DRC

1. Dose Response Relationship
Dose Response Relationship
&
&
Therapeutic Index
Therapeutic Index
Dr Rizwan
Dr Rizwan

2. quantal (cumulative) D/R
curve
tachyphylaxis
graded (quantitative) D/R
curve
therapeutic index
potency
median toxic dose (TD50)
efficacy (effectiveness)
median effective dose
(ED50)
dose/response (D/R)
Objectives

3. What is a dose response
What is a dose response
relationship?
relationship?

4. Systemic description of the
magnitude of the
effect of a drug
as a function of the dose
(very low to very high)

5. Dose response curves
Dose response curves
The relationship of dose to
The relationship of dose to
response can be illustrated
response can be illustrated
as a graph called as dose
as a graph called as dose
response curve.
response curve.

6. Dose-response curves can be used to plot the
Dose-response curves can be used to plot the
results of many kinds of experiments.
results of many kinds of experiments.
The X-axis plots concentration of a drug or
The X-axis plots concentration of a drug or
hormone.
hormone.
The Y-axis plots response, which could be almost
The Y-axis plots response, which could be almost
anything.
anything.
For example, the response might be enzyme
For example, the response might be enzyme
activity, accumulation of an intracellular second
activity, accumulation of an intracellular second
messenger, membrane potential, secretion of a
messenger, membrane potential, secretion of a
hormone, heart rate or contraction of a muscle.
hormone, heart rate or contraction of a muscle.

7. Shape of the curve
Shape of the curve
A standard dose-response curve is
A standard dose-response curve is
defined by four parameters:
defined by four parameters:
the baseline response (Bottom),
the baseline response (Bottom),
the maximum response (Top),
the maximum response (Top),
the slope, and the
the slope, and the
drug concentration that provokes a
drug concentration that provokes a
response halfway between baseline and
response halfway between baseline and
maximum (EC50).
maximum (EC50).

9. Threshold
Threshold
Important aspect of dose response
Important aspect of dose response
relationship.
relationship.
A dose below which there are no
A dose below which there are no
adverse effects from exposure to
adverse effects from exposure to
chemical.
chemical.

10. BIOLOGICAL STIMULUS
BIOLOGICAL STIMULUS
PERCENT RECEPTOR OCCUPANCY
PERCENT RECEPTOR OCCUPANCY
0%
0% 100%
100%
BIOLOGICAL RESPONSE
BIOLOGICAL RESPONSE RECEPTOR RESERVE
RECEPTOR RESERVE
TRETHOLD
TRETHOLD
0%
0% 100%
100%
Max Effect
Max Effect
Threshold Effect
Threshold Effect
Schematic representation of the relationship between threshold, receptor
Schematic representation of the relationship between threshold, receptor
reserve, receptor occupancy, biological stimulus and biological response
reserve, receptor occupancy, biological stimulus and biological response

12. When a threshold is difficult to
When a threshold is difficult to
determine
determine
Look for slope of the dose response
Look for slope of the dose response
curve.
curve.
Why?
Why?

13. A sharp increase in
A sharp increase in
slope suggest
slope suggest
increasingly higher
increasingly higher
risk of toxic
risk of toxic
response as the
response as the
dose increases
dose increases
A relatively flat slope
suggest
that effect of an
increasing dose is
minimal

14. Dose Response Curve
Dose Response Curve
Many dose-response curves follow
Many dose-response curves follow
exactly the shape of a receptor
exactly the shape of a receptor
binding curve. As shown below, 81
binding curve. As shown below, 81
times more agonist is needed to
times more agonist is needed to
achieve 90% response than a 10%
achieve 90% response than a 10%
response.
response.

16. Some dose-response curves however,
Some dose-response curves however,
are
are steeper or shallower
steeper or shallower than the
than the
standard curve.
standard curve.
The steepness is quantified by the
The steepness is quantified by the Hill
Hill
slope,
slope, also called a
also called a slope factor.
slope factor.
A dose-response curve with a standard
A dose-response curve with a standard
slope has a Hill slope of
slope has a Hill slope of 1.0.
1.0.
A steeper curve has a higher slope
A steeper curve has a higher slope
factor, and a shallower curve has a lower
factor, and a shallower curve has a lower
slope factor.
slope factor.

18. Is there any relationship between
Is there any relationship between
shape of curve and potency
shape of curve and potency
A
A Steep curve
Steep curve even at a
even at a
small dose
small dose suggest a
suggest a
chemical of
chemical of high potency
high potency

19. Reason for steep curve
Reason for steep curve
Cooperative interaction of several
Cooperative interaction of several
different actions of drug
different actions of drug
E.g. effect on brain, heart, and
E.g. effect on brain, heart, and
peripheral vessels, all contributing
peripheral vessels, all contributing
to lowering of blood pressure.
to lowering of blood pressure.
Coma caused by sedative
Coma caused by sedative
hypnotics.
hypnotics.

21. Used to measure
Used to measure
Drug potency
Drug potency
Drug efficacy
Drug efficacy
Drug safety
Drug safety

22. POTENCY
POTENCY
CONCENTRATION (EC50) OR DOSE (ED50)
OF A DRUG
REQUIRED TO PRODUCE
50% OF THAT DRUG’S MAXIMUM EFFECT

23. A
B
X
0
Average
Response
Magnitude
DRUG DOSE
Potency
Potency
HI
 A is more potent than B
A is more potent than B

24. A
B
DRUG DOSE
X
0
Average
Response
Magnitude
HI
LO
Maximum Efficacy
Maximum Efficacy
 B has greater max efficacy than A
B has greater max efficacy than A

25. [D] (concentration units)
%
Maximal
Effect
0.01 0.10 1.00 10.00 100.00 1000.00
0.0
0.2
0.4
0.6
0.8
1.0
Partial agonist
Full Agonist
Partial agonist
PARTIAL AGONISTS - EFFICACY
Even though drugs may occupy the same # of receptors, the magnitude
of their effects may differ.

28. Example
Example
Isoproterenol, Epinephrine and Nor
Isoproterenol, Epinephrine and Nor
epinephrine
epinephrine all interact with the same
all interact with the same
receptor and produce the same
receptor and produce the same
maximal effect (efficacy). Thus
maximal effect (efficacy). Thus
isoproternol, epinephrine & nor
isoproternol, epinephrine & nor
epinephrine are equally effective
epinephrine are equally effective
(because all activate the same number
(because all activate the same number
of receptors and are described as full
of receptors and are described as full
agonist)
agonist)
BUT
BUT

29. Dose response curve don’t
Dose response curve don’t
look the same
look the same
What's different?
What's different?

30. Difference between the 3 drugs
Difference between the 3 drugs
is their
is their
POTENCY
POTENCY
ISOPROTERENOL > EPINEPHRINE > NOR EPINEPHRINE

31. Types of dose response curves
Types of dose response curves
Graded
Graded dose response curves
dose response curves
Quantal
Quantal dose response curves
dose response curves

32. What is the difference between Quantal
What is the difference between Quantal
and graded dose-response curves?
and graded dose-response curves?

33. Graded (Quantitative) dose-effect relations
Graded (Quantitative) dose-effect relations
A graph of the relationship between dose
A graph of the relationship between dose
and response.
and response.
minimum detectable response
minimum detectable response and a
and a maximum
maximum
response
response by
by
varying the dose or drug concentration,
varying the dose or drug concentration,
i.e., the curve is continuous.
i.e., the curve is continuous.

34. Graded dose response curves show effects
on a continuous scale And the intensity of the effect
is proportional to the dose

35. Exposure to ethanol
Graded responses between no effect and death

36. Requirements
Requirements
Single biological unit or average of
Single biological unit or average of
many such units for each data point
many such units for each data point
A preparation of a single animal or
A preparation of a single animal or
organ can produce the curve
organ can produce the curve

37. Problem
Problem
Poor predictors of how other specimens
Poor predictors of how other specimens
might respond.
might respond.

38. Plot of the contraction of the intestinal smooth muscle
Plot of the contraction of the intestinal smooth muscle
in response to varied doses of acetylcholine
in response to varied doses of acetylcholine

39. Observation
Observation
The response varies continuously with dose.
The response varies continuously with dose.
Shape
Shape --
-- sigmoidal
sigmoidal
Threshold dose
Threshold dose --
-- The lowest dose that produces a detectable
The lowest dose that produces a detectable
response
response
Dose units --
Dose units -- the
the independent variable
independent variable is plotted on the X-axis as the
is plotted on the X-axis as the
logarithm of the dose. This --
logarithm of the dose. This --
 produces a symmetrical curve
produces a symmetrical curve
 allows a broader range of doses on the graph
allows a broader range of doses on the graph
Response units --
Response units -- the
the dependent variable
dependent variable is plotted on the Y-axis in
is plotted on the Y-axis in
arithmetic units. The scale can be --
arithmetic units. The scale can be --
actual units, e.g., grams of tension, mm change in length, etc.
actual units, e.g., grams of tension, mm change in length, etc.
derived units, e.g., % of maximum response
derived units, e.g., % of maximum response
Abstract summary of data
Abstract summary of data, to allow for easy comparisons and
, to allow for easy comparisons and
mathematical treatment, e.g., ED
mathematical treatment, e.g., ED50
50

40. Quantal (All-or-none; binary) dos
Quantal (All-or-none; binary) dos
Graph of relationship between dose and
Graph of relationship between dose and
effect
effect
describes the
describes the distribution of MINIMUM
distribution of MINIMUM
doses of drug
doses of drug required to produce a
required to produce a
defined degree of a specific response
defined degree of a specific response
in a
in a population
population of subjects.
of subjects.

41. All or None
All or None
Percentage of population
Percentage of population
affected
affected
– >
> threshold response
threshold response
– As function of drug dose
As function of drug dose
NOT
NOT magnitude of drug effects
magnitude of drug effects

43. Purpose
Purpose
To allow
To allow predictions
predictions about what
about what
proportion of a population of
proportion of a population of
subjects will respond to given
subjects will respond to given
doses of the drug or toxin.
doses of the drug or toxin.

44. Defined specific effect and degree of
Defined specific effect and degree of
response
response --
--
The specific effect being
The specific effect being
measured
measured
Only two responses are allowed --
Only two responses are allowed --
Yes or No; 0 or 1
Yes or No; 0 or 1
Response is
Response is quantal
quantal, i.e., not
, i.e., not
continuously variable
continuously variable
increments or decrements by 1
increments or decrements by 1
unit (e.g., individual) at a time.
unit (e.g., individual) at a time.

45. Problem
Problem
Many units (animals, humans,
Many units (animals, humans,
organs) required to create a quantal
organs) required to create a quantal
dose-effect curve.
dose-effect curve.
From these many units, one can make
From these many units, one can make
predictions about what proportion of a
predictions about what proportion of a
similar population will respond to the
similar population will respond to the
drug in the same way
drug in the same way.
.

46. Titration
Titration
Because the plot represents the distribution
Because the plot represents the distribution
of minimum doses that produce the effect,
of minimum doses that produce the effect,
one must titrate the population with
one must titrate the population with
increasing doses until virtually all members
increasing doses until virtually all members
respond.
respond.
In essence, one is finding the
In essence, one is finding the individual
individual
effective dose.
effective dose.
This can be done in two ways
This can be done in two ways

47. Titration of each individual
Titration of each individual
Administer increasing doses of drug to each individual until a
Administer increasing doses of drug to each individual until a
response is elicited, then note the dose.
response is elicited, then note the dose.
Do this for all members of the test population.
Do this for all members of the test population.
very impractical
very impractical ------serious conceptual disadvantages,
------serious conceptual disadvantages,
e.g., multiple doses of drug may produce a false effect
e.g., multiple doses of drug may produce a false effect
compared to a single exposure to a larger dose.
compared to a single exposure to a larger dose.
Titration of groups
Titration of groups
Divide the test population into groups,
Divide the test population into groups,
give each group only one of a series of increasing
give each group only one of a series of increasing
doses.
doses.
Responses will vary, e.g., from no responses in a
Responses will vary, e.g., from no responses in a
group to 100% of responses. Record the % of the
group to 100% of responses. Record the % of the
group responding to each dose.
group responding to each dose.

48. Shape of curve
Shape of curve
"cumulative" dose-effect curve is
"cumulative" dose-effect curve is
sigmoidal
sigmoidal
when % responding is plotted against the
when % responding is plotted against the
log-dose.
log-dose.

49. Description of data
Description of data
One can define the mid-point as
One can define the mid-point as
for the graded curve, i.e., the
for the graded curve, i.e., the
ED
ED50
50, the dose that produces
, the dose that produces
the effect in 50% of the test
the effect in 50% of the test
population.
population.

50. Construction of
Construction of quantal
quantal
(binary) dose-effect curves
(binary) dose-effect curves
Method A: Titrate each animal
Method A: Titrate each animal
Method B -- Titration of groups
Method B -- Titration of groups

51. Method A: Titrate each animal
Method A: Titrate each animal
Sample experiment
Sample experiment
70 rats are given the same initial dose
70 rats are given the same initial dose
Did the dose elicit the
Did the dose elicit the predefined degree of
predefined degree of
response
response in any of the animals? If so, note
in any of the animals? If so, note
the % that responded (Yes or "1") and
the % that responded (Yes or "1") and
remove them from the test population
remove them from the test population
Administer the next higher dose to the
Administer the next higher dose to the
remaining animals
remaining animals
Note the number responding and remove
Note the number responding and remove
them from the test
them from the test
Repeat steps 3 and 4 until ALL of the animals
Repeat steps 3 and 4 until ALL of the animals
have responded.
have responded.

52. BELL SHAPED CURVE
majority of responders in the middle
mean response is approx. 110 mg/kg
fewer responders at the end of bell curve (expected)
known as biological variability
responders at the far left of the mean are typically
hypersusceptible
whereas those at the far right are
resistant

53. Comments
Comments
expensive
expensive in labor, materials, and drug
in labor, materials, and drug
because many animals receive multiple
because many animals receive multiple
doses
doses
Requires
Requires long periods of time
long periods of time to conduct
to conduct
the experiment because one must wait
the experiment because one must wait
until the animals have recovered
until the animals have recovered
completely from the previous dose
completely from the previous dose
Results confounded
Results confounded by previous and
by previous and
multiple exposures to the drug
multiple exposures to the drug

54. Method B -- Titration of groups
Method B -- Titration of groups
Give one and the same dose to
Give one and the same dose to
each animal of a group.
each animal of a group.
From a series of doses, give each
From a series of doses, give each
group one dose.
group one dose.

55. Sample experiment
Sample experiment
Obtain, e.g., 70 rats
Obtain, e.g., 70 rats
Randomly allot them to 7 groups of 10
Randomly allot them to 7 groups of 10
each
each
Select 7 doses and give one dose to
Select 7 doses and give one dose to
each member of a group (70 injections)
each member of a group (70 injections)
Note the
Note the PERCENTAGE
PERCENTAGE of each group
of each group
that responds
that responds
Plot the % responding versus dose
Plot the % responding versus dose

56. Cumulative quantal dose
Cumulative quantal dose
response plot
response plot

58. Both curves provide
Both curves provide
Information regarding
Information regarding
potency.
potency.
Selectivity
Selectivity
But
But
Graded dose response
Graded dose response curve
curve
indicates
indicates
maximum efficacy
maximum efficacy
Quantal dose response
Quantal dose response indicates
indicates
potential variability of
potential variability of
responsiveness
responsiveness
among
among
individuals
individuals

59. Quantal D/R curves used to define
Quantal D/R curves used to define
median effective (and toxic) doses,
median effective (and toxic) doses,
concept of “therapeutic index”
concept of “therapeutic index”
the potential range of inter-subject
the potential range of inter-subject
variability in drug response.
variability in drug response.

62. To use or not to use?
To use or not to use?
Need information
Need information
Therapeutic Index (safety margin)
Therapeutic Index (safety margin)
Decision Making
Decision Making
TI: 10mg/10mg = 1
100mg/10mg = 10
1000mg/10mg = 100 ~
LD50
ED50

63. BIOLOGICAL STIMULUS
BIOLOGICAL STIMULUS
PERCENT RECEPTOR OCCUPANCY
PERCENT RECEPTOR OCCUPANCY
0%
0% 100%
100%
BIOLOGICAL RESPONSE
BIOLOGICAL RESPONSE RECEPTOR RESERVE
RECEPTOR RESERVE
TRETHOLD
TRETHOLD
0%
0% 100%
100%
Max Effect
Max Effect
Threshold Effect
Threshold Effect
Schematic representation of the relationship between threshold, receptor
Schematic representation of the relationship between threshold, receptor
reserve, receptor occupancy, biological stimulus and biological response
reserve, receptor occupancy, biological stimulus and biological response

64. 100
50
0
DRUG DOSE
0 X
ED LD
% subjects
TI = LD50/ ED50
Relatively safe ~
Relatively safe ~

65. 100
50
0
DRUG DOSE
0 X
ED LD
% subjects
TI = LD50/ ED50
Less safe drug ~
Less safe drug ~