Nephrotoxicity methoxyflurane

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. 

Minocycline (Solodyn) [Anribiotic/Tetracycline] Uses Acne Action Tetracycline, bacteriostatic Dose Adults Peds >12y. 1 mg/kg PO daily x l2wk w/ food to X- irritation Caution [C, ] assoc w/ pseudomembranous colitis w/ renal impair Contra Allergy, women of childbearing potential Disp Tabs SE D, HA, fever, rash, joint pain, fatigue, dizziness Interactions T Effects OF digoxin, oral anticoagulants T risk of nephrotox W/ methoxyflurane X- effects W/... 

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

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. 

For more than forty years, the potential for nephrotoxicity, particularly when fluoride induced, has influenced every aspect of the development of new inhaled anesthetics. This concern is based on the experience with methoxyflurane, which was introduced in the US in 1%0 [89]. The exact mechanism(s) responsible for fluoride nephrotoxicity have not been defined. The fluoride ion interferes with normal cell function on several levels. Fluoride inhibits several cellular enzyme systems and diminishes tissue respiration and anaerobic glycolysis [90]. The lethal dose of sodium fluoride in humans is approximately 5 g [90]. In the kidney. 

CrandellWB, Pappas SG, Macdonald A. Nephrotoxicity associated with methoxyflurane anesthesia. Anesthesiology 1966,-27(5) 591-607. 

Cousins MJ, Mazze Rl. Methoxyflurane nephrotoxicity. A study of dose response in man. Jama 1973 225(13) 1611-6. 

Cousins MJ, Mazze Rl, Kosek JC, Elitt BA, Eove EV. The etiology of methoxyflurane nephrotoxicity. J Pharmacol Exp Ther 1974 190(3) 530-41. 

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 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... 

Oxytetracycline enhances the risk of nephrotoxicity from methoxyflurane it also necessitates lowered dosage of oral anticoagulants because of enhanced effects and lowered dosage of digoxin because of increased bioavailabihty. 

Drugs with nephrotoxic potential include ACE inhibitors, acetazolamide. aminoglycosides, aspirin, amphotericin B, cyclosporine, furosemide, gold salts, lithium, methicillin, methoxyflurane, NSAIDs, pentamidine, sulfonamides, tetracyclines (degraded), thiazides, and triamterene. 

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... 

The nephrotoxic effects of methoxyflurane appear to be increased by the use of tetracyciines, and possibiy some aminoglycoside an-tibacteriais and barbiturates. 

The risk of nephrotoxicity with methoxyflurane would therefore appear to be increased by some of these drugs and the concurrent use of tetracycline or nephrotoxic antibiotics should be avoided. Similarly, methoxyflurane should only be used with great caution, if at all, following the chronic use of hepatic enzyme-inducing drugs. 

Cousins MJ, Mazze RI Methoxyflurane nephrotoxicity a stuity of dose respc se in man... 

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