PHARMACOKINETICS： .ppt

1 pharmacokinetics dr abdullatifmahesarkingdr sauduniversityoctober2008d 2 drugabsorption isthepassageofthedrugthroughbodybarriersorcellmembranestoreachitssiteofaction 3 mechanismofdrugmovementsacrosscellmembrane passivediffusion simplediffusion activetransportfacilitateddiffusion needcarrier pinocytosis endocytosis 4 passivediffusion types a aqueousdiffusion filtrationthroughthepores watersolubleandlowmolecularweight b lipiddiffusion lipidsolubleandlowmolecularweight 5 6 characters commenestnonselectiverequirenoenergydependsonconcentrationgradientdependsonlipid waterpartitioncoefficientdependsonpka ofdrug andph ofthemedium 7 pka isthedissociationorinizationconstant isthephatwhichhalfofthesubstanceisionizedandhalfisunionizedphistheionizationofthedrugweakacids bestabsorbedinstomach becauseacidwontbeionized lipidsoluble bestabsorption note strongacidsorbasesarefullyionized polar watersoluble cannotcrosscellmembrane givenivinfusion 8 activetransport relativelynotcommonagainstconcentrationgradientrequirescarrier energyspecifice giodidessaturablewithreceptordependsonlipid watercoefficientironabsorptionuptakeoflevodopabybrain 9 carriermediated alongconcentrationgradientrequirescarrierdoesn tneedenergyselectivesaturablee guptakeofglucose vit b12andintrinsicfactor 10 endocytosis highmolecularweightdrugsthereisengulfmentofthesubstratebythecelle gvita e d k 11 factorsaffectingdrugabsorption a drugs 1 molecularweight2 pka3 lipidwaterpartitioncoefficient 4 drugformulation 12 b patient 1 phofthegut2 rateofthegastricemptying3 presenceofthefoodinthegut4 intestinalmotility transienttime 5 surfaceareaavailableforabsorption6 druginteraction 13 c food 1 reducesabsorptione gaspirin pencillinv tetracyclin erythromycin2 increasesabsorptione gpropranolol diazepam dicoumrol 14 2 distribution 1 ecf extracellularfluid plasma 5 ofbodyweight interstitialfluid 16 ofbodyweight lymph 1 ofbodyweight 2 icf intracellularfluid 35 sumoffluidcontentsofallcellsinthebody3 transcellularfluid 2 cerbrospinal synovial peritoneal pleural digestivesecretion 15 themajorbodyfluidcompartments 1 intravascular onecompartment inblood notfilteredthroughendothelium 2 extravascular 2compartments i ebloodandinterstitialfluidpassendotheliumbutnotcellmembranese gnitroglycerine 3 extravascularandintracellular multicompartment passendotheliumandcellmembranes e gphysostigmine 16 factorsaffectingdistribution cardiacoutputandbloodflow increasedcardiacoutputincreasesthedistributionphysiologicalpropertiesofthedrugpermeablityacrosstissuebarrierplasmaproteinbindingwithdrugtissuebindingwithdrugphpkalipidsolubility fatwaterpartition 17 volumeofdistribution vd itistheamountofdruginthebodytotheconcentrationofthedruginbloodorplasma vd amountofdruginthebodycp concentrationinplasma increaseincp decreasedisthevolumeofdistributionandviceversa 18 drugswithhighvolumeofdistribution higherconcentrationintissuethaninplasmarelativelylipidsolubledistributedintracellularlylowmolecularweight easytocrossbarrier notefficientlyremovedbythehemodialysise gphenyton morphine digoxin tricyclicanti depressantscrossbbborplacentalbarriereasily 19 drugswithlowvolumeofdistribution confinedtoplasmaandinterstitialfluids nottissues distributedinextracellularcompartmentmostlyhighmw eg heparin insulin dextranthesearepolarorlipidinsolubledrugse gcarbenicillin vecuronium gentamycinhighplasmaproteinbindinge gwarfarindon tcrossbbborplacentalbarrier becauseoflipidinsolubilityallskeletalmusclerelaxantshavelowvd 20 physiologicalbarriers bloodbrainbarrier bbb placentalbarrier 21 placentalbarrier drugscrossplacentabysimplediffusionlipidsolubledrugsreadily easily enterthefetalbloodinmotherifgivenmorphine respiratorydepressioninthefetuswarfarin hemorrhage iftakeninthe1st3months congenitalmalformation anti thyroiddrugs neonatalgoiter 22 passageofdrugsintocnsandcsf controlledbybbblipidsolubledrugse ggeneralanesthetics cnsdepressants antibioticschloramphenicolandsulphadiazine inflammationasinmeningitis inmeningitis permeabilityisincreasede gpenicillin gentamycin 23 bindingofdrugs tissuebinding somedrugspossesandaffinityforcertaintissuesandgetaccumulatedintherelike bonee gtetracyclineandheavymetalssuchaslead whichcombinewithcollagen 2 fat drugslikethiopentalandether3 salivaryandthyroidglands iodides4 liver quinacrine 300timemoreinliver chloroquinewithnucleicacid5 hairandskin arsenic combineswithkeratin 24 plasmaproteinbinding albumin acidicdrugsbindwithalbuminsuchaswarfarin phenetoin aspirin sulphonamidesglobulin basicdrugssuchasquinidine diazepam 25 drugsexistsin boundformunboundorfreeformbounddrugsnotavailableforcombinationwithreceptornopharmacologicalactionnotavailableformetabolismnotavailableforexcretionlongdurationofactionmayleadtoclinicallyimportantdrug druginteraction 26 unbounddrug pharmacologicallyactiveavailableformetabolismavailableforexcretionhasshortdurationofaction 27 displacement somedrugscancompetewitheachotherforthesamesiteontheplasmaproteinanddisplacedrugsthusincreasingtheirconcentrationstotoxiclevel e g warfarin strong tolbutamide weak hypoglycemia warfarinisbindingwheretolbutamideisfree effect aspirin strong warfarin weak bleeding 28 terminationofthedrug biotransformationexcretionredistribution 29 resdistribution resdistributionofthedrugfromitssiteofactiontoothertissuese gthiopental 30 metabolism drugmetabol biotransformation itisthechemicalreactionswhichleadtomodificationofdrugssitesofmetabolism hepatic microsomes mitochondria cytoplasm extrahepatic lung blood skin git kidney 31 microsomes microsomalenzymesystem mixedfunctionoxidase mono oxigenase itscomponents cytochromep450flavinoproteinnadphmolecularoxygen mg 32 mitochondria mono amineoxidaseenzyme mao acetylationcytoplasm alcoholdehydrogenaseblood plasma estrasesamidasescatechol omethyltransferases comt intestinalmucosaandlumen gitflora glucouronidase asoreductases gitmucosa monoamimeoxidase mao suphatase 33 typesofmetabolicreaction phaseireaction non synthetic phaseiireaction synthetic 34 phaseireaction makethedrugmorepolar morewatersolulble oxidation reduction hydrolysis oxidarionreaction introducesfunctionalgroup oh nh2 sh canbemirosomalornonmicrosomal 35 microsomal drug o2 nadph h changeddrug h2o nadphe g 1 aliphatichydroxylationphenobarbital hydroxyphenobarbital2 aromatichydroxylationphenacetin 2 hydroxyphenacitin paracetamol 3 oxidationofamineaniline nitrobenzene4 sulphoxidationparathione paroxon 36 non microsomal oxidationbysolubleenzymeincytosolormitochondriaofcellse g1 dehydrogenasesandoxidasesethanol acetaldehyde aceticacid methanol formaldehyde formicacidch3ch2oh ch3cho ch3cooh2 monoamideoxidase noradrenaline 3 hypoxanthine xanthine uricacid 37 reductionreactions microsomalornon microsomalmicrosomasl nitrobenzene anilineno2 nh2non microsomal chloralhydrate trichloroethanolhydrolysis non microsomalonlyester c oandamides c nacetylcholine choline acetate ester procainamide lidocaine amide 38 characteristicsofphaseiproducts resultofdrugmetabolism 1 inactivation abolishtheactivityoxidationofphenobarbitalandalcoholhydrolysisofacetylcholine2 conversionofactivedrugtoanotheractiveone diazepam oxydiazepamcodeine heroin morphinephenylbutazone oxyphenylbutazonepropranolol 4 hydroxypropranolol3 conversionofdrugtotoxicmetabolites paracetamol acetaminopen hepatictoxicity halothane metabolitehepatotoxicity4 activationofpro drugchloralhydrate trichloralhydrate5 productmightundergophaseii 39 phaseiiconjugationreaction syntheticreaction glucuronideconjugationaminoacideg glycineacetylationreactione gco ch3sulphateconjugationso4methylationreactione gch3noradrenaline adrenalineallisnon microsomalenzymeexceptglucouronidation catalyzedbyglucouronyltransferase 40 characteristicsofphaseiiproducts product conjugatepharmacologicallyinactivemorewatersoluble tobeexcretedmorereadilyexcretedinurine 41 modulationoflivermicrosomalenzymes inductioninhibitionlivermicrosomalinducersalcoholbarbituratescigarettesmokingphenytoinrifampicinspironalactonegriseofulvin 42 enzymeinductionresultsin increasemetabolismoftheinducertolerance decreasedpharmacologicalactionofthedrugincreasethemetabolismofco administereddrug druginteraction barbiturate warfarinphenytoin oralcontraceptivesrifampicin hydrocortisoneincreasedmetabolite mediatedtissuetoxicityparacetamolandphenacetinastherapy phenobarbitone hyperbilirubinemia 43 livermicrosomalinhibitors cimetidineerythromycinketoconazolemetronidazoleprobenecidenzymeinhibitionmayretardthemetabolismandexcretionoftheinhibitorandco administereddrugsprolongtheactionoftheinhibitorandco administereddrugs increasedpharmacologicalactivity 44 firstpassmetabolism adrugcanbemetabolizedbeforethedrugreachesthesystemiccirculationsotheamountreachingsystemiccirculationislessthantheamountabsorbedwhere liver gutwall lungresult lowbioavailabilityshortdurationofactionhowisitgivene gmorphinesalbutamol 45 4 excretion mainroutesofexcretionrenalexcretionbiliaryexcretionminorroutesofexcretionexhaledairsalivarysecrtetionssweatmilktears 46 renalexcretion glomerularfiltrationactivetubularsecretionpassivetubularreabsorptionalterationintubularphe g gentamycin ampicillin benzylpencillin digoxincontraindicaited incaseofrenalfailureincaseofelderly 47 glomerularfiltration onlyfreedrug notboundtoalbumin lowmolecularweightdrug below20000 renalplasmaflow 600ml mingfr20 ofrenalplasmaflow 125ml min 48 activetubularsecretion characters selectiverequireenergycarrieragainstconcentrationgardientclearancetoplasmaproteinbounddrugstypessystemforacidicdrugssystemforbasicdrugs 49 systemforacidicdrugs e g ofacidicdrugs salicylates sulphonamides penicillin glucouronideconjugate sulphateconjugate blockedby probenicid inhibitor carrierwillcarrythisdrugso acidicdrugs lo