Transcript Review of Principles - LSU School of Medicine

Principles of Pharmacology:
Pharmacodynamics
Dennis Paul, Ph.D.
[email protected]
Learning Objectives:







Understand the theoretical basis of drugreceptor interactions.
Understand the determinants and types of
responses to drug-receptor interactions.
Know the four major families of receptors.
Define potency and efficacy.
Understand how to compare drug potency
and efficacy.
Understand the consequences of receptor
regulation
Understand measures of drug safety.
Biochemistry:
 L+S
LS
Biochemistry:
 L+S
LS (Langmuir equation)
 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
Ca++
Ca++
Na+
Mg++
Ca++
Mg++
K+
Na+
Ligand-gated Ion Channels
Mg++
Ca++
Na+
K+
Na+
Na+
Ca++
Na+
Na+
Ca++
Na+
Na+
Mg++
G-protein coupled
receptors
NH3+
COOH-
g
a b
GTP
G-protein coupled
receptors
NH3+
COOH-
g
a b
GDP
Receptor-enzyme
Catalytic site
Receptor-enzyme
Catalytic site
Cytosolic-Nuclear
receptors
Cytosolic-Nuclear
receptors
Classical Receptor
Occupancy Theory
Ka
L+R
LR
Kd
Stimulus
Response
L: Ligand (Drug)
R: Receptor
LR: Ligand-Receptor Complex
Ka: Association rate constant
Stimulus: initial effect of drug on
receptor
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: Asymptotic
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



Receptors in an active state initiate
cell signaling.
For any cell, there is an equilibrium
between receptors in active and
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.
Antagonist: drug that binds to receptors
but cannot initiate a cellular response, but
prevent agonists from producing a response;
affinity, but no efficacy. Antagonists
maintain the active-inactive equilibrium.
cont.


Partial agonists: Drug that, no
matter how high the dose, cannot
produce a full response.
Inverse agonist: Drug that binds to
a receptor to produce an effect
opposite that of an agonist. Stabilizes
receptors in the inactive state.
Graded dose-response
curves


Individual responses to varying doses
Concepts to remember:
– Threshold: Dose that produces a justnoticeable effect.
– ED50: Dose that produces a 50% of
maximum response. (EC50: blood
concentration that produces a 50% of
max response)
– Ceiling: Lowest dose that produces a
maximal effect.
Dose-response curve
100
Response
80
60
40
20
0
0
200
400
Dose
600
800
1000
Dose-response curve
100
Response
80
60
40
20
0
0.1
1
10
Dose
100
1000
10000
100
80
60
40
20
0
0.1
= Agonist
1
10
100
1000
10000
100
80
60
40
20
0
0.1
= Agonist
1
10
100
1000
10000
100
80
60
40
20
0
0.1
= Agonist
1
10
100
1000
10000
100
80
60
40
20
0
0.1
= Agonist
1
10
100
1000
10000
100
80
60
40
20
0
0.1
= Agonist
1
10
100
1000
10000
100
80
60
40
20
0
0.1
= Agonist
1
10
100
1000
10000
100
80
60
40
20
0
0.1
= Agonist
1
10
100
1000
10000
Dose-response curve
Ceiling
100
Response
80
60
ED50
40
Threshold
20
0
0.1
1
10
Dose
100
1000
10000
Full vs Partial agonists
100
Full Agonist
% Effect
80
60
40
20
Partial Agonist
0
0.1
1
10
Dose
100
1000
10000
Full vs Partial agonists

These terms are tissue dependent on
– Receptor density
– Cell signaling apparatus
– Other receptors that are present
– Drug history

Partial agonists have both agonist and
antagonist properties.
Inverse Agonist
% Effect
100
80
Full agonist
60
40
Partial agonist
20
0
-20
Inverse agonist
-40
Dose
Relative Potency
100
B
A
Effect
80
60
40
20
0
0.1
1
10
100
Dose
1000
10000
Relative Potency
100
A
B
Effect
80
60
40
20
0
0.1
1
10
100
Dose
1000
10000
Relative Potency
=ED50B/ED50A
320/3.2=100
Relative Efficacy
100
Relative
Efficacy
80
60
40
20
0
0.1
1
10
100
1000
10000
Antagonists


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
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
= Agonist
-10
-9.5
-9
-8.5
= Antagonist
-8
-7.5
-7
-6.5
-6
120
100
80
60
40
20
0
-11
= Agonist
-10
-9
= Antagonist
-8
-7
-6
120
100
80
60
40
20
0
-11
= Agonist
-10
-9
= Antagonist
-8
-7
-6
120
100
80
60
40
20
0
-11
= Agonist
-10
-9
= Antagonist
-8
-7
-6
120
100
80
60
40
20
0
-11
= Agonist
-10
-9
= Antagonist
-8
-7
-6
120
100
80
60
40
20
0
-11
= Agonist
-10
-9
= Antagonist
-8
-7
-6
120
100
80
60
40
20
0
-11
= Agonist
-10
-9
= Antagonist
-8
-7
-6
Competition
1200
Effect
1000
800
600
ID50 or IC50
400
200
0
-11
-10
-9
-8
log [antagonist]
-7
-6
= Agonist
= Antagonist
= Agonist
= Antagonist
= Agonist
= Antagonist
= Agonist
= Antagonist
= Agonist
= Antagonist
= Agonist
= Antagonist
= Agonist
= Antagonist
Competitive antagonists
100
A
B
C
10
100
1000
Response
80
60
40
20
0
0.1
1
Dose
10000
Noncompetitive
antagonists
100
A
Response
80
60
B
40
C
20
0
0.1
1
10
Dose
100
1000
10000
Allosteric and Physiologic
antagonists

Response can be irregular
Allosteric Antagonism
Allosteric Antagonism
Allosteric Antagonism
Allosteric Antagonism
Allosteric antagonists 1
100
A
Response
80
60
40
20
0
0.1
1
10
Dose
100
1000
10000
Allosteric antagonists 2
100
A
Response
80
60
B
40
C
20
0
0.1
1
10
Dose
100
1000
10000
Quantal Dose-Response Curves



Also known as concentration-percent or
dose-percent curves
Used when the dose of a drug to
produce a specified effect in a single
patient is measured (individual effective
dose or concentration.)
The percent of subjects responding at a
dose is plotted.
Percent Responders
Quantal Dose-Response Curves
100
90
80
70
60
50
40
30
20
10
0
1
3.2
10
32
100
Dose
320
1000
3200
Percent Responders
Cumulative Quantal DoseResponse Curves
120
100
80
60
40
20
0
1
3.2
10
32
100
Dose
320
1000
3200
Percent Responders
Cumulative Quantal DoseResponse Curves
120
100
80
60
40
20
0
1
10
100
Dose
1000
10000
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 reexposure 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) can
result in receptor upregulation
Receptor Upregulation


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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.
Desired vs undesired
effects: Indices of drug
safety.
Safety Index
 Therapeutic Index

“Potency means nothing. I can
always give a bigger pill.”
J. Hunter
Safety index: LD1/ED99
ED99
100
80
Sleep
Death
60
40
LD1
20
10
0K
10
K
1K
10
0
10
1
-20
0.
1
0.
00
01
0.
00
1
0.
01
0
Therapeutic index:
LD50/ED50
100
80
Sleep
Death
60
40
20
10
0K
10
K
1K
10
0
10
1
-20
0.
1
0.
00
01
0.
00
1
0.
01
0
Safety Index vs. Therapeutic Index
100
Percent Effect
80
Desired Effect
60
Lethality
Therapeutic Index
40
20
Safety Index
ED50
0
1
10
ED99
100
Dose
LD1
1000
LD50
10000
100000