内分泌系统药理

Drugsaffectingendocrinesystem,Shi-HongZhang张世红shzhang713,1,Thyroidhormonesandantithyroiddrugs（甲状腺激素及抗甲状腺药，1课时）Insulinandoralhypoglycemicdrugs（胰岛素和口服降糖药，1.5课时）Adrenocorticoids（肾上腺皮质激素类药物，1.5课时）,Contents,2,甲状腺激素及抗甲状腺药Thyroidhormonesandantithyroiddrugs,Shi-HongZhang(张世红)shzhang713,Frontview,Thyroidgland,甲状腺素的生物合成,摄取碘碘经氧化而活化（I+），碘化甲状腺球蛋白（TG）中的酪氨酸残基，生成MIT和DIT(peroxidasemediated)MIT、DIT偶联生成T4和T3(peroxidasemediated)甲状腺球蛋白水解，释放T3、T4(proteolyticenzymes)5.受促甲状腺激素(TSH)、T4、T3的调节,三碘甲状腺原氨酸,四碘甲状腺原氨酸,甲状腺激素分泌的调节,甲状腺素的生理作用,1维持正常生长发育2促进代谢和产热3提高交感神经系统的反应性,甲状腺功能低下Hypothyroidism,Cretinism(呆小症),瘿,simplegoiter(单纯性甲状腺肿),HypothyroidismAftertreatment,甲状腺功能亢进Hyperthyroidism,颤抖,腱反射亢进,心慌，心脏肥大,甲状腺肿大，突眼，情绪激动,多食、腹泻、消瘦,甲状腺危象Throidcrisis（storm）,恶心、呕吐高热无力、头昏、昏迷低血钾心律失常、心衰、休克,碘及碘化物(smalldoses)：补碘甲状腺激素,甲状腺功能低下的药物治疗,甲状腺激素的临床应用1.补充疗法：呆小病；甲状腺功能低下（黏液性水肿，不典型及亚临床型甲状腺功能减退）；甲状腺癌切除术后；单纯性甲状腺肿；甲亢内科治疗期间。2.T3抑制试验：服用T3后摄碘率下降50%者为单纯性甲状腺肿，50%者为甲亢,抗甲状腺药（antithyroiddrugs）Thioureaderivatives硫脲类Iodineandiodides碘和碘化物（大剂量）receptorantagonistsRadioiodines放射性碘:131I,甲状腺功能亢进的药物治疗,丙硫氧嘧啶PTU,卡比马唑，甲亢平,甲巯咪唑，他巴唑MMI,Thioureaderivatives,抗甲状腺药,硫脲类,1.药理作用和机制(1)抑制甲状腺过氧化物酶：竞争性被氧化，进而抑制酪氨酸碘化和偶联过程症状改善：2-3weeks基础代谢率恢复正常：1-2months(2)抑制外周组织的T4T3(propylthiouracil丙硫氧嘧啶)减轻重症甲亢和甲状腺危象(3)减弱受体介导的糖代谢：减少心肌、骨骼肌的受体数目(4)免疫抑制作用：减少甲状腺刺激性免疫球蛋白TSI生成（slight）,硫脲类,2.临床应用(1)甲亢的内科治疗:疗程1-2y(2)甲亢手术前准备:PTU，结合大剂量碘剂(3)甲状腺危象的治疗:PTU，结合大剂量碘剂3.不良反应过敏反应：最常见粒细胞缺乏症(0.2%ormore)：最严重GI反应甲状腺肿(goiter):TSH，组织增生充血甲状腺功能减退哺乳和妊娠妇女禁用（PTU除外）。结节性甲状腺肿及甲状腺癌禁用,硫脲类,1.药理作用(1)小剂量:单纯性甲状腺肿(2)短期大量使用:抑制甲状腺激素的合成和释放（抑制TSH，抑制GSH还原酶使甲状腺球蛋白对水解酶不敏感，抑制过氧化物酶，减少酪氨酸的碘化和偶联），长期使用作用消失。腺体缩小变韧，血管减少,碘及碘化物,复方碘溶液（卢戈液），碘酸钾，碘化钾（钠）,2.临床应用(1)单纯性甲状腺肿（小剂量）(2)甲亢的手术前准备:结合硫脲类药物(PTU)(3)甲状腺危象:结合硫脲类药物(PTU)3.不良反应粘膜刺激症状，水肿过敏反应甲状腺功能紊乱,碘及碘化物,1.药理作用(1)Heart:1block(2)CNS:镇静作用(3)Presynaptic2receptor:NErelease(4)DecreaseT3:抑制T4脱碘2.临床应用甲亢的辅助治疗和术前准备；甲状腺危象的紧急处理,receptorantagonists,21,131I,125I,123I破坏甲状腺组织:ray，射程短适用于不宜手术或手术后复发及硫脲类无效或过敏的甲亢患者。甲状腺摄碘功能的检测（射线）,放射性碘（Radioiodines）,Casereport,A47-year-oldwomanconsultedherphysicianbecauseofheartpalpitations,tremulousness,weightlossandheattolerance.Examination:heartrate110,BP150/70,diffuselyenlargedthyroidglands,wide-eyedstare,lidlag,FT440pmol/L(normal:10-31),FT310.6pmol/L(normal:4-10),TSHundetectable(2-10mU/L),TSI.ThediagnosiswasGravessdisease.,Casereport,ContinuedShewasstartedontreatmentwithpropranolol,40mgtid,propylthiouracil(丙硫氧嘧啶)200mgbid.Shebecameeuthyroid(甲状腺功能正常)in6weeks,andthepropranololdosewasgraduallyreducedandfinallydiscontinued.Shecontinuedreceivingamaintenancedoseofpropylthiouracil(50mgbid)for1year,afterwhichthedrugwasdiscontinued.,Casereport,ContinuedThesymptomsofhyperthyroidismrecurred3yearslater,andtreatmentwithpropranololandpropylthiouracilwasreinitiated.However,shedevelopedsevererashoverherwholebody.Therefore,thetreatmentwaschangedwithoralNa131Ifordefinitivecontrolofherhyperthyroidism.,Casereport,ContinuedThreemonthslater,thepatientcomplainedoflethargy,tiredness,afeelingofcoldnessatroomtemperature,puffiness(肿胀)aroundtheeyes,andconstipation.LaboratorytestesshowedloweredlevelofT4andT3,butelevatedlevelofTSH,confirmingthediagnosisofhypothyroidism.Shewasstartedonlevothyroxine0.1mgdaily,and6weekslater,hercomplaintsdisappeared.Shehasremainedwellonthistherapy.,胰岛素及其他降血糖药Insulin14(suppl3):S19-24.,Insulinsecretion,Glucosedisposal,Persistenthepaticglucoseoutput,Glucoseabsorption,Lipogenesis,Lipolysis,Glycogenesis,糖尿病的分型,“Beta-cellfailure”,prediabeticmetabolicsyndrome,糖尿病的症状,糖尿病的并发症,急性并发症Diabeticketoacidosis(酮症酸中毒)Hyperosmoticnonketoticcoma(高渗性非酮症性昏迷）慢性并发症,药物治疗,胰岛素（insulin）口服降糖药双胍类（biguanides）促进胰岛素分泌的药物磺酰脲类（sulfonylureas，SUs）格列奈类（meglitinides，Non-SUs）GLP-1(胰高血糖素样肽-1)agonistsandDPP-4inhibitors胰岛素增敏药：噻唑烷二酮类（thiazolidinediones,TZDs)-葡萄糖苷酶抑制剂-glucosidaseinhibitorsAmylinanalogue胰淀粉样多肽类似物,Insulin胰岛素,FrederickSanger(1918-2013),Insulin,1.药理作用(1)糖代谢:糖原分解，糖原合成,糖异生,转运和氧化，降低血糖水平(2)脂肪代谢：脂肪合成，分解，游离脂肪酸，酮体(3)蛋白质代谢：氨基酸转运和蛋白质合成，蛋白分解(4)加快心率，加强心肌收缩力，减少肾血流(5)促进钾离子进入细胞,Mechanismofinsulinactions:Interactwithinsulinreceptors,2.临床应用(1)1型糖尿病(2)2型糖尿病：血糖极高的初始治疗者、经其他治疗血糖未能控制者(3)严重或急性糖尿病并发症:酮症酸中毒，高渗性非酮症性昏迷(4)糖尿病合并其他严重情况：高热，严重感染，妊娠，创伤，手术等(5)细胞内缺钾：严重心肌缺血、强心苷中毒等,Insulin,3.胰岛素制剂（1）速效胰岛素Regularinsulin正规胰岛素（RI）Monocomponentinsulin单组分胰岛素（McI）Lisproinsulin赖脯胰岛素（颠倒B28、29脯赖顺序）溶解度高可静脉注射（or雾化吸入，Afrezza）起效快，作用时间短（0.5-1hafterinjection,peakat24h,last8h）可用于餐后血糖高者，重症糖尿病初治及严重并发症者,Insulin,3.胰岛素制剂（2）中效胰岛素NeutralprotamineHagedorn(NPH,isophaneinsulin)中性精蛋白锌胰岛素Globinzincinsulin（GZI）珠蛋白锌胰岛素Startworking1-1.5hafterinjection,peakat8-12h,andlast1824h.,Insulin,3.胰岛素制剂（3）长效胰岛素Protaminezincinsulin(PZI)精蛋白锌胰岛素Insulinglargine甘精胰岛素（B链C端加两个精氨酸，A21甘氨酸替代门冬酰胺）Insulindetermir地特胰岛素（去除B30苏氨酸，B29赖氨酸加脂肪酸侧链）Startworking4-8hafters.c.injection,peakat14-20h,andlast24-36h.,Insulin,胰岛素笔,4.不良反应(1)低血糖：交感兴奋症状（sweating,hunger,weakness,tachycardia,blurredvision,headache,etc.),严重者用iv50%glucose治疗(2)过敏反应：治疗用H1受体拮抗剂，糖皮质激素，并用人或高纯度胰岛素替代(3)胰岛素抵抗：acute,chronic(受体前、受体及受体后异常)(4)脂肪萎缩：注射部位，用纯化制剂减少(5)其他：体重增加，屈光不正，水肿等,Insulin,Oralhypoglycemicdrugs口服降血糖药,Biguanides双胍类,1.药理作用增加胰岛素敏感性，改善胰岛素抵抗，增加血糖转运和分解抑制胰高血糖素的作用，减少肝糖原分解和糖异生减少肠吸收葡萄糖,Metformin二甲双胍Phenformin苯乙双胍,2.临床应用2型糖尿病的一线用药，特别是肥胖及单用饮食控制无效者对正常人血糖无影响，降低体重降低心血管意外价格实惠3.不良反应胃肠道反应，乳酸酸中毒（苯乙双胍），肾功能不全、肝功能不全、严重感染、缺氧或接受手术者停用,Metformin,Tolbutamide(D860)甲苯磺丁脲Chlorpropamide氯磺丙脲Gliburide格列本脲（优降糖）Glipizide格列吡嗪（美吡达）Gliclazide格列齐特（达美康）Glimepiride格列美脲（亚莫利）,Oralhypoglycemicdrugs口服降血糖药,促胰岛素分泌剂,磺酰脲类（Sulfonylureas,SUs）,1.药理作用(1)促进胰岛素分泌：阻断细胞ATP-sensitiveK+channel，增加Ca2+内流,Sulfonylureas,1.药理作用2)增加胰岛素与其受体的结合能力(long-termuse)3)促进葡萄糖的利用以及合成糖原和脂肪4)抗利尿作用(氯磺丙脲/格列本脲)：ADH5)抗血小板作用(格列齐特),Sulfonylureas,2.临床应用(1)2型糖尿病：aloneorcombinedwithmetforminorinsulin(2)尿崩症：氯磺丙脲,Sulfonylureas,3.不良反应(1)GIreactions(2)CNSreactions：嗜睡、眩晕(3)低血糖:老年人，肝肾功能不全，黄疸，药物影响(4)其他:白细胞减少，胆汁郁积性黄疸，肝脏损害，体重增加,与胰岛细胞上的SUR1结合促进胰岛素分泌有Repaglinide(瑞格列奈)和Nateglinide(那格列奈)两种疗效与SUs相似，但起效迅速（36h,73,胞浆糖皮质激素受体(GR)转位到核内与GREornGRE结合调节基因转录生物学效应(slow),Glucocorticoiddrugs,糖皮质激素的作用机制,nGRE:negativeGCresponseelement,膜GR/细胞膜/受体外成分胞内信号通路生物学效应(fast),糖皮质激素的作用模式,CBG:corticosteroidbindingglobulinS:glucocorticoidsteroidsGR:glucocorticoidreceptorHSP:heatshockproteinIP:immunophilinGRE:glucocorticoid-responseelement,75,GR的核转位,地塞米松,76,糖皮质激素抑制促炎因子的基因转录（e.g，AP-1andNFB),77,1.药理作用(1)对代谢的影响（糖、脂肪、蛋白质、水盐）(2)抗炎作用(3)抑制免疫和过敏反应(4)抗休克作用(5)其他,Glucocorticoiddrugs,78,(1)对代谢的影响1)糖代谢:糖异生，葡萄糖氧化利用血糖.2)蛋白代谢:合成,分解3)脂肪代谢:血浆胆固醇，脂肪重新分布(向心性肥胖centralobesity:满月脸moonface,水牛背buffalohump,etc.).4)水盐代谢:Na+排泄,K+排泄,Ca2+排泄重吸收,Glucocorticoiddrugs,79,糖皮质激素(cortisol氢化可的松)对盐皮质激素受体的作用,80,(2)抗炎作用1)急性炎症a)减少炎症介质产生诱导脂皮素，抑制PLA2，减少PGs和LTs的产生，抑制COX-2和iNOSb)抑制细胞因子和粘附分子的产生和功能:TNF,IL-1,IL-2,IL-5,IL-6,IL-8,etc.c)诱导炎症细胞凋亡,A.Glucocorticoiddrugs,81,(2)抗炎作用2)慢性炎症:抑制成纤维细胞增殖抑制胶原蛋白合成抑制瘢痕形成,Glucocorticoiddrugs,82,(3)抑制免疫和过敏反应a)induceapoptosisofTandBlymphocytesb)induceDNAdegradationofTandBlymphocytesc)InhibitDNAandproteinsynthesisofTandBlymphocytes(inhibitionofproliferation)d)inhibittranscriptionfactoractivity(eg.AP-1,NF-B)e)Inhibitmastcells(anti-allergic),Glucocorticoiddrugs,83,(4)anti-shockeffect1)improvecardiovascularfunctions2)inhibittheproductionofinflammatoryfactors3)stabilizelysosomemembrane:decreasethereleaseofmyocardialdepressantfactor(MDF)4)increasethetolerancetoendotoxinfrombacteria(4)Permissiveaction:potentiatetheeffectsofcatecholaminesandglucagon,Glucocorticoiddrugs,84,(5)其他作用1）允许作用（permissiveaction）：增强其他激素的作用2）解热作用3）血液和造血器官刺激骨髓造血功能，红细胞/血红蛋白、血小板、中性粒细胞（功能），淋巴细胞4）骨骼:osteoporosis骨质疏松5）CNS:增加兴奋性（情绪高涨，欣快，失眠，精神失常，癫痫等）,Glucocorticoiddrugs,85,3.Clinicaluses(1)Immunediseases1)autoimmunedisorders:rheumaticfever,rheumaticcarditis,rheumaticarthritis,rheumatoidarthritis,osteoarthritis,systemiclupuserythematosus,polyarthritisnodosa,nephriticsyndrome,etc.2)rejectionoforgantransplantation3)allergicdiseases:urticaria(风疹),serumsickness,contactdermatitis,drugallergicreactions,chronicsevereasthma,statusasthmaticus,angioneuroticedema,etc.,Glucocorticoiddrugs,86,3.临床应用(2)Severeinfectionandinflammation1)acutesevereinfections:merelysuppressinflammatorymanifestationsbutattimeslifesavingCaution:combinationwitheffectiveantibioticdrugs;Largedoses;shorttermadministration!Usuallynotusedforviralandfungalinfectionsexceptforthosewithcerebraledemaorseveresystemicsymptoms2)preventionofsequelae(后遗症)ofsometypesofinflammation,suchasinbrain,heart,eye,joint,etc.,A.Glucocorticoiddrugs,87,3.Clinicaluses(3)Septicshock:Caution:largerdose,short-term,andcombinedwitheffectiveantibioticdrugs.(4)Hematologicaldiseases:acutelymphocyticleukemia,lymphomas,aplasticanemia(再生障碍性贫血),hemolyticanemia,granulocytopenia,thrombocytopenia,etc.(5)Topicalapplications:skin,eye,respiratorytract,joint(localinjection)(6)Replacementtherapy,A.Glucocorticoiddrugs,88,4.不良反应(1)长期大剂量应用引起的不良反应1)医源性肾上腺皮质功能亢进（Hypercorticism-likesyndrome）：向心性肥胖（满月脸，水牛背），皮肤变薄，多毛，水肿，高血压，糖尿病，低血钾等2)诱发和加重感染（esp.inpats.withlowimmunefunction）Caution:specificantibioticdrugsshouldbeadministeredwithGCs.Livevirusvaccination!3)消化系统:消化性溃疡、出血、穿孔.,Glucocorticoiddrugs,89,4.不良反应4)心血管系统：高血压、高脂血症、动脉粥样硬化5)骨质疏松、肌肉萎缩、伤口愈合延缓：影响儿童生长发育，骨质疏松导致脊柱压缩性骨折和自发性骨折（esp.in老人、儿童和绝经后妇女），股骨头坏死6)糖尿病7)CNS:行为异常，诱发癫痫和精神病,Glucocorticoiddrugs,90,91,4.不良反应(2)撤药反应1)HPA轴抑制（功能恢复可长达2年）医源性肾上腺皮质功能减退，肾上腺皮质功能危象。防治：缓慢停药，ACTH一周，必要时及时给予足量糖皮质激素2)反跳现象：原有疾病复发或恶化(3)禁忌症精神疾病，癫痫，活动性消化性溃疡，骨折，肾上腺皮质功能亢进，高血压，糖尿病，病毒或真菌感染，etc.,A.Glucocorticoiddrugs,92,Considerbenefit/riskbeforetheuseofGCs!,93,5.用法(1)大剂量冲击疗法：i.v.gtt氢化可的松，地塞米松(2)小剂量替代疗法：口服氢化可的松(3)一般剂量长期疗法：口服泼尼松或泼尼松龙等每日晨给药法隔晨给药法Notes:保护HPA轴(4)局部用药：曲安奈德，倍氯米松等,Glucocorticoiddrugs,94,Plasmaglucocorticoids,95,Someindicationsfortheuseofglucocorticoids,荨麻疹,96,97,Casereport,Thepatientwasa39-year-oldmalephysicianbasedattheintensive-careunitofasmallhospitalinGuangzhou,China,hadnoconcurrentmedicalillness.ManypatientswithSARSwereadmittedtothehospitalwhereheworkedduringtheeightweeksbeforeApril4,2003,whenhepresentedwithasorethroatandalow-gradefever(37.3C).Fivedayslater,hehadahighfever(38.5C)andalowleukocytecount(3.4109perliter;63.6%neutrophilsand26.2%lymphocytes),andhewasadmittedtothehospitalwithsuspectedSARS./doi/pdf/10.1056/NEJM200307313490519,98,Casereport,Thepatientwastreatedwithtwice-dailymethylprednisolone(甲基强的松龙,80mginthemorningand40mgintheevening)fortwodays;thedosewasdecreasedto20mgtwicedailyasthefeversubsidedonApril12.ThefeverrecurredonApril14,andchestradiographyshowedaninfiltrateintheleftlowerlobe;theleukocytecountwas13.5109perliter(94.0%neutrophilsand6.0%lymphocytes).Methylprednisolonewasgivenagain(20mginthemorningand80mgintheevening),andthepatientwastransferredtoalargerhospitalonApril15.,99,Casereport,Intravenousmethylprednisolonetherapy(80mgtwicedaily)wasthenadministered.Thepatientsclinicalconditionimproved;hehadnofeverandcouldwalkwithoutdyspnea.Theinfiltrateintheleftlungdiminishedindensity,andthedoseofmethylprednisolonewasreducedto40mgtwicedailyonApril19.OnApril29,thepatientwasagaindyspneic,andradiographsshowedaleftbasilarinfiltrate.OnMay4,thepatientwastransferredtoauniversityteachinghospital.Methylprednisolone(240mgtwicedaily)wasgiven,butthenextdaytheoxygensaturationfellto60percent,andendotrachealintubationwasperformedtoallowmechanicalventilation.,100,Casereport,Thepatientshowedsignsthatwereconsistentwiththepresenceoftentorialherniation(小脑幕疝);hispupilswerefixedanddilated.Computedtomographicexaminationofthecraniumshoweddiffusecerebraledemawithlocalizedhemorrhage.Enzyme-linkedimmunosorbentassayandindirectimmunofluorescenceestablishedthepresenceofspecificantibodiesagainstaSARS-associatedvirusintheserum.Despitemassivesupportivecare,thepatientdiedonMay7.,101,AutopsyshowedSARS-associatedpathologicchanges,includingconsolidation,hemorrhage,andedemaofthelungs;proliferationanddesquamationofalveolarepithelialcells;exudationofmonocytes,lymphocytes,andplasmacellsinalveoli