第二十九章腎上腺皮質(zhì)激素

TwosystemscontrolallphysiologicThenervoussystemexertspoint-to-pointcontrolthroughnerves,similartosendingmessagesby ephone.Nervouscontroliselectricalinnatureandfast.iTheendocrinesystembroadcastsitshormonalessagestoessentiallyallcellsbysecretionintooodandextracellularfluid.Likearadiobroadcast,quiresareceivertogetthemessage-inthecaseondocrinemessages,cellsmustbearareceptorfortormonebeingbroadcastinordertorespond.i

Gap 生長(zhǎng)因 (endocrine

激素的來 下丘腦神經(jīng) 非內(nèi)分泌腺血 胃腸黏 靶細(xì)

釋放激心房鈉尿肽、胃腸道激激素分類固醇激素（脂類激，膽固醇為前體下丘腦垂體前葉腎上腺皮質(zhì)軸下丘腦垂體前葉 下丘腦垂體前葉炎癥抑制

炎癥抑制TSH,甲狀腺功能低下保

Thehypothalamic–pituitaryaxis.Thecellsoftheanteriorpituitaryareregulatedbyhypothalamichormones,whicharereleasedintotheportalveinsleadingfromthehypothalamustotheanteriorpituitaryviathepituitarystalk.Anteriorpituitaryhormonesarereleasedintotheinferiorpetrosalveinsfordeliverytoendocrineorganselsewhereinthebody.Theposteriorpituitaryconsistsofspecializedneuronsthatsynthesizethepeptidehormones,vasopressinandoxytocin,forreleaseintothesystemiccirculation.激素的作（一）細(xì)胞膜受體(membrane根據(jù)其功能上的差異可分為四大類：G蛋（二）胞內(nèi)受體(intracellular合蛋白DNA結(jié)合區(qū)、核定位序列、激素結(jié)合區(qū)、受體調(diào)激素如：促腎上腺激素、促激素、促甲狀腺受體-

點(diǎn)身中升杜大牙

Pl初ma夕戈夕藥貍學(xué)

泛多多多姿泛辜DNAResponse 激素+配體結(jié)合區(qū)誘導(dǎo)受體變構(gòu)釋放熱休克蛋白 轉(zhuǎn)錄啟 特 表達(dá)合 Glucocorticosteroidsandadaptationtostress.Afterhormonebinding,thesereceptorsaretranslocatedtothenucleuswheretheyleadtotranscriptionofglucocorticosteroid-responsivegenes.Theproductsofthesegenesleadtodiversetargettissueeffectssuchasenhancedgluconeogenesis,lipolysis,tissuecatabolism,inhibitionoflymphocytefunction,pressoreffectsin 對(duì)內(nèi)分泌功能不足的患者，外 第三十七 腎上腺皮質(zhì)激素類藥

1927年Rogoff和Stewart發(fā)現(xiàn) 、氟輕HormonesoftheAdrenalalladrenalcortexhormonesare C=O notstored,synthesizedas糖皮質(zhì)激 功并獲 "Twoglandsin adrenal

+TheadrenalmedullasecretescatecholamineTheadrenalcortexsecretesteroidhormones,whichparticipateintheregulationofmineralbalance,energybalanceandreproductivefunction.AdrenalCortexCellsintheadrenalmedullasynthesizeandsecretenorepinephrineandepinephrine.Increasedrateand ofcontractionoftheheartmuscleConstrictionofbloodDilationofStimulationoflipolysisinfatIncreasedmetabolic【分泌調(diào)下丘 垂體前 腎上腺皮質(zhì) 特點(diǎn)：晝夜節(jié)律性（circadian0:0amMin（5μg/100ml）~ 8-10amMax（20μg/100應(yīng)激狀態(tài)氫化可的松超過正常100Glucocorticosteroidsandadaptationtostress.Avarietyofsensorineuralinputsregulatethepatternofcorticotropinreleasinghormone(CRH)releaseinthehypothalamus.CRHreleasesadrenocorticotropichormone(ACTH).ACTHleadstocortisolproductionintheadrenalzonafasciculata.Cortisolcirculatestoperipheraltissueswhereitbindscytosolicglucocorticosteroidreceptors(GR).Thediurnalcortisolpatternreflectspeakactivityofthehypothalamic–pituitary–adrenalaxisintheearlymorning.表37-1分藥水鹽代（比值糖代（比值抗（比）等效劑半衰（分半效（小時(shí)口服常量（mg/）短氫化可的1可的中5龍5甲潑尼4曲安西04長(zhǎng)地0倍0外氟氫可的-----氟輕1------Onlyabout10%ofcirculatingcortisolis .Theremainingmajoritycirculatesboundto smaproteins,particularlycorticosteroid-bindingglobulin【藥動(dòng)學(xué)】口服、注射均可吸收快而完全?？诜傻乃苫驓浠傻乃珊?～2小時(shí)血藥濃度可達(dá)。一次給藥作用持續(xù)8～12小蛋白結(jié)合，其中80%與皮質(zhì)激素轉(zhuǎn)運(yùn)蛋白（CBG）結(jié)合，另有15%與白蛋白結(jié)合。肝、腎病時(shí)CBG合成減少，可使游離型增多可的松 需在肝內(nèi)轉(zhuǎn)化為氫化可的松 龍才有生物活性，故嚴(yán)重功能不全患者，只宜用氫化可的松 龍 葡萄糖分 機(jī)體組織對(duì)葡萄糖的利用蛋白質(zhì)代謝蛋白質(zhì)分解（胸腺、肌肉、骨和皮膚等）蛋白質(zhì)合成， 氨基酸和尿氮排出負(fù)氮平衡。久用生長(zhǎng)減慢、肌肉消瘦、皮膚變薄、骨質(zhì)疏松、淋巴組織萎脂肪代謝脂肪分解其合成久用血膽固醇含量激 四肢皮下的脂 四肢脂 脂肪重新分 Inadipocytes,glucocorticoidsmodulatebothglucoseandlipidhomeostasis.Fortheformer,glucocorticoidsglucose抗炎作用糖皮質(zhì)激素有強(qiáng)大的抗炎作用，能對(duì) 所引起的炎癥及炎癥過程的不同階段有明顯的在炎癥早期可減輕滲出、水腫、毛細(xì)血管擴(kuò)張、白細(xì)胞浸潤(rùn)及吞噬反應(yīng)，從而改善紅、腫、熱、痛等抗炎作用環(huán) 影響細(xì)胞因子和黏附分1、增加炎癥抑制蛋白脂皮素1生成，抑 2、抑制NOS和COX-2的表GCincreasethesyntesisoflipocortin-1,thathasinhibitoryeffectonphospholipasA2andthereforeinhibittheproductionoflipidmediatorsaswellasinhibitgenescodingforCOX-2.2）抑制表達(dá)細(xì)胞黏附分子和有關(guān)細(xì)胞因的轉(zhuǎn)錄，抑制中性粒細(xì)胞、單核細(xì)胞和M的浸潤(rùn)內(nèi)皮胞的黏和 。細(xì)胞因子（cytokine）促進(jìn)血管內(nèi)皮細(xì) 炎性部位活化內(nèi)皮細(xì)胞、嗜中性白細(xì)胞及 透 成纖維細(xì)胞增生，淋巴細(xì)胞增殖與分化細(xì)胞因子誘導(dǎo) 水腫及組織損 加重炎癥癥狀 GCinhibittheexpressionofmultiple tory toryactionsof BarnesPJ. SinceeosinophilsaredependentofIL-5andGM-CSFwhichareblockedbyGCwhichleadstoapoptosisofeosinophilsandT-lymfocytes. toryactionsof BarnesPJ.患者丁某，男，３８歲。因發(fā)熱、流涕、咳嗽、頭痛、咽喉在詢問患者無青霉素過敏史，進(jìn)行青霉素皮膚過敏試驗(yàn)結(jié)果覺胸悶、氣短、眼前發(fā)黑、呼吸，繼而面色蒼白、大汗立即停止輸液，注射腎上腺素１ｍｇ，讓患者平臥、吸氧、后經(jīng)詢問患者用藥史得知：患者在就診前使用抗生素＋氟美 （３）糖皮質(zhì)激素能抑制花生四烯酸代謝，通過抑制環(huán)氧酶和脂 （４）糖皮質(zhì)激素能增強(qiáng)血管張力，減輕血管充血和降低毛細(xì)血管通透性，增強(qiáng)氣道平滑肌β-腎上腺素受體的反應(yīng)能力。因此，當(dāng)患者近期較大劑量使用糖皮質(zhì)激素后，體內(nèi)仍維持著激素的作用，從而對(duì)抗過敏反應(yīng)，造成青霉素皮試出現(xiàn)假，導(dǎo) 大劑量則能抑制B細(xì)胞轉(zhuǎn)化 抗休克作 炎癥允許作 應(yīng) 退熱作用：減輕和改 、驚 中樞神經(jīng)系 其 作用機(jī) 糖皮質(zhì)激素受體結(jié)合區(qū)：與的調(diào)控區(qū)域的特定端的功能區(qū)τ1組成：兩個(gè)分子的熱休克蛋白90(Hsp90)；抑制性蛋BindingofligandtotheC- increasestheaffinity foritsspecifictargetsiteinTheimagetotherightdepictsapairofglucocorticoidreceptors(blueandgreenonthetop)boundtotheirDNAhormoneresponseelement

SteroidreceptorsaretranscriptionSteroidreceptorsareexamplesofligand-responsivethatareactivatedbybindingaThereareseparateDNA-bindingandligand-binding TheDNAbinding isatypeofzincfingerthathasCysbutnotHisresidues.TheybindtoDNAasdimers.Glucocorticoidandestrogenreceptorseachhavetwozincfingers,thefirstofwhichdeterminestheDNAtargetsequence.Nuclear(zincAproteinthatin ctswithhormones(e.g., glucocorticoids,thyroidhormone)andbindstoanenhancertostimulatetranscriptionSomeremaininthenucleus,butsomemeettheirligandsinthecytosm,formacomplexandthenmoveintothenucleustostimulatetranscriptionTheenhancerelementstheybindtoarecalledhormoneresponseelementsTheproteinshave calledahormone非經(jīng)典作用原理—快速效 受體介導(dǎo)效 生化效 直接抑制陽(yáng)離子循環(huán)（不減少細(xì)胞內(nèi)產(chǎn)生Non-genomicmechanismofglucocorticoid'srapidactiononneurons-membranereceptorhypothesisCHENYizhangHUAShaoyingGUOZuoFUHongandWANGChun'an(DepartmentofPhysiology,InstituteofNeuroscience,Second Thegenomicmechanismofsteroidhormoneactionhasbeenwidelyacceptedinendocrinology.Butthereart-difficultiesininterpretingtherapidactionofsteroidhormoneonnervoussystem.Thenon-genomicmodeofglucocorticoid(GC)actionwasraisedin1987,whichproposedthatGCactedonthemembranereceptoroftheneu-nonAseriesofexperimentsshowedthatthroughthenon-genomicmechanism,GCcoulddepresstheexcitability,in-hibitthesecretion,andaugmenttheuptakeofglutamateofneurons.Theeffectsaremediatedbytheproposedmem-branereceprorofGC.theexistenceofwhichwassubstantiatedbyelectrophysiological,biochemical,andmorphologicalevidences《自然科學(xué)進(jìn)展(英文版)1999- 腎上腺皮質(zhì)功能減退、腎上腺次全切嚴(yán)重 晚 具有迅速而良好的退熱作用 血液病急性淋巴細(xì)胞性白血病、再生性貧血、7局部應(yīng)用對(duì)接觸性皮炎、濕疹 都有療效。宜用氫化可的松 8.急性脊髓損傷：24-36h內(nèi)大劑量可減輕神經(jīng)功能損傷， 消化系統(tǒng)并發(fā) “甾體激素潰瘍甚至造成消化 或穿孔 醫(yī)源性腎上腺皮質(zhì)功能不全 moonfate.g.weightmusclewastingskinthinning,wound【證】曾患或現(xiàn)患嚴(yán)重 痘、霉菌等都是皮質(zhì)激