Phenytoin hepatotoxicity

Convulsions associated with fever often occur in children 3 months to 5 years of age. Epilepsy later develops in approximately 2 to 3% of children who exhibit one or more such febrile seizures. Most authorities now recommend prophylactic treatment with anticonvulsant drugs only to patients at highest risk for development of epilepsy and for those who have multiple recurrent febrile seizures. Phenobarbital is the usual drug, although diazepam is also effective. Phenytoin and carba-mazepine are ineffective, and valproic acid may cause hepatotoxicity in very young patients. 

As with carbamazepine, phenytoin also causes idiosyncratic toxic effects, including hematological and connective tissue toxicities, hepatotoxicity, and teratogenicity (89). Although some of these toxicities have been hypothesized to be caused by P450 oxidative metabolism (92,93) or peroxidase-mediated reactions (94,95), mechanisms for these toxic effects in humans are unknown. 

Kostrubsky SE, Sinclair JF, Strom SC, et al. Phenobarbital and phenytoin increased acetaminophen hepatotoxicity due to inhibition of UDP-glucuronosyl transferases in cultured human hepatocytes. Toxicol Sci 2005 87 146-155. 

With phenytoin, carbamazepine, phenobarbital, primidone, and lamotrigine, hepatotoxicity usually occurs as part of a hypersensitivity reaction, with skin rashes and fever in the early weeks of treatment. More rarely, hepatic disease can develop after many years without signs of hypersensitivity. Once hepatotoxicity develops, mortality... 

Acute hepatotoxicity has been reported with isoflurane (14). The authors hypothesized that induction of cytochrome P-450 by phenytoin had caused enhanced transformation of isoflurane to trifluoroacetic acid. They suggested that caution should be taken in the use of halogenated anesthetics in patients taking drugs that induce cytochrome P-450 isozymes. 

Brackett CC, Bloch ID. Phenytoin as a possible cause of acetaminophen hepatotoxicity case report and review of the literature. Pharmacotherapy 2000 20(2) 229-33. 

Phenytoin can cause vestibulocerebellar, oculomotor, and cognitive dysfunction. It can also cause gingival hyperplasia, hirsutism, and acromegaly-hke facial features. Movement disorders, symptoms of peripheral neuropathy, and endocrine changes are uncommon. Interstitial nephritis, interstitial pneumonia, and hepatotoxicity are rare. High intravenous doses are cardiotoxic. 

Chronic hepatitis is rarely caused by phenytoin (SEDA-18, 67). When it occurs, the signs of hepatotoxicity usually appear after 1-8 weeks in acute cases, and after 4 months to several years in chronic cases (37). Among 16 acute cases, there was fever in 75%, rash in 63%, jaundice in 44%, hepatomegaly in 13%, and lymphadenopathy and splenomegaly in 60% (37). Less common sjmptoms included sore throat, malaise, chills, myalgia, and pruritus. The condition can be fatal. 

It has been proposed that phenytoin can exacerbate the hepatotoxic effects of paracetamol (76). 

The authors suggested that induction of CYP3A4 by phenytoin had encouraged the formation of a hepatotoxic metabolite of paracetamol. 

Levy RH, Rettenmeier AW, Anderson GD, Wilensky AJ, Friel PN, Baillie TA, Acheampong A, Tor J, Guyot M, Loiseau P. Effects of poly therapy with phenytoin, carbama-zepine, and stiripentol on formation of 4-ene-valproate, a hepatotoxic metabolite of valproic acid. Qin Pharmacol Ther 1990 48(3) 225-35. 

HCQ cimetidine increases serum levels absorption decreased when taken with kaolin and magnesium trisilicate MTX decreases effect of phenytoin concomitant use with other hepatotoxic drugs can increase risk of hepatotoxicity. NSAIDs can increase half-life and prolong excretion of MTX however, low doses of MTX with NSAIDs for RA are allowed with close monitoring. 

Transient elevations of the serum transaminases occur in 12% to 15% of patients receiving isoniazid and usually occur within the first 8 to 12 weeks of therapy. Overt hep ato toxicity, however, occurs in only 1% of cases. Risk factors for hepatotoxicity include patient age, preexisting liver disease, excessive alcohol intake, pregnancy, and the postpartum state. Isoniazid also may result in neurotoxicity, most frequently presenting as peripheral neuropathy or, in overdose, as seizures and coma. Patients with pyridox-ine deficiency, such as pregnant women, alcoholics, children, and the malnourished, are at increased risk. Isoniazid may inhibit the metabolism of phenytoin, carbamazepine, primidone, and warfarin." Patients who are being treated with these agents should be monitored closely, and appropriate dose adjustments should be made when necessary. 

Valproic acid In addition to competing for phenytoin plasma protein binding sites, valproic acid inhibits the metabolism of phenytoin, phenobarbital, and lamotrigine. Hepatic biotransformation of valproic acid leads to formation of a toxic metabolite that has been implicated in the hepatotoxicity of the drug. 

Valproic acid often causes gastrointestinal distress and is potentially hepatotoxic. The use of this drug in pregnancy has been associated with teratogenicity (neural tube defects). Valproic acid inhibits the metabolism of barbiturates marked CNS depression may result if such drugs are given concomitantly. Peripheral neuropathy, in the form of diminished deep tendon reflexes in the lower extremities, is associated with chronic use of phenytoin. The answer is (C). 

Toxicity and interactions Neurotoxic effects are common and include peripheral neuritis, restlessness, muscle twitching, and insomnia. These effects can be alleviated (without blocking the antibacterial effect) by administration of pyridoxine. INH is hepatotoxic and may cause abnormal liver function tests, jaundice, and hepatitis. Fortunately, hepatotoxicity is rare in children. INH may inhibit the hepatic metabolism of dmgs, eg, phenytoin. Hemolysis has occurred in patients with glucose-6-phosphate dehydrogenase deficiency. A lupuslike syndrome has been reported. 

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