Page 255 - ILAE_Lectures_2015

Chapter 25

Mechanisms of action of antiepileptic drugs

GRAEME J. SILLS

Department of Molecular and Clinical Pharmacology, University of Liverpool
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Introduction

The serendipitous discovery of the anticonvulsant properties of phenobarbital in 1912 marked
the foundation of the modern pharmacotherapy of epilepsy. The subsequent 70 years saw the
introduction of phenytoin, ethosuximide, carbamazepine, sodium valproate and a range of
benzodiazepines. Collectively, these compounds have come to be regarded as the
‘established’ antiepileptic drugs (AEDs). A concerted period of development of drugs for
epilepsy throughout the 1980s and 1990s has resulted (to date) in 16 new agents being
licensed as add-on treatment for difficult-to-control adult and/or paediatric epilepsy, with
some becoming available as monotherapy for newly diagnosed patients. Together, these have
become known as the ‘modern’ AEDs. Throughout this period of unprecedented drug
development, there have also been considerable advances in our understanding of how
antiepileptic agents exert their effects at the cellular level.

AEDs are neither preventive nor curative and are employed solely as a means of controlling
symptoms (i.e. suppression of seizures). Recurrent seizure activity is the manifestation of an
intermittent and excessive hyperexcitability of the nervous system and, while the
pharmacological minutiae of currently marketed AEDs remain to be completely unravelled,
these agents essentially redress the balance between neuronal excitation and inhibition. Three
major classes of mechanism are recognised: modulation of voltage-gated ion channels;
enhancement of gamma-aminobutyric acid (GABA)-mediated inhibitory neurotransmission;
and attenuation of glutamate-mediated excitatory neurotransmission. The principal
pharmacological targets of currently available AEDs are highlighted in Table 1 and discussed
further below.

Current antiepileptic drug targets

Voltage-gated sodium channels
Voltage-gated sodium channels are responsible for depolarisation of the nerve cell membrane
and conduction of action potentials across the surface of neuronal cells. They are expressed
throughout the neuronal membrane, on dendrites, soma, axons, and nerve terminals. Density
of expression is highest in the axon initial segment (AIS) where action potentials are
generated. Sodium channels belong to a super-family of voltage-gated channels that are
composed of multiple protein subunits and which form ion-selective pores in the membrane.
The native sodium channel comprises a single alpha-subunit protein, which contains the pore-
forming region and voltage sensor, associated with one or more accessory beta-subunit
proteins which can modify the function of the alpha-subunit but are not essential for basic
channel activity. There are four predominant sodium channel alpha-subunit genes expressed
in mammalian brain, denoted SCN1A, SCN2A, SCN3A and SCN8A, which encode the
channels Nav1.1, Nav1.2, Nav1.3 and Nav1.6, respectively. These channels are expressed
differentially in the nervous system. Nav1.3 expression is mainly restricted to the early stages
of development, while Nav1.1 is the major sodium channel in inhibitory interneurons and
Nav1.2 and Nav1.6 are expressed in the AIS of principal excitatory neurons. Nav1.2 appears