Phenytoin …

K K Jain MD†

Neuropharmacology & Neurotherapeutics

Updated 09.13.2021
Released 12.18.1998
Expires For CME 09.13.2024

Phenytoin

Author: K K Jain MD†

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Phenytoin

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Introduction

Historical note and terminology

The era of antiepileptic drugs started with the introduction of bromides in 1857 and was followed by the discovery of the anticonvulsant effect of barbiturates in 1912. Hydantoins, structurally like barbiturates, followed as second generation antiepileptic agents. The main action of hydantoins is to prevent the spread of seizure activity by stabilizing the neuronal membranes through modulating ion fluxes. Phenytoin (diphenylhydantoin) was synthesized in 1908 (04) and was introduced in the treatment of epilepsy in 1938 (15).

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).

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).

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.

Gum hypertrophy

(Contributed by Dr. Sudhir Kothari.)

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.

References

01: Ahn JE, Cloyd JC, Brundage RC, et al. Phenytoin half-life and clearance during maintenance therapy in adults and elderly patients with epilepsy. Neurology 2008;71(1):38-43. PMID 18591503
02: Al Ghamdi RM, Turkistani AN, Ben Ali H. Phenytoin seizure prophylaxis therapy resulting in severe thrombocytopenia after brain tumor debulking surgery. Am J Case Rep 2020;21:e919828.** PMID 31996666
03: Bartollino S, Chiosi F, di Staso S, et al. The retinoprotective role of phenytoin. Drug Des Devel Ther 2018;12:3485-9.** PMID 30410309
04: Biltz H. Über die konstitution der einwirkungsprodukte von substituierten harnstoffen auf benzil und uber einige neue methoden zur darstellung der 5,5-Diphenylhydantoine. Ber Dtsch Chem Ges 1908;41:1379-93.
05: Bird PD. The treatment of autism with low-dose phenytoin: a case report. J Med Case Rep 2015;9:8. PMID 25592685
06: Birse F, Derry S, Moore RA. Phenytoin for neuropathic pain and fibromyalgia in adults. Cochrane Database Syst Rev 2012;5:CD009485. PMID 22592741
07: Caudle KE, Rettie AE, Whirl-Carrillo M, et al. Clinical pharmacogenetics implementation consortium guidelines for CYP2C9 and HLA-B genotypes and phenytoin dosing. Clin Pharmacol Ther 2014;96(5):542-8. PMID 25099164
08: Debenham S, Sabit B, Saluja RS, et al. A critical look at phenytoin use for early post-traumatic seizure prophylaxis. Can J Neurol Sci 2011;38(6):896-901. PMID 22030429
09: Fohner AE, Ranatunga DK, Thai KK, et al. Assessing the clinical impact of CYP2C9 pharmacogenetic variation on phenytoin prescribing practice and patient response in an integrated health system. Pharmacogenet Genomics 2019;29(8):192-9. PMID 31461080
10: Inaba K, Menaker J, Branco BC, et al. A prospective multicenter comparison of levetiracetam versus phenytoin for early posttraumatic seizure prophylaxis. J Trauma Acute Care Surg 2013;74(3):766-71. PMID 23425733
11: Karnes JH, Rettie AE, Somogyi AA, et al. Clinical pharmacogenetics implementation consortium (CPIC) guideline for CYP2C9 and HLA-B genotypes and phenytoin dosing: 2020 update. Clin Pharmacol Ther 2021;109(2):302-9. PMID 32779747
12: Kim SS, Nikoloudaki G, Darling M, Rieder MJ, Hamilton DW. Phenytoin activates Smad3 phosphorylation and periostin expression in drug-induced gingival enlargement. Histol Histopathol 2018;33(12):1287-98. PMID 29916554
13: Krasowski MD, Penrod LE. Clinical decision support of therapeutic drug monitoring of phenytoin: measured versus adjusted phenytoin plasma concentrations. BMC Med Inform Decis Mak 2012;12:7. PMID 22333264
14: López-González MJ, Luis E, Fajardo O, et al. TRPA1 channels mediate human gingival fibroblast response to phenytoin. J Dent Res 2017;96(7):832-9. PMID 28571526
15: Merritt HH, Putnam TJ. Sodium diphenyl hydantoinate in the treatment of convulsive disorders. JAMA 1938;111:1068-73.
16: Murphy R, Daugherty J, Houry D. Contraindications to phenytoin in emergency department patients with seizures. J Emerg Med 2009;37(4):355-8. PMID 18325712
17: Nevitt SJ, Marson AG, Weston J, Tudur Smith C. Carbamazepine versus phenytoin monotherapy for epilepsy: an individual participant data review. Cochrane Database Syst Rev 2017;2:CD001911.** PMID 28240353
18: Osorio S, Escudero-Vilaplana V, Gómez-Centurión I, González-Arias E, García-González X, Díez JL. Inadequate response to imatinib treatment in chronic myeloid leukemia due to a drug interaction with phenytoin. J Oncol Pharm Pract 2019;25(3):694-8. PMID 29199506
19: Pinder C, Young C. Adverse cognitive effects of phenytoin in severe brain injury: a case report. Brain Inj 2011;25(6):634-7. PMID 21534742
20: Raftopoulos R, Hickman SJ, Toosy A, et al. Phenytoin for neuroprotection in patients with acute optic neuritis: a randomised, placebo-controlled, phase 2 trial. Lancet Neurol 2016;5(3):259-69. PMID 26822749
21: Rosillo-de la Torre A, Zurita-Olvera L, Orozco-Suárez S, et al. Phenytoin carried by silica core iron oxide nanoparticles reduces the expression of pharmacoresistant seizures in rats. Nanomedicine (Lond) 2015;10(24):3563-77. PMID 26649451
22: Sakurai M, Kawahara K, Ueda R, Fukui E, Yamada R. A case of toxicity caused by drug interaction between capecitabine and phenytoin in patient with colorectal cancer [Article in Japanese]. Gan To Kagaku Ryoho 2011;38(5):841-3. PMID 21566450
23: Selioutski O, Grzesik K, Vasilyeva ON, et al. Evaluation of phenytoin serum levels following a loading dose in the acute hospital setting. Seizure 2017;52:199-204.** PMID 29073585
24: Shanmugarajah PD, Hoggard N, Aeschlimann DP, et al. Phenytoin-related ataxia in patients with epilepsy: clinical and radiological characteristics. Seizure 2018;56:26-30. PMID 29427835
25: Soskin DP, Kane AJ, Stern TA. Phenytoin toxicity secondary to an oxcarbazepine-phenytoin 2C19 interaction. Psychosomatics 2010;51(6):532-5. PMID 21051688
26: Sudarsan P, Varghese R, Suresh A, Radhakrishnan A. Phenytoin-induced paradoxical seizures and blood dyscrasias in a patient receiving rapid intravenous infusion: a case report. J Pharm Pract 2021;34(2):306-8. PMID 31875759
27: Tacker DH, Robinson R, Perrotta PL. Abbott ARCHITECT iPhenytoin assay versus similar assays for measuring free phenytoin concentrations. Lab Med 2014;45(2):176-81. PMID 24869001
28: Tobler A, Muhlebach S. Intravenous phenytoin: a retrospective analysis of Bayesian forecasting versus conventional dosing in patients. Int J Clin Pharm 2013;35(5):790-7. PMID 23812678
29: Tsang CY, Ng JYW, Yuen SH, Lau IT, Leung YF. Purple glove syndrome caused by intravenous phenytoin: two case reports. Hong Kong Med J 2019;25(6):487-9. PMID 32127502
30: Twardowschy CA, Werneck LC, Scola RH, Borgio JG, De Paola L, Silvado C. The role of CYP2C9 polymorphisms in phenytoin-related cerebellar atrophy. Seizure 2013;22(3):194-7. PMID 23298603

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Phenytoin

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Phenytoin …

Phenytoin

Introduction

Historical note and terminology

Pharmacology

Clinical trials

Indications

Off-label uses

Contraindications

Goals and duration of treatment

Dosing

Special considerations

Interactions

Adverse effects

Media

References

Contributors

Author

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Also in This Category

Anti-LGI1 encephalitis

Self-limited (familial) neonatal epilepsy

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Acupuncture

Epileptic lesions due to malformation of cortical development

Epileptic spasms

Sleep and epilepsy

Neocortical temporal lobe seizures

Phenytoin

Introduction

Historical note and terminology

Pharmacology

Clinical trials

Indications

Off-label uses

Contraindications

Goals and duration of treatment

Dosing

Special considerations

Interactions

Adverse effects

Media

References

Contributors

Author

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Anti-LGI1 encephalitis

Self-limited (familial) neonatal epilepsy

Alcohol withdrawal seizures

Acupuncture

Epileptic lesions due to malformation of cortical development

Epileptic spasms

Sleep and epilepsy

Neocortical temporal lobe seizures

This is an article preview.
Start a Free Account
to access the full version.