Corticosteroids รศ. พญ. มาล ยา มโนรถ. Corticosteroids ภาคว ชาเภส ชว ทยา จ ดประสงค การศ กษา
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1 ภาคว ชาเภส ชว ทยา จ ดประสงค การศ กษา เม อส นส ดการเร ยนการสอน และการศ กษาด วยตนเองเพ มเต ม น กศ กษา สามารถ ทราบถ งชน ดของ glucocorticoid ธรรมชาต ท ส าค ญและกลไกการออกฤทธ ทราบถ งชน ดของ glucocorticoids ส งเคราะห และความแตกต างระหว าง synthetic glucocorticoids ส งเคราะห และ glucocorticoid ธรรมชาต ทราบถ งไกการออกฤทธ mineralocorticoid ธรรมชาต และ mineralocorticoid ส งเคระห ทราบถ งข อบ งช ของการใช corticosteroids ในการร กษาโรคท ม ความผ ดปกต ของต อมหมวกไตและโรคอ นๆ ทราบถ ง toxic effects ของการร กษาด วย glucocorticoid เป นเวลานาน 1
2 Adrenocorticosteroids Emotional stress Trauma Diurnal rhythms negative inhibition Hypothalamus CRF Anterior pituitary gland ACTH Adrenal cortex Adrenal steroids Adrenocorticosteroids Glucocorticoids important effects on intermediary metabolism Mineralocorticoids salt-retaining activity Sex hormones androgenic or estrogenic activity Glucocorticoids Natural steroids : cortisol (hydrocortisone), cortisone Synthetic steroids : prednisolone, triamcinolone 2
3 Natural glucocorticoids : cortisol syntesized in the adrenal cortex from cholesterol exerts a wide range of physiologic varies during the day (circadian rhythm) in plasma : 95% bound to corticosteroid-binding globulin (CBG), 5-10 % : free form half-life min many cortisol metabolites are conjugated with glucuronic acid or sulfate in the liver Normal daily production rates & circulating levels of the predominant corticosteroids Cortisol Aldosterone Rate of secretion under optimal conditions 10 mg/day mg/day Concentration in peripheral plasma 8 A.M. 16 ug/100 ml 0.01 ug/100 ml 4 P.M. 4 ug/100 ml 0.01 ug/100 ml Corticosteroid secretion : diurnal rhythm Stress : increase tenfold 3
4 Mechanism of action H + R (cytosolic receptor) hsp 90 HRC GREs (glucorticorticoid response element : nucleus) Expression Glucocorticoid effects Metabolic effects : * important dose-related effects on carbohydrate, protein, and fat metabolism * stimulate and are required for gluconegenesis, and glycogen synthesis in the fasted state Catabolic effects : * in lymphoid and connective tissue, muscle, fat, and skin * bone (osteoporosis) Anti-inflammatory and immunosuppressive effects Other effects : large doses of glucocorticoid : associated with the development of peptic ulcer (suppressing the immune response against Helicobacter pylori) 4
5 Synthetic glucocorticoids prednisolone, dexamethasone, triamcinolone PO : rapidly and completely absorbed prednisone is rapidly converted to active product prednisolone in the body the actions : similar to cortisol, bind to intracellular receptor Some commonly used natural and synthetic corticosteroid Activity Anti-inflammatory Salt-retaining Topical Short- to medium-acting glucocorticoids (8-12 h) Cortisol Cortisone Prednisolone Intermediate-acting glucocorticoids (12-36 h) Triamcinolone 5 0 5* Long-acting glucocorticoids (36-72 h) Betamethasone Dexamethasone Mineralocorticoids Fludrocortisone Desoxycorticosterone acetate * Acetonitride : up to 100 5
6 Special dosage forms Budesonide & flunisolide : aerosols : asthma Beclomethasone dipropionate, triamcinolone acetonide, budesonide, flunisolide : topical spray for allergic rhinitis (too low to influence adrenal function or have any other systemic effects) Clinical Uses Replacement therapy acute adrenal insufficiency chronic adrenal insufficiency Nonendocrine diseases rheumatic disorders renal diseases : membranous glomerulonephritis allergic disease bronchial asthma skin diseases 6
7 Toxicity Withdrawal of therapy * Acute adrenal insufficiency Continued use of supraphysiologic corticosteroid dose * fluid & electrolyte abnormalities : edema, hypertension * immune responses : increased susceptibility to infection * hyperglycemia * osteoporosis * myopathy : weakness of proximal limb muscles * growth arrest Mineralocorticoids Aldosterone the major natural mineralocorticoid in human secretion : is regulated by ACTH, and reninangiotensin system short half-life (15-20 min) Effects : Na + reabsorption, K + excretion metabolism : similar cortisol Fludrocortisone with both glucocorticoid & mineralocorticoid activity 7
8 Corticosteroid Antagonists Glucocorticoid antagonists Metyrapone : test of adrenal function Ketoconazole : Cushing s disease due to several causes Mifepristone (RU 486) : Cushing s syndrome due to ectopic ACTH production Mineralocorticoid antagonists Spironolactone : 1 O aldosteronism 8
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