01-16 PHARM Thyroid Hormones and Antithyroid Drugs

Question 1

What are the three forms of thyroid hormone in the body?

Answer 1

T4
T3 - distal benzene iodinated ACTIVE
rT3 - prox benzene iodinated INACTIVE

Question 2

Compare T4 vs T3 in terms of:
—T(1/2)
—Amt released by thyroid
—Activity
—Affinity for receptor

Answer 2

T(1/2): T4 ~1wk; T3 ~1d
Amt released: 90% T4, 10% T3
Activity: T3>T4
Affinity for receptor: T3>T4

Question 3

How is T4 converted to T3?

Answer 3

converted to T3 in peripheral tissues by 5’-iodinase

Question 4

Levothyroxine
—Time to reach Css
—ADRs
—Molecular MoA

Answer 4

C_ss: ~5-6 wks
ADRs: Hyperthyroidism, including cardiac sx (e.g. tachycardia, arrhythmias, angina, or infarction)
MoA: TR-RXR heterodimer is sitting on TRE when T3 → TR → displaces CoR(epressor) for CoA → incr mRNA expression

Question 5

Steps of thyroid hormone synthesis

Answer 5

1. Iodine is actively taken up by follicular cells
2. Iodine diffuses to the apex of the cell
3. Iodine is transported into the colloid
4. thyroid peroxidase activates and incorporates I into thyroglobulin
5. thyroid peroxidase then joisn either 2 DITs of 1 DIT + 1 MIT to make T4 or T3
6. thyroglobulin then taken up from colloid back into follicular cell for release to the body via lysosomes

Question 6

Radioactive Iodide (131I)”
—MoA
—Use
—ADRs

Answer 6

—MoA: Radioactive iodide is concentrated in the thyroid gland and incorporated through the normal mechanism; it then destroys thyroid cells by emitting ionizing beta particles.

-T(1/2): 5 days

—Use: This therapy is used to destroy functional thyroid tissue in hyperthyroid patients. Symptoms of hyperthyroidism abate over 2-3 months.

—Adverse effects:
i. Hypothyroidism (Note that conversion of hyperthyroidism to hypothyroidism is frequently the desired effect, as hypothyroidism can be treated with Levothyroxine).”
ii. Ablation of the fetal thyroid gland if given in pregnancy.”
iii. Sore throat & sialitis
Note: The doses of 131I used for the treatment of hyperthyroidism have not been found” to be associated with an increase in the risk of developing cancer.”

Question 7

Thioureas
—Examples
—MoA
—Compare T(1/2)
—Use
—ADRs

Answer 7

—Examples: Methimazole & propylthiouracil
—MoA:
i. These drugs prevent thyroid hormone synthesis by inhibiting thyroid peroxidase, thus inhibiting the iodination of tyrosine residues in thyroglobulin.
ii. The effects of the drugs do not become fully manifest for several weeks. This is because of the existence of preformed thyroid hormone stored in the thyroid gland. For this reason, the drugs are usually initially administered at maximal doses and adjusted when euthyroidism has been reached.
iii. PTU also inhibits the peripheral deiodination of T4 to T3

—T(1/2): meth has longer t1/2 →qD dosing

—USE:
i. short-term basis: reduce hyperthyroid symptoms before or after ablation with radioactive iodide - Note that the drug must be discontinued several days before radioactive iodide treatment. [Pop quiz Why?]
ii. In some patients with Graves’ disease, particularly patients with mild disease, the drugs can be used on a longer-term basis. This is because some patients undergo spontaneous remission during drug therapy. However, the majority of patients do not undergo remission and require ablation therapy.
iii. PTU can also be used on emergency basis, in cases of thyrotoxic crisis. In this case, the drug is used for its effects on the deiodination of T4.
—ADRs:
Agranulocytosis [which usually develops within several months and may present as a fever or sore throat (incidence = 1/500 patients)], hepatitis, jaundice, pruritis and rash)
—ADRs less common w/ methimazole
—PTU Black box warn liver failure
—PTU better for preganancy b/c methimazole assoc’d w/ fetal malformations