Category:Antiarrhythmics

An antiarrhythmic is a medicine used to restore or maintain a normal cardiac rhythm in a patient with an arrhythmia, or to slow the ventricular response to one. The category is conventionally organised by the four-class scheme of the British clinical pharmacologist Miles Vaughan Williams, who in 1970 grouped the antiarrhythmics by their dominant electrophysiological action: class I, the sodium channel blockers; class II, the beta-adrenergic blockers; class III, the potassium channel blockers that prolong the action-potential duration; class IV, the calcium channel blockers that act on the slow inward current of the atrioventricular node.^[1] A fifth informal grouping covers agents that do not fit (digoxin, adenosine, magnesium, ivabradine).

The first effective antiarrhythmic medicine was an accidental observation. The Dutch cardiologist Karel Wenckebach, in Vienna at the turn of the twentieth century, encountered a Dutch sea captain with paroxysmal atrial fibrillation who had discovered that a daily dose of quinine, taken for malaria during his Indonesia voyages, reliably restored his rhythm to sinus. Wenckebach studied the case in 1914 and identified the active stereoisomer; the result was quinidine, a cinchona-bark alkaloid that became the first clinically useful antiarrhythmic and the prototype of the class I sodium channel blockers.^[2] Quinidine remained in routine use for atrial fibrillation and ventricular arrhythmia for sixty years before a meta-analysis in the late 1980s showed an excess of all-cause mortality on chronic use, and the medicine has since been largely retired.

The class expanded during the mid-twentieth century. Procainamide, a derivative of the local anaesthetic procaine, was introduced in 1951 by Mark and Berrgren at the Mayo Clinic after they observed that procaine itself prolonged the cardiac refractory period but was too rapidly hydrolysed by serum esterases to be useful systemically. Lidocaine (Löfgren, 1943, originally as an injectable local anaesthetic) was found in the 1960s to suppress ventricular arrhythmias in the setting of acute myocardial infarction without slowing atrial conduction; the intravenous formulation became the standard agent for monomorphic ventricular tachycardia in coronary-care units for the next thirty years. Flecainide (3M, 1985) and propafenone (Knoll, 1989), the class IC sodium channel blockers with the strongest depression of conduction velocity, were introduced for atrial fibrillation in patients without structural heart disease.

The cautionary chapter of antiarrhythmic pharmacology is the Cardiac Arrhythmia Suppression Trial (CAST). In 1989 the trial, designed to test the hypothesis that pharmacological suppression of asymptomatic post-infarction premature ventricular complexes would reduce sudden cardiac death, randomised 1455 patients to encainide, flecainide, or moricizine, or to placebo, in the months following myocardial infarction. The trial was stopped at the first interim analysis because the active-treatment arms had a three-fold excess of arrhythmic death and total mortality.^[3] The finding reversed twenty years of clinical assumption, restricted the class IC agents to patients without structural heart disease, and informed the methodology of every cardiovascular outcome trial since. Pharmacological suppression of arrhythmia, the CAST trial showed, was not the same as suppression of arrhythmic mortality.

Class III, the potassium channel blockers, contains the medicine that has come closest to a broad-spectrum antiarrhythmic. Amiodarone was synthesised in 1961 by Labaz in Belgium and used initially in Europe for angina; the Argentine cardiologist Mauricio Rosenbaum reported its antiarrhythmic effect in 1976. Amiodarone blocks potassium channels (the class III action), sodium channels (class I), beta-adrenergic receptors (class II), and L-type calcium channels (class IV); the resulting broad pharmacology suppresses essentially every clinically encountered arrhythmia, at the cost of an extraordinary range of organ-specific toxicities (interstitial lung disease, thyroid dysfunction in both directions, hepatitis, photosensitivity, corneal microdeposits, bluish skin discolouration, peripheral neuropathy) and an iodine-containing structure that complicates its long-term use.^[4] Sotalol (1974), a non-selective beta-blocker with class III activity, and dofetilide (Pfizer, 1999) extended the class. The class IV calcium channel blockers verapamil and diltiazem act principally on the AV-node and are used for rate control in atrial fibrillation and termination of paroxysmal supraventricular tachycardia involving the AV-nodal reentry circuit; they share a clinical niche with intravenous adenosine, which by activating the A1 receptor produces a brief and complete AV-nodal block ideal for terminating AVNRT.

The contemporary role of the antiarrhythmic has been narrowed by the parallel development of catheter ablation. Most paroxysmal supraventricular tachycardias, accessory-pathway tachycardias, atrial flutter, idiopathic ventricular tachycardias, and (increasingly) atrial fibrillation are now treated definitively with radiofrequency or cryoballoon ablation by an electrophysiologist; the antiarrhythmic medicines are used principally for rhythm control until an ablation is performed, for rate control as a long-term strategy in atrial fibrillation, and for the suppression of life-threatening ventricular tachyarrhythmias in patients with an implanted cardioverter-defibrillator. The shift from medicine to procedure has been driven by the recognition, prefigured by CAST, that the antiarrhythmic medicines have substantial proarrhythmic potential of their own, and that this proarrhythmia is dose-dependent and reliably present in the agents (the class IA, IC, and III sodium and potassium channel blockers) that prolong cardiac repolarization.

By the Vaughan Williams scheme:

• Class IA (intermediate sodium channel block, moderate repolarisation prolongation): quinidine, procainamide, disopyramide
• Class IB (fast sodium channel block, shortening of action potential): lidocaine (intravenous), mexiletine
• Class IC (strong sodium channel block, no effect on repolarisation): flecainide, propafenone
• Class II (beta-adrenergic blockers; listed under beta-blockers): metoprolol, esmolol, propranolol
• Class III (potassium channel blockers, repolarisation prolongation): amiodarone, sotalol, dofetilide, dronedarone, ibutilide
• Class IV (calcium channel blockers acting on AV-nodal slow current; listed under calcium channel blockers): verapamil, diltiazem
• Outside the scheme (mechanistically distinct): digoxin (vagomimetic AV-nodal slowing), adenosine (A1-receptor mediated AV-nodal block), magnesium salts (torsades de pointes), ivabradine (selective sinus-node I-f current inhibition)

The boundary of this category is "medicine prescribed primarily for the prevention or termination of cardiac arrhythmia." Medicines used for rate control in atrial fibrillation whose principal indication lies elsewhere (the beta-blockers, the non-dihydropyridine calcium channel blockers) are listed under their primary classes and cross-indexed here. The anticoagulants used in atrial fibrillation for stroke prophylaxis are not antiarrhythmics and are collected under anticoagulants and the direct oral anticoagulants. The implantable cardioverter-defibrillator and the various forms of catheter ablation are devices and procedures, not medicines, but a brief mention of each is included on the medicine pages where the comparative roles are described.

This category page is an encyclopedia article about its subject. The actual index of medicines belonging to the category is generated automatically by the wiki engine, from category-membership declarations on the individual medicine pages, and appears at the foot of the page below the references.