PD & Drug Receptors

DRUG RECEPTORS AND PHARMACODYNAMICS
• Pharmacodynamics: What the drug does to

the body
• RECEPTORS
Specific molecules in a biologic system with
which drugs interact to produce changes in
the function of the system
RECEPTORS
Selective in choosing a drug molecule to bind to
avoid constant activation by promiscuous binding of
many different molecules
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
RECEPTORS
RECEPTOR SITE/RECOGNITION SITE
Specific binding region of the macromolecule
High and selective affinity to the drug molecule
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
ENZYMES
Inhibited (or less commonly, activated) by
binding a drug
Eg, dihydrofolate reductase, the receptor for
methotrexate
TRANSPORT PROTEINS
Eg, Na+/K+ ATPase, the membrane receptor
for digitalis
STRUCTURAL PROTEINS
Eg, tubulin, the receptor for colchicine, an
anti-inflammatory drug
Drug - Receptor Binding
D+R DR Complex
Affinity
Affinity – measure of propensity of a drug to bind

receptor; the attractiveness of drug and receptor
– Covalent bonds are stable and essentially
irreversible
– Electrostatic bonds may be strong or weak, but
are usually reversible
2004-2005
Drug Receptor Interaction
DR Complex Effect
Efficacy (or Intrinsic Activity) – ability of a

bound drug to change the receptor in a
way that produces an effect; some drugs
possess affinity but NOT efficacy
2004-2005
DRUG CONCENTRATION AND RESPONSE

DR Curve: Whole Animal
• Graded – response measured on a

continuous scale
• Quantal – response is an either/or
event
– relates dose and frequency of response
in a population of individuals
– often derived from frequency
distribution of doses required to produce
a specified effect
2004-2005
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
8
dose response curves-3
quantal dose response curves (used in populations, response is yes/no)
Therapeutic index =Toxic Dose50/Effective Dose50

2004-2005 (TD50/ED50)
GRADED DOSE-RESPONSE CURVE

Usually hyperbolic but when log dose is used it
becomes a Sigmoid curve with a linear mid-portion.
Why transform: makes it easier to graphically
compare different curves, as expands the scale of the
conc.axis at low conc.( effect is changing rapidly) en
contracts it at high conc.( effect is changing slowing)
Has no biological or pharmacological significance.
Efficacy (Emax) and potency (EC50) are

derived from this curve
The smaller the EC50, the greater the
potency of the drug
Emax
Maximal response that can be produced
by a drug
All receptors are occupied
EC50
Concentration of drug that produces
50% of maximal effect
Smaller EC50–more potent
DRUG RECEPTORS and PHARMACODYNAMICS
Emax
10
Drug effect
EC50
Drug dose
Potency
Relative position of the dose-effect curve along

the dose axis
Has little clinical significance for a given
therapeutic effect
A more potent of two drugs is not clinically
superior
Low potency is a disadvantage only if the dose is
so large that it is awkward to administer
2004-2005
Effectiveness, toxicity, lethality
• ED50 - Median Effective Dose 50; the dose
at which 50 percent of the population or
sample manifests a given effect; used with
quantal dr curves
• TD50 - Median Toxic Dose 50 - dose at
which 50 percent of the population
manifests a given toxic effect
• LD50 - Median Toxic Dose 50 - dose which
kills 50 percent of the subjects
2004-2005
Quantification of drug safety
TD50 or LD50
Therapeutic Index =
ED50
2004-2005
Bmax
Total number of receptor sites
All receptors have been occupied
KD
Equilibrium dissociation constant
Concentration of drug required to
bind 50% of the receptors
KD
Measure of the affinity of a drug
for its binding site on the receptor
Smaller KD–greater affinity of drug
to receptor
Bmax
10
Receptor bound
drug
5
KD
Drug dose
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
ANTAGONIST
Binds but do not activate the receptors
Blocks or competes with agonist
CLASSIFICATION
COMPETITIVE ANTAGONIST
Competes with agonist receptor
Binds to the receptor reversibly without activating
the effector system
CLASSIFICATION
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
CLASSIFICATION
Effects are overcomed by adding
more agonist
Increases the median effective dose
(ED50)
Agonist alone
Agonist effect
Agonist + competitive antagonist
Agonist dose
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
CLASSIFICATION
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
CLASSIFICATION
Concentration-effect curve moves downward
No shift of the curve in the dose axis
Emax is not reached
No increase in median effective dose (ED50) unless
there are spare receptors
CLASSIFICATION
Duration of action is relatively independent
of its own rate of elimination
More dependent on the rate of turnover of receptors
Eg, phenoxybenzamine binding with alpha receptors
Agonist alone
Agonist effect
Agonist + irreversible antagonist
Agonist dose
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
CHEMICAL ANTAGONISM
Eg, protamine used to counteract the
effect of heparin making it unavailable
for interaction with proteins involved in
the formation of blood
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
PHYSIOLOGIC ANTAGONISM
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
SIGNALING MECHANISMS
SIGNALING MECHANISMS
A Few Concepts
1. RECEPTORS are the specific molecular
components of a biologic system with which
drugs interact to produce changes in the
function of the system.
2. INERT BINDING SITES are components of
endogenous molecules that bind a drug without
initiating events leading to any of drug’s effect.
3. EFFECTORS are molecules that translate the
drug-receptor interaction into a change in
cellular activity (adenylyl cyclase, tyrosine
kinase).
4. LIGANDS are Chemicals that bind to receptors.
5. AGONISTS AND PARTIAL AGONISTS: An agonist
is a drug capable of fully activating the effector
system when it binds to the receptor. A partial
agonist produces less than the full effect; even
it has saturated the receptors.
6. ANTAGONISTS are drugs that bind to the
receptor without activating the effector system
for that receptor. It may block the access of
agonist to receptor.
7. INVERSE AGONIST OR NEGATIVE ANTAGONIST
is a ligand produces an effect opposite in the
direction of the agonist.
Inverse Agonist or Negative
Antagonist (two state model)
full inverse
full
agonist antagoni agonist
st
partial inverse
partial agonist
agonist
DRUG RECEPTORS and
PHARMACODYNAMICS
• A full agonist is selective for
the Ra conformation.
• A partial agonist has slightly
greater affinity for Ra than Ri.
• An antagonist has equal
affinity to either conformation.
• Negative antagonist has
preferential affinity for Ri to
Ra.
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
4
Signal transduction
1. enzyme linked
(multiple actions)
2. ion channel linked

(speedy)
3. G protein linked
(amplifier)
4. nuclear (gene) linked
(long lasting)
2004-2005
Structure:
1. G protein-linked receptors •Single polypeptide
chain threaded back
and forth resulting in
7 transmembrane å
helices
•There’s a G protein
attached to the
cytoplasmic side of
the membrane
(functions as a
switch).
•Effector: ion
channels or enzymes
•Effect in seconds
2004-2005
2004-2005
2. Tyrosine-kinase receptors
Structure:
•Receptors exist as individual polypeptides
•Each has an extracellular signal-binding site
•An intracellular tail with a number of tyrosines
and a single å helix spanning the membrane
•Effector: enzyme
•Effect in hours
2004-2005
2004-2005
3. Ion channel
receptors
Structure:
•Protein pores in the
plasma membrane
•Effector: ion
channel
•Effect in
milliseconds
2004-2005
4. Intracellular receptors
Not all signal receptors are located on the plasma membrane. Some are proteins
located in the cytoplasm or nucleus of target cells.
• The signal molecule must be able to pass through plasma membrane.
Effector: gene transcription, takes hours
Examples:
~Nitric oxide (NO)
~Steroid (e.g., estradiol, progesterone, testosterone)
and thyroid hormones of animals).
e
2004-2005
Two benefits of a signal-transduction pathway
1. Signal amplification
2. Signal specificity
A. Signal amplification
•Proteins persist in active form long
enough to process numerous molecules
of substrate
•Each catalytic step activates more
products then in the proceeding steps
2004-2005
2004-2005
INTRACELLULAR 2ND MESSENGERS

A. cAMP ( formation is catalysed by Adenylate cyclase)
• It activates various protein kinases which control cel
function in different ways)
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

A. cAMP
Mediates hormonal responses
Calcium homeostasis by parathyroid
hormone
Heart rate and contraction by beta-
adrenomimetic cathecolamines

B. Inositol triphosphate (IP3) and diacylglycerol(DAG)
• Formation is catalysed by phospholipase C.
• IP3 increases intracellular ca2+, this initiates
various responses like contraction, secretion,
enyme activation; etc.
• DAG activates protein kinase c which controls
various responses by phosphorylating a variaty of
proteins.

C. cGMP
Few signaling roles in a few cell types
like the intestinal mucosa and vascular
smooth muscle cells

C. cGMP
Causes relaxation of vascular smooth
muscles by a kinase-mediated mechanism
THERAPEUTIC INDEX
Ratio of the TD50 (or LD50 ) to the ED50 determined
from the quantal dose-response curves
Increased therapeutic index-wide margin of safety
THERAPEUTIC INDEX
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, ED50 of 3mg and the LD50 is 150 mg
Therapeutic index is 50 (150/3)
THERAPEUTIC WINDOW
Dosage range between the minimum
effective therapeutic concentration or
dose (MEC) and the minimum toxic concentration o
dose (MTC)
More clinically relevant index of safety
THERAPEUTIC WINDOW
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
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 (EC50)
POTENCY
In the quantal dose-response curve, ED50,
TD50, and LD50 are variables in 50% of the
population
RECEPTOR DESENSITIZATION
Response gradually diminishes even if the
drug is still there (after reaching an initial
high level of response)
Reason is not known
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 have an
effect
HYPEREACTIVE RESPONSE
Intensity of the drug is increased or exaggerated
TOLERANCE
Decreased sensitivity acquired as a result of
exposure to the drug
TACHYPHYLAXIS
Tolerance develops after a few doses
VARIATIONS IN DRUG RESPONSIVENESS

Alterations in number/function of receptors
DOWN REGULATION
Decrease in # of receptors
UP REGULATION
Increase in the # of receptors
12
Summary
 most drugs act through receptors ( regulatory proteins)
 there are 4 common signal transduction methods
 the interaction between drug and receptor can be described
mathematically and graphically
 agonists have both affinity (kd) and intrinsic activity ()
 antagonists have affinity only
 antagonists can be competitive (change kd) or
 non-competitive (change ) when mixed with agonists
 agonists desensitize receptors.
 antagonists sensitize receptors.
2004-2005

PD &amp; Drug Receptors

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PD &amp; Drug Receptors

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DRUG RECEPTORS AND PHARMACODYNAMICS

• Pharmacodynamics: What the drug does to

Affinity – measure of propensity of a drug to bind

Efficacy (or Intrinsic Activity) – ability of a

DRUG CONCENTRATION AND RESPONSE

• Graded – response measured on a

GRADED DOSE-RESPONSE CURVE

Therapeutic index =Toxic Dose50/Effective Dose50

GRADED DOSE-RESPONSE CURVE

Efficacy (Emax) and potency (EC50) are

Relative position of the dose-effect curve along

Agonist + competitive antagonist

Agonist + irreversible antagonist

2. ion channel linked

INTRACELLULAR 2ND MESSENGERS

INTRACELLULAR 2ND MESSENGERS

INTRACELLULAR 2ND MESSENGERS

INTRACELLULAR 2ND MESSENGERS

INTRACELLULAR 2ND MESSENGERS

VARIATION OF RESPONSES IN INDIVIDUALS

VARIATION OF RESPONSES IN INDIVIDUALS

VARIATION OF RESPONSES IN INDIVIDUALS

VARIATION OF RESPONSES IN INDIVIDUALS

VARIATION OF RESPONSES IN INDIVIDUALS

VARIATIONS IN DRUG RESPONSIVENESS

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