Antiarrhythmic

agent

Drugs affecting the cardiac action potential. The sharp

rise in voltage ("0") corresponds to the influx of sodium
ions, whereas the two decays ("1" and "3", respectively)
d h di h li i i d h
correspond to the sodium-channel inactivation and the
repolarizing efflux of potassium ions. The
characteristic plateau ("2") results from the opening of
voltage-sensitive calcium channels.

Antiarrhythmic agents, also known as

cardiac dysrhythmia medications, are a
group of pharmaceuticals that are used to
suppress abnormal rhythms of the heart
(cardiac arrhythmias), such as atrial
fibrillation, atrial flutter, ventricular
tachycardia, and ventricular fibrillation.

Many attempts have been made to

classify antiarrhythmic agents. The
problem arises from the fact that many of
the antiarrhythmic agents have multiple
modes of action, making any classification
imprecise.

Vaughan Williams
classification
The Vaughan Williams classification[1]
was introduced in 1970 by Miles Vaughan
Williams.[2]

Miles was the tutor for Pharmacology at

Hertford College, Oxford; one of his
students, Bramah N. Singh,[3] contributed
to the development of the classification
system, and had a subsequent eminent
career in the United States; the system is
therefore sometimes known as the Singh-
Vaughan Williams classification.

The five main classes in the Vaughan

Williams classification of antiarrhythmic
agents are:

Class I agents interfere with the sodium

(Na+) channel.
Class II agents are anti-sympathetic
nervous system agents. Most agents in
this class are beta blockers.
Class III agents affect potassium (K+)
efflux.
Class IV agents affect calcium channels
and the AV node.
 Class V agents work by other or
unknown mechanisms.

With regard to management of atrial

fibrillation, classes I and III are used in
rhythm control as medical cardioversion
agents, while classes II and IV are used as
rate-control agents.
 Known
Class Examples Mechanism Medical uses [4]
as

(Na+) channel block

(intermediate
Ventricular arrhythmias
association/dissociation)
Quinidine and K+ channel blocking Prevention of paroxysmal
Fast- effect; affects QRS recurrent atrial fibrillation
Ajmaline
Ia channel complex (triggered by vagal overactivity)
blockers Procainamide
class 1a prolong the Procainamide in Wolff-
Disopyramide action potential and has Parkinson-White syndrome
intermediate effect on the Increases QT interval
0 phase of depolarization

Na+ channel block (fast

association/dissociation); Treatment and prevention
can prolong QRS complex during and immediately after
Lidocaine
in overdose myocardial infarction, though
Phenytoin
Ib class 1b shorten the this practice is now
Mexiletine action potential of discouraged given the

Tocainide myocardial cell and has increased risk of asystole

weak effect on intiation of
Ventricular tachycardia
phase 0 of depolarization

Prevents paroxysmal atrial

Na+ channel block (slow
fibrillation
Encainide association/dissociation)

Flecainide has no effect on action Treats recurrent

Ic potential and has the tachyarrhythmias of abnormal
Propafenone strongest effect on conduction system
Moricizine initiation phase 0 the
Contraindicated immediately
depolarization
after myocardial infarction

II Beta- Carvedilol Beta blocking Decrease myocardial infarction

blockers Propranolol also shows mortality
Propranolol
some class I action
Prevent recurrence of
Esmolol
tachyarrhythmias
 Timolol Propranolol has sodium
channel-blocking effects
Metoprolol

Atenolol

Bisoprolol

Nebivolol

In Wolff-Parkinson-White
syndrome
Amiodarone
(Sotalol:) ventricular
Sotalol K+ channel blocker tachycardias and atrial
Ibutilide Sotalol is also a beta fibrillation
III Dofetilide blocker[5]Amiodarone has
(Ibutilide:) atrial flutter and
Class III mostly, but also I,
Dronedarone atrial fibrillation
II, & IV activity[6]
E-4031 (Amiodarone): prevention of
paroxysmal atrial fibrillation,[7]
Vernakalant
and haemodynamically stable
ventricular tachycardia[8]

Prevent recurrence of
Calcium paroxysmal supraventricular
Verapamil
IV Channel Ca2+ channel blocker tachycardia
Blockers Diltiazem
Reduce ventricular rate in
patients with atrial fibrillation

Used in supraventricular
Adenosine arrhythmias, especially in heart
Work by other or unknown failure with atrial fibrillation,
Digoxin
V mechanisms (direct nodal contraindicated in ventricular
Magnesium inhibition) arrhythmias. Or in the case of
Sulfate magnesium sulfate, used in
torsades de pointes.

Class I agents
The class I antiarrhythmic agents interfere
with the sodium channel. Class I agents
are grouped by what effect they have on
the Na+ channel, and what effect they have
on cardiac action potentials.

Class I agents are called membrane-

stabilizing agents, "stabilizing" referring to
the decrease of excitogenicity of the
plasma membrane which is brought about
by these agents. (Also noteworthy is that a
few class II agents like propranolol also
have a membrane stabilizing effect.)

Class I agents are divided into three

groups (Ia, Ib, and Ic) based upon their
effect on the length of the action
potential.[9][10]

Ia lengthens the action potential (right

shift)
Ib shortens the action potential (left
shift)
Ic does not significantly affect the
action potential (no shift)
Class Ia

Class Ib
 Class Ic

Class II agents

Class II agents are conventional beta

blockers. They act by blocking the effects
of catecholamines at the β1-adrenergic
receptors, thereby decreasing sympathetic
activity on the heart, which reduces
intracellular cAMP levels and hence
reduces Ca2+ influx. These agents are
particularly useful in the treatment of
supraventricular tachycardias. They
decrease conduction through the AV node.

Class II agents include atenolol, esmolol,

propranolol, and metoprolol.

Class III agents

Class III

Class III agents predominantly block the

potassium channels, thereby prolonging
repolarization.[11] Since these agents do
not affect the sodium channel, conduction
velocity is not decreased. The
prolongation of the action potential
duration and refractory period, combined
with the maintenance of normal
conduction velocity, prevent re-entrant
arrhythmias. (The re-entrant rhythm is less
likely to interact with tissue that has
become refractory). The class III agents
exhibit reverse-use dependence (their
potency increases with slower heart rates,
and therefore improves maintenance of
sinus rhythm). Inhibiting potassium
channels, slowing repolarization, results in
slowed atrial-ventricular myocyte
repolarization. Class III agents have the
potential to prolong the QT interval of the
EKG, and may be proarrhythmic (more
associated with development of
polymorphic VT).

Class III agents include: bretylium,

amiodarone, ibutilide, sotalol, dofetilide,
vernakalant and dronedarone.

Class IV agents

Class IV agents are slow non-

dihydropyridine calcium channel blockers.
They decrease conduction through the AV
node, and shorten phase two (the plateau)
of the cardiac action potential. They thus
reduce the contractility of the heart, so
may be inappropriate in heart failure.
However, in contrast to beta blockers, they
allow the body to retain adrenergic control
of heart rate and contractility.

Class IV agents include verapamil and

diltiazem.

Class V / other agents

Since the development of the original

Vaughan Williams classification system,
additional agents have been used that do
not fit cleanly into categories I through IV.
Agents include:

Digoxin, which decreases conduction of

electrical impulses through the AV node
and increases vagal activity via its
central action on the central nervous
system, via indirect action, leads to an
increase in acetylcholine production,
stimulating M2 receptors on AV node
leading to an overall decrease in speed
of conduction.
Adenosine is used intravenously for
terminating supraventricular
tachycardias.[12]
Magnesium sulfate, an antiarrhythmic
drug, but only against very specific
 arrhythmias [13] which has been used for
torsades de pointes.[14][15]
Trimagnesium dicitrate (anhydrous) as
powder or powder caps in pure
condition, better bioavailability than
ordinary MgO[16]

History

The initial classification system had 4

classes, although their definitions different
from the modern classification. Those
proposed in 1970 were:[2]

1. Drugs with a direct membrane action:

the prototype was quinidine, and
lignocaine was a key example.
 Differing from other authors,
Vaughan-Williams describe the main
action as a slowing of the rising
phase of the action potential.
2. Sympatholytic drugs (drugs blocking
the effects of the sympathetic
nervous system): examples included
bretylium and adrenergic beta-
receptors blocking drugs. This is
similar to the modern classification,
which focuses on the latter category.
3. Compounds that prolong the action
potential: matching the modern
classification, with the key drug
example being amiodarone, and a
 surgical example being
thyroidectomy. This was not a
defining characteristic in an earlier
review by Charlier et al. (1968),[17] but
was supported by experimental data
presented by Vaughan Williams
(1970).[2]:461 The figure illustrating
these findings was also published in
the same year by Singh and Vaughan
Williams.[18]
4. Drugs acting like dephenylhydantoin
(DPH): mechanism of action
unknown, but others had attributed
its cardiac action to an indirect action
on the brain;[19] this drug is better
 known as antiepileptic drug
phenytoin.

Sicilian gambit classification

Another approach, known as the "Sicilian
gambit", placed a greater approach on the
underlying mechanism.[20][21][22]

It presents the drugs on two axes, instead

of one, and is presented in tabular form.
On the Y axis, each drug is listed, in
roughly the Singh-Vaughan Williams order.
On the X axis, the channels, receptors,
pumps, and clinical effects are listed for
each drug, with the results listed in a grid.
It is, therefore, not a true classification in
that it does not aggregate drugs into
categories.[23]

A modernized Oxford
classification by Lei, Huang,
Wu and Terrar
A recent publication has now emerged
with a fully modernised drug
classification.[24] This preserves the
simplicity of the original Vaughan Williams
framework while capturing subsequent
discoveries of sarcolemmal, sarcoplasmic
reticular and cytosolic biomolecules. The
result is an expanded but pragmatic
classification that encompasses approved
and potential anti-arrhythmic drugs. This
will aid our understanding and clinical
management of cardiac arrhythmias and
facilitate future therapeutic developments.
It starts by considering the range of
pharmacological targets, and tracks these
to their particular cellular
electrophysiological effects. It retains but
expands the original Vaughan Williams
classes I to IV, respectively covering
actions on Na+ current components,
autonomic signalling, K+ channel
subspecies, and molecular targets related
to Ca2+ homeostasis. It now introduces
new classes incorporating additional
targets, including:
 Class 0: ion channels involved in
automaticity
Class V: mechanically sensitive ion
channels
Class VI: connexins controlling
electrotonic cell coupling
Class VII: molecules underlying longer
term signalling processes affecting
structural remodeling.

It also allows for multiple drug

targets/actions and adverse pro-
arrhythmic effects. The new scheme will
additionally aid development of novel
drugs under development and is illustrated
below.