbeslowenoughtoallowtheregioninfrontoftheimpulsetorecoverfromtherefractoriness環(huán)路中部分區(qū)域脫離不應(yīng)期恢復(fù)興奮性及傳導(dǎo)性正常傳導(dǎo)單向阻滯與折返Mechanismsofarrhythmias--

Abnormalconductanceandreentry(異常傳導(dǎo)與折返)Atrioventricularre-entranttachycardia.NegativePwavesareseeninleadsII,III,andaVFindicativeofretrogradeconductiontotheatriaoveraseptalaccessorypathway.Mechanismsofarrhythmias--

Abnormalconductanceandreentry(折返激動)Asasortof

re-entry折返,thevortices(vortex漩渦)ofexcitationinthemyocardium(autowavevortices)(心肌自發(fā)形成的微折返)isconsideredtobethemainmechanismoflife-threateningcardiacarrhythmias,includingatrialflutter,paroxysmal

supraventriculartachycardia,andventriculartachycardia.

目前認(rèn)為折返激動是多種致命性快速型心律失常的重要電生理異常的基礎(chǔ)

Mechanismsofarrhythmias-

ChainReactionMechanismofFibrillation

(纖維顫動的鏈?zhǔn)椒磻?yīng)機(jī)制)Oneofthemostimportantfeaturesoffibrillationisthedivisionofimpulses,asdemonstratedinheartA.Whenadepolarizationwavereachesarefractoryareaintheheart,ittravelstobothsidesaroundtherefractoryarea.Thus,asingleimpulsebecomestwoimpulses.Then,wheneachofthesereachesanotherrefractoryarea,it,too,dividestoformtwomoreimpulses.Inthisway,manynewwavefrontsarecontinuallybeingformedintheheartbyprogressivechainreactionsuntil,finally,therearemanysmalldepolarizationwavestravelinginmanydirectionsatthesametime.Furthermore,thisirregularpatternofimpulsetravelcausesmanycircuitousroutesfortheimpulsestotravel,greatlylengtheningtheconductivepathway,whichisoneoftheconditionsthatsustainsthefibrillation.It

alsoresultsinacontinualirregularpatternofpatchyrefractoryareasintheheart.Mechanismsofarrhythmias--

Disturbancesinimpulseformation(沖動形成異常)房顫(atrialfibrillation,irregularlyirregular心律絕對不齊)+室早室性心動過速→心室顫動Hypokalemiaandcardiacelectrophysiologychanges自律性：低鉀使浦氏纖維自律性升高細(xì)胞外低鉀導(dǎo)致浦氏纖維膜Ik1通道對鉀的通透性降低，膜電位變小，膜電位接近閾電位，心肌興奮性升高傳導(dǎo)性：低鉀使心肌傳導(dǎo)減慢膜電位減小，INa通道失活，0相除極化速度下降，傳導(dǎo)減慢嚴(yán)重者發(fā)展至心室顫動心肌復(fù)極不均一，異位搏動可形成折返Mechanismsofarrhythmias-

triggeredautomaticity-afterdepolarization

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

Abnormalimpulseconduction（沖動傳導(dǎo)異常）Disturbanceofimpulseconduction:partialandcompleteblockadewithinanodeorbetweenatriumandventricle

sinoatrialnodeblockade竇房阻滯atrialventricularblockade房室傳導(dǎo)阻滯房室結(jié)羊腸小道傳導(dǎo)緩慢易受影響ThemaintypesofarrhythmiasThetachyarrhythmiasTachycardia：sinus,atrial,AVnode,ventricularEctopicbeat：atrial，AVnodal,ventricularFlatterandFibrillation:atrial,ventricularThebradyarrhythmiasBradycardia:sinusAVblock,(intra-atrial,intra-ventricle…)

Whatkindsofagentscouldstoptachy-arrhythmia用什么藥物阻斷快速型心律失常0FastresponseNa+╳阻止異位興奮Antidysrrhythmicdrugs

抗心律失常藥ClassI：Na+channelblockers鈉通道阻斷劑

Whatkindsofagentscouldstoparrhythmia用什么藥物阻斷快速型心律失常Slowresponse0BackgroundinwardNa+currentsNa+Ca2+╳降低自律性Antidysrrhythmicdrugs

抗心律失常藥ClassI：Na+channelblockers鈉通道阻斷劑

ClassIV：Ca2+channelblockers鈣通道阻滯藥Whatkindsofagentscouldstoparrhythmia用什么藥物可阻斷快速型心律失常交感神經(jīng)興奮釋放腎上腺素及去甲腎上腺素→β受體興奮→L-鈣通道開放→竇房結(jié)及房室交界區(qū)Pacemaker細(xì)胞舒張期自動除極加速→竇性心動過速Antidysrrhythmicdrugs

抗心律失常藥ClassI：Na+channelblockers鈉通道阻斷劑

ClassII：β-adrenergicreceptorblockersβ腎上腺素受體阻斷藥ClassIV：Ca2+channelblockers鈣通道阻滯藥Whatkindsofagentscouldstoptachy-arrhythmia用什么藥物阻斷快速型心律失常3K+╳延長不應(yīng)期Classificationofantidysrrhythmics

抗心律失常藥物類型ClassI：Na+channelblockers鈉通道阻斷劑

ClassII：β-adrenergicreceptorblockersβ腎上腺素受體阻斷藥ClassIII：ProlongAPdurationbyinhibitingK+channel延長動作電位時程藥，鉀通道阻滯藥ClassIV：Ca2+channelblockers鈣通道阻滯藥ClassV：

MiscellaneousWhatkindsofagentscouldstoparrhythmia用什么藥物可阻斷快速型心律失常交感神經(jīng)興奮釋放腎上腺素及去甲腎上腺素→β受體興奮→L-鈣通道開放→竇房結(jié)及房室交界區(qū)Pacemaker細(xì)胞舒張期自動除極加速→竇性心動過速β受體興奮→竇房結(jié)IrIs→復(fù)極加快→動作電位時程縮短→有利于下一心動周期開始ClassII：β-adrenergicreceptorblockersβ腎上腺素受體阻斷藥ClassIV：Ca2+channelblockers鈣通道阻滯藥心肌缺血→交感神經(jīng)興奮釋放腎上腺素及去甲腎上腺素→β受體興奮→蒲氏纖維If增加→Na+內(nèi)流增加→舒張期自動除極加速自律性升高→室性心律失常ClassIaantidysrrhythmics

鈉通道中度阻斷藥-奎尼丁quinidineBlockNa+channelmoderately：slowdownrateofaswellasreduceamplificationofdepolarizationandthusdecreaseautomaticityandconductivitysignificantly,alsoinhibitK+channelTachyarrhythmias各類快速型心律失常

Adverseeffects

心臟不良反應(yīng)嚴(yán)重臨床已基本不用金雞鈉樹皮中的生物堿抗瘧藥奎寧與抗心律失常藥quinidinenormallidocainenormalquinidineClassIbantidysrrhythmics

鈉通道輕度阻斷藥-利多卡因lidocaineBlockNa+channelslightlyandenhanceK+channel：inhibitdepolarizationandpromotepotassiumeffluxthusdecreaseexcitation.Lidocaineshortensrefractoryperiodandthusmakeseffectiverefractoryperiodrelativelylonger.

抑制鈉內(nèi)流并促進(jìn)鉀外流，降低自律性，相對延長有效不應(yīng)期，絕對不應(yīng)期縮短故對傳導(dǎo)抑制少ClassIbantidysrrhythmics

鈉通道輕度阻斷藥-利多卡因lidocaineTherapeuticuses:Symptomaticfrequentprematureventricularcomplexes,ventriculartachycardiaandfibrillation.用于治療有明顯癥狀的多發(fā)室早，以及室性心動過速與室顫Lidocaineisfrequentlygivenbyintravenousinfusiontotreatandpreventventriculardysrrhythmiasintheimmediateaftermathofmyocardialinfarction.靜脈注射最常用于治療及預(yù)防急性心梗導(dǎo)致的室性心律失常Itisalmostcompletelyextractedfromportalcirculationbyhepaticfirst-passmetabolism.肝臟首過消除大iv，需口服維持療效時可用美西律替代Adverseeffect：Relativelysafe,itsadverseeffectsaremainlyduetotheactiononCNSandincludedrowsiness,disorientationandconvulsion.大劑量可致中樞神經(jīng)系統(tǒng)不良反應(yīng)

ClassIIantidysrrhythmics

β腎上腺能受體阻斷藥-Propranolol普荼洛爾Blockβ-adrenergicreceptorsignificantly：byblockingβ-adrenergicreceptorprolongrefractoryperiodsignificantly,blockNa+channelaswellasCa2+channeliv,poTherapeuticuses：Sinustachycardia竇性心動過速(交感興奮，甲狀腺功能亢進(jìn)癥等)Ischemicventriculartachycardia缺血性心室快速心律失常(由于其顯著的抗心肌缺血作用而用于心肌缺血所致的各類快速心律失常)Adverseeffects：Sinusbradycardia,AVblockade竇性心動過緩、房室傳導(dǎo)阻滯Bronchialspasm誘發(fā)或加重支氣管痙攣，支氣管哮喘者asthma慎用Myocardialcontractiondepression抑制心肌收縮力心肌缺血所致竇速PPPamiodaronenormalClassIIIantidysrrhythmics

鉀通道阻斷藥(延長復(fù)極藥)-胺碘酮amiodaroneBlockK+channelsignificantly：prolongrefractoryperiodsignificantly,blockNa+channelaswellasCa2+channelTherapeuticuses:

各類快速型心律失常，作用強(qiáng)，“廣譜抗心律失常藥”iv,poUnwantedeffects心血管:竇性心動過緩

、傳導(dǎo)阻滯

可致長QT綜合征與尖端扭轉(zhuǎn)性室顫含碘，可致甲狀腺功能亢進(jìn)或減退胃腸道反應(yīng)光敏性皮炎角膜色素沉著肺纖維化ClassIIIantidysrrhythmics

鉀通道阻斷藥-索他洛爾sotalolBlockK+channel：prolongrefractoryperiodandisrelativelysaferthanamiodarone變單向阻滯為雙向阻滯從而取消折返單向阻滯與折返ClassIVantidysrrhythmics

鈣拮抗藥-維拉帕米verapamilBlockCa2+channel：blockCa2+channelinatrioventricularnode,slowingdepolarizationandconduction,thereforesuppressingAVre-entrantsupraventriculararrhythmia.ClassIVantidysrrhythmics

鈣拮抗藥-維拉帕米verapamilTherapeuticuse：iv,mainlyforparoxysmalsupraventriculartachycardia陣發(fā)性室上性心動過速(陣發(fā)性房性及交界區(qū)心動過速)Adverseeffects：hypotension，bradycardiaandAVblockade低血壓、心動過緩、房室傳導(dǎo)阻滯

Becareful:calciumblockernifedipine,couldnotbeusedasantidysarrhythmicssinceitincreasessympatheticactivitythroughhypotensioneffectandleadstoarrhythmias.二氫吡啶類(地平類)鈣拮抗藥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經(jīng)系統(tǒng)興奮的情況Classificationofanti-arrhythmic

drugsandtheirprototypes

抗心律失常藥物的分類及其代表藥ClassI：Na+channelblockers鈉通道阻斷劑Ia:quinidine奎尼丁Ib:lidocaine利多卡因Ic:propafenone普羅帕酮(flecanideisnolongerused)ClassII：β-adrenergicreceptorblockersβ受體阻斷藥Propranolol普荼洛爾，metaprolol美多洛爾，bisoprolol比索洛爾ClassIII：ProlongAPdurationbyinhibitinK+channel延長動作電位時程藥，鉀通道阻滯藥Amiodarone胺碘酮ClassIV：Ca2+channelblockers鈣通道阻滯藥Verapamil維拉帕米ClassV：MiscellaneousDigitalis洋地黃類,adenosine腺苷Atropine阿托品，isoproterenol異丙腎上腺素Classificatio