Medetomidine

Medetomidine
Clinical data
AHFS/Drugs.com	Monograph
ATCvet code	QN05CM91 (WHO) ;
Legal status
Legal status	Veterinary use only;
Identifiers
	IUPAC name (RS)-4-[1-(2,3-Dimethylphenyl)ethyl]-3H-imidazole;
CAS Number	86347-14-0 ;
PubChem CID	68602;
DrugBank	DB00633 ;
ChemSpider	61868 ;
UNII	MR15E85MQM;
KEGG	D08165 ;
ChEBI	CHEBI:48552 ;
ChEMBL	ChEMBL77921 ;
CompTox Dashboard (EPA)	DTXSID6048258 ;
ECHA InfoCard	100.242.450
Chemical and physical data
Formula	C13H16N2
Molar mass	200.285 g·mol−1
3D model (JSmol)	Interactive image;
Chirality	Racemic mixture
	SMILES n1cc([nH]c1)C(c2c(c(ccc2)C)C)C;
	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) ; Key:CUHVIMMYOGQXCV-UHFFFAOYSA-N ;
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Medetomidine is a veterinary anesthetic drug 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] It is often used as the hydrochloride salt, medetomidine hydrochloride, a crystalline white solid that can be administered as an intravenous drug solution with sterile water.^{[citation needed]}

Veterinary use

In veterinary anesthesia, medetomidine is used as both a surgical and analgesic in combinations with opioids (butorphanol, buprenorphine etc.) as premedication (before a general anesthetic) in healthy cats and dogs. It is sometimes used in combination with butorphanol and ketamine (given IM) to produce general anaesthesia for short periods in healthy, but fractious felines, that will not allow an intravenous induction agent to be given providing a good degree of muscle relaxation. It has also been used in combination with morphine (or methadone), lidocaine and ketamine in constant rate infusion analgesia in canines. It is often used in so called microdoses for this analgesic effect. It is thought that this family of drugs has a degree of analgesic action, though this is, in comparison to the sedative effect, minor.

It can be given by intramuscular injection (IM), subcutaneous injection (SC) or intravenous injection (IV). When delivered intravenously, a significantly decreased dose is used. Some authors suggest a sublingual route is also effective. It is not recommended for diabetics, it is contraindicated in patients with cardiac disease.

Due to its potent sedative effects it is commonly used in more aggressive animals, where a drug combination with a lesser effect (such as acepromazine plus an opioid, or an opioid plus a benzodiazepine) would not allow the administration of the inductive agent without risk to the veterinarian. As such the use of alpha-two agonists is only recommended in healthy animals.

Side effects

Following administration, marked peripheral vasoconstriction and bradycardia are noted.^[6] Often the dosage of induction agents (e.g. propofol) may be drastically reduced, as may the volumes of anesthetic gases (i.e. halothane, isoflurane, sevoflurane) used to maintain general anesthesia.

Its effects can be reversed using atipamezole distributed as Antisedan by Pfizer. IV use of atipamezole is not licensed, IM is the preferred route. Yohimbine may also be used in an emergency situation, but is not licensed.

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.^[7] 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.^[8] 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.

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, 2023. 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.^[9]^[10]^[11]^[12]^[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^[13] and Pittsburgh, PA. Cases of overdose in Chicago from medetomidine/fentanyl mixtures have been reported In May, 2024.^[14] Massachusetts reported its first cases in August 2024.^[15]

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".^[16]

Other criminal use

Medetomidine was found in combination with the mu-opioid antagonist and kappa-opioid agonist Butorphanol and sedative dopamine antagonist tranquilizer Azaperone in the blood of a 49-year old female homicide victim from Colorado that went missing after a bike ride in 2020. Such a mixture wouldn't be used for recreational use and would instead likely produce dysphoria with heavy sedative effects that may render a person immobile or unable to defend themselves.^[17]^[18]^[19]

References

^ ^a ^b ^c de Andrade Horn P, Berida TI, Parr LC, Bouchard JL, Jayakodiarachchi N, Schultz DC, Lindsley CW, Crowley ML (October 2024). "Classics in Chemical Neuroscience: Medetomidine". ACS Chem Neurosci. doi:10.1021/acschemneuro.4c00583.
^ ^a ^b "Achievements". Orion Corporation. Archived from the original on March 15, 2013.
^ ^a ^b Chaabane P. "The Selektope Story" (PDF). PCI Magazine. Retrieved 12 December 2018.
^ ^a ^b Schwarz, Evan S. (2024). "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. doi:10.15585/mmwr.mm7330a3. ISSN 0149-2195. PMC 11305408. PMID 39088371.
^ Sinclair MD (November 2003). "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): 885–97. PMC 385445. PMID 14664351.
^ "Domitor". Novartis Animal Health Canada. 2003. Archived from the original on 2007-09-24.
^ Dahlström M, Mårtensson LG, Jonsson PR, Arnebrant T, Elwing H (November 2000). "Surface active adrenoceptor compounds prevent the settlement of cyprid larvae of Balanus improvisus". Biofouling. 16 (2–4): 191–203. Bibcode:2000Biofo..16..191D. doi:10.1080/08927010009378444. S2CID 85603381.
^ Lind U, Alm Rosenblad M, Hasselberg Frank L, Falkbring S, Brive L, Laurila JM, et al. (August 2010). "Octopamine receptors from the barnacle balanus improvisus are activated by the alpha2-adrenoceptor agonist medetomidine". Molecular Pharmacology. 78 (2): 237–48. doi:10.1124/mol.110.063594. PMID 20488921. S2CID 17792301.
^ "Medetomidine Rapidly Proliferating Across USA — Implicated In Recreational Opioid Drug Supply & Causing Overdose Outbreaks". www.cfsre.org. Retrieved 2024-06-12.
^ https://www.cfsre.org/images/monographs/Medetomidine-New-Drug-Monograph-NPS-Discovery-112723.pdf ^{[bare URL PDF]}
^ https://www.cfsre.org/images/content/reports/public_alerts/Public_Alert_Medetomidine_052024.pdf ^{[bare URL PDF]}
^ Nelson, Sarah. "What to know about medetomidine, the latest sedative found in illicit Indy drug supplies". The Indianapolis Star. Retrieved 2024-06-12.
^ Whelan, Aubrey (2024-05-18). "Philly health officials detect a veterinary sedative more powerful than xylazine in drug samples". Retrieved 2024-06-12.
^ Dodge, John (2024-05-20). "Powerful animal sedative likely cause of overdose spike in Chicago - CBS Chicago". www.cbsnews.com. Retrieved 2024-06-12.
^ "'More toxic': Potent sedative triggering unexpected spike in overdoses, Mass. hospital warns". Boston 25 News. 2024-08-13. Retrieved 2024-08-14.
^ "Gangs mix another potent sedative into U.S. street drugs causing 'mass overdoses'". NPR.
^ Prentzel, Olivia (2024-04-29). "Suzanne Morphew's death was a homicide and she had tranquilizer in her system, autopsy reveals". The Colorado Sun. Retrieved 2024-06-12.
^ "Suzanne Morphew autopsy: Here are the drugs that were found in her body". KUSA.com. 2024-04-29. Retrieved 2024-06-12.
^ "Suzanne Morphew's autopsy finds animal tranquilizer, other drugs in system". FOX31 Denver. 2024-04-29. Retrieved 2024-06-12.