藥理學(xué)5腎上腺糖皮質(zhì)激素藥課件

1、腎上腺皮質(zhì)激素類藥物 Adrenocorticosteroids北京大學(xué)醫(yī)學(xué)部基礎(chǔ)藥理學(xué)系 祝曉玲Anatomy and function of adrenal cortex腎上腺皮質(zhì)結(jié)構(gòu)和功能球狀帶（鹽皮質(zhì)激素） 15% of adrenal cortexZona glomerulosa- ( mineralocorticoids) 束狀帶（糖皮質(zhì)激素） 78% of adrenal cortexZona fasciculata -(glucocorticoids)網(wǎng)狀帶（腎上腺雄激素 ） 7% of adrenal cortexZona reticularis-(adrenal andro

2、gens）123regulating salt and water metabolismmetabolism and resistance stress.共同的結(jié)構(gòu)特點: C3有酮基， C4-5有雙鍵， C18和C19有甲基 C17上的二碳側(cè)鏈(即C20羰基和C21羥基)為生理活性所必需。皮質(zhì)激素：具有甾體母核的生物活性物質(zhì)的總稱CH3CH3 C1-2為雙鍵以及C6引入-CH3則抗炎作用及對糖代作用, 水鹽代謝作用； C9引入-F，C16引入-CH3或-OH則抗炎作用,水鹽代謝作用。經(jīng)過結(jié)構(gòu)改造，由此獲得多種合成的糖皮質(zhì)激素藥物。 鹽皮質(zhì)激素結(jié)構(gòu)特點： C17上無羥基， C11無氧（11-去氧

3、皮質(zhì)酮）,或有氧但與C18醛基形成內(nèi)脂環(huán)（醛固酮）. Adrenocortical Hormones腎上腺皮質(zhì)激素OH=O糖皮質(zhì)激素結(jié)構(gòu)特點： C17上有羥基， C11位有酮基或羥基。HypothalamusPituitaryAdrenalCRHACTHRegulation of glucocorticoids secretion糖皮質(zhì)激素分泌調(diào)節(jié)Glucocorticoids+exogenous GC(GC)糖皮質(zhì)激素Anti-inflammationImmunosuppressioninhibit+stimulateLong negative feedbackShort negative

4、feedbackHPAa下丘腦垂體腎上腺CRH：促腎上腺皮 質(zhì)激素釋放激素ACTH：促腎上腺 皮質(zhì)激素 糖皮質(zhì)激素分泌：晝夜節(jié)律性(午夜最低，上午8-10時最高)，此節(jié)律性變化受ACTH影響。 在GC血濃度高時，HPAa對影響其分泌的因素不敏感，而在GC血濃度低時則相反。Glucocorticoids, GC 糖皮質(zhì)激素體內(nèi)過程：口服，注射均可。與血漿蛋白結(jié)合率高（90%）肝臟代謝主要在腎排泄 可的松，潑尼松在肝轉(zhuǎn)化為氫化可的松、潑尼松龍而生效。藥物分類： 按t1/2長短而分Physiological effects生理作用Glucose metabolism糖代謝Protein metabo

5、lism蛋白質(zhì)代謝Adipose metabolism 脂肪代謝Salt and water metabolism水鹽代謝Hematopoiesis and destruction of blood cells造血和血細胞破壞Vascular response血管反應(yīng)Enhance ability to handle stress增強抗應(yīng)激Glucocorticoids, GC-naturally secretion: cortisol(皮質(zhì)醇)/ hydrocortisone（氫化可的松）1237456Glucose metabolism糖代謝Glucocorticoids, GC1bloo

6、d glucose血糖, muscle glycogen 肌糖原 and liver glycogen levels 肝糖原by: - gluconeogenesis(糖原異生); - gluconeogenic enzyme activity糖異生酶活性; - hepatic and renal amino acid (aa) uptake, and aa are converted to glucose 肝腎氨基酸攝取，將氨基酸轉(zhuǎn)變成糖; -peripheral glucose uptake and utilization 外周血糖攝取和利用. Promote hyperglycemia

7、and glycosuria促進高血糖和糖尿 diabetic state糖尿病Protein metabolism蛋白質(zhì)代謝2Supraphysiologic glucocorticoid levels cause超生理劑量GC decreased muscle mass, weakness, osteoporosis(骨質(zhì)疏松), Reduced growth in children, delay a wound heals兒童生長、傷口愈合延遲.Promote protein catabolism促進蛋白質(zhì)分解代謝 and inhibit protein synthesis抑制蛋白質(zhì)合成

8、. - catabolism分解代謝 (lymphoid tissue, connective tissue, muscle, fat, skin ) -Protein catabolism蛋白質(zhì)分解negative nitrogen balance負氮平衡 - Transfer aa from muscle and bone to liver, where aa are converted to glucose 轉(zhuǎn)移肌肉和骨中氨基酸至肝轉(zhuǎn)化為葡萄糖.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 游離脂肪酸 - enhanced tendency to ketosis(誘發(fā)酮癥 )Adipose metabolism脂肪代謝3Glucocorticoids, GCA prolonged GC therapy results hypertension, moon face, truncal obesity, buffalo hump, and limbs are thin and small. 長期給GC 高血壓、滿月臉、向心性肥胖、 水牛背、四肢瘦小Salt and water met

10、abolism水鹽代謝Principal mineralocorticoid鹽皮質(zhì)激素: aldosterone(醛固酮)sodium reabsorption and potassium excretion 保鈉排鉀. - intestinal absorption of calcium and promote calcium excretion by the kidney 腸道鈣吸收，腎臟排鈣 - GC mediate weak mineralocorticoid-like effects. 弱的鹽皮質(zhì)激素樣作用Glucocorticoids, GC4 Serum calcium 血鈣，s

11、erum potassium血鉀 , hypertension 高血壓 and osteoporosis骨質(zhì)疏松Large dose of GC（大量GC）: - platelet血小板，neutrophil中性粒細胞, fibrinogen纖維蛋白原 - lymphocyte淋巴細胞, monocyte單核細胞, eosinophil 嗜酸性細胞，basophil嗜堿性細胞 - Inhibit neutrophil function 抑制中性粒細胞功能 Glucocorticoids, GCHematopoiesis and destruction of blood cells造血和血細胞破

12、壞5 GC secretion resistance to stress抗應(yīng)激 -Increased stress應(yīng)激增加: trauma創(chuàng)傷, fright戰(zhàn)斗, infection感染, blooding出血 or debilitating disease衰弱性疾病.Enhance ability to handle stress增強抗應(yīng)激Glucocorticoids, GC76Vascular response血管反應(yīng)sensitivity of vascular smooth muscle to NA血管平滑肌對NA敏感性; capillary permeability毛細血管通透性

13、Pharmacological effects 藥理作用Anti-inflammatory action抗炎Immunosuppression免疫抑制Anti-endotoxin抗內(nèi)毒素Anti-shock抗休克Effects on component of blood對血液影響Central nervous system (CNS) effects中樞作用Additional effects其它Glucocorticoids, GC1237456Anti-inflammatory 抗炎 supraphysiologic dose大劑量: strong effect作用強.- Ameliora

14、te inflammatory symptoms 改善炎癥.- Inhibit proliferation of capillary and fibroblast 抑制毛細血管和成纖維細胞增生 prevent adhesion and scar 防止粘連和疤痕Glucocorticoids, GC1Mechanism抗炎機制 inhibit抑制:- interactions involving cell adhesion molecules 細胞粘附分子相互作用- leukocyte and tissue macrophage function 白細胞和組織巨噬細胞功能- reduced an

15、tigenic and mitogenic responsiveness 降低抗原和有絲分裂原反應(yīng)- 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) 炎癥細胞環(huán)氧酶， 前列腺素合成 Immunosuppressive effects 免疫抑制-de

16、generation of DNA in lymphocyte淋巴細胞DNA變性-induce of apoptosis of lymphocyte 誘導(dǎo)淋巴細胞凋亡-inhibited the activity of NF-kB抑制NF-kB活性- production of antibody降低抗體生成 -inhibiting the release of histamine抑制組胺 , kinin激肽 ,5-HT and other stimulant of sensitivity reaction抑制過敏介質(zhì)釋放 -inhibition of process of immunity抑制

17、免疫過程2Glucocorticoids, GCAntiallergy action 抗過敏Anti-endotoxin抗內(nèi)毒素 tolerance to bacterial endotoxin細菌內(nèi)毒素耐受, diminute heat 退熱and alleviate toxaemia緩解毒血癥. 3Glucocorticoids, GCAnti-shock抗休克4- output of heart心輸出- construction of the myocardium心肌收縮;-Dilution of the capillary blood vessel擴毛細血管, perfusion in

18、 tissue組織灌注.- Stabling membrane of lysosome穩(wěn)定溶酶體膜 production of myocardial depressant factor. 減少心肌抑制因子產(chǎn)生-減少: monocytes單核細胞, lymphocytes淋巴細胞, eosinophils and basophils嗜酸性粒細胞和嗜堿性粒細胞-增加: hemoglobin血紅蛋白, erythrocyte紅細胞, platelets 血小板and polymorphonuclear leukocytes多形核白細胞Effects on component of blood對血液影

19、響5Glucocorticoids, GCCNS excitability增強中樞興奮: euphoria欣快, insomnia失眠, excitement興奮. A few persons少數(shù)人: mania躁狂, depression抑郁, or mood disturbances 精神紊亂.Central nervous system (CNS) effects中樞作用6Glucocorticoids, GC1. temperature體溫 -interfere production of PG前列腺素產(chǎn)生2. CNS - inhibitory neurotransmitter GAB

20、A抑制性神經(jīng)遞質(zhì)GABA, exciting興奮psychoses精神病, epilepsy 癲癇and euphoria欣快3. Bone system - Osteoporosis骨質(zhì)疏松4. gastrointestinal system胃腸道 -inducing ulcer 誘發(fā)潰瘍 -stimulate gastric acid and pepsin production 刺激胃酸、胃蛋白酶產(chǎn)生5. Benefit development of fetal lungs 利于胎肺發(fā)育成熟Additional effects of GC其它作用7Mechanism of Action o

21、f GC作用機制-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 經(jīng)GC受體發(fā)揮作用Clinical uses of GC 臨床應(yīng)用Replacement therapy for adrenal insufficiency (Addisons disease)腎上腺皮質(zhì)功能不全替代治療 -Acute adrenal insufficie

23、ncy (Adrenal crisis ) is a life threatening condition requiring immediate intravenous GC and saline.急性腎上腺皮質(zhì)功能不全(腎上腺危象)危及生命,立即i.v.GC和生理鹽水。 - 2/3 of the dose is administered in the morning to mimic the physiological levels.清晨給予2/3的劑量來模擬體內(nèi)糖皮質(zhì)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).如果原發(fā)性腎上腺功能不全，需加用鹽皮質(zhì)激素，但若為繼發(fā)性腎上腺功能不全（如垂體病變）則不用加鹽皮質(zhì)激素。 1Inflammatory states炎癥-Symptomatic relief; reduce the inflammatory attack, but not cure disease.緩解炎癥癥狀， 降低炎癥侵襲，但不能治愈炎癥。-Combine with sufficient antibiotic in bacterial

25、infections.細菌感染必須合用足量的抗生素。 2Clinical uses of GC 臨床應(yīng)用3Self- immunity Diseases自身免疫性疾病Lupus erythematosus, Rheumatoid arthritis, rheumatic , nephrotic syndrome.紅斑狼瘡，類風(fēng)濕關(guān)節(jié)炎，風(fēng)濕病，腎病綜合征4Allergic Diseases過敏 -inhibiting the release of histamine , kinin ,5-HT and other stimulant of sensitivity reaction抑制組胺、激肽

26、、5-HT 和其它致敏介質(zhì)釋放 -inhibition of process of immunity抑制免疫過程- Severe asthma, serum sickness, angioneurotic edema, prevention and treatment of organ transplant rejection (combination with immunosuppressive agents).重度哮喘、血清病、血管神經(jīng)性水腫，與免疫抑制劑合用防治器官移植后的排斥反應(yīng)。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+糖皮質(zhì)激素 （早期、大量、突擊使用） -增加心輸出量和血壓Clinical uses of GC 臨床應(yīng)用56Leukemia白血病Hematopoietic malignancies, chronic lymphocytic leukemia and multiple myeloma.血液學(xué)惡性腫瘤、慢性淋巴性白血病、多發(fā)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）長期大劑量 糖皮質(zhì)激素： -誘發(fā)加重感染 -誘發(fā)加重胃潰瘍、胃出血和胃穿孔. - 興奮、失眠. （禁忌：精神病和癲癇發(fā)作）Adverse effects of GC 副作用1向心性肥胖欣快(有時抑郁或情緒不穩(wěn)定及其它精神癥狀)還有：負氮平衡,食欲增加,低血鉀,高血壓傾向,消化性潰瘍Withdrawal

29、Reaction撤藥反應(yīng)： Iatrogenic adrenocortical insufficiency醫(yī)源性腎上腺皮質(zhì)功能不全 -Negative feedback, ACTH adrenal cortex atrophy，vomit，nausea, hypotension, hypoglycemia (low blood sugar)-負反饋 ACTH 腎上腺皮質(zhì)萎縮，惡心嘔吐、低血壓、低血糖。 A. Therapy abrupt cessation治療突然中止造成;B. maintenance dosage or following day therapy預(yù)防：應(yīng)給予維持量或隔日療法;

30、C. Promptly treat enough GC. 及時給予足量糖皮質(zhì)激素，待癥狀緩解后，逐漸減量而停藥。 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.停藥反跳 /停藥綜合征 -長期用藥后突然停藥/撤藥太快：病情惡化、發(fā)熱、肌肉和關(guān)節(jié)痛。3Adverse effects of GC 副作用Regimens for prevention of adrenocortical atrophy防止腎上腺皮質(zhì)萎縮療法Cortisol secretion is high in the early morning and low in the late evening (circadian rhythm晝夜節(jié)律). a) Circadian administration每日療法: The daily dose of GC is given in morning. Endogenous cortisol production will have