HYR

1. T HYR OI D AND AN TI TH Y R O I D DRU G S I NS T RUC TO R : Steven A. Rosenzweig, Ph.D. O B JEC T IVES : A f te r s t udy i ng th is un it , you shou l d be a bl e t o: 1 . D e f i ne the b i oche mi ca l bas is f o r h y pe r th yr o i d i s m an d h y poth yr o i d i s m . 2 . D e s cri be t he m echan is m of a c t i on of each d r ug cl as s . 3 . D e s cri be t he pha rm acod y nam ic s and t ox ici t y o f ea c h d r ug cl as s . 4 . E x p l a i n t he u s es and i nd ic at i on s o f e a ch d r ug.

3. Physiology of Thyroid Hormone Regulation

4. B. Active principles of the thyroid gland are thyroxine (T4) and triiodothyronine (T3) T4 DIT T3 MIT

5. Synthesis and Metabolism Thyroid hormone biosynthesis is exceptionally inefficient

7. Synthesis and Metabolism Hashimoto’s Thyroiditis

8. Major steps in synthesis involve: • 1. Uptake of iodide - sodium iodide • a. Iodide in circulation (0.2 to 0.4 µg/dl) is concentrated 20 to 50-fold by gland • b. I- transport is stimulated by TSH and controlled by auto regulation (decreased stores stimulate, increased stores inhibit) • c. I- transport is blocked by antithyroid drugs thiocyanate and perchlorate • 2. Oxidation and Iodination (Organification) • a. Oxidation of I- is effected by H202 and a peroxidase- catalase reaction • b. Enzyme is concentrated at membranes for iodination of monoiodotyrosine (MIT) and diiodotyrosine (DIT) residues in thyroglobulin prior to its storage in thyroid follicle.

9. 3. Formation of T4 and T3 from iodotyrosine (coupling reaction) a. DIT + DIT = T4 (intramolecular coupling) MIT + DIT = T3 These reactions may be catalyzed by the same peroxidase • b. Amount of T4 and T3 formed depends on relative quantities of DIT and MIT; I2 deficiency favors T3 synthesis • c. Synthesis and Storage in colloid space • 4. Secretion of T3 and T4 • Thyroglobulin is taken up by endocytosis and transported in colloid droplets to lysosomes for proteolysis. • 5. Conversion of T4 to T3 via 5’-deiodinase in peripheral tissues; T3 is more potent

10. C. Transport in the circulation • 1. T4 and T3 carried by thyroxine-binding globulin (TBG; Proloid®); affinity for T4 is greater • 2. T4 is also transported by transthyretin (formerly “prealbumin”) • 3. Free hormones are biologically active • a. 0.03% of plasma T4 • b. 0.2 to 0.5% of plasma T3

11. D. Receptors — members of the nuclear receptor superfamily • 1. Located in the nucleus of numerous tissues — transcription factors • 2. TRa, TRb • 3. Nongenomic actions

12. E. Actions of T3 and T4 — “important determinants of genetically coded developmental programs” (Goodman & Gilman) • 1. Growth and development • a. Many effects are mediated through regulation of protein synthesis • b. Cretinism • i. Due to iodine deficiency (endemic cretinism) or to abnormal thyroid development or defect in synthesis of thyroid hormone (sporadic cretinism) • Impaired growth, mental retardation, short extremities, listlessness, large tongue, puffy face • c. Maternal hypothyroidism  suboptimal fetal development

13. TR TR • 2. Stimulation of cardiovascular system • a. Thyroid hormones increase sensitivity to b-adrenergic receptor-mediated actions • Heart rate and cardiac output are increased in hyperthyroidism; ventricular hypertrophy may occur • Calorigenic effect:  heat and energy production,  O2 consumption. d. Cholesterol metabolism:  conversion to bile acids

14. F. Degradation and Excretion • 1. Both T4 and T3 - conjugated in liver to glucuronic and sulfuric acids through the phenolic group, then excreted in the bile. • 2. T4 half-life is 6-7 days (but 3-4 days in hyperthyroidism, 9- 10 days in myxedema) • 3. T3 - half-life is 1-2 days. G. Clinical Uses 1. Replacement therapy in hypothyroidism 2. Obesity (not advised!) 3. TSH suppression (nontoxic goiter, cancer)

15. II. Regulation • A. Thyrotropin (TSH) - pituitary product • 1. Synthesis and secretion of this protein (mw 28,000) are augmented by a hypothalamic product (TRH) and are feedback-inhibited by thyroid hormones • 2. Mechanism of action • a. Binds to a G protein-coupled receptor • b. Increases hormone synthesis and secretion, and increases vascularity of thyroid gland • c. Prolonged stimulation produces hypertrophy and hyperplasia of thyroid cells. • 3. Clinical use - diagnostic test for thyroid function with thyroid 123I uptake and scan

16. B. Thyrotropin Releasing Hormone (TRH) - hypothalamic product • Tripeptide (mw 362), structure is pyroglutamic acid- histidine-proline amide • Stimulates TSH secretion and synthesis • Clinical use - Formerly, provocative test for release of TSH, but no longer available in the U.S.

17. C. Hypothyroidism (myxedema when severe) • 1. Caused by loss of regulatory factor from pituitary (secondary) or disease of thyroid (primary, e.g. Hashimoto’s thyroiditis) • 2. Signs and symptoms related to decreased heat production, decreased sympathetic nervous system activity • 3. Treatment: replacement; levothyroxine is usually preferred • Caution: • In older individuals, thyroid replacement should be gradual because an arrhythmia or a myocardial infarction may be precipitated by abrupt full replacement. Osteoporosis may also be a consequence of long term therapy

18. D. Hyperthyroidism • 1. Due to excess circulating T3 and T4 • 2. May be caused by antibodies of the IgG type (“thyroid stimulating antibody”) which activate TSH receptors (Graves’ disease) • 3. Signs and symptoms related to excessive production of heat, increased motor activity, and increased activity of the sympathetic nervous system - thyrotoxicosis (e.g. hypertension, tachycardia, nervousness, muscle weakness) “Hamburger Thyrotoxicosis”

19. Tiki - suspected of having hyperthyroidism

20. III. Antithyroid Agents A. Four types 1. Synthesis inhibitors (e.g. propylthiouracil) 2. Iodide uptake blockers (e.g. perchlorate) 3. Inhibitors of hormone release (iodide) 4. Gland ablation (131I; surgery) B. Thioamide Drugs (thiourylenes) 1. Structure Propylthiouracil Methimazole

21. TPO Propylthiouracil • 2. Mechanism of action • a. Inhibits organification of tyrosine residues in thyroglubulin • b. Inhibits coupling of MIT and DIT to form T3 and T4 • c. Propylthiouracil inhibits conversion of T4 to T3 (thus might be useful to treat thyroid storm or thyrotoxic crisis) • 3. Pharmacokinetics • a. Rapid absorption • b. Plasma half-life is short • i. 2 hours for propylthiouracil • ii. 4-6 hours for methimazole • c. Concentrated in thyroid • d. Drugs and metabolites are excreted in urine • e. Drugs cross placenta, and may also appear in milk deiodinase

22. 4. Untoward Reactions • a. Agranulocytosis or aplastic anemia • i. Less than 1 in 500, usually occurs in the first few months of treatment. • ii. Onset is rapid, recovery frequent if drug is stopped • b. Skin rash - may subside spontaneously - more common • 5. Therapeutic Uses • a. To treat hyperthyroidism until a spontaneous remission occurs (Graves’ disease) • b. To control severe hyperthyroidism in conjunction with ablation therapy with 131I • c. To prepare patients for thyroidectomy

23. C. Iodide — The oldest remedy for thyroid disorders, acts rapidly, usually within 24 hours • 1. Mechanism of action • a. Inhibits iodotyrosine and iodothyronine synthesis • b. Inhibits thyroid hormone release • c. Causes a rapid reduction in gland vascularity • 2. Uses • a. Immediate preoperative period prior to thyroidectomy after longer term treatment with an antithyroid drug such as propylthiouracil to further shrink the gland and reduce vascularization • b. Protection from radioactive fallout • c. Prophylaxis of endemic goiter • d. Beneficial effects in treating hyperthyroidism eventually wear off

24. Chernobyl 10 million children and adults were administered iodide in Poland after the 1986 nuclear accident

25. 3. Toxicity • a. Occasionally individuals have acute reactions, including angioedema, fever, arthralgia and eosinophilia • b. Iodism: dermatitis, stomatitis and mental depression • D. Radioactive Iodine • 1. 131I — half-life 8 days - emits x-rays and -particles (ablation therapy) • 123I — half-life 13 hours (scanning) • 2. Mechanism of action • a. Trapped by thyroid • b. Incorporated into iodotyrosines and deposited in follicular colloid • c. -particles (131I) destroy parenchymal cells, causing involution of gland

26. 3. Uses • a. 131I in hyperthyroidsm, as an alternative to surgery, especially in patients with contraindications for surgery • b. In treatment of follicular thyroid carcinoma • c. 123I to measure iodine uptake by the thyroid as a diagnostic test for hyper- or hypothyroidism and response to TSH • Toxicity and Contraindications • a. High incidence of hypothyroidism after use • b. Contraindicated 6-12 months before, and during, pregnancy

27. E. Ionic Inhibitors • 1. Chemistry — thiocyanate; also perchlorate and periodates • 2. Uses • a. Rarely used due to toxicity - agranulocytosis and aplastic anemia • b. When other antithyroid drugs are not tolerated

28. Adjunctive Drugs in Hyperthyroidism • Beta adrenergic receptor antagonists: propranolol or atenolol - for suppression of signs and symptoms of thyrotoxicosis, especially cardiovascular complications from increased sympathetic nervous system activity • Calcium channel blockers: e.g. diltiazem to control tachycardia and supraventricular tachyarrhythmias • Dexamethasone: inhibits T4 T3 conversion