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Therapeutic serum concentrations
Xenobioticmg/Lμmol/L
Carbamazepine4–1217–51
Ethosuximide40–100283–708
Gabapentin12–2012–88
Lamotrigine3–14≤19.5
Phenobarbital15–4065–172
Phenytoin10–2040–79
Valproic acid50–120347–833
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A seizure is defined as the clinical manifestation of excessive neuronal activity within the central nervous system (CNS). It is accompanied by varying degrees of motor, sensory, and cognitive dysfunction. Seizures result from one of four possible cellular mechanisms: sustained repeated firing of the sodium channels, excessive calcium conductance, increased excitatory neurotransmission (eg, glutamate), or loss inhibitory neurotransmitter control (eg, γ-aminobutyric acid [GABA]).

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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 effective anticonvulsant therapy was introduced in 1857, when administration of bromides was noted to sedate patients and significantly reduce their seizures. Phenobarbital, another sedative-hypnotic, was first used to treat seizures in 1912. Most of the subsequently introduced anticonvulsants, such as primidone, had chemical structures similar to that of phenobarbital, and sedation was erroneously believed to be an essential component of anticonvulsant therapy.

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The search for nonsedating anticonvulsants led to the introduction of phenytoin in 1938.114 After 1965, benzodiazepines, carbamazepine, and valproic acid (VPA) were introduced and gained wide use as anticonvulsants. These were the only anticonvulsants available until the 1990s, when new anticonvulsants became available for clinical use: gabapentin, lamotrigine, levetiracetam, oxcarbazepine, tiagabine, topiramate, felbamate, vigabatrin, lacosamide and zonisamide.

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Anticonvulsants are also currently used for treating mood disorders, refractory pain syndromes such as trigeminal neuralgia, bruxism, migraine headaches, drug withdrawal syndromes, and social phobias.

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In a review of more than 5000 patient suicides, anticonvulsants were implicated in 8.2% of cases, suggesting a fairly high rate of suicidal ideation among people with access to these medications.71,73 In the last decade, as reported in the American Association of Poison Control Centers (AAPCC) National Poison Data System (NPDS), a shift occurred from predominantly carbamazepine and phenytoin exposures to VPA and newer anticonvulsants (Chap. 135).

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This chapter reviews the toxicity and management of overdoses with anticonvulsants other than the benzodiazepines and barbiturates, which are discussed in Chap. 74.

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The mechanisms of action of anticonvulsants correspond to one of four categories: sodium channel inhibition, calcium channel inhibition, inhibition of excitatory amines, and GABA agonism. Frequently, more than one mechanism accounts for the anticonvulsive action of a drug.

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Electrophysiologic analyses demonstrate that a high-frequency pattern of neuronal firing occurs during seizure activity. This pattern is not observed during normal neuronal activity. Voltage-activated sodium and calcium channels are primarily responsible for this high-frequency firing. Sodium-channel blocking anticonvulsants preferentially bind to inactivated conformations of the voltage-activated sodium channels hindering recovery and preventing them from firing at high frequencies. Phenytoin, carbamazepine, VPA, lamotrigine, topiramate, oxcarbazepine, zonisamide, and felbamate all bind ...

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