Basics of arrhythmias & Antiarrhythmic drugs

ByByIslam GhanemIslam Ghanem

Assistant lecturer-Cardiology-Assistant lecturer-Cardiology-ZagazigZagazig

20142014

AntiarrhythmicsAntiarrhythmics???? ????

– In a textbook In a textbook Interesting but Interesting but sedative.sedative.•Try it if you have insomnia Try it if you have insomnia

– In the lecture In the lecture Confusion ??????????Confusion ??????????•As always As always

– In the exam hall In the exam hall Panic! Panic! •Don’t worry rarely asked Don’t worry rarely asked

Cardiac ElectrophysiologyCardiac Electrophysiology

• A transmembrane electrical gradient (potential) is A transmembrane electrical gradient (potential) is maintained, with the interior of the cell negative maintained, with the interior of the cell negative with respect to outside the cellwith respect to outside the cell

• Caused by unequal distribution of ions inside vs. Caused by unequal distribution of ions inside vs. outside celloutside cell– 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 Maintenance by ion selective channels, active pumps and exchangerspumps and exchangers

Ion Flow and the Action Ion Flow and the Action PotentialPotential

K+

(140 mM)

Na +

(140 mM)K+

(5 mM)

Na +

(5 mM)

Ca2+

(1.8 mM)

Ca2+

(100 nM)

outside

inside

Depolarizing Repolarizing

6

Effect of channels openingEffect of channels opening1. When channel is closed, no current flows through channel 2. When cations (+) enter cell ("inward current"), cell depolarizes

(becomes more positive inside)

depolarizinginward (+) current

+repolarizingoutward (+) 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

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

Membrane currents that underlie the Membrane currents that underlie the cardiac APcardiac AP

heart cell

Voltage-gated Channels of interest to usNa+ (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

TransporterN+/Ca2+ exchanger INCX

Electrophysiology of cardiac Electrophysiology of cardiac tissuetissue

• Impulse generation and transmission Impulse generation and transmission

• Myocardial action potential Myocardial action potential

• Depolarization and repolarization Depolarization and repolarization waves as seen in ECG waves as seen in ECG

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 fibresCapable of generating their own impulseNormally SA node acts as Pacemaker of heart

• NON-AUTOMATIC MYOCARDIAL CONTRACTILE FIBRES (Na+ driven tissues)Cannot generate own impulse Includes atria and ventricles

Impulse generation and Impulse generation and transmissiontransmission

Myocardial action Myocardial action potentialpotential

In automatic tissues In non-automatic tissues

Action potential in Non Action potential in Non automatic myocardial automatic myocardial

contractile tissuecontractile tissue

+30 mV

0 mV

-80 mV

-90 mV

OUTSIDE

MEMBRANE

INSIDE

Na+

0

4

3

21

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

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

•Phase 0:Phase 0: rapid depolarization of cell rapid depolarization of cell membrane during which theirs is fast membrane during which theirs is fast entry of Na ions into the cells through entry of Na ions into the cells through Na channels, this is followed by Na channels, this is followed by repolarization.repolarization.

•Phase 1:Phase 1: is short initial rapid is short initial rapid repolarization due to Ka effluxrepolarization due to Ka efflux

•Phase 2:Phase 2:prolonged plateue phase due prolonged plateue phase due to slow Ca influxto slow Ca influx

•Phases 3:Phases 3: rapid repolarization with Ka rapid repolarization with Ka effluxefflux

•Phase 4:Phase 4: resting phase during which resting phase during which Ka ions return into the cell while Na Ka ions return into the cell while Na and Ka move out of it and resting and Ka move out of it and resting membrane potential is storedmembrane potential is stored

Action potential in nodal Action potential in nodal tissuestissues

+30 mV

0 mV

-80 mV

-90 mV

OUTSIDE

MEMBRANE

INSIDE

Na+

0

4

3

21

K+ Ca++ K+

AtpAtp

K+Na+

K+

Ca++

Na+

K+

Cardiac action potential.mp4

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

Action Potential in AV Action 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

Regulation by autonomic toneParasympathetic/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

Fast channel Vs slow Fast channel Vs slow channel APchannel AP

Fast channel APFast channel AP

• Occurs in atria, Occurs in atria, ventricles, PFventricles, PF

• Predominant ion in Predominant ion in phase-0 is Na+phase-0 is Na+

• Conduction velocity Conduction velocity more more

• Selective channel Selective channel blocker is blocker is tetradotoxin , LA tetradotoxin , LA

Slow channel APSlow channel AP

• Occurs in SA node, A-V Occurs in SA node, A-V nodenode

• Predominant ion in Predominant ion in phase-0 is Caphase-0 is Ca2+2+

• Less Less

• Selective channel Selective channel blockers are calcium blockers are calcium channel blockers channel blockers

Common termsCommon terms

• Automaticity Automaticity – Capacity of a cell to undergo spontaneous Capacity of a cell to undergo spontaneous

diastolic depolarizationdiastolic depolarization

• Excitability Excitability – Ability of a cell to respond to external Ability of a cell to respond to external

stimulus by depolariztionstimulus by depolariztion

• Threshold potential Threshold potential – Level of intracellular negativity at which Level of intracellular negativity at which

abrupt and complete depolarization occurs abrupt and complete depolarization occurs

Common termsCommon terms

• Conduction velocity of impulseConduction velocity of impulse– Determined primarily by slope of action Determined primarily by slope of action

potential and amplitude of phase-0, any potential and amplitude of phase-0, any reduction in slope leads to depression of reduction in slope leads to depression of conduction conduction

25

Comparison of APsComparison of APs

pacemakerdepolarization

spontaneousdepolarization

No pacemakerdepolarization

conducted APto cell triggersdepolarization

No pacemakerdepolarization

conducted APto cell triggersdepolarization

AP from VENTRICULAR MUSCLE

-80 mV

-80 mV

0

maximumdiastolic potential

AP from ATRIAL MUSCLE

AP from SA node or AV node

Cardiac Action Potential – Cardiac Action Potential – Pacemaker CellsPacemaker Cells

• PCs - Slow, continuous depolarization during restSlow depolarization during 0 phase• Continuously moves potential towards threshold for a new action potential (called a phase 4 depolarization)•Funny current (If)

Refractory period

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 muscledepolarization

Ventricular muscledepolarization

Ventricular musclerepolarization

Depolarization &

Repolarization waves seen in

ECG

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

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 Purkinje Propagates through His Purkinje systemsystem

Depolarizes ventricles Depolarizes ventricles beginning from endocardial beginning from endocardial surface of apex to epicardial surface of apex to epicardial surface of basesurface of base

Normal Sinus Rhythm

32

33

Conduction velocity in different tissueConduction velocity in different tissue

very slow

fast

very fast

• A-RHYTHM –IA• Defn- Arrhythmia is deviation of heart from

normal RHYTHM.

• RHYTHM1) HR- 60-1002) Should origin from SAN3) Cardiac impulse should propagate through normal conduction pathway with normal

velocity.

ARRHYTHMIASARRHYTHMIASSinus arrythmia

Atrial arrhythmia

Nodal arrhythmia(junctional)

Ventricular arrhytmia

SVT

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

a) Enhanced automaticityIn cells which normally display spontaneous diastolic depolarization (SA In cells which normally display spontaneous diastolic depolarization (SA Node, AV Node, His-Purkinje System)Node, AV 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

Become ECTOPIC PACEMAKERS.(AV nodal rhythm, idioventricular rhythm, ectopic beats)

Less negative RMP

More negative Threshold point

Ectopic pacemaker activity Ectopic pacemaker activity encouraged byencouraged by

b) Trigerred activity(Afterdepolarizations)

+30 mV

0 mV

-80 mV

-90 mV

+30 mV

0 mV

-80 mV

-90 mV

Delayed After Depolarisation

(DAD)

Intracellular cal. Overload (Ischemia reperfusion, adr.stress, digitalis intoxication or heart failure)

A normal cardiac action potential may be interrupted or followed by an abnormal depolarization

Reaches threshold & causes secondary upstrokes

2 Major forms:

1.Early Afterdepolarization2.Late Afterdepolarization

N.B:Afterdepolarization and Triggered Activity

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)

2. Late Afterdepolarizations

• Secondary deflection after attaining RMP

• Intracellular Ca2+ overload

• Adrenergic stress, digitalis intoxication, ischemia-reperfusion

c. Abnormal impulse c. Abnormal impulse conductionconduction

• Conduction blockConduction block– First degree block First degree block – Second degree block Second degree block – Third degree block Third degree block

• Re-entry phenomenon Re-entry phenomenon

• Accessory tract pathways Accessory tract pathways

INEXCITABLE TISSUE

Re-entryRe-entry

12

Re-entry

Requirements for re-entry Requirements for re-entry circuitcircuit

• Presence of anatomically defined Presence of anatomically defined circuit circuit

• Region of unidirectional block Region of unidirectional block

• Re-entry impulse with slow Re-entry impulse with slow conduction conduction

Wolff-Parkinson-White syndrome

Accessory tract pathwaysAccessory tract pathways

WPW: Initiation of SVTWPW: Initiation of SVT

Supraventricular Supraventricular tachycardiatachycardia

••initiated by a closely initiated by a closely coupled premature coupled premature atrial complex (PAC)atrial complex (PAC)

••blocks in the accessory blocks in the accessory pathwaypathway

••but conducts through but conducts through the AV nodethe AV node

••retrograde retrograde conduction conduction via via accessory pathwayaccessory pathway

••inverted P wave inverted P wave produced by retrograde produced by retrograde conduction visible in conduction visible in the inferior ECG leadsthe inferior ECG leads

SymptomsSymptoms

Management Management Of Of

ArrhythmiasArrhythmias

Requirement to treat an Requirement to treat an arrhythmiaarrhythmia::

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

ManagementManagement

• Acute ManagementAcute Management

• ProphylaxisProphylaxis

• Non PharmacologicalNon Pharmacological

• PharmacologicalPharmacological

Non PharmacologicalNon Pharmacological• AcuteAcute1.1. Vagal ManeuversVagal Maneuvers

2.2. DC CardioversionDC Cardioversion

• ProphylaxisProphylaxis1.1. Radiofrequency AblationRadiofrequency Ablation

2.2. Implantable DefibrillatorImplantable Defibrillator

• PacingPacing (Temporary/ (Temporary/ Permanent) Permanent)

Pharmacological Pharmacological ApproachApproach

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

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

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

+30 mV

0 mV

-80 mV

-90 mV

OUTSIDE

MEMBRANE

INSIDE

Na+

0

4

3

21

K+ Ca++ K+

AtpAtp

K+Na+

K+

Ca++

Na+

Na+ Ca++ K+

RATE

SLOPE

Effective Refractory PeriodRMP

THRESHOLD POTENTIAL

Possible MOA of antiarrythmic agents

Classification of Anti-Arrhythmic Drugs (Vaughan-Williams-Singh..1969)

Phase 4

Phase 0

Phase 1

Phase 2

Phase 3

0 mV

-80mV

II

IIII

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)

Classification based on Classification based on clinical useclinical use

• Drugs used for supraventricular Drugs used for supraventricular arrhythmia`sarrhythmia`s– Adenosine, verapamil, diltiazemAdenosine, verapamil, diltiazem

• Drugs used for ventricular arrhythmias Drugs used for ventricular arrhythmias – Lignocaine, mexelitine, bretylium Lignocaine, mexelitine, bretylium

• Drugs used for supraventricular as well Drugs used for supraventricular as well as ventricular arrhythmiasas ventricular arrhythmias– Amiodarone, Amiodarone, - blockers, disopyramide, - blockers, disopyramide,

procainamide procainamide

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

CLASS I ANTI ARRHYTHMIC CLASS 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 in sodium channels when the channels are open and in activated state and dissociate when the channels are activated state and dissociate when the channels are in resting phase.in resting phase.

• Inhibition of sodium channel decrease rate of rise of Inhibition of sodium channel decrease rate of rise of phase 0 of cardiac membrane action potential and a phase 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 the They also block K channels (class IA) thus, slows the repolarization in ventricular tissue.repolarization in ventricular tissue.

• These drugs have local anesthetic activity and may These drugs have local anesthetic activity and may suppress myocardial contractile force, these affects are suppress myocardial contractile force, these affects are observed at a higher plasma concentration.observed at a higher plasma concentration.

USE DEPENDENCEUSE DEPENDENCE::USE DEPENDENCEUSE DEPENDENCE::

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

Class I anti arrhythmic drugs are Class I anti arrhythmic drugs are classified into three sub classesclassified into three sub classes::

ClassificationClassification::

Class IAClass IA

QuinidineQuinidine

• Historically first antiarrhythmic drug used. Historically first antiarrhythmic drug used.

• In 18th century, the bark of the cinchona In 18th century, the bark of the cinchona plant was used to treat "plant was used to treat "rebellious rebellious palpitationspalpitations““

pharmacological effectspharmacological effects

threshold for excitability threshold for excitability

automaticityautomaticity

prolongs APprolongs AP

QuinidineQuinidine

• Clinical PharmacokineticsClinical Pharmacokinetics

• well absorbed well absorbed

• 80% bound to plasma proteins 80% bound to plasma proteins (albumin)(albumin)

• extensive hepatic oxidative extensive hepatic oxidative metabolismmetabolism

QuinidineQuinidine

•UsesUses

• to maintain sinus rhythm in patients to maintain sinus rhythm in patients

with atrial flutter or atrial fibrillation with atrial flutter or atrial fibrillation

• to prevent recurrence of ventricular to prevent recurrence of ventricular

tachycardia or VFtachycardia or VF

QuinidineQuinidineAdverse EffectsAdverse Effects--

Non cardiacNon cardiac• Diarrhea, thrombocytopenia,Diarrhea, thrombocytopenia,

• cinchonism & skin rashes.cinchonism & skin rashes.

cardiaccardiac marked QT-interval prolongation marked QT-interval prolongation

&torsades de pointes (2-8% )&torsades de pointes (2-8% )

hypotension hypotension

tachycardiatachycardia

Drug interactionsDrug interactions

• Metabolized by CYP450 Metabolized by CYP450

• Increases digoxin levelsIncreases digoxin levels

• Cardiac depression with beta Cardiac depression with beta blockers blockers

• Inhibits CYP2D6 Inhibits CYP2D6

DisopyramideDisopyramide

• Exerts electrophysiologic effects very Exerts electrophysiologic effects very similar to those of quinidine.similar 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

ProcainamideProcainamide

• Lesser vagolytic action , depression of Lesser vagolytic action , depression of contractility & fall in BPcontractility & fall in BP

• Metabolized by acetylation to N-acetyl Metabolized by acetylation to N-acetyl procainamide which can block K+ channels procainamide which can block K+ channels

• Doesn’t alter plasma digoxin levelsDoesn’t alter plasma digoxin levels

• Cardiac adverse effects like quinidine Cardiac adverse effects like quinidine

• Can cause SLE not recommended > 6 Can cause SLE not recommended > 6 months months

• Use: Monomorphic VT, WPW, Preexcited Use: Monomorphic VT, WPW, Preexcited AFAF

Class IB drugsClass IB drugsClass IB drugsClass IB drugs

Lignocaine, phenytoin, mexiletine

Block sodium channels also shorten repolarization

Class IbClass Ib

LignocaineLignocaine • Relatively selective for partially Relatively selective for partially

depolarized cells depolarized cells

• Selectively acts on diseased Selectively acts on diseased myocardium myocardium

• Only in inactive state of Na+ channels Only in inactive state of Na+ channels

• Rapid onset & shorter duration of Rapid onset & shorter duration of action action

• Useful only in ventricular Useful only in ventricular arrhythmias , Digitalis induced arrhythmias , Digitalis induced ventricular arrnhythmias ventricular arrnhythmias

• Lidocaine is not useful in atrial Lidocaine is not useful in atrial arrhythmias??? arrhythmias???

• atrial action potentials are so short atrial action potentials are so short

that the that the NaNa++ channel is in the channel is in the

inactivated state only brieflyinactivated state only briefly

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

Adverse effects

• Relatively safe in recommended doses • Drowsiness, disorientation, muscle twitchings• Rarely convulsions, blurred vision, nystagmus,,

deafness • Increases CHF

• LLocal anaesthetic ocal anaesthetic

• IInactive orally nactive orally

• GGiven IV for antiarrhythmic action iven IV for antiarrhythmic action

• NNa+ channel blockade which occursa+ channel blockade which occurs

• OOnly in inactive state of Na+ channels nly in inactive state of Na+ channels

• CCNS side effects in high doses NS side effects in high doses

• AAction lasts only for 15 minction lasts only for 15 min

• IInhibits purkinje fibres and ventricles but nhibits purkinje fibres and ventricles but

• NNo action on AVN and SAN so o action on AVN and SAN so

• EEffective in Ventricular arrhythmias only ffective in Ventricular arrhythmias only

MexiletineMexiletine

• Oral analogue of lignocaine Oral analogue of lignocaine

• No first pass metabolism in liver No first pass metabolism in liver

• UseUse: : – chronic treatment of ventricular chronic treatment of ventricular

arrhythmias associated with previous MI arrhythmias associated with previous MI – Unlabelled use in diabetic neuropathy Unlabelled use in diabetic neuropathy

• Tremor is early sign of mexiletine Tremor is early sign of mexiletine toxicity toxicity

• Hypotension, bradycardia, widened Hypotension, bradycardia, widened QRS , dizziness, nystagmus may occur QRS , dizziness, nystagmus may occur

TocainideTocainide

• Structurally similar to lignocaine but Structurally similar to lignocaine but can be administered orally can be administered orally

• Serious non cardiac side effects like Serious non cardiac side effects like pulmonary fibrosis, agranulocytosis, pulmonary fibrosis, agranulocytosis, thrombocytopenia limit its use thrombocytopenia limit its use

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

Class IcClass Ic

Propafenone class 1cPropafenone class 1c

• Structural similarity with propranolol Structural similarity with propranolol & has & has -blocking action(Not to be -blocking action(Not to be used with bronchospasm)used with bronchospasm)

• Undergoes variable first pass Undergoes variable first pass metabolism metabolism

• Reserve drug for ventricular Reserve drug for ventricular arrhythmias, re-entrant tachycardia arrhythmias, re-entrant tachycardia involving accesory pathwayinvolving accesory pathway

• Adverse effects: metallic taste, Adverse effects: metallic taste, constipation and is proarrhythmic constipation and is proarrhythmic

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)

Class II: Beta blockers Class II: Beta blockers • -receptor stimulation:

• ↑ automaticity, • ↑ AV conduction velocity, • ↓ refractory period

• -adrenergic blockers competitively block catecholamine induced stimulation of cardiac - receptors

Beta blockersBeta blockers • Depress phase 4 depolarization of Depress phase 4 depolarization of

pacemaker cells, pacemaker cells,

• Slow sinus as well as AV nodal Slow sinus as well as AV nodal conduction :conduction :– ↓ ↓ HR, ↑ PRHR, ↑ PR

• ↑ ↑ ERP, ERP, prolong AP Duration by prolong AP Duration by ↓ AV ↓ AV conduction conduction

• Reduce myocardial oxygen demandReduce myocardial oxygen demand

• Well tolerated, Safer Well tolerated, Safer

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

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

+

Class III drugs Class III drugs

↑APD & ↑RP by blocking the K+ channels

Vm

(mV)

-80mV

0mV

↑ APDBlock IK

Amiodarone Amiodarone • 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)

•Pharmacokinetics:Pharmacokinetics:– Variable absorption 35-65%Variable absorption 35-65%– Slow onset 2days to several Slow onset 2days to several

weeks weeks – Duration of action : weeks to Duration of action : weeks to

months months

•Dose Dose – Loading dose: 5mg/kg over Loading dose: 5mg/kg over

30min.,Then maintenance infusion 30min.,Then maintenance infusion of 50 mg/h. for 24 hr of 50 mg/h. for 24 hr

Amiodarone Amiodarone

Amiodarone Amiodarone

• 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

• AAntiarrhythmic ntiarrhythmic

• MMultiple actions ultiple actions

• IIodine containingodine containing

• OOrally used mainlyrally used mainly

• DDuration of action is very long (t ½ = 3-8 uration of action is very long (t ½ = 3-8 weeks) weeks)

• AAPD & ERP increases PD & ERP increases

• RResistant AF, V tach, Recurrent VF are esistant AF, V tach, Recurrent VF are indications indications

• OOn prolonged use- pulmonary fibrosis n prolonged use- pulmonary fibrosis

• NNeuropathy may occur europathy may occur

• EEye : corneal microdeposits may occur ye : corneal microdeposits may occur

• 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

Newer class III drugs

• Dronedarone: amiodarone like drug Dronedarone: amiodarone like drug without iodine atoms so no pulmonary without iodine atoms so no pulmonary or thyroid toxicity(Not use in severe or thyroid toxicity(Not use in severe HF) HF)

• Vernakalant : Convert 90% of AF Vernakalant : Convert 90% of AF cases in 1hour(Not use in severe HF) cases in 1hour(Not use in severe HF)

• Azimilide Azimilide

• Tedisamil Tedisamil

Calcium channel blockers (Class IV)Calcium channel blockers (Class IV)

• Inhibit the inward movement of calcium ↓ contractility, automaticity , and AV conduction.

• Verapamil & diltiazem

VerapamilVerapamil

• Uses:– Terminate PSVT– control ventricular rate in atrial flutter or

fibrillation

• Drug interactions: – Displaces digoxin from binding sites – ↓ renal clearance of digoxin

Other antiarrhythmics Other 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)

Vm

(mV)

-80mV

0mV

↓ APD

Hyperpolarization

Adenosine

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

• Atropine: Atropine: Used in bradycardia Used in bradycardia

• Digitalis: Digitalis: Atrial fibrillation and atrial Atrial fibrillation and atrial flutter flutter

• Magnesium SOMagnesium SO44: : digitalis induced digitalis induced arrhythmias, Tosades de pointes arrhythmias, Tosades de pointes

Other antiarrhythmics Other antiarrhythmics

DigitalisDigitalis

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

• 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

Digitoxin- hepatic metabolism, highly protein bound, t1/2 7daysToxicity 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

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

Drugs of choices Drugs of choices

S. S. NNo o

Arrhythmia Arrhythmia Drug Drug

11Sinus tachycardia Sinus tachycardia PropranololPropranolol

22Atrial extrasystoleAtrial extrasystolePropranolol,Propranolol,

33AF/Flutter AF/Flutter Esmolol, Esmolol, verapamil ,digoxin verapamil ,digoxin

4 4 PSVTPSVTAdenosine ,esmolol Adenosine ,esmolol

55Ventricular Ventricular Tachycardia Tachycardia

Lignocaine , Lignocaine , procainamide , procainamide , Amiodarone Amiodarone

66Ventricular Ventricular fibrillation fibrillation

Lignocaine, Lignocaine, amiodarone amiodarone

77A-V block A-V block Atropine , isoprenaline Atropine , isoprenaline

Toxicities

Class IClass IConduction slowing can account for Conduction slowing can account for

toxicitytoxicity

Afl 300/minAfl 300/min

Slowing of conduction with Na+ channel Slowing of conduction with Na+ channel blockerblocker

AV Node permits greater no of impulses AV Node permits greater no of impulses

(Drop in Afl 300/min with 2:1 or 4:1 AV (Drop in Afl 300/min with 2:1 or 4:1 AV conduction to 220/min with 1:1 conduction conduction to 220/min with 1:1 conduction HR 220beats/minHR 220beats/min), So should be combined ), So should be combined with BB, Ccb, digitalis.with BB, Ccb, digitalis.

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”

• Rapid, polymorphic ventricular tachycardia •Twist of the QRS complex around the isoelectric baseline

• Fall in arterial blood pressure

• Can degenerate into Ventricular fibrillation

Treatment:

• Withdrawal of offending drug •Magnesium sulphate

•Phenytoin

•Isoproterenol infusion/Pacing

•Defibrillation

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

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