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ANTI-THYROID AGENTS Thyroid Gland Over Trachea Two lobes connected together by isthmus 15 to 20 gms weight Second largest endocrine gland in body Small butterfly shaped gland located at base of neck below the sternocleidomastoid muscles Thyroid is controlledby the hypothalmus and pituitary The thyroid’s job is to make thyroid hormone, which is secreted into the blood and then carried to every tissue in the body. The thyroid gland is to take iodine, found in many foods, and convert it into thyroid hormones: thyroxin (T4) and triiodothyronine (T3). The thyroid gland is controlled by the pituitary gland which produces a hormone called Thyroid stimulating hormone (TSH). Its level goes up when the level of thyroid hormones comes down and vice versa. Thyroid gland is composed over a million cluster of follicles Follicles are spherical & consists of epithelial cells surrounding a central mass (colloid) Normal thyroid gland secretes thyroid hormones Natural hormone compounds having biological activity (Iodide containing ): L-Thyroxine (T4 or tetraiodo-L-thyroxine) Liothyronine (T3 or triiodo-L-thyronine) Both forms are available for oral use Parafollicular (C) cells produce calcitonin Functions 1. Normal human growth & development, esp.CNS 2. In adults,maintain metabolic homeostasis, affecting all organ systems Large preformed hormone stores in thyroid Metabolism of thyroid hormone occurs in liver and brain TSH regulates serum thyroid hormones by a negative feedback system Bind to nuclear thyroid hormone receptors, modulates gene transcription HORMONES T4, T3, Calcitonin Synthesis Of Thyroid hormone Steps 1. Transport of iodide into the thyroid gland by sodium-iodide symporter 2. Iodide is oxidized by thyroidal peroxidase to iodine 3. Tyrosine in thyroglobulin is iodinated and forms MIT & DIT- iodide organification( MIT- monoiodotyrosine, DIT- Diiodotyrosine) 4. Iodotyrosines condensation within thyroglobulin molecule MIT+DIT→T3; DIT+DIT→T4 5. T4, T3, MIT& DIT - released from thyroglobulin by exocytosis & proteolysis of thyroglobulin . 6. The MIT and DIT are deiodinated within the gland, and the iodine is reutilized. 1) Iodide uptake or pump - Rate –limiting step in thyroid hormone synthesis which needs energy - Follicles have in their basement membrane an iodide trapping mechanism which pumps dietary I - into the cell - Normal thyroid: serum iodine is 30-40:1 a. Iodide uptake enhancers: i. TSH ii. Iodine deficiency iii. TSH receptors antibody b. Iodide uptake inhibitors i. Iodide ion ii. Drugs 1. Digoxin 2. Thiocynate 3. perchlorate 2) Iodide oxidation to iodine and Organification - Inside the cells, iodide is oxidized by membrane bound peroxidase system to more reactive iodine (Iodinium or I+), or HOI or E-OI - Iodine immediately reacts with tyrosine residue on a thyroid glycoprotein called “thyroglobulin” to form: MIT and DIT - Both processes are catalyzed by thyroid peroxidase enzyme 3) Coupling - T1& T2 couple together to form T3 & T4 - MIT +DIT = T3 (Tri-iodothyronine) - DIT + DIT = T4 (Thyroxine) - Normally high amount of T4 is formed - Homeostasis: In case of Iodine deficiency more MIT is formed and hence more T3 – leading to more active hormone with less Iodine 4) Storage and release - MIT, DIT, T3 and T4 - all attached to thyroglobulin and stored in the colloid Thyroglobulin molecule - This process is stimulated by TSH - Taken up by follicular cells by the process of endocytosis and broken down by lisosomal proteases - T3 and T4 released and also MIT and DIT - MIT and DIT are deiodinated and reutilized T4 & T3 enter circulation directly from follicular cells Free (unbound) hormone is a small percentage, 0.03%T4 and 0.3%T3 of the total plasma hormone Only unbound form has metabolic activity 5) Peripheral conversion - Peripheral tissues – liver and kidney - T4 to T3 - 1/3rd of T4 undergoes these changes and most of T3 available are derived from liver - Equal amounts of T3 are produced in periphery - Drugs like Propylthiourcil, propranolol and glucocorticoids inhibit peripheral conversion Transport, Metabolism and Excretion – Kinetics • Highly bound to plasma protein • Only 0.04% of T3 and 0.2% T4 are in free form • All Protein Bound Iodine (PBI) in plasma is thyroid hormone – 95% is T4 • Main Plasma proteins for T4 are – TGB, TBP and albumin • Only free form of hormone is available for action and metabolism • Metabolism occurs by deiodination and conjugation, mainly in liver and kidneys • T4 is deiodinated to T3 (active) or rT3 (inactive) by deiodination • Conjugated products are excreted in bile – enterohepatic circulation • Finally excreted in urine T3 Vs T4 • T3 is 5 times more potent > T4 • Half life of T4 is 6-7 days and T3 is 1-2 days – hyper and hypothyroidism • T4 is the major circulating hormone – bound more to plasma proteins • T4 is less active and a precursor of T3 - the major mediator of physiological effects • The term thyroid hormone is used to comprise both T4 plus T3 • T4deiodination to T3 or reverse T3 • T3& reverse T3deiodination to three di-iodothyronines, deiodinated to two monoiodothyronines - (inactive) Mechanism of Action Produce action by combining with TR (Nuclear Thyroid hormone receptor) TR reside in nucleus bound to Thyroid Hormone Response Element (TRE). When T3 Bind to TR it heterodimerizes with Retinoid X receptor (RXR) undergoes conformational change and bind to Co-Activator Induces gene transcription – Produces specific mRNA and Specific Protein synthesis Physiological actions of thyroid hormones 1) Growth & Development - Essential for normal growth and development - Congenital deficiency results in Cretinism - Milestones of development delayed - Retardation and nervous deficit - synapse formation and myelination impaired - Intelligence is impaired, slowness of movements 2) Metabolic Effects: Lipids - ↑ lipolysis, Free fatty acids levels ↑. - Potentiates catecholamines and lipolytic hormones - Suppresses Phosphodiesterase - Cholesterol metabolism accelerates - Hypercholesterolemia and ↓ LDL in Hyperthyroidism 3) Metabolic Effects: Carbohydrates - Carbohydrate metabolism stimulated - Utilization of sugar is enhanced - ↑Glycogenolysis and gluconeogenesis - Faster absorption of glucose - Hyperglycemia and insulin resistance in hyperthyroidism 4) Metabolic Effects: Proteins - Catabolic effects - Protein used as energy source - Negative Nitrogen balance and tissue wasting - Weight loss in Hyperthyroidism 5) Calorigenesis - ↑ BMR – stimulates cellular metabolism - Excess energy released as heat. - Metabolic rate in Brain, Gonads, uterus, Spleen and Lymph node not affected 6) Cardio Vascular System - Hyperdynamic state of circulation: ↑ peripheral demand - Heart rate, contractility and output ↑: fast, Bounding Pulse - Up regulation of β receptors - Atrial fibrillation and other arrhythmias in Hyperthyroidism - Precipitate CHF and Angina, ↑ BP - Reduced myocardial O2 demand in Hypothyroidism 7) Nervous System - Mental retardation in cretinism, Sluggishness - Hyperthyroid persons are o Anxious, Nervous, excitable o Exhibit tremors o Hyperreflexia 8) Skeletal Muscles - Flabby and weak in myxedema - Increased muscle tone, Tremors and weakness in thyrotoxicosis 9) Gastro Intestinal System - Increased peristalsis - Constipation: Hypothyroidism - Diarrhoea: Hyperthyroidism 10) Kidney - Increased urine flow when Patients treated with Thyroid Hormones 11) Haemopoesis - T4 is facilitator for erythropoiesis - Certain Patient who are not responding to hematinic respond to thyroid hormone - Hypochromic, Normochromic in Hypo -Normochromic in Hyper 12) Reproduction - Impaired Fertility, Oligomenorrhoea in hypothyroidism - Normal thyroid function is required for maintenance of pregnancy and lactation - Infertility in Hypo and Hyper in females - Males - ↓Libido, Impotence, Oligozoospermia Therapeutic Uses • As Replacement therapy in deficiency states • Available as l-thyroxine sod. 100, 50, 25 mcg tablets • Liothyronine is available as 5, 25 mcg tabs and Injection • Mixture of T3 and T4 tablets • T4 - consistent potency and prolonged duration ofaction. • 50% - 80% GIT absorption. • T3 for quicker onset of action as in myxedema coma or preparation of a patient for I131 therapy in thyroid cancer Thyroid hormone replacement therapy • Cretinism ( is a condition of severely stunted physical and mental growth due to untreated congenital deficiency of thyroid hormones (congenital hypothyroidism) due to maternal nutritional deficiency of iodine.) • Adult hypothyroidism • • • • Myxoedema (A disease caused by decreased activity of the thyroid gland in adults and characte rized by dry skin, swellings around the lips andnose, mental deterioration, and a s ubnormal basal metabolic rate.) Non toxicgoitre Thyroid nodule (Thyroid nodules are lumps which commonly arise within an otherwise normalthyroid gland.) Carcinoma of thyroid Thyroid inhibitors Hormone Synthesis Inhibitors (THIOAMIDES) - Propylthiouracil, Methimazole, Carbimazole Hormone release Inhibitors - Iodine, NaI, KI Damage to Thyroid tissue - I131 Ionic Inhibitors - Thiocynate (SCN-), Perchlorates(ClO4-), Nitrates (NO3-) β-adrenergic blocking drugs - Propranolol, Atenolol. Hormone Synthesis Inhibitors Inhibit peroxidase → inhibit Hormone synthesis Inhibit iodination and Coupling Onset of action requires 3-4 weeks to develop Peripheral conversion of T4 to T3 only inhibited by Prophylthiouracil Pharmacokinetics Rapidly absorbed, widely distributed and concentrated in thyroid tissue Peak effect with in 1 hour but longer duration(PTU) Carbimazole → Methimazole Cross Placenta and secreted in milk Propylthiouracil can be given in pregnancy Adverse effects Hypothyroidism Skin Rashes Uncommon - Nausea, headache, Pain, Stiffness, Skin Pigmentation, Loss/Graying of Hairs Rare- Granulocytopenia, Hepatitis, Hepatic failure with Propylthiouracil Use: ◦ ◦ Thyrotoxicosis (autoimmune hyperthyroidism) : life long Pre operatively to make euthyroid (is the state of having normal thyroid gland function). Advantage – ◦ Less surgical complication ◦ If hypothyroidism develops then therapy can be stopped normal function Disadvantage – ◦ Long term therapy ◦ Not practicable in unconscious patient ◦ Toxicity specially in pregnancy INHIBITORS OF HORMONE RELEASE IODIDES IODIDE THERAPY • Lugol's solution(5 % iodine + 10 % potassium iodide) orally • Potassium iodideorally 60 mg MECHANISM OF ACTION • Most important action is inhibition of hormone release-'thyroid constipation’. • The mechanism of action is not clear. • Attenuate the effect of TSH on the thyroid gland, so decrease the size & vascularity. • Decrease exocytosis and proteolysis of thyroglobulin. • Excess iodide inhibits its own transport in thyroid cells • Alter the redox potential of cells, thus interfering with iodination • Decrease release of T4 & T3 ADVERSE EFFECTS On Acute Administration Hypersensitivity – Angioedema, Swelling of Larynx, Swelling of Lips and eyelid. Multiple Cutaneous Hemorrhage Serum Sickness – fever, Arthralgia, Thrombocytopenia, Lymphadenopathy (swollen/enlarged lymph nodes) On Chronic use (Dose Related) Brassy taste, Burning in mouth, Tenderness of teeth and gums Rhinorrhea ( persistent watery mucus discharge from the nose), lacrimation, Sneezing, Swelling of eyelids, Skin rashes. Irritation of bronchial mucous glands Enlargement of salivary glands Hypothyroidism and goiter USES • Large doses for thyroid crisis – to reduce release • Preparation for thyroidectomy (Surgical removal of the thyroid gland.) – To make the gland firm, less vascular and easy to operate • Prophylaxis of endemic goitre • Thyroid storm (The condition resulting from excessive activity of the thyroid gland, characterize d by increased basal metabolism.) • Antiseptic on skin / surgical scrub, expectorant RADIOACTIVE IODINE • Administered orally in solution as sodium 131I MECHANISM OF ACTION: • It is rapidly absorbed, concentrated by the thyroid, & incorporated into storage follicles emits β particles & X rays β particles damage the thyroid cells thyroid tissue destroyed by piknosis (a degenerative state of the cell nucleus) replaced by fibrosis ADVANTAGE OF I131 Low treatment cost Convenient, can be given on Out Patient Basis Surgery can be avoided Permanent control DISADVANTAGE OF I131 Permanent Hypothyroidism Lifelong Treatment by Thyroid Hormones Delayed onset of action Can not be used in pregnancy Carcinogenic – avoided in young patients • C/I : Pregnancy Young patients • Adverse effect : – Hypothyroidism – crosses the placenta to destroy the fetal thyroid gland & is excreted in breast milk (baby become hypothyroid) THERAPEUTIC USES Grave’s disease (a disease characterized by an enlarged thyroid and increased basal metabolism du e to excessive thyroid secretion) – failure of Antithyroid drugs Elderly – who can not undergo thyroidectomy Toxic Nodular Goiter (an enlarged thyroid gland characterized by numerous discrete nodules and hypers ecretion of thyroid hormones) Patient with existing heart disease IONIC INHIBITORS • Thiocynate (SCN-), Perchlorates (ClO4-), Nitrates (NO3- ) Inhibit iodide trapping → inhibit Synthesis • Perchlorate, Thiocyanate- block uptake of iodine by the gland through competitive inhibition of the iodide transport mechanism. • Were used, Not Now. Thiocynate – Hepatic, Renal, Brain and Bone marrow toxicity Perchlorates – Aplastic anemia, Agranulocytosis, Rashes, Fever Nitrates–Methaemoglobinaemia (The presence of methemoglobin in the circulating blood) β- adrenergic blocker • Increased tissue sensitivity to catecholamine in hyerthyroidism – increased no. of “β” adrenoceptors (up regulation) – Increased second messenger i.e. cAMP responses • Some symptoms are adrenergic – palpitation, tremor, nervousness, myopathy and sweating etc. • β- blocker provides quick relief (propranolol 20-80mg 6-8 hrly) • Not used as sole therapy – awaiting Carbimazole or I131response, preoperative treatment of subtotal thyroidectomy and Thyroid crisis • Do not alter course of disease and thyroid function tests Other drugs in Hyperthyroidism β Blockers To control Tachycardia, Palpitation, tremors and Tachyarrhythmia. No effect on thyroid function Propranolol, Atenolol. Esmolol Propranolol inhibit peripheral conversion Calcium Channel Blockers: Diltiazem and Verapamil To control tachycardia and tachyarrhythmia To inhibit peripheral conversion Corticosteroids, Propranolol, Iopanoic Acid To bind thyroid hormone in Gut Cholestyramine THANK YOU -PHARMA STREET