Monday, April 13, 2009

Antithyroid Drugs

Antithyroid drugs, which have been in use for more than half
a century, remain cornerstones in the management of hyperthyroidism, especially
for patients with Graves’ disease. Surveys of thyroidologists from the
early 1990s indicate that most practitioners consider antithyroid drugs the treatment of
choice for most young people with Graves’ disease, both in the United States and in
the rest of the world.
1,2
A substantial amount of new information, much of it evidencebased,
3
has become available since the topic was last summarized in the
Journal
in 1984.
4
The present review considers recent pharmacologic and clinical data related to the use
of these compounds.
mechanism of action
Antithyroid drugs are relatively simple molecules known as thionamides, which contain
a sulfhydryl group and a thiourea moiety within a heterocyclic structure (Fig. 1). Propylthiouracil
(6-propyl-2-thiouracil) and methimazole (1-methyl-2-mercaptoimidazole,
Tapazole) are the antithyroid drugs used in the United States. Methimazole is used in
most of Europe and Asia, and carbimazole, a methimazole analogue, is used in the United
Kingdom and parts of the former British Commonwealth. These agents are actively
concentrated by the thyroid gland against a concentration gradient.
5
Their primary
effect is to inhibit thyroid hormone synthesis by interfering with thyroid peroxidase–
mediated iodination of tyrosine residues in thyroglobulin, an important step in the
synthesis of thyroxine and triiodothyronine (Fig. 2).
These medications possess other noteworthy effects (Fig. 3). First, propylthiouracil,
but not methimazole or carbimazole, can block the conversion of thyroxine to triiodothyronine
within the thyroid and in peripheral tissues, but this effect is not clinically
important in most instances. Second, antithyroid drugs may have clinically important
immunosuppressive effects. In patients taking antithyroid drugs, serum concentrations
of antithyrotropin-receptor antibodies decrease with time,
8
as do other immunologically
important molecules, including intracellular adhesion molecule 1
9
and soluble
interleukin-2 and interleukin-6 receptors.
10,11
In addition, there is evidence that antithyroid
drugs may induce apoptosis of intrathyroidal lymphocytes,
12
as well as decrease
HLA class II expression.
13
Also, most studies show an increased number of circulating
suppressor T cells and a decreased number of helper T cells,
14
natural killer cells,
15,16
and activated intrathyroidal T cells
14
during antithyroid-drug therapy.
Despite these multiple lines of evidence, it has been argued that any change in the
immune system must be viewed in the context of a drug-induced simultaneous improvement
in thyroid function that could itself have a beneficial effect on the autoimmune
process in patients with Graves’ disease.
17
However, analyses of animal data
18,19
and
human studies
20
have also suggested that changes in the immune system may not be
predicated solely on changes in thyroid function.