Early Drug Distribution: A Generally Neglected Aspect of Pharmacokinetics of Particular Relevance to Intravenously Administered Anesthetic Agents

Abstract

There is considerable variability in response to intravenously administered anesthetic drugs (e.g., hypnotics, benzodiazepines, and narcotics) that have a rapid onset of effect (such as hypnosis, anxiolysis, and analgesia) and a low margin of safety (because of cardiovascular or respiratory depression, etc.). Although the onset of effect for these drugs occurs seconds to minutes after injection, traditional pharmacokinetic models are based on blood samples that are first obtained after drug effects have peaked. As a result, many studies have failed to provide a pharmacokinetic rationale for dosage adjustments of these drugs.

Population pharmacokinetic–pharmacodynamic analysis for sugammadex‐mediated reversal of rocuronium‐induced neuromuscular blockade

“…Variability in reversal time could, to some extent, be addressed with allometric scaling, but a substantial part of variability remained unidentified. A measure for cardiac output, reflecting the efficiency of the body in transferring sugammadex to the site of action, and/or the use of a recirculatory PK model (involving a nondistributive pathway) could contribute to explaining unidentified variability [41] and the somewhat slower reversal in elderly patients. Unfortunately, a measure for cardiac output was not available in this analysis.…”

Estudio comparativo entre inducción rápida y lenta de propofol en infusión objetivo-controlada: concentración de propofol prevista en la región de acción. Ensayo clínico aleatorizado

“…Ese retraso depende, entre otros factores, de la extracción pulmonar del propofol en el primer paso 14,15 . En el modelo farmacocinético de Marsh ese error inicial es evidente durante los 5 primeros minutos, lo que convierte a ese modelo en algo poco preciso en esos minutos iniciales 7 .…”

“…Como la dosis de bolo depende del tamaño del compartimento central, supervalorar ese volumen puede traer como resultado un gran bolo, que podrá exceder la Ca toda vez que el objeto se aumente 14,15 .…”

Diazepam or midazolam for orotracheal intubation in the ICU?

“…These wide variations in response are typical of benzodiazepines and may be partly explained by high plasma protein binding. 25,26 Obese patients have an increased volume of distribution due to enhanced distribution in peripheral adipose tissues and interactions with other drugs that are metabolized through the cytochrome p450 system can influence the clinical response. 27 Benzodiazepines have synergistic interactions with other drugs like opioids that were simultaneously used in most patients.…”