Historically, seizures were treated by a variety of methods, including ketogenic diets, fluid restriction, and surgical excision of scars or irritable cortical foci. 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. Phenobarbital, a sedative–hypnotic, was first used to treat seizures in 1912. Most of the subsequently introduced antiepileptics such as primidone 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 1938.116 After 1965, benzodiazepines, carbamazepine, and valproic acid (VPA) were introduced and gained wide use as antiepileptics. These antiepileptics were the only new medications available until the 1990s when gabapentin, lamotrigine, levetiracetam, oxcarbazepine, tiagabine, topiramate, felbamate, vigabatrin, lacosamide, and zonisamide were introduced.
Antiepileptics are also currently used for treating mood disorders, refractory pain syndromes such as trigeminal neuralgia, bruxism, migraine headaches, drug withdrawal syndromes, and social phobias. A warning, based on a meta-analysis of placebo-controlled trials, placed the risk of suicide twice as high among patients receiving antiepileptics as compared with those receiving placebo.30,78 More specifically, other authors reported an association between mood disorders treated with antiepileptics and suicides.133 Conversely, others observed that rates of depression are high among patients with epilepsy, whether well controlled with antiepileptics or not.7
This chapter reviews the toxicity and management of overdoses with antiepileptics other than the benzodiazepines and barbiturates, which are discussed in Chap. 74.
The mechanisms of action of antiepileptics are fourfold: sodium or calcium channel inhibition, inhibition of excitatory amines, GABA (γ-aminobutyric acid) related, and binding to synaptic vesicle protein 2A. Some antiepileptics have multiple mechanisms of action.114
During seizures, a high-frequency pattern of neuronal firing is detected. This pattern is uncommon during normal physiologic neuronal activity. Voltage-gated sodium channels (VGSCs) are primarily responsible for this rapid neuronal firing. Under the influence of sodium channel blockers, the VGSCs are maintained partially open with their internal inactivation gates closed. The VGSCs cannot recover from inactivation and are prevented from firing repetitively. Phenytoin, carbamazepine, VPA, lamotrigine, topiramate, oxcarbazepine, and zonisamide all attach themselves to the batrachotoxin binding site (or adjacent area) on the VGSCs, close the inactivation gate, and prolong the recovery from inactivation.113,114,194,198 At therapeutic concentrations, VGSC binding is largely selective. At toxic concentrations, selectivity is lost, and both high-frequency and spontaneous sodium channels are inhibited, including those found in cardiac tissue responsible for action potential initiation leading to electrocardiographic (ECG) disturbances such as QRS complex prolongation and atrioventricular blockade.27,50,92,127,173,178 Lacosamide is unique as it binds to collapsing response mediator protein 2 (CRMP-2), a phosphoprotein ...