Halothane

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Halothane
Halothane.svg
Halothane-3D-vdW.png
Clinical data
Trade names Fluothane
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Routes of
administration 		Inhalation
ATC code
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Legal status
Pharmacokinetic data
Metabolism Hepatic (CYP2E1 [4] )
Excretion Kidney, respiratory
Identifiers
  • 2-Bromo-2-chloro-1,1,1-trifluoroethane
CAS Number
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Chemical and physical data
Formula C2HBrClF3
Molar mass 197.38 g·mol−1
3D model (JSmol)
Density 1.871 g/cm3 (at 20 °C)
Melting point −118 °C (−180 °F)
Boiling point 50.2 °C (122.4 °F)
  • BrC(Cl)C(F)(F)F
  • InChI=1S/C2HBrClF3/c3-1(4)2(5,6)7/h1H Yes check.svgY
  • Key:BCQZXOMGPXTTIC-UHFFFAOYSA-N Yes check.svgY
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Halothane, sold under the brand name Fluothane among others, is a general anaesthetic. [5] It can be used to induce or maintain anaesthesia. [5] One of its benefits is that it does not increase the production of saliva, which can be particularly useful in those who are difficult to intubate. [5] It is given by inhalation. [5]

Contents

Side effects include an irregular heartbeat, respiratory depression, and hepatotoxicity. [5] Like all volatile anesthetics, it should not be used in people with a personal or family history of malignant hyperthermia. [5] It appears to be safe in porphyria. [6] It is unclear whether its usage during pregnancy is harmful to the fetus, and its use during a C-section is generally discouraged. [7] Halothane is a chiral molecule that is used as a racemic mixture. [8]

Halothane was discovered in 1951. [9] It was approved for medical use in the United States in 1958. [3] It is on the World Health Organization's List of Essential Medicines. [10] [11] Its use in developed countries has been mostly replaced by newer anesthetic agents such as sevoflurane. [12] It is no longer commercially available in the United States. [7] Halothane also contributes to ozone depletion. [13] [14]

Medical uses

Packaging of Fluothane brand of halothane Fluothane packaging 01.jpg
Packaging of Fluothane brand of halothane

It is a potent anesthetic with a minimum alveolar concentration (MAC) of 0.74%. [15] Its blood/gas partition coefficient of 2.4 makes it an agent with moderate induction and recovery time. [16] It is not a good analgesic and its muscle relaxation effect is moderate. [17]

Side effects

Side effects include irregular heartbeat, respiratory depression, and hepatotoxicity. [5] It appears to be safe in porphyria. [6] It is unclear whether use during pregnancy is harmful to the baby, and it is not generally recommended for use during a C-section. [7] In rare cases, repeated exposure to halothane in adults was noted to result in severe liver injury. This occurred in about one in 10,000 exposures. The resulting syndrome was referred to as halothane hepatitis, immunoallergic in origin, [18] and is thought to result from the metabolism of halothane to trifluoroacetic acid via oxidative reactions in the liver. About 20% of inhaled halothane is metabolized by the liver and these products are excreted in the urine. The hepatitis syndrome had a mortality rate of 30% to 70%. [19] Concern for hepatitis resulted in a dramatic reduction in the use of halothane for adults and it was replaced in the 1980s by enflurane and isoflurane. [20] [21] By 2005, the most common volatile anesthetics used were isoflurane, sevoflurane, and desflurane. Since the risk of halothane hepatitis in children was substantially lower than in adults, halothane continued to be used in pediatrics in the 1990s as it was especially useful for inhalation induction of anesthesia. [22] [23] However, by 2000, sevoflurane, excellent for inhalation induction, had largely replaced the use of halothane in children. [24]

Halothane sensitises the heart to catecholamines, so it is liable to cause cardiac arrhythmia, occasionally fatal, particularly if hypercapnia has been allowed to develop. This seems to be especially problematic in dental anesthesia. [25]

Like all the potent inhalational anaesthetic agents, it is a potent trigger for malignant hyperthermia. [5] Similarly, in common with the other potent inhalational agents, it relaxes uterine smooth muscle and this may increase blood loss during delivery or termination of pregnancy. [26]

Occupational safety

People can be exposed to halothane in the workplace by breathing it in as waste anaesthetic gas, skin contact, eye contact, or swallowing it. [27] The National Institute for Occupational Safety and Health (NIOSH) has set a recommended exposure limit (REL) of 2 ppm (16.2 mg/m3) over 60 minutes. [28]

Pharmacology

The exact mechanism of the action of general anaesthetics has not been delineated. [29] Halothane activates GABAA and glycine receptors. [30] [31] It also acts as an NMDA receptor antagonist, [31] inhibits nACh and voltage-gated sodium channels, [30] [32] and activates 5-HT3 and twin-pore K+ channels. [30] [33] It does not affect the AMPA or kainate receptors. [31]

Chemical and physical properties

Halothane (2-bromo-2-chloro-1,1,1-trifluoroethane) is a dense, highly volatile, clear, colourless, nonflammable liquid with a chloroform-like sweet odour. It is very slightly soluble in water and miscible with various organic solvents. Halothane can decompose to hydrogen fluoride, hydrogen chloride and hydrogen bromide in the presence of light and heat. [34]

Boiling point:50.2 °C(at 101.325 kPa)
Density:1.871 g/cm3(at 20 °C)
Molecular Weight:197.4 u
Vapor pressure:244 mmHg (32kPa)(at 20 °C)
288 mmHg (38kPa)(at 24 °C)
MAC:0.75vol %
Blood:gas partition coefficient:2.3
Oil:gas partition coefficient:224

Chemically, halothane is an alkyl halide (not an ether like many other anesthetics). [4] The structure has one stereocenter, so (R)- and (S)-optical isomers occur.[ citation needed ]

Synthesis

The commercial synthesis of halothane starts from trichloroethylene, which is reacted with hydrogen fluoride in the presence of antimony trichloride at 130 °C to form 2-chloro-1,1,1-trifluoroethane. This is then reacted with bromine at 450 °C to produce halothane. [35]

Halothane synth.png

Attempts to find anesthetics with less metabolism led to halogenated ethers such as enflurane and isoflurane. The incidence of hepatic reactions with these agents is lower. The exact degree of hepatotoxic potential of enflurane is debated, although it is minimally metabolized. Isoflurane is essentially not metabolized and reports of associated liver injury are quite rare. [36] Small amounts of trifluoroacetic acid can be formed from both halothane and isoflurane metabolism and possibly accounts for cross sensitization of patients between these agents. [37] [38]

The main advantage of the more modern agents is lower blood solubility, resulting in faster induction of and recovery from anaesthesia. [39]

History

An advertisement for Fluothane, published in various American medical journals between 1961 and 1962. The Fluothane Story.png
An advertisement for Fluothane, published in various American medical journals between 1961 and 1962.

Halothane was first synthesized by C. W. Suckling of Imperial Chemical Industries in 1951 at the ICI Widnes Laboratory and was first used clinically by M. Johnstone in Manchester in 1956. Initially, many pharmacologists and anaesthesiologists had doubts about the safety and efficacy of the new drug. But halothane, which required specialist knowledge and technologies for safe administration, also afforded British anaesthesiologists the opportunity to remake their speciality as a profession during a period, when the newly established National Health Service needed more specialist consultants. [40] In this context, halothane eventually became popular as a nonflammable general anesthetic replacing other volatile anesthetics such as trichloroethylene, diethyl ether and cyclopropane. In many parts of the world it has been largely replaced by newer agents since the 1980s but is still widely used in developing countries because of its lower cost. [41]

A meter for measuring halothane. This was used to measure the amount of halothane as flow of inspired gas during anesthesia. Halothane meter.jpg
A meter for measuring halothane. This was used to measure the amount of halothane as flow of inspired gas during anesthesia.

Halothane was given to many millions of people worldwide from its introduction in 1956 through the 1980s. [42] Its properties include cardiac depression at high levels, cardiac sensitization to catecholamines such as norepinephrine, and potent bronchial relaxation. Its lack of airway irritation made it a common inhalation induction agent in pediatric anesthesia. [43] [44] Its use in developed countries has been mostly replaced by newer anesthetic agents such as sevoflurane. [45] It is not commercially available in the United States. [7]

Society and culture

Availability

It is on the World Health Organization's List of Essential Medicines. [10] [11] It is available as a volatile liquid, at 30, 50, 200, and 250 ml per container but in many developed nations is not available having been displaced by newer agents. [46]

It is the only inhalational anesthetic containing bromine, which makes it radiopaque. [47] It is colorless and pleasant-smelling, but unstable in light. It is packaged in dark-colored bottles and contains 0.01% thymol as a stabilizing agent. [20]

Greenhouse gas

Owing to the presence of covalently bonded fluorine, halothane absorbs in the atmospheric window and is therefore a greenhouse gas. However, it is much less potent than most other chlorofluorocarbons and bromofluorocarbons due to its short atmospheric lifetime, estimated at only one year vis-à-vis over 100 years for many perfluorocarbons. [48] Despite its short lifespan, halothane still has a global warming potential 47 times that of carbon dioxide, although this is over 100 times smaller than the most abundant fluorinated gases, and about 800 times smaller than the GWP of sulfur hexafluoride over 500 years. [49] Halothane is believed to make a negligible contribution to global warming. [48]

Ozone depletion

Halothane is an ozone depleting substance with an ODP of 1.56 and it is calculated to be responsible for 1% of total stratospheric ozone layer depletion. [13] [14]

Related Research Articles

General anaesthetics are often defined as compounds that induce a loss of consciousness in humans or loss of righting reflex in animals. Clinical definitions are also extended to include an induced coma that causes lack of awareness to painful stimuli, sufficient to facilitate surgical applications in clinical and veterinary practice. General anaesthetics do not act as analgesics and should also not be confused with sedatives. General anaesthetics are a structurally diverse group of compounds whose mechanisms encompass multiple biological targets involved in the control of neuronal pathways. The precise workings are the subject of some debate and ongoing research.

<span class="mw-page-title-main">Isoflurane</span> General anaesthetic given via inhalation

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.

<span class="mw-page-title-main">Sevoflurane</span> Inhalational anaesthetic

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.

<span class="mw-page-title-main">General anaesthesia</span> Medically induced loss of consciousness

General anaesthesia (UK) or general anesthesia (US) is a method of medically inducing loss of consciousness that renders a patient unarousable even with painful stimuli. This effect is achieved by administering either intravenous or inhalational general anaesthetic medications, which often act in combination with an analgesic and neuromuscular blocking agent. Spontaneous ventilation is often inadequate during the procedure and intervention is often necessary to protect the airway. General anaesthesia is generally performed in an operating theater to allow surgical procedures that would otherwise be intolerably painful for a patient, or in an intensive care unit or emergency department to facilitate endotracheal intubation and mechanical ventilation in critically ill patients. Depending on the procedure, general anaesthesia may be optional or required. Regardless of whether a patient may prefer to be unconscious or not, certain pain stimuli could result in involuntary responses from the patient that may make an operation extremely difficult. Thus, for many procedures, general anaesthesia is required from a practical perspective.

<span class="mw-page-title-main">Theories of general anaesthetic action</span> How drugs induce reversible suppression of consciousness

A general anaesthetic is a drug that brings about a reversible loss of consciousness. These drugs are generally administered by an anaesthetist/anesthesiologist to induce or maintain general anaesthesia to facilitate surgery.

<span class="mw-page-title-main">Anaesthetic machine</span> Medical device to supply a mix of life-support and anaesthetic gases

An anaesthetic machine or anesthesia machine is a medical device used to generate and mix a fresh gas flow of medical gases and inhalational anaesthetic agents for the purpose of inducing and maintaining anaesthesia.

<span class="mw-page-title-main">Anesthetic</span> Drug that causes anesthesia

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.

<span class="mw-page-title-main">Desflurane</span> Chemical compound

Desflurane (1,2,2,2-tetrafluoroethyl difluoromethyl ether) is a highly fluorinated methyl ethyl ether used for maintenance of general anesthesia. Like halothane, enflurane, and isoflurane, it is a racemic mixture of (R) and (S) optical isomers (enantiomers). Together with sevoflurane, it is gradually replacing isoflurane for human use, except in economically undeveloped areas, where its high cost precludes its use. It has the most rapid onset and offset of the volatile anesthetic drugs used for general anesthesia due to its low solubility in blood.

<span class="mw-page-title-main">Bispectral index</span>

Bispectral index (BIS) is one of several technologies used to monitor depth of anesthesia. BIS monitors are used to supplement Guedel's classification system for determining depth of anesthesia. Titrating anesthetic agents to a specific bispectral index during general anesthesia in adults allows the anesthetist to adjust the amount of anesthetic agent to the needs of the patient, possibly resulting in a more rapid emergence from anesthesia. Use of the BIS monitor could reduce the incidence of intraoperative awareness during anaesthesia. The exact details of the algorithm used to create the BIS index have not been disclosed by the company that developed it.

<span class="mw-page-title-main">Enflurane</span> Chemical compound

Enflurane is a halogenated ether. Developed by Ross Terrell in 1963, it was first used clinically in 1966. It was increasingly used for inhalational anesthesia during the 1970s and 1980s but is no longer in common use.

<span class="mw-page-title-main">Inhalational anesthetic</span> Volatile or gaseous anesthetic compound delivered by inhalation

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.

<span class="mw-page-title-main">Halogenated ether</span> Subcategory of ether used in anesthesiology

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 (substituted) alkyl groups. A good example of an ether is the solvent diethyl ether. What differentiates a halogenated ether from other types of ethers is the substitution (halogenation) of one or more hydrogen atoms with a halogen atom. Halogen atoms include fluorine, chlorine, bromine, and iodine.

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.

Alfaxolone/alfadolone is a short acting intravenous anesthetic agent. It was withdrawn from the market due to severe drug reactions. It is composed of a 3:1 mixture of alfaxalone and alfadolone, two neurosteroids.

<span class="mw-page-title-main">Methoxyflurane</span> Chemical compound

Methoxyflurane, sold under the brand name Penthrox among others, is an inhaled medication primarily used to reduce pain following trauma. It may also be used for short episodes of pain as a result of medical procedures. Onset of pain relief is rapid and of a short duration. Use is only recommended with direct medical supervision.

<span class="mw-page-title-main">Flurothyl</span> Chemical compound

Flurothyl (Indoklon) is a volatile liquid drug from the halogenated ether family, related to inhaled anaesthetic agents such as diethyl ether, but having the opposite effects, acting as a stimulant and convulsant. A clear and stable liquid, it has a mild ethereal odor whose vapors are non-flammable. It is excreted from the body by the lungs in an unchanged state.

Emergence delirium is a condition in which emergence from general anesthesia is accompanied by psychomotor agitation. Some see a relation to pavor nocturnus while others see a relation to the excitement stage of anesthesia.

Blood–gas partition coefficient, also known as Ostwald coefficient for blood–gas, is a term used in pharmacology to describe the solubility of inhaled general anesthetics in blood. According to Henry's law, the ratio of the concentration in blood to the concentration in gas that is in contact with that blood, when the partial pressure in both compartments is equal, is nearly constant at sufficiently low concentrations. The partition coefficient is defined as this ratio and, therefore, has no units. The concentration of the anesthetic in blood includes the portion that is undissolved in plasma and the portion that is dissolved. The more soluble the inhaled anesthetic is in blood compared to in air, the more it binds to plasma proteins in the blood and the higher the blood–gas partition coefficient.

Nicholas Peter Franks FRS FRSB has been Professor of Biophysics and Anaesthetics at Imperial College London since 1993. His research focuses on how general anaesthetics act at the cell and molecular levels as well as with neuronal networks. Franks holds patents on use of xenon gas as a neuroprotectant and has published research on the use of the anesthetic properties of xenon.

The effects of early-life exposures to anesthesia on the brain in humans are controversial. Evidence from nonhuman primate research suggests significant developmental neurotoxicity and long-term social impairment, with a dose–response relationship where repeated exposures cause a more severe impact than single ones. Research in humans has not found conclusive clinical evidence of cognitive impairment; however, systematic reviews imply the possibility of greater behavioural impairments in children exposed to anesthesia before the age of three than control subjects.

References

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  45. ↑ Yentis SM, Hirsch NP, Ip J (2013). Anaesthesia and Intensive Care A-Z: An Encyclopedia of Principles and Practice (5 ed.). Elsevier Health Sciences. p. 264. ISBN   9780702053757. Archived from the original on 2017-09-10.
  46. ↑ National formulary of India (4th ed.). New Delhi, India: Indian Pharmacopoeia Commission. 2011. p. 411.
  47. ↑ Miller AL, Theodore D, Widrich J (2022). "Inhalational Anesthetic". StatPearls. Treasure Island (FL): StatPearls Publishing. PMID   32119427 . Retrieved 2023-01-18.
  48. 1 2 Hodnebrog Ø, Etminan M, Fuglestvedt JS, Marston G, Myhre G, Nielsen CJ, et al. (April 24, 2013). "Global warming potentials and radiative efficiencies of halocarbons and related compounds: A comprehensive review" (PDF). Reviews of Geophysics (2. 51 (2): 300–378. Bibcode:2013RvGeo..51..300H. doi:10.1002/rog.20013.{{cite journal}}: CS1 maint: overridden setting (link)
  49. ↑ Hodnebrog Ø, Aamaas B, Fuglestvedt JS, Marston G, Myhre G, Nielsen CJ, et al. (September 2020). "Updated Global Warming Potentials and Radiative Efficiencies of Halocarbons and Other Weak Atmospheric Absorbers". Reviews of Geophysics. 58 (3): e2019RG000691. Bibcode:2020RvGeo..5800691H. doi:10.1029/2019RG000691. PMC   7518032 . PMID   33015672.{{cite journal}}: CS1 maint: overridden setting (link)
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