Halothane elimination

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... 

In contrast, with halothane, partial pressure in blood is low and tissue uptake is high, resulting in a much slower elimination. 

Elimination of halothane may continue for 24 to 48 hours after prolonged administration. Recovery is smooth and reasonably quick. It is currently one of the most popular anaesthetic used due to its non-irritant, non-inflammable, pleasant and rapid action. 

Inhaled anesthetics that are relatively insoluble in blood (ie, possess low blood gas partition coefficients) and brain are eliminated at faster rates than the more soluble anesthetics. The washout of nitrous oxide, desflurane, and sevoflurane occurs at a rapid rate, leading to a more rapid recovery from their anesthetic effects compared with halothane and isoflurane. Halothane is approximately twice as soluble in brain tissue and five times more soluble in blood than nitrous oxide and desflurane its elimination therefore takes place more slowly, and recovery from halothane- and isoflurane-based anesthesia is predictably less rapid. 

The duration of exposure to the anesthetic can also have a significant effect on the recovery time, especially in the case of the more soluble anesthetics (eg, halothane and isoflurane). Accumulation of anesthetics in muscle, skin, and fat increases with prolonged exposure (especially in obese patients), and blood tension may decline slowly during recovery as the anesthetic is slowly eliminated from these tissues. Although recovery may be rapid even with the more soluble agents following a short period of exposure, recovery is slow after prolonged administration of halothane or isoflurane. 

Inhaled anesthetics that are relatively insoluble in blood (low blood gas partition coefficient) and brain are eliminated at faster rates than more soluble anesthetics. The washout of nitrous oxide, desflurane, and sevoflurane occurs at a rapid rate, which leads to a more rapid recovery from their anesthetic effects compared to halothane and isoflurane. Halothane is approximately twice as soluble in brain tissue and five times more soluble in blood than nitrous oxide and desflurane its elimination therefore takes place more slowly, and recovery from halothane anesthesia is predictably less rapid. The duration of exposure to the anesthetic can also have a marked effect on the time of recovery, especially in the case of more soluble anesthetics. Accumulation of anesthetics in tissues, including muscle, skin, and fat, increases with continuous inhalation (especially in obese patients), and blood tension may decline slowly during recovery as the anesthetic is gradually eliminated from these tissues. Thus, if exposure to the anesthetic is short, recovery may be rapid even with the more soluble agents. However, after prolonged anesthesia, recovery may be delayed even with anesthetics of moderate solubility such as isoflurane. 

Clearance of inhaled anesthetics by the lungs into the expired air is the major route of their elimination from the body. However, metabolism by enzymes of the liver and other tissues may also contribute to the elimination of volatile anesthetics. For example, the elimination of halothane during recovery is more rapid than that of enflurane, which would not be predicted from their... 

About 20% of halothane is metabolised and it induces hepatic enzymes, including those of anaesthetists and operating theatre staff. Hepatic damage occurs in a small proportion of exposed patients. Typically fever develops 2 or 3 days after anaesthesia accompanied by anorexia, nausea and vomiting. In more severe cases this is followed by transient jaundice or, very rarely, fatal hepatic necrosis. Severe hepatitis is a complication of repeatedly administered halothane anaesthesia and has an incidence of 1 50000. It follows immime sensitisation to an oxidative metabolite of halothane in susceptible individuals. This serious complication, along with the other disadvantages of halothane and the popularity of sevoflurane for inhalational induction, has almost eliminated its use in the developed world. It remains in common use other parts of the world because it is comparatively inexpensive. 

Example Inhalation Volatile liquids halothane (Fluothane), Route Inhalation Pregnancy category C Pharmacokinetic Metabolized in liver eliminated via ... 

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. 

Answer D. Saturation of the blood with inhaled anesthetics is more rapid if they have a low blood-gas partition coefficient. This results in the more rapid achievement of a partial pressure of the dissolved anesthetic molecules commensurate with their movement out of the blood into the alveolar spaces of the lung, where they are eliminated. Note that the same physicochemical characteristic is responsible for the rapid onset of the anesthetic action of sevoflurane. Although redistribution of anesthetics between tissues occurs, it is not responsible for rapid recovery. MAC values are a measure, of anesthetic potency. With the exception of halothane (and methoxyflurane), inhaled anesthetics are not metabolized to a significant extent. Naloxone is an opioid receptor antagonist. 

Approximately 60 to 80% of absorbed halothane is eliminated unchanged in the exhaled gas in the first 24 hours after its administration, and smaller amounts continue to be exhaled for several days or even weeks. Of the fraction not exhaled, as much as 50% undergoes biotransformation, and the rest is eliminated unchanged by other routes. 

Approximately 60-80% of halothane taken up by the body is eliminated unchanged via the lungs in the first 24 hours after its administration. A substantial amount of the halothane not eliminated in exhaled gas is biotransformed by hepatic CYPs. Trifiuoroacetylchloride, an intermediate in oxidative metabolism of halothane, can trifluoroacetylate several proteins in the liver. An immune reaction to these altered proteins may be responsible for the rare cases of fulminant halothane-induced hepatic necrosis. 

Halothane was first introduced into use as an anesthetic in 1956, and within 2 years, isolated case reports of liver complications and severe hepatitis were reported (Brody and Sweet 1963 Lindenbaum and Leifer 1963). A 1969 epidemiological study by the National Institutes of Health revealed an incidence of fatal hepatic necrosis of about 1 in 35,000 exposures. While concern for hepatotoxicity has virtually eliminated the use of halothane in adults in the US, halothane continues to be used as an anesthetic in children in the US because the incidence of halothane-associated hepatitis in children is between 1 in 82,000 and 1 in 200,000 (Carney and Van Dyke 1972 Kenna et al. 1987 Warner et al. 1984). Over the years, a variety of evidence has accumulated to spawn a range of theories and laboratory models. However, the exact mechanism leading to halothane... 

Biological Elimination Reactions Trichloroethylene (a solvent) Halothane (an inhaled anesthetic) Dichlorodifluoromethane (a refrigerant) Bromomethane (a fumigant)... 

Most of the F NMR studies are related to anaesthetic, psychoactive and antineoplastic drugs. The distribution of anaesthetics in the brain and the pharmacokinetics of their elimination are still a subject of controversy. The feasibility of in vivo F NMR studies of halothane in humans has been recently demonstrated. Resonances attributable to this compound were observed up to 90 min after withdrawal of the anaesthetic agent in eight patients. 

In vivo NMR spectroscopy can be a very useful technique for monitoring the distribution of fluori-nated drugs and their metabolites. These include the PET agent 2-fluoro-2-deoxyglucose, the study of its 3-fluoro-isomer as a probe of aldose reductase activity in brain, the elimination from the brain of fluori-nated anaesthetics, metabolism of halothane in the liver, the distribution and catabolism of the anticancer drug 5-fluorouracil and the uptake of trifluoro-methylthymidine into mouse tumours. 

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