Topiramate is rapidly absorbed (about 2 hours) and is 80% bioavailable. There is minimal food effect on absorption, minimal (15%) plasma protein binding, and only moderate (20–50%) metabolism; no active metabolites are formed. The drug is primarily excreted in the urine (50–80% is unchanged). The monotherapy half-life is 20–30 hours, but drops to 12–15 hours when administered with concomitant enzyme-inducing drugs. Immediate-release formulations are usually administered in two daily doses. Extended-release formulations are available that have been approved for once-daily administration. Although increased levels are seen with renal failure and hepatic impairment, there is no age or gender effect, no autoinduction, and no inhibition of metabolism, and kinetics are linear. Drug interactions 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 alternative modes of contraception are recommended in women taking more than 200 mg/d; however, oral contraceptives with a higher content of ethinyl estradiol (50 mcg) may be satisfactory.
Zonisamide is a broad-spectrum antiseizure drug that is effective for focal and generalized tonic-clonic seizures in adults and children and may also be effective in some myoclonic epilepsies and in infantile spasms. There are reports of improvement in generalized onset tonic-clonic seizures and atypical absence seizures.
There is little information on the mechanism of action of zonisamide. Although it does block voltage-gated sodium channels, other actions may also contribute to its antiseizure activity. Zonisamide has high bioavailability, modest protein binding (>50–60%), and a half-life of 1–3 days, so it can be administered once daily. The drug is extensively metabolized by acetylation to form N-acetyl-zonisamide, which is excreted in the urine unchanged, and by CYP3A4 to form 2-sulfamoylacetylphenol, which is excreted as the glucuronide. Maintenance doses are 200–400 mg/d in adults (maximum 600 mg/d) and 4–8 mg/kg/d in children (maximum 12 mg/kg/d). Adverse effects include drowsiness, cognitive impairment, renal stones, and potentially serious skin rashes. Zonisamide has no clinically significant effects on the pharmacokinetics of other antiseizure drugs. However, antiseizure drugs such as carbamazepine, phenytoin, and phenobarbital that induce CYP3A4 increase the clearance of zonisamide, shortening its half-life; concomitant use with CYP3A4-inducing agents may therefore require an increase in zonisamide dose. Zonisamide, like topiramate, contains sulphur: zonisamide is a sulfonamide, whereas topiramate contains the same sulfonamide structure but is strictly a sulfamate. They have similar pharmacologic actions, including carbonic anhydrase inhibition like acetazolamide, which is also a sulfonamide. Both zonisamide and topiramate are associated with weight loss. They also both (rarely) cause kidney stones and oligohydrosis. Whether these actions are related to the common sulfonamide structure is not known.
Ethosuximide and valproate are effective and well-tolerated treatments for generalized absence seizures in childhood absence epilepsy; lamotrigine is possibly effective. Ethosuximide is considered in this section along with trimethadione, which is of historical interest.