The acute cardiovascular toxicity seen with intravenous phenytoin infusion has frequently been ascribed to its diluent. The vehicle for the older parenteral formulation of phenytoin (Dilantin) is 40% propylene glycol and 10% ethanol, adjusted to a pH of 12 with sodium hydroxide. The glycol component has been shown to cause coma, seizures, circulatory collapse, ventricular dysrhythmias, atrioventricular (AV) node depression, and hypotension in human and animals. 7 Propylene glycol is a strong myocardial depressant and vasodilator and increases vagal tone. Other toxic effects of propylene glycol include hyperosmolality, hemolysis, and lactate-associated metabolic acidosis. Louis and colleagues compared the acute toxicities of intravenous phenytoin and propylene glycol both alone and in combination in a feline model. Phenytoin alone did cause hypotension but did not cause significant electrocardiographic effects and instead partially reversed the toxic effects that occurred when propylene glycol was given.8 Acute toxic effects of propylene glycol are also strongly related to the rate of infusion. This is further evidence for its role in intravenous phenytoin toxicity, a phenomenon that is almost always related to infusion rate. The ethanol diluent fraction of parenteral phenytoin may also precipitate a reaction in patients taking disulfiram. The preparation with glycol is still available in the United States (although the original manufacturer no longer makes it). With intravenous infusion pumps controlling rate of administration, adverse effects are not as common, and phenytoin is less expensive compared with the alternative (see below).
The limitations of this parenteral form of phenytoin (incomplete aqueous solubility, irritating nature of the vehicle, and tendency to precipitate in intravenous solutions) have prompted a search for a more suitable preparation. Recently, a prodrug of phenytoin (fosphenytoin) has been synthesized that is more soluble and less irritating to the tissues. Fosphenytoin is the disodium phosphate ester of phenytoin. It is freely soluble in aqueous solutions and is formulated with TRIS buffer only at a pH of 8.8. Fosphenytoin is converted to phenytoin by phosphatases in the blood and various organs. For simplicity, the concentration and dose of fosphenytoin are expressed in phenytoin equivalents (PEs). The conversion half-life is 10 to 15 min. 9 Fosphenytoin is tolerated intravenously and intramuscularly, and patients can be successfully loaded within 30 min with one or more intramuscular injections without significant side effects. 10
Given intravenously, fosphenytoin can cause pruritis and hypotension. It is not clear whether fosphenytoin administered intravenously can result in therapeutic levels more quickly and with fewer side effects than intravenous phenytoin. Blood pressure and cardiac monitoring are recommended when loading with fosphenytoin intravenously but not intramuscularly. The adverse and toxic effects of fosphenytoin are the same as with phenytoin, except that the effects of glycol and ethanol are not present with fosphenytoin.
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