药理学英文版教学课件：Chapter 21 Antiarrhythmia

AntiarrhythemicDrugs(P148)Bradycardia(缓慢性)arrhythmiaAtropineIsoprenaline（异丙肾上腺素）Tachycardia（快速）arrhythmiaCase148yrsoldmaleParoxysmalventriculararrhythmia2yrs,relapseafterradiofrequencyablation(射频消融术)2hours.Diagnosis:superventriculartachycardia§1BasicCardiacelectrophysiologyStructureofcardiacconductionsystemSchematicrepresentationoftheheartandnormalcardiacelectricalactivityMembranepotential:restingActionpotential(AP)Actionpotentialduration(APD，动作电位时程)Effectiverefractoryperiod(ERP，有效不应期)Membranereaction（膜反应性）Automaticity(自律性)ConductivityElectrophysiologicaltermsyoumustknow!Actionpotential(AP)5phasesphase0:depolarizationphase1:quickrepolarizationphase2:plateauphase3:repolarizationtobeforeAPphase4:restingorautonomicdepolarizationFastresponsecellAP时程中的currentsThetimecourseofthecurrentsintheactionpotentialofHis-PurkinjecellsCurrentsunderlyingdepolarizationinSAnodalcellsSlowresponsecell(慢反应细胞窦房结)AP时程中的currentAcomparisonoftwoAPFastresponsecell(快反应细胞)APphase0:Na+----quick,swingwidephase4autonomicdepolarization:Na+Slowresponsecell（慢反应细胞）APphase0:Ca2+----slow,swingsmallphase4autonomicdepolarization:Ca2+Membranereaction（膜反应性）maximumdiastolicpotential，MDPERPandAPDAPD=Phase0to3,automaticityphase4AutomaticdepolarizationAffectingfactorsRateofphase4automaticdepolarizationAPthresholdMaximumdiastolicpotentialCardiacarrhythmiaTheabnormalheartrateorrhythmPleasePayattentionto心率

&心律TachycardiaifHR>100/minBradycardiaifHR<60/min

Treatmentforbradycardiais:AtropineIsoprenalineI.Disturbanceofimpulseformation1.Increasedautomaticity1).ExistedautomaticitycellsIncreasedphase4automaticdepolarizationrateDecreasedAPthresholdorDecreasedmaximumdiastolicpotential2).Ischemia,anoxiachangeworkingcardiacmuscleintoautomaticitycellmechanismofcardiacarrhythmia(P149)自律细胞频率变化的机制Membranepotentialmv2.Afterdepolarization（后除极）1).Earlyafterdepolarization(EAD)Happenedinphase2or3WhenlongAPDexistCa2+entry2).Delayedafterdepolarization(DAD)Happenedinphase4WhenCa2+overload,Na+entrymVt(s)01234NormalactionpotentialmVt(s)23EarlyafterdepolarizationmVt(s)44DelayedafterdepolarizationTriggeringactivityreentry(折返)----Oneimpulsereentersandexcitesareasoftheheartmorethenonce---circusmovement.Threeconditionsmustbecoexist:ExistaanatomicorfunctionalcircleUnidirectionalblockUnevenERPinthecircleII.impulseconductobstacleA.normalMechanismofreentryAreentrycircuitthatmightoccurinsmallbifurcatingbranchesofthePurkinjesystemwheretheyentertheventricularwall.A:

Normally,electricalexcitationbranchesaroundthecircuit,istransmittedtotheventricularbranches,andbecomesextinguishedattheotherendofthecircuitduetocollisionofimpulses.B:Anareaofunidirectionalblockdevelopsinoneofthebranches,preventinganterogradeimpulsetransmissionatthesiteofblock,buttheretrogradeimpulsemaybepropagatedthroughthesiteofblockiftheimpulsefindsexcitabletissue,ie,therefractoryperiodisshorterthantheconductiontime.Thisimpulsewillthenreexcitetissueithadpreviouslypassedthrough,andareentryarrhythmiawillbeestablished.传导系统正常单向传导阻滞逆向传导建立折返环路AtrioventricularreentryintheWolff-Parkinson-Whitesyndrome预激综合征中房室折返环路的形成

III.LongQTsyndrome(LQTS)

Treatmentofarrhythmias1.Electricaldevices:

pacemakers

(起搏器),cardioversion

(心脏复律),defibrillators

(除纤颤器)2.Electricalablationofabnormalconductionpathways:

catheterablation

(导管消融)3.Surgery(外科手术)4.AntiarrhythmicDrugs

(抗心律失常药)§2BasicPharmacologyofAntiarrhythemicsI.mechanismsofantiarrhythmicsreduceectopic（异位）pacemaker(起搏点)activitymodifyconductionorrefractorinessinreentrycircuitstodisablecircusmovement1.decreasetheautomaticitydecreased4phaseautomaticdepolarizationrateincreasedAPthresholdorincreasedmaximumdiastolicpotentialprolongAPD2.ReduceafterdepolarizationEAD:sodiumorcalciumchannelblockerDAD:potassiumchannelblocker3.DisablecircusmovementChangeconductivitytoendreentry，changeunidirectional（单向）blockintobidirectional（双向）block.ProlongERPClass1:sodiumchannelblockade钠通道阻滞药

1A:

prolongtheAPDanddissociatefromthechannelwithintermediatekinetics1B:havenosignificanteffectsontheAPDanddissociatefromthechannelwithrapidkinetics1C:haveminimaleffectsontheAPDanddissociatefromthechannelwithslowkinetics

Class2:reducesympatheticβ-adrenergicactivityintheheart

β肾上腺素受体拮抗药Class3:prolongationoftheAPD,blockofoutwardoraugmentationofinwardcurrents.延长动作电位时程药-钾通道Class4:blockadeofthecardiaccalciumcurrent

钙通道阻滞药II.Classificationofantiarrhythmicdrug

I.ClassI---sodiumchannelblockers1.ClassIaQuinidine(奎尼丁)PharmacodynemicsBlockNa+,K+andCa2+channelsInhibit0phase&4phasedepolarization(Na+,Ca2+)Prolong3phaserepolarizationandAPD,ERP(K+)BlockMcholinoceptorandαadrenoceptor§4CommonlyUsedDrugsClinicalusesofquinidineBroadspectrum（广谱）Treatmentandpreventionofatrialfibrillation,atrialflutter,supraventriculartachycardiaandventriculartachycardia

AdversereactionofquinidineCinchonism(金鸡纳反应):headache,dizziness,tinnitus,diarrhea,nausea,blurredvisionCardiactoxicityA-VorventricularconductionblockLongQ-TintervalTorsadedepointes（尖端扭转型心律失常）Procainamide(普鲁卡因胺)BlocksodiumchannelssimilartoquinidinebutwithoutMoralphablockeffectsBroadspectrumantiarrhythemics2.ClassIb(p214)

Lidocaine

Lidocaineisalocalanestheticwhichalsoisusefulintheacuteintravenoustherapyofventriculararrhythmias.ItisaclassIBdrug.Pharmacologicaleffects:Lidocaineblocksbothactivated(open)andinactivatedcardiacNa+channels.Recoveryfromblockisveryrapid,solidocaineexertsgreatereffectsindepolarized(e.g.ischemic)and/orrapidlydriventissues.Lidocaineisnotusefulinatrialarrhythmias,probablybecauseatrialactionpotentialaresoshortthattheNa+channelisintheinactivatedstateonlybrieflyanddiastolic(recovery)timesarerelativelongLidocainedecreaseautomaticitybyreducingtheslopeofphase4andalteringthethresholdofexcitability.TherapeuticuseLidocaineisthefirstchoiceforsuppressionofrecurrencesofventriculartachycardiaandfibrillationafterterminationofarrhythmiabycardioversion.Frequentlyusedtotreatarrhythmiasassociatedwithacutemyocardialinfarction.AdverseeffectsLidocaineisoneoftheleastcardiotoxic(心毒性)ofthecurrentlyusedsodiumchannelblockers.Whenalargeintravenousdoseoflidocaineisadministeredrapidly,itsmostcommonadverseeffectsareneurologic:paresthesia（感觉异常）,tremor,confusion,slurredspeech（口齿不清）,andconvulsions.Phenytoin（苯妥英钠）

Theanticonvulsantphenytoin(dilantin)alsoisablockerofinactivatedcardiacNa+channels.

Ithasbeenusedintheacuteandchronicsuppressionofventriculararrhythmiasandindigitalisintoxication.

Phenytoinhasashortτrecovery,andlittleQRSprolongationisobservedduringchronictherapy.3.ClassIc---Propafenone（普罗帕酮）Propafenonehassomestructuralsimilaritytopropranololandpossessesweakβ-blockingactivity.Itsspectrumofactionisverysimilartothatofquinidine.Itspotencyasasodiumchannelblockerissimilartothatofflecainide.Thedrugisusedprimarilyforsupraventriculararrhythmias.Flecainide(氟卡尼)Flecainideisapotentblockerofsodiumand

potassiumchannels.Itis

currently

used

for

patients

with

otherwise

normal

hearts

whohavesupraventriculararrhythmias.Itisveryeffectiveinsuppressingprematureventricularcontractions.Buthavepossibilityofdrug-inducedarrythemiaII.ClassII---βBlockers

PropranololPropranololistheprototypeofthisclass,otherdrugsare:metoprolol,atenolol,timolol,esmolol,etc.Theantiarrhythmiceffectsofpropranololare

due

primary

to

β-receptor

blockade,possiblyalsoresultfromadirectmembraneeffect.reducesinusrate,decreasethespontaneousrateofdepolarizationofectopicpacemakers,slowconductionintheatriaandintheAVnode,andincreasethefunctionalrefractoryperiodoftheAVnode.Clinicalusescontrolsupra-ventriculartachyarrhythmias,includingatrialfibrillation,atrialflutter,andparoxysmalsupraventricalurtachycardiareducestheincidenceofsuddenarrhythmicdeathaftermyocardialinfarction.Itisusefulinventriculararrhythmiasthatareduetoenhancedadrenergicstimulation.III.ClassIII---DrugsthatprolongAPD

Amiodarone(胺碘酮)Cardiaceffects:AmiodaroneisaveryeffectiveblockerofNa+channel,K+channelsandaweakerCa++channelblockermarkedlylengthensAPD,sustainsitslengtheningofAPDquitewellatfastheartrates.Thisisanimportantreasonforitsefficacyagainsttachycardias.anoncompetitiveinhibitorofβ-adrenoceptors.Itisapowerfulinhibitorofabnormalautomaticity.slowsthesinusrateandAVconduction,markedlyprolongstheQTinterval,andprolongsQRSduration.Itincreasesatrial

,

AV

nodal

andventricularrefractoryperiods.

Extracardiaceffects:Amiodaronecausesperipheralvasculardilation,presumablythroughitsaadrenoceptorblockingandcalcium-inhibitingeffects.

Therapeuticuse

BroadspectrumantiarrhythemicAmiodaroneiseffectiveinthetreatmentofbothsupra-ventricularandventriculararrhythmias.Ingeneral,relativelylowmaintenancedosages(100~200mg/d)canbeusedagainstparoxysmalatrialfibrillation.Amiodaroneappearstobequiteeffectiveagainstsupraventriculararrhythmiasinchildren.AdverseeffectsAmiodaroneshowsavarietyoftoxiceffects.someofthemorecommoneffectsincludeinterstitialpulmonaryfibrosis,gastrointestinaltractintolerance,tremor,ataxia,dizziness,neuropathy,muscleweakness,hyper-orhypothyrodism,livertoxicity,photosensitivity,agrayish-blueskindiscoloration.bradycardia,heartblock,etc.Sotalol(索他洛尔)Sotalolisanonselectiveβ-blocker.ItalsoblocksIkcurrent,slowsrepolarizationandprolongsAPD.Itcanbeusedinbothsupra-ventricularandventriculararrhythmias.Majoradverseeffectsofsotalolareassociatewithβ-blockadeandwithprolongationofrepolarization,includingtorsadedepointeswhichisgreaterathigherdosages.Thus,onlylowerdosages(80~160mgtwicedaily)areusuallyusedinatrialfibrillation.

IV.ClassIV---Calciumchannel-blockingdrugsVerapamilshowsgreateractionontheheartthanonvascularsmoothmuscle,whereanifedipineexertsastrongereffectonvascularsmoothmusclethanontheheart,havelittleantiarrhythmicactivity.Diltiazemisintermediateinitsactions.Verapamil(维拉帕米)istheprototypeofthisclass.Pharmacologicaleffects:Verapanmilandd