138 ANTI-EPILEPTICS
Pharmacokinetics
Oralclonazepamis well absorbed and the t1/2is about 30 hours.
Neither therapeutic nor adverse effects appear to be closely
related to plasma concentrations. Control of most types of
epilepsy occurs within the range 30–60 ng/mL. Clonazepamis
extensively metabolized to inactive metabolites.
VIGABATRIN
Use
Vigabatrin, a structural analogue of GABA, increases the
brain concentration of GABA (an inhibitory neurotransmitter)
through irreversible inhibition of GABA transaminase. It is
reserved for the treatment of epilepsy that is unsatisfactorily
controlled by more established drugs. Lower doses should be
used in the elderly and in those with impaired renal function.
Vigabatrinshould be avoided in those with a psychiatric
history.
Adverse effects
- The most common reported adverse event (up to 30%) is
drowsiness. - Fatigue, irritability, dizziness, confusion and weight gain
have all been reported. - Behavioural side effects (e.g. ill temper) may occur.
- Psychotic reactions, including hallucinations and
paranoia, are common. - Nystagmus, ataxia, tremor, paraesthesia, retinal disorders,
visual-field defects and photophobia. Regular testing of
visual fields is recommended. The patient should be
warned to report any visual symptoms and an urgent
ophthalmological opinion should be sought if visual-field
loss is suspected.
Pharmacokinetics
Absorption is not influenced by food and peak plasma con-
centrations occur within two hours of an oral dose. In contrast
to most other anticonvulsants, vigabatrinis not metabolized
in the liver, but is excreted unchanged by the kidney and has a
plasma half-life of about five hours. Its efficacy does not corre-
late with the plasma concentration and its duration of action is
prolonged due to irreversible binding to GABA transaminase.
LAMOTRIGINE
Lamotrigine prolongs the inactivated state of the sodium
channel. It is indicated as monotherapy and adjunctive treat-
ment of partial seizures, generalized tonic–clonic seizures that
are not satisfactorily controlled with other drugs, and seizures
associated with Lennox–Gastaut syndrome (a severe, rare
seizure disorder of young people). It is contraindicated in
hepatic and renal impairment. Side effects include rashes
(rarely angioedema, Steven–Johnson syndrome and toxic epi-
dermal necrolysis), flu-like symptoms, visual disturbances,
dizziness, drowsiness, gastro-intestinal disturbances and
aggression. The patient must be counselled to seek urgent
medical advice if rash or influenza symptoms associated with
hypersensitivity develop.
GABAPENTIN
Gabapentinis licensed as an ‘add-on’ therapy in the treatment
of partial seizures and is also used for neuropathic pain. It is a
GABA analogue, but its mechanism of action is thought to be at
calcium channels. It is generally well tolerated; somnolence is
the most common adverse effect. It is well absorbed after oral
administration and is eliminated by renal excretion; the average
half-life is five to seven hours. It does not interfere with the
metabolism or protein binding of other anticonvulsants.TOPIRAMATE
Topiramate blocks sodium channels, attenuates neuronal
excitation and enhances GABA-mediated inhibition. It is
licensed as monotherapy and as adjunctive therapy of gener-
alized tonic–clonic and partial seizures. Topiramateinduces
cytochrome P450, and its own metabolism is induced by car-
bamazepineandphenytoin.Topiramatehas been associated
with several adverse effects on the eye. Raised intra-ocular
pressure necessitates urgent specialist advice. Other adverse
effects include poor concentration and memory, impaired
speech, mood disorders, ataxia, somnolence, anorexia and
weight loss.TIAGABINE
Tiagabineinhibits the neuronal and glial uptake of GABA.
Tiagabinehas recently been licensed as adjunctive therapy in
the UK for partial seizures with or without secondary general-
ization. Reported adverse events include dizziness, asthenia,
nervousness, tremor, depression and diarrhoea. It has a t1/2of
approximately seven hours, which may be halved by concur-
rent administration of carbamazepineandphenytoin.ETHOSUXIMIDE
Use
Ethosuximideis a drug of choice in absence seizures. It is con-
tinued into adolescence and then gradually withdrawn over
several months. If a drug for tonic–clonic seizures is being
given concurrently, this is continued for a further three years.
It may also be used in myoclonic seizures and in atypical
absences.Adverse effects
Apart from dizziness, nausea and epigastric discomfort, side
effects are rare and it appears safe. Tonic–clonic and absence
seizures may coexist in the same child. Ethosuximideis not
effective against tonic–clonic seizures, in contrast to valproate
which is active against both absence and major seizures and is
used when these coexist.Pharmacokinetics
Ethosuximideis well absorbed following oral administration.
Its plasma t1/2is 70 hours in adults, but only 30 hours in chil-
dren. Thus, ethosuximideneed be given only once daily and
steady-state values are reached within seven days. Plasma
concentration estimations are not usually required.