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| Trade names | Alfaxan |
| Other names | Alphaxalone; Alphaxolone; Alfaxolone; 3α-Hydroxy-5α-pregnane-11,20-dione; PHAX-001; Phaxan, Alphaxalone (BANUK) |
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| Protein binding | 30–50% |
| Metabolism | Hepatic |
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| Excretion | Mostlyrenal |
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| ECHA InfoCard | 100.164.405 |
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| Formula | C21H32O3 |
| Molar mass | 332.484 g·mol−1 |
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Alfaxalone, also known asalphaxalone oralphaxolone and sold under the brand nameAlfaxan and Faxone, is aneuroactive steroid andgeneral anesthetic which is used currently inveterinary practice as aninduction agent foranesthesia and as aninjectable anesthetic.[1][2][3] Though it is more expensive than other induction agents,[4] it often preferred due to the lack of depressive effects on thecardiovascular system. The most common side effect seen in current veterinary practice isrespiratory depression when Alfaxan is administered concurrently with other sedative and anesthetic drugs; whenpremedications are not given, veterinary patients also become agitated and hypersensitive when waking up.
Alfaxalone works as apositive allosteric modulator onGABAA receptors and, at high concentrations, as a directagonist of the GABAA receptor. It is cleared quickly by theliver, giving it a relatively shortterminal half-life and preventing it from accumulating in the body, lowering the chance of overdose.
Alfaxalone is used as aninduction agent, an injectable anesthetic, and asedative in animals.[5] While it is commonly used incats anddogs, it has also been successfully used inrabbits,[6]horses,sheep,pigs, and exotics such asred-eared turtles,axolotl,green iguanas,marmosets,[7] andkoi fish.[8] As an induction agent, alfaxalone causes the animal to relax enough to beintubated, which then allows the administration ofinhalational anesthesia. Premedication (administeringsedative drugs prior to induction) increases the potency of alfaxalone as an induction agent.[7] Alfaxalone can be used instead of gas anesthetics in surgeries that are under 30 minutes, where it is given at a constant rate via IV (constant rate infusion); this is especially useful in procedures such asbronchoscopies or repairingtracheal tears, as there is noendotracheal 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 givenintramuscularly (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 noanalgesic properties.[7]
Though alfaxalone is not licensed for IM orsubcutaneous use in theUnited 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 in2-hydroxypropyl-β cyclodextrin.[14] The cyclodextrin is a large,starch-derived molecule with ahydrophobic 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 oncein vivo.[11][15]
Alfaxalone has been used to performC-sections in pregnant cats; though it crosses theplacental 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 withventricular arrhythmias and forsighthounds.[13][18]
There seems to be marked difference in sex response: anaesthesia in the male rat requires about four times more than in the female.[19]
Alfaxalone has relatively few side effects compared to other anesthetics; most notable is its lack ofcardiovascular depression at clinical doses, which makes it unique among anesthetics.[10][13] The most common side effect is respiratory depression: in addition toapnea, the most prevalent, alfaxalone can also decrease therespiratory rate,minute volume, andoxygen 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 thecentral nervous system, including a reduction incerebral blood flow,intracranial pressure, andbody temperature.[17]
Greyhounds, who are particularly susceptible to anesthetic side effects, can have decreased blood flow and oxygen supply to theliver.[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]
The quick metabolism and elimination of alfaxalone from the body decreases the chance of overdose.[10] It would take over 28 times the normal dose to cause toxicity in cats.[11] Such doses, however, can causelow blood pressure, apnea,hypoxia, and arrhythmia (caused by the apnea and hypoxia).[11]
Alfaxalone is aneuroactive steroid derived fromprogesterone, though it has noglucocorticoid ormineralocorticoid action.[4][10] Instead, it works by acting onGABAA receptors.[20] It binds to the M3/M4 domains of the α subunit andallosterically modifies the receptor to facilitate the movement ofchloride ions into the cell, resulting inhyperpolarization of the post-synaptic nerve (which inhibitsactions potentials). At concentrations over 1 micromolar,[21] alfaxalone binds to a site at the interface between the α and β subunits (near the actual GABA binding site) and acts as a GABA agonist, similar tobenzodiazepines.[17][22] Alfaxalone, however, does not share the benzodiazepine binding site,[23] and actually prefers different GABAA receptors than benzodiazepines do. It works best on theα1-β2-γ2-L isoform.[11] Research suggests that neuroactive steroids increase the expression of GABAA receptors, making it more difficult to buildtolerance.[22]
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 thelungs andkidneys as well.[25] In the liver, it undergoes bothphase I (cytochrome P450-dependent) andphase 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 theurine, though some is excreted in thebile as well.
Alfaxalone, also known as11-oxo-3α,5α-tetrahydroprogesterone,5α-pregnan-3α-ol-11,20-dione, or3α-hydroxy-5α-pregnane-11,20-dione, is asyntheticpregnanesteroid and aderivative ofprogesterone.[1] It is specifically amodification of progesterone in which the C3ketone has beenreduced to ahydroxyl group, thedouble bond between the C4 and C5 positions has been reduced and is now asingle bond, and a ketone has beensubstituted at the C11 position.[1] Alfaxalone is also a derivative ofallopregnanolone, differing from it only by the addition of the C11 ketone.[1] Other closely related steroids includeganaxolone,hydroxydione,minaxolone,pregnanolone, andrenanolone.[1]
In 1941,progesterone and5β-pregnanedione were discovered to haveCNS 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 andalfadolone acetate was released as the anestheticsAlthesin (for human use) and Saffan (for veterinary use).[7][25] The two were dissolved inCremophor EL: a polyoxyelthylatedcastor oilsurfactant.[14]
Althesin was removed from the market in 1984 for causinganaphylaxis; it was later found that this was due to Cremophor EL, which caused the body to releasehistamine, rather than alfaxolone or alfadolone.[7][13][22] Saffan was removed from use for dogs only, but stayed on for other animals, none of which histamine release to the same extent that dogs did.[26] It was still especially valued in cats for its lack of depressant effects on the cardiovascular system, which made it three times less fatal than any other anesthetic on the market at the time.[7][9] The release of histamine caused most cats (69%) to haveedema andhyperemia in their ears and paws;[27] only some also gotlaryngeal orpulmonary edema.[26]
In 1999, alyophilized form of alfaxalone was released for cats.[11] The new drug, Alfaxan, used acyclodextrin as a carrier agent to make alfaxalone more water-soluble rather than Cremophor EL.[13] Alfadolone was not included in the mixture, as its hypnotic effects were quite weak.[26] Anaqueous 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]
Alfaxalone is theINNTooltip International Nonproprietary Name,BANTooltip British Approved Name,DCFTooltip Dénomination Commune Française, andJANTooltip Japanese Accepted Name of alfaxolone.Alphaxalone was the formerBAN of the drug,[1][2] but this was eventually changed.Alphaxolone andalfaxolone are additional alternative spellings.[1][2][3][28]
Alfaxalone was marketed in 1971 in combination with alfadolone acetate under the brand nameAlthesin for human use andSaffan 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 nameAlfaxan.[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 namePhaxan.[14][32]
Alfaxalone is marketed for veterinary use under the brand name Alfaxan in a number of countries, includingAustralia,Belgium,Canada,France,Germany,Ireland,Japan, theNetherlands,New Zealand,South Africa,South Korea,Spain,Taiwan, theUnited Kingdom, and theUnited States.[3][33][34]
{{cite journal}}:ISBN / Date incompatibility (help)[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.