Dexmedetomidine Explained

Watchedfields:changed
Verifiedrevid:458436659
Tradename:Precedex, Dexdor, Igalmi, others
Dailymedid:Dexmedetomidine
Pregnancy Au:B1
Routes Of Administration:Intravenous, transmucosal, intranasal, sublingual
Atc Prefix:N05
Atc Suffix:CM18
Legal Au:S4
Legal Au Comment:[1]
Legal Br:C1
Legal Br Comment:[2]
Legal Us:Rx-only
Legal Us Comment:[3] [4]
Legal Eu:Rx-only
Legal Eu Comment:[5]
Legal Status:Rx-only
Protein Bound:94% (mostly albumin)
Metabolism:Near complete hepatic metabolism to inactive metabolites
Elimination Half-Life:2–4 hours
Excretion:Urine
Index2 Label:as HCl
Cas Number:113775-47-6
Pubchem:68602
Drugbank:DB00633
Chemspiderid:4470605
Unii:67VB76HONO
Kegg:D00514
Kegg2:D01205
Chebi:4466
Chembl:778
Iupac Name:(S)-4-[1-(2,3-Dimethylphenyl)ethyl]-3H-imidazole
C:13
H:16
N:2
Smiles:Cc2cccc([C@H](C)c1c[nH]cn1)c2C
Stdinchi: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
Stdinchikey:CUHVIMMYOGQXCV-NSHDSACASA-N

Dexmedetomidine, sold under the trade name Precedex among others, is a drug used in humans for sedation. Veterinarians use dexmedetomidine for similar purposes in treating cats, dogs, and horses.[6] [7] It is also used in humans to treat acute agitation associated with schizophrenia or bipolar I or II disorder.

Similar to clonidine, it is a sympatholytic drug that acts as an agonist of α2-adrenergic receptors in certain parts of the brain. 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.[8] [9]

Compared with other sedatives, some studies suggest dexmedetomidine may be associated with less delirium.[10] However, this finding is not consistent across multiple studies. 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.[11] Whether this observation has a beneficial psychological impact is unclear.[10] From an economic perspective, dexmedetomidine is associated with lower ICU costs, largely due to a shorter time to extubation.[12]

Procedural sedation

Dexmedetomidine can also be used for procedural sedation such as during colonoscopy.[13] 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.[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]

Adjunct in general anesthesia

It has also been used as an adjunct infusion during general anesthesia. In this application, it has been shown to decrease post-operative delirium, pain, nausea and opioid use.[17] [18] [19] [20]

Other

Dexmedetomidine may be useful for the treatment of the negative cardiovascular effects of acute amphetamines and cocaine intoxication and overdose.[21] Dexmedetomidine has also been used as an adjunct to neuroaxial anesthesia for lower limb procedures.[22] It has been successfully used to treat opioid withdrawal symptoms.[23]

In 2022 it was approved by the FDA for the treatment of agitation in schizophrenia and bipolar disorder.[24]

Side effects

There are no known 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.[25] Common side effects include: hypotension, hypertension, with slight decreases in heart rate, arrhythmias, and hypoxia.[26] [27] Toxic doses may cause first-degree or second-degree atrioventricular block. These adverse events usually occur briefly after administering a loading dose of the drug. Thus, adverse effects may be reduced by omitting a loading dose.[27]

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.

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.[28] 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.[29] In contrast, other sedatives like propofol and benzodiazepines directly increase activity of gamma-aminobutyric acid neurons.[30] 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.[31] As such, dexmedetomidine provides less amnesia than benzodiazepines.[30] Dexmedetomidine also has analgesic effects at the spinal cord level and other supraspinal sites.[30]

SiteKi (nM)SpeciesRef
α15Human[32]
α2A0.0150–2.1Human[33]
α2BHuman
α2C31Human[34]

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.[35] 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.[36] Plasma protein binding of dexmedetomidine is about 94% (mostly albumin).

Dexmedetomidine is metabolized by the liver, largely by glucuronidation (34%) as well as by oxidation via CYP2A6 and other Cytochrome P450 enzymes. As such, it should be used with caution in people with liver disease.[37]

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

It can be absorbed sublingually.

History

Dexmedetomidine was developed by Orion Pharma and is marketed under the names dexdor® and Precedex®; in 1999 the US Food and Drug Administration (FDA) approved it as a short-term sedative and analgesic (<24 hours) for critically ill or injured people on mechanical ventilation in the intensive care unit. 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.[38]

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.[39] The FDA approved dexmedetomidine for use in dogs in 2006 and cats in 2007.[40]

In 2015, the European Medicines Agency and the FDA approved an oromucosal gel form of dexmedetomidine marketed as Sileo by pharmaceutical company Zoetis for use in dogs for relief of noise aversion.[41] [42]

Notes and References

  1. Web site: DEXMEDETOMIDINE FRESENIUS (Fresenius Kabi Australia Pty Ltd) . . https://web.archive.org/web/20230318045443/https://www.tga.gov.au/resources/prescription-medicines-registrations/dexmedetomidine-fresenius-fresenius-kabi-australia-pty-ltd . 2023-03-18 . live.
  2. Web site: Anvisa . Brazilian Health Regulatory Agency . 2023-03-31 . RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial . Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control. live . https://web.archive.org/web/20230803143925/https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 . 2023-08-03 . 2023-08-16 . . pt-BR . 2023-04-04.
  3. Web site: Precedex- dexmedetomidine hydrochloride injection, solution . DailyMed . 2 March 2022 . 8 April 2022 . 8 April 2022 . https://web.archive.org/web/20220408230944/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=4419162d-81d4-49bd-96de-1729440bdb74 . live .
  4. Web site: Igalmi- dexmedetomidine film . DailyMed . 14 December 2022 . 21 January 2023.
  5. Web site: Sileo EPAR . European Medicines Agency . 7 July 2015 . 21 June 2024.
  6. Marly-Voquer C, Schwarzwald CC, Bettschart-Wolfensberger R . The use of dexmedetomidine continuous rate infusion for horses undergoing transvenous electrical cardioversion--A case series . The Canadian Veterinary Journal . 57 . 1 . 70–75 . January 2016 . 26740702 . 4677613 .
  7. Web site: Dexdomitor . 2013-08-02 . https://web.archive.org/web/20130927122231/http://www.dexdomitor.com/ . 2013-09-27 . dead .
  8. Pasin L, Greco T, Feltracco P, Vittorio A, Neto CN, Cabrini L, Landoni G, Finco G, Zangrillo A . 6 . Dexmedetomidine as a sedative agent in critically ill patients: a meta-analysis of randomized controlled trials . PLOS ONE . 8 . 12 . e82913 . 2013-01-01 . 24391726 . 3877008 . 10.1371/journal.pone.0082913 . free . 2013PLoSO...882913P .
  9. Chen K, Lu Z, Xin YC, Cai Y, Chen Y, Pan SM . Alpha-2 agonists for long-term sedation during mechanical ventilation in critically ill patients . The Cochrane Database of Systematic Reviews . 1 . CD010269 . January 2015 . 1 . 25879090 . 6353054 . 10.1002/14651858.CD010269.pub2 .
  10. MacLaren R, Preslaski CR, Mueller SW, Kiser TH, Fish DN, Lavelle JC, Malkoski SP . 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 . March 2015 . 24227448 . 10.1177/0885066613510874 . 25036525 .
  11. Li B, Wang H, Wu H, Gao C . Neurocognitive dysfunction risk alleviation with the use of dexmedetomidine in perioperative conditions or as ICU sedation: a meta-analysis . Medicine . 94 . 14 . e597 . April 2015 . 25860207 . 4554047 . 10.1097/MD.0000000000000597 .
  12. Turunen H, Jakob SM, Ruokonen E, Kaukonen KM, Sarapohja T, Apajasalo M, Takala J . Dexmedetomidine versus standard care sedation with propofol or midazolam in intensive care: an economic evaluation . Critical Care . 19 . 67 . February 2015 . 1 . 25887576 . 4391080 . 10.1186/s13054-015-0787-y . free .
  13. Dere K, Sucullu I, Budak ET, Yeyen S, Filiz AI, Ozkan S, Dagli G . A comparison of dexmedetomidine versus midazolam for sedation, pain and hemodynamic control, during colonoscopy under conscious sedation . European Journal of Anaesthesiology . 27 . 7 . 648–652 . July 2010 . 20531094 . 10.1097/EJA.0b013e3283347bfe . 24778669 . free .
  14. Giovannitti JA, Thoms SM, Crawford JJ . Alpha-2 adrenergic receptor agonists: a review of current clinical applications . Anesthesia Progress . 62 . 1 . 31–39 . 2015-01-01 . 25849473 . 4389556 . 10.2344/0003-3006-62.1.31 .
  15. Ahmed SS, Unland T, Slaven JE, Nitu ME, Rigby MR . Successful use of intravenous dexmedetomidine for magnetic resonance imaging sedation in autistic children . Southern Medical Journal . 107 . 9 . 559–564 . September 2014 . 25188619 . 10.14423/SMJ.0000000000000160 . 43652106 .
  16. He XY, Cao JP, He Q, Shi XY . Dexmedetomidine for the management of awake fibreoptic intubation . The Cochrane Database of Systematic Reviews . 1 . CD009798 . January 2014 . 2020 . 24442817 . 8095023 . 10.1002/14651858.cd009798.pub2 .
  17. Blaudszun G, Lysakowski C, Elia N, Tramèr MR . Effect of perioperative systemic α2 agonists on postoperative morphine consumption and pain intensity: systematic review and meta-analysis of randomized controlled trials . Anesthesiology . 116 . 6 . 1312–22 . June 2012 . 22546966 . 10.1097/ALN.0b013e31825681cb . 3117071 . free .
  18. Kim SY, Kim JM, Lee JH, Song BM, Koo BN . Efficacy of intraoperative dexmedetomidine infusion on emergence agitation and quality of recovery after nasal surgery . British Journal of Anaesthesia . 111 . 2 . 222–8 . August 2013 . 23524149 . 10.1093/bja/aet056 . free .
  19. Patel A, Davidson M, Tran MC, Quraishi H, Schoenberg C, Sant M, Lin A, Sun X . Dexmedetomidine infusion for analgesia and prevention of emergence agitation in children with obstructive sleep apnea syndrome undergoing tonsillectomy and adenoidectomy . Anesthesia and Analgesia . 111 . 4 . 1004–10 . October 2010 . 20705788 . 10.1213/ANE.0b013e3181ee82fa . 35590020 . free .
  20. Tang Y, Song Y, Tian W, Chen G, Gu Y . A systematic review and meta-analysis on the efficacy and safety of dexmedetomidine combined with sevoflurane anesthesia on emergence agitation in children . Translational Pediatrics . 11 . 7 . 1156–1170 . July 2022 . 35957999 . 9360810 . 10.21037/tp-22-172 . free .
  21. Richards JR, Albertson TE, Derlet RW, Lange RA, Olson KR, Horowitz BZ . Treatment of toxicity from amphetamines, related derivatives, and analogues: a systematic clinical review . Drug and Alcohol Dependence . 150 . 1–13 . May 2015 . 25724076 . 10.1016/j.drugalcdep.2015.01.040 .
  22. Mahendru V, Tewari A, Katyal S, Grewal A, Singh MR, Katyal R . 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 . October 2013 . 24249987 . 3819844 . 10.4103/0970-9185.119151 . free .
  23. Upadhyay SP, Mallick PN, Elmatite WM, Jagia M, Taqi S . Dexmedetomidine infusion to facilitate opioid detoxification and withdrawal in a patient with chronic opioid abuse . Indian Journal of Palliative Care . 17 . 3 . 251–4 . September 2011 . 22346054 . 3276827 . 10.4103/0973-1075.92353 . free .
  24. Web site: FDA Okays First Sublingual Med for Agitation in Schizophrenia, BD . 2022-04-11 . Medscape . en . 2022-04-11 . https://web.archive.org/web/20220411224254/https://www.medscape.com/viewarticle/971866 . live .
  25. Ebert TJ, Hall JE, Barney JA, Uhrich TD, Colinco MD . The effects of increasing plasma concentrations of dexmedetomidine in humans . Anesthesiology . 93 . 2 . 382–394 . August 2000 . 10910487 . 10.1097/00000542-200008000-00016 . 20795504 . free .
  26. Web site: Dexmedetomidine Side Effects: Common, Severe, Long Term .
  27. Gertler R, Brown HC, Mitchell DH, Silvius EN . Dexmedetomidine: a novel sedative-analgesic agent . Proceedings . 14 . 1 . 13–21 . January 2001 . 16369581 . 1291306 . 10.1080/08998280.2001.11927725 .
  28. Scott-Warren VL, Sebastian J . 2016 . Dexmedetomidine: its use in intensive care medicine and anaesthesia . BJA Education . 16 . 7 . 242–246 . 10.1093/bjaed/mkv047 . free .
  29. Nelson LE, Lu J, Guo T, Saper CB, Franks NP, Maze M . The alpha2-adrenoceptor agonist dexmedetomidine converges on an endogenous sleep-promoting pathway to exert its sedative effects . Anesthesiology . 98 . 2 . 428–436 . February 2003 . 12552203 . 10.1097/00000542-200302000-00024 . 5034487 . free .
  30. Panzer O, Moitra V, Sladen RN . 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 . July 2009 . 19576524 . 10.1016/j.ccc.2009.04.004 .
  31. Huupponen E, Maksimow A, Lapinlampi P, Särkelä M, Saastamoinen A, Snapir A, Scheinin H, Scheinin M, Meriläinen P, Himanen SL, Jääskeläinen S . 6 . Electroencephalogram spindle activity during dexmedetomidine sedation and physiological sleep . Acta Anaesthesiologica Scandinavica . 52 . 2 . 289–294 . February 2008 . 18005372 . 10.1111/j.1399-6576.2007.01537.x . 34923432 .
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  33. Boyd RE, Press JB, Rasmussen CR, Raffa RB, Codd EE, Connelly CD, Bennett DJ, Kirifides AL, Gardocki JF, Reynolds B, Hortenstein JT, Reitz AB . 6 . Alpha(2) adrenoceptor agonists as potential analgesic agents. 1. (Imidazolylmethyl)oxazoles and -thiazoles . Journal of Medicinal Chemistry . 42 . 25 . 5064–5071 . December 1999 . 10602691 . 10.1021/jm990005a .
  34. Crassous PA, Cardinaletti C, Carrieri A, Bruni B, Di Vaira M, Gentili F, Ghelfi F, Giannella M, Paris H, Piergentili A, Quaglia W, Schaak S, Vesprini C, Pigini M . 6 . Alpha2-adrenoreceptors profile modulation. 3.1 (R)-(+)-m-nitrobiphenyline, a new efficient and alpha2C-subtype selective agonist . Journal of Medicinal Chemistry . 50 . 16 . 3964–3968 . August 2007 . 17630725 . 10.1021/jm061487a .
  35. Venn RM, Karol MD, Grounds RM . Pharmacokinetics of dexmedetomidine infusions for sedation of postoperative patients requiring intensive caret . British Journal of Anaesthesia . 88 . 5 . 669–675 . May 2002 . 12067004 . 10.1093/bja/88.5.669 . free .
  36. Weerink MA, Struys MM, Hannivoort LN, Barends CR, Absalom AR, Colin P . Clinical Pharmacokinetics and Pharmacodynamics of Dexmedetomidine . Clinical Pharmacokinetics . 56 . 8 . 893–913 . August 2017 . 28105598 . 5511603 . 10.1007/s40262-017-0507-7 .
  37. Keating GM . Dexmedetomidine: A Review of Its Use for Sedation in the Intensive Care Setting . Drugs . 75 . 10 . 1119–1130 . July 2015 . 26063213 . 10.1007/s40265-015-0419-5 . 20447722 . free .
  38. Shehabi Y, Ruettimann U, Adamson H, Innes R, Ickeringill M . Dexmedetomidine infusion for more than 24 hours in critically ill patients: sedative and cardiovascular effects . Intensive Care Medicine . 30 . 12 . 2188–2196 . December 2004 . 15338124 . 10.1007/s00134-004-2417-z . 26258023 . free .
  39. Gozalo-Marcilla M, Gasthuys F, Luna SP, Schauvliege S . 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 . April 2018 . 29226340 . 10.1111/jvp.12474 . 3691570 .
  40. Web site: Freedom of Information Summary Supplemental New Animal Drug Application NADA 141-267 Dexdomitor . Food and Drug Administration . 2018-07-01 . 16 August 2010 . 2021-08-28 . https://web.archive.org/web/20210828060527/https://animaldrugsatfda.fda.gov/adafda/app/search/public/document/downloadFoi/828 . live .
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