THYROID AND ANTITHYROID DRUGS

REQUIRED READING: THYROID AND ANTITHYROID DRUGS
Katzung’s Basic and Clinical Pharmacology
13th edition
Chapter 38, pp. 663-677

After attending the lecture and reading the textbook, you should be able to answer these questions.

1. What is the chemical name for the three hormones secreted by the thyroid gland? Can you draw the structures of T3? T4? Where do the ‘iodides’ come from? Are they synthesized by the body? Are they derived from the diet? What is the RDA of iodide in the diet?

2. Describe the biosynthesis of thyroid hormones. Make sure to use terms like iodide trapping, thyroidal peroxidase, tyrosine, MIT, DIT, thyroglobulin, proteolysis of thyroglobulin. What is the ratio of T4 to T3 on thyroglobulin? Which of these is released to a higher degree from the thyroid gland? Which of the two is the more active hormone? How is T4 converted to T3 in the periphery?

3. What are the two chemical activities of thyroidal peroxidase? Compared to T4 and T3, what is the biological activity of rT3? What is the half life of T4? T3? Describe the possible metabolic fates of T4 after it is released from the thyroid gland. Describe the usual relationship among the thyroid gland, the hypothalamus, and the pituitary gland.

4. What are the relevant ADME pharmacokinetic parameters of T3 and T4? For example, which is better absorbed? Are there factors that can affect absorption? Which has the longer half-life?

5. What is the net effect of an ‘activating’ mutation of the TSH receptor? Provide an example of an abnormal thyroid stimulating agent.

6. What happens to T4 when it enters the cell? What is 5’deiodinase? What kind of receptors are thyroid hormone receptors? For example, are they transmembrane spanning receptors? What other types of receptors are related to thyroid receptors? Can T4 bind to T3 receptors?

7. What are the various physiological targets of thyroid hormones? What happens to these tissues in the hyperthyroid state? Remember to detail the effects of the hyperthyroid state on skin, eyes, cardiovascular system, GI, CNS, musculoskeletal and hematopoietic systems as well as on metabolism. (See also Table 38-4 in your text for help, p.670).

8. What are ‘antithyroid agents?’ What are ‘goitrogens?’ How do the thioamides work to reduce the production of thyroid hormones by the thyroid gland? Can you describe three different thioamides that do this? Be sure to include relevant PK differences in your answer. Aside from inhibiting thyroidal peroxidase, what other enzyme is blocked by these agents (hint: it’s in the periphery). Discuss the pertinent pharmacokinetic properties of these thioamides. Do these agents have a fast or a slow onset of pharmacologic effect? What is the most common adverse reaction caused by these agents? What is a rare but serious adverse effects associated with these agents? Carbimazole is a prodrug. How does it work as an anti-thyroid agent? What are its most significant adverse effects? Based on its PK, would you recommend carbimazole over propylthiouracil in pregnancy? Why or why not?

9. What is Grave’s Disease? Is Grave’s Disease frequently associated with exophthalmus and swelling of the periorbital tissues?

10. What is ipodate? What is it’s mechanism of action? What are its most significant adverse effects?

11. What is the antithyroid mechanism of action of I-131 (radioactive iodine)? What is its half-life? Should it be used in pregnant patients? Why or why not?

12. What is the antithyroid mechanism of action of propranolol?

13. List three anion inhibitors of the Na+/I- transporter? Why do such agents have antithyroid activity? What type of toxicity is associated with potassium perchlorate?

14. How do iodides work to block thyroid function? What is the proposed mechanism of iodide’s antithyroid actions? Why might iodides be helpful in preoperative preparation for surgery?

15. How does guanethidine work as a potential anti-thyroid agent? Does it have direct effects on the thyroid gland?

16. What are some of the clinical manifestations of hypothyroidism? What is Hashimoto’s thyroiditis? What is ‘cretinism?’ What is ‘myxedema?’

17. Describe the types of synthetic and animal-derived thyroid hormones available for replacement therapy. What is the preparation of choice for thyroid replacement therapy?

18. How might drugs like lithium or amiodarone affect levels of T4 in the body (Hint: see Table 38-3)? Your patient is hyperthyroid; how can that impact their warfarin dosing (Hint: see Table 38-3, p. 668)?

19. What is ‘thyroid storm?’ What is the presenting syndrome? Which pharmacological agents can be used to treat thyroid storm? What is the rationale behind using each of those reagents?

20. Describe the functional domains of the thyroid hormone receptor? What is the mechanism of thyroid hormone action? Can genes be both activated or inhibited by thyroid hormone?