5.Anti-Arrhythmic Drugs.pdf

Scope: This subject is intended to impart the fundamental knowledge on various aspects
(classification, mechanism of action, therapeutic effects, clinical uses, side effects and
contraindications) of drugs acting on different systems of body and in addition,emphasis
on the basic concepts of bioassay. Objectives: Upon completion of this course the student should be able to
1. Understand the mechanism of drug action and its relevance in the treatment of
different diseases
2. Demonstrate isolation of different organs/tissues from the laboratory animals by
simulated experiments
3. Demonstrate the various receptor actions using isolated tissue preparation

1. Course:Pharmacology II
Unit 1:Pharmacology of Drugs Acting on
Cardiovascular System
Topic: Anti-Arrhythmic Drugs
CO -503T.1: Explain pharmacology of the drugs acting on
various Cardiac complications
BY
Mr. Bhagwat H. Garje (M.Pharm).
Asst. Professor
Department of Pharmacology
SCOPER, Kopergaon
Date: 25/07/2022Lecture No.:

2. Introduction
•IrregularityinCardiacRhythm
•Bradyarrhythmia:Failureofimpulsegeneration resultingin
slowheart rates
•Heart Block:Resultsfromfailureof impulse to propagate
normallyfromatriumtoventricle–usuallydefectinAVnode
or His-Purkinjesystem
•Tachyarrhythmias:Abnormallyrapidheart rhythms
–Commonclinicalcondition
–TreatedbyAntiarrhythmicDrugs–Drugsusedto
preventortreatirregularitiesof CardiacRhythm

3. CausesofArrhythmia
•Rootcauses:Whenthenormalsequenceofimpulse
generation andpropagationisperturbed

4. Arrhythmias –pacemakeracticity
•Enhanced Automaticity: Pacemaker cells or
ordinary fibres
–Results due to patholgical increase in phase 4 slope -
acceleratedpacemakerrate
–Mayresult fromcurrentof Injury
–Physiology: ACh reduces such pacemaker rate –by
decreasingphase4and hyperpolarization
–Ventricular wall cells --may also show such pace
makeractivity –duetoischaemia

5. Triggered Activity
•A normal AP interrupted/followed by a abnormal
depolarization (atriggeringrhythm)
➢DelayedAfterDepolarization:Causedby Digoxin
toxicity, Myocardial Ischaemia or Adrenergic stress or
Heart failure–duetoCa++ overload
➢EarlyAfterDepolarization:Duetointerruptionin
phase3repolarization
➢Causes:Slowheartrate,Hypokalaemiaanddrugs
prolonging QTinterval–quinidine,sotalol,
procainamideetc.(block IK channel)

6. Re-entry
•Oneofthecausesofthemost arrhythmias
•Normally, impulses propagate in synchronized manners
•But,hereone impulsereentersandre-excites areas of heart
more than once –no need for new impulsegeneration
•Re-enteringofimpulsesmaybe
1.Anatomicallydefinedreentry–Circusmovement
type
2.Functionallydefinedreentry-Microentrycircuit

7. Functionallydefined reentry
Ventricular fibrilation
Atrialfibrillation

8. Anatomicallydefinedreentry–Accessory pathway
(WPW syndrome)
Wolf-Parkinson-WhiteSyndrome AVnodalreentry,AtrialflutterandPSVT

9. AtriaandVentriculararrhythmia-Animation
Ventriculararrhythmia Atrialarrhythmia

10. Vaugham-Williams classification
•Class I –Na+ Channel Blockers
–1a: quinidine, procainamide, disopyramide
–1b: lignocaine, mexilitine, phenytoin, propafenone
–1c: Propafenone, Flecainide, Encainide, Moricizine
•Class II –Beta-adrenergic Blockers -Propranolol,
Sotalol, Esmolol and Acebutalol
•Class III –K+ channel blockers: Amiodarone,
Ibutilide, Dofetilide, Sotalol (II + III action) and
bretylium
•Class IV –Ca++ channel blockers: Verapamil,
diltiazem and nifedipine

11. ClassI-antiarrhythmics
ClassIantiarrhythmics:arefurtherclassifiedto
Ia,IbandIc–basedonrepolarizationand potency
ofNa+ blockade–statedependantmanner
Lidocaine Flecainide
Phenytoin Propafenone
Na+blockade:Ic>1a>1b ERP:1a>2c>1b

12. Subclass–I A-quinidine,
procainamide,disopyramide
•Binds to Na+ channels in open state and prevent conduction of ions (Refractory –
Rest –Open –Refractory) -Moderate sodium channel blockade in open state
•Prolong refractoriness by blocking several types of potassium channel
•Delayed Na channel recovery
•Delayed AV conduction
•Useful in conditions where Na+ channels open frequently –ectopic beats -
atrial tachycardia and atrial fibrillation and ventricular arrhythmias
•Abolish reentry –unidirectional block to bidirectional block
•Electrophysiology changes: Lengthen action potential, slow rate of rise of phase 0,
Prolong repolarization ----------------also prolong AV node ERP -ECG changes:
Prolong PR, QRS, QT

13. Subclass-IB
•LowestpotencyforNa+channelblocker -
inactivatedstate
•Donotdelaychannelrecovery
•EPchanges:Shortenactionpotential,Limited
effectonrate ofriseofphase0,Shorten
repolarization -------------no ERP effect on AV node
(shorten)
•ECG:ShortenQT
•UsedinTreatmentandpreventionof ventricular
tachycardiaandfibrillationafterMyocardial
Infarction –lignocaine IV , e.g, lignocaine,
mexilitine,phenytoin,propafenone

14. SubclassIC
•Propafenone,Flecainide,Encainide,Moricizine
•MarkedNa+channel blockadeinopen state–with longestrecovery time
•RefractoryperiodofAVnodeisincreased–markeddelayin conduction
•Electrophysiologychanges:Noeffectonlengthofactionpotential,
Markedlyreducesrateofriseofphase0and----------markeddelay
inAVconductionwithlittleeffectonrepolarization
•ECG:markedlyprolongPRandQRScomplex
•Prolongrefractorinessbyblockingoutward-rectifyingpotassium channels
•General reductionin excitability
•Usedinlifethreateningventricularfibrillationsincetheyhave highestaffinityto
Na+channelsinvolvingAVnode-WPWsyndrome and Paroxysmalatrial
fibrillation

15. IndividualDrugs

16. Antiarrhythmic-Quinidine
•Dextroisomer of Quinine: N+ channel blocking and antivagal action
•Actions:
⚫InhibitionofNachannel–slantedOphaseandDecreasesphase4
⚫ProlongationofAPD–dueto K+channelblock
⚫IncreaseinERP–duetodelayinNa+andK+channelrecovery
⚫Net resultisdelayinconductivityandincreaseinrefractoriness
⚫FallinBP–directcardiacdepression
⚫Otheractionsinclude–alpha blockade,decreased skeletalmusclecontractility,

17. ▪Kinetics:wellabsorbedorally,halflife–10Hrs
▪Uses:
Broadspectrumantiarrhythmic
Atrial fibrillation and flutter, prevention of PSVT and prevention of ventricular
tachycardia
⚫Adverseeffects:Notusednow foradverse effectslike
Proarrhythmia(torsadesdepointes),suddencardiac arrestorVF, cinchonism,
angioedema,vascularcollapseetc.
⚫Availableas200,300mgtabs.And300mg/mlInjections

18. Procainamide
•Procainederivative (amide)
•Identicalactionwith quinidineexcept:
–Minimalantivagalaction
–Lesser suppressionofectopicautomaticity
–LesserdepressionofcontractilityandAVconduction
–No alphablocking action
•Kinetics:
–Absorbedorally andbioavailabilityis 80%
–MetabolizedinlivertoN-acetyl-procainamide(NAPA)–blocksK channeland prolongs
repolarization
•Dosage–250mgtabsand1gm/mlinjections
–Antiarrhythmic–0.5to1gmoralfollowedby0.25-0.50mg every2Hrs
•Uses:MainlyformonomorphicVTsandtoprevent recurrences
•ADRs:Hypersensitivity,flushing,hypertension,torsedesde
pointesandCNSsymptoms–mentalconfusion, hallucinations and
weakness

19. Antiarrhythmic–Lidocaine
(Lignocaine)
•Popularantiarrhythmicandalsolocalanaesthetic(membrane
stabilizingaction)
•LowestpotencyforNa+channelinactivatedstate–ECTOPICFoci
–Enhancephase–4 depolarizationinpartiallydepolarizedor
stretchedPF–Afterdepolarizationantagonized–no effecton
SAN
–Practically no actiononAtrialfibres
–Rateof 0phaseinAVNand ventricles–not affected
–ReductioninAPDinPF andventricularmyocardium
•Actions:
–Selectiveactiononpartiallydepolarizedandcellswithlong
APD–normal ventricularandconductingfibres–notaffected
–Suppressionof automaticityinectopicfoci(reentry)–oneway
ortwoway block
–Enhancedphase-4depolarizationinpartiallydepolarizedor
stretchedPF (APDlong)
–LittleeffectsoncardiaccontractilityandarterialBP

20. Lidocaine–cont.…
•Kinetics:Ineffectiveorally,givenIVlastsfor10-20minutes.
ThereforegivenasIV bolus50-100 mgfollowedby 20-40mg every
10-20minutes.Half-lifeprolongedin CHF(coz.Vd decreases)and
70-80%metabolizedbyliver
•Adverseeffects:Neurological–drowsiness,paresthesia, blurred
vision,nystagmusandfits etc.
–Noproarrhythmiceffects–nocardiotoxicity
•Uses:50-100 mgbolusand10-20mgevery 20minutes
–1
stline of drug in Arrhythmia following acute MI and cardiac
surgery
–Preventionofventriculartachycardia
–Digitalistoxicity–noAVblock
•LAlignocaineVsAntiarrhythmiclignocaine?

21. Betablockers
•Drugsusedarebeta-blockers:Propranolol,Sotalol,Esmolol and
Acebutlol
•Suppressionofadrenergicallymediatedactivity
•Propranolol-Membranestabilizingeffectlikequinidineon heart–
highdoses–clinicaldose:cardiacadrenergic blockade
•Clinicaldoses(antiarrhythmiceffect)-Blockbeta-1
receptorinheartanddecreasesheartrate
1.Decreaseinphase4depolarizationandautomaticityinSA
node,AVN,PFand otherectopicfoci(Adrenalinecauses
ventricularESand fibrilationbyincreasingthephase 4
depolarization!!!)
2.ProlongationofERPofAVN–impedeAVconduction

22. UsesofPropranolol
•Arrhythmiasassociatedwithincreasedsympathetic
activity –sinus tachycardia, atrial extrasystoles provokedby
emotionandexercise
•LesseffectiveinPSVTthanadenosineandverapamil
•Propranololis usedtotreatsympatheticallymediated
arrhythmias-phaeochromocytoma and halothane anaesthesia
–Sinustachycardia,atrialandnodalextrasystoleandnodal
extrasystoleprovokedbyexercise
Does notabolish AForAflbutdecreasesventriculsarrate
•ReducemortalityafterMI –anti-ischaemicaction
•EsmololIV –quicklyterminatesAF andfluttter and
usedin emergencycontrolof arrhythmiadue to anaesthetics

23. Class-III
Antiarrhythmics
•ClassIIIdrugsKchannelblockersprolong repolarization
(increaserefractoriness)byblocking outwardpotassium
conductance
–Prolongation ofCardiacactionpotential
–IncreasedERP
•Drugs–Amiodarone Ibutilide,dofetilide,
sotalol(II+IIIaction) andbretylium
•Bretyliumisused onlyinlifethreatening arrhythmias

24. Amiodarone
LongactingandhighlylipophillicandIodinecontaining compound
MOA:-multipleactions
1.Blockingof delayedrectifierK+channel–prolongs APD
2.WeakclassI(lidocainelike)–depressesconductonin partially
depolarizedand longAPD
3.II(beta-blocker)–NCalphaand beta;andclass IVactions
4.Alsodirectcoronarayand peripheralvasodilator
•Overall–Slowedconductionandsupressedautomaticity
Kinetics:Incompletelyandslowlyabsorbed–dailyoraldoseis
givenforseveraldaysforactionstodevelop,t1/2=3-8 weeks
Dose:400-600mg/dayp.oformanydaysfollowedby100-200 mg/dayas
maintenance(100-300mg slowIV)

25. Amiodarone
Uses:
•Mosttachyarrhythmicconditions–ventricularandsupraventricular
•RecurrentVTandVF
•WPWsyndrome
Adverseeffects:
•Photosensitization–skinpigmentation
•Peripheralneuropathy–weakshoulderandpelvicmuscles
•Myocardialdepression–bradycardia
•Pulmonaryalveolitisandfibrosis–keptbelow200mg
•Cornealmicrodeposits–on longtermuse
•Hypothyroidism,goitre –inhibitionofT4toT3
DrugInteractions:Digoxinandwarfarin(reduced renalclearance)

26. ClassIV-Antiarrhythmics
•Threeimportantclasses:
–Phenylalkylamines–hydrophillicVerapamil
–Dihydropyridines–lipophilicNifedepine
–Benzothiazepines–hydrophilicDiltiazem
•Verapamilanddiltiazem: are useful in
Arrhythmia
•RelativelyselectiveAVnodal L-typecalcium
channelblockers–depressionof Ca++mediated depolarizationand
delayrecovery
–SlowsSA nodeautomaticity
–reducedphase4 depolarizationinSANandPF–
extinctionof latentpacemakersandDAD
–Prolongationof AVNERP–reentryterminated
–Negativeionotropicaction

27. ClassIV–cont...
•Uses:Verapamil
1.PSVT:
•For termination of attack –5 mg IV over 2-3 minutes
(reflexbradycardia)
•For preventionofattack60-120mgorallytds
2.ReduceventricularrateinAtrialfibrillation(AF) andAtrial
flutter–withdigitalis

28. MiscellaneousAgents
Adenosine:
•Endogenously produced important chemical mediator used in
PSVT
•MOA:
–Activationof AChsensitiveK+channel-membrane
hyperpolarization
ofSAnode(G-proteincoupledadenosinereceptorA1)
–depressionof SAnode andalsoslowing of AVconduction
–shortening ofactionpotentialinatriumandreduced
excitability
–Also indirectlyreducesCa++current inAVnode–
depressionof reentryinPSVT

29. Adenosine–cont...
•Veryshorthalf life–20-30sec.-UptakebyRBCs and
endothelialcells(5-AMPandinosine)
•Administered intravenously –available as free baseor ATP
–6 -12 mg/ATP 10 -20 mg given as a rapid intravenous bolus
(administeredovera 1-2 secondperiod)
–Ifthefirstdosedoesnotresultineliminationofthe
supraventricular tachycardia within 1-2 minutes -12 mg
shouldbegivenasarapidintravenousbolus
•ADR: chest tightness, dyspnoea, fall in BP and flushingetc.

30. WhenAntiarrhythmics ?
•Asymptomaticand those whichdonot interfere
haemodynamics –AES, VES, 1st degree block and bundle
branchblock–noneedof treatment
•Therapyneeded:
–LifethreateningVT,TdPandVF
–Causingbreathlessness,hypotensionandcardiac
failure
–Markedpalpitation–PSVT,VT,AF andTdP
–Myocardialinfarction

31. Non-pharmacologicaltreatment
•Acute
–Vagalmanoeuvres
–DCcardioversion
•Prophylaxis
–Radiofrequencyablation
–Implantable defibrillator
•Pacing(external,temporary,permanent)

32. ExpectedQuestions??
•Classificationofantiarrhythmic drugs
•Lidocaineasantiarrhythmicagent
•Amiodaroneasantiarrhythmicagent
•RoleofBetablockers(Propranolol)andCa++ channel
blockers(Verapamil)inArrhythmia
•ShortNote:Adenosine