Phenytoin Toxicity

Phenytoin Toxicity

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Phenytoin is a commonly prescribed anticonvulsant used to treat most types of seizure disorders and status epilepticus, with the exception of absence seizures.

Historically, phenytoin was used as an antidysrhythmic agent, especially in the treatment of dysrhythmias due to digoxin toxicity. It has  fallen out of favor for that use because of the advent of digoxin antibody fragments. Phenytoin is no longer considered appropriate for the management of toxin-induced or alcohol withdrawal seizures.

Signs and symptoms of phenytoin toxicity typically correspond to the serum level, and progress from occasional mild nystagmus at 10-20 mcg/mL (the therapeutic range) to coma and seizures at levels above 50 mcg/mL (see Presentation and Workup). Treatment is supportive (see Treatment and Medication).

Phenytoin blocks voltage-sensitive sodium channels in neurons. This action leads to a delay in neuronal electrical recovery from inactivation. [1] Phenytoin’s inhibitory effect is dependent on the voltage and frequency of neural cell firing by selectively blocking the neurons that are firing at high frequency. Phenytoin prevents the electrical spread of a focus of irritable tissue from entering normal tissue.

Phenytoin administration has been associated with toxic effects. Phenytoin toxicity depends on the route of administration, duration, exposure, and dosage. The route of administration is the most important determinant of toxicity. Phenytoin may be administered orally or intravenously. In addition, fosphenytoin (water-soluble phenytoin prodrug) may be administered intramuscularly.

Phenytoin is a weak acid and has erratic GI absorption. Following ingestion, phenytoin precipitates in the stomach’s acid environment; this characteristic is particularly important in the setting of an intentional overdose. Peak blood levels occur 3-12 hours following single dose ingestion, but absorption can be extended up to 2 weeks, especially in massive overdose. Oral exposures are associated predominantly with CNS symptoms.

The parenteral form of phenytoin is dissolved in 40% propylene glycol and 10% ethanol and adjusted to a pH of 12; sodium hydroxide is added to maintain solubility. Extravasation of the solution may cause skin irritation or phlebitis. Phenytoin administered intravenously at a rate higher than 50 mg/min may cause hypotension and arrhythmias. These complications are believed to be secondary to the diluent, propylene glycol. However, cardiac toxicity was reported even after rapid administration of fosphenytoin that does not contain propylene glycol, suggesting intrinsic phenytoin cardiac toxicity. Orally administered phenytoin is rarely, if ever, associated with cardiac toxicity.

Phenytoin has a small volume of distribution of 0.6 L/kg and is extensively bound to plasma proteins (90%). Blood levels of phenytoin reflect only total serum concentration of the drug. Only the free unbound phenytoin has biological activity. Because CNS tissue levels are higher than in serum, levels may underestimate CNS concentrations of phenytoin. [2]

Population groups that are predisposed to elevated free phenytoin levels include neonates, elderly persons, and individuals with uremia, hypoalbuminemia (due to pregnancy, nephrotic syndrome, malignancy, malnutrition), or hyperbilirubinemia. These patients may exhibit signs of toxicity when drug levels are within the therapeutic range (see Lab Studies). Certain medications can interfere with phenytoin levels.

Hepatic microsomal enzymes primarily metabolize phenytoin. Much of the drug is excreted in the bile as an inactive metabolite, which is then reabsorbed from the intestinal tract and ultimately excreted in the urine. Less than 5% of phenytoin is excreted unchanged in the urine. Individuals with impaired metabolic or excretory pathways may exhibit early signs of toxicity. Genetic polymorphism in the cytochrome enzymes that metabolize phenytoin may be responsible for variable rates of metabolism and thus susceptibility to toxicity, even in individuals taking appropriate doses. [3, 4]

Phenytoin metabolism is dose dependent. Elimination follows first-order kinetics (fixed percentage of drug metabolized during a per unit time) at the low drug concentrations and zero-order kinetics (fixed amount of drug metabolized per unit time) at higher drug concentrations. This change in kinetics reflects the saturation of metabolic pathways. Thus, very small increments in dosage may result in adverse effects.

United States

In the 2016 Annual Report of the American Association of Poison Control Centers’ National Poison Data System, 1584 single exposures to phenytoin were reported. Of these, 540 were unintentional toxicities, 369 were intentional, and 562 were reported as an adverse reaction. In addition eight single exposures to fosphenytoin were reported, five as adverse reactions and two as unintentional. [5]

Death or severe morbidity rarely occurs with an intentional overdose as long as the patient receives good supportive care.

Of the 1584 reported toxic exposures in 2016, 1299 were treated in a health care facility. Of this subset of patients, 201 had no significant outcome, 471 had minor effects, 467 had moderate morbidity, and 45 had major morbidity; five deaths were reported. [5]

Phenytoin is a category D drug. Various congenital anomalies have been reported from usage during pregnancy (see fetal hydantoin syndrome). No scientific data have demonstrated that effect or outcome of acute toxicity is based on sex.

Neonates and elderly patients are at greater risk for toxicity because of impaired metabolism and decreased protein binding. Decreased protein binding contributes to higher levels of biologically active medication at therapeutic measured total phenytoin blood levels (see Lab Studies).

Of the 1584 reported exposures in 2016, a total of 92 were in children younger than 6 years, 46 in patients 6-19 years of age, and 1397 in those 20 years and older. [5]

Colombo E, Franceschetti S, Avanzini G, Mantegazza M. Phenytoin inhibits the persistent sodium current in neocortical neurons by modifying its inactivation properties. PLoS One. 2013. 8 (1):e55329. [Medline]. [Full Text].

Craig S. Phenytoin poisoning. Neurocrit Care. 2005. 3(2):161-70. [Medline].

McCluggage LK, Voils SA, Bullock MR. Phenytoin toxicity due to genetic polymorphism. Neurocrit Care. 2009. 10(2):222-4. [Medline].

Dorado P, López-Torres E, Peñas-Lledó EM, Martínez-Antón J, Llerena A. Neurological toxicity after phenytoin infusion in a pediatric patient with epilepsy: influence of CYP2C9, CYP2C19 and ABCB1 genetic polymorphisms. Pharmacogenomics J. 2012 May 29. [Medline].

Gummin DD, Mowry JB, Spyker DA, Brooks DE, Fraser MO, Banner W. 2016 Annual Report of the American Association of Poison Control Centers’ National Poison Data System (NPDS): 34th Annual Report. Clin Toxicol (Phila). 2017 Dec. 55 (10):1072-1252. [Medline]. [Full Text].

Adams BD, Buckley NH, Kim JY, Tipps LB. Fosphenytoin may cause hemodynamically unstable bradydysrhythmias. J Emerg Med. 2006 Jan. 30(1):75-9. [Medline].

Chokshi R, Openshaw J, Mehta NN, Mohler E 3rd. Purple glove syndrome following intravenous phenytoin administration. Vasc Med. 2007 Feb. 12(1):29-31. [Medline].

Tobler A, Hösli R, Mühlebach S, Huber A. Free phenytoin assessment in patients: measured versus calculated blood serum levels. Int J Clin Pharm. 2016 Apr. 38 (2):303-9. [Medline].

Kiang TK, Ensom MH. A Comprehensive Review on the Predictive Performance of the Sheiner-Tozer and Derivative Equations for the Correction of Phenytoin Concentrations. Ann Pharmacother. 2016 Apr. 50 (4):311-25. [Medline].

Sen S, Ratnaraj N, Davies NA, Mookerjee RP, Cooper CE, Patsalos PN. Treatment of phenytoin toxicity by the molecular adsorbents recirculating system (MARS). Epilepsia. 2003 Feb. 44(2):265-7. [Medline].

[Guideline] Benson BE, Hoppu K, Troutman WG, Bedry R, Erdman A, Höjer J, et al. Position paper update: gastric lavage for gastrointestinal decontamination. Clin Toxicol (Phila). 2013 Mar. 51 (3):140-6. [Medline]. [Full Text].

Dolgin JG, Nix DE, Sanchez J, Watson WA. Pharmacokinetic simulation of the effect of multiple-dose activated charcoal in phenytoin poisoning–report of two pediatric cases. DICP. 1991 Jun. 25(6):646-9. [Medline].

Chan BS, Sellors K, Chiew AL, Buckley NA. Use of multi-dose activated charcoal in phenytoin toxicity secondary to genetic polymorphism. Clin Toxicol (Phila). 2015 Feb. 53 (2):131-3. [Medline].

Cumpston K, Stromberg P, Wills BK, Rose SR. Activated Charcoal Does Not Reduce Duration of Phenytoin Toxicity in Hospitalized Patients. Am J Ther. 2016 May-Jun. 23 (3):e773-7. [Medline].

Ghannoum M, Troyanov S, Ayoub P, Lavergne V, Hewlett T. Successful hemodialysis in a phenytoin overdose: case report and review of the literature. Clin Nephrol. 2010 Jul. 74(1):59-64. [Medline].

Sahoo JN, Gurjar M. Should we do early and frequent charcoal hemoperfusion in phenytoin toxicity?. Indian J Crit Care Med. 2016 Feb. 20 (2):123-5. [Medline]. [Full Text].

De Schoenmakere G, De Waele J, Terryn W, Deweweire M, Verstraete A, Hoste E, et al. Phenytoin intoxication in critically ill patients. Am J Kidney Dis. 2005 Jan;. 45(1):189-92. [Medline].

Skinner CG, Chang AS, Matthews AS, Reedy SJ, Morgan BW. Randomized controlled study on the use of multiple-dose activated charcoal in patients with supratherapeutic phenytoin levels. Clin Toxicol (Phila). 2012 Sep. 50 (8):764-9. [Medline].

Charlene Miller, MD Consulting Staff, Department of Emergency Medicine, Oakwood Hospital Medical Center

Charlene Miller, MD is a member of the following medical societies: American College of Emergency Physicians

Disclosure: Nothing to disclose.

Daniel M Joyce, MD Consulting Staff, Department of Emergency Medicine, Saint Vincent’s and Saint Mary’s Medical Center

Daniel M Joyce, MD is a member of the following medical societies: American College of Emergency Physicians, American Medical Association

Disclosure: Nothing to disclose.

John T VanDeVoort, PharmD Regional Director of Pharmacy, Sacred Heart and St Joseph’s Hospitals

John T VanDeVoort, PharmD is a member of the following medical societies: American Society of Health-System Pharmacists

Disclosure: Nothing to disclose.

Fred Harchelroad, MD, FACMT, FAAEM, FACEP Attending Physician in Emergency Medicine and Medical Toxicology, Excela Health System

Fred Harchelroad, MD, FACMT, FAAEM, FACEP is a member of the following medical societies: American College of Medical Toxicology

Disclosure: Nothing to disclose.

David Vearrier, MD, MPH Associate Professor, Medical Toxicology Fellowship Director, Department of Emergency Medicine, Drexel University College of Medicine

David Vearrier, MD, MPH is a member of the following medical societies: American Academy of Clinical Toxicology, American Academy of Emergency Medicine, American College of Medical Toxicology, American College of Occupational and Environmental Medicine

Disclosure: Nothing to disclose.

Lance W Kreplick, MD, FAAEM, MMM, UHM Staff Physician for Occupational Health and Rehabilitation, Company Care Occupational Health Services; President and Chief Executive Officer, QED Medical Solutions, LLC

Lance W Kreplick, MD, FAAEM, MMM, UHM is a member of the following medical societies: American Academy of Emergency Medicine, American Association for Physician Leadership

Disclosure: Nothing to disclose.

Phenytoin Toxicity

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