Thyroid & antithyroid drug

Detailed information of all terms like Thyroid gland, Thyroxine, Triidothyronine, Calcitonine, growth and development , propylthiouracil, Calorigenesis, tadpole to frog, Oligomenorrhoea, snehal chakorkar, pharmacology, Cretinism, Myxoedema coma, Graves disease, Thiocynates, Perchlorate, Nitrates.
Radioactive iodine, I131

1. Thyroid and Anti-thyroid drugs Miss Snehal S. Chakorkar (M.pharm) Dept Of Pharmacology, 5-Oct-19 1

2. Introduction Thyroid gland secrets 3 main hormones: Thyroxine (T4) Important for growth Both considered as Triidothyronine (T3) and development thyroid hormone Calcitonine - Important for control of plasma Ca2+. Thyroglobuline molecule contains 115 tyrosin residue. Follicle have high blood supply. Functional unit of thyroid – Follicle or acinus – structure of flollicle is cavity surrounded by epithelial cell.- filled with thick colloid – called thymoglobulin ( Large glycoprotein). 5-Oct-19 2

3. Synthesis , storage & secretion of thyroid hormone: Involve following steps; 1)Uptake of plasma iodide by follicle cells. 2)Oxidation of iodide & iodination of tyrosin residues of thyroglobuline. 3) Coupling. 4)Secretion of thyroid hormone. 5)Peripheral conversion of T4 to T3. 1)Uptake of plasma iodide by follicle cells: Regular I2requirement of body is 30-50mg which fulfilled by food & water, about 1/5 is present in thyroid. Iodide is capture from blood & move to lumen by 2 transporter, Na+/I- symporter (NIS)- Locate at basolateral surface of thyrocytes . Pendrin I-/ Cl - Porter( PDS)- At apical membrane. Iodine uptake is energy dependent process energy provided by Na+/ K+ATPase 5-Oct-19 3

4. 2)Oxidation of iodide & iodination of tyrosin residues of thyroglobuline. TSH Iodide Iodinium (I+)/ Hypoiodous acid (HOI)/ Enzyme linked hypoiodate (E-OI) Monoiodotyrosin (3 rd position) Diiodotyrosin (5 th position) Bind to tyrosil residue of thyroglobuline Thyroid peroxidase enzyme Captured Iodide carried across the membrane by pendrine transport & oxidised by thyroid peroxidase enzyme ( Oxidising agent ). 5-Oct-19 4

5. 3) Coupling: Coupling is oxidative reaction catalyzed by same thyroid peroxidase enzyme . Thyroglobuline is efficient protein helps for reaction. Pair of iodinated tyrosil residue couple together to form T3 & T4. 2 molecule of diiodotyrosine -= Thyroxine (T4) 1 molecule of monoiodotyrosine + 1 molecule of diiodotyrosine = Triidothyronine (T3). 5-Oct-19 5

6. 4)Secretion of thyroid hormone: Normal human thyroid secretes- 60-90 μ g of T4 & 10-30 μ g of T3. The iodinated residue of thyrosin get transferred to the interior of the follicles where it store as thyroid colloid. After release it uptake by endocytosis after stimulation of TSH. 5)Peripheral conversion of T4 to T3: Peripheral tissue like liver, kidney convert T4 to T3. Target tissue take T3 from plasma depended upon their metabolic need. While brain and pituitary takes T4 and convert that to T3 with own cell. Drugs like some propylthiouracil inhibit conversion of T4 to T3. 5-Oct-19 6

7. Actions: The T3 & T4 having almost having same functions ; 1) Growth & Development. 2) Intermediary metabolism. 3) Calorigenesis . 4) Cardivascular system. 5) Nervous system. 6)Skeletal muscle. 7)GIT. 8)Kidney. 9) Haemopoiesis . 10) Reproduction. Ref: https://www.cleanpng.com/png-thyroid-hormones-thyroid-nodule-thyroidstimulating-4946478/ 5-Oct-19 7

8. 1) Growth & Development. E essential for normal growth and development. The most remarkable action is metamorphosis of tadpole to frog: the tail is used-up to build lungs, limbs and other organs.  T he action cannot be categorised as catabolic or anabolic. T3 & T4 have role in protein synthesis i.e. translation of genetic code therefore Congenital deficiency of T, and T, resulting in cretinism & delayed development of organs or deficit dendrites ramification, synapse formation & impaired myelination . 2) Intermediary metabolism. Thyroid hormones have marked effect on Thyroid lipid, carbohydrate and protein metabolism. Lipid: T3 & T4 potentiate action of catecholamine & lipolytic action (Increases lipolysis ) Suppress phosphodiestrase - Increases cAMP - Increases plasma free fatty acid. Increases cholesterol metabolism- so causes hypocholesterolemia . 5-Oct-19 8

9. Carbohydrate: T3 & T4 Increases carbohydrate metabolism. Increases sugar utilization by tissue but faster absorption of glucose from blood. Increases absorption & less metabolism causes hyperglycemia & diabetic like state. Therefore hyperthyroidism causes insulin resistance. Protein : T3 & T4 Increases synthesis of certain protein which used as protein source by body. But prolong action causes negative nitrogen balance & weight loss. At low concentration of T3 & T4 inhibit mucoprotein synthesis . T3 & T4 increses the oxygen consumption & heat production. 5-Oct-19 9

10. 3) Calorigenesis : T3 & T4 increases basal metabolic rate by increasing cellular metabolism. Which helps to maintain body temperature during calorigenesis causes oxidative phosphorylation & that release heat but this reaction only occurs in high dose. 4) Cardivascular system: T3 & T4 causes hyperdynamic state of circulation Increses blood volume unknowingly). Also increases heart rate, contractility & output of heart by acting on contractile element. During hyperthyroidism causes arterial fibrillation & other regularity like CHF and angina. 5) Nervous system: T3 & T4 deficency causes mental retardation or cretinism. Also hyperthyroid individuals are anxious, nervous, excitable or produces tremors. 5-Oct-19 10

11. 6)Skeletal muscle: Hypothyroidism causes swelling of skin & underlying tissue. Hyperthyroidism causes increases muscle tone, tremor & weakness. 7)GIT: T3 & T4 causes increased gut activity which causes diarrhea. 8)Kidney: Hypothyroidism causes diuresis . While normal person not causes diuresis . 9) Haemopoiesis : T4 increases process of RBC formation ( Erythropoiesis ) Therefore T4 treatment given to patient suffering from anemia. 10) Reproduction: Thyroid has an indirect effect on reproduction fertility is impaired in hypothyroidism & Oligomenorrhoea (Infrequent menstrual periods). Normal thyroid function is required for maintenance of pregnancy and lactation. 5-Oct-19 11

12. Mechanism Of Action: T3 & T4 penetrate cell by active transport Combine n nuclear thyroid hormone receptor (TR) ( Receptor is steroid & retinoid superfamilly ) T3 has 15 – fold higher binding to TR receptor than T4 . Hormone receptor complex bind to DNA via zinc fingers undergo conformational changes Causes gene transcription Production of specific m-RNA & protein synthesis Gives various metabolic & anatomic effect ( like Tachycardia, Arrhythmia, Increased blood pressure hyperglycemia.) 5-Oct-19 12

13. Relation between T4 & T3: 1) Normally T4 more secrete than T3- but in iodine deficiency this deference decreases. 2) T4 15 times more tightly bound to plasma protein. 3) T3 is 5 times more potent than T4 & acts faster peak effect T3 in 1-2days, T4 in 6-8 days. 4) About 1/3 of T4 will convert in T3. Preparations: 1-Thyroxine more preferred than 1-Thyronine. 5-Oct-19 13

14. Uses: The most important uses of thyroid hormone are as replacement therapy deficiency states: 1)Cretinism 2)Adult hypothyroidism 3) Myxoedema coma 4)Nontoxic goiter 5) Thyroid nodule 6) Papillary carcinoma of thyroid. 7) Other uses. 5-Oct-19 14

15. 1)Cretinism: Caused due to failure of thyroid development (sporadic cretinism). Due to extreme iodine deficiency (endemic cretinism). Mostly during infancy or childhood. Treatment with thyroxine (8-12 ug /kg) daily physical growth and development are restored and further mental retardation is prevented. 2)Adult hypothyroidism( Myxoedema ): commonest endocrine disorders - Caused due to autoimmune thyroiditis , thyroidectomy . Antibodies generated against thyroid peroxidase or thyroglobuline.- Causes adult hypothyroidism. Drugs that can cause hypothyroidism are 13 iodides, lithium and amiodarone which treated with T4 50ug/day. Subclinical hypothyroidism- In this disorder free serum thyroxine level increases but TSH level decreases- This condition treated with T4. 5-Oct-19 15

16. 3) Myxoedema coma: It is an emergency condition were progressive mental deterioration caused due to deficient production of thyroid hormone ( Hypothyroidism). This condition treated with liothyroinine (T3) but high risk of cardiac arrhythmia & angina. I V. dose T3(10 μ g/8hr). 4)Nontoxic goiter: Endemic due to iodine deficiency. Sporadic due to defect in hormone synthesis. In above cases deficiency of thyroid hormone leads to increases TSH causes enlargement of thyroid gland treatment with T4. 5-Oct-19 16

17. 5) Thyroid nodule: When T4 treatment is started TSH synthesis get suppressed causes normal functioning of nodules function while nonfunctional nodules not respond. 6) Papillary carcinoma of thyroid: This is type of cancer caused due to TSH over production; treatment with T4 causes decreased TSH production. 7) Other uses. T4 used for treatment of refractory anemia, mental depression, menstrual disorder or infertility. 5-Oct-19 17

18. A) Anti-thyroid drugs/ Thyroid inhibitors : Definition: “ These are the pharmacological agents which are used to lower the functional capacity of hyperactive thyroid gland” These are the agents used in treatment of thyrotoxicosis ( It is excess secretion of thyroid hormone due to disorders; like Graves disease( auto immune disease) Toxic nodular goiter. Classification: 1)Inhibit hormone synthesis ( Antithyroid drugs): Ex- Pronylthioumcil Methimazole , Carbimazole . 2) Inhibit iodide trapping( Ionic inhibitors): Ex- Thiocynates , Perchlorate , Nitrates. 3) Inhibit homone release: Ex- lodine , lodides of Na and K, Organic iodide. 4) Destroy thyroid tissue: Ex-Radioactive iodine (I131, I125, I123) 1 & 2 class called as Goiterogen. If dose increases causes enlargement of thyroid. By feedback release of TSH 5-Oct-19 18

19. 1) Antithyroid drugs : ( Thioamides ) Hormone synthesis inhibitors called Antithyroid drugs. Mechanism of action: Thiocarbamide ( S-C-N) group essential for activity. Antithyroid drugs bind to thyroid peroxidase and prevent oxidation of iodide/ iodotyrosyl residues; 1)Inhibit iodination of tyrosine residues in thyroglobuline. 2) Inhibit coupling of iodotyrosine residues to form T3 and T4 which occurs as low concentration. Simply this class drug decreases the output of thyroid hormone from the gland so decreases the sign and symptoms of thyrotoxicosis. Propyl Thiouracil - Inhibit conversion of T4-T3- Mostly in type 1st diabetes mellitus- but methamizole & Carbamazole not have this action. 5-Oct-19 19

20. Adverse drug reaction: 1)Hypothyroidism and goiter – Due to over treatment- After stopping of treatment reversible effect is observed. At normal dose goiter not develop because  T4 concentration which maintain TSH level normal. High does: Causes excess TSH production- Enlargement of thyroid gland (Goiter). 2)Other side effects: GI intolerance, Skin rashes, joint pain. 3)Graying or loss of hair, loss of taste, fever & liver damage. 4) Agranulocytosis & Jaundice may occurs. Preparation: Propylthiouracil(50mg-150mg TDS) Methimazole (5-10mg) Carbimaole (5-15mg) (Inhibition T4-T3 peripheral conversion) 5-Oct-19 20

21. Uses: 1)Control thyrotoxicosis in graves disease & toxic nodular goiter. Some times patient take another treatment like cough preparation, contrast media, aminodarone - less responsive to Antithyroid agent. In those cases the dose should be modify depending on the patient. As definitive therapy: In some patient after 1-2 year of treatment remission may occur. After drug withdrawal if symptoms recur again start the treatment. Above situation mostly occurs in patient having short history of graves disease & small goiter. The case like nodular goitre remission are rare or toxic that time surgery or I 131 is preferred. Some cases in elderly patient with multinodular goiter maintenance therapy causes less responsive to I131 so surgery advised. 5-Oct-19 21

22. 2) Preoperatively: Surgery ( thyroidectomy ) is advised to  thyrotoxicosis patients which is very risky so preoperative treatment of carbimazole is given. 3) Treatment along with I 131 : When there is prompt control of severe hyperthyroidism in older patient following sequence of therapy employed; Starting treatment with Antithyroid drug. 1-2 week gap. Radioiodine dosing. Again Antithyroid drug after 5-7 days. Withdrawal of drug after 3 month. Again start I131 treatment. 5-Oct-19 22

23. Advantages of Antithyroid drug over surgery / I131 treatment: No surgical risk, scar or chances of injury to parathyroid or nearest laryngeal nerve. If treatment with Antithyroid shows side effect like hypothyroidism then stoppage of treatment reverse the action. The Antithyroid drugs used for children as well as young adults. Disadvantage: Prolonged (often life long) treatment is needed because stoppage of treatment shows recurrence & relapse rate is high. Not practicable in uncooperative/unintelligent patient. High drug toxicity & side effects. During pregnancy thyroidectomy and I131 are contraindicated because it develops risk of foetal hypothyroidism and goiter. in this condition propylthiouracil is preferred. 5-Oct-19 23

24. B) Iodine/Iodide Even if the iodine is one of the constitute of thyroid hormone but still it acts as faster acting thyroid inhibitor(Antithyroid). In the process of thyroid hormone release in one step iodine is covered in to on vivo iodide (I-) and due to negative feedback mechanism iodide inhibit release of thyroid hormone. Within 1-2 days of starting of treatment causes inhibition of secretion of thyroid hormone while 10-14 days causes marked reduction in vascularity of gland & which causes decreases the size of gland. Iodine mostly orally in solution with potassium Iodide( Lugols iodine) Effect seen in 15-15 days. But further treatment causes thyroid escape & thyrotoxicosis or hyperthyroidism mostly occurs in multinodular goiter. 5-Oct-19 24

25. Mechanism of action: Actual mechanism is unknown; It inhibits own transport in to thyroid cell ( Step 1 in thyroid synthesis) by acting on NIS (Sodium Iodide symporter) It attenuates TSH & cAMP & causes thyroid inhibition. Also excess iodide rapidly interferes with tyrosil ( Iodination step2) Inhibit thyroid ( Wolff chaikoff effect) Inhibition of hormone release causes thyroid constipation. 5-Oct-19 25

26. Uses: 1) Preoperative preparation: For   thyroidectomy in graves disease; iodine for 10 days before surgery will given which makes gland less vascular & easier to remove by operation. 2 ) Thyroid storm: Lugol's iodine (6-10 drops) or iodine containing radiocontrast media ( iopanoic acid) are used orally to stop further release and conversion of T3/T4 from the thyroid. 3 ) Prophylaxis of endemic goiter: It is used as "iodized salt“. 4 ) Antiseptic: The tincture of iodine, povidone iodine is used as antiseptic. 5-Oct-19 26

27. Adverse drug reaction: 1) Acute Acute reaction It occurs in sensitive people. Shows symptoms like swelling of lips, eyelids, angio - edema of larynx (may be dangerous), fever, joint pain, petechial haemorrhages, thrombocytopenia, lymphadenopathy. 2)  Chronic overdose ( iodism ): Inflammation of mucous membranes, salivation, rhinorrhoea , sneezing, lacrimation , swelling of eyelids, burning sensation in mouth, headache, rashes, g.i . symptoms. 3) Long-term use of high doses can cause hypothyroidism & goiter. 4) If high dose given to pregnant women chance to hypothyroidism & goiter in foetus . 5-Oct-19 27

28. C) Radioactive Iodine: Ex- I 131 , I 123 I 125. The stable form of isotope of iodine is I 127 but medically useful isotope is I 131 which having half life 8 days available as sodium salt; given as oral dose. But one of the advantage of radioactive iodine is it produce necrosis of cell (affected thyroid follicular cell) without damaging neighboring tissue. Radioactive iodine administration as sodium salt of I 131 dissolve in water & take orally. Diagnostic : 25-100 μ g given scanning is done at interval ( No damage to thyroid cell occurs with this dose). 5-Oct-19 28

29. Mechanism of action: The isotope emits both beta ( β ) & gama ( δ ) radiation Have shorter range Pass through tissue without damage Penetrate tissue (up to 0.5-2 mm) Pyknosis & necrosis with fibrosis 5-Oct-19 29

30. Therapeutic: The hyperthyroidism is mainly occurs due to grave’s disease or toxic nodular goiter at that time therapeutic dose is 3-6 mg curie. High dose is requirement for toxic multinodular goiter. The response to radio active iodine is start after 2 week & get increased after 3 month. Advantages: Treatment with I 131 is inexpensive. No surgical risk, scar or thyroids/recurrent laryngeal nerves after treatment with I 131 Once hyperthyroidism is controlled, cure is permanently. Disadvantages: 1) Hypothyroidism: About 5-10% patients of Graves' disease treated with 1311 become hypothyroid. 2) Very slow response was observed for treatment with I131. 3) during pregnancy drug is Contraindicated because it causes foetal thyroid destruction. 4)I131 not suitable for young patients more likely to develop hypothyroidism &  genetic damage/cancer . 5-Oct-19 30

31. D) β - Adrenergic blocker: Nonselective B blockers- propranolol used for tretment of thyrotoxicosis because in hyperthyroidism; over activity of sympathetic nervous system was observed i.e. palpitation, tremor, nervousness, myopath , swelling. Very little effect on thyroid function & hyper metabolic state. B blockers used for tretment of hyperthyroidism in following situation; 1) While response to carbimazole , propylthiouracil or I131 is low. 2) B blockers given along with iodide for preoperative preparation before subtotal thyroidectomy . 3) Thyroid storm ( thyrotoxic crisis-It is an emergency due to decompensate hyperthyroidism.) In above condition emergency treatment with B blockers are given. 5-Oct-19 31

32. Reference: Rang H.P. and Dale M.M.: Pharmacology, Churchill Livingstone, Edinbergh . Katzung B.G.: Basic and Clinical Pharmacology, Lange Medical Publications, California. Craig C.R. and Stitzel R.E.: Modern Pharmacology, Little Brown and Co., Boston. Bowman W.C. and Rand M.J.: Textbook of Pharmacology, Blackwell Scientific Publications, Oxford. P.N Bennett & M J Brown: Clinical Pharmacology, Churchill Livingstone, Edinburgh. Tripathi K.D.: Essentials of Medical Pharmacology, Jaypee Brothers, Medical Publishers, New Delhi. 5-Oct-19 32

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