THYROID ANTI THYROID DRUGS By Dr Abdul Latif

THYROID ANTI THYROID DRUGS By : Dr. Abdul Latif Mahesar Department of medical pharmacology KKUH , King Saud University

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Normal thyroid gland secretes T 3 (triiodothyronine) and T 4 (tetraiodothyronine). To maintain Normal growth and development of n n n Nervous Skeletal Reproductive systems 6

It also controls metabolism of n n Fats Carbohydrates Proteins and Vitamins 7

and hence controls n n Normal body temperature Normal energy levels Thyroid status also affects Secretion and degradation of n Catecholamine n Cortisones n Estrogens n progesterone and n insulin 8

n Mental retardation (Cretinism) and dwarfism results due to deficiency of thyroxine in early life. n Hyperactivity of thyroid resembles sympathetic over activity, this may be due to oversensitivity of β-adrenergic receptors or increase in their number. n There may also be increase in the production of catecholamines 9

increased epinephrine activity causes n Tremors n Sweating n Anxiety n Nervousness n lid lag retraction n 10

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Manifestations of Hyperthyroidism n n n Restlessness , nervousness , irritability. Tremors palpitation Weight loss sweating Heat intolerance 13

|Manifestations cont’d Diarrhoea n Short breath n Itching n Tiredness n Light periods n Exophthalmos n 14

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Manifestations of Hypothyroidism n n n n n Fatigue and lack of energy weight gain Dry and cold skin Dry hairs Constipation Slowed thinking Bradycardia Heavy menses Intolerance to cold 17

Causes of hypothyroidism n n n n Drugs Auto immune destruction Blocked hormone formation Impaired synthesis of T 4 Destruction or removal of gland Iodine deficiency Receptor blocking antibodies pituitary or hypothalamic disease. 18

SYNTHESIS OF THYROID HORMONES n Iodide , an ions is actively taken up by the thyroid gland (Iodine trapping)/iodine uptake n Iodine is stored in the thyroid and is concentrated 25 times more n Iodide an ion is then oxidized to iodine by thyroidal peroxidase. 19

n It iodinates tyrosine (with in thyroglobulin, a glycoprotein molecule) to form monoiodotyrosine (MIT) and Di-iodotyrosine (DIT), called organification or iodination. 20

Biosynthesis of thyroid hormones , also showing various sites of anithyroid drug actions 21

n Two molecules of DIT unite to form T 4 (tetra- iodothyroine) and one molecule of MIT and DIT combine to form T 3 (triiodothyronine). n These hormones are released by exocytosis and proteolysis of thyroglobulin. n Ratio of T 4 to T 3 in thyroglobulin is 5: 1 n Most of T 3 in circulation is derived from metabolism of. T 4. 22

HORMONE TRANSPORT. n T 4 and T 3 are reversibly bound to thyroxine binding globulin (TBG). n 0. 04% of total T 4 and 0. 4% of T 3 exist in free form n Starvation , pregnancy , steroid hormones affects their binding 23

Metabolism of thyroxine in to active T 3 and inactive T 3 (r. T 3) 24

Thyroid Hormone Production and Metabolism per day 25

PERIPHERAL METABOLISM n Small amount is biologically inactivated by deamination, decarboxylation conjugation and excreted as Glucuronide or sulphate, but n The primary pathway of peripheral thyroxine metabolism is DEIODINATION. n Deiodination of T 4 at outer ring to active and 3 -4 times more potent T 3. and 26

Metabolism cont’d n De-Iodination of inner ring produces reverse T 3(r. T 3), metabolically inactive. n Drugs like ipodate, β-blockers and corticosteroids; starvation inhibits 5 deiodinase. n This results low T 3 and high r. T 3. 27

Hypothalamic –pitutary – thyroid axix Thyroid regulation 28

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THYROID REGULATION n Thyrotropin releasing hormone (TRH) is secreted by hypothalamic cells in pituitary portal venous system. n It acts on pituitary and causes synthesis and release of thyroid stimulating hormone (TSH). n This in turn acts on thyroid cell to increase release and synthesis of T 3 and T 4. 30

n These thyroid hormones in a negative feed back fashion act on pituitary to block action of TSH and on hypothalamus to inhibit TRH. n Level of iodine in blood also regulates thyroidal secretion independent of TSH. (large doses of iodide inhibits iodine organification) n THYROXINE ISOMERS: Naturally occurring molecules are L- isomers; where as synthetic molecules are D-isomers. D -isomers have only 4% activity of L-isomers. 31

T 3 T 4 T 3 T 3 PP T 4 PB T 3 cytoplasm T 3 Nucleus Response Protein Pre-m RNA m. RNA Mechanims of action of thyroid Mechanism of action of thyroxine at hormones cellular level 32

MECHANISM OF ACTION n Free form of T 3 and T 4 enter cell by diffusion /active transport. T 4 is converted to T 3 and enters nucleus and binds to T 3 receptors, this leads to increased formation of m. RNA and subsequent protein synthesis. 33

Pharmacokinetics of administered thyroid hormones n T 4, best absorbed in duodenum and ileum, this can be altered by food and drugs, such as calcium preparations and antacids containing aluminum, intestinal flora Absorption of T 4 is 80% and of T 3 is 95%. n Absorption is not affected by mild hypothyroidism but impaired in myxedema with ileus, for this parental route is preferred. 34

n In hyperthyroidism metabolic clearance of T 3 and T 4 is increased and their half life is decreased and opposite is true in hypothyrodism. n Enzyme inducers increase metabolism of T 3 and T 4 but concentration is maintained in euthyroid. n Same compensatory mechanism occurs if binding sites are altered as in pregnancy, estrogen therapy and use of oral contraceptives. 35

Thyroid preparations n LEVOTHYROXINE: (T 4) n This is the preparation of choice for thyroid replacement and suppression therapy, because it is stable and has a long (7 days) half life, to be administered once daily. n Oral preparations available are from 0. 025 to 0. 3 mg tablets n For parentral use 200 -500µg (100µg/ml when reconstituted) for injection. 36

n LIOTHYRONINE(T 3): n This is more potent (3 -4 times) and rapid acting than levothyroxine but has a short half life (24 hours) compared to levo, is not recommended for routine replacement therapy, it requires multiple dosing in a day. n It should be avoided in cardiac patients. n Oral preparation available are 5 -50µg tablets n For parentral use 10µg/ml 37

Comparison of T 4 to T 3 n n n T 4 production is more than T 3 T 4 is converted to T 3 in periphery T 3 is more potent than T 4 T 3 acts faster than. T 4 T 3 enters cell easily than T 4 T 3 binds to receptors in nucleus. 38

ANTITHYROID AGENTS: n n Mechanism Agents which interfere production of thyroid hormone . n Agents which modify tissue response to thyroid hormones n Glandular destruction with radiation or surgery. 39

n Drugs : n Thioamides n Iodides n Radio active iodine n Iodinated contrast media n Adrenoceptor- blocking Agents n Anion inhibitors 40

Anti –thyroid agents ( Mechanissm) 41

THIOAMIDES: n Methimazole n Carbimazole n Propylthiouracil n Methimazole is 10 times more active than propylthiouracil. 42

Mechanism of Action n They act by: n Inhibiting thyroidperoxidase –catalysed reaction to block iodine organification. n They block coupling of iodotyrosine n n They inhibit peripheral Deiodination of T 4 to T 3. Onset of drug is slow requiring 3 -4 weeks before stores of T 4 are depleted. 43

Pharmacokinetic comparision between Propylthiouracil and Methimazole Absorption Propylthiouracil Methimazole Rapid but incomplete At variable rates but complete Similar Vol. of Dist. Approximates body waters Protein binding more less accumulation In thyroid Similar Excretion Kidneys as inactive Glucuronide in 24 hrs Excretion slow, 6070% of drug is recovered in urine in 44 48 hrs

Pharmacokinetic comparision between Propylthiouracil and Methimazole Propylthiouracil Methimazole Half life 1. 5 hrs 6 hrs Administration Every 6 -8 hrs As a single dose in 24 hrs Duration of activity 100 mg inhibits iodine organification for 7 hrs 30 mg exerts Antithyroid effect for longer than 24 hrs Pregnancy Preferred, though cross placenta and is conc. in fetal thyroid but is highly protein bound , cross placenta less readily Cross placenta and concentrated by fetal thyroid Nursing mothers Less secreted in breast milk secreted 45

Adverse Effects ( thioamides) n It occurs in 3 -12 % of treated patients n Maculopapular rash and fever are earlier effects. n Urticarial rash, vasculitis, arthralgia , cholestetic jaundice , lymphadenopathy, and hypoprothrombenemia. n Most dangerous complication is agranulocytosis this is infrequent but may be fatal. 46

IODIDES: n They inhibit organification and hormone release. With a dose of > 6 mg /day. n They should be initiated after onset of thioamides therapy. n It also decreases the vascularity of hyperplastic gland (making it valuable for preparation for surgery) n Improvement is rapid within 2 -7 days (valuable in thyroid storm) 47

Iodides cont’d n Well and rapidly absorbed from intestines n Rapidly taken by thyroid gland concentrated there n Moderate increase leads to hormone secretion but substantial excess inhibits hormone release and promotes its storage, making the organ less vascular and firmer. n iodides stores in thyroid delays response to 48

Precautions /toxicity: n Should not be used as a single therapy n Should not be used in pregnancy n May produce iodism causing acniform rash, swelling of salivary glands, mucous membrane ulceration, metallic taste bleeding disorders and rarely anaphylaxis. 49

RADIOACTIVE IODINE n 131 I isotope , administered orally n It is rapidly absorbed, concentrated in thyroid gland stored in follicles. n It has a half life of 5 days n It is easy to administer , effective , painless and less expensive n It causes destruction of parenchyma , necrosis and follicular disruption. 50

Radio active iodine cont’d n Therapeutic effect is due to emission of β-rays. n Patients with age above 40 years only can be treated with this n It crosses placenta and excreted in breast milk n It may cause genetic damage and leukemia and neoplasia , it may be carcinogenic 51

IODINATED CONTRAST MEDIA n Ipodate , iopanoic acid administered orally n Diattrizoate administered intravenously n These drugs rapidly inhibit the conversion of T 4 to T 3. n They are relatively non toxic n Useful adjunctive therapy in thyroid storm n Valuable alternative when thioamides or iodides contraindicated. 52

ADRENOCEPTOR BLOCKING AGENTS: n Many symptoms of thyrotoxicosis mimic , especially those which are associated with sympathetic stimulation. n Beta blocking drugs without intrinsic sympathomimic activity are the agents of choice in these conditions e. g. Propranolol. In conditions where Beta blockers cannot be used then Diltiazem is used. n 53

HYPOTHYRODISM: n It is a syndrome resulting from deficiency of thyroid hormones and manifested by reversible slowing down of all body function. n Infants and children suffer severely , results in dwarfism and irreversible mental retardation n Diagnosed by low free thyroxine and elevated serum TSH n For treatment : replacement therapy is appropriate n Levothroxine is most satisfactory: Infants and children require more T 4 /kg body weight than adults. n n Average dose in children 10 -15 µg/kg/day and in adults: 1. 7 µg/kg/day. It takes 6 -8 weeks to reach steady state level. 54

n In long standing condition, in older patients and in patients with cardiac ailments, treatment is started with reduced dosage. n Thyroxine is given once daily due to long half life. n In older patients and in patients with underlying cardiac diseases treatment is started with reduced dose n levothyroxine is given in a dose of 12. 5 – 25 µg/day for two weeks and then increasing it after every two weeks. 55

ADVERSE EFFECTS OF OVER DOSE n CHILDEREN : Restlessness, insomnia , accelerated bone maturation. n ADULTS : Nervousness, heat intolerance , palpitation, weight loss n Atrial fibrillation and osteoporosis in chronic over treatment with T 4. n 56

MYXEDEMA COMA: n It is an end state of untreated hypothyroidism. n It develops quite and progress slowly to stupor , coma and death. n The treatment of choice is loading dose of levothyroxine intravenously 300 -400µg initially followed by 50µg daily. n I/V T 3 can be used but it may prove cardiotoxic n I/V hydrocortisone it may be used in case of adrenal and pituitary insufficiency. 57

HYPOTHROIDSM AND PREGNANCY. n These woman suffer form anovulatory cycles and infertility n In pregnant hypothyroid patient 20 -30 % increase in thyroxine is required because of elevated maternal TBG and because of early development of fetal brain which depends on maternal thyroxine 58

HYPERTHYROIDISM n This is the syndrome that results when tissue is exposed to high levels of thyroid hormone. n GRAVES' DISEASE Most common form of hyperthyroidism. n It is autoimmune disorder n There is genetic defect in suppressor T lymphocyte , B lymphocytes synthesize antibodies against thyroid antigens. 59

n T 3 and T 4 are elevated and TSH is suppressed. n Radio iodine uptake is elevated. 60

Management of Grave’s disease Drug therapy n surgical thyroidectomy n Destruction of the gland with radioactive iodine n 61

n When patient is young with small gland mild disease n Drug therapy: Methimazole / propylthiouracil until disease undergoes spontaneous remission. n this may take 1 -2 years with 60 -70 % relapse. 62

n therapy is started with large divided doses , then shifted to maintenance therapy with single daily dose. n Propylthiouracil is better than methimazole. n this may lead to increase in TSH and stimulation of thyroid, this can be prevented by addition of levothyroxine. 63

THYROIDECTOMY n A near-total thyriodectomy is the treatment of choice in very large gland or multinodular goiter n In case of large or multinodular goiter and to simplify surgery (to diminish vascularity) saturated solution of potassium iodide 5 drops twice daily for two weeks prior to surgery 64

RADIOACTIVE IODINE 131 I n Preferred in most patients over 21 years of age in a dose of 80 -120µCi/gm of thyroid weight. ( in patients without underlying cardiac disease) n in patients with underlying heart disease , severe disease , elderly patient use methimazole until patient become euthyroid , then stop the medicine for 5 -7 days. n Major complication of this therapy is hypothyroidism which occurs in 80% of patients. 65

Adjuncts Therapy n During acute phase β-blockers without intrinsic sympathomimetic activity are extremely helpful eg : Propranolol 66

THYROID STORM: n It is sudden acute exacerbation of all of the symptoms of thyrotoxicosis, presenting as a life threatening syndrome. n There is hyper metabolism, and excessive adrenergic activity, death may occur due to heart failure and shock. n Vigorous management is mandatory. Propranolol 1 -2 mg slows I/v or 40 -80 mg orally every 6 hours 67

n Potassium iodide 10 drops orally daily or n Iodinated contrast media(Na ipodate 1 g orally daily) n Propylthiouracil 250 mg orally every six hours or 400 mg every six hours rectally. n Hydrocortisone 50 mg I/V every 6 hours to prevent shock. n If above methods fail plasmapheresis or peritoneal dialysis. 68

Thyrotoxicosis during pregnancy n Definitive therapy with 131 I or subtotal thyroidectomy prior to pregnancy to avoid acute exacerbation during pregnancy or after delivery n During pregnancy radioiodine is contraindicated. n Propylthiouracil is better choice during pregnancy. Dose must be kept minimum i. e. , <300 mg daily. 69

ANION INHIBITORS n Perchlorate (Clo 4) ; pertechnetate(Tc. O 4) and thiocynate (SCN) can block uptake of iodide by the gland by competitive inhibition n For this purpose large doses of the drug are required n They are rarely used clinically now days , as it has been shown to cause aplastic anemia. 70