Epimate-50 Mechanism of Action

Pharmacology: Pharmacodynamics: Mechanism of Action: The precise mechanism by which topiramate exerts its antiseizure effect is unknown; however, electrophysiological and biochemical studies of the effects of topiramate on cultured neurons have revealed three properties that may contribute to topiramate's antiepileptic efficacy. First, action potentials elicited repetitively by a sustained depolarization of the neurons are blocked by topiramate in a time-dependent manner, suggestive of a state-dependent sodium channel blocking action. Second, topiramate increases the frequency at which γ-aminobutyrate (GABA) activates GABAA receptors, and enhances the ability of GABA to induce a flux of chloride ions into neurons, suggesting that topiramate potentiates the activity of this inhibitory neurotransmitter. This effect was not blocked by flumazenil, a benzodiazepine antagonist, nor did topiramate increase the duration of the channel open time, differentiating topiramate from barbiturates that modulate GABAA receptors. Third, topiramate antagonizes the ability of kainate to activate the kainate/AMPA (α-amino-3-hydroxy-5-methylisoxazole-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) at the NMDA receptor subtype. These effects of topiramate are concentration-dependent within the range of 1 μM to 200 μM.
Topiramate also inhibits some isoenzymes of carbonic anhydrase (CA-II and CA-IV). This pharmacologic effect is generally weaker than that of acetazolamide, a known carbonic anhydrase inhibitor, and is not thought to be a major contributing factor to topiramate's antiepileptic activity.
Topiramate has anticonvulsant activity in rat and mouse maximal electroshock seizure (MES) tests. Topiramate is only weakly effective in blocking clonic seizures induced by the GABAA receptor antagonist, pentylenetetrazole. Topiramate is also effective in rodent models of epilepsy, which include tonic and absence-like seizures in the spontaneous epileptic rat (SER) and tonic and clonic seizures induced in rats by kindling of the amygdala or by global ischemia.
Pharmacokinetics: Topiramate is readily absorbed after oral doses, with peak plasma concentrations achieved after 2 hours. Bioavailability is not affected by the presence of food. Protein binding is about 9 to 17%. The volume of distribution in women is approximately half that in men. Topiramate crosses placental barrier and is distributed in breast milk.
In healthy subjects topiramate is not extensively metabolized; however, up to 50% of a dose may undergo metabolism in the liver in patients receiving enzyme-inducing drug concomitantly. It is eliminated chiefly in urine; as unchanged drug and metabolites; mean plasma elimination half-life is about 21 hours. Steady-state concentrations are achieved after 4 to 8 days in patients with normal renal function. Clearance is decreased in patients with impaired renal or hepatic function, and steady-state plasma concentrations may not be achieved for 10 to 15 days in the former. Children exhibit a higher clearance and shorter elimination half-life than adults.
The pharmacokinetics of topiramate may be affected by concurrent administration of other antiepileptics.