Dr.

Asmah Nasser
General Concepts
Drug Dose
Administration
Drug Effect
or Response
Pharmaceutical
Pharmacokinetics
Pharmacodynamics
Pharmacotherapeutics
Disintegration
of Drug
Absorption/distribution
metabolism/excretion
Drug/Receptor
Interaction
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
131
and other radioisotopes.
3. Chemical action: The drug reacts extracellularly
according to simple chemical equations. E.g.
antacids neutralising the gastric acid.
4
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
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.


Tricky
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
Acetylcholine
A Cell
Some Effect
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)
Acetylcholine
Atropine
Dude, youre
in my way!
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
Inverse agonist
A Cell
Effect opposite to
that of
the true agonist
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
True agonist
Partial agonist
Oh!!!, I should
Have been here
Submaximal
effect
Types of Receptors
Are they specific?
usually, but not always

Are there subtypes?
sometimes
example:
there are several types of epinephrine receptors
There can be several types of
receptors:

1
Receptors
in Heart

2
Receptors in
Bronchioles
Epinephrine
Examples of specialized receptors
Type Subtype Endogenous Ligand
LIGAND-GATED CHANNELS
Acetylcholine Nicotinic Acetylcholine
GABA A GABA
Glutamate NMDA, kainate, AMPA Glutamate or aspartate
G-PROTEIN-COUPLED RECEPTORS
ACTH - ACTH
Acetylcholine Muscarinic Acetylcholine
Adrenergic
1
,
2
, Epinephrine and norepinephrine
GABA B GABA
Opioid , , Enkephalins
Serotonin 5-HT
1-7
5-HT
Dopamine D
1-5
Dopamine
Adenosine A
1
, A
2a
, A
2b
, A
3
Adenosine
Histamine H
1
, H
2
, H
3
, H
4
Histamine
TYROSINE KINASE RECEPTORS
Insulin - Insulin
NGF - NGF
EGF - EGF
NUCLEAR HORMONE RECEPTORS
Estrogen , Estrogen
Glucocorticoid Type 1 Glucocorticoid, mineralocorticoid
Type 2 Glucocorticoid
Androgens - Testosterone

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
2
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

k
d
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 k
d
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
max
X [D]

K
D
+[D]

E=
Law of mass action
E is observed effect at dose [D] of a drug
E
max
is the maximal response
K
D
is the dissociation constant of a drug receptor
complex
K
D
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
Ca
2+
, K
+
, or Na
+
These ion channels are controlled by the receptors
E.g. G
s
opens Ca
2+
channels in the myocardium and
skeletal muscle and G
i
opens the K
+
channels in
heart
Some receptors also modulate the ion channels
without the intervention of coupling proteins or
2
nd
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

DOSE of drug
%

o
f

R
e
s
p
o
n
s
e

After this point
increase in
dose doesnt
increase the
response
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
ED
50
It is the dose of the drug at which it gives 50% of the
maximal response
A drug with low ED
50
is more potent than a drug with
larger ED
50
Log drug concentration
%

o
f

r
e
s
p
o
n
s
e

100%
50%
0%
10mg
20mg 30mg 40mg 50mg
75%
25%
200mg

Potency of Drug A >Drug B > Drug C
A B
C
Efficacy and Potency
C
Potency

Dose of a drug that required
to produce 50% of maximal
effect (ED
50
)
Relative
Positions of the DRC on x-
axis
More left the DRC, more
potent the drug
Efficacy

Maximum effect of the drug
Height of the curve
on x-axis indicates the
efficacy of the drug
Taller the DRC ,more
efficacious 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

Drug Dose
F
a
l
l

i
n

B
P

Hydralazine.. steep
Thiazides.. Flat
SLOPE
STEEP DRC
Moderate increase in
dose leads to more
increase in response
Dose needs
individualization for
different patients
Unwanted and
Uncommon
FLAT DRC
Moderate increase in 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 (ED
50
), 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 (TD
50
) If the toxic effect is death of the
animal, a median lethal dose (LD
50
) 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 (LD
50
) is estimated only in preclinical
animal studies
LD
50
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

Therapeutic range
E
F
F
E
C
T

8 mg/L 18mg/L 8-18mg/L
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 Vs Noncompetitive
Antagonism
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 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
1. Pharmacokinetic reasons-chronic use leads to
enhanced clearance-less effective concentration
2. 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, K
D
and EC
50
K
D
is the concentration of the agonist at 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 (EC
50
)
Occupation of spare receptors is determined by
comparing the EC
50
with K
d

If EC
50
is less than K
d
, spare receptors are said
to exist


Factors affecting Drug Action
It is a rule rather than an exception that 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: LD
50
=0.5 mg/Kg

Ed
50
=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?