Halothane

(BAN, rINN)
Halothane Chemical formula
Synonyms: Alotano; Halotaani; Halotán; Halotan; Halotanas; Halotano; Halothan; Halothanum; Phthorothanum. (RS)-2-Bromo-2-chloro1,1,1-trifluoroethane.
Cyrillic synonym: Галотан.

💊 Chemical information

CHBrCl.CF3 = 197.4.
CAS — 151-67-7.
ATC — N01AB01.
ATC Vet — QN01AB01.

Pharmacopoeias.

In Chin., Eur., Int., Jpn, and US.

Ph. Eur. 6.2

(Halothane). A clear, colourless, mobile, dense, non-flammable liquid. Distillation range 49° to 51°. Slightly soluble in water; miscible with dehydrated alcohol and with trichloroethylene. Halothane contains 0.01% w/w of thymol. Store at a temperature not greater than 25° in airtight containers. Protect from light.

USP 31

(Halothane). A colourless, mobile, non-flammable, heavy liquid having a characteristic odour resembling that of chloroform. It contains not less than 0.008% and not more than 0.012% of thymol, by weight, as a stabiliser. It should contain not more than 0.03% of water. Distillation range 49° to 51°. Slightly soluble in water; miscible with alcohol, with chloroform, with ether, and with fixed oils. Store in airtight containers at a temperature not greater than 40°. Protect from light. Dispense only in the original container.

Incompatibility.

In the presence of moisture, halothane reacts with many metals. Rubber and some plastics deteriorate when in contact with halothane vapour or liquid.

Stability.

Halothane contains 0.01% w/w of thymol as a stabiliser; some commercial preparations may also contain up to 0.00025% w/w of ammonia. Thymol does not volatilise with halothane and therefore accumulates in the vaporiser. It may give a yellow colour to any remaining liquid; halothane that has discoloured should be discarded.

💊 Adverse Effects

As with other halogenated anaesthetics, halothane has a depressant action on the cardiovascular system and reduces blood pressure; signs of overdosage are bradycardia and profound hypotension. It is also a respiratory depressant and can cause cardiac arrhythmias; there have been instances of cardiac arrest. The sensitivity of the heart to sympathomimetic amines is increased. Adverse effects on the liver have limited its use in recent years (see below); these effects range from liver dysfunction to fatal hepatitis and necrosis and are more frequent following repeated use. Halothane can produce nausea, vomiting, and shivering. Malignant hyperthermia has been reported. See also Adverse Effects of General Anaesthetics.

Effects on the cardiovascular system.

The incidence of cardiac arrhythmias is higher with halothane than with enflurane or isoflurane; also the arrhythmogenic threshold with injected adrenaline is lower with halothane than isoflurane or enflurane. Arrhythmias are considered to be very common in children anaesthetised with halothane and in the UK it is recommended that it should not be used for dental procedures outside hospital in those under 18 years old.

Effects on the kidneys.

Renal failure has been reported after halothane anaesthesia,1,2 sometimes with concurrent liver failure.2
1. Cotton JR, et al. Acute renal failure following halothane anesthesia. Arch Pathol Lab Med 1976; 100: 628–9
2. Gelman ML, Lichtenstein NS. Halothane-induced nephrotoxicity. Urology 1981; 17: 323–7.

Effects on the liver.

Liver damage has been recognised as an adverse effect of halothane for many years.1-3 It may be severe, and associated with a high mortality. Two types of hepatotoxicity are recognised; in type I there is a minor disturbance in liver function shown by increases in liver enzyme values; this may occur in up to 30% of patients given halothane,4 or more if activity is measured by glutathione Stransferase rather than serum aminotransferase.5 Subsequent reexposure to halothane is not necessarily associated with liver damage.2,6 Type II hepatotoxicity, which is rarer, involves massive liver cell necrosis; reported incidences2 range from 1 in 2500 to 1 in 36 000. Type II liver toxicity is characterised by several clinical features: non-specific gastrointestinal upset, delayed pyrexia, jaundice, eosinophilia, serum autoantibodies, rash, and arthralgia.1,3 Biochemical tests of liver function show changes typical of hepatocellular damage; histological features are typified by centrilobular necrosis.1 Several risk factors for development of serious toxicity have become apparent;1-3 they include repeated exposure, previous adverse reactions to halothane (jaundice, pyrexia), female gender, obesity, middle age, genetic predisposition, enzyme induction, and a history of drug allergy. The causes of halothane hepatotoxicity have been debated. Type I reactions may result from toxic products of halothane metabolism, possibly influenced by genetic factors or from an imbalance between hepatic oxygen supply and demand. Changes in cellular calcium homoeostasis may also be involved. Type II reactions are most likely immune-mediated.1,2 It has been suggested4 that metabolism of halothane produces a reactive metabolite which binds covalently to proteins in the endoplasmic reticulum of hepatocytes. In susceptible patients it is believed that these metabolite-modified proteins provoke an immune response which is responsible for the liver damage. Findings7,8have implicated the cytochrome P450 isoenzyme CYP2E1 as having a major role in the metabolism of halothane and patients with high levels of this isoenzyme may be predisposed to developing immune-medicated liver damage after halothane exposure. The UK CSM,9 after receiving 84 further reports of hepatotoxicity between 1978 and 1985, issued the following guidelines on precautions to be taken before using halothane:
a careful anaesthetic history should be taken to determine previous exposure and previous reactions to halothane
repeated exposure to halothane within a period of at least 3 months should be avoided unless there are overriding clinical circumstances. An opinion has been expressed that the 3month interval between exposures would be unlikely to prevent hepatotoxicity2
a history of unexplained jaundice or pyrexia in a patient following exposure to halothane is an absolute contra-indication to its future use in that patient These guidelines were reiterated in 1997 after the CSM were notified of a further 15 cases of acute liver failure all requiring transplantation.10 The problem of patients sensitised to halothane who require subsequent anaesthesia with a volatile anaesthetic has been discussed.4 Although the incidence of hepatotoxicity produced by enflurane appears to be less than with halothane it is of a similar nature and there have been reports of several patients who apparently had cross-sensitivity to both. Hepatotoxicity with isoflurane appears to be rare and it was suggested that for the majority of patients sensitised to halothane, isoflurane would be likely to be free from hepatotoxic effects. However, there has been a report11 of a patient who had had two previous exposures to isoflurane and subsequently developed liver function abnormalities after receiving halothane. Hepatotoxicity with desflurane might also be associated with sensitisation to halothane.
1. Ray DC, Drummond GB. Halothane hepatitis. Br J Anaesth 1991; 67: 84–99
2. Neuberger JM. Halothane and hepatitis: incidence, predisposing factors and exposure guidelines. Drug Safety 1990; 5: 28–38
3. Rosenak D, et al. Halothane and liver damage. Postgrad Med J 1989; 65: 129–35
4. Kenna JG, Neuberger JM. Immunopathogenesis and treatment of halothane hepatitis. Clin Immunother 1995; 3: 108–24.
5. Allan LG, et al. Hepatic glutathione S-transferase release after halothane anaesthesia: open randomised comparison with isoflurane. Lancet 1987; i: 771–4
6. Neuberger J, Williams R. Halothane anaesthesia and liver damage. BMJ 1984; 289: 1136–9
7. Kharasch ED, et al. Identification of the enzyme responsible for oxidative halothane metabolism: implications for prevention of halothane hepatitis. Lancet 1996; 347: 1367–71
8. Kenna JC, et al. Formation of the C[F] CO-protein antigens implicated in the pathogenesis of halothane hepatitis is catalyzed in human liver microsomes in vitro by CYP 2E1. Br J Clin Pharmacol 1997; 43: 209
9. CSM. Halothane hepatotoxicity. Current Problems 18 1986. Also available at: http://www.mhra.gov.uk/home/idcplg? IdcService=GET_FILE&dDocName=CON2024425& RevisionSelectionMethod=LatestReleased (accessed 25/07/08
10. CSM/MCA. Safety issues in anaesthesia: reminder: hepatotoxicity with halothane. Current Problems 1997; 23: 7. Also available at: http://www.mhra.gov.uk/home/idcplg?IdcService=GET_FILE& dDocName=CON2023230&RevisionSelectionMethod= LatestReleased (accessed 16/05/06
11. Slayter KL, et al. Halothane hepatitis in a renal transplant patient previously exposed to isoflurane. Ann Pharmacother 1993; 27: 101.

💊 Precautions

The risk of halothane hepatitis led the UK CSM to issue guidelines on its use (see Effects on the Liver, under Adverse Effects, above). It is also recommended that patients be informed of any reactions and that this be done in addition to the updating of the patients’ medical records. It is recommended in the UK that halothane should not be used for dental procedures outside hospital in patients under 18 years old. Halothane reduces uterine muscle tone during pregnancy and generally its use is not recommended in obstetrics because of the increased risk of postpartum haemorrhage. Premedication with atropine has been recommended to reduce vagal tone and to prevent bradycardia and severe hypotension. Allowance may need to be made for any increase in CSF pressure or in cerebral blood flow. Halothane should be used with caution in patients with phaeochromocytoma. As with other halogenated anaesthetics, patients with known or suspected susceptibility to malignant hyperthermia should not be anaesthetised with halothane. See also Precautions for General Anaesthetics.

Abuse.

A brief review1 of abuse of volatile anaesthetics found that of 14 patients who had ingested or sniffed halothane 10 had died. Another patient who had injected halothane intravenously also died. There has also been another report2 of fatalities resulting from acute pulmonary oedema after intravenous injection of halothane.
1. Yamashita M, et al. Illicit use of modern volatile anaesthetics. Can Anaesth Soc J 1984; 31: 76–9
2. Berman P, Tattersal M. Self-poisoning with intravenous halothane. Lancet 1982; i: 340.

Breast feeding.

No adverse effects have been seen in breastfed infants whose mothers were receiving halothane, and the American Academy of Pediatrics1 considers that it is therefore usually compatible with breast feeding. Trace amounts of halothane have been detected in the breast milk of an anaesthetist exposed to environmental halothane in the operating theatre.2
1. American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 2001; 108: 776–89. Correction. ibid.; 1029. Also available at: http://aappolicy.aappublications.org/cgi/content/full/ pediatrics%3b108/3/776 (accessed 25/05/04
2. Coté CJ, et al. Trace concentrations of halothane in human breast milk. Br J Anaesth 1976; 48: 541–3.

Porphyria.

Halothane has been associated with acute attacks of porphyria and is considered unsafe in porphyric patients.

💊 Interactions

Adrenaline and most other sympathomimetics, and theophylline should be avoided during halothane anaesthesia since they can produce cardiac arrhythmias; the risk of arrhythmias is also increased if halothane is used in patients receiving dopaminergics. The effects of competitive neuromuscular blockers such as atracurium, and of ganglion blockers such as trimetaphan are enhanced by halothane and if required they should be given in reduced dosage. Morphine increases the depressant effects of halothane on respiration. Chlorpromazine also enhances the respiratory depressant effect of halothane. The effects of both ergometrine and oxytocin on the parturient uterus are diminished by halothane. See also Interactions of General Anaesthetics.

Antiepileptics.

For a case of phenytoin intoxication associated with halothane anaesthesia.

Benzodiazepines.

Midazolam has been reported to potentiate the anaesthetic action of halothane.1
1. Inagaki Y, et al. Anesthetic interaction between midazolam and halothane in humans. Anesth Analg 1993; 76: 613–17.

General anaesthetics.

For a report that halothane increases serum concentrations of propofol.

Neuromuscular blockers.

For the potentiation of the neuromuscular blockade of neuromuscular blockers such as atracurium by halothane.

Trichloroethane.

A report1 of 2 patients showing evidence of chronic cardiac toxicity after repeated exposure to trichloroethane. In both cases there was circumstantial evidence of a deterioration after routine anaesthetic use of halothane.
1. McLeod AA, et al. Chronic cardiac toxicity after inhalation of 1,1,1-trichloroethane. BMJ 1987; 294: 727–9.

Xanthines.

For references to increased cardiotoxicity when patients taking theophylline were anaesthetised with halothane.

💊 Pharmacokinetics

Halothane is absorbed on inhalation. It has a relatively low solubility in blood and is more soluble in the neutral fats of adipose tissue than in the phospholipids of brain cells. Up to 80% of inhaled halothane is excreted unchanged through the lungs. Up to 20% is metabolised by the liver by oxidative and, under hypoxic conditions, reductive pathways. Urinary metabolites include trifluoroacetic acid and bromide and chloride salts (oxidative pathway) and fluoride salts (reductive pathway). Halothane diffuses across the placenta and has been detected in breast milk.

💊 Uses and Administration

Halothane is a volatile halogenated anaesthetic given by inhalation. It has a minimum alveolar concentration (MAC) value ranging from 0.64% in the elderly to 1.08% in infants. It is non-flammable and is not explosive when mixed with oxygen at normal atmospheric pressure. It is not irritant to the skin and mucous membranes and does not produce necrosis when spilt on tissues. It suppresses salivary, bronchial, and gastric secretions and dilates the bronchioles. However, its use has diminished due to the risk of hepatotoxicity; in the UK, it is only available on a named-patient basis and in other countries, such as the USA, it has been withdrawn from the market. Halothane is used for the induction and maintenance of general anaesthesia and is given using a calibrated vaporiser to provide close control over the concentration of inhaled vapour. Anaesthesia may be induced with 2 to 4% v/v of halothane in oxygen or mixtures of nitrous oxide and oxygen; induction may also be started at a concentration of 0.5% v/v and increased gradually to the required level. For induction in children a concentration of 1.5 to 2% v/v has been used. It takes up to about 5 minutes to attain surgical anaesthesia and halothane produces little or no excitement in the induction period. The more usual practice is to induce anaesthesia with an intravenous agent. Anaesthesia is maintained with concentrations of 0.5 to 2% v/v depending on the flow rate used; the lower concentration is usually suitable for the elderly. Adequate muscle relaxation is only achieved with deep anaesthesia so a neuromuscular blocker is given to increase muscular relaxation if necessary.

💊 Preparations

Proprietary Preparations

Arg.: Ineltano; Austral.: Fluothane; Austria: Fluothane†; Braz.: Fluothane; Chile: Fluothane†; Cz.: Narcotan; Fr.: Fluothane†; Ger.: Fluothane†; Gr.: Fluothane†; Hung.: Narcotan; India: Fluothane; Indon.: Fluothane; Israel: Fluothane†; Malaysia: Fluothane†; NZ: Fluothane; Pol.: Narcotan; S.Afr.: Fluothane†; Spain: Fluothane; Swed.: Fluothane†; Turk.: Fluothane; USA: Fluothane†.
Published October 22, 2018.