基础医学导论 药物效应动力学学习课件

Chapter1

Pharmacodynamics

药物效应动力学Pharmacologicalaction-OverviewDose-effectrelationshipMechanismsofdrugactionsDrugreceptors1-

PharmacologicalAction-Overview1.1ActionandeffectofdrugAction作用SpecificallyprimaryactionbetweendrugandcellsormoleculesEffect效应Apparentfunctionalandmorphologicalchangesinducedbydrugdirectlyand/orindirectly1.2DirectandindirecteffectsofdrugsDirecteffects（直接效应）:

Effectsresultedfromtheactionofdrugonthetargetorgan(s)ortissue(s)Indirecteffects（间接效应）:Effectsresultedfromfunctionalintegrationoftargetsystem(s)andmodulationsystem(s)1-

PharmacologicalAction-OverviewActiononvascular

1

receptorsBP↑HR↓directindirectAction作用Effect效应Neuroendocrinemodulation1.3Selectivity（选择性）ofdrugeffectSelectivity选择性:

Organs/TissuesSpecificity特异性:

BiomoleculesReasonsofselectivityDrugdistributionBiologicalpropertiesoftissuesororgans1-

PharmacologicalAction-Overviewbronchodilation支气管扩张BP↑heartrate↑Epinephrine肾上腺素Salbutamol沙丁胺醇Selectiveeffectsofβreceptoragonistsonthetreatmentofbronchialasthmabronchodilation支气管扩张1.4Basiceffects（基本作用）ofdrugsExcitation（兴奋）or

Inhibition（抑制）ofthefunctionsofthebodyKillorsuppressthepathogens1-

PharmacologicalAction-Overview1-

PharmacologicalAction-Overview1.5Therapeuticeffectandadversereaction(desirableandundesirableeffects)治疗作用和不良反应Balancetheratioofbenefits/risk!!平衡用药的利弊！！1)Therapeuticeffects治疗作用

(Efficacy疗效)(1)Etiologicaltreatment（对因治疗）

(2)Symptomatictreatment（对症治疗）

(3)Supplementtherapy（补充治疗）

1-PharmacologicalAction-Overview2)Adversedrugreactions(Adverseeffects)不符合用药目的，并对病人带来不适或痛苦的反应（广义）Box1

现在，我国将不良反应定义为上市药品在正常用法用量情况下出现的与用药目的无关的有害反应。以区别于药物过量（overdose），在本课程中将两者合称为“不良反应”。1-Pharmacological

Action-Overview(1)Sideeffect

undesirableeffectsofthatdrugforthattherapeuticindicationatusualdoses,usuallyarenon-deleterious.（治疗剂量时出现的与治疗目的无关的药物作用）GI↓MydriasisGland↓Bladder↓HR↑ConstipationDrymouthBlurringvisionUrineretentionPalpitationAtropine1-

PharmacologicalAction-Overview(2)Toxiceffect

Functionalormorphologicaldamagesproducedbylargerdosesoflongertermsofdruguses.（剂量过大或用药时间过长体内蓄积过多时发生的危害性反应）

Local&systemtoxicityReversible&irreversibletoxicreactionsAcute&delayed/chronictoxicityTeratogenic/carcinogeniceffects1-

PharmacologicalAction-OverviewBox2

药源性疾病(drug-induceddiseases)严重的不良反应可以引起疾病，这种由药物不良反应引起的疾病称为药源性疾病，它主要是不合理用药造成的。药源性疾病实际上是药物不良反应在一定条件下产生的后果，一般来说，药源性疾病不包括因使用药物超过极量所引起的急性中毒。1-

PharmacologicalAction-Overview(3)AftereffectEffectsafterdrugconcentrationinthebodyislowerthanthresholdlevel.(停药后血药浓度已降至阈浓度之下时残存的药理效应)Short-lasting：

e.g.

BarbituratesLong-lasting：

e.g.

Glucocorticoids1-

PharmacologicalAction-Overview(4)Allergicreaction(Hypersensitivity)

Abnormalimmunologicalreactionsinducedbydrugs.(接触药物后发生的异常免疫反应

)

TypesI,II,III,IV

Skin,fever,blood-formingorgans,anaphylacticshock1-PharmacologicalAction-Overview(5)IdiosyncraticreactionsAgeneticallydeterminedabnormalreactivitytoachemical.(少数特异质病人对某些药物特别敏感，反应性质也可能与常人不同

)

Geneticabnormality

Examples:

Deficiencyoferythrocyticglucose-6-phosphatedehydrogenaseHypersensitivitytoscoline1-

PharmacologicalAction-Overview(6)OthersSecondaryreactionAdversereactionsresultingfromprimarytherapeuticeffectsofdrugs.(继发于药物治疗作用之后的不良反应

)Example:Broad-spectrumantibioticsinduceovergrowthofresistantbacteria(superinfection)1-

PharmacologicalAction-OverviewWithdrawalsymptomsClinicalsyndromeappearedorworsenedwhenthedrugisterminated.(突然停药后原有疾病复发或加剧

)Examples:Propranolol

－CHDClonidine

－hypertension

Anti-epilepticdrugs

－epilepsy1-

PharmacologicalAction-OverviewDependence依赖性Anadaptivestatethatdevelopsinresponsetorepeateddrugadministration.Psychologicdependence精神依赖性

ismanifestedbycompulsivedrug-seekingbehavior.Physiologicdependence生理依赖性

ispresentwhenwithdrawalofdrugproducessymptomsandsigns.Drugaddiction药物成瘾

isdefinedasthecompulsive,out-of-controldruguse,despitenegativeconsequences.

Drugabuse药物滥用:

anyuseofadrugfornon-medicalpurposes.(amaladaptivepatternofdruguseleadingtoclinicallysignificantimpairmentordistress)1-

PharmacologicalAction-OverviewBox3

药物不良反应的分型剂量关系密切型(甲型)：是药物固有药理作用的延续和增强，包括的副作用、毒性反应。具有剂量依赖性和可预测性的特点。剂量关系不密切型(乙型)：与药物固有药理作用无关的异常反应，与变态反应或高敏体质有关。具有与剂量无关和难以预测的特点。特殊型（丙型）：药物引起的癌症、畸胎、染色体畸变等。1-

PharmacologicalAction-OverviewTheobservedeffectofadrugasafunctionofitsdoseinthelivingsystem,usuallydrugresultsinagreatermagnitudeofeffectasthedoseincreased.药理效应与剂量在一定范围内成比例，称为剂量-效应关系（量效关系）Invitrostudies:

concentration-effectrelationship2-

Dose-EffectRelationship2.1Dose（concentration）Clinical：Thresholddoses

(阈剂量)

Therapeutic(usual)doses

(治疗量，常用量)

Maximaldoses

(极量)

Toxicdoses

(中毒量)

Lethaldoses

(致死量)

MICandotherconcentrationsExperimental：

invivo-ED50,TD50,LD50,……

invitro

-

IC50,EC50,……2-Dose-EffectRelationship2.2Responses(Effects)（1）Gradedresponses（量反应）：

ResponsechangesquantitativelyMeasurableresponsesinanindividual（2）Quantalresponses（质反应）：

All-or-nonePercentageofthepopulation2-Dose-EffectRelationship2.3Dose-effectcurveordose-responsecurve(量效曲线

)（1）logD-E(logC-E):

S-shapedcurveGraded

invitro：pD2,EC50,IC50,MIC……

invivo：PD100,ID30,……Quantal

mediandoses:ED50,LD50,ID50……

（用药个体的一半出现某种效应所需剂量，半数效量）2-

Dose-EffectRelationshipConcentration-effectcurve(gradedresponse)Dose-effectcurve(quantalresponse)Individualvariabilityof

dose-effectcurve（2）MaximaleffectandpotencyMaximaleffect(最大效应)orefficacy(效能):

differentmaximalmagnitudesofeffectsPotency(效价强度):

differenceindosesthatproduceaneffectatsamelevel（等效剂量）

药物作用强弱及敏感程度的比较2-Dose-EffectRelationshipPotency:

B>A>C>DEfficacy:

A=C=D>BSlope:

D>A,B,CEfficacy:

loopdiuretics>thiazidediuretics;

morphine>aspirinPotency:

differenceintheeffectivedosesofsametypedrugs1.4Riskanditsassessment(安全性评价)（1）Therapeuticindex（治疗指数,TI）

TI＝LD50/ED50，（2）Safetymargin:

LD5～ED95

orLD1～ED992-

Dose-EffectRelationshipTherapeuticindexSafetymargin安全范围Therapeuticindex3-MechanismsofDrugActions3.1Structure-ActivityRelationship(构效关系)Boththeaffinityofadruganditsfunctionalactivityaredeterminedbyitschemicalstructure.Relativelyminormodificationsinthedrugmoleculemayresultinmajorchangesinpharmacologicalproperties.Atropine阿托品Peripheral&Central中枢/外周Scopolamine东莨菪碱Central中枢Anisodamine山莨菪碱Peripheral外周Norepinephrine去甲肾上腺素

receptorEpinephrine肾上腺素

,

receptorsIsoprenaline异丙肾上腺素

receptor3.2Non-specificmechanisms(非特异性机制)（1）Physioc-chemicalreactions

Antacids,mannitol,dextran,……（2）Membrane-stablizing

Generalanesthetics,ethanol,……（3）Disinfectants3-MechanismsofDrugActions3.3Specificmechanisms(特异性机制)

(1)

Receptor

(受体)

(2)Enzyme

(酶)

(3)Ionchannel

(离子通道)

(4)Transporter

(转运体)

(5)Immunesystem

(免疫系统)

(6)Genetherapy(基因治疗)

&geneticengineeringdrugs(基因工程药物)

(7)Others(其他)

3-MechanismsofDrugActionsSpecificmechanisms：ActionsoncellfunctionsEnzyme-targetingdrugsAcetylcholinesteraseinhibitorCyclo-oxygenaseinhibitorAngiotensinconvertingenzymeinhibitorNa+-K+-ATPaseinhinitorH+-K+-ATPaseinhinitorHMG-CoAreductaseinhibitorsMostofantibioticsandanti-tumordrugsDrugsactingonionchannelsFurosemideinhibitsNa+-K+-2Cl--transporterNeurotransmittertransporterinhibitorsTargetsofdrug4-DrugreceptorsKeyeventsinthediscoveryandestablishmentoftheconceptofreceptors4-Drugreceptors4.1ConceptofreceptorsReceptor:

thecomponentofacellororganismthatinteractswithadrugandinitiatesthechainofbiochemicaleventsleadingtothedrug’sobservedeffects.（受体：细胞膜或细胞质的特异性蛋白质，具有识别、结合配体，并发生信号转导的作用）Function:

recognizingandbinding

withaspecificligand;

signaltransductionStructure:

aproteinwith

ligand-bingding

domainand

effector(transducer)domain4-DrugreceptorsLigand:

Chemicalsthatcanbindtoreceptors,includingendogenousorexogenousagonistsandantagonists

(配体：能与受体特异性结合的物质，分为激动剂和拮抗剂；根据来源分为内源性和外源性两类)4-DrugreceptorsCharacteristicsofreceptor（interactionbetweendrugandreceptor)

a)Sensitivity(灵敏性)b)Specificity(特异性)c)Saturability(饱和性)d)Reversibility(可逆性)e)Multiple-variation(多样性)4.2Receptorclassification(1)Gprotein-coupledreceptors

(G蛋白偶联受体,GPCR,7TM受体)(2)Ligand-gatedionchannelreceptors

(含离子通道的受体，配体门控离子通道受体)(3)Receptorsasenzymesorcoupledbyenzymes

(具有酪氨酸激酶活性[或偶联］受体,1TM受体)(4)Cytosolic[ornuclear]receptors

(细胞内受体,

核内受体)4-DrugreceptorsAnotherclassification(1)Cytosolic[ornuclear]receptors(2)Receptorsasenzymes

(3)Receptorscoupledbyenzymes

(4)Ligand-gatedionchannelreceptors(5)Gprotein-coupledreceptorsExamples:McholinoceptorAdrenoceptors5-HTreceptorsDAreceptorsOpioidreceptorsect.Gprotein-coupledreceptors(GPCR)GPCRsignaltransductioncAMP-PKAIP3-Ca2+/PKCPKALigand-gatedionchannelreceptorsExamples:NcholinoceptorGABAAreceptor5-HT3receptorNMDAreceptorReceptorsasenzymesGrowthfactorreceptorsReceptorscoupledbyenzymesCytokinereceptorsCytosolicreceptorsSteroidreceptorsastranscriptfactorsNuclearreceptors:thyroidreceptorasatranscriptfactor4.3InteractionsofdrugandreceptorD＋RDREOccupationtheory:

Drugbindstoitsreceptor,thenproducephysiologicaleffects4-DrugreceptorsBindingpropertiesBindingassay（radioactivetests）KD＝[D][R]/[DR]Bioassay（biologicaleffecttests）E/Emax＝[DR]/[RT]＝[D]/{KD+[D]}4-Drugreceptors（1）Affinity（亲和力）

abilityofdrugtobindtothereceptorLigandbindingtests：KD；KBInvitroeffecttest：EC50,

pD2（negativelogmolarconcentrationoftheagonistwhichproduces50％ofthemaximaleffect）4-Drugreceptors（2）Intrinsicactivity（内在活性）

AbilityofdrugtoproduceeffectsafterbindingtothereceptorE/Emax＝α·[DR]/[RT]4-DrugreceptorsConcentration-effectcurve：differentaffinitysameintrinsicactivityAffinityIntrinsicactivityConcentration-effectcurve：sameaffinitydifferentintrinsicactivityIntrinsicactivityAffinity4.4AgonistsandantagonistsDrugsthatactonreceptorscanbeclassifiedintothreetypesbasedontheiraffinity,intrinsicactivityandproducedphysiologicaleffect

：

Fullagonist(激动药)Partialagonist(部分激动药)Antagonist(拮抗药)4-DrugreceptorsClassificationofdrugsthatactingonreceptors

AffinityIntrinsicactivity

EffectsAgonist

Yes

Yes（100％）

YesAntagonist

YesNone（0％）

None，

blockingagonistPartialYes

Weak（0～100％）

Weak,agonist

blockingagonist4-DrugreceptorsDifferentpatternsofreceptor-actingdrugsBox4Recently，therearenewclassesofdrugsthatactonthereceptors：inverseagonist(反向激动剂)ornegativeantagonist

（负拮抗剂）具有拮抗剂特点，本身又产生与激动剂相反的效应。co-agonist(协同激动剂)与其它激动剂共同发挥效应。4.5Competitiveandnon-competitiveantagonismCompetitiveantagonists:

thatcompetewithagonistforthesamebindingsiteonthereceptor.Responsecurvefortheagonistareshifttotherightwithoutdepressionofmaximalresponse.竞争性拮抗药与激动药并用时，能与激动药相互竞争与受体的结合，降低激动药与受体的亲和力，而不降低内在活性（量效曲线平行右移，最大效能不变）4-DrugreceptorsNon-competitiveantagonists:

thatcause(ornotcause)ashiftoftheresponsecurvetotherightwithdepressionofmaximalresponse.非竞争性拮抗药与激动药并用时，可使亲和力及内在活性均降低，一般可影响受体功能或与受体不可逆性结合。BecauseofIrreversibleorpseudo-irreversiblebindingAllostericeffects4-DrugreceptorsA：Effectofacompetitiveantagonistonagonistconcentration-responsecurveB：

Effectofanon-co