Nephrotoxicity fluoride

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. 

Anesthesia is achieved rapidly and smoothly with sevoflurane, and recovery is more rapid than with isoflurane. However, sevoflurane is chemically unstable when exposed to carbon dioxide absorbents in anesthesia machines, degrading to an olefinic compound (fluoromethyl-2,2-difluoro-l-[trifluoromethyl]vinyl ether, also known as compound A) that is potentially nephrotoxic. In addition, sevoflurane is metabolized by the liver to release fluoride ions, raising concerns about potential renal damage. 

Kassabi M, Braun JP, Burgat-Sacaze V, et al. 1981. Comparison of sodium and stannous fluoride nephrotoxicity. Toxicol Lett 7 463-467. 

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. 

Diamond, G.L., Morrow, P.E., Parmer, B.J., Gelein, R.M., Baggs, R.B. (1989). Reversible uranyl fluoride nephrotoxicity in the Long Evans rat. Fundam. Appl. Toxicol. 13 65-78. 

Mazze RI, Calverley RK, Smith NT. Inorganic fluoride nephrotoxicity prolonged enflurane and halothane anesthesia in volunteers. Anesthesiology 1977 46(4) 265-71. 

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. 

Nuscheler M, Conzen P, Schwender D, Peter K. Fluoridinduzierte Nephrotoxizitat Fakt oder Fiktion [Fluoride-induced nephrotoxicity factor fiction ) Anaesthesist 1996 45(Suppl 1) S32 0. 

Serum and urinary inorganic fluoride concentrations can rise after inhalation of sevoflurane, because of hepatic metabolism (41). The authors concluded that lengthy sevoflurane anesthesia could alter renal function, although there was no other evidence of nephrotoxicity. Although patients with normal renal function are probably not at risk during normal anesthesia with sevoflurane, those with pre-existing renal impairment may be at risk. 

It has been thought that patients with chronically impaired renal function might be at increased risk of nephrotoxicity due to sevoflurane, because of an increased fluoride load due to reduced excretion. However, this was not confirmed in 41 patients undergoing elective surgery, with a stable increased preoperative serum creatinine concentration, who were randomly allocated to receive sevoflurane (n = 21) or enflurane (n = 20) at a fresh gas inflow rate of 41/minute for... 

Halothane (CFgCHBrCl), the first of the modern halogenated volatile anesthetics, was introduced into clinical practice in 1956. It is normally metabolized in an oxidative pathway forming bromide ions and trifluo-roacetic acid, neither of which has potential for tissue toxicity [36, 37]. Reductive metabolism of halothane takes place during low oxygen tension states in the liver [38]. This pathway has been linked to halothane-in-duced liver necrosis through production of free radicals that bind to cellular macromolecules [39, 40]. Reductive metabolism is also associated with production of fluoride ions [41], although the quantities produced are too small to have nephrotoxic importance. 

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). 

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. 

Frascino JA. Effect of inorganic fluoride on the renal concentrating mechanism. Possible nephrotoxicity in man. J Eab Clin Med 1972 79(2) 192-203. 

Brown BR, Jr. Shibboleths and jigsaw puzzles. The fluoride nephrotoxicity enigma. Anesthesiology 1995 82(3) 607-8. 

These results indicate that the metabolic disposition and thereby the pharmacological activity, whether efficacious or toxicological, could be modified by selective substitution of deuterium for hydrogen. A new combination antibacterial contains 3-fluoro-D-alanine-2-d which is an excellent example of selective deuteration to enhance the pharmacological activity of a therapeutic agent.7 The metabolism in vivo of 3-fluoro-D-alanine is reduced several-fold by substitution of deuterium for hydrogen on the 2-position without loss of antibacterial activity. This enhances the therapeutic index of the compound because metabolism of 3-fluoro-D-alanine leads to the formation of an inactive antibacterial and fluoride which is nephrotoxic. 

Halothane and sevoflurane are commonly used for inhaled induction of anesthesia in children, because of their lack of noxious smell. These drugs and isoflurane or desflurane are then used for maintenance of anesthesia according to the preference of the anesthesiologist. Enflurane is rarely used presently because of its airway irritant properties [106]. Therefore, of the ciu-rently used inhaled agents in pediatric patients, only sevoflurane has nephrotoxic potential (fluoride ions and compound A). 

Enflurane and sevoflurane are the only volatile anesthetics that have nephrotoxic potential due to their significant release of fluoride ions during metabolism. In sevoflurane s case also due to biodegradation by the currently used CO2 absorbents in anesthesia circuits. 

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... 

Isoniazid may increase the metabolism of enflurane, isoflurane or sevoflurane in some patients (probably related to isoniazid acetylator phenotype ) and so increase the release of fluoride ions that may cause nephrotoxicity. However, there do not appear to be any reports of a significant clinical effect on renal function. 

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