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9780521704632c17 CUFX213A/Peck 9780521618168 December 28, 2007 13:44
17 Centralnervous systemKinetics
Sodium valproate is well absorbed orally, highly protein bound (approximately 90%)
and undergoes hepatic metabolism to products (some of which are active), which
are excreted in the urine.
Phenobarbitoneis an effective anticonvulsant but its use is associated with signif-
icant sedation, which limits its use. It is a long-acting barbiturate that induces hepatic
enzymes and interacts with other agents (warfarin, oral contraceptives, other anti-
convulsants).
BDZs(see above) are widely used in the emergency treatment of status epilepticus
and act by enhancing the chloride-gating function of GABA.Other agents
Vigabatrin, gabapentin, lamotrigineandpregabalinare newer agents that are used
in the control of persistent partial seizures.
Vigabatrinirreversibly inhibits GABA-transaminase, the enzyme responsible for
the breakdown of GABA and therefore its duration of action is about 24 hours while
its elimination half-life is only 6 hours. It is excreted unchanged in the urine. It
interacts with phenytoin reducing its concentration by about 25% by an unknown
mechanism. It may cause sedation, fatigue, headache, agitation and depression.
Lamotrigineacts on the presynaptic neuronal membrane and stabilizes the inac-
tive Na+channel leading to a reduction in excitatory neurotransmitter release. It
undergoes hepatic metabolism to an inactive conjugate. Its rate of metabolism is
increased by other enzyme-inducing drugs (carbamazepine and phenytoin) but
reduced by sodium valproate. It may precipitate headache, nausea, diplopia, ataxia
and tremor. Approximately 0.1% of adults develop Stevens–Johnson or Lyell’s syn-
drome. The incidence is higher in children.
Gabapentin’smode of action is uncertain but it may bind to Ca^2 +channels within
the brain. It is not plasma protein bound and has a terminal elimination half-life of
5–7 hours. It is excreted unchanged in the urine and does not interfere with other
anticonvulsants as it does not affect hepatic enzyme systems. It is well tolerated.
Gabapentin also has a role to play in the management of chronic pain.
Pregabalinis a potent ligand for the alpha-2-delta subunit of voltage-gated cal-
cium channels in the central nervous system. Once bound there is a reduction in
calcium influx leading to a reduction of excitatory neurotransmitter release. It is a
structural analogue of gamma-aminobutyric acid (GABA – although it bears no phar-
macological resemblance to GABA) and is prepared as the S-enantiomer. Its kinetics
are predictable and its oral bioavailability is >90% and it readily crosses the BBB. Its
terminal elimination half-life is 6 hours. In a manner similar to gabapentin it is not
metabolized so that it does no interact with other anticonvulsants. It is excreted in
the urine unchanged.