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Chapter: Modern Medical Toxicology: Neurotoxic Poisons: Anticonvulsants and Antiparkinsonian Drugs

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Topiramate - Anticonvulsant (Anti-Epileptic) Drug

Topiramate is a recent entrant and is recommended as adjunc-tive therapy for adults with partial seizures.

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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