Chapter 17

### INTRODUCTION

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.

### HISTORY OF DEVELOPMENT

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.

### MECHANISM OF ACTION

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

###### Figure 17–1

Mechanisms of action for selected antiepileptic drugs. AMP, α-amino-hydroxy-5-methylisoxazole-4-propionic acid; GABA, γ-aminobutyric acid; NMDA, ...

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