2. Medical University of Sofia, Faculty of Medicine Department of Pharmacology and Toxicology Thyroid and antithyroid drugs © Assoc. Prof. Iv. Lambev, PhD E-mail: itlambev@mail.bg

3. Thyroxine (T4) and tri-iodthyronine (T3) THYROID DRUGS THYROID DRUGS

4. T3 and T4 are synthesized in the thyroid gland. Inorganic iodine is trapped with great avidity by the gland, oxidized and attached to tyro- sine. Combination of mono- and/or- di-iodinated tyrosine forms T3 and T4. The thyroxine peroxidase is im- portant both in the initial oxidation and the final combination steps.

5. Mono-iodtyrosine (MIT) Tyrosine Di-iodtyrosine (DIT) Inorganic iodine Thyroxine peroxidase Inorganic iodine

6. MIT + DIT DIT + DIT T3 T4 Thyreoglobulin

7. Tyrosine Di-iodtyrosine

8. T4 = L-Thyroxine

9. Synthesis and release of T3 and T4 are controlled by the anterior pitu- itary hormone, thyrotrophin (TSH - thyroid-stimulating hormone). Its secretion is controlled by the hypo- thalamic thyrotrophin-releasing hormone (TRH) and somatostatin. Circulating T3 and T4 exert a nega- tive feedback on the TSH and TRH.

10. Adenohypophysis Glandula Thyreoidea TSH Hypothalamus TRHSomatostatin (+)  (+)  p l a s m a T3< I> IT4

11. Regulation of thyroid hormone synthesis

12. Worldwide iodine nutrition

13. 80 mcg T4 40 mcg T3 200 mcg I 24 hrs:

14. Circulating thyroid hormones are highly protein-bound to TBG (thyroxine-binding globulin). Less than 0.1% from T4 is free. Only the free fraction can bind to specific cell receptors.

15. Plasma T4: 95%T3: 5% Thyroxine-binding globulin 99.91–99.97%

16. AGENTS INLFUENCING PROTEIN- BOUND OF L-THYROXINE (T4) AGENTS INLFUENCING PROTEIN- BOUND OF L-THYROXINE (T4) INCREASE estrogens methadone heroin clofibrate tamoxifen DECREASE glucocorticoids aspirin phenytoin carbamazepine furosemide

17. T3 is much more biologically active than T4. The plasma half-life of T3 is 36 h. T4 has t 1/2 168 h. After entering into cells T4 converts into T3 which binds to receptor protein and inte- racts with DNA in the cell nucleus, causing the synthesis of new messen- ger RNA and hence of new proteins.

18. The main effects of T3 and T4: Stimulating of metabolism (which resulting in a raised basal meta- bolic rate). Promotion of normal growth and maturation, particularly of the CNS and skeleton. Sensitization to the effects of cate- cholamines (DA, NA, Adrenaline).

19. Intracellular (nuclear) steroid/thyroid receptors Effector Coupling Time scale Examples gene transcription via DNA hours steroid receptors thyroid receptors vitamin D receptors

20. T3&T4 – indications: hypothyroidism T3 is reserved for patients with myxoedemic coma.

21. Facial appearance in hypothyroidism

22. Jodthyrox  (T4 + < I) Levothyroxine  (T4) - tabl. 25 mcg Liothyronin  (T3) Thyreoidea siccata  Thyrotrophin (TSH)

23. They are used to treat hyperthyroidism. Thioureas agents Beta-blockers Radioactive iodnie ( 131 I) ANTITHYROID DRUGS ANTITHYROID DRUGS

24. Thioureas agents inhibit thyroxine peroxidase, and therefore synthesis of T3 and T4. Because of long half-life of T4, changes in rate synthesis takes several weeks to low circu- lating concentrations to normal.

25. Carbimazole (prodrug) Thiamazole (Methimazole – USAN) Propylthiouracil Thiamazole - tabl. 5 mg

26. Thioureas – adverse effects Nausea, taste disturbance Agranulocytosis Placental transfer and secretion in breast milk can produce neo- natal hypothyroidism (small doses are probably safe).

27. Beta-blockers have imme- diate symptomatic effect on palpitation and tremor but do not alter the rate of T3 & T4 synthesis. 131 I (t 1/2 8 days) is used to treat multinodular toxic goiters. It is taken up by the abnormal tissue.

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