Topiramate
Topiramate
is a recent entrant and is recommended as adjunc-tive therapy for adults with
partial seizures. It is a sulfamate-substituted monosaccharide, and blocks
action potentials and increases the frequency with which GABA activates GABA(A)
receptors. Topiramate also antagonises the ability of kainate to activate the
kainate/AMPA (alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid;
non-NMDA) subtype of excitatory amino acid (glutamate) receptor, but has no
apparent effect on the activity of N-methyl-D-aspartate (NMDA) receptor
subtype.
Adverse
effects include lethargy, confusion, anxiety, depression, vertigo, tremor, ataxia,
diplopia, nystagmus, paraesthesia, speech disorders, anorexia, fatigue, weight
loss, and nephrolithiasis.
The
recommended total daily dose of topiramate as adjunc-tive therapy is 400 mg/day
in two divided doses. It is recom-mended that therapy be initiated at 50 mg/day
and titrated to an effective dose.
The
oral absorption of topiramate is rapid, with peak plasma concentrations
occurring at approximately 2 hours. Topiramate is only minimally bound to
plasma proteins (approximately 13 to 17%). Volume of distribution is 0.6 to 0.8
L/kg. Topiramate is not metabolised to a significant extent. Most of an oral
dose appears in the urine unchanged (approximately 70%). The plasma elimination
half-life is 18 to 24 hours after oral admin-istration, and is not dose dependant.
Overdose
information is limited. Generalised seizures, metabolic acidosis, and coma have
been reported following topiramate overdose ingestions.
Topiramate
has demonstrated teratogenicity in experimental animal studies. Embryotoxicity
and foetotoxicity have also been observed. No long-term carcinogenicity studies
have been carried out in humans. Mice have developed bladder tumours at doses
of 300 mg/kg topiramate for 21 months.
Treatment
of overdose is symptomatic and supportive.Topiramate is cleared by
haemodialysis. However, there is little experience in the use of haemodialysis
for patients with topiramate poisoning, and clinical indications for its use in
patient management are unclear.
Autopsy
findings in one case of overdose fatality revealed pulmonary oedema, mucous
plugging of the small airways, and cerebral oedema.
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