Alfaxalone

Alfaxalone (3-alpha-hydroxy-5-alpha-pregnane-11,20-dione; CAS 23930-19-0; molecular formula C21H32O3; molecular weight 332.48) is a neurosteroid intravenous anesthetic developed at Glaxo in the 1970s, originally formulated with alfadolone in the human anesthetic Althesin (withdrawn 1984 owing to anaphylactoid reactions traced to the Cremophor EL solubilizer rather than the steroid itself). The compound was reformulated with a 2-hydroxypropyl-beta-cyclodextrin solubilizer as Alfaxan and approved for veterinary use in dogs, cats, and rabbits in the 2000s. Alfaxalone is the principal modern synthetic neurosteroid in clinical use; structurally it is a 3-alpha-hydroxy-5-alpha-pregnane that mirrors the endogenous neurosteroid allopregnanolone. Mechanism is positive allosteric modulation of GABA-A receptors at a steroid-binding site distinct from the benzodiazepine and barbiturate sites, with prolongation of chloride channel open time and direct channel opening at higher concentrations. The cardiovascular profile is favorable for an IV induction agent (less hypotension than propofol at induction doses), and the respiratory profile is similarly favorable (apnea threshold higher than propofol at typical induction doses); these characteristics drive widespread veterinary adoption for cardiac-compromised patients. Human clinical use was discontinued with Althesin and has not returned despite the favorable steroid pharmacology, owing principally to the veterinary market priority and absence of human clinical development. Alfaxalone serves as the canonical reference compound for synthetic neurosteroid GABA-A pharmacology and underpins the design of subsequent neurosteroid drugs including brexanolone, ganaxolone, and zuranolone. Plasma half-life is short (less than 30 minutes); clearance is hepatic and rapid.