Isoflurane

184.49

184.49

1852087

247-897-7

1435

DTXSID3020752

C65978

Clear, colorless liquid

N - Nervous system

2909199090

9.2

2.1

colourless liquid

1.5 g/cm³

48.5 °C

48.5 °C

48-49°C

1.301

soluble in chloroform and ethyl acetate. Not miscible or difficult to mix in water.Solubility in water: poor

Store in tight container as defined in the USP-NF. This material should be handled and stored per label instructions to ensure product integrity.

Vapour pressure, kPa at 20°C: 32

Slight odor

1.51e-14 cm3/molecule*sec

0.03 atm-m3/mole|Henry's Law constant = 2.87X10-2 atm-cu m/mol at 25 °C

Greenhouse Warming Potential = 0.03 (calculated; CFC-12 = 1)|Ozone depletion potential = 0.01 (relative to CFC-11 and CFC-12)|Hydroxyl radical reaction rate constant = 1.51X10-14 cu cm/molec-sec at 25 °C

The vapour is heavier than air and may accumulate in lowered spaces causing a deficiency of oxygen.

UN 3334

3

36/37/38-67-48/20

26-36/37/39-24/25

KN6799000

F,T,Xn

Ventilation along the floor.

Flammable/Toxic

Stable.

P260

H336-H373

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.|SRP: Wastewater from contaminant suppression, cleaning of protective clothing/equipment, or contaminated sites should be contained and evaluated for subject chemical or decomposition product concentrations. Concentrations shall be lower than applicable environmental discharge or disposal criteria. Alternatively, pretreatment and/or discharge to a permitted wastewater treatment facility is acceptable only after review by the governing authority and assurance that "pass through" violations will not occur. Due consideration shall be given to remediation worker exposure (inhalation, dermal and ingestion) as well as fate during treatment, transfer and disposal. If it is not practicable to manage the chemical in this fashion, it must be evaluated in accordance with EPA 40 CFR Part 261, specifically Subpart B, in order to determine the appropriate local, state and federal requirements for disposal.

Isoflurane: ... For induction and maintenance of general anesthesia in horses and dogs.|The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including isoflurane, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.|The Generic Animal Drug and Patent Restoration act requires that each sponsor of an approved animal drug must submit to the FDA certain information regarding patents held for the animal drug or its method of use. The Act requires that this information, as well as a list of all animal drug products approved for safety and effectiveness, be made available to the public. Isoflurane is included on this list.

Not combustible. Gives off irritating or toxic fumes (or gases) in a fire.

|Warning|H336 (95.92%): May cause drowsiness or dizziness [Warning Specific target organ toxicity, single exposure; Narcotic effects]|P260, P261, P271, P304+P340, P312, P314, P403+P233, P405, and P501|Aggregated GHS information provided by 101 companies from 9 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Airborne exposure should be controlled primarily by engineering controls such as general dilution ventilation, local exhaust ventilation, or process enclosure. Local exhaust ventilation is generally preferred to general exhaust because it can control the contaminant at its source, preventing dispersion into the work area. An industrial hygiene survey involving air monitoring may be used to determine the effectiveness of engineering controls. Effectiveness of engineering controls intended for use with highly potent materials should be assessed by use of nontoxic surrogate materials.

As with all fires, evacuate personnel to a safe area. Firefighters should use self-contained breathing equipment and protective clothing.|The product is not flammable.Water fog, dry chemical, or carbon dioxide as appropriate for surrounding fire and materials.Do not use water jet as an extinguisher, as this will spread the fire.

Stop the flow of material, if this is without risk. Dike the spilled material, where this is possible. Prevent entry into waterways, sewer, basements or confined areas. Wear approved respiratory protection, chemically compatible gloves, and protective clothing. Wipe up spillage or collect spillage using a high-efficiency vacuum cleaner. Avoid breathing vapor. Ventilate area and wash spill site. Place spillage in appropriately labeled container for disposal. Small quantities of liquid anesthetic agents may evaporate readily at room temperature.Large Spills: Stop the flow of material, if this is without risk. Dike the spilled material, where this is possible. Cover with plastic sheet to prevent spreading. Absorb in vermiculite, dry sand or earth and place into containers. Following product recovery, flush area with water. Never return spills in original containers for re-use.

Safety glasses with sideshields are recommended. Face shields or goggles may be required if splash potential exists or if corrosive materials are present. Approved eye protection (e.g., bearing the ANSI Z87 or CSA stamp) is preferred. Maintain eyewash facilities in the work area.|As a general rule, when handling USP Reference Standards, avoid all contact and inhalation of dust, mists, and/or vapors associated with the material. Clean equipment and work surfaces with suitable detergent or solvent after use. After removing gloves, wash hands and other exposed skin thoroughly.|Since exposure to WAGs is one possible factor in the findings for these studies, operating room personnel, and pregnant women in particular, should minimize exposure. Precautions include adequate general ventilation in the operating room, the use of a well-designed and well-maintained scavenging system, work practices to minimize leaks and spills while the anesthetic agent is in use, and routine equipment maintenance to minimize leaks.

Personal protection: self-contained breathing apparatus. Ventilation. Collect leaking liquid in sealable containers. Absorb remaining liquid in sand or inert absorbent. Then store and dispose of according to local regulations.

Ventilation along the floor.

A harmful contamination of the air can be reached very quickly on evaporation of this substance at 20 °C.

The substance is irritating to the eyes and skin. The vapour is irritating to the respiratory tract. The substance may cause effects on the central nervous system and cardiovascular system. Exposure at high levels could cause unconsciousness.

Use ventilation, local exhaust or breathing protection.

Protective gloves.

Wear safety spectacles or eye protection in combination with breathing protection.

LC50=15300 ppm/3 hrs (inhalation by rat)

Prospective, serial blood testing often demonstrates minor transient elevations in serum aminotransferase levels in the 1 to 2 weeks after major surgery and halogenated anesthetic agents. Appearance of ALT levels above 10 times the upper limit of normal, however, is distinctly unusual and points to significant hepatotoxicity. Clinically apparent, severe hepatic injury from isoflurane is very rare, only isolated case reports and small case series having been published. The injury is marked by acute elevations in serum aminotransferase levels (5- to 50-fold) and appearance of jaundice within 2 to 21 days of surgery. There are usually minimal increases in alkaline phosphatase and gammaglutamyl transpeptidase levels. Jaundice is usually preceded by a day or two of fever and may be accompanied by rash and eosinophilia. The acute liver injury may be self-limited and resolve within 4 to 8 weeks, but can be severe and associated with acute liver failure. A strong risk factor is previous exposure to any of the halogenated anesthetics and particularly a history of halothane hepatitis or unexplained fever and rash after anesthesia with one of these agents. The differential diagnosis of acute liver injury after surgery and anesthesia is sometimes difficult, and a clinical picture similar to isoflurane hepatitis can be caused by shock or ischemia, other idiosyncratic forms of drug induced liver injury and acute viral or herpes hepatitis.

Isoflurane potentiates the muscle relaxant effect of all muscle relaxants, most notably nondepolarizing muscle relaxants, and MAC (minimum alveolar concentration) is reduced by concomitant administration of N2O.|Increasing numbers of people use cocaine recreationally and may require anesthesia care, having recently abused the drug. However, no data currently exist concerning potential interactions between toxic levels of cocaine and volatile anesthetic agents. This study investigated the effects of cocaine infusion on systemic hemodynamics, myocardial metabolism, and regional organ blood flow in relation to depth of isoflurane anesthesia. Prospective, randomized, controlled trial /was conducted in/ twelve miniature pigs. An open-chest swine model was used. Isoflurane (ISO) was the sole anesthetic, administered at 0.75 and 1.5 minimum alveolar concentration (MAC), and cocaine was infused (n = 6) at a rate of 0.5 mg/kg/min. Control animals (n = 6) received an equivalent amount of normal saline. Systemic and pulmonary arterial pressures and thermodilution cardiac output data were collected at 0.75 MAC and 1.5 MAC ISC. Regional myocardial and blood flows to other organs were measured using radiolabeled microspheres. Arrhythmias and altered ventricular conduction were noted only in the cocaine group, along with significant elevations in diastolic arterial pressure, coronary perfusion pressure, and systemic vascular resistance. Increased subendocardial blood flow occurred during cocaine infusion (p = 0.03); subepicardial perfusion was unchanged. Cerebral (p < 0.01) and spinal cord (p < 0.05) blood flows were reduced in animals receiving cocaine. Other organ blood flows were unchanged with depth of anesthesia or cocaine administration, with the exception of splenic blood flow (p < 0.04). Moderately toxic cocaine levels occurring during isoflurane at 0.75 MAC and 1.5 MAC are associated with hemodynamic abnormalities, a marked increase in systemic vascular resistance, and a tendency to produce cardiac arrhythmias. A reversal of endo/epicardial myocardial perfusion ratio occurs associated with cocaine infusion during ISO anesthesia. This is probably not related to a primary redistribution of subendocardial blood flow and may be related to a combination of increased myocardial oxygen demand and epicardial coronary vasoconstriction. The reductions in cerebral and spinal cord perfusion observed may explain, in part, the neurologic sequelae of cocaine toxicity.|Recent in vitro data indicate that isoflurane can reduce N-methyl-D-aspartate (NMDA) receptor-mediated responses and thereby might reduce excitotoxicity. However, the effect of isoflurane on NMDA receptor-mediated toxicity in vivo is not known. We conducted the present study to evaluate the effect of isoflurane on injury produced by cortical injection of NMDA in vivo and to compare it with dizocilpine, an antagonist of the NMDA receptor. Fasted Wistar-Kyoto rats were anesthetized with isoflurane. NMDA 50 nmoles (5-uL volume) were stereotactically injected into the cortex (2.8 mm lateral and 2.8 mm rostral to the bregma, depth 2 mm) of animals in one of four groups. In the isoflurane groups, the end-tidal concentration of isoflurane was maintained at either electroencephalogram (EEG)-burst suppression (BS) doses (2.2%-2.3%, n = 12) or a 1 minimum alveolar anesthetic concentration (MAC) dose (n = 10). In the dizocilpine group (n = 10), 10 mg/kg dizocilpine was injected IV 15 min before the NMDA injection. In the awake group and the dizocilpine group, anesthesia was discontinued on completion of the NMDA injection, and the animals were allowed to awaken. In the animals in the control group (n = 10), 20 uL of artificial cerebrospinal fluid was injected into the cortex. Injury to the cortex was evaluated 2 days after the NMDA injection. In 1 MAC doses and EEG-BS doses, isoflurane reduced the injury produced by a cortical NMDA injection compared with the awake state (1.74+/-0.49 and 0.96+/-0.46 vs 2.34+/-0.56 cu mm; P = 0.02). Dizocilpine reduced cortical injury (0.56+/-0.27; P = 0.01) compared with the awake state. Injury in the control group was limited to the trauma produced by cannula insertion. In the isoflurane EEG-BS and dizocilpine groups, the injury was not different from the control group. Isoflurane can reduce N-methyl-D-aspartate-mediated cortical injury in vivo in a dose-dependent manner. These data are consistent with the previously demonstrated ability of isoflurane to reduce N-methyl-D-aspartate receptor-mediated responses in vitro.|b-amyloid protein (Ab)-induced neurotoxicity is the main component of Alzheimer's disease (AD) neuropathogenesis. Inhalation anesthetics have long been considered to protect against neurotoxicity. However, recent research studies have suggested that the inhalation anesthetic isoflurane may promote neurotoxicity by inducing apoptosis and increasing Ab levels. We therefore set out to determine whether isoflurane can induce dose- and time-dependent dual effects on Ab-induced apoptosis: protection versus promotion. H4 human neuroglioma cells, primary neurons from naive mice, and naive mice were treated with Ab and/or isoflurane, and levels of caspase-3 cleavage (activation), apoptosis, Bcl-2, Bax, and cytosolic calcium were determined...the treatment with 2% isoflurane for six hours or 30 minutes potentiated, whereas the treatment with 0.5% isoflurane for six hours or 30 minutes attenuated, the Ab-induced caspase-3 activation and apoptosis in vitro. Moreover, anesthesia with 1.4% isoflurane for two hours potentiated, whereas the anesthesia with 0.7% isoflurane for 30 minutes attenuated, the Ab-induced caspase-3 activation in vivo. The high concentration isoflurane potentiated the Ab-induced reduction in Bcl-2/Bax ratio and caused a robust elevation of cytosolic calcium levels. The low concentration isoflurane attenuated the Ab-induced reduction in Bcl-2/Bax ratio and caused only a mild elevation of cytosolic calcium levels. These results suggest that isoflurane may have dual effects (protection or promotion) on Ab-induced toxicity, which potentially act through the Bcl-2 family proteins and cytosolic calcium. These findings would lead to more systematic studies to determine the potential dual effects of anesthetics on AD-associated neurotoxicity.|For more Interactions (Complete) data for Isoflurane (8 total), please visit the HSDB record page.

LD50 Rat oral 4770 mg/kg|LC50 Rat inhalation 15,300 ppm/3 hr|LD50 Rat intraperitoneal 4280 mg/kg|LD50 Mouse oral 5080 mg/kg|For more Non-Human Toxicity Values (Complete) data for Isoflurane (6 total), please visit the HSDB record page.

Use of inhaled anesthetic agents has been associated with rare increases in serum potassium levels that have resulted in cardiac arrhythmias and death in pediatric patients during the postoperative period. Patients with latent as well as overt neuromuscular disease, particularly Duchenne muscular dystrophy, appear to be most vulnerable.

Isoflurane's production and administration as an anaesthetic and solvent for fluorinated materials(1) may result in its release to the environment through various waste streams(SRC).

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 94(SRC), determined from a log Kow of 2.06(2) and a regression-derived equation(3), indicates that isoflurane is expected to have high mobility in soil(SRC). Volatilization of isoflurane from moist soil surfaces is expected to be an important fate process(SRC) given a Henry's Law constant of 2.87X10-2 atm-cu m/mole(4). Isoflurane is expected to volatilize from dry soil surfaces(SRC) based upon a vapor pressure of 330 mm Hg at 25 °C(5). Biodegradation data in soil were not available(SRC, 2012).|AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 94(SRC), determined from a log Kow of 2.06(2) and a regression-derived equation(3), indicates that isoflurane is not expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is expected(4) based upon a Henry's Law constant of 2.87X10-2 atm-cu m/mole(5). Using this Henry's Law constant and an estimation method(4), volatilization half-lives for a model river and model lake are approximately 4 hours and 5.4 days, respectively(SRC). According to a classification scheme(6), an estimated BCF of 11(SRC), from its log Kow(2) and a regression-derived equation(3), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Biodegradation data in water were not available(SRC, 2012).|ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), isoflurane, which has a vapor pressure of 330 mm Hg at 25 °C(2), is expected to exist solely as a vapor in the ambient atmosphere. Vapor-phase isoflurane is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 460 days(SRC), calculated from its rate constant of 1.51X10-14 cu cm/molecule-sec at 25 °C(3). Isoflurane does absorbs light at wavelengths <200 nm(4) and, therefore, is not expected to be susceptible to direct photolysis by sunlight(SRC).

The rate constant for the vapor-phase reaction of isoflurane with photochemically-produced hydroxyl radicals has been reported as 1.51X10-14 cu cm/molecule-sec at 25 °C(1). This corresponds to an atmospheric half-life of about 460 days at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1). Isoflurane has a calculated Greenhouse Warming Potential of 0.03 relative to CFC-12 and potential ozone depletion efficiency of 0.01 (an efficiency of Br relative to Cl of alpha=50 was used)(2). Atmospheric oxidation of isoflurane is expected to yield trifluroacetate(3). Isoflurane is not expected to undergo hydrolysis in the environment due to the lack of functional groups that hydrolyze under environmental conditions(4). Isoflurane absorbs light at wavelengths <200 nm(5) and, therefore, is not expected to be susceptible to direct photolysis by sunlight(SRC). A photochemical half-life of 3,130 years has been calculated(5).

An estimated BCF of 11 was calculated in fish for isoflurane(SRC), using a log Kow of 2.06(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC).

The Koc of isoflurane is estimated as 94(SRC), using a log Kow of 2.06(1) and a regression-derived equation(2). According to a classification scheme(3), this estimated Koc value suggests that isoflurane is expected to have high mobility in soil.

The Henry's Law constant for isoflurane is 2.87X10-2 atm-cu m/mole(1). This Henry's Law constant indicates that isoflurane is expected to volatilize rapidly from water surfaces(2). Based on this Henry's Law constant, the volatilization half-life from a model river (1 m deep, flowing 1 m/sec, wind velocity of 3 m/sec)(2) is estimated as 4 hours(SRC). The volatilization half-life from a model lake (1 m deep, flowing 0.05 m/sec, wind velocity of 0.5 m/sec)(2) is estimated as 5.4 days(SRC). Isoflurane's Henry's Law constant indicates that volatilization from moist soil surfaces may occur(SRC). Isoflurane is expected to volatilize from dry soil surfaces(SRC) based upon a vapor pressure of 330 mm Hg(3).

NIOSH (NOES Survey 1981-1983) has statistically estimated that 33,152 workers (27,151 of these were female) were potentially exposed to isoflurane in the US(1). Occupational exposure to isoflurane may occur through inhalation and dermal contact with this compound at workplaces where isoflurane is produced or adminstered. Exposure to isoflurane among the general population may be limited to those administered the drug, an anaesthetic(SRC).|A mean urine concentration of isoflurane in twenty-four workers in an anesthesia and intensive care unit was 14.3 nmol/L at the end of typical workshifts. This corresponds to an environmental exposure of 43 nmol/cu m. The subjects had a workshift of 6 hours and were exposed to various anesthetic mixtures 30-36 hrs/week for 2-27 years(1). Monitoring of operating theaters in seven unspecified hospitals in and around Toronto, Ontario, Canada indicated a mean isoflurane exposure levels of 1.4, 2.2, 9.1, 1.8, 22.3, 10.5, and 3.2 mg/cu m(2).

For induction and maintenance of general anesthesia.|FDA Label|Sedation of mechanically ventilated patients

Isoflurane is a commonly used inhalational anesthetic and has an excellent safety record. Isoflurane has been linked to rare instances of severe acute liver injury resembling halothane induced liver injury in small case series and individual case reports.

Anesthetics, Halogenated

FORANE (isoflurane, USP) may be used for induction and maintenance of general anesthesia. Adequate data have not been developed to establish its application in obstetrical anesthesia.|In cases of life-threatening status asthmaticus which are refractory to drug therapy, the administration of inhalation anesthetics can be life-saving as they help alleviate bronchial spasm. We had an 11-year-old female patient suffering from status asthmaticus who was moribund from severe CO2 narcosis and was not responding to any of the conventional therapies. She finally fell into ventricular fibrillation. After cardiopulmonary resuscitation, we administered 2.0% isoflurane in oxygen. Within half an hour, her high inspiratory pressure was dramatically decreased, and then the isoflurane concentration was maintained at 1.0%. After 14 hours of isoflurane anesthesia, PaCO2 decreased to the normal level and the isoflurane treatment was discontinued. The endotracheal tube was removed 4 hours later. She had an uneventful recovery and was discharged from the hospital 11 days later. With its low metabolic rate and therefore low organ toxicity, as well as its low arrhythmogenicity with remarkable bronchodilating activity, we feel isoflurane may well be superior to other inhalation anesthetics in the treatment of status asthmaticus.|Vet: Isoflurane, USP is used for induction and maintenance of general anesthesia in horses and dogs.

Anesthetics, Inhalation|In susceptible individuals, isoflurane anesthesia may trigger a skeletal muscle hypermetabolic state leading to high oxygen demand and the clinical syndrome known as malignant hyperthermia. The syndrome includes nonspecific features such as muscle rigidity, tachycardia, tachypnea, cyanosis, arrhythmias, and unstable blood pressure. (It should also be noted that many of these nonspecific signs may appear with light anesthesia, acute hypoxia, etc.) An increase in overall metabolism may be reflected in an elevated temperature, (which may rise rapidly early or late in the case, but usually is not the first sign of augmented metabolism) and an increased usage of the CO2 absorption system (hot canister). PaO2 and pH may decrease, and hyperkalemia and a base deficit may appear.|Since levels of anesthesia may be altered easily and rapidly, only vaporizers producing predictable concentrations should be used. Hypotension and respiratory depression increase as anesthesia is deepened.|Increased blood loss comparable to that seen with halothane has been observed in patients undergoing abortions.|For more Drug Warnings (Complete) data for Isoflurane (24 total), please visit the HSDB record page.

Isoflurane is a general inhalation anesthetic used for induction and maintenance of general anesthesia. It induces muscle relaxation and reduces pains sensitivity by altering tissue excitability. It does so by decreasing the extent of gap junction mediated cell-cell coupling and altering the activity of the channels that underlie the action potential.

Gases or volatile liquids that vary in the rate at which they induce anesthesia; potency; the degree of circulation, respiratory, or neuromuscular depression they produce; and analgesic effects. Inhalation anesthetics have advantages over intravenous agents in that the depth of anesthesia can be changed rapidly by altering the inhaled concentration. Because of their rapid elimination, any postoperative respiratory depression is of relatively short duration. (From AMA Drug Evaluations Annual, 1994, p173) (See all compounds classified as Anesthetics, Inhalation.)

In the postanesthesia period, only 0.17% of the isoflurane taken up can be recovered as urinary metabolites.|It is not known whether this drug is excreted in human milk.

Minimal|Renal and hepatic toxicity of the fluorinated ether volatile anesthetics is caused by biotransformation to toxic metabolites. Metabolism also contributes significantly to the elimination pharmacokinetics of some volatile agents. Although innumerable studies have explored anesthetic metabolism in animals, there is little information on human volatile anesthetic metabolism with respect to comparative rates or the identity of the enzymes responsible for defluorination. The first purpose of this investigation was to compare the metabolism of the fluorinated ether anesthetics by human liver microsomes. The second purpose was to test the hypothesis that cytochrome P450 2E1 is the specific P450 isoform responsible for volatile anesthetic defluorination in humans. Microsomes were prepared from human livers. Anesthetic metabolism in microsomal incubations was measured by fluoride production. The strategy for evaluating the role of P450 2E1 in anesthetic defluorination involved three approaches: for a series of 12 human livers, correlation of microsomal defluorination rate with microsomal P450 2E1 content (measured by Western blot analysis), correlation of defluorination rate with microsomal P450 2E1 catalytic activity using marker substrates (para-nitrophenol hydroxylation and chlorzoxazone 6-hydroxylation), and chemical inhibition by P450 isoform-selective inhibitors. The rank order of anesthetic metabolism, assessed by fluoride production at saturating substrate concentrations, was methoxyflurane > sevoflurane > enflurane > isoflurane > desflurane > 0. There was a significant linear correlation of sevoflurane and methoxyflurane defluorination with antigenic P450 2E1 content (r = 0.98 and r = 0.72, respectively), but not with either P450 1A2 or P450 3A3/4. Comparison of anesthetic defluorination with either para-nitrophenol or chlorzoxazone hydroxylation showed a significant correlation for sevoflurane (r = 0.93, r = 0.95) and methoxyflurane (r = 0.78, r = 0.66). Sevoflurane defluorination was also highly correlated with that of enflurane (r = 0.93), which is known to be metabolized by human P450 2E1. Diethyldithiocarbamate, a selective inhibitor of P450 2E1, produced a concentration-dependent inhibition of sevoflurane, methoxyflurane, and isoflurane defluorination. No other isoform-selective inhibitor diminished the defluorination of sevoflurane, whereas methoxyflurane defluorination was inhibited by the selective P450 inhibitors furafylline (P450 1A2), sulfaphenazole (P450 2C9/10), and quinidine (P450 2D6) but to a much lesser extent than by diethyldithiocarbamate. These results demonstrate that cytochrome P450 2E1 is the principal, if not sole human liver microsomal enzyme catalyzing the defluorination of sevoflurane. P450 2E1 is the principal, but not exclusive enzyme responsible for the metabolism of methoxyflurane, which also appears to be catalyzed by P450s 1A2, 2C9/10, and 2D6. The data also suggest that P450 2E1 is responsible for a significant fraction of isoflurane metabolism. Identification of P450 2E1 as the major anesthetic metabolizing enzyme in humans provides a mechanistic understanding of clinical fluorinated ether anesthetic metabolism and toxicity.|Isoflurane undergoes minimal biotransformation in man.

Isoflurane induces a reduction in junctional conductance by decreasing gap junction channel opening times and increasing gap junction channel closing times. Isoflurane also activates calcium dependent ATPase in the sarcoplasmic reticulum by increasing the fluidity of the lipid membrane. Also appears to bind the D subunit of ATP synthase and NADH dehydogenase. Isoflurane also binds to the GABA receptor, the large conductance Ca²⁺ activated potassium channel, the glutamate receptor and the glycine receptor.

Fresh air, rest. Artificial respiration may be needed. Refer for medical attention.

Remove contaminated clothes. Rinse and then wash skin with water and soap.

First rinse with plenty of water for several minutes (remove contact lenses if easily possible), then refer for medical attention.

Treatment /of Malignant Hyperthermia/ includes discontinuance of triggering agents (e.g., isoflurane), administration of intravenous dantrolene sodium, and application of supportive therapy. Such therapy includes vigorous efforts to restore body temperature to normal, respiratory and circulatory support as indicated, and management of electrolyte-fluid-acid-base derangements. Renal failure may appear later, and urine flow should be sustained if possible.|/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/|/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/|/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

/HUMAN EXPOSURE STUDIES/ The maternal and neonatal effects of isoflurane and halothane combined with 50% N2O - 50% O2 were compared in 60 healthy parturients undergoing primary or repeat cesarean section. All patients had rapid sequence induction of anesthesia with sodium thiamylal 4 mg/kg followed by succinylcholine for tracheal intubation. Patients were randomly assigned to one of three groups of 20 each (inspired 0.5% isoflurane, 1% isoflurane or 0.5% halothane), combined with 50% N2O and O2. After delivery, 67% N2O in O2 was used, supplemented by butorphanol. Maternal blood loss did not differ significantly among the three groups and none of the patients developed intraoperative awareness. At the time of delivery, maternal plasma epinephrine levels were significantly above preinduction levels in the 0.5% isoflurane group but unchanged in the other two groups. Neonatal status as ascertained by Apgar scores, cord acid base status and the Neurologic and Adaptive Capacity Scores (NACS) was equally good in the three groups of patients. Serum inorganic fluoride concentrations in the mother after anesthesia were not significantly above preanesthetic levels in any of the groups and there was no biochemical evidence of renal toxicity. In all neonates fluoride ion concentrations in the first voided urine sample were less than 7 umol/L, a value well below that associated with nephrotoxicity. It is concluded that isoflurane is a safe supplement to N2O - O2 mixture for cesarean section and is a safer alternative to halothane in situations when patients receiving beta-adrenergic therapy require cesarean section since halothane might potentiate arrhythmias caused by beta adrenergic agonists.|/CASE REPORTS/ We describe a patient with tetanus, who received isoflurane for sedation to facilitate controlled mechanical ventilation. Isoflurane was administered for 34 days, resulting in a sustained serum inorganic fluoride ion concentration in excess of 50 umol /per/ L and a peak serum inorganic fluoride ion concentration of 87 umol /per/ L. Although these concentrations are potentially nephrotoxic, no toxicity was evident clinically.|/CASE REPORTS/ Isoflurane is considered a safe inhalational anesthetic. It has a low level of biotransformation, and low hepatic and renal toxicity. In clinical concentrations, it has minimal negative inotropic effect, causes a small reduction in systemic vascular resistance, and, rarely, can cause cardiac arrhythmias. The objective of this report was to present a case of severe hemodynamic instability in a patient with idiopathic scoliosis. Male patient, 13 years old, ASA physical status I, with no prior history of allergy to medications, scheduled for surgical repair of idiopathic scoliosis. After anesthetic induction with fentanyl, midazolam, propofol, and atracurium, 1% isoflurane with 100% oxygen was initiated for anesthesia maintenance. After five minutes, the patient presented severe hypotension (MAP = 26 mmHg) associated with sinus tachycardia (HR = 166 bpm) that did not respond to the administration of vasopressors and fluids. Lung and heart auscultation, pulse oxymetry, capnography, nasopharyngeal temperature, and arterial blood gases did not change. The patient was treated for anaphylaxis and the surgery was cancelled. The clear temporal relationship between the administration of isoflurane and the symptoms suggested the diagnosis of cardiovascular intolerance to inhalational isoflurane. Two weeks later, total intravenous anesthesia was administered without complications. There are no reports of severe hemodynamic instability caused by isoflurane in previously healthy individuals. Anaphylaxis, supraventricular tachycardia with hemodynamic consequences, and increased cardiac sensitivity to isoflurane are discussed as possible causes of the hemodynamic instability. Currently, there is evidence that isoflurane can interfere in the coupling-uncoupling system of myocardial contractility by reducing cytosolic Ca2+ and/or depressing the function of contractile proteins. The fundamental molecular mechanisms of this process remain to be elucidated. This report suggests that the administration of isoflurane was the cause of the hemodynamic changes; the patient probably developed an unusual cardiovascular sensitivity to the drug.|/GENOTOXICITY/ The alkaline single cell gel electrophoresis (comet) assay was applied to study genotoxic properties of two inhalation anesthetics-halothane and isoflurane-in human peripheral blood lymphocytes (PBL). The cells were exposed in vitro to either halothane (2-bromo-2-chloro-1,1,1-trifluoroethane) or isoflurane (1-chloro-2,2,2-trifluoroethyl difluoromethyl ether) at concentrations 0.1-10 mM in DMSO. The anesthetics-induced DNA strand breaks as well as alkali-labile sites were measured as total comet length (i.e., increase of a DNA migration). Both analysed drugs were capable of increasing DNA migration in a dose-dependent manner. In experiments conducted at two different electrophoretic conditions (0. 56 and 0.78 V/cm), halothane was able to increase DNA migration to a higher extent than isoflurane. The comet assay detects DNA strand breaks induced directly by genotoxic agents as well as DNA degradation due to cell death. For this reason a contribution of toxicity in the observed effects was examined. We tested whether the exposed PBL were able to repair halothane- and isoflurane-induced DNA damage. The treated cells were incubated in a drug-free medium at 37 degrees C for 120 min to allow processing of the induced DNA damage. PBL exposed to isoflurane at 1 mM were able to complete repair within 60 min whereas for halothane a similar result was obtained at a concentration lower by one order of magnitude: the cells exposed to halothane at 1 mM removed the damage within 120 min only partly. We conclude that the increase of DNA migration induced in PBL by isoflurane at 1 mM and by halothane at 0.1 mM was not a result of cell death-associated DNA degradation but was caused by genotoxic action of the drugs. The DNA damage detected after the exposure to halothane at 1 mM was in part a result of DNA fragmentation due to cell death.|For more Human Toxicity Excerpts (Complete) data for Isoflurane (10 total), please visit the HSDB record page.

Isoflurane

The substance can be absorbed into the body by inhalation of its vapour and by ingestion.

Cough. Sore throat. Dizziness. Drowsiness. Headache. Unconsciousness.

Redness. Dry skin.

Redness. Pain.

FORANE (isoflurane, USP) is also supplied in the /250 mL/ aluminum bottles.|FORANE (isoflurane, USP) is packaged in 100 mL and 250 mL amber-colored bottles.|Isoflurane USP is packaged in 250mL (NDC 66794-013-25) and 100mL (NDC 66794-013-10) amber-colored bottles./Vet/

Method: OSHA 103; Procedure: gas chromatography using a flame-ionization detector; Analyte: isoflurane; Matrix: air; Detection Limit: 23.0 ppb (174 ug/cu m) with Anasorb CMS; 23.5 ppb (177 ug/cu m) with Anasorb 747.|Analyte: Isoflurane; matrix: solutions; procedure: high performance liquid chromatography with ultraviolet detection at 203 nm; limit of detection: 0.2 mM

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