Current Pharmaceutical Design - Volume 6, Issue 8, 2000

In recent years several new drugs (oxcarbazepine, lamotrigine, topiramate, gabapentin, zonisamide, tiagabine, fosphenytoin, vigabatrin and felbamate) have been added to the therapeutic armamentarium against epilepsy. Some of these represent structural modifications of pre-existing compounds, others were developed with the specific objective of modifying neurotransmitter function, and many more were found to be clinically useful even though their mode of action is unclear or differs from that originally planned. The pharmacokinetics of these drugs differ widely from one agent to another. Some (gabapentin and vigabatrin) are eliminated unchanged in urine and have little or no interaction potential; others (tiagabine, lamotrigine, topiramate, oxcarbazepine, zonisamide, felbamate) are subject to induction of metabolism by concomitant anticonvulsants; lamotrigine is vulnerable to metabolic inhibition by valproate, and felbamate is a powerful enzyme inhibitor in addition to being an inducer of the metabolism of carbamazepine and steroid oral contraceptives. All new antiepileptic drugs have been found to be effective in improving seizure control in patients with partial and secondarily generalized seizures. However, lamotrigine, topiramate, zonisamide and felbamate appear to have broader efficacy against both partial and many generalized seizure types, while vigabatrin is also valuable in the management of infantile spasms. In monotherapy studies, new drugs have not been found to be more efficacious than older agents, but some may offer limited advantages in terms of improved tolerability. On the other hand, serious toxicity restricts considerably the use of vigabatrin and felbamate. Overall, new drugs represent valuable tools in the fight against epilepsy, but because of limited experience and cost considerations their first-line use cannot be recommended in most situations.

In most of the epilepsies and epileptic syndromes, the decision to initiate antiepileptic drug (AED) therapy is often a far simpler one than the decision to stop it. The primary factor that drives a patient to want to discontinue therapy, and a doctor to endorse or recommend this, is a fear of long-term adverse events, a consideration that may be entirely justified as the side effects of vigabatrin and felbamate have proved. On the other hand, seizure recurrence with the attendant implications in employment, driving regulations and social stigmatization is a strong deterrent that discourages withdrawal of therapy. The absence of a clearer understanding of the natural history and prognosis of many individual epilepsy syndromes somewhat hampers the resolution of this dilemma. Hopefully, as our understanding of the epilepsies grows and the prediction of the chances of seizure relapse becomes a more precise science, stopping medication will become a less fraught exercise for both the patient and the doctor.

Issues linked to epileptic women are being reviewed. Ovarian steroid hormones have a number of effects on the brain that predispose to epileptic activity. In particular, estradiol produces changes in the hippocampus synapses predisposing hyperexcitability associated with seizures. Also, menses and menopause periods, in which there are changing levels of steroid ovarian hormones, are associated with a particular appearing of seizures (catamenial epilepsy) and with phenoptypic changes of previous ones. Epilepsy can affect the reproductive system, inducing endocrinal abnormalities (through disruption of cortical regulation of hypothalamus hormone release, and changes in the central nervous system concentration of steroid hormones induced by antiepileptics), infertility (linked to abnormalities in menstrual cycle or to the occurrence of polycytic ovaries, particularly in association with valproate treatment), and sexual disfunction (namely related to physiologic defects). Oral hormonal contraceptives should be performed using a pill with less than or equal to 50micro g of estrogen in order to prevent its potential loss of efficacy induced by enzyme-inducing antiepileptics. Concerning pregnancy, some topics should be discussed with, and advised to epileptic women, including the possibility of withdrawal antiepileptics and the need of folic acid supplementation when planning a pregnancy; the risk of increased seizure frequency during pregnancy, and of the occurrence of obstetric complications; the increased risk of teratogenesis associated with antiepileptic therapy (mainly if in polytheraphy) the need of vitamin K supplementation during the last month of pregnancy in order to avoid newborn haemorrhages and the general absence of risk of breastfeeding even under sustained antiepileptic therapy.

After a short historical review of the development of the pharmaceutical treatment of the epilepsies the author reviews some of the possible strategies to manage patients with the different types of epilepsies and epileptic syndromes using the classical drugs. A strategy used by most of the physicians uses Sodium Valproate as the first line drug for almost all patients. This may be replaced by other drugs according to their efficacy against the different types of seizures to be treated whenever VPA has not enough efficacy or isnt well tolerated. On the other hand epileptologists use the different drugs according to the different epilepsies and epileptic syndromes depending on the relative efficacy of each drug available and the possible side effects. He then describes succinctly the better-known new drugs and makes some comments on the coming drugs now in development. Finally he proceeds to include them in the strategies above described. Lamotrigine and possibly Topiramate are good candidates to replace VPA in the one drug strategy. Lamotrigine, Oxcarbamazepine and possibly Gabapentin may be used in the future as 1 st line drugs in selected patients. Vigabatrin is already used as one of the better alternatives for West syndrome and Oxcarbamazepine has replaced Carbamazepine in countries where its available to the public. Some drawbacks have been apparent with these drugs like the hepatic and haematological toxic effect of Felbamate or the apparently irreversible fields constriction provoked by Vigabatrin, which did limit their use.

Seizures have a variety of etiologies and manifestations. Descriptions of various epiletic seizures as well as electroencephalographic findings have led to a unifying international classification of epileptic seizures and epilepsy syndromes. The development of this classification system and the emergence of several new antiepiletic drugs have led to progress in the refractory pediatric patient particularly disorders which are traditionally difficult to treat such as infantile spasms and the Lennox-Gastaut Syndrome. However, there is limited data regarding optimal use in children.The childhood epilepsy syndromes are reviewed as well as the newer antiepileptic drug treatments felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, tiagabine, topiramate, and zonisamide. Efficacy data and toxicity are discussed from both the adult, and when available, pediatric data.