Phenytoin Flashcards
Indications
- Seizure control in status epilepticus
- To reduce the frequency of generalised or focal seizures in epilepsy, although drugs with fewer side effects are preferred
Mechanisms of action
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.
Adverse effects
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.
Warnings
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).
Interactions
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).
Prescription
Intravenous phenytoin is prescribed for status epilepticus at a loading dose of 20 mg/kg (max 2 g), followed by a maintenance dose of 100 mg 6–8-hrly. Long-term oral phenytoin for chronic epilepsy is commenced at 150–300 mg daily, in 1–2 divided doses. Phenytoin dosage is adjusted according to plasma concentrations. Treatment should not be stopped suddenly, but should be withdrawn gradually under medical supervision, due to risk of seizure recurrence.
Administration
IV phenytoin is given as a slow IV injection or infusion (maximum 50 mg/min) into a large vein. The cannula is flushed before and after injection using 0.9% sodium chloride to prevent venous irritation. Cardiac resuscitation facilities should be available. Oral phenytoin is formulated as phenytoin sodium (tablets or capsules) or phenytoin base (chewable tablets or oral solution). As phenytoin content of these formulations is not identical, plasma concentration monitoring is required if switching between preparations.
Communication
Explain that the aim of treatment is to reduce frequency of seizures. Advise the patient to take phenytoin regularly with or after food and not to miss any doses. Warn them to seek urgent medical advice for skin rashes, bruising or signs of infection (such as high temperature or sore throat), which could indicate hypersensitivity. For women, discuss contraception and pregnancy (see Valproate). Advise them not to drive unless seizure-free for 12 months (or asleep-only seizures over 3 years) and for 6 months after changing or stopping treatment.
Monitoring
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.
