Intro To Antiarrhythmics

2/17/2016
intro_to_antiarrhythmics[TUSOM|Pharmwiki]
IntroductiontoAntiarrhythmicPharmacology(JiTTReading)
Prerequisite
reading:
The
wiki
module
on
Cardiac
Arrhythmias
[http://tmedweb.tulane.edu/pharmwiki/doku.php/cellular_basis_for_arrhythmias].
LearningObjectives
Bytheendoftheselfstudyyoushouldbeableto:
1.Listthethreeprimaryindicationsfortreatmentofcardiacarrhythmias.
2.ListtheprimarychannelorreceptormechanismsbywhichClassI,II,IIIandIVantiarrhythmicdrugsproduce
theireffects
3.Recognizeandcategorizedifferentantiarrhythmicdrugsbytheirmechanismofaction
4.CompareandcontrastthedifferentmechanismsbywhichClassI&ClassIIIdrugsincreasethecardiacERP
5.ExplainhowClassI&ClassIIIdrugscanacutelyabolishareentrantarrhythmia
6.Explainwhatantiarrhythmicdrugclassiscontraindicatedinthechronictreatmentofpatientswithahistoryof
myocardialischemia
7.DescribewhichdrugclassreducestheincidenceofsuddendeathandreinfarctionafteranMI
8.ListtheprimarydrugsusedforacuteandchronictreatmentofAVnodereentry
9.ExplainhowClassIadrugscanproduceadangerousincreaseinventricularratewhenusedalonetotreatatrial
tachyarrhythmias.
10.Citemajorsideeffectsofmajorantiarrhythmicdrugsthatlimittheirclinicalusefulness
11.Explainthemultiplemechanismsbywhichamiodaronemayexertitsantiarrhythmiceffectsagainstatrialand
ventriculararrhythmias.
12.Describe two fundamentally different therapeutic goals of treatment that can be attempted to treat patients
withatrialfibrillation.
Drugs:
ClassI:lidocaine,procainamide,(quinidine:rarelyused)
ClassII:propranolol,metoprolol
ClassIII:amiodarone,dronedarone,sotalol,ibutilide
ClassIV:verapamil,diltiazem
Misc:adenosine
Abbreviations:
AFibAtrialFibrillation
APDActionPotentialDuration
DADDelayedAfterDepolarization
EADEarlyAfterDepolarization
ERPEffectiveRefractoryPeriod
Ih(orIf)thehyperpolarizationactivated(Na&Kselective)pacemakercurrent
IKrtherapidcomponentofthedelayedrectifierKcurrent(HERGgeneproduct)
NSRNormalSinusRhythm
PSVTParoxysmalSupraventricularTachycardia
VFibVentricularFibrillation
VTachorVTVentricularTachycardia
ThreePrimaryIndicationsforTreatmentofCardiacArrhythmias
Cardiacarrhythmiasareafrequentprobleminclinicalpractice.Notallarrhythmiasrequiretreatmentwithpotentially
toxicantiarrhythmicdrugs.Arrhythmiasthattypicallyrequiretreatmentfallinto3basiccategories:
http://tmedweb.tulane.edu/pharmwiki/doku.php/intro_to_antiarrhythmics
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arrhythmiasthatdecreasecardiacoutput(e.g.severebradycardia,ventriculartachycardiaorfibrillation)
arrhythmiasthatarelikelytoprecipitatemoreseriousarrhythmias(e.g.atrialfluttermayleadtosustained
ventriculartachycardia)
arrhythmiasthatarelikelytoprecipitateanembolismduetocreationofvascularstasis(e.g.chronicatrial
fibrillation)
OtherTherapeuticModalitiesforTreatmentofArrhythmias
Whiledrugtherapyisstillthemostcommonmethodfortreatingarrhythmias,othernonpharmacologicaltherapiesare
alsoincurrentuse.Whiledetaileddiscussionofthesetreatmentsisbeyondthescopeofthiscourse,theyinclude:
DC cardioversion (wikipedia [http://en.wikipedia.org/wiki/Cardioversion]), implanting of a pacemaker, or
defibrillatordevice(ICD)
Carotidsinusmassage(vagaltone)
Surgicalorcathetermediatedablationofanectopicfocus,coronarybypasssurgery
Lifestylemodification(avoidingeventsthataggravateanarrhythmiae.g.exertion,emotionalstress,nonideal
diet)
Commonly used procedure in Emergency Departments for patients with Paroxysmal SupraVentricular Tachycardia
(PSVT).Relativelysafe,butshouldbeavoidedinpatientswithcarotidarterydiseaserarelyusedalternativesinclude
theValsalvamaneuver,eyepressure(notrealpopular),placingthefaceincoldwater,orgivingapressoragent.
TheMostCommonlyUsedAntiarrhythmicDrugs
TABLE1:MajorDrugCategories
DrugClass
CellularMechanismofAction
PrototypeDrugs
Ia
NachannelblockersthatAPD
Quinidine,Procainamide,Disopyramide
Ib
NachannelblockersthatslightlyAPD
Lidocaine,Mexiletine,Phenytoin
Ic
Nachannelblockersthatdon'tchangeAPD Propafenone,Flecainide
II
blockers
Propranolol,Atenolol,Esmolol,Metoprolol
III
ProlongAPD(KChannelBlockers)
Amiodarone,Dronedarone,Sotalol,Ibutilide,Bretylium
IV
LtypeCachannelblockers
Verapamil,Diltiazem
Miscellaneous adenosinereceptoragonist
Adenosine
Miscellaneous vagaltone
Digoxin
AmiodaronehasClassIthruClassIVeffects,butClassIIIeffectsseemtobemostprominent.
WhyAreThereDifferentClassesofAntiarrhythmicDrugs?
Each class of antiarrhythmic drugs has different selective affinities for different cardiac ion channels and/or
adrenergicreceptors.
ClassIdrugs:blockcardiacNachannels(somedrugsalsoblockKchannelsseebelow).
ClassIIdrugs:blockbetaadrenergicreceptors.
Class III drugs: block cardiac K channels (in particular the K channel that produces the rapidly activating K
currentIKr).
ClassIVdrugs:blockLtypeCachannels.
Notethatthedrugsineachclassareonlyselectiveforblockingeachionchannelorreceptorsubtype,andfrequently
affectmorethanonechannelorreceptor.Inparticular,thereisheterogeneitywithintheClassIdrugswithregardsto
their selectivity of effect on blocking Na channels vs K channels. These differences resulted in their grouping by
VaughnWilliamsintoClass1a,1b&1csubclassesbasedupontheirinvitroeffectsontheventricularactionpotential
upstroke velocity (dV/dtmax) and action potential duration (APD) observed under normal physiological conditions.
TheseinvitroeffectsresultincorrespondingeffectsontheQRSandQTdurationsinvivo:
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Figure1. The effect of the subtypes of Class I drugs on the cardiac action potential & ECG intervals in the normal
heart in sinus rhythm. Drug effects on the action potential upstroke and conduction parameters in ischemic tissue,
and/orathighheartratesistypicallymoresignificant.
TABLE2:Class1Subclasses
Subclass QRS QT
Currents
Explanation
blocked
Ia
Na&Kr
Ib
Na
Ic
Na
LargeblockofbothopenNa&KChannelsatnormalheartrates,hencebothQRS&QTaffected
Highaffinityforopen&inactivatedNachannelswithrapidunbindingduringdiastole,hencelittlecumulative
effectonQRSinNSRalsoblocksthesmallNaplateaucurrentwhichshortenstheAPD
LargeblockofopenNachannels&veryslowunbindingduringdiastole,QRSmarkedlyprolongedduringNSR
ClassIadrugsarethosewhichprolongboththeQRSandQTofthenormalheart.ThesedrugsprolongtheQTand
cellular APD because they block the rapid potassium current (IKr) at therapeutic concentrations. In addition these
drugs also block cardiac Na channels in the open state, and then dissociate slowly & incompletely during diastolic
intervalsinbetweenbeats.Henceblockaccumulateswitheachsuccessivebeat,resultinginenoughNachannelblock
atnormalsinusratestosignificantlywidentheQRS.
ClassIbdrugsarethosewhichhavelittle effect on the QRS of normal heart hearts at normal heart rates, and
slightly shorten the QT. These drugs interact with sodium channels in both the open and inactivated state, but
becausethetimethatNachannelsspendintheopenstateissobrief(~1msec)undernormalconditions,andbecause
Nachannelsremaininactivatedforseveralhundredmillisecondsduringeachactionpotential,thecontributionofdrug
interactionwithinactivatedchannelsismuchgreaterthanwithopenchannels(Matsubaraetal,1987Clarksonetal.,
1988). Because most drug binding occurs after the upstroke, when Na channels are inactivated, and these drugs
rapidly unbind at normal diastolic potentials, there is little residual Na channel block by the time of the next action
potential at normal heart rates (see below). (However, block can accumulate at very high heart rates, when the
diastolicintervalisshort,orwhenthediastolicmembranepotentialbecomessignificantlydepolarized,asthisslowsthe
rateofdrugdissociationfromNachannels)(Hume&Grant,2012).Inaddition,becausemostoftheinteractionofclass
Ibdrugsoccursduringtheplateau,theyhaveverylittleeffectontissuewithshortactionpotentialdurations,suchas
atrial tissue. In addition, atrial tissue is unlikely to become ischemic (due to differences in wall thickness & vessel
physiology). As a result, Class Ib drugs are ineffective in treating atrial tachyarrhythmias at nontoxic
concentration.TheslightreductionoftheQTbyClassIbdrugsresultsfromtheireffecttoblockthesmallresidual
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plateau Na current (resulting from a small number of Na channels that do not fully inactivate during the action
potentialplateau).Reductionofthisinwardcurrent,whilenotaffectingoutwardKcurrentsresultsinashorteningof
theventricularactionpotentialduration.
The Effect of Class Ib Effects on APD or QT is not Therapeutically
Relevant
Manytexts(e.g.FirstAid)unintentionallyoveremphasizetheeffect
ofClassIbdrugstoshortentheAPD.Thiseffectissmallandofno
clear clinical significance (other than it represents a drug effect on
the action potential). Of clear importance is the effect of all Class I
drugs (1a, 1b & 1c) to increase the ERP of cardiac tissue in
depolarized&ischemictissuetheregionthatispronetoproducing
reentrantexcitation.TheClassIeffectontheERPinischemictissue
is much larger than in normal tissue, and is an effect considered
antiarrhythmic(asdiscussedbelow).
Class Ic drugs are those which have a very large effect to prolong the QRS of normal hearts at normal heart
rates,withlittleeffectontheQT.ThesedrugsareverypotentblockersofopenNachannelsanddissociateveryslowly
andincompletelyfromNachannelsinbetweenheartbeats(e.g.havingdissociationtimeconstantsofmanyseconds).
FurtherCommentsonDrugSelectivity
With regards to selectivity, some Class IV drugs (e.g. verapamil) also block cardiac Na channels to some
extent at therapeutic doses, and some Class Ia drugs (e.g. quinidine) also block some Ltype Ca channels at
therapeuticlevels.Inaddition,ClassIadrugshaveantimuscarinic(orvagolytic)actions as well. These drugs
are not magic bullets for each target, due in part to sequence homologies between the multiple ion channels
involved.
HowDoClassIDrugsExertTheirAntiarrhythmicEffects?
A.SelectiveDepressionofEctopicPacemakerAutomaticity
One mechanism by which Class I drugs can suppress arrhythmias is by selective depression of ectopic pacemaker
automaticity(Figure2).Thereareatleast3waysthatClassIdrugscanproducethiseffect:
ManyClassIdrugsblocktheI hpacemakercurrentexpressedinPurkinjefibers.Henceectopicpacemakers
that utilize Ih for spontaneous diastolic depolarization (Figure 2) will be suppressed in the presence of such
drugs.Thiseffectcanberelativelyselectiveforectopicpacemakersbecausemultiplecurrents(includingtheL
typeCacurrent)areresponsibleforregulatingtheautomaticityintheSAnode.
PartialblockofNachannelscanshift the threshold for producing an action potential to shift to more
positivevoltagelevels,whichprolongstheperiodofdiastolicdepolarizationinbetweenspontaneousbeats.
ClassIadrugsincreasetheactionpotentialdurationbyblockingIKr,whichcanalsocontributemodestlyto
slowingofthespontaneousfiringrateofectopicfoci.
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Figure 2. Three mechanisms by which antiarrhythmic drugs can affect automaticity. In the absence of drug the
ectopicpacemakerutilizedIhtospontaneouslydepolarizetothreshold,morerapidlythanthenormalsinuspacemaker.
Class I antiarrhythmic drugs can decrease the automaticity of an ectopic pacemaker by either 1) blocking the Ih
pacemaker current (thereby decreasing the slope of diastolic depolarization), 2) shifting the threshold for action
potential generation to a more positive potential (increasing threshold) by blocking excitable Na channels, and/or 3)
increasing APD (by blocking IKr). In this hypothetical example, ischemic damage to sympathetic nerves results in a
denervationsupersensitivitythatincreasestheexpressionofbetareceptors,andreducesthedensityofpresynaptic
neuronalNET(norepinephrinereuptaketransporters),whichmakesthezoneoverreacttocirculatingcatecholamines
duringfightorflightsituations.Thiscreatesatleastatransientectopicfoci.
Treatment of Arrhythmias Induced by Abnormal Forms of
Automaticity
ArrhythmiasbelievedtobeduetoEarlyAfterdepolarizations(EAD's)
(e.g. patients with druginduced long QT syndrome or Torsade de
Pointes)aretypicallytreatedbycorrectingimbalancesinK+orMg2+
levels,withdrawalofthedrugsuspectedofcausingthecondition,or
increasing the heart rate by isoproterenol infusion or ventricular
overdrivepacing.ArrhythmiasinducedbyDAD's(e.g.patientswith
digitalis overdose or intracellular Ca overload) may be treated by
correction of electrolyte (K or Ca) levels, blocking the effects of
catecholamines,reductionsinheartrate,loweringofplasmadigoxin
levels, or administration of lidocaine or phenytoin to decrease Na
influx.
B.IncreasingtheERP(byStateDependentBindingtoNaChannels)
Class I antiarrhythmic drugs and related local anesthetic drugs bind to a receptor site within the cardiac sodium
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channel.SinceNachannelsconstantlyfluctuatebetween3differentstates(Rested,OpenandInactivated)duringeach
cardiaccycle,theconformationoftheNachannelanditsdrugreceptorbothundergostatedependentconformational
changeswitheachheartbeat.Becauseofthis,drugaffinityfortheNachannel&itsbindingsitewithinthechannelis
statedependent the affinity of drug for its Na channel receptor is different for each channel state. Class I drugs
haveaverylowaffinityforrestedchannels,butahighaffinityforchannelsineitheropenorinactivatedstates.
Figure 3. The Modulated Receptor Hypothesis. Drugs (D) can bind to Na channels in their three primary states
(R:RestedO:OpenandI:Inactivated).Clinicallyusefuldrugshavealowaffinityforrestedchannels(asindicatedby
thearrows),andahighaffinityforNachannelswhentheyareineithertheopenand/orinactivatedstate.Asaresult,
drugbindingoccursduringanactionpotentialwhenhighaffinitystatesareoccupied,anddrugdissociationoccursat
diastolicpotentialswhenthelowaffinityrestedstateisoccupied.Therateatwhichdrugdissociationoccursisvoltage
dependentbecausethekineticsofchannelgatingfordrugassociatedchannelsisvoltagedependent,similartodrug
free channels, although the gating kinetics are much slower for drugassociated channels (Hondeghem & Katzung,
1977Hume&Grant,2012).
The fraction of drugoccluded channels increases during each action potential upstroke and plateau phase (when
channelstemporarilyexistinhighaffinityopenandinactivatedstates).Duringdiastole,thefractionofdrugoccluded
channels decreases timedependently as channels return to the lowaffinity rested state. As a result, at therapeutic
druglevelsthereisacyclicalpatternofdrugbindingandunbindingthattakesplaceduringeachbeatoftheheart(see
Figure4)(Hondeghem&Katzung,1977Hume&Grant,2012).
Each drug has its own unique characteristics in terms of its affinity for different channel states, and its kinetics of
bindingandunbindingtoeachstate.Forexample,recoveryfromchannelblockatanormaldiastolicrestingpotential
occurswithatimeconstantofafewhundredmillisecondsformostClassIbdrugs(e.g.lidocaine),whereasthetime
constantsforunblockingbyIadrugs(e.g.7secondsforquindine)andClassIcdrugs(e.g.20secondsforflecainide)are
muchlonger.ThistendstogiveeachNachannelblockersomewhatuniquepropertiesatthecellularlevel.
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Figure4.ModulatedReceptorHypothesisbasedcomputersimulationoftimedependentchangesinNachannelstates
andlidocaineblockofNachannelsassociatedwiththecardiacactionpotential.LidocainebindstoNachannelsinopen
(O) and inactivated (I) states but has very low affinity for channels in the rested (R) state. As indicated (middle),
channels are in a rested state during diastole, open transiently during the upstroke, and are in an inactivated state
duringtheplateau.Asshownatthebottom,allchannelsareinadrugfreestateafteralongrest,butlidocainebinding
toopenandinactivatedchannelsdevelopsrapidlyduringtheactionpotential.Theextentofrapidopenchannelblockis
clippedduetotheopenstatebeingrelativelyshortlived(~1msec).Drugchannelinteractioncontinuestoprogress
during the plateau as lidocaine binds to inactivated channels. In the absence of drug, Na channels normally rapidly
returntotherested(excitable)stateattheendofphase3(withatimeconstantof~20msec),resultingintheendof
theERPveryneartheendofthenormalAPD.However,theprocessbywhichexcitabilityrecoversisdifferentinthe
presence of drug, because a large fraction of Na channels become drugassociated during a single beat, and drug
dissociationduringdiastoleisrelativelyslowcomparedtotherecoveryfrominactivationofdrugfreechannels(e.g.
lidocainedissociateswithatimeconstantof~150msec).ThisrelativelyslowprocessofunblockingextendstheERPto
well beyond the duration of the APD, and suppresses the formation of early extrasystoles. The timedependent
dissociationofdrugfromchannelsalsoresultsinanaccumulationofdrugassociated(blocked)channelsathighheart
rates where the unblocking process becomes incomplete inbetween beats (the steadystate effect on the upstroke
velocity or conduction is hence ratedependent). However, for lidocaine the process of drug dissociation is mostly
complete by the end of a normal diastolic interval, resulting in little cumulative block at the time of each action
potentialupstrokeatnormalrestingheartrates.Hencenormaltherapeuticconcentrationsoflidocainehavelittleeffect
on the QRS, despite the fact that ~80% of Na channels become blocked by the end of a typical ventricular action
potential.
To summarize, there are three basic consequences of this state and timedependent nature of drugchannel
interactioninnormalhearttissue:
1.IncreaseinERP.Acriticalnumberofchannelsmustexistinanunblockedrestedstatetoallowconductionof
anactionpotentialtooccur.Sincedrugunbindingisnotinstantaneous,somechannelswillbeblockedatthe
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endoftheactionpotential(seeFigure4).ThisdecreaseinthefractionofNa+conductingchannelsattheend
ofphase3willincreasetheeffectiverefractoryperiodtoatimepointbeyondtheendoftheactionpotential(i.e.
both the ERP and ERP/APD ratio increase). If the ERP is increased beyond the conduction time around a
reentrantcircuit,reentrycannolongeroccur.
2.Selective block of early extrasystoles. Due to the timedependence of drug unbinding, the fraction of
blocked channels will be greater during early vs. late diastolic intervals (see Figure 4). This can result in a
selective suppression of conduction of early extrasystoles. This selectivity is highest for Class Ib drugs, and
minimal for Class Ic drugs. The kinetics of drug unbinding during diastole also become slower as the resting
membrane potential is made more depolarized (see Figure 4). This leads to in an increased accumulation of
blockedchannelsindepolarizedcells.
3.Dependenceofdrugeffectonheartrate.Astheheartratesisincreasedthediastolicintervalwillshorten,
resulting in progressively incomplete drug unbinding, and a ratedependent increase in drug effect to slow
conduction.
4.Selective depression of conduction in depolarized tissue. If the resting membrane potential becomes
depolarized,somechannelswillexistinahighaffinityinactivatedstateatalltimes.Sincedrugsbindtightlyto
inactivatedchannels,thisresultsinaselectivedepressionofconductionindepolarizedtissue(seeFigures5&6).
This can abolish reentry by converting a depolarized (partially ischemic) zone from a region of unidirectional
blocktoaregionofbidirectionalblockbymakingittotallyinexcitable.
Figure 5. Effect of diastolic membrane potential on lidocaine dissociation from Na channels (channel unblocking).
Normal ventricular tissue has a diastolic resting potential near 85 mV, whereas chronically ischemic tissue is more
depolarized(e.g.60mV).Upperright:thetimeconstantforlidocainedissociationfromNachannelsishighlyvoltage
dependent,withthetimeconstantbecomingprogressivelylargeratmoredepolarizedpotentials.Thisisalsoillustrated
at the bottom which shows a pair of ventricular action potentials recorded from normal & ischemic tissue, and the
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percentofNachannelsblockedbylidocaineasafunctionoftime.Thereisamoremarkeddrugeffectinischemictissue
duetobothanincreasedpercentageofinactivated&blockedchannelsatdepolarizedpotentials,andslowerunbinding
kineticsfollowingapreviousactionpotential.Conductionitthesick(depolarized)tissueisselectivelydepressed.(Figure
isadaptedfromSampson&Kass,2011andHume&Grant,2012).
Figure 6. Selective Depression of Excitability in Partially Depolarized Tissue. The graphs are reproduced
transmembranerecordingsfromanischemicandnormalzonesofanepicardialventricularmusclepreparationshowing
theeffectsofpropafenone(2ug/ml)perfusionfor30minutes.Thesketchatthetopshowstherecordingsites.Left
Panel: the ischemic myocardial cells in the absence of drug showed a more depolarized resting potential & reduced
actionpotentialamplitude.RightPanel:propafenoneproducedamarkedlylargerdepressanteffectonactionpotential
properties (upstroke velocity and amplitude) in the ischemic zone compared to normal tissue. Reproduced from RH
Zeileretal.(AmJCardiol198454:424429).
C.HowClassIDrugsPrevent/AbolishReentry
Mostclinicallysignificantarrhythmiasarecausedbyreentry,andreentryhas3primarycriteriaforittooccur:
Table3:3RequirementsforReentry
1.Multipleconductionpathways
2.Unidirectionalconductionblock(conductionblockinonedirection,butnottheother)
3.CT>ERP:ConductiontimearoundthecircuitmustbegreaterthantheERPofanycellinthecircuit
BysubstantiallyincreasingtheERP(aneffectthatistypicallylargestinischemicdepolarizedtissue),ClassIdrugscan
causetheERPwithinthecircuittobegreaterthantheconductiontimearoundthecircuit(abolishingcriteria#3).In
addition, by reducing the excitability of ischemic zones, Class I drugs may also produce a conduction block in both
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directions,whichwouldabolishcriteria#2aswell.Thetakehomemessageis,throughtheirtime&voltagedependent
effectonNachannels,ClassIdrugsmayreducethelikelihoodthatreentrycanoccurbyincreasingtheERP.
Figure7.EffectofClassIantiarrhythmicagentsonreentrantexcitation.Left:Reentrantexcitationintheabsenceof
drug. A region of subendocardial ischemia causes membrane depolarization and inactivation of Na channels.
Consequently normal excitation delivered the Purkinje fibers is not strong enough to penetrate into healthy
myocardiumbelow.Conductionprogressivelyslows(asindicatedbythewavyline)andeventuallyisblocked,producing
ablockinonedirection(unidirectionalblock)asindicatedbytheredline.Meanwhilethestimulusconductedbyother
normalpathwayssucceedsindepolarizingalargemassofventriculartissuethatcanaddtogethertoproducealarge
retrograde stimulus that can conduct slowly through the ischemic zone into the normal Purkinje tissue above, and
establishareentrantcircuit.Thiscanproduceastablearrhythmiasuchasaventriculartachycardia(VTach).Right:
ClassIdrugswillselectivelyincreaseERPanddepressconduction,aneffectthatismoremarkedindepolarizedtissue
(Figures5&6).ClassIdrugscanalsoaffectactionpotentialdurationtoavariableextent(asindicatedbytheorange
arrowattop,right).ClassIadrugsblockIKrtoprolongtheAPD,aneffectthatalsocontributestoprolongingtheERP.
A Caveat on Tissue Selectivity Class Ibs are effective only against ventricular
arrhythmias:
NotallClassIantiarrhythmicsareequallyeffectiveagainstatrialvs.ventriculararrhythmias.
Class Ib drugs (lidocaine, mexiletine, phenytoin) are generally not effective against
supraventricular arrhythmias. In contrast, Class Ia drugs (quinidine, procainamide) are
effectiveagainstbothatrialandventriculararrhythmias.
The proposed explanation for this difference is that Class Ib drugs bind primarily to Na
channels in the inactivated state, a state that Na channels exist in during the action
potentialplateau.Atrialcellshaveaveryshortplateauduration(e.g.1/3rdthedurationof
ventricularmyocytes).OnlyasmallamountofClassIbdrugbindingcanthereforedevelopin
atrialcellsduringnormalsinusrhythm(incontrasttoventricularcells).ClassIaandIcdrugs
bind much more extensively to open Na channels (a state occupied during the action
potentialupstroke),andtheireffectisthereforemuchlessdependentonthelengthofthe
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potentialupstroke),andtheireffectisthereforemuchlessdependentonthelengthofthe
actionpotentialplateau.
TheCurtailedUseofClassIDrugsFollowingtheCASTTrials
In1986theNationalHeart,LungandBloodInstituteinstitutedtwoCardiacArrhythmiaSuppressionTrials(CAST1&
2). In both trials Class Ic drugs encainide, flecainide & moricizine effectively suppressed asymptomatic ventricular
arrhythmiasbutincreasedarrhythmicdeath3.6foldcomparedtoplacebotreatedpatients.(Encainideandmoricizine
have since been withdrawn from the market). A metaanalysis of 61 randomized clinical trials involving 23, 486
patientsshowedthattheroutineuseofClassIdrugsinhighriskpatients(e.g.survivorsofmyocardialinfarction)is
associatedwithanincreasedriskofdeath(McAlister&Teo1997).Asaresult,thecurrentstandardofcareisthat
ClassIdrugshavenoroleinthepreventionofcardiacarrhythmias(andsuddencardiacdeath)inpost
MI patients, and are not recommended in the primary prevention of sudden cardiac death (Zipes et al,
2006). A hypothetical mechanism of druginduced proarrhythmia is illustrated in Figure 8. At present, beta blockers
aretheonlyantiarrhythmicdrugsrecommendedforthepreventionofsuddencardiacdeathinpostMIpatients.
Figure8.OnepossiblemechanismforproarrhythmicsideeffectsofClassIdrugs.LeftPanel:Intheabsenceofdrug,
thepresenceofmildsubendocardialischemiaissufficienttoslowconductionbypartiallyinactivatingNachannels,but
isnotenoughtoproduceconductionblock.Thisisaregionthathasthepotentialtoproducereentryinthepresenceof
Nachannelblockers,orworseningofischemia.RightPanel:InthepresenceofaClassIdrug,Nacurrentamplitudeis
reduced in the ischemic zone, resulting in conduction block for the wavefront coming from small Purkinje fibers
endings.Conductionsucceedsfromtheoppositedirectionbecauseofthemuchlargerelectricalstimulusproducedby
depolarizationofalargeventricularmass.
ClinicalIndicationsforClassIAntiarrhythmics
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Table4:ClinicalIndicationsforClassIDrugs
Procainamide:
Most atrial and ventricular arrhythmias in patients without a history of
ischemicheartdisease
Drug of 2nd or 3rd choice in the CCU for the treatment of sustained
ventriculararrhythmiasfollowinganMI(amiodarone&lidocainearepreferred)
Quinidine:
used primarily for malaria, but not for arrhythmias due to its side effects,
proarrhythmia&betterdrugoptionsbeingavailable
Lidocaine:
Drugof2ndchoice(vsamiodarone)toterminateVTachandprevent
VFibafterDCcardioversion
Usedonlyinahospitalsetting(noteffectiveorally)
Ineffectiveagainstatrialarrhythmias
Flecainide&Propafenone:
Supraventricular arrhythmias in patients without a history of ischemic heart
disease
ClassIIDrugs(Blockers)
Betablockerspreventorterminatetachyarrhythmiascausedbyincreasedsympathetictone,excessivelyhighlevelsof
circulating plasma catecholamines, or tissue supersensitivity to catecholamines. (The latter may develop following a
myocardial infarction that damages sympathetic nerves within the wall of the heart, resulting in a denervation
supersensitivityinregionsdistaltothelesion.)Byreducingtheeffectsofcatecholaminestheymayactto:
reducepacemakerautomaticity(byblockingcatecholaminestimulationofIhandICa)
reduceDelayedAfterDepolarizations(DADs)byantagonizingadrenergicincreasesinCainfluxthrough
LtypeCachannels.(CaioverloadmayoccurinATPdepletedcellsinanischemicenvironment,orcellsexposed
totoxiclevelsofdigitalis)
Table5:ClinicalIndicationsforClassIIDrugs(blockers)
Preventreinfarction&suddendeathinpatientswithahistoryofCHForMI
(clinicaltrialshavedocumentedareducedriskofreinfarction&suddenorarrhythmic
death)
Treatexerciseinducedarrhythmias
Prevent occurrence of AVN reentry (e.g. patients with Paroxysmal SupraVentricular
Tachycardia)
Controlventricularrateinpatientswithsupraventriculartachyarrhythmias
byincreasingtheAVNERP
Propranolol
Propranololisanonselective1/2blocker,andwasthefirstbetablockerdeveloped.Mostbetablockers(selectiveor
nonselective)sharesimilarclinicalefficacyagainstcardiacarrhythmias.
Metoprolol
Metoprololisacommonlyused1selectivebetablocker.
Carvedilol
Carvedilol is a nonselective 1/2 blocker that also blocks receptors, IKr, and at higher doses blocks Ltype Ca
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channels,thetransientoutwardcurrent(Ito)andIKs.Inadditionithasantioxidanteffectsandinhibitsendothelin.
ClassIIIDrugs(DrugsthatSelectivelyIncreaseAPD)
Class III drugs significantly prolong the action potential duration (APD) by blocking IKr (the rapid
component of the delayed rectifier current). Class Ia drugs also share this same effect. Prolongation of the APD
indirectly results in an increase in the ERP due to the longer plateau phase and the resulting delay in
repolarization.TheincreaseinERPisthoughttobetheprimarymechanismbywhichClassIIIdrugs(such
asamiodarone)canexertanantiarrhythmiceffectbymakingERPgreaterthantheConductionTimearounda
reentrantcircuit(Figure9).
Figure9.EffectofClassIIIantiarrhythmicagentsonreentrantexcitation.Left:Reentrantexcitationispresentatthe
PurkinjefiberVentricularmyocardialboarder.Thiscanproduceasustainedventriculararrhythmiasuchasventricular
tachycardia(VTach).Right:ClassIIIagentsblockIKrandprolongtheAPDinthenormalregionoftheheart,resulting
inanincreasedERP.ThiseffectcanpreventorabolishreentrybymakingERPgreaterthantheconductiontime(CT)
aroundareentrantcircuit.
ExtracellularPotassium&IschemicDamageReduceClassIIIDrugEffects
IndirectcontrasttoNachannelblockers,ClassIIIdrugs(e.g.sotalol)havebeenshowntoproducemuchlesseffecton
ischemic tissue compared to normal tissue (Figure 10A). The more pronounced the ischemic injury, or presence of
hyperkalemia,thelessdrugeffectisobserved(Pattersonetal,2007).Theseeffectsappeartobeduetoacombination
ofmechanisms:
infarctedmyocardialcellshaveareducedexpressionoftheIKrchannelgene(Jiangetal,2000)ClassIIIdrugs
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cannotproduceaneffectiftheirtargetisnotexpressed
hyperkalemiaincreasesIKramplitude(Yang&Roden,1996)
hyperkalemiaalsoindependentlyreducestheeffectofdrugsthatblockIKr(e.g.quinidine&sotalol)byshifting
theirdoseresponsecurvetotheright(Figure10B)(Yang&Roden,1996)
ThiscanalsoexplainwhyhypokalemiaisassociatedwithanincreasedlikelihoodforproducingTorsadedepointes,since
it will increase drug effects to the point of producing early after depolarizations (EADs). This interaction can be
reproducedinbothisolatedPurkinjefibersandtransmuralmyocardialpreparationsinvitro(Roden&Hoffman,1985,
Antzelevitch&Burashnikov,2011).
Figure 10. Both ischemic injury and hyperkalemia reduce the effect of Class III drugs. Panel A: Microelectrode
recordings showing the effects of sotalol on normal epicardium and ischemically injured epicardium. Sotalol prolongs
theAPDinnormaltissue,butproduceslittleeffectinaregionpreviouslyexposedto4daysofischemiainsitu.Note
that the recording conditions, including potassium concentration (4 mM) were identical in both situations. (Adapted
fromPattersonetal,2007).PanelB:ConcentrationresponserelationshipforquinidineblockofIKrinthepresenceof
different extracellular K concentrations. Raising external potassium significantly reduced the effect of quinidine, and
lowering potassium concentration intensified quinidine effect. Similar effects were observed with the IKrselective
blockerdofetilide(AdaptedfromYang&Roden,1996).
Amiodarone&Dronedarone
ThemostcommonlyusedClassIIIdrugisamiodarone.Itisalsooneofthemostcommonlyuseddrugs
forchronictreatmentofarrhythmias.Itiseffectiveagainstbothventricularandatrialarrhythmias.
Amiodaronehassomeunusualcharacteristicsincludingaverylonghalflifeofseveralweeks,andarelativelack
of selectivity between multiple antiarrhythmic targets. At therapeutic doses it blocks Na, K, and Ca
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channels, as well as and adrenergic receptors. It is in essence a nonselective antiarrhythmic

shotgun.Whileseveralofitsmultipleeffectslikelycontributetoitsclinicalefficacyasanantiarrhythmic,itsabilityto
prolongtheAPDisconsideredtobemostimportantbymany,henceitsclassificationasClassIIIdrug.
Amiodaronehasmultipleeffectsonthyroidfunctionthatcancauseeitherhypothyroidism (most commonly), or
hyperthyroidism.Thestructureofamiodaronecontainstwoiodinemolecules,andwhentakenattherapeuticdoses
results in a large intake of inorganic iodine. The normal daily iodine intake is ~0.3 mg, whereas a normal 200 mg
maintenance dose releases 6 mg of iodine following hepatic metabolism. In normal patients, high levels of iodine
typicallycontributetoatransientinhibitionofthyroidhormonesynthesisduetoanautoregulatorymechanismwithin
the thyroid (the WolffChaikoff effect). Amiodarone also blocks the conversion of T4 to T3 and one of its active
metabolites blocks T3receptor binding to nuclear receptors (Ross, 2012). These mechanisms are responsible for
amiodarone'shypothyroidsideeffects.
In contrast, in iodinedeficient patients, or patients with latent Graves' disease the excess iodine from amiodarone
providesincreasedsubstrate,resultinginenhancedthyroidhormoneproductionandhyperthyroidism(Ross,2012).
Skindepositsofthedrugcanresultinaphotodermatitisthatcausesagraybluetintoftheskinwhenexposedto
sunlight.
Cornealmicrodepositsarepresentinmostpatients,butareconsideredabenignsideeffect.
Pulmonaryfibrosis is another (potentially lethal) side effect associated with amiodarone, and is seen primarily in
patientstakingveryhighdosesofthedrugitisrarelyseenwithcommonlyuseddoses.
Dronedarone is a newer analog of amiodarone that lacks iodine atoms, and has a similar lack of selectivity for
blocking different ion channels and adrenergic receptors. It has a half life of 24 hours, and lacks the thyroid and
pulmonary toxicity. It has been approved by the FDA for the treatment of atrial fibrillation. The drug also carries a
black box warning against its use in acute decompensated or advanced (class IV) heart failure because of an
increasedriskofmortalityobservedinclinicaltrials(Hume&Grant,2012).
ACaveatonDrugSelectivity
Otherantiarrhythmicdrugsarenotperfectlyselectiveeither.Forexample,attherapeutic
doses quinidine has a blocking effect on K and Ca channels, and in high doses Cachannel
blockers such as verapamil and diltiazem also block Na channels. Everything is relative,
anditdependsonthedose!
Sotalol
Sotalol is Class III antiarrhythmic that consists of a mixture of stereoisomers, one of which (dSotalol) selectively
blocksIKr,andtheother(lsotalol)isanonselectivebetablocker.Theclinicaluseofsotalolhasbeenlimitedbyboth
itsantiarrhythmicefficacy(acommonissueformostantiarrhythmics),anditsClassIIIrelatedassociatedsideeffectof
Torsadedepointes(1.52%incidence).ThereisaBlackBoxWarningthatwhenpatientsaretobeinitiatedonsotalol
therapy,theyshouldbemonitoredforatleast3daysinafacilitythatcanprovidecardiacresuscitationandcontinuous
electrocardiographic monitoring. It is indicated for both lifethreatening ventricular arrhythmias and maintenance of
normalsinusrhythminpatientswithatrialfibrillation/flutter.
Ibutilide
Ibutilide shares a similar ~2% incidence of producing Torsades de pointes. It is indicated as an i.v. injection for the
rapidconversionofatrialfibrillationoratrialflutterofrecentonsettosinusrhythm.Patientswithatrialarrhythmiasof
longerdurationarelesslikelytorespond.
Table6:ClinicalIndicationsforClassIIIDrugs
Sotalol:
Adjuvant drug to reduce ICD (implantable cardioverterdefibrillator) shocks in
patientswithanICD
Drug of 2nd choice to prevent the reoccurrence of atrial fibrillation (rhythm
control)
Amiodarone:
AcutesuppressionofpostMIventriculararrhythmiasintheCoronary
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CareUnit
AdjuvantdrugtoreduceICDshocksinpatientswithanICD
ViablealternativeinpostMIpatientsnoteligiblefor(orhaveaccessto)
anICD to prevent recurrent ventricular tachycardia (it does not produce an
increaseinmortalityinpatientswithcoronaryarterydiseaseorheartfailure)
Drugofchoicetomaintainnormalsinusrhythminpatientswithatrial
fibrillation(rhythmcontrol)
Ibutilide:
Druginduced conversion of AFib to normal sinus rhythm (with a short
termriskofproducingTorsade)
ClassIVDrugs(CaChannelBlockers)
Ca channels behave much like Na channels: their behavior is voltagedependent and is governed by movement of
activation and inactivation gates. However, Ca channels have a more positive threshold for activation, and slower
kinetics of opening and inactivating. In normal atrial and ventricular cells, their primary function is to produce the
actionpotentialplateauandmodulatethestrengthofmusclecontraction.However,inthemoredepolarizedregionsof
theSANandAVN,theyarealsoresponsibleforconductionandrefractoriness.
ThereareatleasttwosubtypesofCachannelspresentincardiactissue(designatedasLandTtypes).Ltypechannels
arefoundinbothventricularandatrialcells,whereasTtypechannelsarebelievedtoalsobeexpressedintheSAnode
andAVnode.LtypeCachannelsareblockedbytherapeuticlevelsoforganicCachannelblockerssuchasverapamil
anddiltiazem.ThesedrugsblockLtypeCachannelsinastatedependentmannermuchlikeClassIdrugs
block Na channels. (As yet there are no clinically approved Ttype Ca channel blockers). The primary cellular
mechanism of action of Ca channel blockers is to slow AVN conduction and increase the AVN ERP (see Figure 11).
Clinically,LtypeCachannelblockersareprimarilyusedto:
Prevent reoccurrence (prophylaxis) of AVN reentry (by AVN ERP) e.g. Paroxysmal SupraVentricular
Tachycardia
Controlventricularrateinpatientswithatrialtachyarrhythmias(byAVNERP)
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Figure11.Effectsof1020mgdiltiazem(D),10mgverapamil(V)and1mgnifedipine(N)ontheERPoftheAVNin
clinicalcases.Thickredlinesdenotemeanvalues.C=control.ThedirectsuppressiveeffectofnifedipineontheAVNis
overcomebyareflexincreaseinsympathetictoneastheresultofafallinbloodpressure.Nifedipineisamorepotent
hypotensiveagentthandiltiazemorverapamil.(AdaptedfromC.Kawaietal.Circulation,63:10351042,1981.)
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Figure12. Treatment of Paroxysmal SupraVentricular Tachycardia (PSVT) caused by AV node reentry. Left Panel:
Reentry can occur in the AV node when a dispersion of refractory periods develops in different pathways due to
acquiredorcongentitalpathology(seearrhythmias).EventsthatincreasevagaltonewilltransientlyincreasetheAV
nodeERPandcanbreakareentrantcircuit.TheseincludecarotidarterymassageorperformingaValsalvamaneuver.
Adenosine i.v. is the recommended treatment for acute conversion of AV nodal reentry back to sinus
rhythm. Nondihydropyridine calcium channel blockers and beta blockers are used prophylactically to
preventtherecurrenceofPSVT.RightPanel:Reestablishmentofnormalsinusrhythminresponsetoanincrease
in AV node ERP, and breaking the reentrant loop. ECG recording obtained from wikipedia
[http://en.wikipedia.org/wiki/File:SVT_Lead_II2.JPG]
Table7:ClinicalIndicationsforClassIVDrugs
Verapamil&Diltiazem:
Prophylaxis against reoccurrence of Paroxysmal Supraventricular
Tachycardia(PSVT)
Drugs of 2nd choice after adenosine for acute conversion of PSVT to sinus
rhythm (adenosine has better outcomes & less severe or prolonged side
effects)
Control of ventricular rate in patients with chronic atrial
fibrillation/flutter)
PreventacuteMIsecondarytocoronaryarteryspasm
TreatmentofidiopathicoutflowtractVT
VerapamilsensitiveidiopathicleftventricularfascicularVT
Alternative drugs for treatment of catecholaminergic polymorphic VT in
patientsintoleranttobetablockers
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Adenosine
Adenosine i.v. is the preferred treatment for ACUTE druginduced conversion of AV node reentry to sinus
rhythm.Adenosinehasahalflifeofafewseconds,andproducesaneffectontheAVnodethatisessentiallyidentical
to that of acetylcholine. Adenosine binds to adenosine receptors in heart tissue and activates the same Gprotein
modulated signal transduction pathway as does acetylcholine (including activation of a large Gprotein modulated
potassiumconductance).AdenosinehasahighersuccessrateinconvertingpatientswithPSVTbacktosinusrhythm,
andsideeffectsthatareshortlivedcomparedtoverapamilordiltiazem.
Notethatmaneuverstoabolishthearrhythmiabyincreasingvagaltone(suchascarotidsinusmassageoraValsalva
maneuver)aretypicallyattemptedfirstbeforedecidingtoadministeradenosineorotherdrugs.Drugsareusedifthese
attemptsareunsuccessful.InadditionDCcardioversioncanbeusedifthepatientishemodynamicallyunstable,and
requiresimmediatetreatment.
Digoxin(IncreasedVagalTone)
Althoughnotclassifiedasanantiarrhythmicagent,lowdosesofdigoxinproducesacardioselectiveincreaseinvagal
tonetotheheart.Thiseffectresultsfrommultipleeffectsofdigoxinincluding:
sensitizationofbaroreceptors
stimulationofcentralvagalnuclei
facilitationofmuscarinictransmissionattheneurocardiacjunction
AnincreaseinvagaltonewillincreasetheAVNERPanddecreaseautomaticityinareaswherevagalinnervationisrich
(primarilyintheSANandatria).Digoxinisoftenusedinthetreatmentofpatientswithsystolicheartfailurewho
have atrial fibrillation, to slow ventricular rate to <90/min. Most other drugs that can be used to achieve the
same goal have undesirable negative inotropic side effects (e.g. beta blockers and calcium channel blockers), which
couldbepotentiallyharmfulinapatienthavingalowejectionfraction.Hencethisremainsaprimaryindicationforthe
useofdigoxin,adrugthathasbeeninuseforover200years.
MajorSideEffectsofAntiarrhythmics
Anticholinergic(ClassIa)
ClassIadrugsproduceanticholinergiceffectsontheheartduetotheirabilitytoblockm2receptors(quinidine)or
blockautonomicganglia(procainamide).Anticholinergicsideeffectsincludeurinaryretention in male patients with
prostate hypertrophy, drymouth,blurred vision, constipation and worsening of preexisting glaucoma. An
additional,potentiallylifethreateningsituationofdangerousaccelerationofventricularrate can also occur when
attemptingtotreatatrialflutterorfibrillationwithaClassIadrugalone(seeFigure13).Whydoesthisoccur?Whyis
thispotentiallyharmful?Whatwouldyoudodifferentlytopreventitfromoccurring?
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Figure13.Effectofquinidineonatrialandventricularratewhenusedalonetotreatatrialflutter.Adogwasplaced
underalphachloraloseanesthesiaandatrialflutterwasinducedbyprogrammedelectricalstimulationoftheatriumat
a frequency of 20 Hz after first crushing the atrial muscle between the superior and inferior vena cavae. The atrial
flutterwasstablewithanatrialrateof400beats/min.Theventricularratewasstableat200beats/minduetoa2:1
AV block. An i.v. infusion of 3 mg/kg quinidine was administered whereupon the atrial rate began to diminish.
However,atthesametimetheventricularratealsorosedangerouslyhightonear300beats/minasthedegreeofAV
blockdiminishedtonear1:1.Shortlyafterwardstherewasanarrestoftheatrialflutter,andbothatrialandventricular
ratesfelltoastablelevelof120150beats/min.Repeatedattemptstoreinitiateflutter(S)wereunsuccessful.The
experimentalpreparationcloselyduplicatestheresponseinclinicalcases.(ReproducedfromGoodman&Gilman'sThe
PharmacologicalBasisofTherapeutics,5thedition,1975.)
NegativeInotropicAction
Thissideeffectisespeciallyimportantwhentreatingpatientswithsystolicheartfailure(lowejectionfraction).Drugs
withaclinicallysignificantnegativeinotropiceffect(indecreasingorderofseverity)include:
Cachannelblockers(verapamil,diltiazem)
blockers(propranolol)
ClassIadrugs(disopyramide,quinidine,procainamide)whichpartiallyblockLtypeCachannels
Bronchoconstriction
Importantinpatientswithasthma.
drugswith2blockingactions(propranolol,higherdosesof1selectiveblockers)
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Neurologicsideeffects(stimulationordepression,convulsions)
ClassIbdrugs(lidocaine,phenytoin,mexiletine)
Proarrhythmia(producingnewarrhythmias)
Class I & Class III antiarrhythmics have the ability to produce new arrhythmias by several possible mechanisms.
(Averageincidenceis10%).Theseinclude:
convertinganareaofdepressedconductioninpartiallydepolarizedtissuetooneofunidirectionalblock,which
wouldmimicthesameeventthatcanbeproducedbyworseningofischemia(seeFigure8).
increasing the dispersion of refractoriness (variability of ERP values in different regions of the heart) a
conditionthatpredisposesthehearttoreentrywhenevertherearemultipleconductionpathwayspresent,as
illustratedbyreentrythatcanoccurintheAVnode(seeFig5B&CintheArrhythmiawikidocument).
productionofEarlyAfterDepolarizations(EADs).EADsarewidelybelievedtobethemechanismunderlyingthe
formationofTorsadedePointes
Drugs,EADs,DispersionofRepolarization&Torsade
Torsade can be produced by more than 40 drugs that block IKr (the rapid component of repolarization current in
ventricularmyocytes).ThisincludesClassIa&mostClassIIIdrugs.Quinidinesyncope(fainting)istypicallycaused
bythisarrhythmia.ThisisonereasonwhypatientsbeinginitializedonmostClassIaorClassIIIdrugsarehospitalized
for the first day or two when initializing treatment (when this event is most likely to occur). Amiodarone is an
exception it has a very low incidence of producing Torsade, perhaps because it behaves like a pharmacological
shotgunitblocksmultiplecurrents,includingthosethatcontributetothedepolarizingupstrokeofactionpotentials
thatproduceEADs.Torsadeispotentiallylifethreateningandistreatedasamedicalemergency.
SeverallinesofevidenceimplicatethateitherEarlyAfterDepolarizations(EADs)orenhancedtransmuraldispersionof
repolarizationcanresultinthetriggeredactivitythatisthegenesisofTorsadedepointes:
TheconditionsthatelicitEADsintissuepreparationsinvitro(slowstimulationrates,lowextracellularpotassium
levels, and treatment with APDprolonging drugs)(Fig 14A) are also associated with a higher incidence of
Torsadedepointesinpatientpopulations.
Heterogeneity in action potential duration results in a myocardium that is more vulnerable to reentrant
excitation, a second likely cause of torsade de pointes. As illustrated in Figure 14B, M cells have an action
potentialdurationthatprolongsdisproportionatelycomparedtoothercelltypesinresponsetoaslowingofheart
rate and/or the presence of drugs that prolong the APD (Anzelevitch & Burashnikov, 2011). M cells are
sensitized to the effects of APDprolonging drugs (e.g. blockers of IKr) due to a larger expression of both an
inwardplateauNacurrentandaNaCaexchangecurrent,andasmallerslowpotassiumcurrent(IKs)compared
tootherventricularmyocytes(Anzelevitch&Burashnikov,2011).Hypokalemiawouldalsoincreasetheeffectof
APDprolongingdrugs(seeFig15B).
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Figure 14. Two proposed mechanisms for formation of Torsade. Panel A: Isolated Purkinje fiber preparation. The
combinationofAPDprolongingdrugs,hypokalemiaandbradycardiacanresultintheformationofEADsandTriggered
Beats in isolated Purkinje fiber preparations. EADs develop when the balance of currents active during phase 2 or 3
shiftsintheinward(vs.outward)direction.PanelB:SlowingoftheheartrateinthepresenceofanAPDprolonging
drug can enhance the normal transmural dispersion of repolarization that normally exists between mid
myocardialcells(Mcells)andepicardialorendocardialcells(Antzelevitch&Fish,2001).Cellsfromthemidwallregion
havealongerAPDcomparedtoendocardialorepicardialcells,andgreatersensitivitytotheeffectsofAPDprolonging
drugs.Underthecombinationofsuchdrugsandslowingoftheheartrate,theMcellAPDwidensdisproportionately,
resultinginanabnormallylargedispersionofAPDvaluesbetweenregions(asindicatedbythewidthbetweenthetwo
verticallines).AdispersionofrepolarizationcaninduceaspreadofcurrentfromthedepolarizedMcellregiontothe
epicardialregionthathasregaineditsexcitability(Antzelevitch&Burashnikov,2011).Thesourcefordepolarizationcan
be either the Ltype Ca current, NaCa exchange current, or a late plateau Na current (indicated by the red arrow)
(FiguremodifiedafterRoden,2004).
DrugSpecificSideEffects
ClassIa
Quinidine
Cardiac:
negativeinotropicaction
vagolytic
snycopeandTorsadedepointes
NonCardiac:
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Cinchonism(tinnitus,visualdisturbances,hearingloss,g.i.upset)
g.i.upset(nausea,vomiting,diarrhea)w/ocinchonism
thrombocytopenia
hypersensitivityreactions
Procainamide
Cardiac:
Negativeinotropicactionsimilartoquinidine
Weakganglionicblockingeffectthatisvagolytic&cancausehypotension
Procainamide is converted to Nacetylprocainamide (NAPA) which has Class III actions (including
proarrhythmia) and has a longer half life than procainamide. NAPA levels accumulate with chronic
therapy
NonCardiac:
Lupuserythematosuslikesyndromethatoccursin2025%ofallpatientsondrugtherapyformore
than1year
ClassIb
Lidocaine
NonCardiac:
CNSexcitationand/ordepression(drowsiness,dissociation),nausea,tremor,vertigo,metallictaste,
numblips,visualandhearingdisturbances.
High concentrations (> 9 g/ml) may cause convulsions & respiratory depression/arrest inhibitory
centersintheCNSaretypicallyinhibitedfirst,resultinginseizureactivityrespiratorydepressionoccurs
athigherdoses
ClassIc
Propafenone
Cardiac:
proarrhythmiainpatientswithischemicheartdisease
betablockingeffectcancause1stor2nddegreeAVNblock
NonCardiac:
aggravationofbronchospasm
ClassII
Propranolol
bradycardia,hypotension,leftventricularfailure,AVNblock,bronchospasm
ClassIII
Amiodarone
cornealmicrodepositsinmostpatients
peripheralneuropathy
PULMONARYFIBROSIS(rarewithnormaltherapeuticdoses,butpotentiallyfatal)
disturbedthyroidfunction(hypoorhyperthyroidism)
photosensitivitywithbluegraydiscoloration
mayprecipitateheartfailure
veryrareincidenceofTorsadedePointes(comparedtootherdrugs)
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Dronedarone
lacksiodine&thyroidsideeffects
Sotalol
nonselectivebetablockade(oneenantiomerisabetablocker,theotherblocksIKr)
Torsadedepointes
Ibutilide
Torsadedepointesin48%ofpatients(reservedforacuteconversionofAFibtosinusrhythm)
ClassIV
Verapamil&Diltaizem
Cardiac:
negativeinotropic,AVNblock,sinusarrest,
NonCardiac:
peripheralvasodilation,constipation
Misc
Adenosine
transient~10seconddepressionofSAnode&AVnode,hypotension
syncope(administerwithpatientinahorizontalposition!)
Treatment of Atrial Fibrillation Antiarrhythmics in Clinical

Context
Atrial fibrillation (AFib) is the most common cardiac arrhythmia, currently affecting more than 2 million
Americans.Itisrarelyaonetimeevent.PatientswhodevelopAFiboncetendtobepredisposedtodevelopingitagain
&again(whichiswhatismeantbythephraseAFibbegetsAFib).Currentresearchindicatesthatthisisprimarily
duetoachangeintheexpressionofionchannelsthatiscausedbyfibrillation(whichmaybemediatedbychangesin
intracellular calcium caused by rapid pacing). This electrical remodeling creates an electrical substrate that is
conducivetoproducingreentry.SomeofthecharacteristicsassociatedwithAFibare:
Symptoms:palpitations,dyspnea,fatigue,decreasedexercisetolerance,chestpain
ECG:lackofPwaves,irregularlyirregulartimingbetweenQRScomplexes&pulsepressure.TheQRScomplex
&Twavesaretypicallynormalinduration&shape
Riskfactors:hypertension,age,CHF,previousAFib
AssociatedPathology:atrialdilation,fibrosis,myocyteapoptosis
Complications:thromboembolism(duetovascularstasisinleftatrium)&stroke
Common Origin & Mechanism: in patients with heart failure, an electrical focus around a left
pulmonary vein combined with an abnormal atria ablation of tissue around the pulmonary vein is one
formofcurrenttherapyforpatientswithcombinedAFib&heartfailure(Khanetal.,2008).
There are two approaches to the treatment of AFib: rate control, allowing AFib to persist but controlling the
ventricularratebydrugsaffectingtheAVnodeERP,andrhythmcontrolwithcardioversiontonormalsinusrhythm
&chronictreatmentwithantiarrhythmicdrugstopreventthereoccurrenceofAFib.
Arguments in favor of rate control include: 1) its easily achievable in most patients 2) avoidance of use of
antiarrhythmic agents with less desirable side effects/toxicity 3) risk of stroke can be reduced by anticoagulant
therapy.
Arguments in favor of rhythm control include: 1) rhythm control reduces the odds of thromboembolism 2) it
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wasthoughtthatpatientswhoremaininAFibhaveaworseoutcomethanthosetreatedwithdrugsthatmaintaina
sinusrhythm.(Ofcourse!Whowouldarguewiththat?.butwhatdoestheevidencesay???)
In 2008, the results of two studies, one in North America, and one in Europe were published in the New England
JournalofMedicine.Inbothstudies,rhythmcontrolprovidednoadvantageoverventricularratecontrolwithrespectto
survival(Fig15A).Onthebasisoftheseresults,ratecontroliscurrentlyconsideredanequallysafeapproachforthe
treatment of AFib, and rhythm control (if it is used) can be abandoned early if it is not fully satisfactory (e.g. the
patient cannot tolerate the side effects of the drugs used to suppress AFib). Surgical procedures (e.g. Mini Maze
procedure) [http://youtu.be/DWXvDXXflmc] involving catheter ablation of ectopic foci around the pulmonary veins may
alsobesuccessfulinpatientswithotherwiserelativelynormalhearts.
Figure15.PanelA:KaplanMeierEstimatesofDeathfromCardiovascularCauses(PrimaryOutcome).Among1376
patientswithatrialfibrillationandcongestiveheartfailurewhowerefollowedforameanof37months,182patients
(27%)intherhythmcontrolgroupdiedfromcardiovascularcauses,ascomparedwith175patients(25%)intherate
controlgroup(hazardratio,1.0695%confidenceinterval,0.86to1.30).(FromRoyetal,2008).PanelB:Kaplan
MeierEstimatesofthePercentageofPatientsRemainingFreeofRecurrenceofAtrialFibrillationinthetwotreatment
groups (hazard ratio for recurrence among patients in the amiodarone group, 0.43 [95 percent confidence interval,
0.32to0.57]).Followupbegan21daysafterrandomization(designatedday0).(From:Royetal,2000).
Currentlyamiodarone appears to be superior to other antiarrhythmics in preventing the reoccurrence of
AFib(Figure15B).
InitialconversionfromAFIbtosinusrhythmcanbeachievedbyeitherDCdefibrillationorbyani.v.bolusofthedrug
Ibutilide (a Class III drug which typically isnt used for any other indication due to high risk of Torsade de pointes.
Torsadeoccurswithinafewhoursin~2%ofpatientsgivenasinglebolusofibutilide.)Patientswhoareplacedonrate
controltreatmentaretypicallygivenmaintenancetherapywitheitherverapamil,diltiazem,abetablockerordigoxin
(digoxinuseismorecommonifthepatienthassystolicHF).
WARNING: Patients who have had AFib for more than 23 days duration must be adequately
anticoagulated, generally for 2 weeks prior to attempting cardioversion. If emergency cardioversion is
considered,atransesophagealechocardiogramcanbeusedtodeterminethepresenceorabsenceofleftatrialthrombi.
TreatmentSummary
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Intro To Antiarrhythmics

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Intro To Antiarrhythmics

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channels, as well as and adrenergic receptors. It is in essence a nonselective antiarrhythmic

Treatment of Atrial Fibrillation Antiarrhythmics in Clinical

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