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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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ABBREVIATIONS

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Abbreviations

ADEs: adverse drug events

ADME: absorption, distribution, metabolism, and elimination

CYP: cytochrome P450

ECG: electrocardiogram

ED50: median effective dose

FDA: U.S. Food and Drug Administration

GI: gastrointestinal

Ig: immunoglobulin

IND: investigational new drug

IRB: institutional review board

LD50: median lethal dose

SSRI: selective serotonin reuptake inhibitor

TI: therapeutic index

WBI: whole-bowel irrigation

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DOSE-RESPONSE

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Conventional Dose-Response Curves

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There is a graded dose-response relationship in an individual and a quantal dose-response relationship in the population (see Figures 3–2, 3–3, and 3–6). 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 increased; 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 LD50 of drugs, as defined in Figure 4–1A.

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Figure 4–1

Dose-response relationships. A. 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 percentage 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), fewer than 5% of the animals exposed to compound Y would die, but about 25% of the animals given compound X would die. B. Depiction of ED and LD. The crosshatched area between the ED91 (10 mg/kg) and the LD9 (100 mg/kg) gives an estimate of the margin of safety.

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One can also determine a quantal dose-response curve for the therapeutic effect of a drug to generate 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 (Figure 4–1B). These two curves can be used to generate a TI, which quantifies the relative safety of a drug:

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(Equation 4–1) Image not available.

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

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Values of TI vary widely, ...

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