药理学教学课件：Chapter 23 Histamine Receptor Antagonists

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