藥理學(xué)總論第三章 受體理論與藥效學(xué)課件

第三章受體理論&藥效學(xué)藥理學(xué)總論_3Pharmacodynamics

Whatadrugdoestothebody…..Theresultsmaynotbeexactlyasshowninthepictures,butadrugshouldheal,cureorhelpthebodyinsomeway!藥理學(xué)總論_3靶點(target)定義：體內(nèi)能夠與特定藥物特異性結(jié)合并產(chǎn)生治療疾病或調(diào)節(jié)生理功能作用的生物大分子。階段：(Accordingtodruggability)確定藥靶候選藥靶潛在藥靶功能蛋白藥理學(xué)總論_3治療藥物的作用靶點治療藥物的作用靶點總數(shù)48317MARCH2000VOL287SCIENCE,p1960轉(zhuǎn)運體11%藥理學(xué)總論_3藥物的基本作用藥物不產(chǎn)生新功能藥物只能通過調(diào)節(jié)機體組織器官原有的生理、生化功能而發(fā)揮作用藥物的基本作用：興奮和抑制使原有的功能水平升高——興奮使原有的功能水平降低——抑制藥理學(xué)總論_3藥物的作用與效應(yīng)(Actionvs.Effect)action=howthedrugworks(初始作用)usuallybyenhancingorinhibitingcellfunction

effect=consequenceofdrugactiononbody局部作用vs.吸收作用藥理學(xué)總論_3Fourconsequentlevelsofdrugaction4.System：alterationofsystemfunction(e.g.cardiovascular,pulmonary,digestive…)1.Molecule(drugtarget):

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

cellularfunctionisphysicallyinhibitedor“turnedon”藥理學(xué)總論_3Example:阿斯匹林作用抑制前列腺素合成酶效應(yīng)解熱&鎮(zhèn)痛

在不同作用水平上可能表現(xiàn)出不同的興奮與抑制藥理學(xué)總論_3治療作用（therapeuticaction)對因治療(Etiologicaltreatment)對癥治療(Symptomatictreatment)補充治療(Supplementarytreatmentorsubstitutiontreatment)不良反應(yīng)(Adversedrugreaction,ADR)

與用藥目的無關(guān)，并造成對病人不利的反應(yīng)。藥物作用的兩重性藥理學(xué)總論_31副作用(sideeffect,副反應(yīng)，sidereaction)

在治療劑量時，出現(xiàn)與治療目的無關(guān)的不適反應(yīng).2毒性反應(yīng)

(toxicreaction)

劑量過大或蓄積過多發(fā)生的危害性反應(yīng)3

后遺效應(yīng)(residualeffect)

停藥以后血藥濃度已降至閾濃度以下時仍殘存的生物效應(yīng)4

停藥反應(yīng)(withdrawalreaction,反跳,reboundreaction)

停藥以后原有疾病加重藥理學(xué)總論_35

變態(tài)反應(yīng)(過敏反應(yīng)，allergicreaction)

機體受藥物刺激后發(fā)生的異常的免疫反應(yīng)。（與原有效應(yīng)、劑量無關(guān)）特異質(zhì)反應(yīng)(idiosyncrasy)

與遺傳有關(guān)，反應(yīng)性質(zhì)可能與常人不同(不可預(yù)期，與其藥理作用無關(guān))7繼發(fā)性反應(yīng):由藥物的治療作用引起的不良后果藥理學(xué)總論_3ToohighdosageortoolongusageHarmfulfunctionalormorphousdamageTeratogenesis(致畸)Carcinogenesis(致癌)Mutagenesis(致突變)Toxiceffect,Toxicity特殊毒性藥理學(xué)總論_3藥理學(xué)總論_31956-1961年，歐美等國使用“反應(yīng)?！敝委熑焉锓磻?yīng)導(dǎo)致海豹樣畸胎1萬多例，死亡5000多人。

藥理學(xué)總論_3PhocomeliaFrancisKelsey藥理學(xué)總論_3ALLDRUGSAREPOISONSTheonlythingthatdeterminesifadrugprovidesabenefitorkillsapatientishowWEadministerit.FromSwitzerlandFirstphysicianusingchemicalstotreatdisease藥理學(xué)總論_3

LD50andtoxicityclassificationToxicityratingCommonlyusedtermSingleoralLD50dosageinrat1Extremelytoxic<1mg/kg2Highlytoxic1-50mg/kg3Moderatelytoxic50-500mg/kg4Slightlytoxic0.5-5g/kg5Practicallynontoxic5-15g/kg6Relativelyharmless>15g/kg藥理學(xué)總論_3藥物作用的選擇性Selectivity:藥物只作用于特定的靶點或靶器官的程度取決于：親和力與反應(yīng)性選擇性高:作用更精確，副作用更少藥-靶結(jié)合的能力結(jié)合后引起效應(yīng)的能力藥理學(xué)總論_3Drug–ReceptorInteractionCh.3藥物受體相互作用藥理學(xué)總論_31.ReceptorAmacromolecularcomponentoftheorganismthatbindsthedrugandinitiatesitseffect.

SecondmessengerPhysio-pharmacologicaleffect藥理學(xué)總論_32.Drug–receptorinteractionChemicalBond:ionic,hydrogen,hydrophobic,VanderWaals,andcovalent.Saturable

飽和性Competitive競爭性Specific特異性Structure-activityrelationships構(gòu)效關(guān)系Transductionmechanisms信號轉(zhuǎn)導(dǎo)機制Endogenousligand(orphanreceptor)藥物-受體相互作用的特征藥理學(xué)總論_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藥理學(xué)總論_3Affinity:(親和力)Thestrengthofbindingbetweenadrugandreceptor

KDisinverselyproportionaltoaffinity[DR]RT

EEmax=100%

0IntrinsicActivity

:(內(nèi)在活性)Theextenttowhichtheligandactivatesthereceptor3.親和力和內(nèi)在活性

藥理學(xué)總論_3Fullagonist：

=1，Efficacy=EmaxPartialagonist:

0<

<1，Efficacy<Emax

Antagonist:

=0，Effficay=0Inverseagonist:

<0，Effficay=-Emax’4.Classificationofdrugs%Maximumeffect100DrugconcentrationFullagonistPartialagonistAntagonist500藥理學(xué)總論_3Competitiveantagonist10-210-1110102103104105Fractionaloccupancy00.11.0Agonistconcentration01101001000AntagonistconcentrationBindstosamesiteforagonist-bindingdomainCompeteswithanagonistforreceptorsHighdosesofanagonistcangenerallyovercomeantagonist藥理學(xué)總論_3NoncompetitiveantagonistAntagonistconcentration01101001.00.50Fractionaloccupancy10-210-1110102AgonistconcentrationBindstoasiteotherthantheagonist-bindingdomainInducesaconformationchangeinthereceptorsuchthattheagonistnolonger“recognizes”theagonistbindingsite.Highdosesofanagonistdonotovercometheantagonistinthissituation藥理學(xué)總論_3EC50=5-concentrationthatproduceshalf-maximalresponseKd=5-concentrationthatoccupies50%ofreceptorsInthiscaseEC50=Kd

;therearenosparereceptorsHalf-maximalresponse10receptorsproducemaximalresponse5receptorsproducehalf-maximalresponseHerethereareatotalof10receptorsEC50,KdandsparereceptorsKd=5-concentrationthatoccupies50%ofreceptors藥理學(xué)總論_3EC50=5-concentrationthatproduceshalf-maximalresponseKd=10-concentrationthatoccupies50%ofreceptorsWhenEC50<Kd

;it

suggestsexistenceof

sparereceptorsHalf-maximalresponse10receptorsproducemaximalresponse5receptorsproducehalf-maximalresponseHerethereareatotalof20receptors–only10arerequiredtoproduceamaximalresponse藥理學(xué)總論_3Whenallreceptorsneedtobeoccupiedforafullresponse:thenEC50=Kdi.e.theconcentrationofadrugwhichproduceshalf-maximalresponse(EC50)willequaltheconcentrationthatoccupieshalfthenumberoftotalreceptors(Kd)Sparereceptorsallowmaximalresponsewithouttotalreceptoroccupancy–increasesensitivityofthesystemsparereceptorscanbind(andinternalize)extraligandpreventinganexaggeratedresponseiftoomuchligandispresent藥理學(xué)總論_3TypeofreceptorsChannellinkedreceptors:

Example:theAChreceptor,signalisneurotransmitter,depolarizationissignal,Na+channelistarget.藥理學(xué)總論_32.

G-proteincoupledreceptors:

SignalthroughtrimericGproteins.Theproteinscanalterthefunctionofmanyproteins.Typeofreceptors藥理學(xué)總論_33.Enzymelinkedreceptors:

Usuallysignalthroughproteinkinasesorproteinphosphatases.Proteinmodificationthenaltersintracellularenzymeactivity.結(jié)合區(qū)Typeofreceptors藥理學(xué)總論_34.Intracellularreceptors

HormonereceptorsSignalbindsdirectlytoanintracellularproteinwhichthenactivatestranscription.Typeofreceptors藥理學(xué)總論_3第二信使PrimitivesignalbindswithreceptorandthentriggersecondmessengerSmall,nonprotein,water-solublemoleculesorionsReadilyspreadthroughoutthecellbydiffusionTwomostwidelyusedsecondmessengersare:1. CycleAMP2. CalciumionsCa2+（cAMP,IP3,DG,)IntracellulareffectReceptorFirstmessengersSecondmessengers藥理學(xué)總論_3SignalamplificationAmplificationAmplificationAmplificationNoamplificationNoamplificationReceptorG-proteinAdenylylcyclaseCycliccAMPProteinkinasesPhosphatestranferredtotargetproteinsResultsinatremendousincreaseinthepotencyoftheinitialsignalpermitsprecisecontrolofcellbehavior10-10MAdrinblood

bloodglucoselevelsby50%藥理學(xué)總論_3受體調(diào)節(jié)：與配體作用過程中相關(guān)數(shù)目和親和力變化稱受體調(diào)節(jié)下調(diào)（衰減性調(diào)節(jié)、耐受）和上調(diào)（上增性調(diào)節(jié)、反跳）同種調(diào)節(jié)：配體使自身受體變化異種調(diào)節(jié)：配體對其他受體進行調(diào)節(jié)藥理學(xué)總論_3藥理學(xué)總論_3治療指數(shù)=C,>B安全范圍>C,>B100D有效量的量效關(guān)系中毒量的量效關(guān)系治療指數(shù)=A,>B安全范圍=B,<A100505010050ABC藥理學(xué)總論_3Dose-effectRelationship量效關(guān)系藥理學(xué)總論_3N=100Produceasameefficacy質(zhì)反應(yīng)(Qualitativeeffect)ImmeasurablePositiveornegative,allornone，aliveordie，effectiveorineffective量效曲線藥理學(xué)總論_3FrequencydistributionEachbarshowsthenumberofpeoplerespondingtothatdose–at100mg21peoplerespond,excludespeoplerespondingtolowerdosesCumulativefrequency–eachbarshowsthenumberofpeoplerespondingtothatdoseandtolowerdoses–at200mgall100peoplerespondQuantaldoseresponsecurve–differentdosesofadrugaregiventoagroupofpeopleandagivenresponseisnoted–e.g.inductionofsleep271629446580889498100251315211564298藥理學(xué)總論_3Quantal(Cumulative)Dose-ResponsecurvesQuantificationofdrugsafetyHeretwoeffectshavebeenrecorded–hypnosisanddeathED50–effectivedosein50%ofpeopleTD50–toxicdosein50%ofpeopleLD50–lethaldosein50%ofpeopleTherapeuticIndex=TD50/ED50(highertheratio,saferthedrug)TherapeuticWindow=TD1-ED>80(thewiderthesafer)藥理學(xué)總論_3TherapeuticwindowTherangeofconcentrationoverwhichadrugistherapeuticallybeneficialandsafe.Drugsw/narrowtherapeuticwindowsrequiresmaller&morefrequentdosesoradifferentmethodofadministrationTherapeuticwindowmayvaryfrompatienttopatientMinimumtoxicconcentrationMinimumeffectiveconcentrationTherapeuticswindow藥理學(xué)總論_3藥理學(xué)總論_3量效曲線量反應(yīng)(Quantitativeresponse)Measurable

Bloodpressure,heartrate,bloodglucose,enzymeactivity藥理學(xué)總論_3作用強度效能強度Quantitativedoseresponsecurve藥理學(xué)總論_3效能vs強度Efficacy:MaximalresponseadrugcanproducePotency:MeasureofdoserequiredtoproducearesponseAismore_________thanB.AandBaremore______thanC.藥理學(xué)總論_3MechanismsofDru