Download Pharmacodynamics (08)

PHARMACODYNAMICS
M.T. Piascik
PHA 824
November 11, 2008
Learning Objectives
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The definition of a drug
The different types of receptors at which drugs
can act
The concept of affinity and those factors that
cause a drug to bind to a receptor
The concept of intrinsic activity
The difference between full and partial
agonists
The definitions of potency and efficacy
The definition of ED50
Learning Objectives
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(cont.)
The concept of spare receptors
The information regarding drugs that can be
obtained from the log-dose response curve
The properties of a competitive antagonist and
how it differs from an irreversible receptor
agonist
The definition of LD50
The concept of a therapeutic index and how it
is calculated
True or False?
A correct definition of a drug is -•
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A chemical substance that interacts with a
receptor to produce a beneficial
therapeutic effect.
Answer—FALSE!!
Correct definition: A drug is a chemical
substance that interacts with a receptor to
produce a physiologic effect– regardless
whether the effect is beneficial.
Drug Properties
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Drug binding to a receptor is mediated by the
chemical structure of the drug that allows it to
interact with complementary surfaces on the
receptor.
Agonists activate cellular signaling pathways to
alter physiologic activity.
Antagonists bind to the receptor but cannot
initiate a change in cellular function.
Occupation of the receptor without activation
results in blockade of the actions of agonists.
Receptor
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Any cellular macromolecule to which a
neurotransmitter or drug binds to initiate
its effects. The endogenous function of a
receptor is to participate in
neurotransmission or physiologic
regulation.
Receptor Types
Proposed Structure of a GPCR
Receptor Specificity
FACTORS GOVERNING DRUG
ACTION
Drug administration
Drug absorption
Drug distribution to
receptor sites
Drug in receptor microenvironment
Drug binds to receptor
Receptor activation of
cell signaling
Physiologic response
PHARMACOKINETIC
PHARMACODYNAMIC
SSSSSSSSS
FACTORS GOVERNING DRUG
ACTION
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Affinity is a measure of the tightness
with which a drug binds to the receptor.
Intrinsic activity is a measure of the
ability of an agonist that is bound to the
receptor to generate an activating
stimulus and produce a change in
cellular activity.
UNDERSTANDING THE
CONCEPT OF AFFINITY
1) Affinity describes the strength of binding to
receptors.
2) k1 describes the rate at which a drug associates
with the receptor while k-1 describes the ease
at which a drug dissociates from its receptor.
UNDERSTANDING THE
CONCEPT OF AFFINITY
UNDERSTANDING THE
CONCEPT OF AFFINITY
Affinity = k 1 /k -1
= __[DR]___
[D] [R]
The term most often used to represent affinity is the equilibrium
dissociation constant or KD
KD = k -1/k 1
= ___[D] [R]___
[DR]
After appropriate mathematical substitution, it can be stated that;
Amount bound to receptor
=
[D]
[D]+KD
• This equation states that the amount of drug bound to the receptor is
dependent on the drug concentration and Kd.
UNDERSTANDING THE
CONCEPT OF AFFINITY
Making the assumption that an effect of a drug is dependent on the number of
receptors occupied, it can be stated that at binding equilibrium, the drug
effect would be also be constant.
Affinity describes the strength of binding to receptors, Drugs that bind with
great avidity to the receptors are said to have high affinity. The term most
often used to represent affinity is the equilibrium dissociation constant or its
abbreviation KD. The description of the strength of binding of drugs to
receptors is very important in pharmacology. KD values are often used to
compare the potency of different drugs as well as in the characterization of
receptors.
The units of the equilibrium dissociation are in concentration, for 1 x 10-8M or
10 nanomolar. There is an inverse relationship between the KD and
affinity. The smaller the KD, the higher the affinity.
AN ILLUSTRATION OF THE
RELATIONSHIP OF AFFINITY AND
DRUG BINDING
Make the following simple calculations and
graphical representations.
AN ILLUSTRATION OF THE
RELATIONSHIP OF AFFINITY AND
DRUG BINDING
Amount bound to receptor
=
[D]
[D]+KD
Terazosin has an equilibrium dissociation constant of 1.0 nM.
Calculate the percentage of receptors occupied at each Terazosin
concentration
Terazosin
0.5 nM
1.0 nM
4.0 nM
10.0 nM
% Receptors
Occupied
AN ILLUSTRATION OF THE
RELATIONSHIP OF AFFINITY AND
DRUG BINDING
Terazosin at 0.5 nM:
0.5
0.5 + 1.0
= ???
AN ILLUSTRATION OF THE
RELATIONSHIP OF AFFINITY AND
DRUG BINDING
Terazosin at 0.5 nM:
0.5
0.5 + 1.0
1.0
At 1.0 nM :
1.0 + 1.0
= 33% Receptor Occupancy
= 50% Receptor Occupancy
AN ILLUSTRATION OF THE
RELATIONSHIP OF AFFINITY AND
DRUG BINDING
Terazosin at 0.5 nM:
0.5
0.5 + 1.0
1.0
At 1.0 nM :
At 4.0 nM :
1.0 + 1.0
= 33% Receptor Occupancy
= 50% Receptor Occupancy
4.0
4.0 + 1.0
= 80% Receptor Occupancy
AN ILLUSTRATION OF THE
RELATIONSHIP OF AFFINITY AND
DRUG BINDING
Terazosin at 0.5 nM:
0.5
0.5 + 1.0
1.0
At 1.0 nM :
At 4.0 nM :
1.0 + 1.0
= 50% Receptor Occupancy
4.0
4.0 + 1.0
At 10.0 nM :
= 33% Receptor Occupancy
= 80% Receptor Occupancy
10.0
10.0 + 1.0
= 90% Receptor Occupancy
AN ILLUSTRATION OF THE
RELATIONSHIP OF AFFINITY AND
DRUG BINDING
Amount bound to receptor
=
[D]
[D]+KD
Epinephrine has an equilibrium dissociation constant of 100 nM.
Calculate the percentage of receptors occupied at each epinephrine
concentration:
Epinephrine
50.0 nM
100.0 nM
400.0 nM
1000 nM
% Receptors
Occupied
AN ILLUSTRATION OF THE
RELATIONSHIP OF AFFINITY AND
DRUG BINDING
Epinephrine at 50.0 nM:
50.0
= ???
50.0 + 100.0
AN ILLUSTRATION OF THE
RELATIONSHIP OF AFFINITY AND
DRUG BINDING
50.0
At 50.0 nM:
50 + 100
= 33% Receptor Occupancy
100.0
At 100.0 nM :
At 400.0 nM :
At 1000.0 nM :
= 50% Receptor Occupancy
100.0 + 100.0
400.0
= 80% Receptor Occupancy
400.0 + 100.0
1000.0
= 90% Receptor Occupancy
1000.0 + 100.0
AN ILLUSTRATION OF THE
RELATIONSHIP OF AFFINITY AND
DRUG BINDING
Amount bound to receptor
Terazosin at:
0.5 nM
1.0 nM
4.0 nM
10.0 nM
=
[D]
[D]+KD
Epinephrine at:
% Receptors Occupied
50 nM
100 nM
400 nM
1000nM
33 %
50 %
80 %
90 %
50% OF RECEPTORS WILL BE OCCUPIED WHEN A DRUG
IS GIVEN AT A CONCENTRATION EQUAL TO ITS KD
AN ILLUSTRATION OF THE
RELATIONSHIP OF AFFINITY AND
DRUG BINDING
Now plot the relationship between concentration and receptor occupancy.
AN ILLUSTRATION OF THE
RELATIONSHIP OF AFFINITY AND DRUG
BINDING
50% OF RECEPTORS WILL BE OCCUPIED WHEN A DRUG
IS GIVEN AT A CONCENTRATION EQUAL TO ITS KD
UNDERSTANDING THE CONCEPT
OF INTRINSIC ACTIVITY
UNDERSTANDING THE CONCEPT
OF INTRINSIC ACTIVITY
MAXIMAL DRUG RESPONSES
AND SPARE RECEPTORS
1) As the concentration of a drug in a human
organ system increases, the response of
that system would be expected to
increase until a maximal response is
obtained.
2) The relationship between the number of
receptors occupied and the physiologic
response is complex.
MAXIMAL DRUG RESPONSES
AND SPARE RECEPTORS
• In many human
physiological
systems, not all
receptors must be
occupied by drug to
achieve a maximal
response.
• A certain number of
receptors are “spare.”
MAXIMAL DRUG RESPONSES
AND SPARE RECEPTORS
The amplification of cellular signaling
pathways is responsible for the
nonlinear relationship between
receptor occupancy and response.
DOSE-RESPONSE CURVES
1)Dose-response relationships are a common way
to portray data in both basic and clinical
science.
2)To present the data, the concentration of the
drug is plotted on the x-axis and the effect
would be presented on the y-axis. A plot of
drug concentration ([D]) versus effect (E/Emax
in the graphs) is a rectangular hyperbola.
3)Most often, the log of the drug concentration is
plotted versus the effect. A plot of the log of
[D] versus Effect is a sigmoid curve.
DOSE-RESPONSE CURVES
The dose at which 50% of the maximal effect is observed is referred to as the ED50
Potency
1) Potency refers to the concentration of a
drug required to produce a given
physiologic effect. Drugs with high
receptor affinity will exhibit greater
potency than those with lower affinity.
Potency
Norepinephrine (NE) has a higher affinity for a receptor than does phenylephrine(PE).
The ED50 for norepinephrine is 100 nM while the ED50 for phenylephrine is 35,000 nM.
Norepinephrine would be said to have greater potency than phenylephine.
Efficacy
1) Efficacy is often used to describe the
maximal level of response a drug can
produce.
Efficacy
Norepinephrine would have a greater efficacy than methoxamine which
in turn would have a greater efficacy than clonidine.
ADDITIONAL CONCEPTS REGARDING
PARTIAL AGONISTS
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Partial agonists can block the actions of full
agonists.
To achieve a maximal effect, partial agonists
must occupy all receptors to produce a
maximal effect.
If a full agonist is given in the presence of a
receptor saturating dose of a partial agonist,
the full agonist cannot access the receptor and
hence its actions will be blocked
ADDITIONAL CONCEPTS REGARDING
PARTIAL AGONISTS
ANTAGONISTS
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Antagonists that
bind in a reversible
manner are referred
to as competitive
antagonists.
Agonists, if given in
high concentrations,
can displace the
antagonist from the
receptor
ANTAGONISTS
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The antagonist [A] and agonist [D] are
competing for the same limited number
of receptors [R].
[[D]
[DR]
+
[R]
+
[A]
[AR]
ANTAGONISTS
Amount of agonist bound to the receptor
In the presence of an antagonist
=
[D]
[D]+Kd(1+[A]/Ka)
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Examine the effect of terazosin (Ka= 1.0 nM) on the occupancy of the alpha1adrenergic receptor by epinephrine ( = KD 100 nM).
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Epinephrine
% Receptors
Occupied
(Teraz = 0)
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50.0 nM
100.0 nM
400.0 nM
1000.0 nM
33
50
80
90
%Receptors
Occupied
(Teraz = 1nM)
% Receptors
Occupied
(Teraz = 10 nM)
ANTAGONISTS
Amount of agonist bound to the receptor
In the presence of an antagonist
=
[D]
[D]+Kd(1+[A]/Ka)
Amt Epi bound at 50 nM in the presence
of 1 nM terazosin
= 50 nM
50 nM+ 100 nM(1+1 nM/1nM)
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Epinephrine
% Receptors
Occupied
(Teraz = 0)
%Receptors
Occupied
(Teraz = 1nM)
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50.0 nM
100.0 nM
400.0 nM
1000.0 nM
33
50
80
90
20
% Receptors
Occupied
(Teraz = 10 nM)
ANTAGONISTS
Amount of agonist bound to the receptor
In the presence of an antagonist
=
[D]
[D]+Kd(1+[A]/Ka)
Amt Epi bound at 50 nM in the presence
of 1 nM terazosin
= 50 nM
50 nM+ 100 nM(1+1 nM/1nM)
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Epinephrine
% Receptors
Occupied
(Teraz = 0)
%Receptors
Occupied
(Teraz = 1nM)
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50.0 nM
100.0 nM
400.0 nM
1000.0 nM
33
50
80
90
20
33
66
83
% Receptors
Occupied
(Teraz = 10 nM)
4
8
26
47
ANTAGONISTS
PE alone
COMPETITIVE ANTAGONISTS
1) Reversible binding to the receptor.
2) The blockade can be overcome by
increasing the agonist concentration.
3) The maximal response of the agonist is
not decreased.
4) The agonist dose-response curve in the
presence of a competitive antagonist is
displaced to the right, parallel to the
curve in the absence of agonist.
Irreversible Receptor
Antagonists
1) Irreversible receptor antagonists are
chemically reactive compounds. These
ligands first bind to the receptor.
Following this binding step, the ligand then
reacts with the functional groups of the
receptor
Irreversible Receptor
Antagonists
APPLICATIONS TO
THERAPEUTICS
• Few drugs interact with one and only one
receptor.
• Such a drug would be said to be specific.
• Most drugs interact with more than one receptor
class and thus have the capability to produce
distinctly different pharmacologic effects. Some
of these effects could be beneficial, some could
be toxic. Such a drug would be said to be
selective.
APPLICATIONS TO
THERAPEUTICS
• Assume a drug can interact with two receptor
systems with the following characteristics;
• Receptor System # 1:
KD= 0.40, effect- lowering of systemic arterial
blood pressure.
• Receptor System # 2:
KD = 40.0, effect- lethal ventricular arrhythmias.
APPLICATIONS TO
THERAPEUTICS
The Therapeutic Index
• The Therapeutic Index is the ratio of the
ED50 of a drug to produce a lethal effect
to the ED50 to produce a therapeutic
effect.
• The dose required to produce death in
50% of a population is referred to as the
LD50.
The Therapeutic Index
The ED50 for the beneficial effect of blood pressure
lowering is 0.4 nM while the LD50 is 40 nM. Therefore,
the therapeutic index will be:
TI = LD50
ED 50
TI = 40.0 nM
TI
0.4 nM
= 100
AN ILLUSTRATION OF THE
RELATIONSHIP OF AFFINITY AND DRUG
BINDING
FACTORS GOVERNING DRUG
ACTION
Drug administration
Drug absorption
Drug distribution to
receptor sites
Drug in receptor microenvironment
Drug binds to receptor
Receptor activation of
cell signaling
Physiologic response
PHARMACOKINETIC
PHARMACODYNAMIC