Dexmedetomidine

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Dexmedetomidine
Dexmedetomidine.svg
Clinical data
Trade namesPrecedex, Dexdor, Dexdomitor, Sileo
AHFS/Drugs.comMonograph
License data
Pregnancy
category
  • AU: B1
Routes of
administration		Intravenous, transmucosal, intranasal
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • US: ℞-only
  • 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[2]
ExcretionUrine
Identifiers
  • (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 Edit this at Wikidata
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 checkY
  • Key:CUHVIMMYOGQXCV-NSHDSACASA-N checkY
  

Dexmedetomidine, sold under the trade name Precedex among others, is an anxiolytic, sedative, and pain medication. Dexmedetomidine is notable for its ability to provide sedation without risk of respiratory depression[citation needed] (unlike other commonly used drugs such as propofol and fentanyl) and can provide cooperative or semi-rousable sedation.

Similar to clonidine, it is a sympatholytic drug that acts as an agonist of α2-adrenergic receptors in certain parts of the brain.[3] Veterinarians use dexmedetomidine for similar purposes in treating cats, dogs, and horses.[4][5] It was developed by Orion Pharma.

Medical uses[]

Intensive care unit sedation[]

Dexmedetomidine is most often used in the intensive care setting for light to moderate sedation. It is not recommended for long-term deep sedation. A feature of dexmedetomidine is that it has analgesic properties in addition to its role as a hypnotic, but is opioid sparing and it is not associated with significant respiratory depression (unlike propofol)[citation needed].

Many studies suggest dexmedetomidine for sedation in mechanically ventilated adults may reduce time to extubation and ICU stay.[6][7] People on dexmedetomidine can be rousable and cooperative, a benefit in some procedures.

Compared with other sedatives, some studies suggest dexmedetomidine may be associated with less delirium.[8] However, this finding is not consistent across multiple studies.[7] 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.[9] Whether this observation has a beneficial psychological impact is unclear.[8] From an economic perspective, dexmedetomidine is associated with lower ICU costs, largely due to a shorter time to extubation.[10]

Procedural sedation[]

Dexmedetomidine can also be used for procedural sedation such as during colonoscopy.[11] 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.[12][13] Dexmedetomidine is also used for procedural sedation in children.[14]

It can be used for sedation required for awake fibreoptic nasal intubation in patients with a difficult airway.[15]

Other[]

Dexmedetomidine may be useful for the treatment of the negative cardiovascular effects of acute amphetamines and cocaine intoxication and overdose.[16][17] Dexmedetomidine has also been used as an adjunct to neuroaxial anesthesia for lower limb procedures.[18]

Dosage and administration[]

Dexmedetomidine can be administered via different routes such as intravenous or perineural which can alter its efficacy.[19] Intravenous infusion of dexmedetomidine is commonly initiated with a loading dose followed by a maintenance infusion. There may be great individual variability in the hemodynamic effects (especially on heart rate and blood pressure), as well as the sedative effects of this drug. For this reason, the dose must be carefully adjusted to achieve the desired clinical effect.[20] No oral formulation of dexmedetomidine is available.[21]

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.[22] Rapid IV administration or bolus has been associated with hypertension due to peripheral α2-receptor stimulation. Bradycardia can be a limiting factor with infusions especially in higher doses.

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.[23]

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.[24] 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.[25] In contrast[clarification needed], other sedatives like propofol and benzodiazepines directly increase activity of gamma-aminobutyric acid neurons.[26] 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.[25][27] As such, dexmedetomidine provides less amnesia than benzodiazepines.[26] Dexmedetomidine also has analgesic effects at the spinal cord level and other supraspinal sites.[26] Thus, unlike other hypnotic agents like propofol, dexmedetomidine can be used as an adjunct medication to help decrease the opioid requirements of people in pain while still providing similar analgesia.

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.[28] 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.[2] 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.[2] As such, it should be used with caution in people with liver disease.[23]

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

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.[29] In 2008 the FDA expanded its indication to include non-intubated people requiring sedation for surgical or non-surgical procedures, such as colonoscopy.

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.[30] The FDA approved dexmedetomidine for use in dogs in 2006 and cats in 2007.[31]

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.[32][33]

References[]

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  2. ^ a b c 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.
  3. ^ 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.
  4. ^ 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.
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  18. ^ 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.
  19. ^ Motaghi et al. Safety and Efficacy of Dexmedetomidine in Breast Surgeries: A Systematic Review and Meta-Analysis.Journal of Perianesthesia Nursing (2020) DOI:10.1016/j.jopan.2020.09.011
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  21. ^ "Drugs@FDA: FDA-Approved Drugs".
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  25. ^ a b 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.
  26. ^ a b c 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.
  27. ^ 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.
  28. ^ 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.
  29. ^ 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.
  30. ^ 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.
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