周宏灏-院士-(封山之作)-药理学总论-PPT-2

1．SimplediffusionPassiveprocess,concentrationgradientdependent,requiresnoenergyMoleculesmovefromareaofhightolowconcentrationRateofdiffusionisproportionalto:lipidsolubility,thegreaterthelipidsolubilitythefastertherateofdiffusionpKaofmoleculesConcentrationdifferencebetweenbothsidesDiffusionthroughlipidbi-layerAcidicdrug: HAH++A

(ionized)

Basicdrug: BH+

H++B(unionized)IontrappingCellmembranesarelesspermeabletoionizedcompoundsH+HAA-HAH+A-BBH+H+H+BBH+Ka=

[H+][A][HA]pKa=pH-log

[A][HA][A][HA]10pH-pKa=Acidicdrug：IonizationdependsonpHandpKaBasicdrug：pKa-pH

A+H+HAHAH++A[A][HA]10pH-pKa=Plasma：pH=7Stomach：pH=411102

105CromolynSodium(色甘酸钠)pKa=2,Acidic=107-2

=105[A][HA]10pH-pKa==104-2

=102TotalTotalExample101100001Smallmoleculesdiffusionthroughaqueouschannels2.FiltrationWatersolubilitySmallmolecular

DiameterofaqueouschannelsinCapillarywall:4-8Å（=1010m)Onlyforwater,ureafiltration>100notpermeableIntracellularcleft:40Å,allsoluteinbloodarepermeableexceptproteinIntracellularcleftIntracellularcleft:bighole3.Carrier-mediatedtransportActivetransportAgainstconcentrationgradientRequirescouplingofenergy(hydrolysisofATP)FacilitateddiffusionAlongconcentrationgradientRequiresnoenergyRequiringcarrier

StructurespecificSaturable(functionalproteinmoleculesarelimited)CompetitiveinhibitionDispositionofdruginthebodyAbsorption,Distribution,MetabolismandExcretionSection2Ch.2TransferofadrugfromitssiteofadministrationtothebloodstreamOralingestionMajorsite:Longertransittime=3hours

LargersurfaceareaofvillusAbundantbloodflowpH5-8goodformostofdrugsintestine1．AbsorptionOralcavity 0.5-l.0m2Stomach 0.1-0.2m2

Smallintestine100m2Largeintestine0.04-0.07m2Rectum 0.02m2Fick’sLawofDiffusionFlux(moleculesperunittime)＝(C1－C2)×Area×PermeabilitycoefficientThicknessFirstpasseliminationMetabolismSiteofactionIntestinewallPortalveinBeforedrugreachesthesystemiccirculation,thedrugcanbemetabolizedintheliverorintestine.StoolPassivediffusion＋

FiltrationRapidandcompleteabsorptionIntramuscular&subcutaneousinjectionInhalationGaseousorvolatilesubstancesandaerosolcanreachtheabsorptivesiteofthelung.Highlyavailableareaofabsorption(alveolusarea=100-200m2;pulmonarycapillaryarea=80m2Rapid,nofirstpasseffect,directlyreachdesiredsiteofaction(asthma,COPD)TransdermalTransdermalskinpatches-LipidsolubledrugscanbeabsorptedviaskinNifedipineGlyceroltrinitrateProcessbywhichadrugreversiblyleaveshebloodstreamandenterstheinterstitialorcellularfluidsofthebody.2．DistributionFreedrugBoundDrugMetabolitesReceptorFreeboundTissueFreeboundExcretionBloodPhysicalandchemicalcharacteristicsofthedrug(lipidtowaterpartitioncoefficient)CardiacoutputCapillarypermeabilityinvarioustissuesLipidcontentofthetissueBindingtoplasmaproteinandtissueFactorsthataffectdrugdistributionPlasmaproteinbindingReversibleequilibriumSaturableDP:Non-permeableNonspecific&competitive[DP][PT]KD+[D][D]D＋PDPKDPlasmaproteinsAlbumin:Weakacidsalpha-acidglycoprotein:WeakbasesEffectsofplasmaproteinbindingFreefraction:active,excreted,metabolizedthemorebinding,thelessactivedrugthemorebinding,thelessexcretedandmetabolized:

“longerhalf-life”DrugA:1000molecules99.9%bound

1moleculesfree100-foldincreaseinfreepharmacologicallyactiveconcentrationatsiteofaction. Effective

TOXIC+

DrugBw/94%bound

90.0%bound100moleculesfreeDruginteractionofplasmaproteinbindingBlood-brainbarrier,BBBTightjunctions

EndothelialcellsandassociatedastrocytesarestitchedtogetherbystructuresTherowofcapillaryepithelialcellsthatregulatestransferofdrugtothebrain.Onlydrugshavingahighlipid-waterpartitioncoefficientwilldiffuseintothebrain.Structure(anumberoftissuelayers)betweenfetalandmaternalblood.Drugsmustbeabletodiffuseacrosslipidbarrierstoenterthefetus.

NobarriereffectondrugtransportPlacentalbarrier3.Metabolism,BiotransformationSitesofmetabolismMostmedsarebiotransformedintheliverItcanoccurinrenaltissue,lungs,bloodplasma,andintestinalmucosaEnzymaticalterationofadrugmoleculeDrugOxidation(CytochromeP450)Conjugation(Glucuronidation,etcConjugationStableadductsMetabolitesNo-polarspeciesBillaryelimination(Stool)Renalelimination(Urine)PolarspeciesPhaseIPhaseIIPhasesofmetabolismX(passivediffusion)XCYP450X-OHUGTX-OGY(activelytransported)YCYP450Y-OHUGTX-OGbileBloodHepatocyteHepatocytePhasesofmetabolismInfluxtransports:OATPs,OATs,OCTs,NTCPEffluxtransports:MRP2,MDR1,BCRP,BSEP,MDR2(OAT:organicaniontransporter;OCT:organiccationtransporter)OxidationCYP1A1/2CYP1B1CYP2A6CYP2B6CYP2E1CYP3A4/5/7CYP2C19CYP2C9CYP2C8Non-CYPenzymesCYP2D6

CytochromeP50superfamily

Theprimaryoxidativeenzymesystemwithintheliver

GeneticdeterminedenzymeactivityGenesEnvironment0%10%20%30%40%50%60%70%80%90%100%DiabetesmellitusLOBreastcancerMI(males)EssentialhypertensionCoronaryarterydiseaseDiabetesmellitusEODiphenylhydantoinLithiumSodiumsalicylateAmobarbitalDicumarolAspirinAntipyrinePhenylbutazoneSpeedsupmetabolism,increasesdrugclearance,decreasesconcentrationsofsubstratesEnzymeinductionNoinducerphenobarbitonebenzo-pyreneClazolimineconcentration（µg/g

tissue）Time（hr）InratsConsequencesofInductionIncreasedrateofmetabolismDecreaseindrugplasmaconcentrationEnhancedoralfirstpassmetabolismReducedbioavailabilityIfmetaboliteisactiveorreactive,increaseddrugeffectsortoxicity

Slowsdownmetabolism,decreasesdrugclearance,increasesconcentrationofsubstratesEnzymeinhibitionConsequencesofInhibitionIncreaseintheplasmaconcentrationofparentdrugReductioninmetaboliteconcentrationExaggeratedandprolongedpharmacologicaleffectsIncreasedlikelihoodofdrug-inducedtoxicityRoutesofexcretionKidney(mostimportant)BiliarytractandthefecesOthers:expiredair,sweat,saliva,tearsandbreastmilk4.ExcretionFiltrationActivesecretionReabsorptionAcidBase99%ofH20+LipidsolubledrugsPlasmaflow650ml/minGlomerularFiltrationRate(GFR):125ml/minUrine1ml/minThewaysbywhichadrugisexcretedbythekidneyorganicaniontransportingpolypeptide,OATPOrganicCationTransportersOCTTheprocessbywhichadrugormetaboliteiseliminatedfromthebodyLiverGutFecesexcretionPortalveinBiliaryexcretion&EnterohepaticrecyclingBileductBiliarySecretionTimecourseofdrugconcentrationSection3Ch.21.Singledose0204060801001200246810Time(min)Plasmaaspirinconcentration(mg/L)CmaxTmaxivorallyAreaundercurve(AUC)ngh/mL

Absorption=elimination1-3hformostofdrugs2.MultipledoseConstantrepeatedadministrationofdrugsCss-max<MTCCss-min>MEC4-5half-life,90%ofsteady-stateconcentrationisreachedin3.3half-livesToproduceaCss>MECand<MTCDrugaccumulationandelimination87.5%94%97%90%3.3TimePlasmaDrugConcentrationMTCMECTimePlasmaDrugConcentrationMTCMECTimeTimeLogConcentrationLoadingdoseUtilizedwhenatherapeuticlevelisdesiredquicklyandaninitiallargerdoseisadministeredfollowedbysubstantiallysmallermaintenancedoses(mayincreaseriskoftoxicityandadverseeffects).EliminationKineticsSection4Ch.2

EliminationkineticsFirstordereliminationkinetics n=1dC/dt=-kCZeroordereliminationkinetics n=0dC/dt=kdC/dt=-kCnRateconstantforeliminationPlasmaconcentrationTimeZeroorderFirstorderFirstorderZeroorder

FirstorderandzeroordereliminationComparisonFirstOrderElimination[drug]decreasesexponentiallyw/timeRateofeliminationisproportionalto[drug]Plotoflog[drug]orln[drug]vs.timearelineart1/2isconstantregardlessof[drug]ZeroOrderElimination[drug]decreaseslinearlywithtimeRateofeliminationisconstantRateofeliminationisindependentof[drug]Notruet1/2Lowconcentration(<10mg/L):FirstorderHighconcentration(>10mg/L):ZeroorderSaturationofmetabolizingenzymeMixdeliminationkineticsImportantParametersinPharmacokinetics

Section5Ch.2Timeittakesfordrugconcentrationstodecreasebyonehalf1.Half-life,T1/2Zeroorderelimination:t1/2=0.5C0/kFirstorder

elimination:

t1/2=0.693/Ket1/2t1/2t1/2t1/2t1/2Slope=-Ke/2.303Time（h）Time（h）PlasmaConcentration`Rateofeliminationproportionaltoplasmaconcentration.`t1/2isdependentondrugamount`ConstantrateofEliminationirrespectiveofplasmaconcentration`t1/2isconstantregardlessofdrugamountPlasmaConcentrationVolumeofbloodinadefinedregionofthebodythatisclearedofadruginaunittime(mL/min).

CLtotal=D/AUCCLtotal=CLrenal＋CLliver＋CLothers2.Clearance，CL

3.Volumeofdistribution,VdVolumeinwhichdrugappearstodistributeVdnotphysicalvolume.Vd=Dose(known)/Cp(known)VdisproportionalityconstantDrugVolume(L/70kg)Mepacrine（阿的平）40000Chloroquine（氯喹）17000Amphetamine（苯丙胺）300Propranolol（普萘洛尔）250Theophylline（氨茶碱）30Tolbutamide（甲苯磺丁脲）6plasma4LIntercellular10LIntracellular28LAcidicdrugsBasicdrugsAmphotericdrugsNeutraldrugsBasicdrugsaccumulateintissuehighVdVdofSelecteddrugsTotal：42LEstimateofhowwellthedrugisdistributed.Value<0.071L/kgindicatethedrugismainlyinthecirculatorysystem.Values>50L/(70kg)indicatethedrughasaccumulatedinspecifictissues.e.g.digoxin5mg0.78ng/mlVd=645L,mainlyinlipidtissueandmuscleincludingcardiacmuscleCalculationofdosagetobegiven:Vd=D/CApplicationofVd4.BioavailabilityDoseDestroyedingutNotabsorbedDestroyedbygutwallDestroyedbyliverTosystemiccirculation4.BioavailabilityRelativeBioavailabilityCompurgationoftwodifferentdrugsordifferentdosageformsofsamedrug F=(AUCtestxDstand)/(AUCstandxDtest)AbsoluteBioavailabilityThefractionofthedoseofadrug(F)thatentersthegeneralcirculatorysystem, F=(AUCev

xDiv)/(AUCivxDev)

ev:extravascularOraladministrationofdigoxin0.5mgPharmaceuticalCo.APharmaceuticalCo.BRelativeBioavailabilityChapter3

PharmacodynamicsDrugActionandMechanismSection1Ch.31.TherapeuticeffectsExpecteddesirableandbeneficialpharmacologicaleffectEtiologicaltreatmentSymptomatictreatmentSupplementarytreatmentorsubstitutiontreatment2.Adversedrugreactions,ADR

Allthereactionsthatcanbringouttheuncomfortableorpainfulreaction,andhavenorelationshipwiththeaimofadministration.ADRarealargeproblem:~5%ofhospitaladmissionsareasaresultofanADR.Reactionsunrelatedtothetherapeuticaimandoccurredattherapeuticdose.1.Sideeffect

DrymouthInhibitionofsalivarysecretionDilatedpupilsBlurredvisionInhibitionofpupillaryconstric