Metabolism of Volatile Anesthetics

Dyke, Russell A. Van; Chenoweth, Maynard B.

doi:10.1097/00000542-196505000-00013

Cited by 80 publications

(13 citation statements)

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“…Since patients are frequently preraedicated prior to anesthesia with agents which increase the biotransformation of anesthetics (Van Dyke and Chenoweth, 1965;Rice, Sbordore, and Masse, 1978), this hypoxic model of halothane hepatotoxicity may more realistically represent the conditions present during clinical anesthesia than previous animal models.…”

Section: Animal Modelsmentioning

confidence: 99%

“…Although halothane may be metabolized by both oxidative and reductive routes (Van Dyke and Chenoweth, 1965;Van Dyke and Gandolfi, 1976), its reductive biotransformation appears to lead to bioactivation rather than to detoxification. Uehleke, Hellmer, and TabarelllPoplawski (1973) and Van Dyke and Gandolfi (1974) found that covalent 14 binding of C halothane metabolites was enhanced after anerobic incubation of the radiolabeled anesthetic with isolated hepatic microsomes.…”

Section: Introductionmentioning

confidence: 99%

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Factors influencing halothane hepatotoxicity in the rat hypoxic model

Jee

Sipes

Gandolfi

et al. 1980

Toxicology and Applied Pharmacology

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Section: Animal Modelsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Factors influencing halothane hepatotoxicity in the rat hypoxic model

Jee

Sipes

Gandolfi

et al. 1980

Toxicology and Applied Pharmacology

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“…If inorganic fluoride formed from methoxyflurane metabolites is in¬ deed the cause of the polyuria and renal failure, several factors would appear to be important in determin¬ ing whether the high output failure syndrome will develop in a particu¬ lar patient: (1) anesthesia; (2) the amount of anes¬ thetic retained which, in turn, would be related to obesity and the rate of metabolism of the methoxyflurane to nonvolatile components; (3) the rate of clearance of the inorganic and organic fluoride.…”

Section: Commentmentioning

confidence: 99%

Toxicity Following Methoxyflurane Anesthesia

Taves

Fry

Freeman

et al. 1970

JAMA

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The concentrations of inorganic fluoride and nonvolatile organic fluoride were measured in a patient with nephrotoxic effects following methoxyflurane anesthesia. Concentrations of both were markedly elevated compared to two patients who received methoxyflurane without subsequent nephrotoxic effects. Indirect evidence suggests that the inorganic fluoride concentration was sufficient to account for the nephrotoxic effects. The prolonged elevation of inorganic fluoride observed can be explained on the basis of the breakdown of the nonvolatile organic fluoride to inorganic fluoride and the poor renal clearance of both types. While methoxyflurane is known to be metabolized to nonvolatile products,1 no studies have explored the possi¬ bility that excessive concentrations of metabolites might cause the polyuric renal failure as described in the previous report by Partner et al (see page 86). There are several possible metabolites of methoxy¬ flurane (CH3-0-CF2-CCl2H), the most likely being chloride and fluoride ions, methoxydifluoracetic acid, hydroxydifluoracetic acid, and oxalic acid. Fluoride and oxalate are both nephrotoxic and are thus of prime toxicologie importance.The acetic acid derivatives are of interest since they would be non¬ volatile intermediates which would not be eliminated by exhalation.We studied inorganic fluoride and nonvolatile organic fluoride concen¬ trations in patients subsequent to methoxyflurane anesthesia. One pa¬ tient (patient 2 reported by Panner et al) died with evidence of nephro¬ toxic effects, and two other pa¬ tients had uneventful postoperative courses. Report of CasesThe patient with evidence of neph¬ rotoxic effects was very obese and was anesthesized four hours for cholecys-tectomy and removal of a common duct stone. Blood samples were drawn on the eighth postoperative day when it was suspected that the patient had nephrotoxic effects secondary to the methoxyflurane anesthesia. Additional samples were obtained 19 and 30 days following surgery. This patient died of renal failure 12 weeks after surgery.Two other patients whose conditions were studied for comparative purposes, were not obese, were anesthetized for two hours, and made uneventful re¬ coveries. Blood samples were obtained from these patients before and after anesthesia and from one patient on two subsequent days. MethodsWe measured inorganic fluoride directly with a fluoride electrode by comparing the voltage readings with those of comparable standards.We measured the nonvolatile or¬ ganic fluoride by the difference be¬ tween acid-labile and inorganic fluoride concentrations.In the acid-labile fluoride deter¬ mination the organically bound See also pages 86 and 96.fluoride is converted to inorganic fluoride by the acid used for the gaseous diffusion of inorganic fluor¬ ide from a sample to a trapping solution. After all of the fluoride was separated from the sample the amount was determined by a pre¬ viously described fluorescent re¬ agent or by the fluoride electrode.

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“…19 Until recently, it was believed that all inhalational anaesthetics except trichlorethylene were eliminated entirely unchanged through the lungs. It appears now that up to 35 per cent of the inhaled anaesthetic vapours may be biodegraded and, in the case of methoxyflurane, toxic products may accumulate in sufficient quantity to injure vital organs -particularly the kidney.…”

mentioning

confidence: 99%

Blood serum fluoride levels with methoxyflurane anaesthesia

Dobkin¹,

Levy

1973

Canad. Anaesth. Soc. J.

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in 1905, reported that diethyl ether and chloroform anaesthesia respectively reduced urine output, and Smith, Rovenstine and associates, ~ in 1939, reported in a similar effect with spinal anaesthesia, close attention has been paid to the effect of all anaesthetics, surgical trauma, and analgesics on the function of the kidney. [4][5] Until approximately 10 years ago, inhalational and parenteral anaesthetics administered judiciously and even in moderate overdose had not been found to cause a direct adverse effect on the renal parenchyma in animals or man unless they accompanied or followed severe surgical trauma and multiple blood transfusions. Nevertheless, urine output is almost invariably reduced during surgical anaesthesia, with reductions in renal blood flow, glomerular filtration rate and osmolar clearance. These effects usually respond to forced diuresis with intravenous fluids (dextrose, saline or balanced salt solutions in water). In our practice, an osmotic diuretic such as mannitol is also given, usually when the urine output falls below 40 ml/hr. These manoeuvres usually increase urine output promptly2 The oliguria which occurs during anaesthesia is followed frequently by a moderate postanaesthetie compensatory polyuria, as glomerular filtration rate and renal blood flow are restored, or the liberation of antidiuretie hormone ceases. These effects may be contingent upon many other factors such as the amount of analgesics administered postoperatively, the presence of preexisting renal or eardiopulmonary disease under drug therapy, and the use of antibiotics or other therapeutic agents that may be nephrotoxie. 5,7Following the clinical introduction of methoxyflurane in 1960, the question of a toxic effect on the kidney arose again, especially in centers where operations were often prolonged. 8,~q,'~ Methoxyflurane anaesthesia produces a similar renal response to that described above. The reduction of glomerular filtration rate with this anaesthetic may result as a consequence of a fall in renal pcrfusion pressure or of constriction of the afferent renal arterioles, all of which cause retention of salt and water. 4 After extensive animal and clinical evaluations, our recommendation was that 1.5 per cent methoxyflurane should never be exceeded and this agent should only be used with nitrous oxide for maintenance of anaesthesia for major or prolonged operations, after induction of anaesthesia with a rapid-acting anaesthetie.11,1~Clear-cut evidence of nephrotoxicity of methoxyflurane vapour itself had still

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Metabolism of Volatile Anesthetics

Cited by 80 publications

References 0 publications

Factors influencing halothane hepatotoxicity in the rat hypoxic model

Factors influencing halothane hepatotoxicity in the rat hypoxic model

Toxicity Following Methoxyflurane Anesthesia

Blood serum fluoride levels with methoxyflurane anaesthesia

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