Antiepileptic drugs 2012: recent advances and trends

Abstract

There are now 24 antiepileptic drugs (AEDs) approved for use in epilepsy in the United States by the Food and Drug Administration. A literature search was conducted using PubMed, MEDLINE, and Google for all English-language articles that discuss newly approved AEDs and the use of AEDs in epilepsy in the United States from January 1, 2008, through December 31, 2011. Five new agents were identified that have come onto the market within the past 2 years. Moreover, 3 trends involving AEDs have become clinically important and must be considered by all who treat patients with epilepsy. These trends include issues of generic substitution of AEDs, pharmacogenomics predicting serious adverse events in certain ethnic populations, and the issue of the suicide risk involving the entire class of AEDs. This article discusses the most recent AEDs approved for use in the United States and the 3 important trends shaping the modern medical management of epilepsy.

FIGURE 1

Figure and legend are modified and reprinted, with permission, from Bialer and White and Rho. Please see text for details. It is important to note that multiple mechanisms of action are ascribed to any given antiepileptic drug (AED). The diagram emphasizes the major mechanism of action for each AED. Part A shows drugs which may prevent seizures by acting upon excitatory synapses and Part B shows drugs which may affect inhibitory synapses. GABA = y-aminobutyric acid; GABA-T = GABA transaminase; GAD = glutamic acid decarboxylase.

FIGURE 2

This illustration further conceptualizes the complex role of voltage gates sodium and potassium channels in neuronal excitability. There are 4 states of the voltage-gated channel opening and closing as it relates to the generation of an action potential: resting, depolarizing, repolarizing, and hyperpolarization. See A-D. The diagram conceptualizes what is occurring at the membrane level that corresponds to the action potential. One sees the sodium channel open correlating to the depolarizing phase. Repolarization occurs with closure of the inactivating gate and activating gate m. Potassium influx correlates with hyperpolarization stabilizing the membrane and bringing the system back to the resting state. Carbamazepine, felbamate lacosamide, lamotrigine oxcarbaxepine, phenytoin, rufinamide, topiramate, zonisamide, and valproic acid all modulate this channel to some degree. Lacosamide appears to modulate the complex slightly differently from the other sodium channels. Ezogabine appears to modulate the system at the potassium channel. Understanding the complexity of this channel helps to better demonstrate how varying antiepileptic drugs functioning at various parts of the channel may have complementary benefits. This has yet to be proven clinically.