Vnitr Lek 2003, 49(9):700-706

[Failure of antiarrhythmia agents and understanding the phenomenon of proarrhythmia].

B Semrád: Interní kardiologická klinika Lékarské fakulty MU a FN Brno, pracovistĕ Bohunice.

The end of 80ies and the beginning of 90ies in arrhythmology was characterized by the demonstration of so called proarrhythmia, when drugs, particularly antiarrhythmic ones, induced serious, frequently fatal arrhythmias. The resulting pharmacotherapeutic skepsis in the treatment of, in particular, ventricular arrhythmias were accompanied at the same time by a powerful development of non-pharmacological modes of treatment of arrhythmias, especially by implantable defibrillators. The causes of proarrhythmia were identified with the evolution of knowledge in the genetic basis of hereditary syndrome of long QT interval. The first mutation was identified in 1991 and other mutations in the four subsequent years. The mutated genes controlling the synthesis of ionic membrane channels cause disorders in the repolarization phase of action potential. Their expression in individual types of myocytes is not homogenous, most affected being the M cells of ventricular myocardium. It results in a dispersion of repolarization which, together with induction of early after depolarization, causes the origin of polymorphic ventricular tachycardia--TdP. In the 90ies of 20th century there were increasingly frequent reports on sudden arrhythmic death in patients, who had been treated with non-cardiac drugs. They were caused by polymorphic ventricular tachycardia associated with the long QT interval. The syndrome was named as acquired syndrome of long QT interval, based on the drug-induced delayed repolarization of myocyte. The slowing-down is caused by affected membrane channels known from the syndrome of hereditary LQTS. The very low frequency of these fatal complications has been explained either by an obscure genetic defect or a disorder in metabolism of the therapeutic drug, but especially due to drug interactions metabolized in a similar way and similarly influencing the function of membrane channels. Sixty drug molecules with proarrhythmic potential have been identified so far, but the list is probably not complete yet.