Drug-Receptor Interaction Course Coordinator Jamaluddin Shaikh, Ph.D. School of Pharmacy, University of Nizwa Lecture-3 September 20, 2011

Dose Response Relationship To understand drug–receptor interactions, it is necessary to quantify the relationship between the drug and the biological effect it produces Since the degree of effect produced by a drug is generally a function of the amount administered, we can express this relationship in terms of a dose–response curve Because we cannot always quantify the concentration of drug in the biophase in the intact individual, it is customary to correlate effect with dose administered

Dose Response Relationship When a graded dose–response relationship exists, the response to the drug is directly related to the number of receptors with which the drug effectively interacts The principles derived from dose–response curves are the same in animals and humans However, obtaining the data for complete dose–response curves in humans is generally difficult or dangerous

Quantal Relationship In addition to the responsiveness of a given patient, one may be interested in the relationship between dose and some specified quantum of response among all individuals taking that drug Such information is obtained by evaluating data obtained from a quantal dose–response curve Anticonvulsants can be suitably studied by use of quantal dose–response curves The construction of a quantal dose–response curve requires that data be obtained from many individuals

Quantal Dose-Response Curve: Effective Dose The quantal dose–response curve represents estimates of the frequency with which each dose elicits the desired response in the population This is done through the calculation of an ED50, the dose that would protect 50% of the animals

Quantal Dose-Response Curve: Lethal Dose Important characteristic of a drug’s activity is its toxic effect and, the ultimate toxic effect is death A curve can be constructed by plotting percent of animals killed by any drug against dose This can calculate by the LD50, the dose that would kill 50% of animals

Therapeutic Index The ratio LD50/ED50 As a general rule, a drug should have a high therapeutic index; however, some important therapeutic agents have low indices The therapeutic index is a rough measure of safety and represents only the starting point in determining whether a drug is safe enough for human use

Graded Response A single animal gives graded responses to graded doses; that is, as the dose is increased, the response increases With graded responses, one can obtain a complete dose–response curve in a single animal

Idealized dose–response curves of three agonists (a, b, c) that increase heart rate but differ in potency, maximum effect, or both. Broken lines indicate 50% of maximum response (horizontal) and individual ED50 values (vertical)

Potency and Intrinsic Activity Another drug characteristic that can be compared by use of ED50 values is potency From the previous curve, less of drug ‘a’ is needed to produce a given response ED50b/ED50a= 3/.3=10, i.e., ‘a’ is 10 times more potent than ‘b’ In contrast, drug c has less maximum effect than either drug a or drug b. Drug c is said to have a lower intrinsic activity than the other two

Equation from Drug-Receptor Interaction K1 D + R D-R K2 K3 Response Affinity is k1/k2, and efficacy is represented by k3 Affinity and efficacy represent kinetic constants that relate the drug, the receptor, and the response at the molecular level Affinity is the measure of the net molecular attraction between a drug and its receptor Efficacy is a measure of the efficiency of the drug–receptor complex in initiating the signal transduction process