《药理学》英文课件 Antiarrhythmic drugs

AntiarrhythmicdrugsOVERVIEWtheheartcontainsspecializedcellsthatexhibitautomaticity,thatis,theycanintrinsicallygeneraterhythmicactionpotentialsintheabsenceofexternalstimuli.INTRODUCTIONTOTHEARRHYTHMIAScardiacarrhythmiasmaycausetheheart(1)tobeattooslowly(sinusbradycardia);(2)tobeattoorapidly(sinusorventriculartachycardia,atrialorventricularprematuredepolarization,atrialflutter);(3)torespondtoimpulsesoriginatingfromsitesotherthantheSAnode;(4)torespondtoimpulsestravelingalongaccessory(extra)pathwaysthatleadtodeviantdepolarizations(A-Vreentry).CausesofarrhythmiasAbnormalautomaticity:TheSAnodeshowsthefastestrateofPhase4depolarizationifcardiacsitesotherthantheSAnodeshowenhancedautomaticity,theymaygeneratecompetingstimuli,EffectofdrugsonautomaticityMostoftheantiarrhythmicagentssuppressautomaticity

(1)bydecreasingtheslopeofPhase4(diastolic)depolarization(2)byraisingthethresholdofdischargetoalessnegativevoltage.AbnormalitiesinimpulseconductionImpulsesfromhigherpacemakercentersarenormallyconducteddownpathwaysthatbifurcatetoactivatetheentireventricularsurface.Aphenomenoncalledreentrycanoccurifaunidirectionalblockcausedbymyocardialinjuryoraprolongedrefractoryperiodresultsinanabnormalconductionpathway.EffectsofdrugsonconductionabnormalitiesAntiarrhythmicagentspreventreentrybyslowingconductionand/orincreasingtherefractoryperiodrequiredtoconvertaunidirectionalblockintoabidirectionalblock.Antiarrhythmicdrugstheantiarrhythmicdrugscanmodifyimpulsegenerationandconduction.CLASSIANTIARRHYTHMICDRUGS

ClassIantiarrhythmicdrugsactbyblockingvoltage-sensitivesodiumchannelsClassIantiarrhythmicdrugsthereforegenerallycauseadecreaseinexcitabilityandconductionvelocity.Use-dependenceClassIdrugsbindmorerapidlytoopenorinactivatedsodiumchannelsthantochannelsthatarefullyrepolarizedfollowingrecoveryfromthepreviousdepolarizationcycle.Therefore,thesedrugsshowagreaterdegreeofblockadeintissuesthatarefrequentlydepolarizing.Thispropertyiscalleduse-dependenceQuinidine

QuinidineistheprototypeClassIAdrug.Athighdoses,itcanactuallyprecipitatearrhythmias,whichcanleadtofatalventricularfibrillation.MechanismofactionQuinidinebindstoopenandinactivatedsodiumchannelsandpreventssodiuminflux,thusslowingtherapidupstrokeduringPhase0.ItalsodecreasestheslopeofPhase4spontaneousdepolarization.ActionsQuinidineinhibitsectopicarrhythmiasandventriculararrhythmiascausedbyincreasednormalautomaticity.QuinidinealsopreventsreentryarrhythmiasTherapeuticusesinthetreatmentofawidevarietyofarrhythmias,includingatrial,AVjunctional,andventriculartachyarrhythmias.Quinidineisusedtomaintainsinusrhythmafterdirectcurrentcardioversionofatrialflutterorfibrillationandtopreventfrequentventriculartachycardia.AdverseeffectsApotentialadverseeffectofquinidineisexacerbationofthearrhythmia.QuinidinemaycauseSAandAVblockorasystole.Attoxiclevels,thedrugmayinduceventriculartachycardia.Cardiotoxiceffectsareexacerbatedbyhyperkalemia.Procainamide

1.Actions:ThisClassIAdrug,aderivativeofthelocalanestheticprocaineshowsactionssimilartothoseofPharmacokineticsProcainamideisabsorbedfollowingoraladministration.Procainamidehasarelativelyshorthalf-lifeof2-3hours.AportionofthedrugisacetylatedinthelivertoN-acetylprocainamide(NAPA),whichhaslittleeffectonthemaximumpolarizationofPurkinjefibersbutprolongsthedurationoftheactionpotential.NAPAiseliminatedviathekidneyAdverseeffectsprocainamidecausesahighincidenceofsideeffects,includingareversiblelupuserythematosus-likesyndromethatdevelopsin25to30%ofpatients.Toxicconcentrationsofprocainamidemaycauseasystoleorinductionofventriculararrhythmias.Centralnervioussystem(CNS)sideeffectsincludedepression,hallucinationandpsychosis.Lidocaine

LidocaineisaClassIBdrug.TheIBagentsrapidlyassociateanddissociatefromsodiumchannels.ClassIBdrugsareparticularlyusefulintreatingventriculararrhythmias.Lidocaineisthedrugofchoiceforemergencytreatmentofcardiacarrhythmias.ActionsLidocaine,shortensphase3repolarizationanddecreasesthedurationoftheactionpotentiallidocainesuppressesarrhythmiascausedbyabnormalautomaticity.abolishesventricularreentry.PharmacokineticsLidocaineisgivenintravenouslybecauseofextensivefirst-passtransformationbytheliverAdverseeffectsLidocainehasafairlywidetoxic-to-therapeuticratio;itshowslittleimpairmentofleftventricularfunction,TheCNSeffectsincludedrowsiness,slurredspeech,confusion,andconvulsions;cardiacarrhythmiasmayalsooccur.CLASSIIANTIARRHYTHMICDRUGS

TheClassIIagentsincludethebeta-adrenergicantagonists.ThesedrugsdiminishPhase4depolarization,thusdepressingautomaticity,prolongingAVconduction,anddecreasingheartrateandcontractility.ClassIIagentsareusefulintreatingtachyarrhythmiascausedbyincreasedsympatheticactivity.PropranololreducestheincidenceofsuddenarrhythmicdeathaftermyocardialinfarctionThemortalityrateinthefirstyearafteraheartattackissignificantlyreducedbypropranolol,partlybecauseofitsabilitytopreventventriculararrhythmias.CLASSIIIANTIARRHYTHMICDRUGSClassIIIagentsblockpotassiumchannelsandthusdiminishtheoutwardpotassiumcurrentduringrepolarizationofcardiaccells.prolongthedurationoftheactionpotentialwithoutalteringPhase0ofdepolarizationortherestingmembranepotential.Instead,theyprolongtheeffectiverefractoryperiod.CLASSIVANTIARRHYTHMICDRUGSarecalciumchannelblockers.Theydecreasetheinwardcurrentcarriedbycalcium,resultinginadecreaseintherateofPhase4spontaneousdepolarizationandslowedconductionintissuesdependentoncalciumcurrents,suchastheAVnodeVerapamilanddiltiazem

Verapamilshowsgreateractionontheheartthanonvascularsmoothmuscle,whereasnifedipine,acalciumchannel-blockerusedtotreathypertensionexertsastrongereffectonvascularsmoothmusclethanontheheart.Diltiazemisintermediateinitsactions.Actionsverapamilanddiltiazem,aremoreeffectiveagainstthevoltage-sensitivechannels,causingadecreaseintheslowinwardcurrentthattriggerscardiaccontractionVerapamflanddiltiazembindonlytoopen,depolarizedchannels,thuspreventingrepolarizationuntilthedrugdissociatesfromthechannel.Thesedrugsar