Pharmacology of antiarrhythmic drugs

Dalmo Antonio Ribeiro Moreira MD, PhD

Electrophysiology and Electrocardiography Section
Dante Pazzanese Institute of Cardiology, São Paulo
Itajubá Medical School, Minas Gerais, Brazil

Introduction

Despite the advances of non-pharmacological therapy of cardiac arrhythmias in the last two
decades, it is important to note that the initial treatment of rhythm disturbances is still the
prerogative of the clinician and for this reason, antiarrhythmic drugs have a role. These
agents are used to stop an arrhythmia when administered in the presence of arrhythmia; for
preventing recurrence of arrhythmia, for relief of haemodynamic disturbance of an
arrhythmia and, finally, to prevent catastrophic effects of a potentially malignant
arrhythmias, while other techniques more effective and safe treatment can not be
employed, such as the use of automatic cardioverter defibrillator in ventricular arrhythmias
with sudden death risk.

From the standpoint of electrophysiology, a cardiac arrhythmia can originate by the

interaction of three variables (Figure 1): a) the presence of an arrhythmogenic substrate, b)
the presence of triggers (represented by extra systoles), c) modulating factors (autonomic
sympathetic or parasympathetic neural influence, pH, ischemia, neurohumoral factors,
etc.).Only after critical and harmonious interaction of these three factors is that a cardiac
arrhythmia can be generated. In practice, antiarrhythmic drugs can act on the substrate,
causing changes in tissue refractoriness or so at the speed of propagation of electrical
impulse, the most important components of the primary arrhythmogenic mechanism known
as re-entry. These effects are based on the actions of different drugs on the electrical
properties of cell membranes, particularly ion channels, as will be discussed later.
Figure 1 - Variables involved in the onset of a cardiac arrhythmia. It requires the presence of an
arrhythmogenic substrate, triggers and modulating factors that influence both the substrate and the
triggers. The drugs generally act in one or more of these variables to normalize heart rhythm.

The drugs may act on the triggers, specifically having an effect on the cellular automatism,
depressing the its automatic activity is even blocking its automatic activity, preventing the
formation of ectopic action potentials that can act on a reentrant circuit and generate an
arrhythmia. Moreover, these agents can block oscillations of phase 3 or 4 of the action
potential, responsible for the generation of early or late after-potentials, respectively,
collectively known by triggered activity.

Finally, the drugs may act on the modulating factors, reducing the effects of autonomic
activity in the generation of arrhythmias, improving myocardial blood flow, reducing the
effects of hormones or other factors that can destabilize the arrhythmogenic substrate and
provide the triggers that generate arrhythmias .

Some drugs work in only one or two of these variables that is, on the substrate, triggers or
modulating factors. Others considered wide spectrum antiarrhythmic agent work on them
all. Because many variables are involved in the arrhythmia genesis, more than one different
type of agent is frequently prescribe to patients in order to obtain the best result in the
pharmacological treatment of cardiac arrhythmias.

Classification of antiarrhythmic drugs

Although old, the classification of antiarrhythmic drugs recommended by Vaughan-Williams

is still the most used nowadays for its simplicity, easy to remember and also consider the
specific action of drugs on membrane ion channels, i.e, sodium channels , calcium and
potassium channels (Table 1) 1. It is noteworthy that the drugs do not belong to one class
only, and may have effects on other classes, such as amiodarone may have multiple
actions on various ion channels (potassium, sodium and calcium). Although other drug
classifications have been published, these were very complex because they considered the
action of the drug on arrhythmogenic mechanisms, ion channels, electrical currents,
membrane receptors and other aspects, which would require the clinician a very extensive
knowledge of cardiac electrophysiology, making the classification impractical. The classic
example of this was the Sicilian gambit2.

Depending on their characteristics of action, antiarrhythmic drugs are classified into four
classes1. The first is subdivided into three subclasses based on its effects on sodium
channels and consequently on the maximum velocity (Vmax) of phase zero of action
potential, on cellular refractoriness and its repolarization1: Class IA, reduce Vmax and
prolong cellular repolarization and refractoriness: quinidine, procainamide and
disopyramide. In practice, these agents act primarily on the arrhythmogenic substrate and
little effect on the triggers. Class IB, lower intensity of the sodium channel blockade,
causing minor reduction of Vmax and shortening of the cellular repolarization and
refractoriness: lidocaine, mexiletine, diphenylhydantoin. These agents act mainly on
triggers and little on the arrhythmogenic substrate.
Table 1 - Classification of antiarrhythmic drugs according to Vaughan-second Williams1

Drug Class Action

I Sodium Channel Blockers
IA - moderate depression of phase 0
Moderate reduction in conduction velocity
Prolongation of repolarization
Quinidine
Procainamide
Disopyramide
IB - Minimum depression of phase 0
Shortening of repolarization
Lidocaine
Mexiletine
Diphenilhidantoin
IC - major depression of phase 0
Significant reduction in conduction velocity
Little effect on repolarization
Propafenone
Flecainide
II Beta-blockers
Propranolol
Atenolol
III Prolongation of repolarization
Amiodarone
Sotalol
IV calcium channel blockers
Verapamil
The Class IC drugs cause intense block of fast sodium channels, reducing extensively the
Vmax of phase zero, but cause less prolongation of cellular repolarization and
refractoriness: propafenone and flecainide. The class IC agents act on the arrhythmogenic
substrate, triggers, and little on the modulating factors. Group II, beta-blockers. have great
effect on the modulating factors and little on the triggers. Group III, causing blockage of
potassium channels (and also partial blockade of calcium and sodium channels),
amiodarone and sotalol. Particularly amiodarone, has effects on the three components that
generate arrhythmias due to its action on multiple ion channels, has anti-adrenergic effects
and acts against the other destabilizing factors of the substrate (anti-ischemic and anti-
renin effects). For this reason this agent is considered the most potent antiarrhythmic drug
today. Group IV, calcium channel blockers: verapamil and diltiazem showing more
significant actions on the factors that destabilize the substrate and little effect on the
triggers.

Class I Drugs

Antiarrhythmic agents, according to the classification above, should modify the

characteristics of the cellular action potential when acting on ion channels (Figure 2).

Thus, the class I drugs, have the property of blocking with variable intensity, the fast
sodium channels and, therefore, slow the rise of phase zero of action potential in a more or
less intense manner, depending on the type of agent3. Thus, we expect a delay in the
propagation speed of electrical impulses within the arrhythmogenic circuit. The class IC
drugs (propafenone, flecainide) cause more intense blockade of fast sodium channels,
followed by the class IA agents and finally the class IB agents
Figure 2 - Action of antiarrhythmic drugs on the characteristics of cellular action potential (see
discussion in the text). The full line corresponds the action potential without drug effect. The class
IA agents slow phase zero of action potential and prolong repolarization. The class IB drugs
decrease action potential duration without affecting conduction velocity. Class III drugs prolong
repolarization by blocking potassium channels. Class IV drugs slow the rise of phase zero of action
potential of cells in the sinus node and the atrioventricular node.

Class II Drugs

Beta blockers are not considered potent antiarrhythmic agents but play a key role in the
treatment of arrhythmias, particularly when associated with true antiarrhythmic drugs such
as amiodarone. Beta-blockers act on specific membrane receptors, altering the pattern of
cellular response to catecholamines and ion channels sensitive to
catecholamines3. Reduce cellular excitability and arrhythmogenic effects caused by
catecholamines, particularly for patients with high adrenergic tone, as in heart failure and
coronary insufficiency. Studies have shown a significant reduction of sudden death rate
caused by ventricular arrhythmias, when a beta-blocker is included in the pharmacologic
therapy.
Class III Drugs

The class III drugs, especially amiodarone (and other similar drugs like ibutilide, dofetilide
and azimilide) exert its main effect on blocking the potassium channels. It may also exert a
modest antagonistic effects on sodium channels (and consequently on the phase zero of
action potential), and cause discrete block of calcium channels3. The potassium channel
blockade is responsible for the prolongation of the action potential and the cell refractory
period, and may interrupt arrhythmias in arrhythmogenic circuit by blocking the spread of
electrical impulse. Due to its systemic action, and also over other factors that may
cooperate to cause arrhythmias, amiodarone is considered a wide spectrum antiarrhythmic
drug. Amiodarone has extra-cardiac side effects that may limit its administration in about
20 to 30% of patients . Interstitial pneumonitis and thyroid disorders are the most
important. Mentioning is also the peripheral neuritis, liver failure and changes in skin
color. To prevent these complications patients should undergo periodic clinical evaluations,
including chest X-rays, investigation of thyroid and liver functions4. Sotalol is a beta-blocker
but has class III antiarrhythmic properties by increasing the duration of the action
potential. Should be administered to patients without ventricular dysfunction, both for the
treatment of atrial and ventricular arrhythmias. Along with quinidine, has important pro-
arrhythmic effects (2-3%).

Class IV Drugs

These agents act by blocking the calcium channels and thus may interfere with the firing
frequency of the sinus node and also on the conduction velocity of the atrioventricular
node3. Are effective in supraventricular tachyarrhythmias using the atrioventricular node as
part of the arrhythmogenic circuit. In atrial fibrillation can be an important tool in reducing
the recurrence of arrhythmia when coupled with other antiarrhythmic drugs such as
propafenone or amiodarone, because of its effect in reducing the electrical remodeling
effects on the atrial tissue5.
Pro-arrhythmic effects of antiarrhythmic drugs

One of the factors limiting the prescription of antiarrhythmic drugs is the risk of potentially
letal pro-arrhythmic effects6 (figure 3). These are caused by triggering polymorphic
ventricular tachycardia called torsades de pointes, which can cause sudden death.
Unfortunately, most patients who require antiarrhythmic therapy, like those with ventricular
dysfunction and frequent ventricular arrhythmias, are the most vulnerable to these serious
complications. The patients at greatest risk are those with complex ventricular arrhythmias,
patients with hypokalemia and / or hypomagnesemia (caused by diuretics), heart failure,
myocardial ischemia, and female. It should be borne in mind that the antiarrhythmic
treatment should always be done very safely to avoid a potentially benign arrhythmia to be
transformed into something severe enough that may lead to sudden death. Example in this
condition are patients with atrial fibrillation with ventricular dysfunction who are at risk of
sudden death when treated with quinidine. Therefore the correct identification of high risk
patients can make antiarrhythmic treatment safer and more effective.

New antiarrhythmic drugs are currently under clinical evaluation whose mechanism of
action is more specific on potassium channels present only in atrial tissue. These agents
will be used in the treatment of atrial tachyarrhythmias such as atrial
fibrillation7. Vernakalant is now available for intravenous use with this purpose8. The great
advantage of these new drugs is the lower risk of pro-arrhythmogenic effects on the
ventricles (the risk of torsades de pointes) and of extra-cardiac side effects, the main
factors limiting the use of drugs currently available.
Figure 3 - Torsades de pointes polymorphic ventricular tachycardia in a 72 year old
female who was taking quinidine for preventing recurrences of atrial fibrillation. See
above, ventricular bigeminy and also QT prolongation; below the polymorphic
ventricular tachycardia that is manifested as a twist along its axis.
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