1. 1 Thyroid Drugs Kaukab Azim, MBBS, PhD

2. Learning Outcomes By the end of the course the students should be able to discuss in detail Physiology, synthesis and feed back control of thyroid hormone synthesis Thyroid disorders: –Hypothyroidism Cretinism, Myxedema coma –Hyperthyroidism Thyroid storm Drugs for the treatment of hypothyroidism and hyperthyroidism 2

3. 3 Thyroid Hormones Thyroid hormones: –Thyroxine T4 (90%) –Triiodothyronine T3 Thyroid gland also secretes Calcitonin – serum calcium lowering hormone

4. 4 Thyroid Hormones - Facts Thyroid hormones are required for the growth and development of all tissues. Thyroid hormone is critical for nervous, reproductive and skeletal growth. Thyroid deprivation in early life results in irreversible mental retardation. Thyroid hormones also augment sympathetic system function primarily by increasing the number of adrenergic receptors.

5. 5 Hypothalamus-pituitary-thyroid axis TSH secretion by anterior pituitary is stimulated by hypothalamic TRH Feedback inhibition of TSH and TRH occurs with high levels of circulating thyroid hormones (T3 & T4) Dopamine, Glucocorticoids and somatostatin can suppress TSH secretion (High dose)

6. 6 Thyroid hormone synthesis Uptake of iodide by thyroid gland Oxidation of iodide Organification –Iodination of tyrosine residues on thyroglobulin – MIT s and DITs ●Coupling – formation of T4 and T3 ●Proteolysis of thyroglubulin and secretion of thyroid hormones ●Conversion of T4 to T3 in peripheral tissues

7. 7 Thyroid hormone synthesis 4. Coupling (Iodide Organification) TBP T4 T3 & Free T4 & T3

8. 8 Outer ringInner ring (T 4 ) Metabolism of thyroid hormones 5’-deiodinase (4X potent than T4)

9. 9 Metabolism of Thyroid hormones Drugs that inhibit deiodination: –Beta blockers –High dose propylthiouracil –Corticosteroids They inhibit the 5 ’ -deiodinase activity necessary for conversion of T4 to T3 resulting in low T3 and high reverse T3 (rT3)

10. 10 Thyroid hormones Mechanism of action T4 and T3 must dissociate from thyroxine binding globulin (TBG) in plasma before entering into the cells. In the cells, T4 is deiodinated to T3 that enters nucleus and attaches to specific receptors which promotes mRNA and protein synthesis.

11. 11 Hypothyroidism Clinical manifestations: –Lethargy –Wt. gain –Bradycardia –Constipation –Cold intolerance –Menstrual irregularities Cretinism (congenital hypothyroidism) Myxedema coma: most extreme manifestations of untreated hypothyroidism

12. 12 Drugs for Hypothyroidism Levothyroxine (T4) It is the treatment of choice for replacement therapy in hypothyroid patients It has a long half life ~7 days; once a day dose. Triiodothyronine (T3) Short half life (1 day)

13. 13 Drugs for Hypothyroidism T4 and T3 given orally. T4 is better for long term replacement therapy I.V. administration in myxedema coma During pregnancy, hypothyroid woman require higher doses

14. Hyperthyroidism Clinical manifestation –Weight loss and with increase in appetite. –Nervousness and irritability. –Palpitations. –Heat intolerance and increased sweating. –Tremors. –Thyroid enlargement –Menstrual irregularities 14

15. 15 Hyperthyroidism Treatment options: Surgical Antithyroid drugs: –By inhibiting uptake of iodine –By inhibiting synthesis –By inhibiting release of hormones from thyroid Medical destruction of thyroid tissue –Radioiodine (I 131 )

16. 16 Drugs for hyperthyroidism Thioamides: Propylthiouracil, Methimazole Inhibit hormone synthesis Iodide salts: KI, Lugol ’ s solution Blocks hormone release Iodinated contrast media: Ipodate Inhibition of peripheral T4 to T3 conversion; inhibits hormone release Anion inhibitors: Perchlorate, thiocyanate block uptake of iodide by thyroid Radioactive iodine ( 131 I) destruction of thyroid tissue Beta-blocker: Propranolol, esmolol Controls heart rate

17. 17 Anion Inhibitors (-) T4T3 5’-deiodinase Propylthiouracil, Ipodate, beta blockers, cortocosteroids (-)

18. 18 1. Thioamides Propylthiouracil, Methimazole Inhibit hormone synthesis –Acts by inhibiting thyroid peroxidase to block iodine organification and coupling reactions These are the major drugs for treatment of mild thyrotoxicosis and in preparation of patients for subtotal thyroidectomy

19. 19 Thioamides Slow onset of action (~ 4 weeks) Propylthiouracil is relatively safe and preferred in pregnancy Methimazole is more potent and longer acting than Propylthiouracil Propylthiouracil also inhibits peripheral deiodination of T4 and T3

20. 20 Thioamides: Adverse drug reactions Common: Maculopapular Rash, Arthralgia, vasculitis Serious side effect: Agranulocytosis

21. 21 2. Iodides: Potassium iodide, Lugol ’ s solution Mechanism of action –Inhibit hormone release –Inhibit organification –Decrease size and vascularity of the hyperplastic gland. Effect is reversible and transient – not for long term as thyroid gland ‘ escapes ’ from its effect after 14 days Contraindicated in pregnancy: fetal goiter

22. 22 3. Iodinated contrast media Ipodate and Iopanoic acid –They inhibit the peripheral conversion of T4 into T3 in the liver, kidney and brain –Inhibition of hormone release is an additional mechanism Adjunctive therapy in the treatment of thyroid storm

23. 23 4. Anion Inhibitors Perchlorate (ClO 4 - ), Pertechnetate (Tco 4 - ), Thiocyanate (SCN - ) competitively block the uptake of iodide Adverse effect: Aplastic anemia

24. 24 5. Radioactive Iodine 131 I is the only isotope used in treatment of thyrotoxicosis while others are used in diagnosis. Emission of beta particles – destroys the thyroid gland. Patients can become hypothyroid – managed with thyroxine (T4) Contraindications: –Pregnancy & lactation –Age <25 yrs

25. Thyroid storm Clinical manifestation –High fever often above 40°C –Fast and often irregular heart beat –Vomiting, diarrhea and agitation. –Heart failure and myocardial infarction may occur. –Death may occur despite treatment. Causes –Patients with known hyperthyroidism whose treatment has been stopped or become ineffective, –Untreated mild hyperthyroidism who have developed an intercurrent illness (such as an infection). 25

26. 26 Thyroid storm Treatment Propranolol /Esmolol / Diltiazem Iodide/ipodate – ipodate also block the T4 to T3 conversion Propylthiouracil Hydrocortisone – blocks the T4 to T3 conversion

27. 27 QsQs