Chapter 20: Pharmacotherapy of the Epilepsies

INTRODUCTION

The epilepsies are common and frequently devastating disorders, affecting approximately 2.5 million people in the U.S. alone. More than 40 distinct forms of epilepsy have been identified. Epileptic seizures often cause transient impairment of awareness, leaving the individual at risk of bodily harm and often interfering with education and employment. Current therapy is symptomatic, as available antiseizure drugs (ASDs) inhibit seizures, but neither effective prophylaxis nor cure is available. Adherence to prescribed treatment regimens is a major problem because of the need for long-term therapy together with unwanted effects of many drugs.

The mechanisms of action of ASDs fall into the following major categories (Porter et al., 2012):

1. Modulation of sodium, potassium, or calcium ion channels. This can include prolongation of the inactivated state of voltage-gated Na⁺ channels, positive modulation of K⁺ channels, and inhibition of Ca²⁺ channels.

2. Enhancement of γ-aminobutyric acid (GABA) neurotransmission through actions on GABA_A receptors, modulation of GABA metabolism, or inhibition of GABA reuptake into the synaptic terminal.

3. Modulation of synaptic release through actions on the synaptic vesicle protein SV2A or Ca²⁺ channels containing the α2δ subunit.

4. Diminishing synaptic excitation mediated by ionotropic glutamate receptors (e.g., α-amino-3-hydroxy 5-methyl-4-isoxazolepropionic acid [AMPA] receptors).

Despite these broad classifications, it is noteworthy that many ASDs act through mechanisms distinct from the primary known mode of action. Furthermore, ASDs with similar mechanistic categories may have disparate clinical uses.

Although many treatments are available, much effort is being devoted to elucidating the genetic causes and the cellular and molecular mechanisms by which a normal brain becomes epileptic, insights that promise to provide molecular targets for both symptomatic and preventive therapies.

ABBREVIATIONS

TERMINOLOGY AND EPILEPTIC SEIZURE CLASSIFICATION

The term seizure (from the Latin sacire meaning “to take possession of”) refers to a transient alteration of behavior due to the disordered, synchronous, and rhythmic firing of populations of brain neurons. The term epilepsy refers to a disorder of brain function characterized by the risk of periodic and unpredictable occurrence of seizures. Seizures can be “nonepileptic,” when evoked in a normal brain by treatments such as electroshock or chemical convulsants, or “epileptic,” when occurring without evident provocation. While agents in current clinical use inhibit seizures, whether any of these prevent the development of epilepsy (epileptogenesis) is uncertain.

Seizures are generally thought to arise from the cerebral cortex and not from other central nervous system (CNS) structures such as the thalamus, brainstem, or cerebellum. Recently, the classification for epileptic ...