药理学-5肾上腺-糖皮质激素药.ppt

药理学-5肾上腺-糖皮质激素药.ppt

《药理学-5肾上腺-糖皮质激素药.ppt》由会员分享，可在线阅读，更多相关《药理学-5肾上腺-糖皮质激素药.ppt（37页珍藏版）》请在冰点文库上搜索。

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,Anatomyandfunctionofadrenalcortex肾上腺皮质结构和功能,球状带（盐皮质激素）15%ofadrenalcortexZonaglomerulosa-（mineralocorticoids）,束状带（糖皮质激素）78%ofadrenalcortexZonafasciculata-（glucocorticoids）,网状带（肾上腺雄激素）7%ofadrenalcortexZonareticularis-（adrenalandrogens）,regulatingsaltandwatermetabolism,metabolismandresistancestress.,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,CH3,CH3,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-去氧皮质酮）,或有氧但与C18醛基形成内脂环（醛固酮）.,AdrenocorticalHormones肾上腺皮质激素,糖皮质激素结构特点：

C17上有羟基，C11位有酮基或羟基。

Hypothalamus,Pituitary,Adrenal,CRH,ACTH,Regulationofglucocorticoidssecretion糖皮质激素分泌调节,Glucocorticoids,+,+,exogenousGC,（GC）糖皮质激素,Anti-inflammationImmunosuppression,inhibit,+,stimulate,Longnegativefeedback,Shortnegativefeedback,HPAa,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,Physiologicaleffects生理作用,Glucosemetabolism糖代谢Proteinmetabolism蛋白质代谢Adiposemetabolism脂肪代谢Saltandwatermetabolism水盐代谢Hematopoiesisanddestructionofbloodcells造血和血细胞破坏Vascularresponse血管反应Enhanceabilitytohandlestress增强抗应激,Glucocorticoids,GC,-naturallysecretion:

cortisol（皮质醇）/hydrocortisone（氢化可的松）,1,2,3,7,4,5,6,Glucosemetabolism糖代谢,Glucocorticoids,GC,1,bloodglucose血糖,muscleglycogen肌糖原andliverglycogenlevels肝糖原by:

-gluconeogenesis（糖原异生）;-gluconeogenicenzymeactivity糖异生酶活性;-hepaticandrenalaminoacid（aa）uptake,andaaareconvertedtoglucose肝肾氨基酸摄取，将氨基酸转变成糖;-peripheralglucoseuptakeandutilization外周血糖摄取和利用.,Promotehyperglycemiaandglycosuria促进高血糖和糖尿diabeticstate糖尿病,Proteinmetabolism蛋白质代谢,2,Supraphysiologicglucocorticoidlevelscause超生理剂量GCdecreasedmusclemass,weakness,osteoporosis（骨质疏松）,Reducedgrowthinchildren,delayawoundheals儿童生长、伤口愈合延迟.,Promoteproteincatabolism促进蛋白质分解代谢andinhibitproteinsynthesis抑制蛋白质合成.-catabolism分解代谢（lymphoidtissue,connectivetissue,muscle,fat,skin）-Proteincatabolism蛋白质分解negativenitrogenbalance负氮平衡-Transferaafrommuscleandbonetoliver,whereaaareconvertedtoglucose转移肌肉和骨中氨基酸至肝转化为葡萄糖.,Promotelipolysis（脂肪分解）,inhibitlipogenesis（抑制脂肪生成）,andfatisredistributed脂肪重分布-increaseinplasmafreefattyacids游离脂肪酸-enhancedtendencytoketosis（诱发酮症）,Adiposemetabolism脂肪代谢,3,Glucocorticoids,GC,AprolongedGCtherapyresultshypertension,moonface,truncalobesity,buffalohump,andlimbsarethinandsmall.长期给GC高血压、满月脸、向心性肥胖、,水牛背、四肢瘦小,Saltandwatermetabolism水盐代谢,Principalmineralocorticoid盐皮质激素:

aldosterone（醛固酮）sodiumreabsorptionandpotassiumexcretion保钠排钾.-intestinalabsorptionofcalciumandpromotecalciumexcretionbythekidney肠道钙吸收，肾脏排钙-GCmediateweakmineralocorticoid-likeeffects.弱的盐皮质激素样作用,Glucocorticoids,GC,4,Serumcalcium血钙，serumpotassium血钾,hypertension高血压andosteoporosis骨质疏松,LargedoseofGC（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-Inhibitneutrophilfunction抑制中性粒细胞功能,Glucocorticoids,GC,Hematopoiesisanddestructionofbloodcells造血和血细胞破坏,5,GCsecretionresistancetostress抗应激-Increasedstress应激增加:

trauma创伤,fright战斗,infection感染,blooding出血ordebilitatingdisease衰弱性疾病.,Enhanceabilitytohandlestress增强抗应激,Glucocorticoids,GC,7,6,Vascularresponse血管反应,sensitivityofvascularsmoothmuscletoNA血管平滑肌对NA敏感性;capillarypermeability毛细血管通透性,Pharmacologicaleffects药理作用,Anti-inflammatoryaction抗炎Immunosuppression免疫抑制Anti-endotoxin抗内毒素Anti-shock抗休克Effectsoncomponentofblood对血液影响Centralnervoussystem（CNS）effects中枢作用Additionaleffects其它,Glucocorticoids,GC,1,2,3,7,4,5,6,Anti-inflammatory抗炎supraphysiologicdose大剂量:

strongeffect作用强.-Ameliorateinflammatorysymptoms改善炎症.-Inhibitproliferationofcapillaryandfibroblast抑制毛细血管和成纤维细胞增生preventadhesionandscar防止粘连和疤痕,Glucocorticoids,GC,1,Mechanism抗炎机制inhibit抑制:

-interactionsinvolvingcelladhesionmolecules细胞粘附分子相互作用-leukocyteandtissuemacrophagefunction白细胞和组织巨噬细胞功能-reducedantigenicandmitogenicresponsiveness降低抗原和有丝分裂原反应-Reductionofprostaglandinandleukotrienesynthesis（inhibitphospholipaseA2activation）前列腺素和白三烯合成（抑制磷脂酶A2活性）-Reductionofcyclooxygenaseininflammatorycells（reducingprostaglandinsynthesis）炎症细胞环氧酶，前列腺素合成,Immunosuppressiveeffects免疫抑制,-degenerationofDNAinlymphocyte淋巴细胞DNA变性-induceofapoptosisoflymphocyte诱导淋巴细胞凋亡-inhibitedtheactivityofNF-kB抑制NF-kB活性-productionofantibody降低抗体生成-inhibitingthereleaseofhistamine抑制组胺,kinin激肽,5-HTandotherstimulantofsensitivityreaction抑制过敏介质释放-inhibitionofprocessofimmunity抑制免疫过程,2,Glucocorticoids,GC,Antiallergyaction抗过敏,Anti-endotoxin抗内毒素,tolerancetobacterialendotoxin细菌内毒素耐受,diminuteheat退热andalleviatetoxaemia缓解毒血症.,3,Glucocorticoids,GC,Anti-shock抗休克,4,-outputofheart心输出-constructionofthemyocardium心肌收缩;-Dilutionofthecapillarybloodvessel扩毛细血管,perfusionintissue组织灌注.-Stablingmembraneoflysosome稳定溶酶体膜productionofmyocardialdepressantfactor.减少心肌抑制因子产生,-减少:

monocytes单核细胞,lymphocytes淋巴细胞,eosinophilsandbasophils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andpolymorphonuclearleukocytes多形核白细胞,Effectsoncomponentofblood对血液影响,5,Glucocorticoids,GC,CNSexcitability增强中枢兴奋:

euphoria欣快,insomnia失眠,excitement兴奋.Afewpersons少数人:

mania躁狂,depression抑郁,ormooddisturbances精神紊乱.,Centralnervoussystem（CNS）effects中枢作用,6,Glucocorticoids,GC,1.temperature体温-interfereproductionofPG前列腺素产生2.CNS-inhibitoryneurotransmitterGABA抑制性神经递质GABA,exciting兴奋psychoses精神病,epilepsy癫痫andeuphoria欣快3.Bonesystem-Osteoporosis骨质疏松4.gastrointestinalsystem胃肠道-inducingulcer诱发溃疡-stimulategastricacidandpepsinproduction刺激胃酸、胃蛋白酶产生5.Benefitdevelopmentoffetallungs利于胎肺发育成熟,AdditionaleffectsofGC其它作用,7,MechanismofActionofGC作用机制,-Receptorsboundtoheatshockproteins（Hsp）-FreeGChormoneentersthecell-Bindstoreceptor,inducingaconformationalchange-ReceptordissociatesfromHspproteins,GC-Rcomplexassociatetoformhomodimers-Homodimersnucleartranslocation-HomodimersbindtoGCresponseelementsoftargetgenes-GenomiceffectsTranscriptionactivated-proteinsynthesized;GC-RinteractwithNFBandAP-1toinhibitgeneexpression,GCactionthroughGCreceptors经GC受体发挥作用,ClinicalusesofGC临床应用,Replacementtherapyforadrenalinsufficiency（Addisonsdisease）肾上腺皮质功能不全替代治疗-Acuteadrenalinsufficiency（Adrenalcrisis）isalifethreateningconditionrequiringimmediateintravenousGCandsaline.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。

-2/3ofthedoseisadministeredinthemorningtomimicthephysiologicallevels.清晨给予2/3的剂量来模拟体内糖皮质激素的生理水平。

-Amineralocorticoidisaddedifthesufficiencyisprimary（adrenal）,butisnotnecessaryforasecondinsufficiency（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。

1,Inflammatorystates炎症-Symptomaticrelief;reducetheinflammatoryattack,butnotcuredisease.缓解炎症症状，降低炎症侵袭，但不能治愈炎症。

-Combinewithsufficientantibioticinbacterialinfections.细菌感染必须合用足量的抗生素。

2,ClinicalusesofGC临床应用,3,Self-immunityDiseases自身免疫性疾病Lupuserythematosus,Rheumatoidarthritis,rheumatic,nephroticsyndrome.红斑狼疮，类风湿关节炎，风湿病，肾病综合征,4,AllergicDiseases过敏-inhibitingthereleaseofhistamine,kinin,5-HTandotherstimulantofsensitivityreaction抑制组胺、激肽、5-HT和其它致敏介质释放-inhibitionofprocessofimmunity抑制免疫过程-Severeasthma,serumsickness,angioneuroticedema,preventionandtreatmentoforgantransplantrejection（combinationwithimmunosuppressiveagents）.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PromptintensiveGCmaybelifesavinginsepticshock.Restorecardiacoutputandreversehypotension.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,ClinicalusesofGC临床应用,5,Long-termandhigherdoses：

-induceandaggravateinfection-induceandaggravateulcer,evenstomachhaemorrhageandperforation.-euphoria,insomnia.（contraindications:

psychiatricandepilepticseizure）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）,AdverseeffectsofGC副作用,1,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,WithdrawalReaction撤药反应：

Iatrogenicadrenocorticalinsufficiency医源性肾上腺皮质功能不全-Negativefeedback,ACTHadrenalcortexatrophy，vomit，nausea,hypotension,hypoglycemia（lowbloodsugar）-负反馈ACTH肾上腺皮质萎缩，恶心呕吐、低血压、低血糖。

A.Therapyabruptcessation治疗突然中止造成;B.maintenancedosageorfollowingdaytherapy预防：

应给予维持量或隔日疗法;C.PromptlytreatenoughGC.及时给予足量糖皮质激素，待症状缓解后，逐渐减量而停药。

AdverseeffectsofGC副作用,2,Reboundreactionandwithdrawalsymptoms-Reductionprocessquitefastorabruptcessationafterlong-termtherapy:

symptomsaggravate,fever,muscularpain,jointpain.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。

3,AdverseeffectsofGC副作用,Regimensforpreventionofadrenocorticalatrophy防止肾上腺皮质萎缩疗法,Cortisolsecretionishighintheearlymorningandlowinthelateevening（circadianrhythm昼夜节律）.a）Circadianadministration每日疗法:

ThedailydoseofGCisgiveninmorning.Endogenouscortisolproductionwillhavealreadybegun,HPAabeingrelativelyinsensitivetoinhibition.Inearlymorninghoursofthenextday,CRH/-ACTHreleaseandadrenocorticalstimulationwillresume.,b）Alternate-daytherapy隔日疗法:

Twicethedailydoseisgivenonalternatemornings.Onthe“off”day,endogenouscortisolproductionisallowedtooccur.Thedisadvantageofeitherregimenisarecrudescence（复发）ofdiseasesymptomsduringtheglucocorticoid-freeinterval.,1.大剂量突击疗法：

严重中毒性感染和各种休克.氢可：

200-300mg静滴,1g/日以上,不超过3天.超大剂量,每次1g静脉注射,4-6次/日.,2.一般剂量长期疗法：

结缔组织病,肾病综合症,支气管哮喘等.强的松口服10-20mg,3次/日,起效后,渐减至最小维持量,维持数月.现主张早晨顿服.,3.小剂量替代疗法：

用于垂体前叶功能减退等病.维持量可的松12.5-25mg/日.,4.隔日疗法：

遵循ACTH分泌的昼夜规律.对慢性病采用隔日早晨一次疗法,用量为一日或两日的总药量.,Aldosterone（醛固酮）Deoxycorticosterone（去氧皮质酮）-mainlyaffectsaltandwatermetabolism，weakeffectsonGlucosemetabolism；-Clinicaluses:

chronicadrenocorticalinsufficiency,correctwaterandsodiumlossandpotassiumretention，maintainwaterandelectrolytesbalanc