thyroid & antithyroid drugs..

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thyroid & antithyroid drugs..

  1. 1. Thyroid & Antithyroid Drugs Fig 1 Fig 2* Thyroid follicles are the structural & functional units of the thyroid gland.* Each follicle is surround mainly by simple cuboidal epithelium and isfilled with a colloid which mainly composed by thyroglobulin.* Thyroid hormones are mainly synthesized in colloid while the simplecuboidal epithelium undertaking thyroglobulin production, iodide intake &thyroid hormones release. 1
  2. 2. ●Synthesis of thyroid hormonesThyroid hormones MIT: monoiodotyrosine triiodothyronine (T3) DIT: diiodotyrosine tetraiodothyronine (T4, thyroxine)Materials iodine & tyrosine Thioamid e drugsSteps1. Iodide is trapped by sodium-iodide symporter2. Iodide is oxidized by thyroidal peroxidase to iodine3. Tyrosine in thyroglobulin is iodinated and forms MIT & DIT4. Iodotyrosines condensation MIT+DIT→T3; DIT+DIT→T4 2
  3. 3. Intra-thyroidal synthesis and processing of thyroidal hormones1. Iodide is taken up at the basolateral cell thyroidal peroxidase membrane and transported to the apical membrane2. Polypeptide chains of Tg (thyroglobulin) are synthesized in the rough endoplasmic reticulum, and posttranslational modifications take place in the Golgi3. 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 lumen5. 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 carbohydrates7. T4 and T3 are released into the circulation8. DIT and MIT are deiodinated, and the iodide and tyrosine are recycled 3
  4. 4. ●Regulation of thyroid function TRH: thyrotropin-releasing hormone TSH: thyroid-stimulating hormone 4
  5. 5. ●Physiological 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 ; 5
  6. 6. hyperthyroidcretinismmyxedema 6
  7. 7. MyxedemaStems from both the hyperthyroid and hypothyroid conditions,results from the accumulation of increased amounts ofhyaluronic acid and chondroitin sulfate in the dermis in bothlesional and normal skin.The mechanism that causes myxedema is still not yetunderstood. 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 speech●Mental dullness ●Lethargy ●Mental problems●Dry skin ●Yellow skin ●Swollen subcutaneous tissue●Weight gain ●Constipation ●Thinning hair● Brittle hair ●Bald patches ●Muscle pains 7
  8. 8. ●Mechanism of actions of thyroid hormones T3, via its nuclear• Some of T4 are converted to T3 in receptor, induces kidney and liver new proteins• The actions of T3 on several organ systems are shown generation which produce effects• BMR: basal metabolic rate; CNS: central nervous system 8
  9. 9. Thyroid drugs ● Representative drugs levothyroxine (L-T4, levoxyl, synthroid) liothyronine (T3, cytomel, triostat) liotrix (T4 plus T3) (euthyroid, thyrolar)● Pharmacokinetics po easily absorbed; the bioavailablity of T4 is 80%, and T3 is95%. Drugs that induce hepatic microsomal enzymes (e.g., rifampin,phenbarbital, phenytoin, and etc) improve their metabolism. 9
  10. 10. ●Pharmacological effect see physiological effect● Clinical use1. 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 inageds 10
  11. 11. Antithyroid drugs● Drugs Class Representative propylthiouracil methylthiouracil Thioamides methimazole carbimazole Iodides KI, NaI Radioactive iodine 131 I β-adrenoceptor blockers propranolol 11
  12. 12. І. Thioamides ◆StructureThe thiocarbamidegroup is essential forantithyroid activity 12
  13. 13. Pharmacological action Inhibition of the synthesis of T3 & T4MechanismAll thioamides inhibit peroxidase-catalyzing reactions Iodine organification First choice for Iodotyrosines condensation thyroid crisisPropylthiouracil also inhibit T4 converting to T3Characteristics① Result appears slowly: in 3-4 w hyperthyroidameliorated, and in 2-3 months BMR normalized;② Long-term use leads to thyroid hyperplasia③ Methimazole is 10 times as potent as propylthiouracil 13
  14. 14. Clinical use treatment of hyperthyroid 1. Mild hyperthyroid and those surgery & 131Inot 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 commonadverse raaction 3. The severe adverse reaction is agranulocytosis 14
  15. 15. Iodides (NaI, KI)Pharmacological action Inhibition of T3 & T4 release and synthesis Decrease of size & vascularity of the hyperplastic glandClinical 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. 15
  16. 16. Radioactive iodine (131I)131 I is the only isotope for treatment of thyrotoxicosis.Its therapeutic effect depends on emission of β rays with aneffective half-life of 5 days & a penetration range of 0.4-2 mm.Woman in pregnancy or lactation is forbidden! β-adrenoceptor blockersβblockers are effective in treatment of thyrotoxicosis.Propranolol is the most widely studied and used. 16

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