肾上腺皮质激素类药物 课件.ppt

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1、肾上腺皮质激素类药物 第1页，此课件共48页哦Adrenocorticosteroids目的目的 了解如何正确运用此类药物的理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。掌握肾上腺皮或减少不良反应。掌握肾上腺皮质激素的主要生理、质激素的主要生理、药理作用，药理作用，临床用途，不良反应及应用注意临床用途，不良反应及应用注意。第2页，此课件共48页哦Adrenocorticosteroids内容内容糖皮激素类的作用糖皮激素类的作用：1）生理作用：对糖，蛋白质，脂肪，水盐代谢的作用。2）药理作用药理作用：抗炎症，抗免疫，抗细菌内毒素，抗休克，血

2、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。第3页，此课件共48页哦Adrenocorticosteroids糖皮质激素的临床应用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。第4页，此课件共48页哦Adrenocorticosteroids常用糖皮质激素类药物：可的松，氢化可的松，泼尼松

3、（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。第5页，此课件共48页哦AdrenocorticosteroidsI.Introduction II.Classification III.Structure-activity relationshipIV.GlucocorticoidsV.MineralocorticoidsVI.ACTH and adrenocortical antagonists第6页，此课件共48页哦AdrenocorticosteroidsClass

4、ificationadrenal cortexMajor hormoneEffects onRegulation byMineralocorticoidszona spherical aldosteronedesoxycorticisteronewater&electrolyte balanceangiotensin&extracellular K+Glucocorticoidszona fasciculatahydrocortisonecortisonecarbohydrate,protein&fat metabolismACTHSex hormonezona reticularis and

5、rogens estrogensACTHAll of adrenocortical hormones are synthesized from cholesterol.第7页，此课件共48页哦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,corticotr

6、ophin)has only a minimal effect on mineralocorticoid production.Drugs are shown in yellow boxes.ADH,antidiuretic hormone(vasopressin);CRF,corticotrophin-releasing factor.第8页，此课件共48页哦Figure 28-5 Biosynthesis of corticosteroids and adrenal androgens.第9页，此课件共48页哦structureringactivityexampleThe 4,5 doub

7、le bondThe 3-keto groupThe 20-keto group17-hydroxyl groupAA DDmaintainingphysiological activity hydrocortisone11-hydroxyl group 17-hydroxyl group CDglucocorticoidscortisol,hydrocortisone The 1,2 double bond AIncreases glucocorticoids activityprednisoneThe 9 fluorination B enhances both glucocorticoi

8、d and mineralocorticoid activityfludrocortisoneThe 1,2 double bond The l6-methyl group The l6-hydroxyl group The 9-fluoro group ADDBIncrease glucocorticoid activity,decrease mineralocorticoid activitytriamcinolone,dexamethasone,betamethasoneStructure-activity relationship第10页，此课件共48页哦Adrenocorticost

9、eroidsIV.Glucocorticoids1.Physiological Functions，small dose 2.Pharmacological effects,large dose3.Pharmacokinetics 4.Mechanism of actions5.Clinical uses6.Adverse effects and contraindication7.Dosage schedule第11页，此课件共48页哦Adrenocorticosteroids2.Pharmacological effectsAnti-inflammatory effect Immunosu

10、pporessive effects Antitoxic action Antishock effect other effects 第12页，此课件共48页哦AdrenocorticosteroidsAnti-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,bio

11、logical,allergic stimuli.第13页，此课件共48页哦Adrenocorticosteroidsa.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 第14页，此课件共48页哦Adrenocorticost

12、eroidsMechanism of anti-inflammatory actionsa.Inhibit inflammatory factors synthesis and release into the blood the formation of lipocortin-1 inhibiting phospholipase A2inhibit generation of induced nitric oxide synthase and cyclooxygenase-2(COX-2)NO,PGE2 Induce generation of ACE decompose the brady

13、kinin第15页，此课件共48页哦Adrenocorticosteroidsb.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

14、antagonist(IL-1RA)第16页，此课件共48页哦Adrenocorticosteroidsc.inhibit generation of induced nitric oxide in macrophagocytes and decrease histamine release from basophils.第17页，此课件共48页哦Adrenocorticosteroids2.Pharmacological effectsAnti-inflammatory effect Immunosupporessive effects Antitoxic action Antishock

15、effect other effects 第18页，此课件共48页哦AdrenocorticosteroidsImmunosupporessive effectsa.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 re

16、actions.d.May mainly inhibit cellular immunity in small doses and humoral immunity in large doses.第19页，此课件共48页哦Adrenocorticosteroids2.Pharmacological effectsAnti-inflammatory effect Immunosupporessive effects Antitoxic action Antishock effect other effects 第20页，此课件共48页哦AdrenocorticosteroidsAntitoxic

17、 action enhance the tolerance of organism to bacterial endotoxinsendotoxins,but not neutralize bacterial endotoxins,and also have no effects on bacterial exotoxin.第21页，此课件共48页哦AdrenocorticosteroidsLarge dose steroids have profound effects on decrease the symptoms of intoxication of infective toxemia

18、 and antithermic action(cooling).Mechanism:第22页，此课件共48页哦AdrenocorticosteroidsThis is due to their inhibition of the release endogenic pyrogenendogenic pyrogen and the sensitivitysensitivity of the heat-regulating-center to the pyrogen.It is also attributed to the remarkable ability of the steroids t

19、o stabilize lysosomal membranes.第23页，此课件共48页哦Adrenocorticosteroids2.Pharmacological effectsAnti-inflammatory effect Immunosupporessive effects Antitoxic action Antishock effect other effects 第24页，此课件共48页哦AdrenocorticosteroidsAntishock effect the supra-large dose steroids is extensive used in clinica

20、l treatment of all kinds of severe shock,especially toxic shock.The mechanism of the action has the relation with the following factors:第25页，此课件共48页哦AdrenocorticosteroidsaIncrease the contraction of the heart muscle and dilate the blood vessels of spasmodic contraction.bDecrease the sensitivity of b

21、lood vessels to some vasocontrictive substances and relieve blood vessels spasm,result in the improvement of microcirculation and reduction of symptoms of toxic shock.第26页，此课件共48页哦Adrenocorticosteroidsc.Stabilization of lysosomal membranes,reduces the formation of myocardial-depressant factor(MDF)th

22、at decrease myocardial contraction force and prevents the release of proteolytic enzymes.d.Anti-inflammation effectse.Immunosupporessive effectsf.Antitoxic action第27页，此课件共48页哦AdrenocorticosteroidsOther effectsa.blood and hematopoietic systemb.CNSc.the development of the fetus.d.appear to antagonize

23、the effect of vitamin D and calcium absorption.e.stimulate excessive production of acid and pepsin in the stomach and may cause peptic ulcer.第28页，此课件共48页哦Adrenocorticosteroids3.Pharmacokinetics Glucocorticoids may be given by a variety of routes.Most are active when given orally.All can be given sys

24、temically,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.第29页，此课件共48页哦AdrenocorticosteroidsHydrocortisone t1

25、/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.第30页，此课件共48页哦Adrenoco

26、rticosteroids4.Mechanism Glucocorticoid effects involve interactions between the steroids and intracellular receptors that belong to the superfamily of receptors that control gene transcription.第31页，此课件共48页哦第32页，此课件共48页哦第33页，此课件共48页哦Figure 28-6 Molecular mechanism of action of glucocorticoids The sc

27、hematic 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 rec

28、eptor(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

29、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 transcripti

30、on 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).第34页，此课件共48页哦Adrenocorticosteroids5.Clinical usesReplacement therapy for patients with

31、 adrenocortical insufficiencya.Chronic adrenocorticoids insufficiency(Addisons disease)b.Acute adrenocorticoids insufficiency(adrenal crisis)第35页，此课件共48页哦AdrenocorticosteroidsSevere infectious diseaseAutoimmune diseases and allergic diseasesShockHematologic disorderstopical uses第36页，此课件共48页哦Adrenoco

32、rticosteroids6.Adverse effects and contraindicationAdverse effectsa.Iatrogenic Cushings syndrome Caused by glucocorticoids therapy with large doses in long-termb.Caused by withdrawal of therapy Contraindications acute adrenal insufficiencyIf therapy is to be stopped,the reduction process should be q

33、uite slow.It will take 2-3 months for the pituitary to become responsive.第37页，此课件共48页哦AdrenocorticosteroidsContraindicationspeptic ulcer,heart disease or hypertension with CHF(congestive heart failure),infectious,herpes simplex infection,psychoses,diabetes,osteoporosis,glaucoma,第39页，此课件共48页哦Adrenoco

34、rticosteroidsDosage schedulediseasesFor examplecommon dose and long termchronic and nonadrenal disorderasthma,rheumatoid arthritisreplacement therapy in a small dosechronic adrenal insufficiencyAddisons diseaselarge doses and short coursesevere diseases Various severe intoxicated infections shocksal

35、ternate-day administration special dosage forms for the use of local therapy第40页，此课件共48页哦AdrenocorticosteroidsV.Mineralocorticoids1.Aldosterone 2.Desoxycortone increases Na+reabsorption in distal tubules and increases K+and H+efflux into the tubules acts on intracellular receptors that modulate DNA

36、transcription,causing synthesis of protein mediators.is used together with a glucocorticoid in replacement therapy.第41页，此课件共48页哦AdrenocorticosteroidsVI.ACTH and inhibitors of adrenocortical hormones1.ACTH2.Mitotan3.Metyrapone Adrenocorticotrophic hormone(ACTH)stimulates synthesis and release of glucocorticoids(e.g.hydrocortisone),and also some androgens,from the adrenal cortex.第42页，此课件共48页哦第43页，此课件共48页哦