Dexmedetomidine

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Dexmedetomidine
Dexmedetomidine.svg
Clinical data
Trade names Precedex, others
Other namesMPV-1440;
AHFS/Drugs.com Monograph
License data
Pregnancy
category
  • AU:B1
Routes of
administration 		Intravenous, injection, sublingual, buccal [1]
ATC code
Legal status
Legal status
Pharmacokinetic data
Protein binding 94% (mostly albumin) [4]
Metabolism Near complete hepatic metabolism to inactive metabolites
Elimination half-life 2–4 hours [9]
Excretion Urine
Identifiers
  • (S)-4-[1-(2,3-Dimethylphenyl)ethyl]-3H-imidazole
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.119.391 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C13H16N2
Molar mass 200.285 g·mol−1
3D model (JSmol)
  • Cc2cccc([C@H](C)c1c[nH]cn1)c2C
  • 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 Yes check.svgY
  • Key:CUHVIMMYOGQXCV-NSHDSACASA-N Yes check.svgY
   (verify)

Dexmedetomidine, sold under the brand name Precedex among others, is a medication used for sedation. [4] Veterinarians use dexmedetomidine for similar purposes in treating cats, dogs, and horses. [10] [11] It is also used in humans to treat acute agitation associated with schizophrenia or bipolar disorder. [5] It is administered as an injection or intravenous solution or as a buccal or sublingual film. [1]

Contents

Similar to clonidine, dexmedetomidine is a sympatholytic drug that acts as an agonist of α2-adrenergic receptors in certain parts of the brain. [12] 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. [13] [14]

Compared with other sedatives, some studies suggest dexmedetomidine may be associated with less delirium. [15] However, this finding is not consistent across multiple studies. [14] 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. [16] Whether this observation has a beneficial psychological impact is unclear. [15] From an economic perspective, dexmedetomidine is associated with lower ICU costs, largely due to a shorter time to extubation. [17]

Procedural sedation

Dexmedetomidine can also be used for procedural sedation such as during colonoscopy. [18] 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. [19] [20] Dexmedetomidine is also used for procedural sedation in children. [21]

It can be used for sedation required for awake fibreoptic nasal intubation in patients with a difficult airway. [22]

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. [23] [24] [25] [26]

Other

Dexmedetomidine may be useful for the treatment of the negative cardiovascular effects of acute amphetamines and cocaine intoxication and overdose. [27] [28] Dexmedetomidine has also been used as an adjunct to neuroaxial anesthesia for lower limb procedures. [29] It has been successfully used to treat opioid withdrawal symptoms. [30]

In 2022 it was approved by the FDA for the treatment of agitation in schizophrenia and bipolar disorder. [31]

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. [32] Common side effects include: hypotension, hypertension, with slight decreases in heart rate, arrhythmias, and hypoxia. [33] [34] 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. [34]

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. [35]

Pharmacology

Pharmacodynamics

Dexmedetomidine at targets [36] [37]
SiteKi (nM)SpeciesRef
α1 5Human [38]
α1A 200Human [39]
α1B 316Human [39]
α1D 79Human [39]
α2A 0.015–16Human [40] [41] [39] [42]
α2B 2.0–34Human [41] [39]
α2C 15–95Human [41] [39] [43]
I1 200Bovine [39]
I2 50Rat [39]
NET >1,000Human [39]

Dexmedetomidine is a highly selective α2-adrenergic receptor agonist. It possesses an α2:α1 selectivity ratio of 1620:1, making it 8 times more selective for the α2-adrenergic receptor than the related drug clonidine. [44] [45] 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 γ-aminobutyric acid (GABA) neurons in the ventrolateral preoptic nucleus. [45] [46] In contrast, other sedatives like propofol and benzodiazepines directly increase activity of GABAergic neurons. [47] 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 (NREM)), as demonstrated by EEG studies. [45] [46] [48] As such, dexmedetomidine provides less amnesia than benzodiazepines. [47] Dexmedetomidine also has analgesic effects at the spinal cord level and other supraspinal sites. [47]

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. [49] 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. [9] The plasma protein binding of dexmedetomidine is about 94% (mostly albumin). [4]

Dexmedetomidine is metabolized by the liver, largely by glucuronidation (34%) as well as by oxidation via CYP2A6 and other cytochrome P450 enzymes. [9] As such, it should be used with caution in people with liver disease or hepatic impairment. [35]

The majority of metabolized dexmedetomidine is excreted in the urine (~95%).[ medical citation needed ]

It can also be absorbed sublingually. [31]

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. [50]

Veterinary use

Dexmedetomidine, under the brand name Dexdomitor (Orion Corporation), was approved in the European Union for use in cats and dogs in 2002, for sedation and induction of general anesthesia. [51] The FDA approved dexmedetomidine for use in dogs in 2006 and cats in 2007. [52]

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. [53] [54]

References

  1. 1 2 Faden J, Musselman M, Citrome L (February 2023). "Sublingual dexmedetomidine: repurposing an anesthetic as an anti-agitation agent". Expert Rev Neurother. 23 (2): 97–106. doi:10.1080/14737175.2023.2174430. PMID   36707066.
  2. ↑ "DEXMEDETOMIDINE FRESENIUS (Fresenius Kabi Australia Pty Ltd)". Department of Health and Aged Care . Archived from the original on 2023-03-18.
  3. ↑ Anvisa (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] (in Brazilian Portuguese). Diário Oficial da União (published 2023-04-04). Archived from the original on 2023-08-03. Retrieved 2023-08-16.
  4. 1 2 3 4 "Precedex- dexmedetomidine hydrochloride injection, solution". DailyMed. 2 March 2022. Archived from the original on 8 April 2022. Retrieved 8 April 2022.
  5. 1 2 "Igalmi- dexmedetomidine film". DailyMed. 14 December 2022. Retrieved 21 January 2023.
  6. ↑ "Sileo EPAR". European Medicines Agency. 7 July 2015. Retrieved 21 June 2024.
  7. ↑ "Dexdomitor EPAR". European Medicines Agency (EMA). 14 December 2009. Retrieved 26 December 2024.
  8. ↑ "Dexdomitor PI". Union Register of medicinal products. 5 September 2002. Retrieved 26 December 2024.
  9. 1 2 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.
  10. ↑ 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.
  11. ↑ "Dexdomitor". Archived from the original on 2013-09-27. Retrieved 2013-08-02.
  12. ↑ 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.
  13. ↑ 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.
  14. 1 2 Chen K, Lu Z, Xin YC, Cai Y, Chen Y, Pan SM (January 2015). "Alpha-2 agonists for long-term sedation during mechanical ventilation in critically ill patients". The Cochrane Database of Systematic Reviews. 1 (1): CD010269. doi:10.1002/14651858.CD010269.pub2. PMC   6353054 . PMID   25879090.
  15. 1 2 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.
  16. ↑ Li B, Wang H, Wu H, Gao C (April 2015). "Neurocognitive dysfunction risk alleviation with the use of dexmedetomidine in perioperative conditions or as ICU sedation: a meta-analysis". Medicine. 94 (14): e597. doi:10.1097/MD.0000000000000597. PMC   4554047 . PMID   25860207.
  17. ↑ Turunen H, Jakob SM, Ruokonen E, Kaukonen KM, Sarapohja T, Apajasalo M, Takala J (February 2015). "Dexmedetomidine versus standard care sedation with propofol or midazolam in intensive care: an economic evaluation". Critical Care. 19 (1): 67. doi: 10.1186/s13054-015-0787-y . PMC   4391080 . PMID   25887576.
  18. ↑ Dere K, Sucullu I, Budak ET, Yeyen S, Filiz AI, Ozkan S, Dagli G (July 2010). "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. doi: 10.1097/EJA.0b013e3283347bfe . PMID   20531094. S2CID   24778669.
  19. ↑ Paris A, Tonner PH (August 2005). "Dexmedetomidine in anaesthesia". Current Opinion in Anesthesiology. 18 (4): 412–418. doi:10.1097/01.aco.0000174958.05383.d5. PMID   16534267. S2CID   20014479.
  20. ↑ Giovannitti JA, Thoms SM, Crawford JJ (2015-01-01). "Alpha-2 adrenergic receptor agonists: a review of current clinical applications". Anesthesia Progress. 62 (1): 31–39. doi:10.2344/0003-3006-62.1.31. PMC   4389556 . PMID   25849473.
  21. ↑ Ahmed SS, Unland T, Slaven JE, Nitu ME, Rigby MR (September 2014). "Successful use of intravenous dexmedetomidine for magnetic resonance imaging sedation in autistic children". Southern Medical Journal. 107 (9): 559–564. doi:10.14423/SMJ.0000000000000160. PMID   25188619. S2CID   43652106.
  22. ↑ 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.
  23. ↑ Blaudszun G, Lysakowski C, Elia N, Tramèr MR (June 2012). "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. doi: 10.1097/ALN.0b013e31825681cb . PMID   22546966. S2CID   3117071.
  24. ↑ Kim SY, Kim JM, Lee JH, Song BM, Koo BN (August 2013). "Efficacy of intraoperative dexmedetomidine infusion on emergence agitation and quality of recovery after nasal surgery". British Journal of Anaesthesia. 111 (2): 222–8. doi: 10.1093/bja/aet056 . PMID   23524149.
  25. ↑ Patel A, Davidson M, Tran MC, Quraishi H, Schoenberg C, Sant M, Lin A, Sun X (October 2010). "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. doi: 10.1213/ANE.0b013e3181ee82fa . PMID   20705788. S2CID   35590020.
  26. ↑ Tang Y, Song Y, Tian W, Chen G, Gu Y (July 2022). "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. doi: 10.21037/tp-22-172 . PMC   9360810 . PMID   35957999.
  27. ↑ 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.
  28. ↑ 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.
  29. ↑ 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.
  30. ↑ Upadhyay SP, Mallick PN, Elmatite WM, Jagia M, Taqi S (September 2011). "Dexmedetomidine infusion to facilitate opioid detoxification and withdrawal in a patient with chronic opioid abuse". Indian Journal of Palliative Care. 17 (3): 251–4. doi: 10.4103/0973-1075.92353 . PMC   3276827 . PMID   22346054.
  31. 1 2 "FDA Okays First Sublingual Med for Agitation in Schizophrenia, BD". Medscape. Archived from the original on 2022-04-11. Retrieved 2022-04-11.
  32. ↑ 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.
  33. ↑ "Dexmedetomidine Side Effects: Common, Severe, Long Term".
  34. 1 2 Gertler R, Brown HC, Mitchell DH, Silvius EN (January 2001). "Dexmedetomidine: a novel sedative-analgesic agent". Proceedings. 14 (1): 13–21. doi:10.1080/08998280.2001.11927725. PMC   1291306 . PMID   16369581.
  35. 1 2 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.
  36. ↑ Liu, Tiqing. "BindingDB BDBM50085683 (+)-4-((S)-alpha,2,3-trimethylbenzyl)imidazole::4-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole::CHEMBL778::DEXMEDETOMIDINE::MPV 1440". BindingDB. Retrieved 11 September 2024.
  37. ↑ "PDSP Database". UNC (in Zulu). Retrieved 11 September 2024.
  38. ↑ Ross TM, Jetter MC, McDonnell ME, Boyd RE, Connelly CD, Martinez RP, et al. (March 2000). "alpha(2) Adrenoceptor agonists as potential analgesic agents. 2. Discovery of 4-(4-Imidazo)-1,3-dimethyl-6,7-dihydrothianaphthene [corrected] as a high-affinity ligand for the alpha(2D) adrenergic receptor". Journal of Medicinal Chemistry. 43 (5): 765–768. doi:10.1021/jm990569e. PMID   10715142.
  39. 1 2 3 4 5 6 7 8 9 Millan MJ, Dekeyne A, Newman-Tancredi A, Cussac D, Audinot V, Milligan G, Duqueyroix D, Girardon S, Mullot J, Boutin JA, Nicolas JP, Renouard-Try A, Lacoste JM, Cordi A (December 2000). "S18616, a highly potent, spiroimidazoline agonist at alpha(2)-adrenoceptors: I. Receptor profile, antinociceptive and hypothermic actions in comparison with dexmedetomidine and clonidine". J Pharmacol Exp Ther. 295 (3): 1192–1205. doi:10.1016/S0022-3565(24)39022-6. PMID   11082457.
  40. ↑ Boyd RE, Press JB, Rasmussen CR, Raffa RB, Codd EE, Connelly CD, et al. (December 1999). "Alpha(2) adrenoceptor agonists as potential analgesic agents. 1. (Imidazolylmethyl)oxazoles and -thiazoles". Journal of Medicinal Chemistry. 42 (25): 5064–5071. doi:10.1021/jm990005a. PMID   10602691.
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  43. ↑ Crassous PA, Cardinaletti C, Carrieri A, Bruni B, Di Vaira M, Gentili F, et al. (August 2007). "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. doi:10.1021/jm061487a. PMID   17630725.
  44. ↑ 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 .
  45. 1 2 3 Weerink MA, Struys MM, Hannivoort LN, Barends CR, Absalom AR, Colin P (August 2017). "Clinical Pharmacokinetics and Pharmacodynamics of Dexmedetomidine". Clin Pharmacokinet. 56 (8): 893–913. doi:10.1007/s40262-017-0507-7. PMC   5511603 . PMID   28105598.
  46. 1 2 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.
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  49. ↑ 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.
  50. ↑ 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.
  51. ↑ 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.
  52. ↑ "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.
  53. ↑ "Recent Animal Drug Approvals". U.S. Department of Health and Human Services. 2 June 2016. Archived from the original on 12 July 2016. Retrieved 3 July 2016. For the treatment of noise aversion in dogs
  54. ↑ "Veterinary medicines: product update". The Veterinary Record. 177 (5): 116–117. August 2015. doi:10.1136/vr.h4051. PMID   26231872. S2CID   42312260.
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