Dexmedetomidine

Dexmedetomidine, sold under the trade name Precedex among others, is a medication used for sedation.[1] It is also used to treat acute agitation associated with schizophrenia or bipolar I or II disorder.[2]

Dexmedetomidine
Clinical data
Trade namesPrecedex, Dexdor, Igalmi, others
AHFS/Drugs.comMonograph
License data
Pregnancy
category
  • AU: B1
Routes of
administration		Intravenous, transmucosal, intranasal, sublingual
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • US: ℞-only [1][2]
  • EU: Rx-only
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Protein binding94% (mostly albumin)[1]
MetabolismNear complete hepatic metabolism to inactive metabolites
Elimination half-life2–4 hours[3]
ExcretionUrine
Identifiers
IUPAC name
  • (S)-4-[1-(2,3-Dimethylphenyl)ethyl]-3H-imidazole
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.119.391
Chemical and physical data
FormulaC13H16N2
Molar mass200.285 g·mol−1
3D model (JSmol)
SMILES
  • Cc2cccc([C@H](C)c1c[nH]cn1)c2C
InChI
  • InChI=1S/C13H16N2/c1-9-5-4-6-12(10(9)2)11(3)13-7-14-8-15-13/h4-8,11H,1-3H3,(H,14,15)/t11-/m0/s1 Y
  • Key:CUHVIMMYOGQXCV-NSHDSACASA-N Y
  (verify)

Similar to clonidine, it is a sympatholytic drug that acts as an agonist of α2-adrenergic receptors in certain parts of the brain.[4] Veterinarians use dexmedetomidine for similar purposes in treating cats, dogs, and horses.[5][6] It was developed by Orion Pharma.

Medical uses

Intensive care unit sedation

Studies suggest dexmedetomidine for sedation in mechanically ventilated adults may reduce time to extubation and ICU stay.[7][8]

Compared with other sedatives, some studies suggest dexmedetomidine may be associated with less delirium.[9] However, this finding is not consistent across multiple studies.[8] At the very least, when aggregating many study results together, use of dexmedetomidine appears to be associated with less neurocognitive dysfunction compared to other sedatives.[10] Whether this observation has a beneficial psychological impact is unclear.[9] From an economic perspective, dexmedetomidine is associated with lower ICU costs, largely due to a shorter time to extubation.[11]

Procedural sedation

Dexmedetomidine can also be used for procedural sedation such as during colonoscopy.[12] It can be used as an adjunct with other sedatives like benzodiazepines, opioids, and propofol to enhance sedation and help maintain hemodynamic stability by decreasing the requirement of other sedatives.[13][14] Dexmedetomidine is also used for procedural sedation in children.[15]

It can be used for sedation required for awake fibreoptic nasal intubation in patients with a difficult airway.[16]

Other

Dexmedetomidine may be useful for the treatment of the negative cardiovascular effects of acute amphetamines and cocaine intoxication and overdose.[17][18] Dexmedetomidine has also been used as an adjunct to neuroaxial anesthesia for lower limb procedures.[19]

In 2022 it was approved by the FDA for the treatment of agitation in schizophrenia and bipolar disorder.[20]

Side effects

There is no absolute contraindication to the use of dexmedetomidine. It has a biphasic effect on blood pressure with lower readings at lower drug concentrations and higher readings at higher concentrations.[21]

Interactions

Dexmedetomidine may enhance the effects of other sedatives and anesthetics when co-administered. Similarly, drugs that lower blood pressure and heart rate, such as beta blockers, may also have enhanced effects when co-administered with dexmedetomidine.[22]

Pharmacology

Pharmacodynamics

Dexmedetomidine is a highly selective α2-adrenergic agonist. It possesses an α2:α1 selectivity ratio of 1620:1, making it eight times more selective for the α2-receptor than clonidine.[23] Unlike opioids and other sedatives such as propofol, dexmedetomidine is able to achieve its effects without causing respiratory depression. Dexmedetomidine induces sedation by decreasing activity of noradrenergic neurons in the locus ceruleus in the brain stem, thereby increasing the downstream activity of inhibitory gamma-aminobutyric acid (GABA) neurons in the ventrolateral preoptic nucleus.[24] In contrast, other sedatives like propofol and benzodiazepines directly increase activity of gamma-aminobutyric acid neurons.[25] Through action on this endogenous sleep-promoting pathway the sedation produced by dexmedetomidine more closely mirrors natural sleep (specifically stage 2 non-rapid eye movement sleep), as demonstrated by EEG studies.[24][26] As such, dexmedetomidine provides less amnesia than benzodiazepines.[25] Dexmedetomidine also has analgesic effects at the spinal cord level and other supraspinal sites.[25]

Pharmacokinetics

Intravenous dexmedetomidine exhibits linear pharmacokinetics with a rapid distribution half-life of approximately 6 minutes in healthy volunteers, and a longer and more variable distribution half-life in ICU patients.[27] The terminal elimination half-life of intravenous dexmedetomidine ranged 2.1 to 3.1 hours in healthy adults and 2.2 to 3.7 hours in ICU patients.[3] Plasma protein binding of dexmedetomidine is about 94% (mostly albumin).[1]

Dexmedetomidine is metabolized by the liver, largely by glucuronidation (34%) as well as by oxidation via CYP2A6 and other Cytochrome P450 enzymes.[3] As such, it should be used with caution in people with liver disease.[22]

The majority of metabolized dexmedetomidine is excreted in the urine (~95%).

It can be absorbed sublingually.[20]

History

Dexmedetomidine was approved in 1999 by the US Food and Drug Administration (FDA) as a short-term sedative and analgesic (<24 hours) for critically ill or injured people on mechanical ventilation in the intensive care unit (ICU). The rationale for its short-term use was due to concerns over withdrawal side effects such as rebound high blood pressure. These effects have not been consistently observed in research studies, however.[28]

Veterinary use

Dexmedetomidine, under the trade name Dexdomitor (Orion Corporation), was approved in the European Union in for use in cats and dogs in 2002, for sedation and induction of general anesthesia.[29] The FDA approved dexmedetomidine for use in dogs in 2006 and cats in 2007.[30]

In 2015, the European Medicines Agency and the FDA approved an oromucosal gel form of dexmedetomidine marketed as Sileo (Zoetis) for use in dogs for relief of noise aversion.[31][32]

References
  1. "Precedex- dexmedetomidine hydrochloride injection, solution". DailyMed. 2 March 2022. Archived from the original on 8 April 2022. Retrieved 8 April 2022.
  2. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/215390s000lbl.pdf Archived 2022-04-28 at the Wayback Machine
  3. Weerink MA, Struys MM, Hannivoort LN, Barends CR, Absalom AR, Colin P (August 2017). "Clinical Pharmacokinetics and Pharmacodynamics of Dexmedetomidine". Clinical Pharmacokinetics. 56 (8): 893–913. doi:10.1007/s40262-017-0507-7. PMC 5511603. PMID 28105598.
  4. Cormack JR, Orme RM, Costello TG (May 2005). "The role of alpha2-agonists in neurosurgery". Journal of Clinical Neuroscience. 12 (4): 375–378. doi:10.1016/j.jocn.2004.06.008. PMID 15925765. S2CID 79899746.
  5. Marly-Voquer C, Schwarzwald CC, Bettschart-Wolfensberger R (January 2016). "The use of dexmedetomidine continuous rate infusion for horses undergoing transvenous electrical cardioversion--A case series". The Canadian Veterinary Journal. 57 (1): 70–75. PMC 4677613. PMID 26740702.
  6. "Dexdomitor". Archived from the original on 2013-09-27. Retrieved 2013-08-02.
  7. Pasin L, Greco T, Feltracco P, Vittorio A, Neto CN, Cabrini L, et al. (2013-01-01). "Dexmedetomidine as a sedative agent in critically ill patients: a meta-analysis of randomized controlled trials". PLOS ONE. 8 (12): e82913. Bibcode:2013PLoSO...882913P. doi:10.1371/journal.pone.0082913. PMC 3877008. PMID 24391726.
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  9. MacLaren R, Preslaski CR, Mueller SW, Kiser TH, Fish DN, Lavelle JC, Malkoski SP (March 2015). "A randomized, double-blind pilot study of dexmedetomidine versus midazolam for intensive care unit sedation: patient recall of their experiences and short-term psychological outcomes". Journal of Intensive Care Medicine. 30 (3): 167–175. doi:10.1177/0885066613510874. PMID 24227448. S2CID 25036525.
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  16. He XY, Cao JP, He Q, Shi XY (January 2014). "Dexmedetomidine for the management of awake fibreoptic intubation". The Cochrane Database of Systematic Reviews. 2020 (1): CD009798. doi:10.1002/14651858.cd009798.pub2. PMC 8095023. PMID 24442817.
  17. Menon DV, Wang Z, Fadel PJ, Arbique D, Leonard D, Li JL, et al. (August 2007). "Central sympatholysis as a novel countermeasure for cocaine-induced sympathetic activation and vasoconstriction in humans". Journal of the American College of Cardiology. 50 (7): 626–633. doi:10.1016/j.jacc.2007.03.060. PMID 17692748.
  18. Richards JR, Albertson TE, Derlet RW, Lange RA, Olson KR, Horowitz BZ (May 2015). "Treatment of toxicity from amphetamines, related derivatives, and analogues: a systematic clinical review". Drug and Alcohol Dependence. 150: 1–13. doi:10.1016/j.drugalcdep.2015.01.040. PMID 25724076.
  19. Mahendru V, Tewari A, Katyal S, Grewal A, Singh MR, Katyal R (October 2013). "A comparison of intrathecal dexmedetomidine, clonidine, and fentanyl as adjuvants to hyperbaric bupivacaine for lower limb surgery: A double blind controlled study". Journal of Anaesthesiology Clinical Pharmacology. 29 (4): 496–502. doi:10.4103/0970-9185.119151. PMC 3819844. PMID 24249987.
  20. "FDA Okays First Sublingual Med for Agitation in Schizophrenia, BD". Medscape. Archived from the original on 2022-04-11. Retrieved 2022-04-11.
  21. Ebert TJ, Hall JE, Barney JA, Uhrich TD, Colinco MD (August 2000). "The effects of increasing plasma concentrations of dexmedetomidine in humans". Anesthesiology. 93 (2): 382–394. doi:10.1097/00000542-200008000-00016. PMID 10910487. S2CID 20795504.
  22. Keating GM (July 2015). "Dexmedetomidine: A Review of Its Use for Sedation in the Intensive Care Setting". Drugs. 75 (10): 1119–1130. doi:10.1007/s40265-015-0419-5. PMID 26063213. S2CID 20447722.
  23. Scott-Warren VL, Sebastian J (2016). "Dexmedetomidine: its use in intensive care medicine and anaesthesia". BJA Education. 16 (7): 242–246. doi:10.1093/bjaed/mkv047. ISSN 2058-5349.
  24. Nelson LE, Lu J, Guo T, Saper CB, Franks NP, Maze M (February 2003). "The alpha2-adrenoceptor agonist dexmedetomidine converges on an endogenous sleep-promoting pathway to exert its sedative effects". Anesthesiology. 98 (2): 428–436. doi:10.1097/00000542-200302000-00024. PMID 12552203. S2CID 5034487.
  25. Panzer O, Moitra V, Sladen RN (July 2009). "Pharmacology of sedative-analgesic agents: dexmedetomidine, remifentanil, ketamine, volatile anesthetics, and the role of peripheral mu antagonists". Critical Care Clinics. 25 (3): 451–69, vii. doi:10.1016/j.ccc.2009.04.004. PMID 19576524.
  26. Huupponen E, Maksimow A, Lapinlampi P, Särkelä M, Saastamoinen A, Snapir A, et al. (February 2008). "Electroencephalogram spindle activity during dexmedetomidine sedation and physiological sleep". Acta Anaesthesiologica Scandinavica. 52 (2): 289–294. doi:10.1111/j.1399-6576.2007.01537.x. PMID 18005372. S2CID 34923432.
  27. Venn RM, Karol MD, Grounds RM (May 2002). "Pharmacokinetics of dexmedetomidine infusions for sedation of postoperative patients requiring intensive caret". British Journal of Anaesthesia. 88 (5): 669–675. doi:10.1093/bja/88.5.669. PMID 12067004.
  28. Shehabi Y, Ruettimann U, Adamson H, Innes R, Ickeringill M (December 2004). "Dexmedetomidine infusion for more than 24 hours in critically ill patients: sedative and cardiovascular effects". Intensive Care Medicine. 30 (12): 2188–2196. doi:10.1007/s00134-004-2417-z. PMID 15338124. S2CID 26258023.
  29. Gozalo-Marcilla M, Gasthuys F, Luna SP, Schauvliege S (April 2018). "Is there a place for dexmedetomidine in equine anaesthesia and analgesia? A systematic review (2005-2017)". Journal of Veterinary Pharmacology and Therapeutics. 41 (2): 205–217. doi:10.1111/jvp.12474. PMID 29226340. S2CID 3691570.
  30. "Freedom of Information Summary | Supplemental New Animal Drug Application | NADA 141-267 | Dexdomitor". Food and Drug Administration. 16 August 2010. Archived from the original on 2021-08-28. Retrieved 2018-07-01.
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