Drug Dose

Administration

Pharmaceutical
Pharmacokinetics
Pharmacodynamics
Pharmacotherapeutics

Disintegration
of Drug
Absorption/distributio
n
metabolism/excretion
Drug/Receptor
Interaction
Drug Effect
or Response

Introduction
Pharmacodynamics: Study of the biochemical
and physiologic effects of drugs and their
mechanisms of action.

Drug action
The main ways by which drugs act are via

interaction with cell proteins, namely

receptors, ion channels, enzymes and
transport/carrier proteins.
In addition, drugs can work by themselves
mechanically or chemically.
Its useful to know what are the basic
principles of drug action.

Principles of Drug action

Stimulation: Enhancement of the level of a

specific biological activity (usually already ongoing

physiological process). E.g. adrenaline stimulates
heart rate.
Depression: Diminution of the level of a specific
biological activity (usually already ongoing
physiological process). E.g. barbiturate depress the
CNS.
Replacement: Replacement of the natural
hormones or enzymes (any substance) which are
deficient in our body. E.g. insulin for treating
diabetes.
Cytotoxic action: Toxic effects on invading micro
organisms or cancer cells.

How does all this

happen?
A drug can produce all the said effects by
virtue of any of the following action
1.Through enzymes: a drug can act by
either stimulating or inhibiting an enzyme
Through receptors: this is when a drug
produces its response by attaching itself to a
protein called as receptor which in turn
regulates the cell function. Receptor action
is the most commonest way of producing
action.

Continuation...
2. Physical action: The physical property is
responsible for drug action. E.g.
radioisotope I and other radioisotopes.
3. Chemical action: The drug reacts
extracellularly according to simple
chemical equations. E.g. antacids
neutralising the gastric acid.

A deeper look into the

receptor
The best-characterized drug receptors are

regulatory proteins, which mediate the

actions of endogenous chemical signals such
as neurotransmitters and hormones.
This class of receptors mediates the effects of
many of the most useful therapeutic agents.
Word Receptor is used as a loose term

Other Receptors
Other classes of proteins that have been

identified as drug receptors include

1. Enzymes, which may be inhibited (or,
less commonly, activated) by binding a
drug (eg, dihydrofolate reductase, the
receptor for the antineoplastic drug
methotrexate)
2. Transport proteins (eg, Na+/K+
ATPase, the membrane receptor for
cardioactive digitalis glycosides)
3. Structural proteins (eg, tubulin)

Agonist & Antagonist

Tricky

When a drug binds to a receptor the

following can occur and based on this the

drugs are classified.
Agonist: when a drug binds to the
receptor and activates it to produce an
effect
Antagonist: when a drug binds to a
receptor and prevents the action of an
agonist, but does not have an action on its
own.

Other terms
Inverse agonist: when a drug activates a

receptor to produce an effect in the

opposite direction to that of the agonist
Partial agonist: when a drug binds to the
receptor and activates it but produces a
submaximal effect (by antagonising the full
effect of the agonist)

Agonist & Inverse Agonist

Affinity & Intrinsic

activity
Affinity: It is the ability of a drug to bind to
the receptor (just bind)
Intrinsic activity: It is the ability of a drug to
activate a receptor following receptor
occupation.

Agonist
Agonists are the chemicals that interact

with a receptor, thereby initiate a chemical

reaction in the cell and produces effect .
ExampleACh is agonist at muscarinic

receptor in heart cell.

Will have both Affinity and maximal
Intrinsic activity

So, what is a receptor

agonist?
Any drug that binds to a receptor and

stimulates the functional activities

e.g.: Ach

Receptor
Some Effect

Acetylcholine
A Cell

Antagonist

A drug that binds to the receptor and

blocks the effect of an agonist for that

receptor
Atropine is antagonist of ACh at
Muscarinic receptors.
Will have only Affinity but no Intrinsic
activity

So, what is a receptor

antagonist?
Any drug that prevents the binding of

an agonist
eg: Atropine (an anticholinergic drug)

Dude, youre
in my way!

Atropine

Acetylcholine

Inverse agonist
Inverse Agonists are the chemicals that

interact with a receptor, but produces

opposite effect of the well recognized agonist
for that receptor
Will have Affinity and negative Intrinsic
activity
Example: Flumazenil is an inverse
agonist of Benzodiazepine

Inverse agonist
Any drug that binds to a receptor and

produces an opposite effect as that of an

agonist

Receptor

Effect opposite to
that of
the true agonist

Inverse agonist
A Cell

Partial agonist
Partial agonist activates receptor to

produce an effect. Less response than a

full agonist .
Partial agonist blocks the agonist action.
Will have Affinity but sub maximal
Intrinsic activity

Partial agonist
Produces a submaximal response

Oh!!!, I should
Have been here

Partial agonist

True agonist

Submaximal effect

Types of Receptors
Are they specific?
usually, but not always
Are there subtypes?
sometimes
example:

there are several types of epinephrine receptors

Epinephrine

1 Receptors
in Heart

2 Receptors in
Bronchioles

A Problem
Epinephrine is a non-specific drug: it is an

agonist for BOTH

1 and 2 receptors

Why might this be a problem

for someone with asthma and

hypertension?

A Solution
More specific agonists have been developed:
eg: terbutaline is a more specific

agonist
that is used for treating people with asthma

Major Concepts
Drugs often work by binding to a receptor
Receptors are found in the cell membrane,

in the cytoplasm, and in the nucleus

Anything that binds to a receptor is a
ligand

Drug-Receptor
interaction
In most cases, a drug (D) binds to a receptor (R)
in a reversible bimolecular reaction

Antagonists can bind to the receptor and occupy

its binding site and, therefore, participate only in

the first equilibrium.
Agonists, on the other hand, have the appropriate
structural features to force the bound receptor
into an active conformation (DR*).
This conformational change leads to a series of
events causing a cellular response.

Assessment of Receptor
Occupation
Measure of Affinity
kd is a relative measure of affinity of a

drug for its receptor.

It varies inversely with the affinity of
the drug for its receptor
High-affinity drugs have lower kd values
and occupy a greater number of drug
receptors than drugs with lower
affinities.

Drug-receptor interaction
Generally the intensity of response

increases with dose

The drug receptor interaction obeys the
law of mass action

E=

Emax X [D]
KD+[D]

Law of mass action

E is observed effect at dose [D] of a drug
Emax is the maximal response
KD is the dissociation constant of a drug

receptor complex
KD is usually equal to the dose of a drug at
which half maximal response is produced

Classification of
receptors

G-protein coupled receptors

Ion channels
Enzymatic receptors
Intracellular receptors (regulates gene

expression)

Ion channels
The cell surface enclose ion channels specific

for Ca2+, K+, or Na+

These ion channels are controlled by the
receptors
E.g. Gs opens Ca2+ channels in the
myocardium and skeletal muscle and Gi opens
the K+ channels in heart
Some receptors also modulate the ion
channels without the intervention of coupling
proteins or 2nd messengers
E.g. benzodiazepines modulating Cl - channels
in the brain

Ion channels

Dose Vs Response
Increases in response until it reaches

maximum, Later it remains constant despite

increase in dose .. Plateau effect

DOSE RESPONSE
CURVE
% of Response

After this point

increase in
dose doesnt
increase the
response

DOSE of drug

Log dose response curve

The dose response

curve is a rectangular
hyperbola
If the doses are plotted
on a logarithmic scale,
the curve becomes
sigmoid
A linear relationship
between log of dose
and the response can
be seen

Efficacy and Potency

Efficacy is the maximal response produced

by a drug
It depends on the number of drug-receptor
complexes formed
Potency is a measure of how much drug is
required to elicit a given response
The lower the dose required to elicit given
response, the more potent the drug is

ED50
It is the dose of the drug at which it gives

50% of the maximal response

A drug with low ED50 is more potent than a
drug with larger ED50

Potency of Drug A >Drug B > Drug C

A

% of response

100%
75%
50%
25%
0%
10mg

20mg

30mg

40mg

50mg

Log drug concentration

200mg

Efficacy and Potency

C

Potency
Dose of a drug that

Efficacy
Maximum effect of the

required to produce 50%

drug
of maximal effect (ED
Height of the curve
50)
on x-axis indicates the
Relative
efficacy of the drug
Positions of the DRC on
Taller the DRC ,more
x-axis
efficacious the drug
More left the DRC, more
potent the drug

Probing question

A 55-year-old woman with congestive heart

failure is to be treated with a diuretic drug.
Drugs X and Y have the same mechanism of
diuretic action. Drug X in a dose of 5 mg
produces the same magnitude of diuresis as
500 mg of drug Y. This suggests that

Drug Y is less efficacious than drug X

Drug X is about 100 times more potent than drug Y
Toxicity of drug X is less than that of drug Y
Drug X is a safer drug than drug Y
Drug X will have a shorter duration of action than drug
Y because less of drug X is present for a given effect

Slope of DRC
The slope of midportion of the DRC varies

from drug to drug

A steep slope indicates small increase in dose
produces a large change in response

Fall in BP

Hydralazine.. steep

Thiazides.. Flat

Drug Dose

SLOPE
STEEP DRC

FLAT DRC

Moderate increase in Moderate increase in

dose leads to more

increase in response
Dose needs

individualization for
different patients
Unwanted and

Uncommon

dose leads to little

increase in response
Dose needs no

individualization for
different patients
Desired and Common

Quantal dose response

curves
The quantal dose-effect curve is often

characterized by stating the median

effective dose (ED50), the dose at which
50% of individuals exhibit the specified
quantal effect.
Similarly, the dose required to produce a
particular toxic effect in 50% of animals is
called the median toxic dose (TD50) If the
toxic effect is death of the animal, a
median lethal dose (LD50) may be
experimentally defined
Quantal dose-effect curves are used to
generate information regarding the margin
of safety (Therapeutic index)

Quantal DRC

Therapeutic index

Therapeutic index (TI)

Lethal dose (LD50) is estimated only in

preclinical animal studies

LD50 is not calculated in humans-OFCOURSE
So we use the term safety margin of a drug

or therapeutic window

Therapeutic
window
It is a more clinically relevant index of
safety
It describes the dosage range between the
minimum effective therapeutic
concentration or dose, and the minimum
toxic concentration or dose
E.g. theophylline has an average minimum
plasma conc of 8 mg/L and the toxic
effects are observed at 18 mg/L
The therapeutic window is 8 18 mg/L

um
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Min
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Therapeutic range
8 mg/L

8-18mg/L

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Clinical significance
Drugs with a low TI should be used with

caution and needs a periodic monitoring

(less safe)
E.g. warfarin, digoxin, theophylline
Drugs with a large TI can be used
relatively safely and does not need close
monitoring (highly safe)
E.g. penicillin, paracetamol
Other terms used: wide safety margin,
narrow safety margin

Synergism and
antagonism
When two drugs are given together or in

quick succession 3 things can happen:

1. Nothing (indifferent to each other)
2. Action of one drug is facilitated by the other
(synergism)
3. Action of one drug may decrease or inhibit
the action of other drug (antagonism)

Synergism
Two types:
1. Additive effect: the effect of two drugs

are in the same direction and simply add

up.
Effect of drug A + B = effect of drug A
and B
2. Supraadditive effect (potentiation): the
effect of combination is greater than the
individual effect of the components.
Effect of drug A + B > effect of drug A +
effect of drug B

Antagonism
Different types of antagonism
1. Physical: based on physical property of a

drug.
E.g. activated charcoal adsorbs alkaloids
and prevents their absorption (in alkaloid
poisoning)
2. Chemical: based on chemical properties
resulting in an inactive product.
E.g. chelating agents complex metals
(used in heavy metal poisoning)

Contd..
3. Physiological antagonism: two drugs act

on different receptors or by different

mechanisms, but have opposite effects
E.g. histamine and adrenaline on
bronchial smooth muscle and BP
E.g. several catabolic actions of the
glucocorticoid hormones lead to
increased blood sugar, an effect that is
physiologically opposed by insulin.
4. Receptor antagonism

Receptor antagonism
This when an antagonist interferes with

the binding of the agonist with its receptor

and inhibits the generation of a response
Receptor antagonism is specific
E.g. an anticholinergic will decrease the
spasm of intestine induced by cholinergic
agonists but not the one induced by
histamine
Receptor antagonism can be competitive
and noncompetitive

Competitive antagonism
Competitive ---

Surmountable
Competes with agonist
in reversible fashion
for same receptor site
Necessary to have
higher concentration
of agonist to achieve
same response

Competitive agonist

Noncompetitive
antagonism
Noncompetitve --Insurmountable
Antagonist binds to
a site different to that
of an agonist
No matter how much
agonist -- antagonism
cannot be overcome

COMPETITIVE
Antagonist binds with

same receptor
Chemical resemblance
with agonist
Parallel rightward shift
of DRC
Apparently reduces
potency of agonist
Intensity of response
depends both on
antagonist and agonist
concentration
Eg: Acetylcholine and
Atropine

NONCOMPETITIVE
Another site of receptor

binding
Does not resemble
Flattening of DRC

Apparently reduces

efficacy of agonist
Intensity of response
depends mainly on
antagonist concentration
Eg: phenoxybenzamine
(for pheochromocytoma)

Receptor Numbers and

Responses

The NUMBER and AFFINITY of receptors may

change
An increase in receptor number is called
UPREGULATION
A decrease in receptor number is called
DOWNREGULATION

Upregulation of Receptors
Upregulation: An increase

in the number of receptors

on the surface of target
cells, making the cells more
sensitive to a hormone or
another agent.
For example, there is an
increase in uterine oxytocin
receptors in the third
trimester of pregnancy,
promoting the contraction
of the smooth muscle of the
uterus

Downregulation of
Receptors
Eg: Downregulation:

prolonged use of propranolol

can DECREASE the number of

1 receptors
Prolonged & frequent use of

short acting 2 receptor

agonists decrease the
number of 2 receptors

Clinical relevance:
A patients response to drug

therapy may change over

time

Rats!
Where did they
all go?!?

Tolerance
Gradual reduction in response to drugs is

1.
2.

called as tolerance
Requirement of higher dose to produce a
given response
It occurs over a period of time
E.g. tolerance to sedative-hypnotics
Many reasons for tolerance
Pharmacokinetic reasons-chronic use
leads to enhanced clearance-less
effective concentration
Pharmacodynamic reasons (reduced
number and/or affinity of the receptors to
the drugs)-downregulation

Tachyphylaxis
Rapid desensitization

to a drug produced by
inoculation with a
series of small
frequent doses.
A rapidly decreasing
response to a drug
following its initial
administration
E.g. ephedrine,
tyramine, nicotine.

Spare receptors
In some cases, the response elicited by a

drug is proportional to the fraction of

receptors occupied
More commonly, a maximal response can
be achieved when only a small fraction of
receptors are occupied by an agonist
Receptors are said to be spare when
maximal response can be elicited by an
agonist at a conc. that does not result in
occupancy of the full complement of
available receptors
No qualitative difference form non
spare receptors

Graphical representation of a spare

receptor (refer to notes section below for explanation)

Spare receptors, KD and

EC
K 50
is the concentration of the agonist at
D

which 50% of the receptors are occupied

If the number of receptors increase many
fold (spare receptors) THEN:
A much lower concentration of agonist is
sufficient to produce 50% of maximal
response (EC50)
Occupation of spare receptors is
determined by comparing the EC50 with Kd
If EC50 is less than Kd, spare receptors
are said to exist

Factors affecting Drug

It is a rule rather than an exception that
Action

there is a large variation in the drug response

for the same dose in different individuals.

Pharmacokinetic handling of the drug

Number or state of receptors
Variations in neurogenic/hormonal tone

Contd..
Body Size/Wt.
The average adult dose refers to individuals of
medium built
For exceptionally obese and lean and for
children the dosage should be calculated
based on body wt.
Individual Dose = BW (Kg)/70 x average adult
dose
Dosage calculation based on surface area
more appropriate for children

Contd..
Age
Extreme care has to be taken while
administering drugs to children and elderly
Drug metabolizing enzymes are very poor and
in case of elderly they might have some other
diseases
Reduced doses are ideal for these age groups.

Contd..
Genetics
Deficiency of some enzymes may lead to drug
toxicity because of poor or absence of
metabolism
Route of drug administration
IV route has quicker and prominent action
when compared to oral route
Psychological role is also a major determinant of
drug effect

Contd..
Pathological states
Any underlying pathology may alter the drug
response
Special care is taken if the patient has renal or
hepatic impairment as the drugs are not
eliminated and it may lead to severe drug
toxicity.
Alzheimers disease memory loss- failure to
take medications

Contd..
Co-administration of other drugs
One drug may affect the drug action of

others, it may be useful or it may be

harmful.
Drug interactions play a very important
part of therapeutics.
Diet & environmental factors too play a
important role in deciding the drug action.

Things
to
know
In pharmacodynamics you SHOULD know by

now:
1. Principles of drug action
2. Agonist & its types
3. Antagonist and its types (on DRC)
4. Spare receptors
5. Affinity-intrinsic activity
6. Potency-efficacy (explain with DRC)
7. Therapeutic index and its calculation
8. Classification of receptors
9. G-protein coupled receptors
10. Second messenger concept (role of cAMP and IP 3
& DAG)
11. Downregulation & upregulation of receptors

Practice Question
When tested under identical conditions with all
statistical requirements rigidly applied, drug X
has the following parameters: LD50=0.5 mg/Kg
Ed50=0.5 g/Kg. The therapetic index is
1. 0.001
2. 0.1
3. 1.0
4. 10
5. 1000

Practice Question

In the absence of other drugs, pindolol causes

an increase in heart rate by activating beta
adrenoceptors. In the presence of highly
effective beta stimulants, however, pindolol
causes a dose-dependent, reversible decrease
in heart rate. Therefore, pindolol is probably

An irreversible antagonist
A physiologic antagonist
A chemical antagonist
A partial agonist
A spare receptor agonist

Practice question

Which line is most efficacious?

Which is more potent?