2第二章藥動(dòng)學(xué)Chapter2機(jī)體對(duì)藥物的作用——藥動(dòng)學(xué)2第二章藥動(dòng)學(xué)Object掌握藥物的體內(nèi)過程及其影響因素，

掌握血漿半衰期、生物利用度、零級(jí)動(dòng)力學(xué)、一級(jí)動(dòng)力學(xué)的概念及意義。熟悉藥動(dòng)學(xué)概念，藥物的轉(zhuǎn)運(yùn)方式，時(shí)量關(guān)系和時(shí)效關(guān)系，血藥穩(wěn)態(tài)濃度的實(shí)現(xiàn)及維持。了解時(shí)量曲線的有關(guān)參數(shù)及意義。2第二章藥動(dòng)學(xué)pharmacokinetics

include:transportation(轉(zhuǎn)運(yùn))transformation

(轉(zhuǎn)化)Absorption

(吸收)Distribution(分布)Excretion

(排泄)Biotransformation(生物轉(zhuǎn)化)

orMetabolism

(代謝)2第二章藥動(dòng)學(xué)drugBlood

Freedrug

Bounddrugmetabolites

distributionexcretionbiotransformationtheprocessofdruginthebody2第二章藥動(dòng)學(xué)biomembranestructure2第二章藥動(dòng)學(xué)§1Transmembranetransportationofdrug

Threetypes:①filtration（濾過）②

simplediffusion

(簡(jiǎn)單擴(kuò)散)③

carrier-madiatedtransport

(載體轉(zhuǎn)運(yùn))2第二章藥動(dòng)學(xué)2第二章藥動(dòng)學(xué)I.Passivetransport

characteristicsofsimplediffusion:1.Dependonconcentrationgradient

(濃度梯度)2.Neednotcarrier(載體)andenergy3.lieonlipid-solubility(脂溶性)ofdrugsimplediffusionfiltration2第二章藥動(dòng)學(xué)MostdrugsWeakacids(弱酸性)Weakbases(弱堿性)Amphoteric

(兩性的)Forexample:PenicillinGsodium

(青霉素G鈉)Atropinesulfate

(硫酸阿托品)2第二章藥動(dòng)學(xué)PenicillinGsodium

(青霉素G鈉)

penicillin-+Na+------water-solubility

ionization

(解離型)∴

Un-ionization

(非解離型)------lipo-solubility

Iontrapping(離子障)解離型藥物極性高(水溶性大),不易通過細(xì)胞膜的脂質(zhì)層的現(xiàn)象.2第二章藥動(dòng)學(xué)Un-ionizationdegree

dependon:

pKa(解離指數(shù))ofthedrugpHoftheenvironment

What’spKaofdrug?弱酸性或弱堿性藥50%解離時(shí)溶液的pH.各藥有其固定的pKa.2第二章藥動(dòng)學(xué)bytheHenderson-Hasselbalchequation:

解離常數(shù)解離指數(shù)2第二章藥動(dòng)學(xué)Forexample:非解離的多,易簡(jiǎn)單擴(kuò)散解離的多,難通過離子障酸酸堿堿促吸收,酸堿堿酸促排泄2第二章藥動(dòng)學(xué)Clinicalsignificance:Overdosagetoxicosis（過量中毒）ofweakacids------usebasicdrugtobasify（堿化）bloodorurine→ionization↑，absorption↓，excretion↑.Forexample:

phenobarbital

（苯巴比妥）

toxicosis

usesodiumbicarbonate

（碳酸氫鈉）iv.gtt.2第二章藥動(dòng)學(xué)II.carrier-mediatedtransportcharacteristicsofactivetransport:

1.conversesconcentrationgradient

2.Needcarrier(載體)andenergy

3.

Saturable(飽和性)

4.Competitiveinhibitionactivetransportfacilitateddiffusion(易化擴(kuò)散)2第二章藥動(dòng)學(xué)characteristicsoffacilitateddiffusion:1.

Obedientsconcentrationgradient(順濃度）

2.Needcarrier

3.

Saturable

4.Competitiveinhibition2第二章藥動(dòng)學(xué)§2Theprocessofdruginthebody

1.AbsorptionWhat’sabsorption?Aprocessofthedrugtraversethecellularmembraneandgetintothecirculation.2第二章藥動(dòng)學(xué)Routsofadministration

1.Gastrointestinaltract(胃腸道)

舌下直腸口服血液循環(huán)肝門V首關(guān)消除2第二章藥動(dòng)學(xué)Firstpasselimination

(首關(guān)消除)藥物經(jīng)胃腸道吸收后第一次通過肝臟被代謝一部分,使進(jìn)入血循環(huán)的有效藥量減少,此作用稱～.Toavoidfirstpasselimination:

sublingual(舌下)

administration

e.gnitroglycerin（硝酸甘油，心絞痛用藥）rectally(直腸)administration

e.gaminophylline

（氨茶堿，平喘藥）2第二章藥動(dòng)學(xué)2.Parenteraladministration(胃腸道外)1)Inhalation(吸入)

2)Localadministration

includeskin,ear,noseoreyedrops……s3)Injection

Intravenous(iv.靜注)Intramuscular(im.肌注)Subcutaneous(sc.皮下)

2第二章藥動(dòng)學(xué)2第二章藥動(dòng)學(xué)2.Distribution

What’sthedistribution? Atransportingprocessofdrugtoallorgansthroughcirculation.2第二章藥動(dòng)學(xué)Factoraffectingdistribution:①Plasmaproteinbindingratio②Bloodflow③combinewithtissue④pKaandpH⑤

Barrier2第二章藥動(dòng)學(xué)D+PDP藥理活性暫時(shí)消失,不能轉(zhuǎn)運(yùn)和轉(zhuǎn)化,存在飽和及競(jìng)爭(zhēng)置換現(xiàn)象.Forexample:A.Warfarin

(華法林)99%bound1%freeB.phenylbutazone

(保泰松)

98%bound2%freeIfcombine

AwithBCompetitivereplacementWarfarinfree

Haemorrhage

(出血)

2第二章藥動(dòng)學(xué)2第二章藥動(dòng)學(xué)distributionandredistribution(再分布)thiopentaliv.先到腦內(nèi)發(fā)揮作用,由于脂溶性極大,很快從腦內(nèi)轉(zhuǎn)移至脂肪組織中貯存的現(xiàn)象。2第二章藥動(dòng)學(xué)combinewithtissueSignificance：

★

relationshipwiththerapeuticactione.giodin(碘)

-----thyroid(甲狀腺)

chloroquine-----infectiveRBC★

relationshipwithadversereaction

e.ggentamicin

-----deaf(耳聾)

2第二章藥動(dòng)學(xué)extracellularfluid

pH=7.4endocellularfluid

pH=7.0WeakacidUn-ionization↑ionization∴分布平衡時(shí),弱酸性藥細(xì)胞外液的濃度﹥細(xì)胞內(nèi)液.2第二章藥動(dòng)學(xué)Barrier(屏障)

phenomenon

Blood-brainbarrier（血腦屏障）BBBcharactersSelectivity2.lipophiliceasycross3.Inflammation(炎癥)

----permeability(通透性)↑2第二章藥動(dòng)學(xué)Placentabarrier（胎盤屏障）Thepermeabilityofplacentabarrierisnotespecial.Note!Takemedicineinthegestation（妊娠期）.otherbarriers2第二章藥動(dòng)學(xué)2第二章藥動(dòng)學(xué)3.Biotransformation

(metabolism)

What`sthebiotransformationofdrug?Thepharmacologicalactivityofdrugischangedbyenzymaticsystem.Siteofmetabolismthemajorsite:liver

theothersite:kidney,lung……2第二章藥動(dòng)學(xué)PhasesofmetabolicreactionsPhase1

Oxidation(氧化)reduction(還原)hydrolysis(水解)

Conjugation（結(jié)合）Phase22第二章藥動(dòng)學(xué)Enzymesforbiotransformation:Hepaticmicrosomaldrug-metabolizingenzymesystem（肝微粒體藥物代謝酶）OrCytochromesP-450（CYP450,細(xì)胞色素P450）(hepaticmixed-functionoxydasesystem，肝混合功能氧化酶系統(tǒng))2第二章藥動(dòng)學(xué)Characteristicsoftheenzymes

⑴mixedfunction⑵

lowspecificity

⑶Individualvariation(個(gè)體差異)

obvious⑷Inducibleandsuppressible

(誘導(dǎo))(抑制)⑸Doubleprobability

(activationandinactivation)2第二章藥動(dòng)學(xué)Enzymerevulsant

(藥酶誘導(dǎo)劑)

somedrugsactivityofcertainenzymemetabolism(ownorotherdrug).

e.gphenobarbital

(苯巴比妥)……

Enzymeinhibitor

(藥酶抑制劑)somedrugsactivityofcertainenzymemetabolismoftheotherdrug.

e.gcimetidine

(西米替丁)……

2第二章藥動(dòng)學(xué)+藥酶誘導(dǎo)劑+藥酶抑制劑2第二章藥動(dòng)學(xué)4.Excretion

What`sexcretion?Aprocessofdrugsaredischargedoutofthebody.

Excretoryroutes:

themajor:

renal(腎)

,biliary（膽）

theothers:

lung（肺）,sweat（汗）,saliva（唾液）,milk（乳汁）……2第二章藥動(dòng)學(xué)①RenalexcretionFiltrationsecretion(Activetransport)renaltubulereabsorption(passivetransport)2第二章藥動(dòng)學(xué)Clinicalsignificance:

Renalfunction↓→excretion↓→drugcumulation

(蓄積)↑;originalform(原形)ofanti-infectivedrugexcretionbythekidney----curetheurinaryinfection(泌尿道感染).2第二章藥動(dòng)學(xué)②Biliaryexcretion（膽汁）Activesecretorychannelsduration↑膽囊門靜脈肝腸循環(huán)2第二章藥動(dòng)學(xué)otherslung----inhalationanesthesiaalcoholmilk----newbornsweatsalivatears2第二章藥動(dòng)學(xué)§3Compartmentmodel

(房室模型)Singlecompartmentopenmodel2第二章藥動(dòng)學(xué)Twocompartmentopenmodel2第二章藥動(dòng)學(xué)§4Eliminationkineticsofdrugs2第二章藥動(dòng)學(xué)§4Eliminationkineticsofdrugs2第二章藥動(dòng)學(xué)§4EliminationkineticsofdrugsDifferentialequationforelimination

(微分方程式)消除速率常數(shù)n=0zero-ordern=1firstorder藥量2第二章藥動(dòng)學(xué)I.Firstordereliminationkinetics

(一級(jí)消除動(dòng)力學(xué))單位時(shí)間內(nèi)藥物消除的比例是恒定的.characteristics1.消除速度與血藥濃度成正比;2.消除半衰期不變.(t1/2=0.693/ke)2第二章藥動(dòng)學(xué)T1/21232第二章藥動(dòng)學(xué)Halflife(半衰期,

t?)

血漿藥物濃度下降一半所需要的時(shí)間.2第二章藥動(dòng)學(xué)II.zeroordereliminationkinetics

(零級(jí)消除動(dòng)力學(xué))單位時(shí)間內(nèi)藥物消除的量是恒定的.characteristics1.消除速度與血藥濃度無關(guān);2.消除半衰期可變.(t1/2=0.5Co/ko)2第二章藥動(dòng)學(xué)III.mixedeliminationkinetics

(混合消除動(dòng)力學(xué))在高濃度時(shí)按零級(jí)動(dòng)力學(xué)消除,當(dāng)血藥濃度低到某水平時(shí)則轉(zhuǎn)為一級(jí)動(dòng)力學(xué)消除.e.g

aspirin……<1gt1/2

2~3h>1gt1/2

15~30h2第二章藥動(dòng)學(xué)§5Dose-timerelationshipof

druginthebodyTime-concentrationcurveofasingledoseAUCiv.2第二章藥動(dòng)學(xué)TmaxAUCpo.口服2第二章藥動(dòng)學(xué)

血藥濃度波動(dòng)性大不能維持有效血藥濃度C-Tcurveofmultiple-dose

①Dosinginterval(給藥間隔

)

toolong122第二章藥動(dòng)學(xué)②Dosinginterval()=1t1/2Steadystateconcentration(Css)

血漿穩(wěn)態(tài)濃度

按t1/2間隔等量連續(xù)給藥,經(jīng)4~5個(gè)t1/2即可達(dá)到穩(wěn)態(tài)血濃(亦稱坪值),此時(shí)給藥速度與消除速度相等.2第二章藥動(dòng)學(xué)2第二章藥動(dòng)學(xué)§6Importantparametersofpharmacokinetics1.

Halflife(t?)

血漿藥物濃度下降一半所需要的時(shí)間.Clinicalsignificance1).確定臨床給藥間隔時(shí)間;2).計(jì)算單次用藥,體內(nèi)藥物基本消除的時(shí)間;3).計(jì)算連續(xù)用藥達(dá)到Css時(shí)間;4).反映肝腎功能.2第二章藥動(dòng)學(xué)2.Bioavailability

（生物利用度）藥物實(shí)際吸收量占給藥量的比值。Clinicalsignificance1）反映藥物吸收的量；2）反映藥物吸收的速度;3）評(píng)價(jià)藥物制劑的質(zhì)量指標(biāo)之一。2第二章藥動(dòng)學(xué)2第二章藥動(dòng)學(xué)Bioavailability（F）Absolute（絕對(duì)）

~Relative

（相對(duì)）~2第二章藥動(dòng)學(xué)同一藥物,同等劑量,不同給藥途徑不同藥物,等效劑量,相同的給藥途徑2第二章藥動(dòng)學(xué)Bioequivalence

（生物等效性）

兩個(gè)藥學(xué)等同的藥品，若它們所含的有效成分的生物利用度無顯著差別，稱為~。四種地高辛片劑（不同藥廠、同劑量）F比較2第二章藥動(dòng)學(xué)Apparentvolumeofdistribution

（Vd，表觀分布容積）體內(nèi)藥量與分布平衡時(shí)的血藥濃度的比值。Clinicalsignificance1、根據(jù)Vd計(jì)算產(chǎn)生預(yù)期藥濃所需的藥物劑量。2、根據(jù)Vd