TERRELL- isoflurane liquid
Piramal Critical Care Inc
Isoflurane, USP, a nonflammable liquid administered by vaporizing, is a general inhalation anesthetic drug. It is l-chloro-2,2,2-trifluoroethyl difluoromethyl ether, and its structural formula is:
Some physical constants are:
Molecular weight 184.5
Boiling point at 760 mm Hg 48.5 o C (uncorr.)
Refractive index n 20 D 1.2990-1.3005
Specific gravity 25 0/25 o C 1.496
Vapor pressure in mm Hg** 20 o C 238
25 o C 295
30 o C 367
35 o C 450
**Equation for vapor pressure calculation:
Partition coefficients at 37°C:
Partition coefficients at 25 o C — rubber and plastic
Conductive rubber/gas 62.0
Butyl rubber/gas 75.0
Polyvinyl chloride/gas 110.0
Butyl acetate/gas ~2.5
Purity by gas chromatography >99.9%
Lower limit of flammability in oxygen or
nitrous oxide at 9 joules/sec. and 23 o C None
Lower limit of flammability in oxygen or Greater than useful nitrous oxide at 900 joules/sec. and 23 o C concentration in anesthesia.
Isoflurane is a clear, colorless, stable liquid containing no additives or chemical stabilizers. Isoflurane has a mildly pungent, musty, ethereal odor. Samples stored in indirect sunlight in clear, colorless glass for five years, as well as samples directly exposed for 30 hours to a 2 amp, 115 volt, 60 cycle long wave U.V. light were unchanged in composition as determined by gas chromatography. Isoflurane in one normal sodium methoxide-methanol solution, a strong base, for over six months consumed essentially no alkali, indicative of strong base stability. Isoflurane does not decompose in the presence of soda lime (at normal operating temperatures), and does not attack aluminium, tin, brass, iron or copper.
Isoflurane is an inhalation anesthetic. The MAC (minimum alveolar concentration) in man is as follows:
|Age||100% Oxygen||70% N 2 O|
|26 ± 4||128||0.56|
|44 ± 7||1.15||0.50|
|64 ± 5||1.05||0.37|
Induction of and recovery from isoflurane anesthesia are rapid. Isoflurane has a mild pungency, which limits the rate of induction, although excessive salivation or tracheobronchial secretions do not appear to be stimulated. Pharyngeal and laryngeal reflexes are readily obtunded. The level of anesthesia may be changed rapidly with isoflurane. Isoflurane is a profound respiratory depressant. RESPIRATION MUST BE MONITORED CLOSELY AND SUPPORTED WHEN NECESSARY. As anesthetic dose is increased, tidal volume decreases and respiratory rate is unchanged. This depression is partially reversed by surgical stimulation, even at deeper levels of anesthesia. Isoflurane evokes a sigh response reminiscent of that seen with diethyl ether and enflurane, although the frequency is less than with enflurane.
Blood pressure decreases with induction of anesthesia but returns toward normal with surgical stimulation. Progressive increases in depth of anesthesia produce corresponding decreases in blood pressure. Nitrous oxide diminishes the inspiratory concentration of isoflurane required to reach a desired level of anesthesia and may reduce the arterial hypotension seen with isoflurane alone. Heart rhythm is remarkably stable. With controlled ventilation and normal PaC02, cardiac output is maintained despite increasing depth of anesthesia, primarily through an increase in heart rate, which compensates for a reduction in stroke volume. The hypercapnia, which attends spontaneous ventilation during isoflurane anesthesia further increases heart rate and raises cardiac output above awake levels. Isoflurane does not sensitize the myocardium to exogenously administered epinephrine in the dog. Limited data indicate that subcutaneous injection of 0.25 mg of epinephrine (50 mL of 1:200,000 solution) does not produce an increase in ventricular arrhythmias in patients anesthetized with isoflurane.
Muscle relaxation is often adequate for intra-abdominal operations at normal levels of anesthesia. Complete muscle paralysis can be attained with small doses of muscle relaxants. ALL COMMONLY USED MUSCLE RELAXANTS ARE MARKEDLY POTENTIATED WITH ISOFLURANE, THE EFFECT BEING MOST PROFOUND WITH THE NONDEPOLARIZING TYPE.
Neostigmine reverses the effect of nondepolarizing muscle relaxants in the presence of isoflurane. All commonly used muscle relaxants are compatible with isoflurane.
Isoflurane can produce coronary vasodilation at the arteriolar level in selected animal models 1,2; the drug is probably also a coronary dilator in humans. Isoflurane, like some other coronary arteriolar dilators, has been shown to divert blood from collateral dependent myocardium to normally perfused areas in an animal model (“coronary steal”) 3. Clinical studies to date evaluating myocardial ischemia, infarction and death as outcome parameters have not established that the coronary arteriolar dilation property of isoflurane is associated with coronary steal or myocardial ischemia in patients with coronary artery disease 4,5,6,7.
Isoflurane undergoes minimal biotransformation in man. In the postanesthesia period, only 0.17% of the isoflurane taken up can be recovered as urinary metabolites.
Isoflurane may be used for induction and maintenance of general anesthesia. Adequate data have not been developed to establish its application in obstetrical anesthesia.
Known sensitivity to isoflurane or to other halogenated agents.
Known or suspected genetic susceptibility to malignant hyperthermia.
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 C0 2 absorption system (hot canister). Pa0 2 and pH may decrease, and hyperkalemia and a base deficit may appear. Treatment 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. (Consult prescribing information for dantrolene sodium intravenous for additional information on patient management.) Renal failure may appear later, and urine flow should be sustained if possible.
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.
Isoflurane markedly increases cerebral blood flow at deeper levels of anesthesia. There may be a transient rise in cerebral spinal fluid pressure, which is fully reversible with hyperventilation.
As with any potent general anesthetic, isoflurane should only be administered in an adequatelyequipped anesthetizing environment by those who are familiar with the pharmacology of the drug and qualified by training and experience to manage the anesthetized patient.
Regardless of the anesthetics employed, maintenance of normal hemodynamics is important to the avoidance of myocardial ischemia in patients with coronary artery disease 4,5,6,7.
Isoflurane, like some other inhalational anesthetics, can react with desiccated carbon dioxide (CO 2 ) absorbents to produce carbon monoxide, which may result in elevated 2 levels of carboxyhemoglobin in some patients. Case reports suggest that barium hydroxide lime and soda lime become desiccated when fresh gases are passed through the CO 2 absorber canister at high flow rates over many hours or days. When a 2 clinician suspects that CO 2 absorbent may be desiccated, it should be replaced before 2 the administration of isoflurane.
As with other halogenated anesthetic agents, isoflurane may cause sensitivity hepatitis in patients who have been sensitized by previous exposure to halogenated anesthetics (see CONTRAINDICATIONS).
Information for Patients
Isoflurane, as well as other general anesthetics, may cause a slight decrease in intellectual function for 2 or 3 days following anesthesia. As with other anesthetics, small changes in moods and symptoms may persist for up to 6 days after administration.
Transient increases in BSP retention, blood glucose and serum creatinine with decrease in BUN, serum cholesterol and alkaline phosphatase have been observed.
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 N 2 O. (See CLINICAL PHARMACOLOGY).
Carcinogenesis, Mutagenesis, Impairment of Fertility
Swiss ICR mice were given isoflurane to determine whether such exposure might induce neoplasia. Isoflurane was given at 1/2, 1/8 and 1/32 MAC for four in-utero exposures and for 24 exposures to the pups during the first nine weeks of life. The mice were killed at 15 months of age. The incidence of tumors in these mice was the same as in untreated control mice, which were given the same background gases, but not the anesthetic.
Pregnancy Category C
Isoflurane has been shown to have a possible anesthetic-related fetotoxic effect in mice when given in doses 6 times the human dose. There are no adequate and wellcontrolled studies in pregnant women. Isoflurane should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted inhuman milk, caution should be exercised when isoflurane is administered to a nursing woman.
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