Halothane hepatic effects

Seyle H (1941) Anaesthetic effect of steroid hormones. Proc Soc exp Biol Med 46 116-121 Sherlock S (1978) Halothane hepatitis. Lancet 2 364-365... 

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. 

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. 

For almost 30 years, from its introduction in 1956, halothane was the standard of comparison for inhaled anesthetics. However, the onset of its anesthetic action is slow compared with many intravenous agents, and the rate of recovery from its anesthetic effects is not rapid. In addition, its hepatic metabolism to a reactive compound may lead to development of halothane-associated hepatitis. 

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. 

A Similar to halothane, but hepatitis unlikely. Only 2 - 5% metabolized, released from fat stores more rapidly than halothane. Wide margin of safety, few side effects other than renal toxicity. ... 

Much attention continues to be paid to liver damage following the use of halothane. Although the cause and effect relationship is now beyond doubt, the value of the drug is such that it is of vital importance to gain a full understanding of this unwelcome complication. The cause of the hepatic damage... 

---