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been proposed that the slow inactivation pathway is more prominent during prolonged
depolarisation, as might be expected during epileptiform discharges.

Calcium channels. Voltage-gated calcium channels represent another important target for
several antiepileptic agents. The efficacy of ethosuximide and zonisamide in generalised
absence epilepsy is believed to be mediated by blockade of the LVA T-type calcium channel
in the soma and dendrites of thalamic relay and reticular neurones. There is anecdotal
evidence that sodium valproate may have a similar action. Lamotrigine limits
neurotransmitter release by blocking both N- and P/Q-types of the HVA calcium channel and
levetiracetam exerts a partial blockade of N-type calcium currents, suggesting a selective
effect on an as yet unidentified sub-class of this particular channel type. Phenobarbital,
felbamate, and topiramate are also believed to influence HVA calcium channel conductance,
though their effects are less well characterised in terms of channel subtypes or interaction
with specific protein subunits. Finally, gabapentin and pregabalin also exert their effects via
HVA calcium channels, but rather than interacting with a traditional channel sub-type such
as N- or L-type, they appear to bind to an accessory subunit termed alpha2-delta-1, which can
modulate the function of various native channels. This subunit is upregulated in dorsal root
ganglion cells of the spinal cord in response to nerve injury, with selective calcium channel
blockade via the alpha2-delta-1 subunit explaining the efficacy of gabapentin and pregabalin
in the treatment of neuropathic pain.

Kv7 channels. Retigabine was licensed for the add-on treatment of refractory focal epilepsy
in the UK in 2011 and has been shown to exert its antiepileptic effects by activation of the
Kv7 class of voltage-gated potassium channels. It is specific for channels containing Kv7.2 to
Kv7.5 subunits, with particular affinity for channel assemblies containing dimers of Kv7.2/7.3
and Kv7.3/7.5 subunits. These channels underlie the M-current in seizure-prone regions of
the brain, such as cerebral cortex and hippocampus. Retigabine enhances the M-current,
increasing rate at which it is activated by depolarisation and decreasing the rate at which it is
subsequently de-activated. It also enhances the M-current at resting membrane potential,
hyperpolarising the cell membrane and reducing overall excitability of neurones. This effect
of retigabine is mediated by binding of the drug within the pore of the channel. A single
amino acid (Trp236) located in the activation gate of the Kv7 alpha-subunit protein is essential
and all four subunits in the channel assembly must contain a tryptophan residue at position
236 for retigabine sensitivity.

GABAA receptors. Activation of the ionotropic GABAA receptor resulting in an enhanced
response to synaptically released GABA is a major AED mechanism. Barbiturates (e.g.
phenobarbital, primidone) and benzodiazepines (e.g. diazepam, clobazam, clonazepam) share
this effect, but they bind to distinct sites on the receptor complex and differentially influence
the opening of the chloride ion pore. All GABAA receptors containing at least one alpha- and
one beta-subunit appear susceptible to activation by barbiturates, with only minor differences
in relative sensitivity. In contrast, benzodiazepines display a much more distinct pattern of
selectivity. Benzodiazepine-sensitive GABAA receptors are typically composed of two alpha-
subunits (alpha1, alpha2, alpha3 or alpha5), two beta-subunits (beta2 or beta3), and a
gamma2 subunit, whereas the delta-containing GABAA receptor which mediates tonic
inhibition is entirely insensitive to benzodiazepines, as are those containing alpha4- and
alpha6-subunits. Functionally, barbiturates increase the duration of chloride channel opening,
while benzodiazepines increase the frequency of opening. Barbiturates are also capable of
direct activation of the GABAA receptor in the absence of GABA, an effect which is believed
to underlie their sedative properties. Several other antiepileptic agents can modulate GABA
responses at the GABAA receptor. These include felbamate and topiramate (whose binding
sites and subunit specificities remain unclear), stiripentol, which has recently been reported
to have greatest selectivity for alpha3-beta3-gamma2 containing receptors, and levetiracetam,