周宏灏院士(封山之作)药理学总论PPT-3

4.Withdrawalreaction

Afterstopofdrugadministration,thesymptomsoforiginaldiseasewouldbeaggravated(reboundreaction）Vasodilatornitroglycerolandtroxerutin(曲克芦丁)

reboundvasoconstrictionanginapectorisattacks

5.AllergyDrug-inducedallergicreaction(hypersensitivity)isanexaggeratedorinappropriateimmunereactionandcausesdamagetothepatientTypeI:anaphylacticreactionTypeII:cytotoxicreactionTypeIII:ImmunecomplexreactionTypeIV:cell-mediatedimmunityreactionNotpredictablereactionsNotrelatedtopharmacologicaleffectsGenericfactor

6.IdiosyncrasyGeneticG-6-PDdeficiencyHaemolysisTakeoxidantdruge.g.aspirinALLDRUGSAREPOISONSTheonlythingthatdeterminesifadrugprovidesabenefitorkillsapatientishowWEadministerit.FromSwitzerlandFirstphysicianusingchemicalstotreatdiseaseDose-effectRelationshipSection2Ch.3N=100ProduceasameefficacyQualitativeeffectImmeasurablePositiveornegative,allornone，aliveordie，effectiveorineffective，spasmsornoDoseresponsecurveDoseresponsecurveQuantitativeresponseMeasurable

Bloodpressure,heartrate,bloodglucose,enzymeactivity作用强度EfficacyPotencyQuantitativedoseresponsecurveEfficacyvsPotencyEfficacy:MaximalresponseadrugcanproducePotency:MeasureofdoserequiredtoproducearesponseAismore_________thanB.AandBaremore______thanC.Mediantoxicdose（TD50orTC50)Medianlethaldose（LD50orLC50）ToxicityDeathTD50TD50andLD50Alsoknownas

therapeuticratioormarginofsafety.

TherapeuticIndexMeasureofthesafetyofadrugTherapeuticwindowTherangeofconcentrationoverwhichadrugistherapeuticallybeneficialandsafe.Drugsw/narrowtherapeuticwindowsrequiresmaller&morefrequentdosesoradifferentmethodofadministrationTherapeuticwindowmayvaryfrompatienttopatientMinimumtoxicconcentrationMinimumeffectiveconcentrationTherapeuticswindowMechanismsofDrugActionSection2Ch.3Fourconsequentlevelsofdrugaction4.System：alterationofsystemfunction(e.g.cardiovascular,pulmonary,digestive…)1.Molecule(drugtarget):

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

cellularfunctionisphysicallyinhibitedor“turnedon”DrugtargetsMoleculardrugtargets–Total:482ReceptorsEnzymesTransportersSymporters（共转运体）Antiporters（反向转运体）IronChannelsSpecificTargetsmetalionSurfactantProteinNucleicAcidsDrug–ReceptorInteractionSection4Ch.3

1.ReceptorAmacromolecularcomponentoftheorganismthatbindsthedrugandinitiatesitseffect.

SecondmessengerPhysio-pharmacologicaleffect2.Drug–receptorinteractionChemicalBond:ionic,hydrogen,hydrophobic,VanderWaals,andcovalent.SaturableCompetitiveSpecificandSelectiveStructure-activityrelationshipsTransductionmechanismsCharacteristicsofDrug-ReceptorInteractions

k1D+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=ConcatEC50Affinity:

Thestrengthofbindingbetweenadrugandreceptor

KDisinverselyproportionaltoaffinity[DR]RTEEmax=100%

0IntrinsicActivity

:

Theextenttowhichtheligandactivatesthereceptor3.AffinityandIntrinsicactivity

Fullagonist：

=100％，Efficacy=EmaxPartialagonist:

0%<<100%，Efficacy<Emax

Antagonist:

=0％，Effficay=04.Classificationofdrugs%Maximumeffect100DrugconcentrationFullagonistPartialagonistAntagonist

50

0Competitiveantagonist10-210-1110102103104105Fractionaloccupancy00.11.0Agonistconcentration01101001000AntagonistconcentrationBindstosamesiteforagonist-bindingdomainCompeteswithanagonistforreceptorsHighdosesofanagonistcangenerallyovercomeantagonistNoncompetitiveantagonistAntagonistconcentration01101001.00.5

0Fractionaloccupancy10-210-1110102AgonistconcentrationBindstoasiteotherthantheagonist-bindingdomainInducesaconformationchangeinthereceptorsuchthattheagonistnolonger“recognizes”theagonistbindingsite.HighdosesofanagonistdonotovercometheantagonistinthissituationSparereceptorsMAXMAXHighaffinityagonistproducedmaximalresponsewithouttotalreceptoroccupancy–increasesensitivityofthesystemMagnitudeofresponseISNOTproportionaltoreceptoroccupancySparereceptorscanbindextraligandpreventinganexaggeratedresponseiftoomuchligandispresent5.TypeofreceptorsChannellinkedreceptors:

Example:theAChreceptor,signalisneurotransmitter,depolarizationissignal,Na+channelistarget.2.

G-proteincoupledreceptors:

SignalthroughtrimericGproteins.Theproteinscanalterthefunctionofmanyproteins.5.Typeofreceptors3.Enzymelinkedreceptors:

Usuallysignalthroughproteinkinasesorproteinphosphatases.Proteinmodificationthenaltersintracellularenzymeactivity.结合区5.Typeofreceptors4.Intracellularreceptors

HormonereceptorsSignalbindsdirectlytoanintracellularproteinwhichthenactivatestranscription.5.Typeofreceptors6.SecondmessengersPrimitivesignalbindswithreceptorandthentriggersecondmessengerSmall,nonprotein,water-solublemoleculesorionsReadilyspreadthroughoutthecellbydiffusionTwomostwidelyusedsecondmessengersare:1. CycleAMP2. CalciumionsCa2+（cAMP,IP3,DG,)IntracellulareffectReceptorFirstmessengersSecondmessengersSignalamplificationAmplificationAmplificationAmplificationNoamplificationNoamplificationReceptorG-proteinAdenylylcyclaseCycliccAMPProteinkinasesPhosphatestranferredtotargetproteinsResultsinatremendousincreaseinthepotencyoftheinitialsignalpermitsprecisecontrolofcellbehavior10-10MAdrinblood

bloodglucoselevelsby50%7.ReceptorregulationSensitization（hypersensitization,supersensitivity）orUp-regulationProlonged/continuoususeofreceptorblockerInhibitionofsynthesisorreleaseofhormone/neurotransmitterDesensitizationorDown-regulationProlonged/continuoususeofagonistInhibitionofdegradationoruptakeofagonistHomologousdesensitizationAffectingresponseselicitedonlybythestimulatedreceptorCanreflectfeedbackfromatransducer(oreffector)uniquetothepathwayofthereceptor(X1)orfromanoff-pathwaycomponent(K)thatissensitivetotheactivationstateofthereceptor.HeterologousdesensitizationActingonseveralreceptorsoronapathwaythatiscommontomanyreceptors.Initiatedbytransducersoreffectorscommontomultiplereceptorsignalingpathways(YorZ).ReceptorregulationChapter4

FactorsaffectingdrugresponsePharmaceuticalFactorsSection1Ch.41.Dose,formulation,routeofadministration2.DrugInteractions（1）Pharmacokineticinteractions：chemicalorphysical;GIabsorption;proteinbinding/distribution;metabolism(stimulation/inhibition);excretion(pH/transportprocesses);changesinpHorelectrolytes.

（2）Pharmacodynamicinteractions：receptor(potentiation/antagonismPharmaceuticalFactorsBiologicalFactorsSection2Ch.4Manyfactorsaffectdrugresponse1.AgeAgerelatedchange:1.livermetabolism;2.renalelimination;3.bodycompositionlivermetabolism-lessamountofdrugmetabolizingenzymesinnewborninfants

Olderpeopleusuallytakemoredrugs,alsomayhavemoredifficultyfollowingcomplicatedinstructionsfortakingdrugs.

DevelopmentalprofileofhepaticdrugmetabolizingenzymesBirthAdulthoodElderlyEnzymelevelMostdrug-metabolizingenzymesCYP3A7Age1.AgeWomenhavemoreCYP3AintheliverEstrogenandprogestininhibitCYP450leadingtoalowerCLofdrugsinwomenWomentendtotakemoremedications,includingdietarysupplements,thanmen2.GenderVdchangedCLchanged3.BodySize/ObesityGFRdecreasedExcretiondecreased4.DiseaseKidneydisease:Liverdisease：Celldamage

ReductionDMEactivityPKchanged4.DiseaseCYP2E1CYP2D6CYP1A2CYP2C195.PlaceboeffectsPha