Isoflurane - Scientific Information
|Form:||Liquid solution, Inhaler|
|Chemical name:||1-chloro-2,2,2-trifluoroethyl difluoromethyl ether|
|Molecular formula and molecular mass:||C3H2ClF5O 184.50|
|Physicochemical properties:||Isoflurane is a nonflammable inhalation anesthetic agent. Isoflurane is a clear, colorless, stable liquid whose purity exceeds 99.9%. No stabilizers are added as these have been found, through controlled laboratory tests, to be unnecessary.|
Isoflurane has the following physical and chemical properties:
As shown by the studies in mouse, rat, dog and rabbit, isoflurane produced a state of general anesthesia on inhalation. Anesthesia of varying depths was produced depending on the dose administered. In general, the anesthesia was characterized by rapid induction with very little salivation, good maintenance and rapid recovery. Recovery was readily affected by discontinuation of isoflurane administration. Relaxation was good, some analgesia was present. The recovery time was dependent on the dose, duration of anesthesia, and the individual animal or animal species. Nausea or vomiting was rare if not absent in dog and rabbits after single or repeated anesthesia.
The minimum alveolar concentration (MAC) of anesthetic preventing movement in 50% of the animals in response to a painful stimulus was determined in ten dogs and the value was found to be 1.46%.
In several studies, dogs anaesthetized with isoflurane at varying exposure times showed physiologically similar effects to halothane and enflurane, but markedly fewer arrhythmias occurred with isoflurane.
Compatibility of isoflurane with epinephrine was assessed by intravenous injection of 10 microg/kg of epinephrine to dogs. The heart was much less sensitive to the arrhythmic effect of epinephrine under isoflurane anesthesia than under halothane. If ventricular fibrillation occurred, the heart was defibrillated and the ability of the beta-adrenergic blocking agent, propranolol, to protect the myocardium against further epinephrine challenge, was assessed by the intravenous injection of 0.5 mg/kg. Propranolol was effective during anesthesia with isoflurane in protecting the myocardium against epinephrine.
Isoflurane produced a negative inotropic effect on the isolated papillary muscle of the cat, causing a work dependent decrease in maximal velocity, peak force, power, and work. Isoflurane altered the contractile state, affecting the cardiac muscle's ability to develop force and shorten. As a result of the study, it was judged that isoflurane was the least myocardial depressant of the group - halothane and isoflurane.
In a final study on cardiovascular effects, halothane and isoflurane inhibited phenylephrine induced contraction of isolated rat aorta in a dose-dependent manner, confirming their cardio-depressive action on smooth muscle.
Isoflurane was administered to thirteen healthy cats with implanted recording electrodes in the brain. Anesthetic concentration was varied and depths to create synchronous spike discharges were reached. Rarely was there motor activity.
Recovery was smooth and uneventful. It was concluded that isoflurane was a fast acting, potent anesthetic with desirable attributes for anesthesia. The electroencephalographic pattern was distinct.
Studies in dogs indicated that isoflurane does not cause EEG spiking or convulsive activity either at high, normal or low levels of arterial PCO2. Twitching or other muscular movement suggesting increased central nervous system hyperactivity is not provoked by isoflurane.
The metabolism of isoflurane by the enzymatic system has been studied in rat and miniature swine.
Metabolic studies have shown that isoflurane is only minimally metabolized when compared with other common anesthetic agents. The amount of isoflurane extracted or metabolized by the liver of three miniature swine exposed to this product over periods of from 20 hours to one week was found to be less than 2% confirming the very low biotransformation of this agent. Other studies, in rats with repeated exposure to sub-anesthetic levels of the agent, suggest that isoflurane is less toxic than other halogenated agents (methoxyflurane).
The LD50 in mice by intraperitoneal injection of isoflurane in olive oil was found to be 6.74 g/kg at 24 hours. The animals showed disorientation and hypnosis. Convulsions occurred at higher doses.
Long-term effects on various organ systems were studied in dogs, monkeys, rats, mice, rabbits and guinea pigs.
A group of 48 mice were anesthetized with 0.015 to 0.15% isoflurane for a total of 35-day. Slower weight gains, and some small liver lesions were the only effects. In a similar study, 31 mice receiving 0.15 to 0.30% isoflurane for 21 days showed no auto- or cross-tolerance build-up to isoflurane anesthesia.
The animals were placed in large plastic bags containing 0.015, 0.05 and 0.15% isoflurane for a 35-day total exposure. Slower weight gains and small liver lesions were the only effects; no other histopathological effects were noted.
In four separate studies, Beagle dogs were exposed to isoflurane 1.0 to 3.0% concentration for 2 to 3 hours per days for 4 days. With the exception of one study where kidney and liver exhibited slight fatty deposits, all other studies showed normal blood, urine, kidney and liver results.
Two groups of 5 Rhesus monkeys each were anaesthetized with 1.0 to 2.5% isoflurane for 4 hours per day for 4 days. Blood results were within normal limits; in some cases, kidney, liver and lung exhibited minute traces of fatty deposits. The minimal changes found in liver and kidney tissues did not indicate that isoflurane was nephrotoxic or hepatotoxic.
Five New Zealand white rabbits were anaesthetized with 0.75% isoflurane for 3 hours for 5 con-secutive days. Histopathological studies revealed fatty infiltration of the kidneys but no liver or lung tissue abnormalities.
Hepatic/Renal toxicity studies were performed on dogs receiving a maximum of 2.25% isoflurane for 4 to 6 hours. Blood and liver results were normal but fatty deposits were seen in kidney histological sections.
Mutagenicity and Carcinogenicity
Mutagenicity studies using rat and hamster tissue were performed by the Ames test and the sister-chromatid exchange test. Results indicate that isoflurane is not mutagenic.
In carcinogenicity studies with 432 Swiss ICR mice and 330 CDBR rats, no tumourigenicity was evident with long-term exposure.
Reproduction and Teratology
A study designed to evaluate the effects of isoflurane upon reproduction performance in rats was conducted. Test animals were subjected to inhalation of test material vapor at a concentration of 0.15 or 0.60% for 2 hours daily on each of 14 days prior to mating. Control animals were subjected to chamber air.
Isoflurane exhibited no deleterious effects upon pre-implantation development or implantation itself. Fertility indices, litter sizes and early resorptions - all measures of possible early problems - were comparable to control values.
Teratogenicity studies on 60 rats and 30 mice (gestation day 6 to 15) with isoflurane exposure of 2 hours per day for 10 days showed no major abnormalities. Fetuses were normal. No visceral or skeletal defects due to exposure were detected. At higher doses, depression of growth rate was noted (0.4% isoflurane in rats) and resorption rates increased (0.3% isoflurane in mice).
Peri-post-natal studies on 20 rats (gestation day 15 to 20) were conducted using 0.1 to 0.4% isoflurane for 2 hours per day for 6 days. No female rats showed any ill-effects.
No treatment related effects were observed on litter numbers, pup weights, appearance, growth rates or survival to weaning.