PHARMACOLOGICALLY INDUCED EMBRYONIC DYSRHYTHMIA AND EPISODES OF HYPOXIA FOLLOWED BY REOXYGENATION - A COMMON TERATOGENIC MECHANISM FOR ANTIEPILEPTIC DRUGS

Antiepileptic drugs (AEDs), such as phenytoin (PHT), carbamazepine (CB Z), trimethadione (TMD), and phenobarbital (PB), have all been associa ted with a similar pattern of malformations, as well as growth retarda tion and developmental delay. Valproic acid (VPA) has been associated with a different pattern of malformations. Recent studies suggest that PHT's fetal adverse effect is related to its membrane stabilizing pha rmacological properties (blockage of voltage-dependent ion channels). During a restricted sensitive period, this results in induction of con centration-dependent bradyarrhythmia in the embryo and episodes of hyp oxia/reoxygenation. The aim of this study was to compare the potential of PHT, CBZ, PB, TMD, and dimethadione (DMD; the active metabolite of TMD) to cause bradyarrhythmias. All of these AEDs exert mainly their pharmacological effect via blockage of ion channels. VPA and vigabatri n (VGB), which are pharmacologically active mainly by other mechanisms , were also tested. C57 BI/6J mouse embryos were cultured in vitro on gestation day 10 in vitro (in 20% rat serum). The drugs were suspended in either water or dimethylsulfoxide and administered into the cultur e medium in increasing concentrations up to 20 times the human therape utic plasma concentration. A scoring system was employed in order to r ank the drugs based on their potential to cause bradycardia, ventricul ar arrhythmia, and cardiac arrest in relation to human therapeutic con centrations. Based on this system, the drugs were ranked as follows: D MD = PHT much greater than PB = CBZ > TMD = VPA much greater than VGB (no potential). The results correlate well with the available clinical /experimental data of the tested AED's potential to induce hypoxia-rel ated fetal adverse effects, such as oral clefts, distal limb defects, growth retardation, and developmental delay. The results support the i dea that adverse fetal effects after in utero exposure to PHT, PB, CBZ , and TMD (via the active metabolite DMD) are initiated via a common p harmacological mechanism: blockage of ion channels in the developing h eart in the early embryo resulting in bradyarrhythmias, hemodynamic al terations, and hypoxia/reoxygenation damage. (C) 1998 Wiley-Liss, Inc.