Doseresponse 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.

In general, biological responses to drugs are graded; that is, the response continuously increases (up to the maximal responding capacity of the given responding system) as the administered dose continuously increases. Expressed in receptor theory terminology, this means that 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. This is one of the tenets of pharmacology.

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. We shall therefore use animal data to illustrate these principles.

Quantal Relationships

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. For example, to assess the potential of new anticonvulsants to control epileptic seizures in humans, these drugs are initially tested for their ability to protect animals against experimentally induced seizures. In the presence of a given dose of the drug, the animal either has the seizure or does not; that is, it either is or is not protected. Thus, in the design of this experiment, the effect of the drug (protection) is all or none. This type of response, in contrast to a graded response, must be described in a noncontinuous manner.

The construction of a quantal dose-response curve requires that data be obtained from many individuals. Although any given patient (or animal) either will or will not respond to a given dose, a comparison of individuals within a population shows that members of that population are not identical in their ability to respond to a particular dose. This variability can be expressed as a type of dose-response curve, sometimes termed a quantal dose-response curve, in which the dose (plotted on the horizontal axis) is evaluated against the percentage of animals in the experimental population that is protected by each dose (vertical axis). Such a dose-response curve for the anticonvulsant phenobarbital is illustrated in Figure 2.2A. Five groups of 10 rats per group were used. The animals in any one group received a particular dose of phenobarbital of 2, 3, 5, 7, or 10 mg/kg body weight. The percentage of animals in each group protected against convulsions was plotted against the dose of phenobarbital. As Figure 2.2A shows, the lowest dose protected none of the 10 rats to which it was given, whereas 10mg/kg protected 10 of 10.With the intermediate doses, some rats were protected and some

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