Relationship between plasma concentration and effect of midazolam after oral and intravenous administration.

Abstract

1 In a double-blind, cross-over study in six healthy volunteers, the effects of different oral doses of midazolam (10, 20 and 40 mg), or 0.15 mg kg-'midazolam administered intravenously and of placebo were investigated. Plasma concentrations of midazolam and of its active a-hydroxy metabolite were measured at the same time. 2 The effect was assessed using objective and subjective methods (reaction time, tracing test, subjects' self-assessment and investigator's subjective assessment). 3 The respective time courses of the plasma concentration and of the effect (reaction time, number of errors in the tracing test) were almost identical. Peak plasma levels and maximum effects were attained within 30 min. In general, the effect after intravenous injection of 0.15 mg kg-' and after an oral dose of 10 mg midazolam lasted for 2 h following administration and its duration was doubled (i.e. to 4 h) after the 20 mg oral dose. Between the logarithm of the plasma concentration and the effect, there is a sigmoidal relationship that is virtually time independent. 4 Particularly in the first few hours after oral administration the effect is intensified by the a-hydroxy metabolite of midazolam which is formed by first-pass metabolism. 5 At identical plasma concentrations of midazolam, the oral dose produced more marked effects than did the intravenous administration. 6 Correlation of the measured effects with the total (midazolam + a-hydroxy midazolam) plasma concentration reveals a closer sigmoidal relationship.

Midazolam, a New More Potent Benzodiazepine, Compared With Diazepam as Sedative During Spinal Analgesia, a Randomised Double Blind Study

“…This is consistent with published evidence for both the drugs [4,6]. Impaired cognitive response with diazepam and midazolam may be related to metabolites [7]. Three midazolam metabolites have been detected; 1-hydroxymethyl midazolam, 4-hydroxy midazolam which are pharmacologically active.…”

“…Their potencies at equivalent molar concentrations appear to be substantially less than that of midzolam . Cresvoiseir and others [7] Spinal anaesthesia may decrease the mean systolic blood pressure, degree of decrease depends on the level of dermatome blockade. Midazolam [8] decreases systemic vascular resistance, cardiac output, stroke index and cardiac index.…”

Rate of change of blood concentrations is a major determinant of the pharmacodynamics of midazolam in rats

“…However, di erences in metabolic pathways between the two species, rat and man, and the interference of di erent (inter)active metabolites must be considered too. In contrast to the rat, in man metabolites of midazolam were found to contribute to the pharmacological e ects of the drug (Crevoisier et al, 1983;Mandema et al, 1992d). It has been suggested that the apparent acute tolerance to the actions of diazepam in man is due to redistribution of the compound from the central nervous system to the peripheral tissues (Greenblatt & Shader, 1986).…”

Hypnotic efficacy and clinical safety of midazolam in shift‐workers.

“…These findings are in agreement with the assessment by the subjects (Table 3 The assessment of psychological profile revealed marked inter-subject differences in handling frustration, personality structure. affective behaviour, and (Ziegler et al, 1981;Crevoisier et al, 1983 Nicholson & Stone (1978a,b) found no effect on sleep latency for either 15 mg or 45 mg oxazepam.…”