GROWTH HORMONE AND IT`S ANTAGONISTS GROUP 2.pptx

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1. GROUP ASSIGNMENT : PHARMACOLOGY. DEPARTMENT : MEDICINE PROGRAM : REGULAR PREPARED BY GROUP 2 . Submitted to : Dagim Samuel ( DVM , B.pharm ,Msc in Pharmacology) 9/3/2024 1

2. NAME ID NUMBER Burkitu Keno 1302980 Nuguse Tamasgen 13021931 Milkias Tura 1304238 Tolasa Mulatu 1302337 Samuel Fayisa 1302029 Dalasa Aguma 1303684 Sena Yohanes 1302087 Sura Waktola 1302183 Alahmudin Mohammedali 1303444 Gurmu Adisu 1307051 9/3/2024 2

3. GROWTH HORMONE AND ITS ANTAGONIST Growth hormone (GH): is a large polypeptide hormone (191 amino acids) produced by the anterior pituitary. Growth hormone, or somatotropin , is a protein that stimulates linear body growth in children and regulates cellular metabolism in both adults and children Childhood deficiency of GH results in short stature. Excessive GH results in gigantism (when too much is present prior to puberty) and acromegaly (when too much is present during adulthood). 9/3/2024 3

4. Functions of GH Promotion of Growth. Promotion of Protein Synthesis. Effect on Carbohydrate Metabolism. stimulates lipolysis, enhances production of free fatty acids, elevates blood glucose, and promotes positive nitrogen balance. 9/3/2024 4

5. Regulation of Release H ypothalamus first releases growth hormone–releasing hormone (GH-RH), which stimulates release of GH from the pituitary. Growth hormone then acts on the liver and other tissues to cause release of insulin-like growth factor-1 (IGF-1). IGF-1 has two actions: 1) promotes growth and 2) acts on the hypothalamus and pituitary to suppress release of GH-RH and GH, thereby completing a negative feedback loop. 9/3/2024 5

6. Cont … It is released during sleep, with maximum release occurring an hour after the onset of sleep. Growth hormone is also released after exercise by hypoglycemia and in response to arginine and levodopa. 9/3/2024 6

7. Pathophysiology Growth Hormone Deficiency : Growth hormone deficiency in children results in short stature. In adults, GH deficiency causes a syndrome characterized by: reduced muscle mass reduced exercise capacity increased mortality from cardiovascular causes and impaired psychosocial function . Onset of GH deficiency may begin in childhood or later in life. 9/3/2024 7

8. Cont …. II. Growth Hormone Excess In children, the resulting syndrome is called gigantism , In adults, the syndrome is called acromegaly . The pathophysiology of both syndromes is similar. The principal difference is that GH excess causes children to grow very tall—as much as 7 to 9 feet. In adults, effects on bone growth result in coarse facial features, splayed teeth and large hands and feet . However, because the epiphyses have already closed height is not increased . 9/3/2024 8

9. Therapeutic Uses of GH( Somatropin ) Pediatric Growth Hormone Deficiency. Pediatric Non–Growth-Hormone-Deficient (NGHD) Short Stature. Pediatric Short Stature Associated with Prader-Willi Syndrome. Adult Growth Hormone Deficiency. GH is approved for pediatric growth failure associated with chronic renal insufficiency, cachexia or wasting in patients with AIDS, Turner's syndrome, and short-bowel syndrome. 9/3/2024 9

10. Preparations and Dosage GH Somatropin . Somatropin [ Humatrope , Nutropin , others] is a form of GH produced by recombinant DNA technology. The structure and actions of somatropin are identical to those of GH produced by the human pituitary. 9/3/2024 10

11. 2. Somatrem Somatrem [ Protropin ] is a form of GH produced by recombinant DNA technology. With the exception of one amino acid, the structure of somatrem is identical to that of GH produced by the human pituitary. The biologic activity of somatrem is indistinguishable from that of naturally occurring GH. 9/3/2024 11

12. Administration Administration is parenteral—IM or subQ . Subcutaneous administration is preferred because it is less painful than IM while being just as safe and effective. Subcutaneous administration can be done using either (1) a traditional syringe and needle, or (2) for some products, a needle-free device 9/3/2024 12

13. 3. MECASERMIN (INSULIN-LIKE GROWTH FACTOR-1) Mecasermin [ Increlex ], produced by recombinant DNA technology, is identical to naturally occurring IGF-1, the compound that mediates the effects of GH. Mecasermin is approved for longterm therapy of growth failure in children with severe primary deficiency of IGF-1. 9/3/2024 13

14. Mecasermin can cause a variety of adverse effects. The most common is hypoglycemia, which develops in nearly 50% of patients, usually during the first weeks of treatment. Hypertrophy of the tonsils develops in 15% of patients, and can be managed by tonsillectomy if needed. 9/3/2024 14

15. Other adverse effects include intracranial hypertension, vomiting, arthralgia, otitis media elevation of serum aminotransferases and lipids, and overgrowth of fat, facial bones, and the kidneys. Like all other foreign proteins, mecasermin can trigger allergic reactions, both local and systemic. Administration is by subQ injection. 9/3/2024 15

16. Adverse Effects and Interactions of GH Adverse Effects Hyperglycemia Neutralizing Antibodies. Carpal Tunnel Syndrome. Fatality in PWS Patients. Interaction with Glucocorticoids. Glucocorticoids can oppose the growth-promoting effects of GH. Glucocorticoid replacement doses must be carefully adjusted to avoid growth inhibition. 9/3/2024 16

17. GROWTH HORMONE ANTAGONISTS Antagonists of GH are used to reverse the effects of GHproducing cells ( somatotrophs ) in the anterior pituitary that tend to form GH-secreting tumors. In adults, GH-secreting adenomas cause acromegaly, which is characterized by abnormal growth of cartilage and bone tissue, and many organs including skin, muscle, heart, liver, and the gastrointestinal tract. 9/3/2024 17

18. Cont … The initial therapy of choice for GH-secreting adenomas is endoscopic transsphenoidal surgery. Medical therapy with GH antagonists is introduced if GH hypersecretion persists after surgery. These agents include : somatostatin analogs and The novel GH receptor antagonist pegvisomant , which prevents GH from activating GH signaling pathways. Radiation therapy is reserved for patients with inadequate response to surgical and medical therapies 9/3/2024 18

19. A.Somatostatin Analogs Somatostatin , a 14-amino-acid peptide is found in the hypothalamus, other parts of the central nervous system, the pancreas, and other sites in the gastrointestinal tract. MOA : It functions primarily as an inhibitory paracrine factor and inhibits the release of GH, TSH, glucagon, insulin, and gastrin. Somatostatin is rapidly cleared from the circulation, with a half-life of 1–3 minutes 9/3/2024 19

20. Cont … Somatostatin has limited therapeutic usefulness because of its short duration of action and multiple effects in many secretory systems. A series of longer-acting somatostatin analogs that retain biologic activity have been developed. Octreotide : the most widely used somatostatin analog is 45 times more potent than somatostatin in inhibiting GH release but only twice as potent in reducing insulin secretion. 9/3/2024 20

21. Cont … Because of this relatively reduced effect on pancreatic beta cells, hyperglycemia rarely occurs during treatment . The plasma elimination half-life of octreotide is about 80 minutes, 30 times longer than that of somatostatin . Octreotide , 50–200 mcg given subcutaneously every 8 hours, 9/3/2024 21

22. Cont … Therapeutic uses reduces symptoms caused by a variety of hormone-secreting tumors: Acromegaly carcinoid syndrome gastrinoma , glucagonoma , insulinoma , VIPoma , and ACTH-secreting tumor. 9/3/2024 22

23. Cont … Other therapeutic use indications include diarrhea—secretory, HIV associated, diabetic, chemotherapy, or radiation induced—and portal hypertension Octreotide is also useful for the acute control of bleeding from esophageal varices . 9/3/2024 23

24. Cont … Adverse effects of octreotide therapy include nausea, vomiting , abdominal cramps , flatulence, steatorrhea with bulky bowel movements. Biliary sludge and gallstones may occur after 6 months of use in 20–30% of patients. 9/3/2024 24

25. Cont … However, the yearly incidence of symptomatic gallstones is about 1%. Cardiac effects include sinus bradycardia (25%) and conduction disturbances (10%). Pain at the site of injection is common, especially with the long-acting octreotide suspension. Vitamin B12 deficiency may occur with long-term use of octreotide . 9/3/2024 25

26. Cont … Lanreotide A long-acting formulation of another octapeptide somatostatin analog, is approved for treatment of acromegaly . Lanreotide appears to have effects comparable to those of octreotide in reducing GH levels and normalizing IGF-1 concentrations. 9/3/2024 26

27. B. Pegvisomant D erivative of a mutant GH, B2036 . Like native GH, pegvisomant has two GH receptor binding sites . one of its GH receptor binding sites has increased affinity for the GH receptor, whereas its second GH receptor binding site has reduced affinity. This differential receptor affinity allows the initial step (GH receptor dimerization ) but blocks the conformational changes required for signal transduction. In clinical trials, pegvisomant was administered subcutaneously to patients with acromegaly; daily treatment for 12 months or more reduced serum levels of IGF-I into the normal 9/3/2024 27

28. Cont … Mechanism of action Pegvisomant blocks the action of growth hormone on the growth hormone receptor to reduce the production of IGF-1. IGF-1 is responsible for most of the symptoms of acromegaly, and the normalization of its levels can control the symptoms . Long-term treatment studies with pegvisomant as a monotherapy have shown it to be safe  and effective . 9/3/2024 28

29. Cont … Therapeutic use: Pegvisomant is  indicated  for the treatment of adults with acromegaly . pegvisomant was administered subcutaneously daily treatment for 12 months or more reduced serum levels of IGF-I into the normal range in 97%. 9/3/2024 29

30. Cont … Side effects: Side effects of pegvisomant include: reactions at the injection site , swelling of the limbs chest pain   hypoglycemia nausea and   hepatitis . 9/3/2024 30

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