药理学PharmacoDynamics(英文版)

1Session14Pharmacodynamics2Objectives•Receptortheory•RelationbetweenDrugconcentrationandresponse•Drugpotency&efficacy•Antagonists–competitiveandunsurmountable•Partialandfullagonists•SpareReceptors•Receptor-mediatedsignalingsystems•Receptor-desensitization•Quantaldose-effectcurves•Therapeuticindex3ReceptorTheoryTheexistenceofreceptorswasfirstinferredfromobservationsofthechemicalandphysiologicalspecificityofdrugeffects.Nowreceptorshavebeenisolatedbiochemicallyandgenesencodingreceptorproteinshavebeenclonedandsequenced.ReceptorsdeterminethequantitativerelationshipbetweendrugdoseandpharmacologiceffectReceptorsareresponsiblefortheselectivityofdrugactionReceptorsmediatetheactionsofpharmacologicagonistsandantagonists4WhatareDrugReceptors?Cellsurfaceorintracellularregulatoryproteins–mediatetheeffectsofendogenouschemicalsignalssuchasneurotransmittersandhormones.e.g.adrenoreceptors,steroidreceptors,acetylcholinereceptors.Enzymes–cellsurface,membrane-spanningorintracellularproteinsinhibited(orlesscommonlyactivated)bythebindingofadrug.e.g.Na+K+ATPaseisthecellsurfacereceptorforcardiacglycosidessuchasdigitalisStructuralproteins–extra-orintracellularproteinsinhibited(orlesscommonlyactivated)bythebindingofadrug.e.g.tubulinisthereceptorforcolchicine-ananti-inflammatoryagent5Exam-typequestionOneofthefollowingisincorrect.Drugreceptors:a.Arefoundonlyatthesurfaceofcellsb.Areresponsiblefortheselectivityofdrugactionc.Mediatetheactionsofpharmacologicagonistsandantagonistsd.Determinethequantitativerelationshipbetweendrugdoseandpharmacologiceffecte.Maybestructuralproteins6RelationbetweenDrugconcentrationandresponseTherelationbetweendrugdoseandtheclinicallyobservedresponsemaybequitecomplex.However,incarefullycontrolledinvitrosystems,therelationshipbetweendrugconcentrationanditseffectisoftensimpleandmaybedescribedwithmathematicalprecision.01020304050607080901000102030405060[Drug]%ofmaximaleffectEffectmaxEC500.5Effectmax01020304050607080901000.010.1110100100010000[Drug](logscale)%ofmaximaleffectEffectmaxEC500.5Effectmax7RelationbetweenDrugconcentrationandresponseThisrelationshipshouldbefamiliartoyou.ThesecurvesareMichaelis-Mentencurvesorrectangularhyperbolae(Biochemistry-Enzymekinetics)€Effect=Effectmax[Drug]EC50+[Drug]EffectmaxisthemaximumresponseofthesystemtothedrugEC50isthatconcentrationofdrugthatproducesaresponseone-halfofthemaximumresponse01020304050607080901000102030405060[Drug]%ofmaximaleffectEffectmaxEC500.5Effectmax8RelationbetweenDrugconcentrationandresponseWhyisthisobserved?Becausedrugbindingtoits“receptor”ischaracterizedbysaturationkinetics.ConsidertheligandLanditscognatereceptorR.€R.L[]R[]L[]=konkoff=KeqTheLawofMassActiontellsusthattheequilibriumconstantforR.Lformationisgivenby:ThefractionoftotalreceptorthatexistsasR.Lis:fR.L=R.L[R]+[R.L]=Lkoffkon+L9PlottingfR.Lversus[L]showsthat:Thusavailablereceptorsare50%occupiedbydrugwhen[drug]=koff/konNotekonisasecondorderrateconstant-unitsareperMperseckoffisafirstorderrateconstant-unitsareperseckoff/konisthedissociationconstantKDoftheR.LcomplexandhasunitsofM00.10.20.30.40.50.60.70.80.910102030405060[L][R.L]/([R]+[R.L])[R.L]=[Rtotal]koff/kon=KD[R.L]=0.5[Rtotal]10RelationbetweenDrugconcentrationandresponseSincethemagnitudeoftheresponseofa“receptor”toadrugmustbeproportionaltotheconcentrationofbounddrug,itmakessensethat:1)Responseanddrugbindingcurvesaresimilar,and2)EC50isrelatedtoKD.11Exam-typequestionForanisolated,simplereceptor(R)systemofthetypeKDforligand(L)binding:a.Isthat[ligand]atwhichmaximumbindingisobservedb.IstheequilibriumconstantforR.Lformationc.HasunitsofperMd.Isasecondorderrate-constante.Isthat[Ligand]atwhichone-halfofthereceptorexistsasR.L.€R+L↔R⋅L12Efficacyisthemaximumeffect(Effectmax)ofadrug.Potency,acomparativemeasure,referstothedifferentdosesoftwodrugsneededtoproducethesameeffect.020406080100120-12-10-8-6-4log[Agonist]%ofmaximaleffect0.5EffectmaxDrugA0.5EffectmaxDrugBDrugCNormallyweplotdataaseffectversuslog[Drug].ThismakesiteasiertodetermineEC50sandtocomparedrugefficacy&potency.Inthisfigure,DrugsA&Bhavethesameefficacy.DrugAhasgreaterpotencythanBorCbecausethedoseofBorCmustbelargertoproducethesameeffectasA.AlthoughDrugChaslowerefficacythanB,itismorepotentthanBatlowerdrugconcentrationsDRUGPotency&Efficacy13Exam-typequestionDrugAhasanEC50of10nMandamaximumeffectof95%.DrugBhasanEC50of75nMandamaximumeffectof100%.DrugChasanEC50of190nMandamaximumeffectof34%.Whichofthefollowingiscorrect?a.DrugBisthemostpotentdrug.b.DrugAhasthehighestefficacy.c.DrugChasthelowestefficacybuthighestpotency.d.DrugAisthemostpotentdrug.e.DrugBshowsthelowestpotency.14GeneralClassesofAntagonistsChemicalAntagonistsOnedrugmayantagonizetheactionofasecondbybindingtoandinactivatingtheseconddrug.e.g.protamine(apositivelychargedproteinatphysiologicpH)binds(sequesters)heparin(anegativelychargedanticoagulant)makingitunavailableforinteractionswithproteinsinvolvedintheformationofbloodclots.PhysiologicalAntagonistsPhysiciansoftenprescribedrugsthattakeadvantageofphysiologicantagonismbetweenendogenousregulat