How to Dose and Monitor Hyperthyroid Cats on Methimazole

Antithyroid drugs, including methimazole and carbimazole, are medications that treat an overactive thyroid (hyperthyroidism) by blocking the thyroid gland's ability to make thyroid hormone. Carbimazole is a "pro-drug" since, after its absorption, it is converted to "active" methimazole in the body; therefore, these drugs can be considered equivalent (1).

Over the 25 years since we first reported the use of methimazole for treatment of cats with hyperthyroidism (2), I have had repeated questions from veterinarians and cat owners about the use of once or twice-daily dosing regimes. In addition, I've had many questions regarding the best time to monitor a hyperthyroid cat's serum thyroid concentrations during methimazole treatment.

The purpose of this post is to review how these drugs actually work to lower serum T4 and T3 values. In addition, I'll provide an overview of my current protocols for dosing and monitoring hyperthyroid cats treated with these drugs.

How Do Antithyroid Drugs Work? What's the Mechanism of Action?
After administration, the thyroid gland takes up and concentrates methimazole from the circulation. Once within the thyroid, methimazole works by inhibiting the production of T4 and T3 from the hyperthyroid cat's thyroid tumor.

More specifically, methimazole blocks thyroid hormone synthesis by inhibiting thyroid peroxidase, an enzyme involved in the oxidation of iodide to iodine, incorporation of iodine into thyroglobulin, and coupling of tyrosine residues to form T4 and T3 (2-7). Methimazole does not block the release of preformed thyroid hormone, so there is generally a delay of 2 to 4 weeks  before serum T4 concentrations return to normal after initializing therapy.

It is important to remember that antithyroid drugs, such as methimazole, do not destroy the thyroid tumor, decrease it's size, or slow the progressive thyroid tumor growth that is characteristic for this disorder. Because the thyroid tumor continues to grow larger over time despite methimazole therapy, the need for higher doses should be anticipated during long term treatment in many cats (6-8).

How Long Does a Dose of Methimazole "Last" After Its Given? 
After oral administration, studies show that methimazole has a relatively short half-life in the circulation—only 2.3 hours and 4.7 hours in hyperthyroid and normal cats, respectively (9,10).  But we must remember that this drug does not work to lower T4 by remaining in the circulation. Rather, this antithyroid drug is taken up by the thyroid gland, the site where it acts to inhibit the production of thyroid hormones.  In accord with that, normal cats show sustained suppression of serum thyroid hormone concentrations for up to 24 hours after a single dose of methimazole (11), proving that this drug inhibits T4 production far beyond its known half-life in the circulation.

Unfortunately, once-daily dosing with methimazole will not be adequate in most cats with hyperthyroidism. In one study of 40 hyperthyroid cats (12), once-daily dosing was much less effective than use of twice-daily administration (the total daily dose given was the same in both groups of cats). In that study, only 54% of cats become euthyroid (i.e., normal thyroid state) after 2 weeks with once daily treatment, whereas 87% of cats became euthyroid with twice-daily administration (12).  Therefore, I strongly recommend twice daily dosing of methimazole to help ensure better control of the cat's hyperthyroid state.

If once-daily treatment is insufficient and twice-daily treatment causes compliance issues, a sustained carbimazole formulation (Vidalta, MSD Animal Health) can be tried at 10 to 15 mg, once a daily (13). However, this drug is not approved for use in the USA and is currently only available in Europe.

For more information about carbimazole and Vidalta, see my last post on Antithyroid Drug Treatment for Hyperthyroidism: Brand Name, Generic, or Compounded Drug? 

Initial Methimazole Dose 
The initial methimazole doses used vary depending on the cat’s pretreatment serum T4 value and the size of the thyroid tumor. In general, however, most cats are started on 1.25 mg to 2.5 mg of methimazole, administered twice daily (4-7). This dose is adjusted according to T4 measurements (see below), as well as the cat's clinical response.

In cats that fail to respond and remain hyperthyroid, the daily doses are slowly titrated upwards to lower serum T4 concentrations into the desired range.  For more information about making dose adjustments, see my blog post on: Treating Cats with Hyperthyroidism: Antithyroid Drugs.

Best Time to Collect Blood (Post-Pill) for Monitoring Cats on Methimazole?
Although one might expect that protocols for monitoring cats on methimazole would be standardized among veterinarians, this is not the case.  Some have stated that the time of serum T4 sampling in relation to the administration of the antithyroid drug is not important, even in cats on once-daily methimazole (11).

However, I strongly disagree with that recommendation. We know that the suppressive effect of methimazole on thyroid secretion is highly variable among hyperthyroid cats, depending on the severity of their disease and size of their thyroid tumor. In addition, we also know that twice daily dosing is more effective and that once daily therapy is less likely to be successful in treatment (12).

The protocol that I use for my hyperthyroid cats is to have the methimazole dosed twice a day (morning and night) and then collect the post-treatment serum T4 sample sometime during the day. Ideally, it would make the most sense to me to take the sample around 6 hours post-pill (half-way between the two methimazole administration times), but the "exact" timing does not appear to  critical.

However, I would recommend that one be consistent in the timing of the post-pill test sample. In other words, do not have your cat tested once in the morning (an hour after the methimaole was given) and then compare those results to another testing time when the sample was collected late in the afternoon (11 hours after the methimazole was administered). In other words, we should try to monitor the post-methimazole serum thyroid hormone values at the same time each hospital visit.

What's the Ideal Serum T4 Concentration for Cats on Methimazole? 
It is important to keep the serum T4 concentration within the mid-normal range and not have even mildly high or high-normal values on methimazole. For example, if the T4 reference range is listed as 0.8-4.0 μg/dl (10-50 nmol/L), my goal is maintain the T4 values between 1.5-2.5 μg/dl (20-32 nmol/L). Recent research indicates that hyperthyroidism may contribute to the development or progression of chronic renal disease in cats (14-16).  Leaving a hyperthyroid cat untreated (or poorly regulated with methimazole or carbimazole) may therefore be detrimental to long-term kidney function and is never recommended.

During long-term treatment, it is also important to avoid inducing hypothyroidism, which may be deleterious to the cat’s kidney function (25,26). If hypothyroidism is suspected, a complete thyroid panel is recommended, including determination of the serum concentrations of total T4, free T4, T3, and TSH (see my previous blog posts on diagnostic testing for more information about these tests). The findings of low serum free T4 with high TSH concentrations is diagnostic for iatrogenic hypothyroidism; in those cats, the daily dose of methimazole  should be decreased.

References:

1. Peterson ME, Aucoin DP. Comparison of the disposition of carbimazole and methimazole in clinically normal cats. Research in Veterinary Science 1993;54:351–355. 
2. Peterson ME, Kintzer PP, Hurvitz AI. Methimazole treatment of 262 cats with hyperthyroidism. Journal of Veterinary Internal Medicine 1988;2:150-157. 
3. Peterson ME: Hyperthyroidism, In: Ettinger SJ, Feldman EC (eds): Textbook of Veterinary Internal Medicine: Diseases of the Dog and Cat (Fifth Edition). Philadelphia, WB Saunders Co. 2000; pp 1400-1419. 
4. Trepanier LA. Medical management of hyperthyroidism. Clinical Techniques in Small Animal Practice 2006;21:22–28.
5. Trepanier LA. Pharmacologic management of feline hyperthyroidism. Veterinary Clinics of North American Small Animal Practice 2007;37:775-788.
6. Mooney CT, Peterson ME. Feline hyperthyroidism. In: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. Quedgeley, Gloucester: British Small Animal Veterinary Association; 2012:92-110. 
7. Baral R, Peterson ME. Thyroid gland disorders. In: Little, S.E. (ed), The Cat: Clinical Medicine and Management. Philadelphia, Elsevier Saunders 2012;571-592. 
8. Peterson ME. Treatment of severe, unresponsive, or recurrent hyperthyroidism in cats. Proceedings of the 2011 American College of Veterinary Internal Medicine Forum. 2011;104-106.
9. Trepanier LA, Peterson ME, Aucoin DP. Pharmacokinetics of intravenous and oral methimazole following single- and multiple- dose administration in normal cats. Journal of Veterinary Pharmacology and Therapuetics 1991;14:367–373.
10. Trepanier LA, Peterson ME. Pharmacokinetics of methimazole in normal cats and cats with hyperthyroidism. Research in Veterinary Science 1991;50:69–74.
11. Rutland BE, Nachreiner RF, Kruger JM. Optimal testing for thyroid hormone concentration after treatment with methimazole in healthy and hyperthyroid cats. Journal of Veterinary Internal Medicine 2009;23:1025-1030. 
12. Trepanier LA, Hoffman SB, Kroll M, et al. Efficacy and safety of once versus twice daily administration of methimazole in cats with hyperthyroidism. Journal of the American Veterinary Medical Association 2003;222:954–958.
13. Frenais R, Rosenberg D, Burgaud S, et al. Clinical efficacy and safety of a once-daily formulation of carbimazole in cats with hyperthyroidism. Journal of Small Animal Practice 2009;50:510-515. 
14. Lapointe C, Bélanger MC, Dunn M, et al. N-acetyl-beta-D-glucosaminidase index as an early biomarker for chronic kidney disease in cats with hyperthyroidism.  Journal of Veterinary Internal Medicine 2008;22:1103-1110. 
15. van Hoek I, Lefebvre HP, Peremans K, et al. Short- and long-term follow-up of glomerular and tubular renal markers of kidney function in hyperthyroid cats after treatment with radioiodine. Domestic Animal Endocrinology 2009;36:45-56.  
16. van Hoek I, Meyer E, Duchateau L, et al. Retinol-binding protein in serum and urine of hyperthyroid cats before and after treatment with radioiodine. Journal of Veterinary Internal Medicine 2009;23:1031-1037. 
17. Williams TL, Peak KJ, Brodbelt D, et al. Survival and the development of azotemia after treatment of hyperthyroid cats. Journal of Veterinary Internal Medicine 2010;24:863-869. 
18. Williams T, Elliott J, Syme H. Association of iatrogenic hypothyroidism with azotemia and reduced survival time in cats treated for hyperthyroidism. Journal of Veterinary Internal Medicine 2010;24:1086-1092.