《药理学》课程教学课件（PPT讲稿）Thyroid and Antithyroid Drug

Chapter 29 Thyroid and Antithyroid Drug

Chapter 29 Thyroid and Antithyroid Drug

【Chemistry】 principal hormones are iodine-containing amino acid derivatives of thyronine-(T4 and T3). 【Thyroid physiology.】 sufficient amounts of the thyroid hormones- triiodothyronine(T3,三碘甲状腺原氨酸)and tetraiodothyronine(T4,thyroxine,甲状腺素) -to maintain normal growth and development,normal body temperature,and normal energy levels

【 Chemistry】 principal hormones are iodine-containing amino acid derivatives of thyronine-(T4 and T3). 【Thyroid physiology】 sufficient amounts of the thyroid hormones￾triiodothyronine(T3，三碘甲状腺原氨酸) and tetraiodothyronine(T4, thyroxine，甲状腺素) –to maintain normal growth and development,normal body temperature,and normal energy levels

1 Biosynthesis of Thyroid Hormones (1)Uptake of Iodide thyroid gland efficiently and actively transports iodide from plasma. (2)Oxidation and iodination: hypoiodous(HOD, Iodide Peroxidasehypoiodateke spee rapidly iodinates monoiodotyrosine(MIT) tyrosine residues diiodotyrosine(DIT). (3)Formation of Thyroxine and Triiodothyonine Two diiodotyrosyl residues Peroxidase thyroxine Monoiodotyrosyl and diiodotyrosyl couplingtriiodothyronine

1 Biosynthesis of Thyroid Hormones (1)Uptake of Iodide : thyroid gland efficiently and actively transports iodide from plasma. (2)Oxidation and iodination: Iodide hypoiodate[ ] (3)Formation of Thyroxine and Triiodothyonine : Two diiodotyrosyl residues thyroxine Monoiodotyrosyl and diiodotyrosyl triiodothyronine Peroxidase rapidly iodinates tyrosine residues monoiodotyrosine(MIT) diiodotyrosine(DIT). hypoiodous(HOI), an enzyme-linked species Peroxidase coupling

(4)Secretion of Thyroid Hormones: proteolysis is an important part of the secretory process.Proteolytic enzymes,which hydrolyze thyroglobulin and release T4 and T3. (5)Conversion of thyroxine to triiodothyronine in peripheral tissues: The primary pathway for the peripheral metabolish of thyroxine is deiodination. Deiodination of T4 produces T3,which is three to four times more potent than T4. metabolism of thyroxine sequential monodeiodination in the peripheral tissues account for about 80% of circulating triiodothyronine

(4)Secretion of Thyroid Hormones: proteolysis is an important part of the secretory process. Proteolytic enzymes, which hydrolyze thyroglobulin and release T4 and T3. (5)Conversion of thyroxine to triiodothyronine in peripheral tissues: The primary pathway for the peripheral metabolish of thyroxine is deiodination. Deiodination of T4 produces T3, which is three to four times more potent than T4. metabolism of thyroxine by sequential monodeiodination in the peripheral tissues account for about 80% of circulating triiodothyronine

THYROID GLAND Transport Peroxidase Thyroglobulin MIT-DlT-TgT4 lodides Proteolysis hiomides SCN-,CIO T4.T3 PERIPHERAL BLOOD TISSUES T4.Ta Ipodate. B-blockers. corticosteroids Figure 38-1.Biosynthesis of thyroid hormones.The sites of action of various drugs that interfere with thyroid hormone biosynthesis are shown

.2.Regulation of Thyroid function (1)Thyroid-pituitary relationships: (2)Autoregulation of the thyroid gland: 。 The thyroid gland also regulates its uptake of iodide and thyroid hormone synthesis by intrathyroidal mechanisms that are independent of TSH.These mechanisms are primarily related to the level of iodine in the blood

• 2．Regulation of Thyroid function • (1)Thyroid-pituitary relationships: (2)Autoregulation of the thyroid gland: • The thyroid gland also regulates its uptake of iodide and thyroid hormone synthesis by intrathyroidal mechanisms that are independent of TSH. These mechanisms are primarily related to the level of iodine in the blood

Acute Circadian and psychosis pulsatile rtythms Severe Cold ”stress Hypothalamus Somato- statin Corticoids dopamine TSH G Thyroid Figure 38-3.The hypothalamic-pituitary-thyroid axis. Acute psychosis or prolonged exposure to cold may activate the axis.Hypothalamic TRH stimulates pituitary TSH release,while somatostatin and dopamine inhibit it TSH stimulates T,and T3 synthesis and release from the thyroid,and they in turn inhibit both TRH and TSH syn- thesis and release.Small amounts of iodide are neces- sary for hormone production,but large amounts inhibit T3 and Ta production and release.(Solid arrows,stimula- tory influence;dashed arrows,inhibitory influence.H, hypothalamus,HPanterior pituitary.)

3.Transport ,degradation and excretion of thyroid hormones The liver is the major site of nondeiodinative degradation of thyroid hormones

• 3. Transport ,degradation and excretion of thyroid hormones The liver is the major site of nondeiodinative degradation of thyroid hormones

Table 38-1.Summary of thyroid hormone kinetics. Variable Volume of distribution 10L 40L Extrathyroidal pool 800g 54g Daily production 75g 25g Fractional turnover per day 10% 60% Metabolic clearance per day 11L 24L Half-life (bioloi 7days 1day Serum levels Total 5-11 ug/dL 95-190ng/dL (64-132 nmol/L) (1.5-2.9 nmol/L Free 07-185na/dL 0.2-052ng/dl (9-24 pmol/L) (3-8 pmol/L) Amount bound 99.96% 99.6% Biologpotency 1 4 Oral absorption 80% 95%

INACTIVATION NH2 Deamination Decarboxylation Conjugation COOH (glucuronide or sulfate) Thyroxine Deiodination ACTIVATION INACTIVATION NH2 NH2 COOH COOH 3.53-Triiodothyronine 335-Triiodothyronine (Tg) (reverse T3) Figure 38-2.Peripheral metabolism of thyroxine.(Modified from Greenspan FS:The Thyroid Gland.In:Greenspan FS, Gardner D [editors]:Basic Clinical Endocrinology,6th ed.McGraw-Hill,2001.)