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Trade names | Penthrane, Metofane, Penthrox, Penthrop, others |
Other names | 2,2-dichloro-1,1-difluoroethyl methyl ether |
AHFS/Drugs.com | Consumer Drug Information |
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Routes of administration | Inhaled |
Drug class | Volatile anesthetic |
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Pharmacokinetic data | |
Metabolism | 70% |
Onset of action | Rapid [4] |
Duration of action | Several minutes [4] |
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ECHA InfoCard | 100.000.870 |
Chemical and physical data | |
Formula | C3H4Cl2F2O |
Molar mass | 164.96 g·mol−1 |
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Methoxyflurane, sold under the brand name Penthrox among others, is an inhaled medication primarily used to reduce pain following trauma. [5] [6] It may also be used for short episodes of pain as a result of medical procedures. [4] Onset of pain relief is rapid and of a short duration. [4] Use is only recommended with direct medical supervision. [5]
Common side effects include anxiety, headache, sleepiness, cough, and nausea. [5] Serious side effects may include kidney problems, liver problems, low blood pressure, and malignant hyperthermia. [5] [4] It is unclear if it is safe in either pregnancy or breastfeeding. [5] It is only recommended in those who have a normal level of consciousness and stable blood pressure and heart rate. [4] It is classified as a volatile anaesthetic. [4]
It was first made in 1948 by William T. Miller and came into medical use in the 1960s. [7] It was used as a general anesthetic from its introduction in 1960 until the late 1970s. [8] In 1999, the manufacturer discontinued methoxyflurane in the United States, and in 2005 the Food and Drug Administration withdrew it from the market. [8] It is still used in New Zealand, Australia, Ireland, and the United Kingdom for pain. [9] [4] [10] [5] [11]
Methoxyflurane is used for relief of moderate or severe pain as a result of trauma. [6] [5] It may also be used for short episodes of pain as a result of procedures. [4]
Each dose lasts approximately 30 minutes. [12] Pain relief begins after 6–8 breaths and continues for several minutes after stopping inhalation. [13] The maximum recommended dose is 6 milliliters per day or 15 milliliters per week because of the risk of kidney problems, and it is not recommended to be used on consecutive days. [4] Despite the potential for kidney problems when used at anesthetic doses, no significant adverse effects have been reported when it is used at the lower doses (up to 6 milliliters) used for pain relief. [14] [15] [16] Due to the risk of kidney toxicity, methoxyflurane is contraindicated in people 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. [15]
It is self-administered to children and adults using a hand-held inhaler device. [17] [14] [18] [15] A non-opioid alternative to morphine, it is also easier to use than nitrous oxide. [4] A portable, disposable, single-use inhaler device, along with a single 3 milliliter brown glass vial of methoxyflurane allows people who are conscious and hemodynamically stable (including children over the age of 5 years) to self-administer the medication, under supervision. [4]
In prehospital care Penthrox offers an alternative to Entonox, it being smaller, lighter and not contraindicated with chest injuries. [19]
The consensus is that the use of methoxyflurane should be restricted only to healthy individuals, in situations where it offers specific advantages and even then, only at dosages less than 2.5 MAC hours. [20] [21] The National Institute for Occupational Safety and Health maintains a recommended exposure limit for methoxyflurane as waste anesthetic gas of 2 ppm (13.5 mg/m3) over 60 minutes. [22]
The first report of nephrotoxicity appeared in 1964, when Paddock and colleagues reported three cases of acute kidney injury, two of whom were found to have calcium oxalate crystals in the renal tubules at autopsy. [23] 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 chronic kidney disease was characterized by vasopressin-resistant high-output kidney 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%). [24]
Compared with halothane, methoxyflurane produces dose-dependent abnormalities in kidney 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. [20] This study provided a model that would be used for the assessment of the nephrotoxicity of volatile anesthetics for the next two decades. [25] Furthermore, the concurrent use of tetracyclines and methoxyflurane has been reported to result in fatal renal toxicity. [26]
Reports of severe and even fatal hepatotoxicity related to the use of methoxyflurane began to appear in 1966.
The biodegradation of methoxyflurane begins immediately. The kidney and liver toxicity observed after anesthetic doses is attributable to one or more metabolites produced by O-demethylation of methoxyflurane. Products of this catabolic process include methoxyfluoroacetic acid (MFAA), dichloroacetic acid (DCAA), and inorganic fluoride. [21] Methoxyflurane nephrotoxicity is dose dependent [24] [27] [28] and irreversible, resulting from O-demethylation of methoxyflurane to fluoride and DCAA. [4] It is not entirely clear whether the fluoride itself is toxic—it may simply be a surrogate measure for some other toxic metabolite. [29] The concurrent formation of inorganic fluoride and DCAA is unique to methoxyflurane biotransformation compared with other volatile anesthetics, and this combination is more toxic than fluoride alone. This may explain why fluoride formation from methoxyflurane is associated with nephrotoxicity, while fluoride formation from other volatile anesthetics (such as enflurane and sevoflurane) is not. [30]
Methoxyflurane has a very high lipid solubility (oil:gas partition coefficient of around 950), which gives it very slow pharmacokinetics [ citation needed ] (induction and emergence characteristics); this being undesirable for routine application in the clinical setting. Initial studies performed in 1961 revealed that in unpremedicated healthy individuals, induction of general anesthesia with methoxyflurane-oxygen alone or with nitrous oxide was difficult or even impossible using the vaporizers available at that time. It was found to be necessary to administer an intravenous anesthetic agent such as sodium thiopental to ensure a smooth and rapid induction. It was further found that after thiopental induction, it was necessary to administer nitrous oxide for at least ten minutes before a sufficient amount of methoxyflurane could accumulate in the bloodstream to ensure an adequate level of anesthesia. This was despite using high flow (liters/minute) of nitrous oxide and oxygen, and with the vaporizers delivering the maximum possible concentration of methoxyflurane. [31]
Similar to its induction pharmacokinetics, methoxyflurane has very slow and somewhat unpredictable emergence characteristics. During initial clinical studies in 1961, the average time to emergence after discontinuation of methoxyflurane was 59 minutes after administration of methoxyflurane for an average duration of 87 minutes. The longest time to emergence was 285 minutes, after 165 minutes of methoxyflurane administration. [31]
The effects of methoxyflurane on the circulatory system resemble those of diethyl ether. [32] 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. [33] 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. [31] [34] [35] [36]
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. [32] 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. [31]
Although the high blood solubility of methoxyflurane is often undesirable, this property makes it useful in certain situations—it persists in the lipid compartment of the body for a long time, providing sedation and analgesia well into the postoperative period. [37] [32] There is substantial data to indicate that methoxyflurane is an effective analgesic and sedative agent at subanesthetic doses. [17] [14] [38] [39] [40] [41] [42] [43] [44] [45] [46] [47] [48] Supervised self-administration of methoxyflurane in children and adults can briefly lead to deep sedation, [14] and it has been used as a patient controlled analgesic for painful procedures in children in hospital emergency departments. [18] During childbirth, administration of methoxyflurane produces significantly better analgesia, less psychomotor agitation, and only slightly more somnolence than trichloroethylene. [40]
Penthrox, commonly known as the "green whistle", has been offered in hospital to women for painful intrauterine device procedures (insertion and removal). [49]
Similar to other inhalational anesthetics, the exact mechanism of action is not clearly defined and likely involves multiple molecular targets in the brain and spinal cord. [50] [51] Methoxyflurane is a positive allosteric modulator of GABAA and glycine receptors as demonstrated in electrophysiology studies. [52] [53] This mechanism is shared with alcohols that produce general anesthesia. [54]
With a molecular formula of C3H4Cl2F2O and a condensed structural formula of CHCl2CF2OCH3, the International Union of Pure and Applied Chemistry (IUPAC) name for methoxyflurane is 2,2-dichloro-1,1-difluoro-1-methoxyethane. It is a halogenated ether in form of a clear, colorless liquid, and its vapor has a strong fruity aroma. It is miscible with ethanol, acetone, chloroform, diethyl ether, and fixed oils. It is soluble in rubber. [12]
With a minimum alveolar concentration (MAC) of 0.16%, [55] methoxyflurane is an extremely potent anesthetic agent. It is a powerful analgesic agent at well below full anesthetic concentrations. [18] [56] [57] [58] [37] 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 [12] [31] [59] |
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Boiling point (at 1 atmosphere) | 104.8 °C |
Minimum alveolar concentration (MAC) | 0.16% [55] |
Vapor pressure (mmHg at 20 °C) | 22.5 |
Partition coefficient (Blood:Gas) | 12 |
Partition coefficient (Oil:Gas) | 950 |
Partition coefficient (Oil:Water) | 400 |
Specific gravity at 25 °C | 1.42 |
Flash point | 63 °C |
Molecular weight (g mol−1) | 164.97 |
Vapor-liquid equilibrium (mL) | 208 |
Flammability limits | 7% in air |
Chemical stabilizer necessary | Yes |
The carbon–fluorine bond, a component of all organofluorine compounds, is the strongest chemical bond in organic chemistry. [60] Furthermore, this bond becomes shorter and stronger as more fluorine atoms are added to the same carbon on a given molecule. Because of this, fluoroalkanes are some of the most chemically stable organic compounds.
Methoxyflurane has been used since the 1970s in Australia as an emergency analgesic for short-term use by the Australian Defence Force and New Zealand Defence Force, [17] the Australian ambulance services, [14] [38] [39] and both St John Ambulance [61] and Wellington Free Ambulance [62] in New Zealand. Since 2018, it has also been used by some emergency medical services in Germany. [63] Methoxyflurane inhalers are nicknamed 'green whistles' due to the green colour of their casing. [64]
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) [65] and the discovery of Teflon (Roy J. Plunkett, 1938), [66] 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 World War 2 nuclear 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 uranium-235 (235U) from uranium-238 (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), [67] 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. [68] 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. [69] Elemental fluorine is needed in the production of UF6.
Obstacles had to be overcome in the handling of both fluorine and UF6. Before the K-25 gaseous diffusion enrichment 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, [70] 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.
Miller and his team continued to develop organofluorine chemistry after the end of World War II and methoxyflurane was made in 1948. [71]
In 1968, Robert Wexler of Abbott Laboratories developed the Analgizer, a disposable inhaler that allowed the self-administration of methoxyflurane vapor in air for analgesia. [72] 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. [43] 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, [43] and for dressing changes on burn patients. [42] When used for labor analgesia, the Analgizer allows labor to progress normally and with no apparent adverse effect on Apgar scores. [43] All vital signs remain normal in obstetric patients, newborns, and injured patients. [43] 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. [40] [41] [44] [45] 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. [17] [14] [18] [15] During 2020 trials of methoxyflurane as an analgesic in emergency medicine were held in the UK. [73]
Anesthesia or anaesthesia is a state of controlled, temporary loss of sensation or awareness that is induced for medical or veterinary purposes. It may include some or all of analgesia, paralysis, amnesia, and unconsciousness. An individual under the effects of anesthetic drugs is referred to as being anesthetized.
Dissociatives, colloquially dissos, are a subclass of hallucinogens that distort perception of sight and sound and produce feelings of detachment – dissociation – from the environment and/or self. Although many kinds of drugs are capable of such action, dissociatives are unique in that they do so in such a way that they produce hallucinogenic effects, which may include dissociation, a general decrease in sensory experience, hallucinations, dream-like states or anesthesia. Despite most dissociatives' main mechanism of action being tied to NMDA receptor antagonism, some of these substances, which are nonselective in action and affect the dopamine and/or opioid systems, may be capable of inducing more direct and repeatable euphoria or symptoms which are more akin to the effects of typical "hard drugs" or common drugs of abuse. This is likely why dissociatives are considered to be addictive with a fair to moderate potential for abuse, unlike psychedelics. Despite some dissociatives, such as phencyclidine (PCP) possessing stimulating properties, most dissociatives seem to have a general depressant effect and can produce sedation, respiratory depression, nausea, disorientation, analgesia, anesthesia, ataxia, cognitive and memory impairment as well as amnesia.
Isoflurane, sold under the brand name Forane among others, is a general anesthetic. It can be used to start or maintain anesthesia; however, other medications are often used to start anesthesia, due to airway irritation with isoflurane. Isoflurane is given via inhalation.
Sevoflurane, sold under the brand name Sevorane, among others, is a sweet-smelling, nonflammable, highly fluorinated methyl isopropyl ether used as an inhalational anaesthetic for induction and maintenance of general anesthesia. After desflurane, it is the volatile anesthetic with the fastest onset. While its offset may be faster than agents other than desflurane in a few circumstances, its offset is more often similar to that of the much older agent isoflurane. While sevoflurane is only half as soluble as isoflurane in blood, the tissue blood partition coefficients of isoflurane and sevoflurane are quite similar. For example, in the muscle group: isoflurane 2.62 vs. sevoflurane 2.57. In the fat group: isoflurane 52 vs. sevoflurane 50. As a result, the longer the case, the more similar will be the emergence times for sevoflurane and isoflurane.
Anesthesiology, anaesthesiology, or anaesthesia is the medical specialty concerned with the total perioperative care of patients before, during and after surgery. It encompasses anesthesia, intensive care medicine, critical emergency medicine, and pain medicine. A physician specialized in anesthesiology is called an anesthesiologist, anaesthesiologist, or anaesthetist, depending on the country. In some countries, the terms are synonymous, while in other countries, they refer to different positions and anesthetist is only used for non-physicians, such as nurse anesthetists.
An anesthetic or anaesthetic is a drug used to induce anesthesia — in other words, to result in a temporary loss of sensation or awareness. They may be divided into two broad classes: general anesthetics, which result in a reversible loss of consciousness, and local anesthetics, which cause a reversible loss of sensation for a limited region of the body without necessarily affecting consciousness.
Awareness under anesthesia, also referred to as intraoperative awareness or accidental awareness during general anesthesia (AAGA), is a rare complication of general anesthesia where patients regain varying levels of consciousness during their surgical procedures. While anesthesia awareness is possible without resulting in any long-term memory of the experience, it is also possible for victims to have awareness with explicit recall, where they can remember the events related to their surgery.
Nitrous oxide is an inhaled gas used as a pain medication and together with other medications for anesthesia. Common uses include during childbirth, following trauma, and as part of end-of-life care. Onset of effect is typically within half a minute, and the effect lasts for about a minute.
Epidural administration is a method of medication administration in which a medicine is injected into the epidural space around the spinal cord. The epidural route is used by physicians and nurse anesthetists to administer local anesthetic agents, analgesics, diagnostic medicines such as radiocontrast agents, and other medicines such as glucocorticoids. Epidural administration involves the placement of a catheter into the epidural space, which may remain in place for the duration of the treatment. The technique of intentional epidural administration of medication was first described in 1921 by Spanish military surgeon Fidel Pagés.
Fluoride toxicity is a condition in which there are elevated levels of the fluoride ion in the body. Although fluoride is safe for dental health at low concentrations, sustained consumption of large amounts of soluble fluoride salts is dangerous. Referring to a common salt of fluoride, sodium fluoride (NaF), the lethal dose for most adult humans is estimated at 5 to 10 g. Ingestion of fluoride can produce gastrointestinal discomfort at doses at least 15 to 20 times lower than lethal doses. Although it is helpful topically for dental health in low dosage, chronic ingestion of fluoride in large amounts interferes with bone formation. In this way, the most widespread examples of fluoride poisoning arise from consumption of ground water that is abnormally fluoride-rich.
Remifentanil, marketed under the brand name Ultiva is a potent, short-acting synthetic opioid analgesic drug. It is given to patients during surgery to relieve pain and as an adjunct to an anaesthetic. Remifentanil is used for sedation as well as combined with other medications for use in general anesthesia. The use of remifentanil has made possible the use of high-dose opioid and low-dose hypnotic anesthesia, due to synergism between remifentanil and various hypnotic drugs and volatile anesthetics.
An inhalational anesthetic is a chemical compound possessing general anesthetic properties that is delivered via inhalation. They are administered through a face mask, laryngeal mask airway or tracheal tube connected to an anesthetic vaporiser and an anesthetic delivery system. Agents of significant contemporary clinical interest include volatile anesthetic agents such as isoflurane, sevoflurane and desflurane, as well as certain anesthetic gases such as nitrous oxide and xenon.
An inhaler is a medical device used for delivering medicines into the lungs through the work of a person's breathing. This allows medicines to be delivered to and absorbed in the lungs, which provides the ability for targeted medical treatment to this specific region of the body, as well as a reduction in the side effects of oral medications. There are a wide variety of inhalers, and they are commonly used to treat numerous medical conditions with asthma and chronic obstructive pulmonary disease (COPD) being among the most notable.
Minimum alveolar concentration or MAC is the concentration, often expressed as a percentage by volume, of a vapour in the alveoli of the lungs that is needed to prevent movement in 50% of subjects in response to surgical (pain) stimulus. MAC is used to compare the strengths, or potency, of anaesthetic vapours. The concept of MAC was first introduced in 1965.
Chloroprocaine is a local anesthetic given by injection during surgical procedures and labor and delivery. Chloroprocaine vasodilates; this is in contrast to cocaine which vasoconstricts. Chloroprocaine is an ester anesthetic.
Patient-controlled analgesia (PCA) is any method of allowing a person in pain to administer their own pain relief. The infusion is programmable by the prescriber. If it is programmed and functioning as intended, the machine is unlikely to deliver an overdose of medication. Providers must always observe the first administration of any PCA medication which has not already been administered by the provider to respond to allergic reactions.
Throughout recorded history, attempts at producing a state of general anesthesia can be traced back to the writings of ancient Sumerians, Babylonians, Assyrians, Egyptians, Indians, and Chinese. Despite significant advances in anatomy and surgical technique during the Renaissance, surgery remained a last-resort treatment largely due to the pain associated with it. However, scientific discoveries in the late 18th and early 19th centuries paved the way for the development of modern anesthetic techniques.
The history of neuraxial anaesthesia dates back to the late 1800s and is closely intertwined with the development of anaesthesia in general. Neuraxial anaesthesia, in particular, is a form of regional analgesia placed in or around the Central Nervous System, used for pain management and anaesthesia for certain surgeries and procedures.
Obstetric anesthesia or obstetric anesthesiology, also known as ob-gyn anesthesia or ob-gyn anesthesiology, is a sub-specialty of anesthesiology that provides peripartum pain relief (analgesia) for labor and anesthesia for cesarean deliveries ('C-sections').
Total intravenous anesthesia (TIVA) refers to the intravenous administration of anesthetic agents to induce a temporary loss of sensation or awareness. The first study of TIVA was done in 1872 using chloral hydrate, and the common anesthetic agent propofol was licensed in 1986. TIVA is currently employed in various procedures as an alternative technique of general anesthesia in order to improve post-operative recovery.