Class IA Antiarrhythmic Drugs

Class IA antiarrhythmic drugs block sodium channels with intermediate kinetics and also block potassium channels, so they slow conduction and prolong action potential duration and QT interval. Quinidine, procainamide and disopyramide are the members. Their use is now limited by proarrhythmia and non-cardiac toxicity, and several are unavailable in many markets.

Members. Quinidine, procainamide, disopyramide and ajmaline (used for provocation testing in Brugada syndrome).

Mechanism. Moderate Nav1.5 blockade with intermediate unbinding slows phase 0 depolarisation. Block of delayed rectifier potassium currents prolongs repolarisation. Quinidine and disopyramide also have anticholinergic effect, and quinidine blocks alpha receptors. Procainamide is converted to N-acetylprocainamide, which has class III action.

Proarrhythmia. Torsades de pointes, called quinidine syncope, occurs at low or therapeutic levels and is promoted by hypokalaemia, hypomagnesaemia, bradycardia and female sex. Anticholinergic action can speed atrioventricular conduction in atrial flutter or fibrillation.

Pharmacokinetics. Quinidine is metabolised by CYP3A4, inhibits CYP2D6 and raises digoxin levels by about twofold. Procainamide undergoes acetylation, with slow acetylators at higher risk of lupus-like syndrome, and both the parent and N-acetylprocainamide accumulate in renal failure. Disopyramide is partly renally cleared.

Historical antimalarial role. Quinidine and its isomer quinine were used for severe falciparum malaria. Artesunate has replaced them.

• Quinidine: atrial fibrillation cardioversion and maintenance in the past; ventricular arrhythmia in Brugada syndrome and short QT syndrome in specialist care.
• Procainamide: intravenous for stable wide-complex tachycardia and pre-excited atrial fibrillation.
• Disopyramide: vagally mediated atrial fibrillation, obstructive hypertrophic cardiomyopathy, and vasovagal syncope.
• Ajmaline: intravenous provocation test.

• Stable monomorphic ventricular tachycardia and pre-excited atrial fibrillation: procainamide intravenously at up to 50 mg/minute to a total of 17 mg/kg, stopping for hypotension, QRS widening by over 50%, or arrhythmia termination. Maintenance 1 to 4 mg/minute. Target procainamide level 4 to 10 micrograms/mL, with parent plus N-acetylprocainamide not over 30 micrograms/mL.
• Atrial fibrillation rhythm control (rarely): quinidine sulphate 200 to 400 mg every 6 to 8 hours, started in hospital after atrioventricular nodal blockade.
• Obstructive hypertrophic cardiomyopathy: disopyramide controlled release 150 to 300 mg twice daily, with a beta blocker to control atrioventricular conduction.
• Brugada provocation: ajmaline 1 mg/kg over 5 minutes with continuous electrocardiogram and resuscitation equipment.
• Selection: use IA drugs only when safer alternatives are not suitable, in specialist care, and in structurally normal hearts for atrial indications.

Contraindications. Long QT syndrome, history of torsades de pointes, second or third degree atrioventricular block without a pacemaker, heart failure with reduced ejection fraction (especially disopyramide), myasthenia gravis, systemic lupus erythematosus (procainamide), uncorrected hypokalaemia, glaucoma and urinary retention (disopyramide), and coronary disease with previous infarction.

Adverse effects. Torsades de pointes, QRS widening, hypotension, diarrhoea, cinchonism (tinnitus, headache, visual disturbance) and thrombocytopenia (quinidine), haemolysis in G6PD deficiency (quinidine), drug-induced lupus and agranulocytosis (procainamide), anticholinergic effects, heart failure and hypoglycaemia (disopyramide).

Interactions. Quinidine raises digoxin levels and warfarin effect, inhibits CYP2D6 (metoprolol, codeine, flecainide), and interacts with other QT-prolonging drugs, amiodarone and anticholinergics. Antacids and urinary alkalinisation reduce quinidine clearance.

Monitoring. Electrocardiogram for QRS and QTc (stop when QTc exceeds 500 ms or rises by over 60 ms, or QRS widens by over 25%), potassium and magnesium, blood count weekly for the first 3 months with procainamide, antinuclear antibody and symptoms of lupus, liver function with quinidine, and drug levels (quinidine 2 to 5 micrograms/mL).

Referral and escalation. Syncope, torsades de pointes or new heart failure needs urgent stopping of the drug and hospital care.

Special groups. Renal impairment: reduce procainamide and disopyramide, and monitor N-acetylprocainamide. Hepatic impairment: reduce quinidine. Older adults: higher anticholinergic and proarrhythmic risk. Pregnancy: limited data, avoid unless essential. Breastfeeding: avoid or use with caution.