Adverse effects of phenobarbital therapy in epileptic dogs

Two poorly understood effects of phenobarbital, the most common drug used to treat canine epilepsy, are (1) serum thyroid hormone alterations, and (2) serum liver enzyme abnormalities. Alterations in concentrations of serum total thyroxine (T4), the major thyroid hormone, have been anecdotally reported to occur in dogs receiving phenobarbital, but at the time of this investigation, this had not been documented. The cause and clinical significance of alterations in serum thyroid hormone concentrations associated with phenobarbital therapy also had not been determined in dogs. Elevated serum liver-associated enzymes have been associated with hepatotoxicity in a retrospective study of dogs receiving phenobarbital (Dayrell-Hart et al. 1991). However, elevated serum liver-associated enzyme activities, especially serum alkaline phosphatase (AP) and serum alanine aminotransferase (ALT), are also commonly found in phenobarbital-treated dogs that do not have clinical signs of liver disease. This has led some to conclude that increased serum AP and ALT activities might also be due to induction of these enzymes, although conclusive evidence of this is lacking. The difficulty faced by veterinarians is differentiating between cases of possible liver enzyme induction and cases of early subclinical liver injury.The goals of this study were to investigate the cause, clinical significance, and risk factors associated with the development of thyroid and liver abnormalities in phenobarbital-treated epileptic dogs. Cross-sectional and prospective investigations of clinically healthy client-owned epileptic dogs receiving phenobarbital were performed to examine these issues. Additionally, samples obtained from these patients were used to perform in vitro investigations of the effects of phenobarbital on the liver.In this study, phenobarbital therapy caused a significant decrease m the serum T4 concentration within 3 weeks of the start of therapy, and the decrease continued for at least 1 year. The cause was most likely an increased metabolism and clearance of the hormone from the body. Dogs with low serum T4 concentrations did not have clinical signs of hypothyroidism, and did not have better or worse seizure control than dogs with normal serum T4 concentrations. Dogs receiving phenobarbital had significantly greater histopathological liver abnormalities than controls. Duration of phenobarbital therapy was a possible risk factor. In vitro studies indicated that increased serum ALT activity was not due to induction of the enzyme in the liver. This suggested that serum ALT concentration might be used as a non-invasive test to differentiate between early liver injury and enzyme induction in dogs with elevated serum liver-associated enzyme activities. Induction of AP activity was not observed in this study, but it is possible that induction was masked by a simultaneous increase in release of the enzyme from the hepatocyte membrane. Additional information discovered during this study, including pancreatitis associated with use of phenobarbital/potassium bromide combination therapy, will also be presented in this thesis.Source: Dissertation Abstracts International, Volume: 62-10, Section: B, page: 4484.Adviser: Alastair Cribb