Adrenocorticosteroids and adrenocortical antagonists

1. Adrenocorticosteroids and adrenocortical antagonists Department of pharmacology Liming zhou 2010,spring

2. ·       Introduction • Natural adrenocortical hormones • ---steroid molecules synthesized in released by the adrenal cortex • Clinical Uses: • 1.diagnosis of adrenal function • 2.treatment of adrenal function disorders • 3.treatment of inflammatory/immunological disorders (at higher doses)

4. physiology • Zona glomerulosa(outermost region) 15% of adrenal cortex --produces mineralocorticoids,which are responsible for regulating salt and water meabolism • Major mineralocorticoid: aldosterone

5. physiology • Zona fasiculata(middle region) 78% of adrenal cortex --produces glucocrticoids,which are concerned with normal metablism and resistance stress. Major glucocorticoid: cortisol

6. physiology • Zona reticularis (innermost region ) 7% of adrenal cortex --produces adrenal androgens Major androgen: dehydroepiandrosterone (DHEA)

7. Corticosteroids including: -- mineralocorticoid -- glucocrticoids -- androgens

8. physiology

9. physiology • The hypothalamus releases a hormone called corticotropin-releasing-hormone (CRH). • The CRH then travels directly to the pituitary gland where they cause the release of adrenocorticotropic hormone (ACTH).

10. physiology • ACTH is released into the bloodstream. • Once in the blood, ACTH travels to the adrenal cortex where it effects the release of corticosteroids.

11. physiology • However, as well as these excitatory processes, there are also inhibitory influences within the HPA. • These inhibitory influences act on CRH neurons and also in the pituitary. • The result of such inhibitions is to reduce the release of ACTH.

12. Relationship of the structure

13. All naturally occurring adrenocortical steroids and the useful, synthetic anti‑inflammatory steroids have the following features

14. C D A B

15. 1. A double bond between carbons 4 & 5 in Ring A. • 2. A ketone (=0) on carbon 3 in Ring A. • 3. Carbons 18, 19, 20, and 21 are present. • 4. Carbons 18 and 19 are methyl groups. • 5. Carbon 20 has a ketone group attached (=0) and carbon 21 has a hydroxyl group attached (‑OH).

16. Glucocorticoids, in addition, have: • 1. A functional oxy group at Carbon 11. Either a ketone or a hydroxyl; actually, those with 11-ketone (cortisone the naturally occurring one) are converted to 11-OH before becoming biologically active.

17. Mineralocorticoids, on the other hand: • 1. Do not have a functional oxy group at Carbon 11. • a. Deoxycorticosterone has no 11‑oxy group. • b. The 11‑oxy group on aldosterone is interfered with by the ‑CHO group at Carbon position 18 (hemiacetal formation).

19. Glucocorticoids Corticosterone Cortisol (Hydrocortisone) Cortisone

20. Glucocorticoids • Glucocorticoids (naturally occurring; cortisol -- hydrocortisone)

21. ·Pharmacokinetics: • Synthesis: • §major glucocorticoid: cortisol • §precursor: cholesterol

22. Characteristics: • Release rate of cortisol controlled by circadian rhythm affected by ACTH pulses

23. 75% of cortisol bound to plasma proteins • cortisol half-life: about 60-90 minutes

25. Cortisol metabolism: • ---20% converted to cortisone (by renal/other tissues with mineralocorticoid receptors) • --- catalyzed by 11-hydroxysteroid dehydrogenase • ---Cortisol and cortisone inactivated in the liver by conversion (3-hydroxysteroid dehydrogenase catalyzed)

26. Some metabolites ultimately excreted in the urine as 11-oxy, 17-ketosteroids ---Some metabolites undergo hepatic conjugation to form glucuronic acid or sulfate derivatives

27. Physiological effects of glucocorticoids • Major metabolic effects: due to direct cellular action • ---Some effects:secondary to homeostatic insulin and glucagon responses • Physiological responses modulated by glucocorticoids ("permissive" effects) • --- catecholamine vascular/bronchial smooth muscle response:

28. Metabolic Effects • Glucocorticoids: stimulate and are required for: ---gluconeogenesis (fasted state, diabetes); ---increasing hepatic and renal amino acid uptake ---increase gluconeogenic enzyme activity • Hepatic effects: ---Simulation of glycogen synthase • ---Increase glucose production from protein • --- stimulating insulin release

29. Metabolic Effects • Adipocytes: —inhibit glucose uptake promoting increased lipolysis — counteracted by enhanced insulin secretion which stimulates lipogenesis • Glucocorticoid effects most prominent in the fasting state, through: —stimulation:gluconeogenesis — stimulation: amino acid release from muscle (catabolism) —inhibition: peripheral glucose uptake — stimulation: lipolysis

30. Catabolic Effects • promotion of catabolism: —lymphoid tissue —connective tissue — muscle — fat — skin • High (supraphysiologic) glucocorticoid levels cause: — decreased muscle mass, weakness • Reduced growth in children (not prevented by growth hormone)

31. Catabolic effects on bone • ---osteoporosis in Cushing's syndrome • ----major limitation in long-term use • Osteoporosis: A disease in which the bones become extremely porous, are subject to fracture, and heal slowly

32. Mechanism of Action: Glucocorticoid action through glucocorticoid receptors

33. Steroid binding globulin Steroid potency Glucocorticoid Glucocorticoid-BG Complex Receptor G-CBG Complex Steroid Complex DNA

34. Receptor Steroid Complex Increase in protein products of the regulatable sequence. Interactions Glucocorticoid potency (and SOME duration effects) Duration Regulatable Nonregulatable

35. Receptor Properties: • · ---member of receptor superfamily that includes: • 1.steroid receptors • 2. thyroid receptors •    3.other receptors (many with unknown function -- "orphan receptors" • · ---Receptors bound to heat shock proteins (Hsp/hsp90)

37. Sequence of activation: • Free glucocorticoid hormone enters the cell • Binds to the receptor, inducing a conformational change • Receptor dissociates from heat shock proteins Hormone-receptor complex associate to form homodimers • Homodimers actively transported to the nucleus • Homodimers bind to glucocorticoid receptor elements (GREs) of target genes • Genomic effects -- protein synthesized; Indirect mediation of some genomic effects by paracrine influences of hormone-regulated cytokines on nearby cells

38. Pharmacological effects • wGlucocorticoid functions: • Regulation of glucose metabolism • Antiinflammation • Immunosuppression • Enhance ability to handle stress

39. Pharmacological effects • Anti-inflammatory/Immunosuppressive Effects : • --Reduce inflammation -- • Leukocyte-mediated; reduced leukocyte infiltration   --glucocorticoid inhibition of interactions involving cell adhesion molecules (especially on endothelial cells)

40. Anti-inflammatory/Immunosuppressive Effects : Glucocorticoids inhibit: • • leukocyte and tissue macrophage function • --reduced antigenic and mitogenic responsiveness • • Macrophage effects: • ·--decreased interferon-gamma, interleukin 1, pyrogen, collagenase, elastase, tumor necrosis factor, plasminogen activator • • Lymphocyte effects: • ·decreased interleukin 2

41. Anti-inflammatory • Reduction of prostaglandin and leukotriene synthesis (resulting from phospholipase A2 activation) •Reduction of cyclooxygenase in inflammatory cells (reducing prostaglandin synthesis)

43. Anti-inflammatory • Glucocorticoids decrease capillary permeability by: • 1. kinin activity • 2. bacterial endotoxin activity • 3. basophils histamine release

44. Pharmacological effects • Increase resistance to stress ---satuation of stress: trauma,fright, infection,blooding or debilitating disease • Raising plasma glucose levers ---provide the body with the energy ---can cause a modest rise in blood pressure --enhancing the vasoconstrictor action

45. Anti-shock effect • 1.---increase the output of heart ---increase construction of the myocardium • 2. Dilution of the capillary blood vessel, increase perfusion in tissue

46. 3. Stabling the membrane of 溶酶体 reducing production of myocardial depressant factor(MDF) • 4. Increasing the tolerance to bacterial endotoxin

47. Immunosuppressive Effects : • Inhibition of immunity system ---special in the lymph tissue •degeneration of DNA in lymphcyte ---induce of apotosis of lymphcyte ---inhibited the activity of NF-kB ---decreasing the production of antibody

48. Immunosuppressive Effects : • Anti-hypersensitivity ---inhibiting the release of histamine , kinin ,5-HT and other stimulant of sensitivity reaction ---inhibition of process of immunity

49. Interfere the blood system • Alter blood cell levers in plasma ---decrease monocytes,lymphocytes,ensinophils and basophils ---increase hemoglobin, erythrocycte,platelets and polymorphonuclear leukocytes

50. Other effects 1. decreasing the temperature ---interfere the production of PG 2. CNS ---decreasing the GABA, increasing the exciting psychoses and epilepsy ---euphoria