Tiêu đề 26. THYROID AND ANTITHYROID AGENTS.pdf ✅

PHARMD GURU Page 1 INTRODUCTION: The thyroid gland is a small, butterfly-shaped gland located in front of the neck, in front of trachea, just below the larynx, with weight of 15-20 g in adults. The gland receives fibers from both sympathetic and parasympathetic division of ANS. The gland consists of thousands of follicles, each a spheroidal sac of epithelial cells (thyrocytes) surrounding a lumen containing colloid, a depot of thyroid hormone precursor, thyroglobulin. SYNTHESIS, STORAGE AND RELEASE OF THYROID HORMONES: Thyroid gland secretes two important hormones, 3,5,3’,5’,-tetrahydrothyronine (thyroxine (T4) and 3,5,3’-triiodothyronine (T3), both of which are iodinated THYROID AND ANTITHYROID AGENTS
PHARMD GURU Page 2 derivatives of tyrosine. Thyroid epithelial cells of gland are responsible for synthesis of thyroid hormones. The major product of the thyroid gland is T4 ( ̴90%). Most T3 (> 80%) is derived from T4 by de-iodination in peripheral tissues (liver, kidneys and muscle). In target cells, most of the effects of T4 results from this conversion to T3. De-iodination can also produce 3,3’,5’- triiodothyronine (reverse T3; rT3) which is physiological inactive. The synthesis of thyroid hormones requires the amino acid tyrosine and the trace mineral iodine. Tyrosines are provided from a large glycoprotein scaffold called thyroglobulin, which is synthesized by thyroid epithelial cells and secreted into the lumen of the follicle colloid is essentially a pool of thyroglobulin. Within thyrocytes, iodide is oxidized to iodine. This reaction is catalyzed by the enzyme thyroid peroxidase in the presence of hydrogen peroxide. Iodine then binds to 3’ position in the tyrosyl ring to yield 3-monoiodotyrosine (MIT). A subsequent addition of another iodine to 5’ position of tyrosyl residue on MIT creates 3,5-diiodotyrosine (DIT). T4 is created by the condensation or coupling of two DIT molecules. Smaller amount of DIT within the thyroid can also condense with MIT to form either T3 or rT3. All these biosynthesis processes within the thyroid gland are controlled by feedback mechanism within the hypothalamic pituitary thyroid axis. Once the T4 and
PHARMD GURU Page 3 T3 thyroid hormones are in circulation, a large fraction binds to other substances called thyroid hormone transport proteins, after which they become inactive. The 3rd hormone, calcitonin, a polypeptide hormone, secreted from interstitial cells is physiologically different and is responsible for the regulation of calcium metabolism. Two other important hormones in the process are Thyroid-Stimulating Hormone (TSH or thyrotropin) and Thyrotropin-Releasing Hormone (TRH). TSH directly influences the whole process of iodine trapping and thyroid hormone production. TSH is secreted by the pituitary gland and monitored by TRH, which is produced in the hypothalamus gland. BIOLOGICAL ACTIONS OF THYROID HORMONES:  Thyroid hormones are essential for normal growth and development and stimulate metabolism in most tissues.  They increase mitochondrial oxidative phosphorylation and maintain amino acid electrolyte transport into cells.  They increase calorigenesis and oxygen consumption in most tissues.  They stimulate the synthesis of proteins that can be structural proteins or enzymes.  They regulate carbohydrate, metabolism, accelerating insulin degradation and increasing gluconeogenesis.  They stimulate lipid metabolism, which leads to fall cholesterol concentration in plasma.  They also increase the sensitivity of the cardiovascular and nervous system to catecholamines, the former leading to increase in heart rate and cardiac output, and the later to increase arousal.  They also exert modulation of gene expression. They enter into the cells and act by binding to specific receptor in the nuclei, where they stimulate the synthesis of a variety of species of mRNA, thus stimulating the synthesis of proteins, including enzymes and hormones.
PHARMD GURU Page 4 METABOLISM OF THYROID HORMONES: Thyroid hormones exert their effect by binding to nuclear receptors in target organs. Both the thyroid hormones are well absorbed after oral administration. They are conjugated with sulfuric acid in liver and excreted in bile. The major pathway of thyroid hormone inactivation is via de-iodination. About 85% of T4 and 50% of T3 are de-iodinated. The reaction occurs in thyroid, pituitary, kidney, liver, placenta and number of other tissues. De-iodination takes place by three different types. Type (1) is removal of iodine from both the rings, which is inhibited by the antithyroid drug like propylthiouracil. Type (2) and (3) are removal of iodine from only outer ring or inner ring respectively, and not affected by propylthiouracil. The 5’-deiodination of T4, produces T3, the more active form of thyroid hormone. This conversion of T4 to T3 occurs largely in the peripheral tissues and in the pituitary. The 5-de-iodination of T4, produces reverse T3 (rT3) which is inactive. Further de-iodination of T3 or rT3 leads to the formation of also inactive product i.e. 3,3’-diiodothyronine. The deiodinated products may be further stripped of iodine (for recovery by the thyroid) or excreted.