藥物效應(yīng)動(dòng)力學(xué)-陳季強(qiáng)課件

浙江大學(xué)醫(yī)學(xué)院陳季強(qiáng)教授Email:chenjq@2010-2011學(xué)年冬學(xué)期

SectionⅥ.PharmacologicalBasisofTherapeutics藥物治療學(xué)基礎(chǔ)(治療學(xué)的藥理學(xué)基礎(chǔ))IntroductionofBMS

浙江大學(xué)醫(yī)學(xué)院陳季強(qiáng)教授2010-2011學(xué)年冬學(xué)期1Chapter2.PharmacokineticsChapter3.FactorsinfluencingeffectofdrugChapter4.Anti-neoplasticsChapter1.PharmacodynamicsBasicConceptofPharmacologySectionⅥ.PharmacologicalBasisofTherapeuticsContentsChapter2.PharmacokineticsCha2SectionⅥ.PharmacologicalBasisofTherapeuticsDrugsBiologicalorganisms

1.Whatispharmacology?BasicConceptofPharmacologyPharmacodynamics

(藥物效應(yīng)動(dòng)力學(xué),

藥效學(xué))Pharmacokinetics(藥物代謝動(dòng)力學(xué),藥動(dòng)學(xué))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(生物轉(zhuǎn)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(臨床前研究):

Pharmacodynamics;

Pharmacokinetics;

Toxicology.

●Clinicaltrials(臨床試驗(yàn)):(2)Processofnewdrugstudy:BasicConceptofPharmacology●Preclinicalstudy(臨床前研究):9▲PhaseⅠ(一期臨床):

20-30位健康志愿者;

▲PhaseⅡ(二期臨床):

≥

100對(duì)病人;

▲PhaseⅢ(三期臨床):

≥300例病人;

▲PhaseⅣ(四期臨床):

≥

2000例病人,

也稱為售后調(diào)查(post-surveillance).

multicenter(多中心):

至少三家醫(yī)院

doublecontrol(雙對(duì)照):

陰性和陽(yáng)性對(duì)照

doubleblind(雙盲):

病人和醫(yī)生●Clinicaltrials(臨床試驗(yàn)):BasicConceptofPharmacology▲PhaseⅠ(一期臨床):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(毒性反應(yīng)):

●Acutetoxicity;

●Chronictoxicity;

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

●Specialtoxicity:▲Teratogenesis(致畸)

②Toxicreaction(毒性反應(yīng)):Adversedrugreaction(ADR)Part1.Basicactionofdrug●Specialtoxicity:▲Teratogen17(2)Adversedrugreaction(ADR):①Sidereaction(副作用);②Toxicreaction(毒性反應(yīng));③Aftereffect(后遺效應(yīng));

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

tCRelationshipbetweenADRsandCp:MTCMEC①Sidereaction②Toxicreaction③AftereffectPart1.Basicactionofdrug

tCRelationshipbetweenADR19

①Sidereaction(副作用);

②Toxicreaction(毒性反應(yīng));

③Aftereffect(后遺效應(yīng));

(2)Adversedrugreaction(ADR):④Allergicreaction(變態(tài)反應(yīng));⑤Idiosyncrasy(特異質(zhì)反應(yīng)).●Drug-induceddisease(藥源性疾病)Part1.Basicactionofdrug①Sidereaction(副作用);②Toxicr20Let’stakearestChapter1.PharmacodynamicsLet’stakearestChapter1.Ph212.Efficacy(效能)&Potency(效價(jià)強(qiáng)度);1.Dose-effectrelationships;3.Individualvariability(個(gè)體差異);4.Safetyevaluation(安全性評(píng)價(jià)).Part2.Dose-effectrelationshipsChapter1.Pharmacodynamics2.Efficacy(效能)&Potency(效價(jià)強(qiáng)度221.Doseeffectrelationships:

(1)Dose:Part2.Dose-effectrelationshipsMaximaldose(極量)Dose0LethaldoseToxicdoseEffectivedoseTherapeuticdoseInvaliddoseMinimaltoxicdoseMinimallethaldoseMinimaleffectivedose(thresholddose)EEmax1.Doseeffectrelationships:P23(2)Response(effect):①Gradedresponse(量反應(yīng))②Quantalresponse(質(zhì)反應(yīng))——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(效應(yīng)強(qiáng)度):Efficacy表示藥物所能達(dá)到最大效應(yīng)的能力;

Potency表示達(dá)到相同效應(yīng)時(shí)藥物劑量大小.logD0ECBADPart2.Dose-effectrelationships2.Efficacy(效能)&Potency(效應(yīng)強(qiáng)度29幾種常用利尿藥的作用及最大效應(yīng)比較Part2.Dose-effectrelationships幾種常用利尿藥的作用及最大效應(yīng)比較Part2.Dose-30

3.Individualvariability(個(gè)體差異):EMean(平均值)

Standarddifference

(標(biāo)準(zhǔn)差,SD)D0Part2.Dose-effectrelationships

31Part2.Dose-effectrelationshipsQuantalresponseD-Ecurve(質(zhì)反應(yīng)量效曲線)4.Safetyevaluation(安全性評(píng)價(jià)):Part2.Dose-effectrelationsh32Part2.Dose-effectrelationshipsTherapeuticindex(TI,治療指數(shù))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.作用于受體:Part3.MechanismofDrugactionSee:Part4.DrugandRe36

有些藥物的化學(xué)結(jié)構(gòu)與正常代謝物非常相似,可以以假亂真地?fù)饺氲酱x過程中,但是,假的總歸是假的,不能發(fā)揮正常物質(zhì)的作用,實(shí)際上會(huì)導(dǎo)致后續(xù)代謝的抑制或阻斷了后續(xù)代謝過程,稱為偽品摻入(counterfeitincorporation),也稱為抗代謝藥(antimetabolite).

例如抗腫瘤藥5-氟尿嘧啶的結(jié)構(gòu)與尿嘧啶極為相似,可以摻入癌細(xì)胞的DNA及RNA中,干擾腫瘤細(xì)胞的核酸及蛋白質(zhì)合成而發(fā)揮抗癌作用.

2.參與或干擾細(xì)胞代謝:Part3.MechanismofDrugaction有些藥物的化學(xué)結(jié)構(gòu)與正常代謝物非常相似,可以以假37

很多無(wú)機(jī)離子、代謝產(chǎn)物、神經(jīng)遞質(zhì)、激素等在體內(nèi)通過載體(carrier)進(jìn)行主動(dòng)轉(zhuǎn)運(yùn),有些藥物化學(xué)結(jié)構(gòu)與體內(nèi)的上述物質(zhì)化學(xué)結(jié)構(gòu)很相似,可以影響或干擾載體對(duì)上述物質(zhì)的轉(zhuǎn)運(yùn)而產(chǎn)生藥理作用.例如,丙磺舒競(jìng)爭(zhēng)性抑制腎小管對(duì)弱酸性代謝產(chǎn)物的主動(dòng)轉(zhuǎn)運(yùn)載體(有機(jī)酸轉(zhuǎn)運(yùn)體),可抑制原尿中尿酸的再吸收,用于防治痛風(fēng);又如利尿藥呋塞米及氫氯噻嗪可抑制腎小管對(duì)鈉、鉀、及氯離子再吸收,而發(fā)揮利尿作用.

3.影響生理物質(zhì)轉(zhuǎn)運(yùn):Part3.MechanismofDrugaction很多無(wú)機(jī)離子、代謝產(chǎn)物、神經(jīng)遞質(zhì)、激素等在體內(nèi)通過38

①直接作用于酶:

例如奧美拉唑通過抑制胃粘膜壁細(xì)胞膜上的H+-K+-ATP酶(質(zhì)子泵)從而抑制胃酸分泌;卡托普利抑制血管緊張素Ⅰ轉(zhuǎn)換酶而治療高血壓;阿司匹林抑制前列腺素合成酶而治療疼痛和炎癥,等.

②影響肝藥酶活性:如苯巴比妥等誘導(dǎo)肝藥酶活性增加而加速另外一些藥物的代謝;氯霉素等能抑制肝藥酶而減慢其他藥物的代謝,等.

4.影響酶的活性而產(chǎn)生作用:Part3.MechanismofDrugaction①直接作用于酶:例如奧美拉唑通過抑制胃粘膜壁細(xì)胞膜上的395.作用于細(xì)胞膜的離子通道:主要的離子通道有Ca2+、K+、Na+及Cl-通道,它們調(diào)節(jié)細(xì)胞膜內(nèi)外無(wú)機(jī)離子的分布.通道的開放或關(guān)閉影響細(xì)胞內(nèi)外無(wú)機(jī)離子的運(yùn)轉(zhuǎn),能迅速改變細(xì)胞功能.有些離子通道是藥物直接作用的靶點(diǎn),藥物可改變離子通道的構(gòu)象,使通道開放或關(guān)閉.例如,阿米洛利阻斷腎小管鈉通道,硝苯地平阻斷鈣通道,吡那地爾激活血管平滑肌鉀通道等.

Part3.MechanismofDrugaction5.作用于細(xì)胞膜的離子通道:Part3.Mechani406.影響核酸代謝:許多藥物通過直接影響核酸代謝而發(fā)揮藥理效應(yīng).如抗癌藥5-氟尿嘧啶通過阻斷DNA的合成,抑制腫瘤細(xì)胞生長(zhǎng);

磺胺類抗菌藥通過抑制細(xì)菌體內(nèi)葉酸的代謝,干擾核酸的合成;

喹諾酮類抑制DNA回旋酶,發(fā)揮殺菌作用;

甾體激素與甲狀腺激素均通過作用于細(xì)胞內(nèi)受體而影響核酸的代謝等.Part3.MechanismofDrugaction6.影響核酸代謝:Part3.Mechanismof41

正常免疫反應(yīng)是機(jī)體消除入侵微生物和自身變異細(xì)胞的重要機(jī)制.某些藥物本身就是免疫系統(tǒng)中的抗體(如丙種球蛋白),或者是抗原(如疫苗).

免疫抑制藥(如環(huán)孢素),可用于抑制器官移植后的排異反應(yīng)、自身免疫性疾病及Rh陽(yáng)性新生兒溶血病等.

免疫增強(qiáng)藥多作為輔助治療藥物,用于免疫缺陷性疾病,如艾滋病、慢性感染及癌癥等.7.影響免疫機(jī)制:Part3.MechanismofDrugaction正常免疫反應(yīng)是機(jī)體消除入侵微生物和自身變異細(xì)胞的42有一些藥沒有特定的作用目標(biāo),其作用也稱為非特異性作用.消毒防腐藥(如石炭酸、福爾馬林等)對(duì)蛋白質(zhì)有變性作用,因而只用于體外殺菌或防腐,不能內(nèi)用;有一些麻醉性催眠藥(包括乙醇)能干擾細(xì)胞膜脂質(zhì)結(jié)構(gòu),因此對(duì)各種細(xì)胞均有抑制作用,進(jìn)入體內(nèi)后,只是中樞神經(jīng)系統(tǒng)對(duì)其相對(duì)比較敏感.8.非特異性作用:Part3.MechanismofDrugaction有一些藥沒有特定的作用目標(biāo),其作用也稱為非特異43有些藥物通過簡(jiǎn)單的物理化學(xué)作用,如酸堿反應(yīng)、滲透壓改變、氧化還原(自由基清除)等,改變機(jī)體內(nèi)環(huán)境.還有些藥物是補(bǔ)充機(jī)體所缺乏的物質(zhì),例如維生素、激素、多種微量元素等.

9.通過理化反應(yīng)發(fā)揮作用:

Part3.MechanismofDrugaction有些藥物通過簡(jiǎn)單的物理化學(xué)作用,如酸堿反應(yīng)、滲44Let’stakearestChapter1.PharmacodynamicsLet’stakearestChapter1.Ph45Part4.DrugandReceptor1.Conceptofreceptor:(1)Receptor(受體)andligand(配體)(2)Characteristicsofreceptor:①Sensitivity(靈敏性)②Specificity(特異性)③Saturability(飽和性)④Reversibility(可逆性)⑤Multiple-variation(多樣性)Chapter1.PharmacodynamicsPart4.DrugandReceptor1.C462.Occupationtheory(占領(lǐng)學(xué)說):

Affinity(親和力)Intrinsicactivity(內(nèi)在活性)

Agonist(激動(dòng)藥),Antagonist(拮抗藥)

L+RLR

Part4.DrugandReceptor2.Occupationtheory(占領(lǐng)學(xué)說):473.Dynamicsofreceptor(受體動(dòng)力學(xué)):(1)Basicformula:[L][R]KD=[LR]KD表示藥物的解離常數(shù)

L+RLRE

Part3.MechanismofDrugaction3.Dynamicsofreceptor(受體動(dòng)力學(xué)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(藥物反應(yīng)動(dòng)力學(xué)基本公式)Part3.MechanismofDrugaction[L][R]49Langmuirfomula:

[LR]

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

=

r(表示藥物與受體結(jié)合的%)

[RT]

r[L]=KD1–r

If:

r=50%,∴KD=[L],

pD2=?logKD

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

表示激動(dòng)藥與受體親和力的大小.

其含義為引起50%Emax所需激動(dòng)藥摩爾濃度的負(fù)對(duì)數(shù).pD2=?

log

[L]Part4.DrugandReceptorlogA(C)pD20Emax50%100%EpD2:表示激動(dòng)藥與受體親和力的大小.Part4.51x,y,z三個(gè)藥與受體的親和力(pD2)不等,但內(nèi)在活性(Emax)相等;a,b,c三個(gè)藥與受體的親和力(pD2)相等,但內(nèi)在活性(Emax)不等.logClogCpD2(B)(A)pD2xpD2ypD2z00cba50100xyzEE(%)Part4.DrugandReceptorx,y,z三個(gè)藥與受體的親和力(pD2)不等,但內(nèi)在52(2)Agonist(激動(dòng)藥),Partialagonist(部分激動(dòng)藥),andAntagonist(拮抗藥):affinitydirecteffectAgonist

+1+Partialagonist

+0~1+*Antagonist

+0–**:intrinsicactivity;*

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

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

50%100%EmaxEmaxEmax(3)CompetitiveantagonismandP54Competitiveantagonism

(競(jìng)爭(zhēng)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

(競(jìng)爭(zhēng)性拮抗55

Competitiveantagonism(競(jìng)爭(zhēng)性拮抗)Part4.DrugandReceptorlogC050100Part4.DrugandReceptorlog56Non-competitiveantagonism

(非競(jìng)爭(zhēng)性拮抗)(1)cannotbecompletelyovercomebyincreasingthedoseof

agonist;(2)D-Ecurveof

agonist

downwardshifttotheright;

(3)Emaxof

agonist

decreases.pA2’

is

theaffinityparameterofnon-competitive

antagonist.Part4.DrugandReceptorNon-competitiveantagonism

(非競(jìng)57logC050100Non-competitiveantagonism(非競(jìng)爭(zhēng)性拮抗)Part4.DrugandReceptorlogC050100Non-competitiveanta58(4)Twomodeltheory(二態(tài)模型學(xué)說):

R*RR*:

activatedstateR:

restingstatePart4.DrugandReceptor(4)Twomodeltheory(二態(tài)模型學(xué)說):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