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Chapter23HistamineReceptorAntagonistsWHATISHISTAMINE?Histamineisachemicalmessengerthatmediatesawiderangeofcellularresponse,including:allergicreactionsLocalinflammatoryreactionsgastricacidsecretioncardiovascularfunctionpossiblyneuro-transmissioninpartsofthebrain.immunallergy.jpgSection1HistamineandClassificationofItsReceptorAntagonists
SynthesisFormedfromhistidinebyhistidinedecarboxylase.
HistidinehistamineStorageintracellulargranules,inacomplexwithacidicproteinandheparinofmastcellsandbasophiliccellsReleaseexocytosisdegranulationHistamineandItsReceptorSynthesisofhistaminehistamine-is-released.jpghistamine-is-released2.jpgAllergichypersensitiveresponsewhereIgEantibodiesonmastcellsarecrosslinkedbyantigens(allergens).Thisinitiatescellulareventsleadingtothereleaseofhistamineandotherpharmacologicalsubstances.
MechanismofactionsThreetypesofhistaminereceptors:H1,H2andH3-RH1receptorsareimportantinproducingsmoothmusclecontractionincreasingcapillarypermeabilitydilatingvascularsmoothmusclestimulatingsensorynerveendingH2receptors:
mediategastricacidsecretionDilatingvascularsmoothmuscleIncreaseheartrateandcontractilityH3receptorsislocatedinpresynapticmembranepossiblymediatethenegativefeedbackofhistaminerelease.受体H1H2H3H4偶联G蛋白GqGsGiGi分布支气管、胃肠道平滑肌、血管平滑肌血管内皮中枢神经胃壁细胞、血管、心肌、中枢神经、肥大细胞中枢组胺能神经末梢突触前膜白细胞(嗜酸性粒细胞)、肥大细胞效应支气管、胃肠道平滑肌收缩;血管扩张、通透性增高、渗出增加、水肿;觉醒反应胃酸分泌、血管扩张、心脏兴奋、抑制肥大细胞释放组胺负反馈调节,抑制组胺释放趋化反应、分泌细胞因子激动剂2-甲基组胺Amthamine(R)-α-甲基组胺4-甲基组胺阻断剂苯海拉明、异丙嗪西咪替丁、雷尼替丁、法莫替丁TiprolisantJNJ7777120组胺受体分布及其主要生理效应receptorActionofhistaminePharmacologicaleffects1.Cardiovascularsystem:(1)heart:positiveinotropism----H1,H2-Rpositivechronotropism----H2-R(2)vessel:dilationBP,peripheralresistanceInsmalldoses,thecardiovasculareffectismainlymediatedbyH1-R.Inlargedoses,H1,H2-R.(3)capillarypermeability,causeedemagastricacid:parietalcell,H2-Rgastricpepsin
salivarygland,bronchialglandadrenalmedulla
–largedoseBronchoconstriction:dyspneic呼吸困难uterusgastrointestinaltract
2.smoothmuscleconstriction3.Secretorytissue4.Nervoussystem--nerveendingspowerfulstimulantofsensorynerveendings:Ache,itchingThe“tripleresponse”
intradermalinjectionofhistaminecausesa“tripleresponse”---areddeningoftheskinandawhealwithasurroundingflare
erythema红斑-papule丘疹-flare红晕“tripleresponse”onterminalvasculature(itching&pain):
5.centralnervoussystemexcitationmodulatorFig.classicaltripleresponseTestingonthearm.Notethewheals(classicaltripleresponse).Clinicalusesmainlyfordiagnosis(1)Testingthesecretionofgastricacid(2)Diagnosisofpheochromocytoma嗜铬细胞瘤(3)Pulmonaryfunctiontesting(4)TooldrugsBetahistine(培他司汀,抗眩啶)Gafeira麻风病HistamineReceptorAntagonistsH1HistaminereceptorantagonistsH2HistaminereceptorantagonistsH3HistaminereceptorantagonistsSection2H1
HistamineReceptorAntagonistsBlockH1-R,notblockthereleaseofanaphylacticmediatorsBlockH1-RandblockthereleaseofanaphylacticmediatorsFirst-generationCetirizine西替利嗪,仙特敏Mequitazine
美喹他嗪,甲喹酚嗪Astemizole
阿司咪唑,息斯敏Acrivastine
阿伐斯汀,新敏乐Mizolastine咪唑斯汀azelastine氮卓斯汀Diphenhydramine
苯海拉明,苯那君Promethazine
异丙嗪,非那根Pyribenzamine曲吡那敏,扑敏宁Chlorpheniramine
氯苯那敏,扑尔敏Phenindamine/cyproheptadine赛庚啶Second-generationpharmacologicactionsofh-rcontractionof
bronchioandgastrointestinalsmoothmusclebloodvesseldilatationcapillarypermeability
localizededema
gastricacidsecretionandtheheartareunmodifiedPharmacologicActions1.H1ReceptorBlockadeInhibit:activatePLAPGI2,EDRFreleasecontractionof
bronchioandgastrointestinalsmoothmusclebloodvesseldilatationcapillarypermeabilityMechanismofActionactivatePKCCa2+release
IP3
DAGPIP2H1receptor
HistaminePLCH1-Rantagonistα-adrenoceptor-blockingactionslocalanesthesiafirst-generationdrugsSedation
Inhibitarousalreaction觉醒反应causedby
histamineAntiparkinsonism---antiemeticactions:CTZ---preventingmotionsickness
---atropine-likeeffects:peripheralM-R
-urinaryretention-blurredvision2.CNS3.Anticholinoceptoractions
first-generationdrugs4.Otheractions:weakclinicaluses
ofh1-r1.Allergicdisorder
urticaria荨麻疹,allergicrhinitissecond-generationdrugsarebetter.2.motionsicknessandnausea
kinesia晕动病,radiationdisease,
pregnancy,drug3.Sedativeandhypnotic,insomnia失眠症
diphenhydramine苯海拉明
promethazine异丙嗪ClinicalUses可减轻症状。第二代还能阻止LTs、5-HT等的释放。reactiontopenicillin-typedrugsReactiontopenicillin-typedrugs.NotetheextentoftherashColdurticariaColdurticaria.Weltiscausedbytheapplicationofanice-cubetotheskin.Notethetailofthewelt,whichformedbecauseice-coldwaterdrippedfromthemeltingice-cube.Adverseeffects
ofh1-rAdverseeffectsDiphenhydramine,promethazine1.CNSSedationSomnolence嗜睡Hypodynamia乏力2.DigestivetractDrymouthNauseaVomitingConstipationDiarrheablurredvisionurinaryretentionGranulopenia粒细胞减少3.OthersSecond-generationH1-RantagonistTerfenadine特非那定,Astemizole
阿司咪唑Cancausetheriskofaparticulartypeoftiptorsionalventriculartachycardia尖端扭转型室性心动过速(specifically
cardiacarrhythmia
causedby
QTinterval
prolongation)Terfenadineisa
prodrug,generallycompletelymetabolizedtotheactiveform
fexofenadine非索非那定
intheliverbytheenzymecytochromeP450
CYP3A4
isoform.Section3H2HistaminereceptorantagonistsGastricacidsecretion
Reducesecretionofgastricacid(H2_R)BloodvesselBlockthedilationofbloodvesselsCimetidine(西咪替丁)PharmacologicActionsblockH2-R→ACcAMPreducethesecretionofgastricacid→↓thevolumeofgastricacid&acidity.ClinicalUsespepticulcerZollinger-ellisonsyndrome卓艾综合症
Gastroxia胃酸过多Digestivetract:constipation,diarrhea,abdominaldistension腹胀CNS:headache,vertigo眩晕,illusionAdverseeffectsCimetidine:-Antiandrogeniceffect:gynecomastia(男子女性型乳房),impotency,galactorrhea(溢乳).-InhibitcytochromeP450parietalcells
Alzheimer'sdisease,attentiondeficit-hyperactivitydisorder(注意力缺陷多动症),
Parkinson'sdiseaseH3receptoragonistdamagescognitiveability认知能力
ofrats,H3receptorantagonistpromotestheabilityoflearningandmemoryonrats.GT2277isinclinicaltrial.Section4H3Histaminereceptorantagonists
Section5
5-HT2receptorantagonists
5-HTisoneofneurotransmitters
--existinpinealbodyandhypothalamus
--regulatingmanyphysiologicalfunctionssuchasslee
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