Halothane anesthesia hepatic metabolism

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. 

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 is a volatile general anesthetic that was introduced into the practice of clinical anesthesia in 1956. Shortly after its introduction two forms of hepatic injury were noted to occur in patients who received halothane anesthesia. A subclinical increase in blood concentration of transaminase enzymes is observed in 20% of patients and has been attributed to lipid peroxidation caused by the free radical formed by reductive metabolism of halothane as shown in Figure 16.7 (39/ 40). The second form of toxicity is a potentially fatal hepatitis-like reaction that is characterized by severe hepatocellular necrosis and is thought to be initiated by the oxidative formation of trifluoroacetyl chloride (Figure 16.7). Fatal hepatic necrosis occurs in only 1 of 35/000 patients exposed to halothane/ but the risk of this adverse event is greater in females and is increased with repeat exposure/ obesity/ and advancing age (40). Because the onset of halothane hepatitis is delayed but is more frequent and occurs more rapidly following multiple exposures/ and because these patients usually are febrile and demonstrate eosinophilia/ this reaction is suspected... 

The effects of halothane on plasma Bj concentrations have been confirmed by subsequent studies using short and long exposures to the anesthetic (A12, H58, M30, R3). It has also been shown that isoflurane has little or no effects on plasma B whereas enflurane has an effect intermediate between halothane and isoflurane (Fig. 23) (A12, H58). In one study, 50% of patients receiving halothane had an abnormal B whereas only 20 and 11% of patients receiving enflurane and isoflurane, respectively, had an abnormality (H58). These results are consistent with the view that the 3-hr rise in GST B, post-halothane anesthesia is caused by reduced hepatic blood flow as enflurane and isoflurane have much less of an effect on hepatic blood flow than does halothane. In addition, the results are also consistent with the 24-hr rise resulting from biotransformation enflurane and isoflurane are metabolized to a far lesser extent than halothane. 

Cimetidine has been shown to impair metabolism of drugs by the mixed function oxidase system by binding to cytochromes P450 and P448 (B8, D5). In animal models cimetidine reduces halothane metabolism and lessens the severity of hepatic injury (P9, W13). It has not been possible to demonstrate any effect of cimetidine administration on the plasma profile obtained in humans post-halothane anesthesia (R4). However, as with nicardipine the doses of cimetidine used were far lower than the doses used in animal models. 

Perhaps more important than potency differences are toxicity differences. Halothane would have the most potential for an improved anesthetic if it can be shown that one enantiomer is less toxic than the racemate. Outside the U.S., halothane is still used but its liver toxicity is so great that a long time period must pass between surgeries that use halothane for anesthesia 34), It has recently been found that both halothane (55) and enflurane (56) show stereoselective hepatic metabolism, a possible indication that one enantiomer of the anesthetics may be less toxic than the other. 

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. 

Halothane hepatitis in children is rare, and occurs in 1 82 000 to 1 200 000 exposures. Children as young as 11 months are not exempt from the risk, contrary to what was once thought and there is a growing number of reports of halothane hepatitis in children (47). It has been noted that sevoflurane is not metabolized to trifluor-oacetic acid and may prove to be a better alternative for repeated anesthesia in children (48). 

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). 

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). 

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