General anaesthetic
Pharmaceutical compound
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]
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] 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.[ 7] 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]
Halothane is colour-coded red on anaesthetic vaporisers .[ 17]
Vaporiser used for halothane
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]
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]
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.
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 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] 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.[ 12] [ 13]
References
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Vilazodone
Xaliproden
Yohimbine
Antagonists: Atypical antipsychotics (e.g., iloperidone , risperidone , sertindole )
AV965
Beta blockers (e.g., alprenolol , carteolol , cyanopindolol , iodocyanopindolol , isamoltane , oxprenolol , penbutolol , pindobind , pindolol , propranolol , tertatolol )
BMY-7,378
CSP-2503
Dotarizine
Ergolines (e.g., metergoline )
FCE-24379
Flopropione
GR-46611
Isamoltane
Lecozotan
Mefway
Metitepine (methiothepin)
MIN-117 (WF-516)
MPPF
NAN-190
Robalzotan
S-15535
SB-649,915
SDZ 216-525
Spiperone
Spiramide
Spiroxatrine
UH-301
WAY-100135
WAY-100635
Xylamidine
5-HT1B
Agonists: Anpirtoline
CGS-12066A
CP-93129
CP-94253
CP-122,288
CP-135807
Eltoprazine
Ergolines (e.g., bromocriptine , dihydroergotamine , ergotamine , methylergometrine (methylergonovine) , methysergide , pergolide )
mCPP
RU-24,969
Serotonin (5-HT)
Triptans (e.g., avitriptan , donitriptan , eletriptan , sumatriptan , zolmitriptan )
TFMPP
Tryptamines (e.g., 5-BT , 5-CT , 5-MT , DMT )
Vortioxetine
5-HT1D
Agonists: CP-122,288
CP-135807
CP-286601
Ergolines (e.g., bromocriptine , cabergoline , dihydroergotamine , ergotamine , LSD , methysergide )
GR-46611
L-694247
L-772405
mCPP
PNU-109291
PNU-142633
Serotonin (5-HT)
TGBA01AD
Triptans (e.g., almotriptan , avitriptan , donitriptan , eletriptan , frovatriptan , naratriptan , rizatriptan , sumatriptan , zolmitriptan )
Tryptamines (e.g., 5-BT , 5-CT , 5-Et-DMT , 5-MT , 5-(nonyloxy)tryptamine , DMT )
5-HT1E
5-HT1F
5-HT2
5-HT2A
Agonists: 25H/NB series (e.g., 25I-NBF , 25I-NBMD , 25I-NBOH , 25I-NBOMe , 25B-NBOMe , 25C-NBOMe , 25TFM-NBOMe , 2CBCB-NBOMe , 25CN-NBOH , 2CBFly-NBOMe )
2Cs (e.g., 2C-B , 2C-E , 2C-I , 2C-T-2 , 2C-T-7 , 2C-T-21 )
2C-B-FLY
2CB-Ind
5-Methoxytryptamines (5-MeO-DET , 5-MeO-DiPT , 5-MeO-DMT , 5-MeO-DPT , 5-MT )
α-Alkyltryptamines (e.g., 5-Cl-αMT , 5-Fl-αMT , 5-MeO-αET , 5-MeO-αMT , α-Me-5-HT , αET , αMT )
AL-34662
AL-37350A
Bromo-DragonFLY
Dimemebfe
DMBMPP
DOx (e.g., DOB , DOC , DOI , DOM )
Efavirenz
Ergolines (e.g., 1P-LSD , ALD-52 , bromocriptine , cabergoline , ergine (LSA) , ergometrine (ergonovine) , ergotamine , lisuride , LA-SS-Az , LSB , LSD , LSD-Pip , LSH , LSP , methylergometrine (methylergonovine) , pergolide )
Flumexadol
IHCH-7113
Jimscaline
Lorcaserin
MDxx (e.g., MDA (tenamfetamine) , MDMA (midomafetamine) , MDOH , MMDA )
O-4310
Oxaflozane
PHA-57378
PNU-22394
PNU-181731
RH-34
SCHEMBL5334361
Phenethylamines (e.g., lophophine , mescaline )
Piperazines (e.g., BZP , quipazine , TFMPP )
Serotonin (5-HT)
TCB-2
TFMFly
Tryptamines (e.g., 5-BT , 5-CT , bufotenin , DET , DiPT , DMT , DPT , psilocin , psilocybin , tryptamine )
Antagonists: 5-I-R91150
5-MeO-NBpBrT
AC-90179
Adatanserin
Altanserin
Antihistamines (e.g., cyproheptadine , hydroxyzine , ketotifen , perlapine )
AMDA
Atypical antipsychotics (e.g., amperozide , aripiprazole , asenapine , blonanserin , brexpiprazole , carpipramine , clocapramine , clorotepine , clozapine , fluperlapine , gevotroline , iloperidone , lurasidone , melperone , mosapramine , ocaperidone , olanzapine , paliperidone , quetiapine , risperidone , sertindole , zicronapine , ziprasidone , zotepine )
Chlorprothixene
Cinanserin
CSP-2503
Deramciclane
Dotarizine
Eplivanserin
Ergolines (e.g., amesergide , LY-53857 , LY-215,840 , mesulergine , metergoline , methysergide , sergolexole )
Fananserin
Flibanserin
Glemanserin
Irindalone
Ketanserin
KML-010
Landipirdine
LY-393558
mCPP
Medifoxamine
Metitepine (methiothepin)
MIN-117 (WF-516)
Naftidrofuryl
Nantenine
Nelotanserin
Opiranserin (VVZ-149)
Pelanserin
Phenoxybenzamine
Pimavanserin
Pirenperone
Pizotifen
Pruvanserin
Rauwolscine
Ritanserin
Roluperidone
S-14671
Sarpogrelate
Serotonin antagonists and reuptake inhibitors (e.g., etoperidone , hydroxynefazodone , lubazodone , mepiprazole , nefazodone , triazoledione , trazodone )
SR-46349B
TGBA01AD
Teniloxazine
Temanogrel
Tetracyclic antidepressants (e.g., amoxapine , aptazapine , esmirtazapine , maprotiline , mianserin , mirtazapine )
Tricyclic antidepressants (e.g., amitriptyline )
Typical antipsychotics (e.g., chlorpromazine , fluphenazine , haloperidol , loxapine , perphenazine , pimozide , pipamperone , prochlorperazine , setoperone , spiperone , spiramide , thioridazine , thiothixene , trifluoperazine )
Volinanserin
Xylamidine
Yohimbine
5-HT2B
Agonists: 4-Methylaminorex
Aminorex
Amphetamines (e.g., chlorphentermine , cloforex , dexfenfluramine , fenfluramine , levofenfluramine , norfenfluramine )
BW-723C86
DOx (e.g., DOB , DOC , DOI , DOM )
Ergolines (e.g., cabergoline , dihydroergocryptine , dihydroergotamine , ergotamine , methylergometrine (methylergonovine) , methysergide , pergolide )
Lorcaserin
MDxx (e.g., MDA (tenamfetamine) , MDMA (midomafetamine) , MDOH , MMDA )
Piperazines (e.g., TFMPP )
PNU-22394
Ro60-0175
Serotonin (5-HT)
Tryptamines (e.g., 5-BT , 5-CT , 5-MT , α-Me-5-HT , bufotenin , DET , DiPT , DMT , DPT , psilocin , psilocybin , tryptamine )
Antagonists: Agomelatine
Atypical antipsychotics (e.g., amisulpride , aripiprazole , asenapine , brexpiprazole , cariprazine , clozapine , N-desalkylquetiapine (norquetiapine) , N-desmethylclozapine (norclozapine) , olanzapine , pipamperone , quetiapine , risperidone , ziprasidone )
Cyproheptadine
EGIS-7625
Ergolines (e.g., amesergide , bromocriptine , lisuride , LY-53857 , LY-272015 , mesulergine )
Ketanserin
LY-393558
mCPP
Metadoxine
Metitepine (methiothepin)
Pirenperone
Pizotifen
Propranolol
PRX-08066
Rauwolscine
Ritanserin
RS-127445
Sarpogrelate
SB-200646
SB-204741
SB-206553
SB-215505
SB-221284
SB-228357
SDZ SER-082
Tegaserod
Tetracyclic antidepressants (e.g., amoxapine , mianserin , mirtazapine )
Trazodone
Typical antipsychotics (e.g., chlorpromazine )
TIK-301
Yohimbine
5-HT2C
Agonists: 2Cs (e.g., 2C-B , 2C-E , 2C-I , 2C-T-2 , 2C-T-7 , 2C-T-21 )
5-Methoxytryptamines (5-MeO-DET , 5-MeO-DiPT , 5-MeO-DMT , 5-MeO-DPT , 5-MT )
α-Alkyltryptamines (e.g., 5-Cl-αMT , 5-Fl-αMT , 5-MeO-αET , 5-MeO-αMT , α-Me-5-HT , αET , αMT )
A-372159
AL-38022A
Alstonine
CP-809101
Dimemebfe
DOx (e.g., DOB , DOC , DOI , DOM )
Ergolines (e.g., ALD-52 , cabergoline , dihydroergotamine , ergine (LSA) , ergotamine , lisuride , LA-SS-Az , LSB , LSD , LSD-Pip , LSH , LSP , pergolide )
Flumexadol
Lorcaserin
MDxx (e.g., MDA (tenamfetamine) , MDMA (midomafetamine) , MDOH , MMDA )
MK-212
ORG-12962
ORG-37684
Oxaflozane
PHA-57378
Phenethylamines (e.g., lophophine , mescaline )
Piperazines (e.g., aripiprazole , BZP , mCPP , quipazine , TFMPP )
PNU-22394
PNU-181731
Ro60-0175
Ro60-0213
Serotonin (5-HT)
Tryptamines (e.g., 5-BT , 5-CT , bufotenin , DET , DiPT , DMT , DPT , psilocin , psilocybin , tryptamine )
Vabicaserin
WAY-629
WAY-161503
YM-348
Antagonists: Adatanserin
Agomelatine
Atypical antipsychotics (e.g., asenapine , clorotepine , clozapine , fluperlapine , iloperidone , melperone , olanzapine , paliperidone , quetiapine , risperidone , sertindole , ziprasidone , zotepine )
Captodiame
CEPC
Cinanserin
Cyproheptadine
Deramciclane
Desmetramadol
Dotarizine
Eltoprazine
Ergolines (e.g., amesergide , bromocriptine , LY-53857 , LY-215,840 , mesulergine , metergoline , methysergide , sergolexole )
Etoperidone
Fluoxetine
FR-260010
Irindalone
Ketanserin
Ketotifen
Latrepirdine (dimebolin)
Medifoxamine
Metitepine (methiothepin)
Nefazodone
Pirenperone
Pizotifen
Propranolol
Ritanserin
RS-102221
S-14671
SB-200646
SB-206553
SB-221284
SB-228357
SB-242084
SB-243213
SDZ SER-082
Tedatioxetine
Tetracyclic antidepressants (e.g., amoxapine , aptazapine , esmirtazapine , maprotiline , mianserin , mirtazapine )
TIK-301
Tramadol
Trazodone
Tricyclic antidepressants (e.g., amitriptyline , nortriptyline )
Typical antipsychotics (e.g., chlorpromazine , loxapine , pimozide , pipamperone , thioridazine )
Xylamidine
5-HT3 –7
5-HT3
Agonists: Alcohols (e.g., butanol , ethanol (alcohol) , trichloroethanol )
m-CPBG
Phenylbiguanide
Piperazines (e.g., BZP , mCPP , quipazine )
RS-56812
Serotonin (5-HT)
SR-57227
SR-57227A
Tryptamines (e.g., 2-Me-5-HT , 5-CT , bufotenidine (5-HTQ) )
Volatiles/gases (e.g., halothane , isoflurane , toluene , trichloroethane )
YM-31636
Antagonists: Alosetron
Anpirtoline
Arazasetron
AS-8112
Atypical antipsychotics (e.g., clozapine , olanzapine , quetiapine )
Azasetron
Batanopride
Bemesetron (MDL-72222)
Bupropion
Cilansetron
CSP-2503
Dazopride
Dolasetron
Galanolactone
Granisetron
Hydroxybupropion
Lerisetron
Memantine
Ondansetron
Palonosetron
Ramosetron
Renzapride
Ricasetron
Tedatioxetine
Tetracyclic antidepressants (e.g., amoxapine , mianserin , mirtazapine )
Thujone
Tropanserin
Tropisetron
Typical antipsychotics (e.g., loxapine )
Volatiles/gases (e.g., nitrous oxide , sevoflurane , xenon )
Vortioxetine
Zacopride
Zatosetron
5-HT4
5-HT5A
5-HT6
Agonists: Ergolines (e.g., dihydroergocryptine , dihydroergotamine , ergotamine , lisuride , LSD , mesulergine , metergoline , methysergide )
Hypidone
Serotonin (5-HT)
Tryptamines (e.g., 2-Me-5-HT , 5-BT , 5-CT , 5-MT , Bufotenin , E-6801 , E-6837 , EMD-386088 , EMDT , LY-586713 , N-Me-5-HT , ST-1936 , tryptamine )
WAY-181187
WAY-208466
Antagonists: ABT-354
Atypical antipsychotics (e.g., aripiprazole , asenapine , clorotepine , clozapine , fluperlapine , iloperidone , olanzapine , tiospirone )
AVN-101
AVN-211
AVN-322
AVN-397
BGC20-760
BVT-5182
BVT-74316
Cerlapirdine
EGIS-12,233
GW-742457
Idalopirdine
Ketanserin
Landipirdine
Latrepirdine (dimebolin)
Masupirdine
Metitepine (methiothepin)
MS-245
PRX-07034
Ritanserin
Ro 04-6790
Ro 63-0563
SB-258585
SB-271046
SB-357134
SB-399885
SB-742457
Tetracyclic antidepressants (e.g., amoxapine , mianserin )
Tricyclic antidepressants (e.g., amitriptyline , clomipramine , doxepin , nortriptyline )
Typical antipsychotics (e.g., chlorpromazine , loxapine )
5-HT7
Antagonists: Atypical antipsychotics (e.g., amisulpride , aripiprazole , asenapine , brexpiprazole , clorotepine , clozapine , fluperlapine , olanzapine , risperidone , sertindole , tiospirone , ziprasidone , zotepine )
Butaclamol
DR-4485
EGIS-12,233
Ergolines (e.g., 2-Br-LSD (BOL-148) , amesergide , bromocriptine , cabergoline , dihydroergotamine , ergotamine , LY-53857 , LY-215,840 , mesulergine , metergoline , methysergide , sergolexole )
JNJ-18038683
Ketanserin
LY-215,840
Metitepine (methiothepin)
Ritanserin
SB-258719
SB-258741
SB-269970
SB-656104
SB-656104A
SB-691673
SLV-313
SLV-314
Spiperone
SSR-181507
Tetracyclic antidepressants (e.g., amoxapine , maprotiline , mianserin , mirtazapine )
Tricyclic antidepressants (e.g., amitriptyline , clomipramine , imipramine )
Typical antipsychotics (e.g., acetophenazine , chlorpromazine , chlorprothixene , fluphenazine , loxapine , pimozide )
Vortioxetine