Inhalation/Respiratory Induction and maintenance of general anaesthesia
Adult: Individualise dosing according to the surgical requirements, patient response, and use of adjunctive agents. Induction: 2-4.5% v/v with oxygen or in oxygen-nitrous oxide mixtures. Maintenance: 0.5-3% v/v. Max: 3% v/v. Doses are administered via calibrated vaporiser. Selection and use of premedication are based on patient’s need and the discretion of anaesthetist.
Inhalation/Respiratory Obstetric analgesia
Adult: Individualise dosing according to the surgical requirements, patient response, and use of adjunctive agents. To provide analgesia for vaginal delivery during childbirth: 0.25-1% v/v. To supplement other general anaesthetics during caesarean section: 0.5-1% v/v. Doses are administered via calibrated vaporiser. Selection and use of premedication are based on patient’s need and the discretion of anaesthetist.
Special Patient Group
Pharmacogenomics:
Enflurane is identified as a triggering agent of malignant hyperthermia (MH). Individuals with malignant hyperthermia susceptibility (MHS) or those carrying certain genetic variants of ryanodine receptor isoform 1 gene (RYR1) and CACNA1S genes are predisposed to potentially fatal hypermetabolic reactions triggered by potent volatile anaesthetics like enflurane. The prevalence of MHS genetic trait is estimated to be between 1/2,000 and 1/3,000, and approx 70% of individuals with MHS have the RYR1 pathogenic variants as the primary pharmacogenetic trait, while approx 1% of patients with MHS have the CACNA1S pathogenic variants.
The European Malignant Hyperthermia Group (EMHG) consortium has identified the 50-MH causative variants in RYR1 or CACNA1S genes that are considered as diagnostic mutations. Clinical Pharmacogenetics Implementation Consortium (CPIC) recommends performing genetic testing and considering the personal family history of individuals in relation to malignant hyperthermia prior to treatment initiation.
Malignant hyperthermia susceptible (MHS)
Patients who are heterozygous for or carriers of at least 1 of the 50 identified RYR1 or CACNA1S MH-causative variant (refer to the detailed CPIC guideline for the list of causative variants). These individuals have increased risk of developing malignant hyperthermia if administered with enflurane.
Recommendation:
Enflurane is relatively contraindicated in these patients, except in instances where the benefits outweigh the risks. CPIC recommends the use of alternative agents such as regional anaesthesia (e.g. neuraxial, peripheral nerve block or local anaesthesia), or non-triggering agent general anaesthesia.
Uncertain susceptibility
Patients who are negative for RYR1 or CACNA1S MH-causative variant. Negative or inconclusive results do not eliminate the risk of susceptibility to malignant hyperthermia.
Recommendation:
CPIC recommends assessing the individual’s clinical findings, family history and other laboratory data, and perform further genetic testing to guide the use of enflurane.
Contraindications
Known or suspected genetic susceptibility to malignant hyperthermia (e.g. presence of RYR1 or CACNA1S pathogenic variants); seizure disorders, head trauma, pre-existing increased intracranial pressure or mass; liver disease (e.g. biliary tract disease, jaundice, hepatic damage) after previous enflurane or other inhalational anaesthetic use.
Special Precautions
Patient with cardiac disease or with risk factors for QT prolongation (e.g. hypertension, congenital long QT syndrome, heart failure, MI, bradycardia, cardiac arrhythmias, coronary artery disease, hypomagnesaemia, hypokalaemia, hypocalcaemia, diabetes mellitus, thyroid disease, malnutrition, alcoholism); neuromuscular disease (e.g. Duchenne muscular dystrophy), myasthenia gravis, more susceptible to cortical stimulation. Renal and hepatic impairment. Elderly. Pregnancy and lactation.
Adverse Reactions
Significant: QT prolongation with risk of ventricular tachycardia and torsade de pointes, uterine relaxation (high concentration), post-anaesthesia emergence delirium or agitation. Rarely, hepatotoxicity (e.g. jaundice, hepatic necrosis or failure). Blood and lymphatic system disorders: Leukocytosis. Cardiac disorders: Arrhythmia. Gastrointestinal disorders: Nausea, vomiting, hypersalivation. Investigations: Elevated WBC count and serum fluoride concentrations; increased serum transaminase. Musculoskeletal and connective tissue disorders: Shivering. Nervous system disorders: Convulsions (high concentration). Respiratory, thoracic and mediastinal disorders: Hypoxia, bronchospasm, respiratory depression. Vascular disorders: Hypotension. Potentially Fatal: Rarely, malignant hyperthermia, and perioperative hyperkalaemia resulting in cardiac arrhythmias (children).
Patient Counseling Information
This drug may impair your mental cognition for some time after administration, if affected, do not drive or operate machinery.
May increase the risk of perioperative hyperkalaemia with succinylcholine. May produce ventricular arrhythmias or hypertension with epinephrine. May increase the risk of QT prolongation with agents that cause electrolyte imbalance or those known to prolong QT interval. May enhance the effects of competitive neuromuscular blockers (e.g. atracurium). May increase the metabolism and risk of hepatotoxicity with isoniazid. May enhance hypotensive effects with MAOIs. May cause carboxyhaemoglobinaemia with desiccated CO2 absorbents in anaesthetic circle breathing systems.
Action
Description: Mechanism of Action: Enflurane is a volatile, halogenated, and inhaled general anaesthetic. The exact mechanism is not yet known; however, it appears to likely affect the lipid matrix of nerve cell membranes in the brain. It may cause local disordering of the lipid membrane matrix and may decrease the molecules that simultaneously alternate between gel and crystalline states, thereby altering the membrane function. Pharmacokinetics: Absorption: Readily absorbed on inhalation. Blood/gas partition coefficient: 1.91. Distribution: Crosses the placenta. Metabolism: Metabolised in the liver (approx 2-10%) by CYP2E1 isoenzyme to form inorganic fluoride. Excretion: Mainly via exhaled gases (80% as unchanged drug).
Chemical Structure
Enflurane_01 Source: National Center for Biotechnology Information. PubChem Database. Enflurane, CID=3226, https://pubchem.ncbi.nlm.nih.gov/compound/3226 (accessed on June 25, 2020)
N01AB04 - enflurane ; Belongs to the class of halogenated hydrocarbons. Used as general anesthetics.
References
Gonsalves SG, Dirksen RT, Sangkuhl K et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for the Use of Potent Volatile Anesthetic Agents and Succinylcholine in the Context of RYR1 or
CACNA1S Genotypes. CPIC Guideline. 2019 Jun;105(6):1338-1344. doi: 10.1002/cpt.1319. Accessed 07/05/2020Annotation of CPIC Guideline for Desflurane, Enflurane, Halothane, Isoflurane, Methoxyflurane, Sevoflurane, Succinylcholine and CACNA1S, RYR1. Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org/. Accessed 07/05/2020.Annotation of FDA Label for Enflurane and CACNA1S, RYR1. Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org/. Accessed 07/05/2020.Anon. CACNA1S - Enflurane. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 07/05/2020.Anon. RYR1 - Enflurane. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 07/05/2020.Buckingham R (ed). Enflurane. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 07/05/2020.Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for the Use of Potent Volatile Anesthetic Agents and Succinylcholine in the Context of RYR1 or CACNA1S Genotypes. Clinical Pharmacogenetics Implementation Consortium (CPIC). https://cpicpgx.org. Accessed 07/05/2020.Enflurane. Gold Standard Drug Database in ClinicalKey [online]. Elsevier Inc. https://www.clinicalkey.com/. Accessed 07/05/2020.Ethrane (Baxter Healthcare Corporation). U.S. FDA. https://www.fda.gov/. Accessed 07/05/2020.
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