TOXICOKINETICS & TOXICODYNAMICS
The term toxicokinetics denotes the absorption, distribution, excre-tion, and metabolism of toxins, toxic doses of therapeutic agents, and their metabolites. The term toxicodynamics is used to denote the injurious effects of these substances on body functions. Although many similarities exist between the pharmacokinetics and toxicoki-netics of most substances, there are also important differences. The same caution applies to pharmacodynamics and toxicodynamics.
The volume of distribution (Vd) is defined as the apparent volume into which a substance is distributed in the body . A large Vd implies that the drug is not readily accessible to mea-sures aimed at purifying the blood, such as hemodialysis. Examples of drugs with large volumes of distribution (> 5 L/kg) include antidepressants, antipsychotics, antimalarials, opioids, propra-nolol, and verapamil. Drugs with a relatively small Vd (< 1 L/kg) include salicylate, ethanol, phenobarbital, lithium, valproic acid, and phenytoin (see Table 3–1).
Clearance is a measure of the volume of plasma that is cleared of drug per unit time . The total clearance for most drugs is the sum of clearances via excretion by the kidneys and metabolism by the liver. In planning a detoxification strategy, it is important to know the contribution of each organ to total clearance. For example, if a drug is 95% cleared by liver metabolism and only 5% cleared by renal excretion, even a dramatic increase in urinary concentration of the drug will have little effect on overall elimination.
Overdosage of a drug can alter the usual pharmacokinetic pro-cesses, and this must be considered when applying kinetics topoisoned patients. For example, dissolution of tablets or gastric emptying time may be slowed so that absorption and peak toxic effects are delayed. Drugs may injure the epithelial barrier of the gastrointestinal tract and thereby increase absorption. If the capac-ity of the liver to metabolize a drug is exceeded, the first-pass effect will be reduced and more drug will be delivered to the circulation. With a dramatic increase in the concentration of drug in the blood, protein-binding capacity may be exceeded, resulting in an increased fraction of free drug and greater toxic effect. At normal dosage, most drugs are eliminated at a rate proportional to the plasma concentration (first-order kinetics). If the plasma concen-tration is very high and normal metabolism is saturated, the rate of elimination may become fixed (zero-order kinetics). This change in kinetics may markedly prolong the apparent serum half-life and increase toxicity.
When considering quantal dose-response data, both the therapeutic index and the overlap of therapeutic and toxic response curves must be considered. For instance, two drugs may have the same therapeu-tic index but unequal safe dosing ranges if the slopes of their dose-response curves are not the same. For some drugs, eg, sedative-hypnotics, the major toxic effect is a direct extension of the therapeutic action, as shown by their graded dose-response curve (see Figure 22–1). In the case of a drug with a linear dose-response curve (drug A), lethal effects may occur at 10 times the normal therapeutic dose. In contrast, a drug with a curve that reaches a plateau (drug B) may not be lethal at 100 times the normal dose.
For many drugs, at least part of the toxic effect may be different from the therapeutic action. For example, intoxication with drugs that have atropine-like effects (eg, tricyclic antidepressants) reduces sweating, making it more difficult to dissipate heat. In tricyclic antidepressant intoxication, there may also be increased muscular activity or seizures; the body’s production of heat is thus enhanced, and lethal hyperpyrexia may result. Overdoses of drugs that depress the cardiovascular system, eg, β blockers or calcium channel blockers, can profoundly alter not only cardiac function but all functions that are dependent on blood flow. These include renal and hepatic elimination of the toxin and that of any other drugs that may be given.