1. P harmacology – III PHL-418 Thyroid and Anti-thyroid Drugs Dr. Hassan Madkhali Assistant Professor Department of Pharmacology E mail: h.madkhali@psau.edu.sa

2. (Male left, female on the right.) 1. Pineal gland 2. Pituitary gland 3. Thyroid gland 4. Thymus 5. Adrenal gland 6. Pancreas 7. Ovary 8. Testis Major endocrine glands https://en.wikipedia.org/wiki/Endocrine_gland

3. Thyroid Gland www.urmc.rochester.edu Thyroid gland location: A butterfly-shaped gland Located in the front of the neck (below Adams apple) Wraps around the trachea It has two lobes connected by a section called the isthmus.

4. Thyroid gland Function Thyroid gland is responsible for the secretion of three hormones essential for proper regulation of metabolism (increase metabolic rate). –Thyroxine (T4) –Triiodothyronine (T3) –Calcitonin

5. T3 and T4 Both produced in the thyroid gland through the iodination and coupling of the amino acid tyrosine. Body needs about 1 mg of iodine per week from the diet. Thyroid Hormone are lipophilic hormone Only T3 can be used in cell to affect cell metabolism. Thyroid secretes: 90% T4 and 10% T3. (Why?) T3 & T4 in blood is bound to carrier protein such as thyroid binding globulin (TBG), albumin and transthyretin Only free T4 and T3 can enter cells (most enters as T4, then transfer to T3 inside the target cell)

6. Biosynthesis of Thyroid Hormones -Human Physiology, p331. Stuart Fox. 10 th ed. -Endocrinology: Basic and Clinical Principles, p 291. Totowa, NJ, Humana Press. Organification Coupling

7. 1.Iodide is taken up at the basolateral cell membrane and transported to the apical membrane. 2.Polypeptide chains of Tg (thyroglobulin) are synthesized in the rough endoplasmic reticulum, and posttranslational modifications take place in the Golgi 3.Newly formed Tg is transported to the cell surface in small apical vesicles. 4.Within the follicular lumen, iodide (I − ) is oxidized to iodine (I 2 ) by thyroperoxidase. 5.Iodine binds to tyrosyl residues on Tg, producing fully iodinated Tg containing MIT, DIT, T4 and a small amount of T3. (organification and coupling), which is stored as colloid in the follicular lumen. 6.Upon TSH stimulation, villi at the apical membrane engulf the colloid and endocytose the iodinated Tg. 7.T4 and T3 are released into the circulation 8.DIT and MIT are deiodinated, and the iodide and tyrosine are recycled Biosynthesis of thyroid hormones

8. How does thyroid hormones exhibited their effects on target cell?

9. Regulation of thyroid function Thyrotropin-releasing hormone (TRH) from hypothalamus releases thyroid-stimulating hormone from anterior pituitary. TSH is stimulated when the blood levels of T3 and T4 are low. TSH acts by stimulation of the thyroid follicular cells by binding to TSH receptor on the basal surface of the thyroid follicle cells. This leads to iodide uptake. T3 and T4 exert negative feedback on both the pituitary production of TSH and the hypothalamic production of TRH.

10. Thyroid hormones effects on metabolism The effect of thyroid hormones on metabolic processes appear to be mediated by activation of nuclear receptors that lead to increase formation of RNA and subsequent protein synthesis (regulating gene expression in targeted cells to increase metabolism). Stimulate carbohydrate metabolism and lipolysis, or the break down of fats. Increase protein synthesis. CNS development. Growth. Cardiac effects: increase cardiac output and heart rate.

11. Thyroid Disorders

12. A) Hypothyroidism Hypothyroidism (underactive thyroid gland) is a condition in which the thyroid gland does not produce enough thyroid hormones to keep the body running normally.

13. Hypothyroidism Laboratory Values TSH – thyroid stimulating hormone will be increased - it is working hard to stimulate the production of T3 and T4 T3 and T4 levels would be low

14. Hypothyroidism All newborns are tested at birth for thyroid function If untreated can lead to retardation due to effects on brain development. While too little iodine in the diet is considered as the most common cause of hypothyroidism in some countries, Hashimoto’s hypothyroidism (an autoimmune disease) is the most common cause of hypothyroidism in USA.

15. Treatment of Hypothyroidism Thyroid drugs such as levothyroxine (brand names: Synthroid or Levothroid), is a synthetic form of T4. It acts by binding to thyroid receptor in the cell nucleus and cause metabolic effects through the gene expression and protein synthesis. Take on empty stomach in the morning Do not take with antacids or iron preparations If on Coumadin may need to use smaller dose of Coumadin Do not stop when feeling better Dosage of other drugs may need to be reduced due to slow metabolism in liver and excretion in urine

16. Synthroid Dosing Adult: 25 to 300 mcg / day Pediatrics: 3-5 mcg / kg / day How provided in 5 mcg, 25 mcg, 75 mcg and 100 mcg tablets IV: 200 mcg per vial in 6 and 10 mL vials.

17. B) Hyperthyroidism Excessive secretion of thyroid hormones. Causes: –Graves’ disease ( is an autoimmune disease that affects the thyroid. It frequently results in hyperthyroidism and an enlarged thyroid. –Plummer’s disease or toxic nodular disease ( is a multinodular goiter associated with a hyperthyroidism). –Thyroid storm: caused by stress or infection

18. TSH would be low T3 and T4 would be high Hyperthyroidism Laboratory Values

19. Treatment of Hyperthyroidism Anti-thyroid Drugs Methimazole and propylthiouracil (PTU) act by inhibiting the enzyme thyroperoxidase. Inhibiting the incorporation of iodine molecules into the amino acid tyrosine. Propylthiouracil has an additional ability to inhibit the conversion of T4 to T3 in the peripheral tissues.

20. Methimazole is usually preferred over propylthiouracil (PTU) because it reverses hyperthyroidism more quickly, and has fewer side effects. Propylthiouracil used to be the drug of choice during pregnancy because it causes less severe birth defects than methimazole. But experts now recommend that propylthiouracil be given during the first trimester only to avoid liver damage that can be caused by PTU. After the first trimester, women should switch to methimazole for the rest of the pregnancy. Treatment of Hyperthyroidism Anti-thyroid Drugs

21. Propylthiouracil or PTU It takes about two weeks before the client will see change. Dosing: adults 300 to 900 mg / day Pediatrics: 50 to 150 mg / day Never discontinue the drugs abruptly Drug therapy is life-long Follow-up is important to monitor dosing and therapeutic effects of the drug therapy.

22. Comparison between Hyper- & Hypothyroidism Signs & Symptoms FeatureHyperthyroidismHypothyroidism HairHair lossDry FaceBulging eyesPuffy face Heartbeat (Pulse)rapidslow WeightWeight lossWeight gain Growth and developmentAccelerated growthImpaired growth Activity/SleepIncrease activity/decrease sleepLethargy/increase sleep Skin characteristicsNormalCoarse/dry GI symptoms Frequent bowl movement/diarrhea & increase appetite Constipation, decrease appetite Psychological aspectNervousnessDepression Plasma levels of T3 & T4IncreaseDecrease Temperature toleranceHeat intoleranceCold intolerance Perspiration (Sweating)ExcessiveAbsent Nervous systemSleeplessnessSleepy MuscleWeaknessCramps & Aches

23. It is a life-threatening, hypermetabolic state induced by excessive release of thyroid hormones. Signs and symptoms: –Tachycardia and cardiac arrhythmias –Fever –Heart failure associated with hypotension –Flushed skin –Confusion / apathetic attitude / behavioral changes Special problem: Thyroid storm or thyroid crisis

24. A. Thyroid hormone receptor agonists 1.Thyroid hormone preparations 1. Levothyroxine (T4) 2. Liothyronine (T3) 3. Liotrix 4. Thyroid USP Note: Both Liotrix & Thyroid USP contains both T4 and T3 in a ratio(T4:T3) of 4:1

25. B. Anti-thyroid drugs 1.Thioamides (PTU & Methimazole) 2.Anion inhibitors of thyroid function 3.Iodide 4.Radioactive iodine

26. Anion inhibitors of thyroid function -Anion inhibitors of thyroid function act by inhibiting the action of the sodium-dependent iodide transporter located on follicular cell’s membrane. - Used in iodide-induced hyperthyroidism. - Since their effects can be overcome by large doses of iodides, their effectiveness some what unpredictable. -Examples: Perchlorate (-CIO 4 ) and Thiocyanate (- SCN).

27. Methimazole (No peripheral effect)

29. Thank you ?