Dexmedetomidine

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Dexmedetomidine
Dexmedetomidine.svg
Clinical data
Trade names Precedex, Dexdor, Igalmi, 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 [7]
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 trade name Precedex among others, is a drug used in humans for sedation. [4] Veterinarians use dexmedetomidine for similar purposes in treating cats, dogs, and horses. [8] [9] 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. [10] 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. [11] [12]

Compared with other sedatives, some studies suggest dexmedetomidine may be associated with less delirium. [13] However, this finding is not consistent across multiple studies. [12] 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. [14] Whether this observation has a beneficial psychological impact is unclear. [13] From an economic perspective, dexmedetomidine is associated with lower ICU costs, largely due to a shorter time to extubation. [15]

Procedural sedation

Dexmedetomidine can also be used for procedural sedation such as during colonoscopy. [16] 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. [17] [18] Dexmedetomidine is also used for procedural sedation in children. [19]

It can be used for sedation required for awake fibreoptic nasal intubation in patients with a difficult airway. [20]

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. [21] [22] [23] [24]

Other

Dexmedetomidine may be useful for the treatment of the negative cardiovascular effects of acute amphetamines and cocaine intoxication and overdose. [25] [26] Dexmedetomidine has also been used as an adjunct to neuroaxial anesthesia for lower limb procedures. [27] It has been successfully used to treat opioid withdrawal symptoms. [28]

In 2022 it was approved by the FDA for the treatment of agitation in schizophrenia and bipolar disorder. [29]

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. [30] Common side effects include: hypotension, hypertension, with slight decreases in heart rate, arrhythmias, and hypoxia. [31] [32] 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. [32]

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. [33]

Pharmacology

Pharmacodynamics

Dexmedetomidine at targets [34] [35]
SiteKi (nM)SpeciesRef
α1 5Human [36]
α1A 200Human [37]
α1B 316Human [37]
α1D 79Human [37]
α2A 0.015–16Human [38] [39] [37] [40]
α2B 2.0–34Human [39] [37]
α2C 15–95Human [39] [37] [41]
I1 200Bovine [37]
I2 50Rat [37]
NET >1,000Human [37]

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. [42] [43] 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. [43] [44] In contrast, other sedatives like propofol and benzodiazepines directly increase activity of GABAergic neurons. [45] 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. [43] [44] [46] As such, dexmedetomidine provides less amnesia than benzodiazepines. [45] Dexmedetomidine also has analgesic effects at the spinal cord level and other supraspinal sites. [45]

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. [47] 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. [7] 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. [7] As such, it should be used with caution in people with liver disease or hepatic impairment. [33]

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

It can also be absorbed sublingually. [29]

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. [48]

Veterinary use

Dexmedetomidine, under the trade 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. [49] The FDA approved dexmedetomidine for use in dogs in 2006 and cats in 2007. [50]

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. [51] [52]

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">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. Depending on the procedure, general anaesthesia may be optional or required. Regardless of whether a patient may prefer to be unconscious or not, certain pain stimuli could result in involuntary responses from the patient that may make an operation extremely difficult. Thus, for many procedures, general anaesthesia is required from a practical perspective.

<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 approved under the brand name Diprivan. Numerous generic versions have since been released. 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">Clonidine</span> Pharmaceutical drug

Clonidine, sold under the brand name Catapres among others, is an α2A-adrenergic agonist medication used to treat high blood pressure, ADHD, drug withdrawal, menopausal flushing, diarrhea, spasticity, and certain pain conditions. The drug is often prescribed off-label for tics. It is used orally, by injection, or as a transdermal skin patch. Onset of action is typically within an hour with the effects on blood pressure lasting for up to eight hours.

<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 structural analog of clonidine and an alpha-2 adrenergic receptor agonist, sold under many trade names worldwide, most notably the Bayer brand name Rompun, as well as Anased, Sedazine and Chanazine.

<span class="mw-page-title-main">Droperidol</span> Antidopaminergic drug

Droperidol is an antidopaminergic drug used as an antiemetic and as an antipsychotic. Droperidol is also often used as a rapid sedative in intensive-care treatment, and where "agitation aggression or violent behavior" are present.

<span class="mw-page-title-main">Butorphanol</span> Opioid analgesic

Butorphanol is a morphinan-type synthetic agonist–antagonist opioid analgesic developed by Bristol-Myers. Butorphanol is most closely structurally related to levorphanol. Butorphanol is available as the tartrate salt in injectable, tablet, and intranasal spray formulations. The tablet form is only used in dogs, cats and horses due to low bioavailability in humans.

<span class="mw-page-title-main">Alpha-2 adrenergic receptor</span> Protein family

The alpha-2 (α2) adrenergic receptor is a G protein-coupled receptor (GPCR) associated with the Gi heterotrimeric G-protein. It consists of three highly homologous subtypes, including α2A-, α2B-, and α2C-adrenergic. Some species other than humans express a fourth α2D-adrenergic receptor as well. Catecholamines like norepinephrine (noradrenaline) and epinephrine (adrenaline) signal through the α2-adrenergic receptor in the central and peripheral nervous systems.

<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">Alpha-adrenergic agonist</span> Class of drugs

Alpha-adrenergic agonists are a class of sympathomimetic agents that selectively stimulates alpha adrenergic receptors. The alpha-adrenergic receptor has two subclasses α1 and α2. Alpha 2 receptors are associated with sympatholytic properties. Alpha-adrenergic agonists have the opposite function of alpha blockers. Alpha adrenoreceptor ligands mimic the action of epinephrine and norepinephrine signaling in the heart, smooth muscle and central nervous system, with norepinephrine being the highest affinity. The activation of α1 stimulates the membrane bound enzyme phospholipase C, and activation of α2 inhibits the enzyme adenylate cyclase. Inactivation of adenylate cyclase in turn leads to the inactivation of the secondary messenger cyclic adenosine monophosphate and induces smooth muscle and blood vessel constriction.

Veterinary anesthesia is a specialization in the veterinary medicine field dedicated to the proper administration of anesthetic agents to non-human animals to control their consciousness during procedures. A veterinarian or a Registered Veterinary Technician administers these drugs to minimize stress, destructive behavior, and the threat of injury to both the patient and the doctor. The duration of the anesthesia process goes from the time before an animal leaves for the visit to the time after the animal reaches home after the visit, meaning it includes care from both the owner and the veterinary staff. Generally, anesthesia is used for a wider range of circumstances in animals than in people not only due to their inability to cooperate with certain diagnostic or therapeutic procedures, but also due to their species, breed, size, and corresponding anatomy. Veterinary anesthesia includes anesthesia of the major species: dogs, cats, horses, cattle, sheep, goats, and pigs, as well as all other animals requiring veterinary care such as birds, pocket pets, and wildlife.

<span class="mw-page-title-main">Dezocine</span> Opioid analgesic

Dezocine, sold under the brand name Dalgan, is an atypical opioid analgesic which is used in the treatment of pain. It is used by intravenous infusion and intramuscular injection.

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

Medetomidine is a veterinary anesthetic drug with potent sedative effects and emerging illicit drug adulterant.

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

Atipamezole, sold under the brand name Antisedan among others, is a synthetic α2 adrenergic receptor antagonist used 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.

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

Romifidine is a drug that is used in veterinary medicine as a sedative mainly in large animals such as horses, although it may be used in a wide variety of species. It is not used in humans, but is closely related in structure to the commonly used drug clonidine.

Alpha-2 blockers are a subset of the alpha blocker class of drugs and are antagonists to the α2 adrenergic receptor. They are mainly used in research, having found limited clinical application in human medicine. They are extensively used in veterinary medicine to reverse the effects of alpha-2 agonist drugs used as sedatives, like xylazine, medetomidine and dexmedetomidine. Alpha-2 blockers increase noradrenaline release.

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.

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">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. ↑ "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.
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  34. ↑ 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.
  35. ↑ "PDSP Database". UNC (in Zulu). Retrieved 11 September 2024.
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