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Pharmacology:
Pharmacodynamics
L+S LS
Biochemistry:
L+S LS
Pharmacology:
L+R LR
Biochemistry:
L+S LS
Pharmacology:
L+R LR Response
Pharmacodynamics
Drugs:
Chemical agents that interact with
components of a biological system
to alter the organism’s function.
Examples of such components, sites of
drug action, are enzymes, ion channels,
neurotransmitter transport systems,
nucleic acids and receptors. Many
drugs act by mimicking or inhibiting the
interactions of endogenous mediators
with their receptors
Receptors:
Regulatory proteins that interact
with drugs or hormones and
initiate a cellular response
– Ion channels
– G-protein coupled receptors
– Receptor-enzymes
– Cytosolic-nuclear receptors
Act as transducer proteins
– Receptor-effector signal transduction
– Post-receptor signal transduction
provides for amplification of the
signal
Ligand-gated Ion
Channels
G-protein coupled
receptors
β γ
G-protein coupled
receptors
Membran
e
β γ
G-protein coupled
receptors
α β γ
Receptor-enzyme
Binding site
Catalytic
site
Cytosolic-Nuclear
receptors
Classical Receptor
Occupancy Theory
KA
L+R LR Stimulus
Response
Kd
L: Ligand (Drug)
R: Receptor
LR: Ligand-Receptor Complex
KA: Affinity constant
Stimulus: initial effect of drug on
Properties of drugs
Affinity: The chemical forces
that cause the drug to
associate with the receptor.
Efficacy: The extent of
functional change imparted to
a receptor upon binding of a
drug.
Properties of a
biological system
Potency: Dose of drug
necessary to produce a specified
effect.
– Dependent upon receptor density,
efficiency of the stimulus-response
mechanism, affinity and efficacy.
Magnitude of effect:
Assymtotic maximal response
– Solely dependent upon intrinsic
efficacy.
– Also called efficacy.
Determinants of
Response
Intrinsic Efficacy (ε): Power of a
drug to induce a response.
Number of receptors in the target
tissue.
Spare receptors
Some tissues have more
receptors than are necessary to
produce a maximal response.
– Dependent on tissue, measure of
response and intrinsic efficacy of the
drug.
Active vs Inactive
states
Active states initiate cell
signaling.
For any cell, there is an
equilibrium between active an
inactive states. The inactive
state usually predominates.
Each state has its own affinity.
Classification of a drug
based on drug-receptor
interactions:
Agonist: Drug that binds to receptors
and initiates a cellular response; has
affinity and efficacy. Agonists promote
the active state.
80
Respons
60
40
e
20
0
0 200 400 600 800 1000
Dose
Dose-response curve
100
80
Respons
60
40
e
20
0
0.1 1 10 100 1000 10000
Dose
100
80
60
40
20
0
0.1 1 10 100 1000 10000
= Agonist
100
80
60
40
20
0
0.1 1 10 100 1000 10000
= Agonist
100
80
60
40
20
0
0.1 1 10 100 1000 10000
= Agonist
100
80
60
40
20
0
0.1 1 10 100 1000 10000
= Agonist
100
80
60
40
20
0
0.1 1 10 100 1000 10000
= Agonist
100
80
60
40
20
0
0.1 1 10 100 1000 10000
= Agonist
100
80
60
40
20
0
0.1 1 10 100 1000 10000
= Agonist
Dose-response curve
100 Ceiling
80
Respons
60
ED50
40
Threshold
e
20
0
0.1 1 10 100 1000 10000
Dose
Full vs Partial agonists
100
Full Agonist
80
% Effect
60
40
20
Partial Agonist
0
0.1 1 10 100 1000 10000
D
Full vs Partial agonists
These terms are tissue dependent
– Receptor density
– Cell signaling apparatus
– Other receptors that are present
– Drug history
Partial agonists have both agonist
and antagonist properties.
Inverse Agonist
100
Full agonist
% Effect
80
60
40
20 Partial agonist
0 1 1 0 1 0 0 1 0 0 0 1 0 0 0 0
D
Relative Potency
100
A B
80
Effec
60
40
t
20
0
0.1 1 10 100 1000 10000
D
Relative Potency
100
A B
80
Effec
60
40
t
20
0
0.1 1 10 100 1000 10000
D
Relative Potency
=ED50B/ED50A
320/3.2=100
Relative Efficacy
100
80 Relative
Efficacy
60
40
20
0
0.1 1 10 100 1000 10000
Antagonists
Competitive: Antagonist binds to
same site as agonist in a reversible
manner.
Noncompetitive: Antagonist binds to
the same site as agonist irreversibly.
Allosteric: Antagonist and agonist
bind to different site on same receptor
Physiologic: Two drugs have
opposite effects through differing
mechanisms
120
100
80
60
40
20
0
-10.5 -10 -9.5 -9 -8.5 -8 -7.5 -7 -6.5 -6
= Agonist =
120
100
80
60
40
20
0
-11 -10 -9 -8 -7 -6
= Agonist =
120
100
80
60
40
20
0
-11 -10 -9 -8 -7 -6
= Agonist =
120
100
80
60
40
20
0
-11 -10 -9 -8 -7 -6
= Agonist =
120
100
80
60
40
20
0
-11 -10 -9 -8 -7 -6
= Agonist =
120
100
80
60
40
20
0
-11 -10 -9 -8 -7 -6
= Agonist =
120
100
80
60
40
20
0
-11 -10 -9 -8 -7 -6
= Agonist =
Competition
1200
1000
800
Effect
600
IC50
400
200
0
-11 -10 -9 -8 -7 -6
log [antagonist]
Competition
120
100
Effect
80
-11 -10 -9 -8 -7 -6
log [antagonist]
= Agonist =
= Agonist =
= Agonist =
= Agonist =
= Agonist =
= Agonist =
= Agonist =
Competitive
antagonists
100
A B C
80
Response
60
40
20
0
0.1 1 10 100 1000 10000
D
Noncompetitive
antagonists
100
A
80
Response
60
B
40
C
20
0
0.1 1 10 100 1000 10000
D
Allosteric and
Physiologic
antagonists
Response can be irregular
Allosteric Antagonism
Allosteric Antagonism
Allosteric Antagonism
Allosteric Antagonism
Allosteric antagonists
1
100
A
80
Response
60
40
20
0
0.1 1 10 100 1000 10000
D
Allosteric antagonists
2
100
A
80
Response
60
B
40
C
20
0
0.1 1 10 100 1000 10000
D
Desired vs undesired
effects: Indices of drug
safety.
Safety Index
Therapeutic Index
Safety index: LD1/ED99
ED99
100
80 Sleep Death
60
40
LD1
20
0
0
K
01
01
10
0K
1
-20 1K
10
0.
00
10
00
0.
10
0.
0.
Therapeutic index:
LD50/ED50
100
80 Sleep Death
60
40
20
0
0
K
01
01
10
0K
1
-20 1K
10
0.
00
10
00
0.
10
0.
0.
Receptor regulation
Reduced responsivity: Chronic
use of an agonist can result in
the receptor-effector system
becoming less responsive
– eg. alpha-adrenoceptor agents
used as nasal decongestants
Myasthenia gravis: decrease in
number of functional
acetylcholine nicotinic receptors
at the neuromuscular junction.
Receptor regulation
Increased responsivity: Chronic
disuse of a receptor-effector
system can result in an increased
responsiveness upon re-exposure
to an agonist.
– Denervation supersensitivity at
skeletal muscle acetylcholine nicotinic
receptors
– Thyroid induced upregulation of cardiac
beta-adrenoceptors
– Prolonged use of many antagonists
(pharmacological as well as functional)
Receptor Upregulation
Most receptors are internalized
and degraded or recycled with age
and use.
Antagonists slow use-dependent
internalization
Inverse agonists stabilize the
receptor in the inactive state to
prevent internalization.
The cell continues to produce
receptors.