1、Chapter 11 Adrenocorticosteroids And Adrenocortical Antagonists,Department of Pharmacology, Medical school of Nankai University Jingling Zhang Tel: 022-23504374 (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
2、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。,Adrenocorticoste
3、roids,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,Introduction Classification Structure-activity relationship Glucocorticoids Mineralocorticoids ACTH and adrenocortical antagonists,Adrenocorticosteroids,All of
4、adrenocortical hormones are synthesized from cholesterol.,Figure 28-4 Regulation of synthesis and secretion of adrenal corticosteroids. The long negative feedback loop is more important than the short loop (dashed lines). Adrenocorticotrophic hormone (ACTH, corticotrophin) has only a minimal effect
5、on mineralocorticoid production. Drugs are shown in yellow boxes. ADH, antidiuretic hormone (vasopressin); CRF, corticotrophin-releasing factor.,Figure 28-5 Biosynthesis of corticosteroids and adrenal androgens.,Structure-activity relationship,Adrenocorticosteroids,Glucocorticoids Physiological Func
6、tions，small dose Pharmacological effects, large dose Pharmacokinetics Mechanism of actions Clinical uses Adverse effects and contraindication Dosage schedule,Adrenocorticosteroids,Pharmacological effects Anti-inflammatory effect Immunosupporessive effects Antitoxic action Antishock effect other effe
7、cts,Adrenocorticosteroids,Anti-inflammatory effectAnti-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,In the early stage of i
8、nflammation, may prominent abate the inflammatory symptoms. 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 Inhibit inflammatory factors synthesis and relea
9、se 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,inhibit the production of inflammatory factors and increase gen
10、eration 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,inhibit generation of induced nitric oxide
11、 in macrophagocytes and decrease histamine release from basophils.,Adrenocorticosteroids,Pharmacological effects Anti-inflammatory effect Immunosupporessive effects Antitoxic action Antishock effect other effects,Adrenocorticosteroids,Immunosupporessive effects Inhibit the functions of leukocytes an
12、d tissue macrophages. Decrease the lymphocytes, monocytes, eosinophils and basophils in number. Inhibition of the production and effects of IL-2, impair delayed hypersensitivity reactions. May mainly inhibit cellular immunity in small doses and humoral immunity in large doses.,Adrenocorticosteroids,
13、Pharmacological effects Anti-inflammatory effect Immunosupporessive effects Antitoxic action Antishock effect other effects,Adrenocorticosteroids,Antitoxic actionenhance the tolerance of organism to bacterial endotoxins, but not neutralize bacterial endotoxins, and also have no effects on bacterial
14、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-
15、regulating-center to the pyrogen. It is also attributed to the remarkable ability of the steroids to stabilize lysosomal membranes.,Adrenocorticosteroids,Pharmacological effects Anti-inflammatory effect Immunosupporessive effects Antitoxic action Antishock effect other effects,Adrenocorticosteroids,
16、Antishock effectthe 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,Increase the contraction of the heart muscle and dilate the blood
17、 vessels of spasmodic contraction. 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,Stabilization of lysosomal membranes, reduces
18、 the formation of myocardial-depressant factor (MDF) that decrease myocardial contraction force and prevents the release of proteolytic enzymes. Anti-inflammation effects Immunosupporessive effects Antitoxic action,Adrenocorticosteroids,Other effects blood and hematopoietic system CNS the developmen
19、t of the fetus. appear to antagonize the effect of vitamin D and calcium absorption. stimulate excessive production of acid and pepsin in the stomach and may cause peptic ulcer.,Adrenocorticosteroids,Pharmacokinetics Glucocorticoids may be given by a variety of routes. Most are active when given ora
20、lly. 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.,Adrenocorticosteroids,Hydrocortisone t1/2 =90 minutes, Tpeak=1-2h. metabolism in th
21、e 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,MechanismGlucocorticoid effects in
22、volve 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 c
23、an control gene expression following translocation to the nucleus. 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 (GRE
24、s) within the promoter sequence (shaded zone) and up-regulates transcription. 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 fall
25、s. 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. Nuclear factor B mechanism. The transcription factors P65 and P50 bind to the NFB site, promoting gene expression. T
26、his is prevented by the presence of the GR, which binds the transcription factors, preventing their action (this may occur in the cytoplasm also).,Adrenocorticosteroids,Clinical uses Replacement therapy for patients with adrenocortical insufficiency Chronic adrenocorticoids insufficiency (Addisons d
27、isease) Acute adrenocorticoids insufficiency (adrenal crisis),Adrenocorticosteroids,Severe infectious disease Autoimmune diseases and allergic diseases Shock Hematologic disorders topical uses,Adrenocorticosteroids,Adverse effects and contraindication Adverse effects Iatrogenic Cushings syndrome Cau
28、sed by glucocorticoids therapy with large doses in long-term 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 syn
29、drome.,Adrenocorticosteroids,Contraindications peptic ulcer, heart disease or hypertension with CHF (congestive heart failure), infectious, herpes simplex infection, psychoses, diabetes, osteoporosis, glaucoma,Adrenocorticosteroids,alternate-day administration special dosage forms for the use of loc
30、al therapy,Adrenocorticosteroids,Mineralocorticoids Aldosterone Desoxycortone,increases Na+ reabsorption in distal tubules and increases K+ and H+ efflux into the tubules acts on intracellular receptors that modulate DNA transcription, causing synthesis of protein mediators. is used together with a
31、glucocorticoid in replacement therapy.,Adrenocorticosteroids,ACTH and inhibitors of adrenocortical hormones ACTH Mitotan Metyrapone,Adrenocorticotrophic hormone (ACTH) stimulates synthesis and release of glucocorticoids (e.g. hydrocortisone), and also some androgens, from the adrenal cortex.,Thank you !,
