Thyroid hormones

thyroid hormone secretion.
mechanism

1. Thyroid Hormones By: K hushboo t hakur M. P harm s em ii D epartment Of Pharmacology Ssr c ollege of p harmacy , s ilvassa .

2. INTRODUCTION THYROID GLAND The  thyroid  gland and  parathyroid  glands are a group of endocrine glands. Thyroid gland secretes 3 hormones : Triiodothyronine (T 3 ), Thyroxine (T 4 ), and Calcitonin. T3 and T4 are produced by thyroid follicles and have similar biological activity.

3. Calcitonin produced by interfollicular ‘C’ cells is chemically and biologically entirely different. Calcitonin considered along with parathormone (PTH), with which it regulate calcium metabolism. Thyroxine was the first hormone synthesized in the laboratory.

4. LOCATION OF THYROID GLAND The   thyroid  gland and  parathyroid  glands, located in the base of the neck. These glands play a vital role in maintaining the body's homeostasis by producing hormones that regulate the body's metabolism and free calcium levels . Parafollicular   cells  (also called  C cells )  are  neuroendocrine  cells  in the thyroid which primary function is to secrete calcitonin. They  are located adjacent to the thyroid follicles and reside in the connective tissue. These  cells are large and have a pale stain compared with the follicular cells or colloid .

5. LOCATION OF THYROID GLAND The thyroid is a butterfly-shaped gland that sits low on the front of the neck. The thyroid gland lies below the Adam’s apple. Along the front of the windpipe. The thyroid has two side lobes, connected by a bridge (isthmus) in the middle.

6. CHEMISTRY AND SYNTHESIS 2 amino acid – tyrosine Condensation T3 & T4 T3 is 3,5,3’- triiodothyronine . T4 is 3,5,3’,5’-tetraiodothyronine.

7. Synthesis, Storage and Release: Thyroid hormones are synthesized and stored in thyroid follicles as a part of thyroglobulin molecule. Thyroglobulin molecule is a glycoprotein synthesized by thyroid cells. I ts MW 660 KDa and contains 10% sugar. T3 and T4 synthesis, storage and release involves the following processes. Iodine uptake Oxidation and iodination Coupling Storage and release Peripheral conversion of T4 to T3.

8. S ynthesis, Storage and Release:

9. TRANSPORT, METABOLISM AND EXCRETION Thyroid hormones are bound to plasma proteins only 0.03 – 0.08 % of T4 and 0.2 – 0.5% of T3. Almost all protein bound iodine (PBI) in plasma is thyroid hormone, of which 90 – 95% is T4 and the rest T3. Binding occur to 3 plasma proteins in the following decreasing order of affinity for T4: Thyroxine binding globulin (TBG) Thyroxine binding prealbumin (trans- th y retin ) Albumin

10. TRANSPORT, METABOLISM AND EXCRETION The normal concentration of PBI is 4-10 dl; only 0.1 – 0.2 μ g/dl of T3, rest is T4. During pregnancy thyroxine binding globulin is increased – PBI levels are elevated. Plasma t1/2 of T4 is 6-7 days and of T3 is 1-2 days. The half- lives are shortened in hyperthyroidism due to faster metabolism and prolonged in hypothyroidism due t slower metabolism.

11. REGULATION OF SECRETION Secretion of hormones from the thyroid is controlled by anterior pituitary by the elaboration of thyrotropin. While TSH secretion itself is regulated by TRH produced in hypothalamus. Somatostatin elaborated by hypothalamus inhibits GH, prolactin and TSH secretion from pituitary.

12. REGULATION OF SECRETION The negative feedback by the thyroid hormones is exercised directly on the pituitary as well as through hypothalamus. The action of TRH on pituitary and that of TSH on thyroid cells is mediated by enhanced cAMP synthesis. High concentration of TSH also acts via IP 3 /DAG which increased intracellular Ca +2 pathway in the thyroid cells.

13. ACTIONS OF THYROID HORMONES The actions of T3 and T4 are qualitatively similar and are nicely depicted in the features of hypo and hyperthyroidism. Growth and Development: T3 and T4 are essential for normal growth and development of tissue including the nervous system. Lack of thyroid hormone during development results in short stature and mental deficits ( cretinism ).

14. ACTIONS OF THYROID HORMONES 2) CVS : T3 and T4 cause a hyperdynamic state of circulation which is partly secondary to increased peripheral demand and partly due to direct cardiac actions. T3 and T4 stimulate heart by direct action on contractile elements (increasing the myosin fraction having greater Ca+2 ATPase activity). Myocardial O2 consumption can be markedly reduced by induction of hypothyroidism.

15. ACTIONS OF THYROID HORMONES 3) Nervous System: T3 and T4 have profound functional effect on CVS. Mental retardation is the hallmark of cretinism; sluggishness and other behavioural features are seen in myxoedema. Hyperthyroid individuals are anxious, nervous, excitable, exhibit tremors and hyperreflexia .

16. ACTIONS OF THYROID HORMONES 4) Skeletal Muscle: Muscles are flabby and weak in myxoedema, while thyrotoxicosis produces increased muscle tone, tremor, and weakness due to myopathy. 5) GIT: Propulsive activity of gut is increased by T3/T4. Hypothyroid patients are often constipated, while diarrhoea is common in hyperthyroidism.

17. ACTIONS OF THYROID HORMONES 6) Kidney: T3 and T4 do not cause diuresis in euthyroid individuals, but the rate of urine flow is often increased when myxoedematous patients are treated with it. 7) Haemopoiesis: Hypothyroid patients suffer from some degree of anaemia w hich is restored only by T4 treatment. Thus, T4 appears to be facilitatory to erythropoiesis.

18. ACTIONS OF THYROID HORMONES 8) Reproduction: Thyroid has an indirect effect on reproduction. Fertility is impaired in hypothyroidism and women suffer from oligomenorrhoea. Normal thyroid function is required for maintenance of pregnancy and lactation.

19. Mechanism of Action Both T3 and T4 penetrate cells by active transport and produce majority of their actions by combining with a nuclear thyroid hormone receptor (TR). TR – which belong to the steroid and retinoid superfamily of intracellular receptors. It bound to the ‘thyroid hormone response element’ (TRE) in the enhancer region of the target genes along with corepressors. This keep gene transcription suppressed.

20. Mechanism of Action When T3 binds to the ligand – binding domain of TR, it heterodimerizes with retinoid X receptor and undergoes a conformation change releasing the corepressor and binding the coactivator . This induces gene transcription Production of specific mRNA and a specific pattern of protein synthesis Various metabolic and anatomic effects.

21. Relation between T3 and T4 Thyroid secrets more T4 than T3, but in iodine deficient state this difference reduced. T4 is the major circulating hormone bcz it is 15 times more tightly bound to plasma proteins. T3 is 5 times more potent than T4 and acts faster. Peak effect of T3 comes in 1-2 days while that of T4 takes 6-8 days.

22. Relation between T3 and T4 T3 is more avidly bound to nuclear receptor than T4 and T4 receptor complex is unable to activate gene transcription. About 1/3 of T4 is converted to T3 in the thyroid cells, liver and kidney by type 1 deiodinase (D1) and released into circulation. T3 is generated within the target cells (skeletal muscle, heart, brain, pituitary) by another type (D2) of deiodinase. Thus, it is concluded that T3 is the active hormone, while T4 is mainly a transport form; function as a prohormone of T3.

23. Marketed Preparations ELTROXIN - - - 25 μ g, 50 μ g, 100 μ g tabs. ROXIN - - - 100 μ g tab. THYRONORM - - - 12.5 μ g , 25 μ g, 50 μ g, 62.5 μ g, 75 μ g, 88 μ g, 100 μ g, 112 μ g, 125 μ g, 137 μ g,150 μ g tabs. THYROX - - - 25 μ g, 50 μ g , 75 μ g , 100 μ g , tabs

24. Marketed Preparations Triiodothyronine (Lithyronine) is not freely available in India. It is occasionally used i.v. along with 1-thyroxine in myxoedema coma. Clinically, 1-thyroxine is preferred for all indications over liothyronine because of more sustained and uniform action as well as lower risk of cardiac arrhythmias.

25. Marketed Preparations

26. Pharmacokinetics and interactions Oral bioavailability of 1- thyroxine is approx. 75%, but severe hypothyroidism can reduce oral absorption, It should be administered in empty stomach to avoid interference by food. Sucralfate, iron, calcium and proton pump inhibitors also reduce 1- thyroxine absorption. CYP3A4 inducers like rifampin, phenytoin, and carbamazepine accelerate metabolism of T4; dose of 1-thyroxine may need enhancement.

27. USES The most important use of thyroid hormone is for replacement therapy in deficiency states: Cretinism: It is due to failure of thyroid development or defect in hormone synthesis or due to extreme iodine deficiency. Treatment with thyroxine --- 8 – 12 μ g/kg daily.

28. USES 2. Adult hypothyroidism (myxoedema): One of the commonest endocrine disorders which develops as a consequence of autoimmune thyroiditis or thyroidectomy. Antiboides against thyroid peroxidase or thyroglobulin are responsible for majority of cases of adult hypothyroidism. Important drugs that can cause hypothyroidism 131 I, iodides, lithium and amiodarone.

29. USES Start with low dose --- 50 μ g of 1- thyroxine daily increase every 2-3 weeks to an optimum of 100 -200 μ g/day. (adjusted by clinical response and serum TSH levels) Further dose adjustments are made at 4-6 weeks intervals needed for reaching steady state. Increase in dose is mostly needed during pregnancy.

30. USES 3. Myxoedema coma: It is an emergency; characterised by progressive mental deterioration due to acute hypothyroidism. Drug choice is 1-thyroxine 200 – 500 μ g i.v. followed by 100 μ g OD. Some authorities recommend adding low dose i.v. T3 10 μ g --- 8 hourly. Oral T4 --- 500 μ g loading dose followed by 100- 300 μ g daily.

31. USES 4. Nontoxic goiter: two type - endemic and sporadic Endemic - due to iodine deficiency dose - - - 150- 200 μ g of iodine daily 5. Thyroid nodule: Certain benign functioning nodules regress when TSH is suppressed by T4 therapy. Non functional nodule not responsive to TSH.