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Anticonvulsants, also known as antiepileptics, are drugs used to treat acute seizures and prevent convulsions in patients with underlying seizure disorder. The first anticonvulsants, phenytoin and phenobarbital, came into clinical use in 1939, and during the next 40 years, four additional drugs were added to what is termed the “first generation” of antiepileptic drugs (Table 191-1). Since 1993, 11 additional agents have been introduced into clinical medicine, termed the “second generation” of antiepileptic drugs. In general, these second-generation agents have few serious adverse side effects and fewer drug interactions than occur with the first-generation agents. For the first-generation anticonvulsants, a therapeutic range for serum levels has been established that can guide therapy during long-term management and that has a correlation with acute toxicity from an overdose. However, consistent therapeutic levels have not been established for the second-generation anticonvulsants, and serum levels are not a useful guide to therapy.

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Table 191-1 Anticonvulsant Drugs
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As noted, the first generation of antiepileptics had the potential for serious toxicity, especially in an overdose. Fortunately, serious toxicity following an overdose of the second-generation agents is uncommon. During 2008, the American Association of Poison Control Centers received reports of 44,264 exposures to anticonvulsants and 85 deaths in which anticonvulsants were mentioned.1 In cases in which the agent was identified, the largest number of deaths occurred with valproate exposure.

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Phenytoin (3-hydroxymethyl-5,5-diphenylhydantoin) is a primary anticonvulsant for partial and generalized tonic-clonic seizures. It is useful in the treatment of non–drug-induced status epilepticus in conjunction with rapidly acting anticonvulsants.2 Phenytoin has been used in the setting of head trauma (in the immediate post-traumatic period) and in the management of some chronic pain syndromes. Historically, it has also been used as an antidysrhythmic agent, especially in the setting of digoxin toxicity, but it is no longer a first-line agent. Morbidity or mortality is extremely rare after intentional phenytoin overdose if good supportive care is provided. Most phenytoin-related deaths have been caused by rapid IV administration or hypersensitivity reactions.

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Phenytoin is available in oral and injectable forms. However, phenytoin has poor solubility in water, and the vehicle for the parenteral formulation of phenytoin is 40% propylene glycol and 10% ethanol, adjusted to a pH of 12 with sodium hydroxide. The acute cardiovascular toxicity seen with IV phenytoin infusion has frequently been ascribed to its diluent. The limitations of this parenteral form of phenytoin (incomplete aqueous solubility, irritating nature of the vehicle, and tendency to precipitate in IV solutions) prompted a search for a more suitable preparation. In 1997, a prodrug of phenytoin, a disodium phosphate ester named fosphenytoin, was introduced that is more water soluble and less irritating to the tissues.3 Fosphenytoin is ...

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