PSB 451 Dose Response Curves
17
Y Formation of second messengers cell effect Agonist Effects of agonists • Agonists activate receptor, cause a change in intracellular biochemistry and a change in cellular effects – e.g. formation of second messenger, firing rate of cell, etc • These responses can be measured in a membrane or cellular assay, a tissue bath, an animal or a human to characterize the effects of agonists – Graded responses: continuous and gradual: measure magnitude of response – Quantal responses: all or nothing: measure frequency of response • To characterize ligands pharmacologically, apply increasing concentrations or administer increasing doses then measure the selected response.
Transcript of PSB 451 Dose Response Curves
YFormation of
second messengers
cell
effectAgonist
Effects of agonists
• Agonists activate receptor, cause a change in intracellular biochemistry and a change in cellular effects– e.g. formation of second messenger, firing rate of cell, etc
• These responses can be measured in a membrane or cellular assay, a tissue bath, an animal or a human to characterize the effects of agonists– Graded responses: continuous and gradual: measure magnitude of response– Quantal responses: all or nothing: measure frequency of response
• To characterize ligands pharmacologically, apply increasing concentrations or administer increasing doses then measure the selected response.
Dose-response curve to agonist A
RESP
ON
SE (%
of m
axim
um)
DOSE (mg) (linear scale) 0 10 20 30 40 50 60 70
100
80
60
40
20
0
-20
-40
Dose of A (mg)
Response(HR)
Response(% of
maximal)
0 70 0
0.01 70 0
0.05 70 0
0.1 75 8.3
0.5 85 25
1 100 50
5 115 75
10 125 92
50 130 100
100 130 100
500 130 100
1000
5000
Dose-response curve to agonist A(graded response)
RESP
ON
SE (%
of m
axim
um)
DOSE (mg) (log scale) 0 0.01 0.1 1.0 10 100 1000 10000
100
80
60
40
20
0
-20
-40
Dose of A (mg)
Response(HR)
Response(% of
maximal)
0 70 0
0.01 70 0
0.05 70 0
0.1 75 8.3
0.5 85 25
1 100 50
5 115 75
10 125 92
50 130 100
100 130 100
500 130 100
1000
5000
Dose-response curves(or concentration-response curves)
• The plateau of the curve shows the maximal effect or “Emax” of the drug in the system– A measure of efficacy or effectiveness of the drug– Magnitude of response increases with increasing dose as more agonist-
receptor complexes formed• The position of the curve along the x-axis shows the potency of the drug
– potency is the amount of drug needed to produce an effect– measured as the dose that produces 50% of the maximal response, or, the
dose that produces a certain response in 50% of subjects– called “ED50”, the median effective dose (or EC50, the median effective
concentration• The lower the ED50, the more potent is the ligand
– Potency is largely related to the affinity of the agonist for the receptor• Efficacy and potency are unrelated. Clinically, efficacy is more important• Curves are useful for visually comparing potency and efficacy of drugs
Dose-response curve to agonist A(graded response)
RESP
ON
SE (%
of m
axim
um)
DOSE (mg) (log scale) 0 0.01 0.1 1.0 10 100 1000 10000
100
80
60
50
40
20
0
-20
-40
Dose of A (mg)
Response(HR)
Response(% of
maximal)
0 70 0
0.01 70 0
0.05 70 0
0.1 75 8.3
0.5 85 25
1 100 50
5 115 75
10 125 92
50 130 100
100 130 100
500 130 100
1000
5000
Emax
1/2max
response
ED50 = 1mg
Dose-response curves to agonists A, B, C (graded resonse)
RESP
ON
SE (%
of m
axim
um)
DOSE (mg) (log scale) 0 0.01 0.1 1.0 10 100 1000 10000
100
80
60
40
20
0
-20
-40
Dose (mg)
Response to A (% of
maximal)
Responseto B (% of maximal)
Response to C (% of maximal)
0 0 0 0
0.01 0 8.3 0
0.05 0 25 8.3
0.1 8.3 50 21
0.5 25 75 33
1 50 92 40
5 75 100 40
10 92 100 40
50 100 100
100 100
500 100
1000
5000
Dose-response curve to agonist D(quantal response)
RESP
ON
SE (%
of t
otal
)
DOSE (mg) (log scale) 0 0.01 0.1 1.0 10 100 1000 10000
100
80
60
40
20
0
-20
-40
Dose of D (mg)
RespondersCumulative Responders
Cumulative Responders(% of total)
0 0 0 0
0.01 0 0 0
0.05 0 0 0
0.1 16 16 8
0.5 34 50 25
1 50 100 50
5 50 150 75
10 34 184 92
50 16 200 100
200 subjects tested for therapeutic response
Therapeutic and adverse effects of agonist D(200 subjects)
Dose of D (mg)
Therapeutic responders
Cumulativetherapeutic responders
Cumulativetherapeutic responders(% of total)
Number ofsubjects
reportinga certainadverseeffect
Cumulativeadverse
responders
Cumulativeadverse
responders(% of total)
Deaths Cumulativedeaths
Cumulativedeaths
(% of total)
0 0 0 0 0 0 0 0 0 0
0.01 0 0 0 0 0 0 0 0 0
0.05 0 0 0 0 0 0 0 0 0
0.1 16 16 8 0 0 0 0 0 0
0.5 34 50 25 0 0 0 0 0 0
1 50 100 50 0 0 0 0 0 0
5 50 150 75 12 12 6 0 0 0
10 34 184 92 28 40 20 0 0 0
50 16 200 100 48 88 44 14 14 7
100 46 134 67 30 44 22
500 42 176 88 50 94 47
1000 18 194 97 48 142 71
5000 6 200 100 49 191 95
10000 9 200 100
Dose-response curves for various responses to agonist D
RESP
ON
SE (%
of t
otal
)
DOSE (mg) (log scale) 0 0.01 0.1 1.0 10 100 1000 10000
100
80
60
40
20
0
-20
-40
Therapeutic effectAdverse effectLethality
Therapeutic Index (TI): = TD50/ED50
Therapeutic Index: a measure of drug safety
Dose-response curves to agonist A and ligands E and F
RESP
ON
SE (%
of m
axim
um)
DOSE (mg) (log scale) 0 0.01 0.1 1.0 10 100 1000 10000
100
80
60
40
20
0
-20
-40
Dose (mg)
Response to A (% of
maximal)
Responseto E (% of maximal)
Response to F (% of maximal)
0 0 0 0
0.01 0 0 0
0.05 0 0 0
0.1 8.3 0 0
0.5 25 -5 0
1 50 -12 0
5 75 -25 0
10 92 -30 0
50 100 -30 0
100 100 -30 0
500 100
1000
5000
Dose-response curves to a full agonist, partial agonist, inverse agonist and neutral antagonist or
inactive compound
Textbook figure 1-6
Neutral antagonist(or an inactive compound)
Effect of various doses of antagonist F (inverse agonist or neutral antagonist) on the response to 5 mg dose of agonist A
RESP
ON
SE (%
of m
axim
um)
DOSE of F (mg) (log scale) 0 0.01 0.1 1.0 10 100 1000 10000
100
80
60
40
20
0
-20
-40
5 mg agonist A after
pretreatment with various doses of F
(mg)
Response(% of
maximal)
0 75
0.1 75
0.5 75
1 75
5 75
10 75
50 65
100 48
500 16
1000 0
Effect of pretreatment with three different fixed doses of antagonist G on the response to agonist B
RESP
ON
SE (%
of m
axim
um)
DOSE (mg) (log scale) 0 0.01 0.1 1.0 10 100 1000 10000
100
80
60
40
20
0
-20
-40
Dose of B (mg)
Response to B alone
Responseto B +
1 mg G
Responseto B +
3 mg G
Responseto B +
10 mg G
0 0 0 0 0
0.01 8.3 0 0 0
0.05 25 0 0 0
0.1 50 18 0 0
0.5 75 40 0 0
1 92 68 12 0
5 100 84 35 0
10 100 96 59 0
50 100 100 81 10
100 92 37
500 100 68
1000 89
5000 100
Effect of competitive or non-competitive antagonists on agonist activity
•Parallel rightward shift of D-R curves•Apparent increase in EC50
•Agonist appears less potent in presence of competitive antagonist•No reduction in Emax
•Surmountable antagonism•Pharmacological antagonism
•Non-competitive antagonist reduces Emax
Effect of allosteric ligands on agonist activity
Partial agonists can also reduce the response of a full agonist
