PROARRHYTHMIC ACTIONS OF ANTIARRHYTHMIC DRUGS - THEORETICAL AND CLINICAL ASPECTS

Proarrhythmic action of an antiarrhythmic drug is defined as 1 )Worsening of preexisting arrhythmia (for example, increase of number of premature beats; frequency, rate, and duration of tachycardias at supraventricular or ventricular level); 2) induction of arrhythmias (supraventricular: for example, atrial tachycardia with block; ventricular: monomorphic or polymorphic ventricular tachycardia, torsade de pointes, ventricular fibrillation); 3) occurrence of bradycardia (sick sinus syndrome; atrio-ventricular and intraventricular conduction disturbances). The pathophysiology of proarrhythmic action is either facilitation of conduction block and reentry, or abnormal impulse formation. Induction of incessant monomorphic ventricular tachycardia or torsade de pointes is of special clinical relevance. Incessant ventricular tachycardia can be experimentally explained by an increase of functional conduction block and decrease of the wavelength of excitation (conduction velocity x refractory period) as actions favoring reentry; this is clinically most frequently seen with the application of class IC (and A)-drugs. Abnormal OT prolongation and torsade de pointes are most likely due to early afterdepolarizations of the cell membrane, and development of triggered activity; these arrhythmias are seen following the application of substances prolonging repolarization (class III and class IA-antiarrhythmic drugs). Independent of the precise electrophysiologic mechanism, arrhythmias may, underclinical conditions, also be provoked secondary to the negative inotropic action of these drugs. Proarrhythmic actions most frequently are concentration-dependent; rarely are they idiosyncratic. Usually, these side-effects are seen during the first days after initiation or increase of the antiarrhythmic drug dose; they may, however, manifest themselves only after a couple of months. The risk of an individual patient to develop proarrhythmic drug action is increased with advanced forms of underlying cardiac disease, presence of malignant ventricular arrhythmias (ventricular tachycardia or ventricular fibrillation) as indication for drug therapy, recent myocardial infarction as well as for pharmacologic reasons due to application of high doses, changes of pharmacokinetics, and drug interactions following the combined use of antiarrhythmic agents.