C H A P T E R 2 3
Antiseizure agents
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barbiturates, benzodiazepines, GABA transaminase
inhibitors, GABA uptake inhibitors, GABA agonists and
GABA prodrugs.
Lamotrigine and lacosamide may inhibit voltage-
sensitive sodium and calcium channels, stabilise nerve
cell membranes and modulate calcium-dependent
presynaptic release of excitatory neurotransmitters.
Levetiracetam is a newer drug, and its mechanism of
action is not understood; its antiepileptic action does not
seem to be associated with any known mechanisms of
inhibitory or excitatory neurotransmission. (See also the
Focus on safe medication administration for informa
tion about potentially serious name confusion that has
occurred with levetiracetam.)
Oxcarbazepine’s exact mechanism of action is also
unknown. It inhibits voltage-sensitive sodium channels,
stabilising hyperexcited nerve cell membranes. It
also increases potassium conductance and modulates
calcium-dependent presynaptic release of excitatory
neurotransmitters. Any or all of these effects may be
responsible for the antiseizure effects of the drug.
Pregabalin has a high binding affinity for voltage-
gated calcium channels in the cerebrovascular system. It
seems to modulate the calcium function in these neurons,
leading to a decreased release of neurotransmitters into
the synaptic cleft and a decrease in cell activity. Pre
gabalin does not show affinity for receptor sites or alter
responses associated with the action of several common
drugs for treating seizures or pain. Pregabalin does not
interact with either GABA-A or GABA-B receptors; it
is not converted metabolically into GABA or a GABA
agonist; it is not an inhibitor of GABA uptake or degra
dation. Tiagabine (not available in New Zealand) binds
to GABA reuptake receptors, causing an increase in
GABA levels in the brain. Because GABA is an inhibi
tory neurotransmitter, the result is a stabilising of nerve
membranes and a decrease in excessive activity.
Topiramate is another newer drug that blocks
sodium channels in neurons with sustained depolaris
ation and increases GABA activity, inhibiting nerve
activity. Topiramate increases the frequency at which
gamma-aminobutyrate (GABA) activates GABA-A
receptors, and enhances the ability of GABA to induce
a flux of chloride ions into neurons, suggesting that
topiramate potentiates the activity of this inhibitory
neurotransmitter. This effect is not blocked by fluma
zenil, a benzodiazepine antagonist, nor does topiramate
increase the duration of the channel opening time,
which differentiates topiramate from barbiturates that
modulate GABA-A receptors.
Pharmacokinetics
These drugs are all given orally. Levetiracetam is also
available for IV use.
Carbamazepine is absorbed from the GI tract
and metabolised in the liver by the cytochrome P450
system. It is excreted in the urine with a half-life of
25–65 hours.
Gabapentin is well absorbed from the GI tract and
widely distributed in the body. It is excreted unchanged
in the urine with a half-life of 5–7 hours.
Lamotrigine and lacosamide are rapidly absorbed
from the GI tract, metabolised in the liver and primar
ily excreted in the urine. The half-life of lamotrigine is
approximately 25 hours.
Levetiracetam is rapidly absorbed from the GI tract,
reaching peak levels in 1 hour. It goes through very
little metabolism, with most of the drug being excreted
unchanged in the urine with a half-life of 6–8 hours.
Oxcarbazepine is completely absorbed from the
GI tract and extensively metabolised in the liver. It
is excreted in the urine with a half-life of 2 and then
9 hours.
Pregabalin is rapidly absorbed orally, reaching peak
levels in 1.5 hours. It is not metabolised but is eliminated
unchanged in the urine with a half-life of 6.3 hours.
Tiagabine is rapidly absorbed from the GI tract,
reaching peak levels in 45 minutes. It is metabolised in
the liver by the cytochrome P450 system. It is excreted
in the urine with a half-life of 4–7 hours.
Topiramate is rapidly absorbed from the GI tract,
reaching peak levels in 2 hours. It is widely distributed
and is excreted unchanged in the urine.
Contraindications and cautions
Contraindications to the drugs used to control partial
seizures include the following conditions: presence of
any known allergy to the drug; bone marrow suppres
sion,
which could be exacerbated by the drug effects
;
and severe hepatic dysfunction,
which could be exacer-
bated and could interfere with the metabolism of the
drugs.
Carbamazepine, gabapentin and oxcarbazine have
been shown to be dangerous to a fetus and should not
be used during pregnancy. Women of childbearing age
should be advised to use contraception. These drugs
enter breast milk and can cause serious adverse effects in
the baby. If any of these drugs is needed during breast
feeding, another method of feeding the baby should be
used.
There are no clear studies about the effects of
lamotrigine, levetiracetam, pregabalin, tiagabine or
topiramate use during pregnancy and breastfeeding.
Therefore, these drugs should not be used during preg
nancy or breastfeeding unless the benefits to the mother
clearly outweigh potential adverse effects in the fetus or
neonate. Men considering fathering a child should be
advised that, in animal studies, males receiving pregab
alin had decreased fertility and associated birth defects
in offspring.
Caution should also be used in the following situ
ations: with renal or hepatic dysfunction,
which could
