Review
Dose issues in antiepileptic therapy

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Abstract

Antiepileptic drug (AED) therapy is complex, with numerous traditional drugs and more than 10 second-generation drugs being approved since the mid-1990s. The burden of epilepsy is compounded by the adverse effects of these drugs, which comprise a variety of manifestations, the most devastating of which is their association with physical and cognitive foetal malformations in babies exposed to these agents in utero. Many effects are dose-related – a clear understanding of these adverse effects is desirable to be able to adjust medications and medication regimens to suit individual patient needs and to try to prevent them, by a careful introduction, slow escalation, well-considered combination and possible pre-exposure testing of patients for their tolerance, to each proposed AED. The overall problem and the profiles of the main agents are outlined from the perspective of dose-related issues.

Introduction

The positive pharmacological effects of drugs, as well as their adverse effects, are related to their dose, which has been known since Paracelsus (1493–1541), a Swiss physician born Theophrastus Phillipus Aureolus Bombastus von Hohenheim, developed a new approach to medicine and philosophy based on observation and experience.

Kim Meador, a leader in the field of research on cognition in epilepsy, has acknowledged the question of dose-related drug effects and referred to Paracelsus in characterising adverse cognitive outcomes related to dosing.1 Recent publications from the international Pregnancy Register EURAP,2 and by Jentink et al.3 on teratogenicity, recognise the validity of a dose-related approach to AED toxicity.

Clinicians have overlooked this issue for decades, ignored dose-related problems and used AED with less than ideal caution. AED have a low therapeutic index, which means that a dose producing benefits may not be much less than a dose producing harm. Stability of doses and of plasma levels is important, and switching medications from generic to designer drugs and vice versa is not recommended by the American Academy of Neurology nor the Epilepsy Society of Australia.

The individual AED illustrate these problems.

Section snippets

Phenobarbitone

This group of drugs is fortunately no longer used as first line. Phenobarbitone and its congeners, methyphenobarbitone and mysoline, are highly effective, but difficult to withdraw. They cause somnolence, habituation, as well as narcosis, in high dose. They are enzyme inducers. The resultant effect on other drugs may be to lower their effectiveness; barbiturates have been repeatedly shown to be teratogenic in a dose-related manner.2, 4

Phenytoin

Phenytoin presents many dose-related problems, especially

Antiepileptic drugs and foetal malformations

Extensive early uncontrolled data, mostly from retrospective studies, suggested for almost three decades that it is not the epilepsy but the use of AED that is predominantly responsible for foetal malformations (FM) in pregnant women with epilepsy. Since the early 2000s, this observation has been complicated by the recognition of cognitive adverse effects on the foetus by the AED.

Initially, a lack of uniformity in data collection hindered a clear-cut definition of the problem of teratogenicity.

Summary

Antiepileptic drug therapy has been highlighted to focus on the profound potential adverse effects due to AED, of which teratogenicity appears the most serious and devastating. These drugs are capable of causing physical malformations, such as neural tube defect, but also possibly cause impaired cognitive development of the foetus. The latter may involve a lower intelligence quotient, language problems, lowered executive skills and autism. It appears that AED doses have a major bearing on these

Conflicts of interest/Disclosures

The Australian Pregnancy Register is indebted for support from the Epilepsy Society of Australia and the Royal Melbourne Hospital Neuroscience Foundation, and financial support from the pharmaceutical industry: Sanofi-Synthelabo, UCB Pharma, Janssen Cilag, Novartis and Sci Gen. The authors declare that they have no further disclosures or conflicts of interest in relation to this research and its publication.

Acknowledgment

I wish to acknowledge the support of MJ Eadie, TJ O’Brien, CM Lander and J Graham.

References (19)

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