Oxazolidinediones

OXAZOLIDINEDIONES

Trimethadione, the first oxazolidinedione (Figure 24–3), wasintroduced as an antiseizure drug in 1945 and remained the drug of choice for absence seizures until the introduction of succinim-ides in the 1950s. Use of the oxazolidinediones—trimethadione, paramethadione, and dimethadione—is now very limited; the lat-ter two are not readily available.These compounds are active against pentylenetetrazol-induced seizures. Trimethadione raises the threshold for seizure discharges after repetitive thalamic stimulation. It—or, more notably, its active metabolite dimethadione—has the same effect on thalamic Ca²⁺ currents as ethosuximide (reducing the T-type Ca²⁺ current). Thus, suppression of absence seizures is likely to depend on inhib-iting the pacemaker action of thalamic neurons.Trimethadione is rapidly absorbed, with peak levels reached within 1 hour after drug administration. It is not bound to plasma proteins. Trimethadione is completely metabolized in the liver by demethylation to dimethadione, which may exert the major antiseizure activity. Dimethadione has an extremely long half-life (240 hours). The therapeutic plasma level range for trimethadione has never been established, although trimethadi-one blood levels higher than 20 mcg/mL and dimethadione levels higher than 700 mcg/mL have been suggested. A dosage of 30 mg/kg/d of trimethadione is necessary to achieve these levels in adults.The most common and bothersome dose-related adverse effect of the oxazolidinediones is sedation. Trimethadione has been asso-ciated with many other toxic adverse effects, some of which are severe. These drugs should not be used during pregnancy.