Clinical Pharmacokinetics and Pharmacodynamics of Dexmedetomidine

Clinical Pharmacokinetics, Jan 2017

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.

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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)


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Weerink, Maud A. S., Struys, Michel M. R. F., Hannivoort, Laura N., Barends, Clemens R. M., Absalom, Anthony R., Colin, Pieter. Clinical Pharmacokinetics and Pharmacodynamics of Dexmedetomidine, Clinical Pharmacokinetics, 2017, pp. 893-913, Volume 56, Issue 8, DOI: 10.1007/s40262-017-0507-7