The Vaughan-Williams classification is one of the most commonly used classifications for antiarrhythmic drugs. Class 1 consists of sodium channel blockers, which in turn is divided into 3 subgroups namely 1A, 1B and 1C. This article discusses the class 1 antiarrhythmic drugs in detail, along with a description of the salient features of individual drugs.

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Quinidine 3d balls

Image: “3D-structure of quinidine” by Harbinary – Own work. License: Public Domain


Antiarrhythmic Drugs

The Vaughan-Williams classification is one of the most commonly used classifications for antiarrhythmic drugs. It is very important to classify a drug so that its possible benefit can be explored. This classification groups the drugs based on their general effect (based on the mechanism of action). The drugs are grouped into 5 classes.

Class 1 consists of sodium channel blockers, which in turn are divided into 3 subgroups namely 1A, 1B and 1C. This will be explained in detail in the mechanism of action category below.

Class 2 consists of beta blockers, which basically reduce the heart rate, conduction and cause a reduction of the sympathetic activity.

Class 3 consists of potassium channel blockers and it works by means of prolonging the repolarization phase, thereby increasing the duration of action potential. This effectively culminates in increasing the effective refractory period.

Class 4 consists of calcium channel blockers and it works by blocking the L-type calcium channels. These channels are normally found along the conduction pathway, especially near the SA node and AV node. By means of blocking these channels, these drugs reduce the heart rate and the conduction of the heart.

Class 5 antiarrhythmic drugs are other agents that cannot be categorized in the above groups.

This article discusses the class 1 antiarrhythmic drugs in detail, along with a description of the salient features of individual drugs.

The action potential

Basic cardiac action potential

Image: “Basic cardiac action potential” by Action_potential2.svg: *Action_potential.png: User:Quasar derivative work: Mnokel (talk) derivative work: Silvia3 (talk) – Action_potential2.svg. License: CC BY-SA 3.0

The trajectory which the action potential follows will be dependent upon the membrane potential of the cardiac cells and it varies between different parts of the heart. There is a normal rise followed by a fall in the action potential.

The phase 0 represents the rapid depolarization phase. It occurs because of the influx of the sodium. Phase 2 and 3 represent the repolarization phase. In both of these cases, there is the prominent efflux of potassium in addition to other ions. In Phase 2, the potential, arising by the efflux of potassium, is balanced by the influx of calcium, thus making the action potential to remain as a horizontal line.

Classification of group 1 antiarrhythmic drugs

Class 1A: Quinidine, procainamide and disopyramide

Class 1B: Lidocaine, tocainide and mexiletine

Class 1C: Flecainide, propafenone and moricizine

Mechanism of Action of Sodium Channel Blockers

Sodium channel blockers act by means of blocking the fast sodium channels. By doing this, the rapid depolarization is blocked. This decreases the slope of the phase 0 of action potential.

When we consider the tissue in which these drugs have an effect, the phase 0 of the atrial and ventricular muscle action potential is dependent upon sodium channels, whereas the phase 0 of the conduction tissue is dependent upon the calcium channels. Thus, the atria and ventricular muscle are effected by class 1 antiarrhythmic drugs.

The differences between the three subgroups within the class 1 are that class 1A causes a moderate reduction in phase 0 slope, the class 1B causes a small reduction in the phase 0 slope and the class 1C causes the pronounced reduction in phase 0 slope as it has the maximum sodium channel blocking property.

The action potential duration occurs with an increase, decrease and zero effect with respect to class 1A, 1B and 1C respectively. Similarly, for the effective refractory period, there occurs an increase, decrease and zero defects with class 1A, 1B and 1C effectively. The potential to cause an increase in the effective refractory period is related to the increase in the efflux of the potassium, which occurs with these drugs rather than the sodium channel blocking property.

The anticholinergic effect, which is seen with this group of drugs, increases the conduction along the sinoatrial and atrioventricular pathway, thus, in a patient with atrial flutter, though the ventricular rate will be reduced by the sodium blocking property of the class 1 antiarrhythmics.

Atrial flutter with variable block

Image: “Atrial flutter with variable block (between 3 and 4 to 1)” by James Heilman, MD. License: CC BY-SA 3.0

The beneficial effect will be nullified by the subsequent increase in the conduction of the impulses from the fast beating atria. The concomitant administration of beta blockers and calcium channel blockers is required in patients with atrial flutter, along with ventricular tachycardia.

Pros & Cons and Main Indication of Sodium Channel Blockers

All the three classes of drugs are indicated for the treatment of ventricular tachyarrhythmias.

In addition, the class 1C drug is very valuable in life-threatening supraventricular tachyarrhythmias (flecainide and propafenone). The class 1A drug also has an effect on the atrial fibrillation, along with flutter and supraventricular tachycardia.

Adverse and Side Effects Related to Sodium Channel Blockers

The side effects are discussed in detail for individual drugs.

The increase or decrease with action potential duration and the effective refractory period can act as a double edged-sword. Both of these mechanisms prevent the re-entry circuits, but, at the same time, increase the potential for causing Torsades de pointes.  The proarrhythmogenic potential is generally seen among this group of drugs.

Disopyramide

Indication of disopyramide

Other than the indications which were discussed above, an important consideration needs to be made in those patients who have uncontrolled atrial fibrillation. The administration of disopyramide will cause an increase in the AV nodal conduction, thereby increasing the risk ventricular rate in these patients.

This effect also occurs with procainamide and quinidine. Treatment with beta blockers, digoxin or a calcium channel blocker is required. The disopyramide is deemed safe in patients with hypertrophic cardiomyopathy and is shown to have beneficial effects.

Side effects of disopyramide

Disopyramide has a significant cardiac toxicity and it decreases the contraction of the heart (negative inotropic effect) and it has the potential to cause arrhythmia. The decrease is seen even with a dose as low as 1 mg/kg and may precipitate a condition of heart failure.

The propensity for causing heart failure increases with the already known case of heart failure patients. The common side effect of disopyramide is related to its anticholinergic effect. This includes the dryness of mouth, hesitancy during urination and the difficulty in passing feces.

In conditions where the cholinergic activity is already decreased, like myasthenia gravis (in this disease antibodies are formed against acetylcholine receptors), the administration of this drug will aggravate the condition.

Acute angle closure glaucoma

Image: “Photograph showing acute angle-closure glaucoma which is a sudden elevation in intraocular pressure that occurs when the iris blocks the eye’s drainage channel—the trabecular meshwork.” by Jonathan Trobe, M.D. – The Eyes Have It. License: CC BY 3.0

The other conditions in which caution needs to be exercised are the acute angle closure glaucoma and urinary retention patients. It causes the widening of the QRS complex and the prolongation of the QT interval in the electrocardiogram. There occurs a risk of hypoglycemia (potential hypothesis is the disopyramide induced inhibition of the K ATP channels) with disopyramide therapy, though it is rare.

Monitoring available for the prevention of side effects

In order to prevent the anticholinergic effect, the monitoring of serum concentrations of mono-N-dealkyldisopyramide, is required in renally deranged patients.

Treatment of side effects

Though the decrease in contractility is self-limiting with disopyramide, acute treatment with diuretics and an inotropic agent might be required.

The anticholinergic effect can be counteracted by means of administering physostigmine and pyridostigmine, both of which increase the cholinergic activity.

The widening of the QRS complex and the prolongation of QT interval require discontinuation of the treatment. Intravenous magnesium, by means of surprising the after depolarization, stands as a therapy in patients requiring treatment for prolongation of QT interval.

Procainamide

Side effects of procainamide

One of the most important known side effects of procainamide is its potential to cause a lupus like syndrome, which is especially common with chronic administration. The blood of these patients will have positive antinuclear antibody titer (where the antibodies are essentially formed against the patient’s own nuclear elements).

Raynauds’ Disease

Image: “Back and front of a hand of a person suffering from Raynaud’s disease” by Vertebro. License: Public Domain

The other side effects include loss of appetite, the sensation of vomiting, headache, loss of sleep, dizzy feeling, hallucination, psychosis (rare but reported), rashes which are characteristically morbilliform in nature, conditions affecting the blood vessels such as Raynaud’s phenomenon and vasculitis of the digital ends.

Similar to the disopyramide, there occurs a potential for prolongation of the QRS complex, QT interval and occurrence of ventricular arrhythmia.

The drug also increases the risk of causing arrhythmias and is an arrhythmogenic agent. The most common arrhythmia, which is caused by these drugs, is a form of polymorphic ventricular tachycardia known as Torsades de pointes.

Bone marrow suppression is one of the dreaded side effects of procainamide which makes patients against the routine use of this drug.

Pancytopenia and agranulocytosis occur in this condition. The cause behind it is not well delineated and it might range from allergic to hypersensitivity.

Treatment of side effects

The symptoms of a lupus like syndrome occur in very few patients and, even in those patients, it is self-limiting after the treatment is stopped. Other alterations include considering alternatives like N-acetyl procainamide, which does not have lupus potential.

The occurrence of bone marrow suppression warrants immediate discontinuation of the drug.

Quinidine

Quinidine structure

Image: “Chemical structure of Quinidine” by Ymwang42 – Using ChemDraw11.0. License: CC0

Quinidine can be used for the treatment of both types of arrhythmia, namely ventricular and atrial.

Special indication for quinidine

Brugada syndrome is a genetic disorder which is associated with the abnormal rhythm in the heart and causing ventricular arrhythmias.

These patients are characterized by the potential to suffer from sudden cardiac death, and an implantable cardioverter defibrillator (ICD), is the gold standard for prevention.

Quinidine has shown promise in this group of patients and a standard alternative treatment. The study which proclaims this effect is a recently published study and was conducted in 96 patients and had a mean follow-up of 113 months.

In a systematic review, where the various antiarrhythmic drugs were evaluated for atrial fibrillation, though the quinidine reduced the recurrence of atrial fibrillation, it was associated with an increased mortality and it was the most proarrhythmogenic agent among the tested class of drug (class 1A, 1C and  3 were included in the systematic review).

Side effects of quinidine

As with other drugs in the class A group, this is also proarrhythmic and has the potential to cause sudden death, thus reducing its routine use. Like disopyramide, it can also precipitate heart failure.

There occurs characteristic arrhythmia with quinidine, namely bigeminy and ventricular premature tachycardia. There also occurs the prolongation of the QT interval (this is related to a delay in repolarization) causing risk of Torsades de pointes and is maximum with this drug.

Torsades de Pointes

Image: “Prolonged QT interval; Torsades de pointes (TdP).” by Jer5150 – Own work. License: CC BY-SA 3.0

The risk of digitalis toxicity is enhanced with quinidine administration and other risk factors include the presence of hypokalemia. On the administration of very large doses rapidly, there occurs a risk of hypotension with quinidine. The reason is the direct vasodilatory property of quinidine. Quinidine is also associated with a hypoglycemic effect and immune mediated reactions.

The quinidine toxicity is described with a characteristics term known as cinchonism. The signs and symptoms of cinchonism include the blurring of vision, a ringing sound in the ears which is known as tinnitus, psychosis, confusion, delirium and headache.

Treatment of side effects

The Torsades de pointes can be treated by artificially increasing the pace of the atria and ventricles and by the intravenous administration of isoproterenol.

A method of prevention is by means of alkalization with sodium bicarbonate (basically the alkalosis enhances the recovery of sodium channels). Intravenous magnesium sulphate, as discussed above, is another alternative.

Lidocaine and Its Analogs

Indication of lidocaine

Lidocaine is available only in IV form and is indicated for ventricular tachycardia. The disopyramide and mexiletine are orally active lidocaine analogs. The patients who have myocardial ischemia, in addition to the arrhythmogenic problems, will benefit from lidocaine and mexiletine, as they have improved efficacy against ischemic myocardium.

Side effects

A chest radiograph of a patient with Idiopathic Pulmonary Fibrosis (IPF).

Image: “A chest radiograph of a patient with Idiopathic Pulmonary Fibrosis (IPF).” by IPFeditor – Own work. License: CC BY-SA 3.0

Tocainide has the potential to cause pulmonary fibrosis in the lungs.

Propafenone and Flecainide: In contraindication to the protective effect seen with the class 1B drugs in patients with myocardial infarction, there occurs an increased risk of death in patients with myocardial infarction when administered with class 1C compounds (CAST trial).

Propafenone, in addition to its sodium blocking property, also has beta blocking and calcium channel blocking activity. Both of these cause decrease in the conduction, along with the conduction pathway and can precipitate and aggravate heart failure.

Flecainide has the potential to induce life- threatening ventricular tachycardia.

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