Chemistry:Medetomidine

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Medetomidine is a veterinary anesthetic medication with potent sedative effects and emerging illicit drug adulterant.[1]

It is a racemic mixture of two stereoisomers, levomedetomidine and dexmedetomidine, the latter being the isomer with the pharmacologic effect as an alpha 2- adrenergic agonist. Effects can be reversed using atipamezole.

It was developed by Orion Pharma.[2] It is approved for dogs in the United States, and distributed in the United States by Pfizer Animal Health and by Novartis Animal Health in Canada under the product name Domitor. Starting in 2022 medetomidine has been detected in the US in samples of illicit drugs and associated with overdoses.

The free base form of medetomidine is sold as an antifouling substance for marine paints.[3]

History

Medetomidine was developed by Orion Pharma and launched in 2007.[2]

Pharmacology

Medetomidine is a racemic mixture of two optical or stereoisomers, levomedetomidine and dexmedetomidine.[4] The latter causes the alpha 2- adrenergic agonist effects.[5]

Medetomidine is an α2-adrenergic receptor agonist that binds at a ratio of 1620:1 with imidazoline receptor activity.[6]

Medetomidine is metabolised in the liver via hydroxylation.[6]

Veterinary use

Medetomidine has supplanted xylazine as a sedative for cats and dogs in several countries. Medetomidine is used off-label in horses.[6]

Atipamezole, an a2 adrenergic antagonist, was developed specifically as a reversal agent for medetomidine.[6]

Side effects

Following administration, marked peripheral vasoconstriction and bradycardia are noted.[7]

Medetomidine administration in sheep activates pulmonary macrophages that damage the capillary endothelium and alveolar type I cells. This in turns causes alveolar haemorrhage and oedema causing hypoxaemia.[6][8][9]

Use in marine paint

The free base form of medetomidine is sold as Selektope as an antifouling substance in marine paints.[3] It is mainly effective against barnacles, as shown in vitro with Balanus improvisus.[10] It has also shown effect on other hard fouling like tube worms. When the barnacle cyprid larva encounters a surface containing medetomidine the molecule interacts with the octopamine receptor in the larva. This causes the settling larva to increase its kicking to more than 100 kicks per minute, which makes becoming sessile nearly impossible.[11] When the larva swims away from the surface, the effect disappears (reversible effect). The larva regains its pre-exposure function and can settle somewhere else.[citation needed]

Illicit use in humans

Component of street drugs

Medetomidine has been found as a component in street drug mixtures in the US starting in 2022,[4][1] containing synthetic opioids in a similar manner as xylazine-fentanyl, such mixtures have been nicknamed "tranq" (short for tranquilizer). The combination of α2 adrenergic agonists with opioids are believed to greatly increase the sedative effects of each drug, which some drug users may perceive as a better or more potent product. The Center for Forensic Science Research and Education (CFSRE) first identified a synthetic opioid blend containing fentanyl and medetomidine sold in Maryland in July, 2022. Additional detections in late 2023 found similar medetomidine mixtures in Missouri, Colorado, Pennsylvania, California, and Maryland found in both drug material and the blood of patients experiencing overdoses.[12][13][14][15][1]

In January 2024 drug mixtures containing medetomidine were identified in the Canadian city of Toronto, ON. In April, 2024 and May, 2024 medetomidine was found in a mixture containing fentanyl and xylazine in Philadelphia, PA[16] and Pittsburgh, PA. Cases of overdose in Chicago from medetomidine/fentanyl mixtures have been reported In May, 2024.[17] Massachusetts reported its first cases in August 2024.[18]

Medetomidine does not respond to naloxone, complicating the medical response to overdoses. During summer 2024 there were "mass overdose events" linked to medetomidine adulterated drugs in Chicago and Philadelphia. Emergency room doctors in Philadelphia reported waves of overdose patients coming in with unusually low heart rates. Public health advisories were issued. Experts warned that it was not business as usual for first responders, emergency room personnel or drug users. One researcher compared experimenting with the current drug supply to "playing Russian roulette".[19]

References

  1. ↑ 1.0 1.1 1.2 "Classics in Chemical Neuroscience: Medetomidine". ACS Chem Neurosci 15 (21): 3874–3883. October 2024. doi:10.1021/acschemneuro.4c00583. PMID 39405508. 
  2. ↑ 2.0 2.1 "Achievements". Orion Corporation. http://orion.fi/en/Research-and-developement/Achievements/. 
  3. ↑ 3.0 3.1 "The Selektope Story". PCI Magazine. https://www.pcimag.com/ext/resources/WhitePapers/2016/The-Selektope-Story-v2.pdf. 
  4. ↑ 4.0 4.1 "Notes from the Field: Detection of Medetomidine Among Patients Evaluated in Emergency Departments for Suspected Opioid Overdoses - Missouri, Colorado, and Pennsylvania, September 2020-December 2023". MMWR. Morbidity and Mortality Weekly Report 73 (30): 672–674. August 2024. doi:10.15585/mmwr.mm7330a3. PMID 39088371. 
  5. ↑ "A review of the physiological effects of alpha2-agonists related to the clinical use of medetomidine in small animal practice". The Canadian Veterinary Journal 44 (11): 885–897. November 2003. PMID 14664351. 
  6. ↑ 6.0 6.1 6.2 6.3 6.4 "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. 
  7. ↑ "Domitor". Novartis Animal Health Canada. 2003. http://www.ah.ca.novartis.com/product/domitor.html. 
  8. ↑ "Histopathologic alterations induced in the lungs of sheep by use of alpha2-adrenergic receptor agonists". American Journal of Veterinary Research (Am J Vet Res) 60 (2): 154–161. February 1999. doi:10.2460/ajvr.1999.60.02.154. PMID 10048544. 
  9. ↑ "The comparative hypoxaemic effect of four alpha 2 adrenoceptor agonists (xylazine, romifidine, detomidine and medetomidine) in sheep". Journal of Veterinary Pharmacology and Therapeutics 20 (6): 464–471. December 1997. doi:10.1046/j.1365-2885.1997.00097.x. PMID 9430770. 
  10. ↑ "Surface active adrenoceptor compounds prevent the settlement of cyprid larvae of Balanus improvisus.". Biofouling 16 (2–4): 191–203. November 2000. doi:10.1080/08927010009378444. Bibcode: 2000Biofo..16..191D. 
  11. ↑ "Octopamine receptors from the barnacle balanus improvisus are activated by the alpha2-adrenoceptor agonist medetomidine". Molecular Pharmacology 78 (2): 237–48. August 2010. doi:10.1124/mol.110.063594. PMID 20488921. https://www.researchgate.net/publication/44617476. 
  12. ↑ "Medetomidine Rapidly Proliferating Across USA — Implicated In Recreational Opioid Drug Supply & Causing Overdose Outbreaks". https://www.cfsre.org/nps-discovery/public-alerts/medetomidine-rapidly-proliferating-across-usa-implicated-in-recreational-opioid-drug-supply-causing-overdose-outbreaks. 
  13. ↑ "Medetomidine". https://www.cfsre.org/images/monographs/Medetomidine-New-Drug-Monograph-NPS-Discovery-112723.pdf. 
  14. ↑ "Medetomidine rapidly proliferating across USA — Implicated in recreational opioid drug supply & causing overdose outbreaks". https://www.cfsre.org/images/content/reports/public_alerts/Public_Alert_Medetomidine_052024.pdf. 
  15. ↑ "What to know about medetomidine, the latest sedative found in illicit Indy drug supplies". https://www.indystar.com/story/news/crime/2024/05/24/what-to-know-about-medetomidine-the-latest-threat-in-street-drugs/73837879007/. 
  16. ↑ "Philly health officials detect a veterinary sedative more powerful than xylazine in drug samples". 2024-05-18. https://www.inquirer.com/health/medetomidine-nitazenes-philadelphia-drug-overdoses-20240518.html. 
  17. ↑ "Powerful animal sedative likely cause of overdose spike in Chicago". 2024-05-20. https://www.cbsnews.com/chicago/news/powerful-animal-sedative-likely-cause-of-overdose-spike-in-chicago/. 
  18. ↑ "'More toxic': Potent sedative triggering unexpected spike in overdoses, Mass. hospital warns". Boston 25 News. 2024-08-13. https://www.boston25news.com/news/local/more-toxic-potent-sedative-triggering-unexpected-spike-opioid-overdoses-mass-hospital-warns/Y7XMSFG6GVGFHBYCLXYZXFUVOI/. 
  19. ↑ "Gangs mix another potent sedative into U.S. street drugs causing 'mass overdoses'". NPR. https://www.npr.org/2024/05/31/nx-s1-4974959/medetomidine-overdose-fentanyl-sedative. 

Further reading

hu:Medetomidin



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