4th unit corticosteroids

Introduction.
Types of Corticosteroids
Biosynthesis of Corticosteroids
Biological Effects
Uses
Classification
Synthesis
Reference

1. 4 th UNIT CORTICOSTEROIDS Prepared by G. Nikitha, M.Pharmacy Assistant Professor Department of Pharmaceutical Chemistry Sree Dattha Institute Of Pharmacy Hyderabad 1 Subject: Medicinal Chemistry-II Year: B.Pharmacy 3 rd Year Semister: 1 st Semister

2. Contents Introduction. Types of Corticosteroids Biosynthesis of Corticosteroids Biological Effects Uses Classification Synthesis Reference 2

3. Introduction Adrenal glands are triangular and highly vascularized glands located above each kidney. Each adrenal gland is structurally and functionally divided into two regions outer adrenal cortex and inner adrenal medulla. Adrenal cortex is divided into three zones viz. zona glomerulosa , zona fasciculate and zona reticularis . Corticosteroids are steroid hormones secreted by the adrenal cortex. These hormones are essential for the survival as they are concerned with the maintenance of water and electrolyte balance, cardiovascular and energy substrate balance and functional status of nervous system and skeletal muscles. Corticosteroids are basically of 3 types. 3

4. Types of Corticosteroids 1. Glucocorticoids Glucocorticoids are secreted by the zona fasciculate of adrenal cortex. They are concerned with carbohydrate, protein and fat metabolism. Cortisol and corticosterone are the two major glucocorticoids. They have carbohydrate storing. Anti-inflammatory, Anti-allergic and anti- corticotrophic properties. 2. Mineralocortiods : Mineralocortiods are secreted by the zona glomerulosa of adrenal cortex. They include aldosterone and deoxycorticosterone . They are concerned K + , Na + and fluid balance. 3. Sex Hormones: Male sex hormones (androgens) are released by zona recticularis of the adrenal cortex. These are released in small amounts and are weak in action. 4

5. Biosynthesis of Corticosteroids Adrenocorticosteroids are 21 carbon compounds containing cyclopentenoperhydrophenantherene ring. They are synthesized in the adrenocortical cells under the influence of ACTH ( adrenocorticotrophin hormone) from cholesterol. 5

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7. Biological Effects and uses They act on carbohydrate and protein metabolism, promote glycogen deposition in liver. They promote lipolysis due to glycogen, growth hormone adrenaline, Thyroxine. They inhibit intestinal absorption and enhance renal excretion of Ca + Uses: Used in the following conditions Acute adrenal insufficiency, chronic adrenal insufficiency, severe allergic reactions, autoimmune disease, asthma, eye diseases, skin diseases. 7

8. Mineralocortiods 8

9. Glucocorticoids 9 Glucocorticoids with moderate-to-low salt retention

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11. 11 Ophthalmic Glucocorticoids

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13. 13 Glucocorticoids used for the treatment of asthma and allergy

14. Mechanism of action Steroids penetrate into the cell as free molecule and bind to cytosolic corticoid receptor. The steroid-receptor complex then forms a homodimer (S-R+S-R) which allows its translocation into the nucleus where it binds to glucocorticoid responsive element (GRE) in the regulatory region of the concerned gene. This result in the transcription of mRNA which is transported to cytoplasm where it causes translation of desired proteins that brings about the final hormone response. 14

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16. Pharmacokinetics: All natural and synthetic corticosteroids are well absorbed orally. Hydrocortisone is highly bound to plasma proteins. All the corticosteroids get metabolized in liver and are excreted in urine. 16

17. Adverse drug effects Short term therapy with small or moderate doses does not produce any side effects. However, long term therapy with large doses is liable to cause certain adverse effects which are enlisted below. On GIT: Acute haemorrhage , gastritis, peptic ulceration intestinal perforation and pancreatitis can occur. These occur due to decrease in the production of PIGI 2 which protects the gastric mucosa. On CNS: Glucocorticoids produce psychological disturbances ranging from euphoria to manic depressive psychosis. However, such reactions are reversible upon discontinuation of therapy. Crushing’s Habitus : prolonged therapy with glucocorticoids causes cushingoid appearance which is characterized by round face, relatively thin limbs. 17

18. On cardiovascular and renal system: Hypertension, hypokalaemic alkalosis and oedema due to Na + and water retention are potential complications. Suppression of Hypothalamo -pituitary Adrenal (HAP) Axis: Sudden cessation or reduction in the dosage of glucocorticoids can precipitate withdrawal syndrome characterized by malaise, fever, nausea, anorexia, myalgia , weakness and postural hypertension. Hence, the therapy should be gradually withdrawn to allow physiological recovery of the normal pituitary and adrenal functions. Osteoporosis and Glycosuria: Osteoporosis is a common adverse effect particularly involving vertebrae and other flat spongy bones. In post-menopausal women, this complication can be fatal. Hyperglycaemia and Glycosuria: A diabetic-like state can be precipitated because of anti-insulin effects of glucocorticoids. However, they are reversible upon discontinuation of therapy. 18

19. Ocular effects: Prolonged topic or systemic use of glucocorticoids is associated with posterior subcapsular effects and glaucoma. Retardation of linear growth: Prolonged glucocorticoids therapy even with small doses can cause growth retardation in children. Supression of inflammation and immune response: Glucocorticoids only dampen the manifestation of a disease, while the disease continues to progress; further, they favour the spread of infectious diseases by impairing the defensive capacity of the body. Delay wounds Healing: They interfere with the healing of wounds and surgical incisions. 19

20. Therapeutic Uses Used in the treatment of Acute Adrenal Insufficiency, Chronic Adrenal Insufficiency, Congenital Adrenal Hyperplasia. Arthritis, Autoimmune disease, Several allergic reactions, Intestinal disease, Ocular disease, Bronchial Asthma, Skin disease 20

21. Cortisone : IUPAC: 17-hydroxy-17-(2-hydroxyacetyl)- 10,13-dimethyl-1,2,6,7,8,9,12,14,15,16-decahydrocyclopenta [a] phenanthrene-3,11-dione Properties and Uses: It is white crystalline powder, which is insoluble in water, soluble in alcohol. It is used i n arthritis, allergic conditions, chronic lymphatic leukemia. 21 Molecular Formula: C 21 H 28 O 5

22. 22 Synthesis:

23. Hydroxycortisone : IUPAC: 11,17-dihydroxy-17-(2-hydroxyacetyl)-10,13-dimethyl-2,6,7,8,9,11,12,14,15,16-decahydro-1 H -cyclopenta[a]phenanthren-3-one 23 It is a glucocorticosteroid and is the most important adrenocortical hormone which is physiologically more active than cortisone. It is isolated by kendoll in 1937. It is used in the treatment of rheumatoid arthritis, rheumatoid fever, severe shock and allergic condition. Molecular Formula:  C 21 H 30 O 5

24. Properties and Uses: It is white crystalline powder, which is soluble in water and alcohol . It is used in anti-inflammatory agent. 24

25. Synthesis: Route-1: From Progesterone 25

26. Route-2: From cortisone acetone 26

27. Prednisolone : IUPAC: 11,17-dihydroxy-17-(2-hydroxyacetyl)- 10,13-dimethyl-7,8,9,11,12,14,15,16-octahydro-6 H -cyclopenta[a]phenanthren-3-one Properties and Uses: It is white crystalline powder, which is sparingly soluble in alcohol . It is four times as potent as hydrocortisone. 27 Molecular Formula:  C 21 H 28 O 5

28. Synthesis: 28

29. Daxametha s one IUPAC: 9-fluoro-11,17-dihydroxy-17-(2-hydroxyacetyl)-10,13,16-trimethyl-6,7,8,11,12,14,15,16-octahydrocyclopenta[a]phenanthren-3-one Properties and Uses: It is white crystalline powder, which is insoluble in water, soluble in alcohol. It is used a s anti-inflammatory , anti-allergic drugs. 29 Molecular Formula: C 22 H 29 FO 5

30. Betamethasone IUPAC: 9-fluoro-11,17-dihydroxy-17- (2-hydroxyacetyl)- 10,13,16-trimethyl-6,7,8,11,12,14,15,16-octahydrocyclopenta[a]phenanthren -3-one Properties and Uses: It is white crystalline powder , odorless, soluble in acetone, alcohol, sparingly soluble in methanol, chloroform, ether. It is used to treat allergies, skin rashes, dermatitis , itching. 30 Molecular Formula: C 22 H 29 FO 5

31. Reference books Text book of Medicinal chemistry volume-1-3 rd edition by V.Alagarasamy. Text book of Medicinal chemistry volume-2-3 rd edition by V.Alagarasamy. Medicinal chemistry by Rama Rao Nadendla. Faye’s Principles of Medicinal Chemistry- 7 th edition by Thoms L.Lemke , Victoria F.Roche , S. Willam Zito . Medicinal Chemistry- 4 th edition by Ashutosh Kar 31

32. Thank you 32