Identification

Name
Enflurane
Accession Number
DB00228  (APRD00234)
Type
Small Molecule
Groups
Approved, Investigational, Vet approved
Description

An extremely stable inhalation anesthetic that allows rapid adjustments of anesthesia depth with little change in pulse or respiratory rate. [PubChem]

Structure
Thumb
Synonyms
  • 2-chloro-1,1,2-trifluoroethyl difluoromethyl ether
  • Alyrane
  • Efrane
  • Enflurane
  • Enflurano
  • Enfluranum
  • Methylflurether
External IDs
Anesthetic 347
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
EnfluraneLiquid99.9 %Respiratory (inhalation)Abbvie1993-12-312012-11-02Canada
EthraneLiquid125 mL/125mLRespiratory (inhalation)Baxter Laboratories1972-08-282012-12-01Us
Ethrane Liq InhLiquid100 %Respiratory (inhalation)Ohmeda Pharmaceutical Products, Division Of Boc Canada Limited1996-09-181997-08-25Canada
Ethrane Liquid InhLiquid100 %Respiratory (inhalation)Baxter Laboratories1997-02-202004-08-05Canada
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
EnfluraneLiquid1 mL/1mLRespiratory (inhalation)Piramal Critical Care Inc1994-07-292014-09-28Us
International/Other Brands
Alyrane (Baxter) / Compound 347 (Dexa Medica) / Endurane (Singapore Pharmawealth Lifesciences) / Enfluran (Cristália) / Ethrane (Abbott)
Categories
UNII
91I69L5AY5
CAS number
13838-16-9
Weight
Average: 184.492
Monoisotopic: 183.971433418
Chemical Formula
C3H2ClF5O
InChI Key
JPGQOUSTVILISH-UHFFFAOYSA-N
InChI
InChI=1S/C3H2ClF5O/c4-1(5)3(8,9)10-2(6)7/h1-2H
IUPAC Name
2-chloro-1-(difluoromethoxy)-1,1,2-trifluoroethane
SMILES
FC(F)OC(F)(F)C(F)Cl

Pharmacology

Indication

Used for the induction and maintenance of general anaesthesia during surgery and cesarean section and also used for analgesia during vaginal delivery.

Pharmacodynamics

Enflurane is an extremely stable halogenated ether inhalation anesthetic that allows rapid adjustments of anesthesia depth with little change in pulse or respiratory rate. Enflurane induces muscle relaxation and reduces pains sensitivity by altering tissue excitability. Induction of and recovery from anesthesia with enflurane are rapid. Enflurane may provide a mild stimulus to salivation or tracheobronchial secretions. Pharyngeal and laryngeal reflexes are readily obtunded. In the cardiovascular system, enflurane is a mild negative inotrope, causing a marked decrease in systemic vascular resistance, thus leading to a decrease in mean arterial pressure. This results in a reflex tachycardia. Enflurane also decreases coronary vascular resistance and sensitizes the myocardium to circulating catecholamines. Enflurane is a strong respiratory depressant. It decreases tidal volume but may increase respiratory rate. It also causes bronchodilatationa and inhibits pulmonary macrophage activity and mucociliary activity. Enflurane principle action in the CNS is general anaesthesia with little analgesic effect. It causes increased cerebral blood flow in concentrations and may induce tonic/clonic muscle activity and epileptiform EEG traces. It also causes a marked decrease in skeletal muscle tone. Actions in the genitourinary system include a decreased renal blood flow and glomerular filtration rate and the tone of pregnant uterus is decreased.

Mechanism of action

Enflurane induces a reduction in junctional conductance by decreasing gap junction channel opening times and increasing gap junction channel closing times. Enflurane also activates calcium dependent ATPase in the sarcoplasmic reticulum by increasing the fluidity of the lipid membrane. It also appears to bind the D subunit of ATP synthase and NADH dehydogenase. Enflurane also binds to and angonizes the GABA receptor, the large conductance Ca2+ activated potassium channel, the glycine receptor, and antagonizes the glutamate receptor receptor. These yield a decreased depolarization and therefore, tissue excitability which results in anesthesia.

TargetActionsOrganism
AGABA-A receptor (anion channel)
positive allosteric modulator
Human
AGlycine receptor (alpha-1/beta)
agonist
Human
UIntermediate conductance calcium-activated potassium channel protein 4
inhibitor
Human
APotassium voltage-gated channel subfamily A member 1
inducer
Human
ACalcium-transporting ATPase type 2C member 1
inhibitor
Human
AGlutamate receptor 1
antagonist
Human
UATP synthase subunit delta, mitochondrial
other/unknown
Human
Absorption

Rapidly absorbed into the circulation via the lungs.

Volume of distribution
Not Available
Protein binding

97%

Metabolism

2.4% of the dose is slowly metabolized hepatically via oxidation and dehalogenation (primarily through the actions of cytochrome P450 2E1). Leads to low levels of serum fluoride (15 µmol/L).

Route of elimination
Not Available
Half life
Not Available
Clearance
Not Available
Toxicity

LD50=5.4 ml/kg (oral, rat). Symptoms of acute overdose include nausea, vomiting, irritation to the eyes, skin and nose/throat, headache, dizziness, and drowsiness. Symptoms of chronic overdose include hypotension, cardiac arrhythmias, respiratory depression, and liver/kidney dysfunction.

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
2,5-Dimethoxy-4-ethylthioamphetamineThe risk or severity of adverse effects can be increased when Enflurane is combined with 2,5-Dimethoxy-4-ethylthioamphetamine.
3,4-MethylenedioxyamphetamineThe risk or severity of adverse effects can be increased when Enflurane is combined with 3,4-Methylenedioxyamphetamine.
4-Bromo-2,5-dimethoxyamphetamineThe risk or severity of adverse effects can be increased when Enflurane is combined with 4-Bromo-2,5-dimethoxyamphetamine.
4-MethoxyamphetamineThe risk or severity of adverse effects can be increased when Enflurane is combined with 4-Methoxyamphetamine.
5-methoxy-N,N-dimethyltryptamineThe risk or severity of adverse effects can be increased when Enflurane is combined with 5-methoxy-N,N-dimethyltryptamine.
7-NitroindazoleThe risk or severity of adverse effects can be increased when Enflurane is combined with 7-Nitroindazole.
AcepromazineThe risk or severity of adverse effects can be increased when Enflurane is combined with Acepromazine.
AceprometazineThe risk or severity of adverse effects can be increased when Enflurane is combined with Aceprometazine.
AcetaminophenThe metabolism of Acetaminophen can be decreased when combined with Enflurane.
AcetazolamideThe risk or severity of adverse effects can be increased when Enflurane is combined with Acetazolamide.
Food Interactions
Not Available

References

Synthesis Reference

Terrell, R.C.; U.S. Patents 3,469,011; September 23,1969 and 3,527,813; September 8, 1970; both assigned to Air Reduction Company, Incorporated.

General References
  1. Link [Link]
External Links
Human Metabolome Database
HMDB0014373
KEGG Drug
D00543
KEGG Compound
C07516
PubChem Compound
3226
PubChem Substance
46505314
ChemSpider
3113
ChEBI
4792
ChEMBL
CHEMBL1257
Therapeutic Targets Database
DAP000799
PharmGKB
PA449461
Wikipedia
Enflurane
ATC Codes
N01AB04 — Enflurane
MSDS
Download (64.9 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
Not AvailableCompletedTreatmentAdjunct to general anesthesia therapy1

Pharmacoeconomics

Manufacturers
  • Abbott laboratories hosp products div
  • Piramal critical care inc
  • Baxter healthcare corp anesthesia critical care
Packagers
  • Apothecon
  • Baxter International Inc.
  • Minrad Inc.
  • Rx Elite
Dosage forms
FormRouteStrength
LiquidRespiratory (inhalation)1 mL/1mL
LiquidRespiratory (inhalation)99.9 %
LiquidRespiratory (inhalation)125 mL/125mL
LiquidRespiratory (inhalation)100 %
Prices
Unit descriptionCostUnit
Ethrane inhalation0.55USD ml
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Not Available

Properties

State
Liquid
Experimental Properties
PropertyValueSource
boiling point (°C)56.5Terrell, R.C.; U.S. Patents 3,469,011; September 23,1969 and 3,527,813; September 8, 1970; both assigned to Air Reduction Company, Incorporated.
water solubility5620 mg/L (at 37 °C)YALKOWSKY,SH & DANNENFELSER,RM (1992)
logP2.10HANSCH,C & LEO,AJ (1985)
Predicted Properties
PropertyValueSource
Water Solubility3.9 mg/mLALOGPS
logP2.24ALOGPS
logP2.8ChemAxon
logS-1.7ALOGPS
pKa (Strongest Basic)-5ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count1ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area9.23 Å2ChemAxon
Rotatable Bond Count3ChemAxon
Refractivity23.07 m3·mol-1ChemAxon
Polarizability9.74 Å3ChemAxon
Number of Rings0ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterNoChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+1.0
Blood Brain Barrier+0.994
Caco-2 permeable+0.6125
P-glycoprotein substrateNon-substrate0.8919
P-glycoprotein inhibitor INon-inhibitor0.9553
P-glycoprotein inhibitor IINon-inhibitor0.9297
Renal organic cation transporterNon-inhibitor0.9293
CYP450 2C9 substrateNon-substrate0.8407
CYP450 2D6 substrateNon-substrate0.9116
CYP450 3A4 substrateNon-substrate0.7179
CYP450 1A2 substrateNon-inhibitor0.5701
CYP450 2C9 inhibitorNon-inhibitor0.8112
CYP450 2D6 inhibitorNon-inhibitor0.9408
CYP450 2C19 inhibitorNon-inhibitor0.5794
CYP450 3A4 inhibitorNon-inhibitor0.9604
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.8702
Ames testNon AMES toxic0.9132
CarcinogenicityCarcinogens 0.7574
BiodegradationNot ready biodegradable0.9642
Rat acute toxicity1.3804 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9576
hERG inhibition (predictor II)Non-inhibitor0.9032
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Download (7.54 KB)
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Mass Spectrum (Electron Ionization)MSsplash10-0gb9-9300000000-03817aefdcc06ee54c49
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as organofluorides. These are compounds containing a chemical bond between a carbon atom and a fluorine atom.
Kingdom
Organic compounds
Super Class
Organohalogen compounds
Class
Organofluorides
Sub Class
Not Available
Direct Parent
Organofluorides
Alternative Parents
Organooxygen compounds / Organochlorides / Hydrocarbon derivatives / Alkyl fluorides / Alkyl chlorides
Substituents
Organic oxygen compound / Hydrocarbon derivative / Organooxygen compound / Organofluoride / Organochloride / Alkyl halide / Alkyl fluoride / Alkyl chloride / Aliphatic acyclic compound
Molecular Framework
Aliphatic acyclic compounds
External Descriptors
organofluorine compound, organochlorine compound, ether (CHEBI:4792)

Targets

Kind
Protein group
Organism
Human
Pharmacological action
Yes
Actions
Positive allosteric modulator
General Function
Inhibitory extracellular ligand-gated ion channel activity
Specific Function
Component of the heteropentameric receptor for GABA, the major inhibitory neurotransmitter in the vertebrate brain. Functions also as histamine receptor and mediates cellular responses to histamine...

Components:
References
  1. Franks NP: Molecular targets underlying general anaesthesia. Br J Pharmacol. 2006 Jan;147 Suppl 1:S72-81. [PubMed:16402123]
  2. Grasshoff C, Antkowiak B: Effects of isoflurane and enflurane on GABAA and glycine receptors contribute equally to depressant actions on spinal ventral horn neurones in rats. Br J Anaesth. 2006 Nov;97(5):687-94. Epub 2006 Sep 13. [PubMed:16973644]
  3. Greenblatt EP, Meng X: Divergence of volatile anesthetic effects in inhibitory neurotransmitter receptors. Anesthesiology. 2001 Jun;94(6):1026-33. [PubMed:11465594]
  4. ChEMBL Compound Report Card [Link]
Kind
Protein group
Organism
Human
Pharmacological action
Yes
Actions
Agonist
General Function
Transmitter-gated ion channel activity
Specific Function
The glycine receptor is a neurotransmitter-gated ion channel. Binding of glycine to its receptor increases the chloride conductance and thus produces hyperpolarization (inhibition of neuronal firing).

Components:
References
  1. Grasshoff C, Antkowiak B: Effects of isoflurane and enflurane on GABAA and glycine receptors contribute equally to depressant actions on spinal ventral horn neurones in rats. Br J Anaesth. 2006 Nov;97(5):687-94. Epub 2006 Sep 13. [PubMed:16973644]
  2. ChEMBL Compound Report Card [Link]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Protein phosphatase binding
Specific Function
Forms a voltage-independent potassium channel that is activated by intracellular calcium (PubMed:26148990). Activation is followed by membrane hyperpolarization which promotes calcium influx. Requi...
Gene Name
KCNN4
Uniprot ID
O15554
Uniprot Name
Intermediate conductance calcium-activated potassium channel protein 4
Molecular Weight
47695.12 Da
References
  1. Namba T, Ishii TM, Ikeda M, Hisano T, Itoh T, Hirota K, Adelman JP, Fukuda K: Inhibition of the human intermediate conductance Ca(2+)-activated K(+) channel, hIK1, by volatile anesthetics. Eur J Pharmacol. 2000 Apr 28;395(2):95-101. [PubMed:10794813]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inducer
General Function
Voltage-gated potassium channel activity
Specific Function
Voltage-gated potassium channel that mediates transmembrane potassium transport in excitable membranes, primarily in the brain and the central nervous system, but also in the kidney (PubMed:1990381...
Gene Name
KCNA1
Uniprot ID
Q09470
Uniprot Name
Potassium voltage-gated channel subfamily A member 1
Molecular Weight
56465.01 Da
References
  1. Matchett GA, Allard MW, Martin RD, Zhang JH: Neuroprotective effect of volatile anesthetic agents: molecular mechanisms. Neurol Res. 2009 Mar;31(2):128-34. doi: 10.1179/174313209X393546. [PubMed:19298752]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
General Function
Signal transducer activity
Specific Function
This magnesium-dependent enzyme catalyzes the hydrolysis of ATP coupled with the transport of the calcium.
Gene Name
ATP2C1
Uniprot ID
P98194
Uniprot Name
Calcium-transporting ATPase type 2C member 1
Molecular Weight
100576.42 Da
References
  1. Kosk-Kosicka D: Plasma membrane Ca(2+)-ATPase as a target for volatile anesthetics. Adv Pharmacol. 1994;31:313-22. [PubMed:7873420]
  2. Kosk-Kosicka D, Roszczynska G: Inhibition of plasma membrane Ca(2+)-ATPase activity by volatile anesthetics. Anesthesiology. 1993 Oct;79(4):774-80. [PubMed:8214757]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Antagonist
General Function
Pdz domain binding
Specific Function
Ionotropic glutamate receptor. L-glutamate acts as an excitatory neurotransmitter at many synapses in the central nervous system. Binding of the excitatory neurotransmitter L-glutamate induces a co...
Gene Name
GRIA1
Uniprot ID
P42261
Uniprot Name
Glutamate receptor 1
Molecular Weight
101505.245 Da
References
  1. Dildy-Mayfield JE, Eger EI 2nd, Harris RA: Anesthetics produce subunit-selective actions on glutamate receptors. J Pharmacol Exp Ther. 1996 Mar;276(3):1058-65. [PubMed:8786535]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Other/unknown
General Function
Transporter activity
Specific Function
Mitochondrial membrane ATP synthase (F(1)F(0) ATP synthase or Complex V) produces ATP from ADP in the presence of a proton gradient across the membrane which is generated by electron transport comp...
Gene Name
ATP5D
Uniprot ID
P30049
Uniprot Name
ATP synthase subunit delta, mitochondrial
Molecular Weight
17489.755 Da
References
  1. Kosk-Kosicka D, Roszczynska G: Inhibition of plasma membrane Ca(2+)-ATPase activity by volatile anesthetics. Anesthesiology. 1993 Oct;79(4):774-80. [PubMed:8214757]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
Metabolizes several precarcinogens, drugs, and solvents to reactive metabolites. Inactivates a number of drugs and xenobiotics and also bioactivates many xenobiotic substrates to their hepatotoxic ...
Gene Name
CYP2E1
Uniprot ID
P05181
Uniprot Name
Cytochrome P450 2E1
Molecular Weight
56848.42 Da
References
  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256]
  2. Drug Interactions: Cytochrome P450 Drug Interaction Table [Link]

Carriers

Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Toxic substance binding
Specific Function
Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloid...
Gene Name
ALB
Uniprot ID
P02768
Uniprot Name
Serum albumin
Molecular Weight
69365.94 Da
References
  1. Liu R, Eckenhoff RG: Weak polar interactions confer albumin binding site selectivity for haloether anesthetics. Anesthesiology. 2005 Apr;102(4):799-805. [PubMed:15791110]
  2. Sawas AH, Pentyala SN, Rebecchi MJ: Binding of volatile anesthetics to serum albumin: measurements of enthalpy and solvent contributions. Biochemistry. 2004 Oct 5;43(39):12675-85. [PubMed:15449957]

Drug created on June 13, 2005 07:24 / Updated on November 02, 2018 04:39