Quantal dose response

The curve is again identical in shape but this time a population has been studied and the frequency of response recorded at various drug doses. It is, therefore, known as a quantal dose-response curve. The marker of potency is now the ED50 and the y axis should be correctly labelled as shown. This is the typical dose-response curve that is tested in the examination. 

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. 

Quantal dose-response curves based on all-or-none responses. A. Relationship between the dose of phenobarbital and the protection of groups of rats against convulsions. B. Relationship between the dose of phenobarbital and the drug s lethal effects in groups of rats. ED50, effective dose, 50% LD50, lethal dose, 50%. 

The quantal dose-response curve is actually a cumulative plot of the normal frequency distribution curve. The frequency distribution curve, in this case relating the minimum protective dose to the frequency with which it occurs in the population, generally is bell shaped. If one graphs the cumulative frequency versus dose, one obtains the sigmoid-shaped curve of Figure 22A. The sigmoid shape is a characteristic of most dose-response curves when the dose is plotted on a geometric, or log, scale. 

The quantal dose-response curve represents estimates of the frequency with which each dose elicits the desired response in the population. In addition to this information, it also would be useful to have some way to express the average sensitivity of the entire population to phenobarbital. This is done through the calculation of an ED50 (effective dose, 50% i.e., the dose that would protect 50% of the animals). This value can be obtained from the dose-response curve in Figure 22A, as shown by the broken lines. The ED50 for phenobarbital in this population is approximately 4mg/kg. 

Inhaled (volatile) anesthetics are delivered to the lungs in gas mixtures in which concentrations and flow rates are easy to measure and control. However, dose-response characteristics of volatile anesthetics are difficult to quantify. Although achievement of an anesthetic state depends on the concentration of the anesthetic in the brain (ie, at the effect site), concentrations in the brain tissue are obviously impossible to measure under clinical conditions. Furthermore, neither the lower nor the upper ends of the graded dose-response curve defining the effect on the central nervous system can be ethically determined because at very low gas concentrations awareness of pain may occur. Moreover, at high concentrations there is a high risk of severe cardiovascular and respiratory depression. Nevertheless, a useful estimate of anesthetic potency can be obtained using quantal dose-response principles for both the inhaled and intravenous anesthetics. 

A threshold also exists for quantal dose responses as well as graded, i.e., there will be a dose below which no individuals respond. However, the concept of a threshold also has to be considered in relation to the variation in sensitivity in the population, especially a human population with great variability. Thus, although there will be a dose at which the greatest number of individuals show a response (see point B in Fig. 2.5), there will be those individuals who are very much more sensitive (point A in Fig. 2.5) or those who are much less sensitive (point C in Fig. 2.5). This consideration is incorporated into risk assessment of chemicals such as food additives, contaminants, and industrial chemicals (see below). 

Quantal Dose-Response Curves and the Median Effective Dose... 

Nevertheless, a useful estimate of anesthetic potency can be obtained using quantal dose-response principles. 

Quantal dose-response curve A graph of the fraction of a population that shows a specified response to increasing doses of a drug... 

In graded dose-response curves, the concentration or dose that produces 50% of the maximum possible response in quantal dose-response curves, the dose that causes the specified response in 50% of the population... 

E. Quantal Dose-Response Relationships When the minimum dose required to produce a specified response is determined in each member of a population, the quantal dose-response relationship is defined (Figure 2-2). When plotted as the fraction of the population that responds at each dose versus the log of the dose administered, a cumulative quantal dose-response curve, usually sigmoid in shape, is obtained. The median effective (ED j,), median toxic (TD, ), and median lethal doses (LD j,) are extracted from experiments carried out in this manner. 

F. Efficacy Efficacy, often called maximal efficacy, is the maximal effect (E,.,.,) an agonist can produce if the dose is taken to very high levels. Efficacy is determined mainly by the nature of the receptor and its associated effector system. It can be measured with a graded dose-respon.se curve (Figure 2-1) but not with a quantal dose-response curve. By definition, partial agonists have lower maximal efficacy than full agonists (see below). 

A pharmacologic antagonist occupies the receptors without activating them. The answer is (A). Quantal dose-response curves provide information about the statistical distribution of sensitivity to a drug. The answer is (E). 

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