Enflurane toxicity

Isoflurane, an isomer of enflurane, together with sevoflurane are the most commonly used inhalation anesthetics in humans. Isoflurane does not sensitize the myocardium to catecholamines, has muscle relaxing action so less neuromuscular blocker is required and causes less hepatotoxicity and renal toxicity than halothane. 

Four highly fluorinated ethers with low boiling points are currently used in anesthesia enflurane, isoflurane, sevoflumne, and desflurane (Figure 8.89). Des-flurane and sevoflurane are now the most used (sevoflurane is especially used in pediatrics). They exhibit the lowest blood-gas partition coefficients, the lowest ratio of toxic metabolites, and the lowest solubilities in lipids. These features limit the retention and, consequently, the metabolism is delayed (Table 8.2). 

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. 

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. 

Isoflurane is a volatile colourless liquid, which is not flanamable at normal anaesthetic concentrations. It is relatively insoluble, and has a lower blood/gas coefficient than halothane or enflurane, which allows rapid adjustment of the depth of anaesthesia. It has a pungent odour and can cause bronchial irritation, which makes inhalational induction unpleasant. Isoflurane is minimally metabolised (0.2%), and none of the breakdown products has been related to anaesthetic toxicity. 

Numerous studies have addressed the same issues raised with enflurane regarding fluoride production and nephrotoxic potential including fluoride levels after prolonged exposure [56,57,59], urine concentrating ability [57, 59-61], the effect of obesity [57, 60], and the effect of preexisting renal function impairment [62,63]. The findings demonstrated that sevoflurane has little or no potential for fluoride-induced nephrotoxicity (For further information see section on mechanisms of fluoride toxicity). 

Perhaps more important than potency differences are toxicity differences. Halothane would have the most potential for an improved anesthetic if it can be shown that one enantiomer is less toxic than the racemate. Outside the U.S., halothane is still used but its liver toxicity is so great that a long time period must pass between surgeries that use halothane for anesthesia 34), It has recently been found that both halothane (55) and enflurane (56) show stereoselective hepatic metabolism, a possible indication that one enantiomer of the anesthetics may be less toxic than the other. 

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