药理学教学课件：Chapter 30 Adrenocorticosteroids Adrenocortical antagonists

Chapter30Adrenocorticosteroids&Adrenocorticalantagonists

Section1.ClassificationofAdrenocorticalHormonesmineralocorticoids:zonaglomerulosaglucocorticoids（GCS）:zonafasciculatasexhormones:

zonareticularisWhatistheadrenalgland?髄質球状帯束状帯网状帯

zonafasciculata:

glucocorticoidregulation?

zonareticularis:

sexhormone皮质zonaglomerulosa:mineralocorticoidWhatareadrenocorticalhormones?

Section2.

Glucocorticoids（GCS）PhysiologicalStatus:Cortisol(考的索，皮质醇，氢化可的松hydrocordisone）Cortisone(可的松，smallamounts).Structure-functionRelationshipElementarystructure：Steroidnucleus.C3ketonegroupC4-5doublebondC17sidechainChemicalConstitutionofGlucocorticoidC17-OH;C11=Oor-OH；Regulationofsecretionhypothalamus（CRH）

anteriorpituitary（ACTH）

adrenalcortex（cortisol）Long-loopfeedbackandshortfeedback.Stringent(缺少)state:10times.Diurnal(每日)rhythmicity：midnight:lowest，earlymorning:highest.PharmacokineticsAbsorption:easy.Distribution:greatthan90%oftheabsorbedgulcocorticoidsareboundtoplasmaprotein,mosttocorticosteroid-bindingglubulin(CBG,皮质类固醇结合球蛋白)andtheremaindertoalbumin.liverMetablism:livermicrosomaloxidizingExcretion:metablitiesareconjugatedtoglucuronicacidorsulfate.physiologicaleffectsPhysiologicalDose:

Glycometabolism：血糖↑Proteinmetabolism：负氮平衡Fatmetabolism：向心性肥胖Water-electrolytemetabolism：保钠排钾，钙磷排泄↑1.Effectsoncarbohydrate(Glycometabolism)①stimulateglyconeogenesis(glyconeogenesis↑).②stimulateglycogendepositioninliver(glycogensynthesis↑).③decreasetheoxidationandutilizationofglucoseinperipheraltissues(intake↓).

thenetresult:↑

thebloodglucoselevel.

2.Effectsonproteinmetabolism

①Decreaseproteinsynthesisintheliver(Inhibitbiosythesis).②Increaseproteinbreakdown(hastenbiolysis).thenetresult:Negativenitrogenbalance.③Supraphysiologicamounts(overdosage):leadtodecreasedmusclemassandweakness(muscularatrophy),decreasedgrowth，skinbecomesthinner，dys-intention。

3.Effectsonfatmetabolism:

①promotethelipolysisinadipocytes→↑releaseoffattyacidsandglycerolintothecirculation(biolysis↑,biosythesis↓).②Supraphysiologicamounts(overdosage):causeredistributionofbodyfat(centralobesity).MechanismPermissiveaction:CA→cAMP→cAMP-dependentkinase→Lipoidase

(脂酶)→Lipodieresis(脂肪分解).hormonebiosythesis4.EffectsonWater-electrolytemetabolism:Mineralocorticoid-likeaction.

Long-term：sodiumandfluidretention；InhibittheabsorptionofCa2+、P→bonerarefaction.

PharmacologicaleffectsAnti-inflammatoryeffectImmunosuppressiveactionIncreaseresistancetostressBloodandhemopoieticsystmeCNSSkeletalmuscleAnti-shockactionEffectsonothersystem

1.anti-inflammatoryeffects:

Increasethetolerancetoinflammationandreducetheinflammatoryresponse.

strong,nonspecificanti-inflammmatoryeffectonboththeearlyphaseandlatephaseofinflammation.Variouskindsinflammations；

Everystage.Earlierperiod：lowercapillarypermeability，congestion，exudation(渗出)，infiltration(浸润)；Relievesymptom.Laterperiod：Mechanocyte(成纤维细胞)，granulation(肉芽组织)tissue.Pyretolysis（解热，退热）.Mechanismofanti-inflammtion（1）Inhibittherecruitmentofinflammatorycells:adhesionmolecule，cytokinetranscription（2）InhibitPLA2andCOX2；PGs↓（3）IL-1-6,8,TNF（4）Reducetheconcentrationofcomplement（5）iNOS：NO；NOTE：Defensefunctionisinhibited.Recoveryisdelayed.2.

ImmunosuppressiveactionImmuneReaction:Sensitiveperiod;Generationanddifferentiationperiod;Effectorphase.MechanismSwallowandprocesstheantigen；Lymphocytetransformation(Acutelymphocyticleukemia)；Inflammatoryresponse；DTH（delayed-typehypersensitivity，迟发型过敏反应）Smalldose:cellimmunity；Largedose:humoralimmunity.3.IncreaseresistancetostressBloodvessel：Increasethesensitivityofbloodvesseltoactivators,decreasecapillarypermeability.Stressreaction：Harmfulstimuli：anaesthesia、infection、intoxation、wound、chilling、scare(惊恐)；Secretionincreases.4.Anti-shockactionLargedose:

(1)Expandbloodvessel,improvemyocardialcontractility，Increasecardiacoutput,improvemicrocirculation.(2)Inhibitthegenerationofinflammatoryfactor，decreasethepermeabilitytovaso-excitormaterial;(3)InhibitthegenerationofMDF;MDF：Depressmyocardialcontractileforce,Decreasedcardiacoutput,Visceralvasoconstriction.(4)Increasethetolerancetoendotoxin.5.BloodandhemopoieticsystemDecreasethenumberoflymphocyte，eosinophilegranulocyte，basophilegranulocyte，lymphomonocyteinperipheralblood(leukemia)；Redbloodcell，hemoglobin↑Platelet，fibrinogen↑，Clottingtimebecomesshorter6.CNSExcitability↑：Euphoria(欣快)，

Excitement，Insomnia，Mentaldisorder.Hyperspasmia(痉挛亢进)epilepsy(largedose).7.OtherEffects(1)Skeletalmuscle：Myopathy(肌病)，weakness(2)Gastricacidandpepsin↑(3)Inhibitsecretionofmeletonin(4)I-intake↓MechanismofActionDepression

Inhibitgeneticexpression:

transcriptionactivitor(AP-1)，

NF-κb（核转录因子），↓COX-2，iNOSInduction

Promotegeneticexpression：mRNA→protein，↑cAMP-dependantkinase.Theglucocorticoidhormone,cortisol,passesthroughtheplasmamembraneintothecytoplasmwhereitbindstothespecific,high-affinityglucocorticoidreceptor(GR).Theresultingcomplexisthenon-DNA-bindingoligomeroftheGR,inwhichthereceptoriscomplexedwithotherproteins.Inthiscomplex,theDNA-bindingdomainofthereceptorisboundbytheheatshockprotein90(hsp90)dimer.Otherproteinsinthiscomplexincludeheatshockprotein70(hsp70)andFKBP52.Dissociationoftheoligomericcomplexyieldsthefreecortisol-receptorsubunitintheDNA-bindingform.Theactivatedreceptorformsahomodimerandistranslocatedtothenucleusthroughthenucleopore.Insidethenucleus,thereceptorcomplexbindstospecificDNAresponsiveelements(GRE)toactivategenetranscription.TheraputicUsesSubstitutivetherapy；Seriousinfection；Autoimmunediseaseandhypersensitivitydisease；Removethesymptomandinhibitscarring.Hematonosis(血液病).SkindiseaseDisordersofeyesBrainEdemaAcutespinalcordinjury1.ReplacementtherapyAddison’sdisease；hypofunctionofanteriorpituitary.2.SeriousinfectionToxicaemiaorshock：ekiri(疫痢),Epidemicmeningitis,toxicpneumonia,etc.Antibioticsareneededatthesametime.Viralinfection：Contraindication.3.Autoimmuneandhypersensitivitydisease(1)Autoimmunedisease:(2)Hypersensitivitydisease：(3)Rejectreaction:skinor/andorgantransplantation(4)Bronchialasthma:inhalation

Easytorecur(复发)4.RemovethesymptomandinhibitscarringEarlierperiod:Relievedamagesofcriticalorgan；laterperiod:

Preventfunctionalimpairment.

5.HematonosisAcutelymphocyticleukemia,aplasticanemiarecidivation(复发).6.SkindiseaseContactdermatitis,eczema(湿疹).7.Disordersofeyes:localapplicationAanterioruveitis(前眼色素层炎),

Outereyeinflammation,Postoperativeinflammation.

8.BrainEdemaParasite(寄生虫),neoplasma

9.AcutespinalcordinjuryInhibitnervefunctionallesion,mediatedbyfreeradical.

10.shock:

Allkindsofshocks.Toxicshock:antibiotics，firstchoice.Allergicshock:Adrenalineisthefirstchoice.Cardiacshock:Hypovolemicshock:fluidreplacement.Adversereaction

1.Long-termcorticosteroidtherapy(1)Iatrogenic(医源性)hypercorticalism:Metabolicdisorder.

Symptom:diabeticurine,hypertension,centralobesity,hypodynamia(乏力),hypopotassemia(低血钾).

Negativenitrogenbalance:musclewasting,thinningofskin,poorwoundhealing.Bonerarefaction:inhibitsclerotized(硬化),resistancetheeffectsofvitaminD，decreasetheabsorptionofcalcium,phosphonium.(2)Induceoraggravateinfection:

Antibioticsshouldbeusedatthesametime.(3)Induceoraggravateulcer：

Gastricacidandpepsin↑(4)Pancreatitis,hepaticadiposeinfiltration(脂肪浸润)

(5)Fetalanomaly(异常),adrenalinsufficiency(6)Cataract(白内障):children(7)Growthanddevelopment：

(8)Psychiatricsymptom：Hyperhedonia(欣快症),insomnia；mentaldisorder,epilepticattack.2.Withdrawal(1)Iatrogenichypoadrenocorticism(adrenalinsufficiency)：InhibitsecretionACTH,adrenalcrisis:Nauseaandvomitting,Debilitation(衰弱),Hypotension,shock.Precaution：①Decreasedosegradually②ACTH；③Glucocorticoidshouldbegivenincaseof

stress.(2)Reboundphenomenon:causeanexacerbationoftheprimarydisease.(3)Withdrawalsymptom：appearanceofotherdiseasesorsymptoms.Usage1.SmalldoseAnteriorpituitaryhypofunction;Chronicadrenocorticalinsufficiency.2.LargedoseCriticaltoxicshock,1g/d,<3d.3.CommondoseChronicDisease:rheumatism,Rheumatoiddisord