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