Dose-Response relationship

Mafuru M
Dose - is a specified quantity of a drug
prescribed to be taken at one time or at stated
interval (or amount of drug administered to a
patient)

Response – Effect shown by the body to a

particular drug e.g, the response following
administration of digoxin is increased force of
contraction of the myocardium

A relationshipshould exist between the

administered dose and the drug response
A relationship used to analyze a kind of
response obtained after administration of a
specific dose of a drug
e.g If 10mg of Omeprazole is administered to
a patient, the response that it should inhibit
proton pump function at 10mg specifically

Dose response relationship has two

components

1. Dose-plasma concentration relationship

2. Plasma concentration-response relationship
 Dose-Response curve
The dose-response relationship can be
measured by a graphical plot called dose-
response curve

Dose-response curve is required for

1. deciding the drug dose

2. comparing dosage to percentage of people
showing different effects
Dose-response curve
 Types of Dose-response curves
Two types of dose-response curve

1. Graded dose-response curves

2. Quantal dose-response curves

 Graded dose-response curves
Graded dose-response curves are
constructed for response that are measured
on a continuous scale e.g heart rate, blood
pressure, plasma glucose etc

Graded dose-response curves relates the

intensity of response to the size of the dose
hence used in characterizing action of the
drug
Graded dose response means slight increase in
drug dose bring small increase in response
e.g increased dose of Histamine cause gradual
contraction of guinea pig ileum

Very low dose of Histamine has no effect and

response is obtained only beyond the threshold
dose of 20 mg

Very high dose of more than 50 mg has no

addition effect and response remain constant at
this maximum level
 Dose-response curve
100
Ceiling
80
Response

60
ED50
40

20
Threshold

0
0.1 1 10 100 1000 10000

Dose
Dose-response curve
 Quantal dose-response curves
Quantal dose-response curves are constructed
for those drugs that elicit all or non response
e.g presence or absence of epileptic seizures

Indicatesthat given dose of drug has or has not

evoked a certain effect in various subjects
under investigation i.e pharmacological effects
are expressed in passive or negative.
Quantal dose-response curves
 Drug potency and Efficacy
Drug potency: refers to amount of drug
needed to produce a response of a given
magnitude.
Relative potency is more meaningful than
absolute potency e.g

If 10 mg of morphine = 100 mg of

pethidine, morphine is 10 times more potent
than pethidine
 Relative Potency

100
A B
80

60
Effect

40

20

0
0.1 1 10 100 1000 10000

Dose
Relative Potency
=ED50B/ED50A

320/3.2=100
Drug Efficacy: Refers to the ability of the
drug to elicit a response when it binds to a
receptor

e.g Morphine produce a degree of analgesia

not obtained with any dose of aspirin, hence
morphine is more efficacious than aspirin
Relative Efficacy
100

80 Relative
Efficacy
60

40

20

0
0.1 1 10 100 1000 10000
Classification of a drug based
on drug-receptor interactions:
 Agonists
• Drugs that bind to physiological receptors and
mimic the regulatory effects of the endogenous
signaling compounds are termed agonists.

• If the drug binds to the same recognition site as the

endogenous agonist (the primary or orthosteric site
on the receptor) the drug is said to be a primary
agonist.

• Allosteric agonists bind to a different region on the

receptor referred to as an allosteric site.
• Partial agonists -Agents that are only partly as
effective as agonists regardless of the
concentration employed.

• Inverse agonists -Many receptors exhibit some

constitutive activity in the absence of a regulatory
ligand; drugs that stabilize such receptors in an
inactive conformation are termed inverse agonists
(produce effect opposite to that of agonist).
 Full vs Partial agonists
100
Full Agonist
80
% Effect

60

40

20
Partial Agonist
0
0.1 1 10 100 1000 10000

Dose
Full vs Partial agonists
These terms are tissue dependent on
◦ Receptor density
◦ Cell signaling apparatus
◦ Other receptors that are present
◦ Drug history
Partialagonists have both agonist and
antagonist properties.
 Inverse Agonist

100

80
Full agonist
% Effect

60

40

20 Partial agonist
0 1 1 0 1 0 0 1 0 0 0 1 0 0 0 0

-20 Inverse agonist

-40

Dose
 Antagonist
• Drugs that block or reduce the action of an agonist are
termed antagonists.
• Antagonism most commonly results from competition
with an agonist for the same or overlapping site on the
receptor (a syntopic interaction)

• Physical antagonist binds to the drug and prevents its

absorption like charcoal binds to alkaloids and prevents
their absorption.
• Chemical antagonist combines with a substance
chemically like chelating agents binds with the metals.
Cont…
• Physiological antagonist produces an
action opposite to a substance but by
binding to the different receptors
• e.g. adrenaline is a physiological antagonist
of histamine because adrenaline causes
bronchodilatation by binding to β2
receptors, which is opposite to
bronchoconstriction caused by histamine
through H1 receptors.
• Pharmacological antagonists produce no
effect , shows no intrinsic activity.
 Antagonists
Competitive: Antagonist binds to same site as
agonist in a reversible manner.
Noncompetitive: Antagonist binds to the same
site as agonist irreversibly.
Allosteric: Antagonist and agonist bind to
different site on same receptor
Physiologic: Two drugs have opposite effects
through differing mechanisms
 120

100

80

60

40

20

0
-10.5 -10 -9.5 -9 -8.5 -8 -7.5 -7 -6.5 -6

= Agonist = Antagonist
 120
100
80
60
40
20
0
-11 -10 -9 -8 -7 -6

= Agonist = Antagonist
 120
100
80
60
40
20
0
-11 -10 -9 -8 -7 -6

= Agonist = Antagonist
 120

100
80

60
40

20
0
-11 -10 -9 -8 -7 -6

= Agonist = Antagonist
 120
100
80
60
40
20
0
-11 -10 -9 -8 -7 -6

= Agonist = Antagonist
 120

100

80

60

40

20

0
-11 -10 -9 -8 -7 -6

= Agonist = Antagonist
 120

100

80

60

40

20

0
-11 -10 -9 -8 -7 -6

= Agonist = Antagonist
 Competition
1200

1000

800
Effect

600
IC50
400

200

0
-11 -10 -9 -8 -7 -6
log [antagonist]
= Agonist = Antagonist
= Agonist = Antagonist
= Agonist = Antagonist
= Agonist = Antagonist
= Agonist = Antagonist
= Agonist = Antagonist
= Agonist = Antagonist
Competitive antagonists

100
A B C
80
Response

60

40

20

0
0.1 1 10 100 1000 10000

Dose
Noncompetitive antagonists
100
A
80

60
B
Response

40
C
20

0
0.1 1 10 100 1000 10000

Dose
 Receptor regulation
 Reduced responsivity: Chronic use of an
agonist can result in the receptor-effector
system becoming less responsive
◦ eg. alpha-adrenoceptor agents used as nasal
decongestants
 Myasthenia gravis: decrease in number
of functional acetylcholine nicotinic
receptors at the neuromuscular junction.
 Receptor regulation
 Increased responsivity: Chronic disuse of a
receptor-effector system can result in an
increased responsiveness upon re-exposure to an
agonist.
◦ Denervation supersensitivity at skeletal muscle
acetylcholine nicotinic receptors

◦ Thyroid induced upregulation of cardiac beta-

adrenoceptors

◦ Prolonged use of many antagonists (pharmacological

as well as functional) can result in receptor
upregulation
 Receptor Upregulation
Most receptors are internalized and degraded
or recycled with age and use.

Antagonists slow use-dependent

internalization

Inverse agonists stabilize the receptor in the

inactive state to prevent internalization.

The cell continues to produce receptors.

 Factors affecting drug response
Age
Weight
Gender
Environmental
Disease state
Ethinicity
End