1. Thyroid and Anti-Thyroid Drugs

2. Objectives Recall the anatomy and physiology of thyroid glands
Describe the effect of thyroid hormones on metabolism
Compare the different mechanism of actions of thyroid and anti thyroid drugs
List clinical uses and adverse effects of thyroid and anti thyroid drugs
Explain the principles underling TSH therapy in diagnosis
Describe the anti thyroid drugs - drug interaction

3. Anatomy and Physiology of the Thyroid Gland

4. www.medscape.com; http://ae.medseek.com/

5. Evaluating Hoarseness: Keeping Your Patient's Voice Healthy - June American Academy of Family Physicians;

6. Anatomy and Physiology of the Thyroid Gland
Member of the Endocrine System
Secretes thyroid hormones, thyroxine and calcitonin, which regulate metabolism and growth.
Located in neck adjacent to the 5th cervical vertebra (C5).
Composed of epithelial cells which specialize in the absorption of iodine and, of course, secretion of thyroid hormones.
Follicles surround a protein core, the colloid, where thyroglobulin, a substrate in thyroid hormone synthesis, and thyroid hormones are stored.

7. 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. .

8. There is a large pool of T4 in the body; it has a low turnover rate and is found mainly in the circulation.
There is a small pool of T3 in the body; it has a fast turnover rate and is found mainly intracellular.

9. Detail of Synthesis:
Thyroid peroxidase (TPO) catalyzes the conversion of iodide (I2) to iodine (I-) using H2O2 as a cofactor.
TPO then catalyzes the addition of iodine to the C-3 and C-5 position of a tyrosine residue of thyroglobulin to form monoiodothyronine MIT or diiodothyronine DIT
2-DIT condense together to form thyroxin, or T4, with four iodine substituent.
2-DIT condense with 1-MIT to form triiodothyronine, or T3, with three iodine substituent, accounts for about 10% of thyroid hormone production.

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; the receptor represses basal transcription when not bound to T3, and activates transcription when bound.

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

13. Regulation of thyroid hormone synthesis
The hypothalamus in the brain secretes thyroid releasing hormone, TRH, that target the pituitary gland which, in turn, secretes thyroid stimulating hormone, TSH. The pituitary gland’s sensitivity toward TRH varies with the body’s need for thyroid hormones.
Protirelin is a synthetic TRH causes increase secretion of TSH used for diagnostic purpose

14. TSH is absorbed into the thyroid, stimulating the thyroid to absorb iodine and synthesize hormones.
Thyroid hormones provide negative feedback for TSH production via a “homeostatic feedback loop.”

15. Regulation of
thyroid
hormone
synthesis

17. TSH
TSH acts on receptors on the membrane of thyroid follicle cells and its main second messenger is cAMP. It controls all aspects of thyroid hormone synthesis: 1-The uptake of iodide by follicle cells, by stimulating transcription of the Na+/I- transporter gene; this is the main mechanism by which it regulates thyroid function

18. 2-The synthesis and secretion of thyroglobulin, 3-The generation of H2O2 and the iodination of tyrosine 4- The endocytosis and proteolysis of thyroglobulin 5- The secretion of T3 and T4 6-The blood flow through the gland. TSH also has a trophic action on the thyroid cells; it stimulates the action of the genes for thyroglobulin, thyroperoxidase and the Na+/I- transporter

21. Detail of thyroid hormones effects on Metabolism
TH serves as a nuclear transcription factor, regulating gene expression in targeted cells to increase metabolism.
Increase size and number of mitochondria in the cell.
Synthesizes cytochromes which feed into the electron transfer chain of cellular respiration, stimulating metabolism through increasing ATP production.
Increase ATPase concentration, the enzyme which cleaves a phosphate group from ATP forming ADP and inorganic phosphate.
Increased K+ and Na+ concentrations in the cell.
Increase the body’s basal metabolic rate, BMR, to maintain electrochemical gradient in cell.
Stimulate carbohydrate metabolism and lipolysis
Affects protein synthesis.
Increase the body’s sensitivity to catecholamine, i.e. adrenaline

22. Abnormalities of thyroid function include
Hyperthyroidism (thyrotoxicosis), either diffuse toxic goiter or toxic nodular goiter Hypothyroidism; in adults this causes myxoedema, in infants, cretinism Simple non-toxic goiter, caused by dietary iodine deficiency, usually with normal thyroid function

23. Hypothyroidism
simple goiter
cretinism

26. Conditions that Impair Thyroid Function: Hypothyroidism
Insufficient amount of thyroid hormone synthesized causing lethargy and weight gain, among other symptoms. Primary hypothyroidism is typically caused by Hashimoto’s Disease, an auto-immune disorder in which the thyroid is destroyed by antibodies. Impaired hypothalamus and pituitary function, typically due to a tumor, can inhibit the secretion of THS, causing secondary hypothyroidism. A diet insufficient in iodine causes hypothyroidism as well.

27. Worldwide iodine nutrition

28. Symptoms of Thyroid Dysfunction: Goiter
Enlarged thyroid, symptom of hypothyroidism. Goiters form for different reasons depending on the cause of hypothyroidism Hashimoto’s disease, also known as chronic lymphocytic thyroiditis, causes goiters due to the accumulation of lymphocytes. The decreased amount of thyroid hormones in the body, due to Hashimoto’s or other thyroid disorders including infection, signals the increased production of TSH which accumulates in the thyroid causing a characteristic goiter. Goiters form due to an insufficient amount of ingested iodine and serve to increase the surface area of the thyroid and aid in its absorption of iodine.

29. Treatment for Hypothyroidism
Thyroxine is the standard replacement therapy for hypothyroidism. Thyroxine has all the actions of endogenous thyroxine; it is given orally. Liothyronine (T3) is the treatment of choice for myxoedema coma. Liothyronine has all the actions of endogenous triiodothyronine; it is given intravenously

30. Treatment for Hypothyroidism
Hormone replacement therapy
Administered orally with a bioavailability ranging from 48%-80%.
Levothyroxine—Synthetic T4
Liothyronine—Synthetic T3
Liotrix—Combination of synthetic T4 and T3
Natural Thyroid Hormones—Thyroid hormones derived from pigs, contains T4 and T3
Armour Thyroid
Dosage specific to individual and is determined by their
TSH serum levels. Typically 1.5μg T4 per kg body weight.

31. Because thyroid hormones serve to increase heart rate, T4, the inactive form, is typically administered to older patients who have an increased risk for heart attack on account of their age. Synthetic T3 is reserved for younger patients, who do not have a history of heart problems and individuals non-responsive to T4 treatment. Dosage for individuals suffering from secondary hypothyroidism determined by the amount of free T4 and T3 circulating in their system. Administering too high of a dosage leads to hyperthyroid symptoms

32. Conditions that Impair Thyroid Function: Hyperthyroidism
The over production of thyroid hormones. Symptoms include fatigue, weight lose, rapid heart beat, anxiety, swollen eyes, and sensitivity to hot temperatures. Causes: Grave’s disease, and autoimmune disorder in which antibodies serve as agonists to the THS receptors on the thyroid’s surface, causing thyroid growth and activation of hormone synthesis and secretion. Thyroid tumors which cause the uncontrolled synthesis and secretion of thyroid hormones. Thyroiditis, inflammation of the thyroid typically caused by infection.

34. Treatment of Hyperthyroidism
Drugs
thioureylenes
iodides
radioactive iodine
beta adrenoceptor blocking agents
'Lugol's iodine
Surgical
Subtotal Thyroidectomy

35. Drugs Treatment for Hyperthyroidism
1-Anti-thyroid drugs—Thioureylenes Inhibits thyroid hormone synthesis by irreversibly binding to TPO inhibiting its ability to break down iodine (I2→I-) and covalently attach it to the tyrosine residue of thyroglobulin. Three thioureylenes available: Propylthiouracil Methimazole Carbamizole─Degraded to methimazole in the body. Best indicated for children ,adolescents ,young adults and pregnant women.
β-Blockers used in the treatment of thyroiditis to treat symptoms.

36. Methimazole 5mg; Propylthiouracil (PTU) 50mg; Carbimazole 5mg, 20mg
MOA:
contain a sulfhydryl group and a thiourea moiety within a heterocyclic structure
inhibit synthesis by acting against iodide organification (both)
coupling of iodotyrosines (both)
blocks conversion of T4 to T3 (PTU)

37. Clinical uses A- Carbimazole (or propylthiouracil)
1-Hyperthyroidism (diffuse toxic goitre), at least 1 year of treatment being necessary; recurrence occurs eventually in over half the patients but can be managed by a repeat course of treatment.
2-Propylthiouracil can be used in patients who suffer sensitivity reactions to carbimazole.
3-Preliminary to surgery for toxic goitre.
4-Part of the treatment of thyroid storm (very severe hyperthyroidism); propylthiouracil is preferred because of its action in decreasing the conversion of T4 to T3 in the tissues

38. Anti-Thyroid Drugs-duration and side effects
Effective in the long-term treatment of hyperthyroidism. 6-8 weeks before maximum effect of the drug achieved. Drug inhibits hormone synthesis, so hormones synthesized prior to drug use will continue to cause hyperthyroid condition. Typical side effects include headache, nausea, vomiting, itchy skin and rash, and muscle aches and pains. Serious liver damage, decreased red and white blood cell synthesis, as well as decreased platelet production have been reported in a few cases. The drug’s interaction with other enzymes responsible for clotting factor synthesis accounts for some of these serious side effects. Administering too high a dosage of anti-thyroid drugs can cause hypothyroidism.

39. β-blockers are effective in treatment of thyrotoxicosis to treat symptoms
Propranolol is the most widely studied and used.

40. Radioactive Iodine 131I
As first-line treatment for hyperthyroidism; recurrence is rare provided the dose is adequate. For treatment of relapse of hyperthyroidism after carbimazole therapy or surgery. Radioiodine, given orally, is selectively taken up by thyroid and damages cells; it emits short-range β radiation, which affects only thyroid follicle cells of.. Hypothyroidism will eventually occur. Woman in pregnancy or lactation is forbidden

41. 131I cytotoxic action is restricted to the cells of the thyroid follicles, resulting in significant destruction of the tissue. 131I has a half-life of 8 days, so by 2 months its radioactivity has effectively disappeared. It is given as one single dose, but its cytotoxic effect on the gland is delayed for 1-2 months and does not reach its maximum for a further 2 months.

42. Iodine dissolved in aqueous potassium iodide ('Lugol's iodine') is used short-term to control thyrotoxicosis preoperatively. It reduces the vascularity of the gland. Iodine, given orally in high doses, transiently reduces thyroid hormone secretion and decreases vascularity of the gland.

43. Thyroid Treatment Potential Drug Interactions
Drugs that reduce thyroid hormone production Lithium Iodine-containing medications Amiodarone (Cordarone) Drugs that reduce thyroid hormone absorption Sucralfate (Carafate) Ferrous sulfate (Slow Fe) Cholestyramine (Questran) Colestipol (Colestid) Aluminum-containing antacids Calcium products

44. Drugs that increase metabolism of thyroxine Rifampin (Rifadin) Phenobarbital Carbamazepine (Tegretol) Warfarin (Coumadin) Oral hypoglycemic agents Drugs that displace thyroid hormone from protein binding Furosemide (Lasix) Mefenamic acid (Ponstel) Salicylates

45. TSH Replacement Drugs
Thyrotropin alpha—A synthetic form of TSH. Administered intravenously. Used in thyroid cancer treatment. Tumors of the hypothalamus or pituitary gland can cause the uncontrolled release of TSH, which accumulates in the thyroid and can cause subsequent follicular or papillary cancer of the thyroid. Partial or total thyroidectomy typical. Following thyroidectomy, the individual is dependent on exogenous thyroid hormones to regulate metabolism, but thyrotropin alpha is also used to suppress the release of endogenous TSH, which could trigger cancerous growth again. Used as a diagnostic tool to determine the reoccurrence of cancer.