Teratogenic potential of almokalant, dofetilide, and d-sotalol: drugs with potassium channel blocking activity

Drugs with class III antiarrhythmic activity are potential human teratogens because of their ability to cause bradycardia in the embryo during the organogenic period. Three drugs with class III antiarrhythmic activity, almokalant, dofetilide and d-sotalol, were compared in vitro using rat embryo culture. Each of these drugs caused a concentration-dependent bradycardia in 11- or 13-day rat embryos. For each drug the effective concentration was considerably greater than the human therapeutic plasma concentration. The reproductive outcome was also compared in vivo in Sprague-Dawley rats by oral administration of almokalant or dofetilide on single days during the organogenic period. Both drugs caused increased resorptions and the same stage-dependent malformations. Dosing on gestational day (GD) 11 was associated with right-sided oblique cleft lip and short tail, while dosing on day 13 caused digital hypoplasia and/or amputation. Susceptibility to these drugs started on GD 9 when the embryonic heart starts beating and ended on GD 15. The malformations were preceded by hemorrhage; which is consistent with the proposed pathogenesis that the drug-induced bradycardia caused embryonic hypoxia/ischemia. This study indicates that the induction of malformations/embryonic death by class III antiarrhythmic drugs which inhibit Ikr is a class effect secondary to a common pharmacological action on the embryonic heart.