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Halothane

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Halothane
Clinical data
Trade namesFluothane
AHFS/DrugsFDA Professional Drug Information
License data
Routes of
administration		Inhalation
ATC code
Legal status
Legal status
Pharmacokineticdata
MetabolismHepatic(CYP2E1[4])
ExcretionKidney,respiratory
Identifiers
  • 2-Bromo-2-chloro-1,1,1-trifluoroethane
CAS Number
PubChemCID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard(EPA)
ECHA InfoCard100.005.270Edit this at Wikidata
Chemical and physical data
FormulaC2HBrClF3
Molar mass197.38g·mol−1
3D model (JSmol)
Density1.871 g/cm3(at 20 °C)
Melting point−118 °C (−180 °F)
Boiling point50.2 °C (122.4 °F)
  • BrC(Cl)C(F)(F)F
  • InChI=1S/C2HBrClF3/c3-1(4)2(5,6)7/h1HcheckY
  • Key:BCQZXOMGPXTTIC-UHFFFAOYSA-NcheckY
(verify)

Halothane,sold under the brand nameFluothaneamong others, is ageneral anaesthetic.[5]It can be used to induce or maintainanaesthesia.[5]One of its benefits is that it does not increase the production ofsaliva,which can be particularly useful in those who are difficult tointubate.[5]It is given byinhalation.[5]

Side effects include anirregular heartbeat,respiratory depression,andhepatotoxicity.[5]Like all volatile anesthetics, it should not be used in people with a personal or family history ofmalignant hyperthermia.[5]It appears to be safe inporphyria.[6]It is unclear whether its usage duringpregnancyis harmful to the fetus, and its use during aC-sectionis generally discouraged.[7]Halothane is achiralmolecule that is used as aracemic mixture.[8]

Halothane was discovered in 1951.[9]It was approved for medical use in the United States in 1958.[3]It is on theWorld Health Organization's List of Essential Medicines.[10]Its use indeveloped countrieshas been mostly replaced by newer anesthetic agents such assevoflurane.[11]It is no longer commercially available in the United States.[7]Halothane also contributes toozone depletion.[12][13]

Medical uses[edit]

Packaging of Fluothane brand of halothane

It is a potent anesthetic with aminimum alveolar concentration(MAC) of 0.74%.[14]Itsblood/gas partition coefficientof 2.4 makes it an agent with moderate induction and recovery time.[15]It is not a goodanalgesicand its muscle relaxation effect is moderate.[16]

Halothane is colour-coded red onanaesthetic vaporisers.[17]

Vaporiser used for halothane

Side effects[edit]

Side effects includeirregular heartbeat,respiratory depression,andhepatotoxicity.[5]It appears to be safe inporphyria.[6]It is unclear whether use duringpregnancyis harmful to the baby, and it is not generally recommended for use during aC-section.[7] In rare cases, repeated exposure to halothane in adults was noted to result in severeliverinjury. This occurred in about one in 10,000 exposures. The resulting syndrome was referred to as halothanehepatitis,immunoallergic in origin,[18]and is thought to result from the metabolism of halothane totrifluoroacetic acidvia 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 byenfluraneandisoflurane.[20][21]By 2005, the most common volatile anesthetics used wereisoflurane,sevoflurane,anddesflurane.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 ifhypercapniahas 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 formalignant 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[edit]

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]TheNational Institute for Occupational Safety and Health(NIOSH) has set arecommended exposure limit(REL) of 2 ppm (16.2 mg/m3) over 60 minutes.[28]

Pharmacology[edit]

The exact mechanism of the action of general anaestheticshas not been delineated.[29]Halothane activatesGABAAandglycine receptors.[30][31]It also acts as anNMDA receptor antagonist,[31]inhibitsnAChandvoltage-gated sodium channels,[30][32]and activates5-HT3andtwin-pore K+channels.[30][33]It does not affect theAMPAorkainate receptors.[31]

Chemical and physical properties[edit]

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 tohydrogen fluoride,hydrogen chlorideandhydrogen bromidein 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: 197.4u
Vapor pressure: 244 mmHg (32kPa) (at 20 °C)
288 mmHg (38kPa) (at 24 °C)
MAC: 0.75 vol %
Blood:gas partition coefficient: 2.3
Oil:gas partition coefficient: 224

Chemically, halothane is analkyl halide(not anetherlike many other anesthetics).[4]The structure has one stereocenter, so (R)- and (S)-optical isomersoccur.[citation needed]

Synthesis[edit]

The commercial synthesis of halothane starts fromtrichloroethylene,which is reacted withhydrogen fluoridein the presence ofantimony trichlorideat 130 °C to form2-chloro-1,1,1-trifluoroethane.This is then reacted withbromineat 450 °C to produce halothane.[35]

Related substances[edit]

Attempts to find anesthetics with less metabolism led tohalogenated etherssuch asenfluraneandisoflurane.The incidence ofhepaticreactions with these agents is lower. The exact degree ofhepatotoxicpotential 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 oftrifluoroacetic acidcan 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[edit]

An advertisement forFluothane,published in various American medical journals between 1961 and 1962.

Halothane was first synthesized byC. W. SucklingofImperial Chemical Industriesin 1951 at the ICIWidnes Laboratoryand was first used clinically by M. Johnstone inManchesterin 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 establishedNational Health Serviceneeded more specialist consultants.[40]In this context, halothane eventually became popular as a nonflammable general anesthetic replacing othervolatile anestheticssuch astrichloroethylene,diethyl etherandcyclopropane.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 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 tocatecholaminessuch asnorepinephrine,and potent bronchial relaxation. Its lack of airway irritation made it a common inhalation induction agent in pediatric anesthesia.[43][44] Its use indeveloped countrieshas been mostly replaced by newer anesthetic agents such assevoflurane.[45]It is not commercially available in the United States.[7]

Society and culture[edit]

Availability[edit]

It is on theWorld Health Organization's List of Essential Medicines.[10]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 onlyinhalational anestheticcontainingbromine,which makes itradiopaque.[47]It is colorless and pleasant-smelling, but unstable in light. It is packaged in dark-colored bottles and contains 0.01%thymolas a stabilizing agent.[20]

Greenhouse gas[edit]

Owing to the presence of covalently bonded fluorine, halothane absorbs in theatmospheric windowand is therefore agreenhouse gas.However, it is much less potent than most otherchlorofluorocarbonsandbromofluorocarbonsdue to its short atmospheric lifetime, estimated at only one year vis-à-vis over 100 years for manyperfluorocarbons.[48]Despite its short lifespan, halothane still has aglobal warming potential47 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 ofsulfur hexafluorideover 500 years.[49]Halothane is believed to make a negligible contribution toglobal warming.[48]

Ozone depletion[edit]

Halothane is anozone depleting substancewith anODPof 1.56 and it is calculated to be responsible for 1% of total stratospheric ozone layer depletion.[12][13]

References[edit]

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