Phenytoin and fosphenytoin

Phenytoin33,50,53-56 is a drug of first choice in established status epilepticus. Its pharmacology and clinical effects are well documented, and there is extensive experience in status epilepticus in adults, children, and the newborn. It is a highly effective anticonvulsant, with the particular advantage of a long duration of action. It can also be continued as chronic therapy. Phenytoin causes relatively little respiratory or cerebral depression, although hypotension is more common. The initial infusion of phenytoin takes 20-30 minutes in an adult, and the onset of action is slow. It is therefore often administered in conjunction with a short acting drug with a rapid onset of action, such as diazepam. The notorious saturable pharmacokinetics of phenytoin cause less problems in the emergency setting than in chronic therapy, but careful serum level monitoring is essential. The usual phenytoin solutions have a pH of 12, and if added to bags containing large volumes of fluid at lower than physiological pH (for example, 5% glucose) precipitation may occur in the bag or tubing; use in a solution of 09% sodium chloride (normal saline) (5-20 mg/ml) is safer. There is also a serious risk of precipitation if other drugs are added to the infusion solution. Administration via a side arm, or directly using an infusion pump, is preferable. Due to the high pH, phenytoin can cause thrombophlebitis (particularly with extravasation), and it is poorly and erratically absorbed after intramuscular injection. Also, its vehicle, propylene glycol, can cause hypotension.

The rate of infusion of phenytoin solution should not exceed 50 mg/min, and it is prudent to reduce this to 20-30 mg/min in the elderly. The adult dose is 15-20 mg/kg, usually about 1000 mg, therefore taking at least 20 minutes to administer. Regrettably, a lower dose is too often given, which results in suboptimal cerebral levels. This is a common and potentially serious mistake. Phenytoin therapy can be continued after intravenous loading by oral or further intravenous daily dosages of 5-6 mg/kg, guided by blood level measurements. For older children, the dose of phenytoin is as for adults. For the newborn a dose of 15-20 mg/kg, injected at a rate not exceeding 1 mg/kg/min, should be given. Phenytoin is usually available as 5 ml ampoules containing phenytoin sodium 250 mg.

In order to overcome the problems associated with phenytoin's physiochemical properties, fosphenytoin (3-phosphoryloxymethyl phenytoin disodium), a water-soluble phenytoin pro-drug, was developed.57,58 It has a pH closer to physiological values than phenytoin and so is less irritant to the infusion site. Furthermore it is, unlike phenytoin, not prepared in propylene glycol, which may improve tolerability. Fosphenytoin is inactive, but is metabolised to phenytoin with a half-life of 8-15 minutes. It is supplied in a ready mixed solution. The equimolar equivalent of 15 mg of fosphenytoin is 1 mg of phenytoin, and the drug is supplied in a ready mixed solution of 50 mg phenytoin equivalents (PE) per millilitre (75 mg/ml). This is to standardise the solution to that of parenteral phenytoin. It should be given intravenously at a maximum rate of 100 mg/min in order to achieve a similar serum concentration time profile to that obtained with the present protocol of giving intravenous phenytoin in status epilepticus. Although it is more expensive than phenytoin, these costs may be balanced by less phlebitis and ease of administration. As it is water soluble, it can also be given as an intramuscular injection, although its rate of absorption by this route is too slow to be of use in status epilepticus and this route of administration is not advised. ECG monitoring is mandatory while administering intravenous phenytoin or fosphenytoin.

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