PHC 222Part(I)

Dr. Huda Al Salem

Lecture (7)

Factors that affect the efficacy

2 -Concentration-Response Curves:Agonist

AntagonistPartial agonistDesensetization

Concentration-Response CurveTo get a quantitative information concerning the dose-response relationship of any drug.. they study the effect of the drug on an isolated tissue (in vitro).

Examples: guinea big ileum or atria, rabbit jejunum, rat atria, canine coronary artery….etc

Concentration-Response CurveAGONIST CRC:

The response due to an agonist increases with increasing concentration of the agonist until it reaches a maximum.

At this point, further increase in dose have no further effect on the response.

How to calculate theDose of the drug?

Concentration-Response Curve

Concentration-Response CurveEC50

Is the concentration of a compound where 50%of its maximal effect isObserved.

EC50 value of a drug will depend on

the biological effect being studied.

Example:

EC50 of Aspirin as analgesic is significantly different from it when used as anticoagulant

Concentration-Response Curve

Agonist CRC is used during preclinical drug development to compare the potency of the different analogues of a lead compound.

Potency is a measure of drug activity

It is proportional to affinity & efficacy

Concentration-Response Curve

AGONIST CRC:1 -Agonists with similar structures acting on the same

receptor will exhibit similar plots

Concentration-Response CurveAGONIST CRC:

2 -The slopes of these plots are not always similar

Concentration-Response CurveANTAGONIST CRC:

Concentration-Response CurveANTAGONIST CRC:Antagonists inhibit the action of an agonist.

Concentration-Response Curve

Two Types of antagonists present1 -Competitive 2- Non-competitive

Concentration-Response Curve

Competitive antagonist Non-competitive antagonist

Non-covalent bonds, reversible

Covalent bonds, irreversible

Its effect can be reversed by increasing the concentration of

the agonist

The action is not dependent on the concentration of the agonist

E d' K E /̂ dZ ͗

Concentration-Response CurvePARTIAL AGONIST:

They are compounds that act as both agonists & antagonistsHow?

They act as antagonists by preventing endogenous ligands from binding to their receptors. But their binding to the receptor results in a weak activation of the receptor.Why?

1 -There is no perfect fit to the receptor site so does not cause enough change in receptor conformation..

2 -It has a structure that can bind to receptor in two different ways

Concentration-Response Curve

DESENSETIZATIONIs the loss of biological response after continuing or increasing dose of a drug.

Other names.. Tachyphylaxis or drug tolerance

It appears that the drug starts by acting as a full agonist but its repeated use results in partial agonistic action.

Rate theory is the only explanation of this phenomenon