药理学教学课件：2 Antiarrhythmics

AntiarrhythmicDrugsLearningplan:ReviewcardiacelectrophysiologyThemechanismofCardiacarrhythmiashappening.AntiarrhythmicdrugsClassificationsprototypedrug---nameThemechanismofaction

Part1.

CardiacElectrophysiology

CardiacElectrophysiologyThepropertieswhicharespeciallyimportantforunderstandingdrugactiononheartare:Impulsegeneration(Automaticity)ConductivityRefractoryperiod(ERP)1.Impulsegeneration

SATwotypesofactionpotential(AP)快反应细胞AP慢反应细胞APPhase0:rapiddepolarizationPhase1,2,3:repolarizationPhase4:diastolicvoltagetimecourse0~3:actionpotentialdurationAPDK+,Cl-

ChannelcurrentsPumpExchangerK+Ca2+Na+Na+Ca2+100msOutside0mVNa+intside-85mV01234FastresponseFastchannelAPL-TypeSlowResponseCells(SAnode,AVnode)Ca2+Ca2+4031SlowchannelAPNonautomaticfibersAutomaticfibers

SA,AVnodesSlowdiastolicdepolarization1.自律性automaticityAutomaticity:Therateofimpulsegenerationdependsonthevalueofmaximaldiastolicpotential,theslopeofphase4depolarizationandthevalueofthresholdpotential.2.ConductionTherateofconductiondependsonmembraneresponsiveness.

Itisassociatedwith1.theVmax(themaximumvelocity/rateofriseofAP)ofdepolarizationofphase0,2.thethresholdpotential,and3.theRP.1)amorepolarizedmembranedepolarizesfasterinatrial,ventricularandPF.2)reducetheslopeof0phase(atthesameRMP),impedeconduction.3.Effectiverefractoryperiod,ERP

ERP:minimumintervalbetweentwopropagating

APs.Thetimebetweenphase0andsufficientrecoveryofsodiumchannelsinphase3.ERP/APDAutonomicinfluencesonparametersofcardiacfunction

Part2.cardiacarrhythmias

AbnormalautomaticityImpairedconductione.gischaemianeurogenicdruginfluences

1.ImpairedconductionReentry2.Enhanced/ectopicpacemakeractivity3.After-depolarizations.EAD/DAD4.Geneimpairandionchanneldysfunction1.Reentry(Mechanism)1.circusmovementitoccursinananatomicallydefinedcircus.extrabeats(prematureimpulse)formationunidirectionalblockofcardiactissueofreentrycircuitingtractoneimpulsereentersandexcitessameareaoftheheartmorethanonetime.Reentry2.Enhanced/ectopicpacemakeractivityTheslopeofphase4depolarizationissteepened.Happeningwhen:mentalstress(tension),drugtoxicity，fever,excitationmyocardialcellsdamagedbyischaemiabecomepartiallydepolarized3.After-depolarizationsEarlyafter-depolarization（EAD）

Occurinphase3,beforerepolarizationiscomplete.EAD-mediatedtriggeringaremostcommonwhenbradycardia,prolongedAPD(certaindrugs).Thesecondarydepolarizationsaccompanyanormal/prematureAPDelayedafter-depolarization(DAD)

Occurinphase4,ResultfromCa2+overload(digitalistoxicity,I/R).AntiarrhythmicDrugs

Basicmechanism:1.Depressesautomaticity

2.ReducetheAfter-depolarizations3.eliminatethereentryAntiarrhythmicDrugsClassification:Basedonthedrug-inducedalterationsofionchannelfunctionandcardiacelectrophysiologicproperties.SubclassIa

blockopenstateNa+channelwithmoderatedelayinchannelrecovery.

Prototype:Quinidine*ProcainamideDisopyramideQuinidineItiscomefromCinchonabark.QuinidineElectrophysiologyeffects:BlockNa+channel(openstate)，

BlockK+channel,ProlongingtheERPandAPDBlockLtypeCa2+channels,(highdose)Depressslopeofphase4+Anticholinergicactionblocktheαrecepter.Pharmacologicactionheart1.DepressesautomaticityinPFsandotherectopicpacemakers(abnormal).Thisisusefulintheprophylaxisofreentrantarrhythmias.(inhibitNa+inward，depressslopeofphase4)

2APDandERPLengthenstheERPandAPD,ERP/APD↑.(depressesK+outwardofphase3,slowrepolarization)0mV-85mV01234ADPERPAntivagalactionaddstothiseffectinatriumandminimizesERPdisparity3.Negativeconductionresponsivenessofmembranedeclines.unidirectionalblock→bidirectionalblockabolishreentrantimpulseinPFs.

Anticholinergicaction:

expeditingconductionofAVnode(blocksNa+channel,depressesNa+inward,reducesdepolarizationrateofphase0,→inhibitsconduction)combinationwithcardiacglycosides(inhibitingconductionofAVnode),treatingatrialfibrillationandflutter.BP

αadrenergicblockingproperty,itdirectlydilatesbloodvessels→fallinBP.Pharmacokineticsorally,Itis80%~90%plasmaproteinbound.t½maybelongerinCHF,hepaticorrenaldiseases,andolderpatientsIncidenceishigh1.Cinchonism(highdose)headache,tinnitus耳鸣,vertigo眩晕,confusedvision,doublevision,psychataxiamentation,delirium谵妄.2.hypotensionandsyncopeblockα-receptor→vasodilation,andinhibitmyocardialcontractionforce.3.Arrhythmias:TorsadesdepointesAdverseeffectsClinicalusesItismainlyusedtomaintainsinusrhythmafterAForAFIhasbeenterminatedbyDCshock,topreventrecurrencesofVT.InteractionsDigoxinEnzymeinducers(phenobarbitone,phenytoin)Digoxinconcentration↑bydecreasingitsrenalandbiliaryclearance.Reducethedurationofactionandsteadystateplasmalevelsofquinidine.ProcainamideItisanalternativedrugtoquinidine,havinglesspotentandlessadverse.SubclassIbblockinactivatedandactivatedNa+channels,enhanceK+outward(shortenAPD),notdepressA-Vconduction.Examples-Lidocaine*PhenytoinMexiletineThepotencyofblockinactivatedNa+channelmorethanthatofopenstate(activatedNa+channel)Lidocaine(Lignocaine)Pharmacologicaction1.depressingautomaticity(therapeuticdose).SuppressingautomaticityinectopicfociandPFs,enhancedphase4depolarization.noinSAnode

PartiallydepolarizedorstretchedPFs,(Na+channelsremaininactivatedforlongerperiod).2.conduction---improvedItmayimproveconductionindepolarizedorstretchedfibersbyincreasingRMPtonearnormalvalues.3.APDandERPInPurkinjefibersandventricularmuscle:ThedrugcanshortenAPDandERP,andERPisreducedtoalesserextent.Thus,ERP/APDratioisincreased.brevityofatrialAP---Na+channelsremaininactivatedforshorterperiod.Inatrialfibers:noeffect(APDandERP)0mV-85mV01234ADPERPPharmacokineticsBecauseofhighfirst-passhepaticmetabolism,i.v.Adverseeffects1.CNS2.Cardiacdepressionandhypotension.Therapeuticuse1.ventriculartachyarrhythmias

CausedbyAMI,open-heartsurgery,digitalistoxicity.phenytoinSimilartothelidocaineItisbettertobeuesedfordigitalistoxicityinducedventriculartachycardia(VT)SubclassIcThemostpotentNa+channelblockers.(openandinactivestate)ExamplesPropafenone普罗帕酮Flecainide*

氟卡尼PropafenoneMarkedlydepressingconductionbyblockingNa+channels.β-adrenoceptorblockingproperties.→Negativeinotropicaction,sinusbradycardiaandbronchospasm.Drugsofthissubclasshavehighproarrhythmicpotential---suddendeathshaveoccurredOrallyabsorbedMetabolism,bioavailability,t1/2differamongindividualsUsesAreservedrugforventriculararrhythmias,reentranttachyarrhythmiasinvolvingtheAVnode/accessorypathway,toMaintainsinusrhythminatrialfibrillationandflutterClassIIAntiadrenergicagents(β-blocker)SuppressAdrenergicallymediatedectopicactivity.

ExamplesPropranolol*Atenolol阿替洛尔Esmolol艾司洛尔Propranololactions:1.Cardiacadrenergicblockade2.Membranestabilizingaction（requirehigherdoses）SuppressionofautomaticityinSAnode,PFandotherectopicfociwhenthishasbeenincreasedunderadrenergicinfluence.

Decreasestheslopeofphase-4depolarization

ProlongingtheERPofA-Vnode,soimpedeA-Vconduction.(anantiadrenergicaction)DepressionofmyocardialcontractilityandBP.ReducethecalciumoverloadUses:

1.Preventsorterminatesarrhythmiasassociatedwithexcesscardiacsympatheticstimulationexerciseoremotioninducedarrhythmias---(inappropriatesinustachycardia,atrialandnodalESs)arrhythmiasseeninpheochromocytoma(adrenalgland)hyperthyroidism甲亢2.VentricularratewerenotadequatelycontrolledbydigitalisaloneinAF/AFI,canusepropranolol.3.β-blockersreducesmortalityinpost-MIpatients—mechanismmaybeantifibrillatoryoranti-ischaemicorboth.AtrialflutterAtrialfibrillationProlongrepolarization(APD)andERPExamplesAmiodarone

胺碘酮

ClassIIIAgentswideningAPAmiodaroneActions:BlockNa+channels,BlockK+channel,BlockCa2+channelsProlongsERPandAPD,

Aniodine-containingConductionisslowedandectopicautomaticityismarkedlydepressed.Noreverseuse-dependencePossessantiadrenergicandCa2+channelsblockingproperties-relaxthevascularsmoothmuscle.Uses:

Widerangeofventricularandsupraventriculararrhythmias.Suppressionventriculartachycardia(VT)andrecurrentventricularfibrillation(VF)MaintainsinusrhythminAtrialFibrillationAmiodarone(Cordarone™)AdverseReactionsToxicpotentialrestrictsuseHypotension,sinusbradycardia,A-Vblock,prolongQ-TintervalCornealmicrodeposits(lipofuscin脂褐素)*altersthyroidfunction*Hypothyroidism:Amiodaroneblockstheperipheralconversionofthyroxine(T4)toitsactivemetabolite,T3.Hyperthyroidism.Common(*)andpotentiallyseriousespeciallywithprolongedtherapy(**)AdverseReactions(continued)pulmonaryalveolitisandfibrosis*;**peripheralneuropathy(*;**)weakofshoulderandpelvic骨盆musclesphotosensitization*Erythema红斑,swellingofareasexposedtolightAmiodarone(Cordarone™)DrugInteractionsIncreasesserumconcentrationsof:DigoxinWarfarinByinhibitmetabolismenzymeinliver.AdditiveA-Vblock+βblocker/calciumcha