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PubMed1976

Toxic nephropathy after low-dose methoxyflurane anesthesia: drug interaction with secobarbital?

Vasopressin-resistant nonoliguric renal insufficiency developed in a 57-year-old man after 2 1/2 hours of low-dose methoxyflurane anesthesia. Secobarbital, 100 mg daily, had been taken for 1 month before. Of 13 patients in whom the influence of methoxyflurane on renal function was being studied, he was the only one to have taken a drug that induces microsomal enzymes. Blood values of methoxyflurane in this patient were lower than group means on all five occasions during anesthesia. Postoperatively his serum inorganic fluoride value reached 114 mumol/l -- more than two standard deviations greater than the group mean. Peak values for serum urea nitrogen, creatinine and uric acid and postvasopressin urine osmolality, and the lowest creatinine clearance in this patient also differed by more than 2 SD from the group mean, and the peak amount of oxalate excreted in his urine was double the group mean. Pretreatment with the barbiturate appears to have altered methoxyflurane metabolism and led to toxic concentrations of metabolites in the blood.

Drug Interactions↗
PubMed1976

Fluoride in bone of rats anesthetized during gestation with enflurane or methoxyflurane.

Fluoride concentrations in maternal and fetal bones were measured following exposure of pregnant rats to methoxyflurane and enflurane anesthesia. Fluoride content in fetal bone increased significantly only after exposure to methoxyflurane, and then only when methoxyflurane was administered after 12 days of gestation, when ossification of fetal bone begins. Fluoride concentrations in maternal bone increased following both anesthetics, except in rats exposed to methoxyflurane after 15 days of gestation, when ossification of many fetal skeletal parts is in progress and fluoride is preferentially deposited in the fetal skeleton.

Anesthesia, Inhalation↗
PubMed1990

Pharmacokinetics of the acetylcholinesterase oxime reactivator, HI-6, in rhesus monkeys (Macaca mulatta): effect of atropine, diazepam, and methoxyflurane anesthesia.

The pharmacokinetics of the bispyridinium oxime HI-6 (CAS reg. no. 34433-31-3; 1-(((4-aminocarbonyl)pyridinio)methoxy)methyl)-2-[hydroxy i mino)methyl)- pyridinium dichloride) was investigated in rhesus monkeys (Macaca mulatta). The effects of methoxyflurane anesthesia, administration of atropine with and without diazepam were determined on the serum half-life (t1/2), clearance rate (CL), and the volume of distribution (Vd) following intramuscular (IM) administration of HI-6 (30 mg kg-1). The control t1/2, CL and Vd of HI-offere 27 min, 8.6 ml min-1 kg-1 and 0.34 l kg-1, respectively. These parameters were unaffected by the co-administration of either atropine (0.5 mg kg-1, IM) or atropine and diazepam (0.5 mg kg-1, IM + 0.2 mg kg-1 IV, respectively). Methoxyflurane anesthesia resulted in a significant increase in the HI-6 t1/2 to 61 min concomitant with a decrease in the CL to 4.1 ml min-1 kg-1 with no change in the Vd. The increase in the t1/2 of HI-6 in methoxyflurane anesthetized monkeys is probably the result of a decrease in the clearance rate and, thus, excretion of HI-6 by the kidneys.

Anesthesia↗
PubMed1975

Maternal and foetal effects of methoxyflurane anaesthesia in the pregnant ewe.

Maternal and foetal cardiovascular, blood gas and acid-base changes were studied during 90 minutes of methoxyflurane anaesthesia. At 1.0 and 1.5 MAC anaesthesia, despite slight to moderate falls in maternal blood pressure, cardiac output and uterine blood flow, no serious foetal deterioration was seen. 2.0 MAC methoxyflurane was associated with marked falls in maternal blood pressure, cardiac output and uterine blood flow. Foetal hypoxaemia and a mixed respiratory and metabolic acidosis developed. Little foetal cardiovascular depression was seen with any level of anaesthesia. There was no direct effect of methoxyflurane on the uterine vasculature.

Acid-Base Equilibrium↗
PubMed1975

Doses of epinephrine causing arrhythmia during enflurane, methoxyflurane and halothane anaesthesia in dogs.

The arrhythmogenic dosage of epinephrine, administered by constant intravenous infusion, was measured in five dogs during enflurane, methoxyflurane and halothane anaesthesia. While premature ventricular contractions were observed in only one of five dogs with enflurane and methoxyflurane, epinephrine-induced arrhythmias were seen in all animals during halothane anaesthesia. Epinephrine dosage and the resultant increase in mean arterial blood pressure at which arrhythmias occurred during halothane anaesthesia were significantly less (p less than 0.05) than with the other anaesthetics. These observations indicate that enflurane and methoxyflurane, as compared to halothane, possess relatively less arrhythmogenic potential as sensitizing agents in the presence of increased circulating catecholamines.

Anesthesia, Inhalation↗
PubMed1983

Methoxyflurane hepatitis: two cases following obstetric analgesia.

Methoxyflurane is utilized in obstetrics for analgesia during labor. It has been recognized as an unpredictable hepatotoxin. Although hepatitis has been seen after its use in anesthesia, only one case of hepatitis has been reported after its use for analgesia in labor. Two more cases of hepatitis following methoxyflurane analgesia are reported. Direct toxic effects of its metabolites and host idiosyncrasy may underlie the hepatic injury from methoxyflurane.

Adult↗
PubMed1995

The stoichiometry of the cytochrome P-450-catalyzed metabolism of methoxyflurane and benzphetamine in the presence and absence of cytochrome b5.

The complete stoichiometry of the metabolism of the cytochrome b5 (cyt b5)-requiring substrate, methoxyflurane, by purified cytochrome P-450 2B4 was compared to that of another substrate, benzphetamine, which does not require cyt b5 for its metabolism. Cyt b5 invariably improved the efficiency of product formation. That is, in the presence of cyt b5 a greater percentage of the reducing equivalents from NADPH were utilized to generate substrate metabolites, primarily at the expense of the side product, superoxide. With methoxyflurane, cyt b5 addition always resulted in an increased rate of product formation, while with benzphetamine the rate of product formation remained unchanged, increased or decreased. The apparently contradictory observations of increased reaction efficiency but decrease in total product formation for benzphetamine can be explained by a second effect of cyt b5. Under some experimental conditions cyt b5 inhibits total NADPH consumption. Whether stimulation, inhibition, or no change in product formation is observed in the presence of cyt b5 depends on the net effect of the stimulatory and inhibitory effects of cyt b5. When total NADPH consumption is inhibited by cyt b5, the rapidly metabolized, highly coupled (approximately equal to 50%) substrate, benzphetamine, undergoes a net decrease in metabolism not counterbalanced by the increase in the efficiency (2-20%) of the reaction. In contrast, in the presence of the slowly metabolized, poorly coupled (approximately equal to 0.5-3%) substrate, methoxyflurane, inhibition of total NADPH consumption by cyt b5 was never sufficient to overcome the stimulation of product formation due to an increase in efficiency of the reaction.

Animals↗
PubMed1976

Changes in kidney and liver function after methoxyflurane (penthrane) anaesthesia.

Three groups of patients receiving methoxyflurane or halothane or pethidine after thiopentone suxamethonium induction were compared. Using multivariate Student t tests with simultaneous confidence intervals, significant differences in the test battery of uric acid, creatinine, blood urea nitrogen and sodium in the methoxyflurane series compared with the other series was found, indicating transient impaired kidney function. Likewise, there was a significant difference between the methoxyflurane and the other series in the s.g.p.t., s.g.o.t., alkaline phosphatase and bilirubin test battery, indicating impaired liver function. This was found after doses less than 16 ml which, so far, had been considered to be without any toxic effects.

Adult↗
PubMed1979

Preservation of the hypoxic pulmonary vasoconstrictor mechanism during methoxyflurane anaesthesia in the dog.

The effect of methoxyflurane on the hypoxic pulmonary vasoconstrictor response in the dog lung was assessed by measuring the redistribution of pulmonary blood flow in response to two levels of unilateral alveolar hypoxia. Methoxyflurane 0.5% had no significant effect on the redistribution of blood flow resulting from the unilateral administration of oxygen 7% or nitrogen and there were no significant differences in PaO2 between the measurements made during unilateral hypoxia with methoxyflurane and those made during unilateral hypoxia in the control periods.

Anesthesia, Inhalation↗
PubMed1975

Methoxyflurane anesthesia in pediatric patients: evaluation of anesthetic metabolism and renal function.

Serum ionic fluoride concentrations during and following low-dose (6.0 mg/100 ml, 3 hours) methoxyflurane anesthesia and elective operation were measured in 13 pediatric patients (mean age 10.2 years; mean weight 34.5 kg). Peak measured serum ionic fluoride concentration was 21.6 plus or minus 3.3 mumol/1 24 hours after anesthesia. In a previously reported study of adult patients (47.5 years; 71.9 kg), the peak measured serum ionic fluoride concentration was 43.9 plus or minus 5.7 mumol/1 24 hours after low-does (6.8 mg/100 ml,3 hours) methoxyflurane anesthesia. Possible explanations for lower serum ionic fluoride concentrations in pediatric patients comared with adults include 1) slower metabolism of nethoxyflurand; 2) increased renal clearance of ionic fluoride from the blood; 3) greater sorage of ionic fluride in bone; 4) more rapid methoxyflurane elimiantion in the postoperative period. Serum uric acid increased (4.4 to 6.4 mg/100 ml, not significant) 24 hours after anesthesia and operation, while blood urea nitrogen and serum creatinine and osmolality were unchanged postoperatively.

Anesthesia, Inhalation↗
PubMed1976

Metabolism of methoxyflurane in man.

Excretion of methoxyflurane was studied in 12 patients receiving anesthesia in a closed rebreathing circuit at a constant alveolar concentration of approximately 0.24 per cent. The mean methoxyflurane uptake was 18 g (range 7.6-31 g) during a mean time of anesthesia administration of 2 hours, 18 minutes (range 55-309 minutes). An average of 19 per cent of the uptake was recovered unchanged in the exhaled air after anesthesia. Urinary excretion of organic fluorine, fluoride, and oxalic acid was equivalent to 29, 7.7 and 7.1 per cent of methoxyflurane uptake, respectively. Approximately a third of the uptake remained unrecovered. It is postulated that a portion of the unrecovered drug became permanently bound to tissues and hence its excretion was delayed beyond the period of the study.

Acetates↗
PubMed1976

Kinetics of methoxyflurane biotransformation with reference to substrate inhibition.

The kinetics of biotransformation of methoxyflurane by rat hepatic microsomes in vitro was studied. The rate of biotransformation as measured by analysis of metabolites continued to increase even at near-saturation concentrations of the anesthetic. Methoxyflurane biotransformation followed either an unbounded curve with empirical formula y = a ln(bx + 1) or an asymptotic curve with formula (see article) No substrate inhibition was observed. Total fluoride Vmax of 135.1 mmumol F-/mg protein/30' was increased to 931.9 by phenobarbital induction; free fluoride Vmax from 39.2 to 403.2. Thus, enzyme induction shifted biotransformation to the production of greater amounts of inorganic free fluoride metabolites than organic fluoride-containing metabolites. Phenobarbital induction caused qualitative as well as quantitative alteration in the biotransformation of methoxyflurane.

Anesthesia, Inhalation↗
PubMed1980

Hepatic and renal effects of low concentrations of methoxyflurane in exposed delivery ward personnel.

During five alternating three-week periods either methoxyflurane-nitrous oxide or nitrous oxide alone was used for obstetrical analgesia. Delivery ward personnel were followed by venous blood samples once a week. Analyses of blood urea nitrogen, serum uric acid, SGOT and SGPT showed significantly elevated levels three days after exposure to methoxyflurane. This study demonstrates the importance of the scavenging of anesthetic gases to reduce the exposure of personnel to inhalational agents used in delivery suites. Since definite alterations in the indices of both hepatic and renal functions were recognized in obstetrical personnel following exposure, a re-evaluation of the use of methoxyflurane for obstetrical analgesia is suggested.

Alanine Transaminase↗
PubMed1985

Hepatic and renal effects of prolonged exposure of rats to 50 p.p.m. methoxyflurane.

Male Fischer 344 rats were exposed to air or to 50 p.p.m. methoxyflurane vapour for a period of 14 weeks. At the end of this period, half of the rats in each group were killed; the remainder breathed air only for a further four weeks (recovery period) before being killed. During the exposure period, growth of the methoxyflurane-exposed rats was markedly depressed, though food consumption was similar in the two groups. Both water consumption and urine volume were increased by methoxyflurane, possibly due to the nephrotoxic effect of fluoride, the concentration of which exceeded 50 micromolar in the sera of all exposed rats. At the end of the exposure period, livers of all exposed rats, but no controls, showed focal hepatocellular degeneration and necrosis, and evidence of liver cell regeneration. Fatty change was prominent. During the recovery period, water consumption and urine volumes returned to near-normal levels. At the end of the recovery period, focal necrosis was still observed in the livers, although fatty change was no longer present. No histological abnormalities were observed in the kidneys of any rats.

Animals↗
PubMed1975

Blood circulation in the kidney of the cat under methoxyflurane (penthrane) anaesthesia.

In order to establish whether methoxyflurane causes any change in renal vascular resistance, the renal venous flow was measured by means of a drop recording technique in six cats under methoxyflurane anaesthesia. Arterial pressure was recorded simultaneously, and the renal vascular resistance was calculated. Methoxyflurane caused a significant reduction of the renal vascular resistance to about 85% of control value at an anaesthetic depth characterised by loss of the corneal reflex. At a deeper anaesthetic stage characterised by steady state circulation and absence of any reflexes, no further significant fall in renal vascular resistance occurred. Autoregulation and depression of the sympathetic activity are assumed to explain the reduction of the renal vascular resistance.

Anesthesia, Inhalation↗
PubMed1978

Cardiac function during induction and early anesthesia with methoxyflurane. An evaluation using systolic time intervals and pressure time indices.

In addition to the standard monitoring of heart rate and blood pressure, the Systolic Time Intervals were used to evaluate cardiac performance, and the Pressure Time Indices (tension time index = TTI; diastolic pressure time index = DPTI) were used to estimate myocardial oxygen balance. Twelve patients with known heart disease were studied during induction with thiopental, intubation, and early anesthesia with methoxyflurane. Cardiac performance diminished after thiopental; and during methoxyflurane it was reflected in increases in pre-ejection period (PEP) and the ratio PEP/LVET. Intubation resulted in a hyperactive state of the heart, as shown by maximal decreases in PEP and PEP/LVET. Myocardial oxygen balance--estimated from the supply/demand ratio (DPTI/TTI)--was impaired after thiopental. After intubation, DPTI/TTI decreased to its lowest value due to an excess of myocardial oxygen demand (TTI) over myocardial oxygen supply (DPTI), signifying a transitory underperfusion of the subendocardium. During methoxyflurane the oxygen balance was gradually restored towards control value. The Systolic Time Intervals and the Pressure Time Indices provided valuable information on cardiac function not available from standard monitoring alone.

Adult↗
PubMed1978

Recovery from anaesthesia in ponies: a comparative study of the effects of isoflurane, enflurane, methoxyflurane and halothane.

The duration and quality of recovery after separate 2 hour anaesthetic periods with equipotent alveolar concentrations of isoflurane, enflurane, halothane and methoxyflurane were evaluated in experimental ponies. Recovery was shortest after isoflurane anaesthesia, followed by enflurane, halothane and finally methoxyflurane, although standing was achieved more rapidly after enflurane than after isoflurane. This sequence of recovery times was compatible with the respective solubilities of the 4 agents. The smoothest recovery was obtained after isoflurane anaesthesia, followed by methoxyflurane, halothane and then enflurane. The isoflurane recovery was characterized by very quiet and prolonged sternal recumbency with excellent coordination upon standing. The chief difficulties with halothane recovery were shivering and delayed coordination upon standing. Enflurane anaesthesia was followed by a very brief period of sternal recumbency but there was considerable shivering and incoordination upon standing. This may have been due to central nervous stimulation during anaesthesia producing a residual excitatory effect. On the basis of this investigation, isoflurane was considered to be the most satisfactory volatile anaesthetic for the horse.

Anesthesia, Inhalation↗
PubMed1981

Effects of thyroid dysfunction on the metabolism of halothane, enflurane and methoxyflurane in rats.

The effect of thyroid dysfunction on the metabolism of halothane (100 ppm), enflurane (100 ppm) and methoxyflurane (300 ppm) was investigated during application by inhalation. In male rats the elimination half-lives from the atmosphere of the exposure system amounted to 0.76h for halothane, 6.84h for enflurane and 0.64h for methoxyflurane. Hyperthyroidism due to three daily injections of 0.1 mg/kg triiodothyronine i.p. significantly shortened the half-lives of all three inhalation anesthetics. Hypothyroidism due to operative removal of the thyroid gland affected the metabolism of halothane only as evidenced by a prolongation of the elimination half-life while enflurane and methoxyflurane half-lives remained unchanged. The observed differences in metabolic rates are explained by different metabolic pathways of the three compounds. They may be important for the manifestation of toxic effects.

Animals↗