DRUG RECEPTORS AND

PHARMACODYNAMICS

F A C U L T Y O F P H A RM A C Y
UNIVERSITY OF SANTO TOMAS
 DRUG RECEPTORS AND
PHARMACODYNAMICS

PHARMACODYNAMICS
Actions/effects of the drug on the body
Determines the group in which the drug
is classified and plays a major role in
deciding whether a group is appropriate
therapy for particular symptom or disease
 DRUG RECEPTORS AND
PHARMACODYNAMICS
RECEPTORS
 Specific molecules in a biologic system with
which drugs interact to produce changes in
the function of the system
 Determine the quantitative relations
between dose or concentration of drug and
pharmacologic effects
 Selective in choosing a drug molecule to
bind to avoid constant activation by
promiscuous binding of many different
molecules
 DRUG RECEPTORS AND
PHARMACODYNAMICS

RECEPTORS
 Changes its function upon binding in such a
way that the function of the biologic system
is altered in order to have pharmacologic
effect
 Selective in ligand-binding characteristics
(respond to proper chemical signals and not to
meaningless ones)
 Mediate the actions of both pharmacologic
agonists and antagonists
 DRUG RECEPTORS AND
PHARMACODYNAMICS

RECEPTORS
 Majority are proteins which provide the
necessary diversity and specificity of shape and
electrical charge
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PHARMACODYNAMICS

RECEPTORS
RECEPTOR SITE/RECOGNITION SITE
 Specific binding region of the
macromolecule
 High and selective affinity to the drug
molecule
 Interaction between the drug and the
receptor is the fundamental event that
initiates the action of the drug
 DRUG RECEPTORS AND
PHARMACODYNAMICS

CLASSIFICATION OF RECEPTORS
1. REGULATORY PROTEINS
2. ENZYMES
3. TRANSPORT PROTEINS
4. STRUCTURAL PROTEINS
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PHARMACODYNAMICS

CLASSIFICATION OF RECEPTORS

REGULATORY PROTEIN
 Best characterized drug receptors
 Mediates the action of endogenous
chemical signals like neurotransmitters,
autacoids and hormones
 Mediates the effects of the most useful
therapeutic agents
 DRUG RECEPTORS AND
PHARMACODYNAMICS
CLASSIFICATION OF RECEPTORS
ENZYMES
 Inhibited (or less commonly, activated)
bybinding a drug
 E.g. dihydrofolate reductase, the
receptor for methotrexate
TRANSPORT PROTEINS
Eg, Na + /K + ATPase, the membrane
receptor for digitalis
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PHARMACODYNAMICS

CLASSIFICATION OF RECEPTORS

STRUCTURAL PROTEINS
 E.g. tubulin, the receptor for colchicine,
an anti-inflammatory drug
 DRUG RECEPTORS AND
PHARMACODYNAMICS

EFFECTORS
 Molecules that translate the drug-receptor
interaction into a change in cellular
activity
 Eg, adenyl cyclase
 Some receptors are also effectors
 A single molecule may incorporate both
the drug binding site and the effector
mechanism
 DRUG RECEPTORS AND
PHARMACODYNAMICS

DRUG CONCENTRATION
AND RESPONSE
 DRUG RECEPTORS AND
PHARMACODYNAMICS
GRADED DOSE-RESPONSE CURVE
 Response of a particular receptor-effector
system is measured against increasing
concentration of a drug
 Graph of the response versus the drug dose
 DRUG RECEPTORS AND
PHARMACODYNAMICS

GRADED DOSE-RESPONSE CURVE

 Sigmoid curve
 Efficacy (E max ) and potency (EC 50 ) are
derived from this curve
 The smaller the EC 50 , the greater the
potency of the drug
 DRUG RECEPTORS AND
PHARMACODYNAMICS
E max
Maximal response that
can be produced by a
drug
All receptors are
occupied
No response even if the
dose is increased
EC 50
Concentration of drug
that produces 50% of
maximal effect
Smaller EC 50 –more
potent
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PHARMACODYNAMICS

B max
 Total number of
receptor sites
 All receptors
have been
occupied
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PHARMACODYNAMICS

KD
Equilibrium
dissociation constant
Concentration of drug
required to bind 50% of
the receptors
Measure of the affinity
of a drug for its binding
site on the receptor
Smaller K D –greater
affinity of drug to
receptor
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PHARMACODYNAMICS

A B C

Agonist effect 0.5

E

Agonist dose
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PHARMACODYNAMICS

A B C

Agonist effect 0.5

E

Agonist dose

CURVE A
Agonist response in the absence of
antagonist
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PHARMACODYNAMICS
A B C

Agonist effect 0.5

E

Agonist dose
CURVE B
 After treatment with low concentration of antagonist,the
curve is shifted to the right
 Maximal response is preserved because the
remainingavailable receptors are still in excess
 DRUG RECEPTORS AND
PHARMACODYNAMICS
A B C

Agonist effect 0.5

E

Agonist dose

CURVE C
Produced after larger concentration of antagonist,
the available receptors are no longer “spare”,
sufficient enough to mediate an undiminished
maximal response
 DRUG RECEPTORS AND
PHARMACODYNAMICS
A B C

Agonist effect 0.5

E

Agonist dose

CURVE D and E
 With higher concentrations of antagonist, reduce the
number of available receptors to the point that maximal
response is diminished
 EC 50 may approximate the K D that characterizesthe
binding affinity of the agonist for the receptor
 DRUG RECEPTORS AND
PHARMACODYNAMICS

COUPLING
 Transduction process between the
occupancy of receptors and production
of specific effect
 Highly efficient coupling can be elicited
by a full agonist and spare receptors
 DRUG RECEPTORS AND
PHARMACODYNAMICS
SPARE RECEPTORS
 Maximal drug response is obtained at less
than maximal occupation of the receptors
 Not qualitatively different from nonspare
receptors, not hidden or unavailable
 Temporal in character, when occupied, they
can be coupled to respond, there is still
effect
 Drugs with low binding affinity for
receptors will be able to produce full
response even at low concentration
 DRUG RECEPTORS AND
PHARMACODYNAMICS

SPARE RECEPTORS
 Compare concentration for 50% of maximal
effect (EC 50) with concentration for 50%
maximal binding (K D )
 K D > EC 50 with spare receptors
 Effect of the drug-receptor interaction may
persist for a longer time than the
interaction itself
 Actual number of receptors may exceed the
number of effectors available
 DRUG RECEPTORS AND
PHARMACODYNAMICS
INERT BINDING SITES
 Non-regulatory molecules of the body
 Binding with these molecules will result to
no detectable change in the functionof the
biologic system
 Buffers the concentration of the drug
 Bound drugs do not contribute directly to
the concentration gradient that drives
diffusion
 Eg, albumin
 DRUG RECEPTORS AND
PHARMACODYNAMICS

AGONIST
 Binds to the receptor and directly or
indirectly bring about an effect
 Full activation of the effector system
PARTIAL AGONIST
 Produces less than the full effect, even
when it has saturated the receptors
 Acts as an inhibitor in the presence of a
full agonist
 DRUG RECEPTORS AND
PHARMACODYNAMICS
ANTAGONIST
 Binds but do not activate the receptors
 Blocks or competes with agonist

CLASSIFICATION OF ANTAGONIST
1. Competitive Antagonist
2. Irreversible Antagonist
3. Chemical Antagonist
4. Physiologic Antanogist
 DRUG RECEPTORS AND
PHARMACODYNAMICS
COMPETITIVE ANTAGONIST
 Competes with agonist receptor
 Binds to the receptor reversibly without
activating the effector system
 Antagonist increases the agonist
concentration needed for a given degree of
response
 Concentration-effect curve is shifted to
higher doses (ie, horizontally to the right
of the dose axis)
 Same maximal effect is reached
 DRUG RECEPTORS AND
PHARMACODYNAMICS
COMPETITIVE ANTAGONIST

 Effects are overcomed by adding more agonist

 Increases the median effective dose (ED 50 )
 DRUG RECEPTORS AND
PHARMACODYNAMICS

COMPETITIVE ANTAGONIST

2 THERAPEUTIC IMPLICATIONS
(1) Degree of inhibition produced by the
competitive antagonist depends on the
concentration of antagonist (eg, propranolol)
(2) Clinical response to a competitive antagonist
depends on the concentration of agonist that
is competing for binding to the receptor
 DRUG RECEPTORS AND
PHARMACODYNAMICS

IRREVERSIBLE ANTAGONIST
Binds with the receptor via covalent bonds
Antagonist’s affinity to the receptor maybe so
high
Receptor is not available to bind the agonist
Duration of action is relatively independent
More dependent on the rate of turnover of
receptors
Eg, phenoxybenzamine binding with alpha
receptors
 DRUG RECEPTORS AND
PHARMACODYNAMICS

IRREVERSIBLE ANTAGONIST
 Concentration-effect curve moves
downward
 No shift of the curve in the dose axis
 E max is not reached
 No increase in median effective dose
(ED 50 ) unless there are spare receptors
DRUG RECEPTORS AND
PHARMACODYNAMICS
 DRUG RECEPTORS AND
PHARMACODYNAMICS
CHEMICAL ANTAGONISM
Does not depend on interaction with the
agonist’s receptor
Drug that interacts directly with the drug
being antagonized to remove it or to
prevent it from reaching its target
Eg, protamine used to counteract the
effect of heparin making it unavailable
for interaction with proteins involved in
the formation of blood
 DRUG RECEPTORS AND
PHARMACODYNAMICS

PHYSIOLOGIC ANTAGONISM
 Makes use of the regulatory pathway
 Effects that are less specific and less easy
to control
 Binds to a different receptor producing an
effect opposite to that produced by the drug
it is antagonizing
 Examples
 Glucocorticoids catabolic effects of increase in sugar
is physiologically opposed by insulin
 Histamine causes bronchoconstriction in asthmatic
patients, opposed by bronchodilators like salbutamol
and epinephrine
 DRUG RECEPTORS AND
PHARMACODYNAMICS

SIGNALING MECHANISMS
5 BASIC TRANSMEMBRANE SIGNALING
MECHANISMS
(1) Lipid soluble drug crossing the plasma
membrane and acts on intracellular
receptor (eg, steroids)
From: Drug Receptors & Pharmacodynamics
Basic & Clinical Pharmacology, 13e, 2015

Date of download: 2/18/2016 Copyright © 2016 McGraw-Hill Education. All rights reserved.
 DRUG RECEPTORS AND
PHARMACODYNAMICS
SIGNALING MECHANISMS
5 BASIC TRANSMEMBRANE SIGNALING
MECHANISMS
(2) Transmembrane receptor protein-
intracellular enzymatic activity is
regulated by a ligand that binds to
the protein’s extracellular domain
 DRUG RECEPTORS AND
PHARMACODYNAMICS

SIGNALING MECHANISMS
5 BASIC TRANSMEMBRANE SIGNALING
MECHANISMS
(3) Transmembrane receptor that binds
and stimulates a protein tyrosine
kinase (eg, insulin)
From: Drug Receptors & Pharmacodynamics
Basic & Clinical Pharmacology, 13e, 2015

Date of download: 2/18/2016 Copyright © 2016 McGraw-Hill Education. All rights reserved.
 DRUG RECEPTORS AND
PHARMACODYNAMICS
SIGNALING MECHANISMS
5 BASIC TRANSMEMBRANE SIGNALING
MECHANISMS
(4) Ligand-gated transmembrane ion
channel which regulates the opening
of the ion channel (eg, GABA, excitatory
acetylcholine)
From: Drug Receptors & Pharmacodynamics
Basic & Clinical Pharmacology, 13e, 2015

Date of download: 2/18/2016 Copyright © 2016 McGraw-Hill Education. All rights reserved.
 DRUG RECEPTORS AND
PHARMACODYNAMICS
SIGNALING MECHANISMS
5 BASIC TRANSMEMBRANE SIGNALING
MECHANISMS
(5) Transmembrane receptor is coupled
with an effector enzyme by G protein
which modulates production of an
intracellular second messenger
[eg, cathecolamine (epinephrine)]
From: Drug Receptors & Pharmacodynamics
Basic & Clinical Pharmacology, 13e, 2015

Date of download: 2/18/2016 Copyright © 2016 McGraw-Hill Education. All rights reserved.
From: Drug Receptors & Pharmacodynamics
Basic & Clinical Pharmacology, 13e, 2015

Date of download: 2/18/2016 Copyright © 2016 McGraw-Hill Education. All rights reserved.
 DRUG RECEPTORS AND
PHARMACODYNAMICS

INTRACELLULAR 2 ND MESSENGERS

A. cAMP (Cyclic adenosine monophosphate)

 Mediates hormonal responses
 Mobilization of stored energy (breakdown of
carbohydrates in the liver stimulated by
cathecolamines
 Conservation of water by the kidneys mediated by
vasopressin
Calcium homeostasis by parathyroid hormone
Heart rate and contraction by beta-adrenomimetic
cathecolamines
From: Drug Receptors & Pharmacodynamics
Basic & Clinical Pharmacology, 13e, 2015

Date of download: 2/18/2016 Copyright © 2016 McGraw-Hill Education. All rights reserved.
 DRUG RECEPTORS AND
PHARMACODYNAMICS
INTRACELLULAR 2 ND MESSENGERS
B. CALCIUM AND PHOSPHOINOSITIDES
 Bind to receptors linked to G proteins
while others bind to receptor tyrosine
kinases
 Crucial step is the stimulation of
membrane enzyme phospholipase C
From: Drug Receptors & Pharmacodynamics
Basic & Clinical Pharmacology, 13e, 2015

Date of download: 2/18/2016 Copyright © 2016 McGraw-Hill Education. All rights reserved.
 DRUG RECEPTORS AND
PHARMACODYNAMICS
INTRACELLULAR 2 ND MESSENGERS
C. cGMP (Cyclic guanosine monophosphate
 Few signaling roles in a few cell types like
the intestinal mucosa and vascular smooth
muscle cells
 Causes relaxation of vascular smooth
muscles by a kinase-mediated mechanism
 DRUG RECEPTORS AND
PHARMACODYNAMICS
RECEPTOR DESENSITIZATION
 Response gradually diminishes even if
thedrug is still there (after reaching an
initial high level of response)
 Reason is UNKNOWN
 DRUG RECEPTORS AND
PHARMACODYNAMICS

STRUCTURE ACTIVITY
RELATIONSHIP
 Cells use more than one signaling
mechanism to respond to the drug
 DRUG RECEPTORS AND
PHARMACODYNAMICS
QUANTAL DOSE-RESPONSE CURVE
Graph of the fraction of a population that
shows a specified response to increasing
doses of a drug
 DRUG RECEPTORS AND
PHARMACODYNAMICS

QUANTAL DOSE-RESPONSE CURVE

 Minimum dose required to produce a
specific response is determined in each
member of the population
 Sigmoid curve
 DRUG RECEPTORS AND
PHARMACODYNAMICS
ED 50
 Median effective dose
 50% of the individuals manifested the
desired therapeutic effect
TD 50
 Median toxic dose
 50% of the individuals manifested the toxic
effects
LD 50
 Median lethal dose
 DRUG RECEPTORS AND
PHARMACODYNAMICS
THERAPEUTIC INDEX
 Ratio of the TD 50 (or LD 50 ) to the ED 50
determined from the quantal dose-response
curves
 Increased therapeutic index-wide margin of
safety
 Represents an estimate of the safety of the
drug
 A very safe drug might be expected to have
a very large toxic dose and a much smaller
effective dose
 Eg, ED 50 of 3mg and the LD 50 is 150 mg
 Therapeutic index is 50 (150/3)
 DRUG RECEPTORS AND
PHARMACODYNAMICS
THERAPEUTIC WINDOW
 Dosage range between the minimum
effective therapeutic concentration or dose
(MEC) and the minimum toxic
concentration or dose (MTC)
 More clinically relevant index of safety
 Eg, theophylline
 MEC=7-10 mg/L (average of 8 mg/L)
 MTC=15-20 mg/L (average of 18 mg/L)
 Therapeutic window=8-18 mg/L
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PHARMACODYNAMICS
MAXIMAL EFFICACY
 Maximal effect (E max ) an agonist can
produce if the dose is taken to very high
levels
 Determined mainly by the nature of
receptors and its associated effectors
 Measured with a graded dose-response
curve but not with quantal dose-
response curve
 DRUG RECEPTORS AND
PHARMACODYNAMICS

POTENCY
 Amount of drug needed to produce a
given effect
 In the graded dose-response curve, the
effect chosen is the 50% of the maximal
effect and the dose is (EC 50 )
 In the quantal dose-response curve,
ED 50 , TD 50 , and LD 50 are variables in
50% of the population
 DRUG RECEPTORS AND
PHARMACODYNAMICS

A C D

Response B  DRUG B is the most potent

 DRUGS A,C AND D have equal
maximal efficacy and greater
maximal efficacy than DRUG B

Log concentration
 DRUG RECEPTORS AND
PHARMACODYNAMICS
VARIATION OF RESPONSES IN INDIVIDUALS

IDIOSYNCRATIC RESPONSE
 Caused by differences in metabolism (genetic)or
immunologic mechanisms
 Response to the drug is unknown or unusual

HYPOREACTIVE RESPONSE
 Intensity of the drug is decreased
 Large dose of the drug is needed to havean effect
 DRUG RECEPTORS AND
PHARMACODYNAMICS
VARIATION OF RESPONSES IN INDIVIDUALS
HYPEREACTIVE RESPONSE
 Intensity of the drug is increased or
exaggerated

TOLERANCE
 Decreased sensitivity acquired as a
result of exposure to the drug
 DRUG RECEPTORS AND
PHARMACODYNAMICS
VARIATION OF RESPONSES IN INDIVIDUALS

TACHYPHYLAXIS
 Tolerance develops after a few doses
 DRUG RECEPTORS AND
PHARMACODYNAMICS

VARIATIONS IN DRUG RESPONSIVENESS

1. Alteration on the concentration of the drug
that reaches the receptor due to
absorption, distribution and elimination
differences
2. Variation in the concentration of the
endogenous ligands (chemicals produced
by the body that binds to receptors, eg,
cathecolamines)
 DRUG RECEPTORS AND
PHARMACODYNAMICS
VARIATIONS IN DRUG RESPONSIVENESS
3. Alterations in number/function of
receptors
DOWN REGULATION
 Decrease in # of receptors
UP REGULATION
 Increase in the # of receptors
 DRUG RECEPTORS AND
PHARMACODYNAMICS
VARIATIONS IN DRUG RESPONSIVENESS
OVERSHOOT PHENOMENON/ REBOUND
HYPERTENSION
 Drug has been taken for a long time, then
abruptly discontinued
 Eg, propranolol (beta-blocker)
 Gradual decrease of taking the drug by
decreasing/tapering the dose
 DRUG RECEPTORS AND
PHARMACODYNAMICS

VARIATIONS IN DRUG RESPONSIVENESS

4. Changes in 2 nd messengers
5. Clinical selectivity
 Give the drug that really acts on the
disease
 No drug causes a single specific effect
only, they are selective but never
specific
 DRUG RECEPTORS AND
PHARMACODYNAMICS

VARIATIONS IN DRUG RESPONSIVENESS

5. Clinical selectivity
 Beneficial and toxic effects may be
mediated by the same receptor-effector
mechanism
D+R DR X (beneficial/toxic)
 DRUG RECEPTORS AND
PHARMACODYNAMICS

WHAT TO DO TO AVOID/CIRCUMVENT
TOXIC EFFECTS
Give low doses
Carefully monitor the patient
Employ ancillary procedures
Use a safer drug
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PHARMACODYNAMICS
HEPARIN
 Low doses for prevention of blood clots
 Very high doses causes internal bleeding
 Monitor PT, PTT and bleeding parameters
STEROIDS
 Give lowest dose possible
 Give adjunctive drugs
 Anatomic selectivity (lungs-by inhalation)
 DRUG RECEPTORS AND
PHARMACODYNAMICS

 Beneficial and toxic effects are mediated

by identical receptors but in different
ways
x (beneficial)
D+R DR y (toxic)
 DRUG RECEPTORS AND
PHARMACODYNAMICS

 Beneficial and toxic effects mediated by

different types of receptor
ANTIHISTAMINES
H 1 receptors – H 1 blocker
H 2 receptors – H 2 blocker

R1 DR 1 X (beneficial)

D +
R2 DR 2 Y (toxic)