Atrial fibrillation and normal or abnormal heart rate rythm concept as a cardiac disorder as a human organ with healthy and unhealthy ecg monitoring in a 3D illustration style.

Antiarrhythmic drugs: mechanism of action and side effects

By Cristiano Antonino On Apr 7, 2023

Antiarrhythmic drugs are drugs used to prevent or correct arrhythmias, i.e. those conditions in which the normal heart rhythm is altered

Pathophysiology of the cardiac cycle and arrhythmia

The phases of the action potential: Phase 0: rapid depolarisation Phase 1: early repolarisation Phase 2: plateau Phase 3: final repolarisation Phase 4: restoration

Cardiac rhythm is due to two processes: the formation of an impulse, normally from the sinus node, and its conduction through the cardiac conduction system.

Arrhythmias are therefore due to abnormal impulse formation, abnormal impulse conduction, or a combination of these.

Antiarrhythmic drugs, acting at various levels of the impulse formation and conduction process, tend to normalise heart rhythm.

Antiarrhythmic drugs, Vaughan Williams classification

The five main classes of the Vaughan Williams classification of antiarrhythmic agents are:

Class I: agents interfere with the sodium (Na+) channel;
Class II: agents are anti-sympathetic agents of the nervous system. Most agents in this class are beta-blockers;
Class III: agents act on potassium efflux (K+);
Class IV: agents act on calcium channels and the AV node;
Other agents: act on heterogeneous mechanisms.

With regard to the management of atrial fibrillation, Classes I and III are used in rhythmic control as medical cardioverse agents, while Classes II and IV are used as heart rate control agents.

Sicilian Gambit classification for anti-arrhythmic drugs

Although Vaughan Williams’ classification is the best known, it is in reality inaccurate, as it takes little account of the difference in the mechanism of arrhythmias, failing to identify a correct and best approach; this is remedied by the ‘Sicilian gambit’ classification.

It presents the drugs on two axes.

On the Y-axis, each drug is listed in the order of the Singh-Vaughan Williams classification.

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 as it does not group drugs into categories.

Mechanism of action of antiarrhythmic drugs

Depending on the type, anti-arrhythmic drugs exert a blocking action on the 3 main channels sodium (the first class), calcium and potassium or beta-adrenergic receptors.

Anti-arrhythmic drugs are able to:

Influence chronotropism (beats per minute) by slowing the heart rate.
Influence dromotropism (impulse conduction velocity along the specific tissue), slowing the impulse conduction velocity from the atria to the ventricles and thus allowing proper emptying of the atrial chambers.
Influence batmotropism (excitability of myocardial cells) by decreasing the threshold of cell activation.

Class IA

Drugs belonging to this class reduce the rate of phase 0 elevation (due to the opening of sodium channels), prolong the duration of the cardiac action potential and dissociate from sodium channels with intermediate kinetics.

Sodium channels are responsible for the rapid excitation of myocardial cells: blocking these channels makes the cells more refractory, placing a significant limitation on the genesis of excessively rapid or ectopic impulses.

This category includes:

Quinidine, used almost exclusively in supraventricular arrhythmias, it succeeds in interrupting flutter and atrial fibrillation, its use at the end of the 20th century was reduced following clinical research.
Procainamide, supraventricular and ventricular arrhythmias has a similar effect to quinidine but is used when resistance to the former is observed.
Disopyramide, often used in combination with mexiletine, prevents recurrences in the case of ventricular tachycardias.

Side effects:

Quinidine (vomiting, abdominal pain, diarrhoea, anorexia)
Procainamide (rash, myalgia, Raynaud’s phenomenon)
Disopyramide (urinary retention, constipation, glaucoma).

Class IB

Although they are able to bind the sodium channel, they do not significantly affect the action potential due to very rapid dissociation kinetics.

They are relatively safe drugs that are mainly used in emergencies (myocardial infarction, prevention of serious arrhythmic events).

Drugs that fall into this category are:

Aprindin, formerly used in extrasystolic ventricular arrhythmias and Wolff-Parkinson-White syndrome. Now fallen into disuse.
Lidocaine, in ventricular arrhythmias and especially in recurrent forms;
Mexiletine, used in acute and chronic tachyarrhythmias, effective results are obtained when administered in combination with propafenone or amiodarone. Due to undesirable effects, treatment must be discontinued in almost 40% of cases.
Phenytoin, used in cases of atrial and ventricular arrhythmias due to drug intoxication.
Tocainide.

Side effects:

Lidocaine (paresthesia, dizziness, confusion, delirium);
Mexiletine (dysarthria, tremor, diplopia, nystagmus);
Phenytoin (dizziness, ataxia, coma, nystagmus, more rarely congenital foetal malformations).

Class IC

Drugs in this category are characterised by slow dissociation kinetics and include:

Flecainide, is mainly used for atrial flutter and atrial fibrillation. It is also used in infancy and foetus.) CAST (name of a clinical trial), however, showed an increased mortality rate from 2.3 to 5.1 for non-Q-wave-related acute myocardial infarction.
Encainide (not marketed in Italy): indications are similar to those of flecainide).
Moricizine, almost as effective as disopyramide against even lethal arrhythmias, although an increase in mortality was found in ventricular arrhythmias present after acute myocardial infarction, especially in patients taking diuretics.
Propafenone, used for paroxysmal atrial fibrillation and supraventricular tachycardia).

Side effects:

Flecainide (sometimes shows proarrhythmic effects);
Propafenone (bronchospasm, dizziness, taste and vision disturbances);
Moricizine (nausea, vomiting, diarrhoea).

Class II

They block beta-adrenergic receptors.

All drugs have more or less the same effects, but what differentiates them is the time of use and side effects.

They are subdivided into beta1 and beta2, with the former having a greater effect on the heart and the latter on the bronchi and blood vessels.

A longer half-life is observed in those that are eliminated through kidney action.

Given their similar action, if one shows no effect, the others will also be useless.

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These agents are particularly useful in the treatment of supraventricular tachycardias.

They decrease conduction through the AV node.

Drugs that fall into this category are:

Acebutolol
Atenolol
Esmolol
Metoprolol
Propranolol
Timolol

Side effects: may cause worsening of asthma or chronic obstructive pulmonary disease, Raynaud’s phenomenon.

Abrupt discontinuation of treatment may cause worsening in angina pectoris.

Class III

They block potassium channels, have a stretching effect on repolarisation and a refractory effect on Purkinje fibres, rendering the reentry circuit inoperable.

Class III agents have the characteristic of prolonging the QT interval of the ECG and can themselves be proarrhythmic.

Drugs that fall into this category are:

Amiodarone, newer Dronedarone used for numerous types of tachyarrhythmias, has an equal or greater positive effect than other similar drugs
Azimilide, usually used to stop atrial fibrillation or flutter
Bunaftine.
Dofetilide, has been shown not to alter the incidence of fatal events when administered following heart attacks.
Ibutilide, used in case of interruption of atrial fibrillation or flutter
Nifekalant.
Sotalol, used in the prophylaxis of supraventricular arrhythmias of the paroxysmal type.
Tedisamil.
Bretylium tosylate, used in the intensive care unit.

Side effects:

Amiodarone (dyspnoea, hypoxaemia, cough, fever, severe pulmonary and gastrointestinal effects do not allow the use of the administration for a long time, although only in 18-37% of cases is the treatment then actually discontinued).
Bretylium (hypotension, nausea, vomiting).

Class IV

They block calcium channels, acting on both physiological and pathological slow fibres. In particular, phenylalkylamines and benzothiazepines are used, which have a use-dependent effect.

They can affect the contractility of the heart, so must be used very carefully in chronic heart failure.

Drugs that fall into this category are:

Diltiazem,
Verapamil, contraindicated in children under 1 year of age

Antiarrhythmic drugs, other agents

In the original Vaughan Williams classification system, some substances are not included, but are nevertheless used in some specific cardiological diseases:

Adenosine is used intravenously in an attempt to interrupt some forms of supraventricular tachycardia.
Digoxin reduces the conduction of electrical impulses through the AV node and is therefore still used in frequency control in atrial fibrillation.
Dronedarone.
Magnesium sulphate is generally only administered in addition to other anti-arrhythmic drugs and if a deficiency results. In the treatment of certain arrhythmias, including peak torsions, they are combined to restore the intracellular pool of this element as quickly as possible, as is also the case with potassium.
Potassium.

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