Halothane hepatitis

Idiosyncratic toxicity Immunoallergic reaction No No 1-5 weeks Any Fever, rash, eosinophilia, arthralgias, hepatitis Halothane Carbamazepine... 

Feher J, Vasarhelyi B, Blazovics A. A halotan hepatitis. [Halothane hepatitis.] Orv Hetil 1993 134(33) 1795-8. 

Halothane reduces splanchnic and hepatic blood flow. Halothane can produce fulminant hepatic necrosis in a small number of patients, a syndrome characterized by fever, anorexia, nausea, and vomiting, developing several days after anesthesia and sometimes accompanied by a rash and peripheral eosinophilia. There is a rapid progression to hepatic failure, with a fatality rate of -50%. This syndrome occurs in about 1 in 10,000 patients receiving halothane and is referred to as halothane hepatitis. Halothane hepatitis may be the result of an immune response to hepatic proteins that become trifluoroacetylated as a consequence of halothane metabolism see Pharmacokinetics, above). 

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]... 

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 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. 

Vergani, D. et al., Antibodies to the surface of halothane-altered rabbit hepatocytes in patients with severe halothane-associated hepatitis, New Engl. J. Med., 303, 66, 1980. 

Bourdi, M. et al., Human cytochrome P450 2E1 is a major autoantigen associated with halothane hepatitis, Chem. Res. Toxicol., 9, 1159, 1996. 

Satoh, H. et al., Human anti-endoplasmic reticulum antibodies in sera of patients with halothane-induced hepatitis are directed against a trifluoroacetylated carboxylesterase, Proc. Nat. Acad. Sci. USA, 86, 322, 1989. 

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. 

Knights KM, Gourlay GK, Cousins MJ. Changes in rat hepatic microsomal mixed function oxidase activity following exposure to halothane under various oxygen concentrations. Biochem Pharmacol 1987 36(6) 897-906. 

There are several examples of autoimmune hepatitis caused by mechanism-based inhibitors in the field of CYPs hepatitis induced by halothane (CYP2E1) [15,16], by tienilic acid (CYP2C9) [17] and by dihydralazine (CYP1A2) [18,19]. 

Brown BR Jr., Sipes IG, Sagalyn AM. 1974b. Mechanisms of acute hepatic toxicity Chloroform, halothane, and glutathione. Anesthesiology 41 554-561. 

Uehleke H, Werner T. 1975. A comparative study on the irreversible binding of labeled halothane, trichlorofluoromethane, chloroform, and carbon tetrachloride to hepatic protein and lipids in vitro and in vivo. Arch Toxicol 34 289-308. 

Toxicology. Halothane causes central nervous system depression, affects the cardiovascular system, and occasionally causes hepatitis. 

Hepatitis occasionally occurs in patients after clinical anesthesia. Typically, 2-5 days after anesthesia, a fever develops, accompanied by anorexia, nausea, and vomiting. There may be a progression to hepatic failure, and death occurs in about 50% of these patients. The incidence of the syndrome is 1 in 10,000 anesthetic administrations, and it is seen most often after repeated administration of halothane over a short period of time. 

Anon Summary of the National Halothane Study. Possible association between halothane anesthesia and postoperative hepatic necrosis. JAMA 197 775-788, 1966... 

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... 

D5. Dawson, B., Adson, M. A., Dockerty, M. B., Fleisher, G. A., Jones, R. R., Hartridge, V. B., Schnelle, N., McGuckin, W. F., and Summerskill, W. H., Hepatic function tests Postoperative changes with halothane or diethyl ether anesthesia. Mayo Clin. Proc. 41, 599-607 (1966). 

Halogenated hydrocarbon inhalation anesthetics may increase intracranial and CSF pressure. Cardiovascular effects include decreased myocardial contractility and stroke volume leading to lower arterial blood pressure. Malignant hyperthermia may occur with all inhalation anesthetics except nitrous oxide but has most commonly been seen with halothane. Especially halothane but probably also the other halogenated hydrocarbons have the potential for acute or chronic hepatic toxicity. Halothane has been almost completely replaced in modern anesthesia practice by newer agents. 

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]. 

In animal studies, volatile anaesthetics reduce portal venous blood flow. However, the hepatic arterial buffer effect is preserved during isoflurane anaesthesia (unlike halothane) with the net effect being no overall change in hepatic blood flow. 

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. 

Although both metabolic and immune factors may be involved in the aetiology of severe hepatitis after halothane the aetiology of postanaesthetic/postsurgical hepatitis is far from clear. A recent study revealed that paediatric anaesthesiologists had high titres of serum autoantibodies which react with specific hepatic proteins. Since the vast majority of these individuals have not developed hepatitis the pathological role of autoantibodies in volatile anaesthetic-induced hepatitis remains questionable (Njoku and co-workers 2002). 

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. 

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