Chemistry:Halothane

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Short description: General anaesthetic
Halothane
Halothane.svg
Halothane-3D-vdW.png
Clinical data
Trade namesFluothane
AHFS/Drugs.comFDA Professional Drug Information
License data
Routes of
administration		Inhalation
ATC code
Legal status
Legal status
Pharmacokinetic data
MetabolismHepatic (CYP2E1[3])
ExcretionKidney, respiratory
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC2HBrClF3
Molar mass197.38 g·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)
  (verify)

Halothane, sold under the brand name Fluothane among others, is a general anaesthetic.[4] It can be used to induce or maintain anaesthesia.[4] 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.[4] It is given by inhalation.[4]

Side effects include an irregular heartbeat, respiratory depression, and hepatotoxicity.[4] Like all volatile anesthetics, it should not be used in people with a personal or family history of malignant hyperthermia.[4] It appears to be safe in porphyria.[5] It is unclear whether its usage during pregnancy is harmful to the fetus, and its use during a C-section is generally discouraged.[6] Halothane is a chiral molecule that is used as a racemic mixture.[7]

Halothane was discovered in 1951.[8] It was approved for medical use in the United States in 1958.[2] It is on the World Health Organization's List of Essential Medicines.[9][10] Its use in developed countries has been mostly replaced by newer anesthetic agents such as sevoflurane.[11] It is no longer commercially available in the United States.[6] Halothane also contributes to ozone depletion.[12][13]

Medical uses

Packaging of Fluothane brand of halothane

It is a potent anesthetic with a minimum alveolar concentration (MAC) of 0.74%.[14] Its blood/gas partition coefficient of 2.4 makes it an agent with moderate induction and recovery time.[15] It is not a good analgesic and its muscle relaxation effect is moderate.[16]

Side effects

Side effects include irregular heartbeat, respiratory depression, and hepatotoxicity.[4] It appears to be safe in porphyria.[5] It is unclear whether use during pregnancy is harmful to the baby, and it is not generally recommended for use during a C-section.[6] 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,[17] 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%.[18] 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.[19][20] 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.[21][22] However, by 2000, sevoflurane, excellent for inhalation induction, had largely replaced the use of halothane in children.[23]

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.[24]

Like all the potent inhalational anaesthetic agents, it is a potent trigger for malignant hyperthermia.[4] 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.[25]

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.[26] 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.[27]

Pharmacology

The exact mechanism of the action of general anaesthetics has not been delineated.[28] Halothane activates GABAA and glycine receptors.[29][30] It also acts as an NMDA receptor antagonist,[30] inhibits nACh and voltage-gated sodium channels,[29][31] and activates 5-HT3 and twin-pore K+ channels.[29][32] It does not affect the AMPA or kainate receptors.[30]

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.[33]

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: 0.75 vol %
Blood:gas partition coefficient: 2.3
Oil:gas partition coefficient: 224

Chemically, halothane is an alkyl halide (not an ether like many other anesthetics).[3] 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.[34]

Halothane synth.png

Related substances

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.[35] 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.[36][37]

The main advantage of the more modern agents is lower blood solubility, resulting in faster induction of and recovery from anaesthesia.[38]

History

An advertisement for Fluothane, published in various American medical journals between 1961 and 1962.
Halothane introduction, 1959

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.[39] 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.[40]

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.[41] 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.[42][43] Its use in developed countries has been mostly replaced by newer anesthetic agents such as sevoflurane.[44] It is not commercially available in the United States.[6]

Society and culture

Availability

It is on the World Health Organization's List of Essential Medicines.[9][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.[45]

It is the only inhalational anesthetic containing bromine, which makes it radiopaque.[46] 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.[19]

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.[47] 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.[48] Halothane is believed to make a negligible contribution to global warming.[47]

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.[12][13]

References

  1. ↑ "Halothane, USP". 18 September 2013. https://dailymed.nlm.nih.gov/dailymed/archives/fdaDrugInfo.cfm?archiveid=120083. 
  2. ↑ 2.0 2.1 "Fluothane: FDA-Approved Drugs". https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=011338. 
  3. ↑ 3.0 3.1 "Halothane". DrugBank. https://go.drugbank.com/drugs/DB01159. 
  4. ↑ 4.0 4.1 4.2 4.3 4.4 4.5 4.6 4.7 WHO Model Formulary 2008. World Health Organization. 2009. pp. 17–8. ISBN 9789241547659. 
  5. ↑ 5.0 5.1 "Porphyrias". British Journal of Anaesthesia 85 (1): 143–53. July 2000. doi:10.1093/bja/85.1.143. PMID 10928003. 
  6. ↑ 6.0 6.1 6.2 6.3 "Halothane - FDA prescribing information, side effects and uses". June 2005. https://www.drugs.com/pro/halothane.html. 
  7. ↑ The Anaesthesia Science Viva Book. Cambridge University Press. 17 June 2004. p. 161. ISBN 9780521682480. https://books.google.com/books?id=RkhPlWywV_IC&pg=PT161. 
  8. ↑ Trends and Changes in Drug Research and Development. Springer Science & Business Media. 2012. p. 109. ISBN 9789400926592. https://books.google.com/books?id=FB_2CAAAQBAJ&pg=PA109. 
  9. ↑ 9.0 9.1 World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. 2019. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO. 
  10. ↑ 10.0 10.1 World Health Organization model list of essential medicines: 22nd list (2021). Geneva: World Health Organization. 2021. WHO/MHP/HPS/EML/2021.02. 
  11. ↑ Anaesthesia and Intensive Care A-Z: An Encyclopedia of Principles and Practice (5 ed.). Elsevier Health Sciences. 2013. p. 264. ISBN 9780702053757. https://books.google.com/books?id=Te7TAAAAQBAJ&pg=PA264. 
  12. ↑ 12.0 12.1 Pharmaceuticals in the Environment: Sources, Fate, Effects and Risks. Springer Science & Business Media. 2013. pp. 33. ISBN 9783662092590. https://books.google.com/books?id=1VXUBgAAQBAJ&pg=PA33. 
  13. ↑ 13.0 13.1 "Volatile anaesthetics and the atmosphere: atmospheric lifetimes and atmospheric effects of halothane, enflurane, isoflurane, desflurane and sevoflurane". British Journal of Anaesthesia 82 (1): 66–73. January 1999. doi:10.1093/bja/82.1.66. PMID 10325839. 
  14. ↑ "Minimum Alveolar Concentration". StatPearls. Treasure Island (FL): StatPearls Publishing. 2022. http://www.ncbi.nlm.nih.gov/books/NBK532974/. Retrieved 2022-08-09. 
  15. ↑ "The blood–gas partition coefficient". Southern African Journal of Anaesthesia and Analgesia 1 (3): 3. ISSN 2220-1181. https://www.researchgate.net/publication/348461499. Retrieved 2022-08-08. [|permanent dead link|dead link}}]
  16. ↑ "Halothane". Anesthesia General. 2010-10-31. http://anesthesiageneral.com/halothane/. 
  17. ↑ "Halothane". LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. January 2018. https://www.ncbi.nlm.nih.gov/books/NBK548151/. Retrieved 2021-01-27. 
  18. ↑ "Halothane metabolism in children". British Journal of Anaesthesia 64 (4): 474–481. April 1990. doi:10.1093/bja/64.4.474. PMID 2334622. 
  19. ↑ 19.0 19.1 "Halothane Toxicity". StatPearls. Treasure Island (FL): StatPearls Publishing. 2022. http://www.ncbi.nlm.nih.gov/books/NBK545281/. Retrieved 2023-01-18. 
  20. ↑ "Determination of the halothane metabolites trifluoroacetic acid and bromide in plasma and urine by ion chromatography" (in en). Journal of Chromatography B: Biomedical Sciences and Applications 692 (2): 413–418. 1997-05-09. doi:10.1016/S0378-4347(96)00527-0. ISSN 0378-4347. PMID 9188831. 
  21. ↑ "Volatile anesthetics isoflurane and sevoflurane directly target and attenuate Toll-like receptor 4 system". FASEB Journal 33 (12): 14528–14541. December 2019. doi:10.1096/fj.201901570R. PMID 31675483. 
  22. ↑ "Inhalation anesthesiology and volatile liquid anesthetics: focus on isoflurane, desflurane, and sevoflurane". Pharmacotherapy 25 (12): 1773–1788. December 2005. doi:10.1592/phco.2005.25.12.1773. PMID 16305297. 
  23. ↑ "Sevoflurane. A review of its pharmacodynamic and pharmacokinetic properties and its clinical use in general anaesthesia". Drugs 51 (4): 658–700. April 1996. doi:10.2165/00003495-199651040-00009. PMID 8706599. 
  24. ↑ "Comparison of sevoflurane and halothane for outpatient dental anaesthesia in children". British Journal of Anaesthesia 79 (3): 280–284. September 1997. doi:10.1093/bja/79.3.280. PMID 9389840. 
  25. ↑ "Potent Inhalational Anesthetics for Dentistry". Anesthesia Progress 63 (1): 42–8; quiz 49. 2016. doi:10.2344/0003-3006-63.1.42. PMID 26866411. 
  26. ↑ "Common Name: Halothene". Hazardous Substance Fact Sheet 969 (1). 1999. https://nj.gov/health/eoh/rtkweb/documents/fs/0969.pdf. 
  27. ↑ "CDC - NIOSH Pocket Guide to Chemical Hazards - Halothane". https://www.cdc.gov/niosh/npg/npgd0310.html. 
  28. ↑ "How does anesthesia work?". Scientific American. 7 February 2005. http://www.scientificamerican.com/article/how-does-anesthesia-work/. 
  29. ↑ 29.0 29.1 29.2 Foundations of Anesthesia: Basic Sciences for Clinical Practice. Elsevier Health Sciences. 2006. pp. 292–. ISBN 978-0-323-03707-5. https://books.google.com/books?id=xaXu1wHmENoC&pg=PA292. 
  30. ↑ 30.0 30.1 30.2 Clinical Anesthesia, 7e: Print + Ebook with Multimedia. Lippincott Williams & Wilkins. 7 February 2013. pp. 116–. ISBN 978-1-4698-3027-8. https://books.google.com/books?id=exygUxEuxnIC&pg=PA116. 
  31. ↑ Modern Anesthetics. Springer Science & Business Media. 8 January 2008. pp. 70–. ISBN 978-3-540-74806-9. https://books.google.com/books?id=JpkkWhPbh2QC&pg=PA70. 
  32. ↑ Allosteric Receptor Modulation in Drug Targeting. CRC Press. 19 June 2006. pp. 143–. ISBN 978-1-4200-1618-5. https://books.google.com/books?id=WRfgvOKfZMcC&pg=PA143. 
  33. ↑ Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996., p. 1761
  34. ↑ Suckling et al.,"PROCESS FOR THE PREPARATION OF 1,1,1-TRIFLUORO-2-BROMO-2-CHLOROETHANE", US patent 2921098, granted January 1960 , assigned to Imperial Chemical Industries 
  35. ↑ "Halogenated Anesthetics". LiverTox: Clinical and Research Information on Drug-Induced Liver Injury 1 (1). 2018-01-01. NBK548851. PMID 31644158. https://pubmed.ncbi.nlm.nih.gov/31644158/. 
  36. ↑ "Effects of trifluoroacetic acid, a halothane metabolite, on C6 glioma cells". Journal of Toxicology and Environmental Health 31 (2): 147–158. October 1990. doi:10.1080/15287399009531444. PMID 2213926. Bibcode: 1990JTEH...31..147M. 
  37. ↑ "Metabolism of halothane in obese Fischer 344 rats". Anesthesiology 71 (3): 431–437. September 1989. doi:10.1097/00000542-198909000-00020. PMID 2774271. 
  38. ↑ "The pharmacology of isoflurane". British Journal of Anaesthesia 56 (Suppl 1): 71S–99S. 1984. PMID 6391530. https://pubmed.ncbi.nlm.nih.gov/6391530/. 
  39. ↑ "Medicating Anaesthesiology: Pharmaceutical Change, Specialisation and Healthcare Reform in Post-War Britain". Social History of Medicine 34 (4): 1343–1365. March 2021. doi:10.1093/shm/hkaa101. 
  40. ↑ "Inhalation Anaesthesia: From Diethyl Ether to Xenon". Modern Anesthetics. Handbook of Experimental Pharmacology. 182. 2008. pp. 121–142. doi:10.1007/978-3-540-74806-9_6. ISBN 978-3-540-72813-9. 
  41. ↑ Electroencephalography: Basic Principles, Clinical Applications, and Related Fields. Lippincott Williams & Wilkins. 2005. p. 1156. ISBN 978-0-7817-5126-1. https://books.google.com/books?id=tndqYGPHQdEC&pg=PA1156. 
  42. ↑ "Mechanisms involved in cardiac sensitization by volatile anesthetics: general applicability to halogenated hydrocarbons?". Critical Reviews in Toxicology 38 (9): 773–803. 2008. doi:10.1080/10408440802237664. PMID 18941968. 
  43. ↑ "Psychometric properties of the Cardiac Depression Scale: a systematic review". Heart, Lung & Circulation 23 (7): 610–618. July 2014. doi:10.1016/j.hlc.2014.02.020. PMID 24709392. 
  44. ↑ (in en) Anaesthesia and Intensive Care A-Z: An Encyclopedia of Principles and Practice (5 ed.). Elsevier Health Sciences. 2013. p. 264. ISBN 9780702053757. https://books.google.com/books?id=Te7TAAAAQBAJ&pg=PA264. 
  45. ↑ National formulary of India (4th ed.). New Delhi, India: Indian Pharmacopoeia Commission. 2011. p. 411. 
  46. ↑ "Inhalational Anesthetic". StatPearls. Treasure Island (FL): StatPearls Publishing. 2022. http://www.ncbi.nlm.nih.gov/books/NBK554540/. Retrieved 2023-01-18. 
  47. ↑ 47.0 47.1 "Global warming potentials and radiative efficiencies of halocarbons and related compounds: A comprehensive review". Reviews of Geophysics (2 51 (2): 300–378. April 24, 2013. doi:10.1002/rog.20013. Bibcode: 2013RvGeo..51..300H. https://centaur.reading.ac.uk/31338/1/ReviewGWP_2nd_rev_v2.pdf. 
  48. ↑ "Updated Global Warming Potentials and Radiative Efficiencies of Halocarbons and Other Weak Atmospheric Absorbers". Reviews of Geophysics 58 (3): e2019RG000691. September 2020. doi:10.1029/2019RG000691. PMID 33015672. Bibcode: 2020RvGeo..5800691H. 

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