Endocrine System, Intro. (Pituitry Hormones & Thyroid Hormones)- ppt by Baqir Naqvi.pptx

Endocrine System Pharmacology, Intro. (Pituitry Hormones & Thyroid Hormones)- ppt ...........

1. Endocrine System (Pituitary & Thyroid Hormones) (Pharmacology & Therapeutics-1) Lecture By Dr. Syed Baqir Raza Naqvi (BSc, Pharm-D, M. Phil-Pharmacology) Nazar College of Pharmacy DAKSON Institute of Health Sciences, Islamabad 1

2. Endocrine System Human body contains two major communication systems including Endocrine System (through hormones) and Nervous System (through nerve impulses) Basic Function of ES: Homeostatic control mechanisms. Endocrine System consists of Endocrine glands that secrete hormones. These are also called ductless glands . Hormones:   ” Chemical messengers that enter the blood, released by endocrine glands to the target cells for that hormone .” 2

3. Difference b/w Nervous & Endocrine Systems 3

4. Nervous System Endocrine System The neuroendocrine system is controlled by the pituitary and hypothalamus and coordinates body functions by transmitting messages between individual cells and tissues. The endocrine system releases hormones into the bloodstream, which carries chemical messengers to target cells throughout the body. Nervous system communicates locally through electrical impulses and neurotransmitters, directed through neurons to other neurons or to specific target organs, such as muscle or glands. Nerve impulses generally act within milliseconds . Hormones have a much broader range of response time than do nerve impulses, requiring from seconds to days, or longer, to cause a response that may last for weeks or months. 4

5. Overview of Endocrine Glands 5

6. Hypothalamic & Pituitary  Hormones Hypothalamus & Pituitary glands are involved in; 1. Neuroendocrine Control 2. Co-ordination . Drugs can agonize or antagonize the effects of hypothalamic and pituitary hormones by following ways; 6

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8. Adrenocorticotropic hormone (ACTH) is produced by the pituitary gland . Its key function is to stimulate the production and release of cortisol from the cortex (outer part) of the adrenal gland . CRH (Corticotrophin releasing Hormone) is responsible for synthesis of ACTH . ACTH is released from the pituitary in pulses with diurnal rhythm (circadian rhythm) , having highest concentration in the early morning and lowest in the late evening. Stress stimulates its secretion , whereas cortisol acting via negative feedback suppresses its release. 1. Adrenocorticotropic hormone (ACTH) 8

9. Functions of Cortisol 9

10. Mechanism of Action ACTH targets on Adrenal Cortex cause activation of G-protein coupled receptors and results in increased production of cAMP which stimulate rate-limiting step, in the adreno-corticosteroid synthetic pathway (cholesterol to pregnenolone ). This pathway ends with the synthesis and release of the adreno-corticosteroids and the adrenal androgens. 10

11. Therapeutic Uses For diagnostic purposes like to distinguish between primary adrenal insufficiency (Addison disease, associated with adrenal atrophy) and secondary adrenal insufficiency (caused by the inadequate secretion of ACTH by the pituitary). Adverse effects Short-term use of ACTH for diagnostic purposes is usually well tolerated. With longer use, toxicities are similar to those of glucocorticoids and include hypertension, peripheral edema, hypokalemia, emotional disturbances, and increased risk of infection . 11

12. Somatotropin is a large polypeptide that is released by the anterior pituitary in response to growth hormone ( GHR)- releasing hormone produced by the hypothalamus. Secretion of GH is inhibited by another pituitary hormone, somatostatin . Functions Protein synthesis, cell proliferation and Bone growth . Somatotropin is synthetic Human GH. Pharmacokinetics Half life= 10-20 min SC. Administration 6-7 weeks. 2. Growth Hormone GH (Somatotropin) 12

13. Mechanism of Action Some of the physiological effects are mediated by direct action on target cells, and few effects mediated by Somatomedins (insulin-like growth factors I and II ( IGF-I and IGF-II). GH is released in a pulsatile manner, with the highest levels occurring during sleep. With increasing age, GH secretion decreases, accompanied by a decrease in lean muscle mass. Synthetic human GH ( somatotropin is produced using recombinant DNA technology. 13

14. Functions of GH 14

15. Functions of Growth Hormone 15

16. 1. On metabolism  On P rotein M etabolism   Increasing amino acid transport through cell membrane.  Increasing RNA translation . Increasing transcription of DNA to RNA. Decreasing catabolism of protein . Promoting anabolism of proteins indirectly.   On Fat M etabolism   GH mobilizes fats from adipose tissue . So, the concentration of fatty acids increases in the body fluids.  On C arbohydrate M etabolism   Decrease in the peripheral utilization of glucose for the production of energy. Increase in deposition of glycogen in cells . Decrease in up take of glucose by the cells. Diabetogenic effect of GH. GH increases the synthesis of proteins, mobilization of lipids and conservation of carbohydrates.   16

17.   2- On B ones In embryonic stage, GH is responsible for the differentiation and development of bone cells.  In bones, GH increases ;  i. Synthesis & deposition of proteins by chondrocytes.   ii. Multiplication of chondrocytes and osteogenic cells by enhancing the intestinal calcium absorption.   iii. Formation of new bones by converting chondrocytes into osteogenic cells. iv. Availability of calcium for mineralization of bone matrix. 17

18. Therapeutic Uses of GH Prader-Willi Syndrome It is an autosomal dominant genetic disease associated with growth failure , obesity, and carbohydrate intolerance of the bones of the rib cage. Noonan syndrome It involves unusual facial characteristics, short stature, heart defects present at birth , bleeding problems, developmental delays, mal formations. 18

19. Turner Syndrome Turner syndrome is a female-only genetic disorder that affects about 1 in every 2,000 baby girls . A girl with Turner syndrome only has 1 normal X chromosome , rather than the usual 2 . This chromosome variation happens randomly when the baby is conceived in the womb . It is not linked to the mother's age. Idiopathic short stature (ISS) This is a heterogeneous population that has in common no identifiable cause of the short stature. 19

20. GH Actions in Adults GH administered to adults increases lean body mass, bone density , and skin thickness , whereas adipose tissue is decreased. GH is an “ anti-aging ” Hormone . So it is off label used by older individuals and by athletes to enhance their performance. R/A: Somatropin is administered by subcutaneous or IM injection. Half Life: Although the half-life of GH is short (approximately 25 minutes), it induces the release of IGF-1 from the liver, which is responsible for subsequent GH-like actions. 20

21. Adverse effects Adverse effects of somatotropin include; P ain at the injection site , edema , arthralgia , myalgia, flu-like symptoms, and an increased risk of diabetes. Somatotropin should not be used in pediatric patients with closed epiphysis , patients with diabetic retinopathy, or obese patients with Prader-Willi syndrome. 21

22. 3. Somatostatin ( Growth hormone–inhibiting hormone) Localities of Smatostatin Present in the ; i )- H ypothalamus . ii)- Pancreas. iii)- G astrointestinal tract. General Functions of Somatostatin It inhibits the release of GH, TSH, glucagon, insulin, and gastrin. Somatostatin binds to distinct receptors, SSTR2 and SSTR5, which suppress GH and thyroid-stimulating hormone release. Octreotide It is Smatostatin analog, more prone to i nhibit GH , no effect on other hormones as much. 22

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24. Octreotide Useful in the treatment of acromegaly caused by hormone-secreting tumors and diarrhea associated with tumors. Administration 50–200 mcg given subcutaneously every 8 hours. Adverse effects A bdominal pain, flatulence, nausea, and steatorrhea. Lantreotide Another Long-acting octapeptide , somatostatin analog, was approved by the FDA in 2007 for treatment of acromegaly. Pegvisomant GH receptor antagonist. 24

25. 4. Gonadotropin-releasing hormone (GnRH) Pulsatile secretion of gonadotropin-releasing hormone (GnRH) from the hypothalamus is essential for the release of the gonadotropins follicle- stimulating hormone (FSH) and luteinizing hormone (LH) from the anterior pituitary. GnRH Synthetic analogs Leuprolide , Goserelin , Nafarelin and Histrelin. 25

26. 26 In Male In Female

27. Therapeutic Uses GnRH Analogs Used in Prostatic cancer , endometriosis , and precocious puberty . Contraindications Contraindicated in pregnancy & breast feeding due to depression, ovarian cyst, diminished libido, sweating and hot flushes. In male cause elevation in testosterone which results in bone pain; hot flushes, edema and gynecomastia. 27

28. i . Follicle Stimulating Hormone (FSH) In males, FSH acts along with testosterone and accelerates the process of spermatogenesis . In females FSH stimulates the theca cells of follicle and causes secretion of estrogen. 28

29. ii. Luteinizing Hormone (LH) In males, LH is known as interstitial cell-stimulating hormone (ICSH) because it stimulates the interstitial cells of Leydig in testes. This hormone is essential for the secretion of testosterone from Leydig cells. In females, LH Induces synthesis of androgens from theca cells of growing follicle and is responsible for ovulation . 29

30. Synthetic Gonadotropin analogs Menotropin The first commercial gonadotropin product was extracted from the urine of postmenopausal women , which contains a substance with FSH-like properties (but with 4% of the potency of FSH) and an LH-like substance . This purified extract of FSH and LH is known as menotropins , or human menopausal gonadotropins (hMG). Folitropin 3 Purified forms; Urofolitropin ( uFSH )  Two DNA recombinant forms of FSH ( rFSH ) are also available ; folitropin alfa and folitropin beta. 30

31. Chorio -gonadotropin alfa ( rhCG ) is a recombinant form of hCG , it is a placental hormone that is excreted in the urine of pregnant women. Administration: Injected via the IM or subcutaneous route. Clinical uses: hMG or FSH over a period of 5 to 12 days causes ovarian follicular growth and maturation , and with subsequent injection of hCG , ovulation occurs. In men who are lacking gonadotropins, treatment with hCG causes external sexual maturation , and with the subsequent injection of hMG or folitropin , spermatogenesis occurs. Adverse effects In females= ovarian enlargement, hypovolemia, multiple pregnancies. In males= gynecomastia. 31

32. 6. Prolactin Prolactin is a peptide hormone that is secreted by the anterior pituitary . Functions Stimulate & maintain lactation while decline in sexual drive & reproductive function. M.O.A The PRH hormone binds to a trans membrane receptor (JAK/STAT superfamily) which activates a tyrosine kinase to promote tyrosine phosphorylation and gene activation . it mediate prolactin-induced mammary epithelial cell differentiation .  D2 agonists are used to inhibit excessive secretion of prolactin in hyperprolactinemic conditions.   For example, ( Bromocriptine & Cabergoline (Ergot Alkaloids), Quinagolide ( Non ergot origin ). 32

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34. Hyperprolactinemia produces a syndrome of amenorrhea and galactorrhea in women , and loss of libido and infertility in men . In the case of large tumors ( macro-adenomas ), it can be associated with symptoms of a pituitary mass, including visual changes due to compression of the optic nerves. The hypogonadism and infertility associated with hyperprolactinemia result from inhibition of GnRH release. 34

35. POSTERIOR PITUITARY HORMONES H ormones of the posterior lobe, are not regulated by releasing hormones (RH) . Instead, they are synthesized in the hypothalamus, transported to the posterior pituitary, and released in response to specific physiologic signals, such as high plasma osmolarity. R/A: Both hormones are administered intravenously . t 1/2 : They have very short half-lives . These includes; i ). Oxytocin. i i). Vasopressin. 35

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37. i . Oxytocin Oxytocin is used in obstetrics to stimulate uterine contraction and induce labor . Oxytocin also causes milk ejection by contracting the myoepithelial cells around the mammary alveoli . Synthetic form is obtained from animal source to induce uterine contraction or reinforced labor. Only used in obstetrics. I/V administration, I/M for control of postpartum bleeding. Adverse effects: Hypertension, uterine rupture, water retention, and fetal death Oxytocin antagonist: Atosiban ( For preterm labor- tocolysis ). 37

38. ii. VASOPRESSIN (ANTIDIURETIC HORMONE, ADH) Antidiuretic & Vasopressor effect Deficiency of Vasopressor= diabetes insipidus . R/A; Vasopressin is administered by I/V or I/M injection . t1/2 of vasopressin is 15 minutes , Metabolism: with renal and hepatic metabolism via reduction of the disulfide bond and peptide cleavage. Mechanism of Action Vasopressin activates two subtypes of G protein-coupled receptors. V1 receptors are found on vascular smooth muscle cells and mediate vasoconstriction. V2 receptors are found on renal tubule cells and reduce diuresis through increased water permeability and water resorption in the collecting tubules. 38

39. VASOPRESSIN ANTAGONISTS i ). Conivaptan ii). Tolvaptan These are used to treat hypernatremia and acute heart failure due to elevated concentration of vasopressin. 39

40. THYROID HORMONES Thyroid gland facilitates normal growth and maturation by maintaining a level of metabolism in the tissues that is necessary for their normal functions. There are two major thyroid hormones; 40 For example

41. Hypothyroidism Inadequate secretion or less secretion of thyroid hormone (hypothyroidism) results in; Bradycardia. P oor resistance to cold. M ental and physical slowing. In children, this can cause mental retardation and dwarfism . 41

42. 42 Hyperthyroidism Excess secretion of thyroid hormones (hyperthyroidism) can cause; Tachycardia. C ardiac arrhythmias. Body wasting . Nervousness , tremor. Heat intolerance.

43. 43 STAGES OF SYNTHESIS OF THYROID HORMONES Synthesis of thyroid hormones occurs in six stages: Thyroglobulin synthesis. Iodide trapping. Oxidation of iodide. Transport of iodine into follicular cavity. Iodination of tyrosine. Coupling reactions.

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45. Thyroid hormone synthesis and secretion The thyroid gland is made up of multiple follicles that consist of a single layer of epithelial cells surrounding a lumen filled with thyroglobulin , which is the storage form of thyroid hormone . Thyroid function is controlled by thyroid-stimulating hormone (TSH ; thyrotropin ), which is synthesized by the anterior pituitary. TSH causes stimulation of iodide (I−) uptake by the thyroid gland . Oxidation to iodine (I2) by a peroxidase is followed by iodination of tyrosines on thyroglobulin . Condensation of two diiodotyrosine residues gives rise to T4 , whereas condensation of a monoiodotyrosine residue with a diiodotyrosine residue generates T3 . The hormones are released into blood stream by proteolytic cleavage of the thyroglobulin. 45

46. Mechanism of action of TH Most of the hormone (T3 and T4) is bound to thyroxine -binding globulin (TBG) in the plasma. The hormones must dissociate from thyroxine -binding globulin before entry into cells. In the cell , T4 is enzymatically deiodinated to T3 , which enters the nucleus and attaches to specific receptors. The activation of these receptors promotes the formation of RNA and subsequent protein synthesis , which is responsible for the effects of T4 . 46

47. Pharmacokinetics Absorption: Both T4 and T3 are absorbed after oral administration . Food, calcium preparations, and aluminum-containing antacids can decrease the absorption of T4 . Distribution: widely distributed throughout body via blood stream. Metabolism: De-iodination is the major route of metabolism of T3 & T4. The hormones are also metabolized via conjugation with glucuronides and sulfates . Excretion: eliminated into the bile , so excreted through feces. 47

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49. Treatment of Hypothyroidism Hypothyroidism usually results from autoimmune destruction of the gland or the peroxidase. Diagnosis: it is diagnosed by elevated TSH. Drugs : i ). Levothyroxine (T4) ii). Liothyronine (T3) Levothyroxine is preferred over T3 liothyronine . T3/T4 combination products liotrix is used for the treatment of hypothyroidism. Dose: Levothyroxine is dosed once daily , and steady state is achieved in 6 to 8 weeks . 49

50. Toxicity is directly related to T4 levels and manifests as; Nervousness. Palpitations and tachycardia. Heat intolerance. U nexplained weight loss. Drugs that induce the cytochrome P450 enzymes , such as phenytoin, rifampin, and phenobarbital, increase the metabolism of the thyroid hormones and may decrease their effectiveness. 50

51. Treatment of hyperthyroidism (thyrotoxicosis) Graves disease, an autoimmune disease that affects the thyroid, is the most common cause of hyperthyroidism. In these situations, TSH levels are reduced due to negative feedback . Negative Feedback inhibition of TRH occurs with high levels of circulating thyroid hormone , which, in turn, decreases secretion of TSH. 51

52. The goal of therapy is to decrease synthesis and/or release of additional hormone. This can be accomplished by; 52

53. 1. Removal of part or all of the thyroid This can be accomplished either by one of following; I). Surgically (Thyroidectomy) II). Destruction of the gland with radioactive iodine (I-131), which is selectively taken up by the thyroid follicular cells. Most patients become hypothyroid as a result of this drug and require treatment with levothyroxine. 53

54. 2. Inhibition of thyroid hormone synthesis 1. Propyl- T hiouracil (PTU) The thioamides , propylthiouracil ( PTU) is concentrated in the thyroid, where it inhibits both the oxidative processes required for iodination of tyrosyl groups and the condensation (coupling) of iodotyrosines to form T3 and T4. PTU also blocks the peripheral conversion of T4 to T3 . ADR’s : PTU may cause Hepatotoxicity and rarely, Agranulocytosis . (Note:- These drugs have no effect on thyroglobulin already stored in the gland. Therefore, clinical effects of these drugs may be delayed until thyroglobulin stores are depleted). 54

55. 2. Methimazole Methimazole is preferred over PTU because it has a longer half-life , allowing for once-daily dosing , and a lower incidence of adverse effects . However , PTU is recommended during the first trimester of pregnancy due to a greater risk of teratogenic effects with methimazole . 55

56. 3 . Blockade of hormone release 56

57. Thank you !