Methoxyflurane
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Clinical data | |
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Trade names | Penthrane, Metofane, Penthrox, Penthrop, others |
Other names | 2,2-dichloro-1,1-difluoroethyl methyl ether |
AHFS/Drugs.com | Consumer Drug Information |
Pregnancy category |
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Volatile anesthetic | |
ATC code | |
Legal status | |
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Pharmacokinetic data | |
Metabolism | 70% |
Onset of action | Rapid[4] |
Duration of action | Several minutes[4] |
Identifiers | |
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JSmol) | |
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Methoxyflurane, sold under the brand name Penthrox among others, is an inhaled medication primarily used to reduce pain following trauma.[5][6] It may also be used for short episodes of pain as a result of medical procedures.[4] Onset of pain relief is rapid and of a short duration.[4] Use is only recommended with direct medical supervision.[5]
Common side effects include
It was first made in 1948 by William T. Miller and came into medical use in the 1960s.[7] It was used as a general anesthetic from its introduction in 1960 until the late 1970s.[8] In 1999, the manufacturer discontinued methoxyflurane in the United States, and in 2005 the Food and Drug Administration withdrew it from the market.[8] It is still used in New Zealand, Australia, Ireland, and the United Kingdom for pain.[9][4][10][5][11]
Medical use
![](http://upload.wikimedia.org/wikipedia/commons/thumb/4/43/%28hospital%2C_medication%2C_painkillers%29_Green_Whistle.jpg/220px-%28hospital%2C_medication%2C_painkillers%29_Green_Whistle.jpg)
Methoxyflurane is used for relief of moderate or severe pain as a result of trauma.[6][5] It may also be used for short episodes of pain as a result of procedures.[4]
Each dose lasts approximately 30 minutes.
It is self-administered to children and adults using a hand-held inhaler device.[17][14][18][15] A non-opioid alternative to morphine, it is also easier to use than nitrous oxide.[4] A portable, disposable, single-use inhaler device, along with a single 3 milliliter brown glass vial of methoxyflurane allows people who are conscious and hemodynamically stable (including children over the age of 5 years) to self-administer the medication, under supervision.[4]
In
Side effects
The consensus is that the use of methoxyflurane should be restricted only to healthy individuals, in situations where it offers specific advantages and even then, only at dosages less than 2.5 MAC hours.[20][21] The National Institute for Occupational Safety and Health maintains a recommended exposure limit for methoxyflurane as waste anesthetic gas of 2 ppm (13.5 mg/m3) over 60 minutes.[22]
Kidney
The first report of nephrotoxicity appeared in 1964, when Paddock and colleagues reported three cases of
Compared with
Liver
Reports of severe and even fatal hepatotoxicity related to the use of methoxyflurane began to appear in 1966.
Mechanism
The biodegradation of methoxyflurane begins immediately. The kidney and liver toxicity observed after anesthetic doses is attributable to one or more metabolites produced by O-demethylation of methoxyflurane. Products of this catabolic process include methoxyfluoroacetic acid (MFAA), dichloroacetic acid (DCAA), and inorganic fluoride.[21] Methoxyflurane nephrotoxicity is dose dependent[24][27][28] and irreversible, resulting from O-demethylation of methoxyflurane to fluoride and DCAA.[4] It is not entirely clear whether the fluoride itself is toxic—it may simply be a surrogate measure for some other toxic metabolite.[29] The concurrent formation of inorganic fluoride and DCAA is unique to methoxyflurane biotransformation compared with other volatile anesthetics, and this combination is more toxic than fluoride alone. This may explain why fluoride formation from methoxyflurane is associated with nephrotoxicity, while fluoride formation from other volatile anesthetics (such as enflurane and sevoflurane) is not.[30]
Pharmacokinetics
Methoxyflurane has a very high lipid solubility (oil:gas partition coefficient of around 950), which gives it very slow pharmacokinetics [citation needed] (induction and emergence characteristics); this being undesirable for routine application in the clinical setting. Initial studies performed in 1961 revealed that in unpremedicated healthy individuals, induction of general anesthesia with methoxyflurane-oxygen alone or with nitrous oxide was difficult or even impossible using the vaporizers available at that time. It was found to be necessary to administer an intravenous anesthetic agent such as sodium thiopental to ensure a smooth and rapid induction. It was further found that after thiopental induction, it was necessary to administer nitrous oxide for at least ten minutes before a sufficient amount of methoxyflurane could accumulate in the bloodstream to ensure an adequate level of anesthesia. This was despite using high flow (liters/minute) of nitrous oxide and oxygen, and with the vaporizers delivering the maximum possible concentration of methoxyflurane.[31]
Similar to its induction pharmacokinetics, methoxyflurane has very slow and somewhat unpredictable emergence characteristics. During initial clinical studies in 1961, the average time to emergence after discontinuation of methoxyflurane was 59 minutes after administration of methoxyflurane for an average duration of 87 minutes. The longest time to emergence was 285 minutes, after 165 minutes of methoxyflurane administration.[31]
Pharmacodynamics
Heart
The effects of methoxyflurane on the circulatory system resemble those of diethyl ether.
Lungs
Unlike diethyl ether, methoxyflurane is a significant respiratory depressant. In dogs, methoxyflurane causes a
Pain
Although the high blood solubility of methoxyflurane is often undesirable, this property makes it useful in certain situations—it persists in the lipid compartment of the body for a long time, providing sedation and analgesia well into the postoperative period.[37][32] There is substantial data to indicate that methoxyflurane is an effective analgesic and sedative agent at subanesthetic doses.[17][14][38][39][40][41][42][43][44][45][46][47][48] Supervised self-administration of methoxyflurane in children and adults can briefly lead to deep sedation,[14] and it has been used as a patient controlled analgesic for painful procedures in children in hospital emergency departments.[18] During childbirth, administration of methoxyflurane produces significantly better analgesia, less psychomotor agitation, and only slightly more somnolence than trichloroethylene.[40]
Penthrox, commonly known as the "green whistle", has been offered in hospital to women for painful intrauterine device procedures (insertion and removal).[49]
Central nervous system
Similar to other
Chemical properties
![A space-filling model, or three-dimensional structure of the methoxyflurane molecule, in red, yellow, green, black and white.](http://upload.wikimedia.org/wikipedia/commons/thumb/4/4e/Methoxyflurane-3D-vdW.png/220px-Methoxyflurane-3D-vdW.png)
With a molecular formula of C3H4Cl2F2O and a condensed structural formula of CHCl2CF2OCH3, the International Union of Pure and Applied Chemistry (IUPAC) name for methoxyflurane is 2,2-dichloro-1,1-difluoro-1-methoxyethane. It is a halogenated ether in form of a clear, colorless liquid, and its vapor has a strong fruity aroma. It is miscible with ethanol, acetone, chloroform, diethyl ether, and fixed oils. It is soluble in rubber.[12]
With a
Property | Value[12][31][59] |
---|---|
atmosphere )
|
104.8 °C |
Minimum alveolar concentration (MAC) | 0.16%[55] |
Vapor pressure (mmHg at 20 °C) | 22.5 |
Partition coefficient (Blood:Gas) | 12 |
Partition coefficient (Oil:Gas) | 950 |
Partition coefficient (Oil:Water) | 400 |
Specific gravity at 25 °C
|
1.42 |
Flash point | 63 °C |
Molecular weight (g mol−1) | 164.97 |
Vapor-liquid equilibrium (mL)
|
208 |
Flammability limits
|
7% in air |
Chemical stabilizer necessary | Yes |
The carbon–fluorine bond, a component of all organofluorine compounds, is the strongest chemical bond in organic chemistry.[60] Furthermore, this bond becomes shorter and stronger as more fluorine atoms are added to the same carbon on a given molecule. Because of this, fluoroalkanes are some of the most chemically stable organic compounds.
History
Methoxyflurane has been used since the 1970s in Australia as an emergency analgesic for short-term use by the
All of the currently used volatile anesthetic agents are
The need for fluorine arose from the need to separate the
Obstacles had to be overcome in the handling of both fluorine and UF6. Before the
Miller and his team continued to develop organofluorine chemistry after the end of World War II and methoxyflurane was made in 1948.[71]
In 1968, Robert Wexler of
Notes
- ^ Anvisa (2023-03-31). "RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 2023-04-04). Archived from the original on 2023-08-03. Retrieved 2023-08-16.
- ^ "Search Page - Drug and Health Product Register". 23 October 2014.
- ^ "List of nationally authorised medicinal products : Active substance: methoxyflurane : Procedure no. PSUSA/00010484/202005" (PDF). Ema.europa.eu. Retrieved 2022-03-12.
- ^ National Prescribing Service (2010). "Methoxyflurane (Penthrox) for analgesia (doctor's bag listing)". NPS RADAR. Canberra, Australia: National Prescribing Service, Department of Health and Ageing. Archived from the originalon 2011-07-27. Retrieved 2011-06-12.
- ^ ISBN 9780857113382.
- ^ PMID 29661381.
- ISBN 9780199642045.
- ^ PMID 17006084.
- ^ "NZ Medsafe Datasheet" (PDF). Medsafe.govt.nz. Retrieved 12 March 2022.
- ISBN 978-0-9929363-6-5. Retrieved 7 January 2019.
- PMID 29302193.
- ^ a b c Medical Developments International Pty. Ltd. (2009). "Penthrox (methoxyflurane) inhalation: product information" (PDF). Springvale, Victoria, Australia: Medical Developments International Limited. Retrieved 2011-06-12.
- ^ Wellness on Wellington (2010). "The green whistle" (PDF). Wellnews. 12 (2): 1. Archived from the original (PDF) on 2011-03-29.
- ^ S2CID 1619160.
- ^ S2CID 40158248.
- ISBN 978-0-9757919-9-8.
- ^ S2CID 38517296. Archived from the original(PDF) on 2011-07-15.
- ^ S2CID 30105092.
- ^ Boyle M, Mallinson T, Worral M, Pearce L, Duff L, Price R (May 2022). "Use of Penthrox® as a Prehospital Analgesic within a Scottish Responder Service".
- ^ PMID 4740737.
- ^ PMID 4596236.
- ^ "CDC - NIOSH Pocket Guide to Chemical Hazards - Methoxyflurane". www.cdc.gov. Retrieved 2015-11-19.
- PMID 14211499.
- ^ S2CID 39661400.
- ^ Barash, Cullen and Stoelting (2009), Ebert and Schmid, Chapter 17: Inhaled Anesthetics, pp. 413–43
- ^ Helsinn Birex Therapeutics Ltd (2009). "By-Mycin 50mg capsules". medicines.ie: Medicines information online. Dublin, Ireland: Irish Pharmaceutical Healthcare Association Ltd. Archived from the original on 2011-07-21. Retrieved 2011-06-12.
- PMID 5029469.
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- ^ PMID 13786945.
- ^ .
- PMID 13770698.
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- PMID 13841124.
- PMID 13841125.
- ^ a b Crankshaw DP (2005). "Methoxyflurane for relief of acute pain: interpretation of uptake and elimination curves (abstract)". Anesthesiology. 103 (Supplement): A756. Archived from the original on 2013-01-17.
- ^ S2CID 11260623.
- ^ S2CID 24955345.
- ^ PMID 5926260.
- ^ PMID 5233333.
- ^ PMID 4903969.
- ^ PMID 5512851.
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- ^ PMID 4534883.
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- ISSN 1322-3127.
- ISSN 1034-4810.
- ABC News Online, 2023-12-19
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- PMID 20735416.
- PMID 9952156.
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- ^ S2CID 10549698.
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- ^ "Clinical Procedures and Guidelines - Comprehensive Edition 2019-22" (PDF). St John New Zealand. p. 510. Retrieved 2021-04-05.
- ^ "Clinical Procedures and Guidelines - Comprehensive Edition 2019-22" (PDF). Wellington Free Ambulance. p. 510. Retrieved 2021-04-05.
- ^ Blaschke2018
- ^ CSIRO. "Delivering the next generation Penthrox 'green whistle'". www.csiro.au. Retrieved 2024-01-28.
- ^ Sneader (2005), Sneader W, Chapter 8: Systematic medicine, pp. 74–87
- ^ DuPont (2010). "Roy Plunkett: 1938". DuPont Heritage. Wilmington, Delaware: E. I. du Pont de Nemours and Company. Retrieved 2011-06-12.
- ^ Cotton (2006), Cotton S, Chapter 10: Binary compounds of the actinides, pp. 155–72
- ^ Rhodes (1986), Rhodes R, Chapter 11: Cross sections, pp. 318–56
- ^ Beaton L (1962). "The slow-down in nuclear explosive production". New Scientist. 16 (309): 141–3.
- ^ Friedlander Jr BP (3 December 1998). "William T. Miller, Manhattan Project scientist and Cornell professor of chemistry, dies at 87". Cornell News. Ithaca, New York: Cornell University. Archived from the original on 7 June 2011. Retrieved 2011-06-12.
- .
- ^ Wexler RE (1968). "Analgizer: Inhaler for supervised self-administration of inhalation anesthesia". Abbott Park, Illinois: Abbott Laboratories. Retrieved 2011-06-12.
- ^ Morriss E (2 April 2020). "New inhaled analgesic can save hospital time and resources". Pharmafield.co.uk. Pharmafield. Retrieved 8 December 2020.
References
- Barash PG, Cullen BF, Stoelting RK, Cahalan MK, Stock MC, eds. (2009). Clinical anesthesia (6th ed.). Philadelphia: Lippincott Williams & Wilkins. ISBN 978-0-7817-8763-5.
- Cotton S (2006). Lanthanide and actinide chemistry (1st ed.). Chichester, England: John Wiley and Sons. ISBN 978-0-470-01006-8.
- ISBN 978-0-684-81378-3.
- Sneader W (2005). Drug discovery: a history. Chichester, England: John Wiley and Sons. ISBN 978-0-471-89980-8.
External links
- "Methoxyflurane". Drug Information Portal. U.S. National Library of Medicine.
- NIOSH Pocket Guide to Chemical Hazards