A number of adverse outcomes of pregnancy are known to occur more often in infants of mothers with epilepsy. Of the three major variables – maternal epilepsy, maternal seizures during gestation, and antiepileptic drugs – it is not always possible to determine which is the most significant. For the outcome congenital malformations, antiepileptic drugs appear to be a significant risk factor. A recent epidemiological study in Iceland suggests that untreated women with epilepsy have approximately the same rate of malformations in their offspring as do treated mothers, 4.8 vs. 5.9%, respectively. This suggests that a portion of the increased risk is secondary to maternal epilepsy itself. On balance however, malformation rates …
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Formation of arene oxides by phenytoin Arene oxides are obligatory intermediates in the metabolism of aromatic compounds to transdihydrodiols. Phenytoin forms a transdihydrodiol metabolite. This metabolite is also formed by neonates exposed to phenytoin in utero. In vitro studies have shown that an oxidative (NADPH/02 dependent) metabolite of phenytoin binds irreversibly to rat liver microsomes. This binding is increased by an inhibitor of epoxide hydrolase (trichloroponene oxide, TCPO) and decreased by conjugation with glutathione. Using human lymphocytes to assess cell defense mechanisms against toxicity, Spielberg et al. (1981) showed that cytotoxicity was enhanced by inhibitors …
[ Continue Reading... ]Antiepileptic drugs as a group do not produce any specific pattern of major malformations. A possible exception to this is the association of sodium valproate and carbamazepine with neural tube defects. Robert and Guibaud (1982) were the first to make this association while working in a birth defects registry in the Rhone Alps region of France. They reported neural tube defects in infants of mothers with epilepsy exposed to valproate. Other studies have revealed an association between carbamazepine exposure in utero and neural tube defects. Subsequent evaluations of these exposures identify spina bifida aperta as the specific neural tube defect associated with the valproate or carbamazepine exposure. Methodologic problems make frequency …
[ Continue Reading... ]A number of new antiepileptic drugs have been marketed since 1993. Gabapentin, felbamate, lamotrigine, levetiracetam, oxcarbazepine, tiagabine, topiramate and zonisamide are all now available in the US. The numbers of reported exposed pregnancies with these drugs is very low, and unfortunately not large enough for one to determine if there is an increased risk of adverse outcome with fetal exposure to these compounds. We know that lamotrigine and levetiracetam concentrations decline during pregnancy and expect that this is also true for the other new antiepileptic drugs. This is what we know to date. Gabapentin Despite its extensive use for a variety of conditions little has been published about its effect on …
[ Continue Reading... ]In distinction to malformations, which are deformities of anatomy requiring medical or surgical intervention to maintain a functionally healthy person, anomalies are abnormalities of structure, which, while varying from the norm, do not constitute a threat to health. Patterns of anomalies in infants of mothers with epilepsy have been noted with certain antiepileptic drug exposure. Five clinical syndromes have been reported in infants of mothers with epilepsy: fetal trimethadione syndrome, fetal hydantoin syndrome, a primidone embryopathy, a fetal valproate syndrome and a fetal carbamazepine syndrome. Fetal trimethadione syndrome In 1970, German and colleagues described a case of a woman with epilepsy treated …
[ Continue Reading... ]There have been case reports of anomalies associated with exposure to the newer (introduced after 1993), antiepileptic drugs, but no drug-specific syndrome of anomalies described. Three children exposed to lamotrigine and valproate have been reported to have dysmorphic facial features of broad nasal bridge, low set ears and hypertelorism. One child was karyotyped as 47, XXX and another simply had epicanthal folds. Clinical and laboratory evidence clearly supports the association of certain anti-convulsants with teratogenic effects, especially facial and distal digital anomalies. However, the existence of drug-specific syndromes is doubtful. Facial dysmor-phism is difficult to quantify and clearly is not drug specific. Infants of epileptic mothers with similar dysmorphic features have …
[ Continue Reading... ]The elderly (65 years) are the fastest growing segment of the population in developed countries. In the USA, older adults presently comprise 13% of the population and are projected to increase to 20% within the next 20 years. Similar demographics exist for many European countries. With advancing age comes increasing morbidity, medication use, and adverse drug reactions. Over two-thirds of older adults have one or more chronic medical problems. As a consequence more elderly take medications than others and the elderly take more drugs per person. In the USA, almost 90% of …
[ Continue Reading... ]The elderly frequently take numerous medications for a variety of medical conditions. The use of polypharmacotherapy leaves the elderly patient at an increased risk for adverse events. There are many medications that are frequently prescribed for ailments that the elderly experience and unfortunately this post cannot address every possible drug interaction. Antihypertensives Carbamazepine Diltiazem and verapamil are inhibitors of cytochrome P450 (CYP) 3A4, which is the major metabolic elimination pathway for carbamazepine. This inhibition may lead to increased carbamazepine blood concentrations and neurotoxicity. carbamazepine is a potent inducer of CYP3A4. As a result, any medications that are metabolized via that pathway are likely to be …
[ Continue Reading... ]Many clinical practitioners are of the opinion that the optimal treatment of epilepsy is best achieved by use of antiepileptic drugs that have several modes of action, and therefore the drugs that are the most effective in this regard are antiepileptic drugs such as carbamazepine, valproate or topiramate whose efficacy relates to several modes of action. Thus, from the pharmacodynamic point of view, these antiepileptic drugs when prescribed as monotherapy in fact comprise polytherapy regimens. On the other hand, because of metabolism, many antiepileptic drugs reach the brain as combinations of the parent drug and their metabolite(s) and this too can be considered a form of …
[ Continue Reading... ]In this post we will review the characteristics of the various interactions between the various antiepileptic drugs, including those that are in development, and what is presently known regarding their mechanism; we will then highlight the benefits this knowledge can offer to optimize the treatment for each type of epilepsy in children. Clinically relevant …
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