SHWETA PPT.ppt
- 1. STEROIDS HORMONSE PRESENTED BY Dr. Shweta Verma PHARMACY ACADEMY IFTM UNIVERSITY MORADABAD-244001
- 2. Steroid Hormones • Steroid hormone biosynthesis • common precursor is cholesterol • first step is degradation of side chain via desmolase and formation of pregnenolone (C21) • pregnenolone can then follow several pathways: – It can be converted to progesterone which can be converted into gluco and mineralocorticoids, C21 (in the adrenal cortex) – It can also be converted through several steps into testosterone (C19) which in turn can be aromatized into estradiol (C18)
- 3. Model of steroid hormone action
- 4. Steroid hormone receptor structure SH SH SH SH SH HS SH SH SH SH Zn Zn DNA BINDING SITE HORMONE BINDING SITE COOH "ZINC FINGERS" H3N TRANSCRIPTIONAL ACTIVATION ELEMENT
- 7. Steroid hormone classes • glucocorticoids • mineralocorticoids • androgens • estrogens • progestins • vitamin D
- 9. Adrenal cortex Composed of 3 layers (zones) • outer zone (zona glomerulosa) – produces aldosterone (mineralocorticoid) • middle zone (zona fasciculata) – produces cortisol (glucocorticoids) • inner zone (zona reticularis) – produces corticosterone and androgens
- 12. Major functions of adrenal steroids • Glucocorticoids – increases gluconeogenesis – increases glycogenesis – increases protein catabolism – decreases antibody response – antiinflammatory response – antineoplastic response • Mineralocorticoids – increase sodium and water retention – promote potassium loss
- 13. GLUCOCORTICOIDS • synthesized from cholesterol • to pregnenolone --------- progesterone ----------- 17-a-hydroxyprogesterone ------------------------ 11-deoxycortisol--------cortisol • requires hydroxylating enzymes • 21-beta hydroxylase • 17-alpha hydroxylase • 11-beta hydroxylase
- 19. GLUCOCORTICOIDS • anti-inflammatory effect – effect on protein synthesis • inhibit protein-translation of inducible COX -II (which also inhibits PG and thromboxanes) • promote synthesis of lipocortins which inhibit phospholipase A2 (this inhibits production of arachidonic acid and hence prostaglandins and leukotrienes) – physiologic effects
- 20. GLUCOCORTICOIDS • antiinflammatory effects – physiologic effects • negative effect on lymphocytes, monocytes and macrophages • inhibit the release of IL-1, IL-2 and IL-6 and TNF-alpha • reduced migration of inflammatory cells to site of injury • decreased lymphocyte production • impairment of delayed-type hypersensitivity
- 21. GLUCOCORTICOIDS • permissive effects (glucocorticoids required for certain actions) – tissue effects • inhibit fibroblasts (connective tissue loss) • negative calcium balance (osteoporosis) • negative nitrogen balance (catabolism) • CNS: euphoria, behavioral changes, psychosis • GI: increase stomach acid and pepsin production • cardiovascular effects (inc. BP, heart rate) • uptake of fat by fat cells • gluconeogenesis • insulin release and glycogen deposition
- 22. Indications for systemic glucocorticoids • ophthalmic diseases • allergic conjunctivitis • keratitis • allergic corneal marginal ulcers • herpes zoster ophthalmicus • iritis and iridocyclitis • optic neuritis • retrobulbar neuritis
- 23. O CH3 CH3 CH2OH OH O HO H H H HYDROCORTISONE O CH3 CH3 CH2OH OH O HO H H H PREDNISOLONE GLUCOCORTICOIDS hydrocortisone is the most active natural glucocorticoid prednisolone is a delta-1 derivative with greater potency (made synthetically)
- 24. O CH3 CH3 CH2OH OH O HO F H H CH3 DEXAMETHASONE (DECADRON) O CH3 CH3 CH2OH OH O HO H H H OH TRIAMCINOLONE GLUCOCORTICOIDS these are synthetic glucocorticoid with more potent glucocorticoid activity
- 25. O CH3 CH3 CH2OCOCH2CH3 OCOCH2CH3 O HO Cl H H CH3 BECLOMETHASONE DIPROPIONATE (BECLOVENT, VANCERIL) O CH3 CH3 CH2OCOC(CH 3)3 OH O HO Cl H H F CH3 CLOCORTOLONE PIVALATE (CLODERM) GLUCORTICOIDS
- 26. O CH3 CH3 CH2OH O O HO H H H O C CH3 CH3 DESONIDE (DESOWEN) O CH3 CH3 CH2OH O O HO F H H O C CH3 CH3 F FLUOCINOLONE ACETONIDE (SYNALAR) GLUCOCORTICOIDS used in dermatological preparations
- 27. O CH3 CH3 CH2OH O O HO F H H O AMCINONIDE (CYCLOCORT) O CH3 CH3 CH2OH O O HO F H H O C CH3 CH3 FLUNISOLIDE (NASALIDE) GLUCOCORTICOIDS
- 28. O CH3 CH3 CH2OCOCH3 CH3 O HO H H H OH F PARAMETHASONE ACETATE (HALDRONE) O CH3 CH3 CH2Cl OH O HO F H H CH3 CLOBETASOL (TEMOVATE) GLUCOCORTICOIDS
- 29. O CH3 CH3 CH2OCOCH3 O O HO H H H O C CH3 CH3 F FLUOCINONIDE (LIDEX) O CH3 CH3 CH2Cl O O HO Cl H H O O CH3 MOMETASONE FUROATE (ELOCON) GLUCOCORTICOIDS used in dermatological preparations
- 31. O CH3 CH3 H O HO Cl H CH3 OH F CLOCORTOLONE (CLODERM) O CH3 CH3 H O HO H H CH3 CH3 CH3 RIMEXOLONE (VEXOL)
- 32. O CH3 CH3 S H O HO F H CH3 O CH2-F F C O Et FLUTICASONE PROPIONATE (CUTIVATE) HO O CH3 CH3 H H H O O Et O O Pr n O HYDROCORTISONE PROBUTATE (PANDEL)
- 33. O CH3 CH3 CH2OH O O HO H H H O C CH3 CH3 F FLURANDRENOLIDE (CORDRAN) O CH3 CH3 CH2OH H O HO H H CH3 DESOXIMETASONE (TOPICORT) GLUCOCORTICOIDS used in dermatological products
- 34. O CH3 CH3 CH2Cl O O HO F H H O C CH3 CH3 HALCINONIDE (HALOG) O CH3 CH3 CH2OCOC2H5 OCOC2H5 O HO H H H CH3 Cl ALCLOMETASONE DIPROPIONATE (ACLOVATE) GLUCOCORTICOIDS
- 35. O CH3 CH3 CH2F F O HO F H H O CH3 COC2H5 FLUTICASONE (FLONASE) O CH3 CH3 CH2OH O O HO H H H O C CH2CH2CH3 H BUDESONIDE (RHINOCORT) GLUCORTICOIDS used in inhalation products for asthma and allergies
- 36. O CH3 CH3 O O O H H H Cl OEt O HO LOPREDNOL ETABONATE (LOTEMAX, ALREX) this
- 43. Products for enteric inflammations
- 44. Indications for systemic glucocorticoids • endocrine disorders • primary or secondary adrenocortical insufficiency • congenital adrenal hyperplasia • nonsuppurative thyroiditis • hypercalcemia associated with cancer • shock unresponsive to conventional therapy
- 45. Indications for systemic glucocorticoids • rheumatic disorders • rheumatoid arthritis • ankylosing spondylitis • acute and subacute arthritis • acute nonspecific tenosynovitis • collagen diseases • systemic lupus erythematosus • acute rheumatic carditis • systemic dermatomyositis
- 46. Indications for systemic glucocorticoids • allergic states • seasonal or perennial allergic rhinitis • bronchial asthma • contact dermatitis • atopic dermatitis • serum sickness • drug hypersensitivity reactions
- 47. Indications for systemic glucocorticoids • Dermatological diseases • pemphigus • bullous dermatitis herpetiformis • severe erythema multiforme (Stevens-Johnson) • exfoliative dermatitis • mycosis fungoides • severe psoriasis
- 48. Indications for systemic glucocorticoids • respiratory diseases • symptomatic sarcoidosis • berylliosis • disseminated pulmonary tuberculosis • pulmonary emphysema • aspiration pneumonitis • diffuse interstitial pulmonary fibrosis
- 49. Indications for systemic glucocorticoids • neoplastic diseases • leukemias and lymphomas in adults • acute leukemia of childhood • hematological disorders • idiopathic and secondary thrombocytopenia in adults • acquired (autoimmune) hemolytic anemia
- 50. Indications for systemic glucocorticoids • miscellaneous • ulcerative colitis (via rectal enemas) • trichinosis • dental inflammatory reactions • tuberculous meningitis
- 51. Indications for systemic mineralocorticoids • replacement therapy for primary and secondary insufficiency in Addison’s disease • treatment of salt-losing adrenogenital syndrome • most common agents: aldosterone, desoxycorticosterone and fludrocortisone (Fluorinef) (most commonly used)
- 52. Adrenocortical insufficiency • Acute adrenocortical insufficiency – adrenal crisis (Waterhouse-Friderichsen syndrome) • weakness, dehydration • abdominal pain, high fever • vomiting and diarrhea • low blood pressure and eosinophilia • increased skin pigmentation • low sodium, high potassium serum levels
- 53. Adrenocortical insufficiency • Chronic adrenocortical insufficiency – Addison’s disease • weakness and anorexia • nausea, vomiting and diarrhea • hypotension • sparce axillary hair • increased skin pigmentation of creases, nipples and pressure areas (due to ACTH production) • eosinophilia and lymphocytosis
- 54. Tests for adrenal insufficiency • ACTH test: • give ACTH and measure cortisol (helps to distinguish between primary and secondar adrenal insufficiency) • primary insufficiency: cortisol levels remain low • secondary insufficiency: cortisol levels increase • metyrapone test: • confirmatory test for secondary adrenal insufficiency • metyrapone inhibits 11-beta hydroxylation and thus cortisol synthesis • should result in high ACTH levels (if not, we know the problem is secondary)
- 55. Mineralocorticoid pathway cholesterol ----- pregnenolone -----progesterone --- -----11-deoxycorticosterone ------corticosterone --------aldosterone corticosterone and aldosterone both have mineralocorticoid activity, however are not used therapeutically Aldosterone is the most powerful agent
- 56. FLUDROCORTISONE C H F OH O H CH2OH O HO FLUDROCORTISONE (FLORINEF) a potent steroid with both glucocorticoid and mineralocorticoid activity. Used mainly for its mineralocorticoid activity in Addison’s disease dose: 0.1 mg 2- 7 X weekly
- 57. Adrenocortical overactivity • Cushing’s syndrome or adrenal hyperfunction • Cushing’s disease or pituitary basophilism – buffalo obesity (moon face and buffalo hump) – easy bruisability (ecchymoses) – purple striae – impotence or amenorrhea – osteoporosis – hypertension, glucosuria – low serum potassium – low eosinophils and lymphopenia
- 58. Toxicity of adrenocorticoids • pituitary-adrenal suppression (adrenal insufficiency) • fluid and electrolyte disturbances • hyperglycemia and glucosuria • increased susceptibility to infections • peptic ulceration • myopathy (weakness of muscles of arms and legs) • osteoporosis and vertebral compression fractures • posterior subcapsular cataracts
- 59. C C CH3 H2N NH2 CH3 O AMPHENONE B N C C N CH3 CH3 O METYRAPONE glucocorticoid antagonists amphenone B block hydroxylation at 11, 17 and 21 position. metyrapone is more selective in blocking beta 11-hydroxylation at low doses. Used more commonly in testing adrenal function.
- 60. C CH H Cl Cl Cl Cl MITOTANE N C2H5 O O H NH2 AMINOGLUTETHIMIDE glucocorticoid antagonists mitotane and aminoglutethimide both interfer with the biosynthesis of glucocorticoids. Aminoglutethimide is also an aromatase inhibitor involved in estrogen biosynthesis
- 61. O O N N C O CH2 N Cl Cl N H H3C O KETOCONAZOLE (NIZORAL) O O S C CH3 O O H H H SPIRONOLACTONE (ALDACTONE) spironolactone is a mineralocorticoid antagonist ketoconazole is a non-specific inhibitor of adrenal and gonadal steroid biosynthesis
- 62. Mineralocorticoid receptor antagonists • compounds or drugs which interfer with the action of aldosterone • currently 2 such drugs are available in the U.S. : spironolactone (Aldactone) and eplerenone (Inspra) • other drugs: canrenone, potassium carenoate (not available in the U.S.)
- 63. THANK YOU