Antithyroid drugs in Graves disease Elaine Moore
Many compounds interfere, directly or indirectly, with the production, release, or action of thyroid hormone. These compounds can be divided into four major categories:
- Antithyroid drug (ATDs)s, which directly interfere with the production of thyroid hormones
- Ionic inhibitors, which block the iodide transport mechanism
- Iodine in high concentration (SSKI, Lugols solution), which inhibit the release of thyroid hormone from the gland and decrease thyroid hormone synthesis
- Radioactive iodine, a form of ionizing radiation that damages the thyroid gland.
In addition, to help reduce symptoms of excess thyroid hormone, beta blockers and calcium channel blockers are sometimes used.
The antithyroid drugs most often used clinically are the thiourelynes, which belong to the family of thionamides. Historically, the two most important ATDs discovered in the early 1940s were the prototype propylthiouracil (PTU) and sulfaguanidine, which is related to methimazole and carbimazole. Other compounds with a thioamide group which have antithyroid properties include imidazole, hydantoin, thiopental, lithium salts, thiazole, thiadiazole, uracil and barbituric acid. Early on, antithyroid drug properties were observed in turnips and in the green parts of cruciferous plants.
How ATDs Work
Antithyroid drugs inhibit the formation of thyroid hormones by interfering with the incorporation of iodine into thyroglobulin and its residual compounds. ATDs also inhibit the coupling of iodine with tyrosine and they inhibit thyroid peroxidase enzyme.
Antithyroid drugs also decrease levels of thyroid stimulating immunoglobulins (TSI) in patients with Graves disease. This suggests that ATDS may have mild immunosuppressant properties. In addition, PTU, but not methimazole, inhibits the conversion of T4 into T3, quickly lowering FT3 as well as FT4 levels.
For this reason, PTU is more often used in cases of thyroid storm or when severe thyrotoxicosis (condition of excess thyroid hormone) is present. PTU is also recommended for pregnant women since it crosses the placental membrane less readily. PTU is also the only thyrostatic drug approved by the American Academy of Pediatrics for nursing mothers. However, PTU has a shorter half-life with a 100 mg dose waning in 23 hours. Doses of carbimazole and methimazole from 1025 mg may cause effects for up to 24 hours. Half of a dose of PTU is gone (its half-life) at 75 minutes compared to 46 hours for methimazole and carbimazole.
Studies show that an initial starting dose of 15 mg methimazole or 20 mg carbimazole is adequate for most patients and less likely to result in adverse effects. For PTU, the usual starting dose is 200300 mg daily. At about 6-8 weeks after starting ATDs, the FT4 level should have fallen into the normal or reference range. At this time, the ATD dose is decreased regardless of the TSH level.
Most patients stay on a maintenance dose of 2.510 mg methimazole or carbimazole or 25150 mg of PTU. The lowest dose needed to keep the FT4 level at least at mid-range is used regardless of the TSH level. TSH stays suppressed for a long time and doesnt indicate hyperthyroidism in patients undergoing treatment.
Euthyroidism (normal thyroid function) is observed when the FT4 level falls into the normal or reference range. High doses of ATDs, which can cause hypothyroidism, should be avoided since hypothyroidism can trigger thyroid antibody production and lead to thyroid eye disease. ATDs are used until remission is achieved, with the highest rates of remission occurring when low doses of ATDs are used long-term (average 4 years).
The incidence of side effects from ATDs as currently used is relatively low with serious reactions, such as liver toxicity or agranulocytosis, affecting less than 0.5 percent of all patients. The most common reaction is a mild rash that generally subsides without treatment especially when the dose is lowered. On occasion, antihistamines or corticosteroids may be required to clear the rash or patients may need to switch to the other ATD. Patients on PTU may develop antineutrophilic cytoplasmic antibodies (ANCAs). These antibodies are not seen in patients using methimazole.
Laurence Brunton, Goodman & Gilmans The Pharmacological Basis of Theraeutics, eleventh edition, 2006: New York, McGraw-Hill Medical Division.
Takata K, Kubota S, Fukata S, et al., Methimazole-Induced Agranulocytosis in Patients with Graves Disease is More Frequent wit an Initial Dose of 30 mg than with 15 mg Daily, Thyroid, May 17, 2009.
M. Weissel, Propylthiouracil: Clinical Overview of its Efficacy and its Side Effects more than 50 Years after the Introduction of its Use in Thyrostatic Treatment, Journal of Clinical Endocrinology and Diabetes, May 15, 2009.