ANALYSIS OF

DOSE RESPONSE RELATIONSHIP

by Lee Eun Jin

• DOSE = amount of drug administered to the patient

• RESPONSE = effect in the body produced by the drug

• Drug + Receptor  Drug-Receptor Complex


Response
Dose-response relationship
 Depends on multiple factors

 A drug usually has one desired effect that causes

a change in a target organ or structure

 It will also have secondary effects because it will

be absorbed by other areas of the body
Main effects and side effects

 Main effect – the effect you want the drug to hav

e

 Side effects – secondary effects that may or may

not be desirable or helpful

 Goal is to use a dose of a drug that is effective, bu

t has minimal side effects
Dosage-response curve
 Making dosage decision

 Compare dosage to the percentage of people showing

different effects

 ED10- effective dose where 10% of people show respo

nse of interest

 Example – dosages of a drug used to increase attentio

n (main effect) but also has 2 side effects
◦ Heart palpitations
◦ death
• The dose-response relationships for drugs may be Graded or quantal.
Graded dose-response curve
• can be constructed for responses that are measured on a continuous scale
• Eg, heart rate.
• Graded dose-response curves relate the intensity of response to the size of
the dose, and hence are useful for characterizing the actions of drugs.
Quantal dose-response curve
• can be constructed for drugs that elicit an all-or-none response
• Eg, presence or absence of epileptic seizures.
• For most drugs, the doses that are required to produce a specified quantal
effect in a population are log normally distributed, so that the frequency
distribution of responses plotted against log dose is a gaussian normal
distribution curve.
• The percentage of the population requiring a particular dose to exhibit the
effect can be determined from this curve.
• When these data are plotted as a cumulative frequency distribution, a
sigmoidal dose-response curve is generated.
 Graded dose response

• means that a slight increase of drug should bring about a small increase in
the response
• For example, increase doses of histamine cause gradual contraction of the
guinea-pig ileum.
• Very low doses of histamine have virtually no effect and responses can be
observed, only beyond a threshold does of about 20ng.
• Again, very high doses of more than 50g have no additional effects, and
the response remains constant at this maximal level.
• Graded dose response means the pharmacological effects of the drugs
expressed in quality or number, such as the heart rate by beat, blood
pressure by mmHg, also the contract of ileum in height effected by the
drugs.
ED50
GRADED DOSE-
RESPONSE CURVE

ED50
• An all-or-none response to a drug and relates to the f
requency with which a specific dose of a drug produc
es a specific response in a population.
• Indicates that a given dose of a drug has or has not evo
ked a certain effect in the various subject under investiga
tion, that is the pharmacological effects are expressed in
passive or negative.
•For example, to test either presence or absence of hypn
osis for a sedative. (e.g., death among the mice in a pre-
clinical study or effective among the patients in a clinical
trial.)
Cumulative
Frequency Distribut
ion
QUANTAL DOSE-RES
PONSE CURVE

Frequency Distribut
ion
 Graded • Continuous scale
• Measured in a single biologic unit
• Relates dose to intensity of effect
rate
(%) Dose
Quantal • All-or-none pharmacologic effect
rate • Population studies
(%)
• Relates dose to frequency of effect

Dose
Dose-Response Curve Information

4 Important Values:
 Potency

 Efficacy

 Slope

 Variability
o Absolute amount of drug required to produce an effect

o More potent drug is the one that requires lower do

to cause same effect

o Measure of amount of drug required for effect

(ED50)
Potency
• refers to the concentration (EC50) or dose (ED50) of a drug required to produce
50% of the drug's maximal effect as depicted by a graded dose-response curve.
• EC50 equals KD when there is a linear relationship between occupancy and
response.
• Often, signal amplification occurs between receptor occupancy and response,
which results in the EC50 for response being much less (ie, positioned to the left
on the abscissa of the log dose-response curve) than KD for receptor
occupancy.
• Potency depends on both the affinity of a drug for its receptor, and the
efficiency with which drug-receptor interaction is coupled to response.
• The dose of drug required to produce an effect is inversely related to potency.
• In general, low potency is important only if it results in a need to administer
the drug in large doses that are impractical.
• Quantal dose-response curves provide information on the potency of drugs
that is different from the information derived from graded dose-response
curves.
• In a quantal dose-response relationship, the ED50 is the dose at which 50% of
individuals exhibit the specified quantal effect
Potency

A B
Therapeutic
Effect
Effect

Dose
Efficacy (Intrinsic activity)
• THE Ability of the drug to elicit a response when it binds to
the receptor.
• Conformational changes in receptors as a result of drug
occupancy initiate biochemical and physiologic events that
characterize the drug's response.
• In some tissues, agonists demonstrating high efficacy can
result in a maximal effect, even when only a small fraction of
the receptors is occupied
Efficacy
• Efficacy – how large an effect the drug produces
• Maximum effect obtained with drug (not potency)

100

Response 50
2

0
1
ED50
Log Drug Concentration [Molar]
 Slope: Effect of incremental increase in dose

 change in effect from change in dose

 Variability: Reproducibility of data

 different for different people

 Threshold (minimal) dose
◦ Least amount needed to produce desired effects
 Maximum effect
◦ Greatest response produced regardless of dose used

A
Therapeutic
Effect
Effect

Dose
 ED50- dose which will be therapeutically
effective in 50% of animals (median effe
100 100 ctive dose)

LD50- dose which will, on average, kill 50

% of animals in a population
50 50

MED- minimum effective dose (the least dose

that is likely to be effective).
ED50 LD50 Also called toxic dose-low(TDL)

Dosage (mg/kg) MTD- maximum tolerated dose (or minimu

m toxic dose) (more than this will produce s
ME igns of toxicity).
D MT Also called highest nontoxic dose (HNTD)
D
Toxic

Therapeutic Range

Subtherapeutic
Therapeutic index (TI): The index used for
judging drug's safety.
TI＝LD50／ED50

ED50

LD50
Factors Altering Drug Responses

 Age
◦ Pediatric or geriatric
◦ Immature or decreased hepatic, renal function
 Weight
◦ Big patients “spread” drug over larger volume
 Gender
◦ Difference in sizes
◦ Difference in fat/water distribution
Factors Altering Drug Responses

 Environment
◦ Heat or cold
◦ Presence or real or perceived threats

 Fever
 Shock
• Toxicity is the degree to which a substance can damage an organism

• Toxicology is the science that deals with the amount o

f an agent that causes an adverse action in some living s
ystem

•‘All substances are poisons; there is none which is not

a poison. The right dose differentiates a poison from a
remedy.’- Paracelus (16th century physician-alchemist)

•‘A poison is any substance or matter which, when appl

ied to the body outwardly, or in any way introduced int
o it, can destroy life by its own inherent qualities, witho
ut acting mechanically, and irrespective of temperature.
’
Principle causes of drug toxicity/side effects

a. the predictable

b. the less predictable

c. the unpredictable
a. the predictable
• excessive action at a primary site (over dosage)
e.g. anaesthetics, warfarin

non-selectivity: acting at unrelated sites (more likely with

• over dosage) e.g. chlorpromazine

• incomplete selective toxicity: acts against the host as

well as the target organism or cell
e.g. protein synthesis inhibitors, antimicrobials, antifungal

• tolerance (dependence & abuse potential)

e.g. benzodiazepines, opioids
unavoidable side-effects
e.g. immunosuppression by corticosteroids – opportuni
stic infections
 a. the predictable

Pharmacokinetic Drug interactions:

• absorption Atropine and

e.g. gastric emptying, gut motility
metoclopramide
•distribution aspirin and warfarin
e.g. displacement from plasma proteins
•metabolism barbiturates and ster
e.g. increased by enzyme induction
• excretion NSAIDS and
e.g. active transport competition
methotrexate
a. the predictable

• Age
- most drugs tested on young to middle-aged vol
unteers
-causing problems such as:
-drug clearance mechanisms (renal and hepatic) are limited in
newborns
-clearance is reduced in elderly (increasing half life)
reduction in lean body mass, serum albumin, total body water.

increased body fat

declined renal function
reduced hepatic blood flow
•Gender reduced activities of cytochrome P450 enzymes
- a relative increase of body fat in females
b. the less predictable

• Genetic factors

e.g. polymorphism in NAT2 in the liver (N-acetyltransferase2).

-metabolises about 16 common drugs (phenytoin, hydralazine)

Plasma esterase – suxamethonium (about 1 in 3000

individuals)

c. the unpredictable

• untoward adverse reactions

• drug allergies and anaphylactic reactions

e.g. penicillin (1 in 50,000 patients exposed)
Multiple dosing
 On continuous steady administration of a drug, plas
ma concentration will rise fast at first then more slo
wly and reach a plateau, where:
rate of administration = rate of elimination i.e.steady
state is reached.

Therefore, at steady state:

Dose (Rate of Administration) = clearance x plasma conc.

steady state conc. = Dose/clearance

 Single dose –
7 Loading dose
6
Therapeutic level
5

4
Plasma Concentration

2 Repeated doses –Maint

enance dose
1

0
0 5 10 15 20 25 30

Time
• Drug development
- Site of action
- Selection of dose and schedule
- Potency, efficacy and safety
- Drug interactions

• Patient management

-Therapeutic drug monitoring

-Risk benefit (therapeutic indices)
Morphine

Aspirin
THERAPEUTIC INDEX – AN INDEX OF SAFETY

Hypnosis Death
 ED99A
ED50A
LD1A

LD1
Margin of Safety =
ED99
 Desired vs undesired effects: Indices
of drug safety.
• Safety Index
• Therapeutic Index
 Safety index: LD1/ED99
ED99
100

80 Sleep Death

60

40
LD1
20

0
0

K
01

01
1

10
1

0K
1

-20 1K
10
0.
00

10
0.
00

10
0.
0.
 Therapeutic index: LD50/ED50

100

80 Sleep Death

60

40

20

0
0

K
01

01
1

10
1

0K
1

-20 1K
10
0.
00

10
0.
00

10
0.
0.
Causes of Variability in Drug Response

Those related to the biological system

1. Body weight and size
2. Age and Sex
3. Genetics - pharmacogenetics
4. Condition of health
5. Placebo effect
 Causes of Variability in Drug Response

• Those related to the conditions of administration

1. Dose, formulation, route of administration.
2. Resulting from repeated administration of drug:
drug resistance; drug tolerance-tachyphylaxis; drug allergy
3. Drug interactions:
chemical or physical;
GI absorption;
protein binding/distribution;
metabolism (stimulation/inhibition);
excretion (pH/transport processes);
receptor (potentiation/antagonism);
changes in pH or electrolytes.
 Effect site
Dose Concentration
Effect

Pharmacokinetics Pharmacodynamics
Absorption Tissue/organ sensitivity
Distribution (target status)
Metabolism
Elimination
Drug interactions
Monitoring drug responses
 Level
 Molecular (e.g., enzyme inhibition, receptor

binding assay)
 Cellular (in vitro tissue culture, blood cells)

 Tissue or organ (in vitro or in vivo)

 Animal disease model

 Endpoint used to measure the effect may be different

at each level
 Overall effect = Sum of multiple drug effects and
physiological responses to drug effects
Endpoints to monitor drug effects

LEVEL ENDPOINT

Molecular Enzyme e inhibition

Cellular Proliferation rate, Apoptosis

Tumor Response (Change in tumor size)

Organism Survival, Quality of life

 DOSE-RESPONSE RELATIONSHIPS

The effect of dose on the

magnitude of
pharmacologic response.

Panel A is a linear graph.

EffectMax • [Drug]
*Effect =
KD + [Drug]

*EC50=drug dose that shows fifty percent of

maximal response.
 DOSE-RESPONSE RELATIONSHIPS

The effect of dose on

the magnitude of
pharmacologic
response.

Panel B is a
semi-logarithmic plot
of the same data.
 Determinants of Drug Activity
1. Potency: the amount of drug to produce an effect
of a given magnitude
2. Efficacy: the maximal response (effect) produced
by drug

Morphine
Biologic effect

Codeine
efficacy 100

Biologic effect(%)
Aspirin

50
potency
0
1 10 100
Log dose Log dose (mg)
 DOSE-RESPONSE RELATIONSHIPS

Typical dose-response
curve
for drugs showing
differences in
potency and efficacy.
 DOSE-RESPONSE RELATIONSHIPS

Effects of drug
antagonists.
 DOSE-RESPONSE RELATIONSHIPS

Effects of partial
agonists.

Full Agonist
RESPONSE

Partial Agonist

Antagonist
-1 0 1 2
Log([A]/KA)
 QUANTAL DOSE-RESPONSE RELATIONSHIPS

Therapeutic Index

 Therapeutic index =
toxic dose(LD50)/effective dose(EC50)

 This is a measure of a drug’s safety

• A large number = a wide margin of safety
• A small number = a small margin of safety
 QUANTAL DOSE-RESPONSE RELATIONSHIPS

Effects of partial
agonists.
 QUANTAL DOSE-RESPONSE RELATIONSHIPS

Effects of partial
agonists.
 Drugs- receptor- response
 Some drugs can act without binding to a receptor
 spare receptors allow maximum response without full receptor
occupancy
 Efficacy is the amount of drug needed to produce an effect.
 Affinity is the attractiveness between 2 drug molecules.
 Agonist are the drugs that block the response.
 Partial agonist has affinity and maximum efficacy.
 Antagonist has efficacy but no affinity.
 Competitive antagonist decreases potency
 Non competitive antagonist decreases efficacy
THANK YOU