Quantal Dose-Effect Relationship

Whereas a graded dose-effect relationship relates drug dose and concentration to the intensity of a 

FIGURE 18.11 Population-based, quantal dose-effect curves plotted in (A) as a frequency distribution histogram relating the threshold dose required to produce an all-or-none effect to the number of patients responding at each threshold dose, and (B) as a cumulative distribution, in which the cumulative fraction of patients responding at each dose is plotted as a function of the dose. 

When administered to an organism, a drug produces a desired therapeutic effect but is also likely to produce at least one toxic effect. As a result, a single dose-effect curve does not adequately characterize the full spectrum of effects from the drug. The toxic effects of a drug can also be described by separate quantal dose-effect curves, and the safety of a drug depends on the degree of separation between the dose that produces the therapeutic effect and the dose that produces unacceptable toxic effects. 

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A quantal dose-effect relationship can also be graphically displayed as a cumulative dose-effect curve/ in which the cumulative percentage of individuals experiencing an effect is plotted as a function of the threshold dose. The normal frequency distribution in Figure 18.11 A takes on a sigmoidal shape when the same data are plotted as a cumulative dose-effect curve (Figure 18.1 IB). The median effective dose (ED50) for the quantal dose-effect relationship is the dose at... 

The Quantal Dose-Effect Relationship Frequency of Anemia as a Function of Chemical Dose in a Test Population of 30 Rats... 

A key feature of a quantal dose-effect relationship is a statistic the median dose, variously annotated as the TDjg or LDjg, which marks the middle of the exposed population with respect to its susceptibility to the quantal toxic effect. Half the population manifests the specified toxic effect at doses less than the TD50, and half the population manifests the specified toxic effect at doses greater than the TD50. 

True or false A quantal dose-effect relationship quantitates the toxicity of a chemical to an individual animal as a function of dose. Explain. 

False. The quantal dose-effect relationship determines the frequency of one specified toxic effect in a population that is exposed to increasing doses of a single chemical. The term quantal refers to the fact that the toxic effect is of a specific, known magnitude. The frequency of the manifestation of the specified toxic effect in the exposed population, i.e., the number of individuals who manifest the specified toxic effect, increases as a function of dose. However, it is impossible to predict which individuals in the at-risk population will manifest the toxic effect at any given dose. 

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. 

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%. 

It is clear from the earlier discussion that the measurable endpoint of toxicity may be a pharmacological, biochemical, or a pathological change, which shows percentage or proportional change. Alternatively, the endpoint of toxicity may be an all-or-none or quantal type of effect such as death or loss of consciousness. In either case, however, there will be a dose-response relationship. The basic form of this relationship is shown in Figure 2.4. 

Dose Rate The chemical s dose delivered per unit lime or the radiation dose delivered per unit time. Dose-Response Curves Demtnstrate the relation between dose and the proportion of individuals responding with a quantal effect (q.v.). In general, dose-response curves are S-shaped (increasing), and they have upper and lower asymptotes, usually but not always 1(X) and 0%. D Response Relationship The systematic relationship between the dose (or effective concentration) of a drug or xenobiotic and the magnitude (or intensity) of the response it elicits. 

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