Antiarrhythmic Drugs

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Arrhythmia result from disorders of impulse
formation (abnormal automaticity),
conduction, or both
Etiology of arrhythmias
Cardiac ischemia.
Excessive discharge or sensitivity to
autonomic transmitters.
Exposure to toxic substances.
Unknown etiology
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Normal conduction pathway
:60-100bpm

1- SA node generates
action potential and
delivers it to the atria
and the AV node

2- The AV node
delivers the impulse to
purkinje fibers

3- purkinje fibers
conduct the impulse to
the ventricles

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 Mechnisms of Arrhythmogenesis

Early
Delayed afterdepolarization

afterdepol
AP arises from sites
other than SA node
arization
↑AP from
SA node
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 This is when the
impulse is not 1-This
conducted from the pathway is
blocked
atria to the ventricles

3-So the cells here will be

reexcited (first by the
original pathway and the
2-The impulse
other from the
from this pathway
retrograde)
travels in a
retrograde fashion
(backward)5
Abnormal anatomic
Here is an
conduction accessory
pathway in the
heart called
Bundle of Kent
•Present only in small
populations
•Lead to reexcitation 
Wolf-Parkinson-White
Syndrome (WPW)

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By Location:
ARRHYTHMIAS Classification
1. Supraventricular arrhythmias
 E.g.sinus bradycardia, sinus tachycardia, paroxysmal
supraventricular tachycardia, atrial flutter, atrial fibrillation
2. Ventricular arrhythmias.
 E.g. VT, VF.

 By Rate:
1. Bradyarrhythmias (those <60 beats/ minute)
2. Tachyarrhythmias (those >100 beats/minute).
Antiarrhythmic Drugs
Antiarrhythmic Drugs directly or indirectly alter
memberane ion conductance which in turn alters cardiac
action potential
Depression of automatic properties in abnormal
pacemaker cells
decreased slope of phase 4 depolarization or elevated
threshold potential
if rate of spontaneous impulse generation of the
automatic foci < SA node
 normal cardiac rhythm can be restored

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9
ECG (EKG) showing
Contraction of
wave segments
ventricles

Plateau
Contraction Repolarization of
of atria ventricles

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Antiarrhythmic Drugs
Altered conduction characteristics in reentrant loop
pathways
shorter refractoriness in area of unidirectional block

allow antegrade conduction

prolong refractoriness in pathways

 prevent retrograde impulse propagation

Antiarrhythmic drugs

alter cardiac conduction in patients + heart disease

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Antiarrhythmic Drugs

Vaughan Williams classification :

Drugs categorized by in vitro electrophysiologic actions

 Class I: Sodium Channel Blocker

 Class II: Beta-Adrenergic blocker
 Class III: potassium Channel Blocker
 Class IV: calcium channel Blocker
 Miscellaneous

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Class I: Sodium Channel Blocker
They act by blocking the sodium channel

Decrease conduction velocity

Helps to abolish tachyarrhythmia caused by reentry

Are subdivided into 3 subgroups

Based on their effects on repolarization and

Potency to wards blocking sodium channel

Class IA
Have high potency as sodium channel blockers (Prolong

QRS interval)
Prolong repolarization (prolong QT interval ) through

blockade of potassium channel

 Drugs :Quinidine, Procainamide, Disopyramide
 Quinidine
Pharmacological actions :
 cardiac depression (depression of all cardiac properties).
 Increase of the action potential duration (prolongation of
ECG)
 Vasodilatation and hypotension (partly due to its alpha
blocking effect ) .
 Direct depression of A-V node automaticity
 Depression of A-V conductivity
 Therapeutic uses
Paroxismal artrial tachycardias , Flutter & Fibrillation

 Absorption and fate :

 It is rapidly and completely absorbed from GIT

 Extensively bound to plasma proteins

 Metabolized in the liver and excreted in urine (its t1/2 is

6hrs)
 Side effects
S-A block or arrest, ventricular tachyarrythmias

Hypotension, syncope or sudden death

Atrial embolism after conversion of atrial fibrillation to

normal rhythm
Cinchonism ( tinnitus , loss of hearing, blurring of vision )

 GIT disturbances & hypersensitivity reactions .

N.B.: Paroxismal tachycardia or tachyarrhythmias are due to

the predominance of atropine like action of quinidine .

Contraindications

Hypotension

Congestive heart failure

history of embolism

complete heart block

subacute bacterial endocarditis

arrhythmias due to digitalis intoxication

Drug interactions
Enzyme inducers e.g. rifampicin reduce the duration

of action of quinidine

Quinidine decrease clearance of digoxin and

increases its plasma level

It potentiates the effect of other vasodilators and

hypotensive drugs.
It increases prothrombin time of patients receiving

oral anticoagulants
Procainamide
Has less inhibitory effect on contractility and less vagal

depressant effect
Unlike quinidine , it has a shorter duration of action and

weakly bound to plasma protein

 Toxicity and side effects :

Similar to those of quinidine ( except cinchonism )

C.N.S. stimulation e.g. confusion and hallucination

Systemic lupus erythematosus like syndrome .

Agranulocytosis , hepatotoxicity .
Diisopyramide
Similar to quinidine but differs in :
 It produces vasoconstriction with unknown mechanism .
As a result , blood pressure is maintained
 It has a calcium channel blocking effect .
 Side effects :
due to atropine like action (dry mouth ,blurring of vision ,
nausea , vomiting , increased intraocular pressure , urine
retention
C.N.S. stimulation (confusion and hallucinations)&
precipitation of heart failure .
Class IB
 Lidocaine, phenytoin , Mexiletine, tocainide:
Are weak Na+ channel blocker (no effect on QRS interval)
Shorten repolarization without affecting conduction velocity;
(decrease QT interval)
Lidocaine may work more like IA agents in diseased tissue
accentuated effects in ischemic tissue caused by local

acidosis & K+ shifts that occur in hypoxia

pH changes alter time local anesthetics occupy the Na+

channel, “trap” drug in the cell; increase receptor access

Used primarily in ventricular arrhythmias
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Lidocaine

is a rapidly acting anti-arrhythmic drug with short

duration
 It is well absorbed from Git but it subjects to
extensive first pass effect ( 30% bioavailability )
It is given only by I.V. route
It does not have atropine - like action
It has minimal effect on the supraventricular
arrhythmias
Lidocain …
is used as an emergency treatment of ventricular
arrhythmias during cardio surgery or general
anaesthesia
It is used also as a local anaesthetic

Side effects :
Mainly central e.g. drowsiness , disorientation and
convulsions
Phenytoin( diphenylhydantoin )
It is similar to lidocaine in its cardiac effects ( increases A -

V transmission and inhibit phase - 0 in purkinje fibres

It posses also an antiepileptic activity .

 N.B. : Rapid administration of phenytion leads to transient

hypotension as a result of peripheral vasodilatation and
depression of myocardial contractility .
 Therapeutic uses :

 Ventricular arrhythmias .
Tocainide ( tonocard)
is an amine analog of lidocaine similar pharmacologically to
lidocaine
It is a membrane stabilizing agent.
 Side effects :
Pulmonary fibrosis
pulmonary oedema
interstitial pneumonitis
bone marrow depression
Agranulocytosis
renal and hepatic impairement
CLASS IC
 Propafenone, flecainide, moricizine, encainide
Potent Na+ blockers( prolong QRS interval)
Little effect on repolarization ( No effect on QT interval)
Profoundly slow conduction velocity
Refractoriness relatively unaltered
Eliminate reentry: slow conduction to point where impulse
is extinguished & cannot propagate
Effective for both ventricular & supraventricular
arrhythmias
ventricular arrhythmia use limited by proarrhythmia risk

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Class II: β-blockers

Include: propranolol, esmolol, acebutolol, satolol

Antiarrythmic mechanism: anti-adrenergic actions
SA & AV nodes influenced by adrenergic innervation

Adrenergic stimulation increases conduction velocity,

shortens refractoriness & increases automaticity of nodal
tissues
β-blockers antagonize these effects

useful for exercise related tachycardia or other

tachycardia induced by high sympathetic tone

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β-blockers …
Useful in tachycardia where nodal tissues are
abnormally automatic or part of a reentrant loop
Interfere with Ca2+ entry into cell by altering
catecholamine-dependent channel integrity & gating
β-blockers decrease incidence MI
unclear mechanism

Prevent arrhythmias in HF patients

attenuate myocardial remodeling

improve ventricular function

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Class III :

 Bretylium, amiodarone, sotalol, ibutilide, dofetilide

block K+ channels
Prolong repolarization by blocking outward
potassium conductance (Prolong QT interval)
Inhibit delayed rectifier current (IK) involved in
phases 2 & 3 of repolarization
Danger of blocking K+ channel too much: causes
arrhythmias such as Torsades de Points

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Class III …
Bretylium depletes catecholamines

increases Ventricular Fibrillation threshold

anti-fibrillatory

effective in Ventricular Tachycardia

Amiodarone & sotalol: effective in most supraventicular &

ventricular tachycardias
Sotalol inhibits outward K+ movement during

repolarization; non selective β-blocking actions

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Amiodarone
Characteristics of all Vaughan Williams classes
Na+ channel blocker with fast on/off kinetics

noncompetitive, nonselective β-blocker actions

blocks K+ channels

small degree of Ca2+ antagonist activity

Quick onset with IV administration

Initial action: β-blockade
Predominant effect with chronic use: prolongation of
repolarization
Low proarrhythmic potential
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Amiodarone
Used in chronic & acute supraventricular/ventricular
arrhythmias
Unusual pharmacologic effects, pharmacokinetics, dosing,
adverse effects
extremely long t½ (15 to 100 days)

large volume of distribution (Vd)

inhibits P-glycoprotein & most CYP-P450 enzymes

 many drug interactions

severe multi-organ toxicities with chronic use

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Class IV : Calcium channel blockers
 sinus and A -V nodal cells are very sensitive to calcium blockers
 Verapamil is the calcium blocker of choice which is effective and
currently used as antiarrhythmic drug
 It acts through ;
 slowing of A -V conduction ,
 slowing of ventricular rate ,
 prolongation of PR interval of E C G and
 decreases the rate of phase (o) depolarization
 It is used for supraventricular arrhythmias
 Digoxin
The principal antiarrhythmic effect is achieved via
prominent vagotonic actions.
The vagotonic influence leads to inhibition of Ca++
currents in the A-V node and activation of acetylcholine-
sensitive potassium channels in the atrium (these
channels are not present in the ventricle).
This results in a slowing of conduction through the A-V
node, a hyperpolarization of the resting membrane
potential, and a shortening of the refractory period in
atrial tissue
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Digoxin is useful in reentrant arrhythmias that use the

A-V node as one limb of the circuit and for limiting A-V
conduction during rapid atrial arrhythmias, such as in
atrial fibrillation.
Digitalis glycosides have theoretical advantages over

other medications that limit conduction through the A-

V-node, such as -blockers and Ca++ channel blockers,
by providing a positive rather than negative inotropic
effect on the ventricles.

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 Adenosin
It is an endogenous nucleoside that is a product of the
metabolism of adenosine triphosphate.
Adenosine receptors are found on myocytes in the atria
and SA and A-V nodes.
Stimulation of these receptors acts via a G-protein
signaling cascade to open an acetylcholine-sensitive
outward potassium current.
This leads to hyperpolarization of the resting membrane
potential, a decrease in the slope of phase 4 spontaneous
depolarization, and shortening of the action potential
duration.
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The effects on the A-V node may result in a conduction

block and the termination of tachycardias that use the A-

V node as a limb of a reentrant circuit.

Adenosine does not affect the action potential of

ventricular myocytes because the adenosine-stimulated

potassium channel is absent in ventricular myocardium.

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  Adenonsin is used for the acute management and termination

of supraventricular tachyarrhythmias, including A-V nodal

reentrant tachycardia.

The most common adverse effects are flushing, chest pain,

and dyspnea.
Adenosine may induce profound bronchospasm in

patients with known reactive airway disease (may

exacerbate asthma)
Adenosine has very short t½ (about 10s) and is used only IV.

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