Methoxyflurane

Methoxyflurane (2,2-dichloro-1,1-difluoroethyl methyl ether; CAS 76-38-0; molecular formula C3H4Cl2F2O; molecular weight 164.97) is a halogenated methyl ethyl ether developed by Ross Terrell in the 1950s and introduced clinically by Abbott in 1962 (Penthrane). The agent was widely used as a general anesthetic through the early 1970s before reports of dose-dependent nephrotoxicity led to withdrawal as a primary anesthetic in 1974 in the United States. The mechanism of methoxyflurane nephrotoxicity is intrarenal defluorination by CYP2E1 producing inorganic fluoride at concentrations sufficient to inhibit ascending limb chloride transport (high-output renal failure with vasopressin-resistant polyuria, the classical methoxyflurane nephropathy). The threshold for clinically apparent renal injury is approximately 50 micromolar plasma fluoride and is exceeded by general anesthetic doses (MAC 0.16 percent for many hours) but not by the brief, low-dose inhaler format reintroduced as Penthrox in Australia and re-approved in the EU and UK in 2018 for procedural analgesia. The Penthrox formulation delivers approximately 3 mL methoxyflurane through a hand-held disposable inhaler (the green whistle), producing analgesia for procedural pain (extremity injuries, dressing changes, fracture reduction) at exposure levels orders of magnitude below the historical nephrotoxic threshold. The blood-gas partition coefficient is 13, the highest in the class, corresponding to slow induction and prolonged emergence; the clinical Penthrox dose is sub-anesthetic and produces only analgesia and mild sedation. Mechanism includes the standard halogenated ether profile plus pronounced TRPA1 modulation contributing to the analgesic phenotype.