藥理學教學課件：pharmacokinetics and factors

1.CompartmentmodelOne-compartmentopenmodelTwo-compartmentopenmodel

Centralcompartment:

plasma,liver,heart,brain,lung.Peripheralcompartment:

bone,adiposetissue,muscle.

Part3

BasicprincipleofpharmacokineticsTwocompartmentopenmodel

(i.v.)Distributionphase(αphase)：

bloodconc.decreasedrapidly,indicatedthatdrugenterintocentralcomp.,thenintoperipheralcomp.

α:speedconstantofdistributionphaseEliminationphase(βphase)：

bloodconc.decreasedslowly,indicatedthatdrugeliminatedfromcentralcomp.,drugconc.inperipheralcomp.decresedinproportion.

β:speedconstantofeliminationphase2.Rateprocessandrelativeparameters

KineticTypesdC/dt=-kCnC:drugconcentration,t:timek:constantZero-orderkineticsFirst-orderkineticsMichaelis-MentenrateprocessThecharacteroffirst-orderkinetics:therateofeliminationisdirectlyproportionaltothedrugdose(linearrelationship);thet1/2keepsconstantandhasnothingtodowiththeamountofdruginthebody.Mostdrugareeliminatedwiththiskindofkineticsintheirmetabolismcapacity.“constantpropotionelimination(恒比消除)”

（1）First-orderkinetics(一級動力學)dc/dt=-keCCt=C0e-kett=logC0/Ctx2.303/kewhenCt=1/2C0,t1/2=log2x2.303/ke

=0.301x2.303/ke=0.693/keFirst-orderkinetics(3)Zero-orderkinetics(零級動力學)Thecharacterofzero-orderkinetics:therateofeliminationisconstant,i.e.,independentofdrugdoses;thet1/2ispositivelyrelatestothedrugdoses(non-constant).“constantelimination(恒量消除)”

Whentheconc.ofdrugexceedsthecapacityofthemetabolismofthebody,thedrugiseliminatedwithzero-orderkinetics.Andthenturntothefirst-orderkineticselimination.Zero-orderkineticsZero-orderKinetics

-dC/dt=KC0=-KC0=-KCt=C0–KtC0isinitialdrugconcentration，

Ctisdrugconcentrationattime

t1/2=0.5xC0/K(3)Michaelis-Mentenrateprocess

(米-曼式速率過程)●Toohighconc.,zero-orderkinetics;●

Therapeuticconc.,，first-orderkinetics.Asp.,phenytoin,propranolol,etc.●

t1/2

changesatdifferentconc.Aprocessoccurswhendrugconcentrationisexceedtheabilityofbodyenzymesystem.Changebetweenzero-orderkineticsandfirst-orderkinetics.Half-life(t1/2)isthetimerequiredforanygivendrugconcentrationinplasmatodecreasebyhalf.t?=0.693/ke,ort1/2=0.7×Vd/CL1.eliminationhalf-lifetime(t1/2)

Part4

Parametersofpharmacokineticst1/2意義：（1）確定給藥間隔，等于或接近該藥的t1/2。（2）反映藥物消除快慢和間接反映肝腎功能（3）預測連續(xù)給藥達穩(wěn)態(tài)的時間，4~5個t1/2。而停藥后經(jīng)4~5個t1/2后，血藥濃度約下降了95％。2.ApparentVolumeofDistribution

(VdorV)Vdisthemeasureoftheapparentspaceinthebodyavailabletocontainthedrug.Vdrelatestheamountofdruginthebodytotheconcentrationofdrug(C)inbloodorplasma:Vd(L/kgorL)=D/CD:AmountofdruginbodyIfadrughastheVdof40L,thedrugcoulddistributeinextra-cellularandintracellularfluids,indicatingitswidespreaddistributioninwholebody.VdIftheVdofadrugisabout3-5L,thisdrugmainlydistributeintheblood.IftheVdofadrugisabout10-20L,thedrugdistributeinplasmaandextacellularfluid.3.Areaunderconcentration-timecurveorareaunderthecurve(AUC)AUCindicatestheareaunderthetime-concentrationcurvewhichcanbecalculatedbytrapezoidareamethod.

AUCisanimportantindextoevaluatetheextentofabsorptionofdrugs;isusuallyappliedinthequalityevaluationofpreparation;tocalculatebioavailability.AUC

Time–Concentration(effect)Curve

時–量（效）曲線,藥時曲線ThreeperiodsinthecurveLatentperiod(潛伏期):Theperiodfromadministrationtothetimewhendrugconcentrationinplasmareachedminimumeffectiveconc.(MEC).Thelengthofthisperioddependsontherateofabsorptionanddistributionofthedrug.Persistentperiod(持續(xù)期):

peakconcentration(Cmax),Thehighestconcentrationofthedrugachievedintheplasmafollowingextra-vascularadministration.peaktime(Tmax,Tpeak)Thetimeofthepeakconcentrationistheperiodoftimerequiredtoachievethepeakconcentrationofdrug.ThreeperiodsinthecurveResidualperiod(殘留期):

accumulativeintoxication(累積中毒)4.Bioavailability(F)Fisdefinedasthefractionofunchangeddrugreachingthesystemiccirculationfollowingadministrationbyanyroute(Table).Absolutebioavailability=AUCpo*Dpo/AUCiv*Div×100%Relativebioavailability=AUCt*Dt/AUCr*Dr×100%po,iv,test(t)orreferenceformulation(r).Foradrugadministeredorally,Fmaybelessthan100%forthreemainreasons---incompleteextentofabsorption;first-passelimination;differentdrugpreparation.Bioavailability5.Clearance(CL)Thevolumeofbodyfluidcontainingadrugthatcanbeeliminatedbythebodyinunittime.CL=Vdxke(L·h-1)=0.693xVd/t1/2Renalclearance(CLr)+hepaticclearance

(CLh)=totalplasmaclearanceCssisdefinedasaconcentrationatatimeofnotnetchangeintheamountofdrugwhenrateofinputequalsrateofoutput.

6.Multiple-doseandrationaldosageregimen(1)Steadystateconcentration（Css）(2)maximumsteadystateconc.，Css-maxminimumsteadystateconc.，Css-min(3)TheaverageconcentrationofCss(平均穩(wěn)態(tài)濃度,Css)

Multiple-doseKinetics

(4)DesignandOptimizationofDosageRegimensThemaintenancedose(維持劑量，Dm)

Inmostclinicalsituations,drugsareadministeredinsuchawayastomaintainasteadystateofdruginthebody,ie,justenoughdrugisgivenineachdosetoreplacethedrugeliminatedsincetheprecedingdose.Theloadingdose負荷量,D*

Whenthetimetoreachsteadystateisappreciable,asitisfordrugswithlongt1/2,itmaybedesirabletoadministeraloadingdosethatpromptlyraisestheconc.ofdruginplasmatothetargetconc..A:6mg/d;B:2mg/次，3次/d;C:12mg/首日，6mg/d；D：4mg/次,3次/d,2mg/次，3次/日(1)highorlowplateauconc.

dependonthemagnitudeofdose;(2)theamplitudeoffluctuationdependonthedosingintervals(3)thetimeachievingplateauconc.:

4～5t1/2.Therepeateddosingregimeninthesamedoseandthesameintervals:ReviewquestionsActivetransportandpassivetransport.RelationshipbetweendrugbiotransformationbyCYP450anddruginteraction.Pharmacokineticparameters:definitionandmeaning.Therepeateddosingregimendesign.Chapter4

FactorsAffectingPharmacodynamicsTwoascpets:bodyanddrug;drugincombination.AgeandSexStateofFunctionandDiseaseGeneticFactors(pharmacogenetics)SpeciesvariationPart1

FactorsFromtheBodyBodyaspectsA.agePhysiologicalcharacteristics;compliance.1.Infant:

neonates,infants,children2.Senile(aged):

B.SexWomen:

menses(menstruation),

pregnancy,fetus,breastfeeding.1.Insufficiencyofliverfunction:

metabolize↓,action↑,

actiontime↑,suchaschloramphenicol

drugactivatedinliver,action↓,suchascortisone2.Renalfailure:

drugexcrete↓,t1/2

prolong,cumulativetoxication,suchasgentamicinC.stateoffunctionAspirin,CardiacglycosidesD.stateofdisease3.Malnutrition:

protein↓,ppbr↓,freedruginplasma↑,drugaction↑,ADR↑4.Gastro-intestinaldiseases:drugabsorption↓5.Cardiacinsufficiency:6.OtherstatesofdiseaseD.stateofdiseaseThedoseandthefrequencyofadministrationrequiredtoachieveeffectivetherapeuticbloodandtissuelevelsvaryindifferentpatientsbecauseofindividualdifferencesindrugdistributionandratesofdrugmetabolismandelimination.IndividualVariationE.individualvariationandgeneticfactorsgeneticfactorsandnongeneticvariables:suchasage,sex,liversize,liverfunction,circadianrhythm,bodytemperaturenutritionalandenvironmentalfactors:suchasconcomitantexposuretoinducersorinhibitorsofdrugmetabolism.DeterminedFactors(1)Quantitativedifference:Anindividualpatientishyporeactiveorhyperreactivetoadruginthattheintensityofeffectofagivendoseofdrugisdiminishedorincreasedincomparisontotheeffectseeninmostindividuals.IndividualVariationWithsomedrugs,theintensityofresponsetoagivendosemaychangeduringthecourseoftherapy;inthesecases,responsivenessusuallydecreasesasaconsequenceofcontinueddrugadministration,producingastateofrelativetolerancetothedrug'seffects.ToleranceWhenresponsivenessdiminishesrapidlyafteradministrationofadrug,theresponseissaidtobesubjecttotachyphylaxis.tachyphylaxis

(快速耐受性)Somepeopleresponsetodrugswithhighsensitivityevenwithsmalldoseadministration.Also,Thetermusuallyreferstoallergicorotherimmunologicresponsestodrugs.Hypersensitivity(2)Quantaldifference:

allergy(hypersensitivereactionoranaphylaxis)IndividualVariation(3)geneticdifferencesidiosyncraticreaction

Extensive(rapid)metabolizer(EM)Poor(slow)metabolizer(PM)IsoniazidgeneticabnormityinmetabolismDrugabnormalreactionrelatedtogenetics：

drugabnormalabsorptionanddistribution(intrinsicfactorandVitB;)

drugabnormalmetabolism(acetylaseandIsoniazid)

geneticmethemoglobinemia(methemoglobinreductaseandsulfonamides)

druginducedhemolyticanemia(G-6-PDandprimaquine)F.Speciesvariation1.Animalspeciesvariation:2.Racial/ethnicdifference:B.Preparation(dosageform):

Part2FactorsFromtheDrugPharmaceuticalequivalanceBioequivalanceslowreleaseformulation(f.)緩釋制劑

controlledreleasef.控釋制劑

extendedreleasef.延遲釋放劑

sustainedreleasef.持續(xù)釋放劑

transdermalpatch透皮貼劑A.dosage(dose):

sedative-hypnoticsD.Timeandintervalofadministeringdrug:circadianrhythm,t1/2,postantibioticeffect(PAE),cumulativeintoxication.Beforemealsoraftermeals;beforesleep,etc.C.theroutesofdrugadministration:iv

inhalation

sublingual

im

is

peros

transdermal;Differentaction:magnesiumsulfateE.Repetitionofdrugadministration:1.Tolerance:

acutetolerance(tachyphylaxis),crosstolerance(交叉耐受性).2.drugresistance:

Inthechemotherapy,theresponseofpathogenandtumorcellstodrugsdecreasesbecauseofgenemutationofpathogen.

3.drugdependence,withdrawalsymptoms

/syndrome:narcoticsorpsychotropicsubstances.WHO定義：藥物依賴性是藥物與機體相互作用所造成的一種精神狀態(tài)，有時也包括身體狀態(tài)，它表現(xiàn)出一種強迫要連續(xù)或定期用該藥的行為和其他反應，為的是要去感受它的精神效應，或是為了避免由于斷藥所引起的不舒適?？梢园l(fā)生或不發(fā)生耐受性。同一個人可以對一種以上藥物產(chǎn)生依賴性.(2)psychicdependence(psychologicaldependence):habituation:nicotine,alcoholdrugdependencephysicaldependence(physiologicaldependence):addiction,euphoria(欣快),withdrawalsyndrome.b.Psychologicaldependence用藥后使人產(chǎn)生一種對藥物欣快感的渴求，這種精神上不能自制的強烈欲望驅(qū)使濫用者周期性或連續(xù)地用藥。a.Physicaldependence大多數(shù)具有依賴性特征的藥物經(jīng)過反復使用所造成的一種適應狀態(tài)，用藥者一旦停藥，將發(fā)生一系列生理功能紊亂，稱戒斷癥狀。

Papaversomniferum

Isit

abeautifulflowerorapoison?LifeisMostImportant!TheWorldissobeautiful.Pleaseloveyourself,loveyourfamilyandthesociety.Nevertotouchthedrugs!F.druginteractionDruginteraction

兩種或以上藥物在體內(nèi)發(fā)生的藥效學或藥動學的作用而影響藥物療效或產(chǎn)生不良反應。1.Pharmacokineticaspect(1)Factorsaffectingabsorption:changeofPH,chelate,emptyandperistalsisofgastrointestinaltract

(3)Factorsaffectingmetabolism:①acceleratingmetabolism:induc