Principles of Pharmacology:

Basic Pharmacodynamics
AYS 2018
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 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++
Mg++
Ca++
Ca++
K+
Mg++
Na+
Na+
Ligand-gated Ion Channels
Mg++ Ca++
Ca++ Na+
Na+ Na+
Ca++
K+
Na+ Na+
Na+
Mg++
Na+
G-protein coupled receptors

NH3+

g
COOH- a b
GTP
G-protein coupled receptors

NH3+

g
COOH- 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 Stimulus Response

Kd
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 just-noticeable 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

80

60
Response

40

20

0
0 200 400 600 800 1000

Dose
 Dose-response curve

100

80

60
Response

40

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

60
Response

ED50
40

20
Threshold

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

Dose
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

100

80
Full agonist
% Effect

60

40

20 Partial agonist
0

-20 Inverse agonist

-40

Dose
Relative Potency

100
A B
80
Effect

60

40

20

0
0.1 1 10 100 1000 10000

Dose
Relative Potency

100
A B
80
Effect

60

40

20

0
0.1 1 10 100 1000 10000

Dose
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 = Antagonist
 120
100
80
60
40
20
0
-11 -10 -9 -8 -7 -6

= Agonist = Antagonist
 120
100
80
60
40
20
0
-11 -10 -9 -8 -7 -6

= Agonist = Antagonist
 120
100
80
60
40
20
0
-11 -10 -9 -8 -7 -6

= Agonist = Antagonist
 120
100
80
60
40
20
0
-11 -10 -9 -8 -7 -6

= Agonist = Antagonist
 120

100

80

60

40

20

0
-11 -10 -9 -8 -7 -6

= Agonist = Antagonist
 120

100

80

60

40

20

0
-11 -10 -9 -8 -7 -6

= Agonist = Antagonist
 Competition

1200

1000

800
Effect

600
ID50 or IC50
400

200

0
-11 -10 -9 -8 -7 -6
log [antagonist]
= Agonist = Antagonist
= Agonist = Antagonist
= Agonist = Antagonist
= Agonist = Antagonist
= Agonist = Antagonist
= Agonist = Antagonist
= Agonist = Antagonist
Competitive antagonists

100
A B C
80
Response

60

40

20

0
0.1 1 10 100 1000 10000

Dose
Noncompetitive antagonists

100
A
80

60
Response

B
40
C
20

0
0.1 1 10 100 1000 10000

Dose
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

Dose
Allosteric antagonists 2

100
A
80

60
Response

B
40
C
20

0
0.1 1 10 100 1000 10000

Dose
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) can result in receptor
upregulation
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.
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
1
10

0
1K

K
01

0K
1
01

-20
10
0.
00

10
0.
00

10
0.
0.
 Therapeutic index: LD50/ED50

100

80 Sleep Death

60

40

20

0
1
10

0
1K

K
01

0K
1
01

-20
10
0.
00

10
0.
00

10
0.
0.
 Safety Index vs. Therapeutic Index

100

80
Percent Effect

Desired Effect Lethality

60
Therapeutic Index
40

20 Safety Index
ED50 ED99 LD1 LD50
0
1 10 100 1000 10000 100000
Dose