Liver halothane

Halothane, as the name implies, contains halogen atoms within its molecular structure (e.g., three F, one Br, and one Cl). Within the human liver, halothane undergoes a dechlorination reaction that leads to the production of an unstable free radical intermediate (Figure 7.9). A free radical is a molecule or molecular fragment that contains one or more unpaired electrons in its outer orbital shell and... 

Liver Halothane hepatitis has again been described [2 ]. Susceptibility factors are increasing age, female sex, obesity, autoimmune disease, and previous exposure to hepatotoxic drugs such as isoniazid or rifampicin. 

Under anaerobic conditions, p,p -DDT is converted to p,p -DDD by reductive dechlorination, a biotransfonnation that occurs postmortem in vertebrate tissues such as liver and muscle and in certain anaerobic microorganisms (Walker and Jefferies 1978). Reductive dechlorination is carried out by reduced iron porphyrins. It is carried out by cytochrome P450 of vertebrate liver microsomes when supplied with NADPH in the absence of oxygen (Walker 1969 Walker and Jefferies 1978). Reductive dechlorination by hepatic microsomal cytochrome P450 can account for the relatively rapid conversion of p,p -DDT to p,p -DDD in avian liver immediately after death, and mirrors the reductive dechlorination of other organochlorine substrates (e.g., CCI4 and halothane) under anaerobic conditions. It is uncertain to what extent, if at all, the reductive dechlorination of DDT occurs in vivo in vertebrates (Walker 1974). 

The production of free radicals has been implicated in the mechanism of liver injury due to a number of drugs and toxins. These include adtiamycin (Pritsos et al., 1992), halothane (Neuberger and Williams, 1984), phenobar-bital and thiopental (Kanazawa and Ashida, 1991), carbon tetrachloride (Williams and Burk, 1990), 1,1,2,2-tetrachloroethane (Paolini aal., 1992), and paraquat and related bipyridylium compounds (Togashi a al., 1990 De Gray etal., 1991 Kanazawa and Ashida, 1991 Petty etal., 1992). 

Kenna, J.G. et al., Metabolic basis for a drug hypersensitivity Antibodies in sera from patients with halothane hepatitis recognize liver neoantigens that contain the trifluoroacetyl group derived from halothane, J. Pharmacol. Exptl. Therap., 245, 1103, 1988. 

Christ DD, Kenna JG, Kammerer W, et al. Enflurane metabolism produces covalently bound liver adducts recognized by antibodies from patients with halothane hepatitis. Anesthesiology 1988 69(6) 833-838. 

Ahr HJ, King LJ, Nastainczyk W, et al. The mechanism of reductive dehalogenation of halothane by liver cytochrome P450. Biochem Pharmacol 1982 31 (3) 383—390. 

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. 

Hughes HM, George IM, Evans JC, et al. 1991. The role of the liver in the production of free radicals during halothane anaesthesia in the rat. Biochem J 277 795-800. 

Halothane (Fluothane) 10-30 Yes Some Minimal Decrease Decrease Rare liver dysfunction... 

Halothane 2.30 3.40 muscle 3.50 brain (white) 2.30 brain (gray) 2.60 liver... 

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. 

Halothane-related hepatitis was first reported in 1958 just two years after the drug s introduction. During subsequent years it became clear from the volume of reports that there was a very small excess risk of liver failure after halothane anaesthesia, particularly when the drug was administered more than once over a short time period. The medicolegal implications of this were profound and did much to promote the search for a safer alternative agent. 

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. 

Volatile anesthetics cause a concentration-dependent decrease in hepatic blood flow ranging from 15% to 45% below the preinduction (baseline) value. Despite transient intraoperative changes in liver function tests, permanent changes in liver enzyme function are rare except following repeated exposures to halothane. 

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. 

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.

Chemicals which can damage (a) the liver include carbon tetrachloride, paracetamol, bromobenzene, isoniazid, vinyl chloride, ethionine, galactosamine, halothane, dimethyl-nitrosamine (b) the kidney include hexachlorobutadiene, cadmium and mercuric salts, chloroform, ethylene glycol, aminoglycosides, phenacetin (c) the lung include paraquat, ipomeanol, asbestos, monocrotaline, sulfur dioxide, ozone, naphthalene (d) the nervous system include MPTP, hexane, organophosphoms compounds, 6-hydroxydopamine, isoniazid (e) the testes include cadmium, cyclophosphamide, phthalates, ethanemethane sulfonate, 1,3-dinitrobenzene (f) the heart include allylamine, adriamycin, cobalt, hydralazine, carbon disulfide (g) the blood include nitrobenzene, aniline, phenyl-hydrazine, dapsone. 

Clearance of inhaled anesthetics by the lungs into the expired air is the major route of their elimination from the body. However, metabolism by enzymes of the liver and other tissues may also contribute to the elimination of volatile anesthetics. For example, the elimination of halothane during recovery is more rapid than that of enflurane, which would not be predicted from their... 

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. 

Madan A, Parkinson A. Characterization of the NADPH-dependent covalent binding of [14-C]-halothane to human liver microsomes a role for CYP2E1 at low substrate concentrations. Drug Metab Dispos 1996 24 1307-1313. 

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