As a follow-up to the October 1998 issue of Antech News, more information is offered about drugs associated with hepatic injury.

Although drugs are usually metabolized without injury to the liver, the central role it plays in drug metabolism makes drug-induced hepatic injury a potential complication of many medications.

Several commonly prescribed medications, outlined below, have been implicated in causing hepatic injury:

In 1988, Peterson et al reported that 4 of 262 cats with hyperthyroidism developed a reversible acute hepatopathy within 2 months of commencing methimazole treatment. These cats had clinical signs of anorexia, vomiting, and icterus, along with sudden elevations of ALT, AST, and ALP. Alternative treatments for hyperthyroid cats experiencing adverse effects of methimazole include I¹³¹ radiation, surgical thyroidectomy, and ipodate - [see July 1998 Antech News].

Hepatic necrosis occurs occasionally in association with use of potentiated sulfonamides. Of 4 cases reported by Twedt et al in 1997, all dogs died despite supportive care. Early recognition of this idiosyncratic drug reaction is important for a favorable outcome. Other recognized side-effects of potentiated sulfonamide use include immune-mediated anemia and thrombocytopenia, epidermal necrolysis, keratoconjunctivitis sicca, polyarthritis, and hypothyroidism.

Orally administered diazepam has been reported by Center et al (1996) to cause idiosyncratic, massive hepatic necrosis in cats. After 5-11 days of initial oral treatment with diazepam, 11 mixed breed cats showed signs of fulminant hepatic failure, including lethargy, ataxia, anorexia and jaundice. All cats were adults with no sex predisposition; dosage ranged from 1-5 mg per day and was given for inappropriate urination in 8 cats, suspected urethral spasm (1) and aggression (2). One of the affected cats was admitted in comatose condition and one had a bleeding diathesis. Despite intensive supportive treatment, 8 cats died within 7-15 days of initiating diazepam therapy, 2 were euthanized and only 1 survived. As markedly elevated liver enzymes were found, the authors recommended performing early surveillance of serum ALT and AST before, and 3-5 days after commencing diazepam to monitor for hepatotoxicity. As a consequence of this report, some clinicians even recommend avoiding diazepam use in cats.

Idiosyncratic hepatocellular toxicosis was recently reported by MacPhail et al (1998) to be associated with administration of carprofen in 21 dogs. All were given carprofen to alleviate signs of musculoskeletal pain. In 18 dogs, clinical signs and physical findings of hepatic toxicity were seen between 5-30 days (mean 19.7 days) of commencing carprofen, and predominantly included anorexia, icterus, vomiting, lethargy and diarrhea. In 2 dogs, signs developed only after 60 and 180 days of carprofen therapy, respectively. Laboratory findings of hepatic disease were present in all 21 dogs (elevated liver enzymes and hyperbilirubinemia), and 18 had histologic evidence of hepatic necrosis. Four dogs died or were euthanized within 3-5 days of initial examination, but the other 17 dogs fully recovered from the drug-induced hepatic disease with supportive care. An intriguing finding was the fact that 13 of the 21 animals were Labrador Retrievers ranging in age from 4-15 years (mean 9.4 years), and all recovered after carprofen was discontinued. The remaining 8 dogs were purebreds of 8 different breeds. Most (13/21) were spayed females; 3 were intact males and 5 were neutered males.

Based on the results of this study, dogs receiving carprofen need to be monitored closely for signs of toxicity. The prognosis for complete recovery appears to be good, if treatment is discontinued before hepatic damage is severe or sustained.

Although albendazole is an effective anthelmintic against Giardia spp, its use is associated with a variety of severe adverse effects including bone marrow suppression, teratogenicity, neurological signs, vomiting, diarrhea, and hepatotoxicity. Because there is no approved animal drug for treatment of giardiasis in dogs, practitioners are forced to use drugs such as fenbendazole, albendazole, metronidazole and quinocrine hydrochloride in an extralabel manner.

Of these drugs, fenbendazole is safe and approved for use as an anthelmintic in dogs, but not for giardiasis. Given the serious potential adverse effects from extralabel use of albendazole for treatment of giardiasis, fenbendazole, the approved benzimidazole anthelmintic for dogs, is the preferred drug for treating canine giardiasis.

References: Peterson et al, J Vet Int Med 1988; 2: 150-157; Twedt et al, J Vet Int Med 1997; 11: 20-23; Center et al, J Am Vet Med Assoc 1996; 209: 618-625; Cornelius, Adv Sm An Med Surg 1997; 10 (8): 1; MacPhail et al, J Am Vet Med Assoc 1998; 212: 1895-1901; Meyer, J Am Vet Med Assoc 1998; 213: 44-46.