Chemistry:Vatinoxan

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Vatinoxan, originally known as MK-467, is an α2-adrenergic receptor antagonist used in veterinary medicine alongside α2-adrenergic receptor agonists to counteract vasoconstriction and hypertension while maintaining sedation.[1][2][3] Vatinoxan does not cross the blood–brain barrier giving it a unique pharmacological profile compared to the other α2-adrenergic receptor antagonists and distinct clinical application.[4]

Medical uses

Vatinoxan mitigates the cardiovascular depression caused by medetomidine and dexmedetomidine, although hypotension may still occur.[4][5][6][7][8][9] Administration of dobutamine, norepinephrine, or phenylephrine has been shown to restore normotension.[4][10][11]

Vatinoxan does not reduce central nervous system depression, as it is unable to cross the blood–brain barrier. However, it may influence the sedative effects of α2-adrenergic receptor agonists.[4]

Combination with medetomidine

A fixed-dose combination of medetomidine with vatinoxan (medetomidine/vatinoxan) is used to provide sedation whilst negating some of the negative cardiovascular effects of medetomidine.[4] This combination medication was approved in the US in 2022, and is sold under the brand name Zenalpha.[12]

Co-administration of vatinoxan and medetomidine improves recovery following atipamezole administration in sheep and dogs.[4][13][14]

Pharmacology

Vatinoxan binds to the α2-adrenergic receptor at a ratio of 105:1 over the α1-adrenergic receptor.[4] Vatinoxan appears to have no clinically relevant effect on the α1-adrenergic receptor based on a study in the horse and sheep.[15][4] Vatinoxan's low lipid solubility, molecular weight, ionisation, and protein binding cause it to poorly antagonise the α2-adrenergic receptors in the central nervous system whilst selectively antagonising peripheral and cardiovascular receptors. These properties make vatinoxan unique to the other α2-adrenergic receptor antagonists.[4]

Research

In a study on horses, vatinoxan administration was found to reduce medetomidine-induced sedation, which the authors hypothesised was due to altered clearance of medetomidine.[4][16] Conversely, a study in sheep reported that co-administration of vatinoxan and medetomidine enhanced sedation.[4][13]

Vatinoxan may also counteract the severe respiratory effects caused by α2-adrenergic receptor agonists in sheep.[4][17][18]

Additionally, vatinoxan has been shown to reduce the minimum alveolar concentration (MAC) of isoflurane and sevoflurane in two studies, although the underlying mechanism remains unclear and warrants further investigation.[4][19][20]

References

  1. ↑ "α2 Receptor Agonists and Antagonists" (in en). Pharmacology in Veterinary Anesthesia and Analgesia. John Wiley & Sons, Ltd. 2024. pp. 36–54. doi:10.1002/9781118975169.ch4. ISBN 978-1-118-97516-9. https://onlinelibrary.wiley.com/doi/abs/10.1002/9781118975169.ch4. Retrieved 2025-08-01. 
  2. ↑ "Vatinoxan: a new development in the clinical use of α2-adrenoceptor agonists in dogs, part 1.". Companion Animal 26 (8): 176–181. September 2021. doi:10.12968/coan.2021.0040. 
  3. ↑ "Vatinoxan: a new development in the clinical use of α2-adrenoceptor agonists in dogs, part 2.". Companion Animal 26 (10): 1–4. November 2021. doi:10.12968/coan.2021.0073. 
  4. ↑ 4.00 4.01 4.02 4.03 4.04 4.05 4.06 4.07 4.08 4.09 4.10 4.11 4.12 "Sedatives and Tranquilizers". Veterinary Anesthesia and Analgesia, The 6th Edition of Lumb and Jones. Wiley Blackwell. 2024. pp. 338–344. ISBN 978-1-119-83027-6. 
  5. ↑ "Effects of vatinoxan on cardiorespiratory function, fecal output and plasma drug concentrations in horses anesthetized with isoflurane and infusion of medetomidine". The Veterinary Journal 251. 2019. doi:10.1016/j.tvjl.2019.105345. PMID 31492389. 
  6. ↑ "Pharmacodynamics and plasma concentrations of dexmedetomidine with or without vatinoxan as a constant-rate infusion in horses anaesthetized with isoflurane—A pilot study". Journal of Veterinary Pharmacology and Therapeutics 44 (5): 754–765. 2021. doi:10.1111/jvp.12992. ISSN 0140-7783. PMID 34159620. 
  7. ↑ "Cardiovascular effects of dexmedetomidine, with or without MK-467, following intravenous administration in cats". Veterinary Anaesthesia and Analgesia 44 (1): 52–62. 2017. doi:10.1111/vaa.12397. PMID 27377604. 
  8. ↑ "The effects of increasing doses of MK-467, a peripheral alpha 2-adrenergic receptor antagonist, on the cardiopulmonary effects of intravenous dexmedetomidine in conscious dogs". Journal of Veterinary Pharmacology and Therapeutics 34 (4): 332–337. 2011. doi:10.1111/j.1365-2885.2010.01242.x. ISSN 0140-7783. PMID 20969603. 
  9. ↑ "Plasma concentration and cardiovascular effects of intramuscular medetomidine combined with three doses of the peripheral alpha2-antagonist MK-467 in dogs". Veterinary Anaesthesia and Analgesia 44 (3): 417–426. 2017. doi:10.1016/j.vaa.2016.04.006. PMID 28552594. https://helda.helsinki.fi/bitstream/10138/311074/1/Restitutti_et_al._2017.pdf. 
  10. ↑ "Cardiovascular effects of dobutamine, norepinephrine and phenylephrine in isoflurane-anaesthetized dogs administered dexmedetomidine–vatinoxan". Veterinary Anaesthesia and Analgesia 49 (6): 546–555. 2022. doi:10.1016/j.vaa.2022.07.007. PMID 36058821. https://helda.helsinki.fi/bitstream/10138/354974/1/PIIS1467298722001106.pdf. 
  11. ↑ "Cardiovascular effects of dexmedetomidine, with or without MK-467, following intravenous administration in cats". Veterinary Anaesthesia and Analgesia 44 (1): 52–62. 2017. doi:10.1111/vaa.12397. PMID 27377604. 
  12. ↑ "Zenalpha- vatinoxan hydrochloride and medetomidine hydrochloride solution". 11 May 2022. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=623f44bf-07c7-4704-8114-5e42e1316fb1. 
  13. ↑ 13.0 13.1 "Sedative effect of intramuscular medetomidine with and without vatinoxan (MK-467), and its reversal with atipamezole in sheep". Veterinary Anaesthesia and Analgesia 45 (6): 788–793. 2018. doi:10.1016/j.vaa.2018.06.009. PMID 30301665. 
  14. ↑ "Cardiovascular and sedation reversal effects of intramuscular administration of atipamezole in dogs treated with medetomidine hydrochloride with or without the peripheral α2-adrenoceptor antagonist vatinoxan hydrochloride". American Journal of Veterinary Research 80 (10): 912–922. 2019. doi:10.2460/ajvr.80.10.912. ISSN 0002-9645. PMID 31556714. 
  15. ↑ "Characterisation of the cardiovascular pharmacology of medetomidine in the horse and sheep". Research in Veterinary Science 65 (2): 149–154. 1998. doi:10.1016/S0034-5288(98)90167-9. PMID 9839894. https://linkinghub.elsevier.com/retrieve/pii/S0034528898901679. Retrieved 2025-07-30. 
  16. ↑ "Effects of vatinoxan on cardiorespiratory function and gastrointestinal motility during constant-rate medetomidine infusion in standing horses". Equine Veterinary Journal 51 (5): 646–652. 2019. doi:10.1111/evj.13085. ISSN 0425-1644. PMID 30793362. 
  17. ↑ "Cardiopulmonary effects of vatinoxan in sevoflurane-anaesthetised sheep receiving dexmedetomidine". The Veterinary Journal 238: 63–69. 2018. doi:10.1016/j.tvjl.2018.07.007. PMID 30103917. 
  18. ↑ "Effects of vatinoxan on xylazine-induced pulmonary alterations in sheep". Journal of Veterinary Pharmacology and Therapeutics 45 (1): 117–125. 2022. doi:10.1111/jvp.13013. ISSN 0140-7783. PMID 34478172. 
  19. ↑ "Effects of dexmedetomidine, with or without vatinoxan (MK-467), on minimum alveolar concentration of isoflurane in cats". Veterinary Anaesthesia and Analgesia 46 (4): 443–451. 2019. doi:10.1016/j.vaa.2019.02.004. PMID 30982711. 
  20. ↑ "Effects of constant rate infusions of dexmedetomidine or MK-467 on the minimum alveolar concentration of sevoflurane in dogs". Veterinary Anaesthesia and Analgesia 44 (4): 755–765. 2017. doi:10.1016/j.vaa.2016.12.058. PMID 28734855. 



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