Volatile anesthetics toxicity

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. 

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. 

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. 

Compounds in which the presence of fluorine atoms enhances the efficiency and selectivity of the biological activity with respect to the nonfluorinated parent compounds. These fluorocompounds should have fewer unfavorable effects. Due to these features (safety of use, better bioavailability, reduced dose, minor toxicity, etc.), these compounds have replaced, sometimes entirely, the nonfluorinated compounds of the same class. Volatile anesthetics and fluoroquinolones can be cited as examples of this category. 

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. 

There are two separate requirements at present for measuring volatile anesthetics in blood. One is retrospect analysis of blood samples. The other is on-line monitoring of blood concentration during animal and clinical toxicity studies. Usually a method allowing analysis of samples within minutes is desired. 

Nephrotoxicity has been found with methoxyflurane when serum fluoride ion concentrations exceeded 50 pmol/l (SEDA-20,106). Although this safety threshold has been applied to other volatile anesthetics as well, renal toxicity has not been reported for the other three anesthetics, even though the threshold can be exceeded during prolonged anesthesia. 

Halothane (CFgCHBrCl), the first of the modern halogenated volatile anesthetics, was introduced into clinical practice in 1956. It is normally metabolized in an oxidative pathway forming bromide ions and trifluo-roacetic acid, neither of which has potential for tissue toxicity [36, 37]. Reductive metabolism of halothane takes place during low oxygen tension states in the liver [38]. This pathway has been linked to halothane-in-duced liver necrosis through production of free radicals that bind to cellular macromolecules [39, 40]. Reductive metabolism is also associated with production of fluoride ions [41], although the quantities produced are too small to have nephrotoxic importance. 

The structure and physical properties of the volatile anesthetics are given in Table 18.5. Toxic degradation products are formed by reaction of the anesthetic agent with the... 

Liver Although chloroform is no longer in use as a volatile anesthetic agent, cases of occupational exposure as well as intentional inhalation and ingestion still present to clinicians. Chloroform was withdrawn from clinical use because it can cause nervous system depression, anoxia secondary to respiratory depression and airway obstruction, cardiac dysrhythmias potentiated by circulating catecholamines, and hepato-toxicity, which is thought to be secondary to oxidative injury caused by free radicals. 

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). 

Toxicity. 1,1-Dichloroethane, like all volatile chlorinated solvents, has an anesthetic effect and depresses the central nervous system at high vapor concentrations. The 1991 American Conference of Governmental Industrial Hygienists (ACGIH) recommends a time-weighted average (TWA) solvent vapor concentration of 200 ppm and a permissible short term exposure level (STEL) of 250 ppm for worker exposure. The oral LD q of... 

Like many volatile halocarbons and other hydrocarbons, inhalation exposure to carbon tetrachloride leads to rapid depression of the central nervous system. Because of its narcotic properties, carbon tetrachloride was used briefly as an anesthetic in humans, but its use was discontinued because it was less efficacious and more toxic than other anesthetics available (Hardin 1954 Stevens and Forster 1953). Depending on exposure levels, common signs of central nervous system effects include headache, giddiness, weakness, lethargy, and stupor (Cohen 1957 Stevens and Forster 1953 Stewart and Witts 1944). Effects on vision (restricted peripheral vision, amblyopia) have been observed in some cases (e.g., Johnstone 1948 Smyth et al. 1936 Wrtschafter 1933), but not in others (e.g., Stewart and Wtts 1944). In several fatal cases, microscopic examination of brain tissue taken at autopsy revealed focal areas of fatty degeneration and necrosis, usually associated with congestion of cerebral blood vessels (Ashe and Sailer 1942 Cohen 1957 Stevens and Forster 1953). 

The study of receptors has not featured as prominently in toxicology as in pharmacology. However, with some toxic effects such as the production of liver necrosis caused by paracetamol, for instance, although a dose-response relation can be demonstrated (see chap. 7), it currently seems that there may be no simple toxicant-receptor interaction in the classical sense. It may be that a specific receptor-xenobiotic interaction is not always a prerequisite for a toxic effect. Thus, the pharmacological action of volatile general anesthetics does not seem to involve a receptor, but instead the activity is well correlated with the oil-water partition coefficient. However, future detailed studies of mechanisms of toxicity will, it is hoped, reveal the existence of receptors or other types of specific targets where these are involved in toxic effects. 

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. 

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. 

Research during World War II produced many new fluorinated compounds and, in the early 1950s, a concerted effort was made to find among them nonflammable volatile compounds suitable for general anesthesia. Of hundreds tested, most, with notable exceptions, were found unsuitable for a variety of reasons, for example, toxicity or low potency. Examples of clinically promising halogenated anesthetics are discussed briefly in this section252. 

Diethyl ether was found to be a much safer anesthetic than chloroform. Like chloroform, ether is more soluble in fatty tissue than in water, so it passes into the central nervous system and takes effect quickly. Ether is also volatile, making it easy to administer. But ether is much less toxic than chloroform because ether degrades to ethanol, which the body can oxidize. 

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