腎上腺皮質激素類藥物第一頁，共四十八頁，編輯于2023年，星期一Adrenocorticosteroids目的了解如何正確運用此類藥物的理論基礎以便充分發(fā)揮療效。避免或減少不良反應。掌握腎上腺皮質激素的主要生理、藥理作用，臨床用途，不良反應及應用注意。第二頁，共四十八頁，編輯于2023年，星期一Adrenocorticosteroids內容糖皮激素類的作用：1）生理作用：對糖，蛋白質，脂肪，水鹽代謝的作用。2）藥理作用：抗炎癥，抗免疫，抗細菌內毒素，抗休克，血液，中樞神經(jīng)系統(tǒng)的影響。分別敘述這些作用的表現(xiàn)及這些表現(xiàn)發(fā)生的可能原因，從有利與不利兩個方面說明抗炎作用與抗免疫作用。第三頁，共四十八頁，編輯于2023年，星期一Adrenocorticosteroids糖皮質激素的臨床應用：嚴重急性感染，緩解癥狀，贏得時間；各種炎癥；過敏反應及自身免疫性疾?。恍菘?；某些血液?。谎a充療法；局部治療皮膚病。不良反應：類似腎上腺皮質功能亢進癥，長期用藥導致功能不全，誘發(fā)或加重感染，誘發(fā)胃潰瘍，延長傷口育合。長期用藥的停藥問題。慎用場合與禁忌癥。第四頁，共四十八頁，編輯于2023年，星期一Adrenocorticosteroids常用糖皮質激素類藥物：可的松，氫化可的松，潑尼松（強的松），潑尼松龍（強的松龍），地塞米松（氟美松），膚氫松，及用法。鹽皮質激素類藥物：醛固酮類的作用，用途。促皮質激素藥物的作用，用途?？蛊べ|激素類藥物的主要臨床應用。第五頁，共四十八頁，編輯于2023年，星期一AdrenocorticosteroidsIntroductionClassificationStructure-activityrelationshipGlucocorticoidsMineralocorticoidsACTHandadrenocorticalantagonists第六頁，共四十八頁，編輯于2023年，星期一AdrenocorticosteroidsClassificationadrenalcortexMajorhormoneEffectsonRegulationbyMineralocorticoidszonasphericalaldosteronedesoxycorticisteronewater&electrolytebalanceangiotensinⅡ&extracellularK+Glucocorticoidszonafasciculatahydrocortisonecortisonecarbohydrate,protein&fatmetabolismACTHSexhormonezonareticularis

androgensestrogensACTHAllofadrenocorticalhormonesaresynthesizedfromcholesterol.第七頁，共四十八頁，編輯于2023年，星期一Figure28-4Regulationofsynthesisandsecretionofadrenalcorticosteroids.

Thelongnegativefeedbackloopismoreimportantthantheshortloop(dashedlines).Adrenocorticotrophichormone(ACTH,corticotrophin)hasonlyaminimaleffectonmineralocorticoidproduction.Drugsareshowninyellowboxes.ADH,antidiuretichormone(vasopressin);CRF,corticotrophin-releasingfactor.第八頁，共四十八頁，編輯于2023年，星期一Figure28-5Biosynthesisofcorticosteroidsandadrenalandrogens.

第九頁，共四十八頁，編輯于2023年，星期一structureringactivityexampleThe4,5doublebondThe3-ketogroupThe20-ketogroup17-hydroxylgroupAADDmaintainingphysiologicalactivityhydrocortisone11β-hydroxylgroup17-hydroxylgroupCDglucocorticoidscortisol,hydrocortisoneThe1,2doublebondAIncreasesglucocorticoidsactivityprednisoneThe9fluorinationBenhancesbothglucocorticoidandmineralocorticoidactivityfludrocortisoneThe1,2doublebondThel6-methylgroupThel6-hydroxylgroupThe9-fluorogroupADDBIncreaseglucocorticoidactivity,

decreasemineralocorticoidactivitytriamcinolone,dexamethasone,betamethasoneStructure-activityrelationship第十頁，共四十八頁，編輯于2023年，星期一AdrenocorticosteroidsGlucocorticoidsPhysiologicalFunctions，smalldosePharmacologicaleffects,largedosePharmacokineticsMechanismofactionsClinicalusesAdverseeffectsandcontraindicationDosageschedule第十一頁，共四十八頁，編輯于2023年，星期一AdrenocorticosteroidsPharmacologicaleffectsAnti-inflammatoryeffectImmunosupporessiveeffectsAntitoxicactionAntishockeffectothereffects第十二頁，共四十八頁，編輯于2023年，星期一AdrenocorticosteroidsAnti-inflammatoryeffectAnti-inflammatoryeffectoflargedoseglucocorticoidsisverystrong.Thehormonescaninhibitinflammatoryreactionscausedbyvariousstimulus,suchasphysical,chemical,biological,allergicstimuli.第十三頁，共四十八頁，編輯于2023年，星期一AdrenocorticosteroidsIntheearlystageofinflammation,mayprominentabatetheinflammatorysymptoms.Inthelatestageofinflammation,mayavoidformationofadhesionandscar,reducesequel.beofgreatvalueandcarrythehazard第十四頁，共四十八頁，編輯于2023年，星期一AdrenocorticosteroidsMechanismofanti-inflammatoryactionsInhibitinflammatoryfactorssynthesisandreleaseintotheblood↑theformationoflipocortin-1→inhibitingphospholipaseA2inhibitgenerationofinducednitricoxidesynthaseandcyclooxygenase-2(COX-2)→NO,PGE2↓InducegenerationofACE→↑decomposethebradykinin第十五頁，共四十八頁，編輯于2023年，星期一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)↑第十六頁，共四十八頁，編輯于2023年，星期一Adrenocorticosteroidsinhibitgenerationofinducednitricoxideinmacrophagocytesanddecreasehistaminereleasefrombasophils.第十七頁，共四十八頁，編輯于2023年，星期一AdrenocorticosteroidsPharmacologicaleffectsAnti-inflammatoryeffectImmunosupporessiveeffectsAntitoxicactionAntishockeffectothereffects第十八頁，共四十八頁，編輯于2023年，星期一AdrenocorticosteroidsImmunosupporessiveeffectsInhibitthefunctionsofleukocytesandtissuemacrophages.Decreasethelymphocytes,monocytes,eosinophilsandbasophilsinnumber.InhibitionoftheproductionandeffectsofIL-2,impairdelayedhypersensitivityreactions.Maymainlyinhibitcellularimmunityinsmalldosesandhumoralimmunityinlargedoses.第十九頁，共四十八頁，編輯于2023年，星期一AdrenocorticosteroidsPharmacologicaleffectsAnti-inflammatoryeffectImmunosupporessiveeffectsAntitoxicaction

Antishockeffectothereffects第二十頁，共四十八頁，編輯于2023年，星期一AdrenocorticosteroidsAntitoxicactionenhancethetoleranceoforganismtobacterialendotoxins,butnotneutralizebacterialendotoxins,andalsohavenoeffectsonbacterialexotoxin.第二十一頁，共四十八頁，編輯于2023年，星期一AdrenocorticosteroidsLargedosesteroidshaveprofoundeffectson

decrease

thesymptomsofintoxicationofinfectivetoxemiaandantithermicaction(cooling).Mechanism:第二十二頁，共四十八頁，編輯于2023年，星期一AdrenocorticosteroidsThisisduetotheirinhibitionofthereleaseendogenicpyrogen

andthesensitivityoftheheat-regulating-centertothepyrogen.Itisalsoattributedtotheremarkableabilityofthesteroidstostabilizelysosomalmembranes.第二十三頁，共四十八頁，編輯于2023年，星期一AdrenocorticosteroidsPharmacologicaleffectsAnti-inflammatoryeffectImmunosupporessiveeffectsAntitoxicaction

Antishockeffectothereffects第二十四頁，共四十八頁，編輯于2023年，星期一AdrenocorticosteroidsAntishockeffect

thesupra-largedosesteroidsisextensiveusedinclinicaltreatmentofallkindsofsevereshock,especiallytoxicshock.Themechanismoftheactionhastherelationwiththefollowingfactors:第二十五頁，共四十八頁，編輯于2023年，星期一AdrenocorticosteroidsIncreasethecontractionoftheheartmuscleanddilatethebloodvesselsofspasmodiccontraction.Decreasethesensitivityofbloodvesselstosomevasocontrictivesubstancesandrelievebloodvesselsspasm,resultintheimprovementofmicrocirculationandreductionofsymptomsoftoxicshock.第二十六頁，共四十八頁，編輯于2023年，星期一AdrenocorticosteroidsStabilizationoflysosomalmembranes,reducestheformationofmyocardial-depressantfactor(MDF)thatdecreasemyocardialcontractionforceandpreventsthereleaseofproteolyticenzymes.Anti-inflammationeffectsImmunosupporessiveeffectsAntitoxicaction第二十七頁，共四十八頁，編輯于2023年，星期一AdrenocorticosteroidsOthereffectsbloodandhematopoieticsystemCNSthedevelopmentofthefetus.appeartoantagonizetheeffectofvitaminDandcalciumabsorption.stimulateexcessiveproductionofacidandpepsininthestomachandmaycausepepticulcer.第二十八頁，共四十八頁，編輯于2023年，星期一AdrenocorticosteroidsPharmacokinetics

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

Inplasma,cortisolisboundtoplasmaproteins.Corticosteroid-bindingglobulin（CBG）Albumin.BothCBG-boundandalbumin-boundsteroidsarebiologicallyinactive.第二十九頁，共四十八頁，編輯于2023年，星期一AdrenocorticosteroidsHydrocortisonet1/2=90minutes,Tpeak=1-2h.metabolismintheliver,finallyexcretedinthe

urine.IfthereisadoublebondbetweenC1-C2orafluorinatomatC9,metabolismisslowed.Cortisoneandprednisoneareinactiveuntilconvertedinthelivertohydrocortisoneandprednisolone,respectively.第三十頁，共四十八頁，編輯于2023年，星期一AdrenocorticosteroidsMechanismGlucocorticoideffectsinvolveinteractionsbetweenthesteroidsandintracellularreceptorsthatbelongtothesuperfamilyofreceptorsthatcontrolgenetranscription.第三十一頁，共四十八頁，編輯于2023年，星期一第三十二頁，共四十八頁，編輯于2023年，星期一第三十三頁，共四十八頁，編輯于2023年，星期一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).第三十四頁，共四十八頁，編輯于2023年，星期一AdrenocorticosteroidsClinicalusesReplacementtherapyforpatientswithadrenocorticalinsufficiencyChronicadrenocorticoidsinsufficiency(Addison’sdisease)Acuteadrenocorticoidsinsufficiency(adrenalcrisis)第三十五頁，共四十八頁，編輯于2023年，星期一AdrenocorticosteroidsSevereinfectiousdiseaseAutoimmunediseasesandallergicdiseasesShockHematologicdisorderstopicaluses第三十六頁，共四十八頁，編輯于2023年，星期一AdrenocorticosteroidsAdverseeffectsandcontraindicationAdverseeffectsIatrogenicCushing‘ssyndrome→Causedbyglucocorticoidstherapywithlargedosesinlong-termCausedbywithdrawaloftherapyContraindicationsacuteadrenalinsufficiencyIftherapyistobestopped,thereductionprocessshouldbequiteslow.Itwilltake2-3monthsforthepituitarytobecomeresponsive.第三十七頁，共四十八頁，編輯于2023年，星期一Figure28-7Cushing'ssyndrome.

第三十八頁，共四十八頁，編輯于2023年，星期一AdrenocorticosteroidsContraindicationspepticulcer,heartdiseaseorhypertensionwithCHF(congestiveheartfailure),infectious,herpessimplexinfection,psychoses,diabetes,osteoporosis,glaucoma,第三十九頁，共四十八頁，編輯于2023年，星期一AdrenocorticosteroidsDosageschedule