Generic Name: isoflurane
Dosage Form: inhalant
Isoflurane, USP, a nonflammableliquid administered by vaporizing, is a general inhalationanesthetic drug. It isl-chloro-2,2,2-trifluoroethyl difluoromethyl ether, and its structural formulais:
Some physical constants are:
Boiling point at 760 mm Hg 48.5° C(uncorr.)
Specificgravity 25° / 25°C 1.496
Vapor pressurein mm Hg**20° C 238
25° C 295
30° C 367
35° C 450
**Equation for vapor pressurecalculation: log10Pvap= A + B/T
A = 8.056
B = -1664.58
T = ° C + 273.16 (Kelvin)
Partitioncoefficients at 37° C:
Partitioncoefficients at 25° C - rubber and plastic
Butylrubber / gas 75.0
Polyethylene / gas ~2.0
Polyurethane / gas ~1.4
Polyolefin / gas ~1.1
Butylacetate / gas ~2.5
Purity by gaschromatography >99.9%
Lower limit offlammability in oxygen ornitrous oxideat 9 joules/sec. and 23° C None
Lower limit offlammability in oxygen or nitrous oxide at 900 joules/sec. and 23° C Greater than usefulconcentration 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 glassfor 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 gaschromatography. Isoflurane in onenormal sodium methoxide-methanol solution, a strong base,for over six months consumedessentially no alkali, indicative of strong base stability. Isofluranedoes not decompose in thepresence of soda lime (at normal operating temperatures), and doesnotattack aluminium, tin, brass, iron or copper.
Terrell Isoflurane - Clinical Pharmacology
Isoflurane is an inhalationanesthetic. The MAC (minimum alveolar concentration) in man is asfollows:
26 ± 4
44 ± 7
64 ± 5
Induction of and recovery fromisoflurane anesthesia are rapid. Isoflurane has a mild pungency,which limits the rate ofinduction, although excessive salivation or tracheobronchial secretions do notappear to be stimulated. Pharyngeal and laryngeal reflexes are readilyobtunded. The level of anesthesia may be changed rapidly with isoflurane.Isoflurane is a profound respiratorydepressant. RESPIRATION MUST BEMONITORED CLOSELY AND SUPPORTED WHEN NECESSARY.
As anesthetic dose is increased,tidal volume decreases and respiratory rate is unchanged. Thisdepression is partially reversedby surgical stimulation, even at deeper levels of anesthesia.Isoflurane evokes a sigh responsereminiscent of that seen with diethyl ether and enflurane,although the frequency is lessthan with enflurane.
Blood pressure decreases withinduction of anesthesia but returns toward normal with surgicalstimulation. Progressiveincreases in depth of anesthesia produce corresponding decreases inblood pressure. Nitrous oxidediminishes the inspiratory concentration of isoflurane required toreach a desired level ofanesthesia and may reduce the arterial hypotension seen with isofluranealone. Heart rhythm is remarkablystable. With controlled ventilation and normal PaCO2, cardiacoutput is maintained despiteincreasing depth of anesthesia, primarily through an increase in heart rate,which compensates for a reduction in stroke volume. The hypercapnia, whichattendsspontaneous ventilation duringisoflurane anesthesia further increases heart rate and raisescardiac output above awakelevels. Isoflurane does not sensitize the myocardium to exogenouslyadministered epinephrine in thedog. Limited data indicate that subcutaneous injection of 0.25 mg ofepinephrine (50 mL of 1:200,000 solution) does not produce an increase inventriculararrhythmias in patientsanesthetized with isoflurane.
Muscle relaxation is oftenadequate for intra-abdominal operations at normal levels of anesthesia. Complete muscle paralysis can be attainedwith small doses of muscle relaxants. ALL COMMONLY USED MUSCLE RELAXANTS AREMARKEDLY POTENTIATED WITH ISOFLURANE, THE EFFECT BEING MOST PROFOUND WITH THENONDEPOLARIZING TYPE. Neostigmine reverses the effect of nondepolarizing musclerelaxants in the presence of isoflurane. All commonly used muscle relaxants arecompatible with isoflurane.
Isoflurane can produce coronaryvasodilation at the arteriolar level in selected animal models1,2;the drug is probably also acoronary dilator in humans. Isoflurane, like some other coronaryarteriolar dilators, has beenshown to divert blood from collateral dependent myocardium tonormally perfused areas in ananimal model (“coronary steal”)3. Clinicalstudies to dateevaluating myocardial ischemia,infarction and death as outcome parameters have notestablished that the coronaryarteriolar dilation property of isoflurane is associated with coronarystealor myocardial ischemia in patients with coronary artery disease4,5,6,7.
Isofluraneundergoes minimal biotransformation in man. In the postanesthesia period, only0.17% of the isoflurane taken up can be recovered as urinary metabolites.
INDICATIONS & USAGE
Isoflurane may be used forinduction and maintenance of general anesthesia. Adequate data have notbeen developed to establish its application in obstetrical anesthesia.
Known sensitivity to isofluraneor to other halogenated agents.
Knownor suspected genetic susceptibility to malignant hyperthermia.
Use of inhaled anesthetic agentshas been associated with rare increases in serum potassium levels that haveresulted in cardiac arrhythmias and death in pediatric patients during the postoperativeperiod. Patient with latent as well as overt neuromuscular disease,particularly Duchenne muscular dystrophy, appear to be most vulnerable.Concomitant use of succinylcholine has been associated with most, but not all,of these cases. These patients also experienced significant elevations in serumcreatinine kinase levels and, in some cases, changes in urine consistent withmyoglobinuria. Despite the similarity in presentation to malignant hyperthermia,none of these patients exhibited signs or symptoms of muscle rigidity or hypermetabolicstate. Early and aggressive intervention to treat the hyperkalemia andresistant arrhythmias is recommended, as is subsequent evaluation for latentneuromuscular disease.
In susceptible individuals,isoflurane anesthesia may trigger a skeletal muscle hypermetabolic state leadingto high oxygen demand and the clinical syndrome known as malignanthyperthermia. The syndrome includes nonspecific features such as musclerigidity, tachycardia, tachypnea, cyanosis, arrhythmias, and unstable bloodpressure. (It should also be noted that many of these nonspecific signs mayappear with light anesthesia, acute hypoxia, etc.) An increase in overallmetabolism may be reflected in an elevated temperature (which may rise rapidlyearly or late in the case, but usually is not the first sign of augmentedmetabolism) and an increased usage of the CO2 absorption system (hotcanister). PaO2 and pH may decrease, and hyperkalemia and a basedeficit may appear. Treatment includes discontinuance of triggering agents(e.g., isoflurane), administration of travenous dantrolene sodium, andapplication of supportive therapy. Such therapy includes gorous efforts torestore body temperature to normal, respiratory and circulatory support as indicated,and management of electrolyte-fluid-acid-base derangements. (Consultprescribing information for dantrolene sodium intravenous for additionalinformation on patient management.) Renal failure may appear later, and urineflow should be sustained if possible.
Since levels ofanesthesia may be altered easily and rapidly, only vaporizers producingpredictable concentrations should be used. Hypotension and respiratorydepression increase as anesthesia is deepened.
Increased blood losscomparable to that seen with halothane has been observed in patients undergoingabortions.
Isoflurane markedly increases cerebral blood flow at deeper levels ofanesthesia. There may be a transient rise in cerebral spinal fluid pressure,which is fully reversible with hyperventilation.
As with any potentgeneral anesthetic, isoflurane should only be administered in an adequately equippedanesthetizing environment by those who are familiar with the pharmacology ofthe drug and qualified by training and experience to manage the anesthetized patient.
Regardless of theanesthetics employed, maintenance of normal hemodynamics is important to theavoidance of myocardial ischemia in patients with coronary artery disease4,5,6,7.
Isoflurane, like someother inhalational anesthetics, can react with desiccated carbon dioxide (CO2)absorbents to produce carbon monoxide, which may result in elevated levels ofcarboxyhemoglobin in some patients. Case reports suggest that barium hydroxidelime and soda lime become desiccated when fresh gases are passed through the CO2absorber canister at high flow rates over many hours or days. When a cliniciansuspects that CO2 absorbent may be desiccated, it should be replacedbefore the administration of isoflurane.
As with other halogenated anesthetic agents, Isoflurane may causesensitivity hepatitis in patients who have been sensitized by previous exposureto halogenated anesthetics (see CONTRAINDICATIONS).
INFORMATION FOR PATIENTS
Isoflurane, as well asother general anesthetics, may cause a slight decrease in intellectual functionfor 2 or 3 days following anesthesia. As with other anesthetics, small changesin moods and symptoms may persist for up to 6 days after administration.
Transient increases in BSPretention, blood glucose and serum creatinine with decrease in BUN, serumcholesterol and alkaline phosphatase have been observed.
Isoflurane potentiates themuscle relaxant effect of all muscle relaxants, most notably nondepolarizingmuscle relaxants, and MAC (minimum alveolar concentration) is reduced byconcomitant administration of N2O. (See CLINICAL PHARMACOLOGY).
CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY
Swiss ICR mice were givenisoflurane 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 andfor 24 exposures to the pups during the first nine weeks of life. The mice werekilled at 15 months of age. The incidence of tumors in these mice was the sameas in untreated control mice, which were given the same background gases, butnot the anesthetic.
Isoflurane has been shown to have a possible anesthetic-relatedfetotoxic effect in mice when given in doses 6 times the human dose. There areno adequate and well-controlled studies in pregnant women. Isoflurane should beused during pregnancy only if the potential benefit justifies the potentialrisk to the fetus.
Adverse reactionsencountered in the administration of isoflurane are in general dose dependent extensionsof pharmacophysiologic effects and include respiratory depression, hypotensionand arrhythmias.
Shivering, nausea,vomiting and ileus have been observed in the postoperative period.
As with all othergeneral anesthetics, transient elevations in white blood count have beenobserved even in the absence of surgical stress. See WARNINGS for informationregarding malignant hyperthermia and elevated carboxyhemoglobin levels.
During marketing,there have been rare reports of mild, moderate and severe (some fatal) postoperativehepatic dysfunction and hepatitis.
Isoflurane has alsobeen associated with perioperative hyperkalemia (see WARNINGS).
There have been rare post-marketing reports of hepatic failure andhepatic necrosis associated with the use of potent volatile anesthetics,including Isoflurane. Due to the spontaneous nature of these reports, theactual incidence and relationship of Isoflurane to these events cannot beestablished with certainty.
In the event ofoverdosage, or what may appear to be overdosage, the following action should betaken:
Stop drug administration, establish a clear airway and initiate assistedor controlled ventilation with pure oxygen.
DOSAGE & ADMINISTRATION
Premedication shouldbe selected according to the need of the individual patient, taking intoaccount that secretions are weakly stimulated by isoflurane, and the heart ratetends to be increased. The use of anticholinergic drugs is a matter of choice.
The concentration ofisoflurane being delivered from a vaporizer during anesthesia should be known.
This may beaccomplished by using:
a) vaporizerscalibrated specifically for isoflurane;
b) vaporizers fromwhich delivered flows can be calculated, such as vaporizers delivering asaturated vapor which is then diluted. The delivered concentration from such avaporizer may be calculated using the formula:
% Isoflurane = 100 PVFV
FT (PA– PV)
PA =Pressure of atmosphere
PV = Vaporpressure of isoflurane
FV = Flowof gas through vaporizer (mL/min)
FT = Totalgas flow (mL/min)
Isoflurane containsno stabilizer. Nothing in the agent alters calibration or operation of these vaporizers.
Induction withisoflurane in oxygen or in combination with oxygen-nitrous oxide mixtures mayproduce coughing, breath holding, or laryngospasm. These difficulties may beavoided by the use of a hypnotic dose of an ultra-short-acting barbiturate.Inspired concentrations of 1.5 to 3.0% isoflurane usually produce surgicalanesthesia in 7 to 10 minutes.
Surgical levels ofanesthesia may be sustained with a 1.0 to 2.5% concentration when nitrous oxideis used concomitantly. An additional 0.5 to 1.0% may be required whenisoflurane is given using oxygen alone. If added relaxation is required,supplemental doses of muscle relaxants may be used.
The level of blood pressure during maintenance is an inverse function ofisoflurane concentration in the absence of other complicating problems.Excessive decreases may be due to depth of anesthesia and in such instances maybe corrected by lightening anesthesia.
How is Terrell Isoflurane Supplied
Isoflurane, USP ispackaged in 100 mL and 250 mL amber-colored bottles.
100 ML - NDC66794-011-10
250 ML - NDC 66794-011-25
Safety and Handling
There is no specificwork exposure limit established for Isoflurane. However, the National Institutefor Occupational Safety and Health Administration (NIOSH) recommends that noworker should be exposed at ceiling concentrations greater than 2ppm of anyhalogenated anesthetic agent over a sampling period not to exceed one hour.
The predicted effects of acute overexposure by inhalation of Isofluraneinclude headache, dizziness or (in extreme cases) unconsciousness. There are nodocumented adverse effects of chronic exposure to halogenated anesthetic vapors(Waste Anesthetic Gases or WAGs) in the workplace.Although results of some epidemiological studies suggest a link betweenexposure to halogenated anesthetics and increased health problems (particularlyspontaneous abortion), the relationship is not conclusive. Since exposure toWAGs is one possible factor in the findings for these studies, operating roompersonnel, and pregnant women in particular, should minimize exposure.Precautions include adequate general ventilation in the operating room, the useof a well-designed and well-maintained scavenging system, work practices tominimize leaks and spills while the anesthetic agent is in use, and routineequipment maintenance to minimize leaks.
Store at room temperature15 ° to 30°C (59 to 86°F). Isoflurane, contains noadditives and has been demonstrated to be stable at room temperature forperiods in excess of five years.
- J.C. Sill, et al, Anesthesiology 66:273-279, 1987
- R.F. Hickey, et al, Anesthesiology 68:21-30, 1988
- C.W. Buffington, et a l, Anesthesiology 66:280-292, 1987
- S. Reiz, et al, Anesthesiology 59:91-97, 1983
- S. Slogoff and A.S. Keats , Anesthesiology 70:179-188, 1989
- K.J. Tuman, et al, Anesthesiology 70:189-198, 1989
- D.T. Mangano, Editorial Views, Anesthesiology 70:175-178, 1989
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