Pharmacology

Pharmacodynamics. Phenytoin inhibits the tonic phase in the electroshock seizure test but is ineffective against pentylenetetrazol-induced convulsions. The primary site of action is the motor cortex where spread of seizure activity is inhibited. Phenytoin can inhibit seizure activity at concentrations that do not compromise other functions and do not have a sedative effect. It reduces the maximal activity of the brainstem centers responsible for the tonic phase of the tonic-clonic (grand mal) seizures. Phenytoin enhances active sodium extrusion and inhibits passive sodium entry leading to normalization of the sodium gradient and stabilization of the membrane. It may also inhibit transmitter release by reducing calcium-dependent phosphorylation of membrane proteins. It may also modulate GABA receptors.

Therapeutic drug monitoring. Measurement of plasma concentrations is often used to optimize clinical efficacy of phenytoin and avoid adverse effects. Pharmacokinetics of phenytoin is altered in cancer patients with chemotherapy-induced gastrointestinal toxicity, which decreases absorption of the drug. Coadministration of valproic acid or carbamazepine leads to significant alterations of the free fraction of phenytoin, which requires drug monitoring.

In critically ill patients, free phenytoin serum concentrations, which represent the pharmacologically active drug, should be measured or calculated to avoid misinterpretation of total serum levels and inappropriate adjustments in the dosage of phenytoin based on this. If it is not possible to measure free phenytoin levels, Sheiner-Tozer equation should be used to calculate an adjusted phenytoin that corrects for the plasma albumin concentration (13). It can supplement the measurement of total phenytoin concentration, particularly for patients with low plasma albumin.

A number of assays are available for measuring free phenytoin serum concentrations. TDx/FLx was widely used but has been discontinued. Results of an evaluation show that accuracy, precision, and correlation of ARCHITECT assay is like TDx/FLx, and it is acceptable for clinical use (27).

Phenytoin often requires rapid intravenous loading followed by dose adjustment according to therapeutic drug monitoring. A study has shown that Bayesian forecasting with the well-defined dose regimen showed significantly better results in reaching therapeutic phenytoin serum levels rapidly and for longer duration as compared to conventional dosing (28).

Pharmacogenetics. Patients with polymorphisms of drug-metabolizing enzymes, eg, cytochrome P450 2C9 poor metabolizers, are likely to develop toxic serum concentrations of phenytoin, even with doses within normal range. Compared with extensive metabolizer genotype, low-intermediate/poor metabolizer genotype is associated with increased dose-adjusted phenytoin blood concentration and increased risk of neurologic side effects with variation on phenytoin prescribing practice and patient responses (09). Routine genotyping is expensive as well as impractical, and monitoring of phenytoin concentrations can be used to prevent toxic levels of the drug. A genotyping study of adult epileptic patients who had been taking phenytoin for over 1 year has linked CYP2C9 polymorphism and a reduction in cerebellar volume (30). Guidelines for genotyping tests have been provided as genetic variations in the CYP2C9 gene and/or variant allele HLA-B*15:02, encoding human leukocyte antigen, are associated with an increased risk of Stevens-Johnson syndrome and toxic epidermal necrolysis as serious adverse reactions to phenytoin treatment, contraindicating the use of this drug (07). The Clinical Pharmacogenetics Implementation Consortium, which can be accessed at the following website:cpicpgx.org, an international consortium, has summarized evidence from the published literature to provide therapeutic recommendations for the use of phenytoin based on CYP2C9 and/or HLA-B genotypes (11).

Clinical trials

Phenytoin was established as an antiepileptic drug prior to the era of controlled clinical trials. However, clinical trials with newer antiepileptic drugs continue to use older drugs such as phenytoin either as a comparison drug or as the basic drug in the case of add-on therapy. Clinical trials have compared monotherapy with the 4 classical drugs: (1) phenobarbital, (2) phenytoin, (3) valproic acid, and (4) carbamazepine. There is no significant difference in efficacy between carbamazepine and phenytoin.

Trials continue to explore other indications. There has been some controversy regarding the effectiveness of phenytoin in reducing posttraumatic seizures. In a prospective multicenter comparison of phenytoin versus levetiracetam for early posttraumatic seizure prophylaxis, there was no difference in seizure rate, adverse drug reactions, or mortality in patients treated by either drug (10).

A systematic review of randomized controlled trials in children or adults with partial onset seizures or generalized onset tonic-clonic seizures comparing carbamazepine monotherapy versus phenytoin monotherapy found no statistically significant difference in efficacy outcomes or adverse reactions between the 2 (17). The reviewers, however, do not recommend that the results alone should be used in choosing between carbamazepine and phenytoin in clinical practice.

Indications

Phenytoin is indicated for the control of generalized tonic-clonic (grand mal) and complex partial (psychomotor, temporal lobe) seizures and for the prevention and treatment of seizures occurring during or following neurosurgery, but not as a prophylactic preoperatively.

The American Academy of Neurology recommended using phenytoin or carbamazepine to prevent early posttraumatic seizures in severe traumatic brain injuries (08). CT scan findings are the main factor for a decision to use phenytoin for this indication. Earlier administration of phenytoin and adequate levels could further prevent early posttraumatic seizures.

Intravenous phenytoin has been used for status epilepticus but has been replaced by fosphenytoin.

Off-label uses

(1) Trigeminal neuralgia. Phenytoin is a second-line therapy (following carbamazepine) for the treatment of trigeminal neuralgia. The only advantage of phenytoin over carbamazepine is that it can be given intravenously for rapid control of an acute attack.

(2) Phenytoin has been used in general practice for the prevention of motion sickness.

(3) Intravenous infusion of phenytoin can relieve neuropathic pain. A review of Cochrane Central Register of Controlled Trials revealed no randomized, double-blind studies of 8 weeks duration or longer to evaluate the usefulness of phenytoin for neuropathic pain (06).

(4) Phenytoin powder is applied topically on skin ulcers to relieve pain and enhance wound healing.

(5) Low-dose phenytoin was shown to enhance social functioning in a patient with an autism spectrum disorder over a follow-up period of 18 months and was well tolerated (05). The exact mechanism of effectiveness of phenytoin is not known, but polymorphism in neuronal voltage-gated sodium channel alpha subunits in polygenic autism spectrum disorder is also the therapeutic target of phenytoin in the brain for its antiepileptic effect.

(6) Phenytoin has been shown to block the hypomanic side effects of prescription corticosteroids.

(7) Posttraumatic stress disorder.

(8) Bipolar disorder.

(9) Phenytoin has been used successfully to terminate status epilepticus in patients with progressive myoclonus epilepsy who had not responded to infusion of benzodiazepines and barbiturates.

(10) Phenytoin has been shown to have a neuroprotective effect in experimental autoimmune encephalomyelitis in mice.

(11) Phenytoin loaded in the silica core of iron oxide nanoparticles reduces prevalence of tonic-clonic seizures in rats with pharmacoresistant seizures associated with brain P-glycoprotein overexpression (21).

(12) Results of a randomized, placebo-controlled, double-blind phase 2 trial indicate a neuroprotective effect of phenytoin in acute optic neuritis at concentrations required to selectively block voltage-gated sodium channels (20).

(13) The retinoprotective effect of phenytoin in patients affected by optic neuritis secondary to multiple sclerosis has been rediscovered (03).

Contraindications

Phenytoin is contraindicated in patients who are hypersensitive to phenytoin or other hydantoins. In a retrospective chart review of patients in emergency departments, 4.5% of seizure patients had a known hypersensitivity to phenytoin (16).

Abrupt withdrawal of phenytoin may lead to status epilepticus. Reduction of dose or discontinuation should be done gradually, and another antiepileptic drug should be substituted.

Phenytoin is not effective for absence (petit mal) seizures.

Goals and duration of treatment

The aim of therapy is to control seizures, and therapy is continued for as long as seizure control is required. Incidence of early posttraumatic seizures can be reduced by prophylactic administration of phenytoin for 1 to 2 weeks, but this does not reduce the mortality rate from head injury. Use of injectable phosphenytoin (PHT) in acute hospital setting requires close monitoring and dose adjustments to achieve adequate and sustained tPHT free serum levels early in treatment (23).

Dosing

The basic dose is 100 mg 3 times a day of the capsule formulation. This is adequate for most adults and can be increased to a maximum of 200 mg 3 times a day if required. The initial dose for children is 5 mg/kg per day in 2 or 3 divided doses to a maximum of 300 mg per day. See the Physicians Desk Reference for details of other dose forms.

The onset of the full effect of phenytoin with regular dosing takes 1 week or longer. If rapid effect is desired, an oral loading dose with 1000 to 1200 mg (20 mg/kg) within 24 hours taken in 300 to 400 mg installments every 4 to 6 hours produces full effect by the second day when a regular dose is resumed.

Special considerations

Pediatric. There are no special precautions for children taking phenytoin, but elderly patients with impaired liver function may be susceptible to hepatoxicity.

Geriatric. Healthy, elderly adults appear to have the same phenytoin pharmacokinetics as younger adults, but age-related changes in patients' sensitivity to the therapeutic and toxic effects of the drug may necessitate reduced dosage (01). Therapy in elderly patients should start with smaller phenytoin doses initially. Subsequent dose adjustments may be based on clinical response and serum drug level measurements.

Pregnancy. An increase of seizure frequency may occur during pregnancy because of altered phenytoin absorption or metabolism. Periodic measurements of phenytoin levels to guide dosage adjustment are recommended.

Several reports suggest an association between the use of antiepileptic drugs, including phenytoin, in pregnancy and a higher incidence of birth defects. For details see the Physicians Desk Reference.

Neonatal coagulation defects have been reported within the first 24 hours in babies born to mothers receiving phenytoin. Vitamin K has been shown to correct or prevent this defect.

Anesthesia. Patients receiving chronic phenytoin therapy may show resistance to certain nondepolarizing neuromuscular blockers such as rocuronium.

Interactions

A large list of drugs (listed in the Physicians Desk Reference) may increase or decrease the level of phenytoin or may be affected by phenytoin. Interaction between tricyclic antidepressants and phenytoin involves inhibition of CYP2C19-catalyzed phenytoin p-hydroxylation. The combination of phenytoin and calcium channel blockers should be used with caution. Lethargy, dysarthria, ataxia, and weakness have been reported with use of a combination of phenytoin and isradipine, a calcium channel blocker used for hypertension. Metabolism of phenytoin may be altered by drugs influencing CYP2C9 or CYP2C19, such as diazepam. Phenytoin toxicity may, therefore, be associated with concurrent diazepam therapy. There is a potential interaction with concomitant administration of delta9-tetrahydrocannabinol, the primary psychoactive constituent of marijuana and phenytoin, which could result in decreased phenytoin concentrations. A case of toxicity caused by elevated plasma levels of phenytoin due to interaction with capecitabine in a patient on chemotherapy for colorectal cancer has been reported (22). Therefore, if these drugs are coadministered, phenytoin levels should be monitored frequently, and its dosage should be adjusted accordingly. Oxcarbazepine, an inhibitor of the 2C19 isoenzyme, interacts with phenytoin, and it can raise levels of phenytoin to produce toxic effects (25). Drug-to-drug interactions with potent inducers of cytochrome P450 isoenzyme CYP3A4, such as phenytoin, could induce inadequate responses to imatinib mesylate, a tyrosine kinase inhibitor used for the treatment of chronic myeloid leukemia, due to increased imatinib clearance resulting in low plasma levels of the drug (18).

Adverse effects

There is a large list of adverse reactions in the Physicians Desk Reference, but the most significant are those involving the nervous system, the hematopoietic system, and the immune system. Gum hyperplasia is also a frequent and bothersome complaint that occurs in up to 50% of patients taking long-term phenytoin.

Experimental studies support an important role of TRPA1 channels in phenytoin-induced gingival enlargement, which offers a therapeutic opportunity by developing a TRPA1 channel blocker (14). Results of another study show that phenytoin upregulates periostin in human gingival fibroblasts in vitro in a transforming growth factor-β-dependent manner, which can be inhibited by compounds such as SB431542 (12).

Neurologic adverse reactions are the most frequent and are usually dose related. These include ataxia, nystagmus, slurred speech, confusion, and dizziness. High-dose phenytoin therapy can cause peripheral neuropathy manifested by distal sensory loss, lower limb areflexia, and mildly reduced conduction velocities of peripheral nerves. Cerebellar ataxia occurs in 40% of patients with epilepsy and chronic exposure to phenytoin, and there is reduction in cerebellar volume even if there is no clinical evidence of ataxia (24). Structural deficits on imaging in these patients suggests a predilection for involvement of the vermis.

Dyskinesias have also been reported with phenytoin. Patients on long-term phenytoin therapy have been reported to deteriorate intellectually in the absence of any signs of oversedation, and all improved after discontinuation of the drug. Phenytoin is associated with adverse cognitive effects in severe brain injury patients, and this resolves after use of the drug (19).

An adult epileptic with a known history of tonic-clonic epilepsy on oral phenytoin 100 mg for the past 6 months was admitted to the emergency room with a history of a seizure; rapid intravenous infusion of 700 mg phenytoin in 100 mL normal saline was administered over 15 minutes, which was followed by a paradoxical seizure (26). There was no recurrence of the seizure following tapering of the dose of phenytoin.

A rare complication of intravenous phenytoin is "purple glove syndrome," which presents with pain, edema, and discoloration at the injection site that spreads to the distal limb. Blister formation, sloughing of skin with ulceration, and a compartment syndrome may develop at the injection site within hours of drug administration. Initial management includes discontinuation of parenteral phenytoin and replacement with another antiepileptic; analgesics; and elevation of the affected limb, with compression, massage, and gentle heat (29).

Phenytoin-induced thrombocytopenia is rare event, but it can have life-threatening consequences. An example is a brain tumor patient who received phenytoin for prophylaxis of seizures, but developed severe thrombocytopenia after surgery, which required replacement of phenytoin by levetiracetam, platelet transfusion, and intravenous immunoglobulin therapy for management (02).

Short-term phenytoin therapy has been used to avoid complications of long-term therapy. Adverse drug reactions are significantly reduced in this regimen, whereas seizure rates do not change.