Hepatotoxicity halothane

Hepatitis following general anesthesia has been linked to use of halothane, though the incidence of severe hepatic necrosis is only about one out of 35,000 halothane administrations. The results of animal experiments suggest that halothane hepatotoxicity may be due to formation of a toxic metabolite produced under anoxic conditions. Hepatotoxicity has not been reported following desflurane administration it may be relevant that this agent is the least metabolized of the fluorinated hydrocarbons. All of the other statements are correct. The answer is (E). 

Janeway CA Jr, Medzhitov R (2002) hmate immrme recognition. AimuRev Immunol 20 197-216 Jee RC, Sipes IG, GandoUi AJ, Brown BR Jr (1980) Factors influencing halothane hepatotoxicity in the rat hypoxic model. Toxicol Appl Pharmacol 52 267—277 Ju C, Pohl LR (2005) Tolerogenic role of Kupffer cells in immune-mediated adverse drug reactions. Toxicology 209 109-112... 

McKenzie H, Parratt D, White RG (1976) IgM and IgG antibody levels to ampicillin in patients with infectious mononucleosis. Clin Exp Immunol 26 214-221 McLain GE, Sipes IG, Brown BR Jr (1979) An animal model of halothane hepatotoxicity roles of enzyme induction and hypoxia. Anesthesiology 51 321-326 Meadows M (2001) Serious liver injury. Leading reason for drug removals, restrictions. FDA Consum 35 8-9... 

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E. S. Reynolds and M. T. Moslen, Halothane hepatotoxicity Enhancement by polychlorinated biphenyl pretreatment, Anesthesiology 47, 19-27 (1977). 

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]. 

Satoh, H. et al., Immunological studies on the mechanism of halothane-induced hepatotoxicity Immunohistochemical evidence of trifluoroacetylated hepatocytes, J. Pharmacol. Exp. Ther., 233, 857, 1985. 

Furst, S.M., Chen, M. and Gandolfi, A.J., Use of halothane as a model for investigating chemical-induced autoimmune hepatotoxicity, Drug Info. J., 30, 301, 1996. 

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. 

Isoflurane, an isomer of enflurane, together with sevoflurane are the most commonly used inhalation anesthetics in humans. Isoflurane does not sensitize the myocardium to catecholamines, has muscle relaxing action so less neuromuscular blocker is required and causes less hepatotoxicity and renal toxicity than halothane. 

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 a fluorinated methyl ethyl ether and is a structural isomer of isoflurane (Figure 3.2). It was synthesised in 1963 and introduced into clinical practice in 1966 at a time when concern was growing about the hepatotoxicity of halothane. Its main advantage over halothane was its resistance to biotransformation (2.5% compared to some 20%). For that reason it was widely used as an alternative to halothane, particularly for multiple administration. 

Postoperative hepatic dysfunction is typically associated with factors such as blood transfusions, hypovolemic shock, and other surgical stresses rather than volatile anesthetic toxicity. However, a small subset of individuals who have been previously exposed to halothane may develop potentially life-threatening hepatitis. The incidence of severe hepatotoxicity following exposure to halothane is in the range of one in 20,000-35,000. Obese patients who have had more than one exposure to halothane during a short time interval may be the most susceptible. There is no specific treatment for halothane hepatitis, and therefore liver transplantation may ultimately be required in the most severe cases. 

Oxidative dehalogenation. Halogen atoms may be removed from xenobiotics in an oxidative reaction catalyzed by cytochromes P-450. For example, the anesthetic halothane is metabolized to trifluoroacetic acid via several steps, which involves the insertion of an oxygen atom and the loss of chlorine and bromine (Fig. 4.28). This is the major metabolic pathway in man and is believed to be involved in the hepatotoxicity of the drug. Trifluoroacetyl chloride is thought to be the reactive intermediate (see chap. 7). 

Halothane is a very widely used anesthetic drug, which may cause hepatic damage in some patients. It seems that there are two types of hepatic damage, however. One is a very rare reaction, idiosyncratic, resulting in serious liver damage with an incidence of about 1 in 35,000. The other form of hepatotoxicity is a mild liver dysfunction, which is more common and occurs in as many as 20% of patients receiving the drug. The two different types probably involve different mechanisms. 

Figure 7.78 Postulated mechanism of halothane immune-mediated hepatotoxicity. This figure is only a partial explanation, involving Tc cells (cytotoxic lymphocytes). See text for complete description. CYP2E1 in liver cell activates the halothane to a reactive acyl chloride shown), which reacts with proteins (e.g., enzymes in the SER). These are transported to cell surface and presented to immune system by APC. Abbreviations APC, antigen-presenting cell SER, smooth endoplasmic reticulum MHCII, major histocompatability complex.

Chen ML, Gandolfi AJ. Characterisation of the humoral immune response and hepatotoxicity after multiple halothane exposures in guinea pigs. Drug Metab Rev 29 103-122. 1997. 

All volatile anesthetics cause a decrease in hepatic blood flow, ranging from 15% to 45% of the preanesthetic flow rate. Despite transient intraoperative changes in liver function tests, permanent changes in liver function rarely occur from the use of these agents. The hepatotoxicity of halothane is discussed below. 

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. 

Halothane (149), first used clinically in the 1950s, is some three times more potent than ether and onset of anesthesia is rapid. Mild, transient hepatotoxicity occurs in about 20% of patients. A much rarer but more severe toxicity has been attributed to a drug-induced hypersensitivity reaction. Under aerobic conditions, halothane is oxidatively metabolized to trifluoroacetyl halide that apparently acylates tissue molecules. The bound trifluoroacetyl moiety functions as a hapten in sensitive individuals triggering the immune response253. 

One possible confound for this experiment is that liver weight changes by up to 15 % during the day as glycogen levels drop (Latour et al. 1999) and so care must be taken in longitudinal studies that animals are always imaged at the same time of day to reduce within animal variance. In addition, care must be exercised with the choice of anaesthetic as anaesthetics such as halothane are hepatotoxic and may influence the outcome of the study when there are several imaging sessions. 

As discussed in Chapter 16, dehalogenation by liver enzymes of a number of inhalation anesthetics (halothane, methoxyflurane) and halogenated solvents yields chemically reactive free radicals that play an important role in the hepatotoxicity of these compounds. Dehalogenation produces a free radical... 

This patient had multiple risk factors for anesthesia-induced hepatitis, including obesity, middle age, female sex, a history of drug allergies, and multiple exposures to fluorinated anesthetic agents. Desflurane has a very low rate of hepatic oxidative metabolism (0.02 versus 20% for halothane), and is considered to be one of the safest volatile agents as far as hepatotoxicity is concerned. Nevertheless, this case shows that it can cause severe hepatotoxicity. 

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