i.drug receptors and pharmacodynamics therapeutic and/or toxic effects of drugs result from their...
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I. DRUG RECEPTORS AND PHARMACODYNAMICS
Therapeutic and/or toxic effects of drugs result from their interactions with molecules in the patient.
Most drugsact by associating with specific macromolecules in ways that alter the macromolecules’ biochemical or biophysical activities
Drug receptor:the component of a cell or organism that interacts with a drug and initiates the chain of biochemical events leading to the drug’s observed effects
I. DRUG RECEPTORS AND PHARMACODYNAMICS
1. Receptors largely determine the quantitative relations between dose or concentration of drug and pharmacologic effects.
2. Receptors are responsible for selectivity of drug action
size, shape and electrical charge of drug are important
3. Receptors are the sites of binding of pharmacologic agents
II. Macromolecular Nature of Drug Receptors
Until recently, the chemical structures and even the existence of receptors for most drugs could only be inferred from the chemical structures of the drugs themselves.
Receptors for many drugs have been biochemically purified and characterized.
Most receptors are proteinspresumably because the
structures of polypeptides provide both the necessary diversity and the necessary specificity of shape and electrical charge.
II. Macromolecular Nature of Drug Receptors
The best-characterized drug receptors are regulatory proteins
mediate the actions of endogenous chemical signals such as neurotransmitters, autacoids and hormones
this class of receptors mediates the effects of many of the most useful therapeutic agents
enzymesmay be inhibited (or, less commonly,
activated)by drugs
(e.g. dihydrofolate reductase- dhfr- the receptor for the antineoplastic drug methotrexate)
II. Macromolecular Nature of Drug Receptors
The best-characterized drug receptors are (cont).
transport proteinsproteins involved in the transport of ions or
other biological molecules
Na+/K+ ATPasethe membrane receptor for cardioactive digitalis glycosides
structural proteinsproteins involved in maintenance of cellular
integritytubulinthe receptor for colchicine, an anti-
inflammatory agent
III. Relation Between Drug Concentration and Response
The relationship between dose of a drug and the clinically-observed response may be quite complex.
in carefully-controlled in vitro systems, however, the relationship between concentration of a drug and its effect is often simple and can be described with mathematical precision.
the idealized relationship underlies the more complex relations between dose and effect that occur when drugs are given to patients.
IIIA. Concentration-Effect Curves and Receptor Binding of Agonists
Even in intact animals or patients,
responses to low doses of drug usually increase in direct proportion to dose.
as doses increase, the response increment diminishes
finally, doses may be reached at which no further increase in response can be achieved.
IIIA. Concentration-Effect Curves and Receptor Binding of Agonists
0
3
6
9
12
0 5 10 15
DRUG CONCENTRATION
DRUG
EFF
ECT
In idealized or in vitro systems, the relationship between drug concentration (C) and effect (E) is described by a hyperbolic curve according to the equation:
E= Emax x CC + EC50
0
3
6
9
12
0 5 10 15
DRUG CONCENTRATION
DRUG
EFF
ECT
IIIA. Concentration-Effect Curves and Receptor Binding of Agonists
Emax: the maximal response that can be produced by the drug.EC50: concentration of the drug that produces 50% of maximal effectE: the effect observed at a particular drug concentrationC: concentration of drug
E= Emax x CC + EC50
Emax
EC50
IIIA. Concentration-Effect Curves and Receptor Binding of Agonists
In these systems, the relation between drug bound to receptors (B) and the concentration of unbound drug (C) is described by the equation:
B = Bmax x C-------------C + Kd
In which Bmax is the total concentration of receptor sites
sites bound to the drug at infinitely high concentrations of free drug.
Kd is the equilibrium dissociation constantrepresents the concentration of free
drug at which half-maximal binding is observed
IIIA. Concentration-Effect Curves and Receptor Binding of Agonists
0
1
0 5 10 15
DRUG CONCEN. (C)
Rece
ptor
-Bou
nd D
rug
(B)
Bmax
KD
Kd is the equilibrium dissociation constantrepresents the concentration of free drug at which half-maximal binding is observed
IIIA. Concentration-Effect Curves and Receptor Binding of Agonists
Kd represents the concentration of free drug at which half-maximal binding is observed.
The Kd characterizes the receptor’s affinity for binding the drug in a reciprocal fashion.
If Kd is high, binding affinity is low.
If Kd is low, binding affinity is high.
IIIA. Concentration-Effect Curves and Receptor Binding of Agonists
Graphic representation of dose-response data is frequently improved by plotting the drug effect against the logarithm of the dose or concentration.
the effect of this mathematical maneuver is to transform a hyperbolic curve into a sigmoidal curve with a linear midportion.
0
1
0 5 10 15
DRUG CONCEN. (C)
Drug
Effe
ct
0
1
1 10
LOG DRUG CONCEN. (C)
Drug
Effe
ct
IIIB. Receptor-Effector Coupling and Spare Receptors
When a receptor is occupied by an agonist, the resulting conformational change is only the first of many steps usually required to produce a pharmacological effect.
The transduction process between occupancy of receptors and drug response is often called coupling.
IIIB. Receptor-Effector Coupling and Spare Receptors
The relative efficiency of receptor occupancy-response coupling is partially determined by the initial conformational change in the receptor.
the effects of full agonists can be considered more efficiently coupled to receptor occupancy than can the effects of partial agonists.
IIIB. Receptor-Effector Coupling and Spare Receptors
High efficiency of receptor-effector interaction may also be the result of spare receptors.
Receptors are said to be spare for a given pharmacologic response when
the maximal response can be elicited by an agonist at a concentration that does not result in occupancy of the full complement of available receptors.
IIIB. Receptor-Effector Coupling and Spare Receptors
spare receptors are not qualitatively different from nonspare receptors.
*not hidden or unavailable*when they are occupied, they can be
coupled to response.
Experimentally, spare receptors may be demonstrated by using irreversible antagonist
to prevent binding of agonist to a proportion of available receptors and showing that high concentrations of agonist can still produce an undiminished maximal response.
IIIB. Receptor-Effector Coupling and Spare Receptors
Thus, a maximal inotropic response of heart muscle to catecholamines can be elicited even under conditions where 90% of the B-adrenoceptors are occupied by a quasi-irreversible antagonist.
Myocardium is said to contain a large proportion of spare B-adrenoceptors.
Spare Receptors
AG
ON
IST E
FFEC
T0
.5A B C
D
E
EC50 (A) EC50 (B) EC50 (C)
EC50 (D,E)
Max Response
When irreversible antagonist concentration is too high, the “spare receptors” are all occupied and the maximal response is diminished!! (see curves D and E).
No
Ant
agon
ist
Low
[Ant
agon
ist]
Hig
h [A
ntag
onis
t]
Very High [Antagonist]
Very Very High [Antagonist]
KD= the concentration of agonist when half the receptors are bound.
Agonist (purple) binding to receptor (light green) elicits a change in receptor conformation. That enables the receptor to bind to and activate a transducing molecule (yellow).
As depicted here, the concentration of agonist is equal to the KD (the concentration of drug at which half of the receptors are occupied).
DrugCell Membrane
Here..the transducing molecule does not mediate receptor action b/cno drug has modulated a conformational change in the receptor. In this case, the transducing molecule is not activated by the receptor.
Spare Receptors- More Drug receptors than Receptor-Effector Molecules
Drug
Cell Membrane
As depicted here, the number of receptors has increased and the KD for agonist binding remains unchanged.
Here the concentration of agonist is much less than the KD (the concentration of drug at which half of the receptors are occupied).
The number of transducing molecules, however, is the same as before…Spare receptors allow a response to be obtained under conditions where the agonist concentration is low.
IIIB. Receptor-Effector Coupling and Spare Receptors
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 C + Kd
IIIB. Receptor-Effector Coupling and Spare Receptors
Imagine a responding cell with four receptors and four effectors. Here the number of effectors does not limit the maximal response, and the receptors are NOT spare in number.
An agonist present at a concentration equal to the KD will occupy 50% of the receptors, and half of the effectors will be activated, producing a half-maximal response.
(ie. Two receptors stimulate two effectors)
IIIB. Receptor-Effector Coupling and Spare Receptors
Now imagine that the number of receptors increases ten fold and but the total number of effectors remains constant.
Most of the receptors are now spare in number.
IIIB. Receptor-Effector Coupling and Spare Receptors
As a result, a much lower concentration of the agonist is sufficient to bind two of the 40 receptors (5% of the receptors)… and this same low concentration of agonist is able to elicit a half-maximal response.
Thus, it is possible to change the sensitivity of tissues with spare receptors by changing the receptor concentration.
IIIC. Competitive and Irreversible Antagonists
Receptor antagonists bind to the receptor but do not activate it.
The effects of antagonists, in general, result from preventing agonists (other drugs or endogenous regulatory molecules) from binding to and activating receptors.
IIIC. Competitive and Irreversible Antagonists
Antagonists can be divided into two classes depending on whether or not they reversibly compete with agonists for binding to receptors:
reversible antagonists (competitive)
irreversible antagonists (noncompetitive)
These two classes of antagonists produce quite different concentration-effect and concentration-binding curves.
IIIC. Competitive and Irreversible AntagonistsIn the presence of a fixed concentration of
agonist, increasing concentrations of a competitive antagonist progressively inhibit the agonist response;
high antagonist concentrations prevent response completely.
conversely, sufficiently high
concentrations of agonist can completely surmount the effect of a given concentration of the antagonist.
IIIC. Competitive and Irreversible Antagonists
In other words:the Emax for the agonist remains the same for any fixed concentration of competitive antagonist.
because the antagonism is competitive, the presence of antagonist increases the agonist concentration required for a given degree of response, and the agonist concentration-effect curve shifts to the right.
Ag
on
ist
Eff
ect
(E)
Agonist Concentration
EmaxAgonist Alone
Agonist + competitive antagonist
EC50 EC50
IIIC. Competitive and Irreversible Antagonists
Ag
on
ist
Eff
ect
(E)
Agonist Concentration
EmaxAgonist Alone
Agonist + competitive antagonist
C C’
The concentration (C’) of an agonist required to produce a given effect in the presence of a fixed concentration [I] of competitive antagonist is greater than the agonist concentration (C) required to produce the same effect in the absence of antagonist.
IIIC. Competitive and Irreversible Antagonists
Ag
on
ist
Eff
ect
(E)
Agonist Concentration
EmaxAgonist Alone
Agonist + competitive antagonist
C C’
The ratio of these two agonist concentrations (the “dose ratio”) is related to the dissociation constant (KI) of the antagonist by the SCHILD EQUATION:
C’ = 1 + [I]/KI---C
IIIC. Competitive and Irreversible Antagonists
Ag
on
ist
Eff
ect
(E)
Agonist Concentration
EmaxAgonist Alone
Agonist + competitive antagonist
C C’
In the presence of a fixed concentration of competitive antagonist, higher concentrations of agonist are required to produce a given effect. Thus, the agonist concentration (C’) required for a given effect in the presence of concentration [I] of antagonist is shifted to the right.
IIIC. Competitive and Irreversible Antagonists
Ag
on
ist
Eff
ect
(E)
Agonist Concentration
EmaxAgonist Alone
Agonist + competitive antagonist
C C’
High agonist concentrations can overcome inhibition by a competitive antagonist.
This is not the case with an irreversible antagonist, which reduces the maximal effect the agonist can achieve
IIIC. Competitive and Irreversible Antagonists
Ag
on
ist
Eff
ect
(E)
Agonist Concentration
EmaxAgonist Alone
Agonist + competitive antagonist
C C’C’ = 1 + [I]/KI
---C
Pharmacologists often use this relation to determine the KI of a competitive antagonist. Even without knowledge of the relationship between agonist occupancy of the receptor and response, the KI can be determined simply and accurately.
IIIC. Competitive and Irreversible Antagonists
Here is a hypothetical example of Schild’s Eqn.(fixed concentration of competitive antagonist):
If C’ is twice C, then [I] = KI
What if C’ is three times the value of C… what is the KI?
3 = 1 + [I]/KI
2= [I]/KI
2*KI= [I]
Ag
on
ist
Eff
ect
(E)
Agonist Concentration
EmaxAgonist Alone
Agonist + competitive antagonist
C C’
C’ = 1 + [I]/KI---C
IIIC. Agonists
Agonist Concentration
EFF
EC
T(%
of
maxim
um
)
IIIC. Agonists
Agonist Concentration
EFF
EC
T(%
of
maxim
um
)
IIIC. Agonists
Agonist Concentration
EFF
EC
T(%
of
maxim
um
)
IIIC. Agonists
Agonist Concentration
EFF
EC
T(%
of
maxim
um
)
IIIC. Agonists
Agonist Concentration
EFF
EC
T(%
of
maxim
um
)
IIIC. Agonists
Agonist Concentration
EFF
EC
T(%
of
maxim
um
)
IIIC. Agonists
Agonist Concentration
EFF
EC
T(%
of
maxim
um
)
Under circumstances where there is only agonist (green), only agonist can bind to the receptor. When all the receptors are saturated, we see maximum effect (Emax)
IIIC. Agonists
Agonist Concentration
EFF
EC
T(%
of
maxim
um
)
Agonist ConcentrationLog-scale
EFF
EC
T(%
of
maxim
um
)
The effect of this mathematical maneuver is to transform the hyperbolic curve into a sigmoid curve with a linear midportion.
IIIC. Competitive and Irreversible AntagonistsC’ = 1 + [I]/KI
---C
Under circumstances where there is only agonist (green), only agonist can bind to the receptor. When all the receptors are saturated, we see maximum effect (Emax)
Emax
Agonist Concentration
EFF
EC
T
IIIC. Antagonists
Agonist Concentration
EFF
EC
T(%
of
maxim
um
)
IIIC. Antagonists
Agonist Concentration
EFF
EC
T(%
of
maxim
um
)
IIIC. Antagonists
Agonist Concentration
EFF
EC
T(%
of
maxim
um
) As you may have noticed,Antagonists bind to receptors, but do not ACTIVATE those receptors
IIIC. Antagonists
Agonist Concentration
EFF
EC
T(%
of
maxim
um
) As you may have noticed,Antagonists bind to receptors, but do not ACTIVATE those receptors
IIIC. Antagonists
Agonist Concentration
EFF
EC
T(%
of
maxim
um
) As you may have noticed,Antagonists bind to receptors, but do not ACTIVATE those receptors
IIIC. Competitive AntagonistsUnder circumstances where there is both agonist (green) and antagonist (red), both can bind to the receptor. Antagonists have the ability to bind the receptor, but they DO NOT ACTIVATE the receptor. So the maximum effect will be diminished, UNLESS more agonist is added.
Emax
Agonist Concentration
EFF
EC
T
AgonistAlone
Agonist +Antagonist
IIIC. Competitive Antagonists
Fixed concentration of AGONIST alone
IIIC. Competitive Antagonists
Fixed [AGONIST] PLUSA low concentration of REVERSIBLE ANTAGONIST
IIIC. Competitive Antagonists
Fixed [AGONIST] PLUSa higher concentration of REVERSIBLE ANTAGONIST
IIIC. Competitive Antagonists
Fixed [AGONIST] PLUSan even higher concentration of REVERSIBLE ANTAGONIST
IIIC. Competitive Antagonists
Fixed [AGONIST] PLUSeven more REVERSIBLE ANTAGONIST!
Are you starting to see the trend?
IIIC. Competitive Antagonists
Eventually you may displace all of the agonist with antagonist.
IIIC. Competitive Antagonists
If the antagonist concentration is now held constant, and we INCREASE the concentration of agonist… we can displace the competitive, or reversible, antagonist.
IIIC. Competitive Antagonists
If the antagonist concentration is now held constant, and we INCREASE the concentration of agonist… we can displace the competitive antagonist (also called ‘reversible’).
IIIC. Competitive Antagonists
If the antagonist concentration is now held constant, and we INCREASE the concentration of agonist… we can displace the competitive antagonist (also called ‘reversible’).
IIIC. Competitive Antagonists
If the antagonist concentration is now held constant, and we INCREASE the concentration of agonist… we can displace the competitive antagonist (also called ‘reversible’).
IIIC. Competitive Antagonists
If the antagonist concentration is now held constant, and we INCREASE the concentration of agonist… we can displace the competitive antagonist (also called ‘reversible’).
IIIC. Competitive Antagonists
If the antagonist concentration is now held constant, and we INCREASE the concentration of agonist… we can displace the competitive antagonist (also called ‘reversible’).
IIIC. WHAT DO WE MEAN BY ‘Competitive Antagonist?’
Agonist
Competitive Antagonist
ACTIVE
NOTACTIVE
ASSUMING that the following conditions apply:*[Agonist] and [Competitive Antagonist] are
the same.
*Affinity of agonist and competitive antagonist for the receptor are similar
IIIC. WHAT DO WE MEAN BY ‘Competitive Antagonist?’
Agonist CompetitiveAntagonist
ACTIVE
NOTACTIVE
ASSUMING that the following conditions apply:*[Agonist] and [Competitive Antagonist] are
the same.
*Affinity of agonist and competitive antagonist for the receptor are similar
IIIC. WHAT DO WE MEAN BY ‘Competitive Antagonist?’
NOTACTIVE
NOTACTIVE
IIIC. WHAT DO WE MEAN BY ‘Competitive Antagonist?’
ACTIVE
ACTIVE
IIIC. WHAT DO WE MEAN BY ‘Competitive Antagonist?’
A competitive antagonist binds reversibly to the same receptor as the agonist.
a dose-response curve performed in the presence of a fixed concentration of antagonist will be shifted to the right; with the same maximum response and shape.
TRANSLATION:The binding of a reversible or COMPETITIVE antagonist can be overcome with increasing concentrations of agonist– like we just saw.
AGONIST CONCENTRATION (Log)
EFF
EC
T No Antagonist Fixed [antagonist]
IIIC. WHAT DO WE MEAN BY ‘IRREVERSIBLE Antagonist?’
Some receptor antagonists bind to the receptor in an IRREVERSIBLE or nearly irreversible fashion (i.e. NON-Competitive)
The antagonist’s affinity for the receptor may be so high that for practical purposes, the receptor is unavailable for binding of agonist.
Other antagonists in this class produce irreversible effects because after binding to the receptor they form covalent bonds with it.
IIIC. WHAT DO WE MEAN BY ‘IRREVERSIBLE Antagonist?’
After occupancy of some proportion of receptors by such an antagonist, the number of remaining unoccupied receptors may be too low for the agonist (even at high concentrations) to elicit maximal response.
Agonist Alone
Agonist + Irreversible Antagonist
AG
ON
IST E
FFE
CT
NOTE: EC50 may not change
AGONIST CONCENTRATION
NOT LOGSCALE
IIIC. WHAT DO WE MEAN BY ‘IRREVERSIBLE Antagonist?’
If spare receptors are present, however, a lower dose of an irreversible antagonist may leave enough receptors unoccupied to allow achievement of maximum response to agonist.
Drug
RE
SPO
NS
E
[Irreversible Antagonist] 0
Fixed [Agonist]
IIIC. WHAT DO WE MEAN BY ‘IRREVERSIBLE Antagonist?’
If spare receptors are present, however, lower dose of an irreversible antagonist (red) may leave enough receptors unoccupied to allow achievement of maximum response to agonist (purple).
RE
SPO
NS
E
Fixed [Agonist]
[Irreversible Antagonist] 0 LOW
IIIC. WHAT DO WE MEAN BY ‘IRREVERSIBLE Antagonist?’
If spare receptors are present, however, lower dose of an irreversible antagonist (red) may leave enough receptors unoccupied to allow achievement of maximum response to agonist (purple).
RE
SPO
NS
E
Fixed [Agonist]
[Irreversible Antagonist] 0 low med
IIIC. WHAT DO WE MEAN BY ‘IRREVERSIBLE Antagonist?’
If spare receptors are present, however, higher doses of an irreversible antagonist (red) may not leave enough receptors to allow achievement of maximum response to agonist (purple).
RE
SPO
NS
E
Fixed [Agonist]
[Irreversible Antagonist] 0 low med high
IIIC. WHAT DO WE MEAN BY ‘IRREVERSIBLE Antagonist?’Because all of the receptors have been saturated and the binding of the irreversible antagonist is so strong, addition of MORE AGONIST will not re-establish the response. Agonist will not be able to displace the irreversible antagonist. There is no competition for receptor binding, as would be the case with a reversible antagonist.
RE
SPO
NS
E
[Agonist] High
[Irreversible Antagonist] 0 HIGH
As long as the receptors are occupied by irreversible antagonist, addition of MORE AGONIST will not re-establish the response
IIIC. WHAT DO WE MEAN BY ‘IRREVERSIBLE Antagonist?’
Therapeutically, irreversible antagonists present distinctive advantages and disadvantages:
Once the irreversible antagonist has occupied the receptor,
it need not be present in unbound form to inhibit agonist responses.
the duration of action, therefore, of such an irreversible antagonist is relatively independent of its
own rate of elimination and more dependent upon the rate of
turnover of receptor molecules.
IIIC. WHAT DO WE MEAN BY ‘IRREVERSIBLE Antagonist?’
Phenoxybenzamine, an irreversible alpha-adrenoceptor antagonist, is used to control the hypertension caused by catecholamines released from pheochromocytoma, a tumor of the adrenal medulla.
If administration of phenoxybenzamine lowers blood pressure, blockade will be maintained even when the tumor episodically releases very large amounts of catecholamine.
In this case, the ability to prevent responses to varying and high concentrations of agonist is a therapeutic advantage.
Overdose, however, can cause major problems.if the alpha-adrenoceptor blockade cannot
be overcome, excess effects of the drug must be antagonized ‘physiologically.’ (By using a pressor agent that does not act via alpha receptors)
IIIC. WHAT DO WE MEAN BY ‘IRREVERSIBLE Antagonist?’
Alpha-adrenoceptors bind to catecholamines (blue spheres), which act as agonists that stimulate increases in blood pressure
BLOOD PRESSURE
IIIC. WHAT DO WE MEAN BY ‘IRREVERSIBLE Antagonist?’
BLOOD PRESSURE
Pheochromocytoma(tumor of adrenal medulla)
Secretes catecholamines which can bind to alpha adrenoceptors and result in elevated BP levels
IIIC. WHAT DO WE MEAN BY ‘IRREVERSIBLE Antagonist?’
BLOOD PRESSURE
Phenoxybenzamineirreversible antagonist that occupies alpha adrenoceptors.
WILL NOT be displaced from receptor by the catecholamines
Overdose, however, can cause major problems.
if the alpha-adrenoceptor blockade cannot be overcome, excess effects of the drug must be antagonized ‘physiologically.’
(By using a pressor agent that does not act via alpha receptors)
IIID. PARTIAL AGONISTS
Agonists can be divided into two classes based on the maximal pharmacologic response that occurs when all receptors are occupied.
PARTIAL agonists (Yellow)FULL agonists (Purple)
Partial agonists produce a lower response at full receptor occupancy than do FULL agonists.
RE
SPO
NS
EEmax
Partial Agonists stimulate a less-than-max response; even when receptors are saturated.
Full Receptor Occupancy
IIID. PARTIAL AGONISTS
As compared with full agonists, partial agonists produce concentration-effect curves that resemble those with full agonists in the presence of an antagonist that irreversibly blocks receptor sites.
Emax
[AGONIST]
EFF
EC
T
Drug 1
Drug 2
Drug 3
Drug 4
PARTIALAGONISTS
FULL AGONIST
IIID. PARTIAL AGONISTS
TRANSFORMATION OF THE LAST GRAPH TO A LOG-SCALE..
Emax
Log [AGONIST]
EFF
EC
T
Drug 1
Drug 3 PARTIALAGONISTS
FULL AGONIST
A partial agonist, by definition, will never achieve the full effect.
sigmoidal curve with linear midportion
IIID. PARTIAL AGONISTS
Radioligand-binding experiments have demonstrated that partial agonists may occupy all receptor sites.
Despite the finding that partial agonists can saturate receptor binding sites, the observation remains that they fail to produce a maximal response comparable to that seen with full agonists.
Increasing concentrations of partial agonist can displace a fixed concentration of full agonist from the receptor.
IIID. PARTIAL AGONISTS
Radioligand-binding experiments have demonstrated that partial agonists may occupy all receptor sites.
Increasing concentrations of partial agonist (yellow) can displace a fixed
concentration of full agonist (purple) from the
receptors.
NOTE: this is not an explanation of radioligand-binding experiments; it is simply an illustration of partial agonists competing for receptor binding with full agonists.
IIID. PARTIAL AGONISTS
Radioligand-binding experiments have demonstrated that partial agonists may occupy all receptor sites.
Increasing concentrations of partial agonist (yellow) can displace a fixed
concentration of full agonist (purple) from the
receptors.
IIID. PARTIAL AGONISTS
Radioligand-binding experiments have demonstrated that partial agonists may occupy all receptor sites.
Increasing concentrations of partial agonist (yellow) can displace a fixed
concentration of full agonist (purple) from the
receptors.
IIID. PARTIAL AGONISTS
Radioligand-binding experiments have demonstrated that partial agonists may occupy all receptor sites.
Increasing concentrations of partial agonist (yellow) can displace a fixed
concentration of full agonist (purple) from the
receptors.
IIID. PARTIAL AGONISTS
Radioligand-binding experiments have demonstrated that partial agonists may occupy all receptor sites.
Increasing concentrations of partial agonist (yellow) can displace a fixed
concentration of full agonist (purple) from the
receptors.
IIID. PARTIAL AGONISTS
partial agonists may occupy all receptor sites.P
erc
en
tag
e o
f M
axim
al B
ind
ing
100
Log [Partial Agonist]
Partial Agonist
Full Agonist (fixed concentration)
The percentage of receptor occupancyresulting from full agonist (present at a single concentration) binding to receptors in the presence of increasing concentrations of a partial agonist.
Because the full agonist (purple) and partial agonist (yellow) compete to bind the same receptor sites, when occupancy by the partial agonist increases, binding of the full agonist decreases.
IIID. PARTIAL AGONISTSSimultaneous treatment with a single concentration of full agonist and increasing concentrations of the partial agonist.
RES
PO
NS
EEmax
Log [Partial Agonist]
Partial Agonist
Full Agonist (fixed concentration)
The response caused by a single concentration of the full agonist (purple) decreases as increasing concentrations of the partial agonist compete to bind the receptor with increasing success. *The response decreases because the partial agonist, now occupying all receptors, is “not as good” at activating the receptor as the full agonist was.
*Response less than Emax
IIID. PARTIAL AGONISTSHOW CAN AN AGONIST BE ‘PARTIAL?’
Envision a receptor as capable of taking on either of two shapes:
The receptor oscillates in an equilibrium between the two conformations even in the absence of ligand. (equilibrium favors inactive conformation)
INACTIVE ACTIVE
RESPONSENO RESPONSE
IIID. PARTIAL AGONISTSHOW CAN AN AGONIST BE ‘PARTIAL?’Remember: most receptors will initially be in the inactive conformation
Addition of full agonist:
INACTIVE ACTIVE
RESPONSENO RESPONSE
Full agonists have negligible affinity for receptors in the inactive conformation.
IIID. PARTIAL AGONISTSHOW CAN AN AGONIST BE ‘PARTIAL?’
Addition of ligand:
INACTIVE ACTIVE
RESPONSENO RESPONSE
Full agonist binds to and stabilizes the active conformation and equilibrium drives the inactive receptors to assume active conformations to compensate.
IIID. PARTIAL AGONISTSHOW CAN AN AGONIST BE ‘PARTIAL?’
Addition of ligand:
INACTIVE ACTIVE
RESPONSENO RESPONSE
Full agonist binds to and stabilizes the active conformation and equilibrium drives the inactive receptors to assume active conformations to compensate.
IIID. PARTIAL AGONISTSHOW CAN AN AGONIST BE ‘PARTIAL?’
Addition of ligand:
INACTIVE ACTIVE
RESPONSENO RESPONSE
Full agonist binds to and stabilizes the active conformation and equilibrium drives the inactive receptors to assume active conformations to compensate.
IIID. PARTIAL AGONISTSHOW CAN AN AGONIST BE ‘PARTIAL?’
Addition of ligand:
INACTIVE ACTIVE
RESPONSENO RESPONSE
Full agonist binds to and stabilizes the active conformation and equilibrium drives the inactive receptors to assume active conformations to compensate.
IIID. PARTIAL AGONISTSHOW CAN AN AGONIST BE ‘PARTIAL?’Remember: most receptors will initially be in the inactive conformation
Addition of partial agonist:
INACTIVE ACTIVE
RESPONSENO RESPONSE
Partial agonist can bind to either active orInactive conformations.
IIID. PARTIAL AGONISTSHOW CAN AN AGONIST BE ‘PARTIAL?’Remember: most receptors will initially be in the inactive conformation
Addition of partial agonist:
These receptors have already bound the partialagonist and will not assume an active conformation.
ACTIVE
RESPONSENO RESPONSE
Partial agonist can bind to either active orInactive conformations.
IIID. PARTIAL AGONISTSHOW CAN AN AGONIST BE ‘PARTIAL?’Remember: most receptors will initially be in the inactive conformation
Addition of partial agonist:
These receptors have already bound the partialagonist and will not assume an active conformation.
ACTIVE
RESPONSENO RESPONSE
Partial agonist can bind to either active orInactive conformations.
IIID. PARTIAL AGONISTS
HOW CAN AN AGONIST BE ‘PARTIAL?’Compared to full agonists, partial agonists have higher affinity for receptors with inactive conformation.
Partial agonists are “ambivalent”… they bind to both inactive and active receptor conformations… in effect, decreasing their maximum effects relative to full agonists.
The ability of a partial agonist to stabilize active receptor will depend on its relative affinity for affinities for inactive and active forms.
The higher the affinity for inactive receptor conformation, the less efficacious the partial agonist.
ANTAGONISTS BIND TO INACTIVE RECEPTOR CONFORMATIONS, explaining their ability to bind without activating a response.
IIIE. Other Mechanisms of Drug Antagonism
Not all of the methods of antagonism involve interactions of drugs or endogenous ligands at a single type of receptor.
CHEMICAL antagonists
PHYSIOLOGIC antagonists
IIIE. Other Mechanisms of Drug Antagonism
Chemical Antagonists (red sphere)in this type of antagonism,one drug may antagonize the actions of
a second drug by binding to and inactivating the second drug
Add chemical antagonist
IIIE. Other Mechanisms of Drug Antagonism
Chemical Antagonists (red sphere)
Add chemical antagonist
I am so happy.Life is GREAT!I am living the dream of every agonist;To activate my receptor.
I am a chemical antagonist. I suppose our agonist over there is about to surprised!!
Foolish agonist,you thoughteverything wasgreat!
HELP!
active inactive
IIIE. Other Mechanisms of Drug Antagonism
Chemical Antagonists (red sphere)One example of chemical antagonism includes:
heparinan anticoagulant that is negatively
charged
protamine a protein that is positively charged at
physiologic pH.
Protamine can be used clinically to counteract the effects of heparin.
One drug antagonizes the effects of the other simply by binding it and making it unavailable for interactions with proteins involved in formation of a blood clot.
IIIE. Other Mechanisms of Drug Antagonism
Physiologic Antagonistsphysiologic antagonism takes advantage of endogenous regulatory pathways
many physiological functions are controlled by opposing regulatory pathways. For example:
INCREASED BLOOD SUGAR
DECREASED BLOOD SUGAR
INSULINGlucocorticoids
IIIE. Other Mechanisms of Drug Antagonism
Physiologic Antagonists
INCREASED BLOOD SUGAR
DECREASED BLOOD SUGAR
INSULINGlucocorticoids
The clinician must sometimes administer insulin to oppose the hyperglycemic effects of glucocorticoid hormone:
IIIE. Other Mechanisms of Drug Antagonism
Physiologic Antagonists
The clinician must sometimes administer insulin to oppose the hyperglycemic effects of glucocorticoid hormone:
whether this is elevated by endogenous synthesis
(such as by a tumor of the adrenal cortex)
or whether this is elevated as a result of glucocorticoid therapy
IIIE. Other Mechanisms of Drug Antagonism
Physiologic Antagonists (another example)To treat bradycardia (abnormally slow heartbeat)
that is caused by increased release of acetylcholine from vagus nerve endings
(after an event such as a myocardial infarction)
the physician could use isoproterenola beta-adrenoceptor agonist that
increases heart rate by mimicking sympathetic stimulation of the heart.
Use of this physiologic antagonist would be less rational than would use of a receptor-specific antagonist such as atropine
(atropine is a competitive antagonist at the receptors at which acetylcholine slows heart rate).
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