Halothane metabolism

Spracklin DK, Hankins DC, Fisher JM, et al. Cytochrome P450 2E1 is the principal catalyst of human oxidative halothane metabolism in vitro. J Pharmacol Exp Ther 1997 281(1) 400-411. 

The primary anion radical of Scheme 3-69 produces the l-chloro-2,2,2-trifluoroethyl radical. Having been spin-trapped in vivo, this radical was detected by the ESC method (Poyer et al. 1981). Ahr et al. (1982) has presented additional evidence for the formation of the radical as an intermediate in halothane metabolism and identified 2-chloro-l,l-difluo-... 

Evidence for the halothane metabolism outlined above has been found in products recovered from the breath and urine of humans subjected to halothane anesthetic during surgery.6 As evidence of reductive metabolites, chlorotrifluoroethane and chlorodifluoroethylene,... 

Kharasch, E.D. et al., Human halothane metabolism, lipid peroxidation, and cytochromes P4502A6 and P4503A4, Eur. J. Clin. Pharmacol., 55, 853-859, 2000. 

Kharasch ED, Hankins D, Mautz D, et al. Identification of the enzyme responsible for oxidative halothane metabolism implications for prevention of halothane hepatitis. Lancet 1996 347 1367-1371. 

The extent of halothane metabolism has been reported to be 17-20% of an administered dose [36]. Oxidation to trifluoroacetic acid is the principal pathway of halothane metabolism, and no fluoride ions are released. Therefore, fluoride-induced renal toxicity is not a concern with 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. 

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). 

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). 

Isoflurane is a respiratory depressant (71). At concentrations which are associated with surgical levels of anesthesia, there is Htde or no depression of myocardial function. In experimental animals, isoflurane is the safest of the oral clinical agents (72). Cardiac output is maintained despite a decrease in stroke volume. This is usually because of an increase in heart rate. The decrease in blood pressure can be used to produce "deHberate hypotension" necessary for some intracranial procedures (73). This agent produces less sensitization of the human heart to epinephrine relative to the other inhaled anesthetics. Isoflurane potentiates the action of neuromuscular blockers and when used alone can produce sufficient muscle relaxation (74). Of all the inhaled agents currently in use, isoflurane is metabolized to the least extent (75). Unlike halothane, isoflurane does not appear to produce Hver injury and unlike methoxyflurane, isoflurane is not associated with renal toxicity. 

An isomer of enflurane named isoflurane (l-chloro-2,2,2-tnfluoroethyl difluoromethyl ether) does not produce uncontrolled movements, is nonflammable, and IS metabolized to an even lesser extent than enflurane [7] As of this wntmg, isoflurane is the fastest growing anesthebc m more economically developed coun tries, but because of cost, it has not overtaken halothane in the rest of the world... 

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). 

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. 

Ueki, M., Mies, G. and Hossmann, K. A. Effect of alpha-chloralose, halothane, pentobarbital and nitrous oxide anesthesia on metabolic coupling in somatosensory cortex of rat. Acta Anaesthesiol. Scand. 36 318-322,1992. 

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. 

Methoxyflurane (Penthmne) is the most potent inhala-tional agent available, but its high solubility in tissues limits its use as an induction anesthetic. Its pharmacological properties are similar to those of halothane with some notable exceptions. For example, since methoxyflurane does not depress cardiovascular reflexes, its direct myocardial depressant effect is partially offset by reflex tachycardia, so arterial blood pressure is better maintained. Also, the oxidative metabolism of methoxyflurane results in the production of oxalic acid and fluoride concentrations that approach the threshold of causing renal tubular dysfunction. Concern for nephrotoxicity has greatly restricted the use of methoxyflurane. 

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]. 

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