Pharmacokinetics Pharmacodynamics Pharmacokinetics Pharmacodynamics

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  • PharmacokineticsPharmacodynamics

  • PharmacokineticsTime course of drug absorption, distribution, metabolism, excretionHow the drugcomes and goes.

  • Pharmacokinetic ProcessesLADME is keyLiberationAbsorptionDistributionMetabolismExcretion

  • LiberationApplies to drugs given orallyComponentsRelease of drug from pill, tablet, capsuleDissolving of active drug in GI fluidsEx: Enteric coated aspirin slows absorption in stomach vs non-coated

  • AbsorptionMovement from administration site into circulation

  • Factors Affecting Liberation/AbsorptionFormulation factorsTablet disintegrationInert ingredient / solvent effectsSolubilityDrug pHConcentration

    Patient factorsAbsorbing surfaceBlood flowEnvironmental pHDisease statesInteractions with food, other drugs

  • Membranes and AbsorptionLipid BilayerSmall, unchargedLarge, unchargedSmall charged ionsH2O, urea, CO2, O2, N2 Glucose SucroseH+, Na+, K+, Ca2+, Cl-, HCO3-DENIED!DENIED!Swoosh!

  • LaChatliers Principlea.k.a. Mass ActionA reaction at equilibriumresponds to stress in away to best return toequilibrium4 Na+4 Cl_4 NaCl+Systemat Equilibrium

  • 44 Cl-4 NaCl+12 NaCl1. System at equilibrium by 82. Stress applied to system3. System responds to stressSystem not atequilibrium!4 Na+4. System returns to equilibrium!4 NaCl dissociateAn example ofLaChatliers Principle

  • IonizationAcidsRelease/Donate H+HA H+ + A-BasesBind/Accept H+ H+ + B- HB

  • Environmental pH and IonizationIf we put an acidic drug in an environment with a lot of H+ (low pH) what will this equilibrium do?HAHANon-ionized form predominates!

  • A real live, actual clinical question...Aspirin is an acidic drug. In the stomach will it exist mostly in ionized or non-ionized form?NON-IONIZEDWhy?

  • How will this affect aspirin absorption?Lipid BilayerIonized form (charged) A-Ionized form (uncharged) HAHA

  • Moral of the story...Acidic drugs are best absorbed from acidic environments

    Basic drugs are best absorbed from basic environments

  • So...To absorption of an acidic drugacidify the environment

    To absorption of an acidic drugalkalanize the environment...

  • DistributionRate of perfusionPlasma protein (albumin) bindingAccumulation in tissuesAbility to cross membranesBlood-brain barrierPlacental barrier

  • Plasma Protein Bindingwarfarin (Coumadin) is highly protein bound (99%). Aspirin binds to the same site on serum proteins as does Coumadin. If a patient on Coumadin also takes aspirin, what will happen?The available Coumadin will increase.1) Why?2) Why do we care?

  • Blood-Brain BarrierThe blood brain barrier consists of cell tightly packed around the capillaries of the CNS. What characteristics must a drug possess to easily cross this barrier? Non-protein bound, non-ionized, and highly lipid solubleWhy?

  • Metabolism (Biotransformation)Two effectsTransformation to less active metaboliteEnhancement of solubilityLiver = primary siteLiver diseaseSlows metabolismProlongs effects

  • Hepatic First-Pass MetabolismAffects orally administered drugsMetabolism of drug by liver before drug reaches systemic circulationDrug absorbed into portal circulation, must pass through liver to reach systemic circulationMay reduce availability of drug

  • EliminationKidneys = primary siteMechanisms dependent upon:Passive glomerular filtrationActive tubular transportPartial reabsorptionHemodialysisRenal diseaseSlows excretionProlongs effects

  • Active Tubular TransportProbenecid is moved into the urine by the same transport pump that moves many antibiotics. Why is probenecid sometimes given as an adjunct to antibiotic therapy?It competes with the antibiotic at the pump and slows its excretion.

  • Urine pH and EliminationA patient has overdosed on phenobartital. Phenobarbital is an acid. If we alkalinalize the urine by giving bicarbonate what will happen to the phenobarbital molecules as they are filtered through the renal tubules? They will ionize...

  • How will this affect phenobarbital reabsorption by the kidney?Non-ionized HA H+ + A-Decreased reabsorptionIncreased eliminationIonized

  • EliminationOther sourcesFecesExhaled airBreast milkSweat

  • Biological Half-life (t 1/2)Amount of time to eliminate 1/2 of total drug amountShorter t 1/2 may need more frequent dosesHepatic disease may increase t1/2

  • A drug has a half life of 10 seconds. You give a patient a dose of 6mg. After 30 seconds how much of the drug remains?TimeAmount

  • Administration RoutesIntravenousFastest, Most dangerousEndotrachealLidocaine, atropine, narcan, epinephrineInhalationBronchodilators via nebulizersTransmucosalRectal or sublingual

  • Administration RoutesIntramuscularDepends on perfusion qualitySubcutaneousDepends on perfusion qualityOralSlow, unpredictable Little prehospital use

  • PharmacodynamicsThe biochemical and physiologic mechanisms of drug actionWhat the drugdoes when it gets there.

  • Drug MechanismsReceptor interactionsNon-receptor mechanisms

  • Receptor InteractionsAgonistReceptorAgonist-ReceptorInteractionLock and key mechanism

  • Receptor InteractionsReceptorPerfect Fit!Induced Fit

  • Receptor InteractionsAntagonistReceptorAntagonist-ReceptorComplexDENIED!CompetitiveInhibition

  • Receptor InteractionsAgonistReceptorAntagonistInhibited-ReceptorDENIED!Non-competitive Inhibition

  • Non-receptor MechanismsActions on EnzymesEnzymes = Biological catalystsSpeed chemical reactionsAre not changed themselvesDrugs altering enzyme activity alter processes catalyzed by the enzymesExamplesCholinesterase inhibitorsMonoamine oxidase inhibitors

  • Non-receptor MechanismsChanging Physical PropertiesMannitolChanges osmotic balance across membranesCauses urine production (osmotic diuresis)

  • Non-receptor MechanismsChanging Cell Membrane PermeabilityLidocaineBlocks sodium channelsVerapamil, nefedipineBlock calcium channelsBretyliumBlocks potassium channelsAdenosineOpens potassium channels

  • Non-receptor MechanismsCombining With Other ChemicalsAntacidsAntiseptic effects of alcohol, phenolChelation of heavy metals

  • Non-receptor MechanismsAnti-metabolitesEnter biochemical reactions in place of normal substrate competitorsResult in biologically inactive productExamplesSome anti-neoplasticsSome anti-infectives

  • Drug Response RelationshipsTime ResponseDose Response

  • Time Response RelationshipsEffect/ResponseTime

  • Time Response RelationshipsEffect/ResponseTimeIVSCIM

  • Dose Response RelationshipsPotencyAbsolute amount of drug required to produce an effectMore potent drug is the one that requires lower dose to cause same effect

  • PotencyWhich drug is more potent?A!Why?TherapeuticEffect

  • Dose Response RelationshipsThreshold (minimal) doseLeast amount needed to produce desired effectsMaximum effectGreatest response produced regardless of dose used

  • Dose Response RelationshipsWhich drug has the lower threshold dose?ABWhich has the greater maximum effect?ABTherapeuticEffect

  • Dose Response RelationshipsLoading doseBolus of drug given initially to rapidly reach therapeutic levelsMaintenance doseLower dose of drug given continuously or at regular intervals to maintain therapeutic levels

  • Therapeutic IndexDrugs safety marginMust be >1 for drug to be usableDigitalis has a TI of 2Penicillin has TI of >100

  • Therapeutic IndexWhy dont we use adrug with a TI
  • Factors Altering Drug ResponsesAgePediatric or geriatricImmature or decreased hepatic, renal functionWeightBig patients spread drug over larger volumeGenderDifference in sizesDifference in fat/water distribution

  • Factors Altering Drug ResponsesEnvironmentHeat or coldPresence or real or perceived threatsFeverShock

  • Factors Altering Drug ResponsesPathologyDrug may aggravate underlying pathologyHepatic disease may slow drug metabolismRenal disease may slow drug eliminationAcid/base abnormalities may change drug absorption or elimination

  • Influencing factorsGenetic effectsLack of specific enzymesLower metabolic ratePsychological factorsPlacebo effect

  • Pediatric PatientsHigher proportion of waterLower plasma protein levelsMore available drugImmature liver/kidneysLiver often metabolizes more slowlyKidneys may excrete more slowly

  • Geriatric PatientsChronic disease statesDecreased plasma protein bindingSlower metabolismSlower excretionDietary deficienciesUse of multiple medicationsLack of compliance

  • Web ResourcesBasic Pharmacokinetics on the Web Manual: Overview of Drugs

  • Web ResourcesMerk Manual: Factors Affecting Drug Response Manual: Pharmacodynamics