Idiosyncratic adverse reactions to aromatic antiepileptic drugs

Abstract

Idiosyncratic reactions are adverse eff ects that cannot be explained by known pharmacological mechanisms of drug action. They occur mostly unpredictably in susceptible individuals, within the fi rst few weeks after beginning of treatment, irrespective of the dosage. They are common in patients treated by antiepileptics. Based on the underlying mechanisms, they can be diff erentiated into direct cytotoxicity or immune-mediated hypersensitivity. Cutaneous hypersensitivity is the most common idiosyncratic reaction to aromatic anticonvulsants. It may range from mild erythematous/maculopapular rash to severe, life-threatening disorders toxic epidermal necrolysis, Stevens-Johnson syndrome, and drug rash with eosinophilia and systemic symptoms (DRESS) syndrome. Aromatic antiepileptics are metabolized by the hepatic cytochrome P450 enzymes. Intermediate arene oxides are subsequently formed. When normal detoxifi cation of arene oxides does not occur, they can cause direct cellular toxicity or they can act as antigens and elicit immune response. Genetic susceptibility is important in the development of idiosyncratic reactions. It is associated with certain HLA subtypes. We present four children aged 5-14.5 years who developed life-threatening idiosyncratic reactions after administration of aromatic anticonvulsants. Although these reactions are rare, gradual administration of antiepileptics is necessary. Development of idiosyncratic reaction requires prompt discontinuation of the causative drug. Because of cross-sensitivity among aromatic anticonvulsants (40%-80%), it is recommended to avoid administering drugs from the same group to the patients that have already suff ered from idiosyncratic reaction.