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{{drugbox
| verifiedrevid = 443852402
| IUPAC_name = 2-Bromo-2-chloro-1,1,1-trifluoroethane
| image = Halothane.png
| width = 120px
| image2 = Halothane-3D-vdW.png
| width2 = 120px


<!--Clinical data-->
| Drugs.com = {{drugs.com|CONS|halothane}}
| pregnancy_category =
| legal_status =
| routes_of_administration =
<!--Pharmacokinetic data-->
| bioavailability =
| protein_bound =
| metabolism = [[Liver|Hepatic]] ([[CYP2E1]]<ref>[http://redpoll.pharmacy.ualberta.ca/drugbank/cgi-bin/getCard.cgi?CARD=APRD00598.txt DrugBank: DB01159 (Halothane)<!-- Bot generated title -->]</ref>)
| elimination_half-life =
| excretion = [[Kidney|Renal]]
<!--Identifiers-->
| CASNo_Ref = {{cascite|correct|CAS}}
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 151-67-7
| ATC_prefix = N01
| ATC_suffix = AB01
| ATC_supplemental =
| PubChem = 3562
| IUPHAR_ligand = 2401
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB01159
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 3441
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = UQT9G45D1P
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D00542
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 5615
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 931
<!--Chemical data-->
| C=2 | H=1 | Br=1 | Cl=1 | F=3
| molecular_weight = 197.381 g/mol
| smiles = C(C(F)(F)F)(Cl)Br
| InChI = 1/C2HBrClF3/c3-1(4)2(5,6)7/h1H
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C2HBrClF3/c3-1(4)2(5,6)7/h1H
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = BCQZXOMGPXTTIC-UHFFFAOYSA-N
}}
'''Halothane''' (trademarked as '''Fluothane''') is an inhalational [[general anesthetic]]. Its [[IUPAC name]] is '''2-bromo-2-chloro-1,1,1-trifluoroethane'''. It is the only [[inhalational anesthetic]] containing a [[bromine]] atom; several other halogenated anesthesia agents lack the bromine atom and do contain the fluorine and chlorine atoms present in halothane. 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.
<!-- Society and culture -->
It is on the [[WHO Model List of Essential Medicines]], the most important medications needed in a basic [[health system]].<ref>{{cite web|title=WHO Model List of EssentialMedicines|url=http://apps.who.int/iris/bitstream/10665/93142/1/EML_18_eng.pdf?ua=1|work=World Health Organization|accessdate=22 April 2014|date=October 2013}}</ref> Its use in developed countries, however, has been almost entirely superseded by newer inhalational anaesthetic agents such as [[sevoflurane]], [[isoflurane]], and [[desflurane]].
==Anesthetic properties==
It is a potent anesthetic with a [[minimum alveolar concentration]] of 0.74%. Its [[blood/gas partition coefficient]] of 2.4 makes it an agent with moderate induction and recovery time. It is not a good [[analgesic]] and its muscle relaxation effect is moderate.<ref>{{cite journal |title=Halothane |url=http://anesthesiageneral.com/halothane/}}</ref>
==Availability==
It is available as a volatile liquid, at 30, 50, 200, and 250 ml per container.<ref> National formulary of India, 4th Ed. New Delhi, India,  Indian Pharmacopoeia commission; 2011: 411 </ref>
==Side effects==
Repeated exposure to halothane in adults was noted in rare cases to result in severe [[liver]] injury. This occurred in about one in 10,000 exposures. The resulting syndrome was referred to as halothane [[hepatitis]], 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%. Concern for hepatitis resulted in a dramatic reduction in the use of halothane for adults. It was replaced in the 1980s by [[enflurane]] and [[isoflurane]]. By 2005, the common volatile anesthetics in use 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. However, by 2000, sevoflurane had largely replaced the use of halothane in children.
Halothane sensitises the heart to catecholamines, so it is liable to cause cardiac arrhythmias, occasionally fatal, particularly if [[hypercapnia]] has been allowed to develop.  This seems to be especially problematic in dental anaesthesia.
Like all the potent inhalational anaesthetic agents, it is a potent trigger for [[malignant hyperthermia]].  Similarly, it relaxes uterine smooth muscle and this may increase blood loss during delivery or termination of pregnancy.
==Pharmacology==
Halothane activates [[GABAA receptor|GABA<sub>A</sub>]] and [[glycine receptor]]s.<ref name="HemmingsHopkins2006">{{cite book|author1=Hugh C. Hemmings|author2=Philip M. Hopkins|title=Foundations of Anesthesia: Basic Sciences for Clinical Practice|url=http://books.google.com/books?id=xaXu1wHmENoC&pg=PA292|year=2006|publisher=Elsevier Health Sciences|isbn=0-323-03707-0|pages=292–}}</ref><ref name="BarashCullen2013">{{cite book|author1=Paul Barash|author2=Bruce F. Cullen|author3=Robert K. Stoelting|coauthors=Michael Cahalan, Christine M. Stock, Rafael Ortega|title=Clinical Anesthesia, 7e: Print + Ebook with Multimedia|url=http://books.google.com/books?id=exygUxEuxnIC&pg=PA116|date=7 February 2013|publisher=Lippincott Williams & Wilkins|isbn=978-1-4698-3027-8|pages=116–}}</ref> It also acts as an [[NMDA receptor antagonist]],<ref name="BarashCullen2013" /> inhibits [[nicotinic acetylcholine receptor|nACh]] and [[voltage-gated sodium channel]]s,<ref name="SchüttlerSchwilden2008">{{cite book|author1=Jürgen Schüttler|author2=Helmut Schwilden|title=Modern Anesthetics|url=http://books.google.com/books?id=JpkkWhPbh2QC&pg=PA70|date=8 January 2008|publisher=Springer Science & Business Media|isbn=978-3-540-74806-9|pages=70–}}</ref><ref name="HemmingsHopkins2006" /> and activates [[5-HT3 receptor|5-HT<sub>3</sub>]] and [[tandem pore domain potassium channel|twin-pore K<sup>+</sup> channel]]s.<ref name="Bowery2006">{{cite book|author=Norman G. Bowery|title=Allosteric Receptor Modulation in Drug Targeting|url=http://books.google.com/books?id=WRfgvOKfZMcC&pg=PA143|date=19 June 2006|publisher=CRC Press|isbn=978-1-4200-1618-5|pages=143–}}</ref><ref name="HemmingsHopkins2006" /> It does not affect the [[AMPA receptor|AMPA]] or [[kainate receptor]]s.<ref name="BarashCullen2013" />
==Chemical and physical properties==
{|
|[[Boiling point]]: ||align=right| 50.2°C || (at 101.325 kPa)
|-
|[[Density]]: ||align=right| 1.868 g/cm³|| (at 20°C)
|-
|[[Molecular Weight]]: ||align=right| 197.4 [[unified atomic mass unit|u]]||
|-
|[[Vapor pressure]]: ||align=right| 244 mmHg (32kPa) || (at 20°C)
|-
| ||align=right|288 mmHg (38kPa) || (at 24°C)
|-
|[[Minimum alveolar concentration|MAC]]: ||align=right| 0.75 || vol %
|-
|[[Blood:gas partition coefficient]]: ||align=right|2.3
|-
|Oil:gas partition coefficient: ||align=right|224
|}
Chemically, halothane is an [[alkyl halide]] (not an [[ether]] like many other anesthetics).<ref>{{cite web |url=http://www.drugbank.ca/drugs/DB01159#taxonomy |title=DrugBank: Halothane (DB01159) |date=17 December 2010}}</ref> The structure has one stereocenter, so (''R'')- and (''S'')-[[optical isomer]]s occur.
==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.<ref>{{Ref patent3 | country = US | number = 2921098 | status = granted | title = PROCESS FOR THE PREPARATION OF 1,1,1-TRIFLUORO-2-BROMO-2-CHLOROETHANE | pubdate = 1958-06-30 | gdate =  January 1960 | pridate= 1954-08-20 | inventor = Suckling et al. | assign1= Imperial Chemical Industries | google_patent_id = 6JpaAAAAEBAJ }}</ref>
[[Image:halothane synth.png|650px]]
==Related substances==
Attempts to find anesthetics with less metabolism led to [[halogenated ether]]s such as enflurane and isoflurane. The incidence of [[liver|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. 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.
The main advantage of the more modern agents is lower blood solubility, resulting in faster induction of and recovery from anaesthesia.
==History==
This [[Haloalkane|halogenated hydrocarbon]] was first synthesized by [[Charles Suckling|C. W. Suckling]] of [[Imperial Chemical Industries]] in 1951 and was first used clinically by M. Johnstone in [[Manchester]] in 1956. Halothane became popular as a nonflammable general anasthetic replacing other [[volatile anesthetic]]s such as [[diethyl ether]] and [[cyclopropane]]. Use of the anesthetic was phased out during the 1980s and 1990s as newer anesthetic agents became popular.  Halothane retains some use in [[veterinary medicine|veterinary]] [[surgery]] and in the [[Third World]] because of its lower cost.
Halothane was given to many millions of adult and pediatric patients worldwide from its introduction in 1956 through the 1980s.<ref name="NiedermeyerSilva2005">{{cite book|last1=Niedermeyer|first1=Ernst|last2=Silva|first2=F. H. Lopes da|title=Electroencephalography: Basic Principles, Clinical Applications, and Related Fields|url=http://books.google.com/books?id=tndqYGPHQdEC&pg=PA1156|year=2005|publisher=Lippincott Williams & Wilkins|isbn=978-0-7817-5126-1|page=1156}}</ref> Its properties include cardiac depression at high levels, cardiac sensitization to [[catecholamine]]s such as [[norepinephrine]], and potent bronchial relaxation. Its lack of airway irritation made it a common inhalation induction agent in pediatric anesthesia. Due to its cardiac depressive effect, it was [[Contraindication|contraindicated]] in patients with cardiac failure. Halothane was also contraindicated in patients susceptible to [[cardiac arrhythmia]]s, or in situations related to high catecholamine levels such as [[pheochromocytoma]].
==References==
{{Reflist|2}}
==Further reading==
* Atkinson, Rushman, Lee. ''A Synopsis of Anaesthesia''. 1987.
* Eger, Eisenkraft, Weiskopf. ''The Pharmacology of Inhaled Anesthetics''. 2003.
{{General anesthetics}}
{{GABAAR PAMs}}
{{Glutamatergics}}
{{Glycinergics}}
{{Cholinergics}}
{{Serotonergics}}
[[Category:General anesthetics]]
[[Category:Hepatitis]]
[[Category:World Health Organization essential medicines]]
[[Category:Organobromides]]
[[Category:Organochlorides]]
[[Category:Organofluorides]]
[[Category:5-HT3 agonists]]
[[Category:GABAA receptor positive allosteric modulators]]
[[Category:Glycine receptor agonists]]
[[Category:Nicotinic antagonists]]
[[Category:NMDA receptor antagonists]]

Revision as of 17:12, 7 April 2015

Halothane
File:Halothane.png
Clinical data
AHFS/Drugs.comMicromedex Detailed Consumer Information
ATC code
Pharmacokinetic data
MetabolismHepatic (CYP2E1[1])
ExcretionRenal
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
E number{{#property:P628}}
ECHA InfoCard{{#property:P2566}}Lua error in Module:EditAtWikidata at line 36: attempt to index field 'wikibase' (a nil value).
Chemical and physical data
FormulaC2HBrClF3
Molar mass197.381 g/mol
3D model (JSmol)
  (verify)

Halothane (trademarked as Fluothane) is an inhalational general anesthetic. Its IUPAC name is 2-bromo-2-chloro-1,1,1-trifluoroethane. It is the only inhalational anesthetic containing a bromine atom; several other halogenated anesthesia agents lack the bromine atom and do contain the fluorine and chlorine atoms present in halothane. 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.

It is on the WHO Model List of Essential Medicines, the most important medications needed in a basic health system.[2] Its use in developed countries, however, has been almost entirely superseded by newer inhalational anaesthetic agents such as sevoflurane, isoflurane, and desflurane.

Anesthetic properties

It is a potent anesthetic with a minimum alveolar concentration of 0.74%. Its blood/gas partition coefficient of 2.4 makes it an agent with moderate induction and recovery time. It is not a good analgesic and its muscle relaxation effect is moderate.[3]

Availability

It is available as a volatile liquid, at 30, 50, 200, and 250 ml per container.[4]

Side effects

Repeated exposure to halothane in adults was noted in rare cases to result in severe liver injury. This occurred in about one in 10,000 exposures. The resulting syndrome was referred to as halothane hepatitis, 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%. Concern for hepatitis resulted in a dramatic reduction in the use of halothane for adults. It was replaced in the 1980s by enflurane and isoflurane. By 2005, the common volatile anesthetics in use 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. However, by 2000, sevoflurane had largely replaced the use of halothane in children.

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

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

Pharmacology

Halothane activates GABAA and glycine receptors.[5][6] It also acts as an NMDA receptor antagonist,[6] inhibits nACh and voltage-gated sodium channels,[7][5] and activates 5-HT3 and twin-pore K+ channels.[8][5] It does not affect the AMPA or kainate receptors.[6]

Chemical and physical properties

Boiling point: 50.2°C (at 101.325 kPa)
Density: 1.868 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).[9] The structure has one stereocenter, so (R)- and (S)-optical isomers occur.

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.[10]

File: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. 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.

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

History

This halogenated hydrocarbon was first synthesized by C. W. Suckling of Imperial Chemical Industries in 1951 and was first used clinically by M. Johnstone in Manchester in 1956. Halothane became popular as a nonflammable general anasthetic replacing other volatile anesthetics such as diethyl ether and cyclopropane. Use of the anesthetic was phased out during the 1980s and 1990s as newer anesthetic agents became popular. Halothane retains some use in veterinary surgery and in the Third World because of its lower cost.

Halothane was given to many millions of adult and pediatric patients worldwide from its introduction in 1956 through the 1980s.[11] 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. Due to its cardiac depressive effect, it was contraindicated in patients with cardiac failure. Halothane was also contraindicated in patients susceptible to cardiac arrhythmias, or in situations related to high catecholamine levels such as pheochromocytoma.

References

  1. ↑ DrugBank: DB01159 (Halothane)
  2. ↑ "WHO Model List of EssentialMedicines" (PDF). World Health Organization. October 2013. Retrieved 22 April 2014.
  3. ↑ "Halothane".
  4. ↑ National formulary of India, 4th Ed. New Delhi, India, Indian Pharmacopoeia commission; 2011: 411
  5. ↑ 5.0 5.1 5.2 Hugh C. Hemmings; Philip M. Hopkins (2006). Foundations of Anesthesia: Basic Sciences for Clinical Practice. Elsevier Health Sciences. pp. 292–. ISBN 0-323-03707-0.
  6. ↑ 6.0 6.1 6.2 Paul Barash; Bruce F. Cullen; Robert K. Stoelting (7 February 2013). Clinical Anesthesia, 7e: Print + Ebook with Multimedia. Lippincott Williams & Wilkins. pp. 116–. ISBN 978-1-4698-3027-8. Unknown parameter |coauthors= ignored (help)
  7. ↑ Jürgen Schüttler; Helmut Schwilden (8 January 2008). Modern Anesthetics. Springer Science & Business Media. pp. 70–. ISBN 978-3-540-74806-9.
  8. ↑ Norman G. Bowery (19 June 2006). Allosteric Receptor Modulation in Drug Targeting. CRC Press. pp. 143–. ISBN 978-1-4200-1618-5.
  9. ↑ "DrugBank: Halothane (DB01159)". 17 December 2010.
  10. ↑ 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 
  11. ↑ Niedermeyer, Ernst; Silva, F. H. Lopes da (2005). Electroencephalography: Basic Principles, Clinical Applications, and Related Fields. Lippincott Williams & Wilkins. p. 1156. ISBN 978-0-7817-5126-1.

Further reading

  • Atkinson, Rushman, Lee. A Synopsis of Anaesthesia. 1987.
  • Eger, Eisenkraft, Weiskopf. The Pharmacology of Inhaled Anesthetics. 2003.


Template:General anesthetics Template:GABAAR PAMs

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