In order to establish the relationship between the severity and the blood/plasma concentrations, the analysis must be specific and quantitative and sometimes include the active metabolites. The relationship is dependent on the mechanism of toxicity ( Ja§.,g.e.Letll.a.l 1994).
Functional toxins (e.g. barbiturates, benzodiazepines, meprobamate, cardiotropic drugs, lithium, theophylline, etc.) impair the function of one or more organs. Patients recover without sequelae if no complications occur during the poisoning. Their toxicity is directly related to the concentration at the target organ or receptor; symptoms appear when the plasma concentration exceeds a threshold level, and the severity increases with the concentration ( Fig 1). The duration of the toxicity is dependent on the plasma half-life and the decrease of the concentration at the target organ. For instance, in barbiturate, meprobamate, or ethanol poisoning, the severity of disturbances of the central nervous system and coma is closely related to the plasma concentration. In acute theophylline poisoning, toxicity is minor at concentrations between 20 and 40 mg/l, moderate at concentrations between 40 and 100 mg/l, and severe at concentrations above 100 mg/l. If the parent compound is metabolized into active metabolites which have not been analyzed, there is not usually a relation between plasma parent drug concentrations and symptoms (Jaeger, etal 1994).
Fig. 1 Toxicokinetic-toxicodynamic relationship for a functional poison (monocompartment kinetics): curve A, concentration; curve B, toxic effect.
Lesional toxins (paraquat, acetaminophen (paracetamol), colchicine, amatoxins, heavy metals, etc.) induce cellular or organ damage. The severity depends on the maximum concentration which has been (or will be) reached at the target organ. If cellular damage has occurred, symptoms may not improve even though the toxin has been eliminated from the target organ. The interpretation has to take into account the plasma concentration and the time at which this concentration has been measured. Depending on the delay following ingestion, the same plasma concentration may be non-toxic, toxic, or lethal ( Fig. 2). In these poisonings, plasma concentrations have a prognostic value: risk of lethal outcome in paraquat poisoning ( PLO.y,dL°°t.,§L§L 1979), and risk of hepatitis in acetaminophen poisoning
Fig. 2 Toxicokinetic-toxicodynamic relationship for a lesional poison: curve A, concentration; curve B, toxic effect.
Some toxins act by both mechanisms: the parent compound is a functional toxin, but after a delay cellular damage due to prolonged cellular hypoxia (carbon monoxide, cyanide) or to the accumulation of cytotoxic metabolites (methanol, ethylene glycol) may occur. The interpretation is based on the kinetic data (plasma concentrations of the parent compound and metabolites) and on the time after ingestion or the duration of the exposure ( Jaegereia/ 1994). In acute short exposure to carbon monoxide, the symptoms correlate well with carboxyhemoglobinemia levels. In prolonged exposure, the severity depends not only on the carboxyhemoglobin level but also on the duration of the cerebral hypoxia. The potential toxicity of methanol is related to the methanol concentration measured in the early phase of the poisoning. The real toxicity depends on the concentrations of the toxic metabolites. If the patient is seen in a later phase, severe symptoms may be present despite low methanol concentrations.
Was this article helpful?