Principles of

Pharmacology:

Pharmacodynamics

Dennis Paul, Ph.D.

dpaul@lsuhsc.edu
Learning Objectives:
 Understand the theoretical basis of
drug-receptor 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 measures of drug safety.
 Understand the consequences of
TEXT:
 CHAPTER 2 –
“PHARMACODYNAMICS:
Mechanisms of Drug Action and the
Relationship between Drug
Concentration and Effect” –
GOODMAN AND GILMAN’S THE
PHARMACOLOGICAL BASIS OF
THERAPEUTICS – 10th edition
Biochemistry:

 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.

 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
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 just-noticeable
effect.
– ED50: Dose that produces a
50% of maximum response.
– Ceiling: Lowest dose that
 Dose-response curve
100

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

-20 Inverse agonist

-40

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.