Dr. Asmah Nasser
General Concepts
Drug Dose
Administration
Pharmaceutical
Pharmacokinetics
Pharmacodynamics
Pharmacotherapeutics
Disintegration
of Drug
Absorption/distribution
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 I131
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
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 .
 Example—ACh 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, you’re
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
Partial agonist
Oh!!!, I should
Have been here
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
There can be several types of
receptors:
Epinephrine
1 Receptors
in Heart
2 Receptors in
Bronchioles
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
α1, α2, β
Epinephrine and norepinephrine
GABA
B
GABA
Opioid
μ, κ, δ
Enkephalins
Serotonin
5-HT1-7
5-HT
Dopamine
D1-5
Dopamine
Adenosine
A1, A2a, A2b, A3
Adenosine
Histamine
H1, H2, H3, H4
Histamine
TYROSINE KINASE RECEPTORS
Insulin
-
Insulin
NGF
-
NGF
EGF
-
EGF
NUCLEAR HORMONE RECEPTORS
Estrogen
α, β
Estrogen
Glucocorticoid
Type 1
Glucocorticoid, mineralocorticoid
Type 2
Glucocorticoid
-
Testosterone
Androgens
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
 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
% of Response
DOSE RESPONSE CURVE
After this point
increase in
dose doesn’t
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
B
C
% of response
100%
75%
50%
25%
0%
10mg
20mg
30mg
40mg
50mg
Log drug concentration
200mg
Efficacy and Potency
C
Potency
Efficacy
 Dose of a drug that required
 Maximum effect of the drug
 Height of the curve
to produce 50% of maximal
effect (ED 50)
 Relative
Positions of the DRC on xaxis
 More left the DRC, more
potent the drug
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
Fall in BP
Hydralazine.. steep
Thiazides.. Flat
Drug Dose
SLOPE
STEEP DRC
FLAT DRC
 Moderate increase in
 Moderate increase in dose
dose leads to more
increase in response
leads to little increase in
 Dose needs
individualization for
different patients
 Unwanted and
Uncommon
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
EFFECT
Therapeutic range
8 mg/L
8-18mg/L
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

1.
2.
3.
When two drugs are given together or in quick
succession 3 things can happen:
Nothing (indifferent to each other)
Action of one drug is facilitated by the other
(synergism)
Action of one drug may decrease or inhibit the
action of other drug (antagonism)
Synergism

1.

2.

Two types:
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
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

1.

2.

Different types of antagonism
Physical: based on physical property of a drug.
E.g. activated charcoal adsorbs alkaloids and
prevents their absorption (in alkaloid poisoning)
Chemical: based on chemical properties
resulting in an inactive product.
E.g. chelating agents complex metals (used in
heavy metal poisoning)
Contd..
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
3.
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 patient’s response to drug
therapy may change over time
Rats!
Where did they
all go?!?
Tolerance





1.
2.
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
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 EC50
 KD 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 (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 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.
 Alzheimer’s 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.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
Principles of drug action
Agonist & its types
Antagonist and its types (on DRC)
Spare receptors
Affinity-intrinsic activity
Potency-efficacy (explain with DRC)
Therapeutic index and its calculation
Classification of receptors
G-protein coupled receptors
Second messenger concept (role of cAMP and IP3 &
DAG)
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 µg/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?