Antiseizure drugs oxazolidinedione

Trimethadione, the first oxazolidinedione (Figure 24-3), was introduced as an antiseizure drug in 1945 and remained the drug of choice for absence seizures until the introduction of succinimides in the 1950s. Use of the oxazolidinediones (trimethadione, paramethadione, and dimethadione) is now very limited. 

The oxazolidinediones contain an oxazolidine heterocyclic ring (Figure 24-1) and are similar in structure to other antiseizure drugs introduced before 1960. The structure includes only short-chain alkyl substituents on the heterocyclic ring, with no attached phenyl group. 

Trimethadione is rapidly absorbed, with peak levels reached within an hour after drug administration. It is distributed to all perfused tissues, with a volume of distribution that approximates that of total body water. It is not bound to plasma proteins. Trimethadione is completely metabolized in the liver by demethylation to 5,5-dimethyl-2,4-oxazolidinedione (dimethadione), which may exert the major antiseizure activity. The clearance of dimethadione is 0.08 L/kg/d this metabolite has an extremely long half-life (240 hours). 

Because oxazolidinediones are toxic, an extensive search was undertaken to replace them with less toxic drugs. Substituting the ring O in the oxazolidinediones with a methylene group gave the antiseizure succinimides. The clinically used succinimides include ethosuximide, methsuximide, and phensuximide, which were introduced between 1951 and 1958 (Fig. 20.11) and widely accepted for the treatment of absence seizures. 

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