Receptor: Any cellular macromolecule that a drug binds to

initiate its effects. The natural function of a receptor is to
participate in neuotransmission or physiologic regulation.

Drug: A chemical substance that interacts with a biological
system to produce a physiologic effect.

Factors Governing Drug Action

Two factors that determine the effect of a drug on
physiologic processes are affinity and 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.


• Affinity and intrinsic activity are independent properties of drugs.
AGONISTS have both affinity, that is, 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.
• The Concept of Affinity
• The binding of a drug to a receptor is determined by the following forces:
• Hydrogen bonds
• Ionic bonds
• Van der Waals forces
• Covalent bonds
• 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.


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. In other words,

[D] [R] k
1
= [DR] k
-1


The rate of formation of the drug-receptor complex is described by k
1
. In
simpler terms k
1
describes the associate of a drug to its receptor.
Similarly, k
-1
is a term that describes the ease at which a drug dissociates
from its receptor.

Affinity is a term that describes the strength of drug binding to its receptor
and is the ratio of k
1
/k
-1
.

Affinity = k
1
/k
-1



Kd = k
-1
/k
1

• A drug which binds with great avidity to the receptor is said to
have high affinity. That is k
1
(drug association) is much greater
than k
-1
(drug dissociation).
• Kd is the equilibrium dissociation constant. There is an
inverse relationship between the Kd and affinity. The smaller
the Kd, the greater the affinity.
• The equilibrium dissociation constant is an important term in
pharmacology. This is a unique value for each drug. The units of
the dissociation constant are some measure of concentration
such as molar, millimolar, micromolar, nanomolar and so forth.
• Dissociation constants are usually small numbers, significantly
less than 1, such as 1 x 10
-8
or 10 nanomolar. A drug that has a
dissociation constant of 1 nanomolar is said to have a higher
affinity than a drug that has a dissociation constant of 1
micromolar. This is because 1 nanomolar is much smaller than 1
micromolar.
• By appropriate manipulation we can write the equation:

• Where [D] is the concentration of drug, [DR] is the concentration of
receptor bound with drug, [RT] is the total number of receptors and Kd
is the equilibrium dissociation constant.
• This equation describes the binding of drugs to pharmacologic
receptors and states that the amount of drug bound to the
receptor is dependent on the DRUG CONCENTRATION AND KD.
• To illustrate, assume that a drug has an equilibrium dissociation of
1nM. How many receptors would be occupied by a drug if it is given at
a concentration of 0.5 nM?
• When a drug is given at a concentration equal to its Kd, 50% of the total
receptor population will be occupied by the drug. To illustrate,
assume a drug with a Kd of 1 nM is given at 1 nM.

Lowering blood
pressure
• The Therapeutic Index
• The Therapeutic Index is the ratio of the ED50 of a drug to produce a
lethal effect to the ED50 to produce a therapeutic effect.
• The dose required to produce death in 50 % of a population is referred
to as the LD50.
• For the drug example above, the ED50 for the beneficial effect of blood
pressure lowering is 0.4 nM while the LD50 is 40 nM. Therefore, the
therapeutic index will be:





• The Therapeutic Index is a measure of the safety of a drug. All other
factors being equal, the larger the difference between the LD50 and
ED50 the safer the drug.







• Drugs that stimulate are called agonists and those that block
are called antagonists.
• Narcotics are classic agonist drugs. These pain medications go
to specific receptors in the body and cause the receptors to shut
down the pain response.
• Non-steroidal medications (including aspirin) are classic
antagonist drugs. Cyclo-oxygenase is an enzyme which is
blocked by the anti-inflammatory medicines. Blocking this
enzyme (antagonist) reduces inflammation and therefore
decreases pain.
• About half of the drugs we use are agonists and the other half
are antagonists. The strength of the drug is determined by how
well they bind the receptor sites or how well they block those
sites.