Chapter11

Adrenocorticosteroids

AndAdrenocorticalAntagonistsDepartmentofPharmacology,MedicalschoolofNankaiUniversityJinglingZhangTel:(office)E-mail:第十一章腎上腺皮質激素類藥物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。第十一章腎上腺皮質激素類藥物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，中樞神經系統的影響。分別敘述這些作用的表現及這些表現發生的可能原因，從有利與不利兩個方面說明抗炎作用與抗免疫作用。第十一章腎上腺皮質激素類藥物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病；休克；某些血液病；補充療法；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，誘發或加重感染，誘發胃潰瘍，延長傷口育合。長期用藥的停藥問題。慎用場合與禁忌癥。第十一章腎上腺皮質激素類藥物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。抗皮質激素類藥物的主要臨床應用。第十一章腎上腺皮質激素類藥物AdrenocorticosteroidsIntroductionClassificationStructure-activityrelationshipGlucocorticoidsMineralocorticoidsACTHandadrenocorticalantagonists第十一章腎上腺皮質激素類藥物AdrenocorticosteroidsClassificationadrenalcortexMajorhormoneEffectsonRegulationbyMineralocorticoidszonasphericalaldosteronedesoxycorticisteronewater&electrolytebalanceangiotensinⅡ&extracellularK+Glucocorticoidszonafasciculatahydrocortisonecortisonecarbohydrate,protein&fatmetabolismACTHSexhormonezonareticularis

androgensestrogensACTHAllofadrenocorticalhormonesaresynthesizedfromcholesterol.第十一章腎上腺皮質激素類藥物Figure28-4Regulationofsynthesisandsecretionofadrenalcorticosteroids.

Thelongnegativefeedbackloopismoreimportantthantheshortloop(dashedlines).Adrenocorticotrophichormone(ACTH,corticotrophin)hasonlyaminimaleffectonmineralocorticoidproduction.Drugsareshowninyellowboxes.ADH,antidiuretichormone(vasopressin);CRF,corticotrophin-releasingfactor.第十一章腎上腺皮質激素類藥物Figure28-5Biosynthesisofcorticosteroidsandadrenalandrogens.

第十一章腎上腺皮質激素類藥物structureringactivityexampleThe4,5doublebondThe3-ketogroupThe20-ketogroup17

-hydroxylgroupAADDmaintainingphysiologicalactivityhydrocortisone11β-hydroxylgroup17

-hydroxylgroupCDglucocorticoidscortisol,hydrocortisoneThe1,2doublebondAIncreasesglucocorticoidsactivityprednisoneThe9

fluorinationBenhancesbothglucocorticoidandmineralocorticoidactivityfludrocortisoneThe1,2doublebondThel6-methylgroupThel6-hydroxylgroupThe9

-fluorogroupADDBIncreaseglucocorticoidactivity,

decreasemineralocorticoidactivitytriamcinolone,dexamethasone,betamethasoneStructure-activityrelationship第十一章腎上腺皮質激素類藥物AdrenocorticosteroidsGlucocorticoidsPhysiologicalFunctions，smalldosePharmacologicaleffects,largedosePharmacokineticsMechanismofactionsClinicalusesAdverseeffectsandcontraindicationDosageschedule第十一章腎上腺皮質激素類藥物AdrenocorticosteroidsPharmacologicaleffectsAnti-inflammatoryeffectImmunosupporessiveeffectsAntitoxicactionAntishockeffectothereffects第十一章腎上腺皮質激素類藥物AdrenocorticosteroidsAnti-inflammatoryeffectAnti-inflammatoryeffectoflargedoseglucocorticoidsisverystrong.Thehormonescaninhibitinflammatoryreactionscausedbyvariousstimulus,suchasphysical,chemical,biological,allergicstimuli.第十一章腎上腺皮質激素類藥物AdrenocorticosteroidsIntheearlystageofinflammation,mayprominentabatetheinflammatorysymptoms.Inthelatestageofinflammation,mayavoidformationofadhesionandscar,reducesequel.beofgreatvalueandcarrythehazard第十一章腎上腺皮質激素類藥物AdrenocorticosteroidsMechanismofanti-inflammatoryactionsInhibitinflammatoryfactorssynthesisandreleaseintotheblood↑theformationoflipocortin-1→inhibitingphospholipaseA2inhibitgenerationofinducednitricoxidesynthaseandcyclooxygenase-2(COX-2)→NO,PGE2↓InducegenerationofACE→↑decomposethebradykinin第十一章腎上腺皮質激素類藥物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)↑第十一章腎上腺皮質激素類藥物Adrenocorticosteroidsinhibitgenerationofinducednitricoxideinmacrophagocytesanddecreasehistaminereleasefrombasophils.第十一章腎上腺皮質激素類藥物AdrenocorticosteroidsPharmacologicaleffectsAnti-inflammatoryeffectImmunosupporessiveeffectsAntitoxicactionAntishockeffectothereffects第十一章腎上腺皮質激素類藥物AdrenocorticosteroidsImmunosupporessiveeffectsInhibitthefunctionsofleukocytesandtissuemacrophages.Decreasethelymphocytes,monocytes,eosinophilsandbasophilsinnumber.InhibitionoftheproductionandeffectsofIL-2,impairdelayedhypersensitivityreactions.Maymainlyinhibitcellularimmunityinsmalldosesandhumoralimmunityinlargedoses.第十一章腎上腺皮質激素類藥物AdrenocorticosteroidsPharmacologicaleffectsAnti-inflammatoryeffectImmunosupporessiveeffectsAntitoxicaction

Antishockeffectothereffects第十一章腎上腺皮質激素類藥物AdrenocorticosteroidsAntitoxicactionenhancethetoleranceoforganismtobacterialendotoxins,butnotneutralizebacterialendotoxins,andalsohavenoeffectsonbacterialexotoxin.第十一章腎上腺皮質激素類藥物AdrenocorticosteroidsLargedosesteroidshaveprofoundeffectson

decrease

thesymptomsofintoxicationofinfectivetoxemiaandantithermicaction(cooling).Mechanism:第十一章腎上腺皮質激素類藥物AdrenocorticosteroidsThisisduetotheirinhibitionofthereleaseendogenicpyrogen

andthesensitivityoftheheat-regulating-centertothepyrogen.Itisalsoattributedtotheremarkableabilityofthesteroidstostabilizelysosomalmembranes.第十一章腎上腺皮質激素類藥物AdrenocorticosteroidsPharmacologicaleffectsAnti-inflammatoryeffectImmunosupporessiveeffectsAntitoxicaction

Antishockeffectothereffects第十一章腎上腺皮質激素類藥物AdrenocorticosteroidsAntishockeffect

thesupra-largedosesteroidsisextensiveusedinclinicaltreatmentofallkindsofsevereshock,especiallytoxicshock.Themechanismoftheactionhastherelationwiththefollowingfactors:第十一章腎上腺皮質激素類藥物AdrenocorticosteroidsIncreasethecontractionoftheheartmuscleanddilatethebloodvesselsofspasmodiccontraction.Decreasethesensitivityofbloodvesselstosomevasocontrictivesubstancesandrelievebloodvesselsspasm,resultintheimprovementofmicrocirculationandreductionofsymptomsoftoxicshock.第十一章腎上腺皮質激素類藥物AdrenocorticosteroidsStabilizationoflysosomalmembranes,reducestheformationofmyocardial-depressantfactor(MDF)thatdecreasemyocardialcontractionforceandpreventsthereleaseofproteolyticenzymes.Anti-inflammationeffectsImmunosupporessiveeffectsAntitoxicaction第十一章腎上腺皮質激素類藥物AdrenocorticosteroidsOthereffectsbloodandhematopoieticsystemCNSthedevelopmentofthefetus.appeartoantagonizetheeffectofvitaminDandcalciumabsorption.stimulateexcessiveproductionofacidandpepsininthestomachandmaycausepepticulcer.第十一章腎上腺皮質激素類藥物AdrenocorticosteroidsPharmacokinetics

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

Inplasma,cortisolisboundtoplasmaproteins.Corticosteroid-bindingglobulin（CBG）Albumin.BothCBG-boundandalbumin-boundsteroidsarebiologicallyinactive.第十一章腎上腺皮質激素類藥物AdrenocorticosteroidsHydrocortisonet1/2=90minutes,Tpeak=1-2h.metabolismintheliver,finallyexcretedinthe

urine.IfthereisadoublebondbetweenC1-C2orafluorinatomatC9,metabolismisslowed.Cortisoneandprednisoneareinactiveuntilconvertedinthelivertohydrocortisoneandprednisolone,respectively.第十一章腎上腺皮質激素類藥物AdrenocorticosteroidsMechanismGlucocorticoideffectsinvolveinteractionsbetweenthesteroidsandintracellularreceptorsthatbelongtothesuperfamilyofreceptorsthatcontrolgenetranscription.第十一章腎上腺皮質激素類藥物第十一章腎上腺皮質激素類藥物第十一章腎上腺皮質激素類藥物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).第十一章腎上腺皮質激素類藥物AdrenocorticosteroidsClinicalusesReplacementtherapyforpatientswithadrenocorticalinsufficiencyChronicadrenocorticoidsinsufficiency(Addison’sdisease)Acuteadrenocorticoidsinsufficiency(adrenalcrisis)第十一章腎上腺皮質激素類藥物AdrenocorticosteroidsSevereinfectiousdiseaseAutoimmunediseasesandallergicdiseasesShockHematologicdisorderstopicaluses第十一章腎上腺皮質激素類藥物AdrenocorticosteroidsAdverseeffectsandcontraindicationAdverseeffectsIatrogenicCushing‘ssyndrome→Causedbyglucocorticoidstherapywithlargedosesinlong-termCausedbywithdrawaloftherapyContraindicationsacuteadrenalinsufficiencyIftherapyistobestopped,thereductionprocessshouldbequiteslow.Itwilltake2-3monthsforthepituitarytobecomeresponsive.第十一章腎上腺皮質激素類藥物Figure28-7Cushing'ssyndrome.

第十一章腎上腺皮質激素類藥物AdrenocorticosteroidsContraindicationspepticulcer,heartdiseaseorhypertensionwithCHF(congestiveheartfailure),infectious,herpessimplexinfection,psychoses,diabetes,osteoporosis,glaucoma,第十一章腎上腺皮質激素類