第十一章 腎上腺皮質(zhì)激素類藥物課件

Chapter11

Adrenocorticosteroids

AndAdrenocorticalAntagonistsDepartmentofPharmacology,MedicalschoolofNankaiUniversityJinglingZhangTel:(office)E-mail:第十一章腎上腺皮質(zhì)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(chǔ)以便充分發(fā)揮療效。避免或減少不良反應(yīng)。掌握腎上腺皮質(zhì)激素的主要生理、藥理作用，臨床用途，不良反應(yīng)及應(yīng)用注意。第十一章腎上腺皮質(zhì)激素類藥物Adrenocorticosteroids內(nèi)容糖皮激素類的作用：1）生理作用：對糖，蛋白質(zhì)，脂肪，水鹽代謝的作用。2）藥理作用：抗炎癥，抗免疫，抗細菌內(nèi)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。第十一章腎上腺皮質(zhì)激素類藥物Adrenocorticosteroids糖皮質(zhì)激素的臨床應(yīng)用：嚴重急性感染，緩解癥狀，贏得時間；各種炎癥；過敏反應(yīng)及自身免疫性疾??；休克；某些血液?。谎a充療法；局部治療皮膚病。不良反應(yīng)：類似腎上腺皮質(zhì)功能亢進癥，長期用藥導(dǎo)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。第十一章腎上腺皮質(zhì)激素類藥物Adrenocorticosteroids常用糖皮質(zhì)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(zhì)激素類藥物：醛固酮類的作用，用途。促皮質(zhì)激素藥物的作用，用途?？蛊べ|(zhì)激素類藥物的主要臨床應(yīng)用。第十一章腎上腺皮質(zhì)激素類藥物AdrenocorticosteroidsIntroductionClassificationStructure-activityrelationshipGlucocorticoidsMineralocorticoidsACTHandadrenocorticalantagonists第十一章腎上腺皮質(zhì)激素類藥物AdrenocorticosteroidsClassificationadrenalcortexMajorhormoneEffectsonRegulationbyMineralocorticoidszonasphericalaldosteronedesoxycorticisteronewater&electrolytebalanceangiotensinⅡ&extracellularK+Glucocorticoidszonafasciculatahydrocortisonecortisonecarbohydrate,protein&fatmetabolismACTHSexhormonezonareticularis

androgensestrogensACTHAllofadrenocorticalhormonesaresynthesizedfromcholesterol.第十一章腎上腺皮質(zhì)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(zhì)激素類藥物Figure28-5Biosynthesisofcorticosteroidsandadrenalandrogens.

第十一章腎上腺皮質(zhì)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(zhì)激素類藥物AdrenocorticosteroidsGlucocorticoidsPhysiologicalFunctions，smalldosePharmacologicaleffects,largedosePharmacokineticsMechanismofactionsClinicalusesAdverseeffectsandcontraindicationDosageschedule第十一章腎上腺皮質(zhì)激素類藥物AdrenocorticosteroidsPharmacologicaleffectsAnti-inflammatoryeffectImmunosupporessiveeffectsAntitoxicactionAntishockeffectothereffects第十一章腎上腺皮質(zhì)激素類藥物AdrenocorticosteroidsAnti-inflammatoryeffectAnti-inflammatoryeffectoflargedoseglucocorticoidsisverystrong.Thehormonescaninhibitinflammatoryreactionscausedbyvariousstimulus,suchasphysical,chemical,biological,allergicstimuli.第十一章腎上腺皮質(zhì)激素類藥物AdrenocorticosteroidsIntheearlystageofinflammation,mayprominentabatetheinflammatorysymptoms.Inthelatestageofinflammation,mayavoidformationofadhesionandscar,reducesequel.beofgreatvalueandcarrythehazard第十一章腎上腺皮質(zhì)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(zhì)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(zhì)激素類藥物Adrenocorticosteroidsinhibitgenerationofinducednitricoxideinmacrophagocytesanddecreasehistaminereleasefrombasophils.第十一章腎上腺皮質(zhì)激素類藥物AdrenocorticosteroidsPharmacologicaleffectsAnti-inflammatoryeffectImmunosupporessiveeffectsAntitoxicactionAntishockeffectothereffects第十一章腎上腺皮質(zhì)激素類藥物AdrenocorticosteroidsImmunosupporessiveeffectsInhibitthefunctionsofleukocytesandtissuemacrophages.Decreasethelymphocytes,monocytes,eosinophilsandbasophilsinnumber.InhibitionoftheproductionandeffectsofIL-2,impairdelayedhypersensitivityreactions.Maymainlyinhibitcellularimmunityinsmalldosesandhumoralimmunityinlargedoses.第十一章腎上腺皮質(zhì)激素類藥物AdrenocorticosteroidsPharmacologicaleffectsAnti-inflammatoryeffectImmunosupporessiveeffectsAntitoxicaction

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

decrease

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

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

Antishockeffectothereffects第十一章腎上腺皮質(zhì)激素類藥物AdrenocorticosteroidsAntishockeffect

thesupra-largedosesteroidsisextensiveusedinclinicaltreatmentofallkindsofsevereshock,especiallytoxicshock.Themechanismoftheactionhastherelationwiththefollowingfactors:第十一章腎上腺皮質(zhì)激素類藥物AdrenocorticosteroidsIncreasethecontractionoftheheartmuscleanddilatethebloodvesselsofspasmodiccontraction.Decreasethesensitivityofbloodvesselstosomevasocontrictivesubstancesandrelievebloodvesselsspasm,resultintheimprovementofmicrocirculationandreductionofsymptomsoftoxicshock.第十一章腎上腺皮質(zhì)激素類藥物AdrenocorticosteroidsStabilizationoflysosomalmembranes,reducestheformationofmyocardial-depressantfactor(MDF)thatdecreasemyocardialcontractionforceandpreventsthereleaseofproteolyticenzymes.Anti-inflammationeffectsImmunosupporessiveeffectsAntitoxicaction第十一章腎上腺皮質(zhì)激素類藥物AdrenocorticosteroidsOthereffectsbloodandhematopoieticsystemCNSthedevelopmentofthefetus.appeartoantagonizetheeffectofvitaminDandcalciumabsorption.stimulateexcessiveproductionofacidandpepsininthestomachandmaycausepepticulcer.第十一章腎上腺皮質(zhì)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(zhì)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(zhì)激素類藥物AdrenocorticosteroidsMechanismGlucocorticoideffectsinvolveinteractionsbetweenthesteroidsandintracellularreceptorsthatbelongtothesuperfamilyofreceptorsthatcontrolgenetranscription.第十一章腎上腺皮質(zhì)激素類藥物第十一章腎上腺皮質(zhì)激素類藥物第十一章腎上腺皮質(zhì)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(zhì)激素類藥物AdrenocorticosteroidsClinicalusesReplacementtherapyforpatientswithadrenocorticalinsufficiencyChronicadrenocorticoidsinsufficiency(Addison’sdisease)Acuteadrenocorticoidsinsufficiency(adrenalcrisis)第十一章腎上腺皮質(zhì)激素類藥物AdrenocorticosteroidsSevereinfectiousdiseaseAutoimmunediseasesandallergicdiseasesShockHematologicdisorderstopicaluses第十一章腎上腺皮質(zhì)激素類藥物AdrenocorticosteroidsAdverseeffectsandcontraindicationAdverseeffectsIatrogenicCushing‘ssyndrome→Causedbyglucocorticoidstherapywithlargedosesinlong-termCausedbywithdrawaloftherapyContraindicationsacuteadrenalinsufficiencyIftherapyistobestopped,thereductionprocessshouldbequiteslow.Itwilltake2-3monthsforthepituitarytobecomeresponsive.第十一章腎上腺皮質(zhì)激素類藥物Figure28-7Cushing'ssyndrome.

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