PHARMCODYNAMICS藥物效應(yīng)動力學(xué)

CHAPTER2PHARMACOLOGYPHARMCODYNAMICSDrugaction:concept,selectivityanddualismReceptortheory:concept,property,signalpathwayConcentration-effectrelationship,structure-activityrelationship

agonist,antagonistImportantpoints：Part1BasicActionsofDrug

1.PropertyandPatternofDrugActionsDrugActions--referredtotheinitialorprimaryinteractionbetweendrugmoleculewithreceptorsonthecells.DrugEffects--Pharmacologicaleffect:physicaleffectssecondarytoinitialdrugaction.Adrenalineactonβreceptorscalledactionofadrenaline,stimulatingheartcalledeffectsofadrenaline.(1)PropertyofDrugEffectsExcitation(stimulation):Thebodyfunctionincreaseorpotentiatedbythedrug.Adrenalineaccelerateheartrateandoutput.Acetylcholinecontractsgastro-intestinalsmoothmuscle.Inhibition:Thebodyfunctiondecreaseorsuppressedbythedrug.Ifdoseincreaselargelyitmayproduceparalysis

orfailure.Diazepam

inducesedationandhypnosis.Aspirinlowerstheelevatedbodytemperature.(2)PatternofDrugActionsLocalaction:Drugsactdirectlyatthelocalpartwithoutabsorption.Localanesthetics,externaluseGeneralaction:Drugsactatorgansandtissuesafterabsorbedintobloodcirculation,orcalledas“absorptiveaction”.DigoxintreatsonCHF.(3)ConceptsofDrugEffectsAdversereaction:Therapeuticeffects:Etiologicaltreatment---permanentcureSymptomatictreatment---temporarysolutionTherapeuticEffects治療作用

Effectsproducedbydrugsarethepurposesforthedruguse,i.e.,thebeneficialeffectsofthedrug.Therapeuticeffectsareusefultopreventortreatdiseases.Etiologicaltreatment對因治療Eliminationoftheetiologicalfactorsbyusingdrugstocurediseases.a.TherapybykillingpathogensIfaninflammationiscausedbytheinvasionofpathogens,theapplicationofsuitableantibioticsispreferred.Genetherapy,immunotherapy.b.Supplementary(replacement)therapyLackofendogenoussubstancemaycausemanykindsofdiseases.Forexample,lackofvitaminAmaycausenightblindness;lackofthyroidhormonescongenitallymaycausecretinism(呆小癥).

Symptomatictreatment

對癥治療Thediseasesymptomimprovementwithouteliminatingthecauseofthedisease.Forinstance,painrelievedbyaspirin;hypertensionloweredbyanti-hypertensivedrugs.Adversereaction

不良反應(yīng)

Anyresponsetodrugthatisnoxiousandunintendedandthatoccursatdoseusedinmanforprophylaxis,diagnosisortherapyofadisease,orforthemodificationofphysiologicalfunction.(WHO)

Sideeffects副反應(yīng)Intherangeoftherapeuticdoses,thedrugeffects,whicharenotrelatedtothecurrenttherapeuticpurpose,arecalledsideeffects.Thepharmacologicalbasisofthepresenceofsideeffectsislowselectivityofthedrug.AdversereactionForinstance,atropineisusedtopreventairwaysecretioncausedbyanesthetics,itsallothereffects,suchasmydriasis,drymouth,belongtothesideeffects;however,ifitisusedinophthalmology(eye),allothereffectssuchas,drymouth,acceleratecardiacrateetc.,belongtothesideeffects.

ToxicReaction毒性反應(yīng)AdversereactionAlldrugsarecapableofproducingtoxicreactionsifthedoseishighenoughordrugslongtermused.A.Accordingtoon-speedofdrugtoxicity:acutetoxicity,chronictoxicity.B.Accordingtothedistributionofdrugtoxicity:localtoxicity,systemictoxicity.C.Accordingtotheextentofdrugtoxicity:Pharmacologicaltoxicity(mostcasesarereversible)Pathologicaltoxicity(partofcasesirreversible)AllergicReaction過敏反應(yīng)AdversereactionHypersensitivereaction:drugallergyisanalteredresponsetoadrugresultingfromaprevioussensitizingexposureandanimmunologicalmechanism.Itisalsoapathologicalallergicreactionofadrug.Someagents,suchasstreptokinase,penicillin,iodides,andsulfonamides.Ⅰ、Ⅱ、Ⅲ、ⅣtypesFeatures:non-relationtodrugdose;difficulttoforesee;Severeallergicshock:penicillin;Skintestbeforedrugusewhichinduceallergy.SecondaryReaction繼發(fā)反應(yīng)AdversereactionADRinducedbydrugtherapeuticeffects.Forexample,broadspectrumantibioticsinducedoubleinfection,i.g.“Pseudomembranouscolitis”,“mycotic

stomatitis”.

Aftereffect(residualeffect)后遺反應(yīng)AdversereactionAfterdrugwithdrawal,drugconcentrationisbelowthethreshold,theeffectstillexists,suchasaftertakingbarbiturates,thepatientfeelshangover,drowsiness,andfatigueinthesecondmorning.Forinstance,Stopadministrationofhydrocortisoneafteritslong-termusewillcausehypoadrenocorticismwhichneedseveralmonthstorecover.

Specialtoxicity特殊毒性AdversereactionCarcinogenesis致癌:Somedrugmaycausecancer.

Teratogenesis致畸:Infewcases,somedrugmayinduceteratogenesis,suchasthalidomide.

Mutagenesis致突變:SomespecialdrugcaninduceDNAchange,resultingincarcinogenesisorteratogenesis.

Withdrawalreaction(rebound)停藥反應(yīng)AdversereactionRapidwithdrawalwhenlong-termuse,somedrugmayleadtoacceleratesymptomsofordinarydisease,suchaswhenstopusepropranololforitslong-termuseinanginapatients,whichcanprovokeanginaattacks,arrhythmias,ormyocardialinfarction,evenmoreseverethanbefore.Idiosyncrasy

特異質(zhì)反應(yīng)AdversereactionDrugidiosyncrasyreferstoanabnormalresponsetoadrugbyanindividual.Itisquitelikelythatidiosyncrasyaregeneticallyabnormalitiesofenzymesandreceptors.Therefore,theseabnormalresponseareoftenreferredtoaspharmacogeneticdisorders.Forexample,hemolyticanemiaelicitedbyprimaquineinpatientswhoseRBCaredeficientinglucose-6-phosphatedehydrogenase(G-6-PD).2.SelectivityorDualismofdrugactionSelectivityorspecificitySelectivitymeansthatadrugbindstooneorafewtypesofreceptorswithhigheraffinitythantootherreceptors.Ideally,adrugonlybindstoonesingletypeofreceptorandcauseonesingleeffect.i.g.DigoxinorAtropinDualismTherapeuticeffectsandadversereactionChangeroleaccordingtodifferenttherapeuticaim.Part2ReceptorTheorya.Langley(1878):

Oppositeactionofatropinewithpilocarpineinsalivaryexcretion.1.DevelopmentofReceptortheoryb.Langley(1906):

Reverseactionof

tubocurarinewithnicotineinskeletalmuscle–“receptivesubstance”c.Ehrlich(1913):

“l(fā)ockandkey(receptoranddrug)”

ReceptorTheory:

the

PrideofPharmacologists！d.Clark(1933):

Acetylcholineonheartcontractioninadose-dependentmanner.e.,β,

N-receptor

(1948)f.Dale,Ahlquist,Gaddum,Schild,Sutherland,etal.

“secondmessengertheory”(1972)

受體學(xué)說：藥理學(xué)的靈魂Receptorslieattheheartofpharmacology.

2.TheConceptandPropertiesofReceptors(1)Concept

Aspecificreceptorcanbedefinedasanybiologicalcomponentofcellsthatspecificallybindwithaendogenousligandorwithaexogenousdrug,andinducepharmacologicaleffects.Chemicalnature:protein,complexofproteinandpolysaccharide2.TheConceptandPropertiesofReceptors(1)Concept

Ligandcanbedefinedassubstancesspecificallycombinetoreceptor.“Firstmessenger”

Endogenousligand:neurotransmitter,hormone,self-activesubstance;

Exogenousligand:drugs;Orphanreceptor:notfoundendogenousligand(2)Propertiesa.Structuralspecificity結(jié)構(gòu)專一性b.Specificity特異性c.Saturability飽和性d.Reversibility可逆性〔R〕+〔L1〕≒〔RL1〕→Effect〔R〕+〔L2〕≒〔RL2〕

e.Highaffinity高親和力(3)InteractionbetweenReceptorandDrugBindingforceforreceptorandligand:VanderWallsforce,ion,hydrogen,covalentbond.

Drug-ReceptorInteractionsk1k2DrugReceptorEffectDrug-ReceptorComplexLigand-bindingdomain

Effectordomain

receptorsonthecellsurface

postsynapticmembranepresynapticmembrane(α2)receptorsinthecytoplasm(CorticosteroidsR)receptorsinthenucleus(thyroxineR

)(4)TheTypesofReceptors(4)TheTypesofReceptorsAccordingtoproteinstructure,transmembranesignalingmechanisms,effectpropertiesandsitesofreceptors,theclassificationsofreceptorsasfollows:

N,GABAreceptorsAch+N2receptor→Na+channelopen→depolarization→skeletalmusclecontractionTheTypesofReceptors(1)Ligand-gatedionchannelreceptors(配體門控離子通道受體,receptorscontainingionchannel)

α,β,D,5-HT,M,Opioid,Purine,PGreceptors(2)Gproteincouplingreceptors(G-蛋白偶聯(lián)受體)TheTypesofReceptorsBasedonitsfunctionandsub-unit,Gproteincanbedividedinto:stimulativeGprotein(Gs),AC

inhibitoryGprotein(Gi),AC

Transducin(Gt),cGMPPDE

ionchannelGprotein(Go),K+channelphospholipaseCGprotein(Gq),PLC

InsulinEpidermalgrowthfactor(上皮生長因子,EGF)Platelet-derivedgrowthfactor(血小板衍生的生長因子,PDGF)Transforminggrowthfactor-β(轉(zhuǎn)化生長因子β,TGF-β)Insulin-likegrowthfactor(胰島素樣生長因子)(3)Tyrosineproteinkinasereceptors

(酪氨酸激酶活性受體)TheTypesofReceptorsCorticosteroids皮質(zhì)激素

MineralocorticoidsSexsteroidsVitaminA,D

Thyroidhormone甲狀腺激素Retinoicacid維甲酸

(4)RegulategenetranscriptionR

(調(diào)節(jié)基因表達(dá)受體)TheTypesofReceptorsBRRRRRRGenomicmechanismofsteroidhormoneaction(5)TheRegulationofReceptorsAgonist-specificdesensitizationReceptordesensitization受體脫敏Isoprenaline-asthma,effect↓ToleranceDown-regulationAntagonist-specifichypersensitizationReceptorhypersensitivity受體超敏Propranolol，reboundUp-regulation

Homospecificregulation

同種調(diào)節(jié)β-receptorisregulatedbyisoprenaline.Heterospecificregulation

異種調(diào)節(jié)β-receptorisregulatedbyglucocorticoidsorThyroidhormone

;γ-GABAreceptorisregulatedbyBenzodiazepines.“Occupationtheory”(Clark,1937)①藥物作用強度與藥物占領(lǐng)受體的數(shù)量成正比,藥物與受體的相互作用是可逆的[D]+[R]=[DR]→→E(6)Receptortheory②藥物濃度與效應(yīng)服從質(zhì)量作用定律;藥物占領(lǐng)受體的數(shù)量取決于受體周圍的藥物濃度、單位面積或單位容積內(nèi)受體總數(shù)。③被占領(lǐng)的受體數(shù)目增多時,藥物效應(yīng)增強,當(dāng)全部受體被占領(lǐng)時,藥物效應(yīng)達(dá)Emax.“modifiedoccupationtheory”①affinity:②intrinsicactivity:

efficacy,maximumeffect,Emax.sparereceptor(備用受體)silentreceptor(靜息受體)

“ratetheory”

k1D+R←→DRk2“allosterictheory”

(變構(gòu)學(xué)說，twostatemodeltheory):restingstate(R),activestate(R*).inducedfit(誘導(dǎo)契合).

Part3PharmacodynamicsPrinciple1.Mechanismofdrugactionspecificdrugactionmechanismnonspecificdrugactionmechanismspecificdrugaction

(1)agonismorantagonismonreceptors(Adr,Prop.)(2)affectingthetransmitterreleaseorhormonesecretion(aramine,largedoseiodide)(3)affectingtheactivityofenzymes(neostigmine)(4)affectingionchannels(nifedipine)(5)affectingtheautocoids(localhormones)(aspirin)nonspecificdrugaction(1)changetheosmoticpressure(mannitol)(2)changethepHvalues(anti-acidagents)(3)lipid-solubility(diethylether)(4)chelatingaction(dimercaprol)(5)supplementtherapy(Vitamin,hormone)2.Intracellularsignaltransductiontransmembranesignalingorsignaltransduction.CascadereactionGproteincoupledreceptor

(GPCR)signaltrans.(2)Intracellularreceptorsignaltransduction(3)Ligandregulatingtransmembraneenzyme(tyrosinekinasereceptor)signaltransduction(4)Ligandorvoltage-gatedionchannelsignaltrans.(5)SecondmessengersGprotein:GTPbindingprotein7transmembraneproteinfamily

α,β,M,5-HTreceptor(1)GPCRsignaltransductionMainGprotein,receptorandeffectorG

proteinRelatedreceptoreffectorGs(Gαs)Gq(Gαq)Gi1,Gi2,Gi3GαiGolfGt1,Gt2Gβγβ-R,5-HT-RAch(M-R)Ach(M-R),NA(α-R)odourphotonAllGPCRsAC↑→cAMP↑PLC↑→IP3,DAG↑AC↓→cAMP↓K+channelopen→HR↓AC↑→cAMP↑PDE↑→cGMP↓(2)IntracellularreceptorsignaltransductionLRRRRRRCorticosteroidsMineralocorticoidsSexsteroids

Thyroidhormone(3)IntracellularreceptorsignaltransductionEGF,PDGF,ANP,TGFβ;tyrosinekinase,serinekinase,GC

(4)Ligandorvoltage-gatedionchannelsignaltransductionLigand:neurotransmitterAch,γ-GABA,GluReceptor:N-R(Na+channel)γ-GABA-R(Cl-channel)Glu-R(Ca2+channel)γ-GABA

receptorInteractionofLigandandReceptorsSecondmessenger:cyclicadenosinemonophosphate(cAMP)，cyclicguanosinemonophosphate(cGMP),inositol1,4,5-triphosphate(IP3)，diacylglycerol(DAG)，calciumion(Ca2+).Firstmessenger:Endogenousligandordrugorautacoid(prostaglans,serotonin).(5)SecondMessengersa.cAMPβ,D1,H2→Gs→cAMP↑α,D2,M,opioid→GI→cAMP↓b.cGMPc.IP3,DAGα1,H1,5-HT1,M1,M3.d.CalciumionCa2+intracellularlessthan1μmole/L.

AdrreceptorAC腺苷酸環(huán)化酶，PIP2二磷酸肌醇磷脂，IP3三磷酸肌醇（增加胞內(nèi)鈣），DG甘油二脂（增加胞外鈣內(nèi)流）a2GiAdenylylcyclaseGsb1a1GpPhaspholipaseCATPcAMPDG+IP3PIP2AchM-R

3.SARandCERofdrugs(1)

structure-activityrelationship(SAR)Therelationshipbetweenthespecificityofdrugactionandthestructureofdrugscalledasstructure-activityrelationship.(1)structuralanalogue:

thesimilarorreverseeffects;(2)stereo-structuralanalogue:

thesimilareffect;(3)theoptical

isomer:

chirality.e.g.quinidineandquinine.quantitativestructure-activityrelationship(QSAR).Potent

(2)Dose-EffectRelationshipConcentration-effectrelationship(CER)Inacertainrangeofdoses,thepharmacologicalresponseisincreasedwiththeincreaseindoseswithoutevidenttoxiceffects,therelationshipbetweendose(orconcentration)andeffectcalledCER.Thecurveofthisrelationshipcalleddose-effectcurve.I.DrugsactonreceptorsDrugscandotwothingstoreceptors:(1)bindtothem(affinity)(2)possiblychangetheirbehaviortowardthehostcellsystem(efficacy).

(1)AgonistAffinitywithefficacy.Fullagonist:α=1Partialagonist：Affinitywithweakintrinsicactivity:α<1Drugsactonreceptors激動劑達(dá)最大效應(yīng)一半時所需濃度的負(fù)對數(shù)值。值越大，親和力越大。pD2(親和力參數(shù))圖藥物與受體的親和力及其內(nèi)在活性對量效曲線的影響A圖a,b,c三藥與受體的親和力（pD2）相等，但內(nèi)在活性（Emax）不等B圖a,b,c三藥與受體的親和力（pD2）不等，但內(nèi)在活性（Emax）相等Partialagonistsproducealowerresponsecomparedwithfullagonists.Partialagonistsproduceconcentration-effectcurvesthatresemblethoseobservedwithfullagonistsinthepresenceofanantagonistthatirreversiblyblocksreceptorsites.partialagonist:dualism(2)

AntagonistAffinitywithoutintrinsicactivity.α=0DrugsactonreceptorsA.CompetitiveantagonistB.Non-competitiveantagonist

Inthepresenceofafixedconcentrationofagonist,increasingconcentrationsofacompetitiveantagonistprogressivelyinhibittheagonistresponse.CompetitiveantagonistpA2istheantagonismparameter.

激動劑與競爭性拮抗劑合用時，激動劑濃度加倍，其效應(yīng)曲線方能達(dá)到單用激動劑最大效應(yīng)，此時所需拮抗劑濃度負(fù)對數(shù)值稱為pA2。此值越大，拮抗力越大。pA2（拮抗參數(shù))：競爭性拮抗藥（A圖）、非競爭性拮抗藥（B圖）

CompetitiveAntagonist特點：拮抗劑(B)與激動劑(A)競爭相同的受體；競爭性拮抗劑其拮抗作用是可逆的；隨拮抗劑濃度增加,激動劑A+B的累積濃度效應(yīng)曲線平行右移；斜率和最大效應(yīng)不變。Somereceptorantagonistsbindtothereceptorinanirreversible,i.e.,notcompetitive.Theantagonist'saffinityforthereceptormaybesohighthatforpracticalpurposes,thereceptorisunavailableforbindingofagonist.non-competitiveantagonist(irreversibleantagonists)特點：●拮抗劑B與激動劑A爭奪非同一受體，它與受體結(jié)合后妨礙A與特異性受體結(jié)合?；蚋偁幫皇荏w，但共價鍵結(jié)合?！癫粩嗵岣逜藥濃度也不能達(dá)到單獨使用A藥時的最大效應(yīng)?！穹歉偁幮赞卓箘〣也可使激動劑A+B的量效曲線右移，斜率降低，最大效應(yīng)降低。II.DrugDoseandDose-EffectRelationshipConcentration-effectRelationship(CER)Dose-effectcurveS–shapeDose-effectRelationship(DER)minimaleffectivedose(minimaleffectiveconcentration):thresholddoseorconcentration.(2)maximaldose:maximumeffect(Emax).Emaxisthemaximalresponsethatcanbeproducedbythedrug,andEC50istheconcentrationofdrugthatproduces50%ofmaximaleffect.Doseconcept(3)minimaltoxicdose(4)therapeuticdoseIII.GradeddoseResponse量反應(yīng)Gradeddoseresponsemeansthepharmacologicaleffectsofthedrugsexpressedinquantityornumber,suchasHRbyrates,BPbymmHg.Maximumefficacy,Potency,MedianeffectiveconcentrationEmaxmeansthatdrugsiscapableofexertingmaximaleffect.Thetermdescribesthemaximalbiologicalresponseproducedbyadrug.Efficacyofadrugdependsonthereceptordensityorthenumberofactivereceptors.Maximumefficacy(最大效應(yīng)，效能,efficacy,Emax)Theter