Antiarrhythmic

Drugs
 Introduction
Cardiac cells: Contractile muscle cells (CMC) and
Special conducting tissue.
Normal cardiac rhythm
Impulse generation: S.A node at a rate of 60-100per min.
Impulse propagation: SAN AVN His-Purkinje CMC
AV nodal delay = 0.15sec
Arrhythmia: Any different from the Normal rhythm.
Abnormal: - Origination, rate/ regularity, conduction.
Arrhythmias can be: Bradyarrhythmia or tachyarrhythmia.
 Three important points to note
Automaticity
The ability of a cell to alter its resting membrane
potential toward the excitation threshold without the
influence of an external stimulus
Conduction velocity
Refractory period
Depolarized cardiac cells are transiently unresponsive
to any activation stimuli. During this interval, most Na+
and some Ca++ channels are inactivated, and the
cardiac myocytes are said to be refractory.
 Phases of cardiac AP
Phase 0: Fast inward Na+ current

Phase 1: Transient outward K+- current

Phase 2: Plateau, due to balanced depolarizing Ca++-

current and repolarizing K+ current
Phase 3: Repolarization of cardiac cell

Phase 4: Resting Membrane Potential

 Mechanism of cardiac Arrhythmias
Brady arrhythmias
Impairment of impulse formation or conduction

Tachyarrhythmias; three major Mechanisms

Enhanced Automaticity/ectopic pacemaker activity
Triggered Automaticity
Transient membrane depolarizations that occur
During repolarization: Early after depolarization /EADs/
After repolarization: Delayed after depolarization /DADs/

Reentry: commonest cause. reentrant arrhythmias.

 Enhanced Automaticity
Increase in the slope of phase 4 depolarization or a
decrease (less negative) in the resting membrane
potential
Activation of -adrenoceptors, hypokalemia, and
stretching of cardiac cells all increase the slope of
phase 4 depolarization and may serve as the trigger for
enhanced automaticity
 Triggered Automaticity
EAD may develop in association with hypokalemia,
hypoxia, acidosis, and a wide range of pharmacological
agents that interfere with outward currents
Antiarrhythmic agents, in particular Sotalol, quinidine, &
dofetilide, may give rise to EAD
EAD prevented or suppressed by the appropriate
adjustment of plasma K+ and/or Mg++ concentrations
Lidocaine or Procainamide may be effective for
termination of the arrhythmia.

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Triggered Automaticity (contd)
DAD may occur in the presence of a rapid heart rate,
digitalis glycosides, hypokalemia, hypercalcemia &
catecholamines which leads to an increase in intracellular
ca2+ that activates an inward ionic current.
The arrhythmia may respond to L-type calcium channel
antagonists or inhibitors of -adrenoceptor.

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 Reentry
Abnormality of impulse conduction.
Cause for 80 to 90% of clinical arrhythmias

Three requirements for a viable reentrant focus

1. Two pathways for impulse conduction

2. An area of unidirectional block in one of these

pathways and

3. A slow conduction in the other pathway

Antiarrhythmic mechanisms in reentry
By converting unidirectional block to
bidirectional block.
By increasing the RP of the cardiac fibers
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 Classification of Anti-arrhythmic
Drugs

Vaughan William's classification

Based on Drugs electrophysiological Mechanism of
Action
Class I: Na++ channel blockers.

Based on effects on the action potential duration (APD)

& kinetics of interact & dissociate from the channel.

Class IA: Prolong APD & Dissociate with intermediate kinetics

Quinidine, Procainamide, Disopyramide

Class IB: Shorten APD & Dissociate with rapid kinetics;

Lidocaine, Phenytoin, Mexiletin, Tocainide

Class IC: No/little effect on APD & Dissociate with slow kinetics

Flecainide, Propafenon
 Class II: Block -adrenergic Receptors.
Propranolol, Acebutolol, Metoprolol

Class III: K+-channel blockers

Amiodarone, Ibutilide, Dofetilide, Sotalol, Bretylium

Class IV: Selective L-type Ca++ channel blockers

Verapamil, Diltiazem

Miscellaneous: Actions do not fit to any of the above

classes
Digoxin (digitalis), Adenosine
 Class I: Na+-channels Blockers
Block voltage gated Na+-channels
Decreased automaticity arising from DAD or EADs
Decreased conduction velocity in fast response tissue
Increased refractoriness
 Na+-channels Blockers (contd)
Class IA
Slow rate of rise of phase 0 and
prolong the ventricular ERP.
Slow conduction velocity.
Decrease the slope of phase 4
depolarization in pacemaker cells,
Application:
Automatic Tachycardia by ing
spontaneous impulse generation of
atrial and ventricular foci
Produces bidirectional block in
reentrant tachycardia
 Na+-channels Blockers (contd)
Class IB
They greater effects on cells with long
action potentials such as Purkinje and
ventricular cells ( decrease APD)
used only in ventricular tachyarrhythmias

Because of rapidly developing and

titratable action it is a good drug in the
emergency setting,

e.g. ventricular arrhythmias following

acute MI, during cardiac surgery,
digitalis intoxication .et
 Na+-channels Blockers (contd)

Class IC
Produce marked depression in the rate of rise
of the membrane action potential (markedly
delay conduction)
Minimal effect on the duration of membrane
action potential.
Application:
In reentrant tachycardia (most types of atrial
arrhythmias & also used for life-threatening
ventricular arrhythmias in absence of structural heart
disease)
 Class II: -AR Blockers
The primary action of drugs in this class is to
suppress adrenergically (sympathetic) mediated
ectopic activity

-Stimulation:
Increase Ca++ current & slow its inactivation.

Increase repolarizing K + & Cl - currents

Increase pace maker current increase sinus HR

under pathophysiological conditions Increase EAD &

DAD mediated arrhythmias
 - blockers: inhibit the effect of -stimulation.
Effect:
Reduce HR

Reduce intracellular Ca++ overload

Inhibit enhanced & triggered automaticity.

Increase AV nodal conduction time.

Prolong AV nodal refractoriness

Application:
Class II agents are useful in treating tachyarrhythmias
caused by increased sympathetic activity
They are also used for atrial flutter and fibrillation and for
AV-nodal reentrant tachycardia
 Class III: K+- channel Blockers
Effect of K+ channel blockade
Increased AP duration: increased refractoriness.

Reduce automaticity

Reduce heterogeneity of refractoriness.

 Amiodarone
Analog of thyroid hormone; multiple pharmacological
effects.
Blocks inactivated Na+ channels, es Ca++-current, blocks
K+ channels, Non competitive & blocker (Class I, II, III,
and IV actions)
Decreases Automaticity, decreases conduction Velocity,
prolongs refractoriness
Class III drugs have a signicant risk of proarrhythmia
because of the prolongation of action potential and the
induction of torsades de pointes.
 Pharmacokinetics
Poorly absorbed (bioavailability of 35%)

Distributed in the lipid

Undergoes hepatic metabolism: active metabolite

Extremely long half life:(several weeks) slow elimination.

Use as a result of its broad spectrum of antiarrhythmic

action, it is very extensively used for a wide variety of
arrhythmias
Effective in almost all types of tachycardias
 Class IV: Ca++-channel blockers (CCB)
Block Ca++- channels in slow response tissue (SA & A-V
nodes) & decreased rate of phase 4 depolarization
Dihydropyridines: little effect on cardiac Ca++

Verapamil, Diltiazem
Effect: slows HR occasionally increased HR

Decreased AV nodal conduction Velocity

Increased AV nodal refractoriness

Uses:
Reentrant arrhythmias around AV node (PSVT)

Reduce Ventricular rate in Atrial Flutter or Atrial

Fibrillation
DAD- mediated arrhythmias.
 Miscellaneous Anti arrhythmic Agents
Adenosine
Naturally occurring Nucleoside product of the metabolism of
ATP.
Its mechanism of action involves activation of an inward
rectifier K+ current and inhibition of calcium current in SA & AV
nodes & atrium
Inhibit effects of sympathetic stimulation.
Shorten AP duration, slow Normal automaticity
Hyper polarization.
Increase AV nodal refractoriness.
Elimination t1/2 = few seconds given IV bolus.
Adverse effects: short lived (approximately 15 seconds)
Use: drug of choice for abolishing acute supraventricular
tachycardia
 Digoxin
Exert inotropic effects through Na+-K+ ATPase which
increase intracellular Ca++ concentration leading to
DADs.
Also has Vagotonic action thus reducing AV-nodal
conduction and delaying repolarization.
Major toxicity is cardiac arrhythmia.
Pharmacotherapy of Some forms of
arrhythmia
 Atrial Fibrillation and atrial flutter
Atrial fibrillation is the most common sustained
arrhythmia observed clinically
Characterized by extremely rapid (400-600 atrial
beats/min) and disorganized atrial activation
Results in ventricular response of about 120-180
beats/minute
Atrial flutter
Characterized by rapid (270-330 atrial beats/min) but
regular atrial activation
Results in 100-300 ventricular beats/min
Reentry is the predominant mechanism for both
 Treatment
Control of the ventricular response
Drugs that slow conduction and increase refractoriness
in the AV node (digoxin, CCB, BB)
Restoration &maintenance
of normal cardiac rhythm
Warfarin (anticoagulant)
Cardioversion (defibrillation)
Class IA, IC and III
 Choice of drugs for cardiac arrhythmias
Type of Acute therapy Chronic therapy and prophylaxis
Arrhythmia First choice Alternatives First choice Alternatives
Atrial Arrhythmia
Atrial Flutter Cardioversion pacing Amiodarone Propafenon
(AFI) Quinidine Verapamil
Esmolol Verapamil Digoxin/Propranolol Dofetilide

Atrial Fibrillation Cardioversion - Amiodarone Propafenone

(AF) Quinidine Verapamil
Esmolol Verapamil Digoxin/Propranolol Dofetilide

supraventricular tachycardia
PSVT Adenosine Esmolol Digoxin Propafenone
Diltiazem Verapamil
Verapamil Propranolol

Ventricular tachycardia (VI)

Acute Ventricular Lidocaine Procainamide Amiodarone Propafenone
tachycardia Cardioversion Mexiletine Dofetilide Mexiletine
Amiodaron Propranolol

Ventricular Electrical Lidocaine Amiodarone Procainamide

fibrillation (VF) defibrillation Amiodarone Dofetilide
Epinephrine