Methoxyflurane toxicity

Isoflurane is a respiratory depressant (71). At concentrations which are associated with surgical levels of anesthesia, there is Htde or no depression of myocardial function. In experimental animals, isoflurane is the safest of the oral clinical agents (72). Cardiac output is maintained despite a decrease in stroke volume. This is usually because of an increase in heart rate. The decrease in blood pressure can be used to produce "deHberate hypotension" necessary for some intracranial procedures (73). This agent produces less sensitization of the human heart to epinephrine relative to the other inhaled anesthetics. Isoflurane potentiates the action of neuromuscular blockers and when used alone can produce sufficient muscle relaxation (74). Of all the inhaled agents currently in use, isoflurane is metabolized to the least extent (75). Unlike halothane, isoflurane does not appear to produce Hver injury and unlike methoxyflurane, isoflurane is not associated with renal toxicity. 

Compounds that Cause Kidney Damage Several drugs and some anesthetic compounds such as methoxyflurane cause kidney damage when present at high doses. Kidney-toxic compounds found in occupational environments include mycotoxins, halogenated hydrocarbons, several metals, and solvents (see Table 5.16). 

Chenoweth, M.B., Leong, B.K.X, Sparschu, G.L. and Torkelson, T.R. (1972). Toxicities of methoxyflurane, halothane and diethyl ether in laboratory animals on repeated inhalation at subanesthetic concentrations. In Cellular Biology and Toxicity of Anesthetics (Fink, B.R., Ed.). Williams Wilkins, Baltimore, pp. 275-284. 

Methoxyflurane damages renal tubules leading to inability to concentrate urine and uraemia. Because of its renal toxicity, it should not be used to achieve profound anaesthesia nor for prolonged periods of time. 

In normal clinical use the peak plasma fluoride concentration rarely exceeds 25 pmohL-l and is well within the threshold for renal toxicity. Significant renal impairment is unlikely in patients with normal renal function. Prolonged enflurane anaesthesia may result in vaso-pressin-resistant type of renal failure with fluoride concentrations of around 30 pmohL-l In contrast to methoxyflurane peak fluoride concentrations occur early (3-4 h) after enflurane and diminish rapidly after discontinuing the agent. 

Direct organ toxicity. Some substances may directly damage cells of a particular organ or system, either because they or their metabolites are specifically toxic to these cells, or because they are concentrated in one area, e.g. the renal fluoride ion toxicity of methoxyflurane, or the liver damage that occurs in paracetamol overdose because of a toxic intermediate product binding to hepatocytes. Secondary effects. Some effects are only indirectly related to the action of the drug, e.g. vitamin deficiency in patients whose gut flora have been modified by broad-spectrum antibiotics. 

The metabolism of enflurane and sevoflurane results in the formation of fluoride ion. However, in contrast to the rarely used volatile anesthetic methoxyflurane, renal fluoride levels do not reach toxic levels under normal circumstances. In addition, sevoflurane is degraded by contact with the carbon dioxide absorbent in anesthesia machines, yielding a vinyl ether called "compound A," which can cause renal damage if high concentrations are absorbed. (See Do We Really Need Another Inhaled Anesthetic ) Seventy percent of the absorbed methoxyflurane is metabolized by the liver, and the released fluoride ions can produce nephrotoxicity. In terms of the extent of hepatic metabolism, the rank order for the inhaled anesthetics is methoxyflurane > halothane > enflurane > sevoflurane > isoflurane > desflurane > nitrous oxide (Table 25-2). Nitrous oxide is not metabolized by human tissues. However, bacteria in the gastrointestinal tract may be able to break down the nitrous oxide molecule. 

Methoxyflurane (see also under H3CO-CF2-CHCl2) ElOa, 53 (Toxicity)... 

Inhaled anesthetics currently in use include halo-genated volatile liquids such as desflurane, enflurane, halothane, isoflurane, methoxyflurane, and sevoflurane (Table 11-1). These volatile liquids are all chemically similar, but newer agents such as desflurane and sevoflurane are often used preferentially because they permit a more rapid onset, a faster recovery, and better control during anesthesia compared to older agents such as halothane.915 These volatile liquids likewise represent the primary form of inhaled anesthetics. The only gaseous anesthetic currently in widespread use is nitrous oxide, which is usually reserved for relatively short-term procedures (e.g., tooth extractions). Earlier inhaled anesthetics, such as ether, chloroform, and cyclopropane, are not currently used because they are explosive in nature or produce toxic effects that do not occur with the more modern anesthetic agents. 

Methoxyflurane This agent is the most potent inhalation anesthetic because of its high solubility in lipid. Prolonged administration of methoxyflurane [meth ox ee FLURE ane] is associated with the metabolic release of fluoride, which is toxic to the kidneys. Therefore, methoxyflurane is rarely used outside of obstetric practice. It finds use in child-birth because it does not relax the uterus when briefly inhaled. 

Nephrotoxicity has been found with methoxyflurane when serum fluoride ion concentrations exceeded 50 pmol/l (SEDA-20,106). Although this safety threshold has been applied to other volatile anesthetics as well, renal toxicity has not been reported for the other three anesthetics, even though the threshold can be exceeded during prolonged anesthesia. 

Modem inhalation anesthetics are fluoiinated to reduce flammabihty. Initially, these inhaled agents were believed to be biochemically inert. Over the past 30 years, however, research findings have demonstrated that not only are inhaled anesthetics metabolized in vivo [27], but their metabolites are also responsible for both acute and chronic toxicities [28,29]. Therefore, the use of some anesthetics has been discontinued, including methoxyflurane because of its nephrotoxicity and other anesthetics are more selectively used, e.g. halothane due to a rare incidence of liver toxicity. Studies have also provided the impetus to develop new agents - isoflurane and desflurane - with properties that lower their toxic potential. The result has been improved safety, but there is room for further improvement as our insight into toxicological mechanisms expands. 

Methoxyflurane is the most potent of the inhalational anesthetics. It is metabolized extensively to fluoride and other nephrotoxic products. Because methoxyflurane does not alter uterine contraction during labor, it is valuable for obstetric anesthesia. Its toxic effects on the respiration and... 

Halothane and naethoxyflurane are metabolized by liver enzymes to a significant extent (see Table 25-2). Metabolism of halothane and methoxyflurane has only a minor influence on the speed of recovery from their anesthetic effect but does play a role in potential toxicity of these anesthetics. 

Methoxyflurane (Fig. 18.6) is seldom used beoause of its propensity to cause renal toxicity. It is the most potent of the agents discussed here, and it has the highest solubility in blood. Induotion and recovery would be expected to be slow. Chemically, it is rather unstable, and as much as 50% of an administered dose can be metabolized. Toxic metabolites significantly limit its utility as a general anesthetic (Fig. 18.7). 

Although few signs of toxicity usually are observed during the short-term, infrequent administration of general anesthetios, a few well-defined toxic effects have been noted. For instance, halothane and methoxyflurane are known to produce hepatotoxicity and nephrotoxicity, respectively. Both of these toxic reactions are believed to result from highly reaotive metabolites of the parent... 

Chenoweth, M. B., B. K. J. Leong, G. L. Spars-chu, and T. R. Torkelson. 1972. Toxicities of methoxyflurane, halothane, and diethyl ether in laboratory animals on repeated inhalation at subanesthetic concentrations. Proceedings of the Symposium on Cellular Biology, Toxicity and Anesthetics, ed. R. B. Fink, pp. 275-85. Baltimore Williams Wilkins. 

Phenytoin toxicity occurred in a child following halothane anaesthesia. A near fatai hepatic reaction occurred in a woman given rifampicin (rifampin) after haiothane anaesthesia, and hepatitis occurred in a patient taking phenobarbitai who was given halothane anaesthesia. See aiso Anaesthetics, generai H- Isoniazid , p.lOO and Anaesthetics, general Methoxyflurane H- Antibacterials or Barbiturates , p.l07. 

The toxicity and metabolism of the fluorinated anaesthetics CF,-CHCIBr (Halothane), CFy-CHj-O-CHiCH, (Fluoroxene), and MeO CF,-CHCIj (Methoxyflurane) have been reviewed (P. H. Rosenberg and M. M. Airaksinen, Fluoride, 1973,6,41), and renal impairment linked with Methoxyflurane anaesthesia has been consider in a review concerning the effects of fluoride on the kidney (J. Jankauskas, Fluoride, 1974, 7, 93). Halothane and Fluoroxene anaesthesiology has been reviewed (S. H. Ngai, Handt. Exp. Pharmakol., 1972, 30, 33 L. E. Morris, ibid., p. 93). 

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