Thyroid hormone and anti thyroid drugs

This slideshow gives you a information about hormone thyroid and its clinical activity and molecular mechanism. And also hormone abnormalities and drugs used to treat them .
hyperthyroidism and hypothyroidism is discussed along with drugs used to overcome those condition.

1. Molecular and cellular mechanism of action of Thyroid hormone, and anti-thyroid drugs 1

2. Contents Introduction Chemistry, Synthesis, storage and release of thyroid hormones Metabolism and excretion Regulation of secretion Action of thyroid hormone through Clinical effects of thyroid hormones Mechanism of action Thyroid hypofunction Thyroid Hyperfunction Therapeutic Uses of Thyroid Hormone Thyroid inhibitors 2

3. INTRODUCTION Hormone is a substance of intense biological activity that is produced by specific cells in the body and is transported through circulation to act on its target cells. Hormone may produce and release directly into blood (endocrine or ductless gland) or may release into the surface of the skin or membrane (exocrine glands) Endocrine gland: ex, thyroxine, thyroid stimulating hormone, growth hormone, etc… Exocrine gland: ex, sweet gland, tears, salivary gland, etc… Thyroid hormone It is a type of hormone belongs to endocrine system, which is secreted in the thyroid gland , which is located at the front of the neck just below the larynx. It is butterfly-shaped and consists of two lobes located either side of the trachea. The thyroid gland secretes 3 hormones—thyroxine (T4), triiodothyronine (T3) and calcitonin. The first two are produced by thyroid follicles, have similar biological activity and the term ‘thyroid hormone’ is restricted to these two hormones. 3

4. thyroid glands have specialized cells called follicles cells, which are the structural and functional units of thyroid gland. Which are made up of cuboidal cells, they make spherical in structure called follicles, there are number of follicles in a thyroid gland. These follicle cells are responsible for the production of thyroid hormones (T 3 and T 4 ). In between the follicles and capillaries there is a unique type of cluster of cells called as parafollicular cells (C cells), which are responsible to produce calcitonin . 4

5. Chemistry, Synthesis, storage and release of thyroid hormones Both T4 and T3 are iodine containing derivatives of thyronine which is a condensation product of two molecules of the amino acid tyrosine. Thyroxine (T 4 ); is 3, 5, 3´, 5´–tetraiodothyronine, while T 3 is 3, 5, 3´ triiodothyronine. The thyroid hormones are synthesized and stored in the thyroid follicles as part of thyroglobulin molecule—which is a glycoprotein synthesized by thyroid cells, MW 660 KDa, contains 10% sugar. Synthesis storage and release of thyroid hormones The major steps in the synthesis, storage, release, and interconversion of thyroid hormones are as follows: 1. uptake of iodide ion (I–) by the gland 2.oxidation of iodide and the iodination of tyrosyl groups of thyroglobulin 3. coupling of iodotyrosine residues by ether linkage to generate the iodothyronines 4. resorption of the thyroglobulin colloid from the lumen into the cell 5. proteolysis of thyroglobulin and the release of thyroxine and triiodothyronine into the blood 6. recycling of the iodine within the thyroid cell via de-iodination of mono- and diiodotyrosines and reuse of the I– 7. conversion of thyroxine (T4) to triiodothyronine (T3) in peripheral tissues as well as in the thyroid. 5

6. Synthesis, storage and release of thyroid hormones 6

7. Uptake of Iodide . The total body content of I 2 , obtained from food and water, is 30–50 mg. Iodine ingested in the diet reaches the circulation in the form of iodide ion (I − ). Under normal circumstances, the I − concentration in the blood is very low (0.2-0.4 μg/dL; ~15-30 nM), but the thyroid cells efficiently and actively transports the ion via a specific membrane-bound protein, called sodium-iodide symporter (NIS) Thyrotropin (thyroid-stimulating hormone [TSH]) stimulates NIS gene expression and promotes insertion of NIS protein into the membrane. The I 2 content of thyroid gland regulates the uptake mechanism: small store activating and large store inhibiting it(uptake mechanism). Note: NIS has been identified in many other tissues, including the salivary glands, gastric mucosa, small intestine, choroid plexus, skin, mammary gland, and also in the placenta, all of which maintain a concentration of iodide greater than that of the blood. The difference is, in these organs the iodine uptake is not stimulated by TSH. 7

8. 2. Oxidation and Iodination. Iodide trapped by follicular cells is carried across the apical membrane by another transporter termed ‘pendrin’ and oxidized by the membrane bound thyroid peroxidase enzyme to iodinium (I + ) ions or hypoiodous acid (HOI) or enzyme-linked hypoiodate (E-OI) with the help of H 2 O 2 . These forms of iodine combine avidly with tyrosil residues of thyroglobulin, apparently without any enzymatic intervention, to form monoiodotyrosine (MIT) and diiodotyrosine (DIT) while these residues are still attached to the thyroglobulin chains. 3. C oupling Pairs of iodinated tyrosil residues couple together to form T3 and T4. Normally much more T4 than T3 is formed, but during I 2 deficiency relatively more MIT is available and a greater proportion of T3 is formed. 8

9. Thus, more active hormone is generated with lesser amount of I 2 . Coupling is an oxidative reaction and is catalysed by the same thyroid peroxidase. Thyroglobulin is the most efficient protein, compared to other similar proteins, in supporting coupling by providing favourable spatial configuration to facilitate the reaction. Oxidation of iodide and coupling are both stimulated by TSH. 9

10. 4 . Resorption of the thyroglobulin colloid from the lumen into the cell Thyroglobulin containing iodinated tyrosil and thyronil residues is transported to the interior of the follicles and remains stored as thyroid colloid till it is taken back into the cells by endocytosis and broken down by lysosomal proteases. 5. Proteolysis and release of thyroid hormone T4 and T3 are synthesized and stored within thyroglobulin, proteolysis is an important part of the secretory process. This process is initiated by endocytosis of colloid from the follicular lumen at the apical surface of the cell, with the participation of a thyroglobulin receptor, megalin. This “ingested” thyroglobulin appears as intracellular colloid droplets, which apparently fuse with lysosomes containing proteolytic enzymes. It is generally believed that thyroglobulin must be completely broken down into its constituent amino acids for the hormones to be released. The uptake of colloid and proteolysis are stimulated by TSH, TSH enhances the degradation of thyroglobulin by increasing the activity of several thiol endopeptidases of the lysosomes. Normal human thyroid secretes 60–90 µg of T4 and 10–30 µg of T3 daily. 10

11. 7. Recycling of the iodine When thyroglobulin is hydrolysed, monoiodotyrosine and diiodotyrosine also are liberated but usually do not leave the thyroid; rather, they are selectively metabolized and the iodine, liberated as I−, is reincorporated into protein. The iodotyrosine deiodinase enzyme, DHAL1, is essential for conserving iodine and mutations of this gene identified are associated with goitrous hypothyroidism . 8. Peripheral conversion of (T4) to (T3) Peripheral tissues, especially liver and kidney, convert T4 to T3. About 30% of T4 secreted by thyroid undergoes this change and most of the T3 in plasma is derived from liver. Target tissues take up T3 from circulation for their metabolic need, except brain and pituitary which take up T4 and convert it to T3 within their own cells. 11

12. In contrast, removal of the iodine on position 5 of the inner ring produces the metabolically inactive 3,3′,5′-triiodothyronine (reverse T3, rT3) The T4 to T3 conversion is carried out by the enzyme iodothyronine deiodinase which exists in 3 forms (D1, D2, D3). 12

13. Transport of Thyroid Hormones in the Blood . Thyroid hormones are avidly bound to plasma proteins—only 0.03–0.08% of T4 and 0.2–0.5% of T3 are in the free form. Almost all protein bound iodine (PBI) in plasma is thyroid hormone, of which 90–95% is T4 and the rest T3. Binding occurs to 3 plasma proteins in the following decreasing order of affinity for T4: ( i ) Thyroxine binding globulin (TBG) (ii) Thyroxine binding prealbumin (transthyretin) (iii) Albumin Binding of thyroid hormones to plasma proteins protects the hormones from metabolism and excretion, resulting in their long half-lives in the circulation. Because of the high degree of binding of thyroid hormones to plasma proteins, changes in either the concentrations of these proteins or the binding affinity of the hormones for the proteins has major effects on the total serum hormone levels . 13

14. Metabolism and excretion Thyroxine(T4) is eliminated slowly from the body, with a t1/2 of 6-8 days. In hyperthyroidism, the t1/2 is shortened to 3-4 days, whereas in hypothyroidism it may be 9-10 days. T3, which is less avidly bound to protein, has a t1/2 of ~1 day. The liver is the major site of non- deiodinative degradation of thyroid hormones; T4 and T3 are conjugated with glucuronic and sulfuric acids through the phenolic hydroxyl group and excreted in the bile. 14

15. Regulation of secretion Thyrotropin or TSH is a glycoprotein hormone with α and β subunits analogous to those of the gonadotropins. TSH is secreted in a pulsatile manner and circadian pattern; its levels in the circulation are highest during sleep at night. TSH secretion is precisely controlled by the hypothalamic peptide thyrotropin-releasing hormone (TRH) and by the concentration of free thyroid hormones in the circulation. Extra thyroid hormone inhibits transcription of both the TRH gene and the genes encoding the α and β subunit of thyrotropin, which suppresses the secretion of TSH and causes the thyroid to become inactive and regress. 15

16. Somatostatin elaborated by hypothalamus inhibits not only GH and prolactin, but also TSH secretion from pituitary. The negative feedback by the thyroid hormones is exercised directly on the pituitary as well as through hypothalamus. The action of TRH on pituitary, the binding of TRH to its receptor, a GPCR, stimulates the Gq -PLC-IP3-Ca2+ pathway and activates PKC, ultimately stimulating the synthesis and release of TSH by the thyrotropes. TSH on thyroid cells is mediated by enhanced cAMP synthesis. 16

17. Action of thyroid hormone through Thyroid hormone crosses the cell membrane primarily via specific transporter protein like monocarboxylic acid transporter 8 (MCT8, SLC16A2). MCT8 transports T4 and T3 bidirectionally across the cell membrane. MCT8 is widely expressed, including in liver, heart, and brain. MCT8 mutations cause Allan-Herndon-Dudley syndrome, characterized by a severe neurological phenotype and abnormal circulating thyroid hormone levels. The organic anion transporter OATP1C1 preferentially transports T4 rather than T3, is highly expressed in brain capillaries. Binding of thyroid hormone : Thyroid hormone action is mediated largely by the binding of T3 to thyroid hormone receptors (TRs), which are members of the nuclear receptor superfamily (steroid hormones, vitamin D, retinoic acid,) 17

18. The TRs have the classic nuclear receptor structure consisting of an amino terminal domain, a centrally located zinc finger DNA binding domain, and a ligand binding domain that occupies the carboxyl terminal half of the protein. T3 binds to TRs with ~10-fold greater affinity than does T4, The transcription of most target genes is repressed by unliganded TRs and induced following the binding of T3. There are two genes that encode TRs, THRA and THRB . THRA encodes the receptor TRα1 and TRα2 . TRα1 plays a very important role in the regulation of heart rate, body temperature, skeletal muscle function, and the development of bone and small intestine. Alternative splicing of the TRα primary transcript results in the production of TRα2, which does not bind T3 because it lacks part of the ligand-binding domain. The THRB gene has two promoters that lead to the production of TRβ1 and TRβ2. TRβ1 is ubiquitous, whereas TRβ2 has a highly restricted pattern of expression. Role of TRβ1 in liver metabolism and TRβ2 in the negative feedback by T3 on hypothalamic TRH and pituitary TSH. TRβ2 also is important in the development of cones in the retina and in inner ear development. 18

19. CLINICAL EFFECTS OF THYROID HORMONES The actions of T4 and T3 are qualitatively similar, they affect the function of practically every body cell. 19

20. Growth and development : The most dramatic example of thyroid hormone action is amphibian metamorphosis, The function is exerted through a critical control of protein synthesis in the translation of the genetic code. Thyroid hormone plays a critical role in brain development. The absence of thyroid hormone during the period of active neurogenesis (up to 6 months postpartum) leads to irreversible mental retardation (cretinism) and is accompanied by multiple morphological alterations in the brain. Retardation and nervous deficit may be because of reduce of axonal and dendritic complexation, synapse formation and impaired myelination. T3 induces the expression of a number of genes that could be important in normal brain development, like, Myelin basic protein, a major component of myelin, is induced by T3 during development, RC3/neurogranin, a protein involved in synaptic plasticity, also is induced by T3. 20

21. Congenital deficiency of T4 and T3 resulting in cretinism. The milestones of development are delayed and practically every organ and tissue of the body suffers. The greatest sufferer, is the nervous system. In adult hypothyroidism also, intelligence is impaired and movements are slow. 2. Intermediary metabolism (intracellular metabolism) Thyroid hormones have marked effect on lipid, carbohydrate and protein metabolism. Lipid: T4 and T3 indirectly enhance lipolysis by potentiating the action of catecholamines and other lipolytic hormones, by suppressing a phosphodiesterase → increased cAMP. As a result, plasma free fatty acid levels are elevated. Lipogenesis is also stimulated. All phases of cholesterol metabolism are accelerated, but its conversion to bile acids dominates. Thus, hyperthyroidism is characterized by hypocholesterolaemia. LDL levels in blood are reduced. 21

22. Carbohydrate: Carbohydrate metabolism is also stimulated. Though utilization of sugar by tissues is increased (mainly secondary to increased BMR), glycogenolysis and gluconeogenesis in liver as well as faster absorption of glucose from intestines more than compensate it → hyperglycaemia and diabetic-like state with insulin resistance occur in hyperthyroidism. Protein: Synthesis of certain proteins is increased, but the overall effect of T3 is catabolic— increased amounts of protein being used as energy source. Prolonged action results in negative nitrogen balance and tissue wasting. Weight loss is a feature of hyperthyroidism. T3, T4 in low concentrations inhibit mucoprotein synthesis which so characteristically accumulates in myxoedema. 22

23. 3 . Calorigenesis : T3 and T4 increase BMR by stimulation of cellular metabolism and resetting of the energystat. This is important for maintaining body temperature. However, metabolic rate in brain, gonads, uterus, spleen and lymph nodes is not significantly affected. 4. CVS : Increase heart rate Increase force of cardiac contractions Increase stroke volume Increase Cardiac output Up-regulate catecholamine receptor By Triiodothyronine directly regulates myocardial gene expression primarily through TRα1, which is expressed at a higher level in cardiomyocytes than TRβ. T3 shortens diastolic relaxation by inducing expression of the sarcoplasmic reticulum ATPase SERCa2. inducing expression of the ryanodine channel. A lso appears to have a direct non-genomic vasodilating effect on vascular smooth muscle. Myocardial O2 consumption can be markedly reduced by induction of hypothyroidism. 23

24. 5 . Nervous system: Critical for normal CNS neuronal development. Enhances wakefulness and alertness Enhances memory and learning capacity Required for normal emotional tone Increase speed and amplitude of peripheral nerve reflexes. 6. GIT: Propulsive activity of gut is increased by T3/T4. Hypothyroid patients are often constipated, while diarrhoea is common in hyperthyroidism. 7. Skeletal muscle: Muscles are flabby and weak in myxoedema, while thyrotoxicosis produces increased muscle tone, tremor and weakness due to myopathy. 8. Renal system: Increase blood flow Increase glomerular filtration rate (GFR) 24

25. 9 . Haemopoiesis: Hypothyroid patients suffer from some degree of anaemia which is restored only by T4 treatment. Thus, T4 appears to be facilitatory to erythropoiesis. Increase RBC mass Increase oxygen dissociation from haemoglobin. 10. Reproduction: Required for normal follicular development and ovulation in the female Required for the normal maintenance of pregnancy Required for normal spermatogenesis in the male Fertility is impaired in hypothyroidism and women suffer from oligomenorrhoea. 25

26. 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 which belongs to the steroid and retinoid superfamily of intracellular receptors. The TR resides in the nucleus even in the unliganded inactive state. It is bound to the ‘thyroid hormone response element’ (TRE) of the target genes along with corepressors. This keeps gene transcription suppressed. When T3 binds to the ligand-binding domain of TR, it heterodimerizes with retinoid X receptor (RXR) 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. The expression of certain genes is repressed by T3 26

27. Thyroid hypofunction Hypothyroidism, is the most common disorder of thyroid function. wo rldwide, hypothyroidism resulting from iodine deficiency remains an common problem. In non-endemic areas where iodine is sufficient, chronic autoimmune thyroiditis accounts for most cases. (This disorder is characterized by high levels of circulating antibodies directed against thyroid peroxidase and, less commonly, against thyroglobulin, worsening the hypothyroidism.) These condition are example for primary hypothyroidism. ( failure of the thyroid gland itself ). Central hypothyroidism occurs much less often and results from diminished stimulation of the thyroid by TSH because of pituitary failure (secondary hypothyroidism) or hypothalamic failure (tertiary hypothyroidism). Hypothyroidism present at birth (congenital hypothyroidism or cretinism) is the most common preventable cause of mental retardation in the world. Diagnosis and early intervention with thyroid hormone replacement prevent the development of cretinism. 27

28. Common symptoms of hypothyroidism include fatigue, lethargy, cold intolerance, mental slowness, depression, dry skin, constipation, mild weight gain, fluid retention, muscle aches and stiffness, irregular menses, and infertility. Common signs include goiter, bradycardia, delayed relaxation phase of the deep tendon reflexes, cool and dry skin, hypertension, nonpitting edema, and facial puffiness. Deficiency of thyroid hormone during the first few months of life causes feeding problems, failure to thrive, constipation, and sleepiness. Retardation of mental development is irreversible if not treated promptly. Childhood hypothyroidism impairs linear growth and bone maturation. Diagnosis requires the finding of an elevated serum TSH or, in cases of central hypothyroidism, a decreased serum free T4. 28

29. Thyroid Hyperfunction. Thyrotoxicosis is a condition caused by elevated concentrations of circulating free thyroid hormones. Increased thyroid hormone production is the most common cause, with the common link of TSH receptor stimulation and increased iodine uptake by the thyroid gland. ( shown by the measurement of the percentage uptake of 123 I or 131 I in a 24-hour radioactive iodine uptake (RAIU) test. ) S ubclinical hyperthyroidism is defined as those with a subnormal serum TSH and normal concentrations of T4 and T3. Graves’ disease is an autoimmune disorder characterized by increased thyroid hormone production, diffuse goiter, by immunoglobulin (Ig)G antibodies that bind to and activate the TSH receptor. S igns and symptoms of thyrotoxicosis is excessive production of heat, increased motor activity, and increased sensitivity to catecholamines produced by the sympathetic nervous system. 29

30. The skin is flushed, warm, and moist; the muscles are weak and tremulous; the heart rate is rapid, the heartbeat is forceful, and the arterial pulses are prominent and bounding. Increased expenditure of energy gives rise to increased appetite and, if intake is insufficient, to loss of weight. There also may be insomnia, difficulty in remaining still, anxiety and apprehension, intolerance to heat, and increased frequency of bowel movements. Angina, arrhythmias, and heart failure may be present in older patients. Patients with long-standing undiagnosed or undertreated thyrotoxicosis may develop osteoporosis due to increased bone turnover. 30

31. Therapeutic Uses of Thyroid Hormone The major indications for the therapeutic use of thyroid hormone are for hormone replacement therapy in patients with hypothyroidism and for TSH suppression therapy in patients with thyroid cancer. Thyroid Hormone Preparations. Synthetic preparations of the sodium salts of the natural isomers of the thyroid hormones are available and widely used for thyroid hormone therapy. Levothyroxine. Levothyroxine sodium (L-T4), is available in tablets and as a lyophilized powder for injection. Absorption of thyroxine occurs in the stomach and small intestine and is incomplete (~80% of the dose is absorbed). Absorption is slightly increased when the hormone is taken on an empty stomach. In situations where patients cannot take oral medications or where intestinal absorption is in question, levothyroxine may be given intravenously 31

32. Liothyronine. Liothyronine sodium (L-T3) is the salt of triiodothyronine and is available in tablets and in an injectable form. Liothyronine absorption is nearly 100% with peak serum levels 2-4 hours following oral ingestion. Liothyronine may be used occasionally when a more rapid onset of action is desired such as in the rare presentation of myxoedema coma or if rapid termination of action is desired such as when preparing a thyroid cancer patient for 131 I therapy. Liothyronine is less desirable for chronic replacement therapy due to the requirement for more frequent dosing (plasma t1/2 is small ), higher cost, and transient elevations of serum T3 concentrations above the normal range. Clinically, l-thyroxine is preferred for all indications over liothyronine because of more sustained and uniform action as well as lower risk of cardiac arrhythmias. 32

33. Uses Thyroid Hormone Replacement Therapy in Hypothyroidism. The goal of therapy is to normalize the serum TSH (in primary hypothyroidism) or free T4 (in secondary or tertiary hypothyroidism) and to relieve symptoms of hypothyroidism. A patient with mild primary hypothyroidism will achieve a normal TSH with substantially less than a full replacement dose, but as the endogenous thyroid function declines, the dose will need to be increased. For individuals having a risk of heart problems and people above age of 50 should be administer with lower daily dose of levothyroxine sodium (12.5-50 μg per day). Subclinical Hypothyroidism Subclinical hypothyroidism is the presence of a mildly elevated serum TSH concentration and a normal free T4 without obvious symptoms . 33

34. 2. Cretinism (Congenital Hypothyroidism) It is due to failure of thyroid development or a defect in hormone synthesis (sporadic cretinism) or due to extreme iodine deficiency (endemic cretinism). It is usually detected during infancy or childhood; but screening of neonates is the best preventive strategy. Treatment with thyroxine (8–12 µg/kg) daily should be started as early as possible, because mental retardation that has already ensued is only partially reversible. 3. Hypothyroidism During Pregnancy The dose of levothyroxine in the hypothyroid patient who becomes pregnant usually needs to be increased because due to the increased serum concentration of TBG induced by estrogen, the expression of type 3 deiodinase by the placenta, and the small amount of transplacental passage of levothyroxine from mother to foetus. Over hypothyroidism during pregnancy is associated with fetal distress and impaired psychoneural development in the progeny . 34

35. 4. Adult hypothyroidism (Myxoedema) This is one of the commonest endocrine disorders which develops as a consequence of autoimmune thyroiditis or thyroidectomy; It may accompany simple goiter if iodine deficiency is severe. Antibodies against thyroid peroxidase or thyroglobulin are responsible for majority of cases of adult hypothyroidism. Important drugs that can cause hypothyroidism are 131I, iodides, lithium and amiodarone. Treatment with T4 is most gratifying. It is often wise to start with a low dose—50 µg of l-thyroxine daily and increase every 2–3 weeks to an optimum of 100–200 µg/day 5. Myxedema Coma . Myxedema coma is a rare syndrome that represents the extreme expression of severe, longstanding hypothyroidism. It is a medical emergency, and even with early diagnosis and treatment, the mortality rate can be as high as 60%. Common precipitating factors include pulmonary infections, cerebrovascular accidents, and congestive heart failure. Drug of choice is l-thyroxine (T4) 200–500 μg i.v. followed by 100 μg i.v. OD till oral therapy can be instituted . 35

36. 6 . Nontoxic goiter It may be endemic or sporadic. Endemic is due to iodine deficiency which may be accentuated by factors present in water (excess calcium), food or milk (goitrin, thiocyanates). A defect in hormone synthesis may be responsible for sporadic cases. In both types, deficient production of thyroid hormone leads to excess TSH → thyroid enlarges, more efficient trapping of iodide occurs and probably greater proportion of T3 is synthesized → enough hormone to meet peripheral demands is produced so that the patient is clinically euthyroid. Thus, treatment with T4 is in fact replacement therapy. 7. Thyroid Cancer . The mainstays of therapy for well differentiated thyroid cancer (papillary, follicular) are surgical thyroidectomy, radioiodine, and levothyroxine to suppress TSH. The rationale for TSH suppression is that TSH is a growth factor for these cancers. 36

37. 8. Thyroid nodule Nodular thyroid disease is the most common endocrinopathy. Like other forms of thyroid disease, nodules are more frequent in women. Exposure to ionizing radiation, especially in childhood, increases the rate of nodule development. Thyroid nodules usually are asymptomatic, although they can cause neck discomfort, dysphagia, and a choking sensation. TSH suppressive therapy with levothyroxine sometimes is prescribed for the patient with a benign thyroid nodule and a normal serum TSH. 9. Empirical uses T4 has been sometimes used in the following conditions without any rationale; response is unpredictable. Refractory anaemias, Mental depression, Menstrual disorders, infertility not corrected by usual treatment, Chronic/non-healing ulcers, Obstinate constipation. 37

38. Novel Thyroid Hormone Analogues and Their Potential Therapeutic Applications Identification of thyroid hormone receptor isoforms and differences in their level of expression has led to the development of isoform-specific thyroid hormone. TRβ Agonists Thyroid hormone has been known to reduce serum cholesterol via effects on hepatic metabolism, but T4 and T3 are not useful as hypocholesterolemic drugs due to the adverse effects of thyrotoxicosis on the heart and other organs . Liver primarily expresses TRβ, whereas the heart primarily expresses TRα. T3 analogues that have a higher affinity for TRβ than TRα and that accumulate preferentially in the liver have been shown to lower serum cholesterol without causing tachycardia in humans and animals. 38

39. Thyroid Hormone Receptor α Agonists . Because TRα1 is expressed preferentially in the heart, specific agonists might find use in the management of heart failure or bradycardia. Thyromimetics with Altered Entry into Cells. Monocarboxylate transporter 8 (MCT8) transports T3 into cells and is highly expressed in the brain. Patients with MCT8 mutations have the Allan-Herndon Dudley syndrome with severe neurological impairment. A thyromimetic that can enter the brain in an MCT8-independent manner could be valuable in treating these patients. The thyroid hormone analogue 3,5- diiodothyropropionic acid (DITPA) has this property in mice. Thyroid Hormone Receptor Antagonists . In principle, thyroid hormone receptor antagonists could be useful therapeutics in the medical management of thyrotoxicosis, and possibly even in the management of cardiac arrhythmias. 39

40. THYROID INHIBITORS A number of compounds are capable of interfering, directly or indirectly, with the synthesis, release, or action of thyroid hormones. CLASSIFICATION 1. Inhibit hormone synthesis (Antithyroid drugs) Propylthiouracil, Methimazole, Carbimazole. 2. Inhibit iodide trapping (Ionic inhibitors) Thiocyanates (–SCN), Perchlorates (–ClO4), Nitrates (–NO3). 3. Inhibit hormone release: Iodine, Iodides of Na and K, Organic iodide. 4. Destroy thyroid tissue Radioactive iodine (131I, 125I, 123I) Adjuvant therapy with drugs that have no specific effects on thyroid hormone synthesis is useful in controlling the peripheral manifestations of thyrotoxicosis. These drugs include inhibitors of the peripheral deiodination of thyroxine to the active hormone, triiodothyronine, β adrenergic receptor antagonists, and Ca2+ channel blockers. 40

41. ANTITHYROID DRUGS (Thioamides) By convention, only the hormone synthesis inhibitors are called antithyroid drugs. Thiourea derivatives were found to produce goiter and hypothyroidism in rats in the 1940s. Open chain compounds were found to be toxic. Subsequently, methyl and propyl thiouracil and thioimidazole derivatives methimazole and carbimazole were found to be safe and effective. 41

42. Mechanism of action Antithyroid drugs bind to the thyroid peroxidase and prevent oxidation of iodide/ iodotyrosyl residues, thereby; ( i ) Inhibit iodination of tyrosine residues in thyroglobulin (ii) Inhibit coupling of iodotyrosine residues to form T3 and T4. Action (ii) has been observed at lower concentration of antithyroid drugs than action ( i ). Thyroid colloid is depleted over time and blood levels of T3/T4 are progressively lowered. Thioamides do not interfere with trapping of iodide and do not modify the action of T3 and T4 on peripheral tissues or on pituitary. Propylthiouracil also inhibits peripheral conversion of T4 to T3 by D1 type of 5’DI, but not by D2 type. This may partly contribute to its antithyroid effects. Methimazole and carbimazole do not have this action 42

43. Pharmacokinetics All antithyroid drugs are quickly absorbed orally, widely distributed in the body, enter milk and cross placenta; are metabolized in liver and excreted in urine primarily as metabolites. All are concentrated in thyroid: intrathyroid t½ is longer: effect of a single dose lasts longer than would be expected from the plasma t½. Carbimazole acts largely by getting converted to methimazole in the body and is longer acting than propythiouracil. Adverse effects Hypothyroidism and goiter can occur due to overtreatment, but is reversible on stopping the drug. It is indicated by enlargement of thyroid, and is due to excess TSH production. Goiter does not develop with appropriate doses which restore T4 concentration to normal so that feedback TSH inhibition is maintained. Important side effects are: g.i. intolerance, skin rashes and joint pain. Loss or greying of hair, loss of taste, fever and liver damage are infrequent. A rare but serious adverse effect is agranulocytosis (1 in 500 to 1000 cases); It is mostly reversible. There is partial cross reactivity between propylthiouracil and carbimazole. Carbimazole is more commonly used in India. Propylthiouracil (600–900 mg/day) may be preferred in thyroid storm for its inhibitory action on peripheral conversion of T4 to more active T3. It is also used in patients developing adverse effects with carbimazole. 43

44. Use Antithyroid drugs control thyrotoxicosis in both Graves’ disease and toxic nodular goiter. Clinical improvement starts after 1–2 weeks or more. Thyrotoxicosis: life long Pre operatively to make euthyroid Advantage Less surgical complication If hypothyroidism develops then therapy can be stopped normal function Disadvantage Long term therapy, Not practicable in unconscious patient, Toxicity specially in pregnancy . 44

45. 2. IONIC INHIBITORS Certain monovalent anions inhibit iodide trapping by NIS into the thyroid probably because of similar hydrated ionic size—T4/T3 cannot be synthesized. Perchlorate, Thiocyanate - block uptake of iodine by the gland through competitive inhibition of the iodide transport mechanism. Perchlorate is 10 times more potent than thiocyanate in blocking NIS, while nitrate is very weak. They are toxic and not clinically used now. Thiocyanates: can cause liver, kidney, bone marrow and brain toxicity. Perchlorates: produce rashes, fever, aplastic anaemia, agranulocytosis . 3. IODINE AND IODIDES Though iodine is a constituent of thyroid hormones, it is the fastest acting thyroid inhibitor. The thyroid status starts returning to normal at a rate commensurate with complete stoppage of hormone release from the gland. 45

46. All facets of thyroid function seem to be affected, but the most important action is inhibition of hormone release ‘thyroid constipation’. Endocytosis of colloid and proteolysis of thyroglobulin comes to a halt. The mechanism of action Excess iodide inhibits its own transport into thyroid cells by interfering with expression of NIS on the cell membrane. In addition, it attenuates TSH and cAMP induced thyroid stimulation. Excess iodide rapidly and briefly interferes with iodination of tyrosyl and thyronil residues of thyroglobulin (probably by altering redox potential of thyroid cells) resulting in reduced T3/T4 synthesis (Wolff- Chaikoff effect). However, within a few days, the gland ‘escapes’ from this effect and hormone synthesis resumes. Use: Thyrotoxic crisis Preparation for thyroidectomy ( decrease the size & vascularity of the hyperplastic gland) Prophylaxis in endemic goiter 46

47. 47 Adverse effect: Acute: swelling of lip, eye lid, face, angineurotic edema of larynx, fever, joint pain, lymphadenopathy, thrombocytopenia Chronic: ulceration of mucous membrane of mouth, salivation, lacrimation, burning sensation in the mouth, rhinorrhoea, GI intolerance. RADIOACTIVE IODINE The stable isotope of iodine is 127 I. Its radioactive isotope of medicinal importance is: 131 I: physical half-life 8 days. The chemical behaviour of 131 I is similar to the stable isotope. 131 I emits X-rays as well as β particles. The 127 I useful in tracer studies, because they traverse the tissues and can be monitored by a counter, while 131 I are utilized for their destructive effect on thyroid cells. 131 I is concentrated by thyroid, incorporated in colloid—emits radiation from within the follicles. The β particles penetrate only 0.5–2 mm of tissue.

48. The thyroid follicular cells are affected from within, undergo pyknosis and necrosis followed by fibrosis when a sufficiently large dose has been administered, without damage to neighbouring tissues. With carefully selected doses, it is possible to achieve partial ablation of thyroid. Radioactive iodine is administered as sodium salt of 131 I dissolved in water and taken orally. Use Diagnostic purpose à 25-100μ curies in thyroid function test Therapeutic use à 3-6 milli curies in toxic nodular goiter, graves disease, thyroid Cancer. 48

49. Advantage: Easy administration , Effectiveness , Low expense , Absence of pain , In patient who have indication of operation but want to avoid operation , Once treated no chance of recurrence. Disadvantage: Hypothyroidism , Latent period of getting response (8-12 weeks) , Contraindicated during pregnancy Not suitable for young patients: they are more likely to develop hypothyroidism later and would then require life-long T4 treatment . Adjuncts to Antithyroid Therapy Hyperthyroidism resembles sympathetic overactivity Propranolol, will control tachycardia, hypertension, and atrial fibrillation Diltiazem, can control tachycardia in patients in whom beta-blockers are contraindicated Barbiturates accelerate T 4 breakdown (by enzyme induction) and are also sedative 49

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51. Why Do Thyroid Disorders Affect Women More Often Than Men? Although millions of men experience thyroid dysfunction, women are 10 times more likely to have a thyroid imbalance. The reasons are uncertain, but according to integrative physician and gynecologists, the phenomenon is linked to female hormones, since estrogen dominance has been implicated as a contributing factor. The interaction between the thyroid and a woman’s reproductive hormones is significant: Hypothyroidism can lead to infertility, miscarriage, osteoporosis, endometriosis, irregular cycles and difficulty in menopause. “Women are most vulnerable after pregnancy and during perimenopause and menopause. — a drop in reproductive hormones that often triggers hypothyroidism — is the main cause of fatigue, weight gain, and depression.” A woman’s hormonal matrix is a bit of a chicken-and-egg scenario. Boosting thyroid function has a beneficial effect on ovaries and adrenals, but the opposite is also true, i.e.. Any changes in ovaries and adrenals leads to thyroid imbalance. Estrogen dominance can contribute to hypothyroid conditions, especially in menopause. men aren’t entirely immune to hormonally triggered hypothyroidism: “Low testosterone often accompanies low thyroid in both men and women.” 51

52. Reference Goodman & Gilman’s The Pharmacological Basis of THERAPEUTICS. Essentials of Medical Pharmacology , KD TRIPATHI . Basic & Clinical Pharmacology , Katzung , RANG AND DALE’S Pharmacology . 52

53. Recently asked questions Explain the mechanism of action and pathological role of thyroid hormone? Explain the molecular mechanism of thyroid hormone. Explain the uses of thyroid hormones Explain the classification? And mechanism of action of anti-thyroid drugs? Write a note on synthesis, storage and release of thyroid hormone. 53

54. THANK YOU 54