藥理學教學課件：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.受體H1H2H3H4偶聯(lián)G蛋白GqGsGiGi分布支氣管、胃腸道平滑肌、血管平滑肌血管內皮中樞神經(jīng)胃壁細胞、血管、心肌、中樞神經(jīng)、肥大細胞中樞組胺能神經(jīng)末梢突觸前膜白細胞（嗜酸性粒細胞）、肥大細胞效應支氣管、胃腸道平滑肌收縮；血管擴張、通透性增高、滲出增加、水腫；覺醒反應胃酸分泌、血管擴張、心臟興奮、抑制肥大細胞釋放組胺負反饋調節(jié)，抑制組胺釋放趨化反應、分泌細胞因子激動劑2-甲基組胺Amthamine（R)-α-甲基組胺4-甲基組胺阻斷劑苯海拉明、異丙嗪西咪替丁、雷尼替丁、法莫替丁TiprolisantJNJ7777120組胺受體分布及其主要生理效應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呼吸困難uterusgastrointestinaltract

2.smoothmuscleconstriction3.Secretorytissue4.Nervoussystem--nerveendingspowerfulstimulantofsensorynerveendings:Ache,itchingThe“tripleresponse”

intradermalinjectionofhistaminecausesa“tripleresponse”---areddeningoftheskinandawhealwithasurroundingflare

erythema紅斑-papule丘疹-flare紅暈“tripleresponse”onterminalvasculature(itching&pain):

5.centralnervoussystemexcitationmodulatorFig.classicaltripleresponseTestingonthearm.Notethewheals(classicaltripleresponse).Clinicalusesmainlyfordiagnosis(1)Testingthesecretionofgastricacid(2)Diagnosisofpheochromocytoma嗜鉻細胞瘤(3)Pulmonaryfunctiontesting(4)TooldrugsBetahistine(培他司汀，抗眩啶）Gafeira麻風病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,新敏樂Mizolastine咪唑斯汀azelastine氮卓斯汀Diphenhydramine

苯海拉明，苯那君Promethazine

異丙嗪，非那根Pyribenzamine曲吡那敏，撲敏寧Chlorpheniramine

氯苯那敏，撲爾敏Phenindamine/cyproheptadine賽庚啶Second-generationpharmacologicactionsofh-rcontractionof

bronchioandgastrointestinalsmoothmusclebloodvesseldilatationcapillarypermeability

localizededema

gastricacidsecretionandtheheartareunmodifiedPharmacologicActions1.H1ReceptorBlockadeInhibit:activatePLAPGI2,EDRFreleasecontractionof

bronchioandgastrointestinalsmoothmusclebloodvesseldilatationcapillarypermeabilityMechanismofActionactivatePKCCa2+release

IP3

DAGPIP2H1receptor

HistaminePLCH1-Rantagonistα-adrenoceptor-blockingactionslocalanesthesiafirst-generationdrugsSedation

Inhibitarousalreaction覺醒反應causedby

histamineAntiparkinsonism---antiemeticactions:CTZ---preventingmotionsickness

---atropine-likeeffects:peripheralM-R

-urinaryretention-blurredvision2.CNS3.Anticholinoceptoractions

first-generationdrugs4.Otheractions：weakclinicaluses

ofh1-r1.Allergicdisorder

urticaria蕁麻疹,allergicrhinitissecond-generationdrugsarebetter.2.motionsicknessandnausea

kinesia暈動病,radiationdisease,

pregnancy,drug3.Sedativeandhypnotic，insomnia失眠癥

diphenhydramine苯海拉明

promethazine異丙嗪ClinicalUses可減輕癥狀。第二代還能阻止LTs、5-HT等的釋放。reactiontopenicillin-typedrugsReactiontopenicillin-typedrugs.NotetheextentoftherashColdurticariaColdurticaria.Weltiscausedbytheapplicationofanice-cubetotheskin.Notethetailofthewelt,whichformedbecauseice-coldwaterdrippedfromthemeltingice-cube.Adverseeffects

ofh1-rAdverseeffectsDiphenhydramine,promethazine1.CNSSedationSomnolence嗜睡Hypodynamia乏力2.DigestivetractDrymouthNauseaVomitingConstipationDiarrheablurredvisionurinaryretentionGranulopenia粒細胞減少3.OthersSecond-generationH1-RantagonistTerfenadine特非那定，Astemizole

阿司咪唑Cancausetheriskofaparticulartypeoftiptorsionalventriculartachycardia尖端扭轉型室性心動過速(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卓艾綜合癥

Gastroxia胃酸過多Digestivetract:constipation,diarrhea，abdominaldistension腹脹CNS:headache,vertigo眩暈,illusionAdverseeffectsCimetidine:-Antiandrogeniceffect:gynecomastia(男子女性型乳房),impotency,galactorrhea(溢乳).-InhibitcytochromeP450parietalcells

Alzheimer'sdisease,attentiondeficit-hyperactivitydisorder(注意力缺陷多動癥),

Parkinson'sdiseaseH3receptoragonistdamagescognitiveability認知能力

ofrats，H3receptorantagonistpromotestheabilityoflearningandmemoryonrats.GT2277isinclinicaltrial.Section4H3Histaminereceptorantagonists

Section5

5-HT2receptorantagonists

5-HTisoneofneurotransmitters

--existinpinealbodyandhypothalamus

--regulatingmanyphysiologicalfunctionssuchasslee