contains 100 billion neurons. When a neuron is injured it may either “hypofunction,”
producing paralysis, or “hyperfunction,” producing seizures. Any insult to a neuron
within the brain’s outer cortex layer has the capacity to produce seizures. Since anti-
convulsants are designed to block the aberrant spread of electrical activity within the
brain (much like antiarrhythmics are designed to block the aberrant spread of electrical
activity within the heart), most molecules traditionally developed as anticonvulsants
function as Na+channel blockers. The parallel similarities between anticonvulsants and
antiarrhythmics—and even local anesthetics—are supported by a variety of other data.
Some anticonvulsants (e.g., phenytoin) have been exploited for potential antiarrhythmic
activity; some antiarrhythmics (e.g., mexiletine) have been studied as potential anti-
convulsants. Certain anticonvulsants (e.g., carbamazepine) may produce cardiac
arrhythmias as side effects. Lidocaine, which is both a local anesthetic and an antiar-
rhythmic, has been used clinically as an anticonvulsant to treat seizures during status
epilepticus(prolonged [>30 min] uncontrolled seizure activity); during status epilepti-
cus, the structural integrity of the blood–brain barrier is compromised, enabling lido-
caine to enter the brain, which it would not normally be able to achieve.
The majority of the time-honored anticonvulsant molecules (phenytoin, carba-
mazepine, valproic acid) exert their therapeutic effects via blockade of the voltage-
gated Na+channel. Other traditional anticonvulsant drugs, such as phenobarbital (which
normally functions by binding to the GABA-A chloride channel), bind and inhibit the
voltage-gated Na+channel when given in large doses (e.g., 20 mg/kg loading dose) for
neurological emergencies such as status epilepticus. A significant number of recently
introduced anticonvulsant drugs (lamotrigine, topiramate) also inhibit the voltage-gated
Na+channel protein. However, it is important to remember that there are a small number
of anticonvulsants that do not block the Na+channel; these latter agents include viga-
batrin, gabapentin, lorazepam, and clobazam.
Structural and theoretical chemistry studies of phenytoin and carbamazepine suggest
that they bind to the Na+channel via a pharmacophore that consists of an aromatic ring and
an amide linkage. This pharmacophore consists of two of the three structural features
found in local anesthetics. The ionizable group, which is characteristic of local anesthetics,
precludes the ability to diffuse across the blood–brain barrier.
422 MEDICINAL CHEMISTRY