Toxic effects may be (1) exaggerations of direct effects of a drug seen at higher dosages, e.g., a barbiturate may produce sedation and drowsiness at therapeutic levels, but cause death at increased dosage levels; or (2) multiple concurrent “side” effects that occur at therapeutic dosages, e.g., an antihistamine, intended to antagonize histamine action in peripheral tissues may also bind to receptors in the CNS and cause drowsiness.
The dose of a drug required to produce a specific response in 50 percent of the individuals within the same population (Figure 5) is the median effective dose (ED50). If the measured endpoint is a toxic effect, the median toxic dose is expressed as TD50. If death is the measured endpoint, the median lethal dose is expressed as LD50. A steep dose-response curve indicates a narrow range between therapeutic, toxic, and lethal dosages.
The margin of safety of a drug is expressed as its therapeutic index, i.e., the ratio of LD50/ED50). The margin of safety may also be established by comparing the 99 percent dose-response curve for the therapeutic effect with the curve for a particular toxic or the lethal effect (Figure 6). The farther apart these curves are the wider the margin of safety. The therapeutic window is the range of doses at which a drug is effective without causing significant adverse effects.
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