Volatile anesthetics metabolism

Cohen EN, Hood N. 1969. Application of low-temperature autoradiography to studies of the uptake and metabolism of volatile anesthetics in the mouse. Anesthesiology 30 306-314. 

Van Dyke RA, Chenoweth MB, Poznak AV. 1964. Metabolism of volatile anesthetics -1. Conversion in vivo of several anesthetics to 14C02 and chloride. Biochem Pharmacol 13 1239-1247. 

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. 

Inhaled anesthetics decrease the metabolic rate of the brain. Nevertheless, the more soluble volatile agents increase cerebral blood flow because they decrease cerebral vascular resistance. The increase in cerebral blood flow is clinically undesirable in patients who have increased intracranial pressure because of a brain tumor or head injury. Volatile anesthetic-induced increases in cerebral blood flow increase cerebral blood volume and further increase intracranial pressure. 

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... 

Cerebral metabolism and oxygen utilization are decreased after thiopental administration in proportion to the degree of cerebral depression. Cerebral blood flow is also decreased, but much less so than oxygen consumption. This makes thiopental a desirable drug for use in patients with cerebral swelling (eg, head trauma, brain tumors), since intracranial pressure and blood volume are not increased (in contrast to the volatile anesthetics). 

Non-cytochrome P450 enzymes may also be involved in oxidative reactions. One such enzyme is alcohol dehydrogenase whose substrates include vitamin A, ethanol, and ethylene glycol. Aldehyde dehydrogenase is another enzyme. Most reduction reactions also involve microsomal enzymes, with the exception of ketone reduction. Nitro compounds are reduced to amines and volatile anesthetics undergo dehalo-genation by microsomal enzymes. Hydrolysis reactions are involved in metabolism of compounds with amide bonds or ester linkages, as in the conversion of aspirin to salicylate (Brown, 2001). 

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. 

Pantuck EJ, PantuckCB, Conney AH. Effect of streptozotocin-induced diabetes In the rat on the metabolism of fluorinated volatile anesthetics. Anesthesiology 1987 66(1 ) 24-8. 

Enflurane and sevoflurane are the only volatile anesthetics that have nephrotoxic potential due to their significant release of fluoride ions during metabolism. In sevoflurane s case also due to biodegradation by the currently used CO2 absorbents in anesthesia circuits. 

Fig. 10.15. CYP2E1-catalyzed metabolism of fluorinated volatile anesthetics to antigenic proteins.

Among volatile anesthetics, isoflurane and desflurane are safe for use in patients with renal impairment and cardiovascular disease. These agents undergo minimal (hepatic) metabolism. 

Toluene, volatile nitrites, and anesthetics, like other substances of abuse such as cocaine, nicotine, and heroin, are characterized by rapid absorption, rapid entry into the brain, high bioavailability, a short half-life, and a rapid rate of metabolism and clearance (Gerasimov et al. 2002 Pontieri et al. 1996, 1998). Because these pharmacokinetic parameters are associated with the ability of addictive substances to induce positive reinforcing effects, it appears that the pharmacokinetic features of inhalants contribute to their high abuse liability among susceptible individuals. 

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