Halothane toxicity

Gut, J., Christen, U., Huwyler, J. Mechanisms of halothane toxicity novel insights. Pharmacol. Ther. 1993 58 133-155... 

Most recorded cases of liver disorders occurred after either repeated exposure (38) or prolonged exposure (39) to halothane. In one case, hepatitis developed 3 weeks after a single halothane anesthetic in a 37-year-old renal transplant recipient who had previously been exposed to isoflurane (40) this report suggests that previous exposure to isoflurane may predispose to subsequent halothane toxicity. 

GLD is increased in serum of patients with hepatocellular damage. Fourfold or fivefold elevations are seen in chronic hepatitis in cirrhosis, increases are only up to twofold. Very large rises in serum GLD occur in halothane toxicity, and notable increases occur in response to some other hepato-toxic agents. 

GLD is more concentrated in the central areas of the liver lobules than in the periportal zones. This pattern of distribution is the reverse of that of ALT. Pronounced release of GLD is therefore to be expected in conditions in which cen-trilobular necrosis occurs (e.g., as a result of ischemia or in halothane toxicity). 

Green S (1995) PPAR a mediator of peroxisome proliferators action. Mutat Res 333 101-109 Gut J, Christen U, Huwyler J (1993) Mechanism of halothane toxicity Novel insights. Phatmac Ther 58 133-155... 

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. 

Parent substances and metaboHtes may be stored in tissues, such as fat, from which they continue to be released following cessation of exposure to the parent material. In this way, potentially toxic levels of a material or metaboHte may be maintained in the body. However, the relationship between uptake and release, and the quantitative aspects of partitioning, may be complex and vary between different materials. For example, volatile lipophilic materials are generally more rapidly cleared than nonvolatile substances, and the half-Hves may differ by orders of magnitude. This is exemplified by comparing halothane and DDT (see Anesthetics Insectcontholtechnology). 

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... 

Halothane remams the leading anesthetic m many parts of the world However, It IS beheved to cause a fuhmnant hepatitis in rare, susceptible mdividuals, especially after repeated use within short intervals It was believed, but now disputed, that this hepatitis resulted from toxic metabohtes [2] (Actually, the major metabolite is tnfluoroacebc acid, which as a salt in body fluids, is benign ) As rare as the hepatitis cases were (1 m 20 000), they frequently resulted m malpractice suits, especially in the United States This problem led to a search for more ideal nonflammable anesthetics that are also metabohzed to a lesser extent [i]... 

Chenoweth, M.B., Leong, B.K.X, Sparschu, G.L. and Torkelson, T.R. (1972). Toxicities of methoxyflurane, halothane and diethyl ether in laboratory animals on repeated inhalation at subanesthetic concentrations. In Cellular Biology and Toxicity of Anesthetics (Fink, B.R., Ed.). Williams Wilkins, Baltimore, pp. 275-284. 

Brown BR Jr., Sipes IG, Sagalyn AM. 1974b. Mechanisms of acute hepatic toxicity Chloroform, halothane, and glutathione. Anesthesiology 41 554-561. 

Reductive dehalogenation reactions catalyzed by P-450 have been studied extensively, primarily because of the interest in compounds such as anesthetics, pesticides, and potentially toxic industrial solvents. An anesthetic named halothane gives anion-radical that undergoes dehalogenation according to the following equation ... 

An effective anesthetic agent must be easy to use, quickly render the patient unconscious, and not produce any toxicity. Dr. William T. G. Morton first publicly demonstrated the use of ether as an effective anesthetic agent at the Massachusetts General Hospital on 16 October 1846 before a crowd of skeptical physicians. Raymundus Lullius, a Spanish chemist, discovered ether (CH3CH2)20 in 1275. Its hypnotic effects were soon appreciated (and enjoyed by some), but for many decades ether was only used to treat the occasional medical ailment. Even with ether, the success of surgical procedures did not improve until the introduction of antiseptic procedures and infection control some 20 years later. Ether was replaced by cyclopropane in 1929, which was replace by halothane in 1956. While anesthetic agents are desirable for the patient, exposure of hospital staff is highly undesirable and an important occupational consideration. 

Usually various anesthetic agents are combined to increase efficacy and at the same time decrease toxicity and shorten the time to recovery. For example induction of anesthesia is obtained with an intravenous agent with a rapid onset of action like thiopentone and then anesthesia is maintained with a nitrous oxide/oxygen mixture in combination with halothane or a comparable volatile anesthetic. 

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. 

Isoflurane, an isomer of enflurane, together with sevoflurane are the most commonly used inhalation anesthetics in humans. Isoflurane does not sensitize the myocardium to catecholamines, has muscle relaxing action so less neuromuscular blocker is required and causes less hepatotoxicity and renal toxicity than halothane. 

The most common use of NjO is in combination with the more potent volatile anesthetics. It decreases the dosage requirement for the other anesthetics, thus lowering their cardiovascular and respiratory toxicities. For example, an appropriate anesthetic maintenance tension for N2O and halothane would be N2O 40% and halothane 0.5%. With this combination in a healthy patient, anesthesia is adequate for major surgery, and the dose-dependent cardiac effects of halothane are reduced. 

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]. 

The metabolism of enflurane and sevoflurane results in the formation of fluoride ion. However, in contrast to the rarely used volatile anesthetic methoxyflurane, renal fluoride levels do not reach toxic levels under normal circumstances. In addition, sevoflurane is degraded by contact with the carbon dioxide absorbent in anesthesia machines, yielding a vinyl ether called "compound A," which can cause renal damage if high concentrations are absorbed. (See Do We Really Need Another Inhaled Anesthetic ) Seventy percent of the absorbed methoxyflurane is metabolized by the liver, and the released fluoride ions can produce nephrotoxicity. In terms of the extent of hepatic metabolism, the rank order for the inhaled anesthetics is methoxyflurane > halothane > enflurane > sevoflurane > isoflurane > desflurane > nitrous oxide (Table 25-2). Nitrous oxide is not metabolized by human tissues. However, bacteria in the gastrointestinal tract may be able to break down the nitrous oxide molecule. 

Postoperative hepatic dysfunction is typically associated with factors such as blood transfusions, hypovolemic shock, and other surgical stresses rather than volatile anesthetic toxicity. However, a small subset of individuals who have been previously exposed to halothane may develop potentially life-threatening hepatitis. The incidence of severe hepatotoxicity following exposure to halothane is in the range of one in 20,000-35,000. Obese patients who have had more than one exposure to halothane during a short time interval may be the most susceptible. There is no specific treatment for halothane hepatitis, and therefore liver transplantation may ultimately be required in the most severe cases. 

The outcomes of the interaction between a chemical and a target molecule will depend both on the attributes and on the function of the target molecule. Thus, a covalent adduct could be formed, which might be recognized as a neo-antigen (e.g., see sect. "Halothane Hepato toxicity," chap. 7), or a mutation could be caused if the target is DNA [see sect. "Benzo(a)pyrene," chap. 7]. 

The induction of unconsciousness may be the result of exposure to excessive concentrations of toxic solvents such as carbon tetrachloride or vinyl chloride, as occasionally occurs in industrial situations (solvent narcosis). Also, volatile and nonvolatile anesthetic drugs such as halothane and thiopental, respectively, cause the same physiological effect. The mechanism(s) underlying anesthesia is not fully understood, although various theories have been proposed. Many of these have centered on the correlation between certain physicochemical properties and anesthetic potency. Thus, the oil/water partition coefficient, the ability to reduce surface tension, and the ability to induce the formation of clathrate compounds with water are all correlated with anesthetic potency. It seems that each of these characteristics are all connected to hydrophobicity, and so the site of action may be a hydrophobic region in a membrane or protein. Thus, again, physicochemical properties determine biological activity. 

Figure 7.77 The metabolism of halothane and its proposed involvement in the toxicity. Pathway 1 (oxidative) and pathway 2 (reductive) are both catalyzed by cytochrome P-450.

Inhaled anesthetics currently in use include halo-genated volatile liquids such as desflurane, enflurane, halothane, isoflurane, methoxyflurane, and sevoflurane (Table 11-1). These volatile liquids are all chemically similar, but newer agents such as desflurane and sevoflurane are often used preferentially because they permit a more rapid onset, a faster recovery, and better control during anesthesia compared to older agents such as halothane.915 These volatile liquids likewise represent the primary form of inhaled anesthetics. The only gaseous anesthetic currently in widespread use is nitrous oxide, which is usually reserved for relatively short-term procedures (e.g., tooth extractions). Earlier inhaled anesthetics, such as ether, chloroform, and cyclopropane, are not currently used because they are explosive in nature or produce toxic effects that do not occur with the more modern anesthetic agents. 

Halothane Illicit use of halothane has been performed by either ingestion or injection. Occupational exposure of nitrous oxide can cause serious toxicity, such as bone marrow and neurologic impairment. Effective ventilation should be provided to control the nitrous oxide pollution in the area of its use. Nitrous oxide has been reported to affect the fertility of male and female workers.235-238... 

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