Chronic antiseizure drug administration prevents the occurrence of seizures, which can, on occasion, be life threatening. Therefore, adequate drug exposure must be continuously maintained. However, many antiseizure drugs also have a narrow therapeutic window; dosing must therefore avoid excessive, toxic exposure. An understanding of the pharmacokinetic properties of the drugs is essential. It is also necessary for the clinician to be cognizant of special factors that affect dosing; these factors include nonlinear relationships between dose and drug exposure and the influence of hepatic or renal impairment on clearance (see Chapters 3 and 4). Further, drug-drug interactions occur with many of the agents—a special issue since the drugs are often used in combination. For some antiseizure drugs, drug-drug interactions are complex (see Chapter 66). For example, addition of a new drug may affect the clearance of the current medication such that the dose of the current medication must be modified. Further, the current medication may necessitate a different dosing of the new drug—different from dosing in a drug-naïve subject. Many antiseizure drugs are metabolized by hepatic enzymes, and some, such as carbamazepine, oxcarbazepine, eslicarbazepine acetate, phenobarbital, phenytoin, and primidone, are strong inducers of hepatic cytochrome P450 and glucuronyl transferase enzymes. A new antiseizure drug may increase the concentration of an existing drug by inhibiting its metabolism; alternatively, the new drug may reduce the concentration by inducing the metabolism of the existing drug. Other antiseizure drugs are excreted in the kidney and are less susceptible to drug-drug interactions. Some antiseizure drugs have active metabolites. The extent of conversion to the active forms can be affected by the presence of other drugs. Some antiseizure drugs, such as phenytoin, tiagabine, valproate, diazepam, and perampanel, are highly (>90%) bound to plasma proteins. These drugs can be displaced from plasma proteins by other protein-bound drugs, resulting in a temporary rise in the free fraction. Since the free (unbound) drug is active, there can be transient toxicity. However, systemic clearance increases along with the increased free fraction, so the elevation in free concentration is eventually corrected. Some antiseizure drugs, notably levetiracetam, gabapentin, and pregabalin, are not known to have drug interactions. Antiseizure drugs can also interact with other medications. Importantly, oral contraceptive levels may be reduced by strong inducers, resulting in failure of birth control.
Presynaptic terminal Phenytoin, carbamazepine, of glutamate neuron lamotrigine, lacosamide, zonisamide, oxcarbazepine
Gabapentin, ˜2° subunit of P/Q-type Ca2+ channel
Na+, Ca2+ Na+, (Ca2+)
Presynaptic terminal of GABA neuron Astrocyte