Toxicokinetic antidotes

Antidotes work by two different global mechanisms, i.e. by affecting either the toxicodynamic properties of the intoxicant (hemodynamics, binding at tissue sites) or the toxicokinetic properties (absorption, distribution, elimination) ( Baud ef a/ 1995). Because the latter group of antidotes may affect elimination, several examples are briefly mentioned here.

Digitalis antigen-binding fragments (Fabs) have very rapid pharmacodynamic effects (reduction of tissue binding and improvement in hemodynamics with reduction in dysrhythmias) and also dramatically decrease the half-life of digoxin in overdose. Likewise, colchicine Fabs (limited clinical availability) have shown promise not only in decreasing pharmacodynamic effects, but also in acting favorably on the pharmacokinetic parameters.

Hydroxocobalamin (vitamin B12a) not only reduces the amount of cyanide available to the tissues (toxicodynamic effect) but diminishes the 1-h half-life of circulating blood cyanide by its rapid irreversible binding of the toxin.

4-Methylpyrazole is virtually devoid of toxicodynamic effects; rather, it acts as a pure toxicokinetic antidote for ethylene glycol and methanol. However, because in this instance it is the metabolic products of these toxins which are responsible for their danger, 4-methylpyrazole achieves its benefit by blocking metabolism, thus prolonging the half-lives of these compounds and allowing the kidneys to eliminate the unchanged product. If renal failure is present, the toxins can then be removed by dialysis.

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