Chapter 48: Antiepileptics

HISTORY AND EPIDEMIOLOGY

Epilepsy affects 6 per 1,000 population in the United States.⁵⁴ More than 50 distinct epileptic syndromes are identified; they are categorized into partial (60%) and generalized (40%) epilepsies.³¹ Partial epileptic seizures arise from localized cortical sites, and generalized epileptic seizures involve both cerebral hemispheres.³¹

Historically, seizures were treated by a variety of methods, including ketogenic diets, fluid restriction, and surgical excision of scars or irritable cortical foci.¹¹⁸ The first truly effective antiepileptic therapy was introduced in 1857, when the administration of bromides was noted to sedate patients and significantly reduce their seizures.¹¹⁸ Phenobarbital, a sedative–hypnotic, was first used to treat seizures in 1912. Most of the subsequently introduced antiepileptics, such as primidone (2-desoxyphenobarbital), had chemical structures similar to that of phenobarbital, and sedation was erroneously believed to be an essential component of antiepileptic therapy.

The search for nonsedating antiepileptics led to the introduction of phenytoin in 1938 and benzodiazepines, carbamazepine, and valproic acid (VPA) in the 1960s. These antiepileptics were the only medications available until the 1990s, when second-generation antiepileptics were introduced: gabapentin, lamotrigine, levetiracetam, oxcarbazepine, tiagabine, topiramate, felbamate, vigabatrin, lacosamide, and zonisamide.

Broad-spectrum antiepileptics are effective in the management of all seizure types. Narrow-spectrum antiepileptics are restricted to patients who have partial (localized) epilepsy with partial or secondarily generalized seizures.⁵⁴ Antiepileptics are also currently used for a host of disorders, including psychiatric illnesses, refractory pain, drug withdrawal syndromes, migraines, cluster headaches, spasms, and chronic cough. Based on reports, in 2009, the Food and Drug Administration issued a warning about increased risk of suicidal thoughts or actions following treatment with carbamazepine, lamotrigine, levetiracetam, oxcarbazepine, phenytoin, tiagabine, topiramate, valproic acid, and zonisamide.^25,50,88

Carbamazepine, lamotrigine, oxcarbazepine, and valproic acid are associated with pregnancy complications such as preeclampsia, premature births, spontaneous abortions, and stillbirths.^8,12

This chapter reviews the toxicity and management of overdoses with antiepileptics other than the benzodiazepines and barbiturates, which are discussed in Chap. 72.

PHARMACOLOGY

The mechanisms of action of antiepileptics include (1) sodium channel blockade; (2) calcium channel blockade; (3) blockade of excitatory amines; (4) GABA (gamma-aminobutyric acid) potentiation; and (5) binding to synaptic vesicle glycoprotein 2A (SV2A). Some antiepileptics have multiple mechanisms of action. Table 48–1 and Figs. 48–1 and 48–2 summarize these effects.