第十一章肾上腺皮质激素类药物 ppt课件_1

Chapter 11 Adrenocorticosteroids And Adrenocortical Antagonists Department of Pharmacology, Medical school of Nankai University Jingling Zhang Tel:(office) E-mail: Adrenocorticosteroids 目的 了解如何正确运用此类药物的理 论基础以便充分发挥疗效。避免 或减少不良反应。掌握肾上腺皮 质激素的主要生理、 药理作用， 临床用途，不良反应及应用注意 。 Adrenocorticosteroids 内容 糖皮激素类的 作用 ： 1）生理作用：对糖，蛋白质，脂肪，水盐代谢的作用 。 2） 药理作用 ：抗炎症，抗免疫，抗细菌内毒素，抗休 克，血液，中枢神经系统的影响。分别叙述这些作 用的表现及这些表现发生的可能原因，从有利与不 利两个方面说明抗炎作用与抗免疫作用 。 Adrenocorticosteroids 糖皮质激素的临床应用 ：严重急性感染，缓 解症状，赢得时间；各种炎症；过敏反应 及自身免疫性疾病；休克；某些血液病； 补充疗法；局部治疗皮肤病。 不良反应 ：类似肾上腺皮质功能亢进症，长 期用药导致功能不全，诱发或加重感染， 诱发胃溃疡，延长伤口育合。长期用药的 停药问题。慎用场合与禁忌症。 Adrenocorticosteroids 常用糖皮质激素类药物：可的松，氢化可的松， 泼尼松（强的松），泼尼松龙（强的松龙） ，地塞米松（氟美松），肤氢松，及用法。 盐皮质激素类药物：醛固酮类的作用，用途。 促皮质激素药物的作用，用途。抗皮质激素类药 物的主要临床应用。 Adrenocorticosteroids I. Introduction II. Classification III. Structure-activity relationship IV. Glucocorticoids V. Mineralocorticoids VI. ACTH and adrenocortical antagonists Adrenocorticosteroids Classification adrenal cortex Major hormone Effects on Regulation by Mineralocorticoids zona spherical aldosterone desoxycorticiste rone water CRF, corticotrophin-releasing factor. Figure 28-5 Biosynthesis of corticosteroids and adrenal androgens. structure ring activity example The 4, 5 double bond The 3-keto group The 20-keto group 17- hydroxyl group A A D D maintaining physiological activity hydrocortisone 11-hydroxyl group 17- hydroxyl group C D glucocorticoids cortisol, hydrocortisone The 1, 2 double bond A Increases glucocorticoids activity prednisone The 9 fluorination B enhances both glucocorticoid and mineralocorticoid activity fludrocortisone The 1, 2 double bond The l6-methyl group The l6-hydroxyl group The 9-fluoro group A D D B Increase glucocorticoid activity, decrease mineralocorticoid activity triamcinolone, dexamethasone, betamethasone Structure-activity relationship Adrenocorticosteroids IV. Glucocorticoids 1. Physiological Functions， small dose 2. Pharmacological effects, large dose 3. Pharmacokinetics 4. Mechanism of actions 5. Clinical uses 6. Adverse effects and contraindication 7. Dosage schedule Adrenocorticosteroids 2. Pharmacological effects Anti-inflammatory effect Immunosupporessive effects Antitoxic action Antishock effect other effects Adrenocorticosteroids Anti-inflammatory effect Anti-inflammatory effect of large dose glucocorticoids is very strong. The hormones can inhibit inflammatory reactions caused by various stimulus, such as physical, chemical, biological, allergic stimuli. Adrenocorticosteroids a. In the early stage of inflammation, may prominent abate the inflammatory symptoms. b. In the late stage of inflammation, may avoid formation of adhesion and scar, reduce sequel. be of great value and carry the hazard Adrenocorticosteroids Mechanism of anti-inflammatory actions a. Inhibit inflammatory factors synthesis and release into the blood the formation of lipocortin-1 inhibiting phospholipase A2 inhibit generation of induced nitric oxide synthase and cyclooxygenase-2 (COX-2) NO, PGE2 Induce generation of ACE decompose the bradykinin Adrenocorticosteroids b. inhibit the production of inflammatory factors and increase generation of anti-inflammatory factors interleukin-1, 2, 5, 6 and 8, (IL-1, 2, 5, 6, 8) tumor necrosis factor- (TNF-) interferon- (IFN-) interleukin-10, 12 (IL-10, 12) Inhibitory kappa B1 (IB1) Interleukin-1 receptor antagonist (IL-1RA) Adrenocorticosteroids c. inhibit generation of induced nitric oxide in macrophagocytes and decrease histamine release from basophils. Adrenocorticosteroids 2. Pharmacological effects Anti-inflammatory effect Immunosupporessive effects Antitoxic action Antishock effect other effects Adrenocorticosteroids Immunosupporessive effects a. Inhibit the functions of leukocytes and tissue macrophages. b. Decrease the lymphocytes, monocytes, eosinophils and basophils in number. c. Inhibition of the production and effects of IL-2, impair delayed hypersensitivity reactions. d. May mainly inhibit cellular immunity in small doses and humoral immunity in large doses. Adrenocorticosteroids 2. Pharmacological effects Anti-inflammatory effect Immunosupporessive effects Antitoxic action Antishock effect other effects Adrenocorticosteroids Antitoxic action enhance the tolerance of organism to bacterial endotoxins, but not neutralize bacterial endotoxins, and also have no effects on bacterial exotoxin. Adrenocorticosteroids Large dose steroids have profound effects on decrease the symptoms of intoxication of infective toxemia and antithermic action (cooling). Mechanism: Adrenocorticosteroids This is due to their inhibition of the release endogenic pyrogen and the sensitivity of the heat-regulating- center to the pyrogen. It is also attributed to the remarkable ability of the steroids to stabilize lysosomal membranes. Adrenocorticosteroids 2. Pharmacological effects Anti-inflammatory effect Immunosupporessive effects Antitoxic action Antishock effect other effects Adrenocorticosteroids Antishock effect the supra-large dose steroids is extensive used in clinical treatment of all kinds of severe shock, especially toxic shock. The mechanism of the action has the relation with the following factors: Adrenocorticosteroids a Increase the contraction of the heart muscle and dilate the blood vessels of spasmodic contraction. b Decrease the sensitivity of blood vessels to some vasocontrictive substances and relieve blood vessels spasm, result in the improvement of microcirculation and reduction of symptoms of toxic shock. Adrenocorticosteroids c. Stabilization of lysosomal membranes, reduces the formation of myocardial- depressant factor (MDF) that decrease myocardial contraction force and prevents the release of proteolytic enzymes. d. Anti-inflammation effects e. Immunosupporessive effects f. Antitoxic action Adrenocorticosteroids Other effects a. blood and hematopoietic system b. CNS c. the development of the fetus. d. appear to antagonize the effect of vitamin D and calcium absorption. e. stimulate excessive production of acid and pepsin in the stomach and may cause peptic ulcer. Adrenocorticosteroids 3. Pharmacokinetics Glucocorticoids may be given by a variety of routes. Most are active when given orally. All can be given systemically, either intramuscularly (im) or intravenously (iv). They may also be given topically. In plasma, cortisol is bound to plasma proteins. Corticosteroid-binding globulin （ CBG） Albumin. Both CBG-bound and albumin-bound steroids are biologically inactive. Adrenocorticosteroids Hydrocortisone t1/2 =90 minutes, Tpeak=1-2h. metabolism in the liver, finally excreted in the urine. If there is a double bond between C1-C2 or a fluorin atom at C9, metabolism is slowed. Cortisone and prednisone are inactive until converted in the liver to hydrocortisone and prednisolone, respectively. Adrenocorticosteroids 4. Mechanism Glucocorticoid effects involve interactions between the steroids and intracellular receptors that belong to the superfamily of receptors that control gene transcription. Figure 28-6 Molecular mechanism of action of glucocorticoids The schematic figure shows three possible ways by which the liganded glucocorticoid receptor can control gene expression following translocation to the nucleus. A. Basic transactivation mechanism. Here, the transcriptional machinery (TM) is presumed to be operating at a low level. The liganded glucocorticoid receptor (GR) dimer binds to one or more positive glucocorticoid response elements (GREs) within the promoter sequence (shaded zone) and up-regulates transcription. B. Basic transrepression mechanism. The transcriptional machinery is constitutively driven by transcription factors (TF). In binding to the negative GRE (nGRE), the receptor complex displaces these factors and expression falls. C. Fos/Jun mechanism. Transcription is driven at a high level by Fos/Jun transcription factors binding to their AP-1 regulatory site. This effect is reduced in the presence of the GR. D. Nuclear factor B mechanism. The transcription factors P65 and P50 bind to the NFB site, promoting gene expression. This is prevented by the presence of the GR, which binds the transcription factors, preventing their action (this may occur in the cytoplasm also). Adrenocorticosteroids 5. Clinical uses Replacement therapy for patients with adrenocortical insufficiency a. Chronic adrenocorticoids insufficiency (Addisons disease) b. Acute adrenocorticoids insufficiency (adrenal crisis) Adrenocorticosteroids Severe infectious disease Autoimmune diseases and allergic diseases Shock Hematologic disorders topical uses Adrenocorticosteroids 6. Adverse effects and contraindication Adverse effects a. Iatrogenic Cushings syndrome Caused by glucocorticoids therapy with large doses in long-term b. Caused by withdrawal of therapy Contraindications acute adrenal insufficiency If therapy is to be stopped, the reduction process should be quite slow. It will take 2-3 months for the pituitary to become responsive. Figure 28-7 Cushings syndrome. Adrenocorticosteroids Contraindications peptic ulcer, heart disease or hypertension with CHF (congestive heart failure), infectious, herpes simplex infection, psychoses, diabetes, os