Clinical Pharmacokinetics and Pharmacodynamics of Dexmedetomidine
Clin Pharmacokinet
Clinical Pharmacokinetics and Pharmacodynamics of Dexmedetomidine
Maud A. S. Weerink 0 1 2
Michel M. R. F. Struys 0 1 2
Laura N. Hannivoort 0 1 2
Clemens R. M. Barends 0 1 2
Anthony R. Absalom 0 1 2
Pieter Colin 0 1 2
0 Department of Anesthesiology, University of Groningen, University Medical Center Groningen , P.O. Box 30001, 9700 RB Groningen , The Netherlands
1 Department of Bioanalysis, Faculty of Pharmaceutical Sciences, Ghent University , Ghent , Belgium
2 Department of Anesthesia and Peri-operative Medicine, Ghent University , Ghent , Belgium
Dexmedetomidine is an a2-adrenoceptor agonist with sedative, anxiolytic, sympatholytic, and analgesicsparing effects, and minimal depression of respiratory function. It is potent and highly selective for a2-receptors with an a2:a1 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 a2-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.
Key Points
Pharmacokinetic studies have shown that body size
and hepatic function have a significant influence on
the pharmacokinetic profile of dexmedetomidine.
Plasma albumin and cardiac output are suggested to
have an impact on the apparent volume of
distribution and clearance. Studies of the influence of
other patient characteristics have produced
inconclusive results.
Unlike sedative drugs such as propofol and the
benzodiazepines, dexmedetomidine does not act at
the gamma-aminobutyric acid (GABA) receptors. It
induces sedation through activation of a2-receptors
in the locus coeruleus and induces a state mimicking
natural sleep. Whilst sedated, respiration is
minimally affected and patients remain rousable.
Side effects are mainly hemodynamic and include
hypertension, hypotension, and bradycardia as a
result of vasoconstriction, sympatholysis, and
baroreflex-mediated parasympathetic activation.
Further research is needed to investigate the clinical
feasibility of different promising off-label
indications, such as use in the pediatric and geriatric
population, intranasal dexmedetomidine
administration, its use as an adjuvant to prolong
peripheral or spinal nerve blocks, and the potential of
dexmedetomidine to reduce opioid consumption.
1 Introduction
Dexmedetomidine is a selective and potent
a2-adrenoceptor agonist that is used for its anxiolytic, sedative, and
analgesic properties [
1
]. It has been registered in USA
since 1999 (Precedex ; Hospira, Lake Forrest, IL, USA).
Originally, it was only approved for intravenous (IV)
administration for sedation of mechanically ventilated
adult patients in the intensive care unit (ICU), for up to
24 h [
2
]. In 2008, an additional indication was granted in
USA, which allowed the use of dexmedetomidine for the
sedation of non-intubated patients prior to and/or during
surgical and other procedures. Since 2011,
dexmedetomidine has been approved in the European Union for the
sedation of adult ICU patients requiring a sedation level at
which patients remain rousable in response to verbal
stimulation (Dexdor ; Orion Corporation, Espoo, Finland)
[
3
]. On a more global perspective, differences in approved
indications of dexmedetomidine exist. In addition to this,
off-label use is frequently reported in the literature.
Compared with clonidine, an a2-agonist that has been
used for several decades, dexmedetomidine has a greater
selectivity for a2-receptors (a2:a1 ratio of 1620:1 vs.
220:1) [
4
]. As central a1-adrenoceptor activation
counteracts the sedative a2 effec (...truncated)