dose–response relationships
TRANSCRIPT
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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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END