第二章藥效學(xué)課件

Chapter2PharmacodynamicsDepartmentofPharmacology,MedicalschoolofNankaiUniversityJinglingZhangTel:(office)E-mail:Pharmacodynamics教學(xué)目的掌握藥效學(xué)的基本概念和藥理作用的基本規(guī)律，為各論藥物的學(xué)習(xí)提供理論基礎(chǔ)。

2Pharmacodynamics教學(xué)內(nèi)容藥物的基本作用和效應(yīng)；器官功能的升高或降低，即興奮和抑制。藥物作用的選擇性和可逆性。藥物作用的臨床效果，即治療作用和不良反應(yīng)。藥物作用原理；藥物作用原理的多樣性；受體和配體的概念，受體在藥物作用中的意義；3Pharmacodynamics親和力（pD2），內(nèi)在活性（），受體激活至效應(yīng)器反應(yīng)的中間過(guò)程；反饋的生理意義。激動(dòng)藥，部分激動(dòng)藥，對(duì)抗藥的共性與個(gè)性，拮抗參數(shù)pA2，藥物的構(gòu)效關(guān)系。藥物作用的量效關(guān)系：質(zhì)反應(yīng)與量反應(yīng)。量效關(guān)系曲線，作用強(qiáng)度與最大效應(yīng)，半數(shù)效應(yīng)量，閾劑量，治療量，極量，中毒量及致死量。4PharmacodynamicsConcept

ofpharmacodynamicsItisthestudyofdrugeffectsandtheirmechanismsofaction.5PharmacodynamicsDrugactionThetherapeuticeffectofdrugandadversedrugreaction(ADR)Dose-effectrelationshipStructure-activityrelationshipTargetsfordrugactionTheoryaboutinteractionofdrugandreceptor6DrugactionDrugactionTypesofdrugactionSelectivityofdrugactionPharmacologicaleffectexcitationinhibition7ThetherapeuticeffectofdrugEtiologicaltreatmentSymptomatictreatmentSupplementarytherapyorreplacementtherapycomplementarythelossofnutrition&metabolismofthebody8adversedrugreactionⅠconceptⅡtypeTheeffectthatisnottheaccordwiththepurposeofdruguse,whichisleadtotheharm&painofthepatient.Thetherapeuticeffect&sideeffectaretheintrinsicpropertiesofthedrug.SideeffectToxiceffectaftereffectAllergicreactionSecondaryreactionWithdrawalreactionIdiosyncrasyreactionDependenceAcutetoxicityChronictoxicity:(carcinogenesis,teratogenesis,mutagenesis)Physicaldependence(withdrawalsyndrome)Psychicdependence9Dose-effectrelationshipConceptDose-effectcurve

TypeGradedresponse;Quantalresponse(All-or-noneresponse)Significance101112Specialpoints：SlopeMinimumeffectiveconcentration，thresholdconcentrationMaximumeffectorEfficacyMedianeffectivedose,ED50TD50LD50PotencyEffectivedose；Toxicdose；Lethaldose；Maximumdosetheeffectcannotincreasewiththeadditionofthedrug.theequivalentdoseamongthedifferentdrugswhichproducethesametherapeuticeffect.1314SafetyTherapeuticindex：

TI=LD50/ED50；Marginofsafety：

ED95～TD5；Structure-activityrelationship1516Dose-effectcurveoftheeffectsandtoxicityofPhenobarbital(Ph)、drugAanddrugB.(*LD50/ED50ofPhandAbothare2.6,thatofBis3.0;#A:ED80=LD10,B:ED80=LD15。)PhissaferthanAandB,AissaferthanBED50LD5017TargetsfordrugactionReceptorsEnzymesIonchannelsCarriermolecules(transporters)Gene18MechanismofdrugactionNonspecificmechanismofdrugactionSpecificMechanismsofdrugaction19NonspecificmechanismofdrugactionOtherpHchangeOsmosisLiposolubleactionOxidation-reductionComplexactionorsorption.20SpecificmechanismofdrugactionInterfereorIncorporateintometabolicprocessofcellsInfluencephysiologicaltransmittersandhormonessecretionInfluencefunctionofthebiologicalmembraneInteractionbetweendrugandreceptorpenetration,barrier,protection;enzyme,ionchannels,carrier,molecule,receptor21InteractionbetweendrugandreceptorConceptofthereceptor

Thetermreceptorisusedindifferentways.Inpharmacology,itdescribesproteinmoleculeswhosefunctionistorecogniseandrespondtoendogenouschemicalsignals.22InteractionbetweendrugandreceptorTheconceptofreceptorsiscentraltopharmacology,andthetermismostoftenusedtodescribethetargetmoleculesthroughwhichsolublephysiologicalmediators-hormones,neurotransmitters,inflammatorymediators,etc.-producetheireffects.23InteractionbetweendrugandreceptorProperty

ofreceptorSensitivitySpecificitySaturabilityReversibilityMultiple-variationAffinityCompetitionTypeofreceptorGproteins-coupledreceptorLigandgatedionchannelreceptorTyrosinekinasereceptorIntracellularreceptors2425262728InteractionbetweendrugandreceptorLigandConceptTypeReceptortheory:Occupationtheory;Ratetheory;Twomodeltheory;ExteriorligandDrug,Toxin,Ag;InnerligandTransmitters,Hormones,Autacoids;Theterm“l(fā)igand”denotesthechemicalagentsthatrecognizeandbindtoreceptors.29Fig.2-7Thetwo-statemodel.Thereceptorisshownintwoconformationalstates,'resting'(R)and'activated'R*,whichexistinequilibrium.30OccupationtheoryA+RAREK1K2Whenreceptorsareoccupied,the

pharmacologicaleffectswilloccur.Theeffectsofdrugaredirectlyproportionaltothenumbersofreceptorsoccupied.31Developmentofoccupationtheory令KD

=

K2

/

K1；A+RAREK1K2Clark（1926）32Developmentofoccupationtheory整理后得：[AR](KD+[A])=[A][RT]因?yàn)?

[RT]=[R]+[AR]，[R]=[RT]-[AR]；代入R得：33DevelopmentofoccupationtheoryWhen[AR]/[RT]=0,E=0.When[A]＞＞KD,[AR]/[RT]=1,[AR]=[RT],E=Emax.When[AR]/[RT]=1/2,E=50%Emax,KD=[A].34InteractionbetweendrugandreceptorpD2(affinityindex)35DevelopmentofoccupationtheoryAriens(1954)：→intrinsicactivity

(內(nèi)在活性)pD2→affinityindex

(親和力指數(shù))Stephenson(1956)：sparereceptor

(儲(chǔ)備受體)

silentreceptor

(沉默受體)(0<<1)WhenpD2ofdrugAisthesameasthatofdrugB,effectofdrugisdecidedby.WhenofdrugAisthesameasthatofdrugB,effectof

drugisdecidedbypD2.36Affinityindex(pD2):A=B=Cintrinsicactivity():A>B>CAffinityindex(pD2):X＞Y＞Zintrinsicactivity():X=Y=Z37ClassificationofthedrugDrugcanbedividedintodifferentgroupaccordingtothereceptortheory:AgonistAbsoluteagonistPartialagonistInverseagonistsPartialagonistcanevokeweakagonisteffectsbutmayalsodisplacefullagonistsfromthebindingsitesandreducetheirbiologiceffect.38ClassificationofthedrugAntagonistCompetitiveantagonistpA2=-log(I)2NoncompetitiveantagonistpA’2=-log(I’)2

Antagonistbindstoareceptorwithoutproducinganyoftheeffectsassociatedwithagonistbinding.39KD=[A]40THEEND!41

測(cè)試題1.下列關(guān)于競(jìng)爭(zhēng)性拮抗藥拮抗參數(shù)（pA2）的描述中不對(duì)的是：A、

pA2值是表示拮抗相應(yīng)激動(dòng)藥的強(qiáng)度；B、pA2大表示拮抗藥與相應(yīng)受體的親和力大；C、pA2值越大對(duì)相應(yīng)激動(dòng)藥拮抗力越強(qiáng)；D、不同亞型受體pA2值不盡相同；E、pA2是拮抗藥摩爾濃度的對(duì)數(shù)值。422、pD2值可以反映藥物與受體親和力，pD2值大說(shuō)明：A、藥物與受體親和力大，用藥劑量??；B、藥物與受體親和力大，用藥劑量大；C、藥物與受體親和力小，用藥劑量??；D、藥物與受體親和力小，用藥劑量大；E、以上均不對(duì)。4350100E%lgCANA+C藥物A、N及A+C的對(duì)數(shù)-效應(yīng)曲線3、已知藥物均作用于同一種受體，指出下列正確的敘述：A、A藥和N藥有同等的效能；B、N藥是一種完全激動(dòng)藥；C、N藥是A藥的一種競(jìng)爭(zhēng)性拮抗藥；D、C藥是A藥的一種競(jìng)爭(zhēng)性拮抗藥；E、N藥作用效價(jià)高于A藥。4445InteractionbetweendrugandreceptorA+I+RAR+IRK1AoriK2Aori[IR]=[I][