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Pharmacology – III PHL-418 Thyroid and Anti-thyroid Drugs Dr. Hassan Madkhali Assistant Professor Department of Pharmacology E mail: [email protected] Topics • • • • • • Endocrine system Introduction Pituitary and hypothalamic hormones Thyroid and anti-thyroid Drugs Adrenal Drugs Pancreatic Drugs Gonadal hormones and inhibitors Major endocrine glands (Male left, female on the right.) 1. Pineal gland 2. Pituitary gland 3. Thyroid gland 4. Thymus 5. Adrenal gland 6. Pancreas 7. Ovary 8. Testis https://en.wikipedia.org/wiki/Endocrine_gland Thyroid Gland www.urmc.rochester.edu Thyroid gland Function • Thyroid gland is responsible for the secretion of three hormones essential for proper regulation of metabolism (increase metabolic rate). – Thyroxine (T4) – Triiodothyronine (T3) – Calcitonin T3 and T4 • Both produced in the thyroid gland through the iodination and coupling of the amino acid tyrosine. • Body needs about 1 mg of iodine per week from the diet. Biosynthesis of thyroid hormones -Human Physiology, p331. Stuart Fox. 10th ed. -Endocrinology: Basic and Clinical Principles, p 291. Totowa, NJ, Humana Press. Biosynthesis of thyroid 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. 4. Within the follicular lumen, iodide (I−) is oxidized to iodine (I2) by thyroperoxidase. 5. Iodine binds to 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. 6. Upon TSH stimulation, villi at the apical membrane engulf the colloid and endocytose the iodinated Tg. 7. T4 and T3 are released into the circulation 8. DIT and MIT are deiodinated, and the iodide and tyrosine are recycled Regulation of thyroid function • Thyrotropin-releasing hormone (TRH) from hypothalamus releases thyroid-stimulating hormone from anterior pituitary. • TSH is stimulated when the blood levels of T3 and T4 are low. • TSH acts by stimulation of the thyroid follicular cells by binding to TSH receptor on the basal surface of the thyroid follicle cells. • This leads to iodide uptake. • T3 and T4 exert negative feedback on both the pituitary production of TSH and the hypothalamic production of TRH. Thyroid hormones effects on metabolism • The effect of thyroid hormones on metabolic processes appear to be mediated by activation of nuclear receptors that lead to increase formation of RNA and subsequent protein synthesis (regulating gene expression in targeted cells to increase metabolism). • Stimulate carbohydrate metabolism and lipolysis, or the break down of fats. • Increase protein synthesis. • CNS development. • Growth. • Cardiac effects: increase cardiac output and heart rate. Thyroid Disorders A- Hypothyroidism • A condition characterized by diminished production of the thyroid hormone. – Primary hypothyroidism stems from an abnormality in the gland itself. – Secondary hypothyroidism begins at the level of the pituitary gland and results from reduced levels of TSH (thyroid stimulating hormone). – Third type is caused by reduction in the amount of TRH of thyrotropin releasing hormone by the hypothalamus. Hypothyroidism - Adults • Presenting clinical manifestations – Weight gain – Constipation – Fatigue – Irregular menstrual cycle in women – Edema – More common in females than males – Cold intolerance. Hypothyroidism • Laboratory value to look at: • TSH – thyroid stimulating hormone will be increased - it is working hard to stimulate the production of T3 and T4 • T3 and T4 levels would be low Hypothyroidism • All newborns are tested at birth for thyroid function • If untreated can lead to retardation due to effects on brain development. • Hashimoto’s hypothyroidism is an autoimmune disease and considered as the most common cause of hypothyroidism in USA. Treatment of Hypothyroidism • Thyroid drugs such as levothyroxine (brand names: Synthroid or Levothroid), is a synthetic form of T4. • It acts by binding to thyroid receptor in the cell nucleus and cause metabolic effects through the gene expression and protein synthesis. • Take on empty stomach in the morning • Do not take with antacids or iron preparations • If on Coumadin may need to use smaller dose of Coumadin • Do not stop when feeling better • Dosage of other drugs may need to be reduced due to slow metabolism in liver and excretion in urine Synthroid Dosing • Adult: 25 to 300 mcg / day • Pediatrics: 3-5 mcg / kg / day • How provided in 5 mcg, 25 mcg, 75 mcg and 100 mcg tablets • IV: 200 mcg per vial in 6 and 10 mL vials. B- Hyperthyroidism • Excessive secretion of thyroid hormones. • Causes: – Graves’ disease (is an autoimmune disease that affects the thyroid. It frequently results in hyperthyroidism and an enlarged thyroid. – Plummer’s disease or toxic nodular disease (is a multinodular goiter associated with a hyperthyroidism). – Thyroid storm: caused by stress or infection Clinical Manifestations • • • • • • • • • • • Diarrhea Flushing Increased appetite Muscle weakness Fatigue Heart palpitations Irritability Nervousness Sleep disturbances Heat intolerance Altered menses Laboratory Values • TSH would be low • T3 and T4 would be high Treatment of Hyperthyroidism Anti-thyroid Drugs • Methimazole and propylthiouracil (PTU) act by inhibiting the enzyme thyroperoxidase. • Inhibiting the incorporation of iodine molecules into the amino acid tyrosine. • Propylthiouracil has an additional ability to inhibit the conversion of T4 to T3 in the peripheral circulation. Treatment of Hyperthyroidism Anti-thyroid Drugs • Methimazole is usually preferred over propylthiouracil because it reverses hyperthyroidism more quickly and has fewer side effects. • Propylthiouracil used to be the drug of choice during pregnancy because it causes less severe birth defects than methimazole. • But experts now recommend that propylthiouracil be given during the first trimester only to avoid liver damage • After the first trimester, women should switch to methimazole for the rest of the pregnancy. Propylthiouracil or PTU • Most common drug used by hyperthyroidism. • Will take about two weeks before the client will see change. • Dosing: adults 300 to 900 mg / day • Pediatrics: 50 to 150 mg / day • Never discontinue the drugs abruptly • Drug therapy is life-long • Follow-up is important to monitor dosing and therapeutic effects of the drug therapy. Special problem: Thyroid storm or thyroid crisis • Signs and symptoms: – Tachycardia and cardiac arrhythmias – Fever – Heart failure – Flushed skin – Confusion / apathetic attitude / behavioral changes – Hypotension A. Thyroid hormone receptor agonists 1. Synthesis of natural thyroid hormone 2. Thyroid hormone preperations 1. Levothyroxine (T4) 2. Liothyronine (T3) 3. Liotrix 4. Thyroid USP B. Anti-thyroid drugs 1. 2. 3. 4. Thioamides Anion inhibitors of thyroid function Iodide Radioactive iodine Anion inhibitors of thyroid function -Anion inhibitors of thyroid function act by inhibiting the action of the sodium-dependent iodide transporter located on follicular cell’s basolateral membranes. - Used in iodide-induced hyperthyroidism. - Since their effects can be overcome by large doses of iodides, their effectiveness some what unpredictable. -Examples: perchlorate (-CIO4) and thiocyanate(SCN). Methimazole Thank you ?