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.
