藥理學(xué)教學(xué)課件：Chapter 11 ANTIARRHYTHMIC DRUGS

1CHAPTER11

ANTIARRHYTHMICDRUGS2

Arrhythmia:--heartdysfunctionscauseabnormalitiesinimpulseformationandconductioninthemyocardium.--cardiacdepolarizationdeviatefromthe

sinusrhythm.--abnormalities:thesiteoforiginofimpulse,itsrateorregularity,oritsconduction.

suchassinusbradycardia;sinustachycardia,ventriculartachycardia.3Normalelectrocardiogram45Arrhythmia6Typesofarrhythmia

Atrialarrhythmia:atrialprematurecontractionatrialtachycardia,ATatrialfibrillation,AFatrialflutter,AFL

Supraventriculartachycardia:paroxysmalsupraventriculartachycardiaTachyarr-hythmiasinusbradycardiaatrio-ventricularblockBradyarr-hythmia

Ventriculararrhythmia:ventricularprematurecontractionventriculartachycardia,VTventricularfibrillation,VFTachyarr-hythmia8TherapyofarrhythmiaIsoprenaline,AtropineBradyarrhythmia:Tachyarrhythmia:Antiarrhythmicdrugs—preventreentry（折返）byslowingconductionand/orincreasingtherefractoryperiodrequiredconvertingaunidirectionalblockintoabidirectionalblock.9

ThePhysiologicalBasisofArrhythmiaTheelectrophysiologyofnormalcardiacrhythmSection110RestpotentialofcardiacmusclecellRestpotentialphenomenonMechanismofrestpotentialActionpotentialofcardiacmusclecellActionpotentialphenomenonMechanismofactionpotentialBioelectricityofcardiacmusclecell11Restpotential:thedifferenceofpotentialbetweeninsideandoutsideofcellmembrane.polarizationrestInside:NegativechargeOutside:Positivecharge12＋＋＋＋＋＋＋＋＋＋＋＋＋＋＋＋＋＋＋－－－－－－－－－－－－－－－outsideinside13MechanismofrestpotentialDistributionandtransportationofion:Outside:[Na+]high,[Cl-]highInside:[K+]

high,[A-]highPermeability:K+>Na+,Cl->A-Outside:positiveInside:negative14A-A-A-A-A-A-A-A-A-A-A-K+K+K+K+K+K+K+K+K+K+K+K+Na+Na+Na+Na+Na+Na+Na+Na+Na+Na+Na+Na+Cl-Cl-Cl-Cl-Cl-Cl-Cl-Cl-Cl-Cl-Cl-Cl-Cl-Cl-Cl-Cl-Cl-K+K+K+K+A-A-A-Na+Na+Cl-A-K+outsideinside15Actionpotential=depolarization+repolarization—fastandreversibleinversionofpotentialbasedontherestpotentialImpulseActionpotentialdepolarizationinsideoutside

+insideoutside+

repolarizationTransient,recover160,4:depolarization;1,2,3:repolarization.17MechanismofactionpotentialDepolarizationimpulse,Na+channelactivationNa+permeability↑Na+influxNegativevoltagechangetopositive18RepolarizationOverdepolarizationNa+channelinactiveNa+permeability↓

K+channelopenK+effluxpositivevoltageNegativeRestpotentiallevelThen,K+permeabilitynormal,Na+channelrecover,receivenewimpulse190:fastdepolarization,Na+fastinflux;1:fastrepolarizationfirstphase,K+transientfastefflux;2:plateauphase,K+efflux;Na+,Ca2+influx;3:fastrepolarizationendphase,K+efflux;4:slowdepolarization,specialNa+influx.1023420ElectrophysiologycharacteristicsofcardiacmusclecellClassofcardiocytesExcitabilityandconductibilityAuto-rhythmicity/AutomaticityMembranereactivityActionpotentialduration(APD)andeffectiverefractoryperiod(ERP)21ClassofcardiacmusclecellsNonautorhythmiccells:excitability,conductibility,contractilityAutorhythmiccells:excitability,conductibility,autorhythmicityConductibility:excitationextendtoalloveronecell,alsotoanothercell,toinducethewholeheartexciteExcitabilityandconductibilityExcitability:theabilitytoproduceactionpotentialafterimpulseRestpotentialabsolutevalue↓Thresholdpotential↓Excitability↑Therateof0phase(depolarization)ConductibilityAutomaticityNoimpulse,automaticrhythmandrhythmicexcitationoccursinsometissuecellsRelatedtotherateof4phase(slowautomaticdepolarization)(slopedegree)AutomaticityOrigin:autorhythmiccellssinuatrialnodewiththehighestautomaticity,excitedfirstlySinusrhythm2425Membranereactivity—Theimportantfactortodecidetheconductionspeed—relationshipbetweenthemaxspeedof0phaseascendingandthelevelofmembranepotential—membranepotential↑(morenegative)Maxascendingspeedof0phase↑

conductingspeed↑2627Actionpotentialduration(APD)andEffectiverefractoryperiod(ERP)APD:phase0phase3ERP:repolarizationto-60mV~-50mV,re-exciteperiod(depolarizationtorepolarizationto-60mV~-50mV)

ERPprolong,tachyarrhythmia↓28292.Theelectrophysiologicalmechanismofarrhythmias(1)

Disturbanceinimpulseformation:

automaticity↑Reason:phase4automaticdepolarizationspeed↑thresholdpotential↓themaxdiastolicpotential↑30(2)

Afterdepolarizationandtriggeredactivity

Afterdepolarization:anotherdepolarizationafter0phase(frequencyfast,amplitudelow),withunstablepotential,easytoinduceabnormalimpulse,thisiscalledtriggeredactivity.

ADEarlyafterdepolarization(EAD)phase2~phase3,Ca2+influx↑Delayedafterdepolarization(DAD)phase4,Na+influx↑32Figure.A.EADandtriggeredactivityB.DADandtriggeredactivity33(3)Disturbanceinimpulseconduction1)Simpleconductiondisturbance:--conduction↓--conductionblockunidirectionalconductionblock2)Reentry(circusmovement)orreentrantexcitation折返激動(dòng)34Figure.Representationofreentry35AntiarrhythmicDrugs:

--Thebasicelectrophysiology

--ClassificationofdrugsSection2

1.Thebasicelectrophysiology1)↓automaticity(autorhythmicity)a.↓slopeofphase4depolarization:↓Na+inorCa2+inb.↑Thresholdpotentialc.↑maximumdiastolicpotential:↑K+outD.↑APD↓K+out37↓slopeof4phase38↑thresholdpotential39↑maxdiastolicpotential40↑APD41

2)↓EADorDAD:

Acceleraterepolarization,BlockNa+in

orCa2+in

3)Avoidreentry:

a.↑c(diǎn)onduction:↓unidirectionalblockb.↓conduction:unidirectionalblock→bidirectionalblockc.↑ERPandAPD,quinidine↓ERPandAPD,Lidocaine422.Classificationofdrugs

ClassⅠSodiumchannel-blocking

agents:IA,IB,ICClassⅡβ-RblockersClassⅢProlongingAPDagentsClassⅣCalciumchannelblockers

43Section3

SpecificAntiarrhythmicAgents

44Table.Actionsofantiarrhythmiadrugs451.ClassⅠSodiumchannel-blockingagentsclass drugNa+ECG

IAquinidineprocainamide++prolongQT IB lidocainemexiletine+noIC propafenoneencainide+++ QRSwiden46

1)ClassⅠA

a.InhibitNa+influxmoderately:↓0phaseVmax,↓conduction(unidirectiontobidirection)↓phase4slope,↓automaticityb.↓K+efflux,prolongERPandAPD

(membranestableaction)

47GroupIAdrugsslowphase0depolarization,prolongactionpotentialandslowconduction.Quinidineblocksodiumchannels.4849Quinidine(奎尼丁)

PharmacologicalEffects:CardiacEffects:

↓autorhythmicity;↓conduction;↑ERP↓myocardialcontractilityExtracardiacEffects:α-adrenergicblockinganticholinergiceffect50PharmacokineticsAbsorption:Rapidlyandalmostcompletelyabsorbedafteroraladministration.Distribution:cardiacmuscleconcentrationis10timeshigherthanplasma’s.Metabolism:Metabolites(hydroxide)stillhasaction.Excretion:kidney,urineacidificationtoimproveexcretion.quinidine51

Broad-spectrum,awidevarietyofarrhythmiaAtrialfibrillation;Atrialflutter;Supraventricularandventriculartachycardia;Supraventricularandventricularprematurecontract

Calciumantagonists,suchasverapamil,areincreasingreplacingquinidineinclinicaluse.quinidineTherapeuticUses52Toxicity:GI:nausea,vomit,etcCVS:Heartfailure(contractility)hypotension(-Rblock)sinusbradycardia

Cinchonism(金雞納反應(yīng)）:blurredvision,tinnitus,disorientationandpsychosisquinidine53procainamide↓autorhythmicity(↓4phaseslope);↓conduction(↓0phaseVmax);↑ERP(↓K+efflux)↓contractility,-RblockandanticholinegiceffectsweaklySupraventricularandventriculararrhythmia,replacequinidine;ventriculartachycardia,noeffectbylidocaine54Disopyramide(丙吡胺)↑ERP,↓contractility>quinidineSupraventricularandventricularprematurecontraction;Paroxysmalsupraventriculartachycardia;Atrialfibrillation,Atrialflutter;ventriculartachycardia,noeffectbylidocaine552)ClassIB

↓Na+influxlightly↑K+efflux,shortentheAPD>ERP，

ERP/APD

↑56Lidocaineandmexiletineblockopenorinactivatedsodiumchannelswhichhasarapidrateofassociationwithsodiumchannels.ClassIBshortenphase3repolarizationanddecreaseAPD.57LidocaineActonPurkinjefibersandventricularcellsa.↓autorhythmicity

↓theslopeofphase4,↑thethresholdforexcitability.Pharmacologicaleffects:58b.

Alteringtheconduction--Myocardialischemia→↓conduction(↓Na+influx)，unidirectionalblock→bidirectionalblock--K+↓→↑K+efflux→↑c(diǎn)onduction→↓unidirectionalblockc.

RelativeincreaseERP(↓2phaseNa+influx)ShortenAPDERP/APD↑Lidocaine59RelativeincreaseERP60

first-passeffect,iv，cardiacmusclewithhighconcentrationat3timesthanplasma;metabolisminliver;excretionbykidney;Pharmacokinetics:LidocaineVentriculararrhythmias,VP(ventricularprematurecontract),VT,VF---thepreferreddrugsforVentriculararrhythmiainducedbyinfarction;---VentricularandSupraventricularArrhythmiainducedbycardiacglycosidesTherapeuticuse:61Mexiletine（美西律）oraladministrationalsohaseffectwhenlidocainehasnoeffect;

VentriculararrhythmiaespeciallyforVentriculararrhythmiainducedbyacuteinfarctionandcardiacglycosides.---Hasthesameactionwithlidocaine62Phenytoinsodium(苯妥英鈉)

IthasbeenusedintheacuteandchronicVentriculararrhythmias,especiallyindigitalisintoxication.---thesameactionanduseswithlidocaine---antiepileptics633)ClassICPropafenone(普羅帕酮)Encainide(恩卡尼)Lorcainide(勞卡尼)Flecainide(氟卡尼)64SeverelyinhibitNa+influx,markedly↓Vmax,↓conduction.↓phase4slope,↓automaticitySeriousadversereactionsareprovocationofpotentiallylethalarrhythmias.

Action:IC65Flecainideandpropafenoneblockopenorinactivatedsodiumchannelswhichhasaslowrateofassociationwithsodiumchannels.GroupICdrugsmarkedlyslowphase0depolarization.66Propafenone

（普羅帕酮）BlockNa+,andCa2+channel(weak),alsoblockβ-R--↓conduction(↓Vmaxof0phase),inallcardiactissues;--↓automaticity(↓slopeof4phaseand↑thresholdpotential);--↑ERPandAPD(moderate)67UsedtotreatSupraventricularandventriculartachycardia;Supraventricularandventricularprematurebeat;Atrialfibrillation.ClinicalusePropafenone68AdverseeffectsDizziness,blurredvision,headache,nausea;Aggravatepreexistingarrhythmias;Hypotension,AtrialVentricularblock,Heartfailure;Inducelife-threateningventriculartachycardiathatisresistanttotreatment.Propafenone69ClassⅡβ-RBlockers

1)β-Rblockingaction2)Membrane-stabilizingeffect(↓Na+in)Propranolol(普奈洛爾)Metoprolol（美托洛爾）Atenolol（阿替洛爾）70Pharmacologicaleffectsa.↓autorhythmicity，↓afterdepolarizationbyCA,preventtriggeredactivity.b.↓conductionofAVnodeandP-f(>100ng/ml)c.↑ERPofAVnode,↓reentryd.Improvemyocardialischemia

↓0phaseNa+in71

Therapeuticuses

Supraventriculararrhythmias,especiallyfortachycardiainducedbysympatheticnerveexcitationandCA↑.

Acutemyocardialinfarction(AMI)

Maycombinewithdigitoxins,quinidine.Propranolol72potassiumchannelblocker

BlockingK+channel,↓K+efflux,↑repolarization,↑APDandERPClassⅢProlongingAPDagents73Amiodarone，dofetilideandsotalolblockpotassiumchannels.ClassⅢdrugsprolongphase3repolarization，withoutalteringphase0.74Amiodarone

（胺碘酮）Pharmacologicaleffects:

delayedrepolarization↓ionschannel:K+,Na+,Ca2+Blockingα,βreceptor751)↓autorhythmicity(sinoatrialnode,↓Na+,Ca2+,Blockingβ-R)2)↓conductionofAVnodeandPurkinjefibers

→↓reentry(↓Na+,Ca2+)

3)↑APDandERP(↓K+)4)Dilatationcoronaryartery,↓myocardialoxygenconsumption

Amiodarone76

Pharmacokinetics:

F:40-50%,longt1/240d,last4~6wTherapeuticuses:Broad-spectrumantiarrhythmicdrug:SevererefractorySupraventricularandVentriculartachyarrhythmia.Usefulnessislimitedbyitstoxicity.Amiodarone77CVSreactions:SinusbradycardiaAtrio-ventricularblockPulmonaryfibrosisHypo-orhyperthyroidismBuffydrugspilldepositatcornea(I)Adverseeffects:Amiodarone78ClassⅣCalciumchannel

blockingagents

BlocktheL-Ca2+channelofcardiacmuscle,↓sinusandAVnode.VerapamilDiltiazem79VerapamilBlockopenorinactivatedcalciumchannels;Slowphase4spontaneousdepolarization;Slowconductionintissuesdependentoncalciumcurrents,suchasSA,AVnodesEffects80Verapamilanddiltiazemblockopenorinactivatedcalsiumchannels.ClassⅣdrugsslowphase4spontaneousdepolarizationandslowconductionintissuesdependentoncalciumcurrents—AVnode.81AntiarrhythmiaEffects1)↓autorhythmicity(SAnodeandAVnode)blockCa2+incardiacmusclecell2)↓conductionofAVnode↓Ca2+,↓Vmax,↓reentry3)↑