Treating Cats with Hyperthyroidism: Antithyroid Drugs

In cats, hyper­thyroidism can be treated in four ways — chronic administration of an antithy­roid drug, surgical thyroidectomy, radioactive io­dine (131-I), or lifelong feeding of an ultra-low iodine diet.

The treatment of choice for an individual cat depends on several factors, including the age of the cat, presence of associated heart or kidney dis­eases or other major medical problems, availability of a skilled surgeon or radioiodine treatment facility, and owner's preference (1-4).

In this post, I’m going to discuss the use of antithyroid drugs for treating cats with hyperthyroidism. This is the most common means that veterinarians use to treat this common condition, so let’s start by discussing the pros and cons of this form of treatment.

The Advantages and Disadvantages of Antithyroid Drugs

Advantages
Chronic management with antithyroid drugs is a practical treatment option for many cats with hyperthyroidism, and offers many advantages. Medical management requires no special facilities and can be prescribed by all veterinarians (1-4). These drugs cause a rapid fall in serum thyroid hormone levels (i.e., the high serum T4 normalizes within 1-3 weeks), which may be desirable in severely affected hyperthyroid cats (5,6).

Anesthesia is avoided, as are the surgical complications associated with thyroidectomy (I’ll be discussing surgical treatment in my next post). In contrast to surgery or radioiodine treatment, hospitalization is not required with medical treatment. Finally, the initial, upfront costs of antithyroid drugs is much less than with either surgical or radioactive iodine treatment.

Disadvantages
Long-term medial management also has many disadvantages. This form of treatment is not curative, is highly dependent on owner and cat compliance, and requires regular biochemical monitoring to ensure the efficacy of treatment (1-4). Side effects are common, occurring in up to 20% of cats (1-6). Even though the initial cost of medical treatment may be far less initially, the cost of ongoing monitoring over a period of months to years can exceed that of thyroidectomy or radioiodine therapy.

These antithyroid drugs also come with other drawbacks. Since they block thyroid hormone synthesis but do not destroy the cat’s thyroid tumor, these drugs never cure the hyperthyroidism and relapse will always occur if daily medication is discontinued (1-6). Most importantly, the benign thyroid tumor — which is present in all cats with hyperthyroidism (7,8) — continues to grow and, after many months, may transform from adenoma to thyroid carcinoma in some cats (9).

Long-term medical management is best reserved for cats of advanced age or for those with concurrent diseases, and for when owners refuse either surgery or radioactive iodine. In addition to long-term treatment, medical management is also advised prior to surgical thyroidectomy to decrease the metabolic and cardiac complications associated with hyperthyroidism. Short-term medical management is often recommended as trial therapy to determine the effect of restoring euthyroidism on kidney function, especially in cats with suspected chronic kidney disease (1-4,10).

Methimazole and Carbimazole: The 2 Antithyroid Drugs

The two drugs methimazole and carbimazole are commonly recommended for managing cats with hyperthyroidism (1-6). A related drug, propylthiouracil, often used in human medicine, is not recommended for cats because of a high incidence of serious adverse reactions —especially anemia and bleeding problems (11).

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 (12). Methimazole does not block the release of preformed thyroid hormone, so there is a delay of 1 to 3 weeks before serum T4 concentrations return to normal after initializing therapy (5, 6).

Carbimazole is a pro-drug of methimazole. That means that after oral administration of carbimazole, it is almost immediately converted to methimazole by the cat (13). So basically, it turns out that carbimazole and methimazole end up being the same drug (1-4).

Different Drug Formulations of Methimazole & Carbimazole

Methimazole Tablets
Methimazole is specifically licensed for treatment of feline hyperthyroidism both in the USA and Europe as 2.5- and 5-mg tablets (Felimazole, Dechra Veterinary Products). It is also available as a generic and brand name drug for human use (Tapazole). For most hyperthyroid cats, a starting dose of 1.25 mg to 2.5 mg methimazole is administered twice daily is recommended (1-4,14).

Carbimazole Tablets
Carbimazole is available for human use in many European countries (brand name, NeoMercazole), Australia and Japan (2-4). This drug is not available as a licensed drug in the USA, but it is available though compounding pharmacies.

As noted above, carbimazole exerts its antithyroid effect through immediate conversion to methimazole when administered orally (13). Serum concentrations of methimazole achieved after carbimazole administration are less than after a similar weight of methimazole such that a 5-mg dose of carbimazole is approximately equal to 3 mg of methimazole (3,6). Because of that, a starting dose of regular carbimazole of 2.5 mg to 5 mg twice daily is commonly recommended for restoring euthyroidism (2-4,6).

Carbimazole is often touted as having a lower incidence of adverse reactions such as vomiting and anorexia (6,15). This may be because it is tasteless whereas methimazole has a bitter taste (3,6). However, Felimazole, as licensed for veterinary use, is sugar-coated; provided the tablet is not crushed, the bitter taste is presumably avoided.

Carbimazole Tablets (Controlled-Release)
A controlled-release formulation of carbimazole (Vidalta, Intervet Schering Plough) is licensed for cats in Europe for once daily administration (16,17). This formulation is not available in the USA.

Administration of this drug with food significantly enhances its absorption (16). The starting dose for controlled release carbimazole is 15 mg administered once daily. In cats with mild hyperthyroidism (total T4 concentration <100 nmol/L or < 8 μg/dl), a 10 mg once daily is recommended (2-4,16).

Transdermal Antithyroid Drugs
Carbimazole and methimazole can be reformulated by a veterinary compounding pharmacy and applied to the non-haired inner portion of a cat’s pinnae (ear lobe) for transdermal administration (18-20). Such custom formulation increases expense of therapy and the stability of the product can never be guaranteed.  To prevent absorption of the drug through one's own skin, it is best to wear gloves or a finger cot for application, and wash your hands afterwards.

Both antithyroid drugs are generally effective in cats when administered at a dose of 1.25 mg to 2.5 mg twice daily transdermally (2-4).  One advantage of using a compounded formulation of methimazole (or carbimazole) over the 2.5- or 5-mg tablets is that it is easier to make smaller or finer dose adjustments.

Transdermal administration is associated with fewer gastrointestinal side effects than the oral route (19,21,22), but some cats resent manipulation of their ears and crusting can occur between doses leading to erythema. These problems can usually be prevented by removing any crusted material and cleaning the ear flap prior to administration.

Monitoring of Hyperthyroid Cats on Antithyroid Drug Treatment

Initial doses of the antithyroid drug vary depending on the cat’s pretreatment serum T4 value and goiter size (i.e., size of the thyroid tumor). In general, however, most cats are started on 1.25-2.5 mg of methimazole or 2.5-5 mg of carbimazole, both administered twice daily (1-4,21-23).

Initial Monitoring
Initially, cats should be reassessed after 2 to 3 weeks and a serum total T4 concentration measured. When monitoring, time of serum T4 sampling in relation to the administration of the antithyroid drug is not overly important (1-4,24). The goal of medical therapy is to maintain total T4 concentrations within the lower half of the reference range (1-4). Low serum T4 values should be avoided, however, because it has been shown that chronic hypothyroidism is deleterious to kidney function and may worsen already present chronic kidney disease (25,26).

If hyperthyroidism persists during antithyroid drug treatment, lack of owner or cat compliance should always first be eliminated as a reason for the failure of therapy. If the serum T4 concentrations remain high with proper treatment, however, the daily dose of methimazole or carbimazole can be increased in 2.5-mg increments, reassessing the cat again in 3 to 4 weeks (1-4).

Long-Term Monitoring and Treatment
For chronic management (once euthyroidism has been achieved), the daily antithyroid drug dosage is adjusted to the lowest possible dose that effectively maintains euthyroidism. Once the dosage has stabilized, the cat should be monitored every 3 to 6 months and as needed clinically. At time of each of these rechecks, a complete physical examination should be perform together with determination of a complete blood count, serum chemistry profile, and serum T4 concentration.

Relapses are common in cats treated with an antithyroid drug. Some cats will become more difficult to medicate over time, whereas others will need higher daily drug dosages to inhibit thyroid hormone secretion as their thyroid tumors continue to grow larger and larger (27).

It is important to keep the serum T4 concentration within the mid-normal range and not have even mildly high or high-normal values. 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 (28-30).  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 again important to avoid inducing hypothyroidism, which may be deleterious to the cat’s kidney function (25,26). If hypothyroidism is suspected (which can develop even if the T4 is low-normal), 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.

Because antithyroid medications have no effect on the underlying lesion, the thyroid nodules continue to grow larger and larger over time. This may necessitate an increased daily dose with time. In some cats, large enough dosages can no longer be administered to control the hyperthyroidism and surgery or radioiodine is needed to control the hyperthyroidism (27).

Side Effects & Adverse Reactions

Most clinical adverse reactions occur within the first 3 months of therapy (1-4). Mild clinical side effects of vomiting, anorexia, or depression occur in approximately 10-15% of cats, usually within the first 3 weeks of therapy (4,5). In most cats, these reactions are transient and do not require permanent drug withdrawal.

Mild Side Effects

Figure 1: Facial excoriations
due to methimazole

Early in the course of drug therapy, mild and transient hematological abnormalities, including leucopenia (low total white blood cell count), lymphocytosis (high lymphocyte count), or eosinophilia (high eosinophil count) develop in up to 15% of cats without any apparent clinical effect (1-6).

Self-induced excoriations of the head and neck (from scratching) occasionally develop, usually within the first 6 weeks of therapy (see Figure 1).

Less commonly, generalized enlargement of lymph nodes may develop during drug treatment (31). If either of these adverse effects occur, the drug must be stopped and another form of treatment given.

Life Threatening Side Effects

Figure 2: Bleeding from gums due
to methimazole

More serious hematological complications occur in less than 5% of cats and include a severe lowering of the white blood cell count (agranulocytosis) or platelet count (thrombocytopenia).  Liver dysfunction, characterized by marked increases in all hepatic enzymes, develops in less than 2% of cats (1-5).

Rarely, cats may also develop a severe bleeding tendency during drug treatment (see Figure 2) (5,32). All of these adverse effects are reversible upon discontinuation of the medication.

The Bottom Line

Short-term or chronic management with antithyroid drugs provides a useful treatment option for many cats with hyperthyroidism. However, this treatment does not cure the disease and requires daily medication for the rest of the cat's life.  Like any prescription drug, methimazole or carbimazole can produce adverse side effects, which may be life-threatening is some cats. For all of these reasons, antithyroid drugs will never be the "treatment of choice" for all cats with hyperthyroidism.

References

1. Peterson ME: Hyperthyroidism in cats. In: Melian C (ed): Manual de Endocrinología en Pequeños Animales (Manual of Small Animal Endocrinology). Barcelona, Multimedica, 2008; 127-168.
2. Baral R, Peterson ME. Thyroid diseases. In: Little, S. (ed), The Cat: Clinical Medicine and Management. Philadelphia, Elsevier Saunders 2012; in press.
3. Mooney CT, Peterson ME: Feline hyperthyroidism, In: Mooney C.T., Peterson M.E. (eds), Manual of Canine and Feline Endocrinology (Fourth Ed), Quedgeley, Gloucester, British Small Animal Veterinary Association, 2012; in press.
4. Peterson ME: Hyperthyroidism in cats, In: Rand, J (ed), Clinical Endocrinology of Companion Animals. New York, Wiley-Blackwell, 2012; in press.
5. Peterson ME, Kintzer PP, Hurvitz AI. Methimazole treatment of 262 cats with hyperthyroidism. Journal of Veterinary Internal Medicine 1988;2:150–157. 
6. Mooney CT, Thoday KL, Doxey DL. Carbimazole therapy of feline hyperthyroidism. Journal of Small Animal Practice 1992;33:228–235. 
7. Gerber H, Peter H, Ferguson DC, et al. Etiopathology of feline toxic nodular goiter. Veterinary Clinics of North America Small Animal Practice 1994;24:541-565.
8. Peterson ME, Ward CR. Etiopathologic findings of hyperthyroidism in cats. Veterinary Clinics of North America Small Animal Practice 2007;37:633-645.
9. Hibbert A, Gruffydd-Jones T, Barrett EL, et al. Feline thyroid carcinoma: diagnosis and response to high-dose radioactive iodine treatment. Journal of Feline Medicine and Surgery 2009;11:116-124.
10. Becker TJ, Graves TK, Kruger JM, et al. Effects of methimazole on renal function in cats with hyperthyroidism. Journal of the American Animal Hospital Association 2000;36:215–223. 
11. Peterson ME, Hurvitz AI, Leib MS, Cavanagh PG, Dutton RE. Propylthiouracil-associated hemolytic anemia, thrombocytopenia, and antinuclear antibodies in cats with hyperthyroidism. Journal of the American Veterinary Medical Association 1984;184:806-808. 
12. Cooper DS. Antithyroid drugs. New England Journal of Medicine 2005;352:905-917.
13. Peterson ME, Aucoin DP. Comparison of the disposition of carbimazole and methimazole in clinically normal cats. Research in Veterinary Science 1993;54:351–355. 
14. Plumb DC. Plumb's Veterinary Drug Handbook (7th Ed). PharmaVet Inc, Stockholm, Wisconsin 2011.
15. Bucknell DG. Feline hyperthyroidism: spectrum of clinical presentions and response to carbimazole therapy. Australian Veterinary Journal 2000;78:462-465. 
16. Frénais R, Burgaud S, Horspool LJ. Pharmacokinetics of controlled-release carbimazole tablets support once daily dosing in cats. Journal of Veterinary Pharmacology and Therapeutics 2008;31:213-219.
17. 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. 
18. Hoffman S, Yoder A, Trepanier L. Bioavailability of transdermal methimazole in a pluronic lecithin organogel (PLO) in healthy cats. Journal of Veterinary Pharmacology and Therapeutics  2002;25:189-193. 
19. Hoffman SB, Marks SL, Taboada J et al. Transdermal methimazole treatment in cats with hyperthyroidism. Journal of Feline Medicine and Surgery 2003;5:77–82. 
20. Buijtels JJ, Kurvers IA, Galac S et al. Transdermal carbimazole for the treatment of feline hyperthyroidism, Tijdschrift voor Diergeneeskunde 2006;131:478-482. 
21. Trepanier LA. Pharmacologic management of feline hyperthyroidism. Veterinary Clinics of North America: Small Animal Practice 2007;37:775-788. 
22. Trepanier LA. Medical management of hyperthyroidism. Clinical Techniques in Small Animal Practice 2006;21:22-28. 
23. Trepanier LA, Hoffman SB, Knoll 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. 
24. 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. 
25. 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. 
26. 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. 
27. 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.
28. 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. 
29. 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.  
30. 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. 
31. Niessen SJ, Voyce MJ, de Villiers L, et al. Generalised lymphadenomegaly associated with methimazole treatment in a hyperthyroid cat. Journal of Small Animal Practice 2007;48:165-168. 
32. Randolph JF, DeMarco J, Center SA, et al. Prothrombin, activated partial thromboplastin, and proteins induced by vitamin K absence or antagonists clotting times in 20 hyperthyroid cats before and after methimazole treatment. Journal of Veterinary Internal Medicine 2000;14:56-59. 

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