Effects of Long‐Term Phenobarbital Treatment on the Thyroid and Adrenal Axis and Adrenal Function Tests in Dogs

Abstract

Phenobarbital can interfere with the thyroid axis in human beings and rats by accelerating hepatic thyroxine metabolism because of enzyme induction. In human beings, it also can interfere with the low-dose dexamethasone suppression test (LDDST) used to assess adrenal function by accelerating dexamethasone metabolism. This effect can cause a lack of suppression of pituitary ACTH and subsequent adrenal cortisol release after dexamethasone administration. The effects of phenobarbital on the thyroid axis, the adrenal axis, and adrenal function tests were prospectively investigated in 12 normal, adult dogs. Phenobarbital was administered at 5 mg per kilogram of body weight (range, 4.8-6.6 mg/kg) PO q12h for 29 weeks, resulting in therapeutic serum concentrations (20-40 g/mL). Serum total thyroxine (TT4), free thyroxine (FT4) by equilibrium dialysis, total triiodothyronine (TT3), thyrotropin (TSH), and cholesterol were determined before and during phenobarbital treatment. LDDST, ACTH stimulation tests, and ultrasonographic evaluation of the adrenal glands were performed before and during treatment. TT4 and FT4 decreased significantly (P Յ .05), TT3 had minimal fluctuation, TSH had only a delayed compensatory increase, and cholesterol increased during phenobarbital treatment. The delayed increase in TSH, despite persistent hypothyroxinemia, suggests that accelerated hepatic thyroxine elimination may not be the only effect of phenobarbital on the thyroid axis. There was no significant effect of phenobarbital on either of the adrenal function tests. With the methods employed, we did not find any effects of the drug on the hormonal equilibrium of the adrenal axis. Key words: Adrenal axis, Adrenal function tests, Phenobarbital, Thyroid axis. In rats and human beings, anticonvulsant drugs have considerable effects on the thyroid gland and thyroid hormone metabolism. Phenobarbital increases hepatic metabolism and biliary excretion of thyroxine by inducing hepatic enzymes, such as thyroxine-glucuronosyltransferase and cytochrome P450 enzymes. [1][2][3][4][5] In rats, a primary increase of hepatic thyroxine uptake stimulates hepatic deiodinative and excretory processes. Increased fecal and deiodinative clearance of thyroxine and triiodothyronine activates the thyroid axis, resulting in increased pituitary thyrotropin (TSH) secretion and subsequent establishment of a new steady state with normal thyroxine concentrations and somewhat increased TSH concentrations.2,4,6 Thyroid gland weight remains increased, indicating chronic stimulation. 2Several textbooks and review articles in the veterinary literature mention that phenobarbital decreases basal serum thyroxine concentrations in dogs.7-10 However, more recent data suggest that phenobarbital treatment at 30-45 mg q12h for 3 weeks has no significant effect on total thyroxine University, Baton Rouge, LA 70803; email: jtaboada@ mail.vetmed.lsu.edu. Submitted June 26, 1998; Revised March 12, 1999, and July 1, 1999; Accepted October 19, 1999 (TT4), free thyroxine (FT4), and TSH ...

Thyroid Function and Serum Hepatic Enzyme Activity in Dogs after Phenobarbital Administration

“…3,8,12 In a retrospective study of 18 dogs with hepatotoxicosis secondary to phenobarbital administration, hypoalbuminemia occurred in 75%, and elevations in ALP, ALT, bile acids, and total bilirubin were documented in 100, 85, 33, and 40%, respectively. 18 The average duration of treatment was 39 months, and 75% of dogs had a serum phenobarbital concentration of greater than 40 g/mL.…”

“…Therefore, the ALP elevations likely were attributable to phenobarbital-induced enzyme changes. 12 In dogs treated with glucocorticoids, the ALP can remain elevated for weeks to months despite discontinuation of the drug.…”

“…22 In the dogs of this study, neither cytologic evidence of hepatocellular damage nor AST elevation occurred, supporting the idea that the ALT elevation was induced secondary to phenobarbital. 12 The half-life of serum ALT is approximately 1-2 days, and ALT is expected to decrease over 1-2 weeks after hepatic damage ceases. 22 In a study of 6 dogs with hepatopathy induced by glucocorticoid administration, ALT elevations persisted for 6 weeks after discontinuation of the steroids.…”

“…Phenobarbital was discontinued in all 12 dogs immediately before the beginning of this study. 12 Serum was collected at week 27 and at weekly intervals thereafter for 10 weeks; thus, data for week 27 represented baseline for this study. Evaluation of liver enzyme activity in serum (ALP, ALT, GGT) and albumin, TT 4 , FT 4 , TSH, and cholesterol concentrations were performed at weeks 1-3, 5, 7, and 9 (ALP, ALT, GGT, albumin, and cholesterol); weeks 1-10 (TT 4 ); weeks 1, 2, 4-6, 8, and 10 (FT 4 ); and weeks 1, 2, 4-8, and 10 (TSH).…”

“…[9][10][11][12] Although the mechanism of these changes remains unproven in dogs, serum T 4 concentration is suspected to be decreased because of increased metabolism and excretion of the hormone secondary to hepatic microsomal enzyme induction, as is the case in humans and rodents. 11,13,14 The length of time necessary for thyroid hormone concentrations to return to normal after discontinuation of long-term phenobarbital administration in the dog is unknown.…”