INTRANASAL ADMINISTRATION OF MIDAZOLAM - PHARMACOKINETIC AND PHARMACODYNAMIC PROPERTIES AND SEDATIVE POTENTIAL

This study investigated the pharmacodynamic effects and sedative poten tial of midazolam administered by the intranasal route to adult volunt eers. A double-blind, randomized, controlled study was carried out on seventeen healthy, male volunteers to study plasma level changes, seda tive effects and variations in vital signs following intranasal admini stration of 0.2 mg/kg and 0.3 mg/kg doses of midazolam. Eight subjects received 0.2 mg/kg midazolam, seven received 0.3 mg/kg. Each subject rested for 15-20 minutes after placement of vital sign monitors and ve nipuncture needles before administration of midazolam. Behavior during the rest period was designated as the control so that each subject ac ted as his own control. Each subject's behavior was assessed on a scal e of 1 (asleep) to 8 (excited). Plasma concentrations of midazolam wer e analyzed using venous blood samples from each of three randomly sele cted subjects for each of the mio doses. Vital signs, monitored contin uously, included electrocardiogram, heart rate, blood pressure, respir atory rate and oxygen saturation (SPO2). Plasma concentration of midaz olam in both groups maintained adequate sedation levels with each grou p sustaining favorable sedation conditions from 15-20 minutes to 55-60 minutes. Individual variations of midazolam plasma concentration with in the 0.3 mg/kg group were greater than those of the 0.2 mg/kg group. Normal vital sign variations due to the nasal instillation of midazol am were observed in both groups. Some minor respiratory depression was observed in the 0.2 mg/kg group. One instance of severe respiratory d epression was observed in the higher dose group. Although both doses o f midazolam were effective, no benefit was observed using a dose of 0. 3 mg/kg. Indeed, a 0.3 mg/kg intranasal dose of midazolam may actually produce severe respiratory depression.