Phenytoin
Examples
Phenytoin Sodium
Indications
All forms of epilepsy, apart from absence seizures.
Phenytoin is given if a benzodiazepine is unsuccessful in terminating a seizure in status epilepticus (see SIGN guidelines.)
Can also be used in Trigeminal Neuralgia if Carbamazepine is ineffective.
In general terms, phenytoin is not used as a first line treatment in Epilepsy, due to its side effect profile, but you may see it given to older patients who have been taking it for many years.
Contraindications
Caution:
- Patients with hepatic impairment
- Patients on warfarin or the oral contraceptive pill as phenytoin reduces their effect
- Patients who may be pregnant - due to an increased risk of congenital malformations
Mechanism
Phenytoin is one of the anti-epileptic drugs which work by binding to the sodium channel of the neuronal membrane. By binding to this sodium channel, phenytoin reduces the influx of sodium into the cell which would lead to an action potential, and therefore reduces the depolarisation of the neurones which are responsible for epileptic seizures.
Very simply put, epilepsy is caused by excessive depolarisation of neurones, and phenytoin prevents this excessive depolarisation by blocking sodium channels and thus preventing an action potential in the neurone.
Administration
Usually given orally, although IV injection is possible and may be required in status epilepticus.
Adverse Reactions
As mentioned, phenytoin has substantial side-effect profile, and this is one of the reasons it is not generally used as first line treatment for epilepsy, and is reserved for patients who have already tried another drug which did not control symptoms.
Among the common side effects are:
- Nausea and vomiting
- Constipation
- Drowsiness
- Headache
- Tremor
- Rashes
- Acne
- Hirsutism
- Gingival hypertrophy
Less common, but serious side effects include:
- Hepatotoxicity
- Blood disorders (anaemia, leucopenia, thrombocytopenia)
- Stevens-Johnson syndrome
In addition to the above, Phenytoin interacts with and affects the metabolism of many drugs, which can lead to serious problems.
The symptoms and signs of phenytoin toxicity are:
- Vertigo
- Ataxia
- Nystagmus
- Confusion
Interactions
As phenytoin is primarily metabolised via the cytochrome P450 system in the liver, there are a whole host of drugs which it can affect. Phenytoin is a powerful inducer of some of the enzymes within this system, and therefore many drugs which are also metabolised via the cytochrome P450 system are metabolised quicker - meaning that higher doses of these drugs must be given to maintain plasma levels. Common examples are are Warfarin and the Oral Contraceptive Pill (mentioned in the epilepsy introductory page.) The doses of these two drugs usually need to be increased when the patient is taking phenytoin, and it is often sensible to suggest other forms of contraception, to avoid taking too high a dose of oestrogen.
A very important point should be noted regarding warfarin and phenytoin. Although whilst a patient remains on phenytoin their warfarin would have to be increased (in order to overcome the enzyme induction described above), it is essential to remember to lower the dose when the patient stops taking phenytoin. This should be done by a specialist under close supervision.
Finally, although it is preferable to use monotherapy wherever possible when treating patients with epilepsy, there are cases where it is necessary for the patient to take more than one anti-epileptic. It is important to note that anti-epileptics are renowned for interacting with each other, and phenytoin is no exception. Specific regimens may be suggested for using combination anti-epileptics and should only be undertaken by a specialist.
Education
See Anti-Epileptic Therapy.
Pharmacokinetics
Phenytoin is primarily metabolised by the cytochrome P450 system, and as mentioned in "Interactions," this has important clinical consequences.
Phenytoin has a narrow therapeutic window of 5 - 20mg/L. There is a non-linear relationship between the dose of phenytoin and its corresponding level, doubling the dose of phenytoin may increase plasma concentration four fold. This is termed zero order kinetics.
Phenytoin has a high affinity to albumin - approximately 80 - 90% of it is bound to albumin. Therefore, patients who have a low albumin, or take medication (e.g. salicylates, valproate) which competitively bind to albumin will cause an increase in phenytoin availability. For those with a low albumin level there is a calculation which can be done to work out their corrected phenytoin level.
