Thyroid and Antithyroid Drugs. Dr. Alia Shatanawi Feb,
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1 Thyroid and Antithyroid Drugs Dr. Alia Shatanawi Feb,
2 Anatomy and histology of the thyroid gland Located in neck adjacent to the 5 th cervical vertebra (C5). Composed of epithelial cells which specialize in the absorption of iodine and, secretion of thyroid hormones. Follicles surround a protein core, the colloid, where thyroglobulin, a substrate in thyroid hormone synthesis, and thyroid hormones are stored. (Follicular Cells)
3 Thyroid Hormones 3 hormones Thyroxine (3,5,3,5 -tetraiodothyronine) or (T 4 ) Triiodothyronine (T 3 ) Calcitonin T 3 and T 4 are iodine containing amino acid derivatives. Every tissue in the body is affected by thyroid hormones. There are no discrete target tissue.
4 Physiological Actions Normalize growth and development, body temperature, and energy levels. Influence the metabolism of proteins, carbohydrates, and lipids. Constant circulating concentrations of T 3 and T 4 are required for their proper effect. Calcitonin is important in the regulation of calcium metabolism
5 Thyroid hormones effects on metabolism TH serves as a nuclear transcription factor, regulating gene expression in targeted cells to increase metabolism. Increase size and number of mitochondria in the cell. Synthesizes cytochromes which feed into the electron transfer chain of cellular respiration, stimulating metabolism through increasing ATP production. Increase ATPase concentration, the enzyme which cleaves a phosphate group from ATP forming ADP and inorganic phosphate. Increased K + and Na + concentrations in the cell. Increase the body s basal metabolic rate (BMR) to maintain electrochemical gradient in cell. Stimulate carbohydrate metabolism and lipolysis, or the break down of fats. Affects protein synthesis. Increase the body s sensitivity to cathecholamines, i.e. adrenaline.
6 The hypothalamic-pituitary-thyroid axis
7 The hypothalamic-pituitary-thyroid axis Acute psychosis or prolonged exposure to cold may activate the axis. Hypothalamic thyroid-releasing hormone (TRH) stimulates pituitary thyroid-stimulating hormone (TSH) release. Somatostatin and dopamine inhibit it TSH stimulates T4 and T3 synthesis and release from the thyroid, and they in turn inhibit both TRH and TSH synthesis and release. Small amounts of iodide are necessary for hormone production, but large amounts inhibit T3 and T4 production and release.
8 The Wolff Chaikoff effect It is a reduction in thyroid hormone levels caused by ingestion of a large amount of iodine, It is an autoregulatory phenomenon that inhibits organification (oxidation of iodide) in the thyroid gland, the formation of thyroid hormones inside the thyroid follicle, and the release of thyroid hormones into the bloodstream
9 Synthesis of thyroid hormones
10 Synthesis of thyroid hormones Follicular cells transport Iodide across the cell. These cells secrete precursor protein thyroglobulin into the follicular lumen. An enzyme thyroperoxidase (TPO) catalyzes the conversion of iodide to iodine using H 2 O 2 as a cofactor. TPO then catalyzes the addition of iodine to the C-3 and C-5 position of a tyrosine residue of thyroglobulin. Two iodinated tyrosine rings condense to form thyroxine, or T4, with four iodine substituents. Triiodothyronine, or T3, with three iodine substituents, accounts for about 10% of thyroid hormone
11 Thyroid Agents: Levothyroxine (T4) (Levoxyl, Levo-T): Oral, parenteral Liothyronine (T3) (Cytomel): Oral, parenteral Liotrix (a 4:1 ratio of T4: T3) (Thyrolar): Oral Thyroid desiccated ( Armour Thyroid): Oral
12 Antithyroid Agents Radioactive iodine ( 131 I) sodium (Iodotope), Oral Methimazole (Tapazole): Oral Potassium iodide: Oral solution, tablets Propylthiouracil [PTU]: Oral Thyrotropin, recombinant human TSH (Thyrogen): Parenteral.
13 Iodine requirement Thyroid hormones synthesis depends on adequate dietary intake of iodine. At least 60 µg/day is required for thyroid hormone synthesis 100 µg is needed to eliminate thyroid follicular cell hyperplasia and thyroid enlargement (iodine deficiency goiter)
14 Hypothyroidism A syndrome resulting from deficiency of thyroid hormones and is manifested largely by a reversible slowing down of all body functions. In infants and children, there is striking retardation of growth and development that results in dwarfism and irreversible mental retardation
15 Hypothyroidism Causes lethargy and weight gain, among other symptoms. Primary hypothyroidism is typically caused by Hashimoto s Disease, an auto-immune disorder in which the thyroid is destroyed by antibodies. Impaired hypothalamus and pituitary function, typically due to a tumor, can inhibit the secretion of TSH, causing secondary hypothyroidism. A diet insufficient in iodine causes hypothyroidism as well.
16 The etiology and pathogenesis of hypothyroidism
17 Symptoms of thyroid dysfunction: Goiter Enlargement of the thyroid gland. Worldwide, over 90% cases of goiter are caused by iodine deficiency. Can be associated with a functional or dysfunctional gland. Can be associated with either hypothyroidism or hyperthyroidism.
18 Goiter The decreased amount of thyroid hormones in the body, due to Hashimoto s or other thyroid disorders including infection, signals the increased production of TSH which accumulates in the thyroid causing a characteristic goiter. Goiters form due to an insufficient amount of ingested iodine and serve to increase the surface area of the thyroid and aid in its absorption of iodine
19 Treatment for Hypothyroidism Hormone replacement therapy. Administered orally with a bioavailability ranging from 48%-80%. Levothyroxine Synthetic T4 Liothyronine Synthetic T3 Liotrix Combination of synthetic T4 and T3 Natural Thyroid Hormones Thyroid hormones derived from pigs, contains T4 and T3 Armour Thyroid
20 Treatment for hypothyroidism Dosage specific to individual and is determined by their TSH serum levels. Because thyroid hormones serve to increase heart rate, T4, the inactive form, is typically administered to older patients who have an increased risk for heart attack on account of their age. Synthetic T3 is reserved for younger patients, who do not have a history of heart problems and individuals nonresponsive to T4 treatment. Some men are inefficient in the conversion of T4 to T3, making combination drugs like Liotrix and Armour Thyroid ideal treatment options. Dosage for individuals suffering from secondary hypothyroidism determined by the amount of free T4 and T3 circulating in their system. Administering too high of a dosage leads to hyperthyroid symptoms.
21 Hyperthyroidism The over-production of thyroid hormones. Symptoms include fatigue, weight lose, rapid heart beat, anxiety, swollen eyes, and sensitivity to hot temperatures. Causes: Grave s disease, and autoimmune disorder in which antibodies serve as agonists to the TSH receptors on the thyroid s surface, causing thyroid growth and activation of hormone synthesis and secretion. Thyroid tumors which cause the uncontrolled synthesis and secretion of thyroid hormones. Thyroiditis, inflammation of the thyroid typically caused by infection.
22 Treatment for Hyperthyroidism Anti-thyroid drugs Inhibits thyroid hormone synthesis by irreversibly binding to TPO inhibiting its ability to break down iodine (I 2 I - ) and covalently attach it to the tyrosine residue of thyroglobulin. Propylthiouracil Methimazole Carbamizole Degraded to methimazole in the body. Radioactive Iodine Thyroidectomy
23 Grave s Ophthalmopathy a protrusion of one or both eyes, caused by inflammation of the eye muscles by attacking autoantibodies
24 Thyrotropin: TSH Replacement Drugs Thyrotropin alpha A synthetic form of TSH. Administered intravenously. Used in thyroid cancer treatment. Tumors of the hypothalamus or pituitary gland can cause the uncontrolled release of TSH, which accumulates in the thyroid and can cause subsequent follicular or papillary cancer of the thyroid. Partial or total thyroidectomy typical. Following thyroidectomy, the individual is dependent on exogenous thyroid hormones to regulate metabolism, but thyrotropin alpha is also used to suppress the release of endogenous TSH, which could trigger cancerous growth again. Used as a diagnostic tool to determine the reoccurrence of cancer.
25 Thyroid treatment: Potential drug interactions Drugs that reduce thyroid hormone production Lithium Iodine-containing medications Amiodarone (Cordarone) Drugs that reduce thyroid hormone absorption Sucralfate (Carafate) Ferrous sulfate (Slow Fe) Cholestyramine (Questran) Colestipol (Colestid) Aluminum-containing antacids Calcium products Drugs that increase metabolism of thyroxine Rifampin (Rifadin) Phenobarbital Carbamazepine (Tegretol) Warfarin (Coumadin) Oral hypoglycemic agents Drugs that displace thyroid hormone from protein binding Furosemide (Lasix) Mefenamic acid (Ponstel) Salicylates
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