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INTRODUCTION

Toxicology is the study of the adverse effects of substances on living organisms. Any substance is considered a poison when exposure results in a damaging physiological effect (toxic effect). Among the agents that can produce toxic effects are pharmaceuticals, illicit drugs, plants and botanicals, and myriad chemicals and pollutants. Chapter 76 focuses on environmental toxicology. This chapter focuses on clinical toxicology, the discipline of toxicology that studies undesired effects of pharmaceutical therapies in humans and the effects and treatment of poisoning.

Toxicological testing is performed in preclinical studies to assess for the toxicity of a substance in animals and in in vitro models (see Chapters 1 and 76). Additional studies, including carcinogenicity, teratogenicity, and effects on fertility, are performed concurrently with the first stages of a clinical trial. More adverse effects may be discovered in postmarketing surveillance as more doses are administered and more patients are exposed to the drug (see Chapter 9).

ABBREVIATIONS

Abbreviations

CYP: cytochrome P450

ED50: median effective dose

GI: gastrointestinal

hERG: human ether-a-go-go gene

Ig: immunoglobulin, as in IgE, IgG, IgM

LD50: median lethal dose

MDAC: multiple-dose activated charcoal

NAPQI: N-acetyl-p-benzoquinonimine

NSAID: nonsteroidal anti-inflammatory drug

PCC: poison control center

PDE5: phosphodiesterase type 5

Pgp: P-glycoprotein (MDR1, ABCB1)

SNRI: serotonin-norepinephrine reuptake inhibitor

TD50: median toxic dose

TI: therapeutic index

WBI: whole-bowel irrigation

DOSE-RESPONSE

Conventional Dose-Response Curves

Dose-response relationships are graded in an individual and quantal in the population (see Figures 3–7 and 3–9). In a graded dose-response, the magnitude of an individual’s response usually increases as the dose of the drug is increased. In a quantal dose relationship, the percentage of the population that responds increases as the dose of the drug increases, but the response is only judged to be either present or absent in a given individual. This quantal dose-response phenomenon is used to determine the LD50 (median lethal dose) of drugs, as defined in Figure 9–1A.

Figure 9–1

Dose-response relationships. A. The midpoint of the curve represents the LD50, or the dose of drug that is lethal in 50% of the population. The LD50 of a compound is determined experimentally, usually by administration of the drug to mice or rats (orally or intraperitoneally). 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 the effective dose (ED) and lethal dose (LD). The crosshatched area between the ED99 (1 mg/kg) and the LD1 (3 mg/kg) gives ...

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