药理学总论第三章 受体理论与药效学课件

第三章受体理论&药效学药理学总论_3Pharmacodynamics

Whatadrugdoestothebody…..Theresultsmaynotbeexactlyasshowninthepictures,butadrugshouldheal,cureorhelpthebodyinsomeway!药理学总论_3靶点(target)定义：体内能够与特定药物特异性结合并产生治疗疾病或调节生理功能作用的生物大分子。阶段：(Accordingtodruggability)确定药靶候选药靶潜在药靶功能蛋白药理学总论_3治疗药物的作用靶点治疗药物的作用靶点总数48317MARCH2000VOL287SCIENCE,p1960转运体11%药理学总论_3药物的基本作用药物不产生新功能药物只能通过调节机体组织器官原有的生理、生化功能而发挥作用药物的基本作用：兴奋和抑制使原有的功能水平升高——兴奋使原有的功能水平降低——抑制药理学总论_3药物的作用与效应(Actionvs.Effect)action=howthedrugworks(初始作用)usuallybyenhancingorinhibitingcellfunction

effect=consequenceofdrugactiononbody局部作用vs.吸收作用药理学总论_3Fourconsequentlevelsofdrugaction4.System：alterationofsystemfunction(e.g.cardiovascular,pulmonary,digestive…)1.Molecule(drugtarget):

theimmediateandfirststepofdrugaction3.Tissue：alterationoftissuefunction(e.g.heart,lung,stomach…)2.Cell:

cellularfunctionisphysicallyinhibitedor“turnedon”药理学总论_3Example:阿斯匹林作用抑制前列腺素合成酶效应解热&镇痛

在不同作用水平上可能表现出不同的兴奋与抑制药理学总论_3治疗作用（therapeuticaction)对因治疗(Etiologicaltreatment)对症治疗(Symptomatictreatment)补充治疗(Supplementarytreatmentorsubstitutiontreatment)不良反应(Adversedrugreaction,ADR)

与用药目的无关，并造成对病人不利的反应。药物作用的两重性药理学总论_31副作用(sideeffect,副反应，sidereaction)

在治疗剂量时，出现与治疗目的无关的不适反应.2毒性反应

(toxicreaction)

剂量过大或蓄积过多发生的危害性反应3

后遗效应(residualeffect)

停药以后血药浓度已降至阈浓度以下时仍残存的生物效应4

停药反应(withdrawalreaction,反跳,reboundreaction)

停药以后原有疾病加重药理学总论_35

变态反应(过敏反应，allergicreaction)

机体受药物刺激后发生的异常的免疫反应。（与原有效应、剂量无关）特异质反应(idiosyncrasy)

与遗传有关，反应性质可能与常人不同(不可预期，与其药理作用无关)7继发性反应:由药物的治疗作用引起的不良后果药理学总论_3ToohighdosageortoolongusageHarmfulfunctionalormorphousdamageTeratogenesis(致畸)Carcinogenesis(致癌)Mutagenesis(致突变)Toxiceffect,Toxicity特殊毒性药理学总论_3药理学总论_31956-1961年，欧美等国使用“反应停”治疗妊娠反应导致海豹样畸胎1万多例，死亡5000多人。

药理学总论_3PhocomeliaFrancisKelsey药理学总论_3ALLDRUGSAREPOISONSTheonlythingthatdeterminesifadrugprovidesabenefitorkillsapatientishowWEadministerit.FromSwitzerlandFirstphysicianusingchemicalstotreatdisease药理学总论_3

LD50andtoxicityclassificationToxicityratingCommonlyusedtermSingleoralLD50dosageinrat1Extremelytoxic<1mg/kg2Highlytoxic1-50mg/kg3Moderatelytoxic50-500mg/kg4Slightlytoxic0.5-5g/kg5Practicallynontoxic5-15g/kg6Relativelyharmless>15g/kg药理学总论_3药物作用的选择性Selectivity:药物只作用于特定的靶点或靶器官的程度取决于：亲和力与反应性选择性高:作用更精确，副作用更少药-靶结合的能力结合后引起效应的能力药理学总论_3Drug–ReceptorInteractionCh.3药物受体相互作用药理学总论_31.ReceptorAmacromolecularcomponentoftheorganismthatbindsthedrugandinitiatesitseffect.

SecondmessengerPhysio-pharmacologicaleffect药理学总论_32.Drug–receptorinteractionChemicalBond:ionic,hydrogen,hydrophobic,VanderWaals,andcovalent.Saturable

饱和性Competitive竞争性Specific特异性Structure-activityrelationships构效关系Transductionmechanisms信号转导机制Endogenousligand(orphanreceptor)药物-受体相互作用的特征药理学总论_3k1D+R<=>DRk2ByLawofmassaction:[D]•[R]•K1=[DR]•K2ThereforeK2/K1=Kd=[D]•[R]/[DR]IfRT=total#ofreceptors,thenRT=[R]+[DR]Replace[R]by(RT-[DR])&rearrange:[DR][D]RTKd+[D]=Occupationtheoryofdrug-receptorinteractionsEffecteffect Max.effect=D=0：effect=0D>>Kd：DR/RT=100%，maxeffectKd=D,Kd=ConcatEC50药理学总论_3Affinity:(亲和力)Thestrengthofbindingbetweenadrugandreceptor

KDisinverselyproportionaltoaffinity[DR]RT

EEmax=100%

0IntrinsicActivity

:(内在活性)Theextenttowhichtheligandactivatesthereceptor3.亲和力和内在活性

药理学总论_3Fullagonist：

=1，Efficacy=EmaxPartialagonist:

0<

<1，Efficacy<Emax

Antagonist:

=0，Effficay=0Inverseagonist:

<0，Effficay=-Emax’4.Classificationofdrugs%Maximumeffect100DrugconcentrationFullagonistPartialagonistAntagonist500药理学总论_3Competitiveantagonist10-210-1110102103104105Fractionaloccupancy00.11.0Agonistconcentration01101001000AntagonistconcentrationBindstosamesiteforagonist-bindingdomainCompeteswithanagonistforreceptorsHighdosesofanagonistcangenerallyovercomeantagonist药理学总论_3NoncompetitiveantagonistAntagonistconcentration01101001.00.50Fractionaloccupancy10-210-1110102AgonistconcentrationBindstoasiteotherthantheagonist-bindingdomainInducesaconformationchangeinthereceptorsuchthattheagonistnolonger“recognizes”theagonistbindingsite.Highdosesofanagonistdonotovercometheantagonistinthissituation药理学总论_3EC50=5-concentrationthatproduceshalf-maximalresponseKd=5-concentrationthatoccupies50%ofreceptorsInthiscaseEC50=Kd

;therearenosparereceptorsHalf-maximalresponse10receptorsproducemaximalresponse5receptorsproducehalf-maximalresponseHerethereareatotalof10receptorsEC50,KdandsparereceptorsKd=5-concentrationthatoccupies50%ofreceptors药理学总论_3EC50=5-concentrationthatproduceshalf-maximalresponseKd=10-concentrationthatoccupies50%ofreceptorsWhenEC50<Kd

;it

suggestsexistenceof

sparereceptorsHalf-maximalresponse10receptorsproducemaximalresponse5receptorsproducehalf-maximalresponseHerethereareatotalof20receptors–only10arerequiredtoproduceamaximalresponse药理学总论_3Whenallreceptorsneedtobeoccupiedforafullresponse:thenEC50=Kdi.e.theconcentrationofadrugwhichproduceshalf-maximalresponse(EC50)willequaltheconcentrationthatoccupieshalfthenumberoftotalreceptors(Kd)Sparereceptorsallowmaximalresponsewithouttotalreceptoroccupancy–increasesensitivityofthesystemsparereceptorscanbind(andinternalize)extraligandpreventinganexaggeratedresponseiftoomuchligandispresent药理学总论_3TypeofreceptorsChannellinkedreceptors:

Example:theAChreceptor,signalisneurotransmitter,depolarizationissignal,Na+channelistarget.药理学总论_32.

G-proteincoupledreceptors:

SignalthroughtrimericGproteins.Theproteinscanalterthefunctionofmanyproteins.Typeofreceptors药理学总论_33.Enzymelinkedreceptors:

Usuallysignalthroughproteinkinasesorproteinphosphatases.Proteinmodificationthenaltersintracellularenzymeactivity.结合区Typeofreceptors药理学总论_34.Intracellularreceptors

HormonereceptorsSignalbindsdirectlytoanintracellularproteinwhichthenactivatestranscription.Typeofreceptors药理学总论_3第二信使PrimitivesignalbindswithreceptorandthentriggersecondmessengerSmall,nonprotein,water-solublemoleculesorionsReadilyspreadthroughoutthecellbydiffusionTwomostwidelyusedsecondmessengersare:1. CycleAMP2. CalciumionsCa2+（cAMP,IP3,DG,)IntracellulareffectReceptorFirstmessengersSecondmessengers药理学总论_3SignalamplificationAmplificationAmplificationAmplificationNoamplificationNoamplificationReceptorG-proteinAdenylylcyclaseCycliccAMPProteinkinasesPhosphatestranferredtotargetproteinsResultsinatremendousincreaseinthepotencyoftheinitialsignalpermitsprecisecontrolofcellbehavior10-10MAdrinblood

bloodglucoselevelsby50%药理学总论_3受体调节：与配体作用过程中相关数目和亲和力变化称受体调节下调（衰减性调节、耐受）和上调（上增性调节、反跳）同种调节：配体使自身受体变化异种调节：配体对其他受体进行调节药理学总论_3药理学总论_3治疗指数=C,>B安全范围>C,>B100D有效量的量效关系中毒量的量效关系治疗指数=A,>B安全范围=B,<A100505010050ABC药理学总论_3Dose-effectRelationship量效关系药理学总论_3N=100Produceasameefficacy质反应(Qualitativeeffect)ImmeasurablePositiveornegative,allornone，aliveordie，effectiveorineffective量效曲线药理学总论_3FrequencydistributionEachbarshowsthenumberofpeoplerespondingtothatdose–at100mg21peoplerespond,excludespeoplerespondingtolowerdosesCumulativefrequency–eachbarshowsthenumberofpeoplerespondingtothatdoseandtolowerdoses–at200mgall100peoplerespondQuantaldoseresponsecurve–differentdosesofadrugaregiventoagroupofpeopleandagivenresponseisnoted–e.g.inductionofsleep271629446580889498100251315211564298药理学总论_3Quantal(Cumulative)Dose-ResponsecurvesQuantificationofdrugsafetyHeretwoeffectshavebeenrecorded–hypnosisanddeathED50–effectivedosein50%ofpeopleTD50–toxicdosein50%ofpeopleLD50–lethaldosein50%ofpeopleTherapeuticIndex=TD50/ED50(highertheratio,saferthedrug)TherapeuticWindow=TD1-ED>80(thewiderthesafer)药理学总论_3TherapeuticwindowTherangeofconcentrationoverwhichadrugistherapeuticallybeneficialandsafe.Drugsw/narrowtherapeuticwindowsrequiresmaller&morefrequentdosesoradifferentmethodofadministrationTherapeuticwindowmayvaryfrompatienttopatientMinimumtoxicconcentrationMinimumeffectiveconcentrationTherapeuticswindow药理学总论_3药理学总论_3量效曲线量反应(Quantitativeresponse)Measurable

Bloodpressure,heartrate,bloodglucose,enzymeactivity药理学总论_3作用强度效能强度Quantitativedoseresponsecurve药理学总论_3效能vs强度Efficacy:MaximalresponseadrugcanproducePotency:MeasureofdoserequiredtoproducearesponseAismore_________thanB.AandBaremore______thanC.药理学总论_3MechanismsofDru