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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
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
Changes its function upon bidning in such
a way that the function of the biologic
system is altered in order to have
pharmacologic effect
Selectiv in ligand-binding characteristics
(respond to proper chemical signals and
not to meaningless ones)
Mediate the actions of both pharmacologic
agonists and antagonists
Majority are proteins which provide the
necessary diversity and specificity of
shape and electrical charge
Interaction between the drug and the
receptor is the fundamental event that
initiates the action of a drug
Receptor Site/Recognition Site
- Specific
binding
region
of
the
macromolecule
- High and selective affinity to the drug
molecule
Classification of Receptors
A. 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
B. Enzymes
- Inhibited (or less commonly, activated) by
binding a drug
- Eg, dihydrofolate reductase, the receptor
for methotrexate
C. Transport Proteins

Eg, Na+/K+ ATPase, the membrane


receptor for digitalis
D. Structural Proteins
- Eg, tubulin, the receptor for colchicine, an
anti-inflammatory drug
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 Concentration and Response
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
Sigmoid curve
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
No response even if the dose is increased
EC50
Concentration of drug that produces 50%
of maximal effect
Smaller EC50 more potent

Bmax
Total number of receptor sites
All receptors have been occupied

DRUG RECEPTORS AND 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 Kd greater affinity of drug to
receptor

Curve A
Agonist Response in the absence of
antagonist
Curve B
After treatment with low concentration of
antagonist, the curve is shifted to the right
Maximal response is preserved because
the remaining available receptors are still
in excess
Curve C
Produced after larger concentration of
antagonist, the available receptors are no
longer spare, sufficient enough to
mediate
an
undiminished
maximal
response

Curve D and E
With higher concentrations of antagonist,
reduce the number of available receptors
to the point that maximal response is
diminished
EC50 may approximate the Kd that
characterizes the binding affinity of the
agonist for the receptor
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
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
Compare concentration for 50% of
maximal effect (EC50 with concentration
for 50% maximal binding Kd)
Kd > EC50 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
Inert Binding Sites
Non-regulatory molecules of the body
Binding with these molecules will result to
no detectable change in the function of the
biologic system
Buffers the concentration of the drug
Bound drugs do not contribute directly to
the concentration gradient that drives
diffusion
Eg, albumin
Agonist
Binds to the receptor and directly or
indirectly bring about an effect
Full activation of the effector system
Partial Agonist

DRUG RECEPTORS AND PHARMACODYNAMICS

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 of Antagonist
A. 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 (eg, horizontally to the right
of the dose axis)
- Same maximal effect is reached
- Effects are overcome by adding more
agonist
- Increases the median effective dose
(ED50)

2 Therapeutic Implications
1) Degree of inhibition produced by
the
competitive
antagonist
depends on the concentration of
antagonist (eg, propanolol)
2) Clinical response to a competitive
antagonist
depends
on
the
concentration of agonist that is
competing for binding to the
receptor
B. Irreversible Antagonist
- Binds with the receptor via covalent bonds
- Antagonists affinity to the receptor maybe
so high
- Receptor is not available to bind the
agonist
- Concentration-effect
curve
moves
downward

No shift of the cruve in the dose axis


Emax is not reached
No increase in median effective dose
(ED50) unless there are spare receptors
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

C. Chemical Antagonist
- Does not depend on interaction with the
agonists 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
D. Physiologic Antagonist
- 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
o Glucocorticoids catabolic effects of
increase in sugar is physiologically
opposed by insulin
o Histamine
causes
bronchoconstriction in asthmatic
patients,
opposed
by
bronchodilators like salbutamol and
epinephrine
Signalling Mechanisms
A. Lipid soluble drug
B. Transmembrane
receptor-protein
intracellular enzymatic activity is regulated

DRUG RECEPTORS AND PHARMACODYNAMICS


by a ligand that binds to the proteins
extracellular domain
C. Transmembrane receptor that binds and
stimulates a protein tyrosine kinase (eg,
insulin)
D. Ligand-gated transmembrane ion channel
which regulates the opening of the ion
channel
(eg,
GABA,
excitatory
acetylcholine)
E. Transmembrane receptor is coupled with
an effector enzyme by G protein which
modulates production of an intracellular
second messenger (eg, cathecolamine
(epinephrine))
Intracellular 2nd Messengers
A. cAMP
- Mediates hormonal responses
o Mobilization of stored energy
(breakdown of carbohydrates in the
liver stimulated by cathecolamines)
o Conservation of water by the
kidneys mediated by vasopressin
o Calcium
homeostasis
by
parathyroid hormone
o Heart rate and contraction by betaadrenomimetic cathecolamines
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
C. cGMP
- Few signalling 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
Receptor Desensitization
Response gradually diminishes even if the
drug is still there (after reaching an initial
high level of response)
Reason is not known
Structure Activity Relationship
Cells use more than one signalling
mechanism to respond to the drug
Quantal Dose-Response Curve
Graph of the fraction of a population that
shows a specified response to increasing
doses of a drug

Minimum dose required to produce a


specific response is determined in each
member of the population
Sigmoid curve

ED50
Median effective dose
50% of the individuals manifested the
desired therapeutic effect
TD50
Median toxic dose
50% of the individuals manifested the toxic
effects
LD50
Median lethal dose
Therapeutic Index
Ratio of the TD50 (or LD50) to the ED50
determined from the quantal doseresponse 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
o Eg, ED50 of 3 mg and the LD50 is
150 mg
o Therapeutic index is 50 (150/3)
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
o MEC = 7-10 mg/L (average of 8
mg/L)
o MTC = 15-20 mg/L (average of 18
mg/L)
o Therapeutic window = 8-18 mg/L
Maximal Efficacy
Maximal effect (Emax) 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-reponse
curve but not with quantal dose-response
curve
Potency

DRUG RECEPTORS AND PHARMACODYNAMICS

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)
In the quantal dose-response curve,
ED50, TD50, and LD50 are variables in
50% of the population

Drug B is the most potent


Drugs A, C, and D have equal maximal
efficacy and greater maximal efficacy than
Drug B
Variation of Reponses in Individuals
A. Idiosyncratic Response
- Caused by differences in metabolism
(genetic) or immunologic mechanisms
- Response to the drug is unknown or
unusual
B. Hyporeactive Response
- Intensity of the drug is decreased
- Large dose of the drug is needed to have
an effect
C. Hypereactive Response
- Intensity of the drug is increased or
exaggerated
D. Tolerance
- Decreased sensitivity acquired as a result
of exposure to the drug
E. Tachyphylaxis
- Tolerance develops after a few doses
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)
3. Alterations in number/function of receptors
- Down regulation: decrease in # of
receptors
- Up regulation: increase in the # of
receptors
- Overshoot Phenomenon/Rebound
Hypertension
o Drug has been taken for a long
time, then abruptly discontinued
o Eg, propanolol (beta-blocker)
o Gradual decrease of taking the
drug by decreasing/tapering the
dose
4. Changes in 2nd 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
- Beneficial and toxic effects may be

mediated by the same receptor-effector


mechanism

What to Do to Avoid/Circumvent Toxic Effects


Give low doses
Carefully monitor the patient
Employ ancillary procedures
Use a safer drug if possible
Beneficial and toxic effects are mediated
by identical receptors but in different ways

Heparin
Low doses for prevention of
blood clots

DRUG RECEPTORS AND PHARMACODYNAMICS


Very high doses causes
internal bleeding
Monitor PT, PTT and
bleeding parameters
Steroids
Give lowest dose possible

Give adjunctive drugs


Anatomic selectivity (lungsby inhalation)
Antihistamines
H1 receptors H1 blocker
H2 receptors H2 blocker