Pharmacology & Therapeutics 90 (2001) 21 – 34

The mechanisms of action of commonly used antiepileptic drugs

Patrick Kwan, Graeme J. Sills*, Martin J. Brodie
Epilepsy Unit, University Department of Medicine and Therapeutics, Western Infirmary, Glasgow G11 6NT, Scotland, UK

Abstract

In the past decade, nine new drugs have been licensed for the treatment of epilepsy. With limited clinical experience of these agents, the
mechanisms of action of antiepileptic drugs may be an important criterion in the selection of the most suitable treatment regimens for
individual patients. At the cellular level, three basic mechanisms are recognised: modulation of voltage-dependent ion channels, enhancement
of inhibitory neurotransmission, and attenuation of excitatory transmission. In this review, we will attempt to introduce the concepts of ion
channel and neurotransmitter modulation and, thereafter, group currently used antiepileptic drugs according to their principal mechanisms of
action. D 2001 Elsevier Science Inc. All rights reserved.

Keywords: Antiepileptic drugs; Mechanisms of action; Epilepsy

Abbreviations: AED, antiepileptic drug; AMPA, a-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid; BGT, betaine g-aminobutyric acid transporter;
BZD, benzodiazepine; CBZ, carbamazepine; ESM, ethosuximide; FBM, felbamate; GABA, g-aminobutyric acid; GABA-T, g-aminobutyric acid transaminase;
GAD, glutamic acid decarboxylase; GAT, g-aminobutyric acid transporter; GBP, gabapentin; LEV, levetiracetam; LTG, lamotrigine; NMDA, N-methyl-D-
aspartate; OXC, oxcarbazepine; PB, phenobarbital; PHT, phenytoin; PRM, primidone; TGB, tiagabine; TPM, topiramate; VGB, vigabatrin; VPA, sodium
valproate; ZNS, zonisamide.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
1.1. Classification of mechanisms of action . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
2. Targets for antiepileptic drug action. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
2.1. Ion channels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
2.1.1. Na+ channels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
2.1.2. Ca2+ channels. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
2.1.3. K+ channels. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
2.2. g-Aminobutyric acid-mediated inhibition . . . . . . . . . . . . . . . . . . . . . . . . . . 23
2.3. Glutamate-mediated excitation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
3. Modulation of ion channels by antiepileptic drugs . . . . . . . . . . . . . . . . . . . . . . . . . 24
3.1. Phenytoin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
3.2. Carbamazepine. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
3.3. Lamotrigine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
3.4. Oxcarbazepine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
3.5. Ethosuximide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
3.6. Zonisamide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
4. Potentiation of g-aminobutyric acid by antiepileptic drugs . . . . . . . . . . . . . . . . . . . . . 26
4.1. Phenobarbital . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
4.2. Benzodiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
4.3. Vigabatrin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
4.4. Tiagabine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28

* Corresponding author. Tel.: +44-141-211-2770; fax: +44-141-334-9329.

E-mail address: g.j.sills@clinmed.gla.ac.uk (G.J. Sills).

0163-7258/01/$ – see front matter D 2001 Elsevier Science Inc. All rights reserved.
PII: S 0 1 6 3 - 7 2 5 8 ( 0 1 ) 0 0 1 2 2 - X
22 P. Kwan et al. / Pharmacology & Therapeutics 90 (2001) 21–34

5. Antiepileptic drugs with multiple mechanisms of action . . . . . . . . . . . . . . . . . . . . . . 28

5.1. Sodium valproate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
5.2. Gabapentin. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
5.3. Felbamate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
5.4. Topiramate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
6. Antiepileptic drugs with unknown mechanisms of action. . . . . . . . . . . . . . . . . . . . . . 30
6.1. Levetiracetam . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
7. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30

1. Introduction 1.1. Classification of mechanisms of action

The serendipitous discovery of phenobarbital (PB) in Practical approaches to drug treatment have resorted
1912 marked the beginning of the modern pharmacotherapy primarily to symptom control, i.e., suppression of seiz-
of epilepsy (Brodie & Dichter, 1996). In the ensuing 70 ures. Although the mechanisms of action of the currently
years, phenytoin (PHT), carbamazepine (CBZ), ethosuxi- marketed AEDs are still not completely understood, they
mide (ESM), sodium valproate (VPA), and a range of ultimately involve alteration of the balance between neu-
benzodiazepines (BZDs) became available and can be ronal excitation and inhibition (White, 1999). At the
regarded as ‘‘established’’ antiepileptic drugs (AEDs; Bro- cellular level, three basic mechanisms are recognised:
die & Dichter, 1996). In the past decade, nine new agents modulation of voltage-dependent ion channels (Na + ,
have been licensed as add-on treatment for difficult-to- Ca 2 + , K + ), enhancement of g-aminobutyric acid
control epilepsy (Table 1) and still more are under evalua- (GABA)-mediated inhibitory neurotransmission, and
tion (Dichter & Brodie, 1996). attenuation of excitatory (particularly glutamate-mediated)
The undoubtedly beneficial expansion of the pharmaco- transmission (Meldrum, 1996).
logical armamentarium for the treatment of epilepsy does, In this review, we will attempt to introduce the concepts
however, complicate selection of the most suitable AED (or of ion channel and neurotransmitter modulation and, there-
combination of AEDs) for individual patients. With limited after, group the currently used AEDs according to their
clinical experience of the new agents, the mechanisms of principal mechanisms of action (Table 1). It is, however,
action of individual AEDs may be an important criterion in increasingly recognised that many AEDs possess multiple
this decision-making process (Brodie, 1999; Brodie & primary mechanisms. In addition, many less well-charac-
Kwan, 2000). terised mechanisms may also contribute to the anticonvul-
sant effect of any given compound. Finally, to complicate
the issue further, the primary mode of action of some AEDs
Table 1 remains to be discovered.
Proposed mechanisms of antiepileptic drug action
# Na + # Ca2 + " K+ " Inhibitory # Excitatory
channels channels channels transmission transmission
Established AEDs 2. Targets for antiepileptic drug action
PHT +++
CBZ +++ 2.1. Ion channels
ESM +++
PB + +++ +
BZDs +++ 2.1.1. Na+ channels
VPA + + ++ + In the nervous system, voltage-gated ion channels control
the flow of cations across surface and internal cell mem-
New AEDs branes (Barchi, 1998). Of these, the Na + channel is argu-
LTG +++ +
OXC +++ + +
ably of principal importance. Voltage-dependent Na +
ZNS ++ ++ channels are responsible for the upstroke of the neuronal
VGB +++ action potential, and ultimately control the intrinsic excit-
TGB +++ ability of the nervous system (Porter & Rogawski, 1992).
GBP + + ++ The neuronal Na + channel has a multi-subunit structure that
FBM ++ ++ ++ ++
TPM ++ ++ ++ ++
forms a Na + -selective, voltage-gated pore through the
LEV + + + plasma membrane. The protein structure undergoes confor-
+++, primary action; ++, probable action; +, possible action. mational alterations in response to changes in membrane
Data from Upton (1994), Schachter (1995), Macdonald & Kelly (1995), potential, regulating conductance through the intrinsic pore
Meldrum (1996), Coulter (1997), and White (1999). (Ragsdale & Avoli, 1998).
 P. Kwan et al. / Pharmacology & Therapeutics 90 (2001) 21–34
The main structural component of the neuronal Na +
channel is the a-subunit, which forms the ion-conducting
pore and confers voltage dependency (Catterall, 1992). In
the mammalian brain, the a-subunit associates with two
auxiliary subunits designated b1 and b2. The b-subunits are
not required for basic Na + channel activity, but they
modulate the expression and function of individual channels
(Ragsdale & Avoli, 1998).
At normal membrane potentials, most Na + channels
exist in a closed, resting state. Upon depolarisation, the
channel activates, facilitating ion flux. Thereafter, the Na +
channel enters an inactivated state, from which it is not
readily re-activated. Repolarisation of the neuronal mem-
brane rapidly converts the channel back to a resting state,
from which it can respond to subsequent depolarisations
(Catterall, 1992; Ragsdale & Avoli, 1998). Neuronal Na +
channels can cycle through these functional states within a
few milliseconds. This characteristic is essential for sustain-
ing the rapid bursts of action potentials necessary for some
normal brain functions, and is implicated in the production
of epileptic discharges. The neuronal Na + channel repre-
sents one of the most important targets for AED action
(Upton, 1994; Macdonald & Kelly, 1995; Meldrum, 1996;
White, 1999).
2.1.2. Ca2+ channels
Voltage-dependent Ca2 + channels share key structural
elements and sequence homology with their Na + channel
counterparts (Barchi, 1998). The a1-subunit of the Ca2 +
channel is the homologue of the a-subunit of the Na +
channel. It forms the Ca2 + -sensitive channel pore and
confers voltage dependency (Catterall, 1995). In the mam-
malian brain, the a1-subunit heterogeneously associates
with other subunits designated b, g, and d.
Voltage-sensitive Ca2 + channels can be broadly classi-
fied into low or high threshold, according to the membrane
potential at which they are activated (Hofmann et al., 1994).
The low-threshold T-type Ca2 + channel is expressed pre-
dominantly in thalamocortical relay neurones, where it is
believed to be instrumental in the generation of the rhythmic
3-Hz spike-and-wave discharge that is characteristic of
generalised absence seizures (Coulter et al., 1989a). High-
threshold Ca2 + channels are subclassified by their pharma-
cological properties into L-, N-, P-, Q-, and R-types (Hof-
mann et al., 1994; Catterall, 1995; Dolphin, 1995). These
channels are distributed throughout the nervous system on
dendrites, cell bodies, and nerve terminals. The N-, P-, and
Q-type channels, in particular, have been implicated in the
control of neurotransmitter release at the synapse (Stefani
et al., 1997).
Interest in Ca2 + channels has heightened in recent years,
following the identification of subunit-specific genetic
mutations that can alter channel structure and/or function
and that have been implicated in several human neurological
diseases (Ophoff et al., 1998). Several AEDs have been
reported to block voltage-sensitive Ca2 + channels in a
23
subtype-specific manner, an effect that may contribute to
their antiepileptic actions (Stefani et al., 1997).
2.1.3. K+ channels
Neuronal K + channels are large protein complexes that
form tetrameric structures, the monomers of which are
structurally and genetically related to the a- and a1-subunits
of the Na + and Ca2 + channel, respectively (Barchi, 1998).
The association of four subunits (monomers) in the neuronal
membrane is required for the formation of a K + -sensitive
pore and, therefore, channel function (Pongs, 1999). More
than 40 distinct K + channel subunits have been identified,
together with several auxiliary subunits. Given heterologous
arrangement, it is possible that countless populations of K +
channels, with individual functions and distributions, are
expressed in the mammalian brain (Pongs, 1999).
At the neuronal level, K + channels are intimately
involved in excitability. They are responsible for the action
potential downstroke or, more specifically, repolarisation of
the plasma membrane in the aftermath of Na + channel
activation (Pongs, 1999). Direct activation of voltage-
dependent K + channels hyperpolarises the neuronal mem-
brane and limits action potential firing (Porter & Rogaw-
ski, 1992). Accordingly, K + channel activators have
anticonvulsant effects in some experimental seizure models
(Gandolfo et al., 1989; Rostock et al., 1996), whereas K +
channel blockers precipitate seizures (Yamaguchi &
Rogawski, 1992).
Potentiation of voltage-sensitive K + channel currents
may prove to be an important target for future AED
development. The novel antiepileptic agent retigabine, cur-
rently undergoing Phase II clinical trial, is believed to exert
its effects, at least in part, by activation of the KCNQ2/
KCNQ3 K + channels (Rundfeldt & Netzer, 2000). Muta-
tions in the KCNQ2/KCNQ3 channels have been reported
in benign neonatal familial convulsions, a generalised epi-
lepsy syndrome (Rogawski, 2000).
2.2. g-Aminobutyric acid-mediated inhibition
GABA is the predominant inhibitory neurotransmitter in
the mammalian CNS, where it is released at up to 40% of all
synapses (Olsen & Avoli, 1997). Impairment of GABA
function is widely recognised to provoke seizures, whereas
facilitation has an anticonvulsant effect (Löscher, 1999).
GABA is synthesised from glutamate, exclusively in
GABAergic neurones, by the action of the enzyme glutamic
acid decarboxylase (GAD; Löscher, 1999). Upon synaptic
release, GABA acts on its three specific receptors, GABAA,
GABAB, and the newly characterised GABAC. GABA
receptors are distinguished by their pharmacology and
function (Johnston, 1996). The GABAA receptor belongs
to the ligand-gated ion channel superfamily, and responds to
GABA binding by increasing Cl  conductance, resulting in
neuronal hyperpolarisation (Rabow et al., 1995). GABAB
receptors are G-protein-linked, activation of which leads to
24 P. Kwan et al. / Pharmacology & Therapeutics 90 (2001) 21–34
an increase in K + conductance (Olsen & Avoli, 1997). It
has recently been proposed that GABAA and GABAB
receptors may have evolved from the GABAC receptor,
which is comparatively simpler in structure and pharmacol-
ogy (Johnston, 1996).
Of the three receptor subtypes, the GABAA receptor,
with its pentameric subunit array and central Cl  ion pore,
is perhaps the best understood (Rabow et al., 1995).
GABAA receptors are composed of various combinations
of 5 subunits, a(1 – 6), b(1 – 3), g(1 – 3), d, and e. Receptor
physiology, pharmacology, and distribution differs, depend-
ing on subunit composition (Mody, 1998). Theoretically,
tens of thousands of different GABAA receptors could
exist, but naturally only 10 or fewer combinations of
subtypes are encountered.
Following receptor activation, GABA is removed from
the synaptic cleft into localised nerve terminals and glial
cells, by specific membrane-bound transport molecules.
Currently, four active transport systems, GABA transporter
(GAT)-1, GAT-2, GAT-3, and betaine GAT (BGT)-1, have
been described (Borden et al., 1992). GABA has a variable
affinity for these transporters, and only GAT-1, predomi-
nantly located in the cerebral cortex and hippocampus, has
GABA as its principal substrate (Guastella et al., 1990).
After removal from the synapse, GABA is either recycled to
the readily releasable neurotransmitter pool (GABAergic
nerve terminals only) or metabolised (neurones and glial
cells) to the inactive molecule succinic acid semialdehyde
by the action of the mitochondrial enzyme GABA-trans-
aminase (GABA-T; Meldrum, 1995).
Several AEDs exert their effects, at least in part, by
actions on the GABAergic system. Increased GABA syn-
thesis, increased release, allosteric receptor facilitation, and
reduced inactivation have all been implicated in the mech-
anisms of action of commonly used agents (Sills et al.,
1999). The GABA system also represents the most success-
ful target for the rational design of novel antiepileptic
compounds (Löscher, 1998).
2.3. Glutamate-mediated excitation
Glutamate is the principal excitatory neurotransmitter in
the mammalian brain (Meldrum, 2000). Focal injection of
glutamate induces seizures in animals, and over-activation
of glutamatergic transmission or abnormal glutamate recep-
tor properties are observed in certain experimental seizure
models and human epilepsy syndromes (Meldrum, 1995).
Inhibition of the neuronal release of glutamate and blockade
of its receptors have received considerable attention in the
search for novel AEDs (Meldrum, 2000).
Glutamate is synthesised from glutamine by the action of
the enzyme glutaminase in glutamatergic neurones (Daikhin
& Yudkoff, 2000). Following synaptic release, glutamate
exerts its pharmacological effects on several receptors,
classified into ionotropic and metabotropic families. Gluta-
mate is removed from the synaptic cleft into nerve terminals
and glial cells by the action of several specific transporters
(Meldrum et al., 1999). Glial glutamate uptake is of princi-
pal importance. Glial cells convert glutamate into glutamine
by the action of the enzyme glutamine synthetase. Gluta-
mine is subsequently transferred to glutamatergic neurones,
completing the cycle (Daikhin & Yudkoff, 2000).
Like GABA receptors, ionotropic glutamate receptors are
comprised of various combinations of subunits forming
tetrameric and pentameric arrays. They are classified into
three specific subtypes, a-amino-3-hydroxy-5-methyl-iso-
xazole-4-propionic acid (AMPA), kainate, and N-methyl-D-
aspartate (NMDA), which form ligand-gated ion channels,
permeable to Na + and, depending on subtype and subunit
composition, Ca2 + ions (Trist, 2000). The NMDA receptor
is further distinguished by having glycine as a co-agonist.
The AMPA and kainate subtypes of the glutamate receptor
are implicated in fast excitatory neurotransmission, whereas
the NMDA receptor, quiescent at resting membrane poten-
tial, is recruited during periods of prolonged depolarisation
(Meldrum, 2000). The metabotropic family of glutamate
receptors, also classified into three distinct subtypes (Groups
I, II, and III), are G-protein linked and predominantly
presynaptic, possibly controlling neurotransmitter release
(Meldrum, 2000).
Although none of the commonly used AEDs exert their
pharmacological effects solely by an action on the glutamate
system, blockade of ionotropic glutamate receptors is
believed to contribute to the antiepileptic activity of several
compounds (Upton, 1994; Macdonald & Kelly, 1995; Mel-
drum, 1996; White, 1999). In addition, several AEDs have
been reported to reduce glutamate release, although this
effect may be more indicative of their actions on neuronal
Ca2 + channels than a direct effect on the glutamate system
(Stefani et al., 1997).
3. Modulation of ion channels by antiepileptic drugs
3.1. Phenytoin
PHT was discovered following a search to identify a
nonsedative analogue of PB (Fig. 1; Merritt & Putnam,
1938). It has become a first-line treatment for partial and
generalised tonic-clonic seizures (Brodie & Dichter, 1996).
PHT is believed to exert its anticonvulsant effect pri-
marily by an action on voltage-dependent Na + channels
(Tunnicliff, 1996), binding to the fast inactivated state of
the channel and reducing the frequency of sustained repet-
itive firing of action potentials, without affecting their
amplitude or duration (McLean & Macdonald, 1983).
PHT inhibits high-frequency repetitive firing in a voltage-
dependent manner, with limitation of firing increased after
depolarisation and removed by hyperpolarisation (Schwartz
& Grigat, 1989). Na + channel blockade with PHT is also
frequency-dependent, being more effective at higher fre-
quencies of neuronal stimulation. An effect on persistent
 P. Kwan et al. / Pharmacology & Therapeutics 90 (2001) 21–34 25

Fig. 1. Molecular structures of the established AEDs.

Na + currents has also been suggested (Lampl et al., 1998). tems have been reported. Whether these additional actions
The precise binding site for PHT on the Na + channel is contribute to the anticonvulsant effects of the drug is unclear.
unclear (Ragsdale et al., 1996), and there may be a
preferential effect on different subtypes of Na + channels 3.3. Lamotrigine
(Song et al., 1996).
PHT has also been reported to block high voltage- Lamotrigine (LTG; Fig. 2) is a new AED that was
activated Ca2 + channels (Schumacher et al., 1998), to developed as a result of a once-presumed link between
attenuate post-ictal glutamate release (Rowley et al., 1995) anticonvulsant and antifolate properties (Reynolds et al.,
and, paradoxically, to reduce K + currents (Nobile & 1966). It has proved to have a broad spectrum of activity,
Vercellino, 1997). There is further unsubstantiated evi- with efficacy for partial, absence, myoclonic, and tonic-
dence to suggest that PHT potentiates the action of GABA clonic seizures (Leach & Brodie, 1995). There is no
at specific molecular subtypes of the GABAA receptor evidence that the anticonvulsant activity of LTG is related
(Granger et al., 1995). to its weak antifolate effect (Macdonald & Kelly, 1995).
Instead, like PHT and CBZ, it inhibits sustained repetitive
3.2. Carbamazepine firing of action potentials (Cheung et al., 1992; Wang et al.,
1993) by blocking Na + channels in a voltage- and use-
CBZ is chemically related to the tricyclic antidepressants dependent manner (Cheung et al., 1992; Lang et al., 1993;
(Fig. 1). First introduced in 1963, it is widely used in the Zona & Avoli, 1997).
treatment of partial and generalised tonic-clonic seizures The broad clinical profile of LTG suggests that its effects
(Brodie & French, 2000). CBZ has been reported to stabilise on the Na + channel may differ from those observed with
the inactive form of the Na + channel in a voltage-, PHT and CBZ. Unlike PHT, LTG acts principally on the
frequency-, and time-dependent fashion (Courtney & Etter, slow inactivated state of the channel (Kuo & Lu, 1997). In
1983). Although similar to PHT in this respect, subtle addition, LTG may exhibit differential sensitivity for the
differences in the mechanisms of action of the two drugs
may exist. Accordingly, CBZ has a greater binding rate
constant, but lower affinity, for the inactivated Na + channel
(Kuo et al., 1997), whereas PHT produces a more pro-
nounced slowing of recovery from the fast inactivated state
(Schwartz & Grigat, 1989).
Inhibition of glutamatergic neurotransmission has also
been implicated in the mechanism of CBZ action. Recent
evidence suggests that it inhibits the rise in intracellular free
Ca2 + induced by NMDA and glycine in rat cerebellar
granule cells (Hough et al., 1996) and blocks veratrine-
induced release of endogenous glutamate (Waldmeier et al.,
1995). Unlike PHT, there is no evidence that CBZ directly
interacts with Ca2 + channels or potentiates the actions of
GABA. However, effects on the serotonin (Dailey et al.,
1997a, 1997b) and adenosine (Marangos et al., 1983) sys- Fig. 2. Molecular structures of some new AEDs.
26 P. Kwan et al. / Pharmacology & Therapeutics 90 (2001) 21–34
various a-subunits of the Na + channel (Coulter, 1997).
These subunits have a markedly different regional distribu-
tion in the brain (Catterall, 1992). Indeed, it has been
suggested that LTG may selectively target Na + channels
on neurones that synthesise glutamate and aspartate (Leach
et al., 1986).
In addition to Na + channel effects, LTG reduces whole-
cell Ca2 + currents in rat amygdalar neurones, possibly via
the N- and P-type channels that have been implicated in
neurotransmitter release (Stefani et al., 1996b, 1997; Wang
et al., 1996). This effect might explain the inhibition of
electrically stimulated glutamate release from rat spinal
dorsal horn slices observed with the drug (Teoh et al.,
1995). It remains possible, however, that LTG possesses
additional unidentified mechanisms that confer its relatively
broader clinical spectrum when compared with other Na +
channel-blocking agents.
3.4. Oxcarbazepine
Oxcarbazepine (OXC; Fig. 3) is a relatively novel AED,
with widespread geographical approval for clinical use
(Tecoma, 1999). It is closely related to CBZ in structure.
The keto substitutions at the 10 and 11 positions of the
dibenzazepine nucleus do not affect the therapeutic profile
of the drug when compared with CBZ, but result in altered
biotransformation and better tolerability (White, 1999). The
structural modifications circumvent the 10,11-epoxide
metabolite of CBZ that is believed to be responsible for
many of its side effects and its ability to induce cytochrome
P450-dependent hepatic metabolism (Tecoma, 1999). OXC
is essentially a pro-drug, and is rapidly and completely
reduced in the liver to its active metabolite, the monohy-
droxy derivative (10,11-dihydro-10-hydroxy CBZ; Edito-
rial, 1989).
In terms of mechanisms of action, OXC appears to exert
its pharmacological effects by blockade of voltage-depend-
ent Na + channels in a manner similar to that reported for
PHT and CBZ (McLean et al., 1994). It also reduces
presynaptic glutamate release, possibly by blocking high-
threshold Ca2 + currents (Calabresi et al., 1995; Stefani et
Fig. 3. Molecular structures of remaining new AEDs.
al., 1995, 1997). Interestingly, unlike any other licensed
AED, OXC may additionally increase K + channel conduc-
tance (McLean et al., 1994).
3.5. Ethosuximide
ESM has been used in the treatment of generalised
absence seizures for over 30 years (Fig. 1; Brodie & Dichter,
1997). It has no consistent efficacy for any other seizure
type. ESM exerts its anti-absence effects by reducing T-type
Ca2 + currents in thalamocortical relay neurones (Coulter et
al., 1989b, 1989c). As discussed in Section 2.1.2, the low-
threshold T-type Ca2 + channel predominates in these neuro-
nes, where it is believed to play a fundamental role in the
generation of the characteristic 3-Hz spike-and-wave dis-
charge of absence epilepsy (Coulter et al., 1989a). ESM
blocks the T-type Ca2 + channel and prevents synchronised
firing. It has no other known mechanisms of action (Rogaw-
ski & Porter, 1990).
3.6. Zonisamide
The development of zonisamide (ZNS; Fig. 3) was, until
recently, suspended following observations linking the drug
to an increased incidence of renal calculi (Leppik et al.,
1993; Leppik, 1999). However, long-term experience in
Japan, where the drug is licensed, failed to substantiate
these concerns. Clinical evidence to date suggests that ZNS
is effective against partial and generalised seizures, and has
particular efficacy in the progressive myoclonic epilepsies
that are often resistant to AED treatment (Dichter & Brodie,
1996; Kyllerman & Ben-Menachem, 1998).
The principal pharmacological action of ZNS involves
modulation of voltage-dependent ion channels. Like LTG,
ZNS enhances slow Na + channel inactivation (Schauf,
1987) and reduces sustained repetitive firing in spinal cord
neurones (Rock et al., 1989). It also blocks low-threshold T-
type Ca2 + currents, which may account for its anti-absence
effects (Suzuki et al., 1992).
ZNS also inhibits carbonic anhydrase, although this
action is believed to be too weak to contribute to its
antiepileptic effect (Leppik, 1999; Rho & Sankar, 1999).
It has also been shown to inhibit ligand binding to GABAA
receptors and the associated BZD recognition site (Mimaki
et al., 1988). Other proposed mechanisms include inhibition
of monoamine release (Kawata et al., 1999) and metabolism
(Okada et al., 1995).
4. Potentiation of g-aminobutyric acid by
antiepileptic drugs
4.1. Phenobarbital
The barbiturates have been used since the early 1900s for
their sedative, anaesthetic, and anticonvulsant properties.
 P. Kwan et al. / Pharmacology & Therapeutics 90 (2001) 21–34
PB (Fig. 1) is still commonly prescribed worldwide for
epilepsy, although its cognitive and behavioural side effects
have limited its use, particularly in the developed world
(Mattson et al., 1985; Brodie & Dichter, 1997). The use of
primidone (PRM; Fig. 1) has been similarly restricted. It is
largely metabolised to PB, although there is evidence to
suggest that it possesses an additional active metabolite.
Variations in the experimental anticonvulsant profiles of PB
and PRM (Bourgeois et al., 1983), and the relatively greater
toxicity of PRM (Mattson et al., 1985), may be conferred by
this metabolite.
PB exerts its pharmacological effects by allosteric acti-
vation of the GABAA receptor, increasing the duration of
Cl  channel opening, without affecting the frequency of
opening or channel conductance (Macdonald et al., 1989;
Twyman et al., 1989). The barbiturates can also activate the
GABAA receptor directly, in the absence of GABA, an
effect that may underlie their sedative properties (Rho et al.,
1996; White, 1999). Additional mechanisms of barbiturate
action have been reported, including blockade of high-
voltage-activated Ca2 + channels (Rogawski & Porter,
1990) and an inhibitory effect on the AMPA/kainate subtype
of glutamate receptor (Davies, 1995).
4.2. Benzodiazepines
More than 50 chemically distinct BZDs are marketed
worldwide. Diazepam, lorazepam, clobazam, and clonaze-
pam are those most commonly used as AEDs (Fig. 4; Brodie
& Dichter, 1996; Dichter & Brodie, 1996). The antiepileptic
BZDs have a broad spectrum of clinical activity, with
efficacy in the partial and idiopathic generalised epilepsies
(Dichter & Brodie, 1996) and for the acute treatment of
status epilepticus (Treiman et al., 1998). The development
Fig. 4. Structures of BDZ compounds commonly used in epilepsy.
27
of tolerance to their pharmacological effects has, however,
restricted their use in chronic treatment regimens (Brodie &
Dichter, 1996).
The BZDs bind to a specific site in the brain (Squires &
Braestrup, 1977), now recognised as the a-subunit of the
GABAA receptor (Macdonald & Kelly, 1995). Binding
results in allosteric activation of the receptor, increasing
the frequency of Cl  channel opening, without affecting
open duration or channel conductance (Study & Barker,
1981; Twyman et al., 1989). Unlike the barbiturates, the
BZDs are unable to directly activate the GABAA receptor in
the absence of GABA (White, 1999).
Augmentation of GABAergic inhibition in the thalamus
can result in the de-inactivation of T-type Ca2 + channels,
triggering a strong low-threshold burst and enhancing
development of the thalamocortical rhythmicity that is
characteristic of absence seizures (Coulter, 1997). Some
GABAergic AEDs accordingly exacerbate absence seizures;
others are without effect, while the BZDs are notable by
their efficacy (Dichter & Brodie, 1996).
This phenomenon is explained by selective augmentation
of GABAA-mediated inhibition within the nucleus reticula-
ris thalami, but not the thalamus itself, reducing the syn-
chronising input to the thalamocortical circuits (Steriade &
Llinas, 1988; Coulter, 1997). A differential distribution of
a-subunits of the GABAA receptor between the nucleus
reticularis thalami and other thalamic nuclei may underlie
this apparent contradiction (Coulter, 1997).
4.3. Vigabatrin
In 1989, vigabatrin (VGB; Fig. 2) became the first of the
new generation of AEDs to be licensed in the United
Kingdom. It was initially approved as adjunctive therapy
for partial seizures with or without secondary generalisation
(Dichter & Brodie, 1996). It has subsequently demonstrated
particular efficacy in the treatment of infantile spasms
(Appleton et al., 1999). Recent evidence of an association
between VGB treatment and concentric visual field con-
striction will, however, limit the future use of the drug
(Kälviäinen et al., 1999).
VGB is an ethyl analogue of GABA that is widely
recognised to exert its pharmacological effects by inhibition
of GABA-T, the enzyme responsible for the catabolism of
GABA (Jung et al., 1977). As a consequence, it elevates
GABA levels, potentiating inhibitory neurotransmission
throughout the brain (Schechter et al., 1977). VGB is classed
as a ‘‘suicide’’ inhibitor. It is transformed by GABA-T to an
active metabolite, which, thereafter, irreversibly binds to the
active site of the enzyme (Lippert et al., 1977).
A single dose of VGB reduces mouse brain GABA-T
activity to  20% of control levels and produces a 4-fold
increase in whole brain GABA concentrations. This effect
persists for over 24 hr, with GABA-T activity and GABA
concentrations only returning to normal upon the synthesis
of new enzyme protein over a period of 4 – 5 days
28 P. Kwan et al. / Pharmacology & Therapeutics 90 (2001) 21–34
(Schechter et al., 1977). Similar effects are also observed in
humans (Petroff et al., 1996b; Petroff & Rothman, 1998).
Preliminary evidence suggests that, in addition to an effect
on GABA-T, VGB may block the uptake of GABA into
glial cells (Leach et al., 1996).
4.4. Tiagabine
Tiagabine (TGB) is a novel AED, recently licensed
widely for the adjunctive treatment of partial seizures with
or without secondary generalisation (Fig. 3; Leach &
Brodie, 1998). It is an analogue of nipecotic acid, a proto-
typic GABA uptake blocker, which is widely recognised to
prevent GABA transport into both neurones and glial cells
(Krogsgaard-Larsen et al., 1987). Nipecotic acid, however,
fails to cross the blood-brain barrier following systemic
administration. This problem is overcome by linking it to a
lipophilic anchor to form TGB, which is able to cross the
blood-brain barrier more readily (Brodie, 1995).
TGB inhibits GABA uptake into synaptosomal mem-
branes, neurones, and glial cells. It has a greater affinity
(2.5-fold) for glial than for neuronal uptake (Braestrup et al.,
1990). TGB has a selective action on the GAT-1 GABA
transporter, with little or no activity on GAT-2, GAT-3, or
BGT-1 (Borden et al., 1994). As a result, the pharmaco-
logical effect of TGB reflects the regional distribution of
GAT-1, and is mainly restricted to the cerebral cortex and
hippocampus (Meldrum & Chapman, 1999).
Unlike VGB, which elevates whole brain GABA con-
centrations, TGB temporarily prolongs the presence of
GABA in the synaptic cleft (Sills et al., 1999). This
important distinction has been confirmed by in vivo micro-
dialysis studies in rats (Fink-Jensen et al., 1992) and in the
hippocampus of a patient with refractory partial epilepsy
(During et al., 1992). In rat hippocampal slices, TGB pro-
longs the duration, but not the magnitude, of the peak
inhibitory postsynaptic current, consistent with delayed
clearance of GABA from the synapse (Roepstorff & Lam-
bert, 1992). Inhibition of GABA uptake is the only known
mechanism of TGB action (Brodie, 1995).
5. Antiepileptic drugs with multiple mechanisms
of action
5.1. Sodium valproate
The antiepileptic properties of VPA were discovered
serendipitously when valproic acid was employed in animal
studies as a solvent for drugs under formal investigation
(Fig. 1; Meunier et al., 1963). VPA has since proved to be
an extremely useful AED, with a broad spectrum of activity
and particular efficacy in the generalised epilepsies (Edito-
rial, 1988; Brodie & Dichter, 1996). However, the precise
mechanisms by which it exerts its antiepileptic effects
remain to be conclusively determined.
VPA has been reported to block voltage-dependent Na +
channels. It reduces sustained repetitive firing of mouse
neurones in culture (McLean & Macdonald, 1986), inhibits
Na + channels in Xenopus leavis myelinated neurones (van
Dongen et al., 1986), and reduces Na + currents in neo-
cortical neurones (Zona & Avoli, 1990). However, rat
hippocampal slice studies suggest that, unlike PHT and
CBZ, VPA has no effect on the recovery of Na + channels
from the inactivated state (Albus & Williamson, 1998).
VPA may also block T-type Ca2 + channels in a manner
similar to that reported for ESM. Such an effect would
explain its efficacy against generalised absence seizures.
However, the reduction of T-type Ca2 + currents observed
with VPA in rat primary afferent neurones is modest and
requires relatively high drug concentrations (Kelly et al.,
1990). In addition, VPA appears to have no effect on Ca2 +
channel conductance in rat thalamic neurones (Coulter
et al., 1989c).
There is evidence to suggest that VPA elevates whole
brain GABA levels and potentiates GABA responses,
possibly by enhancing GAD activity and inhibiting
GABA degradation (Löscher, 1999). Anecdotal reports
suggest that the drug also augments GABA release
(Rowley et al., 1995) and blocks GABA uptake (Sills et
al., 1996). The reproducibility of these effects has, how-
ever, been questioned (Rogawski & Porter, 1990). It is
suggested that the GABAergic effects of VPA exhibit a
degree of regional specificity within the brain and that
inconsistent results reflect the resolution of individual
studies (Löscher, 1999).
Single doses of VPA decrease brain levels of the
excitatory amino acid aspartate, without influencing those
of glutamate or GABA (Schechter et al., 1978). Decreases
in aspartate concentration have been shown to correspond
with the period of anticonvulsant activity in animal models
(Chapman et al., 1983). The relative anticonvulsant poten-
cies of a series of valproate analogues also correlates more
closely with their ability to reduce brain aspartate levels
than with their effects on GABA concentration (Chapman
et al., 1984). The potential contribution of any of the
above effects to the clinical activity of VPA remains to
be determined.
5.2. Gabapentin
Gabapentin (GBP) is a novel compound, structurally
related to GABA, which is effective in the adjunctive
treatment of partial seizures, with or without secondary
generalisation (Fig. 2; Dichter & Brodie, 1996). It was
originally designed as a GABAmimetic that could freely
cross the blood-brain barrier. However, subsequent studies
have shown that GBP does not directly interact with GABA
receptors (Taylor et al., 1998) or transporters (Su et al.,
1995; Macdonald & Greenfield, 1997).
There is evidence that GBP may increase the synthesis
(Taylor et al., 1992) and nonvesicular release of GABA
 P. Kwan et al. / Pharmacology & Therapeutics 90 (2001) 21–34
(Gotz et al., 1993), and may prevent its metabolism (Leach
et al., 1997). Using 1H NMR spectroscopy, GBP has been
shown to elevate GABA concentrations in the occipital
cortex of epileptic patients (Petroff et al., 1996a). Whether
this observation is the result of enhanced synthesis,
increased release, or reduced metabolism of GABA remains
to be determined.
Early efforts to identify the mechanism of action of GBP
proposed an interaction with the L-amino acid transport
system, resulting in alterations in the cytosolic and extrac-
ellular concentrations of several amino acids, including L-
leucine, L-valine, and L-phenylalanine (Su et al., 1995).
Inhibition of branched chain amino acid transferase and
augmentation of glutamate dehydrogenase activities have
also been mooted (Goldlust et al., 1995). Investigations of
Na + channel function suggest that GBP does not affect
sustained repetitive firing in spinal cord neurones (Taylor et
al., 1988), although prolonged exposure reduces high-fre-
quency action potential firing in central neurones (Wamil &
McLean, 1994).
The identification of a specific binding site for GBP in
the mammalian brain, and its subsequent unveiling as the
a2d-subunit of the L-type voltage-dependent Ca2 + channel
(Gee et al., 1996), suggested another potential pharmaco-
logical mechanism. The implications of these findings
remain to be fully investigated, but the lack of effect of
GBP on whole cell Ca2 + currents in human dentate granule
cells acutely isolated from patients with temporal lobe
epilepsy (Schumacher et al., 1998) questions the pharmaco-
logical relevance of this finding.
5.3. Felbamate
Felbamate (FBM; Fig. 2) was licensed in the United
States in 1993 as monotherapy and add-on treatment for
partial-onset and primary generalised tonic-clonic seizures
in adults and for children with Lennox– Gastaut syndrome
(Dichter & Brodie, 1996). Its initial clinical success was
tempered by the significant incidence of aplastic anaemia
and hepatotoxicity revealed in postmarketing surveillance
(Pellock & Brodie, 1997).
FBM is believed to be the first effective AED with a
direct action on the NMDA subtype of glutamate receptor. It
inhibits NMDA/glycine-stimulated increases in intracellular
Ca2 + (Taylor et al., 1995), reduces inward currents evoked
by NMDA application to striatal neurones (Pisani et al.,
1995), and blocks NMDA receptor-mediated excitatory
postsynaptic potentials (Pugliese & Corradetti, 1996). Con-
siderable evidence suggests that FBM interacts with the
strychnine-insensitive glycine recognition site on the
NMDA receptor complex (White et al., 1995b). FBM
inhibits the binding of high-affinity glycine antagonists at
this site (McCabe et al., 1993), and its anticonvulsant effects
in several experimental models are blocked by glycine and
synthetic glycine site compounds (Coffin et al., 1994; White
et al., 1995b).
29
FBM facilitates the effects of diazepam against exper-
imentally induced seizures, implying an additional action at
the GABAA receptor (Gordon et al., 1991). Early studies
failed to demonstrate an effect of FBM on ligand binding to
the GABA, BZD, or picrotoxin recognition sites on the
receptor complex (Ticku et al., 1991). However, subsequent
investigations suggested that, in addition to inhibiting
NMDA responses, FBM potentiated GABAA receptor cur-
rents (Rho et al., 1994). The precise binding site for FBM on
the GABAA receptor remains to be identified, although a
weak interaction with the barbiturate recognition site has
been mooted (Rho et al., 1997).
Additional actions of FBM on voltage-dependent ion
channels have been reported. It reduces voltage-dependent
Na + currents in striatal neurones (Pisani et al., 1995) and
stabilises the inactive state of the a-subunit of Na +
channels transiently expressed in Xenopus oocytes (Taglia-
latela et al., 1996). In cortical and neostriatal neurones,
FBM reduces high-voltage-activated Ca2 + channels, an
effect reversed by the L-type channel antagonist nifedipine,
but not by N- or P-type channel blockers (Stefani et al.,
1996a). The effects of FBM on voltage-activated ion
channels may explain the decrease in veratridine-induced
release of glutamate observed with the drug (Srinivasan
et al., 1996).
5.4. Topiramate
The sulfamate derivative topiramate (TPM; Fig. 2) is
active against partial-onset and generalised seizures in
humans (Wilson & Brodie, 1996; Brodie & French,
2000). TPM has multiple mechanisms of action, including
inhibition of Na + and Ca2 + currents, blockade of the
AMPA/kainate subtype of glutamate receptor, and facilita-
tion of GABA effects at the GABAA receptor. TPM also
inhibits carbonic anhydrase, although, like ZNS, this effect
is not believed to contribute to its antiepileptic action
(Shank et al., 1994).
TPM reduces the number of action potentials within a
burst and decreases burst duration in cultured hippocampal
neurones (DeLorenzo et al., 2000). It also reduces voltage-
dependent Na + currents in cultured cerebellar granule cells
(Zona et al., 1996a, 1996b). In this respect, its action is
similar to that of PHT and CBZ, delaying recovery of Na +
channels from the inactive state. It has also been reported
that TPM blocks whole cell Ca2 + currents, possibly by an
action on the high-voltage-activated L-type channel (Zhang
et al., 2000).
In hippocampal neurones, TPM blocks inward currents
evoked by kainate, but not NMDA (Gibbs et al., 2000),
implying a selective effect on the AMPA/kainate subtype of
the glutamate receptor. TPM also interacts with the GABAA
receptor. It enhances GABA-stimulated Cl  flux into
cerebellar granule neurones and increases Cl  currents
evoked by GABA in mouse cerebral cortical neurones
(White et al., 1997). The GABAA receptor effects of TPM
30 P. Kwan et al. / Pharmacology & Therapeutics 90 (2001) 21–34
are not influenced by flumazenil, suggesting that they do not
involve the BZD recognition site on the receptor complex
(White et al., 1995a). Finally, recent evidence suggests that
brain concentrations of GABA, and its metabolites, are
elevated by TPM in patients with refractory epilepsy (Petr-
off et al., 1999). These effects, however, are not reproduced
in experimental animals (Sills et al., 2000).
6. Antiepileptic drugs with unknown mechanisms
of action
6.1. Levetiracetam
Levetiracetam (LEV; Fig. 3) is the S-enantiomer of the
ethyl analogue of piracetam, a widely used nootropic agent
in the elderly (Löscher & Hönack, 1993). As the most
recently licensed AED, clinical experience with LEV is
limited (Genton & Van Vleymen, 2000). Results of clinical
trials suggest that it is effective against partial seizures with
or without secondary generalisation (Bialer et al., 1999).
However, more extensive investigation of LEV is required
before its full spectrum of clinical activity is revealed.
LEV appears to have a unique mode of action that, at
this time, remains to be clearly characterised. Exhaustive
preclinical investigations suggest that it does not interact
directly with any of the traditional targets, including Na + ,
Ca2 + , and K + channels or the GABA and glutamate
neurotransmitter systems (Noyer et al., 1995). It is believed
to bind to a specific, as yet unidentified, site on the
synaptic plasma membrane. Competitive binding studies
suggest that LEV is not displaced by CBZ, PHT, VPA, PB,
clonazepam, picrotoxin, or bicuculline, but does interact
with ESM, pentylenetetrazol, and bemegride at this site
(Noyer et al., 1995). The implications of these observations
are unclear.
LEV has no effect on whole brain GABA synthesis or
metabolism, or on the concentrations of GABA, glutamate,
or glutamine (Sills et al., 1997). These studies, however, did
not discount the possibility of regionally specific effects on
the GABA system. Accordingly, LEV reduces GABA turn-
over in the striatum of the rat by increasing GABA-T
activity and reducing GAD activity (Löscher et al., 1996).
These modest effects are accompanied by a decrease in
spontaneous neuronal firing of the substantia nigra pars
reticulata, which receives a strong GABAergic input from
the striatum (Löscher et al., 1996).
Other preclinical studies suggest that LEV attenuates
bicuculline-induced increases in neuronal excitability in
the CA3 region of the rat hippocampus (Margineanu &
Wulfert, 1995), possibly by blockade of T-type Ca2 +
channels (Margineanu & Wulfert, 1997). Suppression of
NMDA-induced bursting has also been reported (Birnstiel
et al., 1997). The relative contribution of any, or all, of the
anecdotal effects described above to the antiepileptic action
of LEV remains to be substantiated.
7. Conclusions
For the purposes of this review, it seemed prudent to
categorise the currently used AEDs according to their
principal mechanisms of action. However, it is becoming
apparent that most, if not all, have multiple cellular effects.
Given that the epilepsies are, by definition, a group of
disorders rather than a single disease entity, it is not
surprising that the currently employed AEDs display such
a diverse range of pharmacological actions.
The immediate challenge is to establish the relative
importance of individual mechanisms to the overall anti-
epileptic effect of each drug. The use of AEDs with known
modes of action has the potential to promote the under-
standing of the underlying pathophysiology of seizure dis-
orders and, in turn, to provide a framework for future
targetted drug development.
Despite familiarity with established AEDs and the intro-
duction of nine new agents in the past decade, up to one-third
of epilepsy patients remain resistant to optimum drug treat-
ment (Kwan & Brodie, 2000). Identifying the ‘‘mechanisms
that matter’’ has the potential to address the problem of
refractory epilepsy, at least in part. It is equally fundamental
to the development of a rational basis for future pharmaco-
therapy, centred around AED mechanisms of action and
tailored to the individual patient (Brodie et al., 1997).
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