DRUG RECEPTORS &
PHARMACODYNAMICS
Lecture 3
Dr. Amber Shafi
Pharm-D
3rd semester
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🞂 As concentratio of a drug in
thehuman n system a increases,
organ
respons of that system would the
e to increase until a be
response
expecte ismaximal
obtained.
🞂 d
The level of response is related to
thenumber of receptors However
occupied. this relationship is ,
complex.
🞄 Non-linear occupancy-response
Linear occupancy-response
coupling.
🞄 The concept of "spare" receptors…
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🞂 Linear occupancy-response coupling
◦ Sometimes the biologic effect of the drug
is linearly related to the number of receptors
bound
◦ Drug-regulated ion channels, eg, where the
ion current produced by the drug is
directly proportional to the number of
receptors (ion channels) bound.
◦ Non-linear occupancy-response coupling
🞄 In other cases the biologic response
is a more complex function of drug
🞄 binding to receptors
Receptors linked to enzymatic signal
transductioneg, where the biologic response
cascades,often
increases disproportionately to the number of
receptors occupied by drug.
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Many factorsCan contribute toNonlinear coupling
occupancy-response
Spare receptors are receptors that exist in excess
of those required to produce a full effect.
Receptors are said to be "spare" for a given
pharmacologic response if it is possible to elicit a
maximal biologic response at a concentration of agonist
that does not result in occupancy of the full
complement of available receptors.
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🞂
spar receptor may be
Experimentally, e s
demonstrated by irreversibl
using e
antagonists to prevent binding of agonist to
a
proportion of available receptors and
showing that high concentrations of
agonist can still produce an undiminished
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🞂 Thus, the same maximal inotropic
response
of heart muscle to catecholamines can
be elicited even under conditions where
90% of
the -adrenoceptors are occupied by
a quasi-irreversible antagonist.
Accordingly, myocardial cells are said to
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🞂 Maximal response can be elicited by
activation of relatively few receptors
because the response initiated by an
individual ligand-receptor binding
event persists longer than the binding
event itself.
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🞂Thus, the sensitivity of a cell or tissue
to a particular concentration of
agonist depends not only on the
affinity of the receptor for binding
the agonist (characterized by the
Kd) but also on the degree of spareness
— the total present
receptor number of with
s compared actually the
number biologic
maximal needed to elicit
response. a
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🞂 Theconcept of spare receptors is very
useful clinically because it allows one
to think precisely about the effects of
drug dosage, without needing to
consider biochemical details of the
signaling response.
🞂 The Kd of the agonist-receptor
interaction determines what fraction
(B/Bmax) of total receptors will be
occupied at a given free concentration
(C) of agonist regardless of the receptor
concentration:
🞂 B
= C
Bmax
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Agonist
🞂 drugs bind to and activate the receptor
in some fashion which directly or
indirectly brings about the effect
Pharmacologic antagonist drugs
🞂 by binding to a receptor, compete
with and prevent binding by other
molecules.
🞂 For example, acetylcholine receptor
blockers
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Antagonists
:
◦ Receptor antagonists bind to receptors but do not activate them.
◦ Some antagonists (so-called "inverse agonists"), also reduce receptor
activity below basal levels observed in the absence of bound ligand.
◦ Antagonists can be,
• 🞄 Reversible (competitive).
• 🞄 Irreversible (noncompetitive).
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