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Receptor Pharmacology; elaborations on lecturesLecture Gosens, General pharmacological principles
Pharmacology is the interaction of chemical substances with a living organism, the binding of drug to
a receptor and the biological effect it has.
A drug is a chemical applied to a physiological system that affects its function in a specific way.
Drugs can be specific or non-specific; non-specific drugs are drugs that have a biological effect at
relatively high drug concentrations, these can have the same effect in two different areas. Specific
drugs have a biological effect at relatively low drug concentrations and have a chemical and
biological specificity. These drug directly interact with a target. Most drugs act on target proteins
with high affinity to the drug.
Drugs can bind to receptors, ion channels, enzymes or carriers. Receptors being target molecules
whose function is to recognize and respond to specific endogenous (within system) chemical signals.
These thus form the signalling network in our normal physiological network; by influencing them
with drugs, so inhibition or activation, this communication is influenced and thus the physiology is
changed.
For all drug action the reciprocity is reciprocal, this means that the receptors are for a specific drug
and that the drug is for a specific receptor. This results in high specificity due to high affinity.
However, no drugs are completely specific in their actions, this causes side effects to occur at high
drug concentrations. The drug will bind to other receptors with a lower affinity which will cause a
side effect.
Two types of ligands that can bind to a receptor;
agonist and antagonist. An agonist is a ligand that will
initiate a biological response. An antagonist will bind
to the receptor and will not lead to an initiation of a
biological response. It will occupy the receptor so that
no agonist can bind and thus no response can take
place. A physiological response can be induced by the
binding of the antagonist. If a physiological system
requires the agonist to function than blocking that
receptor can trigger a physiological response. When an agonist binds to a receptor the active state of
the receptor is stabilized. The biggest differences between the active and inactive state occur inside
the cell, this small change can be enough to activate or inactivate a cellular response.
When an agonist causes a drop in blood pressure, this drop in blood pressure will be higher when a
higher dose of agonist is administered. When the receptor is however blocked with an antagonist the
agonist will not have the prolonged effect anymore.
The part which is the steepest on the graph of concentration versus fractional occupancy is the part
where precisely 50% of the drug is bound to the receptor, this is called the KA. In other words, it is the
concentration of ligand at which 50% of the receptor is bound. The fractional occupancy is the
portion of receptor that is bound. A Scatchard analysis is a way to derive the binding constant, KA and
the maximum number of binding sites BMAX. It is found by making the drug radioactive. These only
study the binding of the drug, not the prolonged effect.
The extend to which a drug can activate a system is the efficacy of a drug. The potency describes the
concentration at which 50% of the system is active.
,The efficacy of a drug is most of the time not 1 or 0. An agonist would have an efficacy of 1 and an
antagonist an efficacy of 0. When the efficacy is between 0 and 1 the drug is a partial agonist. A
partial agonist is a ligand that is able to bind to the receptor however, its efficacy of transducing an
effect is not the same as for a full agonist. The EC50 is the concentration of drug that induces half of
the effect of that particular drug, this is thus relative to the drug that is used. The pD2 is the -log
concentration inducing 50% of the maximum effect, -log(EC50). These two terms are only used for
agonists because only agonists have an effect.
A drug can have a efficacy between 0 and 1 because a receptor has several states that can take place.
A receptor can take different conformational states, within these conformational states the efficacy
of a agonist can differ. One conformation can be give a better efficacy than the other.
Receptor reserve means that a
physiological system has more
receptors present in the system
than are needed for the activation
of the response. Then when more
ligands bind to the receptor there
will be no further effect because
the system is already fully active. In
case of receptor reserve the EC50 is
always lower than the binding
constant KA. This is because less
than 50% of the receptors need to be bound in order for 50% of the effect to occur. A partial agonist
will not benefit from the receptor reserve because it is unable to activate the whole system, the
relationship between binding and effect is still the same. Only full agonists will thus benefit from the
receptor reserve. The physiological consequence is that an organ system that expresses very high
levels of the receptor is more sensitive to the drug than an organ system that expresses low levels of
the drug.
The better the drug fits to the binding pocket the more likely it will activate the receptor in full.
When a large chemical group is added to a drug, this wil interfere with its possibility to interact with
the binding pocket so efficacy is lost, this can be continued up to the point that an antagonist is
created.
Reversible competitive antagonism is the most
common form of antagonism. A drug will bind to
the receptor which will fail to activate it, it can be
competed off by the agonist. The maximal
response can still be reached when adding
antagonist it will only take a higher concentration
of agonist. There will thus be a change in EC50 and
no change in efficacy. The dose ratio describes
how much more agonist you need in order to compete out the antagonist.
The schild plot is used to calculate the concentration of antagonist that induces a two fold shift in the
dose response relationship. This concentration is called the pA2 = -log(KB). If a concentration is added
that binds 50% of the receptor than only half of the receptors is still available, therefore twice as
much of agonist is needed to induce half maximal effect.
,When a partial agonist and a full agonist are present in the system and they both want to bind to the
same receptor the partial agonist becomes a partial antagonist. Even though they both activate the
same receptor the partial agonist overrules the full agonist at higher concentrations it can inhibit the
actions of the full agonist. The more full agonist is added, the more partial agonist is needed to
compete the full effect off.
Non-competitive
antagonism is
dependent on
receptor binding
however, it cannot be
competed away by
the antagonist. This is
because the
antagonist binds to
the same site of the receptor but in an irreversible way or the
antagonist binds to a different site of the receptor that cannot be
competed out by the agonist. This will result in a loss in efficacy
however, the EC50 will remain the same. This is because the
antagonist will take away availability for the agonist to activate the receptor and thus to reach an
effect. This is because the antagonist is bound to another binding site which will cause the binding of
the agonist to be ineffective.
When there is receptor reserve the system will not have any problems with it because the amount of
receptors that is needed for activation is still present. Only when the amount of receptors that is
needed for the effect is limited the system will start to have a decline in response. When receptors
are blocked the potency of the system will be lower.
When reversible competitive antagonism occurs there is fast dissociation of antagonist, this is known
as the normal binding model. When irreversible competitive antagonism occurs, there is no
dissociation of antagonist. This is also the case when the antagonist dissociation is very slow, there is
non-competitive antagonist behaviour.
Receptor subtype selectivity is the selectivity of antagonists for a particular receptor. If the binding
constants of the drugs are known you can derive whether they are selective or not. The lower the
binding constant the less concentration is needed to bind to the receptor and thus the less selective
the drug is for that particular receptor.
Kinetic subtype selectivity is the result in differences in binding kinetics of the different receptor
types. The KA-value is the same but the dissociation constants are different.
Lecture Gosens, General pharmacological principles
A receptor appears to be able to activate itself without a
ligand bound to the receptor, this is called constitutive
activity. If an antagonist is thus able to reduce the
equilibrium of the resting state and the active state without
a ligand binding the effect that the activated state would
have will decrease. This is called inverse agonism, it is the
same as antagonism but because it takes away the baseline
activity of the receptor it is referred to as inverse agonism. A neutral antagonist can bind equally well
, to the resting state as well as to the activated state. It will not
differentiate but it will compete with the inverse agonist and the
agonist. When this happens the concentrations of the inverse agonist
and the agonist will have to go up in order to reach maximum activity
or minimum activity. The curves will thus shift to the right.
The activity of a receptor in resting state is thus not always 0% but can
differ depending on the receptor. This explains why the intrinsic
activity of the receptor can be brought back to 0%.
Functional (physiological) antagonism is dependent on a physiological response. In functional
antagonism a receptor is activated that activates the opposite process of the process that you want
to inhibit so that this process is inhibited anyway. It can appear in the form of an agonist in case of
creating an opposing effect but it can also be a proton pump inhibitor that blocks the common
pathway that is activated by individual receptors.
Chemical antagonism is always independent of a receptor. Chemical antagonism can take place in the
absence of a physiological system.
Pharmacokinetic antagonism is a compound that will accelerate the metabolism of a drug. It can be
used when a drug has a really long halve life and it thus takes a while for the drug to be excreted out
of the body. When the drug is not yet excreted out of the body and a new dose of the drug is added
this can result in an overdose. Pharmacokinetic antagonism will then be applied and will speed up
the metabolism of the drug so that it is excreted and no overdose is present anymore.
Desensitization, tachyphylaxis and tolerance are three different names for the exact same thing, loss
of response. When drugs are administered repeatedly they will lose efficacy over time. This can have
various reasons, loss of receptors or a change in the activation potential of the receptor. Other
reasons can be, the exhaustion of mediators, this happens when a too high dose is administered,
enhanced drug metabolism, drugs induce their own metabolism more and more drug will be needed.
Compensatory physiological mechanisms, mechanisms are triggered that compensate for the
presence of the drug, this will result in a loss of effect and it the dose needs to be decreased
gradually because the body will be producing these compensatory mechanisms. Extrusion of drugs
from cells, cells create different ways to avoid the actions of a drug.
Receptor desensitization can occur in nicotinic receptors, the response to Acetylcholine is reduced
over time and the effects of the twitches is lost.
In G-protein-coupled receptors have several phases
of desensitization. The first phase is uncoupling, the
agonists cannot bind to the receptor due to
phosphorylation, this process is mediated by the
GRK mechanism. The GRK are ligand-depending
kinases. The secondary phase is endocytosis, this is
dependent on the binding of a protein called
Arrestin. The receptor is then taken up in the cell
and the process can continue one of two ways, the
third phase. Either it degrades, the receptor is too
damaged in this case and will be broken down or it
will be recycled, the receptor will re-join the membrane again. Receptor desensitization is often
associated with a lot of response and it is considered a problem in drug therapy.
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