Pharmacodynamics(p5)

conceptThestudyofthedrug’seffectstothebodyandtheirmechanismsofaction.Include:EffectsofdrugstothebodyMechanismsofdrugactionTherelationshipbetweendrugconcentrationandeffect§1BasicActionsandEffectsofDrugDrugaction（藥物作用）:primaryactionpharmacologicaleffect（藥理效應）:secondaryactionExcitation

increasedfunctionInhibition

decreasedfunctionLocalaction-directactionSystemicaction–absorptive(吸收)actionSpecificity(特異性):chemicalreactionSelectivity（選擇性）:exa.M-receptorTherapeuticEffects(治療作用)TherapeuticEffectsEtiologicaltreatment（對因治療）Symptomatictreatment（對癥治療）Supplementarytherapy（補充治療）AdverseDrugReaction(ADR)(p6)

1.Sidereaction（副作用）:2.Toxicreaction:ThedosemakesthepoisonAcutetoxicationChronictoxicationSpecialtoxications:Carcinogenesis致癌Teratogenesis致畸:thalidomide（反應停事件）Mutagenesis致突變BtypeofADRteratogenesisDrugaffectsfetation（妊娠）formingteratism（畸胎）,especiallyearlyembryo.Thalidomidehappening（1961）Seal（海豹）abnormitypregnancyreactiongestationreaction3.residualeffect（后遺效應）4.Withdrawalreaction(rebound,)5.Allergicreaction(hypersensitivereaction)6.

Idiosyncraticreaction（特異質(zhì)反應）DrugDoseandDose-EffectRelationship(p6)

Drugdose(dosage，劑量)Dose-effectrelationshiporConcentration-effectrelationshipDose-effectcurve（量效曲線）:dose-responsecurveGradedresponse（量反應）quantalresponse（質(zhì)反應）

E(%)10050EC500102030EmaxE(%)100500logC0.111030pD2Dose-responserelationshipGraded量Quantal質(zhì)? Measuredinasinglebiologicunit? RelatesdosetointensityofeffectMean±standarddifference(x±s)(ttest)? All-or-nonepharmacologiceffect? Populationstudies(χ2test)? Relatesdosetofrequencyofeffect?ContinuousscaleDoseBPmmHgDoserate(%)Dose-responserelationship↓

↘

↙

├─┴┴─────┴─╂─┴───┴──D(C)

thresholddosemaximaldoseminimaltoxicdoseminimallethaldose↑commondosedose-effectcurveElgD(C)EmaxEKDD(C)hyperbolasymmetryScurve50%Someusefulpointsinthecurveminimaleffectivedosemaximaleffect,Emaxconcentrationfor50%ofmaximaleffect,EC50efficacypotencyE(%)100500logCEmax=efficacypotency50%EmaxlogEC50slopecmin1.gradedresponsecurves①Thresholddose（閾劑量）：Minimaleffectivedose(MEC)②Efficacy(Emax，效能)

：Maximaleffectofadrugorthelimitofthedrugresponse.③Potency（效價強度）

：Doseinducinggiveneffect,oradose(KD)inducing50%Emax.Efficacyisusuallymoreimportantthanpotencyinselectingdrugsforclinicaluse.Gradedresponse

（斜率）：Slopeat50%Emax(slope↑→rangeofcommondose↓→lesssafety）

:Thelimitofdosesafelypermittedinpharmacopeiaforsomedrugs.

：Theeffectivedoseinmostofpatients.maximaldose＞commondose＞thresholddose④Slope⑤Maximaldose（極量）⑥Commondose（常用量）GradedresponseAboutdose----attention:maximaldose

≠Efficacy(效能)doseMinimaltoxicdoseMinimallethaldoseThresholddoseIneffectivedoseTherapeuticdoseToxicdoseLethaldosageMaximaldose

PotencyandEfficacyE

B

A

C

lgD(C)potency：efficacy：thresholddose：slope：Ａ＞Ｂ＞ＣＢ＞C＞ＡＣ＞Ｂ＞ＡＡ＝Ｂ＞Ｃ2.quantalresponsescurvesD(mg/kg)55.86.67.68.71011.513.315.217.620distribution12569865431cumulative1381423313742464950頻數(shù)累積曲線頻數(shù)分布

對數(shù)劑量反應頻數(shù)5040302010logD

Individualvariation:variationofsensitivitytoadrugamongpopulation(patientsoranimals).

Supersensitivityortolerancetoadrugareproducedinafewpopulation,mostofthemaremiddlesensitivity.EDdistributioncumulativesupersensitivitytolerance3.TheSafetyofDrug(p8)

(Medianeffectivedose)：Thedoseatwhich50%ofindividuals(experimentalanimals)exhibitsspecifiedeffect.

（Medianlethaldose）：Thedoserequiedtoproducedeathin50%ofanimals.

ED50TI＝LD50／ED50LD50Therapeuticindex(TI):Theindexusedfor

judgingdrug'ssafety.marginofsafety:ED95~TD5orLD1~ED99Therapeuticwindow(治療窗)Structure-activityrelationship(SAR，構效關系)§2MechanismsofdrugactionReceptoractionNon-receptoraction

Non-receptoraction(p8)1.PhysicalandChemicalReaction2.JoiningorInterferingwithCellMetabolismcounterfeitincorporation(偽品摻入)antimetabolite(抗代謝藥)AffectingNucleotideAcidMetabolism3.AffectingTransportationofPhysicalSubstances4.AffectingEnzymeActivity

5.AffectingIonChannelsonCellMembrane6.AffectingImmunologyFunction7.Genetherapy§3Drugsandreceptors(p9)Theeffectsofmostdrugsresultsfromtheirinteractionswithreceptorsofthecells.Drugscandotwothingstoreceptors:(1)bindtothem(affinity：親和力)and(2)possiblychangethebehaviorofhostcellsystem(efficacyorintrinsicactivity內(nèi)在活性).DevelopmentofReceptortherory(1)Langley(1878):foundoppositeeffectsofatropineandpilocarpineinsalivaryexcretionofcats.(2)Langley(1905):foundoppositeeffectsoftubocurarineandnicotineinskeletalmuscle–

“receptivesubstance”

(3)Ehrlich(1908):“l(fā)ockandkey(receptor)”TheConceptandPropertiesofReceptorsConceptRECEPTOR:Thereceptivesubstancesofacelloranorganismthatspecificallyinteractswiththeirligands(配體correspondingdrugs,transmitterorhormone)andinitiatesthechainofbiochemicalandphysiologicalchanges.LIGAND：Acorrespondingdrug,transmitterorhormonebindingtoareceptor

Drug-ReceptorInteractionsk1k2DrugReceptorEffectDrug-ReceptorComplexLigand-bindingdomainEffectordomainPropertiesofreceptorsa.Senitivityb.Specificityc.Saturability（飽和性）d.Reversibility（可逆性）e.Multiple-variation（多態(tài)性）TypesofBonds（鍵）andAttractiveForcesrelatedtoDrug-ReceptorBindingInorderofdecreasingbondstrength:Covalent(共價鍵，irreversible;leastcommon)Ionic(離子鍵，+/-)Hydrogen(氫鍵，H-O)HydrophobicInteractions（疏水鍵）VanderWaals(dipole偶極interactions)Occupationtheory(Clark,1926)extentofdrugeffectsisinproportionwiththenumberofreceptorsoccupiedbydrugs.[D]+[R]=[DR]→→EKD=[D][R]/[DR](KD:dissociationconstant)Because[RT]=[R]+[DR](RT:totalreceptors)

[R]=[RT]-[DR]

KD=[D][R][DR]KD=[D]（[RT]-[DR]）[DR]

E=[DR]=[D]Emax[RT]KD+[D][D]=0E=0if[D]>>>KDE=EmaxEC50KD=[D][DR]=50%[RT]summarybecauseonlyDRiseffectiveE/Emax=[DR]/[RT]=[D]/（KD+[D]）

When[D]=0,E=0When[D]>>KD,[DR]/[RT]=100%,Emax[DR]max=[RT]When[DR]/[RT]=50%,EC50,KD=[D]KDexpressaffinity（親和力）

ofDtoRThemoretheKD,thelittletheaffinitypD2=-logKDIntrinsicactivity（內(nèi)在活性）(byAriens1954，):α0<α≤100%E/Emax=α[DR]/[RT]

AgonistandAntagonist

(1)Agonist（激動藥）

havebothaffinityandintrinsicactivityFullagonist:α=1Partialagonist(mixedagonist)Affinitywithweakintrinsicactivity:α<1(2)Antagonist（拮抗藥）

haveAffinitybutwithoutintrinsicactivityα=0Competitiveantagonist:

a.Thresholdconcentrationsareincreased;

b.Curvesisparallelshiftedtotheright

c.Emaxisunchanged.

CompetitiveAntagonistpA2istheantagonismparameter

pA2=-log[I]inthepresenceofcertainamountantagonist[I],

doubletheagonistconcentrationgetthesameeffectasthatwithoutantagonist.(sewmachine)Thenegativelogarithmof[I]molarity

(mol)a.Thresholdconcentrations↓b.Emaxisunchanged;c.Curvesisshiftedtotheleftatlowconcentrationofagonist(partialagonistwouldlikeagonist).d.Curvesisshiftedtotherightathighconcentrationofagonist(likeantagonist).partialagonist:Inthepresenceofafixedconcentrationofpartialagonist,dose-effectcurvesoftheagonistwouldbealteredfollowingincreasingconcentrationofagonist.CompetitiveantagonismlgCEAA+P'A+P''AB

non-competitiveantagonist：

a.Thresholdconcentrationsarenotchangedsomuch;b.Shiftedtotheright;c.Emaxisdecreased.Otherreceptortheory（p10）twomodeltheory:activereceptor:(Ra)inactivereceptor:(Ri)inverseagonist二態(tài)模型Ri

Ra

D

Ri

D

Ra

TheTypesofReceptors（p10）Accordingtoproteinstructure,transmembranesignalingmechanisms,effectpropertiesandsitesofreceptors,theclassificationsofreceptorsasfollows:

IonChannelsReceptorsasEnzymesGProtein-CoupledreceptorsystemsCytosolicReceptorsTranscriptionFactorsGTPGDPGProtein-CoupledReceptorEffector(1)GproteincouplingreceptorsGs,Gi,Gt(transducin),Goα,β,D,5-HT,M,Opioid,Purine,PG

β1adrenoceptor(2)Ligand-gatedionchannelreceptors(receptorscontainingionchannel)N,GABAreceptorsAch+N2receptor→Na+channelopen→depolarization→skeletalmusclecontraction.N2receptor(3)ReceptorswithtyrosinekinaseactivityInsulinEpidermalgrowthfactor(EGF)Platelet-derivedgrowthfactor(PDGF)Transforminggrowthfactor-β(TGF-β)Insulin-likegrowthfactor(4)IntracellularreceptorsCorticosteroidsMineralocorticoidsSexsteroidsVitaminA,DThyroidhormoneRetinoicacid維甲酸

BRRRRRRGenomicmechanismofsteroidhormoneactionCellsignaltransduction(p12)TheSecondMessengers（第二信使）

(1)Cyclicadenosine-3’,5’-monophosphate(cAMP)β,D1,H2→Gs→cAMP↑α,D2,M,opioid→GI→cAMP↓(2)Cyclicguanosine-3’,5’-monophosphate(cGMP)(3)Phosphatidylinositol（肌醇磷脂）

α1,H1,5-HT1,M1,M3.(4)CalciumionCa2+intracellularlessthan1μmole/L.TheRegulationofReceptors(p13)a.ReceptordesensitizationDown-regulationToleranceb.ReceptorhypersensitivityUp-regulationrebound反跳

Propranolol普萘洛爾

Exercises1.Intrinsicactivityisadrug’sabilitytoelicit:

a)Strongreceptorbindingb)Weakreceptorbindingc)Responsed)Excretione)Distribution2.Onagradeddose-responsecurve(ordrug-receptorcurveinalaboratory),atwhatpointdoesresponseincreasethemostrapidly?

a)Initiallyb)AtEC50c)AtLD50d)At90%maximalresponseefficacy(Emax)e)Atsteady-state3.Whichofthefollowingistheequilibriumdissociationconstant,wheretheconcentrationoffreedrugisathalf-maximalbinding?

a)EC