Trimethadione is an oxazolidinedione antiseizure drug introduced in 1945. It is no longer marketed in the USA but is available elsewhere. Trimethadione is effective in the treatment of generalized absence seizures and was the drug of choice for this seizure type until the introduction of ethosuximide. Trimethadione has numerous dose-related and idiosyncratic side effects, including hemeralopia (day blindness). Because of the high propensity for side effects, trimethadione and the related oxazolidinediones paramethadione and dimethadione, the major metabolite of trimethadione, are now rarely used.
Valproate is the drug of first choice for the treatment of myoclonic seizures. Other drugs effective in the treatment of this seizure type are levetiracetam, zonisamide, topiramate, and lamotrigine.
Valproate in combination with lamotrigine and a benzodiazepine is the most widely used treatment for atonic seizures. Topiramate, felbamate, and lamotrigine are used in the treatment of Lennox-Gastaut syndrome; clinical trials have shown improvement in atonic seizures. The sodium channel-blocking antiseizure drugs phenobarbital and vigabatrin should be used with caution because they may worsen atonic seizures. Clobazam and rufinamide, discussed in this section, are also used in the treatment of seizures associated Lennox-Gastaut syndrome and have been demonstrated in clinical trials to reduce the frequency of atonic seizures.
Clobazam is widely used for the treatment of focal seizures in many countries, although it is not approved for that indication in the United States, where its only approved use is for treatment of seizures associated with Lennox-Gastaut syndrome in patients 2 years of age or older. Clobazam is a 1,5-benzodiazepine and structurally different from other marketed benzodiazepines, which are 1,4-benzodiazepines. Like the 1,4-benzodiazepines, however, clobazam is a positive allosteric modulator of GABAA receptors and has similar pharmacologic activities and adverse effects. In addition, while tolerance occurs to clobazam in animal models within days to weeks of chronic administration, retrospective studies assessing the extent of tolerance in the clinical setting have suggested that tolerance is not a prominent issue in clinical treatment. Side effects that occur in a dose-dependent fashion include somnolence and sedation, dysarthria, drooling, and behavioral changes, including aggression. Withdrawal symptoms may occur with abrupt discontinuation. Clobazam has a half-life of 18 hours and is effective at dosages of 0.5–1 mg/kg/d. Clobazam is metabolized in the liver by CYP and non-CYP transformations, with up to 14 metabolites; however, the major metabolite is desmethylclobazam (norclobazam). With long-term administration of clobazam, levels of norclobazam, which has a longer half-life than clobazam, are 8to 20-times higher than those of the parent.
Norclobazam has antiseizure activity, although it is weaker than clobazam. Nevertheless, because norclobazam levels are so much higher at steady state, seizure protection during chronic therapy is likely mainly due to norclobazam. Clobazam is a moderate inhibitor of CYP2D6 and has been shown to significantly increase the levels of drugs metabolized by this isoenzyme such as phenytoin and carbamazepine. Reduced dosing may be required when these antiseizure drugs are used in combination with clobazam.