-抗心律失常药物的离子流机制和临床应用进展(英文)课件

抗心律失常药物的离子流机制

和临床应用进展Gan-XinYan,MD,PhD,F.A.C.CMainLineHealthHeartCenterJeffersonMedicalCollegeCase1(病例1)A45year-oldfemaleisreferredtoyourofficebecauseofsymptomaticparoxysmalatrialfibrillation.Shealsohasahistoryofasthma.ShetriedCa++blockersanddofetilidebefore,butnoneofthemsuppressedatrialfibrillation.Shehasnotbeenonanymedicationsforacoupleofweeks.Herrecentechocardiogramandstresstestwerenormal.Inyouroffice,12leadECGshowsatrialfibrillationwithventricularresponsesat80beatsperminute.Shestatesthatshealwaysknowstheonsetofatrialfibrillationthatoccurswhenshetakesanaporishungry.QuestionforCase1(病例1)Whichofthefollowingantiarrhythmicdrugsisthebestchoiceforthepatient?Amiodarone;Propafenone(心律平);Sotalol;Disopyramide.QuestionLidocaine(利多卡因)andmexiletineareClassIbantiarrhythmicdrugs.WhichofthefollowingarrhythmiasismostlikelysuppressedbytheClassIbantiarrhythmicdrugs?Why?AVnodalorAVreentrytachycardiaVentriculararrhythmiasinthesettingofmyocardialischemiaVentricularfibrillationinpeoplewithstructurallynormalheartsAtrialarrhythmiasBasicElectrophysiology基础电生理Na+EXTRACELL.INTRA-CELL.Em145mM15mM70mvCa++2mM0.1uM132mvK+5mM145mM-100mvElectricaldrivingforce;ChemicalGradient;IonChannelPermeability(voltageandtimedependent)

0mV-85mVGenesisofCardiacRestingandActionPotentialsIIIIIIIVExtracellularINa

SodiumChannel(SCN5A)DomainsCOOHNH2******R1623QR1644HT1645M******S1710L1786*T1620MR1512WA1924TR1232WR1432G1397*T1304ME1784KD1790G1795insDN1325SIVS22+2T>CL567QT632MIVS7+4insAADKPQ1505-1507G1406RY1795HR1192QA735VR367HG298SG514CA1924TD1595NDK1500BrugadasyndromeLongQTsyndrome3ConductionDiseaseBrugada/ConductionDiseaseBrugada/LQT3/ConductionDiseaseAtrial

standstillMajorIonicCurrentsinVentricularActionPotential012234TheStatesofVoltage-DependentIonicChannelChannelStateStateofthemgateStateofthehgateResting(R)ClosedOpenOpen(O)OpenOpenInactivated(I)OpenClosedNachannelisdeactivatedatpotentialpositivethan-60mV!RelationshipbetweenVolatge-dependentIonChannelStatusesandActionPotentialINa-mediatedactionpotentials(钠通道介导的动作电位,restingmembranepotential<-70mV):fastphase0upstrokeandconductionvelocitythatissuppressedbyINablockers.

Atria,His-Purkinjeconductiontissues,ventricles,accessorypathways;ICa,L-mediatedactionpotentials(钙通道介导的动作电位,restingmembranepotential>-60mV):slowphase0upstrokeandconductionvelocitythatissuppressedbyICa,Lblockers.

SinusandAVnodes.TwoTypesofActionPotentials:DeterminedbyRestingPotentialsHeartElectricalSystemandActionPotentialFeatures-50mV-60mV-85mV-85mV-80mVIonicCurrentsandDiseasesIonicCurrentsInhibitorsDiseasesINaIa:Quinidine,procainamideIb:Lidocaine,mexiletineIc:flecainide,propafenoneConductionDisease;atrialstandstill.Brugadasyndrome;Longsyndrome(LQT3)ICa,LVerapamil,diltiazem

LQT8(Timothysyndrome)

IKsAzimilideLongQTsyndrome(LQT1,LQT5,LQT6)IKrDofetilide,sotalolandmanynon-cardiacdrugsLongQTsyndrome(LQT2)ItoQuinidineBrugadasyndrome,idiopathicVFGenesisofCardiacArrhythmiasAbnormalImpulseFormation

Automaticity:enhancedpacemaker; TriggeredActivity:earlyafterdepolarization(EAD)anddelayedafterdepolarization(DAD)

Reentry(CircusMovement)

ElectricalObstacle(suchasscartissueduetoMI)

FunctionalBlock(relativelargerdispersionofrepolarization)ReentryMechanismSpatialExcitableGapThewavelength=conductionvelocityxrefractoryperiodForexample:ifconductionvelocityis1.0m/s,andrefractoryperiodis0.4s(400ms),thewavelengthisequalto0.4m(400mm).Forexample:ifconductionvelocityis0.1m/s,andrefractoryperiodis0.4s(400ms),thewavelengthisequalto0.04m(40mm).Therefore,conductionslowingisamajorcontributortoreentranttachycardia!!Tricuspidormitralvalvesarealsotheelectricalobstacles.Canareentry(circusmovement)arrhythmiaoccuralongthetricuspidormitralvalves?CourtesyofMayoClinicAntiarrhythmicEffectsonReentryArrhythmiascanbepotentiallyArchivedviatheFollowingMechanisms

Tosuppressthetriggerthatisabletopenetrateintothereentrycircuit

betablockers,calciumchannelblockersToincreasethewavelengthbyprolongingeffectiverefractoryperiod(ERP)

APDprolongationbyinhibitingoutwardcurrents:dofetilide,sotalol,azimilideetc Inwardcurrentinhibition(nochangeordecreaseinAPDbutanincreaseinERP):lidocaine,flecainideetcforsodiummediatedactionpotentialandcalciumchannelblockerscalcium-mediatedactionpotential

Toincreaseconductionvelocity

Drugondevelopmenttoincreasegapjunctioncoupling; RFablationtogetridofslowandunidirectionalconduction

Todecreasereentrantcircuit

Reducingdispersionofrepolarization

forfunctionalreentry

Mazeprocedure?

Case2(病例2)A65year-oldmalewithapastmedicalhistoryofmyocardialinfarction,by-passsurgery5yearsagoandstatuspostICDimplantwhowasadmittedwithmultipleICDshocks.ICDinterrogationshowedventriculartachycardiawithcyclelengthsofabout340msandadequateICDtherapy.Inhospital,cardiacenzymeswerenegativeandcardiaccatheterizationshowedpatentgrafts.Duringhishospitalstay,hehadmultipleepisodesmoremonomorphicVTwithsamemorphology.ThispatientthenunderwentVTablation.Inonespot,electricalsignalwasfragmentedandtheonsetofthissignalwas60msearlierthanthebeginningofQRSduringVT.RFablationwasdeliveredatthisspot.

Afterablation,noVTwasinducible.

QuestionforCase2(病例2)RFablationtosuppressVTinthispatientisprimarilybecause:RFablationgeneratesanewscar,therefore,thereentrycircuitisprolonged;RFablationgeneratesanewconductionblock,therefore,thereentrycircuitisinterrupted;RFablationabolishesthetrigger,therefore,VTcannotbeinitiated;RFablationabolishesthespotwithslowconduction,therefore,thewavelengthbecomeslongerthanthereentrycircuit.VaughanWilliamsClassificationofAntiarrhythmicDrugs

ClassActionDrugsISodiumChannelBlockade

IaModeratephase0depressionandconductionslowing,prolongingofactionpotentialdurationQuinidine,procainamide,disopyramideIbMildeffectonphase0upstroke;Nochangeorshorteningofactionpotentialduration

Lidocaine,mexiletine,tocainide

IcMarkedphase0depressionandconductionslowing,littleeffectonrepolarization

flecainide,propafenone,moricizine

IIBeta-AdrenergicBlockade

Propanolol,metoprolol,atenolol,esmolol,IIIPotassiumChannelBlockade

d,l-sotalol,dofetilide,amiodarone,ibutilide

IV

CalciumChannelBlockade

Verapamil,diltiazem

EffectsOfAntiarrhythmicDrugClassesOnTheECGPRQRSQTJTHRIaIbIcIIIIIIVClinicalApplicationsofClassIAntiarrhythmicDrugsClassIa:tosuppressatrialandventriculararrhythmias;tounmaskconcealedBrugadasyndrome,suchasbyuseofprocainamide;ClassIb:totreatventriculararrhythmiasparticularlyinthesettingofmyocardialischemia;mexilitinemaybeusefulinLQT3;ClassIc:tosuppress

supraventricular

tachycardiasincludingatrialfibrillationandatrialflutter;tounmaskconcealedBrugadasyndrome,suchasbyuseofflecainide.ASpecificSideEffectAssociatedwiththeSodiumChannelBlockersStrongerUse-dependenceofINablockade:

Flecainideandpropafenone,etc;Case3(病例3)A28yo-oldfemalewithcongenitalheartdiseasewhodevelopedatrialfibrillation5yearsago.Shehadbeentreatedwithflecainide(classIc)andremainedinnormalsinusrhythmandasymptomaticuntilrecentlywhenshepresentedtoER.Shefeltverylightheaded.ECG1ofCase3(病例3)SBPwasabout80mmHg,shewasalert;Intravenousamiodaronewasgiven.ECG2ofCase3(病例3)CardiacArrhythmiaSuppressionTrial(CAST)

TheincreasedmortalityassociatedwiththeclassIcdrugs,flecainideandencainide,inpatientswithcoronaryarterydiseaseandleftventricularsystolicdysfunction!!

However,proarrhythmiaratesarenearlyzerowhenclassIcdrugsareusedforatrialarrhythmiasinpatientswithastructurallynormalheart.Case4(病例4)

A37yo-oldmalewithahistoryofpalpitationwhoisadmittedwithsyncope.Echocardiogramshowsastructurallynormalheart.HispreviousECGisshownbelow:

ECG2ofCase4(病例4)atERECGTracing3ofCase4(病例4)10minutesafterInitiationofIntravenousDiltiazemQuestionofCase4(病例4)IfthispatientwashemodynamicallystableattheER,whichofthefollowingdrugsisthebestchoiceforthetreatmentofthepatient’swidecomplextachycardia?Andwhy?Procainamide,iv;Digoxin,iv;Verapamil,iv;Adenosineiv;QuestionClassicIaandIcdrugslikeprocainamideandflecainidecanbeusedtounmaskconcealedformoftheBrudadasyndrome.Whycan’tQuinidine,alsoaclassIadrug,beusedforsuchdiagnosis?QuinidineblocksIto(transientoutwardcurrent),sothatitunlikelycausesSTelevationinpatientswithconcealedBrugadasyndrome;QuinidineprolongsQTmarkedly,sothatitmayinitiateventricularfibrillationinpatientsconcealedBrugadasyndrome;QuinidineisaweakerINainhibitor,sothatitunlikelycausesSTelevationinpatientswithconcealedBrugadasyndrome;QuinidineprolongsQRSdurationmarkedly,sothatititunlikelycausesSTelevationinpatientswithconcealedBrugadasyndrome;CellularMechanismsResponsibleforSTSegmentElevationYan,etalJACC2003;42:402-409

CanineLeftVentricleYan,etal,Circulation1996;93:372-379CanineRightVentricleYan,etal,Circulation1999;100:1660-1666JWaveandSTSegmentElevation

Ito-mediatedactionpotentialspikeanddomeismoreprominentinrightventricularepicardium.EffectofQuinidineintheJWaveSyndromeYan,etal,Circulation1999;100:1660-1666TheRolesofIto-mediatedEpicardialAPSpikeandDomeinSTSegmentElevationandVFduringAcuteMyocardialInfarction

YanGX,etal:Phase2reentryasatriggertoinitiateventricularfibrillationduringearlyacutemyocardialischemia.Circulation2004;110:1036-1041Beta-adrenergicBlockersUsedprimarilyforsinus/AVnodeeffectsMayhavedirecteffectsonatrialandventriculararrhythmiasespeciallyinhighcatecholaminestates(abnormalpulseformation)Afewbetablockersexhibitintrinsicsympathomimeticactivity(ISA,pindolol,acebutolol)i.e.partialagonistactivitywhichmaybeusefulinpatientswhoshowsignificantbradycardiaswhenonaregularbetablocker.Newcomplexagents(e.g.carvedilol)mayactviaothermechanisms

ClassIIIAntiarrhythmicDrugsPrimarilycauseQTorAPDprolongationandthereforeincreaseERPandthereentrywavelength

Usefulinsuppressingreentryarrhythmiassuchasatrialfibrillation/flutterandmonomorphicVTDrugsblockoneorseveralbutdifferentKchannels e.g.Dofetilide,sotalolblockIKr AzimilideblocksIKr

andIKs

TedisamilblocksnearlyallKchannelsQuestion2ofCase2(病例2)A65year-oldmalewithapastmedicalhistoryofmyocardialinfarction,by-passsurgery5yearsagoandstatuspostICDimplantwhowasadmittedwithmultipleICDshocks.ICDinterrogationshowedventriculartachycardiawithcyclelengthsofabout340msandadequateICDtherapy.Inhospital,cardiacenzymeswerenegativeandcardiaccatheterizationshowedpatentgrafts.Duringhishospitalstay,hehadmultipleepisodesmoremonomorphicVTwithsamemorphology.IfthereisnoRFablationfacilityinyourhospital,whichofthefollowingdrugsyouwouldliketotryfirst:Mexilitine(美西律)Sotalol(索他洛尔)Amiodarone(胺碘酮)Propaferone(心律平

)Amiodarone–PartISympatholyticeffects/weakbeta-blockerWeakclassIbeffectsPotentclassIIIeffectsWeakclassIVeffectsMetabolic/thyroideffectsActivemetabolite(desethylamiodarone)Multiplehalf-lives(3compartments)Amiodarone–PartIIMultipleantiarrhythmicactionsPoorlycharacterizedkinetics;loadingneededLVEFstabilityorimprovementRaisesDFTsRareproarrhythmia;commonbradycardiaMultipleorgantoxicity;toxicitysurveillanceASpecificSideEffectAssociatedwithIKrBlockade

ReverseUse-dependence:IKr

blockerslikeDofetilide,sotalol,ibutilide,etc.

Amiodaronehasnosignificantreverseuse-dependence.

TdPAssociatedwithQTProlongingAgentsQTc=645ms“paroxysmalventricularfibrillation”.Quinidine

SyncopeAllTdPswereinitiatedbyanR-on-Tectopicbeat.Thereisnoexception!Yan,etalCirculation2001;103:2851-2856R-on-TR-on-TR-on-TR-on-TPropagationofphase2EADtocellswithashorterAPDproducesanewactionpotential,whichmanifestsasanR-on-TectopicbeatontheECGEarlyAfterdepolarization(EAD)+EnhancedTransmuralDispersionRepolarization(TDR)R-on-TEctopicBeatsTorsadedePointes(TdP)ClassIVAntiarrhythmicdrugs

(Non-dihydropyridineCalciumChannelBlockers)Affectcalcium-dependentslowactionpotentialsinthesinusandatrioventricularnodes;Verapamilanddiltiazemaremainlyusedinsupraventricular

tachycardiasandforratecontrol