Chemistry:Dexmedetomidine

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Dexmedetomidine, sold under the brand name Precedex among others, is a medication used for sedation.[1] Veterinarians use dexmedetomidine for similar purposes in treating cats, dogs, and horses.[2][3] It is also used in humans to treat acute agitation associated with schizophrenia or bipolar disorder.[4] It is administered as an intravenous solution or as a buccal or sublingual film.[5]

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

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][22] Dexmedetomidine has also been used as an adjunct to neuroaxial anesthesia for lower limb procedures.[23] It has been successfully used to treat opioid withdrawal symptoms.[24]

In 2022 it was approved by the FDA for the treatment of agitation in schizophrenia and bipolar disorder.[25]

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.[26] Common side effects include: hypotension, hypertension, with slight decreases in heart rate, arrhythmias, and hypoxia.[27][28] 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.[28]

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.[29]

Pharmacology

Pharmacodynamics

Dexmedetomidine at targets[30][31]
Site Ki (nM) Species Ref
α1 5 Human [32]
α1A 200 Human [33]
α1B 316 Human [33]
α1D 79 Human [33]
α2A 0.015–16 Human [34][35][33][36]
α2B 2.0–34 Human [35][33]
α2C 15–95 Human [35][33][37]
I1 200 Bovine [33]
I2 50 Rat [33]
NET >1,000 Human [33]

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.[38][39] 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.[39][40] In contrast, other sedatives like propofol and benzodiazepines directly increase activity of GABAergic neurons.[41] 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.[39][40][42] As such, dexmedetomidine provides less amnesia than benzodiazepines.[41] Dexmedetomidine also has analgesic effects at the spinal cord level and other supraspinal sites.[41]

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.[43] 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.[44] The 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.[44] As such, it should be used with caution in people with liver disease or hepatic impairment.[29]

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

It can also be absorbed sublingually.[25]

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.[45]

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.[46] The FDA approved dexmedetomidine for use in dogs in 2006 and cats in 2007.[47] Dexmedetomidine has supplanted xylazine as a sedative for cats and dogs in several countries. Dexmedetomidine is used off-label in horses.[48]

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.[49][50]

A study of dogs anaesthetised with isoflurane found that a constant rate infusion of dexmedetomidine improved ventilation, oxygenation, and respiration.[48][51]

References

  1. ↑ 1.0 1.1 Cite error: Invalid <ref> tag; no text was provided for refs named Precedex FDA label
  2. ↑ "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. PMID 26740702. 
  3. ↑ "Dexdomitor". http://www.dexdomitor.com/. 
  4. ↑ Cite error: Invalid <ref> tag; no text was provided for refs named Igalmi FDA label
  5. ↑ "Sublingual dexmedetomidine: repurposing an anesthetic as an anti-agitation agent". Expert Rev Neurother 23 (2): 97–106. February 2023. doi:10.1080/14737175.2023.2174430. PMID 36707066. 
  6. ↑ "The role of alpha2-agonists in neurosurgery". Journal of Clinical Neuroscience 12 (4): 375–378. May 2005. doi:10.1016/j.jocn.2004.06.008. PMID 15925765. 
  7. ↑ "Dexmedetomidine as a sedative agent in critically ill patients: a meta-analysis of randomized controlled trials". PLOS ONE 8 (12). 2013-01-01. doi:10.1371/journal.pone.0082913. PMID 24391726. Bibcode: 2013PLoSO...882913P. 
  8. ↑ 8.0 8.1 "Alpha-2 agonists for long-term sedation during mechanical ventilation in critically ill patients". The Cochrane Database of Systematic Reviews 1 (1). January 2015. doi:10.1002/14651858.CD010269.pub2. PMID 25879090. 
  9. ↑ 9.0 9.1 "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. doi:10.1177/0885066613510874. PMID 24227448. 
  10. ↑ "Neurocognitive dysfunction risk alleviation with the use of dexmedetomidine in perioperative conditions or as ICU sedation: a meta-analysis". Medicine 94 (14). April 2015. doi:10.1097/MD.0000000000000597. PMID 25860207. 
  11. ↑ "Dexmedetomidine versus standard care sedation with propofol or midazolam in intensive care: an economic evaluation". Critical Care 19 (1). February 2015. doi:10.1186/s13054-015-0787-y. PMID 25887576. 
  12. ↑ "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. doi:10.1097/EJA.0b013e3283347bfe. PMID 20531094. 
  13. ↑ "Dexmedetomidine in anaesthesia". Current Opinion in Anesthesiology 18 (4): 412–418. August 2005. doi:10.1097/01.aco.0000174958.05383.d5. PMID 16534267. 
  14. ↑ "Alpha-2 adrenergic receptor agonists: a review of current clinical applications". Anesthesia Progress 62 (1): 31–39. 2015-01-01. doi:10.2344/0003-3006-62.1.31. PMID 25849473. 
  15. ↑ "Successful use of intravenous dexmedetomidine for magnetic resonance imaging sedation in autistic children". Southern Medical Journal 107 (9): 559–564. September 2014. doi:10.14423/SMJ.0000000000000160. PMID 25188619. 
  16. ↑ "Dexmedetomidine for the management of awake fibreoptic intubation". The Cochrane Database of Systematic Reviews 2020 (1). January 2014. doi:10.1002/14651858.cd009798.pub2. PMID 24442817. 
  17. ↑ "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. doi:10.1097/ALN.0b013e31825681cb. PMID 22546966. 
  18. ↑ "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. doi:10.1093/bja/aet056. PMID 23524149. 
  19. ↑ "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. doi:10.1213/ANE.0b013e3181ee82fa. PMID 20705788. 
  20. ↑ "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. doi:10.21037/tp-22-172. PMID 35957999. 
  21. ↑ "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. August 2007. doi:10.1016/j.jacc.2007.03.060. PMID 17692748. 
  22. ↑ "Treatment of toxicity from amphetamines, related derivatives, and analogues: a systematic clinical review". Drug and Alcohol Dependence 150: 1–13. May 2015. doi:10.1016/j.drugalcdep.2015.01.040. PMID 25724076. 
  23. ↑ "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. doi:10.4103/0970-9185.119151. PMID 24249987. 
  24. ↑ "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. doi:10.4103/0973-1075.92353. PMID 22346054. 
  25. ↑ 25.0 25.1 "FDA Okays First Sublingual Med for Agitation in Schizophrenia, BD" (in en). http://www.medscape.com/viewarticle/971866. 
  26. ↑ "The effects of increasing plasma concentrations of dexmedetomidine in humans". Anesthesiology 93 (2): 382–394. August 2000. doi:10.1097/00000542-200008000-00016. PMID 10910487. 
  27. ↑ "Dexmedetomidine Side Effects: Common, Severe, Long Term". https://www.drugs.com/sfx/dexmedetomidine-side-effects.html. 
  28. ↑ 28.0 28.1 "Dexmedetomidine: a novel sedative-analgesic agent". Proceedings 14 (1): 13–21. January 2001. doi:10.1080/08998280.2001.11927725. PMID 16369581. 
  29. ↑ 29.0 29.1 "Dexmedetomidine: A Review of Its Use for Sedation in the Intensive Care Setting". Drugs 75 (10): 1119–1130. July 2015. doi:10.1007/s40265-015-0419-5. PMID 26063213. 
  30. ↑ "BindingDB BDBM50085683 (+)-4-((S)-alpha,2,3-trimethylbenzyl)imidazole::4-[(1S)-1-(2,3-dimethylphenyl)ethyl-1H-imidazole::CHEMBL778::DEXMEDETOMIDINE::MPV 1440"]. https://www.bindingdb.org/rwd/bind/chemsearch/marvin/MolStructure.jsp?monomerid=50085683. 
  31. ↑ "PDSP Database" (in zu). https://pdsp.unc.edu/databases/pdsp.php?receptorDD=&receptor=&speciesDD=&species=&sourcesDD=&source=&hotLigandDD=&hotLigand=&testLigandDD=&testFreeRadio=testFreeRadio&testLigand=Dexmedetomidine&referenceDD=&reference=&KiGreater=&KiLess=&kiAllRadio=all&doQuery=Submit+Query. 
  32. ↑ "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. March 2000. doi:10.1021/jm990569e. PMID 10715142. https://www.bindingdb.org/rwd/jsp/dbsearch/Summary_ki.jsp?entryid=50009620&ki_result_id=50118025&reactant_set_id=50118025&energyterm=kJ/mole&kiunit=nM&icunit=nM. 
  33. ↑ 33.0 33.1 33.2 33.3 33.4 33.5 33.6 33.7 33.8 "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. December 2000. doi:10.1016/S0022-3565(24)39022-6. PMID 11082457. 
  34. ↑ "Alpha(2) adrenoceptor agonists as potential analgesic agents. 1. (Imidazolylmethyl)oxazoles and -thiazoles". Journal of Medicinal Chemistry 42 (25): 5064–5071. December 1999. doi:10.1021/jm990005a. PMID 10602691. https://www.bindingdb.org/rwd/jsp/dbsearch/Summary_ki.jsp?entryid=50003533&ki_result_id=51152970&reactant_set_id=51152970&energyterm=kJ/mole&kiunit=nM&icunit=nM. 
  35. ↑ 35.0 35.1 35.2 "Ligand efficacy and potency at recombinant alpha2 adrenergic receptors: agonist-mediated [35S]GTPgammaS binding". Biochem Pharmacol 55 (7): 1035–1043. April 1998. doi:10.1016/s0006-2952(97)00631-x. PMID 9605427. 
  36. ↑ "A combined ligand- and structure-based approach for the identification of rilmenidine-derived compounds which synergize the antitumor effects of doxorubicin". Bioorg Med Chem 24 (14): 3174–3183. July 2016. doi:10.1016/j.bmc.2016.05.043. PMID 27265687. 
  37. ↑ "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. doi:10.1021/jm061487a. PMID 17630725. https://www.bindingdb.org/rwd/jsp/dbsearch/Summary_ki.jsp?entryid=50020830&ki_result_id=50069440&reactant_set_id=50069440&energyterm=kJ/mole&kiunit=nM&icunit=nM. 
  38. ↑ "Dexmedetomidine: its use in intensive care medicine and anaesthesia". BJA Education 16 (7): 242–246. 2016. doi:10.1093/bjaed/mkv047. 
  39. ↑ 39.0 39.1 39.2 "Clinical Pharmacokinetics and Pharmacodynamics of Dexmedetomidine". Clin Pharmacokinet 56 (8): 893–913. August 2017. doi:10.1007/s40262-017-0507-7. PMID 28105598. 
  40. ↑ 40.0 40.1 "The alpha2-adrenoceptor agonist dexmedetomidine converges on an endogenous sleep-promoting pathway to exert its sedative effects". Anesthesiology 98 (2): 428–436. February 2003. doi:10.1097/00000542-200302000-00024. PMID 12552203. 
  41. ↑ 41.0 41.1 41.2 "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. doi:10.1016/j.ccc.2009.04.004. PMID 19576524. 
  42. ↑ "Electroencephalogram spindle activity during dexmedetomidine sedation and physiological sleep". Acta Anaesthesiologica Scandinavica 52 (2): 289–294. February 2008. doi:10.1111/j.1399-6576.2007.01537.x. PMID 18005372. 
  43. ↑ "Pharmacokinetics of dexmedetomidine infusions for sedation of postoperative patients requiring intensive caret". British Journal of Anaesthesia 88 (5): 669–675. May 2002. doi:10.1093/bja/88.5.669. PMID 12067004. 
  44. ↑ 44.0 44.1 "Clinical Pharmacokinetics and Pharmacodynamics of Dexmedetomidine". Clinical Pharmacokinetics 56 (8): 893–913. August 2017. doi:10.1007/s40262-017-0507-7. PMID 28105598. 
  45. ↑ "Dexmedetomidine infusion for more than 24 hours in critically ill patients: sedative and cardiovascular effects". Intensive Care Medicine 30 (12): 2188–2196. December 2004. doi:10.1007/s00134-004-2417-z. PMID 15338124. 
  46. ↑ "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. doi:10.1111/jvp.12474. PMID 29226340. 
  47. ↑ "Freedom of Information Summary | Supplemental New Animal Drug Application | NADA 141-267 | Dexdomitor". Food and Drug Administration. 16 August 2010. https://animaldrugsatfda.fda.gov/adafda/app/search/public/document/downloadFoi/828. 
  48. ↑ 48.0 48.1 "Sedatives and Tranquilizers". Veterinary Anesthesia and Analgesia, The 6th Edition of Lumb and Jones. Wiley Blackwell. 11 September 2024. pp. 338–344. ISBN 978-1-119-83027-6. 
  49. ↑ "Recent Animal Drug Approvals". U.S. Department of Health and Human Services. 2 June 2016. https://www.fda.gov/AnimalVeterinary/Products/ApprovedAnimalDrugProducts/ucm363948.htm. "For the treatment of noise aversion in dogs" 
  50. ↑ "Veterinary medicines: product update". The Veterinary Record 177 (5): 116–117. August 2015. doi:10.1136/vr.h4051. PMID 26231872. 
  51. ↑ "Respiratory and hemodynamic effects of 2 protocols of low-dose infusion of dexmedetomidine in dogs under isoflurane anesthesia". Canadian Journal of Veterinary Research 84 (2): 96–107. April 2020. PMID 32255904. 



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