Unit 01 (C) Thyroid & Anti-Thyroid Drugs, Educational Platform.pptx

Unit 01 (C) Thyroid & Anti-Thyroid Drugs, Educational Platform.pptx

1. Unit-VI C Thyroid and Anti-Thyroid Drugs\ By: Muhammad Aurangzeb Lecturer-INS/KMU

2. Objectives By the completion of this section the learners will be able to: Review the physiologic effects of thyroid hormone. Identify effects of hypo and hyper secretions of thyroid hormone . Discuss actions, indications, side effects of thyroid and anti-thyroid drugs . Integrate the influence of thyroid and anti-thyroid drugs on the metabolism of other drugs. Calculate drug dosages accurately. Abdullah Danish, Educational Platform

3. Thyroid Gland Thyroid is an endocrine gland. It has two lobes, which are connected in the middle by an isthmus. Thyroid gland facilitates normal growth and maturation by maintaining a level of metabolism in the tissues that is optimal for their normal function. Abdullah Danish, Educational Platform

4. Thyroid gland secretes three hormones: 1. Tetraiodothyronine or T4 (thyroxine) 2. Tri- iodothyronine or T3 3. Calcitonin T4 is otherwise known as thyroxine and it forms about 80% of the total secretion, whereas T3 is only 20%. Hormones of thyroid gland Abdullah Danish, Educational Platform

5. Synthesis of thyroid hormones Synthesis of thyroid hormones takes place in thyroglobulin Substances needed for hormone: Iodine and tyrosine are essential for the formation of thyroid hormones. Iodine is consumed through diet. It is converted into iodide and absorbed from GI tract. Tyrosine is also consumed through diet and is absorbed from the GI tract. For the synthesis of normal quantities of thyroid hormones, approximately 1 mg of iodine is required per week or about 50 mg per year. Abdullah Danish, Educational Platform

6. Abdullah Danish, Educational Platform

7. Synthesis of thyroid hormones occurs in five stages: 1. Thyroglobulin synthesis 2. Iodide trapping 3. Oxidation of iodide 4. Transport of iodine into follicular cavity 5. Iodination of tyrosine 6. Coupling reactions. Synthesis of thyroid hormones Abdullah Danish, Educational Platform

8. Synthesis of thyroid hormones thyroid peroxidase Abdullah Danish, Educational Platform

9. Synthesis of Thyroid Hormones Thyroid hormones are synthesized by iodination of tyrosine residues on thyroglobulin within the lumen of the thyroid follicle. The thyroglobulin is endocytosed and thyroxin (T4) and triiodothyronine (T3) are secreted. Synthesis and secretion of T3 and T4 are regulated by thyroid-stimulating hormone (TSH; thyrotrophin ) and influenced by plasma iodide. Abdullah Danish, Educational Platform

10. Abdullah Danish, Educational Platform

11. The effect of thyroid hormones on metabolism Stimulate metabolism generally causing increased oxygen consumption increased metabolic rate Influence growth and development. Within cells, the T4 is converted to T3, which interacts with a nuclear receptor, and activates transcription of mRNA and synthesis of different types of proteins. Abdullah Danish, Educational Platform

12. Hormone Loop ↓Metabolic rate  Detected by hypothalamus  Stimulates anterior pituitary  Secretes TSH  Blood stream  target organ  thyroid Stimulate Thyroid to secrete T3/T4  Blood stream  target organs  adrenal medulla  Secretes Epinephrine & Norepinephrine  ↑Metabolic rate Abdullah Danish, Educational Platform

13. The thyroid gland is influenced by hormones produced by two other organs: The pituitary gland, located at the base of the brain, produces thyroid stimulating hormone (TSH) The hypothalamus produces thyrotropin releasing hormone (TRH). Low levels of thyroid hormones in the blood are detected by the hypothalamus and the pituitary. TRH is released, stimulating the pituitary to release TSH. Increased levels of TSH, in turn, stimulate the thyroid to produce more thyroid hormone, thereby returning the level of thyroid hormone in the blood back to normal. The three glands and the hormones they produce make up the "Hypothalamic - Pituitary - Thyroid axis. Thyroid Axis Abdullah Danish, Educational Platform

14. Regulation of thyroid hormone synthesis Abdullah Danish, Educational Platform

15. Transport of Thyroid Hormones T 4 and T 3 in plasma - bound to protein - thyroxine- binding globulin (TBG) – Reversibly Only about 0.04% of total T 4 & 0.4% of T 3 exist in the free form. Abdullah Danish, Educational Platform

16. Functions of thyroid hormone Metabolic function CHO metabolism:  glycogenolysis Increase gluconeogenesis  glucose absorption from GIT Enhance glycolysis – rapid uptake of glucose by the cell. Net result -  blood glucose level On protein metabolism:  protein catabolism On fat metabolism:  mobilization of fat, oxidation of FA   FFA On BMR:  BMR Action on blood: Thyroxine accelerates erythropoietic activity and increases blood volume. Abdullah Danish, Educational Platform

17. Cont… Growth :  growth On GIT:  appetite & food intake.  rate of secretion of digestive juice.  motility of GIT  diarrhea often result in hyperthyroidism On CVS: Enhance tissue sensitivity to catecholamines  cardiac output On nervous system: excitable effect, inability to sleep Has role on development of brain in fetal & 1 st few weeks of postnatal life Muscle weakness due to protein catabolism Abdullah Danish, Educational Platform

18. Normal Hyperthyroidis m Hypothyroidism/Deficiency States I nt er m ed i a r y Metabolism Lipid: indirectly enhances lipolysis; elevated plasma free fatty acid; Hy p e r c hole s t e r ol emia Carbohydrate: metabolism stimulated; tissue utilization of sugar increased; glycogenolysis and gluconeogenesis increased, faster absorption of glucose from intestine Hyperglycaemia, diabetic like stale, insulin resistance Protein: overall catabolic, prolong action: negative nitrogen balance and tissue wasting. Weight loss Abdullah Danish, Educational Platform

19. Normal Hyperthyroidism Hypothyroidism/Deficiency states Calorigenesis Increase BMR; Metabolic rates in brain, gonads, uterus, spleen, lymph nodes, not significantly affected. Ca r di o v ascular System Hyperdynamic state of circulation due: increased peripheral demand, direct cardiac actions. Fast bounding pulse Atrial fibrillation, arrhythmias Congestive Heart Failure, angina Reduced Myocardial O 2 demand Nervous System Profound functional effects Anxious, nervous, excitable, tremors, hyperreflexia Mental Retardation (Cretinism) Sluggishness, behavioural symptoms (Myxedema) Skeletal Muscle Increased Muscle tone, tremor, weakness due to myopathy Flaccid and weak (Myxedema) Gastrointestinal Increases propulsive activity Diarrhoea Constipation Abdullah Danish, Educational Platform

20. Normal Hyperthyroidism Hypothyroidism/Deficiency State Hematopoiesis Facilitates erythropoiesis Anaemia G r o wth a n d Development Maturation of nervous system Muscle wasting, weight loss Co ng e ni t al d e fici e n c y l e ad i n g to Cretinism Delayed developmental milestones Retardation and nervous deficit A d ul t: I m pai r ed i nt e l l i g ence a n d slow movements Abdullah Danish, Educational Platform

21. Disease of Thyroid gland Hyp e rt h y r oid i s m / T h y r o t o xi c osi s /G r a v e ’ s disease Increased secretion of thyroid hormones Hypothyroidism – Too little thyroid hormone production Cretinism (in children) Myxedema (in adult) Abdullah Danish, Educational Platform

22. Hypothyroidism is usually treated by oral administration of L-thyroxine 75-200 micrograms daily Other drug is liothyronine (T3) and liotrix (T3 plus T4) Levothyroxine (T4) is preferred over T3 (liothyronine or T3/T4 combination products ( liotrix ) for the treatment of hypothyroidism. Pharmacokinetics: Orally easily absorbed; the bioavailability of T4 is 80%, and T3 is 95 %. T4 is better tolerated than T3 preparations and has a longer half-life. Levothyroxine is dosed once daily, and steady state is achieved in 6 to 8 weeks. Drugs for hypothyroidism Abdullah Danish, Educational Platform

23. 12 Mechanism of actions of thyroid hormones T3, via its nuclear receptor, induces new proteins generation which produce effects Sensitization of adrenergic receptors to catecholamines  tachycardia, arrhythmia, raised BP , Abdullah Danish, Educational Platform

24. Adverse reactions Overmuch leads to thyrotoxicosis Symptoms of hyperthyroidism Abdullah Danish, Educational Platform

25. Hyperthyroidism Intolerance to heat as the body produces lot of heat due to increased basal metabolic rate caused by excess of thyroxine Increased sweating Decreased body weight due to fat mobilization Diarrhea due to increased motility of GI tract Muscular weakness because of excess protein catabolism Nervousness, extreme fatigue, inability to sleep, mild tremor in the hand Polycythemia Tachycardia Abdullah Danish, Educational Platform

26. Abdullah Danish, Educational Platform

27. Anti-thyroid Drugs Thioamides Propylthiouracil Methimazole/Carbimazole β - adrenoceptor blockers Propranolol: It is used in the management of hyperthyroid symptoms Inhibitor of hormone release Iodides of Na, k Organic iodides Radioactive iodine I 131 (Radioactive iodine) Abdullah Danish, Educational Platform

28. Thioamides Methimazole (carbimazole) Propyl thiouracil (PTU) These 2 are the major drugs used in the treatment of thyrotoxicosis (Carbimazoles converted to methimazole in vivo). MOA: These drug inhibit thyroid hormone production by Inhibiting thyroid peroxidase which is required in intrathyroidal oxidation of Iodide. Inhibiting the iodination of tyrosine Inhibiting coupling of MIT and DIT to form thyroid hormones Propylthiouracil also inhibits peripheral conversion of T4 TO T3 by inhibiting DID -1 enzyme Abdullah Danish, Educational Platform

29. Mechanism of action of Thioamides Abdullah Danish, Educational Platform

30. Therapeutic uses of thioamides These drugs controls thyrotoxicosis in both graves disease and toxic nodular goiter. Clinical improvement starts after 1-2 weeks Propylthiouracil : 50-150mg TDS followed by 25-50 mg BD-TDS for maintenance Carbimazole: 5-15 mg TDS initially Maintenance dose is 2.5-10mg daily in 1-2 divided doses Abdullah Danish, Educational Platform

31. Skin rashes- Maculopapular pruritic rash – most common Fever Hepatic abnormalities- Hepatitis & cholestatic jaundice can be fatal Nausea & GI distress An altered sense of taste or smell may occur with methimazole The most dangerous – agranulocytosis (granulocyte count < 500 cells/mm 2 ). Adverse effects of thioamides Abdullah Danish, Educational Platform

32. Iodides salts Iodide salts inhibit organification (iodination of tyrosine) and thyroid hormone release. These salts also decrease the size & vascularity of the hyperplastic thyroid gland. Since iodide salts inhibit the release as well as the synthesis of the hormone, their onset of action occurs rapidly within 2-7 days. This effect is transient because the thyroid gland escapes from iodide block after several weeks of treatment. Abdullah Danish, Educational Platform

33. Iodides salts Iodide salts are used in thyroid storm(severe thyrotoxicosis) & to prepare the patient for surgical resections of the hyperactive thyroid. The usual forms of this drug are lugol's solution(iodine & potassium iodide) and saturated solution of potassium iodide. Lugols solution: 5% iodine in 10% KI solution : 5- 10drops/day Iodide salts (sod/pot) 100-300 mg/day Abdullah Danish, Educational Platform

34. Adverse effects Acute adverse effects occurs in individuals who are sensitive to iodine. Manifestations are Swelling of lips, eyelids, Angioedema of larynx Fever Joint pain Petechial hemorrhage Chronic overdose Inflammation of mucous membrane Salivation Sneezing Swelling of eyelids GI disturbance Abdullah Danish, Educational Platform

35. Radioactive iodine Radioactive iodine is administered as sodium salt of 131 I Dissolved in water and taken orally. 131 I emits x ray as well as β particles 131 I is concentrated by thyroid, incorporated in colloid- emits radiation from within the follicles. β particles penetrates around 0.5-2 mm of tissue Thyroid follicular cells are affected within undergoes pyknosis and necrosis followed by fibrosis when a large dose is given. Abdullah Danish, Educational Platform

36. Use s Diagnostic purpose  25-100 μ curies in thyroid function test Therapeutic use  3-6 milli curies in toxic nodular goiter, graves disease, thyroid Ca. Adverse effect : Hypothyroidism crosses the placenta to destroy the fetal thyroid gland & is excreted in breast milk (baby become hypothyroid) Abdullah Danish, Educational Platform

37. Beta blockers Propranolol is used to rapidly alleviate manifestations of thyrotoxicosis that are due to sympathetic over activity e.g.: Palpitation, tremor, nervousness and sweating, In addition they reduce peripheral conversion of T4 to T3 Abdullah Danish, Educational Platform

38. β- blockers β- blockers are used in hyperthyroidism in following situations: While awaiting response to propylthiouracil or carbimazole Along with iodide for preoperative preparation before subtotal thyroidectomy Thyrotoxic crisis Propranolol 1-2mg slow I.V may be followed by 40- 80 mg oral every 6 hrly . Abdullah Danish, Educational Platform

39. Thyroid storm Thyroid storm presents with extreme symptoms of hyperthyroidism. The treatment of thyroid storm is the same as that for hyperthyroidism, except that the drugs are given in higher doses and more frequently. β-blockers , such as metoprolol or propranolol, are effective in blunting the widespread sympathetic stimulation that occurs in hyperthyroidism. Abdullah Danish, Educational Platform

40. References Lippincott Illustrated Reviews: Pharmacology Sixth Edition Abdullah Danish, Educational Platform

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