Dexmedetomidine

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Dexmedetomidine
Dexmedetomidine.svg
Clinical data
Trade names Precedex, Dexdor, Igalmi, others
AHFS/Drugs.com Monograph
License data
Pregnancy
category
  • AU:B1
Routes of
administration 		Intravenous, transmucosal, intranasal, sublingual
ATC code
Legal status
Legal status
Pharmacokinetic data
Protein binding 94% (mostly albumin) [3]
Metabolism Near complete hepatic metabolism to inactive metabolites
Elimination half-life 2–4 hours [5]
Excretion Urine
Identifiers
  • (S)-4-[1-(2,3-Dimethylphenyl)ethyl]-3H-imidazole
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
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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
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Dexmedetomidine, sold under the trade name Precedex among others, is a drug used in humans for sedation. [3] 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. [4]

Contents

Similar to clonidine, it is a sympatholytic drug that acts as an agonist of α2-adrenergic receptors in certain parts of the brain. [8] 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. [9] [10]

Compared with other sedatives, some studies suggest dexmedetomidine may be associated with less delirium. [11] However, this finding is not consistent across multiple studies. [10] 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. [12] Whether this observation has a beneficial psychological impact is unclear. [11] From an economic perspective, dexmedetomidine is associated with lower ICU costs, largely due to a shorter time to extubation. [13]

Procedural sedation

Dexmedetomidine can also be used for procedural sedation such as during colonoscopy. [14] 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. [15] [16] Dexmedetomidine is also used for procedural sedation in children. [17]

It can be used for sedation required for awake fibreoptic nasal intubation in patients with a difficult airway. [18]

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. [19] [20] [21] [22]

Other

Dexmedetomidine may be useful for the treatment of the negative cardiovascular effects of acute amphetamines and cocaine intoxication and overdose. [23] [24] Dexmedetomidine has also been used as an adjunct to neuroaxial anesthesia for lower limb procedures. [25] It has been successfully used to treat opioid withdrawal symptoms. [26]

In 2022 it was approved by the FDA for the treatment of agitation in schizophrenia and bipolar disorder. [27]

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. [28] Common side effects include: hypotension, hypertension, with slight decreases in heart rate, arrhythmias, and hypoxia. [29] [30] 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. [30]

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. [31]

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. [32] 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. [33] In contrast[ clarification needed ], other sedatives like propofol and benzodiazepines directly increase activity of gamma-aminobutyric acid neurons. [34] 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. [33] [35] As such, dexmedetomidine provides less amnesia than benzodiazepines. [34] Dexmedetomidine also has analgesic effects at the spinal cord level and other supraspinal sites. [34]

SiteKi (nM)SpeciesRef
α1 5Human [36]
α2A 0.0150–2.1Human [37]
α2B NDHuman
α2C 31Human [38]

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. [39] 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. [5] Plasma protein binding of dexmedetomidine is about 94% (mostly albumin). [3]

Dexmedetomidine is metabolized by the liver, largely by glucuronidation (34%) as well as by oxidation via CYP2A6 and other Cytochrome P450 enzymes. [5] As such, it should be used with caution in people with liver disease. [31]

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

It can be absorbed sublingually. [27]

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. [40]

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. [41] The FDA approved dexmedetomidine for use in dogs in 2006 and cats in 2007. [42]

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. [43] [44]

Related Research Articles

General anaesthetics are often defined as compounds that induce a loss of consciousness in humans or loss of righting reflex in animals. Clinical definitions are also extended to include an induced coma that causes lack of awareness to painful stimuli, sufficient to facilitate surgical applications in clinical and veterinary practice. General anaesthetics do not act as analgesics and should also not be confused with sedatives. General anaesthetics are a structurally diverse group of compounds whose mechanisms encompass multiple biological targets involved in the control of neuronal pathways. The precise workings are the subject of some debate and ongoing research.

<span class="mw-page-title-main">Anesthesia</span> State of medically-controlled temporary loss of sensation or awareness

Anesthesia or anaesthesia is a state of controlled, temporary loss of sensation or awareness that is induced for medical or veterinary purposes. It may include some or all of analgesia, paralysis, amnesia, and unconsciousness. An individual under the effects of anesthetic drugs is referred to as being anesthetized.

<span class="mw-page-title-main">General anaesthesia</span> Medically induced loss of consciousness

General anaesthesia (UK) or general anesthesia (US) is a method of medically inducing loss of consciousness that renders a patient unarousable even with painful stimuli. This effect is achieved by administering either intravenous or inhalational general anaesthetic medications, which often act in combination with an analgesic and neuromuscular blocking agent. Spontaneous ventilation is often inadequate during the procedure and intervention is often necessary to protect the airway. General anaesthesia is generally performed in an operating theater to allow surgical procedures that would otherwise be intolerably painful for a patient, or in an intensive care unit or emergency department to facilitate endotracheal intubation and mechanical ventilation in critically ill patients.

<span class="mw-page-title-main">Propofol</span> Intravenous medication used in anesthesia

Propofol is the active component of an intravenous anesthetic formulation used for induction and maintenance of general anesthesia. It is chemically termed 2,6-diisopropylphenol. The formulation was originally approved under the brand name Diprivan. Numerous generic offerings of this formulation now exist. Intravenous administration is used to induce unconsciousness after which anesthesia may be maintained using a combination of medications. It is manufactured as part of a sterile injectable emulsion formulation using soybean oil and lecithin, giving it a white milky coloration.

<span class="mw-page-title-main">Midazolam</span> Benzodiazepine used for anesthesia and procedural sedation

Midazolam, sold under the brand name Versed among others, is a benzodiazepine medication used for anesthesia and procedural sedation, and to treat severe agitation. It induces sleepiness, decreases anxiety, and causes anterograde amnesia.

Premedication is using medication before some other therapy to prepare for that forthcoming therapy. Typical examples include premedicating with a sedative or analgesic before surgery; using prophylactic (preventive) antibiotics before surgery; and using antiemetics or antihistamines before chemotherapy.

<span class="mw-page-title-main">Remifentanil</span> Synthetic opioid analgesic

Remifentanil, marketed under the brand name Ultiva is a potent, short-acting synthetic opioid analgesic drug. It is given to patients during surgery to relieve pain and as an adjunct to an anaesthetic. Remifentanil is used for sedation as well as combined with other medications for use in general anesthesia. The use of remifentanil has made possible the use of high-dose opioid and low-dose hypnotic anesthesia, due to synergism between remifentanil and various hypnotic drugs and volatile anesthetics.

<span class="mw-page-title-main">Xylazine</span> Veterinary anesthetic, sedative and analgesic

Xylazine is a drug used for sedation, anesthesia, muscle relaxation, and analgesia in animals such as horses, cattle, and other non-human mammals. It is an analog of clonidine and an agonist at the α2 class of adrenergic receptor.

<span class="mw-page-title-main">Etomidate</span> Short-acting anaesthetic and sedative drug

Etomidate is a short-acting intravenous anaesthetic agent used for the induction of general anaesthesia and sedation for short procedures such as reduction of dislocated joints, tracheal intubation, cardioversion and electroconvulsive therapy. It was developed at Janssen Pharmaceutica in 1964 and was introduced as an intravenous agent in 1972 in Europe and in 1983 in the United States.

<span class="mw-page-title-main">Detomidine</span> Chemical compound

Detomidine is an imidazole derivative and α2-adrenergic agonist, used as a large animal sedative, primarily used in horses. It is usually available as the salt detomidine hydrochloride. It is a prescription medication available to veterinarians sold under various trade names.

<span class="mw-page-title-main">Medetomidine</span> Chemical compound

Medetomidine is a synthetic drug used as both a surgical anesthetic and analgesic. It is often used as the hydrochloride salt, medetomidine hydrochloride, a crystalline white solid. It is an α2 adrenergic agonist that can be administered as an intravenous drug solution with sterile water.

<span class="mw-page-title-main">Ro48-6791</span> Chemical compound

Ro48-6791 is a drug, an imidazobenzodiazepine derivative developed by Hoffman-LaRoche in the 1990s.

<span class="mw-page-title-main">Atipamezole</span> Veterinary drug

Atipamezole, is a synthetic α2 adrenergic receptor antagonist indicated for the reversal of the sedative and analgesic effects of dexmedetomidine and medetomidine in dogs. Its reversal effect works by competing with the sedative for α2-adrenergic receptors and displacing them. It is mainly used in veterinary medicine, and while it is only licensed for dogs and for intramuscular use, it has been used intravenously, as well as in cats and other animals(intravenous use in cats and dogs is not recommended due to the potential for cardiovascular collapse. This occurs due to profound hypotension caused by reversal of the alpha 1 effects while the reflex bradycardia is still in effect.). There is a low rate of side effects, largely due to atipamezole's high specificity for the α2-adrenergic receptor. Atipamezole has a very quick onset, usually waking an animal up within 5 to 10 minutes.

Procedural sedation and analgesia (PSA) is a technique in which a sedating/dissociative medication is given, usually along with an analgesic medication, in order to perform non-surgical procedures on a patient. The overall goal is to induce a decreased level of consciousness while maintaining the patient's ability to breathe on their own. Airway protective reflexes are not compromised by this process and therefore endotracheal intubation is not required. PSA is commonly used in the emergency department, in addition to the operating room.

<span class="mw-page-title-main">Propofol infusion syndrome</span> Medical condition

Propofol infusion syndrome (PRIS) is a rare syndrome which affects patients undergoing long-term treatment with high doses of the anaesthetic and sedative drug propofol. It can lead to cardiac failure, rhabdomyolysis, metabolic acidosis, and kidney failure, and is often fatal. High blood potassium, high blood triglycerides, and liver enlargement, proposed to be caused by either "a direct mitochondrial respiratory chain inhibition or impaired mitochondrial fatty acid metabolism" are also key features. It is associated with high doses and long-term use of propofol. It occurs more commonly in children, and critically ill patients receiving catecholamines and glucocorticoids are at high risk. Treatment is supportive. Early recognition of the syndrome and discontinuation of the propofol infusion reduces morbidity and mortality.

<span class="mw-page-title-main">Coinduction (anesthetics)</span>

Coinduction in anesthesia is a pharmacological tool whereby a combination of sedative drugs may be used to greater effect than a single agent, achieving a smoother onset of general anesthesia. The use of coinduction allows lower doses of the same anesthetic agents to be used which provides enhanced safety, faster recovery, fewer side-effects, and more predictable pharmacodynamics. Coinduction is used in human medicine and veterinary medicine as standard practice to provide optimum anesthetic induction. The onset or induction phase of anesthesia is a critical period involving the loss of consciousness and reactivity in the patient, and is arguably the most dangerous period of a general anesthetic. A great variety of coinduction combinations are in use and selection is dependent on the patient's age and health, the specific situation, and the indication for anesthesia. As with all forms of anesthesia the resources available in the environment are a key factor.

<span class="mw-page-title-main">Alex Bekker</span> Physician, author and academic

Alex Bekker is a physician, author and academic. He is a professor and chair at the Department of Anesthesiology, Rutgers New Jersey Medical School. He is also professor at the Department of Physiology, Pharmacology & Neurosciences. He serves as the Chief of Anesthesiology Service at the University Hospital in Newark.

Total intravenous anesthesia (TIVA) refers to the intravenous administration of anesthetic agents to induce a temporary loss of sensation or awareness. The first study of TIVA was done in 1872 using chloral hydrate, and the common anesthetic agent propofol was licensed in 1986. TIVA is currently employed in various procedures as an alternative technique of general anesthesia in order to improve post-operative recovery.

<span class="mw-page-title-main">Remifentanilic acid</span> Inactive metabolite of remifentanil

Remifentanilic acid is a metabolite of the potent short-acting synthetic opioid analgesic drug remifentanil. It is an analog of fentanyl and remifentanil, but is not active as an opioid in its own right.

<span class="mw-page-title-main">Ciprofol</span> Intravenous medication used in general anaesthesia

Ciprofol is a novel 2,6-disubstituted phenol derivative that is used for the intravenous induction of general anesthesia. A short-acting and highly selective γ-aminobutyric acid agonist, ciprofol is 4–6 times more potent than other phenol derivatives such as propofol or fospropofol.

References

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  2. ↑ 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.
  3. 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.
  4. 1 2 "Igalmi- dexmedetomidine film". DailyMed. 14 December 2022. Retrieved 21 January 2023.
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  6. ↑ 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.
  7. ↑ "Dexdomitor". Archived from the original on 2013-09-27. Retrieved 2013-08-02.
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  11. 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.
  12. ↑ 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.
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  21. ↑ 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.
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  35. ↑ 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.
  36. ↑ 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.
  37. ↑ 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.
  38. ↑ 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.
  39. ↑ 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.
  40. ↑ 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.
  41. ↑ 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.
  42. ↑ "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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  44. ↑ "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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