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Pharmacological Classification: Anticonvulsant (Antiepileptic).
Pharmacology: Pharmacodynamics: Mechanism of Action: Topiramate is an antiepileptic agent classified as a sulfamate-substituted monosaccharide.
Three pharmacological properties of topiramate have been identified that may contribute to its anticonvulsant activity: Topiramate reduces the frequency at which action potentials are generated when the neurons are subjected to a sustained depolarisation indicative of a state-dependent blockade of voltage-sensitive sodium channels.
Topiramate markedly enhances the activity of GABA at some types of GABA receptors, thereby enhancing GABA-induced influx of chloride into neurons.
Topiramate weakly antagonises the excitatory activity of kainate/AMPA subtype of glutamate receptor but has no apparent effect on the activity of N-methyl-D-aspartate (NMDA) at the NMDA receptor subtype.
Topiramate also inhibits some isoenzymes of carbonic anhydrase, This pharmacological effect is generally weak and may not be a major contributing factor to the antiepileptic activity of topiramate.
Pharmacokinetics: Topiramate is well absorbed after oral administration. The relative bioavailability is about 80%. Food does not affect the bioavailability of topiramate. Protein binding is low, 13 to 17%. The time to peak concentration (Tmax) is approximately 2 hours following administration of a 400 mg oral dose. The volume of distribution is 0,6-0,8 L/kg with values for women circa 50% of those for males. In patients with normal renal function, steady state is reached in about 4 days. The pharmacokinetics of topiramate are linear, with dose-proportional increases in plasma concentration over the range of 200 to 800 mg a day. The mean elimination half-life (t½) is 21 hours, following single or multiple dosing. Approximately 70% of an administered dose is excreted unchanged in the urine and the remainder undergoes metabolism by hydroxylation, hydrolysis and glucuronidation with no one metabolite accounting for more than 5% of an oral dose. Topiramate clearance is reduced by 42% in patients with moderate renal function impairment and by 54% in patients with severe renal impairment as compared with the clearance in subjects with normal renal function. Children exhibit a higher clearance and shorter elimination half-life than adults.
Consequently, the plasma concentration of topiramate for the same mg/kg dose may be lower in children compared to adults. The clearance of topiramate may be decreased in patients with impaired hepatic function.
