药理学5肾上腺糖皮质激素药课件

1、肾上腺皮质激素类药物 Adrenocorticosteroids北京大学医学部基础药理学系 祝晓玲Anatomy and function of adrenal cortex肾上腺皮质结构和功能球状带（盐皮质激素） 15% of adrenal cortexZona glomerulosa- ( mineralocorticoids) 束状带（糖皮质激素） 78% of adrenal cortexZona fasciculata -(glucocorticoids)网状带（肾上腺雄激素 ） 7% of adrenal cortexZona reticularis-(adrenal andro

2、gens）123regulating salt and water metabolismmetabolism and resistance stress.共同的结构特点: C3有酮基， C4-5有双键， C18和C19有甲基 C17上的二碳侧链(即C20羰基和C21羟基)为生理活性所必需。皮质激素：具有甾体母核的生物活性物质的总称CH3CH3 C1-2为双键以及C6引入-CH3则抗炎作用及对糖代作用, 水盐代谢作用； C9引入-F，C16引入-CH3或-OH则抗炎作用,水盐代谢作用。经过结构改造，由此获得多种合成的糖皮质激素药物。 盐皮质激素结构特点： C17上无羟基， C11无氧（11-去氧

3、皮质酮）,或有氧但与C18醛基形成内脂环（醛固酮）. Adrenocortical Hormones肾上腺皮质激素OH=O糖皮质激素结构特点： C17上有羟基， C11位有酮基或羟基。HypothalamusPituitaryAdrenalCRHACTHRegulation of glucocorticoids secretion糖皮质激素分泌调节Glucocorticoids+exogenous GC(GC)糖皮质激素Anti-inflammationImmunosuppressioninhibit+stimulateLong negative feedbackShort negative

4、feedbackHPAa下丘脑垂体肾上腺CRH：促肾上腺皮 质激素释放激素ACTH：促肾上腺 皮质激素 糖皮质激素分泌：昼夜节律性(午夜最低，上午8-10时最高)，此节律性变化受ACTH影响。 在GC血浓度高时，HPAa对影响其分泌的因素不敏感，而在GC血浓度低时则相反。Glucocorticoids, GC 糖皮质激素体内过程：口服，注射均可。与血浆蛋白结合率高（90%）肝脏代谢主要在肾排泄 可的松，泼尼松在肝转化为氢化可的松、泼尼松龙而生效。药物分类： 按t1/2长短而分Physiological effects生理作用Glucose metabolism糖代谢Protein metabo

5、lism蛋白质代谢Adipose metabolism 脂肪代谢Salt and water metabolism水盐代谢Hematopoiesis and destruction of blood cells造血和血细胞破坏Vascular response血管反应Enhance ability to handle stress增强抗应激Glucocorticoids, GC-naturally secretion: cortisol(皮质醇)/ hydrocortisone（氢化可的松）1237456Glucose metabolism糖代谢Glucocorticoids, GC1bloo

6、d glucose血糖, muscle glycogen 肌糖原 and liver glycogen levels 肝糖原by: - gluconeogenesis(糖原异生); - gluconeogenic enzyme activity糖异生酶活性; - hepatic and renal amino acid (aa) uptake, and aa are converted to glucose 肝肾氨基酸摄取，将氨基酸转变成糖; -peripheral glucose uptake and utilization 外周血糖摄取和利用. Promote hyperglycemia

7、and glycosuria促进高血糖和糖尿 diabetic state糖尿病Protein metabolism蛋白质代谢2Supraphysiologic glucocorticoid levels cause超生理剂量GC decreased muscle mass, weakness, osteoporosis(骨质疏松), Reduced growth in children, delay a wound heals儿童生长、伤口愈合延迟.Promote protein catabolism促进蛋白质分解代谢 and inhibit protein synthesis抑制蛋白质合成

8、. - catabolism分解代谢 (lymphoid tissue, connective tissue, muscle, fat, skin ) -Protein catabolism蛋白质分解negative nitrogen balance负氮平衡 - Transfer aa from muscle and bone to liver, where aa are converted to glucose 转移肌肉和骨中氨基酸至肝转化为葡萄糖.Promote lipolysis(脂肪分解), inhibit lipogenesis（抑制脂肪生成 ）, and fat is redist

9、ributed脂肪重分布 - increase in plasma free fatty acids 游离脂肪酸 - enhanced tendency to ketosis(诱发酮症 )Adipose metabolism脂肪代谢3Glucocorticoids, GCA prolonged GC therapy results hypertension, moon face, truncal obesity, buffalo hump, and limbs are thin and small. 长期给GC 高血压、满月脸、向心性肥胖、 水牛背、四肢瘦小Salt and water met

10、abolism水盐代谢Principal mineralocorticoid盐皮质激素: aldosterone(醛固酮)sodium reabsorption and potassium excretion 保钠排钾. - intestinal absorption of calcium and promote calcium excretion by the kidney 肠道钙吸收，肾脏排钙 - GC mediate weak mineralocorticoid-like effects. 弱的盐皮质激素样作用Glucocorticoids, GC4 Serum calcium 血钙，s

11、erum potassium血钾 , hypertension 高血压 and osteoporosis骨质疏松Large dose of GC（大量GC）: - platelet血小板，neutrophil中性粒细胞, fibrinogen纤维蛋白原 - lymphocyte淋巴细胞, monocyte单核细胞, eosinophil 嗜酸性细胞，basophil嗜碱性细胞 - Inhibit neutrophil function 抑制中性粒细胞功能 Glucocorticoids, GCHematopoiesis and destruction of blood cells造血和血细胞破

12、坏5 GC secretion resistance to stress抗应激 -Increased stress应激增加: trauma创伤, fright战斗, infection感染, blooding出血 or debilitating disease衰弱性疾病.Enhance ability to handle stress增强抗应激Glucocorticoids, GC76Vascular response血管反应sensitivity of vascular smooth muscle to NA血管平滑肌对NA敏感性; capillary permeability毛细血管通透性

13、Pharmacological effects 药理作用Anti-inflammatory action抗炎Immunosuppression免疫抑制Anti-endotoxin抗内毒素Anti-shock抗休克Effects on component of blood对血液影响Central nervous system (CNS) effects中枢作用Additional effects其它Glucocorticoids, GC1237456Anti-inflammatory 抗炎 supraphysiologic dose大剂量: strong effect作用强.- Ameliora

14、te inflammatory symptoms 改善炎症.- Inhibit proliferation of capillary and fibroblast 抑制毛细血管和成纤维细胞增生 prevent adhesion and scar 防止粘连和疤痕Glucocorticoids, GC1Mechanism抗炎机制 inhibit抑制:- interactions involving cell adhesion molecules 细胞粘附分子相互作用- leukocyte and tissue macrophage function 白细胞和组织巨噬细胞功能- reduced an

15、tigenic and mitogenic responsiveness 降低抗原和有丝分裂原反应- Reduction of prostaglandin and leukotriene synthesis (inhibit phospholipase A2 activation) 前列腺素和白三烯合成（抑制磷脂酶A2 活性）- Reduction of cyclooxygenase in inflammatory cells (reducing prostaglandin synthesis) 炎症细胞环氧酶， 前列腺素合成 Immunosuppressive effects 免疫抑制-de

16、generation of DNA in lymphocyte淋巴细胞DNA变性-induce of apoptosis of lymphocyte 诱导淋巴细胞凋亡-inhibited the activity of NF-kB抑制NF-kB活性- production of antibody降低抗体生成 -inhibiting the release of histamine抑制组胺 , kinin激肽 ,5-HT and other stimulant of sensitivity reaction抑制过敏介质释放 -inhibition of process of immunity抑制

17、免疫过程2Glucocorticoids, GCAntiallergy action 抗过敏Anti-endotoxin抗内毒素 tolerance to bacterial endotoxin细菌内毒素耐受, diminute heat 退热and alleviate toxaemia缓解毒血症. 3Glucocorticoids, GCAnti-shock抗休克4- output of heart心输出- construction of the myocardium心肌收缩;-Dilution of the capillary blood vessel扩毛细血管, perfusion in

18、 tissue组织灌注.- Stabling membrane of lysosome稳定溶酶体膜 production of myocardial depressant factor. 减少心肌抑制因子产生-减少: monocytes单核细胞, lymphocytes淋巴细胞, eosinophils and basophils嗜酸性粒细胞和嗜碱性粒细胞-增加: hemoglobin血红蛋白, erythrocyte红细胞, platelets 血小板and polymorphonuclear leukocytes多形核白细胞Effects on component of blood对血液影

19、响5Glucocorticoids, GCCNS excitability增强中枢兴奋: euphoria欣快, insomnia失眠, excitement兴奋. A few persons少数人: mania躁狂, depression抑郁, or mood disturbances 精神紊乱.Central nervous system (CNS) effects中枢作用6Glucocorticoids, GC1. temperature体温 -interfere production of PG前列腺素产生2. CNS - inhibitory neurotransmitter GAB

20、A抑制性神经递质GABA, exciting兴奋psychoses精神病, epilepsy 癫痫and euphoria欣快3. Bone system - Osteoporosis骨质疏松4. gastrointestinal system胃肠道 -inducing ulcer 诱发溃疡 -stimulate gastric acid and pepsin production 刺激胃酸、胃蛋白酶产生5. Benefit development of fetal lungs 利于胎肺发育成熟Additional effects of GC其它作用7Mechanism of Action o

21、f GC作用机制-Receptors bound to heat shock proteins (Hsp) -Free GC hormone enters the cell -Binds to receptor, inducing a conformational change -Receptor dissociates from Hsp proteins, GC-R complex associate to form homodimers -Homodimers nuclear translocation -Homodimers bind to GC response elements of

22、 target genes-Genomic effects Transcription activated-protein synthesized; GC-R interact with NFB and AP-1 to inhibit gene expressionGC action through GC receptors 经GC受体发挥作用Clinical uses of GC 临床应用Replacement therapy for adrenal insufficiency (Addisons disease)肾上腺皮质功能不全替代治疗 -Acute adrenal insufficie

23、ncy (Adrenal crisis ) is a life threatening condition requiring immediate intravenous GC and saline.急性肾上腺皮质功能不全(肾上腺危象)危及生命,立即i.v.GC和生理盐水。 - 2/3 of the dose is administered in the morning to mimic the physiological levels.清晨给予2/3的剂量来模拟体内糖皮质激素的生理水平。 -A mineralocorticoid is added if the sufficiency is

24、primary (adrenal), but is not necessary for a second insufficiency (pituitary).如果原发性肾上腺功能不全，需加用盐皮质激素，但若为继发性肾上腺功能不全（如垂体病变）则不用加盐皮质激素。 1Inflammatory states炎症-Symptomatic relief; reduce the inflammatory attack, but not cure disease.缓解炎症症状， 降低炎症侵袭，但不能治愈炎症。-Combine with sufficient antibiotic in bacterial

25、infections.细菌感染必须合用足量的抗生素。 2Clinical uses of GC 临床应用3Self- immunity Diseases自身免疫性疾病Lupus erythematosus, Rheumatoid arthritis, rheumatic , nephrotic syndrome.红斑狼疮，类风湿关节炎，风湿病，肾病综合征4Allergic Diseases过敏 -inhibiting the release of histamine , kinin ,5-HT and other stimulant of sensitivity reaction抑制组胺、激肽

26、、5-HT 和其它致敏介质释放 -inhibition of process of immunity抑制免疫过程- Severe asthma, serum sickness, angioneurotic edema, prevention and treatment of organ transplant rejection (combination with immunosuppressive agents).重度哮喘、血清病、血管神经性水肿，与免疫抑制剂合用防治器官移植后的排斥反应。Shock休克Prompt intensive GC may be lifesaving in septi

27、c shock. Restore cardiac output and reverse hypotension. 感染性休克：足量有效的抗生素+糖皮质激素 （早期、大量、突击使用） -增加心输出量和血压Clinical uses of GC 临床应用56Leukemia白血病Hematopoietic malignancies, chronic lymphocytic leukemia and multiple myeloma.血液学恶性肿瘤、慢性淋巴性白血病、多发性骨髓瘤。Long-term and higher doses： -induce and aggravate infection

28、-induce and aggravate ulcer, even stomach haemorrhage and perforation . - euphoria, insomnia.（contraindications : psychiatric and epileptic seizure）长期大剂量 糖皮质激素： -诱发加重感染 -诱发加重胃溃疡、胃出血和胃穿孔. - 兴奋、失眠. （禁忌：精神病和癫痫发作）Adverse effects of GC 副作用1向心性肥胖欣快(有时抑郁或情绪不稳定及其它精神症状)还有：负氮平衡,食欲增加,低血钾,高血压倾向,消化性溃疡Withdrawal

29、Reaction撤药反应： Iatrogenic adrenocortical insufficiency医源性肾上腺皮质功能不全 -Negative feedback, ACTH adrenal cortex atrophy，vomit，nausea, hypotension, hypoglycemia (low blood sugar)-负反馈 ACTH 肾上腺皮质萎缩，恶心呕吐、低血压、低血糖。 A. Therapy abrupt cessation治疗突然中止造成;B. maintenance dosage or following day therapy预防：应给予维持量或隔日疗法;

30、C. Promptly treat enough GC. 及时给予足量糖皮质激素，待症状缓解后，逐渐减量而停药。 Adverse effects of GC 副作用2Rebound reaction and withdrawal symptoms-Reduction process quite fast or abrupt cessation after long-term therapy: symptoms aggravate, fever, muscular pain, joint pain.停药反跳 /停药综合征 -长期用药后突然停药/撤药太快：病情恶化、发热、肌肉和关节痛。3Adverse effects of GC 副作用Regimens for prevention of adrenocortical atrophy防止肾上腺皮质萎缩疗法Cortisol secretion is high in the early morning and low in the late evening (circadian rhythm昼夜节律). a) Circadian administration每日疗法: The daily dose of GC is given in morning. Endogenous cortisol production will have