药物效应动力学-陈季强课件

浙江大学医学院陈季强教授Email:chenjq@2010-2011学年冬学期

SectionⅥ.PharmacologicalBasisofTherapeutics药物治疗学基础(治疗学的药理学基础)IntroductionofBMS

浙江大学医学院陈季强教授2010-2011学年冬学期1Chapter2.PharmacokineticsChapter3.FactorsinfluencingeffectofdrugChapter4.Anti-neoplasticsChapter1.PharmacodynamicsBasicConceptofPharmacologySectionⅥ.PharmacologicalBasisofTherapeuticsContentsChapter2.PharmacokineticsCha2SectionⅥ.PharmacologicalBasisofTherapeuticsDrugsBiologicalorganisms

1.Whatispharmacology?BasicConceptofPharmacologyPharmacodynamics

(药物效应动力学,

药效学)Pharmacokinetics(药物代谢动力学,药动学)SectionⅥ.PharmacologicalBas32.What

is

the

research

of

pharma-cology?BasicConceptofPharmacology(1)Pharmacodynamics(PD):Drugaction;Mechanismsofdrugaction(2)Pharmacokinetics(PK):

Absorption(吸收),Distribution(分布),Biotransformation(生物转化),Excretion(排泄)(3)Influencefactors

topharmaco-dynamicsand

pharmacokinetics2.Whatistheresearchofpha4

(1)Toexplainthedrugactionandmechanismsofdrugaction,andtodirectclinicaladministration;

(2)Researchanddevelopmentofnewdrugs;

(3)Toexplorethesecretsofthelife.3.ThetasksofPharmacology:BasicConceptofPharmacology(1)Toexplainthedrugaction5(1)Preclinicalpharmacology:

●

Researchobject:

animal;

▲

Experimentalpharmacology:

invivo

andinvitro;

▲

Experimentaltherapeutics:

animalmodelofdisease;

▲

Pharmacokinetics;

▲

Toxicology.4.Theresearchmethodsofphar-macology:

●

Thecontentsofresearch:BasicConceptofPharmacology(1)Preclinicalpharmacology:6

●Theobjectofresearch:

Humanbeing;

●Thecontentsofresearch:

▲

Therapeuticeffects;

▲

Adversedrugreactions(ADR);

▲

Pharmacokinetics.(2)Clinicalpharmacology:BasicConceptofPharmacology●Theobjectofresearch:7(1)Sourceofnewdrugs:●Naturecomponentsofplantorothers;●Syntheticandsemi-syntheticchemicals;●Geneticrecombination.5.Researchanddevelopmentofnewdrugs:BasicConceptofPharmacology(1)Sourceofnewdrugs:●Natu8

●Preclinicalstudy(临床前研究):

Pharmacodynamics;

Pharmacokinetics;

Toxicology.

●Clinicaltrials(临床试验):(2)Processofnewdrugstudy:BasicConceptofPharmacology●Preclinicalstudy(临床前研究):9▲PhaseⅠ(一期临床):

20-30位健康志愿者;

▲PhaseⅡ(二期临床):

≥

100对病人;

▲PhaseⅢ(三期临床):

≥300例病人;

▲PhaseⅣ(四期临床):

≥

2000例病人,

也称为售后调查(post-surveillance).

multicenter(多中心):

至少三家医院

doublecontrol(双对照):

阴性和阳性对照

doubleblind(双盲):

病人和医生●Clinicaltrials(临床试验):BasicConceptofPharmacology▲PhaseⅠ(一期临床):20-30位健康志愿10Chapter1.PharmacodynamicsPart1.BasicactionofdrugPart2.Dose-effectrelationshipPart3.MechanismofdrugactionPart4.DrugandReceptorSectionⅥ.PharmacologicalBasisofTherapeuticsChapter1.PharmacodynamicsPar111.Actionandeffectofdrug:(1)Conceptofactionandeffect:

①Action:

e.g.:

Noradrenaline(NA)stimulat-ing

receptorofbloodvessel

②Effect:

▲VasoconstrictionandBP;

▲AfterBP

,reflexheartrate

.Chapter1.PharmacodynamicsPart1.Basicactionofdrug1.Actionandeffectofdrug:C12(2)Basicexpressionofdrugaction:●

Excitation:

functionoforgansorsystems●

Inhibition:

functionoforgansorsystemsPart1.Basicactionofdrug(2)Basicexpressionofdruga13①Definitionofselectivity;

②Selectivityisrelative;

③Clinicalsignificance.(3)Selectivityofdrugeffect:Part1.Basicactionofdrug①Definitionofselectivity;②14(1)Therapeuticeffect:

①Etiologicaltreatment;

②Symptomatictreatment;

③Supplementtherapy.2.Therapeuticeffect&adversedrugreaction——Dualismofdrugaction.Part1.Basicactionofdrug(1)Therapeuticeffect:①Etiolo15①Sidereaction(副作用);②Toxicreaction(毒性反应):

●Acutetoxicity;

●Chronictoxicity;

●Specialtoxicity:(2)Adversedrugreaction(ADR):▲Mutagenesis(致突变),▲Carcinogenesis(致癌),▲Teratogenesis(致畸).Part1.Basicactionofdrug①Sidereaction(副作用);②Toxicrea16

●Specialtoxicity:▲Teratogenesis(致畸)

②Toxicreaction(毒性反应):Adversedrugreaction(ADR)Part1.Basicactionofdrug●Specialtoxicity:▲Teratogen17(2)Adversedrugreaction(ADR):①Sidereaction(副作用);②Toxicreaction(毒性反应);③Aftereffect(后遗效应);

Part1.Basicactionofdrug(2)Adversedrugreaction(ADR):18

tCRelationshipbetweenADRsandCp:MTCMEC①Sidereaction②Toxicreaction③AftereffectPart1.Basicactionofdrug

tCRelationshipbetweenADR19

①Sidereaction(副作用);

②Toxicreaction(毒性反应);

③Aftereffect(后遗效应);

(2)Adversedrugreaction(ADR):④Allergicreaction(变态反应);⑤Idiosyncrasy(特异质反应).●Drug-induceddisease(药源性疾病)Part1.Basicactionofdrug①Sidereaction(副作用);②Toxicr20Let’stakearestChapter1.PharmacodynamicsLet’stakearestChapter1.Ph212.Efficacy(效能)&Potency(效价强度);1.Dose-effectrelationships;3.Individualvariability(个体差异);4.Safetyevaluation(安全性评价).Part2.Dose-effectrelationshipsChapter1.Pharmacodynamics2.Efficacy(效能)&Potency(效价强度221.Doseeffectrelationships:

(1)Dose:Part2.Dose-effectrelationshipsMaximaldose(极量)Dose0LethaldoseToxicdoseEffectivedoseTherapeuticdoseInvaliddoseMinimaltoxicdoseMinimallethaldoseMinimaleffectivedose(thresholddose)EEmax1.Doseeffectrelationships:P23(2)Response(effect):①Gradedresponse(量反应)②Quantalresponse(质反应)——all-or-noneresponsePart2.Dose-effectrelationships(2)Response(effect):①Gradedr24(3)Doseeffectcurve:

①Dose-effectcurve:(D,C)

EmaxD(C)EED50(EC50)050100Part2.Dose-effectrelationships(3)Doseeffectcurve:EmaxD(C)E25②Dose-effectcurve(logDorlogC)

EmaxlogD(C)ED50050E(%)100Part2.Dose-effectrelationships②Dose-effectcurve(logDorlo26③Dose-effectcurve(logDorlogC)

EmaxlogD(C)ED50050E(%)100Part2.Dose-effectrelationshipsslope(斜率)84%16%③Dose-effectcurve(logDorlog27●Dose-effectrelationships

ED50:

50%effectivedose

LD50:

50%lethaldose●

Concentration-effectrelationships

EC50:

50%effectiveconcentration

Part2.Dose-effectrelationships●Dose-effectrelationships282.Efficacy(效能)&Potency(效应强度):Efficacy表示药物所能达到最大效应的能力;

Potency表示达到相同效应时药物剂量大小.logD0ECBADPart2.Dose-effectrelationships2.Efficacy(效能)&Potency(效应强度29几种常用利尿药的作用及最大效应比较Part2.Dose-effectrelationships几种常用利尿药的作用及最大效应比较Part2.Dose-30

3.Individualvariability(个体差异):EMean(平均值)

Standarddifference

(标准差,SD)D0Part2.Dose-effectrelationships

31Part2.Dose-effectrelationshipsQuantalresponseD-Ecurve(质反应量效曲线)4.Safetyevaluation(安全性评价):Part2.Dose-effectrelationsh32Part2.Dose-effectrelationshipsTherapeuticindex(TI,治疗指数)TI=LD50/ED50Part2.Dose-effectrelationsh33

Therapeuticindex(TI)=LD50/ED50

Marginofsafety:ED95~LD5

orED99~LD1

EABA’B’

logDLD50LD50ED50ED500Part2.Dose-effectrelationshipsTherapeuticindex(TI)=LD5034Part3.MechanismofDrugaction1.Actiononreceptor;

2.Interferingcellmetabolism;3.Influencingtransportation;4.Actiononenzyme;5.Actononionchannel;6.Actiononnucleicacid;

7.Influencing

immunesystem;

8.Non-specialaction;9.Physicochemicalreaction.Chapter1.PharmacodynamicsPart3.MechanismofDrugacti35

See:Part4.DrugandReceptor

1.作用于受体:Part3.MechanismofDrugactionSee:Part4.DrugandRe36

有些药物的化学结构与正常代谢物非常相似,可以以假乱真地掺入到代谢过程中,但是,假的总归是假的,不能发挥正常物质的作用,实际上会导致后续代谢的抑制或阻断了后续代谢过程,称为伪品掺入(counterfeitincorporation),也称为抗代谢药(antimetabolite).

例如抗肿瘤药5-氟尿嘧啶的结构与尿嘧啶极为相似,可以掺入癌细胞的DNA及RNA中,干扰肿瘤细胞的核酸及蛋白质合成而发挥抗癌作用.

2.参与或干扰细胞代谢:Part3.MechanismofDrugaction有些药物的化学结构与正常代谢物非常相似,可以以假37

很多无机离子、代谢产物、神经递质、激素等在体内通过载体(carrier)进行主动转运,有些药物化学结构与体内的上述物质化学结构很相似,可以影响或干扰载体对上述物质的转运而产生药理作用.例如,丙磺舒竞争性抑制肾小管对弱酸性代谢产物的主动转运载体(有机酸转运体),可抑制原尿中尿酸的再吸收,用于防治痛风;又如利尿药呋塞米及氢氯噻嗪可抑制肾小管对钠、钾、及氯离子再吸收,而发挥利尿作用.

3.影响生理物质转运:Part3.MechanismofDrugaction很多无机离子、代谢产物、神经递质、激素等在体内通过38

①直接作用于酶:

例如奥美拉唑通过抑制胃粘膜壁细胞膜上的H+-K+-ATP酶(质子泵)从而抑制胃酸分泌;卡托普利抑制血管紧张素Ⅰ转换酶而治疗高血压;阿司匹林抑制前列腺素合成酶而治疗疼痛和炎症,等.

②影响肝药酶活性:如苯巴比妥等诱导肝药酶活性增加而加速另外一些药物的代谢;氯霉素等能抑制肝药酶而减慢其他药物的代谢,等.

4.影响酶的活性而产生作用:Part3.MechanismofDrugaction①直接作用于酶:例如奥美拉唑通过抑制胃粘膜壁细胞膜上的395.作用于细胞膜的离子通道:主要的离子通道有Ca2+、K+、Na+及Cl-通道,它们调节细胞膜内外无机离子的分布.通道的开放或关闭影响细胞内外无机离子的运转,能迅速改变细胞功能.有些离子通道是药物直接作用的靶点,药物可改变离子通道的构象,使通道开放或关闭.例如,阿米洛利阻断肾小管钠通道,硝苯地平阻断钙通道,吡那地尔激活血管平滑肌钾通道等.

Part3.MechanismofDrugaction5.作用于细胞膜的离子通道:Part3.Mechani406.影响核酸代谢:许多药物通过直接影响核酸代谢而发挥药理效应.如抗癌药5-氟尿嘧啶通过阻断DNA的合成,抑制肿瘤细胞生长;

磺胺类抗菌药通过抑制细菌体内叶酸的代谢,干扰核酸的合成;

喹诺酮类抑制DNA回旋酶,发挥杀菌作用;

甾体激素与甲状腺激素均通过作用于细胞内受体而影响核酸的代谢等.Part3.MechanismofDrugaction6.影响核酸代谢:Part3.Mechanismof41

正常免疫反应是机体消除入侵微生物和自身变异细胞的重要机制.某些药物本身就是免疫系统中的抗体(如丙种球蛋白),或者是抗原(如疫苗).

免疫抑制药(如环孢素),可用于抑制器官移植后的排异反应、自身免疫性疾病及Rh阳性新生儿溶血病等.

免疫增强药多作为辅助治疗药物,用于免疫缺陷性疾病,如艾滋病、慢性感染及癌症等.7.影响免疫机制:Part3.MechanismofDrugaction正常免疫反应是机体消除入侵微生物和自身变异细胞的42有一些药没有特定的作用目标,其作用也称为非特异性作用.消毒防腐药(如石炭酸、福尔马林等)对蛋白质有变性作用,因而只用于体外杀菌或防腐,不能内用;有一些麻醉性催眠药(包括乙醇)能干扰细胞膜脂质结构,因此对各种细胞均有抑制作用,进入体内后,只是中枢神经系统对其相对比较敏感.8.非特异性作用:Part3.MechanismofDrugaction有一些药没有特定的作用目标,其作用也称为非特异43有些药物通过简单的物理化学作用,如酸碱反应、渗透压改变、氧化还原(自由基清除)等,改变机体内环境.还有些药物是补充机体所缺乏的物质,例如维生素、激素、多种微量元素等.

9.通过理化反应发挥作用:

Part3.MechanismofDrugaction有些药物通过简单的物理化学作用,如酸碱反应、渗44Let’stakearestChapter1.PharmacodynamicsLet’stakearestChapter1.Ph45Part4.DrugandReceptor1.Conceptofreceptor:(1)Receptor(受体)andligand(配体)(2)Characteristicsofreceptor:①Sensitivity(灵敏性)②Specificity(特异性)③Saturability(饱和性)④Reversibility(可逆性)⑤Multiple-variation(多样性)Chapter1.PharmacodynamicsPart4.DrugandReceptor1.C462.Occupationtheory(占领学说):

Affinity(亲和力)Intrinsicactivity(内在活性)

Agonist(激动药),Antagonist(拮抗药)

L+RLR

Part4.DrugandReceptor2.Occupationtheory(占领学说):473.Dynamicsofreceptor(受体动力学):(1)Basicformula:[L][R]KD=[LR]KD表示药物的解离常数

L+RLRE

Part3.MechanismofDrugaction3.Dynamicsofreceptor(受体动力学48[L][R]∵

RT=[R]+[LR],KD=[LR][R]=[RT]–[LR][L]([RT]–[LR])∴KD=[LR][L][RT]=–[L][LR][LR][L]=[RT]KD+[L]——Langmuirfomula(药物反应动力学基本公式)Part3.MechanismofDrugaction[L][R]49Langmuirfomula:

[LR]

[L]=[RT]KD+[L]Let:[LR]

=

r(表示药物与受体结合的%)

[RT]

r[L]=KD1–r

If:

r=50%,∴KD=[L],

pD2=‒logKD

=‒log[L](50%Emax)Part3.MechanismofDrugactionLangmuirfomula:Part3.Mecha50pD2:

表示激动药与受体亲和力的大小.

其含义为引起50%Emax所需激动药摩尔浓度的负对数.pD2=‒

log

[L]Part4.DrugandReceptorlogA(C)pD20Emax50%100%EpD2:表示激动药与受体亲和力的大小.Part4.51x,y,z三个药与受体的亲和力(pD2)不等,但内在活性(Emax)相等;a,b,c三个药与受体的亲和力(pD2)相等,但内在活性(Emax)不等.logClogCpD2(B)(A)pD2xpD2ypD2z00cba50100xyzEE(%)Part4.DrugandReceptorx,y,z三个药与受体的亲和力(pD2)不等,但内在52(2)Agonist(激动药),Partialagonist(部分激动药),andAntagonist(拮抗药):affinitydirecteffectAgonist

+1+Partialagonist

+0~1+*Antagonist

+0–**:intrinsicactivity;*

:weak,partiallyantagonizetheeffectofagonist;**:antagonizingtheeffectofagonist.Part4.DrugandReceptor(2)Agonist(激动药),Partialagoni53(3)Competitiveantagonismandnon-competitiveantagonism:Competitiveantagonist(B)

Non-competitiveantagonist(B’)Part4.DrugandReceptorAgonist(A)Agonist(A)logC0logC0

50%100%EmaxEmaxEmax(3)CompetitiveantagonismandP54Competitiveantagonism

(竞争性拮抗)(1)canbeovercomebyincreasingthedoseof

agonist;(2)D-E

curve

of

agonist

parallelshifttotheright;(3)Emaxof

agonist

isunchanged.pA2

is

the

affinity

parameter

of

com-petitive

antagonist.Part4.DrugandReceptorCompetitiveantagonism

(竞争性拮抗55

Competitiveantagonism(竞争性拮抗)Part4.DrugandReceptorlogC050100Part4.DrugandReceptorlog56Non-competitiveantagonism

(非竞争性拮抗)(1)cannotbecompletelyovercomebyincreasingthedoseof

agonist;(2)D-Ecurveof

agonist

downwardshifttotheright;

(3)Emaxof

agonist

decreases.pA2’

is

theaffinityparameterofnon-competitive

antagonist.Part4.DrugandReceptorNon-competitiveantagonism

(非竞57logC050100Non-competitiveantagonism(非竞争性拮抗)Part4.DrugandReceptorlogC050100Non-competitiveanta58(4)Twomodeltheory(二态模型学说):

R*RR*:

activatedstateR:

restingstatePart4.DrugandReceptor(4)Twomodeltheory(二态模型学说):P59(1)Accordingtoligand:Adreceptor:

1,

2,

1,

2

Achreceptor:M1,M2,M3,M4,M5,

NN,NMDAreceptor:

D1,D2Histaminereceptor:H1,H2Opioidreceptor:

,

,

GABAreceptor,etc.4.Classificationofreceptors:Part4.DrugandReceptor(1)Accordingtoligand:Adr60②G-proteincoupledreceptor:

e.g.Adreceptor,DAreceptor,andMreceptor

①ligandgatedionchannelreceptor:

e.g.N-receptor,GABAreceptor③tyrosinekinasereceptor:

e.g.insulinreceptor④intracellularreceptor:

e.g.corticoidreceptor(2)According

to

mechanism

of

action:Part4.DrugandReceptor②G-proteincoupledreceptor:61①ligandgatedionchannelrece