Basics of arrhythmias&antiarrhythmic drugs prepared by Islam Ghanem Ahmed Ghanem Assistant lecturer of cardiology Zagazig university 2014

1. Basics of arrhythmias &
Antiarrhythmic drugs
ByBy
Islam GhanemIslam Ghanem
Assistant lecturer-Cardiology-ZagazigAssistant lecturer-Cardiology-Zagazig
20142014

3. AntiarrhythmicsAntiarrhythmics????????
– In a textbookIn a textbook  Interesting butInteresting but
sedative.sedative.
• Try it if you have insomniaTry it if you have insomnia
– In the lectureIn the lecture  Confusion ??????????Confusion ??????????
• As alwaysAs always
– In the exam hallIn the exam hall  Panic!Panic!
• Don’t worry rarely askedDon’t worry rarely asked

4. Cardiac ElectrophysiologyCardiac Electrophysiology
• A transmembrane electrical gradient (potential) isA transmembrane electrical gradient (potential) is
maintained, with the interior of the cell negative withmaintained, with the interior of the cell negative with
respect to outside the cellrespect to outside the cell
• Caused by unequal distribution of ions inside vs. outsideCaused by unequal distribution of ions inside vs. outside
cellcell
– Na+ higher outside than inside cellNa+ higher outside than inside cell
– Ca+ much higher “ “ “ “Ca+ much higher “ “ “ “
– K+ higher inside cell than outsideK+ higher inside cell than outside
• Maintenance by ion selective channels, active pumpsMaintenance by ion selective channels, active pumps
and exchangersand exchangers

5. Ion Flow and the Action PotentialIon Flow and the Action Potential
K+
(140 mM)
Na +
(140 mM)
K+
(5 mM)
Na +
(5 mM)
Ca2+
(1.8 mM)
Ca2+
(100 nM)
outside
inside
Depolarizing Repolarizing

6. 6
Effect of channels openingEffect of channels opening
1. When channel is closed, no current flows through channel
2. When cations (+) enter cell ("inward current"), cell depolarizes
(becomes more positive inside)
depolarizing
inward (+)
current
+
repolarizing
outward (+)
current
+
1. When channel is closed, no current flows through channel
2. When cations (+) enter cell ("inward current"), cell depolarizes
(becomes more positive inside)
3. When cations (+) exit cell ("outward current"), cell polarizes
(becomes more negative inside)

7. 7
Channel-Channel-typestypes
Voltage-gated channels: channels that open or close in response to
changes in membrane potential. Central to the AP and conducted AP.
"Background" channels: channels that are NOT voltage-gated and NOT
ligand gated. Generally they are open. Important to set "resting" or
"diastolic" potential.
Ligand-gated channels: channels that open or close in response to a
drug, neurohormone, etc. We will discuss later.
voltage-gated
background

8. 8
Membrane currents that underlie the cardiac APMembrane currents that underlie the cardiac AP
heart cell
Voltage-gated Channels of interest to us
Na+ (
INa)
Ca2+
(L-type; T-type)
ICa,L and ICa,T
K+
(rapid, slow,
transient outward)
IKR, IKS, ITO)
Both Na+
and K+
("funny")
IF
Transporter
N+
/Ca2+
exchanger
INCX

9. Electrophysiology of cardiacElectrophysiology of cardiac
tissuetissue
• Impulse generation and transmissionImpulse generation and transmission
• Myocardial action potentialMyocardial action potential
• Depolarization and repolarization wavesDepolarization and repolarization waves
as seen in ECGas seen in ECG

10. Types of cardiac tissue
(on the basis of impulse generation)
• AUTOMATIC/ PACEMAKER/ CONDUCTING
FIBRES
(Ca++ driven tissues)
Includes SA node, AV node, bundle of His,
Purkinje fibres
Capable of generating their own impulse
Normally SA node acts as Pacemaker of heart
• NON-AUTOMATIC MYOCARDIAL CONTRACTILE
FIBRES (Na+ driven tissues)
Cannot generate own impulse
Includes atria and ventricles

11. Impulse generation andImpulse generation and
transmissiontransmission

12. Myocardial action potentialMyocardial action potential
In automatic tissues In non-automatic tissues

13. Action potential in NonAction potential in Non
automatic myocardialautomatic myocardial
contractile tissuecontractile tissue

14. +30 mV
0 mV
-80 mV
-90 mV
OUTSIDE
MEMBRANE
INSIDE
Na+
0
4
3
2
1
K+
Ca++ K+
AtpAtp
K+
Na+
K+
Ca++
Na+
K+
Na+
Resting
open
Inactivated
Phase zero
depolarization
Phase zero
depolarization
Early
repolarization
Early
repolarization Plateau phasePlateau phase
Rapid
Repolarization
phase
Rapid
Repolarization
phase
Phase 4
depolarization
Phase 4
depolarization

15. Phase 0:
RapidDepolarisation
(Na+
influx)
Phase 1:
Early Repolarisation
(Inward Na+
current
deactivated,
Outflow of K+
):
Transient Outward Current
Phase 2:
Plateau Phase
(Slow inward Ca2+
Current balanced by
outward delayed rectifier K+
Current)
Phase 3:
Late Repolarisation
(Ca 2+
current inactivates,
K+
outflow)
Action Potential of Cardiac Muscle

16. • Phase 0:Phase 0: rapid depolarization of cellrapid depolarization of cell
membrane during which theirs is fastmembrane during which theirs is fast
entry of Na ions into the cells throughentry of Na ions into the cells through
Na channels, this is followed byNa channels, this is followed by
repolarization.repolarization.
• Phase 1:Phase 1: is short initial rapidis short initial rapid
repolarization due to Ka effluxrepolarization due to Ka efflux
• Phase 2:Phase 2:prolonged plateue phase dueprolonged plateue phase due
to slow Ca influxto slow Ca influx
• Phases 3:Phases 3: rapid repolarization with Karapid repolarization with Ka
effluxefflux
• Phase 4:Phase 4: resting phase during which Karesting phase during which Ka
ions return into the cell while Na and Kaions return into the cell while Na and Ka
move out of it and resting membranemove out of it and resting membrane

17. Action potential in nodalAction potential in nodal
tissuestissues

18. +30 mV
0 mV
-80 mV
-90 mV
OUTSIDE
MEMBRANE
INSIDE
Na+
0
4
3
2
1
K+
Ca++ K+
AtpAtp
K+
Na+
K+
Ca++
Na+
K+
Cardiac action potential.mp4

19. Action Potential of SA Node
 RMP not stable and full
repolarisation at -60mV
 Spontaneous
Depolarisation occurs due
to:
• Slow, inward Ca2+
currents
• Slow, inward Na+
currents
called “Funny Currents”
-50mV T-type
Ca2+
channels
-40mV L-type
Ca2+
channels
-35mV
Phase 3:
Repolarisation

20. Action Potential in AVAction Potential in AV
NodeNode
• Very similar to SA Node
• Causes delay of
conduction
• It gives time for atrial
contraction and filling of
the ventricles.
• Site of action of many
antiarrhythmics

21. Regulation by autonomic tone
Parasympathetic/Vagus Nerve
stimulation:
• Ach binds to M2 receptors
• Activate Ach dependent outward K+
conductance (thus hyperpolarisation)
• ↓ phase 4 AP
Sympathetic stimulation:
• Activation of β1 receptors
• Augmentation of L-type Ca2+
current
• Phase 4 AP more steeper

22. Fast channel Vs slow channelFast channel Vs slow channel
APAP
Fast channel APFast channel AP
• Occurs in atria, ventricles,Occurs in atria, ventricles,
PFPF
• Predominant ion in phase-Predominant ion in phase-
0 is Na+0 is Na+
• Conduction velocity moreConduction velocity more
• Selective channel blockerSelective channel blocker
is tetradotoxin , LAis tetradotoxin , LA
Slow channel APSlow channel AP
• Occurs in SA node, A-VOccurs in SA node, A-V
nodenode
• Predominant ion inPredominant ion in
phase-0 is Caphase-0 is Ca2+2+
• LessLess
• Selective channelSelective channel
blockers are calciumblockers are calcium
channel blockerschannel blockers

23. Common termsCommon terms
• AutomaticityAutomaticity
– Capacity of a cell to undergo spontaneousCapacity of a cell to undergo spontaneous
diastolic depolarizationdiastolic depolarization
• ExcitabilityExcitability
– Ability of a cell to respond to external stimulusAbility of a cell to respond to external stimulus
by depolariztionby depolariztion
• Threshold potentialThreshold potential
– Level of intracellular negativity at which abruptLevel of intracellular negativity at which abrupt
and complete depolarization occursand complete depolarization occurs

24. Common termsCommon terms
• Conduction velocity of impulseConduction velocity of impulse
– Determined primarily by slope of actionDetermined primarily by slope of action
potential and amplitude of phase-0, anypotential and amplitude of phase-0, any
reduction in slope leads to depression ofreduction in slope leads to depression of
conductionconduction

25. 25
Comparison of APsComparison of APs
pacemaker
depolarization
spontaneous
depolarization
No pacemaker
depolarization
conducted AP
to cell triggers
depolarization
No pacemaker
depolarization
conducted AP
to cell triggers
depolarization
AP from VENTRICULAR MUSCLE
-80 mV
-80 mV
0
maximum
diastolic
potential
AP from ATRIAL MUSCLE
AP from SA node or AV node

26. Cardiac Action Potential –Cardiac Action Potential –
Pacemaker CellsPacemaker Cells
• PCs - Slow, continuous
depolarization during rest
Slow depolarization
during 0 phase
• Continuously moves
potential towards
threshold for a new action
potential (called a phase
4 depolarization)
•Funny current (If)

27. Refractory period

28. The Normal EKGThe Normal EKG
P
Q
R
S
T
Right Arm
Left Leg
QTPR
0.12-0.2 s approx. 0.44 s
Atrial muscle
depolarization
Ventricular muscle
depolarization
Ventricular
muscle
repolarization

29. Depolarization
&
Repolarization
waves seen in
ECG

30. ECG is used as a rough guide to some
cellular properties of cardiac tissue
• P wave: atrial depolarization
• PR-Interval reflects AV nodal conduction time
• QRS DURATION reflects conduction time in
ventricles
• T-wave: ventricular repolarization
• QT interval is a measure of ventricular APD

31. SA Node fires at 60-100 beats/secSA Node fires at 60-100 beats/sec
Spreads through atriaSpreads through atria
Enters the AV NodeEnters the AV Node
(Delay of 0.15 sec)(Delay of 0.15 sec)
Propagates through His PurkinjePropagates through His Purkinje
systemsystem
Depolarizes ventricles beginningDepolarizes ventricles beginning
from endocardial surface of apex tofrom endocardial surface of apex to
epicardial surface of baseepicardial surface of base
Normal Sinus Rhythm

32. 32

33. 33
Conduction velocity in different tissueConduction velocity in different tissue
very slow
fast
very fast

34. • A-RHYTHM –IA
• Defn- Arrhythmia is deviation of heart from
normal RHYTHM.
• RHYTHM
1) HR- 60-100
2) Should origin from SAN
3) Cardiac impulse should propagate through
normal conduction pathway with normal
velocity.

35. ARRHYTHMIASARRHYTHMIAS
Sinus arrythmia
Atrial arrhythmia
Nodal arrhythmia
(junctional)
Ventricular arrhytmia
SVT

36. Mechanisms of cardiac arrythmia
• Abnormal impulse generation:
• Depressed automaticity
• Enhanced automaticity
• Triggered activity (after depolarization):
• Delayed after depolarization
• Early after depolarization
• Abnormal impulse conduction:
• Conduction block
• Re-entry phenomenon
• Accessory tract pathways

37. a) Enhanced automaticity
In cells which normally display spontaneous diastolic depolarization (SA Node, AVIn cells which normally display spontaneous diastolic depolarization (SA Node, AV
Node, His-Purkinje System)Node, His-Purkinje System)
Automatic behavior in sites that ordinarily lack pacemaker activityAutomatic behavior in sites that ordinarily lack pacemaker activity
CAUSES:
Ischaemia/digitalis/catecholamines/acidosis/
hypokalemia/stretching of cardiac cells
Nonpacemaker nodal tissues: membrane potential
comes to -60mv
Increased slope of phase 4 depolarisation

38. Less negative RMP
More negative Threshold
Ectopic pacemaker activityEctopic pacemaker activity
encouraged byencouraged by

39. b) Trigerred
activity(Afterdepolarizations)+30 mV
0 mV
-80 mV
-90 mV

40. +30 mV
0 mV
-80 mV
-90 mV
Delayed After
Depolarisation
(DAD)
Intracellular cal. Overload (Ischemia
reperfusion, adr.stress, digitalis intoxication
or heart failure)

41. A normal cardiac action potential may be
interrupted or followed by an abnormal
depolarization
Reaches threshold & causes secondary upstrokes
2 Major forms:
1.Early Afterdepolarization
2.Late Afterdepolarization
N.B:Afterdepolarization and Triggered
Activity

42. 1. Early
Afterdepolarization
• Phase 3 of repolarization
interrupted
• Result from inhibition of
Delayed Rectifier K+
Current
• Marked prolongation of Action
Potential
• The mechanism of torsades de
pointes (R on T)

43. 2. Late
Afterdepolarizations
• Secondary deflection after
attaining RMP
• Intracellular Ca2+
overload
• Adrenergic stress, digitalis
intoxication, ischemia-
reperfusion

44. c. Abnormal impulse conductionc. Abnormal impulse conduction
• Conduction blockConduction block
– First degree blockFirst degree block
– Second degree blockSecond degree block
– Third degree blockThird degree block
• Re-entry phenomenonRe-entry phenomenon
• Accessory tract pathwaysAccessory tract pathways

45. INEXCITABLE
TISSUE
Re-entryRe-entry
1
2

46. Re-entry

47. Requirements for re-entry circuitRequirements for re-entry circuit
• Presence of anatomically defined circuitPresence of anatomically defined circuit
• Region of unidirectional blockRegion of unidirectional block
• Re-entry impulse with slow conductionRe-entry impulse with slow conduction

48. Wolff-Parkinson-White
syndrome
Accessory tract pathwaysAccessory tract pathways

49. WPW: Initiation of SVTWPW: Initiation of SVT
SupraventricularSupraventricular
tachycardiatachycardia
••initiated by a closelyinitiated by a closely
coupled premature atrialcoupled premature atrial
complex (PACcomplex (PAC))
••blocks in the accessoryblocks in the accessory
pathwaypathway
••but conducts through thebut conducts through the
AV nodeAV node
••retrograderetrograde conduction viaconduction via
accessory pathwayaccessory pathway
••inverted P wave producedinverted P wave produced
by retrograde conductionby retrograde conduction
visible in the inferior ECGvisible in the inferior ECG
leadsleads

50. SymptomsSymptoms

51. ManagementManagement
OfOf
ArrhythmiasArrhythmias

52. Requirement to treat an arrhythmiaRequirement to treat an arrhythmia::
1.1. ↓↓ COCO::
• Slow contractions (bradyarrhythmias)Slow contractions (bradyarrhythmias)
• Fast contractions (tachyarrhythmias)Fast contractions (tachyarrhythmias)
• Asynchronous contractions (V Tach, V Fib)Asynchronous contractions (V Tach, V Fib)
2.2. Convert to serious Arrhythmias:Convert to serious Arrhythmias:
• Afl → VTach, V Tach → VFAfl → VTach, V Tach → VF
3.3. Thrombus formation:Thrombus formation:
• AF→ Stasis in Atrium→ Thrombus formation→ EmbolismAF→ Stasis in Atrium→ Thrombus formation→ Embolism

53. ManagementManagement
• Acute ManagementAcute Management
• ProphylaxisProphylaxis
• Non PharmacologicalNon Pharmacological
• PharmacologicalPharmacological

54. Non PharmacologicalNon Pharmacological
• AcuteAcute
1.1. Vagal ManeuversVagal Maneuvers
2.2. DC CardioversionDC Cardioversion
• ProphylaxisProphylaxis
1.1. Radiofrequency AblationRadiofrequency Ablation
2.2. Implantable DefibrillatorImplantable Defibrillator
• PacingPacing (Temporary/ Permanent)(Temporary/ Permanent)

55. Pharmacological ApproachPharmacological Approach
Drugs may be antiarrhythmic by:Drugs may be antiarrhythmic by:
• Suppressing the initiator mechanismSuppressing the initiator mechanism
• Altering the re-entrant circuitAltering the re-entrant circuit
1.1.Terminate an ongoing arrhythmiaTerminate an ongoing arrhythmia
2.2.Prevent an arrhythmiaPrevent an arrhythmia

56. Antiarrhythmic drugs: Ideal properties
• Good for all types of arrhythmia
• Prevent reentry (one-way to two way block)
• Increase refractory period
• Block the effects of catecholamines
• Reduce excitability
• Little or no effects on contractility (inotropy)
• Use-dependent block

57. The reality of anti-arrhythmic drugs
• Must match the type of drug to the type of arrhythmia
• The paradox: in the wrong circumstance drugs
may actually trigger arrhythmias
• “Therapeutic window” in many patients is small

58. +30 mV
0 mV
-80 mV
-90 mV
OUTSIDE
MEMBRANE
INSIDE
Na+
0
4
3
2
1
K+
Ca++ K+
AtpAtp
K+
Na+
K+
Ca++
Na+
Na+ Ca++ K+
RATE
SLOPE
Effective Refractory Period
RMP
THRESHOLD POTENTIAL
Possible MOA of antiarrythmic agents

59. Classification of Anti-Arrhythmic Drugs
(Vaughan-Williams-Singh..1969)
Phase 4
Phase 0
Phase 1
Phase 2
Phase 3
0 mV
-
80m
V
II
I
III
IV
Class I: block Na+
channels
Ia (quinidine, procainamide,
disopyramide) (1-10s)
Ib (lignocaine, mixilitine,
phenytoin) (<1s)
Ic (flecainide, propafenone)
(>10s)
Class II: ß-adrenoceptor antagonists
(atenolol, sotalol)
Class III: prolong action potential and
prolong refractory period
(amiodarone, dofetilide, sotalol)
Class IV: Ca2+
channel antagonists
(verapamil, diltiazem)

60. Classification based on clinicalClassification based on clinical
useuse
• Drugs used for supraventricularDrugs used for supraventricular
arrhythmia`sarrhythmia`s
– Adenosine, verapamil, diltiazemAdenosine, verapamil, diltiazem
• Drugs used for ventricular arrhythmiasDrugs used for ventricular arrhythmias
– Lignocaine, mexelitine, bretyliumLignocaine, mexelitine, bretylium
• Drugs used for supraventricular as well asDrugs used for supraventricular as well as
ventricular arrhythmiasventricular arrhythmias
– Amiodarone,Amiodarone, ββ- blockers, disopyramide,- blockers, disopyramide,
procainamideprocainamide

61. Class I: Na+
Channel Blockers
• IA: Ʈrecovery moderate (1-10sec)
Prolong APD
• IB: Ʈrecovery fast (<1sec)
Shorten APD in some heart
tissues
• IC: Ʈrecovery slow(>10sec)
Minimal effect on APD

62. CLASS I ANTI ARRHYTHMICCLASS I ANTI ARRHYTHMIC
DRUGSDRUGS
• It is largest class of Anti arrhythmic drugs.It is largest class of Anti arrhythmic drugs.
• Class I anti arrhythmic drugs act by blocking voltage-Class I anti arrhythmic drugs act by blocking voltage-
sensitive sodium (Nasensitive sodium (Na++
) channels. These drugs bind to) channels. These drugs bind to
sodium channels when the channels are open and insodium channels when the channels are open and in
activated state and dissociate when the channels areactivated state and dissociate when the channels are
in resting phase.in resting phase.
• Inhibition of sodium channel decrease rate of rise ofInhibition of sodium channel decrease rate of rise of
phase 0 of cardiac membrane action potential and aphase 0 of cardiac membrane action potential and a
slowing of conduction velocity.slowing of conduction velocity.
• They also block K channels (class IA) thus, slows theThey also block K channels (class IA) thus, slows the
repolarization in ventricular tissue.repolarization in ventricular tissue.
• These drugs have local anesthetic activity and mayThese drugs have local anesthetic activity and may
suppress myocardial contractile force, these affects aresuppress myocardial contractile force, these affects are
observed at a higher plasma concentration.observed at a higher plasma concentration.

63. USE DEPENDENCEUSE DEPENDENCE::USE DEPENDENCEUSE DEPENDENCE::
• Class I drugs bind more rapidly to open orClass I drugs bind more rapidly to open or
inactivated sodium channels than to channels thatinactivated sodium channels than to channels that
are fully repolarized following recovery from theare fully repolarized following recovery from the
previous depolarization cycle. Therefore, theseprevious depolarization cycle. Therefore, these
drugs show a greater degree of blockade indrugs show a greater degree of blockade in
tissues that are frequently depolarizing (fortissues that are frequently depolarizing (for
example, during tachycardia, when the sodiumexample, during tachycardia, when the sodium
channels open often). This property is called use-channels open often). This property is called use-
dependence (or state-dependence) and it enablesdependence (or state-dependence) and it enables
these drugs to block cells that are discharging atthese drugs to block cells that are discharging at
an abnormally high frequency, without interferingan abnormally high frequency, without interfering
with the normal, low-frequency beating of thewith the normal, low-frequency beating of the
heart.heart.

64. Class I anti arrhythmic drugs areClass I anti arrhythmic drugs are
classified into three sub classesclassified into three sub classes::
ClassificationClassification::

67. Class IAClass IA

68. QuinidineQuinidine
• Historically first antiarrhythmic drug used.Historically first antiarrhythmic drug used.
• In 18th century, the bark of the cinchonaIn 18th century, the bark of the cinchona
plant was used to treat "plant was used to treat "rebelliousrebellious
palpitationspalpitations““
pharmacological effectspharmacological effects
threshold for excitabilitythreshold for excitability
automaticityautomaticity
prolongs APprolongs AP

69. QuinidineQuinidine
• Clinical PharmacokineticsClinical Pharmacokinetics
• well absorbedwell absorbed
• 80% bound to plasma proteins (albumin)80% bound to plasma proteins (albumin)
• extensive hepatic oxidative metabolismextensive hepatic oxidative metabolism

70. QuinidineQuinidine
• UsesUses
• to maintain sinus rhythm in patients withto maintain sinus rhythm in patients with
atrial flutter or atrial fibrillationatrial flutter or atrial fibrillation
• to prevent recurrence of ventricularto prevent recurrence of ventricular
tachycardia or VFtachycardia or VF

71. QuinidineQuinidine
Adverse EffectsAdverse Effects--
Non cardiacNon cardiac
• Diarrhea, thrombocytopenia,Diarrhea, thrombocytopenia,
• cinchonism & skin rashes.cinchonism & skin rashes.
cardiaccardiac
marked QT-interval prolongationmarked QT-interval prolongation
&torsades de pointes (2-8% )&torsades de pointes (2-8% )
hypotensionhypotension
tachycardiatachycardia

72. Drug interactionsDrug interactions
• Metabolized by CYP450Metabolized by CYP450
• Increases digoxin levelsIncreases digoxin levels
• Cardiac depression with beta blockersCardiac depression with beta blockers
• Inhibits CYP2D6Inhibits CYP2D6

73. DisopyramideDisopyramide
• Exerts electrophysiologic effects very similarExerts electrophysiologic effects very similar
to those of quinidine.to those of quinidine.
• Better tolerated than quinidineBetter tolerated than quinidine
• exert prominent anticholinergic actionsexert prominent anticholinergic actions
• Negative ionotropic action.Negative ionotropic action.
• A/E-A/E-
• precipitation of glaucoma,precipitation of glaucoma,
• constipation, dry mouth,constipation, dry mouth,
• urinary retentionurinary retention

74. ProcainamideProcainamide
• Lesser vagolytic action , depression ofLesser vagolytic action , depression of
contractility & fall in BPcontractility & fall in BP
• Metabolized by acetylation to N-acetylMetabolized by acetylation to N-acetyl
procainamide which can block K+procainamide which can block K+
channelschannels
• Doesn’t alter plasma digoxin levelsDoesn’t alter plasma digoxin levels
• Cardiac adverse effects like quinidineCardiac adverse effects like quinidine
• Can cause SLE not recommended > 6Can cause SLE not recommended > 6
monthsmonths

75. Class IB drugsClass IB drugsClass IB drugsClass IB drugs
Lignocaine, phenytoin,
mexiletine
Block sodium channels
also shorten
repolarization

76. Class IbClass Ib

77. LignocaineLignocaine
• Relatively selective for partiallyRelatively selective for partially
depolarized cellsdepolarized cells
• Selectively acts on diseased myocardiumSelectively acts on diseased myocardium
• Only in inactive state of Na+ channelsOnly in inactive state of Na+ channels
• Rapid onset & shorter duration of actionRapid onset & shorter duration of action
• Useful only in ventricular arrhythmias ,Useful only in ventricular arrhythmias ,
Digitalis induced ventricular arrnhythmiasDigitalis induced ventricular arrnhythmias

78. • Lidocaine is not useful in atrialLidocaine is not useful in atrial
arrhythmias???arrhythmias???
• atrial action potentials are so short thatatrial action potentials are so short that
thethe NaNa++
channel is in the inactivated statechannel is in the inactivated state
only brieflyonly briefly

79. Pharmacokinetics
• High first pass metabolism
• Metabolism dependent on hepatic blood flow
• T ½ = 8 min – distributive, 2 hrs – elimination
• Propranolol decreases half life of lignocaine
• Dose= 50-100 mg bolus followed by 20-40 mg
every 10-20 min i.v

80. Adverse effects
• Relatively safe in recommended doses
• Drowsiness, disorientation, muscle twitchings
• Rarely convulsions, blurred vision, nystagmus,,
deafness
• Increases CHF

81. • LLocal anaestheticocal anaesthetic
• IInactive orallynactive orally
• GGiven IV for antiarrhythmic actioniven IV for antiarrhythmic action
• NNa+ channel blockade which occursa+ channel blockade which occurs
• OOnly in inactive state of Na+ channelsnly in inactive state of Na+ channels
• CCNS side effects in high dosesNS side effects in high doses
• AAction lasts only for 15 minction lasts only for 15 min
• IInhibits purkinje fibres and ventricles butnhibits purkinje fibres and ventricles but
• NNo action on AVN and SAN soo action on AVN and SAN so
• EEffective in Ventricular arrhythmias onlyffective in Ventricular arrhythmias only

82. MexiletineMexiletine
• Oral analogue of lignocaineOral analogue of lignocaine
• No first pass metabolism in liverNo first pass metabolism in liver
• UseUse::
– chronic treatment of ventricular arrhythmiaschronic treatment of ventricular arrhythmias
associated with previous MIassociated with previous MI
– Unlabelled use in diabetic neuropathyUnlabelled use in diabetic neuropathy
• Tremor is early sign of mexiletine toxicityTremor is early sign of mexiletine toxicity
• Hypotension, bradycardia, widened QRS ,Hypotension, bradycardia, widened QRS ,
dizziness, nystagmus may occurdizziness, nystagmus may occur

83. TocainideTocainide
• Structurally similar to lignocaine but canStructurally similar to lignocaine but can
be administered orallybe administered orally
• Serious non cardiac side effects likeSerious non cardiac side effects like
pulmonary fibrosis, agranulocytosis,pulmonary fibrosis, agranulocytosis,
thrombocytopenia limit its usethrombocytopenia limit its use

84. Class I C drugs
Encainide, Flecainide, Propafenone
Class I C drugs
Encainide, Flecainide, Propafenone
Have minimal effect on
repolarization
Are most potent sodium
channel blockers
Have minimal effect on
repolarization
Are most potent sodium
channel blockers
• Risk of cardiac arrest ,
sudden death so not used
commonly
• May be used in severe
ventricular arrhythmias
• Risk of cardiac arrest ,
sudden death so not used
commonly
• May be used in severe
ventricular arrhythmias

85. Class IcClass Ic

86. Propafenone class 1cPropafenone class 1c
• Structural similarity with propranolol & hasStructural similarity with propranolol & has
ββ-blocking action(Not to be used with-blocking action(Not to be used with
bronchospasm)bronchospasm)
• Undergoes variable first pass metabolismUndergoes variable first pass metabolism
• Reserve drug for ventricular arrhythmias,Reserve drug for ventricular arrhythmias,
re-entrant tachycardia involving accesoryre-entrant tachycardia involving accesory
pathwaypathway
• Adverse effects: metallic taste,Adverse effects: metallic taste,
constipation and is proarrhythmicconstipation and is proarrhythmic

87. Flecainde (Class Ic)
• Potent blocker of Na & K channels with slow
unblocking kinetics
• Blocks K channels but does not prolong APD & QT
interval
• Maintain sinus rhythm in supraventricular
arrhythmias
• Cardiac Arrhythmia Suppression Test (CAST Trial):
When Flecainide & other Class Ic given
prophylactically to patients convalescing from
Myocardial Infarction it increased mortality by
2½ fold. Therefore the trial had to be
prematurely terminated (Don't use in SHD)

88. Class II: Beta blockersClass II: Beta blockers
• β-receptor stimulation:
• ↑ automaticity,
• ↑ AV conduction velocity,
• ↓ refractory period
• β-adrenergic blockers competitively block
catecholamine induced stimulation of cardiac
β- receptors

89. Beta blockersBeta blockers
• Depress phase 4 depolarization ofDepress phase 4 depolarization of
pacemaker cells,pacemaker cells,
• Slow sinus as well as AV nodal conduction :Slow sinus as well as AV nodal conduction :
– ↓↓ HR, ↑ PRHR, ↑ PR
• ↑↑ ERP,ERP, prolong AP Duration byprolong AP Duration by ↓ AV↓ AV
conductionconduction
• Reduce myocardial oxygen demandReduce myocardial oxygen demand
• Well tolerated, SaferWell tolerated, Safer

91. Esmolol
• β1 selective agent
• Very short elimination t1/2 :9 mins
• Metabolized by RBC esterases
• Rate control of rapidly conducted AF
• Use:
• Arrythmia associated with anaesthesia
• Supraventricular tachycardia

92. Use in arrhythmia
• Control supraventricular arrhythmias
• Atrial flutter, fibrillation, PSVT
• Treat tachyarrhythmias caused by adrenergic
• Hyperthyroidism Pheochromocytoma,
during anaesthesia with halothane
• Digitalis induced tachyarrythmias
• Prophylactic in post-MI
• Ventricular arrhythmias in prolonged QT
syndrome
+

93. Class III drugsClass III drugs
↑APD & ↑RP by
blocking the K+
channels

94. Vm
(mV)
-80mV
0mV
↑ APD
Block IK

96. AmiodaroneAmiodarone
• Iodine containing long acting drug
• Mechanism of action: (Multiple actions: Class
I, II, III, VI)
–Prolongs APD by blocking K+
channels
–blocks inactivated sodium channels
–β blocking action , Blocks Ca2+
channels
–↓ Conduction, ↓ectopic automaticity
(Broad spectrum, but 2nd
choice
antiarrhythmic)

97. • Pharmacokinetics:Pharmacokinetics:
– Variable absorption 35-65%Variable absorption 35-65%
– Slow onset 2days to several weeksSlow onset 2days to several weeks
– Duration of action : weeks to monthsDuration of action : weeks to months
• DoseDose
– Loading dose: 5mg/kg overLoading dose: 5mg/kg over
30min.,Then maintenance infusion of30min.,Then maintenance infusion of
50 mg/h. for 24 hr50 mg/h. for 24 hr
AmiodaroneAmiodarone

98. AmiodaroneAmiodarone
• Uses:
– Can be used for both supraventricular and
ventricular tachycardia
• Adverse effects:
– Cardiac: heart block , QT prolongation, bradycardia,
cardiac failure, hypotension
– Pulmonary: pneumonitis leading to pulmonary
fibrosis
– Bluish discoloration of skin, corneal microdeposits
– GIT disturbances, hepatotoxicity
– Blocks peripheral conversion of T4to T3 can cause
hypothyroidism or hyperthyroidism

99. • AAntiarrhythmicntiarrhythmic
• MMultiple actionsultiple actions
• IIodine containingodine containing
• OOrally used mainlyrally used mainly
• DDuration of action is very long (t ½ = 3-8uration of action is very long (t ½ = 3-8
weeks)weeks)
• AAPD & ERP increasesPD & ERP increases
• RResistant AF, V tach, Recurrent VF areesistant AF, V tach, Recurrent VF are
indicationsindications
• OOn prolonged use- pulmonary fibrosisn prolonged use- pulmonary fibrosis
• NNeuropathy may occureuropathy may occur
• EEye : corneal microdeposits may occurye : corneal microdeposits may occur

100. • Bretylium:
– Adrenergic neuron blocker used in resistant
ventricular arrhythmias
• Sotalol:
– Non selective Beta blocker (Class II, III)
• Dofetilide, Ibutilide :
– Selective K+
channel blocker, less adverse events
– use in AF to convert or maintain sinus rhythm
– May cause QT prolongation

101. Newer class III drugs
• Dronedarone: amiodarone like drugDronedarone: amiodarone like drug
without iodine atoms so no pulmonary orwithout iodine atoms so no pulmonary or
thyroid toxicity(Not use in severe HF)thyroid toxicity(Not use in severe HF)
• Vernakalant : Convert 90% of AF cases inVernakalant : Convert 90% of AF cases in
1hour(Not use in severe HF)1hour(Not use in severe HF)
• AzimilideAzimilide
• TedisamilTedisamil

102. Calcium channel blockers (Class IV)Calcium channel blockers (Class IV)
• Inhibit the inward
movement of calcium
↓ contractility,
automaticity , and AV
conduction.
• Verapamil & diltiazem

103. VerapamilVerapamil
• Uses:
– Terminate PSVT
– control ventricular rate in atrial flutter or
fibrillation
• Drug interactions:
– Displaces digoxin from binding sites
– ↓ renal clearance of digoxin

104. Other antiarrhythmicsOther antiarrhythmics
• Adenosine :
– Purine nucleoside having short and rapid action
(Seconds)
– IV suppresses automaticity, AV conduction and
dilates coronaries
– Drug of choice for PSVT
– Adverse events:
• Nausea, dyspnoea, flushing, headache, bronchospasm
(The antidote: Theophylline)

105. Vm
(mV)
-80mV
0mV
↓ APD
Hyperpolarization
Adenosine

106. Adenosine
• Acts on specific G protein-coupled adenosine
receptors
• Activates AcH sensitive K+ channels channels in SA
node, AV node & Atrium
• Shortens APD, hyperpolarization & ↓ automaticity
• Inhibits effects of ↑ cAMP with sympathetic
stimulation
• ↓ Ca currents
• ↑AV Nodal refractoriness & inhibit DAD’s

107. • Atropine:Atropine: Used in bradycardiaUsed in bradycardia
• Digitalis:Digitalis: Atrial fibrillation and atrial flutterAtrial fibrillation and atrial flutter
• Magnesium SOMagnesium SO44:: digitalis induceddigitalis induced
arrhythmias, Tosades de pointesarrhythmias, Tosades de pointes
Other antiarrhythmicsOther antiarrhythmics

108. DigitalisDigitalis

109. Digitalis
• Acts by blocking Na+
/K+
ATPase→ +ve Inotropic effect
• Antiarrhythmic actions exerted by AV Nodal
Refractoriness by:
Vagotonic actions→ inhibit Ca2+
currents in AV node
•Activation of IKAch in atrium: hyperpolarization & shortening of
APD in atria
•↑ Phase 4 slope→ ↑ Rate of automaticity in ectopic
pacemakers

110. • ECG: PR prolongation, ST segment depession
• Adverse Effects:
 Non cardiac: Nausea, disturbance of cognition,
yellow vision
 Cardiac: Digitalis induced arrhythmias
• PK: Digoxin- 20-30% protein bound, slow
distribution to effector sites, loading dose given,
t1/2
36hrs, renal elimination

111. Digitoxin- hepatic metabolism, highly protein
bound, t1/2
7days
Toxicity results with amiodarone & quindine
(↓ clearance) Thus dose has to be decreased
•Used in terminating re-entrant arrhythmia
involving AV Node & controlling ventricular rate
in AF

112. Magnesium
• Its mechanism of action is unknown but may
influence Na+/K+ATPase, Na+ channels,
certain K+ channels & Ca2+ channels
• Use: Digitalis induced arrhythmias if
hypomagnesemia present, refractory
ventricular tachyarrythmias, Torsade de
pointes even if serum Mg2+ is normal
• Given 2g over 10mins

113. Drugs of choicesDrugs of choices
S.S.
NN
oo
ArrhythmiaArrhythmia DrugDrug
11 Sinus tachycardiaSinus tachycardia PropranololPropranolol
22 Atrial extrasystoleAtrial extrasystole Propranolol,Propranolol,
33 AF/FlutterAF/Flutter Esmolol, verapamilEsmolol, verapamil
,digoxin,digoxin
44 PSVTPSVT Adenosine ,esmololAdenosine ,esmolol
55 VentricularVentricular
TachycardiaTachycardia
Lignocaine , procainamideLignocaine , procainamide
, Amiodarone, Amiodarone

115. Toxicities

116. Class IClass I
Conduction slowing can account forConduction slowing can account for
toxicitytoxicity
Afl 300/minAfl 300/min
Slowing of conduction with Na+ channel blockerSlowing of conduction with Na+ channel blocker
AV Node permits greater no of impulsesAV Node permits greater no of impulses
(Drop in Afl 300/min with 2:1 or 4:1 AV conduction(Drop in Afl 300/min with 2:1 or 4:1 AV conduction
to 220/min with 1:1 conductionto 220/min with 1:1 conduction HRHR
220beats/min220beats/min), So should be combined with BB,), So should be combined with BB,
Ccb, digitalis.Ccb, digitalis.

117. Class II
• Bradycardia & exacerbation of CCF in patients
with low ejection fraction
Class Ia & Class III
• Excessive QT prolongation & torsades de
pointes
• ‘‘Twisting of points”

118. • Rapid, polymorphic ventricular tachycardia
•Twist of the QRS complex around the
isoelectric baseline
• Fall in arterial blood pressure
• Can degenerate into Ventricular fibrillation

119. Treatment:
• Withdrawal of offending drug
•Magnesium sulphate
•Phenytoin
•Isoproterenol infusion/Pacing
•Defibrillation

120. Digitalis Induced Arrhythmias
• Can cause virtually any arrhythmia
• DAD related tachycardia with impairment of
SAN & AVN
• Atrial tachycardia with AV block is classic
• Ventricular bigeminy
• Bidirectional ventricular tachycardia
• AV junctional tachycardia
• Various degrees of AV block
• Sever intoxication: Severe bradycardia with
hyperkalemia

121. Treatment
• Sinus bradycardia & AV block: Atropine
• Digitalis induced tachycardia responds to Mg2+
• Antidigoxin (DIGIBIND) binds to digoxin &
digitoxin thereby enhancing their renal excretion
• SA & Node AV Node dysfunction may require
temporary pacing