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Download Pharmacokinetics  Pharmacodynamics - Homepages  bakerl/psy613/PhPPT fileWeb view2009-09-15Principles of Pharmacology Pharmacokinetics  Pharmacodynamics * * * * * * * * * * * * * * * Pharmacokinetics Movement of drugs in the body Four Processes Absorption Distribution Metabolism Excretion Drug concentration at

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  • Principles of Pharmacology

    Pharmacokinetics &Pharmacodynamics

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  • Pharmacokinetics

    Movement of drugs in the bodyFour ProcessesAbsorptionDistributionMetabolismExcretion Drug concentration at sites of action influenced by several factors, such as:Route of administrationDoseCharacteristics of drug molecules (e.g., lipid solubility)

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  • Drug Absorption

    Routes of Drug AdministrationOral (per os, p.o.)Inhalationvapors, gases, smokeMucous membranesintranasal (sniffing)sublingualrectal suppositoriesInjection (parenteral)intravenous (IV)intramuscular (IM)subcutaneous (SC)intraperitoneal (IP; nonhumans only)Transdermal

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  • DRUG ABSORPTION

    Lipid solubilitypKa = pH at which 50% of drug molecules are ionized (charged) Only uncharged molecules are lipid soluble.The pKa of a molecule influences its rate of absorption through tissues into the bloodstream.pH varies among tissue sites e.g., stomach: 3-4, intestines: 8-9

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  • pKa and Lipid Solubility

    Image from McKim, 2007, p. 14

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  • Routes of Drug Administration

    Oral Drug AdministrationAdvantages: relatively safe, economical, convenient, practicalDisadvantages: Blood levels are difficult to predict due to multiple factors that limit absorption.Some drugs are destroyed by stomach acids.Some drugs irritate the GI system.

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  • Routes of Drug Administration

    Advantages of Injection RoutesAbsorption is more rapid than with oral administration.Rate of absorption depends on blood flow to particular tissue site (I.P. > I.M. > S.C.).Advantages specific to I.V. injectionNo absorption involved (inject directly into blood).Rate of infusion can be controlled.A more accurate prediction of dose is obtained.

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  • Routes of Drug Administration

    Disadvantages/Risks of InjectionA rapid onset of action can be dangerous in overdosing occurs.If administered too fast, heart and respiratory function could collapse.Drugs insoluble in water or dissolved in oily liquids can not be given I.V.Sterile techniques are necessary to avoid the risk of infection.

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  • Drug Distribution

    Cell MembranesCapillariesDrug affinities for plasma proteinsBound molecules cant cross capillary wallsBlood Brain BarrierTight junctions in capillariesLess developed in infantsWeaker in certain areas, e.g. area postrema in brain stem Cerebral trauma can decrease integrityPlacentaNot a barrier to lipid soluble substances.

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  • Termination of Drug Action

    Biotransformation (metabolism)Liver microsomal enzymes in hepatocytes transform drug molecules into less lipid soluble by-products.Cytochrome P450 enzyme family

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  • Termination of Drug Action

    Elimination Two-stage kidney process (filter, absorption)Metabolites that are poorly reabsorbed by kidney are excreted in urine.Some drugs have active (lipid soluble) metabolites that are reabsorbed into circulation (e.g., pro-drugs)Other routes of elimination: lungs, bile, skin

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  • Termination of Drug Action

    Kidney Actionsexcretes products of body metabolismclosely regulates body fluids and electrolytesThe human adult kidney filters approx. 1 liter of plasma per minute, 99.9% of fluid is reabsorbed.Lipid soluble drugs are reabsorbed with the water.

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  • Termination of Drug Action

    Factors Influencing BiotransformationGeneticEnvironmental (e.g., diet, nutrition)Physiological differences (e.g., age, gender differences in microsomal enzyme systems)Drug InteractionsSome drugs increase or decrease enzyme activitye.g., carbamazepine stimulates CYP-3A3/4e.g., SSRIs inhibit CYP-1A2, CYP-2C

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  • Drug Time Course

    Time Course Studies important forpredicting dosages/dosing intervalsmaintaining therapeutic levelsdetermining time to eliminationElimination Half-Lifetime required for drug blood levels to be reduced by 50%Approx. 6 half-lives to eliminate drug from body With repeated regular interval dosing, steady-state concentration reached in approx. 6 x half-life

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  • Therapeutic Drug Monitoring

    TDM important for clinical decisionsPlasma levels rough approximation of tissue/receptor concentrationsTDM goalsassess medication complianceavoid toxicityenhance therapeutic response

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  • Tolerance & Dependence

    Mechanisms of ToleranceMetabolic (Pharmacokinetic, Dispositional)Cellular-Adaptive (Pharmacodynamic)Behavioral ConditioningDependenceAbstinence SyndromeNot all addictive drugs produce physical dependence.Some nonaddictive therapeutic drugs (e.g. SSRIs) can produce physical dependence.

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  • Pharmacodynamics

    Drug actions at receptor sites and the physiological/chemical/behavioral effects produced by these actionsStudies of drug mechanisms of action at the molecular levelProvides basis for rational therapeutic uses and the design of new, superior therapeutic agents

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  • Drug-Receptor Interactions

    Receptors found on membrane spanning proteinsContinuous series of amino acid loopsLigands (neurotransmitters, drugs) attach inside spaces between coils, held by ionic attractionsReversible ionic binding of ligand activates receptor by changing protein structure.Intensity of transmembrane signal is determined by percentage of receptors occupied.Drugs may influence transmembrane signal by binding to neurotransmitter receptor or to nearby site.

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  • Drug-Receptor Interactions

    Drug/Receptor BindingMimic actions of neurotransmitter at same site (agonist)Bind to nearby site and facilitate neurotransmitter binding (agonist)Block actions of neurotransmitter at same site (antagonist)

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  • Receptor Structures

    Ion Channel ReceptorsCarrier ProteinsG Protein-Coupled ReceptorsEnzymes

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  • Drug-Receptor Specificity

    Alterations to a drugs chemical structure may influence potencye.g., amphetamine vs. methamphetamineMany drugs have multiple sites of actionSome sites of action are responsible for side effectse.g., tricyclic antidepressants: sedation, dry mouth, blurred vision

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  • Dose-Response Relationships

    PotencyEfficacy

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  • Dose-Response Functions

    Efficacy (ED50 = median effective dose)Lethality (LD50 = median lethal dose)Therapeutic Index = LD 50 /ED 50

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    Sedation

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