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412 Chapter 16 Epilepsy
GABA
GLUTAMATE
Box 16.1
Accelerators and brakes in the brain: the molecular substrates of epilepsy
Glutamate, acting on its ion-channel receptors, is the
main excitatory inuence keeping brain activity going
(the accelerator pedal). Balancing this is
-aminobutyric acid (GABA), the major brake in the
brain. Interestingly, these two compounds are closely
related structurally—glutamate is an amino acid with
two carboxylic acid (–COOH) groups, and GABA is
formed when one of these is removed by a specic
enzyme, glutamic acid decarboxylase.
Some of the interconversions between these two key
brain amino acid neurotransmitters are shown in
Figure a. GABA breakdown by GABA-transaminase,
and GABA removal from the synapse by uptake into
nerve terminals and glial cells by the GABA
transporter GAT-1 are both targets for AEDs (e.g.
tiagabine). ere is also a suggestion that steps in the
tricarboxylic acid cycle (Krebs cycle) are aected by
AEDs. For example, sodium valproate reportedly
inhibits succinate semialdehyde dehydrogenase. e
relevance of this to the therapeutic response is,
however, speculative.
Glutamate receptors can be divided into four
categories: the three subtypes of ionotropic receptors
and the family of metabotropic receptors. We are only
concerned here with ionotropic receptors.
Ionotropic receptors (ligand-gated ion channels)
have receptor and channel moieties which are part of
the same protein. is protein entity is composed of
several transmembrane subunits which together form
mono- or heteromultimeric structures. Other
examples of ionotropic receptors are GABAA (see
below), and nicotinic acetylcholine receptors (see
Chapter 2).
Ionotropic glutamate receptors are subdivided into
NMDA, AMPA, and kainate receptors. e ion channel
is opened when glutamate binds to the receptorbinding site (i.e. the channels are ligand gated). Other
conditions may also be required. For example, glycine
acts as a co-transmitter with glutamate at the NMDA
receptor illustrated in Figure b—both glycine and
glutamate must bind to their separate sites on the
The brake
COOH
CH
The GAT-1
transporter
Figure a Glutamate and GABA are very closely related.
removed by
NH
2
GABA-transaminase
Succinic
semialdehyde
Succinate
semialdehyde
dehydrogenase
CH
CH
Glutamic acid
decarboxylase
2
2
2
Succinate
The accelerator
NH
α-ketoglutarate
Tricarboxylic acid
2
cycle
COOH
CH
2
CH
2
CH
COOH
removed by
Excitatory
amino acid
transporters
16.2 The biological basis of epilepsy: brakes and accelerators 413
Glycine GABA
BenzodiazepineGlutamate
Box 16.1 Accelerators and brakes in the brain: the molecular substrates of epilepsy
receptor for the channel to open. It should also be
noted that this requirement for glycine binding has
been exploited in the development of new
antipsychotic drugs, as discussed in Chapter 18, Box
18.2. In this novel strategy for antipsychotic
medication the objective is to increase activity at
NMDA receptors. is is in contrast with antiepileptic
therapy, where the aim is to decrease the inuence of
glutamate relative to GABA.
All ionotropic glutamate receptors have integral ion
channels for Na+ and/or Ca2+ which upon opening
allow the ions to enter along their concentration
gradients to depolarize the cell. e ionotropic
glutamate receptors are widespread, and so glutamate
has a major excitatory role in the brain.
GABA receptors GABAA receptors are also ionotropic,
but in this case the ion channel is permeable to Cl–,
which enters the cell to cause hyperpolarization of the
cell membrane. GABAB receptors are
7-transmembrane G-protein-coupled receptors (see
Chapter 2), and are coupled through Gi to the
inhibition of adenylyl cyclase, thereby lowering
intracellular cyclic AMP levels. e GABAB receptors
are found at pre-synaptic sites (decreasing release of
GABA and other neurotransmitters), and also
post-synaptically (leading indirectly to an increase in
K+ permeability and a dampening down of
excitability). erefore GABA action is always
inhibitory. GABA receptors, like those for glutamate,
are widespread within the brain.
at the correct level of activity at GABA receptors in
the brain is essential to prevent seizure activity is not
in doubt. is is shown by the following observations.
• Administration of the GABAA antagonists picrotoxin
and biculline cause seizures.
• Knockout mice which are missing the gene
encoding one of the GABAB subunits (GABAB1) show
major epileptic activity.
In addition to binding GABA, these receptors also
have binding sites for benzodiazepines, which act as
allosteric regulators making it easier for GABA to bind.
Benzodiazepines thereby enhance the inhibitory
eect of GABA.
+
Na
2+
Ca
Outside cell
Cell
membrane
Inside cell
The NMDA glutamate
receptor
• Open channel allows
+
and Ca2+ into cell
Na
• Cell becomes depolarized
—excitatory
Figure b Glutamate NMDA receptors and GABAA receptors are similar in many respects, but
have opposite effects on neuronal excitability.
Opened by
glutamate
binding
GATE
Opened
by GABA
binding
–
Cl
The GABA
for GABA
• Open channel allows Cl
• Cell becomes hyperpolarized—
inhibitory
receptor
A
–
into cell
414 Chapter 16 Epilepsy
Seizure activity
Normal
Glutamate GABA
Drug therapy
Increases GABA
Decreases glutamate
Figure 16.2 Imbalance between the activity of glutamate and
GABA in the brain results in unrestrained excitatory influence of
glutamate (i.e. weighing down the seesaw).
Drugs may restore the balance by increasing the GABA influence (e.g.
tiagabine, vigabatrin, and benzodiazepines) or reducing glutamate activity
(e.g. topiramate and sodium valproate). Note that many AEDs mix such
actions with others. For example, topiramate both increases the GABA
influence and blocks sodium channels. Blocking voltage-sensitive sodium
channels and/or calcium channels is common to many AEDs, and this
may itself reduce release of neurotransmitters, particularly glutamate, thus
indirectly reducing the neurotransmitter’s influence.
concentration gradient. e two eects of this inux of
Ca2+ are:
• a contribution to depolarization and therefore action
potential ring
• the exocytotic release of neurotransmitters, including
glutamate, at nerve terminals, and thus stimulation of
adjoining cells in the neural network.
ere are a number of dierent types of voltage-gated
Ca2+ channels, namely L-, N-, P/Q-, R-, and T-types; this
is important to us because dierent AEDs interact with
dierent types of Ca2+ channel. T-type channels have a
number of subtypes, and serve a range of neuronal
functions. ey open in response to very small
depolarizations (e.g. to –60 mV), which do not cause
other Ca2+ channel subtypes to open. T-type channel
activation is particularly associated with the early
initiation of bursting activity in neurons. e other Ca2+
channel types (L-, N-, P/Q-, and R-types) open only with
larger depolarizations (e.g. to around –40 mV), and are
more closely associated with Ca2+ entry at nerve
terminals, and therefore with neurotransmitter release.
GABA
Glutamate
are AEDs. L-type channel inhibition is, however,
considered to be one of the mechanisms of action of some
AEDs (see below). is means that either L-type channel
inhibition is not connected with the way these AEDs
work, or it only contributes to the antiepileptic eect
when it occurs in combination with other mechanisms of
action.
16.2.5 The biological basis of epilepsy:
do we have a GABA hypothesis?
When a biological theory is proposed for a complex
disorder it may be considered useful even if we know it
does not encompass all, or even most, aspects of the
disorder. is is true, for example, of the dopamine
hypothesis for schizophrenia, which, as we shall see in
Chapter 18, has been useful in understanding drug
action, despite its limitations. We can therefore consider a
simple GABA hypothesis for epilepsy.
Hypothesis: Epilepsy is caused by a global or regional
inadequacy in GABA inuence on brain function, due to
either decient GABA inuence, or elevated glutamate
inuence.
We have encountered some of these channels before,
notably L-type Ca2+ channels, when considering the
cardiovascular system in Chapter 7. You may recall that
there are many clinically available L-type channel
blockers, and it is instructive to note that none of these
is hypothesis, either explicitly stated or assumed, has
driven much drug discovery, resulting in new AEDs which
benet many patients, and can therefore be considered a
useful starting point when thinking about the biological
basis of epilepsy.
16.2 The biological basis of epilepsy: brakes and accelerators 415
Box 16.2
The use-dependent Na+ channel-blocking action of some
antiepilepsy drugs
40
+
channels
Na
open—Na
enters cell—
0
potential res
–40
–70
Figure c A typical neuronal action potential.
The opening of voltage-sensitive Na+ channels is central to action potential generation. In a resting cell, there is a
membrane potential across the plasma membrane such that the inside of the cell is negative relative to the outside.
When Na+ enters and the cell is depolarized, this potential is reversed and the inside becomes transiently positive
before it returns to being negative as the resting state is restored.
action
+
Na
channels
resting
+
Threshold
1—5 msec
Figure c illustrates the involvement of voltagesensitive Na+ channels in the action potential. When
the cell is resting, the channels are in their closed
state. As the membrane polarity is raised from its
baseline of –70 mV (or below) to about –40 mV (their
‘threshold’), the resting channels open and Na+ enters
the cell as the action potential is red. e channels
then close, but at this point they remain, transiently, in
a refractory state, when they cannot be opened.
A use-dependent Na+ channel-blocking AED binds
preferentially to this refractory state. Figure d shows
action potentials ring at very high frequency, as may
occur in neurons during an epileptic seizure. e
+
channels close and for a
Na
short time are refractory—i.e.
they cannot be opened
+
channels then return to the
Na
resting state—available for
opening when the membrane
polarity is raised to threshold
+
Reminder: Na
the membrane is at its resting potential
(around –70 mV). As the potential is
raised the channels will open. The
potential at which this occurs (~ –40 mV)
is threshold—the channels ip open, Na
rushes in, and the action potential is red.
channels are closed when
introduction of an AED (red bar) delays the return of
refractory channels to the resting state, so delaying the
availability of sucient Na+ channels to support the
high ring rate. Consequently the rate of ring falls.
However, when the cell is ring at a normal rate to
begin with (bottom panel) there is sucient time for
the channels to return to the resting state even with
the delay imposed by the drug, and so there is no
eect on ring rate. Consequently, a use-dependent
drug will not interfere with normal patterns of
neuronal activity in the brain, but will reduce the rate
of action potential generation in neurons ring at
abnormally high frequency.
+
416 Chapter 16 Epilepsy
Membrane polarity: –70 mV → –40 mV → +40 mV
Box 16.2 The use-dependent Na+channel-blocking action of some antiepilepsy drugs
Resting Open Refractory
+
channel-blocking AED
Na
Na+ channel-blocking AED
Figure d Some AEDs selectively bind to the refractory state of the voltage-
sensitive Na+ channels.
Upon closing, the channels transiently enter a refractory state—they are closed, but are unable
to be opened even if the membrane is depolarized. Use-dependent Na+ channel blockers
selectively target these refractory channels, binding to them and ‘delaying’ the channels in this
state. This shift in equilibrium will have most effect on rapidly firing neurons (upper trace),
without affecting slowly firing neurons (lower trace). In this latter case, even with the ‘delay’
there is sufficient time for the refractory channels to return to the resting state (available for
opening) before their involvement is required again in generating an action potential. There is
therefore no effect on the frequency of these action potentials.
16.3 Three mechanisms in the drug treatment of epilepsy
e objective of therapy with AEDs is to prevent the
occurrence of seizures while minimizing unwanted
eects. e target in this area of clinical pharmacology is
clear and simple—the elimination of seizures. At the end
of this section we discuss the strategy in treating epilepsy,
noting that the goal is to achieve this target with just one
drug, while recognizing that this is not always possible.
e issue of unwanted eects and drug interactions is
serious with AEDs, and one reason for striving to use only
one drug is to minimize these. Monotherapy is also likely
to improve compliance, another important consideration
with AED use.
AEDs are a frustrating subject for those seeking a rational
science-based understanding of prescribing. e action
of drugs is complex, involving many dierent cellular
16.3 Three mechanisms in the drug treatment of epilepsy 417
mechanisms, often combined in one drug. It is perhaps
the multiple cellular sites of actions that are essential for
an eective clinical response. Consequently, in the
development of new AEDs the best strategy for drug
companies is probably not to seek agents with a single
molecular target.
Furthermore, the mechanism of action of AEDs
responsible for the clinical eect is sometimes unknown.
is is true of both newer drugs and the older, rstgeneration drugs. Despite these issues we can introduce
some of the known actions of AEDs by considering three
broad types of cellular mechanism:
• decreasing sustained high frequency ring of action
potentials
• increasing GABA inuence
• blocking T-type Ca2+ channels.
16.3.1 Decreasing sustained high
frequency firing of action potentials
As described above, epileptic activity is characterized by
the very high frequency of action potentials in neurons
within the aected regions. ree actions of AEDs target
these rapidly-ring neurons.
• Delaying recovery of Na+ channels by selective binding
to the refractory state has been referred to in Section
16.2.3, and is explored further in Box 16.2. e objective
is to damp down the activity of the rapidly ring
neurons, while leaving normal activity unaected.
• Antagonist action at AMPA and NMDA glutamate
receptors reduces the propagation of excitability
through the neural network.
• Blocking L-, N-, P/Q-, and R-type voltage-sensitive
Ca2+ channels may reduce the excitability of neurons
and the release of neurotransmitters, including
glutamate. Note that blocking T-type Ca2+ channels is
discussed as a separate mechanism of action (Section
16.3.3).
AEDs acting in these various ways to reduce high
frequency neuronal discharges include carbamazepine,
gabapentin, lamotrigine, phenytoin, topiramate, and
possibly sodium valproate.
16.3.2 Increasing GABA influence
From an experimental point of view it is of interest to
note that the convulsant drugs picrotoxin and
bicuculline have their eect by blocking GABAA
receptors, downregulating the inhibitory GABA inuence
on neuronal excitability. Such drugs do not have a
clinical use. Perhaps not surprisingly, then, drugs that
enhance the GABA inuence are often anticonvulsant.
Two mechanisms for raising the GABA inuence can be
identied.
1. Increasing GABA levels in the synapse. is is achieved
by AEDs in at least two ways:
a) inhibiting uptake from the synapse by blocking the
GABA transporter, GAT-1
b) reducing GABA breakdown by inhibiting GABA
transaminase (see Box 16.1, Figure a).
2. Enhancing the function of GABA receptors. For
example, benzodiazepines act on a binding site in the
GABAA receptor (see Box 16.1, Figure b) to
allosterically modulate GABA binding, making binding
easier.
e consequences of these two interventions are not the
same. e rst, increasing GABA levels at the synapse, will
stimulate both GABAA and GABAB receptors. e second,
the action of benzodiazepines, will enhance the inuence
of GABAA receptors only. is dierence in GABA
receptor stimulation may have profound clinical
consequences. An example is the important observation
that some GABA-enhancing drugs (resulting in
stimulation of both types of GABA receptor) used to treat
epilepsy can precipitate certain seizure types. is may
relate to actions at the dierent GABA receptors and is
considered in Box 16.3.
Drugs acting mainly through these mechanisms include
benzodiazepines, tiagabine, topiramate, vigabatrin, and
sodium valproate.
16.3.3 Blocking T-type Ca2+ channels
is cellular mechanism is placed in a separate
category largely because the AED ethosuximide,
believed to derive its therapeutic eect mainly by
blocking T-type Ca2+ channels, has a separate prole of
clinical use (see below), being used for absence
seizures. Understandably this has led to the suggestion
that T-type channel inhibition prevents this type of
seizure. is idea receives some support from the
observation that sodium valproate, which acts in part
by blocking T-type channels, can also be eective
against absence seizures.
418 Chapter 16 Epilepsy
Box 16.3
Proepileptic effects of antiepileptic drugs
It is recognized that some AEDs precipitate or
exacerbate certain types of seizure. is presents a
challenge to our understanding of epilepsy and
normal brain function. However, it must be said that
our knowledge of this issue is imperfect, and is mostly
limited to the exacerbation of absence seizures by
certain AEDs.
e most common observation is that absence
seizures can be elicited by GABA-enhancing drugs.
How can a pathology that is due to uncontrolled
excitation be made worse by increasing the main
inhibitory inuence in the brain? e simple
explanation is that some of this inhibition is exerted
on pathways which are themselves inhibitory, leading
to a net excitatory eect. is is illustrated in Figure e.
AEDs may increase GABA inuence by increasing its
concentration at the synapse, resulting in increased
activity at GABAA and GABAB receptors. Alternatively,
drugs can act at the GABAA receptor selectively. We
have noted that absence seizures may be precipitated
by the non-specic GABA-enhancing drugs (e.g.
vigabatrin and tiagabine). In contrast,
benzodiazepines (e.g. clonazepam), which bind and
enhance the GABAA receptor/Cl– channel but do not
aect GABAB receptors, do not worsen absence
seizures and are used in their management. is has
led to the suggestion that it is specically the GABAB
stimulatory eect that presents a problem with
absence seizures. is has been incorporated into the
model in Figure e.
is is a highly complex area, as illustrated by the
following points.
1) We know, for example, that in the hippocampus
GABAB receptors can inhibit glutamate release
from some neurons and GABA release from others.
However, the overall role of GABA in the brain to
prevent seizure activity is not in doubt (see
Box 16.1).
2) An important complicating issue is that the eect of
manipulating GABA at its dierent receptors
depends on the brain region involved. is may be
true for both GABAA and GABAB receptors.
A drug that increases
the stimulation of an
inhibitory GABA
receptor here …….
B
GABA
–
GABA
–
GABA
GABA
receptors
–
A
GABA
receptors
Figure e Hypothetical scheme indicating how GABAB receptor
agonists may enhance excitability in a neuronal network.
GABAergic (i.e. GABA-releasing) neurons are shown with red axons and
terminals; glutamatergic (i.e. glutamate-releasing) are shown with green
axons and terminals. Cell bodies with GABA receptors are shown in red,
open where these are GABAA receptors and solid for GABAB receptors. In
this hypothetical scheme we can see that an agonist at an inhibitory GABAB
receptor, such as those found in the hippocampus (within the temporal
lobe), may reduce the inhibitory influence of GABAA receptors on glutamate
release, and so lead to excitation. This can precipitate epileptiform activity.
B
Glutamate
Glutamate
……. will increase
activity at the glutamate
neurons here
+
+
Excitation
16.4 Drugs used in the treatment of epilepsy 419
Box 16.3 Proepileptic effects of antiepileptic drugs
3) ere is a prospect of regional selectivity for AEDs
in the future; there are, for example, two known
subtypes of GABAB receptors, GABAB1 and GABAB2.
Four further isoforms of GABAB1 have been cloned
which have specic regional distributions in the
brain. Possible future development of drugs
selective for these isoforms may help to resolve the
issue of proepileptic activity of some AEDs.
e issue of enhancement of absence seizures with
AEDs is not limited to GABA-enhancing drugs. It has
also been associated with one of the other main AED
mechanisms of action: delay of Na+ channel recovery
in rapidly-ring neurons (Box 16.2). is means that
carbamazepine, for example, may precipitate absence
seizures.
e outcome at the present time for clinical use is that
ethosuximide or sodium valproate can be used for
absence seizures; both act, at least in part, by blocking
T-type Ca2+ channels.
But just when you thought you had reached the end of
this set of complexities, it must also be noted that
proepileptic eects are not limited to absence
seizures: there is concern that using ethosuximide
alone in patients with both absence and tonic–clonic
seizures may risk increasing the frequency of
generalized tonic–clonic seizures.
16.4 Drugs used in the treatment of epilepsy
An orderly classication of AEDs on the basis of the
mechanism of action at the cellular and molecular level
cannot be made, because so many of these drugs have
multiple actions. In addition, it is not fully understood
how many (if not most) of them work. Knowing which
drugs are most useful against which types of seizure is
obviously important, but not satisfactory as a basis for
classication because many drugs have diverse clinical
applications. Here, then, we divide drugs into two
categories: older, rst-generation drugs and newer,
second-generation drugs. Brief comments about the
mechanisms of action and clinical use of the major drugs
in each category are provided. It should be noted that not
all AEDs are mentioned. In the nal section (Section
16.5), the strategy for treating epilepsy with drugs is
discussed.
16.4.1 First-generation AEDs
In most cases of epilepsy these are likely to be the rst
drugs tried.
Sodium valproate
is is one of the drugs available as rst-line medication
for all seizure types, and is particularly favoured as a rst
drug for primarily generalized seizures. It is also used in
migraine and as a mood stabilizer, for example as an
alternative to lithium for bipolar disorder (Chapter 19).
ere is no adequate account of sodium valproate’s
mechanism of antiepileptic action. As with many other
AEDs, its therapeutic response is likely to be the result of
several mechanisms acting in concert, including:
• enhanced GABA inuence—inhibition of GABA
transaminase and succinate semialdehyde
dehydrogenase (see Box 16.1, Figure a)
• decreased glutamate inuence by moderation of
NMDA receptors
• blocking T-type Ca2+ channels
• use-dependent blocking of voltage-sensitive Na+
channels.
Adverse eects include risk of teratogenicity (birth
defects) and liver toxicity, especially in young children.
Carbamazepine
is is a drug of choice for partial and primarily
generalized tonic–clonic seizures. e principal
mechanism of action is probably use-dependent blocking
of voltage-sensitive Na+ channels (Box 16.2). It is not used
for absence seizures as, like other drugs with this mode of
action, it may exacerbate this type of seizure (Box 16.3). In
addition, carbamazepine has been shown to enhance
GABA function and block L-type Ca2+ channels. Like
sodium valproate, it is also used for other conditions
including pain disorders, particularly trigeminal
420 Chapter 16 Epilepsy
neuralgia (a type of neuropathic pain), as well as bipolar
illness (Section 19.3). Carbamazepine is widely used in
the treatment of epilepsy. It should, however, be noted
that the drug is a strong inducer of hepatic microsomal
CYP enzymes, and its use is therefore complicated by
numerous drug interactions.
Phenytoin
Like carbamazepine, phenytoin is a rst-choice drug for
partial and primarily generalized tonic–clonic seizures; it
is not used for absence seizures. Its main action is thought
to be use-dependent blocking of voltage-sensitive Na+
channels. e metabolism of phenytoin shows saturation
kinetics; hence plasma drug level monitoring is important
to aid dosing.
Fosphenytoin is a pro-drug of phenytoin, and can be
administered by intramuscular injection in situations
where taking phenytoin orally is not possible, for instance
to combat seizures during neurosurgery.
Benzodiazepines
Not commonly rst-line drugs for epilepsy,
benzodiazepines are also used in the treatment of
insomnia and anxiety (Chapter 19). ey are of great
pharmacological interest because of the mechanism by
which they interact with the GABAA receptor, with its
intrinsic Cl– channel (see Box 16.1, Figure b) so as to
• increase the anity of the GABAA receptor for GABA
• increase the current through the GABAA receptor Cl–
channel.
ese eects combine to selectively enhance the
inuence at the GABAA receptor. Clonazepam is available
to treat all forms of epilepsy, but its use may be limited by
its tendency to produce drowsiness. Diazepam, along
with midazolam and clonazepam, can be given
intravenously to treat status epilepticus. e rapid onset
of action of benzodiazepines, in contrast with that of
many AEDs, makes them particularly useful for this
condition where the need for treatment is urgent.
Phenobarbital
is barbiturate is one of the oldest antiepileptic drugs.
Typical of this drug group, it has some highly unwelcome
pharmacokinetic properties, including powerful
induction of hepatic CYP enzymes. It therefore lowers the
plasma concentration of several clinically important
drugs (e.g. oral contraceptives, steroids, and warfarin)
when taken concurrently. Phenobarbital is now rarely
used due to its high toxicity in overdose, when it causes
respiratory and circulatory failure, and coma. Primidone
is a pro-drug metabolized to phenobarbital, and therefore
has similar uses.
Ethosuximide
Unusually for an AED, the use of this drug is limited to
essentially one seizure type—absence seizures. It is also
unusual in that its molecular mode of action is relatively
selective as a T-type Ca2+ channel blocker. Ethosuximide
and sodium valproate are the drugs of choice for absence
seizures. However, in approximately 50% of patients who
suer from both absence seizures and tonic–clonic seizures,
ethosuximide leaves the tonic–clonic aspect untreated. In
addition, reported adverse eects include possible
exacerbation of tonic–clonic seizures in some patients with
this mixed epilepsy. Sodium valproate remains a sensible
option for the treatment of such individuals.
16.4.2 Second-generation AEDs
e last 20 years or so have seen the introduction of a
bewildering variety of AEDs, some developed with
specic cellular/molecular targets, and most commonly
aimed at mechanisms which enhance GABA function.
Some of these drugs are introduced here.
Lamotrigine
Lamotrigine is a drug of choice for partial seizures
(including secondarily generalized) and primary
generalized tonic–clonic seizures. It may be rst line, or
second line after sodium valproate or carbamazepine if
these drugs have not proved eective. It may be used
alone or in combination with another drug. It is believed
to act mainly as a use-dependent Na + channel blocker
(Box 16.2) but, in contrast with other drugs with this
mechanism of action (e.g. carbamazepine and
phenytoin), it can be used to treat absence seizures.
Topiramate
Topiramate can be used either alone or in combination
with other agents for partial and primary generalized
tonic–clonic seizures. It is, however, more widely
prescribed for non-epileptic conditions (migraine and
bipolar disorders) and combines several mechanisms of
action, including:
• use-dependent blocking of voltage-sensitive Na+
channels
16.5 Strategy and side effects in the drug treatment of epilepsy 421
• enhanced GABAA receptor function
• blocking action of glutamate at AMPA receptors
• blocking L-type Ca2+ channels.
Gabapentin
is is an AED initially designed to interact directly with
GABA receptors as a GABA-mimetic. It failed to do this,
but was found to have antiepileptic properties
nevertheless. It is used mainly for partial seizures,
either alone or more commonly as an add-on therapy.
Gabapentin has other widespread uses, including
treatment of neuropathic pain and prophylaxis of
migraine. Its mechanisms of action may include
interaction with voltage-sensitive Ca2+ channels.
Pregabalin is a more potent analogue of gabapentin,
but otherwise is very similar. Both drugs are generally
better tolerated than other AEDs, the most usual
adverse eects being sedation, dizziness, and ataxia
(aected speech, balance, and coordination). ey also
have the advantage of few drug interactions, again
unlike most AEDs, facilitating their use in combination
with other drugs.
Vigabatrin
Vigabatrin is used as an add-on drug to treat partial
seizures when monotherapy has failed. is drug is an
irreversible inhibitor of GABA transaminase, increasing
GABA concentration in the synapse (see Box 16.1). It suers
from common and serious visual eld disturbance side
eects, and therefore should only be used as a last resort.
Tiagabine
is is another drug available as an add-on in the prevention
of partial seizures. Tiagabine inhibits neuronal and glial
uptake of GABA by the GAT-1 transporter, increasing and
prolonging GABA inuence at the synapse (see Box 16.1).
Oxcarbazepine
is is a chemical derivative of carbamazepine, but with
the advantage over the parent compound of not inducing
hepatic CYP enzymes, and consequently suering fewer
drug interactions. It is a use-dependent voltage-sensitive
Na+ channel blocker (Box 16.2), which may be used as
adjunct therapy in the treatment of partial and generalized
seizures. Oxcarbazepine is also used in bipolar disorder.
16.5 Strategy and side effects in the drug treatment of epilepsy
e objective of antiepileptic drug therapy for all patients
is the elimination of seizures with only one drug. is is
achieved more often in children than in adults. e initial
drug should be a rst-generation AED, but the exact drug
chosen will depend on the individual patient, particularly
with respect to their age, nature of seizures,
comorbidities, and potential interactions with other
drugs being taken. is last consideration is of particular
importance with AEDs, and guidance from an
appropriate reference source should be sought. Many of
the antiepileptics (e.g. carbamazepine, oxcarbazepine,
phenytoin, barbiturates, and topiramate) are inducers of
hepatic enzymes, and this can lead to reduced
eectiveness of many drugs. Amongst those aected are
oral contraceptives, and patients may be advised to use
non-hormonal contraceptive methods (e.g. barrier
methods) instead.
All epileptic drugs have a limited window for eective
treatment with minimum adverse eects, meaning that
dosage is very important and that it may be necessary,
where possible, to monitor plasma levels of the drug. For
example, as mentioned previously, phenytoin plasma
levels are considered important, although sodium
valproate plasma levels are less critical. Target plasma
concentrations can be obtained from a reference source.
If a single drug is not eective or not acceptable due to
side eects (see below), its use should be tapered and a
second drug introduced and used alone. is pursuit of
monotherapy may be abandoned if a maximal dose of a
single drug that does not have unacceptable side eects
brings benet but does not deliver adequate control. at
drug may be continued and a further drug, an add-on
(adjunct therapy), considered. However, before
combination therapy is considered, it is important to
ensure that monotherapy failure is not due to poor
compliance, a common problem with drugs used
prophylactically.
e selection of drug combinations for AED polytherapy
is likely to be based on clinical considerations, but it is of
interest to note that combinations based on
complementary mechanisms of action have been
reported to be useful. It has been suggested, for example,
that combining a Na+ channel blocker with a drug that