Phenytoin

Phenytoin is no longer used as a first-line treatment for epilepsy. It is as effective as the other anti-convulsants,¹ but because of its saturation kinetics and the necessity of routinely monitoring its concentration is more problematic. Another problem with phenytoin is its side effect profile, particularly with chronic use.

• Phenytoin is a highly protein bound drug that undergoes saturable hepatic metabolism. It is readily displaced from the hepatic cytochrome P450 isoenzymes that are responsible for its metabolism.
• Small changes in dose or the introduction of a drug that displaces phenytoin from its protein binding sites or inhibits its metabolism can result in an unpredictable increase in phenytoin levels.
• The phenytoin dosage at which saturation of hepatic enzymes occurs varies from one patient to another. Accurate titration and use of phenytoin is very difficult without blood tests to monitor the drug level.

• Porphyria

• Hepatic impairment (reduce dose)
• Pregnancy:
  • First trimester use is associated with increased risk of congenital malformations.² Adequate folate supplements should be given to mother, e.g. folic acid 5 mg daily.
  • Third trimester use may cause vitamin K deficiency and risk of neonatal bleeding.
• Avoid sudden withdrawal.
• Manufacturer recommends blood counts (but evidence of practical value unsatisfactory).
• Patients or their carers should be told how to recognise signs of blood or skin disorders, and advised to seek immediate medical attention if symptoms such as fever, sore throat, rash, mouth ulcers, bruising, or bleeding develop.
• Leucopenia which is severe, progressive or associated with clinical symptoms requires withdrawal.
• Take preferably with, or after food.

Avoid the following if possible, or monitor frequently:

• Phenytoin is an enzyme inducer and so can accelerate the metabolism of a number of lipid-soluble drugs, including:
  • Carbamazepine
  • Sodium valproate
  • Ethosuximide
  • Anticoagulants
  • Steroids
  • Cyclosporin
• Because its metabolism is saturable, the drug provides a target for drugs such as allopurinol, amiodarone, cimetidine and imipramine.
• Protein binding displacement interactions with antiepileptic drugs are only clinically relevant when there is concomitant enzyme inhibition, as is the case with the combination of phenytoin and sodium valproate.

• Phenytoin can produce a range of dose-related and idiosyncratic adverse effects including rash, hepatotoxicity and blood dyscrasias.
• Reversible cosmetic changes (gum hyperplasia, acne, hirsutism, facial coarsening), although often mild.
• Symptoms of neurotoxicity (drowsiness, dysarthria, tremor, ataxia, cognitive difficulties) become increasingly likely with levels above 80 mcmol/L. The patient will complain of mental slowing and unsteadiness, and neurological examination will reveal cerebellar signs. Permanent cerebellar damage may be a consequence of chronic toxicity, so it is important to examine the patient regularly. In some of these patients, cerebellar atrophy will be apparent on brain imaging, although hard evidence for cause and effect is not readily available.
• A paradoxical increase in seizure frequency may also occur with marked phenytoin toxicity.
• The diagnosis of phenytoin toxicity should be made on clinical grounds and not assumed from a high level.

• Sampling time in relation to dose is not critical, but phenytoin may take up to 4 weeks to achieve steady-state. The plasma concentration for optimum response is 10-20 mg/litre (40-80 micromol/litre).
• Saliva phenytoin concentrations are significantly correlated with plasma free phenytoin concentrations. The benefits of monitoring salivary rather than plasma total phenytoin have been shown in patients with uraemia and those also receiving valproic acid therapy.

• Phenytoin is used in SE, but valproate has greater efficacy³
• 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 usual phenytoin solutions have a pH of 12 and, if added to bags containing large volumes of fluid at lower than physiological pH (e.g. 5% glucose), precipitation may occur in the bag or tubing. A solution of 0.9% sodium chloride (normal saline) 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 and is poorly absorbed after intramuscular injection
• ECG monitoring is mandatory during intravenous administration of both phenytoin and fosphenytoin.

When only parenteral administration is possible, fosphenytoin, which is a pro-drug of phenytoin, may be convenient.

• Fosphenytoin is inactive, but is metabolised to phenytoin.
• Fosphenytoin is more expensive than phenytoin, but causes less phlebitis and less hypotension, is easier to give and is better tolerated.
• ECG monitoring is mandatory during intravenous administration of both phenytoin and fosphenytoin.