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 directly No absorption involved (inject directly

into blood).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 to Sterile techniques are necessary to avoid the risk of infection.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 substances.Not a barrier to lipid soluble 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 reduced time required for drug blood levels to be reduced

by 50%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-lifestate concentration reached in approx. 6 x half-life

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, Dispositional)Metabolic (Pharmacokinetic, 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 receptor Reversible ionic binding of ligand activates receptor

by changing protein structure.by changing protein structure. Intensity of transmembrane signal is determined by Intensity of transmembrane signal is determined by

percentage of receptors occupied.percentage of receptors occupied. Drugs may influence transmembrane signal by Drugs may influence transmembrane signal by

binding to neurotransmitter receptor or to 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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