Chapter 21: Pharmacotherapy of the Epilepsies

INTRODUCTION

Epileptic seizures often cause transient impairment of consciousness, leaving the individual at risk of bodily harm and often interfering with education and employment. Therapy is symptomatic: Available drugs inhibit seizures, but neither effective prophylaxis nor cure is available. The mechanisms of action of antiseizure drugs fall into 3 major categories:

1. Limiting the sustained, repetitive firing of neurons, an effect mediated by promoting the inactivated state of voltage-activated Na⁺ channels

2. Enhancing synaptic inhibition mediated γ-aminobutyric acid (GABA), a drug effect that may occur via presynaptic or postsynaptic action

3. Inhibition of voltage-activated Ca²⁺ channels responsible for T-type Ca²⁺ currents

Drugs effective against the most common forms of epileptic seizures, partial and secondarily generalized tonic-clonic seizures, appear to work by one of the first two mechanisms. Drugs -effective against the less common absence seizure work by the third mechanism.

TERMINOLOGY AND EPILEPTIC SEIZURE CLASSIFICATION

The term seizure 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 periodic and unpredictable occurrence of seizures. Seizures are thought to arise from the cerebral cortex, not from other CNS structures. Epileptic seizures are classified as partial seizures, those beginning focally in a cortical site, and generalized seizures, those that involve both hemispheres widely from the outset. The behavioral manifestations of a seizure are determined by the functions normally served by the cortical site at which the seizure arises. For example, a seizure involving motor cortex is associated with clonic jerking of the body part controlled by this region of cortex. A simple partial seizure is associated with preservation of consciousness. A complex partial seizure is associated with impairment of consciousness. The majority of complex partial seizures originate from the temporal lobe. Examples of generalized seizures include absence, myoclonic, and tonic-clonic. The type of epileptic seizure is one determinant of the drug selected for therapy. Table 21–1 presents more detailed information on the classification of seizures and available medications.