TeacherOfMedicine: Phenytoin

To control seizures in status epilepticus where benzodiazepines are ineffective.
To reduce the frequency of generalised or focal seizures in epilepsy, although drugs with fewer adverse effects and interactions (e.g. valproate, lamotrigine, levetiracetam) are usually preferred.

The mechanism of action of phenytoin is incompletely understood.
Phenytoin reduces neuronal excitability and electrical conductance among brain cells, which inhibits the spread of seizure activity.
It appears to do this by binding to neuronal Na+ channels in their inactive state, prolonging inactivity and preventing Na+ influx into the neuron.
This prevents a drift in membrane potential from the resting (−70 mV) to the threshold (−55 mV) value required to trigger an action potential.
A similar effect in cardiac Purkinje fibres may account for both antiarrhythmic and cardiotoxic effects of phenytoin.

Long-term phenytoin treatment can cause a change in appearance, with skin coarsening, acne, hirsutism and gum hypertrophy.
Dose-related neurological effects include cerebellar toxicity (e.g. nystagmus, ataxia and discoordination) and impaired cognition or consciousness.
Phenytoin can cause haematological disorders and osteomalacia by inducing folic acid and vitamin D metabolism.
Hypersensitivity reactions to phenytoin range from mild skin rash to the rare life-threatening antiepileptic hypersensitivity syndrome (see Carbamazepine).
Phenytoin toxicity (due to overdose or injudicious IV infusion) can cause death through cardiovascular collapse and respiratory depression.

Phenytoin is metabolised by the liver with zero-order kinetics (i.e. at a constant rate irrespective of plasma concentrations) for concentrations at or above the therapeutic range.
Moreover, the therapeutic index is low, implying that the safety margin between therapeutic and toxic doses is narrow. Phenytoin dosage should therefore be reduced in hepatic impairment.
In utero phenytoin exposure is associated with craniofacial abnormalities and reduced IQ (fetal hydantoin syndrome).
Women with epilepsy planning pregnancy should discuss treatment with a specialist and take high-dose folic acid before conception (see Valproate).

Phenytoin is an enzyme inducer, so reduces plasma concentrations and efficacy of drugs metabolised by P450 enzymes, e.g. warfarin, and oestrogens and progestogens.
Phenytoin is itself metabolised by these enzymes, so its plasma concentrations and adverse effects are increased by cytochrome P450 inhibitors, e.g. amiodarone, diltiazem and fluconazole.
Complex interactions can occur with other antiepileptic drugs as most alter drug metabolism.
The efficacy of antiepileptic drugs is reduced by drugs that lower the seizure threshold (e.g. SSRIs, tricyclic antidepressants, antipsychotics, tramadol).

Phenytoin levels do not need to be monitored routinely but trough levels, immediately before dose should be checked if:

Plasma phenytoin concentrations measured immediately before the next dose should be 10–20 mg/L.
If needed, make small changes in dose (e.g. by 50 mg) at a time, as zero-order kinetics makes the effect of change difficult to predict.
After a dose change, wait at least 7 days before repeating blood tests to determine new steady state plasma concentrations.
Monitor efficacy by comparing seizure frequency before and after starting or changing treatment.
Monitor blood pressure, cardiac rhythm, respiratory rate and oxygen saturations to look for adverse effects during IV treatment.

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