Halothane metabolites

It is also likely that direct cytotoxicity of halothane metabolites is important in the process, causing cellular stress by lipid peroxidation and covalent binding to target proteins (Fig. 7.77). Then the cytokines produced by this stress cause upregulation of costimulatory molecules, which provides the second signal for the immune response to occur. 

Halothane also reduces liver blood flow during anesthesia, and this could increase the release of potentially hepatotoxic halothane metabolites. The role of reduced halothane metabolites and inorganic fluoride, which may covalently link to liver macromolecules, has been stressed in keeping with this hypothesis is the observation of halothane hepatitis in patients who simultaneously take enzyme-inducing agents, for example barbiturates (41) or rifampicin (42). 

Kenna JG, Knight TL, van Pelt FN. Immunity to halothane metabolite-modified proteins in halothane hepatitis. Ann NY Acad Sci 1993 685 646-61. 

Wood CL, Gandolfi AJ, Van Dyke RA. Lipid binding of a halothane metabolite. Relationship to lipid peroxidation in vitro. Drug Metab Dispos 1976 4(4) 305-13. 

Van Dyke RA, Gandolf AJ. Anaerobic release of fluoride from halothane. Relationship to the binding of halothane metabolites to hepatic cellular constituents. Drug Metab Dispos 1976 4(1) 40-4. 

Baker MT, Van Dyke RA. Reductive halothane metabolite formation and halothane binding in rat hepatic microsomes. Chem-Biol Interact 1984 49 121-132. 

Gas Chromatographic Method for the Halothane Metabolites, Trifluoro-acetic Acid and Bromide in Biological Fluids... 

The toxic effect depends both on lipid and blood solubility. I his will be illustrated with an example of anesthetic gases. The solubility of dinitrous oxide (N2O) in blood is very small therefore, it very quickly saturates in the blood, and its effect on the central nervous system is quick, but because N,0 is not highly lipid soluble, it does not cause deep anesthesia. Halothane and diethyl ether, in contrast, are very lipid soluble, and their solubility in the blood is also high. Thus, their saturation in the blood takes place slowly. For the same reason, the increase of tissue concentration is a slow process. On the other hand, the depression of the central nervous system may become deep, and may even cause death. During the elimination phase, the same processes occur in reverse order. N2O is rapidly eliminated whereas the elimination of halothane and diethyl ether is slow. In addition, only a small part of halothane and diethyl ether are eliminated via the lungs. They require first biotransformation and then elimination of the metabolites through the kidneys into the... 

Halothane remams the leading anesthetic m many parts of the world However, It IS beheved to cause a fuhmnant hepatitis in rare, susceptible mdividuals, especially after repeated use within short intervals It was believed, but now disputed, that this hepatitis resulted from toxic metabohtes [2] (Actually, the major metabolite is tnfluoroacebc acid, which as a salt in body fluids, is benign ) As rare as the hepatitis cases were (1 m 20 000), they frequently resulted m malpractice suits, especially in the United States This problem led to a search for more ideal nonflammable anesthetics that are also metabohzed to a lesser extent [i]... 

The answer is d. (Hardman, pp 308-313.) Halothane is a substituted alkane general anesthetic. It undergoes significant metabolism in humans with about 20% of the absorbed dose recovered as metabolites. Halothane can cause postoperative jaundice and hepatic necrosis with repeated administration in rare instances. 

A classic drug associated with hepatotoxicity is halothane. It is associated with antibodies against trifluoroacetylated protein due to the binding of the reactive metabolite of halothane [59,60], However, in addition, it is also associated with autoantibodies, such as antibodies against Cyp 2E1, the major P450 responsible for oxidation of halothane [61]. 

FIGURE 4.62 Oxidative dehalogenation of halothane to form areactive acid chloride intermediate and structures of other anesthetics that can form similar reactive metabolites. 

In contrast, the reactivity of trifluoroacetyl chloride, the reactive metabolite of halothane discussed in Chapter 4 under oxidative dehalogenation (Fig. 8.7), is due to the electron-withdrawing effect of the carbonyl and trifluoromethyl groups, which makes it very electrophilic, more reactive than most other molecules that have chloride as the leaving group (Fig. 8.7). 

Halothane (boiling point BP] 50 °C), enfhirane (BP 56 °C), isoflurane (BP 48 °C), and the obsolete methoxyflu-rane (BP 104 °C) have to be vaporized by special devices. Part of the administered halothane is converted into hepatotoxic metabolites (B). Liver damage may result from halothane anesthesia. With a single exposure, the risk involved is unpredictable however, there is a correlation with the frequency of exposure and the shortness of the interval between successive exposures. 

Saillenfait AM, Route MB, Ban M, et al Postnatal hepatic and renal consequences of in utero exposure to halothane or its oxidative metabolite trifluoroacetic acid in the rat. J ApplToxicom )-. -%, 1997... 

Schweizer, O., Howland, W. S., Sullivan, C., and Vertes, E., The effect of ether and halothane on blood levels of glucose, pyruvate, lactate and metabolites of the tricarboxylic acid cycle in normotensive patients during operation. Anes-thesiology 28, 814-822 (1967). 

The oxidative metabolism leads to the formation of reactive species (epoxides, quinone-imines, etc.), which can be a source of toxicity. Consequently, slowing down or limiting these oxidations is an important second target in medicinal chemistry. Thus, the metabolism of halothan (the first modern general anaesthetic) provides hepatotoxic metabolites inducing an important rate of hepatitis the oxidation of the non-fluorinated carbon generates trifluoroacetyl chloride. The latter can react with proteins and lead to immunotoxic adducts [54], The replacement of bromine or chlorine atoms by additional fluorine atoms has led to new families of compounds, preferentially excreted by pulmonary way. These molecules undergo only a very weak metabolism rate (1-3%) [54,55]. 

Enflurane is metabolised by the cytochrome P-450 series, specifically P-450 2E1, but the agent is much less extensively metabolised than halothane (see above). Metabolites include trifluoroacetic acid (TEA) and inorganic fluoride ion. A small number of cases of enflurane hepatitis have been reported but the overall incidence of liver damage following enflurane anaesthesia is estimated to be 1 in 800000. Clinical studies have failed to detect any significant effects of enflurane on liver function even when given repeatedly. 

Chloro-1,1,1-trifluoroethane is used as a chemical intermediate in the production of the anaesthetic halothane. Human exposure occurs due to its presence as a low-level impurity in, and as a metabolite of, halothane (lARC, 1986). 

The mechanisms underlying hepatotoxicity from halothane remain unclear, but studies in animals have implicated the formation of reactive metabolites that either cause direct hepatocellular damage (eg, free radical intermediates) or initiate immune-mediated responses. With regard to the latter mechanism, serum from patients with halothane hepatitis contains a variety of autoantibodies against hepatic proteins, many of which are in a trifluoroacetylated form. These trifluoroacetylated proteins could be formed in the hepatocyte during the biotransformation of halothane by liver drug-metabolizing enzymes. However, TFA proteins have also been identified in the sera of patients who did not develop hepatitis after halothane anesthesia. 

Evidence for the halothane metabolism outlined above has been found in products recovered from the breath and urine of humans subjected to halothane anesthetic during surgery.6 As evidence of reductive metabolites, chlorotrifluoroethane and chlorodifluoroethylene,... 

The principal antigenic proteins seem to be associated with the smooth endoplasmic reticulum. This is not particularly surprising since it is the probable site of metabolite formation via P450. Trifluoroacyl adducts have also been detected on the outer surface of hepatocytes, although it is not clear how they arrive there. In halothane-induced hepatitis the number of exposures does seem to be important, with about four being optimum. 

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