Chapter 2: Drug Action and Handling Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.

Chapter 2:Chapter 2:

Drug Action and HandlingDrug Action and Handling

Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.

22Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.

Chapter 2 OutlineChapter 2 Outline

Drug Action and HandlingDrug Action and Handling Characterization of drug actionCharacterization of drug action Mechanism of action of drugsMechanism of action of drugs PharmacokineticsPharmacokinetics Routes of administration and dose formsRoutes of administration and dose forms Factors that alter drug effectsFactors that alter drug effects



The dental health care worker must be The dental health care worker must be familiar with some basic principles of familiar with some basic principles of pharmacology to discuss drugs used in pharmacology to discuss drugs used in dentistry and those that patients may be dentistry and those that patients may be takingtaking Understanding how drugs work, what effects they Understanding how drugs work, what effects they

can have, and what problems they can cause can can have, and what problems they can cause can aid communicationaid communication

cont’d…cont’d…



Haveles (p. 12)Haveles (p. 12) Historically, drugs were discovered by Historically, drugs were discovered by

randomly searching for active components randomly searching for active components among plants, animals, minerals, and soilamong plants, animals, minerals, and soil

Today, organic synthetic chemistry Today, organic synthetic chemistry researchers are responsible primarily for researchers are responsible primarily for developing new drugsdeveloping new drugs




Parent compounds that exhibit known Parent compounds that exhibit known pharmacologic activity are chemically pharmacologic activity are chemically modified to produce congeners or analogs: modified to produce congeners or analogs: agents of similar chemical structure with agents of similar chemical structure with similar pharmacologic effectsimilar pharmacologic effect This technique of modifying a chemical molecule This technique of modifying a chemical molecule

to provide more useful therapeutic agents evolved to provide more useful therapeutic agents evolved from studies of the relationship between chemical from studies of the relationship between chemical structure and the biologic activity, called the structure and the biologic activity, called the structure-activity relationshipstructure-activity relationship (SAR) (SAR)


Characterization of Drug ActionCharacterization of Drug Action

Haveles (pp. 12-14)Haveles (pp. 12-14) Log dose effect curveLog dose effect curve PotencyPotency EfficacyEfficacy Chemical signaling between cellsChemical signaling between cells


Log Dose Effect CurveLog Dose Effect Curve

Haveles (pp. 12-13) (Fig. 2-1)Haveles (pp. 12-13) (Fig. 2-1) The effect a drug exerts on biologic systems The effect a drug exerts on biologic systems

can be related quantitatively to the dose of can be related quantitatively to the dose of the drug giventhe drug given A curve will result if the dose of the drug is plotted A curve will result if the dose of the drug is plotted

against the intensity of the effectagainst the intensity of the effect



Log Dose Effect CurveLog Dose Effect Curve

Haveles (pp. 12-13) (Fig. 2-2)Haveles (pp. 12-13) (Fig. 2-2) If this curve is replotted using the log of the dose (log If this curve is replotted using the log of the dose (log

dose) versus the response, another curve is dose) versus the response, another curve is producedproduced The potency and efficacy of the drug’s action may be The potency and efficacy of the drug’s action may be

determined from this curvedetermined from this curve


PotencyPotency

Haveles (p. 13) (Fig. 2-3)Haveles (p. 13) (Fig. 2-3) Potency of a drug is a function of the amount of the Potency of a drug is a function of the amount of the

drug required to produce an effectdrug required to produce an effect Potency is shown by the location of that drug’s curve along Potency is shown by the location of that drug’s curve along

the log-dose axis (x-axis)the log-dose axis (x-axis) More of a less-potent drug is required to produce a More of a less-potent drug is required to produce a

desired effect equivalent to that of a more potent drugdesired effect equivalent to that of a more potent drug


Efficacy Efficacy

Haveles (pp. 13-14) (Fig. 2-5)Haveles (pp. 13-14) (Fig. 2-5) Efficacy is the maximal intensity of effect or response Efficacy is the maximal intensity of effect or response

that can be produced by a drugthat can be produced by a drug Administering more drug will not increase the efficacy but Administering more drug will not increase the efficacy but

can often increase the probability of an adverse reactioncan often increase the probability of an adverse reaction The efficacy of a drug increases as the height of the The efficacy of a drug increases as the height of the

curve increasescurve increases



EfficacyEfficacy

““The efficacy and the potency of a drug are The efficacy and the potency of a drug are unrelated”unrelated” Drugs may be equally efficacious, but differ in potencyDrugs may be equally efficacious, but differ in potency

Death is the endpoint when measuring the lethal Death is the endpoint when measuring the lethal dosedose The median lethal dose (LDThe median lethal dose (LD5050) is the dose when one half of ) is the dose when one half of

the subjects diethe subjects die


Chemical Signaling Among CellsChemical Signaling Among Cells

Haveles (p. 14)Haveles (p. 14) The brain regulates the body through the autonomic The brain regulates the body through the autonomic

nervous systemnervous system Messages from the brain must be transmitted to many part Messages from the brain must be transmitted to many part

of the body commanding the parts to “do something”of the body commanding the parts to “do something” Complex mechanisms for transmitting these messages allow Complex mechanisms for transmitting these messages allow

for amplification or damping of the effectfor amplification or damping of the effect



Chemical Signaling Among CellsChemical Signaling Among Cells

Haveles (p. 14)Haveles (p. 14) Neurotransmitters are chemicals responsible for Neurotransmitters are chemicals responsible for

transporting a wide variety of messages across the transporting a wide variety of messages across the synapsesynapse Chemical signaling involves release of neurotransmitters Chemical signaling involves release of neurotransmitters

and local substances and hormone secretionand local substances and hormone secretion


NeurotransmittersNeurotransmitters

Haveles (p. 14) (Fig. 2-6)Haveles (p. 14) (Fig. 2-6) Messengers that move the electrical impulses from a Messengers that move the electrical impulses from a

nerve are transmitted across the synapse via nerve are transmitted across the synapse via neurotransmittersneurotransmitters The neurotransmitters are released and quickly travel across The neurotransmitters are released and quickly travel across

the synapse to the receptorthe synapse to the receptor At least fifty different agents can transmit messagesAt least fifty different agents can transmit messages


Local SubstancesLocal Substances

Some organs secrete chemicals that work near them Some organs secrete chemicals that work near them These chemicals are not released into systemic circulationThese chemicals are not released into systemic circulation



Local Substances Local Substances

Prostaglandins and histamine are examples of local Prostaglandins and histamine are examples of local substancessubstances Histamines can produce a localized allergic reactionHistamines can produce a localized allergic reaction Prostaglandins contract uterine muscles and become Prostaglandins contract uterine muscles and become

important when a baby is bornimportant when a baby is born• When released in the stomach, they protect its liningWhen released in the stomach, they protect its lining


HormonesHormones

Secreted to produce effects throughout the bodySecreted to produce effects throughout the body Examples include insulin, thyroid hormone, and Examples include insulin, thyroid hormone, and

adrenocorticosteroidsadrenocorticosteroids Reactions are usually slower than the ones associated with Reactions are usually slower than the ones associated with

neurotransmittersneurotransmitters


Mechanism of Action of DrugsMechanism of Action of Drugs

Haveles (pp. 14-16)Haveles (pp. 14-16) Nerve transmissionNerve transmission ReceptorsReceptors Agonists and antagonistsAgonists and antagonists



Mechanism of Action of DrugsMechanism of Action of Drugs

Haveles (p. 14)Haveles (p. 14) Drugs elicit pharmacologic effects after they Drugs elicit pharmacologic effects after they

have been distributed to their sites of actionhave been distributed to their sites of action The effect occurs because of a modulation in the The effect occurs because of a modulation in the

function of an organism function of an organism Drugs do not impart a new function to an Drugs do not impart a new function to an

organismorganism They either produce the same action as an They either produce the same action as an

endogenous agent or block the action of an endogenous agent or block the action of an endogenous agentendogenous agent


Nerve TransmissionNerve Transmission

Haveles (pp. 14-15)Haveles (pp. 14-15) Transmission of impulses travels along the Transmission of impulses travels along the

nerve producing a nerve action potentialnerve producing a nerve action potential The action potential is triggered by the The action potential is triggered by the

neurotransmitter released at the previous synapseneurotransmitter released at the previous synapse




The processes involved in the drug’s effect The processes involved in the drug’s effect begin with the drug-receptor interactionbegin with the drug-receptor interaction The receptors interact with both endogenous The receptors interact with both endogenous

substances and drugssubstances and drugs This drug-receptor interaction results in a This drug-receptor interaction results in a

conformational (shape) change, which may allow conformational (shape) change, which may allow the drug inside the cell to produce its effect, or it the drug inside the cell to produce its effect, or it may cause release of a second messenger, which may cause release of a second messenger, which then produces the effectthen produces the effect




Many of the effects involve altering enzyme-regulated Many of the effects involve altering enzyme-regulated reactions or regulatory processes for protein reactions or regulatory processes for protein synthesis after a series of reactionssynthesis after a series of reactions Similar to a chain reactionSimilar to a chain reaction


ReceptorsReceptors

Haveles (p. 15)Haveles (p. 15) Once a drug passes through a biologic Once a drug passes through a biologic

membrane, it is carried to many different membrane, it is carried to many different areas of the body, or site of action, to exert its areas of the body, or site of action, to exert its therapeutic effect or adverse effecttherapeutic effect or adverse effect To do this, the drug must bind with the receptor To do this, the drug must bind with the receptor

site on the cell membranesite on the cell membrane



ReceptorsReceptors

Haveles (p. 15) (Fig. 2-7)Haveles (p. 15) (Fig. 2-7) Drug receptors appear to consist of many large Drug receptors appear to consist of many large

molecules that exist either on the cell membrane or molecules that exist either on the cell membrane or within the cell itselfwithin the cell itself More than one receptor type or identical receptors can be More than one receptor type or identical receptors can be

found at the site of actionfound at the site of action Usually, a specific drug will bind with a specific receptor in a Usually, a specific drug will bind with a specific receptor in a

lock-and-key fashionlock-and-key fashion



ReceptorsReceptors

Haveles (p. 15) (Fig. 2-8)Haveles (p. 15) (Fig. 2-8) Different drugs often compete for the same receptor Different drugs often compete for the same receptor

sitessites The drug with stronger affinity for the receptor will bind to The drug with stronger affinity for the receptor will bind to

more receptors than the drug with weaker affinitymore receptors than the drug with weaker affinity Drugs with stronger affinity for receptor sites are more Drugs with stronger affinity for receptor sites are more

potent than drugs with weaker affinity for receptor sitespotent than drugs with weaker affinity for receptor sites


Agonists and AntagonistsAgonists and Antagonists

Haveles (pp. 15-16) (Fig. 2-9)Haveles (pp. 15-16) (Fig. 2-9) When a drug combines with a receptor, it may When a drug combines with a receptor, it may

produce enhancement or inhibition of the produce enhancement or inhibition of the functionfunction These drugs are classified as either agonists or These drugs are classified as either agonists or

antagonistsantagonists


AgonistAgonist

Haveles (p. 15)Haveles (p. 15) An agonist is a drug thatAn agonist is a drug that

Has affinity for the receptorHas affinity for the receptor Combines with the receptorCombines with the receptor Produces an effect Produces an effect


Antagonists Antagonists

Haveles (pp. 15-16) (Fig. 2-9)Haveles (pp. 15-16) (Fig. 2-9) An antagonist counteracts the action of the An antagonist counteracts the action of the

agonistagonist Three different types of antagonistsThree different types of antagonists

• Competitive antagonistCompetitive antagonist

• Noncompetitive antagonistNoncompetitive antagonist

• Physiologic antagonistPhysiologic antagonist


Competitive AntagonistCompetitive Antagonist

A drug thatA drug that Has affinity for a receptorHas affinity for a receptor Combines with the receptorCombines with the receptor Produces no effectProduces no effect

This causes a shift to the right in the dose-response This causes a shift to the right in the dose-response curvecurve The antagonist competes with the agonist for the receptorThe antagonist competes with the agonist for the receptor The outcome depends on the relative affinity and The outcome depends on the relative affinity and

concentrations of each agentconcentrations of each agent


Noncompetitive AntagonistNoncompetitive Antagonist

Binds to a different receptor site than the agonistBinds to a different receptor site than the agonist This reduces the maximal response of the agonistThis reduces the maximal response of the agonist


Physiologic AntagonistPhysiologic Antagonist

Has affinity for a different receptor site than the Has affinity for a different receptor site than the agonistagonist Decreases the maximal effect of the agonist by producing an Decreases the maximal effect of the agonist by producing an

opposite effect via different receptorsopposite effect via different receptors



Haveles (p. 16)Haveles (p. 16) Transport carriers are systems available for Transport carriers are systems available for

moving neurotransmitters or drugs into the moving neurotransmitters or drugs into the cellcell Neurotransmitter precursors must be taken into Neurotransmitter precursors must be taken into

the cell by an active transport pumpthe cell by an active transport pump The precursor for norepinephrine is tyramine, The precursor for norepinephrine is tyramine,

therefore it must be pumped into the celltherefore it must be pumped into the cell After the neurotransmitter is synthesized, it is After the neurotransmitter is synthesized, it is

placed in granules that await a signal to dump placed in granules that await a signal to dump their contents into the synapsetheir contents into the synapse




The neurotransmitter can take three paths after it is The neurotransmitter can take three paths after it is releasedreleased It can be broken down by enzymesIt can be broken down by enzymes It can migrate to the receptor and interact to produce an It can migrate to the receptor and interact to produce an

effecteffect It can be taken up by the presynaptic nerve endingIt can be taken up by the presynaptic nerve ending

• Reuptake is an easy way to recover the neurotransmitter for Reuptake is an easy way to recover the neurotransmitter for future use future use


PharmacokineticsPharmacokinetics

Haveles (pp. 16-22)Haveles (pp. 16-22) Passage across body membranesPassage across body membranes AbsorptionAbsorption DistributionDistribution Half-lifeHalf-life Blood-brain barrierBlood-brain barrier RedistributionRedistribution Metabolism (biotransformation)Metabolism (biotransformation)



PharmacokineticsPharmacokinetics

Haveles (p. 16)Haveles (p. 16) The study of how a drug enters the body, The study of how a drug enters the body,

circulates within the body, is changed by the circulates within the body, is changed by the body, and leaves the bodybody, and leaves the body

Factors influencing movement are described Factors influencing movement are described in four major steps (ADME)in four major steps (ADME) AbsorptionAbsorption DistributionDistribution MetabolismMetabolism ExcretionExcretion


Passage Across Body Passage Across Body MembranesMembranes

Haveles (pp. 16-17)Haveles (pp. 16-17) Passive transferPassive transfer Specialized transportSpecialized transport




Haveles (pp. 16-17)Haveles (pp. 16-17) The amount of drug passing through a cell The amount of drug passing through a cell

membrane and the rate at which a drug moves membrane and the rate at which a drug moves are important in describing the time course of are important in describing the time course of action and the variation in individual response to action and the variation in individual response to a druga drug Before a drug is absorbed, distributed, metabolized, Before a drug is absorbed, distributed, metabolized,

and eliminated, it must pass through various and eliminated, it must pass through various membranes such as cellular membranes, blood membranes such as cellular membranes, blood capillary membranes, and intracellular membranescapillary membranes, and intracellular membranes

These membranes share physicochemical These membranes share physicochemical characteristics that influence the passage of drugs characteristics that influence the passage of drugs across their bordersacross their borders

cont’d… cont’d…


Passage Across Body Passage Across Body Membranes Membranes

Haveles (p. 16)Haveles (p. 16) Membranes are composed of lipids, proteins, Membranes are composed of lipids, proteins,

and carbohydratesand carbohydrates Membrane lipids make the membrane relatively Membrane lipids make the membrane relatively

impermeable to ions and polar moleculesimpermeable to ions and polar molecules Membrane proteins make up the structural Membrane proteins make up the structural

components of the membrane and help move the components of the membrane and help move the molecules across the membrane during the molecules across the membrane during the transport process transport process

Membrane carbohydrates are combined with Membrane carbohydrates are combined with either proteins or lipidseither proteins or lipids




The lipid molecules orient themselves to form The lipid molecules orient themselves to form a fluid bimolecular leaflet with hydrophobic a fluid bimolecular leaflet with hydrophobic (lipophilic) ends in and hydrophilic charged (lipophilic) ends in and hydrophilic charged ends outends out Throughout the membrane is a system of pores Throughout the membrane is a system of pores

through which low–molecular-weight and small-through which low–molecular-weight and small-size chemicals can passsize chemicals can pass




The physicochemical properties of drugs that The physicochemical properties of drugs that influence their passage across biologic membranes influence their passage across biologic membranes are lipid solubility, degree of ionization, and molecular are lipid solubility, degree of ionization, and molecular size and shapesize and shape Mechanisms of transfer are passive transfer and specialized Mechanisms of transfer are passive transfer and specialized

transporttransport


Passive TransferPassive Transfer

Haveles (pp. 16-17) (Fig. 2-10)Haveles (pp. 16-17) (Fig. 2-10) Lipid-soluble substances move across the Lipid-soluble substances move across the

lipoprotein membrane by a passive transfer lipoprotein membrane by a passive transfer process called process called simple diffusion simple diffusion Directly proportional to concentration gradient of Directly proportional to concentration gradient of

the drug across the membrane and the degree of the drug across the membrane and the degree of lipid solubilitylipid solubility



Passive TransferPassive Transfer

Water-soluble molecules small enough to pass Water-soluble molecules small enough to pass through membrane pores may be carried through through membrane pores may be carried through pores by bulk flow of waterpores by bulk flow of water This process of filtration through single-cell membrane may This process of filtration through single-cell membrane may

occur with drugs having a molecular weight of 200 or lessoccur with drugs having a molecular weight of 200 or less Drugs with molecular weights of 60,000 can “filter” through Drugs with molecular weights of 60,000 can “filter” through

capillary membranescapillary membranes


Specialized TransportSpecialized Transport

Haveles (pp. 16-17) (Fig. 2-14)Haveles (pp. 16-17) (Fig. 2-14) Certain substances are transported across Certain substances are transported across

cell membranes by processes more complex cell membranes by processes more complex than simple diffusion or filtrationthan simple diffusion or filtration Active transport is a process by which a substance Active transport is a process by which a substance

is transported against a concentration or is transported against a concentration or electrochemical gradientelectrochemical gradient

Facilitated diffusion does not move against a Facilitated diffusion does not move against a concentration gradientconcentration gradient

Pinocytosis may explain the passage of Pinocytosis may explain the passage of macromolecular substances into cellsmacromolecular substances into cells


AbsorptionAbsorption

Haveles (p. 17)Haveles (p. 17) Effect of ionizationEffect of ionization

Weak acidsWeak acids Weak basesWeak bases

Oral absorptionOral absorption Absorption from injection siteAbsorption from injection site




Haveles (p. 17)Haveles (p. 17) The process by which drug molecules are The process by which drug molecules are

transferred from the site of administration to the transferred from the site of administration to the circulating bloodcirculating blood Requires the drug to pass through biologic Requires the drug to pass through biologic

membranesmembranes




The rate of absorption of a drug involves these The rate of absorption of a drug involves these factorsfactors Physicochemical factorsPhysicochemical factors The site of absorption, which is determined by the route of The site of absorption, which is determined by the route of

administrationadministration The drug’s solubilityThe drug’s solubility


Effect of Ionization Effect of Ionization

Haveles (p. 17) (Fig. 2-10)Haveles (p. 17) (Fig. 2-10) Drugs that are weak electrolytes dissociate in Drugs that are weak electrolytes dissociate in

solution and equilibrate into a nonionized form solution and equilibrate into a nonionized form and an ionized formand an ionized form The nonionized, or uncharged, portion acts similar The nonionized, or uncharged, portion acts similar

to a nonpolar, lipid-soluble compound that readily to a nonpolar, lipid-soluble compound that readily crosses body membranescrosses body membranes

The ionized portion will traverse these membranes The ionized portion will traverse these membranes with greater difficulty because it is less lipid solublewith greater difficulty because it is less lipid soluble



Effect of IonizationEffect of Ionization

Haveles (p. 17)Haveles (p. 17) The pH of tissues at the site of administration The pH of tissues at the site of administration

and dissociation characteristics (acid and dissociation characteristics (acid dissociation constant, or pKdissociation constant, or pKaa) of the drug will ) of the drug will

determine the amount of drug in the ionized determine the amount of drug in the ionized and nonionized stateand nonionized state The proportion in each state will determine the The proportion in each state will determine the

ease with which the drug will penetrate tissueease with which the drug will penetrate tissue


Weak AcidsWeak Acids

When the pH at the site of absorption When the pH at the site of absorption increases, the hydrogen ion concentration increases, the hydrogen ion concentration fallsfalls This results in an increase in the ionized form (AThis results in an increase in the ionized form (A––), ),

which cannot easily penetrate tissueswhich cannot easily penetrate tissues If the pH of the site falls, the hydrogen ion If the pH of the site falls, the hydrogen ion

concentration will riseconcentration will rise This results in an increase in the un-ionized form This results in an increase in the un-ionized form

(HA), which can more easily penetrate tissues(HA), which can more easily penetrate tissues


Weak BasesWeak Bases

If the pH of the site rises, the hydrogen ion If the pH of the site rises, the hydrogen ion concentration will fallconcentration will fall This results in an increase in the un-ionized form This results in an increase in the un-ionized form

(B), which can more easily penetrate tissues(B), which can more easily penetrate tissues If the pH of the site falls, the hydrogen ion If the pH of the site falls, the hydrogen ion

concentration will riseconcentration will rise This results in an increase in the ionized form This results in an increase in the ionized form

(BH(BH++), which cannot easily penetrate tissues), which cannot easily penetrate tissues



In summaryIn summary Weak acids are better absorbed when the pH is Weak acids are better absorbed when the pH is

less than the pKless than the pKaa

Weak bases are better absorbed with the pH is Weak bases are better absorbed with the pH is greater than the pKgreater than the pKaa




Haveles (p. 17)Haveles (p. 17) In the presence of infection, the acidity of the In the presence of infection, the acidity of the

tissue increases (and the pH decreases), and tissue increases (and the pH decreases), and the effect of local anesthetics decreasesthe effect of local anesthetics decreases In the presence of infection, the (HIn the presence of infection, the (H++) increases ) increases

because of accumulating waste products in the because of accumulating waste products in the infected areainfected area

The increase in (HThe increase in (H++) leads to an increase in ) leads to an increase in ionization and a decrease in penetration of the ionization and a decrease in penetration of the membrane by local anestheticmembrane by local anesthetic


Oral AbsorptionOral Absorption Haveles (p. 17)Haveles (p. 17)

Unless the drug is administered as a solution, Unless the drug is administered as a solution, the absorption of the drug in the gastrointestinal the absorption of the drug in the gastrointestinal (GI) tract involves release from a dose form such (GI) tract involves release from a dose form such as a tablet or capsuleas a tablet or capsule

This release requires the following steps before This release requires the following steps before absorption can take placeabsorption can take place Disruption: initial disruption of coating or shellDisruption: initial disruption of coating or shell Disintegration: contents must break apartDisintegration: contents must break apart Dispersion: particles must spreadDispersion: particles must spread Dissolution: drug must be dissolved in GI fluidDissolution: drug must be dissolved in GI fluid


Absorption from Injection SiteAbsorption from Injection Site

Haveles (p. 17)Haveles (p. 17) Depends on solubility of the drug and the Depends on solubility of the drug and the

blood flow at that siteblood flow at that site Drugs with low water solubility are absorbed very Drugs with low water solubility are absorbed very

slowly after intramuscular injectionslowly after intramuscular injection Drugs in suspension are absorbed much more Drugs in suspension are absorbed much more

slowly than those in solutionslowly than those in solution Drugs that are the least soluble will have the Drugs that are the least soluble will have the

longest duration of actionlongest duration of action


DistributionDistribution

Haveles (pp. 17-19)Haveles (pp. 17-19) Basic principlesBasic principles All drugs occur in two forms in blood: bound to All drugs occur in two forms in blood: bound to

plasma proteins and the free drugplasma proteins and the free drug The free drug is the form that exerts the The free drug is the form that exerts the

pharmacologic effectpharmacologic effect The bound drug is a reservoir for the drugThe bound drug is a reservoir for the drug




The proportion in each form is dependent on The proportion in each form is dependent on the properties of that specific drug (percent the properties of that specific drug (percent protein bound)protein bound) Within each body compartment, the drug is split Within each body compartment, the drug is split

between the bound drug and the free drugbetween the bound drug and the free drug Only the free drug can pass across cell Only the free drug can pass across cell

membranesmembranes



DistributionDistribution For a drug to exert its activity, it must be made For a drug to exert its activity, it must be made

available at its site of action in the bodyavailable at its site of action in the body The mechanism by which this is accomplished is The mechanism by which this is accomplished is

distribution—the passage of the drug into various distribution—the passage of the drug into various body fluid compartments such as plasma, interstitial body fluid compartments such as plasma, interstitial fluids, and intracellular fluidsfluids, and intracellular fluids

The manner in which a drug is distributed in the body The manner in which a drug is distributed in the body will determine how rapidly it produces the desired will determine how rapidly it produces the desired response, the duration of that response, and, in some response, the duration of that response, and, in some cases, whether a response will occur at allcases, whether a response will occur at all




Drug distribution occurs when a drug moves Drug distribution occurs when a drug moves to various sites in the body, including its site to various sites in the body, including its site of action in specific tissuesof action in specific tissues Drugs are also distributed to areas where no Drugs are also distributed to areas where no

action is desired (nonspecific tissues)action is desired (nonspecific tissues) Some drugs are poorly distributed to certain Some drugs are poorly distributed to certain

regionsregions Some drugs are distributed to their site of action Some drugs are distributed to their site of action

and then redistributed to another tissue siteand then redistributed to another tissue site




The distribution is determined by several The distribution is determined by several factors factors Size of the organSize of the organ Blood flow to the organBlood flow to the organ Solubility of the drugSolubility of the drug Plasma protein–binding capacityPlasma protein–binding capacity Presence of barriers (blood-brain barrier, placenta)Presence of barriers (blood-brain barrier, placenta)


Distribution by PlasmaDistribution by Plasma

Haveles (p. 18)Haveles (p. 18) After absorption from the site of After absorption from the site of

administration, a drug is distributed to its site administration, a drug is distributed to its site of action by blood plasmaof action by blood plasma Biologic activity is related to the concentration of Biologic activity is related to the concentration of

free, unbound drug in plasmafree, unbound drug in plasma Drugs are bound reversibly to plasma Drugs are bound reversibly to plasma

proteins such as albumin and globulinproteins such as albumin and globulin The bound drug is considered a storage siteThe bound drug is considered a storage site Only the unbound form is biologically active Only the unbound form is biologically active


Half-LifeHalf-Life

Haveles (p. 18) (Fig. 2-11)Haveles (p. 18) (Fig. 2-11) The amount of time that passes for the The amount of time that passes for the

concentration of a drug to fall to one half of its concentration of a drug to fall to one half of its blood level (tblood level (t1/21/2)) When the half-life is short, the duration of action is When the half-life is short, the duration of action is

shortshort When the half-life is long, the duration of action is When the half-life is long, the duration of action is

longlong



Half-LifeHalf-Life

Only 3% to 6% of the drug remains after four or five Only 3% to 6% of the drug remains after four or five half-lives; we can say the drug is essentially gonehalf-lives; we can say the drug is essentially gone Conversely, about four or five half-lives of repeated dosing Conversely, about four or five half-lives of repeated dosing

are needed for a drug’s level to build up to a steady state in are needed for a drug’s level to build up to a steady state in the bodythe body


Blood-Brain BarrierBlood-Brain Barrier

Haveles (pp. 18-19)Haveles (pp. 18-19) The tissue sites of distribution should be The tissue sites of distribution should be

considered before administration of a drugconsidered before administration of a drug To penetrate the central nervous system, a drug To penetrate the central nervous system, a drug

must cross the blood-brain barriermust cross the blood-brain barrier Passage of a drug across this barrier is Passage of a drug across this barrier is

related to the drug’s lipid solubility and related to the drug’s lipid solubility and degree of ionizationdegree of ionization To diffuse transcellularly, the drug must penetrate To diffuse transcellularly, the drug must penetrate

the epithelial and basement membrane cellsthe epithelial and basement membrane cells


PlacentaPlacenta

Haveles (p. 19)Haveles (p. 19) Involves simple diffusion according to the Involves simple diffusion according to the

degree of lipid solubilitydegree of lipid solubility The placenta may act as a selective barrier The placenta may act as a selective barrier

against a few drugs; most drugs pass easily against a few drugs; most drugs pass easily across the placental barrieracross the placental barrier

When agents are administered to the mother, they When agents are administered to the mother, they are concomitantly administered to the fetusare concomitantly administered to the fetus


Enterohepatic CirculationEnterohepatic Circulation

Haveles (p. 19)Haveles (p. 19) Most drugs are absorbed in the intestines, Most drugs are absorbed in the intestines,

distributed through serum, pass to specific distributed through serum, pass to specific and nonspecific sites of action, and then go to and nonspecific sites of action, and then go to the liver, where they are metabolized before the liver, where they are metabolized before being excreted via the kidneysbeing excreted via the kidneys For enterohepatic circulation, the steps are the For enterohepatic circulation, the steps are the

same until the drug is metabolizedsame until the drug is metabolized



Enterohepatic CirculationEnterohepatic Circulation

With enterohepatic circulation, after the drug With enterohepatic circulation, after the drug is metabolized, the metabolite is secreted via is metabolized, the metabolite is secreted via bile into the intestinebile into the intestine The metabolite is broken down by enzymes and The metabolite is broken down by enzymes and

releases the drugreleases the drug The drug is then absorbed again and the process The drug is then absorbed again and the process

continuescontinues After being taken up by the liver a second time, After being taken up by the liver a second time,

these drugs are again secreted into the bilethese drugs are again secreted into the bile This circular pattern continues, with some drug This circular pattern continues, with some drug

escaping with each passingescaping with each passing This process prolongs the effect of a drugThis process prolongs the effect of a drug


Redistribution Redistribution

Haveles (p. 19)Haveles (p. 19) The movement of a drug from the site of The movement of a drug from the site of

action to nonspecific sites of actionaction to nonspecific sites of action The drug’s duration of action can be affected by The drug’s duration of action can be affected by

redistribution of the drug from one organ to redistribution of the drug from one organ to anotheranother

If redistribution occurs between specific sites If redistribution occurs between specific sites and nonspecific sites, a drug’s action will be and nonspecific sites, a drug’s action will be terminatedterminated


MetabolismMetabolism(Biotransformation)(Biotransformation)

Haveles (pp. 19-22)Haveles (pp. 19-22) First-pass effectFirst-pass effect

Phase IPhase I Phase IIPhase II

ExcretionExcretion KineticsKinetics Renal routeRenal route Extrarenal routesExtrarenal routes Biliary excretionBiliary excretion Other Other SalivaSaliva Gingival crevicular fluidGingival crevicular fluid


MetabolismMetabolism Haveles (p. 19)Haveles (p. 19)

The body’s way of changing a drug so that it can The body’s way of changing a drug so that it can be more easily excreted by the kidneysbe more easily excreted by the kidneys Many drugs undergo metabolic transformation or Many drugs undergo metabolic transformation or

change, most commonly in the liverchange, most commonly in the liver The metabolite formed is usually more polar and less The metabolite formed is usually more polar and less

lipid soluble than the parent compoundlipid soluble than the parent compound This means renal tubular absorption of the metabolite This means renal tubular absorption of the metabolite

will be reduced because renal tubular absorption will be reduced because renal tubular absorption favors lipid-soluble compoundsfavors lipid-soluble compounds



MetabolismMetabolism

Haveles (p. 19) (Fig. 2-12)Haveles (p. 19) (Fig. 2-12) Drugs can be metabolized by three different Drugs can be metabolized by three different

meansmeans Active to inactiveActive to inactive

• An inactive metabolite is formed from an active parent An inactive metabolite is formed from an active parent drug (most common process)drug (most common process)

Inactive to activeInactive to active• An inactive parent drug (prodrug) may be transformed to An inactive parent drug (prodrug) may be transformed to

an active compoundan active compound Active to activeActive to active

• An active parent drug may be converted to a second An active parent drug may be converted to a second active compound, which is then converted to an inactive active compound, which is then converted to an inactive productproduct


First-Pass EffectFirst-Pass Effect

Haveles (pp. 19-20)Haveles (pp. 19-20) Metabolism of drugs may be divided into two Metabolism of drugs may be divided into two

general types: phase I and phase IIgeneral types: phase I and phase II If the drug has no functional groups with which to If the drug has no functional groups with which to

combine, then it must undergo a phase I reactioncombine, then it must undergo a phase I reaction


Phase I ReactionPhase I Reaction

HavelesHaveles (pp. 19-20) (pp. 19-20) In phase I reactions, lipid molecules are In phase I reactions, lipid molecules are

metabolized by the three processes ofmetabolized by the three processes of OxidationOxidation ReductionReduction HydrolysisHydrolysis


OxidationOxidation

When a drug that is administered does not When a drug that is administered does not possess an appropriate functional group that possess an appropriate functional group that is suitable for combining with body acids is suitable for combining with body acids (conjugation), the body has more difficulty (conjugation), the body has more difficulty detoxifying the drugdetoxifying the drug An enzyme system responsible for the oxidative An enzyme system responsible for the oxidative

metabolism of many drugs is located in the livermetabolism of many drugs is located in the liver The enzymes are located in the endoplasmic The enzymes are located in the endoplasmic

reticulum and are called reticulum and are called microsomal enzymesmicrosomal enzymes


HydrolysisHydrolysis

Some ester compounds are metabolized by Some ester compounds are metabolized by hydrolysishydrolysis Hydrolytic enzymes found in plasma and in a Hydrolytic enzymes found in plasma and in a

variety of tissues break up esters and add watervariety of tissues break up esters and add water Ester local anesthetics are inactivated by plasma Ester local anesthetics are inactivated by plasma

cholinesterasescholinesterases


ReductionReduction

Many reduction reactions are mediated by Many reduction reactions are mediated by enzymes found in hepatic microsomesenzymes found in hepatic microsomes


Microsomal EnzymesMicrosomal Enzymes

Haveles (pp. 20-21) (Fig. 2-13; Table 2-1)Haveles (pp. 20-21) (Fig. 2-13; Table 2-1) Phase I reactions are carried out by Phase I reactions are carried out by

microsomal or cytochrome P-450 enzymes, microsomal or cytochrome P-450 enzymes, known as known as mixed function oxidasesmixed function oxidases in the liver in the liver Phase I metabolism may be affected by other drugs Phase I metabolism may be affected by other drugs

that alter microsomal enzyme inhibition or inductionthat alter microsomal enzyme inhibition or induction



Microsomal EnzymesMicrosomal Enzymes

Induction: the P-450 hepatic microsomal Induction: the P-450 hepatic microsomal enzymes can be induced (the amount of enzymes can be induced (the amount of enzyme increased) by some drugs and by enzyme increased) by some drugs and by smoking tobaccosmoking tobacco Hepatic enzymes can be divided into many Hepatic enzymes can be divided into many

categories called categories called isoenzymesisoenzymes Inhibition: inhibition of the metabolism of Inhibition: inhibition of the metabolism of

certain drugs may occur through several certain drugs may occur through several mechanismsmechanisms With inhibition, the blood levels and action of the With inhibition, the blood levels and action of the

drugs metabolized by these enzymes will be drugs metabolized by these enzymes will be increasedincreased


Phase II ReactionsPhase II Reactions

Haveles (p. 20)Haveles (p. 20) Phase II reactions involve conjugation with Phase II reactions involve conjugation with

the following agents: glucuronic acid, acetic the following agents: glucuronic acid, acetic acid, or an amino acidacid, or an amino acid The most common conjugation, called The most common conjugation, called

glucuronidation, occurs with glucuronic acidglucuronidation, occurs with glucuronic acid The enzymes that mediate the conjugation are The enzymes that mediate the conjugation are

called called transferasestransferases


ExcretionExcretion

Haveles (pp. 20-22)Haveles (pp. 20-22) Drugs may be excreted by any of several Drugs may be excreted by any of several

routes, but renal excretion is most importantroutes, but renal excretion is most important Extrarenal routes include the lungs, bile, GI tract, Extrarenal routes include the lungs, bile, GI tract,

sweat, saliva, and breast milksweat, saliva, and breast milk Drugs may be excreted unchanged or as Drugs may be excreted unchanged or as

metabolitesmetabolites


KineticsKinetics

Haveles (pp. 18, 20) (Fig. 2-11)Haveles (pp. 18, 20) (Fig. 2-11) The mathematical representation of the way The mathematical representation of the way

in which drugs are removed from the bodyin which drugs are removed from the body The most common mechanism is first-order The most common mechanism is first-order

kineticskinetics



KineticsKinetics

Haveles (pp. 20, 22) (Fig. 2-14)Haveles (pp. 20, 22) (Fig. 2-14) A few drugs, such as aspirin and alcohol, exhibit A few drugs, such as aspirin and alcohol, exhibit

zero-order kineticszero-order kinetics With zero-order kinetics, the rate of metabolism remains With zero-order kinetics, the rate of metabolism remains

constant over time, and the same amount of the drug is constant over time, and the same amount of the drug is metabolized per unit of time, regardless of dosemetabolized per unit of time, regardless of dose

With high doses, the metabolism of the drug cannot With high doses, the metabolism of the drug cannot increase, and the duration of action of the drug can be increase, and the duration of action of the drug can be greatly prolongedgreatly prolonged


Renal RouteRenal Route

Haveles (pp. 20-21)Haveles (pp. 20-21) Elimination of substances in the kidney can Elimination of substances in the kidney can

occur through three routesoccur through three routes Glomerular filtration (most common)Glomerular filtration (most common)

• The unchanged drug or its metabolites are filtered through The unchanged drug or its metabolites are filtered through the glomeruli and concentrated in renal tubular fluidthe glomeruli and concentrated in renal tubular fluid

Active tubular secretionActive tubular secretion• The drug is transported from the bloodstream, across renal The drug is transported from the bloodstream, across renal

tubular epithelial cells, and into renal tubular fluidtubular epithelial cells, and into renal tubular fluid Passive tubular diffusionPassive tubular diffusion

• Favors resorption of nonionized, lipid-soluble compoundsFavors resorption of nonionized, lipid-soluble compounds• More ionized metabolites have more difficulty penetrating More ionized metabolites have more difficulty penetrating

the cell membranes of the renal tubules and are likely to be the cell membranes of the renal tubules and are likely to be retained in tubular fluid and eliminated in urineretained in tubular fluid and eliminated in urine


Extrarenal Routes Extrarenal Routes

Haveles (p. 21)Haveles (p. 21) Gases used in general anesthesia are Gases used in general anesthesia are

excreted across lung tissue by simple excreted across lung tissue by simple diffusiondiffusion Alcohol is partially excreted by the lungsAlcohol is partially excreted by the lungs


Biliary ExcretionBiliary Excretion

Haveles (p. 21)Haveles (p. 21) The major route by which systemically The major route by which systemically

absorbed drugs enter the GI tract and are absorbed drugs enter the GI tract and are eliminated in feceseliminated in feces Drugs excreted in bile may be reabsorbed from Drugs excreted in bile may be reabsorbed from

the intestines (enterohepatic circulation)the intestines (enterohepatic circulation) This enterohepatic circulation prolongs a drug’s This enterohepatic circulation prolongs a drug’s

actionaction


OtherOther

Haveles (p. 21)Haveles (p. 21) Breast milk and sweatBreast milk and sweat

Minor routes of eliminationMinor routes of elimination Distribution of drugs in breast milk may be a Distribution of drugs in breast milk may be a

potential source of undesirable effects for the potential source of undesirable effects for the nursing infantnursing infant


SalivaSaliva

Haveles (p. 21)Haveles (p. 21) Drugs can be excreted in salivaDrugs can be excreted in saliva

They are usually swallowed and their fate is the They are usually swallowed and their fate is the same as drugs ingested orallysame as drugs ingested orally

Most drugs secreted in the salivary glands Most drugs secreted in the salivary glands enter saliva by simple diffusionenter saliva by simple diffusion

Drug levels in saliva have been studied to Drug levels in saliva have been studied to see if they can be used to monitor therapy see if they can be used to monitor therapy with certain agentswith certain agents


Gingival Crevicular Fluid (GCF)Gingival Crevicular Fluid (GCF)

Haveles (p. 22) Haveles (p. 22) Drugs excreted in the GCF produce a higher Drugs excreted in the GCF produce a higher

level of drug in the gingival crevices, which level of drug in the gingival crevices, which can increase their usefulness in the treatment can increase their usefulness in the treatment of periodontal diseaseof periodontal disease Tetracycline is concentrated in GCFTetracycline is concentrated in GCF This means that the drug level in GCF will be This means that the drug level in GCF will be

several times higher than the blood levelseveral times higher than the blood level


Routes of Administration and Dose Routes of Administration and Dose FormsForms

Haveles (pp. 22-25)Haveles (pp. 22-25) Routes of administrationRoutes of administration

Oral routeOral route Rectal routeRectal route Intravenous routeIntravenous route Intramuscular routeIntramuscular route Subcutaneous routeSubcutaneous route Intradermal routeIntradermal route Intrathecal routeIntrathecal route Intraperitoneal routeIntraperitoneal route Inhalation routeInhalation route Topical routeTopical route Other routesOther routes

Dose formsDose forms


Routes of AdministrationRoutes of Administration

Haveles (pp. 22-23) (Fig. 2-15)Haveles (pp. 22-23) (Fig. 2-15) Route of administration affects both the onset Route of administration affects both the onset

and duration of responseand duration of response Onset: the time required for the drug to begin to Onset: the time required for the drug to begin to

have its effecthave its effect Duration: the length of a drug’s effectDuration: the length of a drug’s effect




The routes can be classified as The routes can be classified as enteralenteral or or parenteralparenteral Drugs given by the enteral route are placed directly into the Drugs given by the enteral route are placed directly into the

GI tract by oral or rectal administrationGI tract by oral or rectal administration The parenteral route bypasses the GI tract and includes The parenteral route bypasses the GI tract and includes

injection routes, inhalation, and topical administrationinjection routes, inhalation, and topical administration• In practice, parenteral usually means injectionIn practice, parenteral usually means injection




Haveles (p. 22)Haveles (p. 22) Oral administration is considered safest, least Oral administration is considered safest, least

expensive, and most convenient, but the expensive, and most convenient, but the parenteral route has certain advantagesparenteral route has certain advantages




Haveles (p. 22)Haveles (p. 22) Advantages of the parenteral routeAdvantages of the parenteral route

Injection results in fast absorption, which produces Injection results in fast absorption, which produces a rapid onset and more predictable response than a rapid onset and more predictable response than oral administrationoral administration

Useful for emergencies, unconsciousness, lack of Useful for emergencies, unconsciousness, lack of cooperation, or nauseacooperation, or nausea

Some drugs must be administered by injection to Some drugs must be administered by injection to remain activeremain active




Haveles (pp. 22-23) (Fig. 2-15)Haveles (pp. 22-23) (Fig. 2-15) Disadvantages of the parenteral route Disadvantages of the parenteral route

Asepsis must be maintained to prevent infectionAsepsis must be maintained to prevent infection An intravascular injection may occur by accidentAn intravascular injection may occur by accident Administration by injection is more painfulAdministration by injection is more painful Removing the drug is difficult Removing the drug is difficult Adverse effects may be more pronouncedAdverse effects may be more pronounced Self-medication is difficultSelf-medication is difficult More dangerous and expensive than oral medicationMore dangerous and expensive than oral medication


Oral RouteOral Route

Haveles (pp. 22-23)Haveles (pp. 22-23) The simplest way to introduce a drug into the The simplest way to introduce a drug into the

bodybody Allows for many different dose forms: tablets, Allows for many different dose forms: tablets,

capsules, and liquids are conveniently givencapsules, and liquids are conveniently given



Oral RouteOral Route

Advantages of the oral routeAdvantages of the oral route A large absorbing area present in the small intestineA large absorbing area present in the small intestine Slower onset of action than parenterally administered agentsSlower onset of action than parenterally administered agents



Oral RouteOral Route Disadvantages of the oral routeDisadvantages of the oral route

Stomach and intestinal irritation may result in nausea and Stomach and intestinal irritation may result in nausea and vomitingvomiting

Certain drugs, such as insulin, are inactivated by GI tract acidity Certain drugs, such as insulin, are inactivated by GI tract acidity or enzymesor enzymes

Some orally administered drugs may be inactivated by the Some orally administered drugs may be inactivated by the hepatic (liver) portal circulation hepatic (liver) portal circulation (first-pass effect)(first-pass effect)

Blood levels after oral administration are less predictable than Blood levels after oral administration are less predictable than for parenteral administrationfor parenteral administration

Drug interactions can occur when two drugs are in the stomachDrug interactions can occur when two drugs are in the stomach The oral route necessitates greater patient cooperationThe oral route necessitates greater patient cooperation


Rectal RouteRectal Route

Haveles (p. 23)Haveles (p. 23) Drugs may be given as suppositories, creams, or Drugs may be given as suppositories, creams, or

enemasenemas May be used if the patient is vomiting or unconsciousMay be used if the patient is vomiting or unconscious May be used for either a local or systemic effect, but May be used for either a local or systemic effect, but

because most drugs are poorly and irregularly absorbed because most drugs are poorly and irregularly absorbed rectally, this route is not often used to achieve a systemic rectally, this route is not often used to achieve a systemic drug effectdrug effect


Intravenous RouteIntravenous Route

Haveles (p. 23)Haveles (p. 23) Produces the most rapid drug responseProduces the most rapid drug response

The absorption phase is bypassedThe absorption phase is bypassed More predictable drug response than oral More predictable drug response than oral

administrationadministration The route of choice for an emergency situationThe route of choice for an emergency situation Disadvantages include phlebitis caused by local Disadvantages include phlebitis caused by local

irritation, drug irretrievability, allergy, and side effects irritation, drug irretrievability, allergy, and side effects related to high plasma concentration of the drugrelated to high plasma concentration of the drug


Intramuscular RouteIntramuscular Route

Haveles (p. 24)Haveles (p. 24) Absorption of drugs injected into the muscle occurs Absorption of drugs injected into the muscle occurs

as a result of high blood flow through skeletal muscle as a result of high blood flow through skeletal muscle Somewhat irritating drugs may be tolerated if given by the Somewhat irritating drugs may be tolerated if given by the

intramuscular routeintramuscular route May be used for injection of suspensions for a May be used for injection of suspensions for a

sustained effectsustained effect

Injections are usually into the deltoid or gluteal massInjections are usually into the deltoid or gluteal mass


Subcutaneous RouteSubcutaneous Route

Haveles (p. 24)Haveles (p. 24) Injection of solutions or suspensions of drugs into Injection of solutions or suspensions of drugs into

subcutaneous tissue to gain access to systemic subcutaneous tissue to gain access to systemic circulationcirculation If irritating solutions are injected, sterile abscesses may If irritating solutions are injected, sterile abscesses may

resultresult Commonly used for administration of insulinCommonly used for administration of insulin


Intradermal RouteIntradermal Route

Haveles (p. 24)Haveles (p. 24) Small amounts of drugs, such as local anesthetics, Small amounts of drugs, such as local anesthetics,

may be injected into the epidermismay be injected into the epidermis Produces a small bump (bleb) as the liquid is injected just Produces a small bump (bleb) as the liquid is injected just

under the skinunder the skin Used for tuberculin skin testUsed for tuberculin skin test


Intrathecal RouteIntrathecal Route

Haveles (p. 24)Haveles (p. 24) Injection of solutions into the spinal subarachnoid Injection of solutions into the spinal subarachnoid

spacespace May be used for spinal anesthesia or for the treatment of May be used for spinal anesthesia or for the treatment of

certain forms of meningitiscertain forms of meningitis


Intraperitoneal RouteIntraperitoneal Route

Haveles (p. 24)Haveles (p. 24) Placing fluid into the peritoneal cavity, where Placing fluid into the peritoneal cavity, where

exchange of substances can occurexchange of substances can occur A drug may be absorbed through mesenteric veinsA drug may be absorbed through mesenteric veins

May be used for peritoneal dialysisMay be used for peritoneal dialysis Used as a substitute for the failing kidney to manage Used as a substitute for the failing kidney to manage

patients with renal failurepatients with renal failure


Inhalation RouteInhalation Route

Haveles (pp. 24-25)Haveles (pp. 24-25) May be used in the administration of gaseous, May be used in the administration of gaseous,

microcrystalline, liquid, or powdered form of drugsmicrocrystalline, liquid, or powdered form of drugs An example of inhalers being used for their local effects are An example of inhalers being used for their local effects are

those used to treat asthmathose used to treat asthma General anesthetic in the form of volatile liquids or gases are General anesthetic in the form of volatile liquids or gases are

examples of the use of the inhalation route for systemic examples of the use of the inhalation route for systemic effectseffects


Topical RouteTopical Route

Haveles (p. 25)Haveles (p. 25) Application to body surfacesApplication to body surfaces

May administered to skin, oral mucosa, and even May administered to skin, oral mucosa, and even sublinguallysublingually

May be intended to produce either local or May be intended to produce either local or systemic effectssystemic effects

Generally used on skin for local effectGenerally used on skin for local effect



Topical RouteTopical Route

Rarely, systemic side effects can occur from Rarely, systemic side effects can occur from topical administration of drugs for their local topical administration of drugs for their local effecteffect An example is administration of topical An example is administration of topical

corticosteroids over a large portion of the body, corticosteroids over a large portion of the body, resulting in symptoms of systemic toxicityresulting in symptoms of systemic toxicity

Interruptions in the mucous membranes or Interruptions in the mucous membranes or mucosal inflammation increase the likelihood mucosal inflammation increase the likelihood of a systemic effectof a systemic effect

Examples of drugs applied topically for a Examples of drugs applied topically for a systemic effect include transdermal patches systemic effect include transdermal patches and sublingual spray or tablet administrationand sublingual spray or tablet administration


Subgingival Strips and Gels Subgingival Strips and Gels

Haveles (p. 25)Haveles (p. 25) Dental-specific topical application involves the Dental-specific topical application involves the

placement of drug-impregnated strips or gels placement of drug-impregnated strips or gels subgingivallysubgingivally Doxycycline gel (Atridox), and the chlorhexidine-containing Doxycycline gel (Atridox), and the chlorhexidine-containing

chip (PerioChip) are examples of agents administered into chip (PerioChip) are examples of agents administered into the gingival crevicethe gingival crevice


Transdermal PatchTransdermal Patch

Haveles (p. 25) (Fig. 2-16)Haveles (p. 25) (Fig. 2-16) Designed to provide continuous controlled release Designed to provide continuous controlled release

through a semipermeable membrane over a given through a semipermeable membrane over a given period after application of drug to the intact skinperiod after application of drug to the intact skin Eliminates the need for repeated oral dosingEliminates the need for repeated oral dosing

The most common problems with transdermal The most common problems with transdermal patches are local irritation, erythema, and edemapatches are local irritation, erythema, and edema


Topical AnesthesiaTopical Anesthesia

Haveles (p. 25)Haveles (p. 25) Applied directly to mucous membranes and rapidly Applied directly to mucous membranes and rapidly

absorbed into systemic circulationabsorbed into systemic circulation An example is the combination of lidocaine and prilocaine An example is the combination of lidocaine and prilocaine

(Oraqix)(Oraqix)


Sublingual and Buccal RoutesSublingual and Buccal Routes

Haveles (p. 25)Haveles (p. 25) Two ways in which drugs can be applied topicallyTwo ways in which drugs can be applied topically

The mucous membranes of the oral cavity provide a The mucous membranes of the oral cavity provide a convenient absorbing surface for the systemic administration convenient absorbing surface for the systemic administration of many drugsof many drugs

Absorption of many drugs into systemic circulation occurs Absorption of many drugs into systemic circulation occurs rapidlyrapidly

• Avoids both first-pass effect and GI acid and enzymesAvoids both first-pass effect and GI acid and enzymes


Other Routes Other Routes

Haveles (p. 25)Haveles (p. 25) Drugs such as progestins (Norplant), can be Drugs such as progestins (Norplant), can be

implanted under the skin to release a drug over a implanted under the skin to release a drug over a long duration (5 years)long duration (5 years)

Pumps that deliver intravenous drugs can be Pumps that deliver intravenous drugs can be implanted in the bodyimplanted in the body When insulin pumps are used, they can be programmed When insulin pumps are used, they can be programmed

externallyexternally


Dose FormsDose Forms

Haveles (pp. 25-26) (Table 2-2)Haveles (pp. 25-26) (Table 2-2) The most commonly used dose forms in dentistry are The most commonly used dose forms in dentistry are

the tablet and capsule given orallythe tablet and capsule given orally Liquid solutions or suspensions are often prescribed for Liquid solutions or suspensions are often prescribed for

childrenchildren For injection, the drug may be in solution, such as For injection, the drug may be in solution, such as

local anesthetic, or it may be in suspension, such as local anesthetic, or it may be in suspension, such as procaine penicillin Gprocaine penicillin G


Factors that Alter Drug EffectsFactors that Alter Drug Effects Haveles (pp. 25-27)Haveles (pp. 25-27)

Patient compliancePatient compliance Psychologic factorsPsychologic factors ToleranceTolerance Pathologic statePathologic state Time of administrationTime of administration Route of administrationRoute of administration Sex Sex Genetic variationGenetic variation Drug interactionsDrug interactions Age and weightAge and weight EnvironmentEnvironment OtherOther


Patient CompliancePatient Compliance

Haveles (p. 25)Haveles (p. 25) Through either lack of understanding or Through either lack of understanding or

motivation, patients often do not take their motivation, patients often do not take their medication as prescribed or not at allmedication as prescribed or not at all May result from faulty communication, inadequate May result from faulty communication, inadequate

patient education, or the patient’s health belief patient education, or the patient’s health belief systemsystem


Psychologic FactorsPsychologic Factors

The attitude of the prescriber and the dental The attitude of the prescriber and the dental staff can affect the efficacy of the drug staff can affect the efficacy of the drug prescribedprescribed A placebo is a dose form that looks similar to the A placebo is a dose form that looks similar to the

active agent but contains no active ingredientsactive agent but contains no active ingredients The magnitude of the placebo effect depends on The magnitude of the placebo effect depends on

the patient’s perception; individual variation is the patient’s perception; individual variation is largelarge


ToleranceTolerance

Defined as the need for an increasingly larger Defined as the need for an increasingly larger dose to get the same effect as with the original dose to get the same effect as with the original dose, or a decreased effect after repeated dose, or a decreased effect after repeated administration of a given dose of a drugadministration of a given dose of a drug Cross-toleranceCross-tolerance may occur with related compounds may occur with related compounds People under stress may need a larger dose for an People under stress may need a larger dose for an

effecteffect Tachyphylaxis is the very rapid development Tachyphylaxis is the very rapid development

of toleranceof tolerance


Pathologic StatePathologic State

Diseased patients may respond to medication Diseased patients may respond to medication differently than other patientsdifferently than other patients Patients with hyperthyroidism are extremely Patients with hyperthyroidism are extremely

sensitive to the toxic effects of epinephrinesensitive to the toxic effects of epinephrine Patients with liver or kidney disease may Patients with liver or kidney disease may

metabolize or excrete drugs differently, potentially metabolize or excrete drugs differently, potentially leading to increased duration of drug actionleading to increased duration of drug action


Time of AdministrationTime of Administration

The time of administration, especially in The time of administration, especially in relation to meals, may alter the response to relation to meals, may alter the response to the drugthe drug Certain drugs with a sedative action are best Certain drugs with a sedative action are best

administered at bedtimeadministered at bedtime


Route of AdministrationRoute of Administration

Enteral routes are slower, less predictable, and safer Enteral routes are slower, less predictable, and safer than parenteral routesthan parenteral routes


SexSex

Women may be more sensitive than men to Women may be more sensitive than men to certain drugs, perhaps because of their certain drugs, perhaps because of their smaller size or their hormonessmaller size or their hormones

Pregnancy alters the effects of certain drugsPregnancy alters the effects of certain drugs Women of child-bearing age should avoid Women of child-bearing age should avoid

teratogenic drugsteratogenic drugs The health care provider should determine The health care provider should determine

whether the patient is pregnant before whether the patient is pregnant before administering any agentadministering any agent


Genetic VariationGenetic Variation

Differences in patient responses to drugs Differences in patient responses to drugs have been associated with variations in ability have been associated with variations in ability to metabolize certain drugsto metabolize certain drugs Certain populations have a higher incidence of Certain populations have a higher incidence of

adverse effects to some drugs—a genetic adverse effects to some drugs—a genetic predispositionpredisposition


Drug InteractionsDrug Interactions

A drug’s effect may be modified by previous A drug’s effect may be modified by previous or concomitant administration of another drugor concomitant administration of another drug Many mechanisms exist by which drug Many mechanisms exist by which drug

interactions may modify a patient’s treatmentinteractions may modify a patient’s treatment


Age and WeightAge and Weight

The child’s weight should be used to The child’s weight should be used to determine the child’s dosedetermine the child’s dose The manufacturer’s recommendations for The manufacturer’s recommendations for

children’s dosing would be bestchildren’s dosing would be best Older patients may respond differently to Older patients may respond differently to

drugs than younger patientsdrugs than younger patients Whether it is caused by changes in renal or liver Whether it is caused by changes in renal or liver

function or whether being elderly predisposes this function or whether being elderly predisposes this sensitivity is controversialsensitivity is controversial


EnvironmentEnvironment

The environment contains many substances The environment contains many substances that may affect the action of drugsthat may affect the action of drugs Smoking induces enzymes; therefore higher doses Smoking induces enzymes; therefore higher doses

of benzodiazepines are needed to produce the of benzodiazepines are needed to produce the same effect as compared with nonsmokerssame effect as compared with nonsmokers

Chemical contaminants such as pesticides or Chemical contaminants such as pesticides or solvents can have an effect on a drug’s actionsolvents can have an effect on a drug’s action


OtherOther

The action of drugs can be altered by the The action of drugs can be altered by the patient-provider interactionpatient-provider interaction If the patient “believes” in the substance or If the patient “believes” in the substance or

process, then the patient’s opinion will enhance process, then the patient’s opinion will enhance the drug’s effectthe drug’s effect

The attitude of both the patient and the provider The attitude of both the patient and the provider can alter the physiology of the bodycan alter the physiology of the body

Chapter 2: Drug Action and Handling Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.

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