Overview of Pharmacodynamics

WHAT IS PHARMACODYNAMICS ?
Dr Rizwan Ashraf

Action of a drug on the body
Receptor interactions.
Mechanisms of therapeutic action.
Dose-response phenomena.
Toxic action
Drug Interaction

• A drug will not work unless it is bound
• AGREED or NOT AGREED

PARTICULAR CONSTITUENTS OF CELLS & TISSUES IN
ORDER TO PRODUCE AN EFFECT
• PROTEINS
• DNA
• RECEPTORS ?

ARE THERE DRUGS THAT ACT WITHOUT BEING BOUND
TO ANY OF THE TISSUE CONSTITUENTS
YES
OR
NO

YES
• OSMOTIC DIURETICS
• OSMOTIC PURGATIVES
• ANTACIDS
• HEAVY METALS CHELATING AGENTS

BUT
PRINCPLES REMAIN TRUE FOR GREAT
MAJORITY
THAT IS _____________________
______________________________.

Most drugs act through
Receptors

Drug Receptor
A component of a cell with which a
drug interacts to produce a
Response (Drug’s observed effects)
• Usually a protein

Receptors mediate the actions of both
pharmacologic agonists and
antagonists.
AGONIST
Some drugs and many natural ligands,
such as hormones and neurotransmitters,
regulate the function of receptor
macromolecules as agonists; ie, they
activate the receptor.
ANTAGONIST
Drugs act as pharmacological antagonists
binds to receptors but do not activate
receptor, instead they interfere with the
ability of an agonist to activate the
receptor.

Sites capable of serving as
Target for Drug Action
•Enzymes
•Receptors
•Ion channels
•Carriers

Enzymes
• Acetyl cholinesterase
• Cyclooxygenase
• Xanthine oxidase
• Angiotensin converting enzyme
• Dopa Decarboxylase
Receptors
• Nicotinic receptors
• Beta adrenoceptors
• Histamine receptors
• Opioid receptors
• Dopamine receptors
• Insulin receptors
• Estrogen receptors
Ion channels
• Voltage gated sodium channels
Local anesthetics
• Renal tubule sodium channels
Amiloride, aldosterone
• GABA gated chloride channels
Benzodiazepines
Carriers
Transport proteins
Na / K ATPase pump
Cardiac glycosides
H+
/K+
(Proton) pump
Omeprazole
Structural proteins
Tubulin (Receptor for ----- Colchicine)

Types of Receptors
Ligand gated ion channels
(Ionotropic receptors)
Nicotinic acetylcholine receptors
(nAChR), GABAA receptors
 G protein coupled receptors (GPCRs) /
Seven - transmembrane (7-TM)
or Serpentine Receptors
(Metabotropic receptors)
Largest receptor family, so named
because receptor polypeptide
chain “snakes” across the plasma
membrane seven times.
(Acetylcholine muscarinic receptors,
Adrenoceptors)

 Tyrosine Kinase linked receptors ------------
Mediates the first step in signaling by -------- Insulin, Epidermal
Growth factor (EGF), Platelet derived growth factor (PDGF),
Atrial natriuretic peptide (ANP), Transforming growth factor beta
(TGF-β)
- These receptors are polypeptides consisting of an extracellular
hormone binding domain and a cytoplasm enzyme domain
which may be a protein kinase,a serine kinase or a guanylyl
cyclase.
 Cytokine Receptors:
respond to heterogeneous group of ligands, which include
Growth hormone, Erythropoietin, and Interferon's
 Nuclear Receptors
(for steroid hormones, thyroid hormone, vitamin D)

Drug Receptor Bonds
• Drug interacts with receptors by means of chemical forces or bonds
3 major types
• Covalent ………………… Phenoxybenzamine, Cyclophosphamide
• Electrostatic
• Hydrophobic
• Covalent bonds: are very strong and in many cases not reversible.
• Electrostatic bonds: is much more common than covalent bonding in drug
receptor interactions but weaker than covalent bonds.
• Hydrophobic bonds: are usually quite weak and are important in interactions
of highly lipid soluble drugs with lipid of cell membrane.

D + R DR Complex
Drug - Receptor Binding

Theories of the
relationship between
binding and response

Occupation theory
D + R  DR  RESPONSE
 Response is proportional to the fraction of occupied receptors
 Maximal response occurs when all the receptors are occupied

Ariens
response is proportional to the fraction of
occupied receptors & intrinsic activity
Stephenson
 Response is a FUNCTION of occupancy
 Maximum response can be produced without 100% occupation
i.e. tissues have spare receptors

Receptors are said to be “spare”
for a given pharmacological response
when the maximal response can be elicited
by an agonist at a concentration that does
not result in occupancy of the full
complement of available receptors

Spare receptors
More receptors available than needed to elicit --------------------
Maximum Response.
 Agonist bind only a portion of receptors for full effect
 Allow maximal response without total receptor occupancy
– increase sensitivity of the tissues

Some Terminologies Regarding Drug- Receptor Interaction
Affinity
Intrinsic activity
Efficacy
Potency
Ligand

Intrinsic activity:
ability of a drug to produce an effect
Affinity:
measure of propensity of a drug to bind
receptor; the attractiveness of drug and
receptor
Efficacy:
Potential maximum therapeutic
response that a drug can produce.
Potency:
Amount of drug needed to produce an
effect.

POTENCY
OR
EFFICACY
Which one is important while
selecting a drug for therapy ?
A drug with low potency and
high efficacy may be better
than a drug with low efficacy
and high potency.

Ligand:
Molecules that binds to a receptor

Classification of Ligands
a. Agonist
b. Partial agonist
c. Antagonist
Pharmacological vs. Physiological vs. Chemical
Pharmacological antagonists
- Competitive (Surmountable)
• Reversible
• Irreversible
- Noncompetitive
- Insurmountable

Agonists
• Drugs that produce a response.
• Drugs that interact with and activate receptors;
• They possess both affinity and efficacy.
Types
• Full agonists
An agonist with maximal efficacy (response)
 has affinity plus intrinsic activity
• Partial agonists
An agonist with less then maximal efficacy
 has affinity and less intrinsic activity

Response
Dose
Full agonist
Partial agonist
Agonist Dose-Response Curves
PARTIAL AGONISTS
- EFFICACY
Even though drugs may
occupy the same #
of receptors, the
magnitude of their
effects may differ.

Agonists differing in Potency and Maximum Efficacy

Antagonists
• Interact with the receptor but do
NOT change the receptor.
• Have affinity but NO -------
Efficacy
• Block the action of other
drugs.
• Effect only observed in
presence of agonist.

Antagonist
An antagonist is atype of
receptor ligand or drug
that blocks or dampensa
biological response by
binding to and blocking a
receptor rather than
activating itlike an agonist.

Antagonists
 Haveaffinity but NOefficacy
 Mediate their effects bybinding
to the active site orto
the allosteric site on areceptor.
 Block the action of otherdrugs
 Effect only observed in presence of
agonist
 Reversibleor Irreversible

Typesof Antagonists
Competitive
(Surmountable)
decreaseapparent
Potency
Noncompetitive
Decreaseapparent
Maximum efficacy

Phenoxybenzamine, an irreversible α-
adrenoceptor antagonist
R
Ag

In the presence of afixed
concentration of agonist,
Increasing concentrations
of acompetitive
antagonist progressively
inhibit the agonist
response;
High antagonist
concentrations prevent
the response almost
completely.

• .
Competitive A
competitive
antagonist
binds to the
samesite asthe
agonist but does
not activate it,
thus blocks the
agonist's action.
Noncompetitive
Anon-
competitive
antagonist
binds to an
allosteric (non-
agonist) siteon
the receptor
to prevent
activation of
the receptor.
Theydo not
compete with
agonists for
binding at the
active site.

Summary
(T or F)
 Pharmacodynamics is the study of absorption, distribution,
metabolism and elimination of drug.
 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

Dose Response Relationship
&
Therapeutic Index
The right dose
differentiates a
poison and a remedy." -
Paracelsus
66

What is Dose-Response relationship?

WHAT IS THE RELATIONSHIP BETWEEN AMOUNT OF DRUG IN THE
BODY AND THE EFFECT OF THE DRUG?
WHY BE CONCERNED ABOUT
DOSE-EFFECT RELATIONSHIPS?
• Predict the effects of changing the dose.
• Information about efficacy and adverse effects.

Dose response curves
The relationship of _____ to ________
can be illustrated as a graph called as
Dose-Response Curve

0 250 500 750 1000 1250
0
50
100
150
[DRUG]free
[D-R]
0.01 0.1 1 10 100 1000 10000
0
50
100
150
[DRUG]free
[D-R]
[D]free versus [R-D] Log [D]free versus [R-D]
A plot of [D]free versus [R-D] is hyperbolic A plot of log [D]free versus [R-D] is sigmoidal

• 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:
• Baseline response (Bottom),
• Maximum response (Top),
• 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 effects
from exposure to
chemical.

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
Relatively flat slope
suggest that effect of an
increasing dose is
minimal

• 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.

Dose response curves
Used to measure
• Drug potency
• Drug efficacy
• Drug safety

POTENCY
CONCENTRATION (EC50) OR DOSE (ED50)
OF A DRUG
REQUIRED TO PRODUCE
50% OF THAT DRUG’S MAXIMUM EFFECT
The term “potency” refers to the EC50 of a drug.
The lower the EC50, the greater the potency.

A
B
X0
Average
Response
Magnitude
DRUG DOSE
Potency
HI
A is more potent than B

A
B
DRUG DOSE
X0
Average
Response
Magnitude
HI
LO
Maximum Efficacy
B has greater maximum efficacy than A

0.01 0.1 1 10 100 1000 10000
0
50
100
150
Dose
Response
Concentration of Agonist
Agonist A Agonist B
Agonist A and Agonist B
are both full agonists.
However, agonist A is
more potent than agonist B.
y-axis is Response

0.01 0.1 1 10 100 1000 10000
0
50
100
150
Dose
Response
Dose = ED50Response = 1/2 Maximal Response
The dose which causes 1/2 maximal response is called
the ED50.
ED50
Maximal Response 1/2 Maximal Response
y-axis is Response

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

Graded dose response curve
The increase in drug dosage are plotted
against the increase in drug response.

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

Effect of various conc. of ACh on isolated small intestine of rabbit showing Graded
Response

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

Graded dose response curve
Used to compare the
• ________ of similar drugs
&
• __________ [ ED50 ]
• ED50 can be used to
compare the ________ of
drugs that produce same
response
Potency
Effective dose
Potency

GRADED DOSE-RESPONSE CURVE
Following valuable data can be drawn
Threshold dose:
Dose which produces first noticeable response
ED50/EC50 (Median Effective Dose or Concentration):
Dose or conc. which produces 50% of maximal response
• Drugs with same action at a receptor but with different potency
show parallel DRC
• Potencies of two drugs can be compared by ED50
ED100 / EDmax (ceiling effect):
Conc. which produces maximal response

Quantal (All-or-none)
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 effect:
Alive or dead;
Asleep or awake;
Pain free or in pain
Performed on population of subjects
Plot the frequency or percentage of individuals
showing an effect as a function of dose

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

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

Following valuable data can be drawn from
Quantal Dose Response curve
A) Median Effective Dose (ED50)
Dose of a drug required to produce 50% of maximum response
B) Median lethal dose (LD50)
Dose of a drug required to kill 50% of experimental animals;
measurement of toxicity
C) Median toxic dose (TD50)
Dose producing toxicity in 50% animals or humans
D) Therapeutic Index
Ratio of the median lethal dose to median effective dose

Quantal Dose-Effect Distribution
Threshold Dose
# of
Subjects
0
10
20
30
40
50
1 3 5 7 9 11 13 15
ED50

Cumulative Dose-Effect Curve
Dose
Cumulative%of
Subjects
0
20
40
60
80
100
1 3 5 7 9 11 13 15
DOSE LEVEL
NO. OF
SUBJECTS
NO.
RESPONDING % RESPONSE
1 10 0 0
2 10 1 10
3 10 3 30
4 10 5 50
5 10 7 70
6 10 8 80
7 10 9 90
8 10 10 100

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

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.

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

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

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.

Cumulative quantal dose response plot

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

Both curves provide
Information regarding
• Potency
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 dose
• Median dose
• Median dose
• ___________
• ______________________
effective
toxic
lethal
Potency
Therapeutic index

121
Therapeutic Index (TI) = Toxic Dose/Therapeutic Dose

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

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

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

Interactive dose response relationship
• http://nutrition.uvm.edu/nfs253
/dose-response.html

Overview of Pharmacodynamics

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