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==Overview==
==Overview==


'''Methoxyflurane''' ([[International Nonproprietary Name|INN]]), formerly marketed as '''Penthrane''' by [[Abbott Laboratories]], is a [[halogenated ether]] that was in clinical use as a [[Inhalational anaesthetic|volatile inhalational anesthetic]] from its introduction by [[Joseph F. Artusio]] ''et al'' in 1960 until the late 1970s. It was first [[chemical synthesis|synthesized]] in the late 1940s by [[William T. Miller]] and his team of [[chemist]]s following their involvement in the [[Manhattan Project]].<ref name=Miller1948/>
'''Methoxyflurane''' ([[International Nonproprietary Name|INN]]), formerly marketed as '''Penthrane''' by [[Abbott Laboratories]], is a [[halogenated ether]] that was in clinical use as a [[Inhalational anaesthetic|volatile inhalational anesthetic]] from its introduction by [[Joseph F. Artusio]] ''et al'' in 1960 until the late 1970s. It was first [[chemical synthesis|synthesized]] in the late 1940s by [[William T. Miller]] and his team of [[chemist]]s following their involvement in the [[Manhattan Project]].


Methoxyflurane is an extremely [[Potency (pharmacology)|potent]] and highly [[Lipophilicity|lipid soluble]] anesthetic agent, characterized by very slow induction (onset of action) and emergence (offset or dissipation) times. It is [[Flammability|non-flammable]], has relatively mild [[Hemodynamics|hemodynamic]] effects, and it does not predispose the heart to [[cardiac dysrhythmia|rhythm disturbances]]. It is, however, a significant [[Hypoventilation|respiratory depressant]]. Methoxyflurane has powerful [[analgesic]] (pain-relieving) properties at well below full anesthetic doses. It was utilized in self-administration devices for [[obstetrics|obstetric]] analgesia, in a manner that foreshadowed the [[patient-controlled analgesia]] [[infusion pump]]s of today.
Methoxyflurane is an extremely [[Potency (pharmacology)|potent]] and highly [[Lipophilicity|lipid soluble]] anesthetic agent, characterized by very slow induction (onset of action) and emergence (offset or dissipation) times. It is [[Flammability|non-flammable]], has relatively mild [[Hemodynamics|hemodynamic]] effects, and it does not predispose the heart to [[cardiac dysrhythmia|rhythm disturbances]]. It is, however, a significant [[Hypoventilation|respiratory depressant]]. Methoxyflurane has powerful [[analgesic]] (pain-relieving) properties at well below full anesthetic doses. It was utilized in self-administration devices for [[obstetrics|obstetric]] analgesia, in a manner that foreshadowed the [[patient-controlled analgesia]] [[infusion pump]]s of today.


The [[biodegradation]] of methoxyflurane produces [[Inorganic compound|inorganic]] [[fluoride]] and [[dichloroacetic acid]] (DCAA). The combined effects of these two [[Chemical compound|compounds]] may be responsible for the [[toxicity]] of methoxyflurane to some of the major [[Human_anatomy#Major_organ_systems|organs]] of the human body. Methoxyflurane was determined to be [[Nephrotoxicity|nephrotoxic]] (damaging to the kidneys) in a dose-dependent response and [[hepatotoxicity|hepatotoxic]] (damaging to the liver) at anesthetic doses in 1973, and the drug was abandoned as a [[General anaesthetic|general anesthetic]] in the late 1970s.<ref name="Mazze, Richard I. M pp 843">Mazze, Richard I. M.D. Methoxyflurane Revisited: Tale of an Anesthetic from Cradle to Grave. Anesthesiology, October 2006; Vol 105(4), pp 843–846</ref> In 1999, the manufacturer discontinued distribution of methoxyflurane in the United States and Canada, and on September 6, 2005, the Food and Drug Administration determined that it should be withdrawn from the market for safety concerns.<ref name="Mazze, Richard I. M pp 843"/> It is however still used in Australia as an emergency analgesic for the initial management of pain due to acute [[Trauma (medicine)|trauma]], as well as for brief painful procedures such as changing of [[Dressing (medical)|wound dressings]] or for [[Casualty movement|transport of injured people]].
The [[biodegradation]] of methoxyflurane produces [[Inorganic compound|inorganic]] [[fluoride]] and [[dichloroacetic acid]] (DCAA). The combined effects of these two [[Chemical compound|compounds]] may be responsible for the [[toxicity]] of methoxyflurane to some of the major [[Human_anatomy#Major_organ_systems|organs]] of the human body. Methoxyflurane was determined to be [[Nephrotoxicity|nephrotoxic]] (damaging to the kidneys) in a dose-dependent response and [[hepatotoxicity|hepatotoxic]] (damaging to the liver) at anesthetic doses in 1973, and the drug was abandoned as a [[General anaesthetic|general anesthetic]] in the late 1970s. In 1999, the manufacturer discontinued distribution of methoxyflurane in the United States and Canada, and on September 6, 2005, the Food and Drug Administration determined that it should be withdrawn from the market for safety concerns. It is however still used in Australia as an emergency analgesic for the initial management of pain due to acute [[Trauma (medicine)|trauma]], as well as for brief painful procedures such as changing of [[Dressing (medical)|wound dressings]] or for [[Casualty movement|transport of injured people]].


==Medical use==
==Medical use==
Methoxyflurane has been extensively used since the 1970s in Australia as an emergency analgesic for short-term use, mostly by the [[Australian Defence Force|Australian]] and [[New Zealand Defence Force|New Zealand]] Defence Forces,<ref name=McLennan2007/> and the [[Emergency medical services in Australia|Australian ambulance services]].<ref name=Babl2006/><ref name=Buntine2007/><ref name=Johnston2011/> The drug is currently only available from one manufacturer (Medical Developments International, Melbourne, Victoria, Australia). It is self-administered to children and adults using the [[Penthrox inhaler]], a hand-held inhaler device.<ref name=McLennan2007/><ref name=Babl2006/><ref name=Babl2007/><ref name=Grindlay2009/> A non-[[opioid]] alternative to [[morphine]], it is also easier to use than nitrous oxide.<ref name=RADAR2010/> As of 2010, methoxyflurane was listed under the [[Pharmaceutical Benefits Scheme]] for the initial management of pain due to acute trauma, as well as for brief painful procedures such as changing of wound dressings or for patient transport.<ref name=RADAR2010/> A portable, disposable, single-use inhaler device (the Penthrox inhaler), along with a single 3&nbsp;milliliter brown glass vial of methoxyflurane is provided in doctor's kits that allows conscious hemodynamically stable patients (including children over the age of 5&nbsp;years) to self-administer the drug, under supervision.<ref name=RADAR2010/> The device is often referred to as the "green whistle", due to its appearance.<ref name=Wellness2010/>
Methoxyflurane has been extensively used since the 1970s in Australia as an emergency analgesic for short-term use, mostly by the [[Australian Defence Force|Australian]] and [[New Zealand Defence Force|New Zealand]] Defence Forces, and the [[Emergency medical services in Australia|Australian ambulance services]].The drug is currently only available from one manufacturer (Medical Developments International, Melbourne, Victoria, Australia). It is self-administered to children and adults using the [[Penthrox inhaler]], a hand-held inhaler device.A non-[[opioid]] alternative to [[morphine]], it is also easier to use than nitrous oxide. As of 2010, methoxyflurane was listed under the [[Pharmaceutical Benefits Scheme]] for the initial management of pain due to acute trauma, as well as for brief painful procedures such as changing of wound dressings or for patient transport. A portable, disposable, single-use inhaler device (the Penthrox inhaler), along with a single 3&nbsp;milliliter brown glass vial of methoxyflurane is provided in doctor's kits that allows conscious hemodynamically stable patients (including children over the age of 5&nbsp;years) to self-administer the drug, under supervision. The device is often referred to as the "green whistle", due to its appearance.


Each 3&nbsp;milliliter dose lasts approximately 30&nbsp;minutes.<ref name=Penthrox2009/> Pain relief begins after 6–8 breaths and continues for several minutes after stopping inhalation.<ref name=Wellness2010/> The maximum recommended dose is 6&nbsp;milliliters per day or 15&nbsp;milliliters per week because of the risk of cumulative dose-related nephrotoxicity, and it should not be used on consecutive days.<ref name=RADAR2010/> Despite the potential for renal impairment when used at anesthetic doses, no significant adverse effects have been reported in the literature when it is used at the lower doses (up to 6&nbsp;milliliters) used for producing analgesia and sedation.<ref name=Babl2006/><ref name=Grindlay2009/><ref name=Rossi2008/> Due to the risk of organ (especially renal) [[toxicity]], methoxyflurane is [[Contraindication|contraindicated]] in patients with pre-existing [[Nephropathy|kidney disease]] or [[diabetes mellitus]], and is not recommended to be administered in conjunction with tetracyclines or other potentially nephrotoxic or [[Enzyme inducer|enzyme-inducing]] drugs.<ref name=Grindlay2009/>
Each 3&nbsp;milliliter dose lasts approximately 30&nbsp;minutes. Pain relief begins after 6–8 breaths and continues for several minutes after stopping inhalation. The maximum recommended dose is 6&nbsp;milliliters per day or 15&nbsp;milliliters per week because of the risk of cumulative dose-related nephrotoxicity, and it should not be used on consecutive days.Despite the potential for renal impairment when used at anesthetic doses, no significant adverse effects have been reported in the literature when it is used at the lower doses (up to 6&nbsp;milliliters) used for producing analgesia and sedation. Due to the risk of organ (especially renal) [[toxicity]], methoxyflurane is [[Contraindication|contraindicated]] in patients with pre-existing [[Nephropathy|kidney disease]] or [[diabetes mellitus]], and is not recommended to be administered in conjunction with tetracyclines or other potentially nephrotoxic or [[Enzyme inducer|enzyme-inducing]] drugs.


==Chemical and physical properties==
==Chemical and physical properties==
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[[File:Methoxyflurane-3D-vdW.png|thumb|left|alt=A apace-filling model, or three-dimensional structure of the methoxyflurane molecule, in red, yellow, green, black and white.|[[Space-filling model]] (three-dimensional molecular structure) of methoxyflurane]]
[[File:Methoxyflurane-3D-vdW.png|thumb|left|alt=A apace-filling model, or three-dimensional structure of the methoxyflurane molecule, in red, yellow, green, black and white.|[[Space-filling model]] (three-dimensional molecular structure) of methoxyflurane]]


With a [[Chemical formula|molecular formula]] of C<sub>3</sub>H<sub>4</sub>Cl<sub>2</sub>F<sub>2</sub>O and a [[Structural_formula#Condensed_formulas|condensed structural formula]] of CHCl<sub>2</sub>CF<sub>2</sub>OCH<sub>3</sub>, 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 [[Miscibility|miscible]] with [[ethanol]], [[acetone]], [[chloroform]], [[diethyl ether]], and fixed [[oil]]s. It is soluble in [[Natural rubber|rubber]].<ref name=Penthrox2009/>
With a [[Chemical formula|molecular formula]] of C<sub>3</sub>H<sub>4</sub>Cl<sub>2</sub>F<sub>2</sub>O and a [[Structural_formula#Condensed_formulas|condensed structural formula]] of CHCl<sub>2</sub>CF<sub>2</sub>OCH<sub>3</sub>, 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 [[Miscibility|miscible]] with [[ethanol]], [[acetone]], [[chloroform]], [[diethyl ether]], and fixed [[oil]]s. It is soluble in [[Natural rubber|rubber]].


With a [[minimum alveolar concentration]] (MAC) of 0.2%, methoxyflurane is an extremely potent anesthetic agent. It is a powerful analgesic agent at well below full anesthetic concentrations.<ref name=Babl2007/><ref name=Torda1963/><ref name=Tomlin1973/><ref name=Tomi1993/><ref name=Crankshaw2005/> Because of its low volatility and very high [[boiling point]] (104.8&nbsp;°C at 1&nbsp;atmosphere), methoxyflurane has a low [[vapor pressure]] at [[Standard conditions for temperature and pressure|ambient temperature and atmospheric pressure]]. It is therefore quite difficult to vaporize methoxyflurane using conventional [[Anaesthetic vaporiser|anesthetic vaporizers]].
With a [[minimum alveolar concentration]] (MAC) of 0.2%, methoxyflurane is an extremely potent anesthetic agent. It is a powerful analgesic agent at well below full anesthetic concentrations. Because of its low volatility and very high [[boiling point]] (104.8&nbsp;°C at 1&nbsp;atmosphere), methoxyflurane has a low [[vapor pressure]] at [[Standard conditions for temperature and pressure|ambient temperature and atmospheric pressure]]. It is therefore quite difficult to vaporize methoxyflurane using conventional [[Anaesthetic vaporiser|anesthetic vaporizers]].


{| class="wikitable"
{| class="wikitable"
! Property
! Property
! Value<ref name=Penthrox2009/><ref name=Wyant1961/><ref name=McIntyre1962/>
! Value
|-
|-
| [[Boiling point]] (at 1&nbsp;[[atmosphere (unit)|atmosphere]])
| [[Boiling point]] (at 1&nbsp;[[atmosphere (unit)|atmosphere]])
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|}


The carbon–fluorine bond, a component of all organofluorine compounds, is the strongest [[chemical bond]] in organic chemistry.<ref name=Hagan2008/> Furthermore, this bond becomes shorther and stronger as more fluorine atoms are added to the same carbon on a given molecule. Because of this, [[fluorocarbon|fluoroalkanes]] are some of the most [[Chemical stability|chemically stable]] organic compounds.
The carbon–fluorine bond, a component of all organofluorine compounds, is the strongest [[chemical bond]] in organic chemistry. Furthermore, this bond becomes shorther and stronger as more fluorine atoms are added to the same carbon on a given molecule. Because of this, [[fluorocarbon|fluoroalkanes]] are some of the most [[Chemical stability|chemically stable]] organic compounds.


==Pharmacokinetics==
==Pharmacokinetics==
Methoxyflurane has a very high lipid solubility (oil:gas [[partition coefficient]] of around 950), which gives it very slow [[pharmacokinetics]] (induction and emergence characteristics); this being undesirable for routine application in the clinical setting. Initial studies performed in 1961 revealed that in [[General_anaesthesia#Premedication|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 [[General_anaesthetic#Injection|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 [[Circulatory system|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.<ref name=Wyant1961/>
Methoxyflurane has a very high lipid solubility (oil:gas [[partition coefficient]] of around 950), which gives it very slow [[pharmacokinetics]] (induction and emergence characteristics); this being undesirable for routine application in the clinical setting. Initial studies performed in 1961 revealed that in [[General_anaesthesia#Premedication|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 [[General_anaesthetic#Injection|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 [[Circulatory system|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.


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&nbsp;minutes after administration of methoxyflurane for an average duration of 87&nbsp;minutes. The longest time to emergence was 285&nbsp;minutes, after 165&nbsp;minutes of methoxyflurane administration.<ref name=Wyant1961/>
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&nbsp;minutes after administration of methoxyflurane for an average duration of 87&nbsp;minutes. The longest time to emergence was 285&nbsp;minutes, after 165&nbsp;minutes of methoxyflurane administration.


==Pharmacodynamics==
==Pharmacodynamics==
;Cardiovascular effects
;Cardiovascular effects
The effects of methoxyflurane on the circulatory system resemble those of diethyl ether.<ref name=Siebecker1961/> In dogs, methoxyflurane anesthesia causes a moderate [[hypotension|decrease in blood pressure]] with minimal changes in [[heart rate]], and no significant effect on [[blood sugar]], [[epinephrine]], or [[norepinephrine]]. [[Bleeding]] and increased [[arterial blood gas|arterial]] [[partial pressure]] of [[carbon dioxide]] (PaCO<sub>2</sub>) both induce further decreases in blood pressure, as well as increases in blood glucose, epinephrine and norepinephrine.<ref name=Millar1961/> In humans, methoxyflurane produces some decrease in blood pressure, but [[cardiac output]], [[stroke volume]], and [[total peripheral resistance]] are only minimally depressed. Its effect on the [[pulmonary circulation]] is negligible, and it does not predispose the heart to [[cardiac dysrhythmia]]s.<ref name=Wyant1961/><ref name=Artusio1960/><ref name=VANPOZNAK1960-1/><ref name=VANPOZNAK1960-2/>
The effects of methoxyflurane on the circulatory system resemble those of diethyl ether. In dogs, methoxyflurane anesthesia causes a moderate [[hypotension|decrease in blood pressure]] with minimal changes in [[heart rate]], and no significant effect on [[blood sugar]], [[epinephrine]], or [[norepinephrine]]. [[Bleeding]] and increased [[arterial blood gas|arterial]] [[partial pressure]] of [[carbon dioxide]] (PaCO<sub>2</sub>) both induce further decreases in blood pressure, as well as increases in blood glucose, epinephrine and norepinephrine. In humans, methoxyflurane produces some decrease in blood pressure, but [[cardiac output]], [[stroke volume]], and [[total peripheral resistance]] are only minimally depressed. Its effect on the [[pulmonary circulation]] is negligible, and it does not predispose the heart to [[cardiac dysrhythmia]]s.


;Respiratory effects
;Respiratory effects
Unlike diethyl ether, methoxyflurane is a significant respiratory depressant. In dogs, methoxyflurane causes a [[Dose-response relationship|dose-dependent]] decrease in [[respiratory rate]] and a marked decrease in [[respiratory minute volume]], with a relatively mild decrease in [[tidal volume]]. In humans, methoxyflurane causes a dose-dependent decrease in tidal volume and minute volume, with respiratory rate relatively constant.<ref name=Siebecker1961/> The net effect of these changes is profound respiratory depression, as evidenced by [[hypercapnia|CO<sub>2</sub> retention]] with a concomitant decrease in arterial [[pH]] (this is referred to as a [[respiratory acidosis]]) when anesthetized subjects are allowed to breathe spontaneously for any length of time.<ref name=Wyant1961/>
Unlike diethyl ether, methoxyflurane is a significant respiratory depressant. In dogs, methoxyflurane causes a [[Dose-response relationship|dose-dependent]] decrease in [[respiratory rate]] and a marked decrease in [[respiratory minute volume]], with a relatively mild decrease in [[tidal volume]]. In humans, methoxyflurane causes a dose-dependent decrease in tidal volume and minute volume, with respiratory rate relatively constant. The net effect of these changes is profound respiratory depression, as evidenced by [[hypercapnia|CO<sub>2</sub> retention]] with a concomitant decrease in arterial [[pH]] (this is referred to as a [[respiratory acidosis]]) when anesthetized subjects are allowed to breathe spontaneously for any length of time.


;Gastrointestinal effects
;Gastrointestinal effects
In a series of 500 consecutive obstetric [[patient]]s, Boisvert and Hudon observed vomiting in 12 (4.8%) patients during or after administration of methoxyflurane anesthesia. These findings compared favorably with those reported for [[cyclopropane]] (42%), [[trichloroethylene]] (28%) and halothane (4.6%).<ref name=Boisvert1962/> In another study of 645 obstetric patients, Romagnoli and Korman observed 8 cases (1.2%) of [[Postoperative nausea and vomiting|postoperative vomiting]], one of whom was [[retching]] before the administration of the anesthetic.<ref name=Romagnoli1962/>
In a series of 500 consecutive obstetric [[patient]]s, Boisvert and Hudon observed vomiting in 12 (4.8%) patients during or after administration of methoxyflurane anesthesia. These findings compared favorably with those reported for [[cyclopropane]] (42%), [[trichloroethylene]] (28%) and halothane (4.6%).In another study of 645 obstetric patients, Romagnoli and Korman observed 8 cases (1.2%) of [[Postoperative nausea and vomiting|postoperative vomiting]], one of whom was [[retching]] before the administration of the anesthetic.


;Analgesic effects
;Analgesic effects
Although the high blood solubility of methoxyflurane is often undesirable, this property makes it useful in certain situations—it persists in the [[Compartment (pharmacokinetics)|lipid compartment]] of the body for a long time, providing [[sedation]] and analgesia well into the postoperative period.<ref name=Crankshaw2005/><ref name=Siebecker1961/> There is substantial data to indicate that methoxyflurane is an effective analgesic and sedative agent at subanesthetic doses.<ref name=McLennan2007/><ref name=Babl2006/><ref name=Buntine2007/><ref name=Johnston2011/><ref name=Major1966/><ref name=Dragon1967/><ref name=Packer1969/><ref name=Romagnoli1970/><ref name=Firn1972/><ref name=Josephson1974/><ref name=Lewis1984/><ref name=Komesaroff1995/><ref name=Chin2002/> Supervised [[self-administration]] of methoxyflurane in children and adults can briefly lead to deep sedation,<ref name=Babl2006/> and it has been used as a patient controlled analgesic for painful procedures in children in hospital [[emergency department]]s.<ref name=Babl2007/> During [[childbirth]], administration of methoxyflurane produces significantly better analgesia, less [[psychomotor agitation]], and only slightly more [[somnolence]] than trichloroethylene.<ref name=Major1966/>
Although the high blood solubility of methoxyflurane is often undesirable, this property makes it useful in certain situations—it persists in the [[Compartment (pharmacokinetics)|lipid compartment]] of the body for a long time, providing [[sedation]] and analgesia well into the postoperative period. There is substantial data to indicate that methoxyflurane is an effective analgesic and sedative agent at subanesthetic doses. Supervised [[self-administration]] of methoxyflurane in children and adults can briefly lead to deep sedation, and it has been used as a patient controlled analgesic for painful procedures in children in hospital [[emergency department]]s. During [[childbirth]], administration of methoxyflurane produces significantly better analgesia, less [[psychomotor agitation]], and only slightly more [[somnolence]] than trichloroethylene.


In 1968, Robert Wexler of Abbott Laboratories developed the Analgizer, a disposable [[inhaler]] that allowed the self-administration of methoxyflurane vapor in air for analgesia.<ref name=Wexler1968/> The Analgizer consisted of a [[polyethylene]] cylinder 5&nbsp;inches long and 1&nbsp;inch in diameter with a 1&nbsp;inch long mouthpiece. The device contained a rolled [[Candle wick|wick]] of [[polypropylene]] [[felt]] which held 15&nbsp;[[Litre#SI_prefixes_applied_to_the_litre|milliliters]] of methoxyflurane. Because of the simplicity of the Analgizer and the [[Pharmacology|pharmacological]] characteristics of methoxyflurane, it was easy for patients to self-administer the drug and rapidly achieve a level of [[Procedural sedation and analgesia|conscious analgesia]] which could be maintained and adjusted as necessary over a period of time lasting from a few minutes to several hours. The 15&nbsp;milliliter supply of methoxyflurane would typically last for two to three hours, during which time the user would often be partly [[Amnesia|amnesic]] to the sense of pain; the device could be refilled if necessary.<ref name=Romagnoli1970/> The Analgizer was found to be safe, effective, and simple to administer in obstetric patients during childbirth, as well as for patients with [[bone fracture]]s and [[joint dislocation]]s,<ref name=Romagnoli1970/> and for dressing changes on [[burn]] patients.<ref name=Packer1969/> When used for labor analgesia, the Analgizer allows labor to progress normally and with no apparent [[adverse effect]] on [[Apgar score]]s.<ref name=Romagnoli1970/> All [[vital signs]] remain normal in obstetric patients, newborns, and injured patients.<ref name=Romagnoli1970/> The Analgizer was widely utilized for analgesia and sedation until the early 1970s, in a manner that foreshadowed the patient-controlled analgesia infusion pumps of today.<ref name=Major1966/><ref name=Dragon1967/><ref name=Firn1972/><ref name=Josephson1974/> The Analgizer inhaler was withdrawn in 1974, but use of methoxyflurane as a sedative and analgesic continues in Australia and New Zealand in the form of the [[Penthrox inhaler]].<ref name=McLennan2007/><ref name=Babl2006/><ref name=Babl2007/><ref name=Grindlay2009/> Trials of methoxyflurane as an analgesic in emergency medicine are going on in the UK.
In 1968, Robert Wexler of Abbott Laboratories developed the Analgizer, a disposable [[inhaler]] that allowed the self-administration of methoxyflurane vapor in air for analgesia. The Analgizer consisted of a [[polyethylene]] cylinder 5&nbsp;inches long and 1&nbsp;inch in diameter with a 1&nbsp;inch long mouthpiece. The device contained a rolled [[Candle wick|wick]] of [[polypropylene]] [[felt]] which held 15&nbsp;[[Litre#SI_prefixes_applied_to_the_litre|milliliters]] of methoxyflurane. Because of the simplicity of the Analgizer and the [[Pharmacology|pharmacological]] characteristics of methoxyflurane, it was easy for patients to self-administer the drug and rapidly achieve a level of [[Procedural sedation and analgesia|conscious analgesia]] which could be maintained and adjusted as necessary over a period of time lasting from a few minutes to several hours. The 15&nbsp;milliliter supply of methoxyflurane would typically last for two to three hours, during which time the user would often be partly [[Amnesia|amnesic]] to the sense of pain; the device could be refilled if necessary. The Analgizer was found to be safe, effective, and simple to administer in obstetric patients during childbirth, as well as for patients with [[bone fracture]]s and [[joint dislocation]]s, and for dressing changes on [[burn]] patients. When used for labor analgesia, the Analgizer allows labor to progress normally and with no apparent [[adverse effect]] on [[Apgar score]]s. All [[vital signs]] remain normal in obstetric patients, newborns, and injured patients. The Analgizer was widely utilized for analgesia and sedation until the early 1970s, in a manner that foreshadowed the patient-controlled analgesia infusion pumps of today. The Analgizer inhaler was withdrawn in 1974, but use of methoxyflurane as a sedative and analgesic continues in Australia and New Zealand in the form of the [[Penthrox inhaler]].Trials of methoxyflurane as an analgesic in emergency medicine are going on in the UK.


==Biodegradation and toxicity==
==Biodegradation and toxicity==
{{See|Drug metabolism|Fluoride poisoning}}
{{See|Drug metabolism|Fluoride poisoning}}


The first report of nephrotoxicity appeared in 1964, when Paddock and colleagues reported three cases of acute renal insufficiency, two of whom were found to have calcium [[oxalate]] crystals in the renal tubules at autopsy.<ref name=Paddock1964/> In 1966, Crandell and colleagues reported a series in which 17/95 (18%) of patients developed an unusual type of [[nephropathy]] after operations in which methoxyflurane was used as a general anesthetic. This particular type of [[renal insufficiency]] was characterized by [[vasopressin]]-resistant [[Nephrogenic diabetes insipidus|high-output renal failure]] (production of large volumes of poorly concentrated urine) with a negative fluid balance, pronounced weight loss, elevation of serum sodium, chloride, [[osmolality]] and blood urea nitrogen. The urine of these patients was of a relatively fixed [[specific gravity]] and an osmolality very similar to that of the serum. Furthermore, the high urine output persisted a challenge test of fluid deprivation. Most cases resolved within 2–3 weeks, but evidence of renal dysfunction persisted for more than one year in 3 of these 17 cases (18%), and more than two years in one case (6%).<ref name=Crandell1966/>
The first report of nephrotoxicity appeared in 1964, when Paddock and colleagues reported three cases of acute renal insufficiency, two of whom were found to have calcium [[oxalate]] crystals in the renal tubules at autopsy. In 1966, Crandell and colleagues reported a series in which 17/95 (18%) of patients developed an unusual type of [[nephropathy]] after operations in which methoxyflurane was used as a general anesthetic. This particular type of [[renal insufficiency]] was characterized by [[vasopressin]]-resistant [[Nephrogenic diabetes insipidus|high-output renal failure]] (production of large volumes of poorly concentrated urine) with a negative fluid balance, pronounced weight loss, elevation of serum sodium, chloride, [[osmolality]] and blood urea nitrogen. The urine of these patients was of a relatively fixed [[specific gravity]] and an osmolality very similar to that of the serum. Furthermore, the high urine output persisted a challenge test of fluid deprivation. Most cases resolved within 2–3 weeks, but evidence of renal dysfunction persisted for more than one year in 3 of these 17 cases (18%), and more than two years in one case (6%).
Reports of severe and even fatal hepatotoxicity related to the use of methoxyflurane began to appear in 1966. These reports prompted anesthesiologists to subject this agent to intense and systematic scrutiny. A study published in 1973 by Cousins and Mazze demonstrated that compared with halothane, methoxyflurane produces dose-dependent and deleterious abnormalities in [[renal function]]. The authors showed that [[Asymptomatic|subclinical]] nephrotoxicity occurred following methoxyflurane at minimum alveolar concentration (MAC) for 2.5 to 3&nbsp;hours (2.5 to 3&nbsp;MAC hours), while overt toxicity was present in all patients at dosages greater than five MAC hours.This landmark study provided a model that would be used for the assessment of the nephrotoxicity of volatile anesthetics for the next two decades.


Reports of severe and even fatal hepatotoxicity related to the use of methoxyflurane began to appear in 1966. These reports prompted anesthesiologists to subject this agent to intense and systematic scrutiny. A study published in 1973 by Cousins and Mazze demonstrated that compared with halothane, methoxyflurane produces dose-dependent and deleterious abnormalities in [[renal function]]. The authors showed that [[Asymptomatic|subclinical]] nephrotoxicity occurred following methoxyflurane at minimum alveolar concentration (MAC) for 2.5 to 3&nbsp;hours (2.5 to 3&nbsp;MAC hours), while overt toxicity was present in all patients at dosages greater than five MAC hours.<ref name=Cousins1973/> This landmark study provided a model that would be used for the assessment of the nephrotoxicity of volatile anesthetics for the next two decades.<ref name=Barash2009-17/>
The biodegradation of methoxyflurane begins immediately after the onset of exposure. The [[nephrotoxicity|kidney]] and [[hepatotoxicity|liver]] toxicity observed after anesthetic doses is attributable to one or more [[metabolite]]s produced by O-[[demethylation]] of methoxyflurane. Significant products of this [[catabolism|catabolic process]] include methoxyfluoroacetic acid (MFAA), dichloroacetic acid (DCAA), and inorganic fluoride. This effect is so predictable and reproducible that methoxyflurane now serves as a pharmacologic model of fluoride-related nephrotoxicity, one with which newer drugs are compared. It is not entirely clear whether the fluoride itself is toxic—it may simply be a [[Surrogate endpoint|surrogate measure]] for some other [[Toxication|toxic metabolite]]. 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.Furthermore, the concurrent use of [[tetracycline]]s and methoxyflurane has been reported to result in fatal renal toxicity.


The biodegradation of methoxyflurane begins immediately after the onset of exposure. The [[nephrotoxicity|kidney]] and [[hepatotoxicity|liver]] toxicity observed after anesthetic doses is attributable to one or more [[metabolite]]s produced by O-[[demethylation]] of methoxyflurane. Significant products of this [[catabolism|catabolic process]] include methoxyfluoroacetic acid (MFAA), dichloroacetic acid (DCAA), and inorganic fluoride. This effect is so predictable and reproducible that methoxyflurane now serves as a pharmacologic model of fluoride-related nephrotoxicity, one with which newer drugs are compared.<ref name=Barash2009-17/> It is not entirely clear whether the fluoride itself is toxic—it may simply be a [[Surrogate endpoint|surrogate measure]] for some other [[Toxication|toxic metabolite]]. 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.Furthermore, the concurrent use of [[tetracycline]]s and methoxyflurane has been reported to result in fatal renal toxicity.
Based on the findings of these and other studies in the early 1970s, the current 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&nbsp;MAC hours. Partly because of these warnings, but also because of the development of newer volatile anesthetics such as enflurane, [[isoflurane]], [[desflurane]] and sevoflurane, the clinical use of methoxyflurane as a general anesthetic in humans was largely abandoned in the mid-1970s.
 
Based on the findings of these and other studies in the early 1970s, the current 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&nbsp;MAC hours.<ref name=Cousins1973/><ref name=Gottlieb1974/> Partly because of these warnings, but also because of the development of newer volatile anesthetics such as enflurane, [[isoflurane]], [[desflurane]] and sevoflurane, the clinical use of methoxyflurane as a general anesthetic in humans was largely abandoned in the mid-1970s.


==History==
==History==
{{See|Drug development|Gaseous diffusion|Manhattan Project|Medicinal chemistry|Organofluorine compounds}}
{{See|Drug development|Gaseous diffusion|Manhattan Project|Medicinal chemistry|Organofluorine compounds}}


All of the currently used volatile anesthetic agents are organofluorine compounds. Aside from the [[Thomas_Midgley,_Jr.#Synthesis_of_Freon|synthesis of Freon]] ([[Thomas Midgley, Jr.]] and [[Charles F. Kettering]], 1928)<ref name=Sneader2005/> and the discovery of [[Polytetrafluoroethylene|Teflon]] ([[Roy J. Plunkett]], 1938),<ref name=Dupont2010/> the field of [[organofluorine chemistry]] had not attracted a great deal of attention up to 1940 because of the extreme reactivity of elemental [[fluorine]], which had to be produced [[in situ]] for use in chemical reactions. The development of organofluorine chemistry was a [[government spin-off|spin-off]] from the [[Manhattan Project]], during which elemental fluorine was produced on an industrial scale for the first time.
All of the currently used volatile anesthetic agents are organofluorine compounds. Aside from the [[Thomas_Midgley,_Jr.#Synthesis_of_Freon|synthesis of Freon]] ([[Thomas Midgley, Jr.]] and [[Charles F. Kettering]], 1928) and the discovery of [[Polytetrafluoroethylene|Teflon]] ([[Roy J. Plunkett]], 1938), the field of [[organofluorine chemistry]] had not attracted a great deal of attention up to 1940 because of the extreme reactivity of elemental [[fluorine]], which had to be produced [[in situ]] for use in chemical reactions. The development of organofluorine chemistry was a [[government spin-off|spin-off]] from the [[Manhattan Project]], during which elemental fluorine was produced on an industrial scale for the first time.


The need for fluorine arose from the need to separate the [[Isotopes of uranium|isotope]]<sup>235</sup>U from <sup>238</sup>U because the former, present in natural [[uranium]] at a concentration of less than 1% is [[fissile]] (capable of sustaining a [[Chain_reaction#Nuclear_chain_reactions|nuclear chain reaction]] of [[nuclear fission]] with [[Neutron_temperature#Thermal_neutrons|thermal neutrons]]),<ref name=Cotton2006/> whereas the latter is not. Members of the [[MAUD Committee]] (especially [[Francis Simon]] and [[Nicholas Kurti]]) proposed the use of [[gaseous diffusion]] for isotope separation, since, according to [[Graham's law]] the rate of diffusion is inversely proportional to molecular mass.<ref name=Rhodes1986/> After an extensive search, [[uranium hexafluoride]], UF<sub>6</sub>, was determined to be the most suitable compound of uranium to be used for the gaseous diffusion process.<ref name=Beaton1962/> Elemental fluorine is needed in the production of UF<sub>6</sub>.  
The need for fluorine arose from the need to separate the [[Isotopes of uranium|isotope]]<sup>235</sup>U from <sup>238</sup>U because the former, present in natural [[uranium]] at a concentration of less than 1% is [[fissile]] (capable of sustaining a [[Chain_reaction#Nuclear_chain_reactions|nuclear chain reaction]] of [[nuclear fission]] with [[Neutron_temperature#Thermal_neutrons|thermal neutrons]]), whereas the latter is not. Members of the [[MAUD Committee]] (especially [[Francis Simon]] and [[Nicholas Kurti]]) proposed the use of [[gaseous diffusion]] for isotope separation, since, according to [[Graham's law]] the rate of diffusion is inversely proportional to molecular mass. After an extensive search, [[uranium hexafluoride]], UF<sub>6</sub>, was determined to be the most suitable compound of uranium to be used for the gaseous diffusion process.Elemental fluorine is needed in the production of UF<sub>6</sub>.  


Significant obstacles had to be overcome in the handling of both fluorine and UF<sub>6</sub>. Before the [[K-25]] gaseous diffusion [[chemical plant|plant]] could be built, it was first necessary to develop [[Reactivity (chemistry)|non-reactive]] [[chemical compound]]s that could be used as [[coating]]s, [[lubricant]]s and [[gasket]]s for the surfaces which would come into contact with the UF<sub>6</sub> gas (a highly reactive and [[corrosive substance]]). William T. Miller,<ref name=obituary/> professor of [[organic chemistry]] at [[Cornell University]], was co-opted to develop such materials, because of his expertise in organofluorine chemistry. Miller and his team developed several novel non-reactive [[chlorofluorocarbon]] [[polymer]]s that were used in this application.
Significant obstacles had to be overcome in the handling of both fluorine and UF<sub>6</sub>. Before the [[K-25]] gaseous diffusion [[chemical plant|plant]] could be built, it was first necessary to develop [[Reactivity (chemistry)|non-reactive]] [[chemical compound]]s that could be used as [[coating]]s, [[lubricant]]s and [[gasket]]s for the surfaces which would come into contact with the UF<sub>6</sub> gas (a highly reactive and [[corrosive substance]]). William T. Miller, professor of [[organic chemistry]] at [[Cornell University]], was co-opted to develop such materials, because of his expertise in organofluorine chemistry. Miller and his team developed several novel non-reactive [[chlorofluorocarbon]] [[polymer]]s that were used in this application.
 
[[Charles Suckling]] synthesized [[halothane]] in 1951. Halothane was the first organofluorine anesthetic agent to be introduced into clinical practice in 1956.Miller and his team continued to develop organofluorine chemistry after the end of [[World War II]] and methoxyflurane was synthesized in 1948.


[[Charles Suckling]] synthesized [[halothane]] in 1951. Halothane was the first organofluorine anesthetic agent to be introduced into clinical practice in 1956.<ref name=Raventos1956/> Miller and his team continued to develop organofluorine chemistry after the end of [[World War II]] and methoxyflurane was synthesized in 1948.<ref name=Miller1948/>
{{Reflist|2}}
{{Reflist|2}}


==Notes==
<ref name=Artusio1960>{{cite journal|author=Artusio JF, Van Poznak A, Hunt RE, Tiers RM, Alexander MA|title=A clinical evaluation of methoxyflurane in man|journal=Anesthesiology|volume=21|issue=5|pages=512–7|year=1960|pmid=13794589|doi=10.1097/00000542-196009000-00009|url=http://journals.lww.com/anesthesiology/Citation/1960/09000/A_Clinical_Evaluation_of_Methoxyflurane_in_Man.9.aspx}}</ref>
<ref name=Babl2006>{{cite journal|author=Babl FE, Jamison SR, Spicer M, Bernard S|title=Inhaled methoxyflurane as a prehospital analgesic in children|journal=Emergency Medicine Australasia|volume=18|issue=4|pages=404–10|year=2006|pmid=16842312|doi=10.1111/j.1742-6723.2006.00874.x}}</ref>
<ref name=Babl2007>{{cite journal|author=Babl F, Barnett P, Palmer G, Oakley E, Davidson A|title=A pilot study of inhaled methoxyflurane for procedural analgesia in children|journal=Pediatric Anesthesia|volume=17|issue=2|pages=148–53|year=2007|pmid=17238886|doi=10.1111/j.1460-9592.2006.02037.x}}</ref>
<ref name=Barash2009-17>[[#refBarash2009|Barash, Cullen and Stoelting (2009)]], Ebert and Schmid, ''Chapter 17: Inhaled Anesthetics'', pp. 413–43</ref>
<ref name=Beaton1962>{{cite journal|author=Beaton L|title=The slow-down in nuclear explosive production|journal=New Scientist|volume=16|issue=309|pages=141–3|year=1962|url=http://books.google.com/?id=pp8mxf-9E_sC&pg=PA141&lpg=PA141&dq=%22The+slow-down+in+nuclear+explosive+production%22#v=onepage&q=%22The%20slow-down%20in%20nuclear%20explosive%20production%22&f=false}}</ref>
<ref name=Boisvert1962>{{cite journal|author=Boisvert M, Hudon F|title=Clinical evaluation of methoxyflurane in obstetrical anaesthesia: A report on 500 cases|journal=Canadian Anaesthetists' Society Journal|volume=9|issue=4|pages=325–30|year=1962|doi=10.1007/BF03021269|url=http://www.springerlink.com/content/12m441074h75t62t/fulltext.pdf}}</ref>
<ref name=Brenner1971>{{cite journal|author=Brenner AI, Kaplan MM|title=Recurrent hepatitis due to methoxyflurane anesthesia|journal=New England Journal of Medicine|volume=284|issue=17|pages=961–2|year=1971|pmid=5551804|doi=10.1056/NEJM197104292841707}}</ref>
<ref name=Buntine2007>{{cite journal|author=Buntine P, Thom O, Babl F, Bailey M, Bernard S|title=Prehospital analgesia in adults using inhaled methoxyflurane|journal=Emergency Medicine Australasia|volume=19|issue=6|pages=509–14|year=2007|pmid=18021102|doi=10.1111/j.1742-6723.2007.01017.x}}</ref>
<ref name=Chin2002>{{cite journal|author=Chin R, McCaskill M, Browne G, Lam L|title=A randomised controlled trial of inhaled methoxyflurane pain relief in children with upper limb fracture (abstract)|journal=Journal of Paediatrics and Child Health|volume=38|issue=5|pages=A13–4|year=2002|issn=1034-4810|doi=10.1046/j.1440-1754.2002.00385.x}}</ref>
<ref name=Cotton2006>[[#refCotton2006|Cotton (2006)]], Cotton S, ''Chapter 10: Binary compounds of the actinides'', pp. 155–72</ref>
<ref name=Cousins1973>{{cite journal|author=Cousins MJ, Mazze RI|title=Methoxyflurane nephrotoxicity: a study of dose response in man (abstract)|journal=Journal of the American Medical Association|volume=225|issue=13|pages=1611–6|year=1973|pmid=4740737|doi=10.1001/jama.1973.03220410023005|url=http://jama.ama-assn.org/cgi/content/abstract/225/13/1611}}</ref>
<ref name=Crandell1966>{{cite journal|author=Crandell WB, Pappas SG, Macdonald A|title=Nephrotoxicity associated with methoxyflurane anesthesia|journal=Anesthesiology|volume=27|issue=5|pages=591–607|year=1966|pmid=5918999|doi=10.1097/00000542-196609000-00010|url=http://journals.lww.com/anesthesiology/Abstract/1966/09000/Nephrotoxicity_Associated_with_Methoxyflurane.10.aspx}}</ref>
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<ref name=Delia1983>{{cite journal|author=Delia JE, Maxson WS, Breen JL|title=Methoxyflurane hepatitis: two cases following obstetric analgesia|journal=International Journal of Gynaecology & Obstetrics|volume=21|issue=1|pages=89–93|year=1983|pmid=6133801|doi=10.1016/0020-7292(83)90076-0}}</ref>
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<ref name=Dupont2010>{{cite web|title=Roy Plunkett: 1938|author=DuPont|work=DuPont Heritage|publisher=E. I. du Pont de Nemours and Company|location=Wilmington, Delaware|year=2010|url=http://www2.dupont.com/Heritage/en_US/1938_dupont/1938_indepth.html|accessdate=2011-06-12}}</ref>
<ref name=Firn1972>{{cite journal|author=Firn S|title=Methoxyflurane analgesia for burns dressings and other painful ward procedures in children|journal=British Journal of Anaesthesia|volume=44|issue=5|pages=517–22|year=1972|pmid=5044082|doi=10.1093/bja/44.5.517}}</ref>
<ref name=Gottlieb1974>{{cite journal|author=Gottlieb LS, Trey C|title=The effects of fluorinated anesthetics on the liver and kidneys|journal=Annual Review of Medicine|volume=25|pages=411–29|year=1974|pmid=4596236|doi=10.1146/annurev.me.25.020174.002211}}</ref>
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<ref name=Jones1972>{{cite journal|author=Jones NO|title=Methoxyflurane nephrotoxicity – a review and a case report|journal=Canadian Anaesthetists' Society Journal|volume=19|issue=2|pages=152–9|year=1972|pmid=5029469|doi=10.1007/BF03005045|url=http://www.springerlink.com/content/bl1g733076mnw031/fulltext.pdf}}</ref>
<ref name=Josephson1974>{{cite journal|author=Josephson CA, Schwartz W|title=The Cardiff inhaler and Penthrane. A method of sedation analgesia in routine dentistry|journal=Journal of the Dental Association of South Africa|volume=29|issue=2|pages=77–80|year=1974|pmid=4534883}}</ref>
<ref name=Joshi1974>{{cite journal|author=Joshi PH, Conn HO|title=The syndrome of methoxyflurane associated hepatitis|journal=Annals of Internal Medicine|volume=80|issue=3|pages=395–401|year=1974|pmid=4816183|doi=10.7326/0003-4819-80-3-395}}</ref>
<ref name=Kharasch2006-1>{{cite journal|author=Kharasch ED, Schroeder JL, Liggitt HD, Park SB, Whittington D, Sheffels P|title=New insights into the mechanism of methoxyflurane nephrotoxicity and implications for anesthetic development (part 1): Identification of the nephrotoxic metabolic pathway|journal=Anesthesiology|volume=105|issue=4|pages=726–36|year=2006|pmid=17006072|doi=10.1097/00000542-200610000-00019|url=http://journals.lww.com/anesthesiology/Fulltext/2006/10000/New_Insights_into_the_Mechanism_of_Methoxyflurane.19.aspx}}</ref>
<ref name=Kharasch2006-2>{{cite journal|author=Kharasch ED, Schroeder JL, Liggitt HD, Ensign D, Whittington D|title=New insights into the mechanism of methoxyflurane nephrotoxicity and implications for anesthetic development (part 2): Identification of nephrotoxic metabolites|journal=Anesthesiology|volume=105|issue=4|pages=737–45|year=2006|pmid=17006073|doi=10.1097/00000542-200610000-00020|url=http://journals.lww.com/anesthesiology/Fulltext/2006/10000/New_Insights_into_the_Mechanism_of_Methoxyflurane.20.aspx}}</ref>
<ref name=Klein1966>{{cite journal|author=Klein NC, Jeffries GH|title=Hepatotoxicity after methoxyflurane administration (abstract)|journal=Journal of the American Medical Association|volume=197|issue=12|pages=1037–9|year=1966|pmid=5953207|doi=10.1001/jama.1966.03110120143040|url=http://jama.ama-assn.org/content/197/12/1037.extract}}</ref>
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<ref name=Major1966>{{cite journal|author=Major V, Rosen M, Mushin WW|title=Methoxyflurane as an obstetric analgesic: a comparison with trichloroethylene|journal=British Medical Journal|volume=2|issue=5529|pages=1554–61|year=1966|pmid=5926260|doi=10.1136/bmj.2.5529.1554|pmc=1944957}}</ref>
<ref name=Mazze1976>{{cite journal|author=Mazze RI|title=Methoxyflurane nephropathy|journal=Environmental Health Perspectives|volume=15|pages=111–9|year=1976|pmid=1001288|doi=10.2307/3428393|jstor=3428393|pmc=1475154}}</ref>
<ref name=McIntyre1962>{{cite journal|author=McIntyre JWR, Gain EA|title=Methoxyflurane|journal=Canadian Anaesthetists' Society Journal|volume=9|issue=4|pages=319–24|year=1962|doi=10.1007/BF03021268|url=http://www.springerlink.com/content/11686702235806h8/fulltext.pdf}}</ref>
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<ref name=Millar1961>{{cite journal|author=Millar RA, Morris ME|title=A study of methoxyflurane anaesthesia|journal=Canadian Anaesthetists' Society Journal|volume=8|issue=3|pages=210–5|year=1961|pmid=13770698|doi=10.1007/BF03028110|url=http://www.springerlink.com/content/b211176881343221/fulltext.pdf}}</ref>
<ref name=Miller1948>{{cite journal|last1=Miller Jr|first1=WT|last2=Fager|first2=EW|last3=Griswold|first3=PH|authorlink1=William T. Miller|title=The Addition of Methyl Alcohol to Fluoroethylenes|journal=Journal of the American Chemical Society|volume=70|issue=1|pages=431–2|year=1948|doi=10.1021/ja01181a526|url=}}</ref>
<ref name=Min1977>{{cite journal|author=Min KW, Cain GD, Sabel JS, Gyorkey F|title=Methoxyflurane hepatitis|journal=Southern Medical Journal|volume=70|issue=11|pages=1363–4|year=1977|pmid=918705|url=http://journals.lww.com/smajournalonline/citation/1977/11000/methoxyflurane_hepatitis.37.aspx|doi=10.1097/00007611-197711000-00037}}</ref>
<ref name=obituary>{{cite web|last=Friedlander Jr.|first=BP|title=William T. Miller, Manhattan Project scientist and Cornell professor of chemistry, dies at 87|work=[[Cornell Chronicle|Cornell News]]|publisher=Cornell University|location=Ithaca, New York|date=3 December 1998|url=http://www.news.cornell.edu/releases/Nov98/Millerobit.bpf.html|accessdate=2011-06-12}}</ref>
<ref name=Okuno1985>{{cite journal|author=Okuno T, Takeda M, Horishi M, Okanoue T, Takino T|title=Hepatitis due to repeated inhalation of methoxyflurane in subanaesthetic concentrations|journal=Canadian Anaesthetists' Society Journal|volume=32|issue=1|pages=53–5|year=1985|pmid=3971205|doi=10.1007/BF03008538|url=http://www.springerlink.com/content/x13v765670k75626/fulltext.pdf}}</ref>
<ref name=Packer1969>{{cite journal|author=Packer KJ, Titel JH|title=Methoxyflurane analgesia for burns dressings: experience with the Analgizer|journal=British Journal of Anaesthesia|volume=41|issue=12|pages=1080–5|year=1969|pmid=4903969|doi=10.1093/bja/41.12.1080|url=}}</ref>
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<ref name=Raventos1956>{{cite journal|author=Raventós, J|authorlink=Jaume Raventos|title=The action of fluothane—a new volatile anaesthetic|journal=British Journal of Pharmacology and Chemotherapy|volume=11|issue=4|pages=394–410|year=1956|pmid=13383118|pmc=1510559|doi=10.1111/j.1476-5381.1956.tb00007.x}}</ref>
<ref name=Rhodes1986>[[#refRhodes1986|Rhodes (1986)]], Rhodes R, ''Chapter 11: Cross sections'', pp. 318–56</ref>
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<ref name=Romagnoli1970>{{cite journal|author=Romagnoli A, Busque L, Power DJ|title=The "analgizer" in a general hospital: a preliminary report|journal=Canadian Anaesthetists' Society Journal|volume=17|issue=3|pages=275–8|year=1970|pmid=5512851|doi=10.1007/BF03004607|url=http://www.springerlink.com/content/q0201511n4880696/fulltext.pdf}}</ref>
<ref name=Rossi2008>{{cite book|editor-last=Rossi|editor-first=S|title=[[Australian Medicines Handbook]]|publisher=Australian Medicines Handbook Pty, Ltd|location=Adelaide|edition=10th|year=2009|isbn=978-0-9757919-9-8}}</ref>
<ref name=Rubinger1975>{{cite journal|author=Rubinger D, Davidson JT, Melmed RN|title=Hepatitis following the use of methoxyflurane in obstetric analgesia|journal=Anesthesiology|volume=43|issue=5|pages=593–5|year=1975|pmid=1190532|doi=10.1097/00000542-197511000-00025|url=http://journals.lww.com/anesthesiology/citation/1975/11000/hepatitis_following_the_use_of_methoxyflurane_in.25.aspx}}</ref>
<ref name=Siebecker1961>{{cite journal|author=Siebecker KL, James M, Bamforth BJ, Orth OS|title=The respiratory effect of methoxyflurane on dog and man|journal=Anesthesiology|volume=22|issue=1|pages=143|year=1961|doi=10.1097/00000542-196101000-00044|url=http://journals.lww.com/anesthesiology/citation/1961/01000/the_respiratory_effects_of_methoxyflurane_on_dog.44.aspx}}</ref>
<ref name=Sneader2005>[[#refSneader2005|Sneader (2005)]], Sneader W, ''Chapter 8: Systematic medicine'', pp. 74–87</ref>
<ref name=Stefanini1970>{{cite journal|author=Stefanini M, HerlandA, Kosyak, EP|title=Fatal massive necrosis of the liver after repeated exposure to methoxyflurane|journal=Anesthesiology|volume=32|issue=4|pages=374–8|year=1970|pmid=5437870|doi=10.1097/00000542-197004000-00019|url=http://journals.lww.com/anesthesiology/Citation/1970/04000/Fatal_Massive_Necrosis_of_the_Liver_after_Repeated.19.aspx}}</ref>
<ref name=Tomi1993>{{cite journal|author=Tomi K, Mashimo T, Tashiro C, Yagi M, Pak M, Nishimura S, Nishimura M, Yoshiya I|title=Alterations in pain threshold and psychomotor response associated with subanaesthetic concentrations of inhalational anaesthetics in humans|journal=British Journal of Anaesthesia|volume=70|issue=6|pages=684–6|year=1993|pmid=8329263|doi=10.1093/bja/70.6.684}}</ref>
<ref name=Tomlin1973>{{cite journal|author=Tomlin PJ, Jones BC, Edwards R, Robin PE|title=Subjective and objective sensory responses to inhalation of nitrous oxide and methoxyflurane|journal=British Journal of Anaesthesia|volume=45|issue=7|pages=719–25|year=1973|pmid=4730164|doi=10.1093/bja/45.7.719}}</ref>
<ref name=Torda1963>{{cite journal|author=Torda TAG|title=The analgesic effect of methoxyflurane|journal=Anaesthesia|volume=18|issue=3|pages=287–9|year=1963|pmid=13981361|doi=10.1111/j.1365-2044.1963.tb13548.x}}</ref>
<ref name=VANPOZNAK1960-1>{{cite journal|author=Van Poznak A, Artusio JF|title=Anesthetic properties of a series of fluorinated compounds: I. fluorinated hydrocarbons|journal=[[Toxicology and Applied Pharmacology]]|volume=2|issue=4|pages=363–73|year=1960|pmid=13841124|doi=10.1016/0041-008X(60)90002-8|url=http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WXH-4DDP54P-60&_user=10&_coverDate=07%2F31%2F1960&_rdoc=1&_fmt=high&_orig=search&_origin=search&_sort=d&_docanchor=&view=c&_searchStrId=1532683936&_rerunOrigin=google&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=ea1ade15ca100c5a4140e028fd54adfe&searchtype=a}}</ref>
<ref name=VANPOZNAK1960-2>{{cite journal|author=Van Poznak A, Artusio JF|title=Anesthetic properties of a series of fluorinated compounds: II. fluorinated ethers|journal=Toxicology and Applied Pharmacology|volume=2|issue=4|pages=374–8|year=1960|pmid=13841125|doi=10.1016/0041-008X(60)90003-X|url=http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WXH-4DDP54P-61&_user=10&_coverDate=07%2F31%2F1960&_rdoc=1&_fmt=high&_orig=search&_origin=search&_sort=d&_docanchor=&view=c&_searchStrId=1532686591&_rerunOrigin=google&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=4eb31182828bdd42abcd056cd2ed3ef7&searchtype=a}}</ref>
<ref name=Wellness2010>{{cite journal|author=Wellness on Wellington|title=The green whistle|journal=Wellnews|publisher=Wellness on Wellington|location=Rowville, Victoria, Australia|volume=12|issue=2|pages=1|year=2010|url=http://www.wellonwell.com.au/newsletters/news44a.pdf}}</ref>
<ref name=Wexler1968>{{cite web|title=Analgizer: Inhaler for supervised self-administration of inhalation anesthesia|author=Wexler RE|publisher=Abbott Laboratories|location=Abbott Park, Illinois|year=1968|url=http://www.trademarkia.com/analgizer-72302697.html|accessdate=2011-06-12}}</ref>
<ref name=Wyant1961>{{cite journal|author=Wyant GM, Chang CA, Rapicavoli E|title=Methoxyflurane (penthrane): a laboratory and clinical study|journal=Canadian Anaesthetists' Society Journal|volume=8|issue=5|pages=477–87|year=1961|pmid=13786945|doi=10.1007/BF03021373|url=http://www.springerlink.com/content/ywt26v0452115517/fulltext.pdf}}</ref>
}}
==References==
{{Refbegin}}
* <span id="refBarash2009" class="citation">{{cite book|editor1-last=Barash|editor1-first=PG|editor2-last=Cullen|editor2-first=BF|editor3-last=Stoelting|editor3-first=RK|editor4-last=Cahalan|editor4-first=MK|editor5-last=Stock|editor5-first=MC|title=Clinical anesthesia|publisher=Lippincott Williams & Wilkins|location=Philadelphia|edition=6th|year=2009|isbn=978-0-7817-8763-5|url=http://books.google.ca/books?id=-YI9P2DLe9UC}}</span>
* <span id="refCotton2006" class="citation">{{cite book|title=Lanthanide and actinide chemistry|edition=1st|author=Cotton S|publisher=John Wiley and Sons, Ltd.|location=Chichester, England|year=2006|isbn=978-0-470-01006-8|url=http://books.google.com/?id=SvAbtU6XvzgC&pg=PA164&lpg=PA164&dq=%22Graham's+law%22+%22uranium+enrichment%22#v=onepage&q=%22Graham's%20law%22%20%22uranium%20enrichment%22&f=false}}</span>
* <span id="refRhodes1986" class="citation">{{cite book|last=Rhodes|first=R|authorlink=Richard Rhodes|title=The making of the atomic bomb|year=1986|publisher=Simon & Schuster|location=New York|isbn=978-0-684-81378-3|url=http://books.google.com/?id=aSgFMMNQ6G4C&printsec=frontcover&dq=%22The+Making+of+the+Atomic+Bomb%22#v=onepage&q&f=false}}</span>
* <span id="refSneader2005" class="citation">{{cite book|title=Drug discovery: a history|author=Sneader W|publisher=John Wiley and Sons, Ltd.|location=Chichester, England|year=2005|isbn=978-0-471-89980-8|url=http://books.google.com/?id=mYQxRY9umjcC&printsec=frontcover&dq=Drug+Discovery+history&cd=1}}</span>
{{Refend}}
==Further reading==
* {{Cite pmid|3335658}}
* {{Cite pmid|496064}}
* {{Cite pmid|5556243}}
* Crankshaw DP, Eagle A, Komesaroff D. Methoxyflurane dosage with the Penthrox inhaler for analgesia during short painful procedures (abstract). Anaesth. Intensive Care 2004; 32(3): 428.
* {{Cite pmid|490224}}
* {{Cite pmid|7218059}}
* {{Cite pmid|495468}}
* {{Cite pmid|5143658}}
* {{Cite pmid|1059442}}
* {{Cite pmid|5103772}}
* {{Cite pmid|7879937}}
* {{Cite pmid|717928}}
* {{cite conference|author1=Komesaroff D|author2=Crankshaw DP|title=Methoxyflurane analgesia with the Penthrox Inhaler: Emergency Department and Hospital Ward Applications|year=2004|conference=Teaching and Research Conference|location=Victoria University of Technology, Melbourne, Australia}}
* Laird SM, Gray BM. Intermittent inhalation of methoxyflurane and trichloroethylene as an analgesic in burns dressings procedures. Br. J. Anaesth. 1971; 43: 149–59.
* {{cite journal|author=Lindblad P, Zack M, Adami H-O, Ericson A|title=Maternal and perinatal risk factors for Wilms’ tumor: a nationwide nested case control study in Sweden|journal=International Journal of Cancer|volume=51|issue=1|pages=38–41|year=1992|doi=10.1002/ijc.2910510108}}
* {{Cite pmid|6081001}}
* Metropolitan Ambulance Service/Rural Ambulance Service. Clinical practice guideline D020. Version 4, 2005. Methoxyflurane (Penthrane).
* {{cite journal|author=Miller WT|title=My early days in fluorine chemistry|journal=Journal of Fluorine Chemistry|volume=18|issue=4|pages=305–21|year=1981|doi=10.1016/S0022-1139(00)82652-4|url=http://ecommons.cornell.edu/bitstream/1813/3125/1/CCB_030.pdf}}
* {{Cite pmid|3231916}}
* National Institute for Occupational Safety and Health. Pocket guide to chemical hazards, methoxyflurane. Publication number 2005-149.
* {{Cite pmid|5007074}}
* {{Cite pmid|4895340}}
* {{Cite pmid|3452163}}


==External links==
==External links==

Latest revision as of 20:18, 7 April 2015

Methoxyflurane
Clinical data
Synonyms2,2-dichloro-1,1-difluoroethyl methyl ether
Pregnancy
category
  • AU: C
  • US: C (Risk not ruled out)
Routes of
administration		Inhalation
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
Pharmacokinetic data
Metabolism70%
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
E number{{#property:P628}}
ECHA InfoCard{{#property:P2566}}Lua error in Module:EditAtWikidata at line 36: attempt to index field 'wikibase' (a nil value).
Chemical and physical data
FormulaC3H4Cl2F2O
Molar mass164.966 grams mole−1
3D model (JSmol)
 ☒N☑Y (what is this?)  (verify)

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

Methoxyflurane (INN), formerly marketed as Penthrane by Abbott Laboratories, is a halogenated ether that was in clinical use as a volatile inhalational anesthetic from its introduction by Joseph F. Artusio et al in 1960 until the late 1970s. It was first synthesized in the late 1940s by William T. Miller and his team of chemists following their involvement in the Manhattan Project.

Methoxyflurane is an extremely potent and highly lipid soluble anesthetic agent, characterized by very slow induction (onset of action) and emergence (offset or dissipation) times. It is non-flammable, has relatively mild hemodynamic effects, and it does not predispose the heart to rhythm disturbances. It is, however, a significant respiratory depressant. Methoxyflurane has powerful analgesic (pain-relieving) properties at well below full anesthetic doses. It was utilized in self-administration devices for obstetric analgesia, in a manner that foreshadowed the patient-controlled analgesia infusion pumps of today.

The biodegradation of methoxyflurane produces inorganic fluoride and dichloroacetic acid (DCAA). The combined effects of these two compounds may be responsible for the toxicity of methoxyflurane to some of the major organs of the human body. Methoxyflurane was determined to be nephrotoxic (damaging to the kidneys) in a dose-dependent response and hepatotoxic (damaging to the liver) at anesthetic doses in 1973, and the drug was abandoned as a general anesthetic in the late 1970s. In 1999, the manufacturer discontinued distribution of methoxyflurane in the United States and Canada, and on September 6, 2005, the Food and Drug Administration determined that it should be withdrawn from the market for safety concerns. It is however still used in Australia as an emergency analgesic for the initial management of pain due to acute trauma, as well as for brief painful procedures such as changing of wound dressings or for transport of injured people.

Medical use

Methoxyflurane has been extensively used since the 1970s in Australia as an emergency analgesic for short-term use, mostly by the Australian and New Zealand Defence Forces, and the Australian ambulance services.The drug is currently only available from one manufacturer (Medical Developments International, Melbourne, Victoria, Australia). It is self-administered to children and adults using the Penthrox inhaler, a hand-held inhaler device.A non-opioid alternative to morphine, it is also easier to use than nitrous oxide. As of 2010, methoxyflurane was listed under the Pharmaceutical Benefits Scheme for the initial management of pain due to acute trauma, as well as for brief painful procedures such as changing of wound dressings or for patient transport. A portable, disposable, single-use inhaler device (the Penthrox inhaler), along with a single 3 milliliter brown glass vial of methoxyflurane is provided in doctor's kits that allows conscious hemodynamically stable patients (including children over the age of 5 years) to self-administer the drug, under supervision. The device is often referred to as the "green whistle", due to its appearance.

Each 3 milliliter dose lasts approximately 30 minutes. Pain relief begins after 6–8 breaths and continues for several minutes after stopping inhalation. The maximum recommended dose is 6 milliliters per day or 15 milliliters per week because of the risk of cumulative dose-related nephrotoxicity, and it should not be used on consecutive days.Despite the potential for renal impairment when used at anesthetic doses, no significant adverse effects have been reported in the literature when it is used at the lower doses (up to 6 milliliters) used for producing analgesia and sedation. Due to the risk of organ (especially renal) toxicity, methoxyflurane is contraindicated in patients with pre-existing kidney disease or diabetes mellitus, and is not recommended to be administered in conjunction with tetracyclines or other potentially nephrotoxic or enzyme-inducing drugs.

Chemical and physical properties

Further information: Organofluorine
A apace-filling model, or three-dimensional structure of the methoxyflurane molecule, in red, yellow, green, black and white.
Space-filling model (three-dimensional molecular structure) of methoxyflurane

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.

With a minimum alveolar concentration (MAC) of 0.2%, methoxyflurane is an extremely potent anesthetic agent. It is a powerful analgesic agent at well below full anesthetic concentrations. Because of its low volatility and very high boiling point (104.8 °C at 1 atmosphere), methoxyflurane has a low vapor pressure at ambient temperature and atmospheric pressure. It is therefore quite difficult to vaporize methoxyflurane using conventional anesthetic vaporizers.

Property Value
Boiling point (at 1 atmosphere) 104.8 °C
Minimum alveolar concentration (MAC) 0.2
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. Furthermore, this bond becomes shorther 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.

Pharmacokinetics

Methoxyflurane has a very high lipid solubility (oil:gas partition coefficient of around 950), which gives it very slow pharmacokinetics (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.

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.

Pharmacodynamics

Cardiovascular effects

The effects of methoxyflurane on the circulatory system resemble those of diethyl ether. In dogs, methoxyflurane anesthesia causes a moderate decrease in blood pressure with minimal changes in heart rate, and no significant effect on blood sugar, epinephrine, or norepinephrine. Bleeding and increased arterial partial pressure of carbon dioxide (PaCO2) both induce further decreases in blood pressure, as well as increases in blood glucose, epinephrine and norepinephrine. In humans, methoxyflurane produces some decrease in blood pressure, but cardiac output, stroke volume, and total peripheral resistance are only minimally depressed. Its effect on the pulmonary circulation is negligible, and it does not predispose the heart to cardiac dysrhythmias.

Respiratory effects

Unlike diethyl ether, methoxyflurane is a significant respiratory depressant. In dogs, methoxyflurane causes a dose-dependent decrease in respiratory rate and a marked decrease in respiratory minute volume, with a relatively mild decrease in tidal volume. In humans, methoxyflurane causes a dose-dependent decrease in tidal volume and minute volume, with respiratory rate relatively constant. The net effect of these changes is profound respiratory depression, as evidenced by CO2 retention with a concomitant decrease in arterial pH (this is referred to as a respiratory acidosis) when anesthetized subjects are allowed to breathe spontaneously for any length of time.

Gastrointestinal effects

In a series of 500 consecutive obstetric patients, Boisvert and Hudon observed vomiting in 12 (4.8%) patients during or after administration of methoxyflurane anesthesia. These findings compared favorably with those reported for cyclopropane (42%), trichloroethylene (28%) and halothane (4.6%).In another study of 645 obstetric patients, Romagnoli and Korman observed 8 cases (1.2%) of postoperative vomiting, one of whom was retching before the administration of the anesthetic.

Analgesic effects

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. There is substantial data to indicate that methoxyflurane is an effective analgesic and sedative agent at subanesthetic doses. Supervised self-administration of methoxyflurane in children and adults can briefly lead to deep sedation, and it has been used as a patient controlled analgesic for painful procedures in children in hospital emergency departments. During childbirth, administration of methoxyflurane produces significantly better analgesia, less psychomotor agitation, and only slightly more somnolence than trichloroethylene.

In 1968, Robert Wexler of Abbott Laboratories developed the Analgizer, a disposable inhaler that allowed the self-administration of methoxyflurane vapor in air for analgesia. The Analgizer consisted of a polyethylene cylinder 5 inches long and 1 inch in diameter with a 1 inch long mouthpiece. The device contained a rolled wick of polypropylene felt which held 15 milliliters of methoxyflurane. Because of the simplicity of the Analgizer and the pharmacological characteristics of methoxyflurane, it was easy for patients to self-administer the drug and rapidly achieve a level of conscious analgesia which could be maintained and adjusted as necessary over a period of time lasting from a few minutes to several hours. The 15 milliliter supply of methoxyflurane would typically last for two to three hours, during which time the user would often be partly amnesic to the sense of pain; the device could be refilled if necessary. The Analgizer was found to be safe, effective, and simple to administer in obstetric patients during childbirth, as well as for patients with bone fractures and joint dislocations, and for dressing changes on burn patients. When used for labor analgesia, the Analgizer allows labor to progress normally and with no apparent adverse effect on Apgar scores. All vital signs remain normal in obstetric patients, newborns, and injured patients. The Analgizer was widely utilized for analgesia and sedation until the early 1970s, in a manner that foreshadowed the patient-controlled analgesia infusion pumps of today. The Analgizer inhaler was withdrawn in 1974, but use of methoxyflurane as a sedative and analgesic continues in Australia and New Zealand in the form of the Penthrox inhaler.Trials of methoxyflurane as an analgesic in emergency medicine are going on in the UK.

Biodegradation and toxicity

Further information: Drug metabolism and Fluoride poisoning

The first report of nephrotoxicity appeared in 1964, when Paddock and colleagues reported three cases of acute renal insufficiency, two of whom were found to have calcium oxalate crystals in the renal tubules at autopsy. In 1966, Crandell and colleagues reported a series in which 17/95 (18%) of patients developed an unusual type of nephropathy after operations in which methoxyflurane was used as a general anesthetic. This particular type of renal insufficiency was characterized by vasopressin-resistant high-output renal failure (production of large volumes of poorly concentrated urine) with a negative fluid balance, pronounced weight loss, elevation of serum sodium, chloride, osmolality and blood urea nitrogen. The urine of these patients was of a relatively fixed specific gravity and an osmolality very similar to that of the serum. Furthermore, the high urine output persisted a challenge test of fluid deprivation. Most cases resolved within 2–3 weeks, but evidence of renal dysfunction persisted for more than one year in 3 of these 17 cases (18%), and more than two years in one case (6%). Reports of severe and even fatal hepatotoxicity related to the use of methoxyflurane began to appear in 1966. These reports prompted anesthesiologists to subject this agent to intense and systematic scrutiny. A study published in 1973 by Cousins and Mazze demonstrated that compared with halothane, methoxyflurane produces dose-dependent and deleterious abnormalities in renal function. The authors showed that subclinical nephrotoxicity occurred following methoxyflurane at minimum alveolar concentration (MAC) for 2.5 to 3 hours (2.5 to 3 MAC hours), while overt toxicity was present in all patients at dosages greater than five MAC hours.This landmark study provided a model that would be used for the assessment of the nephrotoxicity of volatile anesthetics for the next two decades.

The biodegradation of methoxyflurane begins immediately after the onset of exposure. The kidney and liver toxicity observed after anesthetic doses is attributable to one or more metabolites produced by O-demethylation of methoxyflurane. Significant products of this catabolic process include methoxyfluoroacetic acid (MFAA), dichloroacetic acid (DCAA), and inorganic fluoride. This effect is so predictable and reproducible that methoxyflurane now serves as a pharmacologic model of fluoride-related nephrotoxicity, one with which newer drugs are compared. It is not entirely clear whether the fluoride itself is toxic—it may simply be a surrogate measure for some other toxic metabolite. 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.Furthermore, the concurrent use of tetracyclines and methoxyflurane has been reported to result in fatal renal toxicity.

Based on the findings of these and other studies in the early 1970s, the current 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. Partly because of these warnings, but also because of the development of newer volatile anesthetics such as enflurane, isoflurane, desflurane and sevoflurane, the clinical use of methoxyflurane as a general anesthetic in humans was largely abandoned in the mid-1970s.

History

Further information: Drug development, Gaseous diffusion, Manhattan Project, Medicinal chemistry, and Organofluorine compounds

All of the currently used volatile anesthetic agents are organofluorine compounds. Aside from the synthesis of Freon (Thomas Midgley, Jr. and Charles F. Kettering, 1928) and the discovery of Teflon (Roy J. Plunkett, 1938), the field of organofluorine chemistry had not attracted a great deal of attention up to 1940 because of the extreme reactivity of elemental fluorine, which had to be produced in situ for use in chemical reactions. The development of organofluorine chemistry was a spin-off from the Manhattan Project, during which elemental fluorine was produced on an industrial scale for the first time.

The need for fluorine arose from the need to separate the isotope235U from 238U because the former, present in natural uranium at a concentration of less than 1% is fissile (capable of sustaining a nuclear chain reaction of nuclear fission with thermal neutrons), whereas the latter is not. Members of the MAUD Committee (especially Francis Simon and Nicholas Kurti) proposed the use of gaseous diffusion for isotope separation, since, according to Graham's law the rate of diffusion is inversely proportional to molecular mass. After an extensive search, uranium hexafluoride, UF6, was determined to be the most suitable compound of uranium to be used for the gaseous diffusion process.Elemental fluorine is needed in the production of UF6.

Significant obstacles had to be overcome in the handling of both fluorine and UF6. Before the K-25 gaseous diffusion plant could be built, it was first necessary to develop non-reactive chemical compounds that could be used as coatings, lubricants and gaskets for the surfaces which would come into contact with the UF6 gas (a highly reactive and corrosive substance). William T. Miller, professor of organic chemistry at Cornell University, was co-opted to develop such materials, because of his expertise in organofluorine chemistry. Miller and his team developed several novel non-reactive chlorofluorocarbon polymers that were used in this application.

Charles Suckling synthesized halothane in 1951. Halothane was the first organofluorine anesthetic agent to be introduced into clinical practice in 1956.Miller and his team continued to develop organofluorine chemistry after the end of World War II and methoxyflurane was synthesized in 1948.


External links

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