药理学总论绪言

PRINCIPLESOFPHARMACOLOGYPRINCIPLESOFPHARMACOLOGYpharmacokinetics,pharmacokinetics,))pharmacodynamicspharmacodynamics,,))pharmacology)pharmacology)nnnnnn((drugs)drugs)vvvv((preparation)preparation)PharmacokineticsPharmacokineticsvvvvvvFreeBoundSYSTEMICCIRCULATIONnn((passivetransport)passivetransport)ØØØØØØpHpHpKapH10[HA]][ApKapH[HA]][Alog[HA]][AlogpHpKa[HA]]][A[HKaAHHA-----+-+=-=-==+ÛpKapKa50%50%pHpHHandersonHanderson--HasselbalchHasselbalchØØpHpHpH-pKa10??????[B]][BHpHpKa[B]][BHlog[B]][BHlogpHpKa][BH[B]logpHpKa][BH][B][HKaBHBH=-=+=-==+⇔++++++++ØØpHpHpKa=5.4+pH=7.4pH=7.4pH=1.4pH=1.4[[HA]HA]11[[AA--]]100100101101[[HA]HA]11[[AA--]]0.00010.00011.00011.0001ØØpHpHpKa-pHpKa-pH2121101101pHpH++=21pH-pKapH-pKa21101101pHpH++=QQnn((activetransport)activetransport)ØØvvNaNa++--KK++--ATPATPvvvv(())ADMEADMEnnabsorptionabsorptionnndistributiondistributionnnmetabolismmetabolismnneliminationeliminationvvØØØØIVIVØØØØØØØØ(())llFirstPassEffect,FirstPassEffect,ØØ(())ØØ(())llParenteralParenteral••••intravenous(IV)intravenous(IV)intramuscular(IM)intramuscular(IM)subcutaneous(SCorSQ)subcutaneous(SCorSQ)••nnExample:Example:NitroglycerinNitroglycerinRouteRoute••IVIV••SLSL••TransdermalTransdermalOnsetOnset……....………………immediateimmediate…………..……………….1.1--3min3min…….40.40--60min60minvvØØProteinbindingProteinbinding••D+PDPD+PDP••••••••ØØ(())ØØØØPHPHPH=7.0PH=7.0PH=7.4PH=7.4PH=7.4PH=7.4CCCCCCCCØØBBB!BBB!••••vvBloodBrainBarrierBloodBrainBarriermembranebarriers)membranebarriers)membranebarriers)vvPlacentalbarriersPlacentalbarriersvvvvØØ(())ØØØØnnAChEAChE,MAO,MAOnnØØnnnnvvvvexcretionexcretionØØ..RenalSystemRenalSystemnn(())nn(())nn(())nnpHpHacidicurineacidicurine==––alkalinedrugseliminatedalkalinedrugseliminated––aciddrugsreabsorbedaciddrugsreabsorbedalkalineurinealkalineurine==--aciddrugseliminatedaciddrugseliminated--alkalinedrugsabsorbedalkalinedrugsabsorbednnrenaldisease/decreasedclearancerenaldisease/decreasedclearance••affectsdrugdosageaffectsdrugdosagehepatoenteralhepatoenteralcirculation)circulation)liverliverbilebilegallbladdergallbladderGItrackGItrackbloodblood§§••§§§§nn§§nnnnnnlowlowhighhightoxictoxicterminationterminationdurationdurationonsetonsetTherapeuticTherapeuticresponseresponseSignsofSignsoftoxicitytoxicityNoNoidentifiableidentifiableresponseresponseDrugconcentrationatbloodplasmaDrugconcentrationatbloodplasma..timetimektCCt-=0lnln§§ØØkt0teCCkCdtdC-⋅=-=1tkCCt303.2loglog0-=kkttCCkt693.02lnlnln2/10==-=§§Øا§••••••ØØØØ••••••ktCCkdtdCkCdtdCt-=-=-=00§§00§§§§00§§((compartmentmodel)compartmentmodel)§§((compartmentmodel)compartmentmodel)••HalfHalf--LifeLifett1/21/2))Give100mgofadrugGive100mgofadrug1half1half--lifelife……………………..50..502half2half--liveslives……………………25253half3half--liveslives…………..……..12.5..12.54half4half--liveslives……………………6.256.255half5half--liveslives……………………3.1253.1256half6half--liveslives…………………….1.56.1.56!!55tt1/21/23%3%§§§55halfhalf--lives=97%ofdrugeliminatedlives=97%ofdrugeliminated••apparentvolumeofapparentvolumeofdistributiondistributionVVdd))L/kgorL)L/kgorL)CXVdCX/=QQVdVd==§§§••clearanceclearanceClCl))ml/minorL/hr)ml/minorL/hr)KVCld⋅=§§§§••steadystateconcentration,steadystateconcentration,CCssss))CCssssVdtDFCVdDFVdeDFCtkttt2/1ssssmax44.1)5.01()1(2/1××=-=-=-ssssssssCCCCMMMminmaxCssCssVdtCttkAkAR1/21/21/2⋅⋅=〉⋅〈⋅⋅===⋅=R1.441.44R1R1.44693.0RtRss1/2sssst1/2tA⋅⋅⋅=FD1.44ssDDttCssCss••tt1/21/2((loadingdose)loadingdose)••loadingdose=Aloadingdose=AmaxmaxAAmaxmax/F/F••loadingdose=loadingdose=Css)Css)VVdd/F/F••55tt1/21/297%97%••2/1/max)21(11)1()1()1(tnnnnrrDFrrDFAAt-=-==---=11halfhalf--lifelife……………………....50%50%CssCss(Ass)(Ass)2half2half--liveslives……………………75%75%Css(AssCss(Ass))3half3half--liveslives…………..……..87.5%..87.5%CssCss(Ass)(Ass)4half4half--liveslives……………………93.8%93.8%CssCss(Ass)(Ass)5half5half--liveslives……………………96.9%96.9%CssCss(Ass)(Ass)6half6half--liveslives…………………….98.4%.98.4%CssCss(Ass)(Ass)