4.7.7 GABAergic Drugs: AnticonvulsantsBenzodiazepines and barbiturates are used as anticonvulsant drugs in the treatment of
epilepsy. Epilepsy, a medical disorder characterized by recurrent seizures, has many
different forms. The four most common seizure types are generalized tonic–clonic
seizures (old name: grand mal seizures), generalized absence seizures (petit mal
seizures), complex partial seizures (psychomotor or temporal lobe seizures), and simple
partial seizures (focal seizures).
The drug of choice for generalized tonic–clonic seizures is an iminostilbene deriva-
tive called carbamazepine (1.5), with hydantoins such as phenytoin (4.194) being a
close second. Other drugs useful in the treatment of simple partial, complex partial, and
generalized tonic–clonic seizures include valproic acid (4.132), topiramate (4.195),
lamotrigine (4.196), vigabatrin (4.168), gabapentin (4.197), tiagabine (4.170), pheno-
barbital (4.198), and primidone (4.199). The drug of choice for absence epilepsy is
ethosuximide (4.200), with valproic acid (4.132), clobazam (4.185), lamotrigine
(4.196), and topiramate (4.195) being acceptable alternatives. Vigabatrin can actually
worsen absence seizures.
These various drugs have differing mechanisms of action. Carbamazepine and
phenytoin block the voltage-gated sodium channel. In addition, carbamazepine may
increase available adenosine A 1 receptors; it has been proposed that adenosine is a nat-
ural anticonvulsant. Lamotrigine also blocks the voltage-gated sodium channel, but in
addition decreases brain levels of glutamate. Topiramate likewise blocks the sodium
channel, as well as being a GABAAagonist, a glutamate antagonist (at the AMPA site),
and a carbonic anhydrase inhibitor. Phenobarbital binds to the GABAAreceptor and, at
high concentrations, also blocks the voltage-gated sodium channel; primidone is meta-
bolically converted to phenobarbital in the liver following its administration. Valproic
acid blocks the voltage-gated sodium channel and the T-type Ca^2 +channel at routine
NEUROTRANSMITTERS AND THEIR RECEPTORS 279