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 microg/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 < or = .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.

Phenobarbitone‐induced haematological abnormalities in idiopathic epileptic dogs: prevalence, risk factors, clinical presentation and outcome

“…Total T4 and free T4 are suppressed in a significant proportion of dogs on PB and may be seen with or without an increase in TSH concentration. While clinical signs of hypothyroidism are more rarely documented, a mild non-regenerative anaemia could be a potential consequence of PB administration (Muller and others 2000, Daminet and Ferguson 2003). A mild normocytic normochromic non-regenerative anaemia could be the result of the chronic stress response induced by a frequent seizure activity; however, the majority of the dogs in the present study population had abnormalities in two or more cell lineages and the majority of dogs that have seizures do not have anaemia.…”

Diagnosis of Spontaneous Canine Hyperadrenocorticism: 2012 ACVIM Consensus Statement (Small Animal)

“…In veterinary medicine, the ability of glucocorticoids of any form, progestagens and ketoconazole to suppress cortisol secretion is known. No effect on the ACTH stimulation test was documented overall or individually in healthy dogs treated with phenobarbital for 8 (n = 12) or 29 weeks (n = 12) or in epileptic dogs treated for 1 year (n = 5) or >2 years (n = 5).…”

“…In veterinary medicine, only phenobarbital has been studied. Available evidence suggests no effect of phenobarbital on LDDST results, although occasionally phenobarbital‐treated dogs may not show suppression …”

Hypothyroidism

“…In dogs, phenobarbital treatment at therapeutic dosages decreases serum T 4 and fT 4 concentrations into the range consistent with hypothyroidism (Gaskill et al, 1999;Kantrowitz et al, 1999;Gieger et al, 2000;Muller et al, 2000). Although the mechanism remains unproven in dogs, increased metabolism and excretion of T 4 secondary to hepatic microsomal enzyme induction is believed to be the primary cause, although other mechanisms such as displacement of T 4 from plasma protein binding sites may also play a role.…”