Alfaxalone

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Alfaxalone
Chemical structure of alfaxalone
Bottle of Alfaxan; contains an opaque white liquid
Clinical data
Trade namesAlfaxan
Other namesAlphaxalone; Alphaxolone; Alfaxolone; 3α-Hydroxy-5α-pregnane-11,20-dione; PHAX-001; Phaxan, Alphaxalone (BAN UK)
AHFS/Drugs.comInternational Drug Names
License data
Drug class
  • Neuroactive steroid
  • General anesthetic
ATCvet code
Legal status
Legal status
Pharmacokinetic data
Protein binding30–50%
MetabolismHepatic
Metabolites
  • Alfaxalone glucuronide (major in dogs)
  • 20-Hydroxyalfaxalone sulfate (major in cats)
Elimination half-life
  • 25 min (dogs)
  • 45 min (cats)
renal
Identifiers
  • (3R,5S,8S,9S,10S,13S,14S,17S)-17-acetyl-3-hydroxy-10,13-dimethyl-1,2,3,4,5,6,7,8,9,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthren-11-one
JSmol)
  • O=C2[C@H]3[C@H]([C@@H]1CC[C@H](C(=O)C)[C@@]1(C)C2)CC[C@H]4C[C@H](O)CC[C@]34C
  • InChI=1S/C21H32O3/c1-12(22)16-6-7-17-15-5-4-13-10-14(23)8-9-20(13,2)19(15)18(24)11-21(16,17)3/h13-17,19,23H,4-11H2,1-3H3/t13-,14+,15-,16+,17-,19+,20-,21+/m0/s1 checkY
  • Key:DUHUCHOQIDJXAT-OLVMNOGESA-N checkY
  (verify)

Alfaxalone, also known as alphaxalone or alphaxolone and sold under the brand name Alfaxan, is a

premedications
aren't given, veterinary patients also become agitated and hypersensitive when waking up.

Alfaxalone works as a

terminal half-life
and preventing it from accumulating in the body, lowering the chance of overdose.

Veterinary use

Alfaxalone is used as an

endotracheal tube in the way.[4][9] Once the administration of alfaxalone stops, the animal quickly recovers from anesthesia.[10]

Alfaxalone can be used as a sedative when given

intramuscularly (IM), though this requires a larger volume (and not all countries allow alfaxalone to be administered IM).[11][12]

Despite its use as an anesthetic, alfaxalone itself has no analgesic properties.[7]

Available forms

Though alfaxalone is not licensed for IM or

subcutaneous use in the United States (as both cause longer recoveries with greater agitation and hypersensitivity to stimuli), it is routinely used IM in cats, and is licensed as such in other countries.[4][13]

Alfaxalone is dissolved in 2-hydroxypropyl-β cyclodextrin.[14] The cyclodextrin is a large, starch-derived molecule with a hydrophobic core where alfaxalone stays, allowing the mixture to be dissolved in water and sold as an aqueous solution. They act as one unit, and only dissociate once in vivo.[11][15]

Specific populations

Alfaxalone has been used to perform

placental barrier and had some effects on the kittens, there is no respiratory depression and no lasting effect. Alfaxalone has also been found to be safe in young puppies and kittens.[16][17]

Alfaxalone has been noted to be a good anesthetic agent for dogs with

There seems to be marked difference in sex response: anaesthesia in the male rat requires about four times more than in the female.[19]

Side effects

Alfaxalone has relatively few side effects compared to other anesthetics; most notable is its lack of

minute volume, and oxygen saturation in the blood.[17] Alfaxalone should be administered slowly over a period of at least 60 seconds or until anesthesia is induced, as quick administration increases the risk of apnea.[5][13] Alfaxalone has some depressive effects on the central nervous system, including a reduction in cerebral blood flow, intracranial pressure, and body temperature.[17]

Greyhounds, who are particularly susceptible to anesthetic side effects, can have decreased blood flow and oxygen supply to the liver.[17]

When no premedications are used, alfaxalone causes animals (especially cats) to be agitated when recovering.[4][13] Dogs and cats will paddle in the air, vocalize excessively, may remain rigid or twitch, and have exaggerated reactions to external stimuli such as light and noise. For this reason, it is recommended that animals recovering from anesthesia by alfaxalone stay in a quiet, dark area.[17]

Overdose

The quick metabolism and elimination of alfaxalone from the body decreases the chance of overdose.

hypoxia, and arrhythmia (caused by the apnea and hypoxia).[11]

Pharmacology

Pharmacodynamics

GABAA receptor and the location of various ligand-binding sites.

Alfaxalone is a

benzodiazepines.[17][22] Alfaxalone, however, does not share the benzodiazepine binding site,[23] and actually prefers different GABAA receptors than benzodiazepenes do. It works best on the α1-β2-γ2-L isoform.[11] Research suggests that neuroactive steroids increase the expression of GABAA receptors, making it more difficult to build tolerance.[22]

Pharmacokinetics

Alfaxalone is metabolized quickly and does not accumulate in the body; its use as an induction agent thus doesn't increase the time needed to recover from anesthesia.[4][10] If it administered more slowly by diluting it in sterile water, less actual alfaxalone is needed.[9] Alfaxalone binds to 30–50% of plasma proteins,[24] and has a terminal half-life of 25 minutes in dogs and 45 minutes in cats when given at clinical doses (2 mg/kg and 5 mg/kg respectively). The pharmacokinetics are nonlinear in cats and dogs.[14][25]

Most alfaxalone metabolism takes place in the liver, though some takes place in the

phase II (conjugation-dependent) metabolism. The phase I products are the same in cats and dogs: allopregnatrione, 3β-alfaxalone, 20-hydroxy-3β-alfaxalone, 2-hydroxyalfaxalone, and 2α-hydroxyalfaxalone.[11][17] In dogs, the phase II metabolites are alfaxalone glucuronide (the major metabolite), 20-hydroxyalfaxalone sulfate, and 2α-hydroxyalfaxalone glucuronide. In cats, there is a greater production of 20-hydroxyalfaxalone sulfate than alfaxalone glucuronide; cats also have 3β-alfaxalone-sulfate, which is not present in dogs.[11][17]

Alfaxalone is mostly excreted in the urine, though some is excreted in the bile as well.

Chemistry

Progesterone (left) and its derivative, alfaxolan (right); the differences are highlighted in pink.

Alfaxalone, also known as 11-oxo-3α,5α-tetrahydroprogesterone, 5α-pregnan-3α-ol-11,20-dione, or 3α-hydroxy-5α-pregnane-11,20-dione, is a

hydroxyl group, the double bond between the C4 and C5 positions has been reduced and is now a single bond, and a ketone has been substituted at the C11 position.[1] Alfaxalone is also a derivative of allopregnanolone, differing from it only by the addition of the C11 ketone.[1] Other closely related steroids include ganaxolone, hydroxydione, minaxolone, pregnanolone, and renanolone.[1]

History

In 1941,

CNS depressant effects in rodents. This began a search to make a synthetic steroid that could be used as an anesthetic. Most of these efforts were aimed at making alfaxalone more water-soluble.[22]

In 1971, a combination of alfaxalone and

Cremophor EL: a polyoxyelthylated castor oil surfactant.[14]

Althesin was removed from the market in 1984 for causing

hyperemia in their ears and paws;[27] only some also got laryngeal or pulmonary edema.[26]

In 1999, a

aqueous form of Alfaxan was released in Australia in 2000–2001, and Saffan was finally removed from the market in 2002. Alfaxan was released in the UK in 2007, central Europe in 2008, Canada in 2011, and the United States in 2012.[11][12]

Currently, a human form of alfaxalone is in development under the name "Phaxan": alfaxalone will be dissolved in 7-sulfo-butyl-ether-β-cyclodextrin, which, unlike the cyclodextrin used in Alfaxan, is not toxic to people.[14]

Society and culture

Generic names

Alfaxalone is the

INNTooltip International Nonproprietary Name, BANTooltip British Approved Name, DCFTooltip Dénomination Commune Française, and JANTooltip Japanese Accepted Name of alfaxolone. Alphaxalone was the former BAN of the drug,[1][2] but this was eventually changed. Alphaxolone and alfaxolone are additional alternative spellings.[1][2][3][28]

Brand names

Alfaxalone was marketed in 1971 in combination with alfadolone acetate under the brand name Althesin for human use and Saffan for veterinary use.[17][29] Althesin was withdrawn from the market in 1984, whereas Saffan remained marketed.[30] A new formulation containing alfaxalone only was introduced for veterinary use in 1999 under the brand name Alfaxan.[17][29] Following the introduction of Alfaxan, Saffan was gradually discontinued and is now no longer marketed.[30][31] Another new formulation containing alfaxalone alone is currently under development for use in humans with the tentative brand name Phaxan.[14][32]

Availability

Alfaxalone is marketed for veterinary use under the brand name Alfaxan in a number of countries, including Australia, Belgium, Canada, France, Germany, Ireland, Japan, the Netherlands, New Zealand, South Africa, South Korea, Spain, Taiwan, the United Kingdom, and the United States.[3][33][34]

References

  1. ^ .
  2. ^ .
  3. ^ a b c "Alfaxalone". Drugs.com.
  4. ^ a b c d e f Rezende M (June 2015). "Reintroduced Anesthetic Alfaxalone" (PDF). Clinician's Brief. Archived from the original (PDF) on July 23, 2015. Retrieved July 14, 2017.
  5. ^ a b "ALFAXAN- alfaxalone injection, solution". DailyMed. US National Library of Medicine. Retrieved July 15, 2017.
  6. .
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  11. ^ .
  12. ^ a b Zeltzman P (November 17, 2014). "Why Administering Alfaxalone Requires A Bit of Education". Veterinary Practice News. Retrieved July 14, 2017.
  13. ^ a b c d e f g Nieuwendijk H (March 2011). "Alfaxalone". Veterinary Anesthesia & Analgesia Support Group. Retrieved July 14, 2017.
  14. ^ .
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  26. ^ .
  27. ^ Liao PT (August 2016). Anesthetic and Cardio-pulmonary Effects of Propofol or Alfaxalone with or without Midazolam Co-Induction in Fentanyl Sedated Dogs (PDF) (DVM). Guelph, Ontario: University of Guelph.
  28. ^ "Substance Name: Alfaxalone [INN:BAN:DCF:JAN]". ChemIDplus. US National Library of Medicine.
  29. ^ .
  30. ^ .
  31. .
  32. ^ "Alfaxalone (PHAX-001; Phaxan)". AdisInsight. Retrieved 27 July 2017.
  33. ^ Official website of Alfaxan
  34. PMID 25428797
    . [Alfaxalone] is approved in some countries (e.g., Australia, New Zealand, Europe, Korea, Japan, USA and Canada) as an IV anesthetic agent in dogs and cats.