alfaxalone alfaxalone alfaxalone, also known as alphaxalone or alphaxolone and sold under the brand name alfaxan, is a neuroactive steroid and general anesthetic which is used currently in veterinary practice as an induction agent for anesthesia and as an injectable anesthetic. though it is more expensive than other induction agents, it often preferred due to the lack of depressive effects on the cardiovascular system. the most common side effect seen in current veterinary practice is respiratory depression when alfaxan is administered concurrently with other sedative and anesthetic drugs; when premedications aren't given, veterinary patients also become agitated and hypersensitive when waking up. alfaxaloneclinical datatrade namesalfaxanother namesalphaxalone; alphaxolone; alfaxolone; 3α-hydroxy-5α-pregnane-11,20-dione; phax-001; phaxan, alphaxalone (ban uk)ahfs/drugs.cominternational drug nameslicense data us dailymed: alfaxan drug class neuroactive steroid general anesthetic atcvet codeqn01ax05 (who) legal statuslegal status au: s4 (prescription only) ca: ℞-only us: schedule iv (by veterinarian only) pharmacokinetic dataprotein binding30–50%metabolismhepaticmetabolites alfaxalone glucuronide (major in dogs) 20-hydroxyalfaxalone sulfate (major in cats) elimination half-life 25 min (dogs) 45 min (cats) excretionmostly renalidentifiers iupac name (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-tetradecahydrocyclopentaphenanthren-11-one cas number23930-19-0 ypubchem cid104845iuphar/bps5461drugbankdb11371 ychemspider94637 yuniibd07m97b2akeggd07282 ychemblchembl190279 ycomptox dashboard (epa)dtxsid9022576 echa infocard100.164.405 chemical and physical dataformulac21h32o3molar mass332.484 g·mol−13d model (jsmol)interactive image smiles o=c23(1cc(c(=o)c)1(c)c2)cc4c(o)cc34c inchi 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 ykey:duhuchoqidjxat-olvmnogesa-n y (verify) alfaxalone works as a positive allosteric modulator on gabaa receptors and, at high concentrations, as a direct agonist of the gabaa receptor. it is cleared quickly by the liver, giving it a relatively short terminal half-life and preventing it from accumulating in the body, lowering the chance of overdose. veterinary use alfaxalone is used as an induction agent, an injectable anesthetic, and a sedative in animals. while it is commonly used in cats and dogs, it has also been successfully used in rabbits, horses, sheep, pigs, and exotics such as red-eared turtles, axolotl, green iguanas, marmosets, and koi fish. as an induction agent, alfaxalone causes the animal to relax enough to be intubated, which then allows the administration of inhalational anesthesia. premedication (administering sedative drugs prior to induction) increases the potency of alfaxalone as an induction agent. 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 as bronchoscopies or repairing tracheal tears, as there is no endotracheal tube in the way. once the administration of alfaxalone stops, the animal quickly recovers from anesthesia. 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). despite its use as an anesthetic, alfaxalone itself has no analgesic properties. 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. alfaxalone is dissolved in 2-hydroxypropyl-β cyclodextrin. 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. specific populations alfaxalone has been used to perform c-sections in pregnant cats; though it crosses the 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. alfaxalone has been noted to be a good anesthetic agent for dogs with ventricular arrhythmias and for sighthounds. side effects alfaxalone has relatively few side effects compared to other anesthetics; most notable is its lack of cardiovascular depression at clinical doses, which makes it unique among anesthetics. the most common side effect is respiratory depression: in addition to apnea, the most prevalent, alfaxalone can also decrease the respiratory rate, minute volume, and oxygen saturation in the blood. 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. alfaxalone has some depressive effects on the central nervous system, including a reduction in cerebral blood flow, intracranial pressure, and body temperature. greyhounds, who are particularly susceptible to anesthetic side effects, can have decreased blood flow and oxygen supply to the liver. when no premedications are used, alfaxalone causes animals (especially cats) to be agitated when recovering. 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. overdose the quick metabolism and elimination of alfaxalone from the body decreases the chance of overdose. it would take over 28 times the normal dose to cause toxicity in cats. such doses, however, can cause low blood pressure, apnea, hypoxia, and arrhythmia (caused by the apnea and hypoxia). pharmacology pharmacodynamics gabaa receptor and the location of various ligand-binding sites. alfaxalone is a neuroactive steroid derived from progesterone, though it has no glucocorticoid or mineralocorticoid action. instead, it works by acting on gabaa receptors. it binds to the m3/m4 domains of the α subunit and allosterically modifies the receptor to facilitate the movement of chloride ions into the cell, resulting in hyperpolarization of the post-synaptic nerve (which inhibits actions potentials). at concentrations over 1 micromolar, 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 to benzodiazepines. alfaxalone, however, does not share the benzodiazepine binding site, and actually prefers different gabaa receptors than benzodiazepenes do. it works best on the α1-β2-γ2-l isoform. research suggests that neuroactive steroids increase the expression of gabaa receptors, making it more difficult to build tolerance. 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. if it administered more slowly by diluting it in sterile water, less actual alfaxalone is needed. alfaxalone binds to 30–50% of plasma proteins, 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. most alfaxalone metabolism takes place in the liver, though some takes place in the lungs and kidneys as well. in the liver, it undergoes both phase i (cytochrome p450-dependent) and 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. 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. 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.