indication

For the control of generalized tonic-clonic (grand mal) and complex partial (psychomotor, temporal lobe) seizures and prevention and treatment of seizures occurring during or following neurosurgery.

pharmacology

Phenytoin is an antiepileptic drug which can be useful in the treatment of epilepsy. The primary site of action appears to be the motor cortex where spread of seizure activity is inhibited. Phenytoin reduces the maximal activity of brain stem centers responsible for the tonic phase of tonic-clonic (grand mal) seizures. Phenytoin acts to dampen the unwanted, runaway brain activity seen in seizure by reducing electrical conductance among brain cells. It lacks the sedation effects associated with phenobarbital. There are some indications that phenytoin has other effects, including anxiety control and mood stabilization, although it has never been approved for those purposes by the FDA. Phenytoin is primarily metabolized by CYP2C9.

mechanism of action

Phenytoin acts on sodium channels on the neuronal cell membrane, limiting the spread of seizure activity and reducing seizure propagation. By promoting sodium efflux from neurons, phenytoin tends to stabilize the threshold against hyperexcitability caused by excessive stimulation or environmental changes capable of reducing membrane sodium gradient. This includes the reduction of post-tetanic potentiation at synapses. Loss of post-tetanic potentiation prevents cortical seizure foci from detonating adjacent cortical areas.

toxicity

Oral, mouse: LD₅₀ = 150 mg/kg; Oral, rat: LD₅₀ = 1635 mg/kg. Symptoms of overdose include coma, difficulty in pronouncing words correctly, involuntary eye movement, lack of muscle coordination, low blood pressure, nausea, sluggishness, slurred speech, tremors, and vomiting.

biotransformation

Primarily hepatic

absorption

Bioavailability 70-100% oral, 24.4% for rectal and intravenous administration. Rapid rate of absorption with peak blood concentration expected in 1½ to 3 hours.

half life

22 hours (range of 7 to 42 hours)

route of elimination

Most of the drug is excreted in the bile as inactive metabolites which are then reabsorbed from the intestinal tract and excreted in the urine. Urinary excretion of phenytoin and its metabolites occurs partly with glomerular filtration but, more importantly, by tubular secretion.

drug interactions

Acenocoumarol: Increased hydantoin levels and risk of bleeding

Alprazolam: Phenytoin may increase the metabolism of alprazolam via CYP3A4.

Aminophylline: Decreased effect of both products

Amiodarone: Amiodarone may increase the therapeutic and adverse effects of phenytoin.

Anisindione: Increased hydantoin levels and risk of bleeding

Aprepitant: The CYP3A4 inducer, phenytoin, may decrease the effect of aprepitant.

Atracurium: Phenytoin decreases the effect of the muscle relaxant

Betamethasone: The enzyme inducer, phenytoin, may decrease the effect of the corticosteroid, betamethasone.

Bleomycin: The antineoplasic agent decreases the effect of hydantoin

Capecitabine: Capecitabine increases the effect of hydantoin

Carboplatin: The antineoplasic agent decreases the effect of hydantoin

Carmustine: The antineoplasic agent decreases the effect of hydantoin

Chloramphenicol: Increases phenytoin, modifies chloramphenicol

Chlordiazepoxide: Phenytoin may increase the metabolism of chlordiazepoxide via CYP3A4.

Chlorotrianisene: The enzyme inducer, phenytoin, decreases the effect of the hormone agent, chlorotrianisene.

Chlorpheniramine: The antihistamine increases the effect of hydantoin

Cimetidine: Cimetidine may increase the therapeutic effect of phenytoin.

Ciprofloxacin: Ciprofloxacin may decrease the therapeutic effect of phenytoin.

Cisplatin: The antineoplasic agent decreases the effect of hydantoin

Clarithromycin: Clarithromycin may increase the therapeutic and adverse effects of phenytoin.

Clomifene: The enzyme inducer, phenytoin, decreases the effect of the hormone agent, clomifene.

Clorazepate: Phenytoin may increase the metabolism of clorazepate via CYP3A4.

Clozapine: Phenytoin may decrease the effect of clozapine.

Colesevelam: Colesevelam may decrease the serum concentration of Phenytoin. Phenytoin should be administered at least 4 hours prior to colesevelam.

Conjugated Estrogens: The enzyme inducer, phenytoin, decreases the effect of the hormone agent, conjugated estrogens.

Cortisone acetate: The enzyme inducer, phenytoin, may decrease the effect of the corticosteroid, cortisone acetate.

Cyclosporine: The hydantoin decreases the effect of cyclosporine

Dasatinib: Phenytoin may decrease the serum level and efficacy of dasatinib.

Delavirdine: The anticonvulsant, phenytoin, decreases the effect of delavirdine.

Dexamethasone: The enzyme inducer, phenytoin, may decrease the effect of the corticosteroid, dexamethasone.

Diazepam: Phenytoin may increase the metabolism of diazepam via CYP3A4.

Diazoxide: Diazoxide decreases the efficacy of phenytoin.

Dicumarol: Increased hydantoin levels and risk of bleeding

Diethylstilbestrol: The enzyme inducer, phenytoin, decreases the effect of the hormone agent, diethylstilbestrol.

Disopyramide: The hydantoin decreases the effect of disopyramide

Disulfiram: Disulfiram may increase the therapeutic and adverse effects of phenytoin.

Dopamine: Risk of severe hypotension

Doxacurium chloride: Phenytoin decreases the effect of the muscle relaxant

Doxycycline: The anticonvulsant, phenytoin, may decrease the effect of doxycycline.

Dyphylline: Decreased effect of both products

Estradiol: The enzyme inducer, phenytoin, decreases the effect of the hormone agent, estradiol.

Estriol: The enzyme inducer, phenytoin, decreases the effect of the hormone agent, estriol.

Estrone: The enzyme inducer, phenytoin, decreases the effect of the hormone agent, estrone.

Estropipate: The enzyme inducer, phenytoin, decreases the effect of the hormone agent, estropipate.

Ethinyl Estradiol: This product may cause a slight decrease of contraceptive effect

Felbamate: Increased phenytoin levels and decreased felbamate levels

Felodipine: The hydantoin decreases the effect of felodipine

Fluconazole: Fluconazole may increase the therapeutic and adverse effects of phenytoin.

Fludrocortisone: The enzyme inducer, phenytoin, may decrease the effect of the corticosteroid, fludrocortisone.

Fluorouracil: Fluorouracil increases the effect of hydantoin

Fluoxetine: Fluoxetine increases the effect of phenytoin

Flurazepam: Phenytoin may increase the metabolism of flurazepam via CYP3A4.

Fluvoxamine: Fluvoxamine may increase the therapeutic effect of phenytoin.

Folic Acid: Folic acid may decrease the levels of phenytoin.

Furosemide: The hydantoin decreases the effect of furosemide

Gabapentin: Gabapentin may increase the therapeutic and adverse effects of phenytoin.

Gefitinib: The CYP3A4 inducer, phenytoin, may decrease the serum concentration and therapeutic effects of gefitinib.

Hydrocortisone: The enzyme inducer, phenytoin, may decrease the effect of the corticosteroid, hydrocortisone.

Imatinib: The hydantoin decreases the levels of imatinib

Irinotecan: The hydantoin decreases the effect of irinotecan

Isoniazid: Isoniazid increases the effect of phenytoin in 20% of patients

Itraconazole: Phenytoin decreases the effect of itraconazole

Lamotrigine: Phenytoin may reduce levels of lamotrigine

Levodopa: The hydantoin decreases the effect of levodopa

Levonorgestrel: Phenytoin decreases the contraceptive effect

Lopinavir: Levels of both drugs are affected

Mebendazole: The hydantoin decreases the efficiency of mebendazole

Medroxyprogesterone: The enzyme inducer, phenytoin, may decrease the effect of medroxyprogesterone.

Megestrol: The enzyme inducer, phenytoin, may decrease the effect of megestrol.

Mestranol: This product may cause a slight decrease of contraceptive effect

Methadone: The hydantoin decreases the effect of methadone

Methotrexate: The antineoplasic agent decreases the effect of hydantoin

Methoxsalen: The hydantoin decreases the effect of psoralene

Methylprednisolone: The enzyme inducer, phenytoin, may decrease the effect of the corticosteroid, methylprednisolone.

Metocurine: Phenytoin decreases the effect of the muscle relaxant

Metyrapone: The combination renders the test invalid

Mexiletine: The hydantoin decreases the effect of mexiletine

Midazolam: Phenytoin may increase the metabolism of midazolam via CYP3A4.

Mirtazapine: The hydantoins may reduce mirtazapine plasma concentrations and pharmacological effects

Mivacurium: Phenytoin decreases the effect of the muscle relaxant

Nisoldipine: Phenytoin decreases the efficiency of nisoldipine

Norethindrone: This product may cause a slight decrease of contraceptive effect

Omeprazole: Omeprazole increases the effect of hydantoin

Oxcarbazepine: Oxcarbazepine increases the effect of hydantoin

Oxtriphylline: Decreased effect of both products

Oxyphenbutazone: The NSAID, oxphenbutazone, may increase the therapeutic and adverse effects of phenytoin.

Pancuronium: Phenytoin decreases the effect of the muscle relaxant

Paramethasone: The enzyme inducer, phenytoin, may decrease the effect of the corticosteroid, paramethasone.

Phenylbutazone: The NSAID, phenylbutazone, may increase the therapeutic and adverse effects of phenytoin.

Posaconazole: Modifications of drug levels for both agents

Praziquantel: Markedly lower praziquantel levels

Prednisolone: The enzyme inducer, phenytoin, may decrease the effect of the corticosteroid, prednisolone.

Prednisone: The enzyme inducer, phenytoin, may decrease the effect of the corticosteroid, prednisone.

Quetiapine: Phenytoin decreases the effect of quetiapine

Quinestrol: The enzyme inducer, phenytoin, decreases the effect of the hormone agent, quinestrol.

Quinidine: The anticonvulsant, phenytoin, decreases the effect of quinidine.

Rifampin: Rifampin may decrease the therapeutic and adverse effects of phenytoin.

Sertraline: Sertraline increases the effect of hydantoin

Sirolimus: The hydantoin decreases sirolimus levels

Sucralfate: Sucralfate decreases the effect of hydantoin

Sulfadiazine: The sulfonamide increases the effect of hydantoin

Sulfamethizole: The sulfonamide increases the effect of hydantoin

Sunitinib: Possible decrease in sunitinib levels

Tacrolimus: Phenytoin may decrease the blood concentration of Tacrolimus. Monitor for changes in the therapeutic/toxic effects of Tacrolimus if Phenytoin therapy is initiated, discontinued or altered.

Telithromycin: Phenytoin may decrease the plasma concentration of Telithromycin by increasing its metabolism. Consider alternate therapy.

Temsirolimus: Phenytoin may increase the metabolism of Temsirolimus decreasing its efficacy. Concomitant therapy should be avoided.

Theophylline: Decreased effect of both products

Thiotepa: Possible increase in thiotepa levels

Ticlopidine: Ticlopidine may decrease the metabolism and clearance of phenytoin. Consider alternate therapy or monitor for adverse/toxic effects of phenytoin if ticlopidine is initiated, discontinued or dose changed.

Tipranavir: Phenytoin decreases the concentration of Tipranavir. Monitor for decreased Tipranavir efficacy.

Tobramycin: Increased risk of nephrotoxicity

Tolbutamide: Tolbutamide, a strong CYP2C9 inhibitor, may decrease the metabolism and clearance of Phenytoin. Consider alternate therapy or monitor for changes in Phenytoin therapeutic and adverse effects if Tolbutamide is initiated, discontinued or dose changed.

Topiramate: Increased phenytoin/decreased topiramate

Tramadol: Phenytoin may decrease the effect of Tramadol by increasing Tramadol metabolism and clearance.

Trazodone: The CYP3A4 inducer, Phenytoin, may decrease Trazodone efficacy by increasing Trazodone metabolism and clearance. Monitor for changes in Trazodone efficacy/toxicity if Phenytoin is initiated, discontinued or dose changed.

Tretinoin: The strong CYP2C8 inducer, Phenytoin, may increase the metabolism and clearance of oral Tretinoin. Consider alternate therapy to avoid failure of Tretinoin therapy or monitor for changes in Tretinoin effectiveness and adverse/toxic effects if Phenytoin is initiated, discontinued or dose changed.

Triamcinolone: The enzyme inducer, phenytoin, may decrease the effect of the corticosteroid, triamcinolone.

Triazolam: Phenytoin may increase the metabolism of triazolam via CYP3A4.

Trimethoprim: Trimethoprim increases the effect of hydantoin

Trioxsalen: The hydantoin decreases the effect of psoralene

Triprolidine: The CNS depressants, Triprolidine and Phenytoin, may increase adverse/toxic effects due to additivity. Monitor for increased CNS depressant effects during concomitant therapy.

Tubocurarine: Phenytoin decreases the effect of the muscle relaxant

Vecuronium: Phenytoin decreases the effect of the muscle relaxant

Verapamil: Verapamil may increase the serum concentration of Phenytoin by decreasing its metabolism. Monitor for changes in the therapeutic/adverse effects of Phenytoin if Verapamil is initiated, discontinued or dose changed.

Vigabatrin: Vigabatrin decreases the effect of hydantoin

Vinblastine: The antineoplasic agent decreases the effect of hydantoin

Voriconazole: Voriconazole may increase the serum concentration of phenytoin by decreasing its metabolism. Phenytoin may increase the serum concentration of voriconazole by increasing its metabolism. Consider alternate antifungal therapy or monitor for voriconazole therapy failure and phenytoin toxicity.

Warfarin: Warfarin may increase the serum concentration of phenytoin possibly by competing for CYP2C9 metabolism. Phenytoin may increase the anticoagulant effect of warfarin. Monitor phenytoin levels, prothrombin time, and therapeutic and adverse effects of both agents during concomitant therapy.