Reduction of thyroid activity and hormone effects can be accomplished by agents that interfere with the production of thyroid hormones, by agents that modify the tissue response to thyroid hormones, or by glandular destruction with radiation or surgery. Goitrogens are agents that suppress secretion of T3 and T4 to subnormal levels and thereby increase TSH, which in turn produces glandular enlargement (goiter). The antithyroid compounds used clinically include the thioamides, iodides, and radioactive iodine.
FIGURE 38–4 Model of the interaction of T3 with the T3 receptor. A: Inactive phase—the unliganded T3 receptor dimer bound to the thyroid hormone response element (TRE) along with corepressors acts as a suppressor of gene transcription. B: Active phase—T3 and T4 circulate bound to thyroid-binding proteins (TBPs). The free hormones are transported into the cell by a specific transport system. Within the cytoplasm, T4 is converted to T3 by 5′-deiodinase (5′DI); T3 then moves into the nucleus. There it binds to the ligand-binding domain of the thyroid receptor (TR) monomer. This promotes disruption of the TR homodimer and heterodimerization with retinoid X receptor (RXR) on the TRE, displacement of corepressors, and binding of coactivators. The TR-coactivator complex activates gene transcription, which leads to alteration in protein synthesis and cellular phenotype. TR-LBD, T3 receptor ligand-binding domain; TR-DBD, T3 receptor DNA-binding domain; RXR-LBD, retinoid X receptor ligand-binding domain; RXR-DBD, retinoid X receptor DNA-binding domain; T3, triiodothyronine; T4, tetraiodothyronine, L-thyroxine. (Adapted, with permission, from Gardner DG, Shoback D [editors]: Greenspan’s Basic & Clinical Endocrinology, 8th ed. McGraw-Hill, 2007. Copyright © The McGraw-Hill Companies, Inc.) methimazole (other than agranulocytosis or hepatitis). The chemical structures of these compounds are shown in Figure 38–5. The The thioamides methimazole and propylthiouracil are major thiocarbamide group is essential for antithyroid activity. drugs for treatment of thyrotoxicosis. In the United Kingdom, carbimazole, which is converted to methimazole in vivo, is widely used. Methimazole is about ten times more potent than propylthiouracil and is the drug of choice in adults and children. Due Methimazole is completely absorbed but at variable rates. It is readily to a black box warning about severe hepatitis, propylthiouracil accumulated by the thyroid gland and has a volume of distribution should be reserved for use during the first trimester of pregnancy, similar to that of propylthiouracil. Excretion is slower than with pro-in thyroid storm, and in those experiencing adverse reactions to pylthiouracil; 65–70% of a dose is recovered in the urine in 48 hours.
TABLE 38–4 Manifestations of thyrotoxicosis and hypothyroidism.
1The anemia of hyperthyroidism is usually normochromic and caused by increased red blood cell turnover. The anemia of hypothyroidism may be normochromic, hyperchromic, or hypochromic and may be due to decreased production rate, decreased iron absorption, decreased folic acid absorption, or to autoimmune pernicious anemia. LDH, lactic dehydrogenase; AST, aspartate aminotransferase.
FIGURE 38–5 Structure of thioamides. The thiocarbamide moiety is shaded in color.