Halothane lipid solubility

The toxic effect depends both on lipid and blood solubility. I his will be illustrated with an example of anesthetic gases. The solubility of dinitrous oxide (N2O) in blood is very small therefore, it very quickly saturates in the blood, and its effect on the central nervous system is quick, but because N,0 is not highly lipid soluble, it does not cause deep anesthesia. Halothane and diethyl ether, in contrast, are very lipid soluble, and their solubility in the blood is also high. Thus, their saturation in the blood takes place slowly. For the same reason, the increase of tissue concentration is a slow process. On the other hand, the depression of the central nervous system may become deep, and may even cause death. During the elimination phase, the same processes occur in reverse order. N2O is rapidly eliminated whereas the elimination of halothane and diethyl ether is slow. In addition, only a small part of halothane and diethyl ether are eliminated via the lungs. They require first biotransformation and then elimination of the metabolites through the kidneys into the... 

That the lipid solubility versus anesthetic potency relationship is not above criticism has been intimated for a number of years by a number of authors. Summaries of the relevant facts and comments are found in the reviews of Halsey and Kaufman . It is only since 1974, however, that the possible importance of polar interactions has become a target of intense discussions. General anesthetics have widely different chemical structures and it has never been possible to classify them on chemical grounds. Xenon, nitrous oxide, ethylene, cyclopropane, ether, chloroform, C Fg, SFg, CFj—CHClj, CFj-CHClBr (halothane), CHjOCF.CHCf, (methoxyflurane) can all exert anesthetic action. (This aspect will be discussed in more detail in the next section). Looking at the formulas of these different molecules it is hard to believe that they all associate with the same site and with the same type of forces. A series of observations have been made in recent years that substantiate this scepticism. 

Chloroform was fast acting and nonflammable, but also had two serious limitations. The first was that it caused liver injury in many patients. The second was that a small fraction of patients given chloroform developed lethal disturbances of the electrical conduction system in the heart, leading to sudden death. Fortunately, ether and chloroform have long since been replaced by safer drugs. Three that were popular at the time of your surgery were halothane (the one you received), enflurane, and isoflurane (see Figure 4.12 for structures). None is nearly as lipid soluble as ether, but halothane is nonetheless nearly twice as soluble as isoflurane enflurane has an intermediate solubility. 

The mean total lipids for the samples in Table VI were 384 mg/100 mL for human blood and 588 mg/100 mL for dog blood. Least-squares fits of sulfur hexafluoride and halothane solubilities vs. total blood lipids content for all blood samples gave correlation coefficients of R = 0.82 for halothane and 0.70 for SF6. For the cholesterol fraction, the R s were 0.90 and 0.76, respectively. For the phospholipid component, the R s were 0.63 and 0.62, respectively, while for triglycerides and fatty acids, R was less than 0.40 for both gases. 

Figure 6. Relationship between solubility of halothane and total blood lipids. Dog and human data were pooled (correlation coefficient, R =...

Multiple gas equilibration has been used to measure anesthetic gases in blood, plasma, and dextrose solutions. Halothane and sulfur hexafluoride solubilities were correlated with total blood lipids. The technique is routinely used in ventilation-perfusion measurements. 

In another investigation of the comparative value of lipid and hydration hypotheses (Eger et aL 1969), the minimal anaesthetic concentrations of the following agents were plotted against the relevant physical properties carbon tetrafluoride, sulphur hexafluoride, nitrous oxide, xenon, cyclopropane, fluorexene (trifluoroethyl vinyl ether), diethyl ether, enflurane (see above), halothane, chloroform, and methoxyflurane (see above). (These anaesthetics have been arranged here in order of increasing lipid/water solubility.) The results of this study showed an excellent correlation between... 

---