Enflurane inhaled anesthetic

The anesthesiologist selects the anesthetic drug that will produce safe anesthesia, analgesia (absence of pain), and in some surgeries, effective skeletal muscle relaxation. General anesthesia is most commonly achieved when the anesthetic vapors are inhaled or administered intravenously (IV). Volatile liquid anesthetics produce anesthesia when their vapors are inhaled. Volatile liquids are liquids that evaporate on exposure to air. Examples of volatile liquids include halothane, desflurane, and enflurane. Gas anesthetics are combined with oxygen and administered by inhalation. Examples of gas anesthetics are nitrous oxide and cyclopropane. 

The distribution of anesthetic throughout the entire body may be viewed as an equilibration process (Fig. 7.1.13), with tissues characterized by high blood flows reaching equilibration faster than muscle and fatJ4 Nevertheless, an anesthetic that is excessively soluble in blood will not partition substantially into brain and other tissues. The anesthetic properties of nitrous oxide and diethyl ether have been known since the 1840s. Zeneca Pharmaceuticals introduced the first modem inhalation anesthetic fluothane in 1957. Methoxyfluorane followed in 1960, enflurane 1973, isoflurane 1981, desflurane by Anaquest (Liberty Comer, NJ) in 1992, and sevoflurane by Abbott Laboratories in 1995J6 ... 

Selection of a specific anesthetic or combination of anesthetics is made depending on the type of medical intervention. For a long time, ether, chloroform, tricholoroethylene, ethyl chloride or chloretane, and also cyclopropane were widely used as inhalation anesthetics. Today, the following anesthetics are used most regularly in medicine halothane, enflurane, isoflurane, metoxyflurane, and nitrous oxide. Researchers are also actively exploring the use of xenon as an anesthetic. 

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. 

Inhalation anesthetics, such as isoflurane, enflurane, halothane, and nitrous oxide, potentiate the action of nondepolarizing blockers, either through modification of end plate responsiveness or by alteration of local blood flow. The extent of potentiation depends on the anesthetic and the depth of anesthesia. The dose of muscle relaxant should be reduced when used with these anesthetics. 

Chlorofluorocarbon (CFC) replacements have recently been used for their lower stability and because they have carbon-hydrogen bonds, which means that their atmospheric lifetime is expected to be much shorter than those of CFCs. The adsorption properties of l,l,2-trichloro-l,2,2-trifluoroethane (CFC 113) and its replacement compounds, l,l-dichloro-2,2,2-trifluoroethane (HCFC123), 1,1-dichloro-l-fluoroethane (HCFC141b), and l,l-dichloro-l,2,2,3,3-pentafluoropropane (HCFC225ca) on four kinds of activated carbons were investigated. The adsorption isotherms of inhalational anesthetics (halothane, chloroform, enflurane, isoflurane, and methoxyflurane) on the activated carbon were measured to evaluate the action mechanism of inhalational anesthesia. The anesthesia of CFC replacements can be estimated by the Freundlich constant N of the adsorption isotherms (Tanada et al., 1997). 

The concentration of an inhaled anesthetic in the inspired gas mixture has direct effects on both the maximum tension that can be achieved in the alveoli and the rate of increase in its tension in arterial blood. Increases in the inspired anesthetic concentration increase the rate of induction of anesthesia by increasing the rate of transfer into the blood according to Fick s law (see Chapter 1). Advantage is taken of this effect in anesthetic practice with inhaled anesthetics that possess moderate blood solubility (eg, enflurane, isoflurane, and halothane). For example, a 1.5% concentration of isoflurane may be administered initially to increase the rate of rise in the brain concentration the inspired concentration is subsequently reduced to 0.75-1% when an adequate depth of anesthesia is achieved. In addition, these moderately soluble anesthetics are often administered in combination with a less soluble agent (eg, nitrous oxide) to reduce the time required for loss of consciousness and achievement of a surgical depth of anesthesia. 

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 change heart rate either directly by altering the rate of sinus node depolarization or indirectly by shifting the balance of autonomic nervous system activity. Bradycardia can be seen with halothane, probably because of direct vagal stimulation. In contrast, enflurane, and sevoflurane have little effect, and both desflurane and isoflurane increase heart rate. In the case of desflurane, transient sympathetic activation with elevations in catecholamine levels can lead to marked increases in heart rate and blood pressure when high inspired gas concentrations are administered. 

With the exception of nitrous oxide, all inhaled anesthetics in current use cause a dose-dependent decrease in tidal volume and an increase in respiratory rate. However, the increase in respiratory rate is insufficient to compensate for the decrease in volume, resulting in a decrease in minute ventilation. All volatile anesthetics are respiratory depressants, as indicated by a reduced response to increased levels of carbon dioxide. The degree of ventilatory depression varies among the volatile agents, with isoflurane and enflurane being the most depressant. All volatile anesthetics in current use increase the resting level of Paco2 (the partial pressure of carbon dioxide in arterial blood). 

Inhaled (volatile) anesthetics potentiate the neuromuscular blockade produced by nondepolarizing muscle relaxants in a dose-dependent fashion. Of the general anesthetics that have been studied, inhaled anesthetics augment the effects of muscle relaxants in the following order isoflurane (most) sevoflurane, desflurane, enflurane, and halothane and nitrous oxide (least) (Figure 27-9). The most important factors involved in this interaction are the following (1) nervous system depression at sites proximal to the neuromuscular junction (ie, central nervous system) (2) increased muscle blood flow (ie, due to peripheral vasodilation produced by volatile anesthetics), which allows a larger fraction of the injected muscle relaxant to reach the neuromuscular junction and (3) decreased sensitivity of the postjunctional membrane to depolarization. 

Literally hundreds of substances in addition to ether and chloroform have subsequently been shown to act as inhaled anesthetics. Halothane, enflurane, isoflurane, and methoxyflurane are at present the most commonly used agents in hospital operating rooms. All four are potent at relatively low doses, are nontoxic, and are nonflammable, an important safety feature. 

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. 

The chemical structures of the currently available inhaled anesthetics are shown in Figure 25-1. Nitrous oxide, a gas at ambient temperature and pressure, continues to be an important component of many anesthesia regimens. Halothane, enflurane, isoflurane, desflurane, sevoflurane, and methoxyflurane are volatile liquids. 

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... 

Of the inhaled anesthetics, nitrous oxide increases cerebral blood flow the least. However, when 60% nitrous oxide is added to halothane anesthesia, cerebral blood flow usually increases more than with halothane alone. At low doses, all of the halogenated agents have similar effects on cerebral blood flow. At larger doses, enflurane and isoflurane increase cerebral blood flow less than halothane. If the patient is hyperventilated before the anesthetic is given (reducing PaCCU), the increase in intracranial pressure from inhaled anesthetics can be minimized. 

Biressi, G., Quattrini, F., Juza, M., Mazzotti, M., Schurig, V., and Morbidelli, M. (2000) Gas chromatographic simulated moving bed separation of the enantiomers of the inhalation anesthetic enflurane. Chem. Engineer. Sci. 55, 4537-4547. 

J. Meinwold, W. R. Thompson, D. L. Pearson, W. H. Konig, T. Runge, and W. Francki, Inhalation anesthetics stereochemistry Optical resolution of haloethane, enflurane and isoflurane, Science, 251 560 (1991). 

Uptake curves for inhaled anesthetics Figure 11.6 illustrates the uptake curves for four inhalation anesthetics. The solubility in blood, as well as tissues, is in the following order halothane > enflurane > isoflurane > nitrous oxide. Because of its low solubility, the partial pressure of nitrous oxide in the inspired mixture and the body most rapidly achieves a steady-state. 

Halothane, enflurane, and isoflurane are widely used inhalation anesthetics currently administered in racemic form. Nothing is known about... 

Isoflurane is a potent inhalation anesthetic. An isomer of enflurane, it has many of the same adverse effects. It is hardly metabolized (about 0.2%), which has encouraged its prolonged use as a sedative agent or bronchodilator in patients with acute severe asthma. However, it may not be as inert in all patients. 

Inhalation anesthetics potentiate the neuromuscular blocking action of mivacurium, as with other nondepolarizing relaxants. With isoflurane (3) and enflurane (18) the ED95 is reduced by about 25% and the duration of action is somewhat prolonged, although the extent of this is not clear. Halothane has much less of an effect (19 0). 

The main applications of enantiomeric separation by GC concern precise determination of enantiomeric composition of chiral research chemicals, drugs, intermediates, metabolites, pesticides, flavors and fragrances, etc. CHIRBASE, a database of chiral compounds, provides comprehensive structural, experimental, and bibliographic information on successful and unsuccessful chiral separations, and rule sets for each CSP and information about the processes of chiral separations. According to CHIRBASE, an appropriate CSP is available for almost every racemic mixture of compounds ranging form apolar to polar. Some 22,000 separations of enantiomers, involving 5,500 basic chiral compounds and documented in 2,200 publications, have been achieved by GC. This method is particularly suitable for volatile compounds such as inhalation anesthetic agents, e.g., enflurane, isoflurane, desflurane, and racemic a-ionone. 

Although gas chromatography (GC) is a well established method for the analytical determination of enantiomeric purity, the number of preparative applications is quite limited. Most of these preparative applications by gas chromatography have been recently reviewed [181] and were performed on a relatively small scale. The method is particularly suited for volatile compounds such as the inhalation anesthetic agents enflurane, isoflurane and desflurane [182] and it has also been recently applied to the resolution of racemic a-ionone [183]. The feasibility of separating the enantiomers by gas phase simulated moving bed chromatography has also been demonstrated for the first time and was applied to the anesthetic enflurane (Fig. 6.18) [184]. However, the productivity of the system was relatively low. 

Enflurane is indicated to provide analgesia for vaginal delivery, and in combination with other anesthetic agents, it is used for delivery by cesarean section. It does provide adequate muscular relaxation. Enflurane, an inhalation anesthetic, produces rapid induction and recovery. It obtunds pharyngeal and laryngeal reflexes and causes salivary... 

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