Class III antiarrhythmic drugs, like almokalant, dofetilide and ibutilide, cause a spectrum of malformations in experimental teratology studies. The pattern of developmental toxic effects is very similar to those reported for phenytoin, which is an established human and animal teratogen. The toxic effects are characterised by embryonic death, decreased fetal weights, and stage specific malformations, such as distal digital reductions, orofacial clefts and cardiovascular defects. Class III antiarrhythmics decrease the excitability of cardiac cells by selectively blocking the rapid component of the delayed rectified potassium channel (IKr), resulting in prolongation of the repolarisation phase of the action potential. Phenytoin, which decrease the excitability of neurones, has recently also been shown to block IKr, in addition to its known blockade of sodium channels. Animal studies indicate that IKr is expressed in the embryo and that the embryonic heart is extremely susceptible to IKr-blockers during a restricted period in early development. At concentrations not affecting the maternal heart, the embryonic heart reacts with bradycardia, arrhythmia and cardiac arrest when exposed to such drugs. Available studies strongly support the idea that birth defects after in utero exposure to both selective and non-selective IKr-blockers (like phenytoin) are initiated by concentration dependent embryonic bradycardia/arrhythmia resulting in 1) hypoxia; explaining embryonic death and growth retardation, 2) episodes of severe hypoxia, followed by generation of reactive oxygen species within the embryo during reoxygenation, causing orofacial clefts and distal digital reductions, and 3) alterations in embryonic blood flow and blood pressure, inducing cardiovascular defects.

No abstract

This first comparison of mRNA expression, potassium currents, and action-potential characteristics, with and without a specific K(r)-channel blocker in human, rat, and rabbit embryos provides evidence of K(r)-channel inhibition as a common mechanism for embryonic malformations and death.

No abstract

The stage specificity of observed visceral and skeletal defects correlates well with what has been reported in the literature after temporary interruption of oxygen supply during the same stages of development. The protective effect by PBN present further evidence that the teratogenicity of potent I(Kr)-blockers is related to induction of hypoxia- reoxygenation injury due to embryonic cardiac arrhythmia.

No abstract

Observations of low postmortem blood concentrations of antiepileptic drugs in cases of sudden unexpected death in epilepsy (SUDEP) have led to the assumption that noncompliance may play a role in SUDEP. However, the reliability of postmortem drug levels has been questioned. The purpose of this study was to analyze possible postmortem changes in blood concentrations of carbamazepine (CBZ) and phenytoin (PHT). New Zealand white rabbits were fed with PHT or CBZ until assumed steady state. A blood sample was then drawn for determination of serum and whole blood concentrations of CBZ and PHT, after which the rabbits were killed and stored at 6 degrees C. A further blood sample for drug analysis was obtained 72 hours after death. Antemortem serum concentrations of CBZ were not significantly different from whole blood concentration 72 hours after death. In contrast, antemortem whole blood concentrations of PHT were only 65% of the corresponding serum concentrations, and postmortem PHT blood levels were even lower, being 35% of antemortem serum concentrations. In conclusion, blood concentrations of CBZ seem to be stable during 72 hours after death under these experimental conditions. However, postmortem PHT concentrations should be interpreted with caution and low postmortem concentrations do not necessarily imply a poor compliance.

No abstract