Classical antiseizure agents conform to the general structure shown above, and are divided into 4 classes, the barbiturates, the hydantoins, the oxazolidinediones and the succinimides. In general, the structure of the R1 and R2 substituents determine the specificity of the compound. When these two substituents are both lower alkyls such as methyl, ethyl, etc., the compounds tend to be used for absence seizures, but not in generalized tonic/clonic seizures. If one or both of these substituents is aromatic, the compounds are active against generalized tonic/clonic seizures, and are inactive against absence seizures.
Barbiturates.
The general structure of the barbiturates is shown below. Although used primarily for their sedative/hypnotic activity, barbiturates also have good activity against grand mal and partial seizures. There are two useful analogues, phenobarbital (R1 = H, R2 = ethyl and R3 = phenyl) and mephobarbital (R 1 = methyl, R2 = ethyl and R3 = phenyl), which is metabolized by N-methylation to its active constituent, phenobarbital.
Hydantoins.
The general structure for the hydantoins is shown in the figure directly above. The most familiar agent in this class (R 1 = H, R2 = R3 = phenyl) is phenytoin (Dilantin), which has low water solubility, and is a weaker acid than barbituric acid. Phenytoin is used for all types of seizure except absence, and produces a low degree of sedation. More about phenytoin later.....
Oxazolidinediones.
Trimethadione (below) is the only oxazolidinedione that is currently available, and it is seldom used. It is active against absence seizures.
Succinimides.
There are two significant succinimides, phensuximide (Milontin) (R1 = methyl, R2 = H, R3 = phenyl) and ethosuximide (Zarontin) (R1 = H, R2 = ethyl, R3 = methyl). Because of lower alkyl substituents, ethosuximide is used occasionally for absence seizures.
Over the past 5 years, a handful of new agents have been approved for use as antiseizure medications. Fosphenytoin is a pro-drug form of phenytoin, and is rapidly cleaved by phosphatases in vivo to form phenytoin, as shown below. Fosphenytoin has minimal activity before it is cleaved, but is a water soluble drug form which is suitable for intravenous injection. This preparation will be used to avoid the venous irritation produced when using parenteral phenytoin for status epilepticus (or other IV applications of the drug).
In addition to fosphenytoin, three new antiseizure compounds have been marketed since 1993, felbamate, gabapentin and lamotrigine (shown below).
Felbamate appears to act by reducing seizure spread, and by raising the seizure threshold. Gabapentin, which was synthesized as an analogue of gamma-aminobutyric acid (GABA) but has no gabaergic activity, acts by an unknown mechanism. Lamotrigine inhibits the release of excitatory neurotransmitters, primarily glutamate, by blocking the voltage dependent sodium channels, thereby stabilizing the presynaptic membrane.
The drug known as tiagabine (Gabatril) reportedly blocks GABA reuptake as the major mode of anticonvulsant activity. The drugs zonisamide (Zonagran) and topiramate (Topomax) are characterized by their acidic sulfonamide or sulfateamino groups, respectively, which are relatively small, and they also possess bulky hydrophobic groups at the other end of their structure. These compounds both appear to act as sodium channel blockers. Zonisamide also blocks calcium T-channels, while topiramate increases the effect of GABA while serving as an antagonist at kainic acid/AMPA receptors. All three of the drugs above are used for partial seizures. Topiramate can also be used off-label in the treatment of migraine.
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