Vaughan-Williams Classification
Antiarrhythmic drugs are traditionally divided into four main classes, with a fifth class (miscellaneous agents) conventionally added:
- Class I — sodium channel blockers (subclasses IA, IB, IC);
- Class II — beta-blockers;
- Class III — potassium channel blockers;
- Class IV — calcium channel blockers;
- Class V — adenosine, digoxin, ivabradine, ranolazine, vernakalant, magnesium sulfate, potassium preparations.
The key to understanding drug action is knowing the action potential phases of fast (ventricular myocardium) and slow (SA and AV nodal) tissues. Slow tissue is calcium-dependent, while fast tissue is sodium-dependent.
Class II: Beta-blockers
Drugs ending in "-olol" (metoprolol, bisoprolol, esmolol, carvedilol) act predominantly on the AV node. They slow phase 4 of spontaneous diastolic depolarization and prolong phase 0, reducing the rate of impulse generation.
The main indication is heart rate control in atrial fibrillation and flutter: these drugs do not restore sinus rhythm, but they reduce the number of impulses passing through the AV node to the ventricles. They are also used for atrial premature beats and ventricular tachycardias (reduction of sympathetic influences).
Adverse effects: bronchospasm (use with caution in asthma and COPD), bradycardia and AV blocks, heart failure decompensation, masking of hypoglycemia symptoms in diabetics.
Class I: Sodium channel blockers
Mnemonic for block potency: C > A > B ("Double Quarter Pounder, Lettuce, Fries Please").
- IA — quinidine, procainamide, disopyramide: moderately slow phase 0 and additionally block potassium channels, prolonging the action potential and QT interval. Risk of torsades de pointes. Procainamide is the drug of choice when WPW syndrome is combined with atrial fibrillation. Quinidine causes cinchonism, procainamide causes drug-induced lupus, and disopyramide has a pronounced anticholinergic effect.
- IB — lidocaine, mexiletine: bind to the inactivated state of the sodium channel, effective at high heart rates. They do not prolong the QT interval; they shorten it. Drugs of choice for ventricular tachycardia, especially post-myocardial infarction, and for torsades de pointes.
- IC — flecainide, propafenone: the most potent blockers of phase 0. Used for rhythm restoration in paroxysmal AF only in structurally normal hearts. Contraindicated in CAD, LVH, prior myocardial infarction, and HFrEF due to a high proarrhythmic effect up to ventricular fibrillation.
Class IV: Calcium channel blockers
Non-dihydropyridine blockers verapamil and diltiazem inhibit L-type calcium channels in the slow tissue of the AV node and atria. They slow conduction through the AV node and suppress early and late afterdepolarizations.
Indications: heart rate control in AF/AFL, termination of supraventricular tachycardias. Strictly contraindicated in ventricular tachycardia: the drug does not affect the ventricles, but it blocks the AV node and causes systemic vasodilation with hypotension, which can lead to myocardial ischemia and progression to ventricular fibrillation.
Adverse effects: bradycardia, AV blocks, decompensation of chronic heart failure, constipation, peripheral edema. The antidote in overdose is calcium salts.
Class III: Potassium channel blockers
Main drugs — amiodarone, dronedarone, sotalol, dofetilide, ibutilide. Potassium channel blockade prolongs phase 3 of repolarization and increases the QT interval.
Amiodarone is unique: it blocks both rapid (IKr) and slow (IKs) potassium channels, as well as sodium channels, calcium channels, and beta-adrenoreceptors. It rarely causes torsades de pointes, and is effective in AF, VT, including in the setting of structural heart disease. Adverse effects are due to its iodine content (~40%): thyroid dysfunction, pulmonary fibrosis, hepatotoxicity, corneal deposits, and blue-gray skin pigmentation. Monitoring of TSH, T3, T4, pulmonary function tests, liver function tests, and ECG is required.
Sotalol, dofetilide, and ibutilide frequently cause torsades de pointes (sotalol — up to 60% of cases). Sotalol additionally possesses beta-blocking activity.
Class V: Adenosine, Digoxin, and others
- Adenosine — activates A1 receptors, opens potassium channels, and blocks calcium channels. Causes transient AV block for 6–10 seconds. Drug of choice for paroxysmal supraventricular tachycardia due to a re-entry mechanism. Adverse effects: sense of impending doom, bronchospasm, flushing, coronary steal syndrome. Contraindicated in WPW with AF.
- Digoxin — blocks Na⁺/K⁺-ATPase, increases intracellular calcium, exerts a positive inotropic effect, and activates the vagus nerve. Used in AF in the setting of HFrEF. Narrow therapeutic window, risk of hyperkalemia, ventricular arrhythmias, cholinergic effects. Particularly dangerous in hypokalemia. Antidote — Digibind.
- Ivabradine blocks If channels of the sinus node; ranolazine blocks late sodium currents; vernakalant is a multi-channel blocker for AF cardioversion.
- Magnesium sulfate — drug of choice for torsades de pointes; potassium preparations are used in hypokalemic arrhythmias.
Clinical Scenarios and Therapy Monitoring
Atrial Fibrillation and Flutter:
- Rate control — beta-blockers, verapamil/diltiazem, digoxin (in HFrEF).
- Rhythm control (cardioversion) — procainamide (IA), flecainide and propafenone (IC, in healthy hearts only), amiodarone, ibutilide.
- Anticoagulation is mandatory prior to pharmacological or electrical cardioversion to prevent thromboembolism from the left atrial appendage.
Supraventricular Tachycardia (AVNRT, AVRT): adenosine; in WPW with AF — procainamide only, AV nodal blockade is contraindicated.
Torsades de Pointes: discontinuation of QT-prolonging drugs; magnesium sulfate; lidocaine; heart rate acceleration. QT is prolonged by Class IA and III antiarrhythmics (except amiodarone), macrolides, fluoroquinolones, antipsychotics, antidepressants, antiemetics; exacerbated by hypokalemia and hypomagnesemia.
Ventricular Tachycardias: beta-blockers always; in post-infarction VT — lidocaine; in the absence of infarction — amiodarone.
Key points
- Slow tissue (SA and AV nodes) is calcium-dependent; fast tissue (ventricular myocardium) is sodium-dependent — the choice of class depends on this.
- Beta-blockers and non-dihydropyridine CCBs control heart rate in AF, but do not restore rhythm.
- Class IC drugs are contraindicated in any structural heart disease due to their proarrhythmic effect.
- Lidocaine is the drug of choice for post-myocardial infarction ventricular tachycardia and an adjunctive treatment for torsades de pointes.
- Amiodarone is the most effective and versatile antiarrhythmic, but requires monitoring of the thyroid, lungs, liver, and ECG.
- In torsades de pointes, the drug of choice is magnesium sulfate; QT-prolonging agents must be discontinued.
- In WPW syndrome combined with AF, adenosine, beta-blockers, CCBs, and digoxin are prohibited; procainamide is used.
- Digoxin has a narrow therapeutic window, is dangerous in hypokalemia, and its antidote is Digibind.