Enflurane

(BAN, USAN, rINN)
Enflurane Chemical formula
Synonyms: Anaesthetic Compound No. 347; Compound 347; Enfluraani; Enfluran; Enflurano; Enfluranum; Methylflurether; NSC-115944. 2-Chloro-1,1,2-trifluoroethyl difluoromethyl ether; 2-Chloro-1
Cyrillic synonym: Энфлуран.

💊 Chemical information

Chemical formula: C3H2ClF5O = 184.5.
CAS — 13838-16-9.
ATC — N01AB04.
ATC Vet — QN01AB04.

Pharmacopoeias.

In Jpn and US.

USP 31

(Enflurane). A clear colourless volatile liquid having a mild sweet odour. Non-flammable. Distilling range 55.5° to 57.5°. Slightly soluble in water; miscible with organic solvents, with fats, and with oils. Store in airtight containers at a temperature not exceeding 40°. Protect from light.

💊 Adverse Effects

As with other halogenated anaesthetics, respiratory depression, hypotension, and arrhythmias have been reported although the incidence of arrhythmias is lower with enflurane than with halothane. It sensitises the myocardium to sympathomimetics to a lesser extent than halothane. Compared with halothane, enflurane has a stimulant effect on the CNS and convulsions may occur when concentrations of enflurane are high or hypocapnia is present. Malignant hyperthermia has also been reported. Asthma and bronchospasm may occur. There have been reports of elevated serum-fluoride concentrations although resulting renal damage appears to be rare. There have been changes in measurements of hepatic enzymes and a number of reports of liver damage. Shivering, nausea, and vomiting have been reported in the postoperative period. See also Adverse Effects of General Anaesthetics.

Effects on the blood.

The development of carboxyhaemoglobinaemia in patients anaesthetised with volatile anaesthetics is discussed under Precautions, below.

Effects on the kidneys.

The nephrotoxicity of volatile anaesthetics has been reviewed.1 Although enflurane released inorganic fluoride it appeared to be safe in patients with normal renal function. It had also been given to patients with mild to moderate renal impairment without any further deterioration. There was an increase in serum-fluoride concentrations when enflurane was given to a group of patients who had been receiving isoniazid, but there was no change in kidney function. Pretreatment of patients with a single dose of disulfiram before anaesthesia was found to produce a consistent and almost complete inhibition of enflurane metabolism as shown by substantial reductions in plasma-fluoride concentrations and urinary excretion of fluoride.2
1. Mazze RI. Nephrotoxicity of fluorinated anaesthetic agents. Clin Anaesthesiol 1983; 1: 469–83
2. Kharasch ED, et al. Clinical enflurane metabolism by cytochrome P450 2E1. Clin Pharmacol Ther 1994; 55: 434–40.

Effects on the liver.

A review1 of 58 cases of suspected enflurane hepatitis considered enflurane to be the likely cause of the liver damage in 24. There was biochemical evidence of liver damage in 23 of these cases. Histology reports were available for 15 patients and all showed some degree of hepatocellular necrosis and degeneration. While the incidence of liver damage from enflurane seemed to be lower than from halothane, the character of the injury was similar. Another review2 of the same cases plus an additional 30 (88 in all) came to different conclusions; the main author was a consultant to the manufacturer of enflurane. Of the 88 patients with suspected enflurane hepatitis, 30 were rejected because of insufficient evidence and 43 were considered to have other factors known to produce liver injury. This left 15 possible cases of enflurane hepatitis compared with the 24 identified by the first review. While agreeing that in the rare patient unexplained liver damage follows enflurane anaesthesia, it was considered that the incidence was too small to suggest an association. No consistent histological pattern was identified in this study. See also under Adverse Effects in Halothane.
1. Lewis JH, et al. Enflurane hepatotoxicity: a clinicopathologic study of 24 cases. Ann Intern Med 1983; 98: 984–92
2. Eger EI, et al. Is enflurane hepatotoxic? Anesth Analg 1986; 65: 21–30.

Effects on respiration.

Overall, enflurane is considered to produce more respiratory depression than halothane or isoflurane.1,2
1. Quail AW. Modern inhalation anaesthetic agents: a review of halothane, isoflurane and enflurane. Med J Aust 1989; 150: 95–102
2. Merrett KL, Jones RM. Inhalational anaesthetic agents. Br J Hosp Med 1994; 52: 260–3.

💊 Precautions

Enflurane should be used with caution in patients with convulsive disorders. High concentrations of enflurane may cause uterine relaxation. In order to minimise the risk of developing elevated carboxyhaemoglobin levels, carbon dioxide absorbents in anaesthetic apparatus should not be allowed to dry out when delivering volatile anaesthetics such as enflurane. As with other halogenated anaesthetics, patients with known or suspected susceptibility to malignant hyperthermia should not be anaesthetised with enflurane. See also Precautions for General Anaesthetics.

Abuse.

Report1 of a fatality in a 29-year-old student nurse anaesthetist who had applied enflurane to the herpes simplex lesions of her lower lip. She was found with an empty 250 mL bottle of enflurane.
1. Lingenfelter RW. Fatal misuse of enflurane. Anesthesiology 1981; 55: 603.

Carbon dioxide absorbents.

Significant carboxyhaemoglobinaemia may develop rarely during anaesthesia with volatile anaesthetics given by circle breathing systems containing carbon dioxide absorbents.1 The effect is only seen when the absorbent has become excessively dried out. The use of barium hydroxide lime (which is not available in the UK) as an absorbent produces more carbon monoxide than soda lime, particularly at low water content. No cases of this complication had been reported to date in the UK.
1. CSM/MCA. Safety issues in anaesthesia: volatile anaesthetic agents and carboxyhaemoglobinaemia. 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)

Porphyria.

Enflurane is considered to be unsafe in patients with porphyria because it has been shown to be porphyrinogenic in animals.

💊 Interactions

Care is advised if adrenaline or other sympathomimetics are given to patients during enflurane anaesthesia. The effects of competitive neuromuscular blockers such as atracurium are enhanced by enflurane. See also Interactions of General Anaesthetics.

Antibacterials.

For the effects of isoniazid on enflurane defluorination, see Effects on the Kidneys under Adverse Effects, above.

Antidepressants.

It appeared likely that the enflurane-induced seizure activity seen in 2 patients could have been enhanced by amitriptyline.1 It may be advisable to avoid the use of enflurane in patients requiring tricyclic antidepressants, especially when the patient has a history of seizures or when hyperventilation or high enflurane concentrations are a desired part of the anaesthetic technique.
1. Sprague DH, Wolf S. Enflurane seizures in patients taking amitriptyline. Anesth Analg 1982; 61: 67–8.

Disulfiram.

For the effect of disulfiram on the metabolism of enflurane, see Effects on the Kidneys under Adverse Effects, above.

💊 Pharmacokinetics

Enflurane is absorbed on inhalation. The blood/gas partition coefficient is low. It is mostly excreted unchanged through the lungs. Up to 10% of inhaled administered enflurane is metabolised in the liver, mainly to inorganic fluoride.
1. Bengtson JP, et al. Uptake of enflurane and isoflurane during spontaneous and controlled ventilation. Anaesth Intensive Care 1992; 20: 191–5
2. Devchand D, et al. The uptake of enflurane during anaesthesia. Anaesthesia 1995; 50: 491–5.

💊 Uses and Administration

Enflurane is a volatile halogenated anaesthetic given by inhalation. It is an isomer of isoflurane. It has anaesthetic actions similar to those of halothane. Enflurane has a minimum alveolar concentration (MAC) value ranging from 1.7% in middle age to 2.5% in children. Enflurane is given using a calibrated vaporiser for induction and maintenance of general anaesthesia; it is also used in subanaesthetic doses to provide analgesia in obstetrics and other painful procedures (below). To avoid CNS excitement a short-acting barbiturate or other intravenous induction agent is recommended before the inhalation of enflurane. Anaesthesia may be induced using enflurane alone with oxygen or in nitrous oxide-oxygen mixtures. In general, enflurane concentrations of 2 to 4.5% v/v produce surgical anaesthesia in 7 to 10 minutes. Anaesthesia may be maintained with a concentration of 0.5 to 3% v/v of enflurane; a concentration of 3% v/v should not be exceeded during spontaneous respiration. Although enflurane is reported to possess muscle relaxant properties, neuromuscular blockers may nevertheless be required. Postoperative analgesia may be necessary. Concentrations of 0.25 to 1% v/v of enflurane are used to provide analgesia for vaginal delivery during childbirth and of 0.5 to 1% v/v to supplement other general anaesthetics during caesarean section.

Pain.

Enflurane is used in subanaesthetic doses to provide analgesia in obstetrics and other painful procedures although a study1was unable to confirm that it had an analgesic effect at subanaesthetic concentrations.
1. Tomi K, et al. Alterations in pain threshold and psychomotor response associated with subanaesthetic concentrations of inhalation anaesthetics in humans. Br J Anaesth 1993; 70: 684–6.

💊 Preparations

Proprietary Preparations

Arg.: Enforan; Inhelthran†; Austral.: Ethrane†; Austria: Ethrane; Braz.: Enfluthane; Etrane; Denm.: Efrane†; Fin.: Efrane†; Ger.: Ethrane†; Indon.: Ethrane; Irl.: Ethrane; Israel: Alyrane; Ethrane; Ital.: Ethrane†; Mex.: Enfran; Ethrane; Neth.: Ethrane†; NZ: Ethrane†; Philipp.: Alyrane; Ethrane; Rus.: Ethrane (Этран)†; S.Afr.: Ethrane; Swed.: Efrane†; Switz.: Ethrane†; Turk.: Ethrane; UK: Alyrane†; USA: Ethrane; Venez.: Ethrane.
Published October 18, 2018.