Antiarrythmic

Drugs

 The term cardiac arrhythmia is used to describe an abnormal

cardiac rhythm of any type.
Normal sinus rhythm is between 60-100 beats per min.
Arrhythmias occur due to structural heart disease or external
factors. But can occur in the absence of any cardiac disease.

NORMAL ELECTRO PHYSIOLOGY OF HEART

Normal cardiac impulse originates from pacemaker cells in SA
node by spontaneous depolarization of cell membrane during
diastole.
The rate of depolarization is accelerated by sympathetic activity
and slowed down by vagal stimulation.
From SA node impulse is propagated through atrial myocardia to
AV node. From AV node conduction proceeds distally via bundle of
His, bundle bronches and Purkinje fibres causing rapid activation
of both ventricles.
AV node and His-Purkinje system arealso capable of spontaneous
pace maker activity but at slower rates.
SA node - 70 times /min
AV node - 45 times /min
His-Purkinje system - 25 times /min

Rapid repolarization
Plateau

Depolarization
Final repolarization
Absolute
refractory periodRelative refractory period
Spontaneous depolarization
Resting membrane
potential

Mechanisms of
arrythmias
Arrhythmias can arise as the result of

Abnormal impulse generation.

Abnormal impulse conduction.

AUTOMATICITY

Causes

Ischaemia
Sympathetic stimulation
Hypokalaemia
Drug toxicity - digoxin.

Spontaneous depolarization

Ectopic pacemakers may develop when a site in the

myocardium develops a more rapid phase 4 depolarization
than the SA node.

Threshold potential

Triggered activity
appearance of automaticity as a result of external stimuli and
may occur in tissues, which do not have physiological
automaticity.

Re-entry
Most sustained tachycardias whether atrial, junctional or
ventricular arises on the basis of reentry.
if an impulse arrives at an area of tissue when it is refractory to
the stimulus, this impulse will be conducted by an alternative
route.

If the arrhythmia
arises from atria, SA
node, or AV node it is
called
supraventricular
arrhythmia

If the arrhythmia
arises from the
ventricles it is called
ventricular
arrhythmia

Types of Arrhythmia
Supraventricular Arrhythmias
Sinus Tachycardia: high sinus rate of 100-180 beats/min,
occurs during exercise or other conditions that lead to increased
SA nodal firing rate
Atrial Tachycardia: a series of 3 or more consecutive atrial
premature beats occurring at a frequency >100/min
Paroxysmal Atrial Tachycardia (PAT): tachycardia which
begins and ends in acute manner
Atrial Flutter: sinus rate of 250-350 beats/min.
Atrial Fibrillation: uncoordinated atrial depolarizations

ventricular Arrhythmias
Ventricular Premature Beats (VPBs): caused by ectopic
ventricular foci; characterized by widened QRS.
Ventricular Tachycardia (VT): high ventricular rate caused
by abnormal ventricular automaticity or by intraventricular
reentry; can be sustained or non-sustained (paroxysmal);
characterized by widened QRS; rates of 100 to 200 beats/min;
life-threatening.
Ventricular Flutter - ventricular depolarizations >200/min.
Ventricular Fibrillation - uncoordinated ventricular
depolarizations

Antiarrythmic drugs

 Action of drugs
In case of abnormal generation:

Decrease of phase 4
slope (in pacemaker
cells)

Raises the threshold

In case of abnormal conduction:

conduction velocity
(remember phase 0)

ERP
(so the cell wont be
reexcited again)

Classification of anti arrhythmic drugs

Vaughan-William classification of anti arrhythmic drugs is the

most commonly used classification.
It is based on the effects on the cardiac action potential. In this
classification there are 4classes.

Class

Action

Notes

Na+ channel blocker

Change the slope of

phase 0

Can abolish
tachyarrhythmia
caused by
reentry circuit

blocker

heart rate and

conduction velocity

Can indirectly
alter K and Ca
conductance

III

K+ channel blocker

1. action potential
duration (APD) or
effective refractory
period (ERP).
2. Delay
repolarization.

Inhibit reentry
tachycardia

IV

Ca channel blocker

Slowing the rate of rise

in phase 4 of SA
node(slide 12)

conduction
velocity in SA
and AV node

Mechanism

II

++

 Class I (membrane stabilizers)

These drugs restrict the influx of sodium during phase 0 by inhibiting
fast sodium channels and thus slow the rate of depolarization. So
limiting the responsiveness to excitation of cardiac cells.
The class is subdivided according to the effects of drugs on the
duration of AP.
Class 1a
Class 1b
Class 1c

Indications: SV and ventricular arrhythmias.

IA
Increase
the duration of AP

IB
Decrease
the duration

IC
No effect on
the duration

Class Ia:
Lengthens action potential duration and refratoriness.
E.g. Quinidine, procainamide, disopyramide.

Class Ib:
These drugs shorten the cardiac action potential duration and
refratoriness.
E.g.Lignocaine, Mixiletine, Tocainide, Phenytoin.

Class Ic:
These drugs have negligible effect on action potential
duration.
E.g. Flecainide, Propafenone.

Class II (adrenoceptor antagonists)

Reduce the background sympathetic tone in heart, reduce

automatic discharge (phase 4) and protect against adrenergically
stimulated ectopic pacemakers.
Eg Propranolol, sotolol. esmolol

Class III
Lengthens refractoriness (phase 3) without affecting sodium
influx in phase 0 by reducing influx of K+ into the cell.
Prolongation of action potential and increased refractoriness
prevent re entrant arrhythmias.
Eg Amiodarone, Bretylium, Sotolol
No pure class III drugs are yet available.

Class IV
Depress the slow influx of calcium current(phase 2) and
prolong conduction and refractoriness particularly on SA and
AV nodes.
Effective on terminating paroxysmal SVT.
Eg - verapamil

Others
Digoxin
Adenosine

Antiarrithmic drugs are classified according to their

major action, But many have other class effects also.
Eg Amiodarone has class I, II,III and IV effects.

Individual drugs

Class 1a

Quinidine:
It is not used frequently now because safer and more effective
drugs are available.
Action: It blocks Na+ current Na+ channel blocking causes an
increased threshold for excitability and decreased automaticity.
It also produces -adrenergic blockade and vagal inhibition.
Thats why intravenous quinidine therapy is associated with
marked hypotension and tachycardia.
The vagolytic action of quinidine results in increased AV nodal
transmission of atrial tachy arrhythmias (atrial fibrillation / atrial
flutter), therefore quinidine must never be used alone to treat atrial
fibrillation or atrial flutter.

Pharmacokinetics:
Mode of administration - oral and IV (rarely).
It is well absorbed after oral
administration. 80% is bound to plasma protein including
albumin and acute phase reactant (a1 acid glycoprotein).
75% of drug metabolized by liver and rest excreted unchanged
via kidney.
Some metabolites are active and accumulate when renal
function is impaired.

Drug interaction:
It is a potent inhibitor of cytochrome P450 2D6.
Therefore metabolism of drugs which under go extensive
metabolism by this enzyme will be affected.
Metabolism of Propafenone will be reduced and result in
increased plasma concentration of Propafenone and
increase the b-blockade.
Plasma digoxin concentration will be increased (may
cause digitalis toxicity) by displacing from binding and
impairing renal excretion and digoxin
dose must be reduced when both drugs are used together.

Adverse effects
Non cardiac:
Diarrhoea is the most common adverse effect usually occurs during
first several days of therapy
Diarrhoea induced hypokalaemia may potentiate torsade de pointes
due to quinidine.
Cinchonism, a symptom complex which includes head ache,
tinnitus, dizziness, hot and flushed skin, nausea, abdominal pain,
rashes, visual disturbance and confusion. It also can produce number
of immunological reactions. Common one is thrombocytopenia,
Haemolytic anaemia
Drug fever and rashes.
Rarely can cause hepatitis, bone marrow depression and lupus
syndrome. None of the

Cardiac
Marked QT interval prolongation
Torsades de pointes. Quinine associated torsades de
pointes generally occurs at therapeutic or even subtherapeutic concentrations.
High concentration of quinidine can cause ventricular
tachycardias.
Quinidine can exacerbate heart failure (negative
inotrophic effect) or conduction system disease
Hypotension.

Disopyramide
It has similar electrophysiological effect as Quinidine, but
both drugs have different adverse
effect.
It has antimuscarinic activity.
Pharmacokinetics
T is 6 hrs.
It is used in oral and iv forms.
It is well absorbed and variably bound to plasma protein.
High doses may be needed in patients taking enzyme
inducers such as phynytoin.
It is metabolized in liver and also excreted unchanged by
kidneys.

Adverse effects:
Its antimascarnic effect - glaucoma, constipation, dry
mouth, blurred vision and urinary retention
Because of its negative inotrophic effect
cardiac failure
hypotension.
Torsades de pointes
Gastrointestinal symptoms
rashes
Agranulocytosis
cholestatic jaundice psychosis.

Therapeutic value
Ventricular dysrrhythmia especially after myocardial
infarction and supra ventricular
dyscarrhythmias.
It also used to maintain the sinus rhythym in patients with
artial fibrillation or flutter
Paroxysmal supra ventricular tachycardia
WPWS.

Class Ib:

Lignocaine (Lidocaine)
It is a local anaesthetic, useful as acute intravenous therapy in the
management of ventricular arrhythmias specially after myocardial
infarction.
Action: It blocks Na+ channels.
It is not useful in atrial arrhythmias.
Lignocaine decreases the automaticity by reducing the slope of phase
4 and altering the threshold for excitability.

Pharmacokinetics:
T is 90 min.
Though it is well absorbed, undergoes extensive hepatic firss pass
metabolism and makes the oral route inappropriate.

Adverse effects:
Uncommon unless infusion is rapid there is significant heart
failure.
Seizures
Tremor
Dysarthria
Confusion, sleepiness and dizziness
Blurred vision.
Hypotension
bradycardia.
Nystagmus is an early sign of lignocaine toxicity.
Hypersensitivity reactions
Sweating

Therapeutic use:
Treatment of acute ventricular arrhythmias especially
after myocardial infarction.
Local anaesthesia
Topical application to relieve urethral pain or to relieve
the discomfort of catheterization.
IV form may be useful in some form of neuropathic pain.

Mexiletine
These are the oral analogs of lidocaine
Mexiletine is used for chronic treatment of ventricular
arrhythmias associated with previous myocardial
infarction
T1/2 10 hrs
Adverse effects

Seizures
Tremor
Dysarthria
Confusion, sleepiness and dizziness
Blurred vision.
Hypotension
arrythmias

Class Ic

Flecainide
Slows the conduction in all cardiac muscles.
Drug of choice for artioventricular re entrant tachy
arrythmias.
Pharmacokinetics

t is 14 hrs
It is well absorbed
It is available in oral and intravenous forms.
Partly eliminated unchanged by kidneys and partly metabolized
by liver.

Adverse effects:
Dizziness, visual disturbances, nausea, vomiting, peripheral
neuropathy and parasthesia.
It may exacerbate cardiac failure in patient with poor left
ventricular function.
Themost serious side effects are provocation or exacerbation of
potentially lethal arrhythmias.
Contra indication:
Sick sinus syndrome, heart failure, haemodynamically
significant valvular heart disease, patient with history of
myocardial infarction who have asymptomatic ventricular
ectopic or asympatomatic non sustained ventricular
tachycardia.

Therapeutic use:
Treatment should be initiated in hospital since flecainide
increased mortality in patients convalescing myocardial
infarction,probably due to induction of lethal ventricular
arrhythmias.
Therefore now the indication for the use of flecainide is
restricted to
Serious symptomatic ventricular arrhythmias in patients
resistant or intolerant to other treatment.
Junctional re-entry tachycardia
For paroxysmal atrial fibrillation.

Propafenone

Its major effect is to slow conduction in fast-response tissue.

It also has b- adrenoceptor blocking activity.
It is given orally and well absorbed.
It undergoes extensive hepatic metabolism.

Adverse effects:
Exacerbation of cardiac failure
Ventricular dysrrhythmias
Adverse effects of b-blockade such as bradycardia and bronchospasm.

Therapeutic use:
Chronic therapy with oral propafenone is used to maintain sinus rhythym
in patients with supra ventricular tachycardias including atrial fibrillation.
It also can be used in ventricular arrhythmias in patients whose left
ventricular function is preserved.

Class II

-blockers
-blockers are also effective in the treatment of arrhythmias due
to their b-adrenoceptor blocking action and direct membrane
effect.
Therapeutic use:
b-blockers can be used in conjunction with digoxin in the control of
ventricular response to atrial fibrillation especially in patients with
thyrotoxicosis.
Treatment of suproventricular tachycardia
Also can be used to control arrhythmias following myocardial
infarction.
WPWS
Digoxin induced dysrrhythmias.