1. 1 Chapter 33 Thyroid & Antithyroid Drugs Fig 1Fig 2 ＊ Thyroid follicles are the structural & functional units of the thyroid gland. ＊ Each follicle is surround mainly by simple cuboidal epithelium and is filled with a colloid which mainly composed by thyroglobulin. ＊ Thyroid hormones are mainly synthesized in colloid while the simple cuboidal epithelium undertaking thyroglobulin production, iodide intake & thyroid hormones release.

2. 2 ● Synthesis of thyroid hormones Thyroid hormones triiodothyronine (T3) tetraiodothyronine (T4, thyroxine) Materials iodine & tyrosine Steps 1. Iodide is trapped by sodium-iodide symporter thyroidal peroxidase 2. Iodide is oxidized by thyroidal peroxidase to iodine 3. Tyrosine in thyroglobulin is iodinated and forms MIT & DIT 4. Iodotyrosines condensation MIT+DIT→T3; DIT+DIT→T4 Thioamide drugs MIT: monoiodotyrosine DIT: diiodotyrosine

3. 3 Intra-thyroidal synthesis and processing of thyroidal hormones 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 (AV) 4.Within the follicular lumen, iodide is activated and iodinates 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 5.Upon TSH stimulation, villi at the apical membrane engulf the colloid and endocytose the iodinated Tg as either colloid droplets (CD) or small vesicles (MPV) 6.Lysosomal proteolysis of the droplets or vesicles hydrolyzes Tg to release its iodinated amino acids and carbohydrates 7.T4 and T3 are released into the circulation 8.DIT and MIT are deiodinated, and the iodide and tyrosine are recycled thyroidal peroxidase

4. 4 ● Regulation of thyroid function TRH: thyrotropin-releasing hormone TSH: thyroid-stimulating hormone

5. 5 ●P hysiological actions of thyroid hormones To normalize growth and development, body temperature, and energy levels ▲ Insufficiency → cretinism (infant & child), and myxedema (adult); ▲ Excess→hyperthyroid To enhance CNS excitability & sensitivity of CVS to NA ＃ T3 is 3 to 4 times more potent than T4 in heat production; ＃ T4 in colloid is about 4 times more numerous than T3 ;

6. 6 cretinism myxedema hyperthyroid

7. 7 Stems from both the hyperthyroid and hypothyroid conditions, results from the accumulation of increased amounts of hyaluronic acid and chondroitin sulfate in the dermis in both lesional and normal skin.hyperthyroidhypothyroid hyaluronic acidchondroitin sulfatedermis The mechanism that causes myxedema is still not yet understood. Sympotoms include: ● Skin thickening ● Coarse skin ● Change in facial appearance ● Thickening nose ● Swollen lips ● Puffiness around the eyes ● Jelly-like infiltrations in subcutaneous tissues ● Slow speechsubcutaneous ● Mental dullness ● Lethargy ● Mental problems ● Dry skin ● Yellow skin ● Swollen subcutaneous tissuesubcutaneous ● Weight gain ● Constipation ● Thinning hair Constipation ● Brittle hair ● Bald patches ● Muscle pains Myxedema

8. 8 Some of T4 are converted to T3 in kidney and liver The actions of T3 on several organ systems are shown BMR: basal metabolic rate; CNS: central nervous system ● Mechanism of actions of thyroid hormones T3, via its nuclear receptor, induces new proteins generation which produce effects

9. 9 ● Representative drugs levothyroxine (L-T4, levoxyl, synthroid) liothyronine (T3, cytomel, triostat) liotrix (T4 plus T3) (euthyroid, thyrolar) Thyroid drugs ● Pharmacokinetics po easily absorbed; the bioavailablity of T4 is 80%, and T3 is 95%. Drugs that induce hepatic microsomal enzymes (e.g., rifampin, phenbarbital, phenytoin, and etc) improve their metabolism.

10. 10 ● Pharmacological effect see physiological effect ● Clinical use 1.Hypothyroidism: cretinism & myxedema; 2.simple goiter: for pathogeny remaining unclear (endemic goiter directly supply iodine) 3. Others: ● Adverse reactions Overmuch leads to thyrotoxicosis; Angina or myocardial infarction usually appears in ageds

11. 11 Class Representative Thioamides propylthiouracil methylthiouracil methimazole carbimazole Iodides KI, NaI Radioactive iodine β-adrenoceptor blockers 131 I propranolol Antithyroid drugs ● Drugs

12. 12 The thiocarbamide group is essential for antithyroid activity І. Thioamides ◆ Structure

13. 13 Pharmacological action T3 & T4 Inhibition of the synthesis of T3 & T4 Mechanism All thioamides inhibit peroxidase-catalyzing reactions Iodine organification Iodotyrosines condensation Propylthiouracil also inhibit T4 converting to T3 Characteristics ① Result appears slowly: in 3-4 w hyperthyroid ameliorated, and in 2-3 months BMR normalized; ② Long-term use leads to thyroid hyperplasia ③ Methimazole is 10 times as potent as propylthiouracil First choice for thyroid crisis

14. 14 Clinical use treatment of hyperthyroid 1. Mild hyperthyroid and those surgery & 131 I not permitted; 2. Operation preparation; 3. Thyroid crisis (comprehensive therapy). Adverse reactions 1. Long-term use leads to thyroid hyperplasia; 2. Pruritic maculopapular rash is the most common adverse raaction 3. The severe adverse reaction is agranulocytosis

15. 15 Iodides (NaI, KI) Pharmacological action T3 & T4 release and synthesis Inhibition of T3 & T4 release and synthesis Decrease of size & vascularity of the hyperplastic gland Decrease of size & vascularity of the hyperplastic gland Clinical use Ministrant treatment of hyperthyroid 1. Operation preparation; 2. Thyroid crisis. Adverse reactions 1. Acneiform rash (similar to that of bromism); 2. Swollen salivary glands, mucous membrane ulcerations, and etc.

16. 16 Radioactive iodine ( 131 I) 131 I is the only isotope for treatment of thyrotoxicosis. Its therapeutic effect depends on emission of β rays with an effective half-life of 5 days & a penetration range of 0.4-2 mm. Woman in pregnancy or lactation is forbidden! β-adrenoceptor blockers βblockers are effective in treatment of thyrotoxicosis. Propranolol is the most widely studied and used.