Class IA Antiarrhythmic Agents

Mechanism of action and electrophysiology

The mechanism of action of subclass IA drugs is based on blocking cardiomyocyte ion channels — fast sodium ($Na^+$) and potassium ($K^+$). This directly affects the phases of the action potential (AP):

• Phase 0 (depolarization): prolonged. The slope of the AP curve becomes flatter due to slowed sodium influx, which clinically means a decrease in impulse conduction velocity.
• Phase 3 (repolarization): prolonged due to potassium channel blockade. The curve shifts to the right, and the overall duration of the action potential increases.
• Phase 4 (diastolic depolarization): prolonged, the slope of spontaneous depolarization decreases, leading to reduced automaticity.

The result of this electrophysiological effect is the widening of the AP complex and an increase in the effective refractory period (ERP).

Indications for use

Drugs in this group are versatile: they affect all regions of the heart. Due to their ability to suppress ectopic pacemakers (more markedly in the AV junction, less so in the sinus node), they are used for rhythm disorders of any origin.

Key indications include:

• Ventricular extrasystoles and tachyarrhythmias.
• Supraventricular extrasystoles and tachycardias.
• Atrial fibrillation (both paroxysmal and permanent forms).
• Atrial flutter.

Comparative characteristics of drugs

Despite their common mechanism, the representatives of this group have important pharmacological and pharmacokinetic differences.

• Quinidine: the dextrorotatory isomer of quinine (an alkaloid of the cinchona bark). It has high bioavailability (70–80%) when taken per os. In addition to its direct depressant effect on the heart, it exerts a vagolytic (anticholinergic) effect and blocks $\beta$-adrenoceptors, causing peripheral vasodilation and a moderate decrease in blood pressure. It is excreted by the kidneys, and urine acidification accelerates its excretion.
• Procainamide (novocainamide): unlike quinidine, it suppresses myocardial contractility less and lacks $\beta$-adrenoblocking activity, but has a moderate ganglion-blocking effect (also causes hypotension). In the liver, it is converted into an active metabolite — N-acetylprocainamide. The rate of this conversion depends on genetic polymorphism (patients are divided into "fast" and "slow" acetylators). In renal failure, the metabolite can accumulate.
• Disopyramide (Rhythmodan): distinguished by the strongest negative inotropic effect (significantly reduces myocardial contractility) and a potent M-cholinolytic (atropine-like) effect.

Side and proarrhythmic effects

The use of quinidine-like agents is associated with a high risk of adverse reactions.

Cardiac and hemodynamic effects:

• Negative inotropic effect (reduced contractility, risk of heart failure).
• Suppression of atrioventricular conduction (AV block).
• Arterial hypotension.

Arrhythmogenic action: The drugs can provoke new arrhythmias. Prolongation of repolarization increases the risk of early afterdepolarization, which triggers torsades de pointes tachycardia. Additionally, the vagolytic effect disinhibits AV conduction, and the suppression of conduction can paradoxically accelerate the rhythm in the re-entry phenomenon (the impulse begins to travel faster along the "short circuit").

Extracardiac effects:

• Quinidine: dyspepsia, neurosensory disorders (tinnitus, hearing and vision impairment), thrombocytopenia.
• Procainamide: seizures, immunoallergic reactions (fever, rash, agranulocytosis, lupus-like syndrome).
• Disopyramide: dry mouth, accommodation paralysis, obstipation (constipation), and urinary retention.

Class and exam questions

What else to study on this topic

• Mechanism of development of torsades de pointes tachycardia
• The influence of urine pH on the pharmacokinetics and excretion of quinidine
• Lupus-like syndrome during procainamide therapy
• The Re-entry phenomenon and the effect of slowed conduction on it

Other topics in the "Antiarrhythmic Agents" section

Prepared by WhiteCoat Pro faculty in accordance with the medical school curriculum. For educational purposes only.