臨床藥理Arrhyth培訓(xùn)資料課件

治療心律失常藥物

Antiarrhythmicagents一、BasicConcept

正常心率（竇性心律）：Theelectricalimpulsethattriggersanormalcardiaccontractionoriginatesatregularintervalsinthesinoatrialnode,usuallyatafrequencyof60-100beatsperminute.Thisimpulsespreadsrapidlythroughtheatriaandenterstheatrioventricularnode,thenpropagatesovertheHis-Purkinjesystemandinvadesallpartsoftheventricles.第一頁(yè)，共五十二頁(yè)。心律失常： Arrhythmiasconsistofcardiacdepolarizationsthatdeviatefromtheabovedescriptioninoneormoreaspects—ie,thereisanabnormalityinthesiteoforiginoftheimpulse,itsrateorregularity,oritsconduction。第二頁(yè)，共五十二頁(yè)。心律失常分類(lèi)總的可分快速型和過(guò)緩型

（然后根據(jù)發(fā)生部位和性質(zhì)再分）快速型：房早，房速，房顫；室早，室速，室顫過(guò)緩型（緩慢型）：房室傳導(dǎo)阻滯，束支傳導(dǎo)阻滯，竇性心動(dòng)過(guò)緩等，阿托品，擬腎上腺素藥物等有一定作用。第三頁(yè)，共五十二頁(yè)。心律失常的治療學(xué)分類(lèi)就臨床治療的觀點(diǎn)，心律失常可分為三類(lèi)：良性（無(wú)器質(zhì)性病變）benignarrhythmias:VPBs,sinustachycardiausingAnxiolyticsandSedatives可能惡性（輕中度器質(zhì)性病變）potentialmalignantarrhythmias：ParoxysmalSupraventricularTachycardia,monomorphicventriculartachycardia,atrialfibrillation惡性（重度器質(zhì)性病變）malignantarrhythmias(life-threateningarrhythmias)：sustainedventriculartachycardia,polymorphicventriculartachycardia,

ventricularfibrillation第四頁(yè)，共五十二頁(yè)。二、PathophysiologyArrhythmiasdevelopbecauseofabnormalimpulsegeneration,abnormalpropagationorbothBradyarrhythmiasWhicharisethroughabnormalitiesofintrinsicautomaticbehaviororconduction,principallywithintheatrioventricularnodeandtheHis-Purkinje'snetwork.第五頁(yè)，共五十二頁(yè)。Tachyarrhythmias

ThreemechanismshavebeenassociatedwithmanytachyarrhythmiasAlteredautomaticity:Factorsthatincreaseautomaticityinclude

mechanicalstretchbeta-adrenergicstimulationhypokalemiaTriggeredautomaticity:EarlyAfterdepolarization(EAD)早后除極 whichisassociatedwithsignificantprolongationoftheactionpotentialduration.FactorsthatpredisposetoEAD: bradycardialowextracellularK+certaindrugs,includingsomeantiarrhythmics第六頁(yè)，共五十二頁(yè)。Torsadesdepointes,apolymorphicventriculararrhythmia-associatedwithProlongationofcardiacrepolarization(prolongedQ-Tinterval)PossiblyinducedbyearlyafterdepolarizationsDelayedafterdepolarization(DAD)遲后除極.FactorsthatpredisposetoDADinclude: excessiveadrenergicactivitydigitalistoxicityhighintracellularCa2+reentry:Mostclinicallysignificanttachyarrhythmiasareprobablyduetoreentry.第七頁(yè)，共五十二頁(yè)。Afterdepolarizationsandtriggeredactivity

第八頁(yè)，共五十二頁(yè)。SymptomsandSignsPalpitations(awarenessoftheheartbeat)areoftendisagreeableandmayariseequallyfromincreasedforceofcontractionandfromrhythmdisturbance.Theyshouldbeinvestigatedtodefinethecauseandtoallayanxiety.Arrhythmiasthatcausehemodynamicupsetareusuallysustainedbradycardiasortachycardiasandmaybelifethreatening.Resultingdizzinessandsyncopearecommon.Thesearrhythmiasrequireurgentattentionand,often,hospitalization.第九頁(yè)，共五十二頁(yè)。Somearrhythmiascausefewornosymptomsbutareassociatedwithanadverseprognosis.Muchevidencesuggeststhatprognosisisnotnecessarilyimprovedbytheirsuppression.Otherarrhythmias,althoughsymptomatic,arebenign.Thenatureandseverityofunderlyingheartdiseaseareoftenofgreaterprognosticsignificancethanisthearrhythmiaitself.

第十頁(yè)，共五十二頁(yè)。TreatmentMostcardiacarrhythmiascausenosymptoms,havenohemodynamicimportance,andhavenoprognosticsignificancebutmaycauseanxietyinapatientwhobecomesawareofthem.Somepatientswithbenignarrhythmiasremaindisableddespitereassurance.Behaviormodificationtherapyoftenhelpswhenreassurancehasfailed.Inrarecases,aprecipitatingfactormaybeidentifiedandmodified(eg,excessiveintakeofcaffeineoralcohol).第十一頁(yè)，共五十二頁(yè)。Drugtreatment:Antiarrhythmicdrugtherapyisthemainstayofmanagementformostimportantarrhythmias.Thereisnouniversallyeffectivedrug;allhaveimportantsafetylimitationsandcanaggravateorpromotearrhythmias(arrhythmogenesis,proarrhythmia).Drugselectionisdifficultandofteninvolvestrialanderror.第十二頁(yè)，共五十二頁(yè)?？剐穆墒СＫ幬锓诸?lèi)Willams分類(lèi)法分為四類(lèi)：Ⅰ類(lèi)：鈉通道阻斷劑，又再分為a,b,c三亞類(lèi)Ⅱ類(lèi)：beta-受體阻斷劑Ⅲ類(lèi)：鉀通道阻斷劑（動(dòng)作電位時(shí)程延長(zhǎng)藥）Ⅳ類(lèi)：鈣通道阻斷劑其它類(lèi)：強(qiáng)心苷、腺苷、鎂，等第十三頁(yè)，共五十二頁(yè)。分類(lèi)

阻斷鈉通道抑制0相Vmax延長(zhǎng)APD阻鉀外流Ⅰa類(lèi)++ ++ + +Ⅰb類(lèi) + + - -Ⅰc類(lèi) +++ +++ - -第十四頁(yè)，共五十二頁(yè)。ClassIdrugsareNachannelblockers,includingolderantiarrhythmicdrugs(eg,quinidine).Allreducethemaximalrateofdepolarizationoftheactionpotentialandtherebyslowconduction.Theyaresubclassifiedbasedonthekineticsoftheirreceptoreffects:classIa--drugswithintermediateonsetandoffset;classIb--drugswithshorteffects;classIc--drugswithprolongedeffects.第十五頁(yè)，共五十二頁(yè)。第Ⅰ類(lèi)藥鈉通道阻滯藥Ⅰa類(lèi)代表藥主要有奎尼?。╭uinidine）、普魯卡因胺(procainamide)Ⅰb類(lèi)代表藥主要有利多卡因（lidocaine）、苯妥英鈉(phenytoinsodium)、美西律（mexiletine）Ⅰc類(lèi)代表藥主要有心律平（普羅帕酮，propafenone），氟卡尼(flecainide，氟卡胺)，恩卡尼(encainide，恩卡胺)第十六頁(yè)，共五十二頁(yè)。奎尼?。╭uinidine）Ⅰa類(lèi)代表藥藥理作用：阻鈉內(nèi)流，阻鉀外流，A傳導(dǎo)：抑制0相，減慢傳導(dǎo)，P-R延長(zhǎng)。B自律性：抑制4相鈉內(nèi)流除極，降低自律性，抑制異位節(jié)律C時(shí)程：延長(zhǎng)APD，ERP，QRS增寬另外，通過(guò)鈉鈣交換降低細(xì)胞內(nèi)鈣，抑制心肌收縮，阻斷α受體降血壓應(yīng)用：為廣譜抗心律失常藥，對(duì)房性，室性，早搏、心動(dòng)過(guò)速均有效。第十七頁(yè)，共五十二頁(yè)。不良反應(yīng)：較嚴(yán)重的為心律失常：多相性室性心動(dòng)過(guò)速（尖端扭轉(zhuǎn)性室速，torsadedepoints）,可演變成室顫。低血壓——擴(kuò)張血管，抑制心肌金雞鈉反應(yīng)：頭痛，頭暈，耳鳴，視聽(tīng)力減退。第十八頁(yè)，共五十二頁(yè)。利多卡因（lidocaine）Ⅰb類(lèi)代表藥阻鈉內(nèi)流，促鉀外流？自律性：4相除極減慢，提高興奮閾，降低自律性，時(shí)程：縮短APD，相對(duì)延長(zhǎng)ERP傳導(dǎo)：增加病變區(qū)心肌的舒張電位，改善浦氏纖維傳導(dǎo)，消除折返主要用于室性心動(dòng)過(guò)速。首過(guò)效應(yīng)大，多iv給藥。副作用：嗜睡，共濟(jì)失調(diào)，驚厥等中樞神經(jīng)反應(yīng)，心臟毒性較低，過(guò)量也可導(dǎo)致心律失常，傳導(dǎo)阻滯第十九頁(yè)，共五十二頁(yè)。心律平（普羅帕酮，propafenone），氟卡胺，英卡胺等，Ⅰc類(lèi)強(qiáng)阻鈉內(nèi)流，抑制0相，減慢傳導(dǎo)，P-R顯著延長(zhǎng)，QRS增寬，降低室性早搏作用強(qiáng)，但無(wú)抗室顫作用，甚至可能加重（CAST結(jié)果）。但只要不用于患嚴(yán)重器質(zhì)性心臟病的病人，還是很安全的。心律平兼有慢通道及β受體阻斷作用。第二十頁(yè)，共五十二頁(yè)。ClassIIdrugsmaybetheleasttoxicandmostpowerfuldrugsavailable,yettheirantiarrhythmiceffectsareoftenoverlooked.Whereasrelativelyfewarrhythmiasareprimarilycausedbysympatheticoveractivity,mostaremodulatedbyautonomictone.β-Blockershavepoorefficacyinconventionalantiarrhythmictests(eg,VEBsuppression),buttheyraisethethresholdtoVFandmaybepotentpreventersofVF.Ingeneral,β-blockersarewelltoleratedbutmaydepressleftventricularfunction,particularlyinantiarrhythmicdoses.Theyarecontraindicatedinbronchospasticairwaydiseaseandshouldbeusedcautiouslyinotherlungdiseases.GIdisturbances,insomnia,andnightmaresmayoccur.第二十一頁(yè)，共五十二頁(yè)。普萘洛爾（propranolol）Ⅱ類(lèi)

用于交感神經(jīng)活動(dòng)亢進(jìn)所致的室性、房性心律失常交感神經(jīng)興奮或兒茶酚胺釋放增多時(shí),心肌自律性增高,傳導(dǎo)速度增快,不應(yīng)期縮短,易引起快速性心律失常。普萘洛爾則能阻止這些反應(yīng)。第二十二頁(yè)，共五十二頁(yè)。ClassIIIdrugsinterferewiththeKchanneltoaltertheplateauphaseoftheactionpotentialandincreaserefractoriness.Conductionvelocityislittleaffected,but,theoretically,thedischargerateofautomaticfociisreduced.Thesedrugscanbeproarrhythmic.第二十三頁(yè)，共五十二頁(yè)。胺碘酮（amiodarone）

兼有1-4類(lèi)的作用，以3類(lèi)為主，為廣譜抗心律失常藥，但不良反應(yīng)多，且藥動(dòng)學(xué)復(fù)雜。

本藥有顯著抗心律失常作用，臨床用于多種室上性和室性心律失常。臨床顯示可能降低心梗后的心律失常致死率，是臨床常用的抗心律失常藥物。索他洛爾(sotalol)

原為β受體阻斷藥,后因明顯延長(zhǎng)APD而用作Ⅲ類(lèi)抗心律失常藥。d-異構(gòu)體無(wú)β阻斷作用，只延長(zhǎng)ADP，有抗室性心律失常，抗室顫的作用，但可誘發(fā)尖端扭轉(zhuǎn)性室速。第二十四頁(yè)，共五十二頁(yè)。Amiodarone

apowerfulclassIIIantiarrhythmic.Ithasfewcardiovascularadverseeffectsand,perhapsthroughitsmodestvasodilatoraction,produceslittleornoleftventriculardepression.Sinoatrialnodeactivityislittleaffected.Amiodarone,byprolongingrefractoriness,maycreatehomogeneousconditionsofrepolarizationthroughouttheheart.TheQTintervalonECGisprolonged,andnouppersafelimittothiseffecthasbeensuggested.Theeliminationt1/2is>50days,withsubstantialdelayinonsetofaction.TheECGshouldbemonitoredcontinuously,asthereisariskofinducingatrioventricularblock.第二十五頁(yè)，共五十二頁(yè)。維拉帕米（verapamil）

Ⅳ類(lèi)

抑制竇房結(jié)，延長(zhǎng)AV傳導(dǎo)及不應(yīng)期，主要用于室上性心動(dòng)過(guò)速?？杉又貍鲗?dǎo)阻滯和心肌抑制。 一般不主張與β阻斷劑合用，因二者均抑制心肌傳導(dǎo)和收縮。第二十六頁(yè)，共五十二頁(yè)。ClassIVdrugsareCablockers(Caentryblockers).

verapamilanddiltiazeminfluenceatrioventricularnodalelectrophysiologyandmayalterthatofCa-dependentischemiccells.第二十七頁(yè)，共五十二頁(yè)。其它類(lèi)地高辛（洋地黃類(lèi)）用于房顫，減慢室率。特別適用于心衰伴有房顫的患者。腺苷iv用于終止室上性心動(dòng)過(guò)速。第二十八頁(yè)，共五十二頁(yè)?？剐穆墒СＫ幬锏闹滦穆墒СＷ饔脦缀跛械目剐穆墒СＫ幬锒加谢蚨嗷蛏俚闹滦穆墒СＷ饔谩roarrhythmiaduetosodiumchannelblock（Ⅰ類(lèi)）Fourdistinctformsofproarrhythmiahavebeenassociatedwithtreatmentwithsodiumchannelblockers.1atrialflutter心率慢時(shí)房室傳導(dǎo)快，使室率快2slowconductionintherimofanoldmyocardialinfarctionplaysaprominentroleinthegenesisandmaintenanceofsustainedmonomorphicventriculartachycardia.3reducesexcitabilityoftheheart.ICDs(植入性心臟起搏器)increasedoutputofthedevicesmayberequired.

第二十九頁(yè)，共五十二頁(yè)。4CAST啟示Thefourthproarrhythmiasyndromeoccurringduringtreatmentwithsodiumchannelblockersisanincreaseinmortalityduringlong-termtreatment.ThiswasestablishedbytheCardiacArrhythmiaSuppressionTrial(CAST),alandmarkstudythattested,inaplacebo-controlled,randomized,double-blindfashion,thethen-prevailingwisdomthatsuppressionofVPCsinpatientsconvalescingfromamyocardialinfarctionwouldreducetheincidenceofsuddendeath.第三十頁(yè)，共五十二頁(yè)。InCAST,patientswithVPCsandarecentmyocardialinfarctionwererandomlyassignedtooneofthreesodiumchannelblockertherapies,whichwasthentitratedtothedosethatappearedtosuppressVPCsona24-hourHoltermonitor.Oncetheeffectivedoseanddrugwereestablished,patientswererandomlyassignedtocontinuedrugorplacebo.Remarkably,mortalityamongpatientsrandomizedtodrugwas2to3timesthatamongthoserandomizedtoplacebo.第三十一頁(yè)，共五十二頁(yè)。Themechanismunderlyingthisstriking,andpreviouslyundefined,effectofsodiumchannelblockremainsuncertain.However,conductionslowingwithanincreasedriskofsustainedventriculararrhythmias(includingventricularfibrillation)seemslikely.* CardiacArrhythmiaSuppressionTrial(CAST)NEnglJMed.1989;321(6):406-12NEnglJMed.1992;327(4):227-33第三十二頁(yè)，共五十二頁(yè)。ProarrhythmiaduetoQTprolongationⅢ類(lèi)Insomepatients,therapywithactionpotentialprolongingdrugssuchassotalol,quinidine,oributilidecanbeassociatedwithmarkedprolongationoftheQTintervalandinductionofamorphologicallydistinctivepolymorphicventriculartachycardia,torsadesdepointes.Torsadesdepointes(尖端扭轉(zhuǎn)性室速)canalsooccurduringtreatmentwith“noncardiovascular”drugs;commonexamplesincludeterfenadine,cisapride,haloperidol,andthioridazine(Tanetal.1995).第三十三頁(yè)，共五十二頁(yè)。第三十四頁(yè)，共五十二頁(yè)?？剐穆墒СＫ帒?yīng)用原則消除誘發(fā)和促發(fā)因素：低鉀血癥，低鎂血癥；心肌缺血缺氧；甲亢；一些藥物（強(qiáng)心苷、抗心律失常藥、茶堿、紅霉素等）選用合適藥物：竇速-β阻斷藥、維拉帕米；房顫降低室率-強(qiáng)心苷，房顫轉(zhuǎn)律維持-胺碘酮、奎尼丁；陣發(fā)室上速-腺苷、維拉帕米；室速-利多卡因、胺碘酮個(gè)體化用藥：根據(jù)年齡、體質(zhì)、心、肝、腎功能及電解質(zhì)情況調(diào)整用藥方案注意用藥禁忌和不良反應(yīng)：心律失常，心臟收縮力抑制，心臟傳導(dǎo)抑制，低血壓，甲狀腺功能改變，肺纖維化第三十五頁(yè)，共五十二頁(yè)。治療高脂血脂藥及抗動(dòng)脈粥樣斑塊藥動(dòng)脈粥樣硬化動(dòng)脈粥樣硬化（atherosclerosis，AS，以下簡(jiǎn)稱(chēng)動(dòng)粥）是一種主要侵犯主動(dòng)脈、冠狀動(dòng)脈及腦動(dòng)脈等大中動(dòng)脈的全身動(dòng)脈系統(tǒng)疾病，是常見(jiàn)的心、腦血管疾病的病理基礎(chǔ)。在血壓突然升高等一些因素的作用下，粥樣斑塊處就可破裂出血，或形成血栓堵塞血管，如發(fā)生在冠狀動(dòng)脈，則造成心肌梗死，如發(fā)生在腦血管，則形成出血性中風(fēng)或缺血性中風(fēng)。動(dòng)粥的病因尚不完全明了，但已知有很多因素能促進(jìn)動(dòng)粥病變的發(fā)生和發(fā)展，如脂質(zhì)代謝紊亂、血管內(nèi)皮損傷、高血壓、糖尿病、肥胖、吸煙、高脂飲食等。其中血脂代謝紊亂是動(dòng)粥發(fā)病的重要因素，現(xiàn)有的抗動(dòng)粥藥大多與此相關(guān)。第三十六頁(yè)，共五十二頁(yè)。1高膽固醇及高甘油三酯等高血脂癥是促進(jìn)動(dòng)脈粥樣硬化的一個(gè)重要危險(xiǎn)因素。 LDL、IDL及VLDL，特別是前二者，都是血漿膽固醇的主要載體，與動(dòng)粥形成關(guān)系最為密切。LDL的蛋白部分可在肝外組織細(xì)胞內(nèi)進(jìn)行降解，而膽固醇則不能。如無(wú)法將其運(yùn)回肝臟，則膽固醇將堆積，沉著在動(dòng)脈壁，形成動(dòng)粥斑塊，如沉積在皮膚、肌腱處則形成各種黃色瘤。近年發(fā)現(xiàn)脂蛋白（a）[Lp(a)]也是致動(dòng)粥的一種獨(dú)立危險(xiǎn)因素。Lp（a）是一種較LDL更大更致密的脂蛋白，由apoB100和apo(a)結(jié)合而成，其中的脂蛋白apo(a)可抑制組織纖溶酶原激活物（t-PA）與纖溶酶原的結(jié)合，促進(jìn)血栓及動(dòng)脈粥樣硬化的形成。動(dòng)物實(shí)驗(yàn)和臨床研究結(jié)果均證明，降低膽固醇和LDL，可延緩動(dòng)脈粥樣硬化的進(jìn)展。第三十七頁(yè)，共五十二頁(yè)。2血管內(nèi)皮的損傷在動(dòng)粥發(fā)病過(guò)程中是一個(gè)必要因素。細(xì)胞LDL受體介導(dǎo)LDL進(jìn)入細(xì)胞內(nèi)生成膽固醇；而非受體介導(dǎo)的LDL進(jìn)入巨噬細(xì)胞及平滑肌細(xì)胞變成泡沫細(xì)胞，沉積于動(dòng)脈內(nèi)膜下，形成粥樣斑塊。然而，并非所有的脂蛋白濃度升高都有促動(dòng)粥作用，HDL則有助于減少膽固醇經(jīng)LDL進(jìn)入細(xì)胞及增加膽固醇離開(kāi)細(xì)胞的速率，表明HDL是對(duì)抗動(dòng)脈粥樣硬化的脂蛋白。第三十八頁(yè)，共五十二頁(yè)。Background:Atherosclerosisisadiseaseoflarge-sizedandmedium-sizedmusculararteriesandischaracterizedbyendothelialdysfunction,vascularinflammation,andthebuildupoflipids,cholesterol,calcium,andcellulardebriswithintheintimaofthevesselwall.Thisbuildupresultsinplaqueformation,vascularremodeling,acuteandchronicluminalobstruction,abnormalitiesofbloodflow,anddiminishedoxygensupplytotargetorgans.第三十九頁(yè)，共五十二頁(yè)。Pathophysiology:Themechanismsofatherogenesisremainuncertain.The”response-to-injury”.Endothelialinjurycausesvascularinflammationandafibroproliferativeresponseensues.第四十頁(yè)，共五十二頁(yè)。Probableoxidizedlow-densitylipoprotein(LDL)cholesterolcausesendothelialinjury;

infectiousagents;toxins,includingthebyproductsofcigarettesmoking;hyperglycemia;andhyperhomocystinemia.Circulatingmonocytesinfiltratetheintimaofthevesselwall,andthesetissuemacrophagesactasscavengercells,takingupLDLcholesterolandformingthecharacteristicfoamcellofearlyatherosclerosis.Theseactivatedmacrophagesproducenumerousfactorsthatareinjurioustotheendothelium.Endothelialinjury第四十一頁(yè)，共五十二頁(yè)。Thefattystreakmayprogresstoformafibrousplaque,theresultofprogressivelipidaccumulationandthemigrationandproliferationofsmoothmusclecells.Platelet-derivedgrowth,insulinlikegrowthfactor,transforminggrowthfactorsalphaandbeta,thrombin,andangiotensinIIarepotentmitogensthatareproducedbyactivatedplatelets,macrophages,anddysfunctionalendothelialcellsthatcharacterizeearlyatherogenesis,vascularinflammation,andplatelet-richthrombosisatsitesofendothelialdisruption.第四十二頁(yè)，共五十二