Principles and Current Issues of Antiepileptic Drug Therapy

The armamentarium to treat epilepsy includes today more than twenty drugs. These are classically distinguished as standard, traditional or first generation antiepileptic drugs (AEDs), which include phenobarbital, phenytoin, carbamazepine, valproic acid, ethosuximide and benzodiazepines, and new or second generation AEDs, which are vigabatrin, lamotrigine, felbamate, gabapentin, oxcarbazepine, tiagabine, topiramate, stiripentol, pregabalin, levetiracetam, rufinamide, zonisamide. More recently, other four compounds have been introduced, i.e., lacosamide, retigabine, eslicarbazepine acetate and perampanel, also defined as third generation AEDs. The mechanism of antiepileptic action is mainly mediated by increase in inhibitory GABA activity and/or prolongation of sodium and/or calcium channel inactivation. From a pharmacokinetic point of view, the most relevant difference characterizing a number of the recent AEDs as compared to the traditional ones is the lack of or a milder induction of hepatic enzymes with consequent reduced risk of drug-drug interactions. Concerning therapeutic features, valproic acid exhibits the broadest spectrum of action and still remains the only AED which can be used to treat all types of seizures, from absences and other primarily generalized seizures to focal ones, and almost all syndromes. Among the recent compounds, lamotrigine, topiramate, levetiracetam and zonisamide have shown to be efficacious in primarily generalized seizures and in some idiopathic generalized epilepsies, but their effect against absence seizures is less potent than that of valproic acid or even irrelevant. All AEDs, except ethosuximide, exhibit similar efficacy against focal seizures and, apart from traditional drugs, lamotrigine, oxcarbazepine, gabapentin, topiramate and levetiracetam, and ZNS in Europe, have the indication of mono-therapy. Some of the new compounds have specific paediatric indications: vigabatrin against infantile spasms in West syndrome, felbamate and rufinamide against mixed seizures in the Lennox-Gastaut syndrome, and stiripentol against some types of seizures in Dravet syndrome. In spite of this variety of AEDs, the percentage of patients with refractory epilepsy has not changed over the last 50 years and is still stabilized around 30-40%. Adverse events are observed in one-third of patients on AED therapy. Frequent, unspecific and usually dose dependent CNS side effects occur with almost all AEDs and encompass sedation, somnolence, fatigue, and dizziness, usually attenuating or even disappearing over time. Acute idiosyncratic effects, such as skin rush, may be particularly troubling and may configure a hypersensitivity syndrome with rapid degeneration to a severe and even life-threatening condition. Felbamate and vigabatrin are used exceptionally because of high incidence of aplastic anemia and liver failure occurring with the first and irreversible loss of visual field occurring with the second one. Subtle and slowly developing adverse effects, like bone mineral density reduction associated especially with traditional enzyme-inducing AEDs, require a continuous monitoring of the patient clinical condition. Antiepileptic therapy has special implications for women of child bearing age with regard to contraception, pregnancy and teratogenicity. There is some evidence that teratogenic effects, particularly frightening with valproic acid, with > 400mg/day dose of carbamazepine, and with polytherapies, are less frequent with lamotrigine. Given the large number of available AEDs, opportunities to tailor drug therapy on the individual patient are various. Treatment decisions, however, are complex and need to be individualised on the basis of careful evaluation of a number factors related to drug, disease and the patient. Choice of first-line therapy for a specific form of epilepsy, the time at which the drug should be started, and which strategy is most appropriate after failure of the first drug are key decision steps. Patient-specific factors include age, sex, childbearing potential, co-morbidities, and concomitant medications. Future directions include discovery of drugs with an improved safety profile, with more potent anti-seizure effect, able to prevent epileptogenesis and, possibly, to interact with specific genetic substrates.

Keywords: Traditional antiepileptic drugs (AEDs), second and third generation AEDs, neuronal membrane stabilization, ion channels modulation, GABA transmission, pharmacokinetics, drug interactions, pregnancy, adverse effects of AEDs, clinical indications of AEDs, refractory epilepsy.