Pharmacokinetics of midazolam given as an intranasal spray to adult surgical patients

Abstract

The aim of this study was to determine the bioavailability and absorption kinetics of midazolam given as an intranasal (i.n.) spray. In addition, plasma concentrations of the active metabolite, 1-hydroxymidazolam, were measured to give an indication of enteral absorption. An i.v. and i.n. midazolam dose were given in a crossover study to 14 adult surgical patients. Individual uptake profiles of i.n. midazolam were estimated by numerical deconvolution. After an i.n. dose of 0.15 mg kg-1, maximum arterial plasma concentrations were 192 (SD 48) micrograms litre-1 at 14 (2) min. Uptake of midazolam was rapid and bioavailability was 83 (15)%. Formation of the 1-hydroxy metabolite after i.n. administration did not exceed that after the i.v. dose. This demonstrates that under optimal conditions absorption of midazolam via the nasal mucosa was virtually complete. In this case little midazolam was swallowed and subjected to first-pass metabolism in the liver and therefore pharmacologically important amounts of active metabolite were not produced. Routinely administering i.n. midazolam under the assumption that the bioavailability is approximately 50% (as reported previously in the literature) may lead to overdosing in some patients.

Preoperative Oral Sedation with Midazolam and Paracetamol vs Sedation Nasally with Midazolam and Ketamine for Children Scheduled for Dental Treatment

“…The premedication must be acceptable, and atraumatic route of administration should be available [16] [17] [18].…”

Intranasal Delivery of Two Benzodiazepines, Midazolam and Diazepam, by a Microemulsion System

“…The interest in intranasal drug delivery arises from the unique advantages presented by the nasal cavity such as: 1) A large surface area available for drug deposition and absorption, 2) The nasal epithelium is thin and highly vascularized, 3) Absorbed substances are transported directly into the systemic circulation thereby avoiding the first pass metabolic effect, and 4) In some cases, drug can be absorbed directly into the CNS by passing the tight blood brain barrier [19]. Intranasal midazolam has already been explored during the last decade and a number of clinical works revealed the potential of its administration via the nasal route [9][10][11]17,[20][21][22][23]. Nevertheless, there are still issues waiting to be resolved.…”

EFEITOS ANESTÉSICOS DA ADMINISTRAÇÃO INTRANASAL OU INTRAMUSCULAR DA ASSOCIAÇÃO DE MIDAZOLAM E CETAMINA RACÊMICA OU S+ EM PERIQUITO AUSTRALIANO (Melopsittacus undulatus)

“…Além disso, a cetamina racêmica apresenta menor potência anestésica quando comparada à cetamina S+ (16,20) , justificando o maior tempo de latência no grupo IMR. A via intranasal apresenta rápida absorção (21) , justificando diferença observada nos tempos de decúbito e tempo de anestesia, sendo que os grupos INS e INR apresentaram tempos menores que nos grupos IMS e IMR. Bigham & Moghaddam (13) relataram que a via intranasal proporciona rápida biotransformação, resultando em efeitos de curta duração em aves.…”

“…O maior tempo de recuperação observado nas aves em que se administrou cetamina S+ pode sugerir que esta formulação apresente maior potência anestésica em periquitos, assim como descrito em ratos (16) e cães (17) . Avaliando o tempo de recuperação de INS e IMR, a diferença observada pode ser explicada pela maior potência da cetamina S+ que, mesmo apresentando maior biotransformação pela via IN (21) , pode ter resultado em concentrações sub-anestésicas de cetamina que não proporcionaram anestesia porém acarretaram maior tempo de recuperação, sendo necessários mais estudos com cetamina S+ em periquitos para confirmar esta teoria. Os resultados de tempo de recuperação divergem dos observados nos estudos de Beier et al (14) e Bitencourt et al (15) , os quais encontraram menor tempo de recuperação quando utilizaram a via IN em pombas e papagaios comparada à via IM.…”