Anti thyroid drugs

Pharmacology what are hypothyroidism and hyperthyroidism and anti thyroid drugs

1. Anti Thyroid Drugs BY Muhammad Asad Faisal shahzad Alya anum DOCTOR OF PHARMACY 4 th smester

2. Introduction The neuroendocrine system, which is controlled by the pituitary and hypothalamus, coordinates body functions by transmitting messages between individual cells and tissues. This contrasts with the nervous system which communicates locally by electrical impulses and neurotransmitters directed through neurons to other neurons or to specific target organs, such as muscle or glands The endocrine system releases hormones into the bloodstream, which carries these chemical messengers to target cells throughout the body The thyroid gland is the source of two fundamentally different types of hormones, iodothyronines and calcitonin .

3. Biosynthesis of Thyroid Hormones The major steps in the synthesis are UPTAKE OF PLASMA IODIDE BY THE FOLLICLE CELLS Iodide is captured from the blood and moved to the lumen by two transporters : the Na+/I− symporter (NIS) located at the basolateral surface of the thyrocytes and pendrin 1 (PDS), an I−/Cl − OXIDATION OF IODIDE AND IODINATION OF TYROSINE RESIDUES The oxidation of iodide and its incorporation into thyroglobulin (termed the organification of iodide) is catalysed by thyroperoxidase Iodination occurs after the tyrosine has been incorporated into thyroglobulin The reaction forms mono- and diiodotyrosyl residues in thyroglobulin just prior to its extracellular storage in the lumen of the thyroid follicle

4. Biosynthesis of Thyroid Hormones Formation of Thyroxine and Triiodothyronine from Iodotyrosines of two diiodotyrosyl residues to form T4 or of one monoiodotyrosyl and one diiodotyrosyl residues to form T3. The same peroxidase catalyzes these oxidative reactions SECRETION OF THYROID HORMONE The thyroglobulin molecule is taken up into the follicle cell by endocytosis (Fig. 33.1). The endocytotic vesicles then fuse with lysosomes, and proteolytic enzymes act on thyroglobulin, releasing T4 and T3 to be secreted into the plasma

5. Synthesis and secretion of thyroid hormone

6. REGULATION OF THYROID FUNCTION Hypothalamic cells secrete thyrotropin releasing hormone (TRH) into the capillaries of the pituitary portal system. TRH stimulates the synthesis & release of thyroid stimulating hormone (TSH). TSH stimulates an adenylyl cyclase-mediated mechanism in the thyroid gland to increase the synthesis& release of T 4 & T 3 T 4 & T 3 act in a negative feedback fashion (mechanism) to block the action of TRH on the pituitary gland & on the hypothalamus to inhibit the synthesis & release of TRH(detail from rang and dale pg 412)

7. REGULATION OF THYROID FUNCTION

8. Mechanism of Action Both T4 and T3 must dissociate from thyroxine-binding plasma proteins prior to entry into cells, either by diffusion or by active transport. Within the cell, T 4 is converted to T 3 by 5’- deiodinase, and the T 3 enters the nucleus where T 3 binds to a specific T 3 receptor protein , Large numbers of thyroid hormone receptors are found in the most hormone-responsive tissues (pituitary, liver, kidney, heart, skeletal muscle, lung, and intestine ), while few receptor sites occur in hormone-unresponsive tissues (spleen, testes).

9. Pharmacological actions of thyroid hormones E FFECTS ON METABOLISM The thyroid hormones produce a general increase in the metabolism of carbohydrates, fats and proteins There is an increase in oxygen consumption and heat production, which is manifested as an increase in the measured basal metabolic rate EFFECTS ON GROWTH AND DEVELOPMENT The thyroid hormones have a critical effect on growth, partly by a direct action on cells, and also indirectly by influencing growth hormone production and

10. Pharmacological actions of thyroid hormones Cardiovascular Effects In hyperthyroidism, there is tachycardia, increased stroke volume, increased cardiac index, cardiac hypertrophy, decreased peripheral vascular resistance, and increased pulse pressure. In hypothyroidism, there is bradycardia, decreased cardiac index, pericardial effusion, increased peripheral vascular resistance, decreased pulse pressure, and elevation of mean arterial pressure.

11. THERAPEUTIC USES OF THYROID HORMONE The major indications for the therapeutic use of thyroid hormone are for hormone replacement therapy in patients with hypothyroidism or cretinism and for TSH suppression therapy in patients with thyroid cancer and occasionally those with nontoxic goiter.

12. ABNORMALITIES OF THYROID FUNCTION HYPERTHYROIDISM ( THYROTOXICOSIS In thyrotoxicosis , there is excessive activity of the thyroid hormones , resulting in a high metabolic rate, an increase in skin temperature and sweating, and a marked sensitivity to heat Types Diffuse toxic goitr (Grave desease ) is indicated by the name, patients with exophthalmic goitre have protrusion of the eyeballs e it is an autoimmune disorder caused by IgG antibodies that bind to and activate the TSH receptor. Because of the persistent activation of the TSH receptor,there is increasedsecretion of thyroid bormone

13. Diffuse toxic goitr (Grave desease

14. HYPOTHYROIDISM A decreased activity of the thyroid results in hypothyroidism, failure of the thyroid gland to produce sufficient thyroid hormone example myxoedema .

15. The Antithyroid Drugs: Reduction of thyroid activity and hormone effects can be accomplished by agents that interfere with the production of thyroid hormones, A large number of compounds interfere either directly or indirectly with the synthesis, release, or action of thyroid hormones

16. Classification of Antithyroid Drugs Inhibitor of hormone synthesis Carbimazole Methimazole Propylthiouracil Inhibitor of hormone release Iodine Iodides of Na, k Organic iodides Radioactive iodine 131 I (Radioactive i odine ) Ionic inhibitors Thiocynate (-SCN) Perchlorates (-ClO4) Nitrates(NO3)

17. I nhibitor of hormone synthesis Methimazole ( carbimazole ) Propyl thiouracil (PTU) These 2 are the major drugs used in the treatment of thyrotoxicosis ( Carbimazoles converted to methimazole in vivo). MOA : These drug inhibit thyroid hormone production by a) inhibiting thyroid peroxidase which is required in intrathyroidal oxidation of Iodide. b) by inhibiting the iodination of tyrosine c) by inhibiting coupling of MIT and DIT to form thyroid hormones d) propylthiouracil also inhibits peripheral conversion of T 4 TO T 3 by inhibiting DID -1 enzyme

18. Carbimazole - More potent given in a single daily dose -Completely absorbed & readily accumulated in thyroid gland -Excreted in urine but slower than PTU. -Has some immunosuppressive action leading to decrease in serum TSH receptor antibodies. -Has little effect on conversion of T4 to T3 -Crosses placenta. -It is excreted in breast milk.

19. Adverse effect The most common adverse effect is a maculopapular pruritic rash (4–6%), at times accompanied by systemic signs such as fever. Rare adverse effects include an urticarial rash vasculitis , a lupus-like reaction, lymphadenopathy , acute arthralgia

20. Propyl thiouracil ( PTU) Dose is 10 times that of Carbimazole given every 6-8 hrs. Rapidly absorbed with a bioavailability of 50-80 % Excreted in urine within 24 hrs Has no immunosuppressive effect It inhibits the peripheral conversion of T 4 to T 3 Crosses placenta less readily, Preferable in pregnancy Not excreted in breast milk

21. THERAPEUTIC USES The antithyroid drugs are used as definitive treatment of hyperthyroidism, to control the disorder in anticipation of a spontaneous remission in Graves’ diseas

22. Inhibitor of hormone release Iodine Iodides of Na, k Organic iodides Mechanism of action Iodide salts inhibit organification (iodination of tyrosine) and thyroid hormone release. These salts also decrease the size & vascularity of the hyperplastic thyroid gland inhibition of thyroglobulin proteolysis The usual forms of this drug are lugol's solution(iodine & potassium iodide) and saturated solution of potassium iodide

23. therapeuticUse of Iodide Iodide salts are used in thyroid storm(severe thyrotoxicosis) & to prepare the patient for surgical resections of the hyperactive thyroid Adverse effect They include acneiform rash (similar to that of bromism ), swollen salivary glands, mucous membrane ulcerations, conjunctivitis, rhinorrhea, drug fever, metallic taste , bleeding disorders, and rarely, anaphylactoid reactions

24. Radioactive iodines Radioactive iodine is administered as sodium salt of 131 I dissolved in water and taken orally. 131 I emits x ray as well as β particles USES Most common indication is hyperthyroidism due to Graves’ disease or Toxic nodular goitre . Response is slow , it starts after 2 weeks and gradually increases reaching peak at 3 month.

25. ANION INHIBITORS Includes monovalent anioins such as perchlorate ( ClO 4 – ), pertechnetate ( TcO 4 – ), thiocyanate (SCN – ) MOA block uptake of iodide by the gland through competitive inhibition of the iodide transport mechanism