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Receptor: Any cellular macromolecule that a drug binds toinitiate its effects. The natural function of a receptor is toparticipate in neuotransmission or physiologic regulation.

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

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Factors Governing Drug Action

Two factors that determine the effect of a drug onphysiologic processes are affinity and intrinsic activity .

Affinity is a measure of the tightness that a drug bindsto the receptor.

Intrinsic activity is a measure of the ability of a drugonce bound to the receptor to generate an effectactivating stimulus and producing a change in cellularactivity.

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Affinity and intrinsic activity are independent properties of drugs. AGONISTS have both affinity , that is, the ability to bind to thereceptor, as well as intrinsic activity , the ability to produce ameasurable 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 noeffect is produced. Because they are bound to the receptor, they canprevent binding of agonists.

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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 bythis expression.

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This is a reversible reaction and when at equilibrium, the rate of drug-receptor complex formation [DR] is equal to the rate of drug-receptorcomplex 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. Insimpler 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 dissociatesfrom its receptor.

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

Affinity = k 1 /k -1

Kd = k -1 /k 1

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A drug which binds with great avidity to the receptor is said tohave high affinity. That is k 1(drug association) is much greaterthan k -1(drug dissociation).

Kd is the equilibrium dissociation constant . There is aninverse relationship between the Kd and affinity. The smallerthe Kd, the greater the affinity.

The equilibrium dissociation constant is an important term inpharmacology. This is a unique value for each drug. The units ofthe 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 adissociation constant of 1 nanomolar is said to have a higheraffinity than a drug that has a dissociation constant of 1micromolar. This is because 1 nanomolar is much smaller than 1micromolar.

By appropriate manipulation we can write the equation:

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Where [D] is the concentration of drug, [DR] is the concentration ofreceptor bound with drug, [RT] is the total number of receptors and Kdis the equilibrium dissociation constant.

This equation describes the binding of drugs to pharmacologicreceptors and states that the amount of drug bound to thereceptor is dependent on the DRUG CONCENTRATION AND KD.

To illustrate, assume that a drug has an equilibrium dissociation of1nM. How many receptors would be occupied by a drug if it is given at

a concentration of 0.5 nM?

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When a drug is given at a concentration equal to its Kd, 50% of the totalreceptor population will be occupied by the drug. To illustrate,assume a drug with a Kd of 1 nM is given at 1 nM.

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Lowering bloodpressure

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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 referredto 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, thetherapeutic index will be:

The Therapeutic Index is a measure of the safety of a drug. All otherfactors being equal, the larger the difference between the LD50 andED50 the safer the drug.

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Drugs that stimulate are called agonists and those that blockare called antagonists .

Narcotics are classic agonist drugs. These pain medications goto specific receptors in the body and cause the receptors to shutdown the pain response.

Non-steroidal medications (including aspirin) are classicantagonist drugs. Cyclo-oxygenase is an enzyme which isblocked by the anti-inflammatory medicines. Blocking thisenzyme (antagonist) reduces inflammation and thereforedecreases pain.

About half of the drugs we use are agonists and the other halfare antagonists. The strength of the drug is determined by howwell they bind the receptor sites or how well they block thosesites.

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