臨床藥理學(xué)課件：Drug Interactions

DrugInteractions2ExampleExcessiveterfenadineLethalarrhythmiasKetoconazoleisanenzymeinhibitorTerfenadine+ketoconazole:IncreasetheserumconcentrationofterfenadineIn1998,terfenadinewasremovedfrommarket.3OutlineIntroduction

-Definition-Drugslikelytobeinvolvedininteractions-OutcomesofdruginteractionsMechanismsofdruginteractions-Pharmacokineticinteractions-Pharmacodynamicinteractions

-PharmaceuticalinteractionsHigh-riskclinicalsettings聯(lián)合用藥(Concomitantdrugs)Concomitantdrugsaretwoormoredrugsusedorgivenatoralmostatthesametime(oneaftertheother,onthesameday,etc.).同時或在一定間隔時間內(nèi)使用兩種或兩種以上的藥物，稱為聯(lián)合用藥(Concomitantdrugs)。聯(lián)合用藥品種偏多，使藥物相互作用的發(fā)生率增加，影響藥物療效或毒性增加。因此在給病人用藥時，應(yīng)十分小心，應(yīng)盡量減少用藥種類，減少藥物相互作用引起的藥物不良反應(yīng)。2023/12/845IntroductionDruginteractionmeansthemodificationoftheeffectofadrug（objectdrug）byconcurrentadministrationofotherdrugs（precipitatingdrug）.Adruginteractioncanresultineitheranincreasedordecreasedeffectoftheobjectdrug.E.g.,terfenadine+ketoconazoleobjectdrugprecipitatingdrugtheobjectsdrugs（目標(biāo)藥物）：在聯(lián)合用藥中，藥效發(fā)生變化的藥物theprecipitatingdrugs（促發(fā)藥物）：在聯(lián)合用藥中，引起其他藥物發(fā)生變化的藥物。67DrugslikelytobeinvolvedininteractionsLikelytobetheprecipitatingdrugs（促發(fā)藥物）highlyproteinboundphenylbutazone,aspirin,sulfonamidesalterthemetabolismofotherdrugsenzymeinducers–anticonvulsants,rifampicin,griseofulvinenzymeinhibitors–allopurinol,chloramphenicol,cimetidineaffectrenalclearanceofobjectdrugsdiuretics,probenecid8Likelytobetheobjectsdrugs（目標(biāo)藥物）asteepdose-responsecurvealowtherapeuticindexanticoagulants,anticonvulsants2023/12/89TypesofDrugInteractionsAddition：作用強(qiáng)度等于單獨(dú)用藥的作用強(qiáng)度之和阿托品與氯丙嗪可引起膽堿能神經(jīng)功能過度低下的中毒癥狀；氨基糖甙類抗生素與硫酸鎂合用，可加強(qiáng)硫酸鎂引起的呼吸麻痹。Doseaddition：A劑量(B劑量)=?A劑量+?B劑量Effectaddition：AB聯(lián)合用藥強(qiáng)度=A作用強(qiáng)度+B作用強(qiáng)度Synergism：聯(lián)合用藥的效果大于單獨(dú)用藥效應(yīng)的總和鎮(zhèn)靜催眠藥與抗精神病藥合用的中樞抑制作用。AB聯(lián)合用藥﹥A效應(yīng)+B效應(yīng)Potentiation：指一種藥物可使組織或受體對另一藥物的敏感性增強(qiáng)排鉀性利尿劑使心臟對洋地黃的敏感性增強(qiáng)，導(dǎo)致心率失常。Antagonism：一種藥物部分或全部阻斷另一藥物的作用，合用時引起藥效降低ChemicalPhysiologicalorfunctionalCompetitiveNoncompetitive1011InconsequentialDesirableorbeneficialincrease

theeffectoftherapydecreasethesideeffectdecreasetolerancetreatmentcomplications-Adverse(0～22%)E.g.,terfenadine+ketoconazoleOutcomesofdruginteractions

12MechanismsofDrugInteractionsPharmacokineticinteractions（PK）-ADME:Absorption,distribution,metabolism,elimination-AchangeinserumconcentrationandtheamountofdrugavailableatthesiteofactionPharmacodynamicinteractions（PD）-Moleculartarget,electrolytebalanceorthebioactivesystem-WithoutalterationsinpharmacokineticparametersPharmaceuticalinteractions-theprinciplestopreventpharmaceuticalinteractions13PKinteractions-AbsorptionAlteringGItractpH

-E.g.,salicylate+NaHCO3

MostdrugsareweakacidsorbasespHchangesAchangeintheionizedandun-ionizedspeciesAbsorptionisapHdependentprocess14Ketoconazole+Ranitidine

PiscitelliSetal.AntimicrobAgentsChemother1991;35:1765-177115PKinteractions-AbsorptionChelationForminganinsolublecomplexintheGItractTetracyclines,quinoloneantibiotics+ferroussulfate(Fe+2),antacids(Al+3,Ca+2,Mg+2),dairyproducts(Ca+2)16PKinteractions-Absorption17PKinteractions-AbsorptionAlterationinGImotilityIncreasemotility-metoclopramide,cisapride,domperidoneE.g.,paracetamol+metroclopramideDecreasemotility-anticholinergicdrugs(atropine,probanthine),chlorpromazine,diphenhydramine18PKinteractions-AbsorptionBinding-bycholestyramineE.g.,warfarin+cholestyramine-bycharcoalE.g.,carbamazepine+charcoal19PKinteractions-AbsorptionAdministrationwithfoodFormanydrugs,changetherateofabsorptionIndinavir–fewerisabsorbedintosystemiccirculationtogetherwithhighfatmeal,AUCandCmaxdecreasedby80%Saquinavir-administrationwithhighfatmealincreasesAUCby57%,forlowFdrug20PKinteractions-DistributionProteinBindingInteractions

CompetitionbetweendrugsforplasmaortissueproteinbindingsitesWhendrugswithhighlyaffinityforthesameproteinareusedtogether,acompetitivedisplacementinteractionmayoccur,resultinginatransientincreaseinthefreeconcentrationofthedisplaceddrug.E.g.,warfarin+phenylbutazone21ProteinBindingInteractions

DrugAalbuminDrugB22PKinteractions-DistributionTocauseaclinicallysignificanteffect

if

:-highlyproteinbound(＞90%)-asmallvolumeofdistribution-anarrowtherapeuticindex-arapidonsetofaction23PKinteractions-DistributionProteinBindingInteractions

Thedisplaceddrugs(theobjectdrugs)warfarin,phenytoin,tolbutamidethedisplacingdrugs(theprecipitantdrugs)phenylbutazone,sulfonamides,salicylates,chloralhydrate24PKinteractions-MetabolismDRUG+－25PKinteractions-MetabolismEnzymeinducer-adrugorsubstancethatincreasesthemetabolicactivityofanenzymeusuallybyincreasingtheamountofthatenzymeexpressedincells.26InducersofenzymeactivityBarbiturates(phenobarbital)(2B)Isoniazid(2E1)CarbamazepinePrimidone(2B)Charcoal-broiledfood(1A2)Rifabutin(3A4)DexamethasoneRifampin(3A4)Ethanol(chronic)(2E1)Tobaccosmoke(1A2)Griseofulvin27PKinteractions-MetabolismOutcomeofinduction:ActiveDruginactive:ResultinginalowerplasmaconcentrationandadecreasedeffectE.g.,PhenobarbitalandwarfarinDrug

Toxicmetabolites:ResultinginanincreasedtoxiceffectE.g.,isoniazidacetylisoniazidDrug

Activemetabolite:ResultinginanincreasedpharmacologicaleffectE.g.,losartanEX-317428PKinteractions-MetabolismEnzymeinhibitoradrugorsubstancethatinhibitstheactionofanenzyme.Theinhibitionmaybecompetitive(competitionforactivesite)ornoncompetitive(conformationalchange)accordingtotheprinciplesofabimolecularinteraction.TwotypesInhibitorsofCYPenzymeInhibitorsofspecificmetabolicpathways29InhibitorsofCYPenzymesystemAmiodaroneKetoconazole(3A4)CimetidineMetronidazoleCiprofloxacin(1A2)Miconazole(3A4)DiltiazemNefazodone(3A4)Erythromycin(3A4)OralcontraceptivesEthanol(Acute)Paroxetine(2D6)Fluconazole(3A4)PhenylbutazoneFluoxetine(2C9,2C19,2D6)Quinidine(2D6)Fluvoxamine(1A2,2C19,3A4)SulfinpyrazoneGrapefruit(3A4)ValproateIsoniazid(2E1)VerapamilItraconazole(3A4)30PKinteractions-MetabolismOutcomeofinhibition:ActiveDrugs:ResultinginanincreasedtherapeuticeffectandtoxiceffectE.g.,cimetidineandwarfarinProdrugs:ResultinginareducedthetherapeuticeffectE.g.,tamoxifenandantidepressants(suchasParoxetine)31PKInteractions-ExcretionAlterationsofurinepH:resultinchangesofdrugexcretionduetoalteredpassivereabsorptionE.g.,Phenobarbital+NaHCO3

UrinepHIncreasetheexcretionUrineacidificationWeakbasicdrugs:amitriptyline,antihistamines,aminophylline,chloroquine,

imipramine,morphine,

mecamylamine,pethidine,quinidineUrinealkalinizationWeakacidicdrugs:phenobarbital,para-aminosalicylicacid,nitrofurantoin,sulfonamides,salicylates,coumarin,streptomycin32PKinteractions-Excretion33PKInteractions-ExcretionCompetitionforsecretionviatheactivetransport

MostdruginteractionsofeliminationsystemhappenatsiteofactiveanionandcationtransportE.g.,penicillinandprobenecidPrecipitantdrugDose（mg/d）t1/2ofpenicillin（min）ProbenecidAspirinPhenylbutazoneIndometacinSulfaphenazole10003000600751000104±4672±36102±6352±1950±1534PDInteractions-DirectDirectpharmacodynamicinteractions-thesamemoleculartarget-similartherapeuticeffectsDrugResponseOutcomeA(5)+B(5)10SummationA(5)+B(5)＞10SynergismA(5)+B(5)＜10Antagonism35PDInteractions-DirectDirectpharmacodynamicinteractionsAntagonismatthesamesiteE.g.,warfarin+vitaminKSynergismatthesamesiteE.g.,tubocurarine+aminoglycosidesantibioticsSummationofsimilareffectsatdifferentsitesE.g.,alcohol+benzodiazepines36PDInteractions-IndirectIndirectpharmacodynamicinteractionsFluidandelectrolytebalanceFurosemideCorticosteroidAmphotercinBserum[K+]↓DigotinQuinidineSotalolProcainamideAmiodarone○Arrhythmia↑37Pharmaceuticalinteractions1)Giveintravenousdrugsbybolusinjectionifpossibleorviaaninfusionburette.2)Donotadddrugstoinfusionsolutionsotherthandextroseorsaline.aminoacidnutrientsolutioncannotbemixedwithanydrugthefollowingdrugscan’tbeaddedintoglucosesolution:aminophylline,barbiturates,erythromycinetc.Salinecan’tbeaddedbyamphotericin3)Avoidmixingdrugsinthesameinfusionsolution,unlessthemixtureisknowtobesafe(e.g.potassiumchloridewithinsulin).4)Readthemanufacturer’sliteraturetolookforspecificwarningsandtocheckthatthedrugissuitableforintravenousadministration.3839Pharmaceuticalinteractions5)Mixthedrugthoroughlyintheinfusionsolutionandcheckbothsoonafterandlaterduringtheinfusionforvisiblechanges,suchasturbidity,precipitation,orcolorchange.However,theabsenceofsuchchangesdoesnotguaranteetheabsenceofaninteraction.6)Preparesolutionsonlywhentheyareneeded.7)Labelallinfusionbottlesclearlywiththenameanddoseofdrugaddedandthetimesofstartingandendingtheinfusion.8)Usetwoseparateinfusionsitesiftwodrugsmustbeinfusedsimultaneously,unlessyouaresurethatthereisnointeractio