Mechanism of Action and Electrophysiology
The mechanism of action of subclass IA agents is based on the blockade of cardiomyocyte ion channels—specifically fast sodium ($Na^+$) and potassium ($K^+$) channels. This directly affects the phases of the action potential (AP):
- Phase 0 (depolarization): Prolonged. The slope of the AP curve becomes shallower due to delayed sodium influx, which clinically manifests as a decreased impulse conduction velocity.
- Phase 3 (repolarization): Prolonged due to potassium channel blockade. The curve shifts to the right, and the total duration of the action potential increases.
- Phase 4 (diastolic depolarization): Prolonged, with a reduced slope of spontaneous depolarization, leading to decreased automaticity.
The net result of these electrophysiological effects is a 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. Because of 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.
Main indications include:
- Ventricular premature beats and tachyarrhythmias.
- Supraventricular premature beats and tachycardias.
- Atrial fibrillation (both paroxysmal and persistent forms).
- Atrial flutter.
Comparative Characteristics of the Drugs
Despite a shared mechanism, individual agents in this group possess important pharmacological and pharmacokinetic differences.
- Quinidine: A dextrorotatory isomer of quinine (cinchona bark alkaloid). It has high oral bioavailability (70–80%) when taken per os. In addition to its direct depressant effect on the heart, it exhibits vagolytic (anticholinergic) effects and blocks $\beta$-adrenoceptors, causing peripheral vasodilation and a moderate drop in blood pressure. It is excreted by the kidneys, and urine acidification accelerates its excretion.
- Procainamide: Unlike quinidine, it has less negative inotropic effect on myocardial contractility and lacks $\beta$-blocking activity, but possesses moderate ganglionic-blocking properties (also causing hypotension). In the liver, it is converted into an active metabolite—N-acetylprocainamide (NAPA). The rate of this conversion depends on genetic polymorphism (patients are categorized as "fast" or "slow" acetylators). In renal failure, this metabolite can accumulate.
- Disopyramide: Exhibits the strongest negative inotropic effect (significantly reducing myocardial contractility) and potent antimuscarinic (atropine-like) effects.
Adverse 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 (decreased contractility, risk of heart failure).
- Depression of atrioventricular conduction (AV block).
- Arterial hypotension.
Arrhythmogenic Effect: These drugs can provoke new arrhythmias. Prolonged repolarization increases the risk of early afterdepolarizations (EADs), which trigger torsades de pointes tachycardia. Furthermore, vagolytic action disinhibits AV conduction, and depressed conduction can paradoxically accelerate the rhythm during a re-entry phenomenon (impulses begin to travel faster along a "short circuit").
Extracardiac Effects:
- Quinidine: Dyspepsia, sensorineural disturbances (tinnitus, hearing and vision impairment), thrombocytopenia.
- Procainamide: Seizures, immunoallergic reactions (fever, rash, agranulocytosis, drug-induced lupus-like syndrome).
- Disopyramide: Dry mouth, blurred vision (cycloplegia), constipation, and urinary retention.