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Chapter: Basic & Clinical Pharmacology : Antiseizure Drugs


Topiramate is a substituted monosaccharide that is structurally different from all other antiseizure drugs.


Topiramate is a substituted monosaccharide that is structurally different from all other antiseizure drugs.

Mechanism of Action

Topiramate blocks repetitive firing of cultured spinal cord neu-rons, as do phenytoin and carbamazepine. Its mechanism of action, therefore, is likely to involve blocking of voltage-gated Na+ channels. It also acts on high-voltage activated (L-type) Ca2+ chan-nels. Topiramate potentiates the inhibitory effect of GABA, acting at a site different from the benzodiazepine or barbiturate sites. Topiramate also depresses the excitatory action of kainate on glu-tamate receptors. The multiple effects of topiramate may arise through a primary action on kinases altering the phosphorylation of voltage-gated and ligand-gated ion channels.

Clinical Uses

Clinical trials of topiramate as monotherapy demonstrated effi-cacy against partial and generalized tonic-clonic seizures. The drug is also approved for the Lennox-Gastaut syndrome, and may be effective in infantile spasms and even absence seizures. Topiramate is also approved for the treatment of migraine headaches. The use of the drug in psychiatric disorders is controversial; convincing controlled data are lacking. Dosages typically range from 200 to 600 mg/d, with a few patients tolerating dosages higher than 1000 mg/d. Most clinicians begin at a low dose (50 mg/d) and increase slowly to prevent adverse effects. Several studies have used topiramate in monotherapy with encouraging results. Although no idiosyncratic reactions have been noted, dose-related adverse effects occur most frequently in the first 4 weeks and include somnolence, fatigue, dizziness, cognitive slowing, paresthesias, nervousness, and confusion. Acute myopia and glaucoma may require prompt drug withdrawal. Urolithiasis has also been reported. The drug is teratogenic in animal models, and hypospa-dias has been reported in male infants exposed in utero to topira-mate; no causal relationship, however, could be established.


Topiramate is rapidly absorbed (about 2 hours) and is 80% bio-available. There is no food effect on absorption, minimal (15%) plasma protein binding, and only moderate (20–50%) metabo-lism; no active metabolites are formed. The drug is primarily excreted unchanged in the urine. The half-life is 20–30 hours. Although increased levels are seen with renal failure and hepatic impairment, there is no age or gender effect, no autoinduction, no inhibition of metabolism, and kinetics are linear. Drug interac-tions do occur and can be complex, but the major effect is on topiramate levels rather than on the levels of other antiseizure drugs. Birth control pills may be less effective in the presence of topiramate, and higher estrogen doses may be required.

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