Dynamics

2. A RECEPTOR IS THE SPECIFIC CHEMICAL CONSTITUENT OF THE CELL
WITH WHICH A DRUG INTERACTS TO PRODUCE IT’S
PHARMACOLOGICAL EFFECTS.
Some receptor sites have been
identified with specific parts of proteins and nucleic acids.
In most cases, the chemical nature of the receptor site remains
obscure.
DRUG RECEPTORS

3. Receptor : Any cellular macromolecule that a drug binds to
initiate its effects.
Drug : A chemical substance that interacts with a
biological system to produce a physiologic effect.
All drugs are chemicals but not all chemicals are
drugs.
The ability to bind to a receptor is mediated by the chemical
structure of the drug that allows it to Interact with complementary
surfaces on the receptor.
Once bound to the receptor an agonist activates or enhances
cellular activity. Examples of agonist action are drugs that bind
to beta receptors in the heart and increase the force of myocardia
contraction
or drugs that bind to alpha receptors on blood vessels to
increase blood pressure. The binding of the agonist often triggers
a series of biochemical events that ultimately leads to the alteration in
function.

4. HOW DRUGS ACT
l. Enzyme Inhibition:
Drugs act within the cell by modifying normal biochemical reactions.
Enzyme inhibition may be reversible or non reversible;
competitive or non-competitive.
Antimetabolites may be used which mimic natural metabolites. Gene functions may
be suppressed.
2. Drug-Receptor Interaction:
Drugs act on the cell membrane by physical and/or chemical interactions-
usually through specific drug receptor sites known to be located on the membrane.
Some receptor sites have been identified with specific parts of proteins and nucleic
acids. In most cases, the chemical nature of the receptor site remains obscure.
3. Non-specific Interactions:
Drugs act exclusively by physical means outside of cells. These sites include external
surfaces of skin and gastro-intestinal tract. Drugs also act outside of cell membranes
by chemical interactions. Neutralization of stomach acid by antacids is a good
example

5. Dose-Response Curves
Dose-response relationships are a common way to portray data in both basic and
clinical science.
For example, a clinical study may examine the effect of increasing
amounts of an analgesic on pain threshold.
To present the data, the concentration of the drug would be plotted on the x-axis
and the effect on pain threshold would be presented on the y-axis.
A plot of drug concentration ([D]) versus effect (E/Emax)
(or for that matter DR/RT) is a rectangular hyperbola. Notice how the drug effect
reaches a plateau or maximum.
This is because there are a finite number of receptors.
Hence, the response must eventually reach a maximum. However, the
hyperbolic plot is a cumbersome graph because drug concentrations often vary
over 100 to 1000-fold. This necessitates a long X-axis. To overcome this problem,
the log of the drug concentration is plotted versus the effect. A plot of the log of [D]
versus E/Emax is a sigmoid curve.

6. As illustrated below, the position and shape of the log-dose response
curve is dependent on the affinity of the ligand for the receptor and its
intrinsic activity. Affinity determines the position of the dose-response
curve on the X-axis, while intrinsic activity affects the magnitude of the
response.

7. In most physiological systems in which drugs will be administered, the relationship between
receptor occupancy and response is not linear but some unknown function f of receptor
occupancy. In the graph, this unknown function is presented as being hyperbolic. As the
graph depicts in this type of system, all receptors do not have to be occupied to produce a
full response. Because of this hyperbolic relationship between occupancy and response,
maximal responses are elicited at less than maximal receptor occupancy. A certain number
of receptors are "spare." Spare receptors are receptors which exist in excess of those
required to produce a full effect. There is nothing different about spare receptors. They are
not hidden or in any way different from other receptors.

8. Norepinephrine and phenylephrine are full agonists with intrinsic activity values
of 1. However, Norepinephrine has a higher affinity for the receptor. As is
illustrated, affinity affects the position of the dose-response curve on the x-axis.

9. Factors Governing Drug Action
Two factors that determine the effect of a drug on physiologic processes are
1. Affinity
2.Intrinsic activity.
Affinity is a measure of the tightness that a drug binds to the receptor.
Intrinsic activity is a measure of the ability of a drug once bound to the
receptor to generate an effect activating stimulus and producing a change
in cellular activity.

11. The binding of a drug to a receptor is determined by the following
forces:
1.Hydrogen bonds
2.Ionic bonds
3.Van der Waals forces
4.Covalent bonds
Understanding Affinity
To bind to a receptor the functional group on a drug must interact with
complementary surfaces on the receptor. The binding of a drug, illustrated
here as D, to the receptor, illustrated as R, can be described by this
expression.

13. Agonists initiate changes in second messengers.
Once bound to the receptor an agonist activates or enhances cellular
activity. Examples of agonist action are drugs that bind to beta receptors in
the heart and increase the force of myocardial contraction or drugs that
bind to alpha receptors on blood vessels to increase blood pressure.
The binding of the agonist often triggers a series of biochemical events that
ultimately leads to the alteration in function.
The biochemicals that initiate these changes are referred to as second messe
or antagonists.
Antagonists have the ability to bind to the receptor but do not initiate a
change in cellular function. Because they occupy the receptor, they can
prevent the binding and the action of agonists. Hence the term antagonist.
Antagonists are also referred to as blockers.

14. Affinity and intrinsic activity are independent properties of drugs.
Agonists have both affinity - the ability to bind to the receptor
as well as intrinsic activity-the ability to produce a measurable effect.
Antagonists, on the other hand, only have affinity for the receptor.
This property allows antagonists to bind to the receptor. However,
because antagonists do not have intrinsic activity at the receptor no
effect is produced. Because they are bound to the receptor, they can
prevent binding of agonists. This is a diagram of a G-protein coupled
receptor. Notice how the amino acids that make up the receptor protein
can contribute functional groups to allow a drug to bind to this receptor.

16. This is a reversible reaction and when at equilibrium, the rate of drug-receptor
complex formation [DR] is equal to the rate of drug-receptor complex dissociation.
The rate of formation of the drug-receptor complex is described by k1. The rate at
which the drug receptor complex dissociates is described by k-1. The binding of
many, but not all, drugs to the receptor is a reversible process which reaches an
equilibrium. The practical consequence of this is when binding is in equilibrium
the amount of drug bound to the receptor is constant.

17. To summarize, the key features of a competitive antagonist are:
1.Reversible binding to the receptor.
2.The blockade can be overcome by increasing the agonist concentration.
3.The maximal response of the agonist is not decreased.
4.The agonist dose-response curve in the presence of a competitive antagonist is
displaced to the right parallel to the curve in the absence of agonist.

18. Antagonists
Antagonists exhibit affinity for the receptor but do not have intrinsic activity at the receptor. An
antagonist that binds to the receptor in a reversible mass-action manner is referred to as a
competitive antagonist.
Because the antagonist does not have intrinsic activity, once it binds to the receptor,
it blocks binding of agonists to the receptor. A key point about competitive antagonists is that
like agonists, they bind in a reversible manner. This has important implications regarding the
effect competitive antagonists have on the configuration of the dose-response curve of agonists

19. Because competitive antagonists bind in a reversible manner,
agonists, if given in high concentrations, can displace the
antagonist from the receptor and the
agonist can then produce its effect. The antagonist action can,
in effect, be surmounted.
Because the antagonist can be completely displaced, the
agonist is still able to produce the
same maximal effect observed prior to antagonist treatment.
However, because higher agonist
concentrations were necessary to displace the antagonist, the
agonist dose-response curve is
shifted to the right in the presence of a competitive antagonist.
This can be illustrated with two
equilibrium equations:

20. Irreversible Receptor Antagonists
Another type of antagonist is referred to as an irreversible receptor antagonist. The
properties of irreversible antagonists are markedly different from competitive
antagonists. Irreversible receptor antagonists are chemically reactive compounds.
These ligands first bind to the receptor. Following this binding step, the ligand then
reacts with the functional groups of the receptor. The consequence of this chemical
reaction is that the ligand becomes covalently bound to the receptor. Because a
chemical bond is formed, an irreversible ligand does not freely dissociate from the
receptor. It remains attached to the receptor for a long period of time. The synthesis
of new receptor protein may be required to generate a receptor free of an
irreversible blocker. Because the ligand is covalently bound to the receptor, the
binding of agonists, and hence their pharmacologic activity, are blocked. Unlike
competitive antagonists, the blocking activity of irreversible receptor antagonists can
not be overcome by increasing the agonist concentration.

21. The antagonism therefore
cannot be overcome by increasing the agonist
concentration. Recall, that the effect
of an agonist is proportional to the active
drug-receptor complexes formed. Because
an irreversible receptor antagonist reduces
the total number of active receptors,
[RT], the maximal pharmacologic effect Emax
is also decreased. The reduction in
maximal agonist reponse is the hallmark of
irreversible antagonists. The shape of the
dose-response curve is also altered because of
this decrease in maximal effect. The
dose-response is shifted to the right and the
maximal response is depressed.

22. To summarize, the properties of irreversible receptor blockers are:
1.Chemically reactive compound, therefore covalently binds with the receptor
2.The receptor is irreversibly inactivated and the blockade can not be overcome with
increasing agonist concentration..
3. Shifts the agonist dose-response curve to the right and depresses maximal responsiveness.

23. Applications to Therapeutics
Few drugs interact with one and only one receptor. Such a drug would be
said to be specific, that is producing effects by specifically interacting with a
single receptor. Most drugs interact with several receptors and thus have
the capability to produce distinctly different pharmacologic effects. Some
of these effects could be beneficial, some could be toxic. Such a drug would
be said to be a selective. The factors that determine which particular effect
of a drug will be observed are the affinity and intrinsic activity of a drug .