2. DRUG:
The WHO (1966) defined it as -
"Drug is any substance or product that is used
or is intended to be used to modify or explore
physiological systems or pathological states
for the benefit of the recipient."
3. RECEPTOR:
It describes protein molecules whose
function is to recognise and respond to
endogenous chemical signals.
Other macromolecules with which drugs
interact to produce their effects are known
as drug targets.
8. pA2:
A pA2 value determines the important relationship
between two drugs "competing" for effect on the same
receptor.
The two drugs are "competitive" if increasing or reducing
one drug decreases or increases the effect of the other,
respectively.
The pA2 value indicates the concentration of antagonist
when double the agonist is required to have the same
effect on the receptor as when no antagonist is present.
9. Defined as: The negative logarithm to base 10 of the
molar concentration of an antagonist that makes it
necessary to double the concentration of the agonist
needed to elicit the original submaximal response
obtained in the absence of antagonist.
10.
11. DRUG SPECIFICITY:
The strength of the reversible interaction between a drug
and its receptor.
It is defined as the affinity of one for the other.
A drug that interacts with a single type of receptor that is
expressed on only a limited number of differentiated cells
will exhibit high specificity.
12. If, however, a receptor is expressed ubiquitously
on a variety of cells throughout the body, drugs
acting on such a widely expressed receptor will
exhibit widespread effects, and could produce
serious side effects or toxicities if the receptor
serves important functions in multiple tissues.
13. The pharmacological properties of many drugs
differ depending upon whether the drug is used
acutely or chronically.
In some cases, chronic administration of a drug
causes a down-regulation or desensitization of
receptors that can require dose adjustments to
maintain adequate therapy.
14. Quantitative Aspects of Drug
Interactions with Receptors
The basic currency of receptor pharmacology is
the dose-response (or concentration-response)
curve.
The drug effects can be measured for
quantitative assessment of its safety and efficacy.
17. Thus, measuring agonist potency by comparison
of EC50 values is one method of measuring the
capability of different agonists to induce a
response in a test system and for predicting
comparable activity in another.
18. Pharmacodynamic Variability: Individual and
Population Pharmacodynamics
Individuals vary in the magnitude of their response to the
same concentration of a single drug or to similar drugs,
and a given individual may not always respond in the
same way to the same drug concentration.
Attempts have been made to define and measure
individual "sensitivity" (or "resistance") to drugs in the
clinical setting, and progress has been made in
understanding some of the determinants of sensitivity to
drugs that act at specific receptors.
19. Drug responsiveness may change because of
disease or because of previous drug
administration.
Receptors are dynamic, and their concentration
and function may be up- or down-regulated by
endogenous and exogenous factors.
The variability in pharmacodynamic response in
the population may be analyzed by constructing
a quantal concentration-effect curve.
20. The dose of a drug required to produce a
specified effect in 50% of the population is the
median effective dose ED50
In preclinical studies of drugs, the median lethal
dose (LD50) is determined in experimental animals.
The LD50/ED50 ratio is an indication of the
therapeutic index, which is a statement of how
selective the drug is in producing its desired
effects versus its adverse effects.
21.
22. The binding of drugs to receptors :
The binding of drugs to receptors can often be
measured directly by the use of drug molecules
(agonists or antagonists) labelled with one or
more radioactive atoms (usually 3H, 14C or 125I).
23. The usual procedure is to incubate samples of the
tissue (or membrane fragments) with various
concentrations of radioactive drug until
equilibrium is reached.
The bound radioactivity is measured after
removal of the supernatant.
24. The amount of non-specific binding is estimated
by measuring the radioactivity taken up in the
presence of a saturating concentration of a (non-
radioactive) ligand that inhibits completely the
binding of the radioactive drug to the receptors,
leaving behind the non-specific component.
This is then subtracted from the total binding to
give an estimate of specific binding .
25.
26. The binding curve defines the relationship
between concentration and the amount of drug
bound (B), allowing the affinity of the drug for the
receptors to be estimated, as well as the binding
capacity (Bmax), representing the density of
receptors in the tissue.
27.
28. It has also been shown, in skeletal muscle and
other tissues, that denervation leads to an
increase in the number of receptors in the target
cell, a finding that accounts, at least in part, for
the phenomenon of denervation supersensitivity.
29. Non-invasive imaging techniques, such as
positron emission tomography (PET), can also be
used to investigate the distribution of receptors in
structures such as the living human brain.
30. Docking studies:
Docking is a method which predicts the preferred orientation
of one ligand when bound in an active site to form a stable
complex.
The ligand is docked onto the receptor and the interactions are
checked. The scoring function generates score, depending on
which the best fit ligand is selected.
31. Types:
Rigid Docking (Lock and Key)
In rigid docking, the internal geometry of both the receptor
and ligand are treated as rigid. In the rigid molecule docking ,
we relate to the molecules as rigid objects that cannot change
their spatial shape during the docking process.
Flexible Docking (Induced fit)
An enumeration on the rotations of one of the molecules
(usually smaller one) is performed. Every rotation the energy is
calculated; later the most optimum pose is selected.
The Schild plot is a pharmacological method of receptor classification. To construct a Schild plot, the dose-effect curve for an agonist is determined in the presence of various concentrations of a competitive antagonist. From this experiment the pA2 is determined which is a measure of affinity of the antagonist for its receptor (i.e., the equilibrium dissociation constant). As such, the Schild Plot is sometimes referred to as pA2 analysis. Once the actual experiments are completed a series of dose ratios (DR) are calculated for a given effect. For example the ratio of the dose of agonist (A') to produce a specific effect (e.g., half maximal effect) in the presence of the antagonist (B) to the dose required in the absence of the antagonist (A) is calculated. This is determined for several doses of antagonist and then log ((A'/A) -1) versus the negative log B is plotted (this can also be plotted versus log B, but negative log B is more convenient). If the regression of log ((A'/A) -1) on -log B is linear with a slope of -1, then this indicates that the antagonism is competitive and by definition the agonist and antagonist act at the same recognition sites.
