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 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 Webhttp://pharmacy.creighton.edu/pha443/pdf/Default.aspMerk Manual: Overview of Drugshttp://www.merck.com/pubs/mmanual_home/sec2/5.htm
Web ResourcesMerk Manual: Factors Affecting Drug Responsehttp://www.merck.com/pubs/mmanual_home/sec2/8.htmMerk Manual: Pharmacodynamicshttp://www.merck.com/pubs/mmanual_home/sec2/7.htm