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沈阳药科大学 药物化学教研室

沈阳药科大学 药物化学教研室. Adrenal Corticoids. Learning Objectives. Gain an understanding of: 1. Adrenocorticoids affect both carbohydrate metabolism (glucocorticoids) and modulate water balance and Na + /K + transport (mineralocorticoid)

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沈阳药科大学 药物化学教研室

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  1. 沈阳药科大学药物化学教研室 Adrenal Corticoids

  2. Learning Objectives Gain an understanding of: 1. Adrenocorticoids affect both carbohydrate metabolism (glucocorticoids) and modulate water balance and Na+/K+ transport (mineralocorticoid) 2. The nature of the stress activated pathways that control adrenocorticoid secretion 3. Structures of the major mineralo- and glucocorticoids 4. Biosynthesis of mineralo- and glucocorticoids 5. Anti-inflammatory effects of glucocorticoids and the use of pharmacological doses for treatment of inflammation 6 Structure-activity relationships for glucocorticoid activity 7. Development of synthetic glucocorticoids with reduced mineralocorticoid activity 8. Toxicity of adrenal corticoids

  3. ADRENAL CORTICOIDS 1563 Existence of adrenal gland discovered by Eustachio 1849 Addison attributed “bronzed skin” disease to malfunctioning Adrenal glands 1856 Brown-Sequard removed adrenals of cats and dogs who promptly died proving properly functioning adrenals essential for survival 1894 Adrenal divided into medulla secreting adrenaline and the cortex. 1938 Reichstein isolates 29 new substances from adrenal cortex all are steroids 1948 Kendall isolates pure cortisone 1950 Kendall, Reichstein and Hench awarded Nobel prize for medicine

  4. pineal HUMAN ORGANS OF THE ENDOCRINE SYSTEM hypothalmus Steroid hormones are synthesised primarily in Adrenal Cortex -Adrenocorticoids Ovaries , testes - Sex steroids pituitary parathyroid thyroid thymus stomach adrenal Steroid secretion is generally controlled by peptides secreted from the: Hypothalmus and pituitary pancreas kidney duodenum ovary uterus testes

  5. BIOLOGICAL EFFECTS OF ADRENOCORTICOIDS Modulation of carbohydrate metabolism - Glucocorticoids increases levels of glycogen in the liver and circulating glucose early effects stimulate immune system prolonged secretion leads to immune suppression and cell death basal rhythmic secretion increased during periods of stress Modulation of water balance, promotion of Na+/ K+ transport -Mineralocorticoids promotes Na+ uptake in tubular epithelial cells modulates K+ ion transport control of water reabsorption secreted only during periods of stress Glucocorticoid and mineralocorticoid receptors have been discovered and each class of compound can interact with each receptor Secretion of cortisol during stress is essential for life

  6. Humoral pathway STRESS RAS pathway STRESS ACTIVATED PATHWAYS (-) Limbic system Visceral brain Norepinephrine (-) Neuronal pathway Endocrine Hypothalmus CRF 41 residues Renin (-) Fight or flight Anterior pituitary Angiotensin I & II ACTH 39 residues Adrenal cortex Adrenal cortex cortisol glycogen Aldosterone GR receptor increased blood pressure Sodium uptake Antiinflammatory effects cell death

  7. Corticosterone Cortisol (hydrocortisone) Cortisone MAJOR NATURAL GLUCOCORTICOIDS

  8. BIOSYNTHESIS OF GLUCOCORTICOIDS H O O O H O C H O H O C H 2 O 2 O H O H O H H O H O O O O O BIOSYNTHESIS OF GLUCOCORTICOIDS H O O H O cholesterol 11b,17a(OH)2-progesterone 17a-hydroxy- pregnenolone e f b O H O O H c,d e f pregnenolone 17a-hydroxy- progesterone 11-deoxycortisol Cortisol b. 17a-hydroxylase c. 5-ene-3b-hydroxy dehydrogenase d. 3-oxo-4,5-isomerase e. 21-hydroxylase f. 11b-hydroxylase e c,d H O C H 2 O O O H 17a,21(OH)2- pregnenolone O Cortisone

  9. Hydrocortisone Oxidation GLUCOCORTICOID - METABOLISM Cortisone Oxidation/reduction Reduction Acid metabolites 3-keto-D4 and 20-keto reduced

  10. MAJOR NATURAL MINERALOCORTICOIDS Aldosterone desoxycorticosterone

  11. BIOSYNTHESIS OF MINERALOCORTICOIDS 18-hydroxy- corticosterone pregnenolone Aldosterone c,d e f g progesterone deoxycortico- sterone cortico- sterone c. 5-ene-3b-hydroxy dehydrogenase d. 3-oxo-4,5-isomerase e. 21-hydroxylase f. 11b-hydroxylase g. 18-hydroxylase Aldosterone (hemiacetal form)

  12. ANTIINFLAMMATORY EFFECTS OF GLUCOCORTICOIDS April, 19481 Gram cortisone isolated by Kendall September 21, 1948 Hench administers 100mg of cortisone by intra- muscular injection to patient Mrs. G. suffering chronic Rheumatoid Arthritis September 28, 1948 Mrs. G. first time in years walks downtown to go shopping. Represented a new approach to therapy with natural hormones by utilising a dose much higher than that naturally produced by the body ie. pharmacological rather than physiological dose.

  13. MODE OF ACTION GLUCOCORTICOIDS IN PREVENTING INFLAMMATION Intracellular membrane phospholipids Steroid + receptor Phospholipase A2 Arachidonic acid Synthesis lipocortin or annexin 1 prostaglandin Represses inducible COX2 inhibits Release into cytosol or from cell INFLAMMATION

  14. THERAPEUTIC APPLICATION ADRENOCORTICOIDS Glucocorticoids Agonists - adrenal insufficiency - rheumatoid disease and allergic manifestations (eg. severe asthma, rheumatoid arthritis, rheumatic fever) Palliative therapy only not curative Antagonists - Cushings Syndrome Mineralocorticoids Agonists - adrenal insufficiency, generally glucocorticoids used in this application Antagonists - Cushings syndrome - test functioning of hypothalamico-pituitary axis

  15. CORTISONE PREPARATIONS Cortisone is primarily used as its 21-acetate because of increased stability and longer duration of action Other 21-ester derivatives available include: Hydrocortisone cypionate R = Oral or intramuscular dose usually 25 mg 4 times daily Topically 1 to 2.5% lotion Hydrocortamate sodium succinate R = Na+ -OOCCH2CH2CO- (water soluble) Intraveinous emergency treatment

  16. RELATIVE POTENCIES OF CORTICOSTEROIDS Compound Na+ Hepatic Antiinflammatory retention glycogen effect deposition Cortisol 1 1 1 Cortisone 0.8 0.8 0.8 Corticosterone 15 0.35 0.3 11-desoxycortico- sterone 100 0 0 Aldosterone 3000 0.3 ? Most natural or synthetic compounds have some activity at both GR and MR receptors

  17. Large doses of steroids used for treating rheumatoid arthritis resulted in significant side effects including excessive Na+ retention and K+ excretion STRUCTURE-ACTIVITY GLUCOCORTICOIDS Intensive efforts for compounds with reduced mineralocorticoid activity Structure-activity for glucocorticoid activity Required for activity 3-keto group 4,5-double bond 11- oxygen (keto or alcohol) 17-b ketol sidechain

  18. 9a-bromo analogue Synthetic Corticosteroids 1/3 activity of cortisone acetate 11-epicortisol 11 times activity of cortisone acetate Fludrocortisone Glucocorticoid activity inversely Proportional to size of 9a-halogen

  19. D-corticoids Prednisolone (GR 4 MR unchanged) SYNTHETIC GLUCOCORTICOIDS Methylprednisolone (GR 5 MR unchanged) Rheumatoid arthritis 2-4 mg /day Greater activity allows smaller doses D-corticoids to be used reducing side effects Prednisone and Prednisolone can be used interchangeably Prednisone (GR 4 MR unchanged)

  20. Conformational Change in D-Corticoids Ring A of 5a-pregnan-3-one Flattened boat Chair Ring A of pregn-4-en-3-one Half-chair

  21. SYNTHETIC GLUCOCORTICOIDS betamethasone GR 35 fold Fludrocortisone (GR activity 11) Rheumatic and dermatologic disorders Short period use only MR activity 300-800 fold MR activity triamcinolone acetonide triamcinolone GR 5 fold Used topically for treatment of psoriasis and other skin conditions 20% more effective than prednisolone Unusual toxic side effects

  22. Prolonged use TOXICITY OF ADRENOCORTICAL STEROIDS Primarily results in fluid and electrolyte disturbances eg. hypertension, hyperglycemia, glycosuria Increased susceptibility to infection including tuberculosis Peptic ulcers, osteoporosis, myopathy, central obesity, behavioral disturbances Withdrawal effects Prolonged adrenocorticoid use results in pituitary- adrenal suppresion This system may take as long as 1 to 2 years to recover Patients may need supplemental corticosteroids during this period

  23. THERAPEUTIC USE OF CORTICOSTEROIDS 1. Appropriate dose in each case is determined by trial and error 2. Single dose of corticosteroid is virtually without harmful effect 3. A few days of usage is unlikely to produce harmful effects except at extreme doses. 4. Prolongation of treatment increases the incidence of disabling or life threatening effects 5. Corticosteroids are neither specific or curative treatment 6. Abrupt cessation of prolonged high dose treatment may induce adrenal insufficiency serious enough to be life threatening.

  24. ADRENOCORTICOID ANTAGONISTS Diuretic response of increased Na+ excretion and K+ retention Spironolactone progesterone mifeprestone mineralocorticoid antagonist glucocorticoid antagonist

  25. INHIBITORS OF BIOSYNTHESIS OF CORTICOSTEROIDS Metyrapone inhibits 11b-hydroxylation reaction Used for diagnosis hypothalmus- pituitary malfunction Ketoconazole blocks cholesterol sidechain cleavage in the adrenal (Cushings Syndrome) Trilostane inhibits 3b-hydroxysteroid dehydrogenase (Cushings Syndrome - currently not recommended)

  26. 1. Glucocorticoids modulate carbohydrate metabolism ie cortisol, cortisone 2. Mineralocorticoids modulate water balance and Na+/K+ transport ie aldosterone and desoxycorticosterone 3. Biosynthesis of corticosteroids starts with cholesterol the pregnenolone then progesterone and then final hormone 4. Antiinflammatory effects of glucocorticoids mediated by inhibition of phospholipase A2, inducible COX2 and annexin I 5. 17-esterification facilitates administration 6. All corticosteroids contain both glucocorticoid and mineralocorticoid activity 7. SAR for glucocorticoid activity: 3-keto, 4,5-double bond, 11-oxy, 17-b ketol all essential for activity Summary

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