Page 707 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 38 Thyroid & Antithyroid Drugs 693

A
Nucleus

Coactivator
Corepressor

TR-LBD TR-LBD

TR-DBD TR-DBD

TRE

Cytoplasm
TBPs
T 4 T 3

B
Corepressor T 4 T 3

Coactivator
T 4
TR-LBD 5'Dl
RXR-LBD
TR-LBD T 3
TR-DBD RXR-DBD TR-DBD
Transcription T 3

TRE

FIGURE 38–4 Model of the interaction of T 3 with the T 3 receptor. A: Inactive phase—the unliganded T 3 receptor dimer bound to the
thyroid hormone response element (TRE) along with corepressors acts as a suppressor of gene transcription. B: Active phase—T 3 and T 4
circulate bound to thyroid-binding proteins (TBPs). The free hormones are transported into the cell by a specific transport system. Within
the cytoplasm, T 4 is converted to T 3 by 5′-deiodinase (5′DI); T 3 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, T 3 receptor ligand-binding domain; TR-DBD, T 3 receptor DNA-binding
domain; RXR-LBD, retinoid X receptor ligand-binding domain; RXR-DBD, retinoid X receptor DNA-binding domain; T 3 , triiodothyronine; T 4 ,
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.)

THIOAMIDES 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 Pharmacokinetics
used. Methimazole is about ten times more potent than propyl-
thiouracil 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.