Introduction

The ideal drug for the treatment of status epilepticus (SE) should be effective, have a rapid onset of action, produce minimal sedation, have a long duration of action, and be safe. No agent presently available has all of these properties. In general, the available drugs are relatively safe if used properly, and all are effective, although they may differ in their potency. No single drug has all of the desired properties. The benzodiazepines have a rapid onset of action but are short-acting and are sedative. Phenytoin has a long half-life and produces minimal sedation but does not have as rapid an onset of action as the benzodiazepines. This chapter reviews the physicochemical properties of phenytoin and demonstrates that its onset of action occurs as soon as adequate concentrations are attained. Its lack of speed in clinical settings is due to its chemical properties rather than its mechanism of action.

Phenytoin was synthesized in 1908 and was introduced for the treatment of epilepsy in 1938 (31). It was the first anticonvulsant drug tested in animal models prior to use in humans. These early studies demonstrated that an agent did not have to be hypnotic to be effective in controlling seizures (35). Parenteral use, both intramuscularly (IM) and intravenously (IV), began in the 1950s, and the first reports of its use for the treatment of SE date to this period (32). The delay in development of a parenteral form was due to the physicochemical properties of phenytoin. Because it is a weak organic acid, it is very poorly soluble in aqueous solutions. Only 20.5µg/mL is in solution at pH 9.1 and 1,520µg/mL at pH 10 (13). During the 1950s a low-volume (high-concentration) solution for both IM and IV use was formulated, but a number of pharmaceutical compromises had to be made. The aqueous vehicle contains 40% propylene glycol and 10% ethanol, has a pH adjusted to 12 with sodium hydroxide, and has 50mg of phenytoin sodium per milliliter (46mg of phenytoin acid per 1mL). Only many years later, during the 1970s, was it recognized that this formulation should not be used IM because it causes muscle necrosis, is painful, and is poorly absorbed (44, 46). Over the past two decades the parenteral form has been used primarily for the treatment of SE or as parenteral replacement of the oral dose. However, because of its pH and propylene glycol content, phenytoin is a hazardous drug when given IV and must be used very carefully. A new compound, fosphenytoin, is highly water soluble and has overcome most of the risks of phenytoin (21).