Atipamezole

Atipamezole (brand name Antisedan, also available in generic forms^[1] as Revertidine),^[2] 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.

Atipamezole

Clinical data
Trade names	Antisedan
AHFS/Drugs.com	Veterinary Use International Drug Names
Routes of administration	IM (licensed), IV (off-label)
Drug class	Reversal agent
ATCvet code	QV03AB90 (WHO)
Legal status
Legal status	Veterinary use only
Pharmacokinetic data
Metabolism	Hepatic
Onset of action	Less than 3 min.
Elimination half-life	2.6 hours (dogs)
Excretion	Urine
Identifiers
IUPAC name 4-(2-Ethyl-1,3-dihydroinden-2-yl)-3H-imidazole
CAS Number	104054-27-5^N
PubChem CID	71310
DrugBank	DB11481^Y
ChemSpider	64427^Y
UNII	03N9U5JAF6
KEGG	D03002^Y
ChEMBL	ChEMBL353972^Y
CompTox Dashboard (EPA)	DTXSID2049135
Chemical and physical data
Formula	C14H16N2
Molar mass	212.296 g·mol^−1
3D model (JSmol)	Interactive image
SMILES [nH]1cc(nc1)C3(Cc2c(cccc2)C3)CC
InChI InChI=1S/C14H16N2/c1-2-14(13-9-15-10-16-13)7-11-5-3-4-6-12(11)8-14/h3-6,9-10H,2,7-8H2,1H3,(H,15,16)^Y Key:HSWPZIDYAHLZDD-UHFFFAOYSA-N^Y
^NY (what is this?)  (verify)

It was originally released in 1996 and is sold in the U.S. by Zoetis.^[3]

Medical uses

Atipamezole is a veterinary drug whose prime purpose is to reverse the effects of the sedative dexmedetomidine (as well as its racemic mixture, medetomidine).^{[note 1][4][5]} It can also be used to reverse the related sedative xylazine.^[6] While it reverses both the sedative and analgesic (pain-relieving) effects of dexmedetomidine, atipamezole may not entirely reverse the cardiovascular depression that dexmedetomidine causes.^[4][7][8]

Atipamezole is licensed in the United States for intramuscular injection (IM) in dogs; it is, however, used off-label in cats, rabbits,^[9] and farm animals such as horses and cows,^[7] as well as in zoo medicine for reptiles (including tortoises, turtles, and alligators), armadillos, hippopotamuses, giraffes, okapi, and others.^[10][11] It has been given intravenously (IV), subcutaneously, intraperitoneally and, in red-eared sliders, intranasally.^[12][13] IV administration is recommended in emergencies.^[7][14]

Atipamezole has also been used as an antidote for various toxicities in dogs. For example, the anti-tick medication amitraz is commonly ingested by dogs who eat their anti-tick collars.^[15] Amitraz works by the same mechanism as dexmedetomidine and is thus easily reversed by atipamezole.^[16][17] Atipamezole also reverses the hypotension caused by tizanidine (a muscle relaxant) toxicity, and relieves toxicity from decongestants such as ephedrine and pseudoephedrine.^[18]

Available forms

Atipamezole is sold at 5 mg/mL for ease of use: 5 times as much atipamezole as medetomidine is needed for full reversal, and because medetomidine is sold as 1 mg/mL, 1 mL of atipamezole reverses 1 mL of medetomidine.^[19] When the enantiomerically pure version of medetomidine (dexmedetomidine) was released, it was sold at 0.5 mg/mL, because it was twice as strong as medetomidine. As such, 1 mL of atipamezole also reverses 1 mL of dexmedetomidine.^[5][7]

Specific populations

Atipamezole is not recommended for animals that are pregnant, lactating, or slated for breeding.^[20]

Contraindications

While there are no absolute contraindications to atipamezole, it is recommended against being given with anticholinergics, as both can cause dramatic increases in heart rate.^[6][16] Atipamezole should also not be given too soon after an animal has been given dexmedetomidine mixed with ketamine or telazol(tiletamine); because it reverses only the dexmedetomidine, the ketamine or telazol will still be active, and the animal can wake up excited, delirious, and with muscle contractions.^[21] Some recommend not using it in dogs sedated with ketamine at all, since they can convulse due to the excitement effect.^[22]

Side effects

Atipamezole's low rate of side effects is due to its high specificity for ɑ₂-adrenergic receptors; it has very little affinity for ɑ₁-adrenergic receptors and no affinity for most serotonin, muscarinic, and dopamine receptors.^[7][23][24] There is occasional vomiting, hypersalivation, and diarrhea. It can potentially cause CNS excitement, which can lead to tremors, tachycardia (increased heart rate), and vasodilation. The vasodilation leads to a transient decrease in blood pressure, which (in dogs) increases to normal within 10 minutes.^[4] There have been reports of transient hypoxemia.^[21] The chance of side effect can be minimized by administering atipamezole slowly.^[7]

 

Atipamezole is sold as "Antisedan".

There is a possibility of the sedation reversing abruptly, leading to nervous, aggressive, or delirious dogs.^[4] Such cases are more associated with IV administration^[14] (which has a faster onset than IM administration). The rapid administration of atipamezole leads to sudden displacement of dexmedetomidine from peripheral ɑ₂-adrenergic receptors; this can cause a sudden drop in blood pressure, which is followed by a reflex tachycardia and hypertension.^[7][22][25]

There have been some cases where IV administration of atipamezole lead to death via cardiovascular collapse. This is thought to be combination of sudden hypotension added onto the low heart rate caused by sedatives.^[7]

There is some possibility of the animal relapsing into sedation after being given atipamezole, made more likely if the original sedative was given IV.^[4]

Rats and monkeys have experienced increased sexual activity after being given atipamezole.^[26][27]

Overdose

The LD₅₀ of atipamezole for rats is 44 mg/kg when given subcutaneously. The minimum lethal dose in dogs is over 5 mg/m²; dogs have tolerated getting ten times the standard dose.^[4][28] Signs of overdose include panting, trembling, vomiting, and diarrhea, as well as increased blood levels of creatinine kinase, aspartate transaminase, and alanine transaminase. Dogs who received atipamezole without first receiving dexmedetomidine have shown no clinical signs other than mild muscle tremors.^[4][19]

Pharmacology

Mechanism of action

 

The structures of dexmedetomidine and atipamezole, with the similarities in blue.

Atipamezole is a competitive antagonist at ɑ₂-adrenergic receptors that competes with dexmedetomidine, an ɑ₂-adrenergic receptors agonist. It does not directly interact with dexmedetomidine;^[29] rather, their structural similarity allows atipamezole to easily compete for receptor binding sites.^[7]

Atipamezole reverses analgesia by blocking norepinephrine feedback inhibition on nociceptors.^[7][26]

Site	Ki (nM)	Species	Ref
α1	3160	Human	^[30]
α2A	1.9	Human	^[31]
α2B	2.2	Human	^[31]
α2C	4.2	Human	^[31]
The Ki refers to a drug's affinity for a receptor. The smaller the Ki, the higher the affinity for that receptor.

Pharmacokinetics

Out of the three ɑ₂-antagonists commonly used in veterinary medicine (atipamezole, yohimbine, and tolazine), atipamezole shows the highest preference for ɑ₂- over ɑ₁-receptors, binding to them with a ratio of 8526:1.^[7] It shows no preference for a particular ɑ₂-receptor subtype.^[26]

Atipamezole has a rapid onset: it reverses the decreased heart rate caused by sedation within three minutes. The animal usually begins waking up within 5–10 minutes. In a study of over 100 dogs, more than half could stand up within 5 minutes, and 96% could stand up within 15. Atipamezole reaches maximum serum concentration within 10 minutes of IM administration.^[4] Atipamezole is distributed extensively to the tissues; at a particular time, concentrations in the brain reach two to three times the concentration in the plasma.^[23]

Atipamezole undergoes heavy first-pass metabolism in the liver,^[23] which includes the glucuronidation at nitrogen during.^[32] Metabolites are mostly excreted in the urine.^[33]

The elimination half-life is 2.6 hours in dogs and 1.3 hours rats.^[4][16]

Research

Atipamezole's effects on cognitive function have been studied in rats and in humans. While low doses in rats improved alertness, selective attention, learning, and recall, higher doses generally impaired cognitive function (most likely due to norepinephrine overactivity).^[26] In rats, it has also been shown to improve cognitive function decreased by strokes or brain lesions.^[16] Studies in humans have found it to increase focus but decrease multitasking abilities.^[23] Atipamezole has also been researched in humans as a potential anti-Parkinsonian.^[23]

Because atipamezole increases sexual activity in monkeys, there have been claims of its potential to treat erectile dysfunction.^[27]

See also

• Detomidine
• Flumazenil
• Naloxone

Notes

1. Because dexmedetomidine is the only pharmacologically active component of medetomidine, they will both be referred to as dexmedetomidine from here on out.

References

1. "Atipamezole". Drugs.com. Retrieved 2019-08-07.
2. "Revertidine". Modern Veterinary Therapeutics. Retrieved 2019-08-07.
3. Ettinger SJ, Feldman EC (2009). Textbook of Veterinary Internal Medicine - eBook (7th ed.). Elsevier Health Sciences. p. 61. ISBN 978-1-4377-0282-8.
4. "Antisedan for Animal Use". Drugs.com. Retrieved 24 February 2018.
5. Cote 2010, p. 1623.
6. Papich MG (2010). Saunders Handbook of Veterinary Drugs – E-Book: Small and Large Animal. Elsevier Health Sciences. p. 56. ISBN 978-1-4377-0192-0.
7. Riviere JE, Papich MG (2009). Veterinary Pharmacology and Therapeutics (illustrated ed.). John Wiley & Sons. pp. 352–355. ISBN 978-0-8138-2061-3.
8. Talke P, Harper D, Traber L, Richardson CR, Traber D (February 1999). "Reversal of medetomidine induced sedation by atipamezole in sheep: Effects on organ blood". Anesthesia & Analgesia. 88 (2S): 391S. doi:10.1097/00000539-199902001-00388. ISSN 0003-2999.
9. Kim MS, Jeong SM, Park JH, Nam TC, Seo KM (October 2004). "Reversal of medetomidine-ketamine combination anesthesia in rabbits by atipamezole". Experimental Animals. 53 (5): 423–428. doi:10.1538/expanim.53.423. PMID 15516790.
10. Heaton-Jones TG, Ko JC, Heaton-Jones DL (March 2002). "Evaluation of medetomidine-ketamine anesthesia with atipamezole reversal in American alligators (Alligator mississippiensis)". Journal of Zoo and Wildlife Medicine. 33 (1): 36–44. doi:10.1638/1042-7260(2002)033[0036:EOMKAW]2.0.CO;2. PMID 12216791. S2CID 25527884.
11. Miller RE, Fowler ME (2014). Fowler's Zoo and Wild Animal Medicine, Volume 8 – E-Book (revised ed.). Elsevier Health Sciences. pp. 29, 358, 587, 605. ISBN 978-1-4557-7399-2.
12. Mader DR, Divers SJ (2013). Current Therapy in Reptile Medicine and Surgery - E-Book. Elsevier Health Sciences. pp. 143, 387. ISBN 978-0-323-24293-6.
13. Wang-Fischer Y (2008). Manual of Stroke Models in Rats. CRC Press. p. 65. ISBN 978-1-4200-0952-1.
14. Fish 2008, p. 371.
15. DeClementi C (2007). "Chapter 91: Prevention and treatment of poisoning". In Gupta R (ed.). Veterinary Toxicology. Oxford: Academic Press. pp. 1139–1158. doi:10.1016/B978-012370467-2/50188-7. ISBN 978-0-12-370467-2.
16. Bahri L (May 2008). "Pharm Profile: Atipamezole". Compendium. 30 (5).
17. Gupta RC (2007). "Chapter 46: Amitraz". Veterinary Toxicology. Oxford: Academic Press. pp. 514–517. doi:10.1016/B978-012370467-2/50143-7. ISBN 978-0-12-370467-2.
18. Cote 2010, pp. 126, 285.
19. Clarke KW, Trim CM (2013). Veterinary Anaesthesia E-Book (11th ed.). Elsevier Health Sciences. p. 91. doi:10.1016/B978 (inactive 1 August 2023). ISBN 978-0-7020-5423-5.{{cite book}}: CS1 maint: DOI inactive as of August 2023 (link)
20. L.S.A., List of C.F.R. Sections Affected. National Archives of the United States. 2004. p. 221. ISBN 978-0-16-072065-9.
21. Schenck P (2009). Saunders Comprehensive Review of the NAVLE – E-Book. Elsevier Health Sciences. p. 402. ISBN 978-1-4377-1448-7.
22. Dugdale A (2011). Veterinary Anaesthesia: Principles to Practice. John Wiley & Sons. pp. 257, 368. ISBN 978-1-118-27933-5.
23. Pertovaara A, Haapalinna A, Sirviö J, Virtanen R (1 September 2005). "Pharmacological properties, central nervous system effects, and potential therapeutic applications of atipamezole, a selective alpha2-adrenoceptor antagonist". CNS Drug Reviews. 11 (3): 273–288. doi:10.1111/j.1527-3458.2005.tb00047.x. PMC 6741735. PMID 16389294.
24. Sawyer D (2008). The Practice of Veterinary Anesthesia: Small Animals, Birds, Fish and Reptiles. Manson Series. CRC Press. p. 42. ISBN 978-1-59161-034-2.
25. Divers SJ, Mader DR (2005). Reptile Medicine and Surgery - E-Book (2 ed.). Elsevier Health Sciences. p. 444. ISBN 978-1-4160-6477-0.
26. Fish 2008, pp. 53–54.
27. Annual Reports in Medicinal Chemistry. Vol. 34. Academic Press. 1999. p. 78. ISBN 978-0-08-058378-5.
28. "Safety Data Sheet" (PDF). Zoetis. 20 March 2017.
29. Grant D (2006). Pain Management in Small Animals. Elsevier Health Sciences. pp. 191, 199. ISBN 978-0-7506-8812-3.
30. Blaxall HS, Murphy TJ, Baker JC, Ray C, Bylund DB (October 1991). "Characterization of the alpha-2C adrenergic receptor subtype in the opossum kidney and in the OK cell line". The Journal of Pharmacology and Experimental Therapeutics. 259 (1): 323–329. PMID 1656026.
31. Vacher B, Funes P, Chopin P, Cussac D, Heusler P, Tourette A, Marien M (October 2010). "Rigid analogues of the α2-adrenergic blocker atipamezole: small changes, big consequences". Journal of Medicinal Chemistry. 53 (19): 6986–6995. doi:10.1021/jm1006269. PMID 20809632.
32. Kaivosaari S, Salonen JS, Taskinen J (March 2002). "N-Glucuronidation of some 4-arylalkyl-1H-imidazoles by rat, dog, and human liver microsomes". Drug Metabolism and Disposition. 30 (3): 295–300. doi:10.1124/dmd.30.3.295. PMID 11854148.
33. Peterson ME, Kutzler M (2010). Small Animal Pediatrics – E-Book: The First 12 Months of Life. Elsevier Health Sciences. p. 226. ISBN 978-1-4377-0195-1.

Further reading

• Cote E (2010). Clinical Veterinary Advisor – E-Book: Dogs and Cats (2nd, revised ed.). Elsevier Health Sciences. ISBN 978-0-323-06876-5.
• Fish RE (2008). Anesthesia and Analgesia in Laboratory Animals. American College of Laboratory Animal Medicine series. Academic Press. ISBN 978-0-12-373898-1.

External links

•   Media related to Atipamezole at Wikimedia Commons
• Official website of Antisedan.