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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
Bmax
Total number of receptor sites
All receptors have been occupied
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
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
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
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
Heparin
Low doses for prevention of
blood clots