Drug metabolism halothane

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. 

Ranek L, Dalhoff K, Poulsen HE, Brosen K, Flachs H, Loft S, Wantzin P. Drug metabolism and genetic polymorphism in subjects with previous halothane hepatitis. Scand J Gastroenterol 1993 28(8) 677-80. 

Pumford N R, Halmes N C, Hinson J A 1997 Covalent binding of xenobiotics to specific proteins in the liver. Drug Metabolism Reviews 29 39-57 Purchase I F 1966 Cardiac arrhythmias occur during halothane anaesthesia in cats. British Journal of Anaesthesia 38 13-22... 

A number of experimental and clinical reports have suggested that a variety of factors unrelated to drug metabolism and direct hepatotoxicity may also influence susceptibility to DILL In addition, the nature of idiosyncratic liver injuries suggests that a majority of these reactions involve an immune mechanism. Hepatic cellular dysfunction and death have the ability to initiate immunological reactions, including both adaptive and innate immune responses. This inflammatory process has been implicated in the development of liver injury induced by such drugs as APAP, dihydralazine, and halothane (Laskin and Gardner 2003 Liu and Kaplowitz 2002 Luster et al. 2001). 

It seems possible that the general adverse hepatotoxic effects of halothane can slow the normal rate of phenytoin metabolism. One suggested explanation for the increased adverse effects on the liver is that, just as in animals, pre-treatment with phenobarbital and phenytoin increases the rate of drug metabolism and therefore the hepatotoxicity of halogenated hydrocarbons, including carbon tetrachloride and halothane. As well as increased metabolism, the halothane-rifampicin interaction might also involve additive hepatotoxicity. 

Malignant hyperthermia (MH) is an autosomal-dominant pharmacogenetic disorder that is triggered by exposure to inhalation of general anesthetics, such as halothane. In susceptible individuals, these drugs can induce tachycardia, a greatly increased body metabolism, muscle contracture and an elevated body temperature (above 40°C) with a rapid rate of increase. Many cases of MH are linked to a gene for type 1 ryanodine receptor (RyRl). 

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. 

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). 

As well as atmospheric sources, pyrolysis of fluorine-containing polymers, which may occur in engine oil additives, non-stick cookware or incinerated medical equipment (i.e. syringes) and household waste, may also produce TFA. This process may also produce perfluorinated alkanes and cycloalkanes, which have significant GWP, and have estimated tropospheric half-lives of more than 2000 years. Trifluoroacetate may also be produced by metabolism of trifluoromethyl-containing drugs such as Prozac, and anaesthetics including halothane and iso-fluorane [4],... 

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. 

It is instructive to examine which drugs are substrates for various isoforms of CYP enzymes. Table 11.2 lists some of the substrates for different CYP isoforms (10, 11). There are several examples of a single compound that is metabolized by multiple CYP enzymes (acetaminophen, diazepam, caffeine, halothane, warfarin, testosterone, zidovudine), and CYP enzymes that metabolize bioactive endogenous molecules (prostaglandins, steroids) as well as drugs. 

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. 

Eventually these reactions result in the oxidative destruction of cellular membrane and serious tissue damage in the liver even though <0.5% of CCI4 is ever metabolized. An essential involvement of lipid peroxidation in the events leading to death of hepatocytes has been proved in the acute intoxication as well as with other haloalkanes such as bromotrichloromethane (CBrCls), dibromoethane, and halothane. Lipid peroxidation is also involved in the hepatotoxicity of ethanol, allyl alcohol, and some drugs like adriamycin. 

Halothane is a widely used anesthetic drug that occasionally results in severe hepatitis. About 60-80% of the dose is eliminated in unmetabolized form during the 24 h following administration to patients. This compound is metabolized in the presence of CYP monooxygenase CYP2F1 according to the two main pathways depicted in Figure 33.26. 

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. 

Plummer, J. L., Wanwimolruk, S., Jenner, M. A., Hall, P. M., and Cousins, M. J., Effects of cimetidine and ranitidine on halothane metabolism and hepatotoxicity in an animal model. Drug Metab. Dispos. 12, 106-110 (1984). 

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