Documenti di Didattica
Documenti di Professioni
Documenti di Cultura
Basic Pharmacodynamics
AYS 2018
Learning Objectives:
•L+S LS
Biochemistry:
•Pharmacology:
•L+R LR
Biochemistry:
•L+S LS
•Pharmacology:
•L+R LR Response
Pharmacodynamics
Drugs:
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
• Partial agonists: Drug that, no matter how high the dose, cannot
produce a full response.
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
100
80
Full agonist
% Effect
60
40
20 Partial agonist
0
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
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
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
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
20 Safety Index
ED50 ED99 LD1 LD50
0
1 10 100 1000 10000 100000
Dose