Diazepam actions and plasma concentrations following ethanol ingestion

Abstract

In eight normal volunteers, the combination of ethanol (0.5 g/kg) and diazepam (10 mg) administered orally produced a greater decrease in motor performance on a pursuit rotor than diazepam alone. The pharmacologic effect of diazepam was enhanced by 73% and this potentiation was associated with significantly greater diazepam concentrations (p less than 0.01) than after diazepam alone. The failure to observe any increase in the concentrations of the principal metabolite, N-desmethyl diazepam, during the period of enhanced pharmacologic effect precludes any change in the demethylating metabolic process as being responsible. The data suggest (0.10 greater than p greater than 0.05) a trend to a smaller volume of distribution of diazepam when ethanol is administered prior to diazepam ingestion. The subjects showed acute tolerance to the effects of diazepam. Lower plasma concentrations on the ascending side of the plasma diazepam concentration versus time profile were linked with the same pharmacologic responses associated with a greater drug concentration on the descending portion, of the same curve.

Pharmacodynamics of the anticonvulsant effect of oxazepam in aging BN/BiRij rats

“…Interestingly, the presence of endogenous n-butyl 13 carboline-3-carboxylate, which possesses inverse agonist properties, has indeed been demonstrated (Novas et al, 1988;Medina et al, 1989). In man also, the occurrence of tolerance/withdrawal phenomena with regard to the pharmacological effects of benzodiazepines appears to be ubiquitous (Bliding, 1974;Greenblatt et al, 1977;1981;Macleod et al, 1977;Greenblatt & Shader, 1978;Ellinwood et al, 1983;1985;1987;Salzman et al, 1983;Ashton et al, 1988). Thus a decrease in the efficiency of homeostatic control mechanisms may be a realistic explanation for the increase in sensitivity to the pharmacological actions of benzodiazepines in the elderly.…”

Interactions of benzodiazepines on psychomotor skills.

“…The time course of this combined action is complex and inadequately analyzed but may be important. The clearest effect may be seen when ethanol is given before diazepam so that their concentrations in the blood are rising at the same time (Laisi et al, 1979;MacLeod et al, 1977;Sellers et al, 1980). If moderate doses (10 to 20 mg) of diazepam are given well before ethanol (0.8 to 1 g/kg), the rapid peak concentration of plasma diazepam (Ellinwood et al, 1983) may not coincide with rising BACs and inebriation, and the combined effect could be less than expected.…”

“…It has been documented that in experimental conditions ingestion of ethanol (0.5 to 1 g/kg of body weight) increases chemically assayed plasma diazepam concentrations without improving its enteral absorption (Divoll & Greenblatt, 1981;MacLeod et al, 1977) which is rapid and complete without additives. In fact, ethanol may slightly retard the diazepam absorption (Divoll & Greenblatt, 1981;Sellers & Holloway, 1978).…”

Diazepam pharmacokinetics after intravenous administration in alcohol withdrawal.

“…The coefficient of variation of duplicate determinations was less than 2%. Diazepam and desmethyldiazepam concentrations were determined by gas chromatographic method (MacLeod et al, 1977). Pharmacokinetic analyses were conducted in two ways.…”