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INTRODUCTION

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Pharmacology intersects with toxicology when the physiological response to a drug is an adverse effect. A poison is any substance, including any drug, that has the capacity to harm a living organism. Poisoning generally implies that damaging physiological effects result from exposure to pharmaceuticals, illicit drugs, or chemicals.

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DOSE-RESPONSE

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There is a graded dose-response relationship in an individual and a quantal dose-response relationship in the population (see Chapters 2 and 3). Graded doses of a drug given to an individual usually result in a greater magnitude of response as the dose increases. In a quantal dose-response relationship, the percentage of the population affected increases as the dose is raised; the relationship is quantal in that the effect is judged to be either present or absent in a given individual. This quantal dose-response phenomenon is used to determine the median lethal dose (LD50) of drugs, as defined in Figure 4–1.

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Figure 4–1

Dose-response relationships. The LD50 of a compound is determined experimentally, usually by administration of the chemical to mice or rats (orally or intraperitoneally). The midpoint of the curve representing percent of population responding (response here is death) versus dose (log scale) represents the LD50, or the dose of drug that is lethal in 50% of the population. The LD50 values for both compounds are the same (~10 mg/kg); however, the slopes of the dose-response curves are quite different. Thus, at a dose equal to one-half the LD50 (5 mg/kg), less than 5% of the animals exposed to compound B would die, but 30% of the animals given compound A would die.

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One can also determine a quantal dose-response curve for the therapeutic effect of a drug to generate a median effective dose (ED50), the concentration of drug at which 50% of the population will have the desired response, and a quantal dose-response curve for lethality by the same agent. These 2 curves can be used to generate a therapeutic index (TI), which quantifies the relative safety of a drug:

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TI = LD50/ED50

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Clearly, the higher the ratio, the safer the drug.

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Values of TI vary widely, from 1-2 to >100. Drugs with a low TI must be administered with caution (e.g., cardiac glycoside digitalis and cancer chemotherapeutic agents). Agents with very high TI (e.g., penicillin) are extremely safe in the absence of a known allergic response in a given patient. Note that use of median doses fails to consider that the slopes of the dose-response curves for therapeutic and lethal (toxic) effects may differ (Figure 4–1). As an alternative the ED99 for the therapeutic effect can be compared to the LD1 for lethality (toxic effect), ...

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