Pharmacokinetics and Pharmacodynamics of Midazolam After Intranasal Administration

Abstract

This study aimed to characterize the pharmacokinetics and pharmacodynamics of midazolam after intranasal administration to healthy volunteers. Eight participants were given 0.25 mg/kg intranasally and 2 mg intravenously in a randomized, crossover fashion. Blood samples for determination of plasma concentrations of midazolam and measures of cognitive function (using the digit symbol substitution test) were obtained at baseline and 5, 10, 20, 30, 45, 60, 90, 120, 180, 240, and 360 minutes after administration of study medications. Plasma samples were analyzed by gas chromatography (% coefficient of variation < 10%). Pharmacokinetic data were fitted using iterative two-stage analysis to a two-compartment model. Pharmacodynamic data were fitted by a baseline subtraction Hill-type model. The mean (SD) for total clearance, distributional clearance, volume of distribution in the central compartment, volume of distribution in the peripheral compartment, absorption rate constant, bioavailability, and half-life were 0.57 (0.26) L/hr/kg, 0.31 (0.29) L/hr/kg, 0.27 (0.14) L/kg, 0.67 (0.11) L/kg, 2.46 (1.72) hr-1, 50% (13%), and 3.1 (0.84) hours, respectively. The mean (SD) for the concentration at which the effect is half maximal (EC50) and the maximal effect or the maximal change in effect measure from baseline (Emax) were 63.1 (21.2) ng/mL and 52.8 (21.1) correct substitutions, respectively. After intranasal administration, midazolam concentrations rapidly achieve values considered sufficient to induce conscious sedation and produce predictable changes in digit symbol substitution score.

Efeitos anestésicos da administração intranasal ou intramuscular de cetamina S+ e midazolam em pomba-rola (Streptotelia sp.)

“…A mucosa intranasal é uma via com alta permeabilidade para a absorção de anestésicos, com rápida e completa absorção no homem (Robertson & Eberhart 1994, Bjorkmann et al 1997, Burstein et al 1997. O local exato de absorção da via intranasal não é totalmente elucidado, mas devido à grande vascularização desta região, os fármacos atingem rapidamente a circulação sistêmica.…”

“…Alguns possíveis efeitos adversos da administração intranasal em aves incluem aerossaculite devido a contaminação dos sacos aéreos craniais devido a flora presente na cavidade nasal das aves A biodisponibilidade média do midazolam após administração intranasal varia de 76+12%, sendo a concentração sérica efetiva alcançada em menos de 10 minutos em crianças (Haschke et al 2010). Outros estudos revelaram menor biodisponibilidade em humanos (55-57%), entretanto, sendo maior do que as vias oral ou retal, pois não há o metabolismo de primeira passagem (Wallbergh et al 1991, Burstein et al 1997.…”

Intranasal Delivery of Antiepileptic Medications for Treatment of Seizures

“…[25][26][27][28][29][30][31][32][33][34] The main considerations from these data might be whether maximum plasma concentrations represented by C max are within ranges known to produce pharmacologic effects, and the second consideration is whether the concentrations are achieved rapidly enough to be appropriate for treating a seizure. Well-designed nasal preparations may demonstrate a pharmacokinetic profile in which the rate and extent of drug exposure is superior to intramuscular injection and approximates IV infusion (FIG.…”

Intranasale Midazolamapplikation zur Anxiolyse bei der Magnetresonanztomographie

“…Wegen eines hohen First-Pass-Effektes in der Leber ist die Wirkung bei oralen und rektalen Applikationsformen unzuverlässig (Bioverfügbarkeit 30-70%). Als intranasal appliziertes Spray wird die Substanz rasch und fast vollständig (83%) durch die Schleimhaut direkt in den systemischen Kreislauf resorbiert und die maximale Wirkung in wenigen Minuten erreicht [2,3,18].…”