Thyroid and Parathyroid

1. Phamacotherapeutical management of Thyroid Dysfunction Presented by : Mr. Nirav S. Vachhani M.Pharm Pharmacology (Sem-2) Guided by : Dr. Rina H. Gokani S. J. Thakkar pharmacy college, Rajkot.

2. Thyroid 2

3. Introduction: The thyroid gland was described by Galen and was named " glandulae thyroidaeae " by Wharton in 1656 . The thyroid gland is the source of two fundamentally different types of hormones. The iodothyronine hormones include Thyroxine (T4) and 3,5,3 ’-triiodothyronine ( T3) They are essential for normal growth and development and play an important role in energy metabolism. 3

4. Anatomy: 4

5. Physiology: Biosynthesis of Thyroid Hormones : 5

6. Regulation of Thyroid Function : 6

7. The ratio of T4 and T3 secreted :- 10:1 Approximate Values for Thyroid Hormone Plasma Concentrations and Various Kinetic Parameters .   T 4 T 3 Plasma concentration     Total 7.77 mg/dL 0.14 mg/ dL Free 1.554 ng/dL 0.389 ng/dL Total hormone in free form 0.02% 0.3% Plasma half-life 6.7 days 0.75 days Volume of distribution 10 L 40 L Metabolic clearance rate 1.1 L/day 24 L/day Total production rate 85.47 mg/day 33.6 mg/day From thyroid secretion 100% 20% 7

8. Actions of Thyroid Hormones : 8

9. Evaluation of Thyroid Diseases: Thyroid Function test : commonly in use for estimating the iodine, TBG, free T4 and free T3 concentrations are as follow : Protein-bound iodine: It is a measure of organically bound iodine in blood (normal 4-8 ug /dl: myxoedema 2ug/dl; thyrotoxicosis 10-12 ug /dl ). Serum T4: It is measured by radio- immuno assay (normal 5-12 ug /dl). Serum T3 assay can also be done (normal 80-180 ng /dl). 9

10. Serum TBG: It is measured by radio- immuno assay or immuno electrophoresis, and the ratio of T4 to TBG is used as an index of free hormone activity . Free thyroxine index and effective thyroxine ratio: These are calculated from the serum T4 and serum TBG level. There is a good correlation between these values and free T4 levels. Direct free T4 measurement are tedious and difficult. Scintillography : The radio iodine uptake by the gland is recorded photographically and scanned . 10

11. T 3 suppression test: In the standard test, the pretreatment radioactive iodine uptake (RAIU) is determined. Then T 3 (as Cytomel ) 25 ug tid , is given for 7-10 days. On the last day a repeat RAIU is performed. In a normal person the RAIU will be suppressed by 50% or less of the original value. Whereas in Graves’ disease there is no suppresion as the thyroid is functioning autonomously. Clinical history and physical examination : 11

12. Thyroid Imaging : Radioactive imaging Ultrasound waves CT/MRI scan 12

13. Diseases of the Thyroid : Two significant functional disorders characterized by distinct clinical syndromes are : Hyperthyroidism : Associated with excessive release of Thyroid hormones. Hypothyroidism : Associated with Thyroid hormone deficiency. 13

14. Hyperthyroidism : The term hyperthyroidism is restricted to those conditions in which thyroid hormone production and release are increased due to gland hyper function. The condition is more frequent in females and is associated with rise in both T3and T4 levels in blood, though the increase in T3 is generally greater than that of T4 . Etiopathogenesis : Primary : Graves’ disease Toxic multi-nodular goiter Toxic adenoma Secondary : TSH hyper secretion by a pituitary tumor 14

15. Clinical manifestation : Mainly referable to Hypermetabolic state Over activity of the sympathetic nervous system 15

16. Diagnosis : Autonomous thyroid function Low TSH Elevated T3 / T4 Thyroid scan diffuse elevated iodine uptake Thyroid ultrasound 16

17. Treatment : Choices: Antithyroid drugs Radioactive iodine therapy Surgery Choice depends on: Age Severity of the disease Size of the gland Coexistent pathology ( Ophthalmoplegia ) Other factors: Patient’s preference Pregnancy 17

18. Antithyroid drugs : Propyl thiouracil (PTU) = 100-300 mg TID Methimazole ( Tapazole ) = 10-20 mg TID then OD Carbimazole = 40 mg OD MOA : Inhibits the organic binding of iodine and coupling of iodotyrosine PTU can also lower conversion of T4 to T3; it can also decrease thyroid autoantibody levels. 18

19. Disadvantages of these drugs : Crosses the placenta --> inhibits fetal thyroid function Excreted in breast milk Side effects: Skin rashes Fever Peripheral neuritis Polyarthritis Granulocytopenia ( reversible) 19

20. Radioactive Iodine Therapy : MOA : 131 I is taken up and trapped Emission of α - particle Destroy thyroid tissue Advantages : Avoidance of surgery (no injury to nerve / parathyroid gland) Reduce cost & ease of treatment 20

21. D isadvantages : Lifelong thyroxin replacement therapy Slower correction of hyperthyroidism Higher relapse rate Adverse effect of ophthalmopathy Development of Hypothyroidism after thyroid ablation Suitable for : Small or moderate size goiter Relapse after medical and surgical therapy Antithyroid drug and surgery are contraindicated Contraindicated : Pregnant / breast feeding Ophthalmopathy (progression of eye signs) Young age (children/adolescence) ----> Infertility / carcinoma 21

22. Thyroid Surgery : Mainly Suitable for : Young patient With Graves’ ophthalmopathy Pregnant Advantages : Immediate cure of the disease Low incidence of hypothyroidism Potential removal of coexisting thyroid carcinoma Disadvantages : Complication ---> nerve injury (1%) and hypoparathyroidism (13% transient/ 1% permanent). Hematoma Hypertrophic scar formation 22

23. Hypothyroidism : Hypothyroidism is a hypometabolic clinical state resulting from either Inadequate production of thyroid hormones for prolonged periods , F rom resistance of the peripheral tissues to the effects of thyroid hormones (rarely). Depending on whether the hypothyroidism arises from an intrinsic abnormality in the thyroid or results from hypothalamic or pituitary disease, divided into primary and secondary categories . 23

24. Causes of hypothyroidism : Primary Postablative (after surgery or radioiodine therapy) Primary idiopathic hypothyroidism Hashimoto thyroiditis* Iodine deficiency* Congenital biosynthetic defect ( dyshormonogenetic goiter )* Secondary Pituitary or hypothalamic failure (uncommon) 24

25. Clinical manifestation : Mainly referable to Cretinism Myxoedema 25

26. Cretinism : A cretinism is a child with severe hypothyroidism present at birth or developing within first two years of postnatal life. Clinical features : Impaired development of skeletal system & CNS Severe mental retardation Coarse facial features A protruding tongue Umbilical hernia 26

27. Treatment of Cretinism : Iodine only if iodine deficiency is the caus e. Levothyroxine (T4): Average dose 1.6 ug /kg Age > 50-60 or cardiac disease:  must start at a low dose (25 ug /d) Recheck thyroid hormone levels every 4-6 weeks after a dose change Aim for a normal TSH level Liothyronine ( T3): Tablet ( Cytomel ®) : 5-10 ug /d (starting) : 25 ug /d (maintenance) Injection ( Triostat ®) : 50-100 ug 27

28. Myxoedema : Myxoedema coma is a rare syndrome that represents the extreme expression of severe, long-standing hypothyroidism. Common precipitating factors include : P ulmonary infections, C erebrovascular accidents , C ongestive heart failure Clinical features : Hypothermia , which may be profound; Respiratory depression Unconsciousness Dry & rough skin 28

29. Treatment of Myxoedema : Levothyroxine 500 mg/day Livothyronine 75 mg/day Other Rewarming with blankets C orrection of hyponatremia Treatment of the precipitating incident 29

30. Parathyroid 30

31. Introduction: The parathyroid glands are usually 4 in number: T he superior pair derived from the 3rd branchial pouch Inferior pair from the 4th branchial pouch of primitive foregut 31

32. Anatomy: composed of solid sheets and cords of parenchymal cells 32

33. Regulation of Parathyroid Function : 33

34. Actions of Parathyroid Hormones : 34

35. Diseases of the Parathyroid : The major parathyroid disorders are its functional disorders: H ypoparathyroidism H yperparathyroidism 35

36. Hypoparathyroidism : When the parathyroid glands do not secrete sufficient PTH, the osteocytic reabsorption of exchangeable calcium decreases and the osteoclasts become almost totally inactive. As a result, calcium reabsorption from the bones is so depressed that the level of calcium in the body fluids decreases. When the parathyroid glands are suddenly removed, the calcium level in the blood falls from the normal of 9.4 mg/dl to 6 to 7 mg/dl within 2 to 3 days. 36

37. Aetiology : Most common cause : Surgery for thyroid diseases Neck exploration Adenoma Clinical manifestation: Most of due to Hypocalcaemia  Increased neuromuscular excitablity Major symptoms Numbness around mouth Muscle spasm Irritability Cataract Positive chvostek’s sign Positive trousseau’s sign 37

38. Treatment: For sever, acute treatment: 10% calcium gluconate IV injection For chronic treatment: PTH therapy (not currently practised ) Maintenance treatment: Vitamin D preparations 38

39. Drug Preparations Activity Ergocalciferol ( calciferol , vitamine D 2 ) Calciferol injection 7.5 mg (3000000 units/ml) Calciferol tablets 250µg (10000 units) and 1.25mg (50 000 units) Calcium and ergocalciferol tablet (2.4 mmol of calcium + 400 units of ergocalciferol ) Requires renal and hepatic activation Colecalciferol ( vitamin D 3 ) A range of preparation containing calcium (500-600mg) and colecalciferol (200-440 units) Requires renal and hepatic activation 39

40. Alfacalcidiol (1α- hydroxycolecalciferol ) Alfacalcidiol capsule 250ng, 500ng and 1µg Alfacalcidiol injection 2µg/ml Requires hepatic activation Calcitriol (1, 25 – dihydroxycolecalciferol) Calcitriol capsule 250ng and 500 ng Calcitriol injection 1µg/ml Active Dihydrotachysterol Dihydrotachysterol oral injection 250mg/ml Requires hepatic activation 40

41. Hyperparathyroidism : Hyperparathyroidism is the clinical state that results from increased production of PTH by the parathyroid gland . Hyperparathyroidism is further categorized as follow: Primary Hyperparathyroidism Secondary Hyperparathyroidism Tertiary Hyperparathyroidism 41

42. Primary Hyperparathyroidism: Aetiology : Cause of primary hyperparathyroidism is a tumor of one of the parathyroid gland. Much more frequently in women. Common causes: Parathyroid adenomas 80% Carcinoma of parathyroid 2-3% Primary hyperplasia 15% Clinical features: Elevated levels of parathyroid hormone Hypercalcaemia Hypercalciuria Kidney stones 42

43. Secondary Hyperparathyroidism: In secondary hyperparathyroidism, high levels of PTH occur as a compensation for hypocalcemia rather than as a primary abnormality of the parathyroid glands. Etiology : Chronic renal insufficiency Vitamin D deficiency Intestinal malabsorption syndromes Clinical features: Mild hypocalcaemia Renal osteodystrophy Soft tissue calcification 43

44. Tertiary Hyperparathyroidism: Tertiary hyperparathyroidism is a complication of secondary hyperparathyroidism in which hyper function in spit of removal of the cause of secondary hyperplasia. Possibly , hyperplastic nodule in the parathyroid gland develops which becomes partially autonomous and continue to secrete large quantities of parathyroid hormone without regard to the needs of the body. 44

45. Treatment of Hyperparathyroidism: ( i) Surgical removal of the diseased gland. ( ii) Intravenous saline infusion to correct dehydration. ( iii) Intravenous infusion of 0.1 M solution of basic sodium phosphate to promote calcium excretion. ( iv) Isotonic sodium sulphate and sodium chloride administered intravenously to induce calciuresis . ( v) Disodium edetate (EDTA). It chelates calcium, but is too toxic for routine use. In an emergency 50 mg/kg in 500 ml saline may be given intravenously. ( vi) Mithramycin . It is a cytotoxic agent and reduces serum calcium levels. In an emergency 25 mcg/kg/day may be given IV for 3 to 4 days. 45

46. (vii) Calcitonin 5 to 25 mcg/kg may be of therapeutic value, but experience with this agent is limited. (viii) Glucocorticosteroids may be tried. They are claimed to be effective in hypercalcaemia of vitamin D therapy. (ix) Haemodialysis may be of value when all other measures have failed. Thus , effective pharmacotherapy for hyperparathyroidism is not available. Mainly the treatment is operative . 46

47. Summery: The thyroid gland is the source of two fundamentally different types of hormones. Thyroxine (T4) and 3,5,3’-triiodothyronine (T3) The ratio of T4 and T3 secreted :- 10:1 The evaluation of Thyroid function is maninly done by Thyroid function test. Diseases of Thyroid include Hyperthyroidism Hypothyroidism Treatment of these include Antithyroid drugs Radioactive iodine therapy Surgery 47

48. Parathyroid : The Parathyroid gland gland derived from 3 rd and 4 th bronchial pouch. The gland mainly secrets the Pararthyroid hormone. The main action of PTH on the Kidney, Bone and Small intestine. There are two main diseases related to PTH. Hypoparathyroidism Hyperparathyroidism Treatment: 48 Hypothyroidism Ergocalciferol Colecalciferol Alfa Calciferol Calcitriol Dihydrotachysterol Hyperparathyroidism Surgery IV infusin of NaPO4 Disodium Edetate Mithramycine Calcitonin

49. References: 49

50. 50