For anesthesiologists, a working knowledge of antiepileptic mechanisms of action is helpful when caring for patients with known or suspected seizure disorders. This chapter provides a brief overview of how antiepileptics work and how to use them when managing a seizure in the perioperative period.

Although potassium bromide was the original antiepileptic drug discovered in 1857, treatment of epilepsy began in earnest with the discovery of the anticonvulsant effects of phenobarbital. Although barbiturates had been first synthesized in 1864, Alfred Hauptmann, a young resident psychiatrist in 1912, was often awoken at night when epileptic patients fell out of bed while having tonic-clonic seizures. He administered phenobarbital, thinking it was a sedative, so patients would sleep through the night. He discovered that they had fewer seizures during the night and into the next day.

Although effective, phenobarbital often oversedated patients. In 1936, phenytoin was introduced as a nonsedating alternative to phenobarbital. Some 30 years later, phenytoin was followed by carbamazepine, diazepam, and valproate, all introduced in the mid-1960s. All were found to be effective in treating seizures.

In 1975, the Anticonvulsant Drug Development Program was initiated in the United States and sparked the discovery of 28,000 new drugs for the treatment of epilepsy. Most of these had similar mechanisms of action, and only those with novel mechanisms, improved efficacy, and fewer side effects have been evaluated.¹ Some of the older medications have proven efficacy and are familiar to prescribers, but the newer medications have additional benefits. There is a reduction in the amount of refractory seizures, improved efficacy, and decreased side effects. Research continues on finding better drugs for the treatment of seizures.

Seizures result when the electrical balance along neuronal cell membranes renders them hyperexcitable within the central nervous system.² Treatment focuses on either augmenting inhibitory or inhibiting excitatory processes. Multiple sites may contribute to seizure activity. One postulated mechanism is an inherited change in sodium channel proteins, which makes the channel hyperexcitable. Elevated levels of glutamate and calcium may also be causes for epileptic activity. A decrease in inhibition may also result in epilepsy; for example, mutations leading to ineffective γ-aminobutyric acid (GABA) may be a possible cause. These causes of seizure activity are common targets for pharmacologic intervention.

Several groups of medications, each group with a different mechanism of action, can be used to increase seizure thresholds. Selected groups and their associated mechanism of action are presented (Figure 17–1). More than one medication may be required to control seizures; up to 50% of epilepsy patients do not have adequate control with one medication.³ To improve efficacy, multiple sodium channel blocking agents can be used simultaneously.^2,4

Sodium Channel Blockers

Conductance of neuronal action potentials is via voltage-gated sodium channels embedded in axon membranes. Antiepileptic drugs bind to the inactive configuration of sodium channels and keep them closed, decreasing conductance of action potentials. Partial seizures and tonic-clonic seizures respond to antagonism of sodium channels. Common sodium channel blocking antiepileptic drugs include carbamazepine and phenytoin. Newer blockers include lamotrigine and oxcarbazepine.

Lidocaine is also a sodium channel blocker, which has been investigated in treatment of seizures. It is thought to be both proconvulsant as well as anticonvulsant. This is dose dependent. At toxic levels, lidocaine blocks the inhibitory cortical neurons, thereby increasing cortical irritability, and it ultimately results in seizure activity prior to coma. At therapeutic doses (0.5–5.0 mg/kg), lidocaine may be an effective treatment for seizures because of its activity on the sodium channel of excitatory neruons.⁵

Calcium Channel Blockers

Voltage-gated calcium channels are found throughout neural tissue and stabilize normal rhythmic brain activity. There are several types in neural tissue; some include L-, N-, and T-type. T and L stand for “transient” and “long,” respectively, referring to the length of activation. N stands for neural or non-L. Calcium channels consist of 5 protein subunits.⁶ The α₁ subunit determines the channel type. It is sensitive to membrane voltage changes and contains the ion pore that facilitates movement of calcium ions. Several calcium channel blockers are used as antiepileptics. Lamotrigine, gabapentin, pregabalin, carbamazepine, and topiramate inactivate L-type channels. Ethosuximide, a prototype drug, inactivates T-type channels. Antagonism of T-type calcium channels is an effective treatment of absence seizures.

Both gabapentin and pregabalin work on the calcium channels by way of binding to the α₂δ ligand on the calcium channel. This results in similar action to these other medications that block the calcium channel. Both drugs are now more commonly used in the treatment of neuropathic pain but are also appropriate treatments of epilepsy.

γ-Aminobutyric Acid Receptor Agonist/Reuptake Inhibitors

GABA is a naturally occurring inhibitory neurotransmitter that regulates neuronal excitability throughout the central nervous system. GABA exerts an effect through receptors embedded in nerve cell membranes in the presynaptic and postsynaptic regions of a synaptic cleft. GABA receptors allow negatively charged chloride ions to flow into cells and positively charged potassium ions to flow out of cells. This ion flux hyperpolarizes neurons decreasing their ability to reach an action potential. GABA is cleared from the synaptic cleft by transport proteins and is then either recycled or metabolized by GABA-transaminase.^2,3

Several antiepileptic drugs exert their action on the GABA system. GABA agonists include benzodiazepines and phenobarbital. Benzodiazepines mimic GABA and increase the frequency, whereas phenobarbital increases the duration of GABA ion channel opening. Topiramate and felbamate activate the GABA receptors with similar effects. Tiagabine blocks transporter proteins, reducing GABA reuptake. Vigabatrin prevents GABA metabolism by antagonizing GABA-transaminase. Both of these processes thereby increase the amount of GABA available for activity. Although not well understood, gabapentin, lamotrigine, and valproate all increase GABA concentrations via unknown mechanism.^2,6

Reduction in Glutamate-Mediated Excitation

The most important excitatory neurotransmitters include glutamate and aspartate. Excitation occurs by glutamate binding to glutamate receptors, resulting in an increase of sodium and calcium into and potassium out of neural cells. Glutamate can be targeted either by reducing its release from synaptic vesicles or blocking its action at the ligand-gated ion channel it binds. There are 5 binding sites on glutamate receptors, and 2 of these are α-amino-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) and N-methyl-d-aspartate (NMDA).² Antiepileptic drugs inhibit glutamate activity via the AMPA binding site (topiramate) and the NMDA binding site (felbamate and magnesium).³

Ketamine is a common anesthetic used for the management of pain in the operating room. It is a known NMDA antagonist. The data about its effects in epilepsy are conflicting.

Other Mechanisms of Action

Newer drugs have unique mechanisms of action. For example, pregabalin, like gabapentin, is structurally related to GABA and originally thought to mimic GABA. However, these agents do not influence the GABAergic system. They bind to a subunit of calcium channels, the α₂δ site, reducing calcium influx and decreasing release of excitatory neurotransmitters.³ Another example is levetiracetam, which binds to a specific synaptic vesicle protein. It has little effect on normal neural function but effectively suppresses epilepsy.²

Dosing regimens for common antiepileptic medications are presented in Table 17–1.² This table includes medications used to treat chronic epilepsy and to treat seizures perioperatively.