drug receptors & pharmacodynamics

8/4/2019 Drug Receptors & Pharmacodynamics

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Drug Receptors &

Pharmacodynamics

Nancy Bruton-Maree, CRNA, MS

Raleigh School of Nurse Anesthesia

UNCG


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Pharmacodynamics

The component of a cell or organism that interactswith a drug & initiates the chain of events leading tothe drugs observed effect is a receptor

Receptors have become the central focus ofinvestigation of drug effects & their mechanisms ofaction (Pharmacodynamics)


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Receptor Concept

Receptors largely determine the quantitativerelations between dose or concentration of drug &pharmacologic effects

Receptors are responsible for selectivity of drugaction

Receptors mediate the actions of pharmacologicagonists & antagonists


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Common Definitions

Orphan receptors their ligands have not beenidentified

Regulatory proteins Proteins which medicate theactions of endogenous chemical signals

Classes of proteins

Enzymes one of the types of receptors that has been identifiedwhich may be inhibited by binding a drug

Transport proteins

Structural proteins


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Relation Between Drug Concentration &Response

This can be described with mathematical precision This is an idealized relationship that underlies the

more complex relations between dose & effect thatoccur when a drug is given to a patient.


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Concentration-Effect Curve & ReceptorBinding of Agonists

Responses to low doses of a drug usually increasein direct proportion to dose

As doses increase, the response incrementdiminishes

Doses may be reached at which no further increasein response can be achieved


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Equation Used to Develop Curve

E = Emax X C C + EC50

E = effect observed at concentration C

EMAX = the maximal response that can be producedby the drug

EC50 = the concetration of drug that produces 50%of maximal effect


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Relationship Between Drug Concentration& Drug Effect or Receptor Bound Drug


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The Drug Concentration at Which Effect or ReceptorOccupancy is Half-Maximal Are Denoted by EC50 & Kd


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Hyperbolic Relationship

Resembles the mass action law, which describesassociation between 2 molecules of a given affinity

This resemblance suggests that drug agonists actby binding to a distinct class of biologic moleculeswith a characteristic affinity for the drug receptor

Drug bound to receptors (B) relates to theconcentration of free (unbound) drug (C) as

depicted in the previous slide


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Previous Curve

Equation B = Bmax X C C + Kd Bmax = indicates the total concentration of receptor sites

Kd = the concentration of free drug at which half-maximalbinding is observed. This constant characterizes thereceptors affinity for binding the drug in a reciprocal

fashion

If the Kd is low, the binding affinity is high and vice versa

The EC50 & Kd may be identical, but need not be


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Other Facts About Curves

Dose-response data are often presented as a plotof the drug effect (ordinate) against the logarithm ofthe dose or concentration (abscissa)

This makes the curve sigmoid in shape with a linearmidportion

This expands the scale of the concentration axis atlow concentrations (where the effect is changing

rapidly) & compresses it at high concentrations(where the effect is changing slowly), but has nospecial biologic or pharmacologic significance.


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Receptor-Effector Coupling & SpareReceptors

Coupling the transduction process that links drugoccupancy of receptors & pharmacologic response

The relative efficiency of occupancy-responsecoupling is partially determined by the initialconformational change in the receptor

The effect of full agonists can be considered moreefficiently coupled to receptor occupancy than can

the effects of partial agonists


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Receptor occupancy into cellular response couplingefficiency is also determined by the biochemicalevents that transduced

Sometimes the biologic effect of the drug is linearlyrelated to the number of receptors bound

This is often true for the drug-regulated ionchannels in which the ion current produced by the

drug is directly proportional to the number ofreceptors bound


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Factors that contribute to non-linear occupancy-response coupling

spare receptors receptors are spare for a givenpharmacologic response if it is possible to elicit a

maximal biologic response at a concentration of agonistthat does not result in occupancy of the full complementof available receptors


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What does Temporal mean? Maximal response can be elicited by activation of relatively

few receptors because the response initiated by an individualligand-receptor binding event persists longer than the bindingevent itself

Spare in number If the concentration or amount of cellularcomponents other than the receptors limits the coupling ofreceptor occupancy to response, then a maximal responsecan occur without occupancy of all receptors; thus thesensitivity of a cell or tissue to a particular concentration of

agonist depends not only on the affinity of the receptor forbinding the agonist but also on the degree of spareness (thetotal number of receptors present compared with the numberactually needed to elicit a maximal response.


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Receptor-Effector Coupling


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Concept of Spare Receptor Coupling

B Bmax = C C + Kd

The Dd of the agonist-receptor interaction

determines what fraction (B/Bmax) of total receptorswill be occupied at a given free concentration (C) ofagonist regardless of the receptor concentration


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Competitive & Irreversible Antagonists

Receptor antagonists bind to receptors but do notactivate them

The primary action of antagonists is to preventagonists from activating receptors

Inverse agonist also an antagonist but can reducereceptor activity below basal levels observed in theabsence of bound ligand


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Competitive & Irreversible Antagonists

Competitive Antagonist In the presence of a fixedconcentration of agonist, increasing concentrations of areversible antagonist progressively inhibit the agonistresponse

High antagonist concentration prevent response completely. However, sufficiently high concentrations of agonist can

surmount the effect of a given concentration of theantagonist.

Because the antagonism is competitive, the presence ofantagonist increases the agonist concentration required fora given degree of response and so the agonistconcentration-effect curve is shifted to the right.


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Competitive Antagonism


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Competitive v. Irreversible Antagonism

The concentration of the agonist required toproduce a given effect in the presence of a fixedconcentration of competitive antagonist is greaterthan the concentration of the agonist required to

produce the same effect when the antagonist is notpresent.

The ratio of the two agonists concentration is

related to the dissociation constant of theantagonist by the Schild equation


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Noncompetitive Antagonist


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Schild Equation

C C = 1 + [I] Ki

C is the concentration of an agonist required to produce agiven effect in the presence of a fixed concentration [I] of

competitive antagonist

[I] is the fixed concentration of the antagonist

C the agonist concentration required to produce the sameeffect in the absence of the antagonist

Ki is the dissociation constant of the antagonist


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Importance of Schild Equation

The degree of inhibition produced by a competitiveantagonist depends on the concentration ofantagonist

Clinical response to a competitive antagonistdepends on the concentration of agonist that iscompeting for binding to receptors


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Irreversible Antagonism

This type of antagonism may be irreversible ornearly irreversible

It involves forming covalent bonds or binding sotightly to receptors that the receptor is unavailableto the agonist

P ibl R l f I ibl


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Possible Reversal of IrreversibleAntagonism

Ad t & Di d t f I ibl


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Advantages & Disadvantages of IrreversibleAntagonism

Once the irreversible antagonist has occupied thereceptor, it need not be present in unbound form toinhibit agonist responses

Therefore, the duration of action of such anirreversible antagonist is relatively independent ofits own rate of elimination & more dependent on therate of turnover of receptor molecules


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Noncompetitive Antagonists

Noncompetitive antagonists can function in differentways:

By binding to a site on the receptor protein separate fromthe agonist binding site which prevents receptor

activation without blocking agonist binding Although these drugs can act noncompetitively, their

action is reversible if they do not bind covalently

Allosteric modulators function without inactivating the

receptor & alter receptor function without inactivating thereceptor


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Partial Agonists

There are two classes of agonists based on themaximal pharmacologic response that occurs whenall receptors are occupied.

The two classes are full agonist & partial agonist


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Receptor-Effector Coupling


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Partial Agonist v. Full Agonist


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Partial Agonists

Facts Failure of a partial agonist to produce a maximal

response is not due to decreased affinity for bindingreceptors

Partial agonists competitively inhibit the responsesproduced by full agonists

Many drugs used as antagonists are actually weak partialagonists


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Partial Agonist


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Other Mechanisms of Drug Antagonism

Chemical antagonist one drug acts as a chemicalantagonist of the other simply by ionic binding that makesthe other drug unavailable for interactions with the proteinsinvolved in the outcome (i.e., blood clotting)

Physiologic antagonist between endogenous regulatorypathways mediated by different receptors. The use ofphysiologic antagonists produces effects that are lessspecific & less easy to control than are the effects of areceptor-specific antagonism


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Signaling Mechanisms & Drug Action

Questions to answer: Why do some drugs produce effects that persist for minutes, hours,

or even days after the drug is no longer present in the body?

Why do responses to other drugs rapidly diminish with prolonged orrepeated administration?

How do cellular mechanisms for amplifying external chemical signalsexplain the phenomenon of spare receptors?

Why do chemically similar drugs often exhibit extraordinaryselectivity in their actions?

Do these mechanism provide targets for enveloping new drugs?

Five Basic Mechanisms of Transmembrane


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Five Basic Mechanisms of TransmembraneSignaling

Lipid-soluble ligand that crosses the membrane & acts as anintracellular receptor

Transmembrane receptor protein whose IC enzymatic activity isallosterically regulated by a ligand that binds to a site on theproteins EC domain

Transmembrane receptor that binds & stimulates a proteintyrosine kinase

Ligand-gated transmembrane ion channel that can be induced toopen or close by the binding of ligand

Transmembrane receptor protein that stimulates a GTP-bindingsignal transducer protein (G protein)which in turn modulatesproduction of an IC second messenger.


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Five Basic Mechanism


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IC Receptors for Lipid-Soluble Agents

Classes include: Steroids

Thyroid hormone

The receptors for these stimulate transcription ofgenes by binding to response elements on DNAnear the gene whose expression is to be regulated


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IC Receptors

Two Therapeutically Important


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Two Therapeutically ImportantConsequences

All of these hormones produces their effect after acharacteristic lag period of 30 minutes to severalhours

The time required to synthesize new proteins

The effects of these agents can persist for hours ordays after the agonist concentration has beenreduced to zero

The persistence is due to slow turnover of mostenzymes & proteins, which can remain active in cells forhours or days after synthesis.

Ligand Regulated Transmembrane Enzymes


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Ligand-Regulated Transmembrane EnzymesIncluding Receptor Tyrosine Kinases

Signalling is by trophic hormones Examples are insulin, epidermal growth factor (EGF),

platelet-deriving growth factor (PDGF), atrial natriureticpeptide (ANP), & transforming growth factor- (TGF-)

Receptors are polypeptides consisting of an EC hormone-binding domain & a cytoplasmic enzyme domain

May be a protein tyrosine kinase, a serine kinase, or aguanylyl cyclase

The two domains are connected by a hydrophobic segmentof the polypeptide that crosses the lipid bilayer of theplasma membrane

Ligand-Regulated Transmembrane


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Ligand-Regulated TransmembraneEnzymes


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What Limits Intensity & Duration of Action

Down-regulation occurs when tyrosine kinasesare involved

Ligand-binding induces accelerated endocytosis ofreceptors from the cell surface, followed by the

degradation of receptors from the cell surface.

When this process occurs at a rate faster than denovo synthesis of receptors, the total number of

cell-surface receptors is reduced.


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Cytokine Receptors

Phosphorylated tyrosine residues on the receptorscytoplasmic surface then set in motion a complexsignaling dance by binding another set of proteins,called STATs

The bound STATs are themselves phosphorylatedby the JAKs, 2 STAT molecules dimerize theSTAT/STAT dimer dissociates form the receptor &

travels to the nucleus, where it regulatestranscription of specific genes.


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Cytokine Receptors


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Ligand- and Voltage-Gated Channels

Natural ligands are Acetylcholine

Serotonin

GABA

Glutamate

Each of their receptors transmits its signal acrossthe plasma membrane by increasing

transmembrane conductance of the relevant ion &thereby altering the electrical potential across themembrane


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Ligand- & Voltage-Gated Receptors

The time elapsed between the binding of the agonist to aligand-gated channel & the cellular response can often bemeasured in milliseconds

Ligand-gated ion channels can be regulated by multiple

mechanisms, including phosphorylation and endocytosis Voltage-gated channels do not bind neurotransmitters

directly but are controlled by membrane potential

Such channels are also important drug targets

G C


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Ligand- & Voltage-Gated Channels

G P i & S d M


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G Proteins & Second Messengers

Second messengers are cyclic adenosine-3,5 -monophophate (cAMP), calcium ion, &phophoinositides

G proteins usually use a transmembrane signaling

system with 3 separate components

EC ligand

Receptor

Activated G protein The concentration of second messenger changes

G P i & S d M


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G Protein & Second Messenger

For cAMP, the effector enzyme is adenylyl cyclase Examples of G protein receptors

adrenoceptors

Glucagon receptors

Thyrotropin receptors

Dopamine receptors

Serotonin receptors

G P t i & S d M


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G Protein & Second Messenger

Duration of activation of adenylyl cyclase dependson the longevity of GTP binding to the G protein

Receptors coupled to G proteins are GPCRs

They make up a family of seven-transmembrane(7TM) or serpentine receptors

G P t i & S d M


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G Proteins & Second Messengers

G P t i & S d M


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G Proteins & Second Messenger

GPCRs exist as homodimers & heterodimers


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R t R l ti D iti ti


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Receptor Regulation - Desensitization

R t R l ti D R l ti


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Receptor Regulation Down Regulation

Well Established Second Messengers


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Well Established Second Messengers

cAMP Calcium & Phophoinositides

cGMP

cAMP Second Messenger Pathway


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cAMP Second Messenger Pathway

Calcium & Phosphoinositides


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Calcium & Phosphoinositides

Some of the hormones, neurotransmitters, &growth factor that trigger this pathway bind toreceptors liked to G proteins; others bind toreceptor tyrosine kinases

Crucial step is stimulation of a membrane enzyme,phospholipase C which splits a minor phospholipidcomponent of the membrane, phophatidylinosital-4,5-bisphophate, into 2 second messengers,diacylglycerol and inositol-1,4,5-trisphosphate

Ca2+ Phosphoinositide Signaling Pathway


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Ca2+ -Phosphoinositide Signaling Pathway

Cyclic Guanosine Monophosphate


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Cyclic Guanosine Monophosphate

cGMP establishes signals in only a few cells Cell-surface receptors stimulate membrane-bound

guanylyl cyclase to produce cGMP

cGMP acts by stimulating a cGMP-dependentprotein kinase

Termination is by enzymatic degradation of thecyclic nucleotide & by phosphorylation of kinase

substrates

cGMP


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cGMP

Interplay Among Signaling Mechanisms


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Interplay Among Signaling Mechanisms

Calcium-phosphoinositide & cAMP signalingpathways oppose one another in some cells butcompliment each other in other cells

Phosphorylation


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Phosphorylation

Supplies amplification & flexible regulation Amplification the attachment of a phosphoryl

group to a serine, threonine, or tyrosine residuepowerfully amplifies the initial regulatory signal by

recording a molecular memory that the pathwayhas been activated

Dephosphorylation erases the memory

Phosphorylation


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Phosphorylation

Flexible regulation differing substrate specificitiesof the multiple protein kinases regulated by secondmessengers provide branch points in signalingpathways that may be independently regulated

Receptor Classes & Drug Development


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Receptor Classes & Drug Development

Structure-activity relationship the agonist orantagonist that occupies the same receptor as theagonist must fit the receptor like a lock & key

If two agonists exhibit identical relative potencies in

producing 2 distinct effects, it is likely that the 2effects are mediated by similar or identical receptormolecules

The same neurotransmitter can act on differentreceptor types

Dose & Response In Patients


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Dose & Response In Patients

Graded Dose-Response Relationships to chooseamong drugs & to determine appropriate doses of adrug, one must know

Pharmacologic potency

Maximal efficacy

In relation to the desired therapeutic effect wanted

Graded Dose-Response Curves


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Potency


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Potency

Refers to the concentration (EC50 ) or dose (ED50 )of a drug required to produce 50% of that drugs

maximal effect

Potency determines the administered dose of drug

Potency depends in part on

Affinity of receptors for binding the drug

The Efficiency with which drug-receptor interaction is

coupled to response

Potency


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Potency

Potency of a drug should be stated in dosage units Relative potency, the ratio of equi-effective doses,

may be used in comparing 2 drugs

Efficacy


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Efficacy

A drugs clinical effectiveness depends not on itspotency but on it maximal efficacy & its ability toreach the relevant receptors

This can depend on

Its route of administration

Absorption

Distribution

Clearance from blood

Clearance from its site of action

Maximal Efficacy


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Maximal Efficacy

Efficacy is shown on the response axis The drugs propensity to cause toxic effects may

limit the ability to utilize its maximal efficiacy

Efficacy may be determined by

The drugs mode of interactions with the receptors

By characteristics of the receptor-effector systeminvolved



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Graded Dose Response Curves

Shape of Dose-Response Curves


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Shape of Dose Response Curves

Curves A, B, & C in the preceding slide approximate theshape of a simple Michaelis-Menton relation. Not all clinicalresponses do this

Extremely steep dose-response curves like curve D mayhave important clinical consequences if the upper portion ofthe curve represents an undesirable extent of response

Steep dose-response curves can result from cooperativeinteractions of several different actions of a drug

Quantal Dose-Effect Curves


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Quantal Dose Effect Curves

These curves determine the dose of drug requiredto produce a specified magnitude of effect in alarge number of patients or experimental animals

They plot the cumulative frequency distribution of

responders v. the log dose

A specific quantal effect may be chosen on thebasis of clinical relevance, for preservation of safety

of experimental subjects, or it may be an inherentlyquantal event

Quantal Dose-Effect Curves


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Quantal Dose Effect Curves

The frequency distribution of such responses areplotted against the log of the dose, which producesa gaussian normal curve variation

When these responses are summated, the resulting

cumulative frequency distribution constitutes aquantal dose-effect curve or the proportion orpercentage of individuals who exhibit the effectplotted as a function of log dose

Quantal Dose-Effect Curve


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Quantal Dose Effect Curve


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Both curve types give information about potency &selectivity of drugs

Graded dose-response curves indicate maximalefficacy of a drug

Quantal dose-effect curves indicate potentialvariability of responses among individuals

Variation In Drug Responsiveness


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Variation In Drug Responsiveness

Idiosyncratic drug responses

Idiosyncratic responses

Immunologic mechanisms (hypersensitivity)

Quantitative variations

Hyporeactive

Hyperreactive Tolerance

Tachyphylaxis

Need to consider:

Propensity of a drug to produce tolerance or tachyphylaxis Effects of sex, age, body size, disease states, genetic factors,

simultaneous administration of other drugs

Four Mechanisms That Contribute ToV i ti I D R


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Variation In Drug Response

Alteration in concentration of drug that reachesreceptor

Variation in concentration of an endogenousreceptor ligand

Alterations in number or function of receptors

Changes in components of response distal to thereceptor

Clinical Selectivity: Beneficial v. ToxicEff t f D


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Effects of Drugs

Beneficial & toxic effects mediated by the samereceptor-effector mechanism

Beneficial & toxic effects mediated by identicalreceptors but in different tissues or by different

effector pathways Beneficial & toxic effects mediated by different

types of receptors


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drug receptors & pharmacodynamics

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