第十一章 肾上腺皮质激素类药物课件

Chapter11

Adrenocorticosteroids

AndAdrenocorticalAntagonistsDepartmentofPharmacology,MedicalschoolofNankaiUniversityJinglingZhangTel:(office)E-mail:第十一章肾上腺皮质激素类药物Adrenocorticosteroids目的了解如何正确运用此类药物的理论基础以便充分发挥疗效。避免或减少不良反应。掌握肾上腺皮质激素的主要生理、药理作用，临床用途，不良反应及应用注意。第十一章肾上腺皮质激素类药物Adrenocorticosteroids内容糖皮激素类的作用：1）生理作用：对糖，蛋白质，脂肪，水盐代谢的作用。2）药理作用：抗炎症，抗免疫，抗细菌内毒素，抗休克，血液，中枢神经系统的影响。分别叙述这些作用的表现及这些表现发生的可能原因，从有利与不利两个方面说明抗炎作用与抗免疫作用。第十一章肾上腺皮质激素类药物Adrenocorticosteroids糖皮质激素的临床应用：严重急性感染，缓解症状，赢得时间；各种炎症；过敏反应及自身免疫性疾病；休克；某些血液病；补充疗法；局部治疗皮肤病。不良反应：类似肾上腺皮质功能亢进症，长期用药导致功能不全，诱发或加重感染，诱发胃溃疡，延长伤口育合。长期用药的停药问题。慎用场合与禁忌症。第十一章肾上腺皮质激素类药物Adrenocorticosteroids常用糖皮质激素类药物：可的松，氢化可的松，泼尼松（强的松），泼尼松龙（强的松龙），地塞米松（氟美松），肤氢松，及用法。盐皮质激素类药物：醛固酮类的作用，用途。促皮质激素药物的作用，用途。抗皮质激素类药物的主要临床应用。第十一章肾上腺皮质激素类药物AdrenocorticosteroidsIntroductionClassificationStructure-activityrelationshipGlucocorticoidsMineralocorticoidsACTHandadrenocorticalantagonists第十一章肾上腺皮质激素类药物AdrenocorticosteroidsClassificationadrenalcortexMajorhormoneEffectsonRegulationbyMineralocorticoidszonasphericalaldosteronedesoxycorticisteronewater&electrolytebalanceangiotensinⅡ&extracellularK+Glucocorticoidszonafasciculatahydrocortisonecortisonecarbohydrate,protein&fatmetabolismACTHSexhormonezonareticularis

androgensestrogensACTHAllofadrenocorticalhormonesaresynthesizedfromcholesterol.第十一章肾上腺皮质激素类药物Figure28-4Regulationofsynthesisandsecretionofadrenalcorticosteroids.

Thelongnegativefeedbackloopismoreimportantthantheshortloop(dashedlines).Adrenocorticotrophichormone(ACTH,corticotrophin)hasonlyaminimaleffectonmineralocorticoidproduction.Drugsareshowninyellowboxes.ADH,antidiuretichormone(vasopressin);CRF,corticotrophin-releasingfactor.第十一章肾上腺皮质激素类药物Figure28-5Biosynthesisofcorticosteroidsandadrenalandrogens.

第十一章肾上腺皮质激素类药物structureringactivityexampleThe4,5doublebondThe3-ketogroupThe20-ketogroup17

-hydroxylgroupAADDmaintainingphysiologicalactivityhydrocortisone11β-hydroxylgroup17

-hydroxylgroupCDglucocorticoidscortisol,hydrocortisoneThe1,2doublebondAIncreasesglucocorticoidsactivityprednisoneThe9

fluorinationBenhancesbothglucocorticoidandmineralocorticoidactivityfludrocortisoneThe1,2doublebondThel6-methylgroupThel6-hydroxylgroupThe9

-fluorogroupADDBIncreaseglucocorticoidactivity,

decreasemineralocorticoidactivitytriamcinolone,dexamethasone,betamethasoneStructure-activityrelationship第十一章肾上腺皮质激素类药物AdrenocorticosteroidsGlucocorticoidsPhysiologicalFunctions，smalldosePharmacologicaleffects,largedosePharmacokineticsMechanismofactionsClinicalusesAdverseeffectsandcontraindicationDosageschedule第十一章肾上腺皮质激素类药物AdrenocorticosteroidsPharmacologicaleffectsAnti-inflammatoryeffectImmunosupporessiveeffectsAntitoxicactionAntishockeffectothereffects第十一章肾上腺皮质激素类药物AdrenocorticosteroidsAnti-inflammatoryeffectAnti-inflammatoryeffectoflargedoseglucocorticoidsisverystrong.Thehormonescaninhibitinflammatoryreactionscausedbyvariousstimulus,suchasphysical,chemical,biological,allergicstimuli.第十一章肾上腺皮质激素类药物AdrenocorticosteroidsIntheearlystageofinflammation,mayprominentabatetheinflammatorysymptoms.Inthelatestageofinflammation,mayavoidformationofadhesionandscar,reducesequel.beofgreatvalueandcarrythehazard第十一章肾上腺皮质激素类药物AdrenocorticosteroidsMechanismofanti-inflammatoryactionsInhibitinflammatoryfactorssynthesisandreleaseintotheblood↑theformationoflipocortin-1→inhibitingphospholipaseA2inhibitgenerationofinducednitricoxidesynthaseandcyclooxygenase-2(COX-2)→NO,PGE2↓InducegenerationofACE→↑decomposethebradykinin第十一章肾上腺皮质激素类药物Adrenocorticosteroidsinhibittheproductionofinflammatoryfactorsandincreasegenerationofanti-inflammatoryfactorsinterleukin-1,2,5,6and8,(IL-1,2,5,6,8)↓tumornecrosisfactor-α(TNF-α)↓interferon-γ(IFN-γ)↓interleukin-10,12(IL-10,12)↑InhibitorykappaB1(IκB1)↑Interleukin-1receptorantagonist(IL-1RA)↑第十一章肾上腺皮质激素类药物Adrenocorticosteroidsinhibitgenerationofinducednitricoxideinmacrophagocytesanddecreasehistaminereleasefrombasophils.第十一章肾上腺皮质激素类药物AdrenocorticosteroidsPharmacologicaleffectsAnti-inflammatoryeffectImmunosupporessiveeffectsAntitoxicactionAntishockeffectothereffects第十一章肾上腺皮质激素类药物AdrenocorticosteroidsImmunosupporessiveeffectsInhibitthefunctionsofleukocytesandtissuemacrophages.Decreasethelymphocytes,monocytes,eosinophilsandbasophilsinnumber.InhibitionoftheproductionandeffectsofIL-2,impairdelayedhypersensitivityreactions.Maymainlyinhibitcellularimmunityinsmalldosesandhumoralimmunityinlargedoses.第十一章肾上腺皮质激素类药物AdrenocorticosteroidsPharmacologicaleffectsAnti-inflammatoryeffectImmunosupporessiveeffectsAntitoxicaction

Antishockeffectothereffects第十一章肾上腺皮质激素类药物AdrenocorticosteroidsAntitoxicactionenhancethetoleranceoforganismtobacterialendotoxins,butnotneutralizebacterialendotoxins,andalsohavenoeffectsonbacterialexotoxin.第十一章肾上腺皮质激素类药物AdrenocorticosteroidsLargedosesteroidshaveprofoundeffectson

decrease

thesymptomsofintoxicationofinfectivetoxemiaandantithermicaction(cooling).Mechanism:第十一章肾上腺皮质激素类药物AdrenocorticosteroidsThisisduetotheirinhibitionofthereleaseendogenicpyrogen

andthesensitivityoftheheat-regulating-centertothepyrogen.Itisalsoattributedtotheremarkableabilityofthesteroidstostabilizelysosomalmembranes.第十一章肾上腺皮质激素类药物AdrenocorticosteroidsPharmacologicaleffectsAnti-inflammatoryeffectImmunosupporessiveeffectsAntitoxicaction

Antishockeffectothereffects第十一章肾上腺皮质激素类药物AdrenocorticosteroidsAntishockeffect

thesupra-largedosesteroidsisextensiveusedinclinicaltreatmentofallkindsofsevereshock,especiallytoxicshock.Themechanismoftheactionhastherelationwiththefollowingfactors:第十一章肾上腺皮质激素类药物AdrenocorticosteroidsIncreasethecontractionoftheheartmuscleanddilatethebloodvesselsofspasmodiccontraction.Decreasethesensitivityofbloodvesselstosomevasocontrictivesubstancesandrelievebloodvesselsspasm,resultintheimprovementofmicrocirculationandreductionofsymptomsoftoxicshock.第十一章肾上腺皮质激素类药物AdrenocorticosteroidsStabilizationoflysosomalmembranes,reducestheformationofmyocardial-depressantfactor(MDF)thatdecreasemyocardialcontractionforceandpreventsthereleaseofproteolyticenzymes.Anti-inflammationeffectsImmunosupporessiveeffectsAntitoxicaction第十一章肾上腺皮质激素类药物AdrenocorticosteroidsOthereffectsbloodandhematopoieticsystemCNSthedevelopmentofthefetus.appeartoantagonizetheeffectofvitaminDandcalciumabsorption.stimulateexcessiveproductionofacidandpepsininthestomachandmaycausepepticulcer.第十一章肾上腺皮质激素类药物AdrenocorticosteroidsPharmacokinetics

Glucocorticoidsmaybegivenbyavarietyofroutes.Mostareactivewhengivenorally.Allcanbegivensystemically,eitherintramuscularly(im)orintravenously(iv).Theymayalsobegiventopically.

Inplasma,cortisolisboundtoplasmaproteins.Corticosteroid-bindingglobulin（CBG）Albumin.BothCBG-boundandalbumin-boundsteroidsarebiologicallyinactive.第十一章肾上腺皮质激素类药物AdrenocorticosteroidsHydrocortisonet1/2=90minutes,Tpeak=1-2h.metabolismintheliver,finallyexcretedinthe

urine.IfthereisadoublebondbetweenC1-C2orafluorinatomatC9,metabolismisslowed.Cortisoneandprednisoneareinactiveuntilconvertedinthelivertohydrocortisoneandprednisolone,respectively.第十一章肾上腺皮质激素类药物AdrenocorticosteroidsMechanismGlucocorticoideffectsinvolveinteractionsbetweenthesteroidsandintracellularreceptorsthatbelongtothesuperfamilyofreceptorsthatcontrolgenetranscription.第十一章肾上腺皮质激素类药物第十一章肾上腺皮质激素类药物第十一章肾上腺皮质激素类药物Figure28-6Molecularmechanismofactionofglucocorticoids

Theschematicfigureshowsthreepossiblewaysbywhichtheligandedglucocorticoidreceptorcancontrolgeneexpressionfollowingtranslocationtothenucleus.Basictransactivationmechanism.Here,thetranscriptionalmachinery(TM)ispresumedtobeoperatingatalowlevel.Theligandedglucocorticoidreceptor(GR)dimerbindstooneormore'positive'glucocorticoidresponseelements(GREs)withinthepromotersequence(shadedzone)andup-regulatestranscription.Basictransrepressionmechanism.Thetranscriptionalmachineryisconstitutivelydrivenbytranscriptionfactors(TF).Inbindingtothe'negative'GRE(nGRE),thereceptorcomplexdisplacesthesefactorsandexpressionfalls.Fos/Junmechanism.TranscriptionisdrivenatahighlevelbyFos/JuntranscriptionfactorsbindingtotheirAP-1regulatorysite.ThiseffectisreducedinthepresenceoftheGR.Nuclearfactor

κBmechanism.ThetranscriptionfactorsP65andP50bindtotheNFκBsite,promotinggeneexpression.ThisispreventedbythepresenceoftheGR,whichbindsthetranscriptionfactors,preventingtheiraction(thismayoccurinthecytoplasmalso).第十一章肾上腺皮质激素类药物AdrenocorticosteroidsClinicalusesReplacementtherapyforpatientswithadrenocorticalinsufficiencyChronicadrenocorticoidsinsufficiency(Addison’sdisease)Acuteadrenocorticoidsinsufficiency(adrenalcrisis)第十一章肾上腺皮质激素类药物AdrenocorticosteroidsSevereinfectiousdiseaseAutoimmunediseasesandallergicdiseasesShockHematologicdisorderstopicaluses第十一章肾上腺皮质激素类药物AdrenocorticosteroidsAdverseeffectsandcontraindicationAdverseeffectsIatrogenicCushing‘ssyndrome→Causedbyglucocorticoidstherapywithlargedosesinlong-termCausedbywithdrawaloftherapyContraindicationsacuteadrenalinsufficiencyIftherapyistobestopped,thereductionprocessshouldbequiteslow.Itwilltake2-3monthsforthepituitarytobecomeresponsive.第十一章肾上腺皮质激素类药物Figure28-7Cushing'ssyndrome.

第十一章肾上腺皮质激素类药物AdrenocorticosteroidsContraindicationspepticulcer,heartdiseaseorhypertensionwithCHF(congestiveheartfailure),infectious,herpessimplexinfection,psychoses,diabetes,osteoporosis,glaucoma,第十一章肾上腺皮质激素类