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conductance, resulting in
neuronal hyperpolarisation (Rabow et al., 1995). GABA
B
receptors are G-protein-linked, activation of which leads to
P. Kwan et al. / Pharmacology & Therapeutics 90 (2001) 2134 23
an increase in K
+
conductance (Olsen & Avoli, 1997). It
has recently been proposed that GABA
A
and GABA
B
receptors may have evolved from the GABA
C
receptor,
which is comparatively simpler in structure and pharmacol-
ogy (Johnston, 1996).
Of the three receptor subtypes, the GABA
A
receptor,
with its pentameric subunit array and central Cl
ion pore,
is perhaps the best understood (Rabow et al., 1995).
GABA
A
receptors are composed of various combinations
of 5 subunits, a
(16)
, b
(13)
, g
(13)
, d, and e. Receptor
physiology, pharmacology, and distribution differs, depend-
ing on subunit composition (Mody, 1998). Theoretically,
tens of thousands of different GABA
A
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 (Loscher, 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, Ca
2 +
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
Ca
2 +
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) 2134 24
Na
+
currents has also been suggested (Lampl et al., 1998).
The precise binding site for PHT on the Na
+
channel is
unclear (Ragsdale et al., 1996), and there may be a
preferential effect on different subtypes of Na
+
channels
(Song et al., 1996).
PHT has also been reported to block high voltage-
activated Ca
2 +
channels (Schumacher et al., 1998), to
attenuate post-ictal glutamate release (Rowley et al., 1995)
and, paradoxically, to reduce K
+
currents (Nobile &
Vercellino, 1997). There is further unsubstantiated evi-
dence to suggest that PHT potentiates the action of GABA
at specific molecular subtypes of the GABA
A
receptor
(Granger et al., 1995).
3.2. Carbamazepine
CBZ is chemically related to the tricyclic antidepressants
(Fig. 1). First introduced in 1963, it is widely used in the
treatment of partial and generalised tonic-clonic seizures
(Brodie & French, 2000). CBZ has been reported to stabilise
the inactive form of the Na
+
channel in a voltage-,
frequency-, and time-dependent fashion (Courtney & Etter,
1983). Although similar to PHT in this respect, subtle
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
Ca
2 +
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 Ca
2 +
channels or potentiates the actions of
GABA. However, effects on the serotonin (Dailey et al.,
1997a, 1997b) and adenosine (Marangos et al., 1983) sys-
tems have been reported. Whether these additional actions
contribute to the anticonvulsant effects of the drug is unclear.
3.3. Lamotrigine
Lamotrigine (LTG; Fig. 2) is a new AED that was
developed as a result of a once-presumed link between
anticonvulsant and antifolate properties (Reynolds et al.,
1966). It has proved to have a broad spectrum of activity,
with efficacy for partial, absence, myoclonic, and tonic-
clonic seizures (Leach & Brodie, 1995). There is no
evidence that the anticonvulsant activity of LTG is related
to its weak antifolate effect (Macdonald & Kelly, 1995).
Instead, like PHT and CBZ, it inhibits sustained repetitive
firing of action potentials (Cheung et al., 1992; Wang et al.,
1993) by blocking Na
+
channels in a voltage- and use-
dependent manner (Cheung et al., 1992; Lang et al., 1993;
Zona & Avoli, 1997).
The broad clinical profile of LTG suggests that its effects
on the Na
+
channel may differ from those observed with
PHT and CBZ. Unlike PHT, LTG acts principally on the
slow inactivated state of the channel (Kuo & Lu, 1997). In
addition, LTG may exhibit differential sensitivity for the
Fig. 1. Molecular structures of the established AEDs.
Fig. 2. Molecular structures of some new AEDs.
P. Kwan et al. / Pharmacology & Therapeutics 90 (2001) 2134 25
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 Ca
2 +
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 Ca
2 +
currents (Calabresi et al., 1995; Stefani et
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
Ca
2 +
currents in thalamocortical relay neurones (Coulter et
al., 1989b, 1989c). As discussed in Section 2.1.2, the low-
threshold T-type Ca
2 +
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 Ca
2 +
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 Ca
2 +
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 GABA
A
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. Fig. 3. Molecular structures of remaining new AEDs.
P. Kwan et al. / Pharmacology & Therapeutics 90 (2001) 2134 26
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 GABA
A
receptor, increasing the duration of
Cl
flux into
cerebellar granule neurones and increases Cl
currents
evoked by GABA in mouse cerebral cortical neurones
(White et al., 1997). The GABA
A
receptor effects of TPM
P. Kwan et al. / Pharmacology & Therapeutics 90 (2001) 2134 29
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 (Loscher & Honack, 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
+
,
Ca
2 +
, 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 (Loscher 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 (Loscher 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 Ca
2 +
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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