Thyroid and antithyroid drugs

This discussion was conducted over 2 classes. The slides are intended for BDS students. Please refer to books for further information.

1. Drugs Used In Thyroid Disorders Dr. Pravin Prasad MBBS, MD Clinical Pharmacology Assistant Professor, Department of Clinical Pharmacology Maharajganj Medical Campus, Kathmandu 8 June 2020 (26 Jestha 2077), Monday

2. Hypothyroidism and Dental presentations Salivary gland enlargement Compromised periodontal health- delayed bone resorption Macroglossia, Glossitis Dysgeusia Delayed dental eruption, Enamel hypoplasia Anterior open bite Micrognathia Thick lips Mouth breathing

3. By the end of this discussion, BDS 2 nd year students will be able to: Understand the physiology of thyroid hormone Explain the actions of thyroid hormone Elaborate the mechanism of action of endogenous as well as exogenous thyroid hormone preparations List the uses of Thyroid hormone supplements

4. Thyroid hormones: Introduction Hormone Source Remarks Triiodothyroxine , T 3 Thyroid follicles Referred as thyroid hormones Tetraiodothyroxine , T 4

5. Thyroid Hormones: Introduction Ref: http://biology.clc.uc.edu/fankhauser/Labs/Anatomy_&_Physiology/A&P202/Endocrine_System/histology_jpgs/thyroid_400x_P2252255lbd.JPG

6. Thyroid Hormone: Synthesis Membrane Bound Membrane Bound TSH

7. Thyroid Hormone: Synthesis Iodide Uptake Sodium-iodide symporter Stimulated by Thyroid stimulating hormone Oxidation and Iodination Transported to apical membrane of thyroid cells by Pendrin Oxidized by Thyroid Peroxidase enzyme (Stimulated by TSH) Binds to tyrosil residue bound to Thyroglobulin chain (DIT, MIT formed)

8. Thyroid Hormone: Synthesis Coupling Requires thyroid peroxidase, stimulated by TSH MIT+ DIT = T3 DIT + DIT = T4 (more common) Storage and release Stored as thyroid colloid Released by endocytosis (TSH stimulated) T 3 and T 4 reaches circulation Peripheral conversion of T 4 to T 3

9. Thyroid Hormone: Transport Avidly bound to plasma proteins; 0.03%-0.08% T 4 & 0.2-0.5% T 3 in free form Bound to 3 plasma proteins: Thyroxine Binding Globulin (TBG) Thyroxine Binding prealbumin (trans- thyretin ) Albumin

10. Thyroid Hormone: Metabolism and Excretion Metabolic inactivation occurs by deiodination and glucuronide /sulphate conjugation Primary site: Liver, others: salivary glands, kidney Plasma half lives: T4: 6-7 days T3: 1-2 days Excreted in bile  undergoes deconjugation  significant enterohepatic circulation  finally excreted in urine.

11. Thyroid Hormones: Regulation of Secretion Somatostatin (-)

12. Thyroid Hormones: Actions Intermediary Metabolism Lipid: indirectly enhances lipolysis; elevated plasma free fatty acid; Lipogenesis also stimulated Carbohydrate: metabolism stimulated; tissue utilization of sugar increased; glycogenolysis and gluconeogenesis increased, faster absorption of glucose from intestine Protein: overall catabolic, prolong action: negative nitrogen balance and tissue wasting. Calorigenesis Increase BMR

13. Thyroid Hormones: Actions Cardiovascular System Hyperdynamic state of circulation due: increased peripheral demand, direct cardiac actions. Fast bounding pulse Nervous System Profound functional effects Gastrointestinal Increases propulsive activity

14. Thyroid Hormones: Actions Reproduction Indirect effect on Reproduction Maintenance of pregnancy and lactation Hematopoiesis Facilitates erythropoiesis Growth and Development Maturation of nervous system

15. Thyroid Hormone Receptors TR α and TR β Tissue distribution varies

16. Thyroid Hormones Mechanism of Action: Immediate action: Sensitization of adrenergic receptors to catecholamines  tachycardia, arrhythmia, raised BP, tremor, hypoglycaemia Long term action: Penetrates cells by active transport Binds to nuclear thyroid hormone receptor bound to the thyroid hormone response element (TRE) Conformation changes occur (heterodimerization of receptor with retinoid X receptor (RXR)) Releases co-repressor and binding of coactivator occurs Gene transcription induced  production of specific mRNA and protein synthesis  metabolic and anatomic effects.

17. Thyroid Hormone: Mechanism of Action

18. Thyroid Formulations Available as: l-thyroxine (levothyroxine): oral, injectable More sustained and uniform action Triiodothyroxine : injectable form Higher risk of cardiac arrhythmia

19. Levothyroxine: Pharmacokinetics Oral bioavailability: ~ 75% Should be administered in empty stomach CYP3A4 inducers: increase the metabolism of levothyroxine

20. Thyroid Hormones: Uses Cretinism Adult Hypothyroidism Myxoedema coma Nontoxic Goitre Thyroid Nodule Papillary carcinoma of thyroid Empirical use

21. Chandna S, Bathla M. Oral manifestations of thyroid disorders and its management. Indian J Endocrinol Metab . 2011 Jul;15(Suppl 2):S113-6. doi : 10.4103/2230-8210.83343. PMID: 21966646; PMCID: PMC3169868. López-Santacruz DDSH. D., Herrera-Badillo DDSD. A., Márquez-Preciado DDSR., Torre-Delgadillo DDSG., & Rosales-Berber DDSM. Ángel . (2019). Improvement in Oral Health and Compliance in a Child with Congenital Hypothyroidism. Case Report.  Odovtos - International Journal of Dental Sciences ,  21 (3), 45-51. https://doi.org/10.15517/ijds.2019.37850

22. THANK YOU

23. Anti-thyroid Drugs Dr. Pravin Prasad MBBS, MD Clinical Pharmacology Assistant Professor, Department of Clinical Pharmacology Maharajganj Medical Campus, Kathmandu 15 June 2020 (1 Asar 2077), Monday

24. Hyperthyroidism and Dental presentations Increased susceptibilities to caries, periodontal disease Enlargement of extra glandular thyroid tissue Burning mouth syndrome Accelerated dental eruption Maxillary and Mandibular osteoporosis Development of connective tissue diseases like Sjogren’s syndrome, SLE

25. Classification Inhibits Hormone synthesis ( Thioamides ) Propylthiouracil , Methimazole , Carbimazole Inhibits iodine trapping (ionic inhibitors) Thicynates , Perchlorates, Nitrates Inhibits hormone release Iodine, Iodides of Na and K, Organic Iodide Destroy Thyroid Tissue Radioactive iodine ( 131 I, 125 I, 123 I)

26. Antithyroid Drugs Mechanism of Action: Binds to the Thyroid Peroxidase and prevent oxidation of iodide/ iodotyrosil residues thereby: Inhibit iodination of tyrosine residues in thyroglobulin Inhibit coupling of iodotyrosine residues to for T 3 and T 4 Thyroid colloid is depleted over time and blood levels of thyroid hormones are progressively lowered. Propylthiouracil also inhibits peripheral conversion of T4 to T3 by Deiodinase (D1)

27. Comparing thioamides

28. Thioamides : Pharmacokinetics Well absorbed orally Widely distributed (enters milk and placenta) Higher concentration in thyroid, longer intrathyroid half life Metabolised in liver Excreted in urine

29. Thioamides : Adverse Effects Due to Overtreatment: Hypothyroidism, goiter Important side effects: Gastrointestinal intolerance, skin rashes, joint pain Infrequent side effects: Loss or graying of hair, loss of taste, fever, liver damage Rare but serious: Agranulocytosis

30. Thioamides : Uses Control Thyrotoxicosis in: Grave’s Disease Toxic Nodular Goiter Can be used as: Definitive therapy for Grave’s Disease Preoperatively in thyrotoxic patients Along with 131 I Propylthiouracil: early pregnancy, thyroid storm

31. Ionic Inhibitors Mechanism of Action Inhibits iodide trapping by NIS into the thyroid  T 3 and T 4 not synthesised Toxic and not clinically used these days

32. Iodine and Iodides Fastest acting thyroid inhibitor Peak effects seen after 10-15 days Mechanism of Action (not clear): Inhibition of hormone release- ‘thyroid constipation’ Endocytosis of colloid and proteolysis of thyroglobulin stopped Excess of iodine inhibits its own transport by interfering with expression of NIS Attenuates TSH induced thyroid stimulation Rapid and brief interference with iodination of tyrosil and thyronil residues of Thyroglobulin

33. Iodine and Iodides: Uses Preoperative preparation Thyroid storm Prophylaxis of endemic goiter As antiseptic

34. Iodine and Iodide: Adverse Effects Acute Reaction Chronic overdose ( iodism ) Long term use of high doses: Hypothyroidism and goitre Flaring of acne in adolescents Pregnancy/Lactating mothers: Foetal/infantile goitre and hypothyroidism Aggravation of thyrotoxicosis in multinodular goitre

35. Radioactive Iodine 131 I emits X-rays and β -particles X-rays: tracer studies β -particles: destructive effect on thyroid tissues Mechanism of Action: Concentrated by thyroid, incorporated into colloid  emits radiation from within the follicle  undergo pyknosis and necrosis followed by fibrosis Partial ablation can be achieved

36. Radioactive Iodine Administered as sodium salt of 131 I dissolved in water and taken orally. Use: Diagnostic: 25-100 mcCurie is given: no damage to thyroid cells occur at this dose Therapeutic: Hyperthyroidism due to Grave’s disease or Toxic nodular goitre Average Dose: 3-6 mCurie ; higher dose for toxic multinodular goitre

37. Beta blockers in Hyperthyroidism Non selective beta blockers ( Propanolol ) Control the symptoms of hyperthyroidism (thyrotoxicosis) Symptoms due to sympathetic overactivity Indications: While awaiting response to thioamides or 131 I. Along with iodide for preoperative preparation Thyroid storm (thyrotoxic crisis)