Pharmacokinetics-and-Pharmacodynamics

1LESSON1IntroductiontoPharmacokineticsandPharmacodynamicsPharmacokineticsiscurrentlydefinedasthestudyofthetimecourseofdrugabsorption,distribution,metabo-lism,andexcretion.Clinicalpharmacokineticsistheapplicationofpharmacokineticprinciplestothesafeandeffectivetherapeuticmanagementofdrugsinanindividualpatient.Primarygoalsofclinicalpharmacokineticsincludeenhancingefficacyanddecreasingtoxicityofapatient’sdrugtherapy.Thedevelopmentofstrongcorrelationsbetweendrugconcentrationsandtheirpharmacologicresponseshasenabledclinicianstoapplypharmacoki-neticprinciplestoactualpatientsituations.Adrug’seffectisoftenrelatedtoitsconcentrationatthesiteofaction,soitwouldbeusefultomonitorthisconcentration.Receptorsitesofdrugsaregenerallyinac-cessibletoourobservationsorarewidelydistributedinthebody,andthereforedirectmeasurementofdrugcon-centrationsatthesesitesisnotpractical.Forexample,thereceptorsitesfordigoxinarethoughttobewithinthemyocardium.Obviouslywecannotdirectlysampledrugconcentrationinthistissue.However,wecanmeasuredrugconcentrationinthebloodorplasma,urine,saliva,andothereasilysampledfluids(Figure1-1).Kinetichomogeneitydescribesthepredictablerelationshipbetweenplasmadrugconcentrationandconcentrationatthereceptorsitewhereagivendrugproducesitsthera-peuticeffect(Figure1-2).Changesintheplasmadrugconcentrationreflectchangesindrugconcentrationsatthereceptorsite,aswellasinothertissues.Asthecon-centrationofdruginplasmaincreases,theconcentrationofdruginmosttissueswillincreaseproportionally.Similarly,iftheplasmaconcentrationofadrugisdecreasing,theconcentrationintissueswillalsodecrease.Figure1-3isasimplifiedplotofthedrugcon-centrationversustimeprofileafteranintravenousdrugdoseandillustratesthisconcept.COBJECTIVESAftercompletingLesson1,youshouldbeableto:1.Defineanddifferentiatebetweenpharmacokineticsandclinicalpharmacokinetics.2.Definepharmacodynamicsandrelateittopharma-cokinetics.3.Describetheconceptofthetherapeuticconcentra-tionrange.4.Identifyfactorsthatcauseinterpatientvariabilityindrugdispositionanddrugresponse.5.Describesituationsinwhichroutineclinicalphar-macokineticmonitoringwouldbeadvantageous.6.Listtheassumptionsmadeaboutdrugdistributionpatternsinbothone-andtwo-compartmentmodels.7.Representgraphicallythetypicalnaturallogofplasmadrugconcentrationversustimecurveforaone-compartmentmodelafteranintravenousdose.2ConceptsinClinicalPharmacokineticsThepropertyofkinetichomogeneityisimportantfortheassumptionsmadeinclinicalpharmacokinet-ics.Itisthefoundationonwhichalltherapeuticandtoxicplasmadrugconcentrationsareestablished.Thatis,whenstudyingconcentrationsofadruginplasma,weassumethattheseplasmaconcentrationsdirectlyrelatetoconcentrationsintissueswherethediseaseprocessistobemodifiedbythedrug(e.g.,thecentralnervoussysteminParkinson’sdiseaseorboneinosteomyelitis).Thisassumption,however,maynotbetrueforalldrugs.CLINICALCORRELATEDrugsconcentrateinsometissuesbecauseofphysi-calorchemicalproperties.Examplesincludedigoxin,whichconcentratesinthemyocardium,andlipid-solubledrugs,suchasbenzodiazepines,whichcon-centrateinfat.BASICPHARMACODYNAMICCONCEPTSPharmacodynamicsreferstotherelationshipbetweendrugconcentrationatthesiteofactionandtheresultingeffect,includingthetimecourseandintensityofthera-peuticandadverseeffects.Theeffectofadrugpresentatthesiteofactionisdeterminedbythatdrug’sbindingwithareceptor.Receptorsmaybepresentonneuronsinthecentralnervoussystem(i.e.,opiatereceptors)todepresspainsensation,oncardiacmuscletoaffecttheintensityofcontraction,orevenwithinbacteriatodis-ruptmaintenanceofthebacterialcellwall.Formostdrugs,theconcentrationatthesiteofthereceptordeterminestheintensityofadrug’seffect(Fig-ure1-4).However,otherfactorsaffectdrugresponseaswell.Densityofreceptorsonthecellsurface,themech-anismbywhichasignalistransmittedintothecellbysecondmessengers(substanceswithinthecell),orregu-latoryfactorsthatcontrolgenetranslationandproteinproductionmayinfluencedrugeffect.ThismultilevelFIGURE1-1.Bloodisthefluidmostoftensampledfordrugconcentrationdetermination.FIGURE1-2.Relationshipofplasmatotissuedrugconcentrations.FIGURE1-3.Drugconcentrationversustime.FIGURE1-4.Relationshipofdrugconcentrationtodrugeffectattherecep-torsite.Lesson1:IntroductiontoPharmacokineticsandPharmacodynamics3regulationresultsinvariationofsensitivitytodrugeffectfromoneindividualtoanotherandalsodeter-minesenhancementofortolerancetodrugeffects.Inthesimplestexamplesofdrugeffect,thereisarela-tionshipbetweentheconcentrationofdrugatthereceptorsiteandthepharmacologiceffect.Ifenoughconcentra-tionsaretested,amaximumeffect(Emax)canbedeter-mined(Figure1-5).Whenthelogarithmofconcentrationisplottedversuseffect(Figure1-5),onecanseethatthereisaconcentrationbelowwhichnoeffectisobservedandaconcentrationabovewhichnogreatereffectisachieved.Onewayofcomparingdrugpotencyisbytheconcen-trationatwhich50%ofthemaximumeffectisachieved.Thisisreferredtoasthe50%effectiveconcentrationorEC50.Whentwodrugsaretestedinthesameindividual,thedrugwithalowerEC50wouldbeconsideredmorepotent.Thismeansthatalesseramountofamorepotentdrugisnee