Methoxyflurane
Encyclopedia
Methoxyflurane is a halogenated ether
that was in clinical use as an volatile inhalational anesthetic
from its introduction by Joseph F. Artusio et al in 1960 until around 1974. It was first synthesized
in the late 1940s by William T. Miller
and his team of chemist
s following their involvement in the Manhattan Project
. Methoxyflurane is classified as a halogenated hydrocarbon
under the ATC code N01
(anesthetics) subgroup of the Anatomical Therapeutic Chemical Classification System
, but its chemical structure
indicates that it is better described as a halogenated ether
.
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 pump
s 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) and hepatotoxic
(damaging to the liver) at anesthetic doses in 1973, and the drug was quickly abandoned as a general anesthetic
. 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
.
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 iscontraindicated
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.
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 clear, colorless liquid
, and its vapor
has a strong fruity aroma. It is miscible
with ethanol
, acetone
, chloroform
, diethyl ether
, and fixed oil
s. 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
.
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.
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.
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 dysrhythmia
s.
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 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 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 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. The Analgizer consisted of a polyethylene
cylinder 5 inches in length 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 fracture
s 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 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
.
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 metabolite
s produced by O-demethylation
of methoxyflurane. Significant products of this catabolic process
include methoxyfluoroacetic acid (MFAA), dichloroacetic acid (DCAA), and inorganic fluoride. Methoxyflurane nephrotoxicity is dose dependent and irreversible, resulting from O-demethylation of methoxyflurane to fluoride and DCAA. 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.
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 isotope
235U 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 compound
s that could be used as coating
s, lubricant
s and gasket
s 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
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.
Halogenated ether
A halogenated ether is a subcategory of a larger group of chemicals known as ethers. An ether is an organic chemical that contains an ether group — an oxygen atom connected to two alkyl groups...
that was in clinical use as an volatile inhalational anesthetic
Inhalational anaesthetic
An inhalational anaesthetic is a chemical compound possessing general anaesthetic properties that can be delivered via inhalation. They are administered by anaesthetists through an anaesthesia mask, laryngeal mask airway or tracheal tube connected to some type of anaesthetic vaporiser and an...
from its introduction by Joseph F. Artusio et al in 1960 until around 1974. It was first synthesized
Chemical synthesis
In chemistry, chemical synthesis is purposeful execution of chemical reactions to get a product, or several products. This happens by physical and chemical manipulations usually involving one or more reactions...
in the late 1940s by William T. Miller
William T. Miller
William T. Miller was a professor of organic chemistry at Cornell University. His experimental research included investigations into the mechanism of addition of halogens, especially fluorine, to hydrocarbons...
and his team of chemist
Chemist
A chemist is a scientist trained in the study of chemistry. Chemists study the composition of matter and its properties such as density and acidity. Chemists carefully describe the properties they study in terms of quantities, with detail on the level of molecules and their component atoms...
s following their involvement in the Manhattan Project
Manhattan Project
The Manhattan Project was a research and development program, led by the United States with participation from the United Kingdom and Canada, that produced the first atomic bomb during World War II. From 1942 to 1946, the project was under the direction of Major General Leslie Groves of the US Army...
. Methoxyflurane is classified as a halogenated hydrocarbon
Haloalkane
The haloalkanes are a group of chemical compounds derived from alkanes containing one or more halogens. They are a subset of the general class of halocarbons, although the distinction is not often made. Haloalkanes are widely used commercially and, consequently, are known under many chemical and...
under the ATC code N01
ATC code N01
-N01AB Halogenated hydrocarbons:-N01AB Halogenated hydrocarbons:-N01AB Halogenated hydrocarbons::N01AB01 Halothane:N01AB02 Chloroform:N01AB03 Methoxyflurane:N01AB04 Enflurane:N01AB05 Trichloroethylene:N01AB06 Isoflurane:N01AB07 Desflurane:N01AB08 Sevoflurane...
(anesthetics) subgroup of the Anatomical Therapeutic Chemical Classification System
Anatomical Therapeutic Chemical Classification System
The Anatomical Therapeutic Chemical Classification System is used for the classification of drugs. It is controlled by the WHO Collaborating Centre for Drug Statistics Methodology , and was first published in 1976....
, but its chemical structure
Chemical structure
A chemical structure includes molecular geometry, electronic structure and crystal structure of molecules. Molecular geometry refers to the spatial arrangement of atoms in a molecule and the chemical bonds that hold the atoms together. Molecular geometry can range from the very simple, such as...
indicates that it is better described as a halogenated ether
Ether
Ethers are a class of organic compounds that contain an ether group — an oxygen atom connected to two alkyl or aryl groups — of general formula R–O–R'. A typical example is the solvent and anesthetic diethyl ether, commonly referred to simply as "ether"...
.
Methoxyflurane is an extremely potent
Potency (pharmacology)
In the field of pharmacology, potency is a measure of drug activity expressed in terms of the amount required to produce an effect of given intensity. A highly potent drug evokes a larger response at low concentrations, while a drug of lower potency evokes a small response at low concentrations...
and highly lipid soluble anesthetic agent, characterized by very slow induction (onset of action) and emergence (offset or dissipation) times. It is non-flammable
Flammability
Flammability is defined as how easily something will burn or ignite, causing fire or combustion. The degree of difficulty required to cause the combustion of a substance is quantified through fire testing. Internationally, a variety of test protocols exist to quantify flammability...
, has relatively mild hemodynamic
Hemodynamics
Hemodynamics, meaning literally "blood movement" is the study of blood flow or the circulation.All animal cells require oxygen for the conversion of carbohydrates, fats and proteins into carbon dioxide , water and energy in a process known as aerobic respiration...
effects, and it does not predispose the heart to rhythm disturbances
Cardiac dysrhythmia
Cardiac dysrhythmia is any of a large and heterogeneous group of conditions in which there is abnormal electrical activity in the heart. The heart beat may be too fast or too slow, and may be regular or irregular.Some arrhythmias are life-threatening medical emergencies that can result in cardiac...
. It is however a significant respiratory depressant
Hypoventilation
In medicine, hypoventilation occurs when ventilation is inadequate to perform needed gas exchange...
. Methoxyflurane has powerful analgesic
Analgesic
An analgesic is any member of the group of drugs used to relieve pain . The word analgesic derives from Greek an- and algos ....
(pain-relieving) properties at well below full anesthetic doses. It was utilized in self-administration devices for obstetric
Obstetrics
Obstetrics is the medical specialty dealing with the care of all women's reproductive tracts and their children during pregnancy , childbirth and the postnatal period...
analgesia, in a manner that foreshadowed the patient-controlled analgesia
Patient-controlled analgesia
Patient-controlled analgesia is any method of allowing a person in pain to administer their own pain relief. The infusion is programmable by the prescriber...
infusion pump
Infusion pump
An infusion pump infuses fluids, medication or nutrients into a patient's circulatory system. It is generally used intravenously, although subcutaneous, arterial and epidural infusions are occasionally used....
s of today.
The biodegradation
Biodegradation
Biodegradation or biotic degradation or biotic decomposition is the chemical dissolution of materials by bacteria or other biological means...
of methoxyflurane produces inorganic
Inorganic compound
Inorganic compounds have traditionally been considered to be of inanimate, non-biological origin. In contrast, organic compounds have an explicit biological origin. However, over the past century, the classification of inorganic vs organic compounds has become less important to scientists,...
fluoride
Fluoride
Fluoride is the anion F−, the reduced form of fluorine when as an ion and when bonded to another element. Both organofluorine compounds and inorganic fluorine containing compounds are called fluorides. Fluoride, like other halides, is a monovalent ion . Its compounds often have properties that are...
and dichloroacetic acid
Dichloroacetic acid
Dichloroacetic acid, often abbreviated DCA, is the chemical compound with formula . It is an acid, an analogue of acetic acid, in which two of the three hydrogen atoms of the methyl group have been replaced by chlorine atoms. The salts and esters of dichloroacetic acid are called dichloroacetates...
(DCAA). The combined effects of these two compounds
Chemical compound
A chemical compound is a pure chemical substance consisting of two or more different chemical elements that can be separated into simpler substances by chemical reactions. Chemical compounds have a unique and defined chemical structure; they consist of a fixed ratio of atoms that are held together...
may be responsible for the toxicity
Toxicity
Toxicity is the degree to which a substance can damage a living or non-living organisms. Toxicity can refer to the effect on a whole organism, such as an animal, bacterium, or plant, as well as the effect on a substructure of the organism, such as a cell or an organ , such as the liver...
of methoxyflurane to some of the major organs of the human body. Methoxyflurane was determined to be nephrotoxic
Nephrotoxicity
Nephrotoxicity is a poisonous effect of some substances, both toxic chemicals and medication, on the kidneys. There are various forms of toxicity. Nephrotoxicity should not be confused with the fact that some medications have a predominantly renal excretion and need their dose adjusted for the...
(damaging to the kidneys) and hepatotoxic
Hepatotoxicity
Hepatotoxicity implies chemical-driven liver damage.The liver plays a central role in transforming and clearing chemicals and is susceptible to the toxicity from these agents. Certain medicinal agents, when taken in overdoses and sometimes even when introduced within therapeutic ranges, may injure...
(damaging to the liver) at anesthetic doses in 1973, and the drug was quickly abandoned as a general anesthetic
General anaesthetic
A general anaesthetic is a drug that brings about a reversible loss of consciousness. These drugs are generally administered by an anaesthesia provider to induce or maintain general anaesthesia to facilitate surgery...
. It is however still used in Australia as an emergency analgesic for the initial management of pain due to acute trauma
Trauma (medicine)
Trauma refers to "a body wound or shock produced by sudden physical injury, as from violence or accident." It can also be described as "a physical wound or injury, such as a fracture or blow." Major trauma can result in secondary complications such as circulatory shock, respiratory failure and death...
, as well as for brief painful procedures such as changing of wound dressings
Dressing (medical)
A dressing is an adjunct used by a person for application to a wound to promote healing and/or prevent further harm. A dressing is designed to be in direct contact with the wound, which makes it different from a bandage, which is primarily used to hold a dressing in place...
or for transport of injured people
Casualty movement
The casualty movement is the procedures used to move a casualty from the initial location to the ambulance....
.
Medical use
Methoxyflurane has been extensively used since the 1970s in Australia as an emergency analgesic for short-term use, mostly by the AustralianAustralian Defence Force
The Australian Defence Force is the military organisation responsible for the defence of Australia. It consists of the Royal Australian Navy , Australian Army, Royal Australian Air Force and a number of 'tri-service' units...
and New Zealand
New Zealand Defence Force
The New Zealand Defence Force consists of three services: the Royal New Zealand Navy; the New Zealand Army; and the Royal New Zealand Air Force. The Commander-in-Chief of the NZDF is His Excellency Rt. Hon...
Defence Forces, and the Australian ambulance services
Emergency medical services in Australia
Emergency medical services in Australia are provided by state ambulance services, which are a division of each state or territorial government, and by St John Ambulance in both Western Australia and the Northern Territory.-Land Ambulance:...
. 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
Opioid
An opioid is a psychoactive chemical that works by binding to opioid receptors, which are found principally in the central and peripheral nervous system and the gastrointestinal tract...
alternative to morphine
Morphine
Morphine is a potent opiate analgesic medication and is considered to be the prototypical opioid. It was first isolated in 1804 by Friedrich Sertürner, first distributed by same in 1817, and first commercially sold by Merck in 1827, which at the time was a single small chemists' shop. It was more...
, it is also easier to use than nitrous oxide. As of 2010, methoxyflurane was listed under the Pharmaceutical Benefits Scheme
Pharmaceutical Benefits Scheme
The Pharmaceutical Benefits Scheme or PBS is a program of the Australian Government that provides subsidised prescription drugs to residents of Australia. The PBS ensures that all Australians have affordable and reliable access to a wide range of necessary medicines.-History:The PBS was established...
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
Toxicity
Toxicity is the degree to which a substance can damage a living or non-living organisms. Toxicity can refer to the effect on a whole organism, such as an animal, bacterium, or plant, as well as the effect on a substructure of the organism, such as a cell or an organ , such as the liver...
, methoxyflurane iscontraindicated
Contraindication
In medicine, a contraindication is a condition or factor that serves as a reason to withhold a certain medical treatment.Some contraindications are absolute, meaning that there are no reasonable circumstances for undertaking a course of action...
in patients with pre-existing kidney disease
Nephropathy
Nephropathy refers to damage to or disease of the kidney. An older term for this is nephrosis.-Causes:Causes of nephropathy include administration of analgesics, xanthine oxidase deficiency, and long-term exposure to lead or its salts...
or diabetes mellitus
Diabetes mellitus
Diabetes mellitus, often simply referred to as diabetes, is a group of metabolic diseases in which a person has high blood sugar, either because the body does not produce enough insulin, or because cells do not respond to the insulin that is produced...
, and is not recommended to be administered in conjunction with tetracyclines or other potentially nephrotoxic or enzyme-inducing
Enzyme inducer
An enzyme inducer is a type of drug which binds to an enzyme and increases its metabolic activity.Classic examples: barbiturates , antiepileptics and rifampin....
drugs.
Physical properties
With a molecular formulaChemical formula
A chemical formula or molecular formula is a way of expressing information about the atoms that constitute a particular chemical compound....
of C3H4Cl2F2O and a condensed structural formula of CHCl2CF2OCH3, the International Union of Pure and Applied Chemistry
International Union of Pure and Applied Chemistry
The International Union of Pure and Applied Chemistry is an international federation of National Adhering Organizations that represents chemists in individual countries. It is a member of the International Council for Science . The international headquarters of IUPAC is located in Zürich,...
(IUPAC) name for methoxyflurane is 2,2-dichloro-1,1-difluoro-1-methoxyethane. It is a clear, colorless liquid
Liquid
Liquid is one of the three classical states of matter . Like a gas, a liquid is able to flow and take the shape of a container. Some liquids resist compression, while others can be compressed. Unlike a gas, a liquid does not disperse to fill every space of a container, and maintains a fairly...
, and its vapor
Vapor
A vapor or vapour is a substance in the gas phase at a temperature lower than its critical point....
has a strong fruity aroma. It is miscible
Miscibility
Miscibility is the property of liquids to mix in all proportions, forming a homogeneous solution. In principle, the term applies also to other phases , but the main focus is usually on the solubility of one liquid in another...
with ethanol
Ethanol
Ethanol, also called ethyl alcohol, pure alcohol, grain alcohol, or drinking alcohol, is a volatile, flammable, colorless liquid. It is a psychoactive drug and one of the oldest recreational drugs. Best known as the type of alcohol found in alcoholic beverages, it is also used in thermometers, as a...
, acetone
Acetone
Acetone is the organic compound with the formula 2CO, a colorless, mobile, flammable liquid, the simplest example of the ketones.Acetone is miscible with water and serves as an important solvent in its own right, typically as the solvent of choice for cleaning purposes in the laboratory...
, chloroform
Chloroform
Chloroform is an organic compound with formula CHCl3. It is one of the four chloromethanes. The colorless, sweet-smelling, dense liquid is a trihalomethane, and is considered somewhat hazardous...
, diethyl ether
Diethyl ether
Diethyl ether, also known as ethyl ether, simply ether, or ethoxyethane, is an organic compound in the ether class with the formula . It is a colorless, highly volatile flammable liquid with a characteristic odor...
, and fixed oil
Oil
An oil is any substance that is liquid at ambient temperatures and does not mix with water but may mix with other oils and organic solvents. This general definition includes vegetable oils, volatile essential oils, petrochemical oils, and synthetic oils....
s. It is soluble in rubber.
With a minimum alveolar concentration
Minimum alveolar concentration
Minimum alveolar concentration or MAC is a concept used to compare the strengths, or potency, of anaesthetic vapours; in simple terms, it is defined as the concentration of the vapour in the lungs that is needed to prevent movement in 50% of subjects in response to surgical stimulus...
(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
Boiling point
The boiling point of an element or a substance is the temperature at which the vapor pressure of the liquid equals the environmental pressure surrounding the liquid....
(104.8 °C at 1 atmosphere), methoxyflurane has a low vapor pressure
Vapor pressure
Vapor pressure or equilibrium vapor pressure is the pressure of a vapor in thermodynamic equilibrium with its condensed phases in a closed system. All liquids have a tendency to evaporate, and some solids can sublimate into a gaseous form...
at ambient temperature and atmospheric pressure
Standard conditions for temperature and pressure
Standard condition for temperature and pressure are standard sets of conditions for experimental measurements established to allow comparisons to be made between different sets of data...
. It is therefore quite difficult to vaporize methoxyflurane using conventional anesthetic vaporizers
Anaesthetic vaporiser
An anaesthetic vaporiser is a device generally attached to an anaesthetic machine which delivers a given concentration of a volatile anaesthetic agent.The design of these devices takes account of varying*ambient temperature*fresh gas flow...
.
| Property | Value |
|---|---|
| Boiling point Boiling point The boiling point of an element or a substance is the temperature at which the vapor pressure of the liquid equals the environmental pressure surrounding the liquid.... (at 1 atmosphere Atmosphere (unit) The standard atmosphere is an international reference pressure defined as 101325 Pa and formerly used as unit of pressure. For practical purposes it has been replaced by the bar which is 105 Pa... ) |
104.8 °C |
| Minimum alveolar concentration Minimum alveolar concentration Minimum alveolar concentration or MAC is a concept used to compare the strengths, or potency, of anaesthetic vapours; in simple terms, it is defined as the concentration of the vapour in the lungs that is needed to prevent movement in 50% of subjects in response to surgical stimulus... (MAC) |
0.2 |
| Vapor pressure Vapor pressure Vapor pressure or equilibrium vapor pressure is the pressure of a vapor in thermodynamic equilibrium with its condensed phases in a closed system. All liquids have a tendency to evaporate, and some solids can sublimate into a gaseous form... (mmHg at 20 °C) |
22.5 |
| Partition coefficient Partition coefficient In chemistry and the pharmaceutical sciences, a partition- or distribution coefficient is the ratio of concentrations of a compound in the two phases of a mixture of two immiscible solvents at equilibrium. The terms "gas/liquid partition coefficient" and "air/water partition coefficient" are... (Blood:Gas) |
12 |
| Partition coefficient (Oil:Gas) | 950 |
| Partition coefficient (Oil:Water) | 400 |
| Specific gravity Specific gravity Specific gravity is the ratio of the density of a substance to the density of a reference substance. Apparent specific gravity is the ratio of the weight of a volume of the substance to the weight of an equal volume of the reference substance. The reference substance is nearly always water for... at 25 °C |
1.42 |
| Flash point Flash point The flash point of a volatile material is the lowest temperature at which it can vaporize to form an ignitable mixture in air. Measuring a flash point requires an ignition source... |
63 °C |
| Molecular weight Molecular mass The molecular mass of a substance is the mass of one molecule of that substance, in unified atomic mass unit u... (g mol−1) |
164.97 |
| Vapor-liquid equilibrium Vapor-liquid equilibrium Vapor–liquid equilibrium is a condition where a liquid and its vapor are in equilibrium with each other, a condition or state where the rate of evaporation equals the rate of condensation on a molecular level such that there is no net vapor-liquid interconversion... (mL) |
208 |
| Flammability Flammability Flammability is defined as how easily something will burn or ignite, causing fire or combustion. The degree of difficulty required to cause the combustion of a substance is quantified through fire testing. Internationally, a variety of test protocols exist to quantify flammability... limits |
7% in air |
| Chemical stabilizer Stabilizer (chemistry) In chemistry a stabilizer is a chemical which tends to inhibit the reaction between two or more other chemicals. It can be thought of as the antonym to a catalyst... necessary |
Yes |
The carbon–fluorine bond, a component of all organofluorine compounds, is the strongest chemical bond
Chemical bond
A chemical bond is an attraction between atoms that allows the formation of chemical substances that contain two or more atoms. The bond is caused by the electromagnetic force attraction between opposite charges, either between electrons and nuclei, or as the result of a dipole attraction...
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
Fluorocarbon
Fluorocarbons, sometimes referred to as perfluorocarbons or PFCs, are organofluorine compounds that contain only carbon and fluorine bonded together in strong carbon–fluorine bonds. Fluoroalkanes that contain only single bonds are more chemically and thermally stable than alkanes...
are some of the most chemically stable
Chemical stability
Chemical stability when used in the technical sense in chemistry, means thermodynamic stability of a chemical system.Thermodynamic stability occurs when a system is in its lowest energy state, or chemical equilibrium with its environment. This may be a dynamic equilibrium, where individual atoms...
organic compounds.
Pharmacokinetics
Methoxyflurane has a very high lipid solubility (oil:gas partition coefficientPartition coefficient
In chemistry and the pharmaceutical sciences, a partition- or distribution coefficient is the ratio of concentrations of a compound in the two phases of a mixture of two immiscible solvents at equilibrium. The terms "gas/liquid partition coefficient" and "air/water partition coefficient" are...
of around 950), which gives it very slow pharmacokinetics
Pharmacokinetics
Pharmacokinetics, sometimes abbreviated as PK, is a branch of pharmacology dedicated to the determination of the fate of substances administered externally to a living organism...
(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
Oxygen
Oxygen is the element with atomic number 8 and represented by the symbol O. Its name derives from the Greek roots ὀξύς and -γενής , because at the time of naming, it was mistakenly thought that all acids required oxygen in their composition...
alone or with nitrous oxide
Nitrous oxide
Nitrous oxide, commonly known as laughing gas or sweet air, is a chemical compound with the formula . It is an oxide of nitrogen. At room temperature, it is a colorless non-flammable gas, with a slightly sweet odor and taste. It is used in surgery and dentistry for its anesthetic and analgesic...
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
Sodium thiopental
Sodium thiopental, better known as Sodium Pentothal , thiopental, thiopentone sodium, or Trapanal , is a rapid-onset short-acting barbiturate general anaesthetic...
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
Circulatory system
The circulatory system is an organ system that passes nutrients , gases, hormones, blood cells, etc...
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 effectsThe effects of methoxyflurane on the circulatory system resemble those of diethyl ether. In dogs, methoxyflurane anesthesia causes a moderate decrease in blood pressure
Hypotension
In physiology and medicine, hypotension is abnormally low blood pressure, especially in the arteries of the systemic circulation. It is best understood as a physiologic state, rather than a disease. It is often associated with shock, though not necessarily indicative of it. Hypotension is the...
with minimal changes in heart rate
Heart rate
Heart rate is the number of heartbeats per unit of time, typically expressed as beats per minute . Heart rate can vary as the body's need to absorb oxygen and excrete carbon dioxide changes, such as during exercise or sleep....
, and no significant effect on blood sugar
Blood sugar
The blood sugar concentration or blood glucose level is the amount of glucose present in the blood of a human or animal. Normally in mammals, the body maintains the blood glucose level at a reference range between about 3.6 and 5.8 mM , or 64.8 and 104.4 mg/dL...
, epinephrine
Epinephrine
Epinephrine is a hormone and a neurotransmitter. It increases heart rate, constricts blood vessels, dilates air passages and participates in the fight-or-flight response of the sympathetic nervous system. In chemical terms, adrenaline is one of a group of monoamines called the catecholamines...
, or norepinephrine
Norepinephrine
Norepinephrine is the US name for noradrenaline , a catecholamine with multiple roles including as a hormone and a neurotransmitter...
. Bleeding
Bleeding
Bleeding, technically known as hemorrhaging or haemorrhaging is the loss of blood or blood escape from the circulatory system...
and increased arterial
Arterial blood gas
An arterial blood gas is a blood test that is performed using blood from an artery. It involves puncturing an artery with a thin needle and syringe and drawing a small volume of blood. The most common puncture site is the radial artery at the wrist, but sometimes the femoral artery in the groin or...
partial pressure
Partial pressure
In a mixture of ideal gases, each gas has a partial pressure which is the pressure which the gas would have if it alone occupied the volume. The total pressure of a gas mixture is the sum of the partial pressures of each individual gas in the mixture....
of carbon dioxide
Carbon dioxide
Carbon dioxide is a naturally occurring chemical compound composed of two oxygen atoms covalently bonded to a single carbon atom...
(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
Cardiac output
Cardiac output is the volume of blood being pumped by the heart, in particular by a left or right ventricle in the time interval of one minute. CO may be measured in many ways, for example dm3/min...
, stroke volume
Stroke volume
In cardiovascular physiology, stroke volume is the volume of blood pumped from one ventricle of the heart with each beat. SV is calculated using measurements of ventricle volumes from an echocardiogram and subtracting the volume of the blood in the ventricle at the end of a beat from the volume...
, and total peripheral resistance
Total peripheral resistance
Vasculature throughout the entire body can be thought of as two separate circuits - one is the systemic circulation, while the other is the pulmonary circulation. Total peripheral resistance is the sum of the resistance of all peripheral vasculature in the systemic circulation...
are only minimally depressed. Its effect on the pulmonary circulation
Pulmonary circulation
Pulmonary circulation is the half portion of the cardiovascular system which carries Oxygen-depleted Blood away from the heart, to the Lungs, and returns oxygenated blood back to the heart. Encyclopedic description and discovery of the pulmonary circulation is widely attributed to Doctor Ibn...
is negligible, and it does not predispose the heart to cardiac dysrhythmia
Cardiac dysrhythmia
Cardiac dysrhythmia is any of a large and heterogeneous group of conditions in which there is abnormal electrical activity in the heart. The heart beat may be too fast or too slow, and may be regular or irregular.Some arrhythmias are life-threatening medical emergencies that can result in cardiac...
s.
Respiratory effects
Unlike diethyl ether, methoxyflurane is a significant respiratory depressant. In dogs, methoxyflurane causes a dose-dependent
Dose-response relationship
The dose-response relationship, or exposure-response relationship, describes the change in effect on an organism caused by differing levels of exposure to a stressor after a certain exposure time...
decrease in respiratory rate
Respiratory rate
Respiratory rate is also known by respiration rate, pulmonary ventilation rate, ventilation rate, or breathing frequency is the number of breaths taken within a set amount of time, typically 60 seconds....
and a marked decrease in respiratory minute volume
Respiratory minute volume
Respiratory minute volume is the volume of gas inhaled or exhaled from a person's lungs in one minute. It is an important parameter in respiratory medicine due to its relationship with blood carbon dioxide levels...
, with a relatively mild decrease in tidal volume
Tidal volume
Tidal volume is the lung volume representing the normal volume of air displaced between normal inspiration and expiration when extra effort is not applied.Typical values are around 500ml or 7ml/kg bodyweight.-Mechanical Ventilation:...
. 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
Hypercapnia
Hypercapnia or hypercapnea , also known as hypercarbia, is a condition where there is too much carbon dioxide in the blood...
with a concomitant decrease in arterial pH
PH
In chemistry, pH is a measure of the acidity or basicity of an aqueous solution. Pure water is said to be neutral, with a pH close to 7.0 at . Solutions with a pH less than 7 are said to be acidic and solutions with a pH greater than 7 are basic or alkaline...
(this is referred to as a respiratory acidosis
Respiratory acidosis
Respiratory acidosis is a medical condition in which decreased ventilation causes increased blood carbon dioxide concentration and decreased pH ....
) when anesthetized subjects are allowed to breathe spontaneously for any length of time.
Gastrointestinal effects
In a series of 500 consecutive obstetric patient
Patient
A patient is any recipient of healthcare services. The patient is most often ill or injured and in need of treatment by a physician, advanced practice registered nurse, veterinarian, or other health care provider....
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
Cyclopropane
Cyclopropane is a cycloalkane molecule with the molecular formula C3H6, consisting of three carbon atoms linked to each other to form a ring, with each carbon atom bearing two hydrogen atoms...
(42%), trichloroethylene
Trichloroethylene
The chemical compound trichloroethylene is a chlorinated hydrocarbon commonly used as an industrial solvent. It is a clear non-flammable liquid with a sweet smell. It should not be confused with the similar 1,1,1-trichloroethane, which is commonly known as chlorothene.The IUPAC name is...
(28%) and halothane (4.6%). In another study of 645 obstetric patients, Romagnoli and Korman observed 8 cases (1.2%) of postoperative vomiting
Postoperative nausea and vomiting
Postoperative nausea and vomiting is an unpleasant complication affecting about a third of the 10% of the population undergoing general anaesthesia each year. This equates to about two million people in the United Kingdom annually.-Impact:...
, one of whom was retching
Retching
Retching is a process in the human body where gastric contents are forced into the esophagus but do not enter the pharynx. Retching usually precedes vomiting, when the upper esophageal sphincter remains closed. If the upper esophageal sphincter is open, vomiting occurs. It can also be caused by a...
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
Compartment (pharmacokinetics)
In pharmacokinetics, a compartment is a defined volume of body fluids. It is distinguished from anatomic compartments, which are bounded by fasciae...
of the body for a long time, providing sedation
Sedation
Sedation is the reduction of irritability or agitation by administration of sedative drugs, generally to facilitate a medical procedure or diagnostic procedure...
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
Self-administration
Self-administration is, in its medical sense, the process of a subject administering a pharmacological substance to him-, her-, or itself. A clinical example of this is the subcutaneous "self-injection" of insulin by a diabetic patient....
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
Emergency department
An emergency department , also known as accident & emergency , emergency room , emergency ward , or casualty department is a medical treatment facility specialising in acute care of patients who present without prior appointment, either by their own means or by ambulance...
s. During childbirth
Childbirth
Childbirth is the culmination of a human pregnancy or gestation period with the birth of one or more newborn infants from a woman's uterus...
, administration of methoxyflurane produces significantly better analgesia, less psychomotor agitation
Psychomotor agitation
Psychomotor agitation is a series of unintentional and purposeless motions that stem from mental tension and anxiety of an individual. This includes pacing around a room, wringing one's hands, pulling off clothing and putting it back on and other similar actions...
, and only slightly more somnolence
Somnolence
Somnolence is a state of near-sleep, a strong desire for sleep, or sleeping for unusually long periods . It has two distinct meanings, referring both to the usual state preceding falling asleep, and the chronic condition referring to being in that state independent of a circadian rhythm...
than trichloroethylene.
In 1968, Robert Wexler of Abbott Laboratories developed the Analgizer, a disposable inhaler
Inhaler
An inhaler or puffer is a medical device used for delivering medication into the body via the lungs. It is mainly used in the treatment of asthma and Chronic Obstructive Pulmonary Disease . Zanamivir , used to treat influenza, must be administered via inhaler...
that allowed the self-administration of methoxyflurane vapor in air for analgesia. The Analgizer consisted of a polyethylene
Polyethylene
Polyethylene or polythene is the most widely used plastic, with an annual production of approximately 80 million metric tons...
cylinder 5 inches in length and 1 inch in diameter with a 1 inch long mouthpiece. The device contained a rolled wick
Candle wick
A candle wick is a string, cord, or wooden object that holds the flame of a candle. A candle wick works by capillary action, drawing the fuel to the flame. When the liquid fuel, typically melted candle wax, reaches the flame it then vaporizes and combusts. The candle wick influences how the...
of polypropylene
Polypropylene
Polypropylene , also known as polypropene, is a thermoplastic polymer used in a wide variety of applications including packaging, textiles , stationery, plastic parts and reusable containers of various types, laboratory equipment, loudspeakers, automotive components, and polymer banknotes...
felt
Felt
Felt is a non-woven cloth that is produced by matting, condensing and pressing woollen fibres. While some types of felt are very soft, some are tough enough to form construction materials. Felt can be of any colour, and made into any shape or size....
which held 15 milliliters of methoxyflurane. Because of the simplicity of the Analgizer and the pharmacological
Pharmacology
Pharmacology is the branch of medicine and biology concerned with the study of drug action. More specifically, it is the study of the interactions that occur between a living organism and chemicals that affect normal or abnormal biochemical function...
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
Amnesia
Amnesia is a condition in which one's memory is lost. The causes of amnesia have traditionally been divided into categories. Memory appears to be stored in several parts of the limbic system of the brain, and any condition that interferes with the function of this system can cause amnesia...
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
Bone fracture
A bone fracture is a medical condition in which there is a break in the continuity of the bone...
s and joint dislocations, and for dressing changes on burn
Burn
A burn is an injury to flesh caused by heat, electricity, chemicals, light, radiation, or friction.Burn may also refer to:*Combustion*Burn , type of watercourses so named in Scotland and north-eastern England...
patients. When used for labor analgesia, the Analgizer allows labor to progress normally and with no apparent adverse effect
Adverse effect
In medicine, an adverse effect is a harmful and undesired effect resulting from a medication or other intervention such as surgery.An adverse effect may be termed a "side effect", when judged to be secondary to a main or therapeutic effect. If it results from an unsuitable or incorrect dosage or...
on Apgar score
Apgar score
The Apgar score was devised in 1952 by the eponymous Dr. Virginia Apgar as a simple and repeatable method to quickly and summarily assess the health of newborn children immediately after birth...
s. All vital signs
Vital signs
Vital signs are measures of various physiological statistics, often taken by health professionals, in order to assess the most basic body functions. Vital signs are an essential part of a case presentation. The act of taking vital signs normally entails recording body temperature, pulse rate ,...
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
Penthrox inhaler
The Penthrox inhaler, manufactured and marketed by Medical Developments International , is a hand-held inhaler device which can be used for the self-administration of methoxyflurane for analgesia .-Indications:...
.
Biodegradation and toxicity
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 oxalateOxalate
Oxalate , is the dianion with formula C2O42− also written 22−. Either name is often used for derivatives, such as disodium oxalate, 2C2O42−, or an ester of oxalic acid Oxalate (IUPAC: ethanedioate), is the dianion with formula C2O42− also written (COO)22−. Either...
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
Nephropathy
Nephropathy refers to damage to or disease of the kidney. An older term for this is nephrosis.-Causes:Causes of nephropathy include administration of analgesics, xanthine oxidase deficiency, and long-term exposure to lead or its salts...
after operations in which methoxyflurane was used as a general anesthetic. This particular type of renal insufficiency was characterized by vasopressin
Vasopressin
Arginine vasopressin , also known as vasopressin, argipressin or antidiuretic hormone , is a neurohypophysial hormone found in most mammals, including humans. Vasopressin is a peptide hormone that controls the reabsorption of molecules in the tubules of the kidneys by affecting the tissue's...
-resistant high-output renal failure
Nephrogenic diabetes insipidus
Nephrogenic diabetes insipidus is a form of diabetes insipidus due primarily to pathology of the kidney. This is in contrast to central/neurogenic diabetes insipidus, which is caused by insufficient levels of antidiuretic hormone /Argenine Vasopressin...
(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
Specific gravity
Specific gravity is the ratio of the density of a substance to the density of a reference substance. Apparent specific gravity is the ratio of the weight of a volume of the substance to the weight of an equal volume of the reference substance. The reference substance is nearly always water for...
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
Renal function
Renal function, in nephrology, is an indication of the state of the kidney and its role in renal physiology. Glomerular filtration rate describes the flow rate of filtered fluid through the kidney...
. The authors showed that subclinical
Asymptomatic
In medicine, a disease is considered asymptomatic if a patient is a carrier for a disease or infection but experiences no symptoms. A condition might be asymptomatic if it fails to show the noticeable symptoms with which it is usually associated. Asymptomatic infections are also called 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
Nephrotoxicity
Nephrotoxicity is a poisonous effect of some substances, both toxic chemicals and medication, on the kidneys. There are various forms of toxicity. Nephrotoxicity should not be confused with the fact that some medications have a predominantly renal excretion and need their dose adjusted for the...
and liver
Hepatotoxicity
Hepatotoxicity implies chemical-driven liver damage.The liver plays a central role in transforming and clearing chemicals and is susceptible to the toxicity from these agents. Certain medicinal agents, when taken in overdoses and sometimes even when introduced within therapeutic ranges, may injure...
toxicity observed after anesthetic doses is attributable to one or more metabolite
Metabolite
Metabolites are the intermediates and products of metabolism. The term metabolite is usually restricted to small molecules. A primary metabolite is directly involved in normal growth, development, and reproduction. Alcohol is an example of a primary metabolite produced in large-scale by industrial...
s produced by O-demethylation
Demethylation
Demethylation is the chemical process resulting in the removal a of methyl group from a molecule.A common way of demethylation is the replacement of a methyl group by a hydrogen atom, resulting in a net loss of one carbon and two hydrogen atoms....
of methoxyflurane. Significant products of this catabolic process
Catabolism
Catabolism is the set of metabolic pathways that break down molecules into smaller units and release energy. In catabolism, large molecules such as polysaccharides, lipids, nucleic acids and proteins are broken down into smaller units such as monosaccharides, fatty acids, nucleotides, and amino...
include methoxyfluoroacetic acid (MFAA), dichloroacetic acid (DCAA), and inorganic fluoride. Methoxyflurane nephrotoxicity is dose dependent and irreversible, resulting from O-demethylation of methoxyflurane to fluoride and DCAA. 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
Surrogate endpoint
In clinical trials, a surrogate endpoint is a measure of effect of a certain treatment that may correlate with a real clinical endpoint but doesn't necessarily have a guaranteed relationship...
for some other toxic metabolite
Toxication
Toxication is the process of metabolism in which the metabolite of a compound is more toxic than the parent drug or chemical. A parent drug or chemical that was previously non-toxic may be called a protoxin.Toxication may involve:...
. The concurrent formation of inorganic fluoride and DCAA is unique to methoxyflurane biotransformation
Biotransformation
Biotransformation is the chemical modification made by an organism on a chemical compound. If this modification ends in mineral compounds like CO2, NH4+, or H2O, the biotransformation is called mineralisation....
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
Enflurane
Enflurane is a halogenated ether that was commonly used for inhalational anesthesia during the 1970s and 1980s. Developed by Ross Terrell in 1963, it was first used clinically in 1966....
and sevoflurane
Sevoflurane
Sevoflurane , also called fluoromethyl hexafluoroisopropyl ether, is a sweet-smelling, nonflammable, highly fluorinated methyl isopropyl ether used for induction and maintenance of general anesthesia. Together with desflurane, it is replacing isoflurane and halothane in modern anesthesiology...
) 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
Isoflurane
Isoflurane is a halogenated ether used for inhalational anesthesia. Together with enflurane and halothane, it replaced the flammable ethers used in the pioneer days of surgery. Its name comes from being a structural isomer of enflurane, hence they have the same empirical formula...
, desflurane
Desflurane
Desflurane is a highly fluorinated methyl ethyl ether used for maintenance of general anesthesia. Like halothane, enflurane and isoflurane, it is a racemic mixture of and optical isomers...
and sevoflurane, the clinical use of methoxyflurane as a general anesthetic in humans was largely abandoned in the mid-1970s.
History
All of the currently used volatile anesthetic agents are organofluorine compounds. Aside from the synthesis of Freon (Thomas Midgley, Jr.Thomas Midgley, Jr.
Thomas Midgley, Jr. was an American mechanical engineer and chemist. Midgley was a key figure in a team of chemists, led by Charles F. Kettering, that developed the tetraethyllead additive to gasoline as well as some of the first chlorofluorocarbons . Over the course of his career, Midgley was...
and Charles F. Kettering, 1928) and the discovery of Teflon
Polytetrafluoroethylene
Polytetrafluoroethylene is a synthetic fluoropolymer of tetrafluoroethylene that finds numerous applications. PTFE is most well known by the DuPont brand name Teflon....
(Roy J. Plunkett, 1938), the field of organofluorine chemistry
Organofluorine chemistry
Organofluorine chemistry describes the chemistry of organofluorine compounds, organic compounds that contain the carbon–fluorine bond. Organofluorine compounds find diverse applications ranging from oil- and water-repellents to pharmaceuticals, refrigerants and reagents in catalysis...
had not attracted a great deal of attention up to 1940 because of the extreme reactivity of elemental fluorine
Fluorine
Fluorine is the chemical element with atomic number 9, represented by the symbol F. It is the lightest element of the halogen column of the periodic table and has a single stable isotope, fluorine-19. At standard pressure and temperature, fluorine is a pale yellow gas composed of diatomic...
, which had to be produced in situ
In situ
In situ is a Latin phrase which translated literally as 'In position'. It is used in many different contexts.-Aerospace:In the aerospace industry, equipment on board aircraft must be tested in situ, or in place, to confirm everything functions properly as a system. Individually, each piece may...
for use in chemical reactions. The development of organofluorine chemistry was a spin-off
Government spin-off
Government spin-off is civilian goods which are the result of military or governmental research. One prominent example of a type of government spin-off is technology that has been commercialized through NASA funding, research, licensing, facilities, or assistance. NASA spin-off technologies have...
from the Manhattan Project
Manhattan Project
The Manhattan Project was a research and development program, led by the United States with participation from the United Kingdom and Canada, that produced the first atomic bomb during World War II. From 1942 to 1946, the project was under the direction of Major General Leslie Groves of the US Army...
, 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 isotope
Isotopes of uranium
Uranium is a naturally occurring radioactive element that has no stable isotopes but two primordial isotopes that have long half-life and are found in appreciable quantity in the Earth's crust, along with the decay product uranium-234. The average atomic mass of natural uranium is 238.02891 u...
235U from 238U because the former, present in natural uranium
Uranium
Uranium is a silvery-white metallic chemical element in the actinide series of the periodic table, with atomic number 92. It is assigned the chemical symbol U. A uranium atom has 92 protons and 92 electrons, of which 6 are valence electrons...
at a concentration of less than 1% is fissile
Fissile
In nuclear engineering, a fissile material is one that is capable of sustaining a chain reaction of nuclear fission. By definition, fissile materials can sustain a chain reaction with neutrons of any energy. The predominant neutron energy may be typified by either slow neutrons or fast neutrons...
(capable of sustaining a nuclear chain reaction of nuclear fission
Nuclear fission
In nuclear physics and nuclear chemistry, nuclear fission is a nuclear reaction in which the nucleus of an atom splits into smaller parts , often producing free neutrons and photons , and releasing a tremendous amount of energy...
with thermal neutrons), whereas the latter is not. Members of the MAUD Committee
MAUD Committee
The MAUD Committee was the beginning of the British atomic bomb project, before the United Kingdom joined forces with the United States in the Manhattan Project.-Frisch & Peierls:...
(especially Francis Simon
Francis Simon
Sir Francis Simon, born Franz Eugen Simon , was a German and later British physical chemist and physicist who devised the method, and confirmed its feasibility, of separating the isotope Uranium-235 and thus made a major contribution to the creation of the atomic bomb.-Early life:He was born to a...
and Nicholas Kurti
Nicholas Kurti
Professor Nicholas Kurti FRS was a Hungarian-born physicist who lived in Oxford, UK, for most of his life. In his era, he was one of the leading experimental physicists....
) proposed the use of gaseous diffusion
Gaseous diffusion
Gaseous diffusion is a technology used to produce enriched uranium by forcing gaseous uranium hexafluoride through semi-permeable membranes. This produces a slight separation between the molecules containing uranium-235 and uranium-238 . By use of a large cascade of many stages, high separations...
for isotope separation, since, according to Graham's law
Graham's law
Graham's law, known as Graham's law of effusion, was formulated by Scottish physical chemist Thomas Graham in 1846. Graham found experimentally that the rate of effusion of a gas is inversely proportional to the square root of the mass of its particles...
the rate of diffusion is inversely proportional to molecular mass. After an extensive search, uranium hexafluoride
Uranium hexafluoride
Uranium hexafluoride , referred to as "hex" in the nuclear industry, is a compound used in the uranium enrichment process that produces fuel for nuclear reactors and nuclear weapons. It forms solid grey crystals at standard temperature and pressure , is highly toxic, reacts violently with water...
, 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
K-25
K-25 is a former uranium enrichment facility of the Manhattan Project which used the gaseous diffusion method. The plant is located in Oak Ridge, Tennessee, on the southwestern end of the Oak Ridge Reservation.-History:...
gaseous diffusion plant
Chemical plant
A chemical plant is an industrial process plant that manufactures chemicals, usually on a large scale. The general objective of a chemical plant is to create new material wealth via the chemical or biological transformation and or separation of materials. Chemical plants use special equipment,...
could be built, it was first necessary to develop non-reactive chemical compound
Chemical compound
A chemical compound is a pure chemical substance consisting of two or more different chemical elements that can be separated into simpler substances by chemical reactions. Chemical compounds have a unique and defined chemical structure; they consist of a fixed ratio of atoms that are held together...
s that could be used as coating
Coating
Coating is a covering that is applied to the surface of an object, usually referred to as the substrate. In many cases coatings are applied to improve surface properties of the substrate, such as appearance, adhesion, wetability, corrosion resistance, wear resistance, and scratch resistance...
s, lubricant
Lubricant
A lubricant is a substance introduced to reduce friction between moving surfaces. It may also have the function of transporting foreign particles and of distributing heat...
s and gasket
Gasket
thumb|sright|250px|Some seals and gaskets1. [[o-ring]]2. fiber [[Washer |washer]]3. paper gaskets4. [[cylinder head]] [[head gasket|gasket]]...
s 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
Organic chemistry
Organic chemistry is a subdiscipline within chemistry involving the scientific study of the structure, properties, composition, reactions, and preparation of carbon-based compounds, hydrocarbons, and their derivatives...
at Cornell University
Cornell University
Cornell University is an Ivy League university located in Ithaca, New York, United States. It is a private land-grant university, receiving annual funding from the State of New York for certain educational missions...
, was co-opted to develop such materials, because of his expertise in organofluorine chemistry. Miller and his team developed several novel non-reactive chlorofluorocarbon
Chlorofluorocarbon
A chlorofluorocarbon is an organic compound that contains carbon, chlorine, and fluorine, produced as a volatile derivative of methane and ethane. A common subclass are the hydrochlorofluorocarbons , which contain hydrogen, as well. They are also commonly known by the DuPont trade name Freon...
polymer
Polymer
A polymer is a large molecule composed of repeating structural units. These subunits are typically connected by covalent chemical bonds...
s that were used in this application.
Charles Suckling
Charles Suckling
Charles Walter Suckling, Commander of the Order of the British Empire is a British chemist who first synthesised halothane, a volatile inhalational anaesthetic in 1951, while working at the Imperial Chemical Industries Central Laboratory in Widnes.-Biography:He was born in Teddington, London,...
synthesized halothane
Halothane
Halothane is an inhalational general anesthetic. Its IUPAC name is 2-bromo-2-chloro-1,1,1-trifluoroethane. It is the only inhalational anesthetic agent containing a bromine atom; there are several other halogenated anesthesia agents which lack the bromine atom and do contain the fluorine and...
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
World War II
World War II, or the Second World War , was a global conflict lasting from 1939 to 1945, involving most of the world's nations—including all of the great powers—eventually forming two opposing military alliances: the Allies and the Axis...
and methoxyflurane was synthesized in 1948.
Further reading
- 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.
- Laird SM, Gray BM. Intermittent inhalation of methoxyflurane and trichloroethylene as an analgesic in burns dressings procedures. Br. J. Anaesth. 1971; 43: 149–59.
- Metropolitan Ambulance Service/Rural Ambulance Service. Clinical practice guideline D020. Version 4, 2005. Methoxyflurane (Penthrane).
- National Institute for Occupational Safety and Health. Pocket guide to chemical hazards, methoxyflurane. Publication number 2005-149.
External links
- Sheffield Museum of Anaesthesia: the Analgizer
- Medical Developments International Limited: Penthrox® (methoxyflurane)