Enflurane

Absorption

Enflurane is rapidly absorbed into the circulation through the lungs. The minimum alveolar concentration is oxygen is 1.68%.

Toxicity

The LD50 of enflurane in rats is 14000 ppm/3 hour(s) when inhaled. There is limited information in the literature about enflurane overdose. Hepatotoxicity, cardiotoxicity, nephrotoxicity, and neurotoxicity are expected. One report in the literature of an enflurane overdose describes an accidental fatal overdose in a 21-year-old male. About 72 hours after death, high amounts of enflurane were found in the brain, blood, and subcutaneous fat. Gas chromatographic studies revealed enflurane concentrations of 350 mg/l-1 in the brain, 130 mg/l-1 in the blood, and 100 mg/l-1 in the subcutaneous fat.
In the event of an enflurane overdose, immediately stop the administration of enflurane, establish a patent airway, and administer pure oxygen by assisted or controlled ventilation.

Description

Enflurane is a clear, colorless liquid with amild, sweet odor, which easily turns into a nonflammablegas. Molecular weight = 184.50; Specific gravity(H2O:1) = 1.52; Boiling point = 56.7 ℃; Vaporpressure 5 175 mmHg; Relative vapor density (air 5 1)=1.92. Hazard Identification (based on NFPA-704 M RatingSystem): Health 2, Flammability 1, Reactivity 0. Veryslightly soluble in water

Chemical properties

Clear, colorless liquid; mild, sweet odor. Soluble in organic solvents; slightly soluble in water.

Chemical properties

Enflurane is a clear, colorless liquid that easily turns into a nonflammable gas. Mild, sweet odor

Chemical properties

The halogenated methyl ethyl ether enflurane is a geometric isomer of isoflurane and boasts similar properties. It is no longer in use in modern clinical practice largely because of some unfavourable adverse effects. Enflurane has been associated with: tonic–clonic muscle activity; epileptiform EEG changes; sensitisation of the myocardium to catecholamines causing dysrhythmias; and hepatotoxicity as a result of its significant liver metabolism.

Originator

Ethrane,Ohio Medical,US,1972

The Uses of Enflurane

Clinical anesthetic.

The Uses of Enflurane

Ethrane is widely used clinically as an anes thesia (by inhalation). Workers in operatingrooms are susceptible to inhaling this compound at low concentrations.

The Uses of Enflurane

Anesthetic in clinical anesthesia

Background

Enflurane is a halogenated inhalational anesthetic initially approved by the FDA in 1972. Since this date, it has been withdrawn from the US market. Unlike its other inhalational anesthetic counterparts including isoflurane and halothane, enflurane is known to induce seizure activity. In addition, it is known to cause increased cardio depressant effects when compared to other inhaled anesthetics.

Indications

Enflurane may be used for both the induction and maintenance of general anesthesia. It can also be used to induce analgesia for vaginal delivery. Low concentrations of enflurane can also be used as an adjunct to general anesthetic drugs during delivery by Cesarean section.

Definition

ChEBI: An ether in which the oxygen atom is connected to 2-chloro-1,1,2-trifluoroethyl and difluoromethyl groups.

Manufacturing Process

Preparation of the Intermediate CHCl2OCF2CHFCl: To a 3-necked roundbottomed flask fitted with a Dry Ice condenser, a fritted glass gas inlet tube, a thermometer and a stirrer, was charged 1,180 grams (8 mols) of CH3OCF2CHFCl.After flushing the system with nitrogen, chlorine gas was added via the inlet tube while the reaction was stirred and illuminated with a 300 watt incandescent lamp. The chlorination was rapid and exothermic and the reactor was cooled to hold the temperature between 30° and 35°C. The effluent gases were led from the top of the condenser to a water scrubber which was titrated at intervals with standard base. When a total of 1.45 mols of HCl per mol of ether was titrated the reaction was stopped. The crude product obtained weighed 1,566 grams which corresponded to the addition of 1.41 mols of chlorine per mol of the starting ether. The product was flash distilled to yield 1,480 grams of product which had the following composition as determined by vapor phase chromatography: 45.3% CH2ClOCF2CHFCl; 50.5% CHCl2OCF2CHFCl, plus a small amount of CH2ClOCF2CFCl2; 1.8% CHCl2OCF2CFCl2 and 2.1% CCl3OCF2CHFCl.
Fractional distillation of this mixture using a 5 x 120 cm column packed with ?" Penn State packing yielded 670 grams of product containing 95% CH2ClOCF2CHFCl and 5% CHCl2OCF2CHFCl; BP 55° to 60°C at 100 mm, nD20 = 1.3748 to 1.3795; and 670 grams of CHCl2OCF2CHFCl (95% pure, containing 5% CH2ClOCF2CFCl2); BP 60°C at 100 mm, nD20 = 1.3870 to 1.3875. The still bottoms were comprised mostly of CCl3OCF2CHFCl and CHCl2OCF2CFCl2.
Preparation of CHF2OCF2CHFCl: To a mixture of 2,172 grams (10 mols) CHCl2OCF2CHFCl prepared as described above (containing approximately 5% CH2ClOCF2CFCl2) and 40 grams (2% by weight) SbCl5 was added anhydrous hydrogen fluoride while the temperature was maintained at 0-5°C. The reaction was carried out in a 3-necked stainless steel flask fitted with a stainless steel stirrer, a thermocouple well and a copper Dry Ice condenser.
The amount of hydrogen fluoride added was measured by titration of the HCl given off. At the end of the reaction (total HCl evolved: 1.98 mols per mol of starting ether) the mixture was poured into water and the organic layer (1,803 grams, nD20 = 1.3080) recovered. The crude product was flash distilled in a 60 x 2 cm column packed with ?" Penn State packing giving 1,594 grams of substantially pure CHF2OCF2CHFCl, BP 56° to 57°C. By further distillation 1,450 grams of the pure ether were obtained, BP 56.5°C, nD20 = 1.3030 as described in each of the patents cited as references.

Therapeutic Function

Anesthetic

Biological Functions

Enflurane (Ethrane) depresses myocardial contractility and lowers systemic vascular resistance. In contrast to halothane, it does not block sympathetic reflexes, and therefore, its administration results in tachycardia. However, the increased heart rate is not sufficient to oppose enflurane’s other cardiovascular actions, so cardiac output and blood pressure fall. In addition, enflurane sensitizes the myocardium to catecholamine-induced arrhythmias, although to a lesser extent than with halothane. Enflurane depresses respiration through mechanisms similar to halothane’s and requires that the patient’s ventilation be assisted.
Neuromuscular transmission is depressed by enflurane, resulting in some skeletal muscle paralysis.Although muscle relaxation is inadequate for many surgical procedures, the anesthetic enhances the action of neuromuscular blocking agents, thereby lowering the dose of the paralytic agent needed and minimizing side effects.
Deep anesthesia with enflurane is associated with the appearance of seizurelike electroencephalographic (EEG) changes. Occasionally frank tonic–clonic seizures are observed. Consequently, other inhalational agents are usually given to patients with preexisting seizure disorders.
Another concern associated with the use of enflurane is its biotransformation, which leads to increased plasma fluoride. Following lengthy procedures in healthy patients, fluoride may reach levels that result in a mild reduction in renal concentrating ability.Thus, enflurane should be used cautiously in patients with clinically significant renal disease.

General Description

2-CHLORO-1,1,2-TRIFLUOROETHYL DIFLUOROMETHYL ETHER (Ethrane, 2-chloro-1,1,2-trifluoroethyldifluoromethyl ether) is a nonflammable halogenated hydrocarbon that exists as a clear, colorless, odorless to sweet, volatile liquid at ordinary temperature and pressure. Bp: 56.8°C. Density 1.50 g cm-3 at room temperature. Used as an anesthetic.

General Description

Enflurane is a volatile liquid (bp＝56.5°C) with a blood:gas partition coefficient of 1.8 and an MAC of 1.68%.Approximately 2% to 8% of the drug is metabolized primarilyat the chlorofluoromethyl carbon. Little chlorofluoroaceticacid is produced suggesting minor metabolism at thedifluoromethyl carbon. Difluoromethoxydifluoroacetate andfluoride ion have been reported as metabolites. Enfluranemay increase heart rate, cause cardiac arrhythmias, increasecerebral blood flow, and increase intracranial pressure but allto a smaller degree than halothane. Enflurane also causeselectroencephalographic (EEG) patterns consistent withelectrical seizure activity. It has caused tonic–clonic convulsiveactivity in patients when used at high concentrations orduring profound hypocarbic periods. Enflurane is thereforenot recommended in patients with seizure disorders.

Reactivity Profile

The material 2-CHLORO-1,1,2-TRIFLUOROETHYL DIFLUOROMETHYL ETHER is incompatible with the following oxidizing materials, peroxides, combustible materials. Although nonflammable, a fire may cause 2-CHLORO-1,1,2-TRIFLUOROETHYL DIFLUOROMETHYL ETHER to decompose to toxic compounds including phosgene, hydrogen chloride, and hydrogen fluoride. Decomposes slowly in the light.

Hazard

Volatile with anesthetic properties, but nonflammable. Cardiac and central nervous system impairment. Questionable carcinogen.

Health Hazard

The acute toxicity of ethrane by inhalation,ingestion, or intraperitoneal or subcutaneousapplications in rodents was found tobe low to very low at concentrationsof <1000 ppm in air or dosages below1000 mg/kg. In humans it causes anesthesiaat 1.5–2% concentrations (by volume of air).Exposure to concentrations above this levelcan be dangerous. The target organs arethe central nervous system, cardiovascularsystem, kidney, and bladder. The symptomsare anesthesia, respiratory depression, andseizure. Hypotension can occur due toits action on the cardiovascular system.Exposure to a 1% concentration in air for6 hours caused anuria in humans
LC50 value, inhalation (mice): 8100 ppm/3 h
LD50 value, oral (mice): 5000 mg/kg
The pure liquid can cause mild to moder ate irritation of the eyes.
Inhalation of ethrane vapors produced teratogenic effects in mice and rats. Theseeffects pertained to specific developmen tal abnormalities in the urogenital, mus culoskeletal, and central nervous systems.These reproductive effects, however, weremanifested at high exposure levels in therange of LC50 concentrations.
Under the conditions of its use, the con centrations of ethrane in air should be toolow to produce any adverse health effects onhumans. However, it should be borne in mindthat this compound is highly volatile [vaporpressure 175 torr at 20°C (68°F)] and its con centration in air can go up from a spill orimproper handling in confined space.
Inhalation of its vapors resulted in lungand liver tumors in mice. There is no evi dence of its carcinogenic actions in humans.

Fire Hazard

Noncombustible liquid; flash point >94°C (200°F); low reactivity. Pressure buildup in a closed bottle may occur at elevated temper atures.

Pharmacokinetics

Enflurane rapidly induces anesthesia via the stimulation of inhibitory neural channels and the inhibition of excitatory neural channels. Muscle relaxation, obtundation of pharyngeal and laryngeal reflexes, and lowering of blood pressure are some of the main pharmacodynamic effects of this drug. Enflurane also decreases cardiac muscle contractility.
High concentrations of enflurane may lead to uterine relaxation and increase the risk of uterine bleeding during delivery. Rare but clinically significant elevations in ALT may indicate hepatoxicity from the use of enflurane. In some susceptible patients, enflurane may cause malignant hyperthermia.

Clinical Use

Enflurane was introduced into medical practice in the United States in 1973 and is a clear, colorless, nonflammable general liquid with a mild, sweet odor. Although relatively stable chemically, enflurane does not attack aluminum, copper, iron, or brass and is soluble in rubber (partition coefficient = 74), which can prolong induction/recovery times, as seen with halothane.Enflurane has an intermediate solubility in blood and significant potency. Most of its pharmacological properties are similar to those of halothane, although there may be slightly less nausea, vomiting, arrhythmias, and postoperative shivering than observed with halothane. High concentrations of enflurane, however, are more likely to produce convulsions and circulatory depression. Enflurane also relaxes the uterus and, thus, should not be used as an anesthetic during labor. Metabolism via CYP2E1 accounts for 2% of an inhaled dose and includes transformation to the fluoride ion and fluoromethoxydifluoroacetic acid. During recovery, enflurane leaves the fatty tissues rapidly and, therefore, is not available for a prolonged period of time for significant metabolism to proceed.

Safety Profile

Mildly toxic by inhalation, ingestion, and subcutaneous routes. Human systemic effects by inhalation: decreased urine volume or anuria. An experimental teratogen. Experimental reproductive effects. Human mutation data reported. An eye irritant. Questionable carcinogen with experimental carcinogenic data. An anesthetic. When heated to decomposition it emits very toxic fumes of Fand Cl-. See also ETHERS.

Synthesis

Enflurane is prepared by dichlorination of the methyl group of 1-chloro-1,2,2-trifluoro-2- methoxyethane and replacement of these two chlorine atoms by fluorine , :

Potential Exposure

FDA-proprietary drug, used as an anesthetic (gas). Axphyxiant

First aid

If this chemical gets into the eyes, remove any contact lenses at once and irrigate immediately for at least15 min, occasionally lifting upper and lower lids. Seek medical attention immediately. If this chemical contacts the skin,remove contaminated clothing and wash immediately withsoap and water. Seek medical attention immediately. If thischemical has been inhaled, remove from exposure, begin rescue breathing (using universal precautions, including resuscitation mask) if breathing has stopped and CPR if heart actionhas stopped. Transfer promptly to a medical facility. Whenthis chemical has been swallowed, get medical attention.Give large quantities of water and induce vomiting. Do notmake an unconscious person vomit

Metabolism

Enflurane is metabolized by the CYP2E1 enzyme in the liver to produce inorganic fluoride ions, the major metabolite of enflurane metabolism. One reference indicates that enflurane is only 2-5% eliminated after oxidative metabolism in the liver, however more recent evidence suggests that about 9% is eliminated via hepatic oxidation.

storage

Prior to working with enflurane you should betrained on its proper handling and storage. Store in tightlyclosed containers in a cool, well-ventilated area. Check oxygen content before entering confined spaces. Where possible, automatically pump liquid from drums or other storagecontainers to process containers. Procedures for the handling, use, and storage of cylinders should be in compliancewith OSHA 1910.101 and 1910.169, as with the recommendations of the Compressed Gas Association.

Shipping

UN1851 Medicine, liquid, toxic, n.o.s., Hazard Class: 6.1; Labels: 6.1-Poisonous materials. Cylinders must be transported in a secure upright position, in a wellventilated truck. Protect cylinder and labels from physical damage. The owner of the compressed gas cylinder is the only entity allowed by federal law (49CFR) to transport and refill them. It is a violation of transportation regulations to refill compressed gas cylinders without the express written permission of the owner.

Incompatibilities

Incompatible with oxidizers (chlorates, nitrates, peroxides, permanganates, perchlorates, chlorine, bromine, fluorine, etc.); contact may cause fires or explosions. Keep away from alkaline materials, strong bases, strong acids, oxoacids, and epoxides. Decomposes on heating, forming toxic and corrosive fumes of hydrogen chloride, hydrogen fluoride, and phosgene. Decomposes in strong sunlight

Waste Disposal

Return refillable compressed gas cylinders to supplier