Dose–Response Relationships

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DoseResponse Relationships

WESAM RADHI KADHUM


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Graded doseresponse relations

The dose-responserelationship, or exposure-

response relationship,

descr

ibes the change in effecton an organism caused by

differing levels of exposure (or

doses) to a stressor (usually a

chemical) after a certainexposure time.


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1. Potency: Two important properties of drugs can bedetermined by graded doseresponse curves.

The first is potency, a measure of the amount ofdrug necessary to produce an effect of a givenmagnitude.For a number ofreasons, the concentration producingan effect that is fifty percent of the maximum is usedto determine potency; it commonly designated as theEC

50.

Half maximal effective concentration (EC50)


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In this figure, the EC50

for Drugs A and B areindicated.

Drug A is more potent

than Drug B because

less Drug A is needed

to obtain 50 percent

effect.

Thus, therapeutic

preparations of drugs

will reflect the potency.


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For example, candesartan and irbesartan are

angiotensinr

eceptor

blocker

s that ar

e usedalone or in combination to treat hypertension.

Candesartan is more potent than irbesartan

because the dose range for candesartan is 4 to

32 mg, as compared to a dose range of 75 to

300 mg for irbesartan.

Candesartan would be Drug A and irbesartan

would be Drug B.


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Semilogarithmic plots are oftenemployed, because the range ofdoses (or concentrations) mayspan several orders ofmagnitude.

By plotting the log of theconcentration, the completerange of doses can be graphed.

As shown in Figure B, the

curves become sigmoidal inshape. It is also easier tovisually estimate the EC50.


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A dr

ug with gr

eater

efficacy is moretherapeutically beneficialthan one that is more

potent. This figure shows theresponse to drugs of differing potency and

efficacy.


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3. Drugreceptor binding (Affinity) :

We can mathematically express the

relationship between the percentage (or

fraction) of bound receptors and the drugconcentration:


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Where [D] = the concentration of free drug;

[DR] = the concentration of bound drug; [Rt] =the total concentration of receptors, and is

equal to the sum of the concentrations of

unbound (fr

ee)r

eceptor

s and boundr

eceptor

sand; Kd = [D][R]/[DR], and is the dissociation

constant for the drug from the receptor.


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The value ofKd can be used to determine the

affinity of a drug for its receptor.

Affinity describes the strength of the

interaction (binding) between a ligand and its

receptor. The higher the Kd value, the weaker the

interaction and the lower the affinity.

The converse occurs when a drug has a low Kd. The binding of the ligand to the receptor is

strong, and the affinity is high.


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As the concentration of freedrug increases, the ratio of

the concentrations of boundreceptors to total receptorsapproaches unity.

Doses are often plotted on alogarithmic scale, because therange from lowest to highestconcentrations of doses oftenspans several orders ofmagnitude.

It is important to note thesimilarity between thesecurves and those representingthe relationship between

dose and effect.


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4. Relationship of binding to effect: The binding

of the drug to its receptor initiates events thatultimately lead to a measurable biologic

response.

The mathematical model that describes d

rugconcentration and receptor binding can be

applied to dose (drug concentration) and

response (or effect), providing the following

assumptions are met:


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1)The magnitude of the response is proportional

to the amount of receptors bound oroccupied.

2) The Emax occurs when all receptors are bound.


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5. A

gonists: If a dr

ug binds to ar

eceptor

andproduces a biologic response that mimics theresponse to the endogenous ligand, it isknown as an agonist.

For example, phenylephrine is an agonist at1-adrenoceptors, because it produceseffects that resemble the action of theendogenous ligand, norepinephrine.

Explain How?


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6. Antagonists: Antagonists are drugs that

decrease the actions of another drug orendogenous ligand.

Antagonism may occur in several ways. Many

antagonists act on the identical receptor

macromolecule as the agonist.

Antagonists, however, have no intrinsic

activity and, therefore, produce no effect by

themselves.


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Plotting the effect of thecompetitive antagonist

characteristically causes a

shift of the agonist dose

response curve to the right.


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Home Work

Differentiate between:

Functional antagonism and Partial agonists

References: Basic and clinical pharmacology / edited by Bertram G. Katzung;

associate editors, Susan B. Masters, Anthony J. Trevor. 11th ed New

York: McGraw Hill, 2009.

Goodman and Glimans manual of pharmacology and therapeutics /

Laurence Brunton[ et al.]. New York: Mc Graw-Hill, 2008.

Loppincotts illustrated reviews Pharmacology / Richard A.Harvey,

Pamela C.Champe. -- 4rd edPhiladelphia Lippincott Williams and

Wilkins, 2009.


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