Methoxyflurane metabolism

B.S. Selinsky, M.E. Perlman, R.E. London, In vivo nuclear magnetic resonance studies of hepatic methoxyflurane metabolism. I. Verification and quantitation of methoxydifluoroacetate. Mol. Pharmacol. 33 (1988) 559-566. 

Mazze RI,Trudell JR, Cousins MJ. Methoxyflurane metabolism and renal dysfunction clinical correlation in man. Anesthesiology 1971 35(3) 247-52. 

Methoxyflurane metabolism produces inorganic fluorine, fluoride and oxalic acid. These are excreted through the urine and may cause renal damage. 

Canova-Davis E, Waskell L (1984) The identification of the heat-stable mierosomal protein required for methoxyflurane metabolism as cytochrome b5. J Biol Chem 259 2541-2546... 

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 (Penthmne) is the most potent inhala-tional agent available, but its high solubility in tissues limits its use as an induction anesthetic. Its pharmacological properties are similar to those of halothane with some notable exceptions. For example, since methoxyflurane does not depress cardiovascular reflexes, its direct myocardial depressant effect is partially offset by reflex tachycardia, so arterial blood pressure is better maintained. Also, the oxidative metabolism of methoxyflurane results in the production of oxalic acid and fluoride concentrations that approach the threshold of causing renal tubular dysfunction. Concern for nephrotoxicity has greatly restricted the use of methoxyflurane. 

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. 

In the case of the newest agent, sevoflurane, induction of anesthesia is achieved rapidly and smoothly, and recovery is more rapid than most other inhaled anesthetics including isoflurane. However, sevoflurane is chemically unstable when exposed to carbon dioxide absorbents, degrading to an olefinic compound (fluoromethyl-2,2-difluoro-l-[trifluoromethyl]vinyl ether, compound A) that is potentially nephrotoxic. In addition, sevoflurane is metabolized by the liver to release fluoride ions, raising concerns about possible renal damage similar to that caused by methoxyflurane. Sevoflurane comes close to having the characteristics of an ideal gas anesthetic, but a relatively insoluble compound that has greater chemical stability could be a useful alternative in the future. 

Kharasch ED, Hankins DC, Thummel KE. Human kidney methoxyflurane and sevoflurane metabolism. Intrarenal fluoride production as a possible mechanism of methoxyflurane nephrotoxicity. Anesthesiology 1995 82 689-699. 

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. 

SCHEME 11.18 The metabolism of carbon tetrachloride is characterized by the formation of free radicals. Halo thane and methoxyflurane are sinailarly metabolized. 

Methoxyflurane, enflurane, isoflurane, and sevoflurane all release inorganic fluoride ions as a result of hepatic metabolism. Fluoride is nephrotoxic. 

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. 

CookTL, Beppu WJ, Hitt BA, Kosek JC, Mazze Rl. A comparison of renal effects and metabolism of sevoflurane and methoxyflurane In enzyme-induced rats. Anesth Anaig 1975 54(6) 829-35. 

Kharasch ED, Schroeder JL, Liggitt EID, Park SB, Whittington D, Sheffels P. New insights into the mechanism of methoxyflurane nephrotoxicity and implications for anesthetic development (part 1) Identification of the nephrotoxic metabolic pathway. Anesthesiology 2006 105(4) 726-36. 

Methoxyflurane is as much as 70% metabolized. Apparently. all labile sites are attacked. Metabolites include dichl-oroacctate. difluoromethoxyacetate. oxalate, and fluoride... 

Answer D. Saturation of the blood with inhaled anesthetics is more rapid if they have a low blood-gas partition coefficient. This results in the more rapid achievement of a partial pressure of the dissolved anesthetic molecules commensurate with their movement out of the blood into the alveolar spaces of the lung, where they are eliminated. Note that the same physicochemical characteristic is responsible for the rapid onset of the anesthetic action of sevoflurane. Although redistribution of anesthetics between tissues occurs, it is not responsible for rapid recovery. MAC values are a measure, of anesthetic potency. With the exception of halothane (and methoxyflurane), inhaled anesthetics are not metabolized to a significant extent. Naloxone is an opioid receptor antagonist. 

Kharasch ED, Elankins DC, Thummel KE. Eluman Kidney Methoxyflurane and Sevoflurane Metabolism. Anesthesiology 1995 ... 

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). 

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