Renal toxicity methoxyflurane

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. 

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. 

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. 

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. 

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). 

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 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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