Bruno Mégarbane - Department of Medical and Toxicological Intensive Care Medicine, Lariboisière Hospital, INSERM U۱۱۴۴, Paris-Diderot University, Paris, France

Pharmacokinetic/pharmacodynamic (PK/PD) relationships describe the quantitative relationships between the drug-induced effects and the concurrent corresponding drug concentrations in an individual. Since a long time, rough qualitative relationships have been described between neurological presentation and plasma ethanol concentration in acute ethanol ingestion. However, to date, precise quantitative PK/PD relationships have not been extensively studied. We studied PK/PD relationships in ethanol poisonings. Plasma concentrations were measured using an enzymatic assay. Coma depth was assessed using the Glasgow Coma Scale (GCS). Non-linear regression was used for modeling PK/PD relationships. The PK/PD relationships were well fitted with the sigmoidal Emax model. A maximal toxic effect (GCS of ۳) was associated with a wide range of plasma ethanol concentrations, suggesting the saturation of drug targets at high doses. During the course of poisoning, the relationships between the depth of coma and the corresponding plasma concentrations were of sigmoidal shape. The elevated values of the Hill coefficient showed that a small decrease in plasma concentrations near the EC۵۰ was associated with a dramatic improvement in the level of consciousness. In chronic alcoholic patients, EC۵۰ was higher than in non-tolerant. Analyzing blood concentrations with respect of the delay elapsed since the ingestion may help predicting the time of awakening and thus the evaluation of outcome. In conclusion, PK/PD relationships are helpful in suggesting mechanisms of inter-individual variability of central neurological response to ethanol.

Alcoholic Neuropathy, Pharmacokinetics, Pharmacodynamics, Ethanol