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  • PrinciplesofPharmacology

    Pharmacokinetics&Pharmacodynamics

    Mr. D.Raju, M.pharm,Lecturer

    PHL-358-PHARMACOLOGY AND THERAPEUTICS-I

  • Pharmacokinetics

    Movementofdrugsinthebody FourProcesses

    Absorption Distribution Metabolism Excretion

    Drugconcentrationatsitesofactioninfluencedbyseveralfactors,suchas: Routeofadministration Dose Characteristicsofdrugmolecules(e.g.,lipidsolubility)

  • DrugAbsorption

    RoutesofDrugAdministration Oral(peros,p.o.) Inhalation

    vapors,gases,smoke Mucousmembranes

    intranasal(sniffing) sublingual rectalsuppositories

    Injection(parenteral) intravenous(IV) intramuscular(IM) subcutaneous(SC) intraperitoneal (IP;nonhumansonly)

    Transdermal

  • DRUGABSORPTION Lipidsolubility pKa =pHatwhich50%ofdrugmoleculesareionized(charged) Onlyunchargedmoleculesarelipidsoluble.

    ThepKa ofamoleculeinfluencesitsrateofabsorptionthroughtissuesintothebloodstream.

    pHvariesamongtissuesites e.g.,stomach:34,intestines:89

  • DrugDistribution

    CellMembranes Capillaries

    Drugaffinitiesforplasmaproteins Boundmoleculescantcrosscapillarywalls

    BloodBrainBarrier Tightjunctionsincapillaries Lessdevelopedininfants Weakerincertainareas,e.g.areapostrema inbrainstem

    Cerebraltraumacandecreaseintegrity Placenta

    Notabarriertolipidsolublesubstances.

  • TerminationofDrugAction

    Biotransformation(metabolism) Livermicrosomal enzymesinhepatocytestransformdrugmoleculesintolesslipidsolublebyproducts.

    Cytochrome P450enzymefamily

  • TerminationofDrugAction

    Elimination Twostagekidneyprocess(filter,absorption) Metabolitesthatarepoorlyreabsorbedbykidneyareexcretedinurine.

    Somedrugshaveactive(lipidsoluble)metabolitesthatarereabsorbedintocirculation(e.g.,prodrugs)

    Otherroutesofelimination:lungs,bile,skin

  • TerminationofDrugAction

    KidneyActions excretesproductsofbodymetabolism closelyregulatesbodyfluidsandelectrolytes Thehumanadultkidneyfiltersapprox.1literofplasmaperminute,99.9%offluidisreabsorbed.

    Lipidsolubledrugsarereabsorbedwiththewater.

  • TerminationofDrugAction

    FactorsInfluencingBiotransformation Genetic Environmental(e.g.,diet,nutrition) Physiologicaldifferences(e.g.,age,genderdifferencesinmicrosomal enzymesystems)

    DrugInteractions Somedrugsincreaseordecreaseenzymeactivity

    e.g.,carbamazepine stimulatesCYP3A3/4 e.g.,SSRIsinhibitCYP1A2,CYP2C

  • DrugTimeCourse

    TimeCourseStudiesimportantfor predictingdosages/dosingintervals maintainingtherapeuticlevels determiningtimetoelimination

    EliminationHalfLife timerequiredfordrugbloodlevelstobereducedby50% Approx.6halflivestoeliminatedrugfrombody Withrepeatedregularintervaldosing,steadystateconcentrationreachedinapprox.6xhalflife

  • Tolerance&Dependence

    MechanismsofTolerance Metabolic(Pharmacokinetic,Dispositional) CellularAdaptive(Pharmacodynamic) BehavioralConditioning

    Dependence AbstinenceSyndrome Notalladdictivedrugsproducephysicaldependence.

    Somenonaddictive therapeuticdrugs(e.g.SSRIs)canproducephysicaldependence.

  • Pharmacodynamics

    Drugactionsatreceptorsitesandthephysiological/chemical/behavioraleffectsproducedbytheseactions Studiesofdrugmechanismsofactionatthemolecularlevel

    Providesbasisforrationaltherapeuticusesandthedesignofnew,superiortherapeuticagents

  • DrugReceptorInteractions

    Receptorsfoundonmembranespanningproteins Continuousseriesofaminoacidloops

    Ligands (neurotransmitters,drugs)attachinsidespacesbetweencoils,heldbyionicattractions Reversibleionicbindingofligand activatesreceptorbychangingproteinstructure.

    Intensityoftransmembrane signalisdeterminedbypercentageofreceptorsoccupied.

    Drugsmayinfluencetransmembrane signalbybindingtoneurotransmitterreceptorortonearbysite.

  • DrugReceptorInteractions

    Drug/ReceptorBinding Mimicactionsofneurotransmitteratsamesite(agonist)

    Bindtonearbysiteandfacilitateneurotransmitterbinding(agonist)

    Blockactionsofneurotransmitteratsamesite(antagonist)

  • ReceptorStructures

    IonChannelReceptors CarrierProteins GProteinCoupledReceptors Enzymes

  • DrugReceptorSpecificity

    Alterationstoadrugschemicalstructuremayinfluencepotency e.g.,amphetaminevs.methamphetamine

    Manydrugshavemultiplesitesofaction Somesitesofactionareresponsibleforsideeffects

    e.g.,tricyclicantidepressants:sedation,drymouth,blurredvision

  • DoseResponseRelationships

    Potency Efficacy

  • DoseResponseFunctions

    Efficacy(ED50=medianeffectivedose) Lethality(LD50=medianlethaldose) TherapeuticIndex=LD50 /ED50

    Principles of PharmacologyPharmacokinetics &PharmacodynamicsPharmacokineticsDrug AbsorptionDRUG ABSORPTIONDrug DistributionTermination of Drug ActionTermination of Drug ActionTermination of Drug ActionTermination of Drug ActionDrug Time CourseTolerance & DependencePharmacodynamicsDrug-Receptor InteractionsDrug-Receptor InteractionsReceptor StructuresDrug-Receptor SpecificityDose-Response RelationshipsDose-Response Functions

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