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PrinciplesPrinciples of of PharmacologyPharmacology
Pharmacokinetics Pharmacokinetics &&
PharmacodynamicsPharmacodynamics
PharmacokineticsPharmacokinetics Movement of drugs in the bodyMovement of drugs in the body Four ProcessesFour Processes
AbsorptionAbsorption DistributionDistribution MetabolismMetabolism Excretion Excretion
Drug concentration at sites of action Drug concentration at sites of action influenced by several factors, such as:influenced by several factors, such as: Route of administrationRoute of administration DoseDose Characteristics of drug molecules (e.g., lipid Characteristics of drug molecules (e.g., lipid
solubility)solubility)
Drug AbsorptionDrug Absorption Routes of Drug AdministrationRoutes of Drug Administration
Oral (per os, p.o.)Oral (per os, p.o.) InhalationInhalation
vapors, gases, smokevapors, gases, smoke Mucous membranesMucous membranes
intranasal (sniffing)intranasal (sniffing) sublingualsublingual rectal suppositoriesrectal suppositories
Injection (parenteral)Injection (parenteral) intravenous (IV)intravenous (IV) intramuscular (IM)intramuscular (IM) subcutaneous (SC)subcutaneous (SC) intraperitoneal (IP; nonhumans intraperitoneal (IP; nonhumans
only)only) Transdermal Transdermal
DRUG ABSORPTIONDRUG ABSORPTION Lipid solubilityLipid solubility pKa = pH at which 50% pKa = pH at which 50%
of drug molecules are of drug molecules are ionized (charged) ionized (charged) Only uncharged molecules are Only uncharged molecules are
lipid soluble.lipid soluble. The pKa of a molecule The pKa of a molecule
influences its rate of absorption influences its rate of absorption through tissues into the through tissues into the bloodstream.bloodstream.
pH varies among tissue sites pH varies among tissue sites e.g., stomach: 3-4, intestines: 8-9e.g., stomach: 3-4, intestines: 8-9
pKa and Lipid SolubilitypKa and Lipid Solubility
Image from McKim, 2007, p. 14
Routes of Drug Routes of Drug AdministrationAdministration
Oral Drug AdministrationOral Drug Administration Advantages: Advantages:
relatively safe, economical, convenient, relatively safe, economical, convenient, practicalpractical
Disadvantages: Disadvantages: Blood levels are difficult to predict due to Blood levels are difficult to predict due to
multiple factors that limit absorption.multiple factors that limit absorption. Some drugs are destroyed by stomach Some drugs are destroyed by stomach
acids.acids. Some drugs irritate the GI system.Some drugs irritate the GI system.
Routes of Drug Routes of Drug AdministrationAdministration Advantages of Injection RoutesAdvantages of Injection Routes
Absorption is more rapid than with Absorption is more rapid than with oral administration.oral administration.
Rate of absorption depends on blood Rate of absorption depends on blood flow to particular tissue site (I.P. > flow to particular tissue site (I.P. > I.M. > S.C.).I.M. > S.C.).
Advantages specific to I.V. injectionAdvantages specific to I.V. injection No absorption involved (inject No absorption involved (inject
directly into blood).directly into blood). Rate of infusion can be controlled.Rate of infusion can be controlled. A more accurate prediction of dose is A more accurate prediction of dose is
obtained.obtained.
Routes of Drug Routes of Drug AdministrationAdministration
Disadvantages/Risks of InjectionDisadvantages/Risks of Injection A rapid onset of action can be A rapid onset of action can be
dangerous in overdosing occurs.dangerous in overdosing occurs. If administered too fast, heart and If administered too fast, heart and
respiratory function could collapse.respiratory function could collapse. Drugs insoluble in water or Drugs insoluble in water or
dissolved in oily liquids can not be dissolved in oily liquids can not be given I.V.given I.V.
Sterile techniques are necessary Sterile techniques are necessary to avoid the risk of infection.to avoid the risk of infection.
Drug DistributionDrug Distribution Cell MembranesCell Membranes CapillariesCapillaries
Drug affinities for plasma proteinsDrug affinities for plasma proteins Bound molecules can’t cross capillary wallsBound molecules can’t cross capillary walls
Blood Brain BarrierBlood Brain Barrier Tight junctions in capillariesTight junctions in capillaries Less developed in infantsLess developed in infants Weaker in certain areas, e.g. area Weaker in certain areas, e.g. area
postrema in brain stem postrema in brain stem Cerebral trauma can decrease integrityCerebral trauma can decrease integrity
PlacentaPlacenta Not a barrier to lipid soluble Not a barrier to lipid soluble
substances.substances.
Termination of Drug ActionTermination of Drug Action Biotransformation (metabolism)Biotransformation (metabolism)
Liver microsomal enzymes in Liver microsomal enzymes in hepatocytes transform drug hepatocytes transform drug molecules into less lipid soluble by-molecules into less lipid soluble by-products.products.
Cytochrome P450 enzyme familyCytochrome P450 enzyme family
Termination of Drug ActionTermination of Drug Action
Elimination Elimination Two-stage kidney process (filter, Two-stage kidney process (filter,
absorption)absorption) Metabolites that are poorly reabsorbed by Metabolites that are poorly reabsorbed by
kidney are excreted in urine.kidney are excreted in urine. Some drugs have active (lipid soluble) Some drugs have active (lipid soluble)
metabolites that are reabsorbed into metabolites that are reabsorbed into circulation (e.g., pro-drugs)circulation (e.g., pro-drugs)
Other routes of elimination: lungs, bile, Other routes of elimination: lungs, bile, skinskin
Termination of Drug ActionTermination of Drug Action
Kidney ActionsKidney Actions excretes products of body metabolismexcretes products of body metabolism closely regulates body fluids and closely regulates body fluids and
electrolyteselectrolytes The human adult kidney filters approx. 1 The human adult kidney filters approx. 1
liter of plasma per minute, 99.9% of liter of plasma per minute, 99.9% of fluid is reabsorbed.fluid is reabsorbed.
Lipid soluble drugs are reabsorbed with Lipid soluble drugs are reabsorbed with the water.the water.
Termination of Drug ActionTermination of Drug Action Factors Influencing BiotransformationFactors Influencing Biotransformation
GeneticGenetic Environmental (e.g., diet, nutrition)Environmental (e.g., diet, nutrition) Physiological differences (e.g., age, Physiological differences (e.g., age,
gender differences in microsomal gender differences in microsomal enzyme systems)enzyme systems)
Drug InteractionsDrug Interactions Some drugs increase or decrease Some drugs increase or decrease
enzyme activityenzyme activity e.g., carbamazepine stimulates CYP-3A3/4e.g., carbamazepine stimulates CYP-3A3/4 e.g., SSRIs inhibit CYP-1A2, CYP-2Ce.g., SSRIs inhibit CYP-1A2, CYP-2C
Drug Time CourseDrug Time Course
Time Course Studies important forTime Course Studies important for predicting dosages/dosing intervalspredicting dosages/dosing intervals maintaining therapeutic levelsmaintaining therapeutic levels determining time to eliminationdetermining time to elimination
Elimination Half-LifeElimination Half-Life time required for drug blood levels to be time required for drug blood levels to be
reduced by 50%reduced by 50% Approx. 6 half-lives to eliminate drug from body Approx. 6 half-lives to eliminate drug from body With repeated regular interval dosing, steady-With repeated regular interval dosing, steady-
state concentration reached in approx. 6 x half-state concentration reached in approx. 6 x half-lifelife
Therapeutic Drug MonitoringTherapeutic Drug Monitoring
TDM important for clinical decisionsTDM important for clinical decisions Plasma levels rough approximation of Plasma levels rough approximation of
tissue/receptor concentrationstissue/receptor concentrations TDM goalsTDM goals
assess medication complianceassess medication compliance avoid toxicityavoid toxicity enhance therapeutic responseenhance therapeutic response
Tolerance & DependenceTolerance & Dependence Mechanisms of ToleranceMechanisms of Tolerance
Metabolic (Pharmacokinetic, Metabolic (Pharmacokinetic, Dispositional)Dispositional)
Cellular-Adaptive (Pharmacodynamic)Cellular-Adaptive (Pharmacodynamic) Behavioral ConditioningBehavioral Conditioning
DependenceDependence Abstinence SyndromeAbstinence Syndrome Not all addictive drugs produce physical Not all addictive drugs produce physical
dependence.dependence. Some nonaddictive therapeutic drugs (e.g. Some nonaddictive therapeutic drugs (e.g.
SSRIs) can produce physical dependence.SSRIs) can produce physical dependence.
PharmacodynamicsPharmacodynamics
Drug actions at receptor sites and Drug actions at receptor sites and the physiological/chemical/behavioral the physiological/chemical/behavioral effects produced by these actionseffects produced by these actions Studies of drug mechanisms of action at Studies of drug mechanisms of action at
the molecular levelthe molecular level Provides basis for rational therapeutic Provides basis for rational therapeutic
uses and the design of new, superior uses and the design of new, superior therapeutic agentstherapeutic agents
Drug-Receptor InteractionsDrug-Receptor Interactions
Receptors found on membrane spanning Receptors found on membrane spanning proteinsproteins Continuous series of amino acid loopsContinuous series of amino acid loops
Ligands (neurotransmitters, drugs) attach Ligands (neurotransmitters, drugs) attach inside spaces between coils, held by ionic inside spaces between coils, held by ionic attractionsattractions Reversible ionic binding of ligand activates Reversible ionic binding of ligand activates
receptor by changing protein structure.receptor by changing protein structure. Intensity of transmembrane signal is determined Intensity of transmembrane signal is determined
by percentage of receptors occupied.by percentage of receptors occupied. Drugs may influence transmembrane signal Drugs may influence transmembrane signal
by binding to neurotransmitter receptor or to by binding to neurotransmitter receptor or to nearby site.nearby site.
Drug-Receptor InteractionsDrug-Receptor Interactions
Drug/Receptor BindingDrug/Receptor Binding Mimic actions of neurotransmitter at Mimic actions of neurotransmitter at
same site (agonist)same site (agonist) Bind to nearby site and facilitate Bind to nearby site and facilitate
neurotransmitter binding (agonist)neurotransmitter binding (agonist) Block actions of neurotransmitter at Block actions of neurotransmitter at
same site (antagonist)same site (antagonist)
Receptor StructuresReceptor Structures
Ion Channel ReceptorsIon Channel Receptors Carrier ProteinsCarrier Proteins G Protein-Coupled ReceptorsG Protein-Coupled Receptors EnzymesEnzymes
Drug-Receptor SpecificityDrug-Receptor Specificity
Alterations to a drug’s chemical Alterations to a drug’s chemical structure may influence potencystructure may influence potency e.g., amphetamine vs. methamphetaminee.g., amphetamine vs. methamphetamine
Many drugs have multiple sites of Many drugs have multiple sites of actionaction Some sites of action are responsible for Some sites of action are responsible for
side effectsside effects e.g., tricyclic antidepressants: sedation, e.g., tricyclic antidepressants: sedation,
dry mouth, blurred visiondry mouth, blurred vision
Dose-Response RelationshipsDose-Response Relationships
PotencyPotencyEfficacyEfficacy
Dose-Response FunctionsDose-Response Functions Efficacy (EDEfficacy (ED50 50 = median effective = median effective
dose)dose) Lethality (LDLethality (LD50 50 = median lethal dose)= median lethal dose) Therapeutic Index = LD Therapeutic Index = LD 5050 /ED /ED 5050
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