Clinical Pharmacokinetics and Pharmacodynamics of Dexmedetomidine

Abstract

Dexmedetomidine is an α2-adrenoceptor agonist with sedative, anxiolytic, sympatholytic, and analgesic-sparing effects, and minimal depression of respiratory function. It is potent and highly selective for α2-receptors with an α2:α1 ratio of 1620:1. Hemodynamic effects, which include transient hypertension, bradycardia, and hypotension, result from the drug’s peripheral vasoconstrictive and sympatholytic properties. Dexmedetomidine exerts its hypnotic action through activation of central pre- and postsynaptic α2-receptors in the locus coeruleus, thereby inducting a state of unconsciousness similar to natural sleep, with the unique aspect that patients remain easily rousable and cooperative. Dexmedetomidine is rapidly distributed and is mainly hepatically metabolized into inactive metabolites by glucuronidation and hydroxylation. A high inter-individual variability in dexmedetomidine pharmacokinetics has been described, especially in the intensive care unit population. In recent years, multiple pharmacokinetic non-compartmental analyses as well as population pharmacokinetic studies have been performed. Body size, hepatic impairment, and presumably plasma albumin and cardiac output have a significant impact on dexmedetomidine pharmacokinetics. Results regarding other covariates remain inconclusive and warrant further research. Although initially approved for intravenous use for up to 24 h in the adult intensive care unit population only, applications of dexmedetomidine in clinical practice have been widened over the past few years. Procedural sedation with dexmedetomidine was additionally approved by the US Food and Drug Administration in 2003 and dexmedetomidine has appeared useful in multiple off-label applications such as pediatric sedation, intranasal or buccal administration, and use as an adjuvant to local analgesia techniques.

Development of a Model of Hemispheric Hypodensity (“Big Black Brain”)

“…The anesthetic protocol in Experimental Phase 3 included dexmedetomidine, which causes a transient increase in blood pressure, 44 which may have explained the improved blood pressure. Although a series of children with AHT who developed HH more frequently required vasopressors, 3 low blood pressure may not be a key driver of the pathophysiology.…”

“…46 The amount of dexmedetomidine we found necessary to induce anesthesia in piglets was 10 to 100 times greater than required in children. 44,47 Chlorpromazine, used to treat psychotic mania, was added to the combination. After sedation was achieved, rocuronium was given to induce muscle relaxation (no more frequently than every 45 min).…”

Anestesia loco regional más sedación con dexmedetomidina para cirugía de Mohs con reconstrucción

“…A pesar de que se ha sugerido un efecto analgésico (inferior al de los opioides), mediado por receptores alfa-2 a nivel central, la analgesia inducida por la dexmedetomidina no es clara y puede estar explicada en relación con la disminución o alteracion en la percepción de la ansiedad (15,16,26).…”

“…El uso de la dexmedetomidina se ha asociado en ocasiones a eventos adversos como bradicardia, hipertension, hipotensión e inclusive paro cardíaco, por lo que se debe tener precaución en pacientes que dependen de una adecuada frecuencia cardiaca para mantener gasto cardiaco, como aquellos con trastornos de la conduccion auriculo-ventricular, pacientes hipovolémicos u otros problemas cardiacos (15,23,27). …”

“…Medicamentos como la dexmedetomidina han demostrado una adecuada respuesta clínica y baja tasa de complicaciones respiratorias, así como menor incidencia de delirium (10)(11)(12)(13)(14) A pesar de los beneficios de dexmedetomidina para sedación, también se ha asociado a eventos adversos graves como bradicardia severa, hipotensión e incluso, paro cardiaco (15)(16)(17). Su uso en diferentes procedimientos, asociados a diferentes modalidades de anestesia tambien se ha visto relacionado con episodios de bradicardia, que requieren de manejo con atropina para la prevención de complicaciones hemodinámicas mas severas (18,19).…”