Bromine Halothane

Halothane Halothane, 2-bromo-2-chloro-l,l,l-trifluorethane (1.1.2), is made by the addition of hydrogen fluoride to tricholoroethylene and simultaneous substitution of chlorine atoms in the presence of antimony(lll) chloride at 130 °C. The resulting 2-chloro-l,l,l-tri-fluorethane (1.1.1) undergoes further bromination at 450 °C to form halothane [1-3]. 

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]. 

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). 

The spectrum of halothane (CF3—CHClBr) is shown in Fig. 11. The presence of the bromine atom gives rise to a Br - (C—Br) type valeiK e-shell transition. Its. center is near 49000 an" (c 340). TheJ>and of next hi ier fi uency... 

Halothane is stable when stored in amber glass bottles or when 0.01 weight percent thymol is added. Exposure of unstabilized halothane to light causes slow decomposition with formation of volatile acids and bromine (5, 13). It has been reported that 2,3-dichlorohexafluoro-2-butene is formed when halothane is heated in the presence of copper and oxygen (19, 20) or evaporated at room temperature in the presence of air and copper (20) other investigators either dispute or do not confirm these observations (21-25). 

Scipioni et al (58) report a somewhat different set of impurities for halothane made by high temperature bromination of 2-chloro-1,1,1-trifluoroethane on a laboratory scale, and they also investigated the changes in concentrations with changes in reaction temperature and contact time. 

Halothane in 1 to 2 g. tissue samples was determined by x-ray spectrographic (fluorescence) analysis for bromine in 10 ml. hexane extracts (81). 

Bromination of 2-chloro-l, 1,1-trifluoroethane yields halothane which is isolated from the reaction product by fractional distillation. 

A knowledge of blood bromide levels is occasionally important as in patients treated with bromosedatives, or anaesthetised with halothane or suffering from drug abuse. The normal bromide level in serum is less than 0.1 mmol dm but in cases of bromide intoxication can rise to above 40 mmol dm and both levels are measurable by the bromide ion-selective electrode as long as the bromine is... 

In SED VII and VIII, reference was made to the possible deleterious effects of low concentrations of anaesthetic agents in the atmosphere of operating rooms. More specifically, the influence on abortion rates and congenital anomalies of children bom to female anaesthetists was described. Desbaumes et al. (2C) measured brominated metabolites of halothane in the urine of 18 members of the operating theatre staff and found a striking difference between women and men (14.59 mg/1 and 3.04 mg/1 respectively). This difference may be explained by the fact that women staff members are more likely to be continuously present in the operating theatre or that they retain halothane more easily in their body fat. Only the first explanation is consistent with the sex difference in fluroxene toxicity found in mice (3), as this toxicity was more marked in males. 

---