Dose Response Relationship & Therapeutic Index

Dr Rizwan

Objectives
dose/response (D/R) median effective dose (ED50)

efficacy (effectiveness)
potency graded (quantitative) D/R curve quantal (cumulative) D/R curve

median toxic dose (TD50)

therapeutic index

tachyphylaxis

What is a dose response relationship?

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

Dose response curves

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

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

Shape of the curve

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

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

Schematic representation of the relationship between threshold, receptor reserve, receptor occupancy, biological stimulus and biological response

BIOLOGICAL STIMULUS

0%
TRETHOLD BIOLOGICAL RESPONSE

100%
RECEPTOR RESERVE

Threshold Effect

Max Effect

PERCENT RECEPTOR OCCUPANCY

0%

100%

When a threshold is difficult to determine

Look for slope of the dose response curve.

Why?

A sharp increase in slope suggest increasingly higher risk of toxic response as the dose increases

A relatively flat slope suggest that effect of an increasing dose is minimal

Dose Response Curve

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

Some dose-response curves however, are steeper or shallower than the standard curve.

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

Is there any relationship between shape of curve and potency

A Steep curve even at a small dose suggest a chemical of high potency

Reason for steep curve

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

Used to measure
Drug potency Drug efficacy Drug safety

POTENCY
CONCENTRATION (EC50) OR DOSE (ED50) OF A DRUG REQUIRED TO PRODUCE 50% OF THAT DRUGS MAXIMUM EFFECT

Potency
HI

B A

Average Response Magnitude

DRUG DOSE

A is more potent than B

Maximum Efficacy
HI

B A

Average Response Magnitude LO 0 DRUG DOSE X

B has greater max efficacy than A

PARTIAL AGONISTS - EFFICACY

Even though drugs may occupy the same # of receptors, the magnitude of their effects may differ.

Full Agonist
1.0

% Maximal Effect

Partial agonist
0.8

0.6

Partial agonist

0.4

0.2

0.0 0.01

0.10

1.00

10.00

100.00

1000.00

[D] (concentration units)

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

BUT

Dose response curve dont look the same

What's different?

Difference between the 3 drugs is their

POTENCY

ISOPROTERENOL > EPINEPHRINE > NOR EPINEPHRINE

Types of dose response curves Graded dose response curves Quantal dose response curves

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

Graded (Quantitative) dose-effect relationships

A graph of the relationship between dose and response.
minimum detectable response and a maximum response by varying the dose or drug concentration,

i.e., the curve is continuous.

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

Exposure to ethanol Graded responses between no effect and death

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

Problem
Poor predictors of how other specimens

might respond.

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

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

Quantal (All-or-none; binary) dose-effect relationships

Graph of relationship between dose and effect
describes the distribution of MINIMUM doses of drug required to produce a defined degree of a specific response in a population of subjects.

All or None
Percentage of population affected
> threshold response As function of drug dose

NOT magnitude of drug effects

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

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

Problem
Many units (animals, humans, organs) required to create a quantal dose-effect curve.

From these many units, one can make predictions about what proportion of a similar population will respond to the drug in the same way.

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

Titration of each individual

Administer increasing doses of drug to each individual until a response is elicited, then note the dose. Do this for all members of the test population.

very impractical ------serious conceptual disadvantages,

e.g., multiple doses of drug may produce a false effect compared to a single exposure to a larger dose.

Titration of groups
Divide the test population into groups, give each group only one of a series of increasing doses. Responses will vary, e.g., from no responses in a group to 100% of responses. Record the % of the group responding to each dose.

Shape of curve
"cumulative" dose-effect curve is

sigmoidal
when % responding is plotted against the log-dose.

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

Construction of quantal (binary) dose-effect curves

Method A: Titrate each animal Method B -- Titration of groups

Method A: Titrate each animal

Sample experiment
1. 70 rats are given the same initial dose 2. Did the dose elicit the predefined degree of

response in any of the animals? If so, note the % that responded (Yes or "1") and remove them from the test population 3. Administer the next higher dose to the remaining animals 4. Note the number responding and remove them from the test Repeat steps 3 and 4 until ALL of the animals have responded.

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

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

Method B -- Titration of groups

Give one and the same dose to each animal of a group.

From a series of doses, give each group one dose.

Sample experiment
1. Obtain, e.g., 70 rats

2. Randomly allot them to 7 groups of 10

each 3. Select 7 doses and give one dose to each member of a group (70 injections) 4. Note the PERCENTAGE of each group that responds 5. Plot the % responding versus dose

Cumulative quantal dose response plot

Both curves provide

Information regarding

potency. Selectivity

But
Graded dose response curve
indicates maximum efficacy Quantal dose response indicates potential variability of responsiveness among individuals

Quantal D/R curves used to define

median effective (and toxic) doses, concept of therapeutic index the potential range of inter-subject variability in drug response.

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

Schematic representation of the relationship between threshold, receptor reserve, receptor occupancy, biological stimulus and biological response

BIOLOGICAL STIMULUS

0%
TRETHOLD BIOLOGICAL RESPONSE

100%
RECEPTOR RESERVE

Threshold Effect

Max Effect

PERCENT RECEPTOR OCCUPANCY

0%

100%

TI = LD50/ ED50
ED
100

LD

% subjects 50

DRUG DOSE

Relatively safe ~

TI = LD50/ ED50
ED
100

LD

% subjects 50

DRUG DOSE

Less safe drug ~