Mechanisms of action of antiepileptic drugs: the search for synergy

Abstract

The aim is to review rational polytherapy of antiepileptic drugs in terms of conventional and novel mechanisms of action, consider combinations that might be beneficial when used as polytherapy, and discuss whether animal models can predict clinical efficacy. Many patients with epilepsy require concurrent treatment with more than one antiepileptic drug (rational polytherapy), but there is little information available as to which drugs might work best in combination. Conventional antiepileptic drugs act by blocking sodium channels or enhancing gamma-aminobutyric acid function. Some newer antiepileptic drugs have novel mechanisms of action, including impairment of the slow inactivation of sodium channels, binding to the presynaptic vesicle protein SV2A, binding to the calcium channel alpha2delta subunit, and opening select potassium channels. Several antiepileptic drugs have multiple or uncertain mechanisms of action. Quantitative techniques such as isobolography can be used to compare the efficacy and side effects of antiepileptic drug combinations in animals. However, neither such methods nor antiepileptic drug mechanisms of action have yet proven useful in predicting clinical benefit in patients. Animal models can be used to help predict drug combinations that might be effective clinically, based on novel mechanisms of action. However, at this point, antiepileptic drug choice in patients with epilepsy remains empirical.