DoseResponse Relationships

1
Dose-Response Relationships

• Lecture 5

2
Dose Drug Effects

• Pharmacodynamics
• what the drug does to the body
• Effects of drug depends on dose
• In general...
• as dose increases, effects increase
• to a maximum
• then effects decrease

3
Peak Effects as Function of Dose
max
Behavior
min
lo
hi
Drug amount (dose)
4
Dose-response Relationship

• Weight of individual important
• Dose
• amount of drug per body weight
• mg/kg
• milligrams/kilogram
• Helps achieve equal blood concentrations
• often not tightly controlled in humans

5
Dose-response Relationship

• Drug effects are variable
• Probability statements
• Group dose-response curves
• All or none
• Graded
• Different for each individual effect
• i.e., temperature, respiration, euphoria, etc.

6
All or None

• Percentage of population affected
• gt threshold response
• As function of drug dose
• NOT magnitude of drug effects

7
Graded

• Average response magnitude
• in population
• percentage of maximum response
• as function of drug dose

8
Dose-Response Curve

• How response changes as function of dose
• S-shaped curves
• Slope important
• Gradual
• ? dose ? small response change
• Steep
• ? dose ? large response change

9
Dose-Response Curve Slope
Hi
Response
Lo
0
X
DRUG DOSE
10
Dose-Response Curve All or None
100
population
50
0
0
X
DRUG DOSE

• ED50 effective dose in 50 of population

• LD50 lethal dose in 50 of population

11
Drug Response Curve Graded
HI
Average Response Magnitude
LO
0
X
DRUG DOSE

• Effect magnitude information

12
Potency vs. Efficacy

• Potency
• relative term
• drug A has same effect as drug B...
• but at lower dose
• Maximum efficacy
• maximum response magnitude
• more drug ? no effect if increased
• but might increase side effects

13
Maximum Efficacy
HI
Average Response Magnitude
LO
0
X
DRUG DOSE

• B has greater max efficacy than A

14
Potency
HI
Average Response Magnitude
LO
0
X
DRUG DOSE

• A is more potent than B

15
Predicting Drug Effects

• Dose-response Curve
• represents mean from groups
• Predict individuals response to drug?
• Variability
• standard error of the mean

16
Standard Error
HI
Average Response Magnitude
LO
0
X
DRUG DOSE

• Gives idea of response range
• Prediction represents probability

17
Decision Making

• To use or not to use?
• Need information
• Therapeutic Index (safety margin)

• TI 10mg/10mg 1
• 100mg/10mg 10
• 1000mg/10mg 100

18
TI LD50/ ED50
ED
LD
100
subjects
50
0
0
X
DRUG DOSE

• Relatively safe

19
TI LD50/ ED50
ED
LD
100
subjects
50
0
0
X
DRUG DOSE

• Less safe drug

20

• Slope of curve important

100
ED
LD
Population
50
0
0
X
DRUG DOSE
21
Side Effects

• Drug effects other than desired effects
• Drugs have multiple effects!
• TI for side effects

• TD50 toxic dose

22

• Comparing different variables
• same drug
• all or none

A
B
100
population
50
0
0
X
DRUG DOSE

• sex, age, etc.
• or tolerance