Anesthetics halothane, isoflurane

The inhalational anesthetics halothane, isoflurane, and enflu-rane all have been reported to have a positive effect in children and adults with severe asthma that is unresponsive to standard medical therapy. The proposed mechanisms for inhalational anesthetics include direct action on bronchial smooth muscle, inhibition of airway reflexes, attenuation of histamine-induced bronchospasm, and interaction with /32-adrenergic receptors. Well-controlled trials with these agents have not been completed. Potential adverse effects include myocardial depression, vasodilation, arrhythmias, and depression of mucociliary function. In addition, the practical problem of delivery and scavenging these agents in the intensive care environment as opposed to the operating room is a concern. The use of volatile anesthetics cannot be recommended based on insufficient evidence of efficacy. 

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. 

Jaloszynski P, Kujawski M, Wasowicz M, et al Genotoxicity of inhalation anesthetics halothane and isoflurane in human lymphocytes studied in vitro using the comet assay. Mutat Res-. 439(2) 199-206, 1999... 

Metabotropic G-protein linked receptors are also modulated by general anesthetics. In particular, the current produced through activation of muscarinic receptors (Ml) for acetylcholine and the serotonergic receptor 5HT2 is inhibited by halothane, isoflurane and enflurane (Lin et al., 1993 Minami et al., 1994 Durieux, 1995). Ketamine inhibits muscarinic receptors although there is no stereospecificity of inhibition (Durieux Nietgen, 1997). The S-isomer of ketamine is more potent as an anesthetic than the R-isomer (Benthuysen et al., 1989). It is thus unlikely that the Ml muscarinic receptor plays a role in... 

Inhalation anesthetics still in use include nitrous oxide and the halogenated hydrocarbon inhalation anesthetics such as halothane, isoflurane, methoxyflurane and sevoflurane. 

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). 

Halothane, isoflurane, and enflurane have similar depressant effects on the EEG up to doses of 1-1.5 MAC. At higher doses, the cerebral irritant effects of enflurane may lead to development of a spike-and-wave pattern and mild generalized muscle twitching (ie, myoclonic activity). However, this seizure-like activity has not been found to have any adverse clinical consequences. Seizure-like EEG activity has also been described after sevoflurane, but not desflurane. Although nitrous oxide has a much lower anesthetic potency than the volatile agents, it does possess both analgesic and amnesic properties when used alone or in combination with other agents as part of a balanced anesthesia technique. 

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. 

Ide et al. (1998) used airway occlusion in cats as a noxious respiratory stimulus that induces a visceral sensation of choking for determination of minimum alveolar anesthetic concentrations during halothane, isoflurane, and sevoflurane anesthesia. These values were compared with MAC values for somatic noxious stimuli such as toe pinch or tetanic stimulus. The authors recommended this method as a new concept for MAC determination. 

Figure 15 Enantiomer separation of inhalation anesthetics halothane and isoflurane on a 25-m fused silica capillary with per-pe-a-CD at 35°C.

Halothane, isoflurane, and sevoflurane are potent coronary vasodilators, able to produce some degree of coronary steal in ischemic regions. Despite this, halothane may preferentially dilate large coronary arteries and/or interfere with platelet aggregation. If these experimental effects are confirmed, halothane may be the anesthetic of choice in the non-failing ischemic heart (3). 

Isoflurane has a lower blood gas partition coefficient than halothane, so more rapid induction and recovery would be anticipated. A number of studies have tried to compare the speed and quality of recovery from isoflurane and halothane, with variable results. In clinical cases undergoing either halothane or isoflurane maintenance anesthesia, more rapid recovery from isoflurane was not evident but coordination at the time of recovery was judged to be significantly worse in horses anesthetized with isoflurane than with halothane (Bramlage et al 1993). Another study examined the recovery from halothane and isoflurane anesthesia... 

Halothane, isoflurane and desflurane do not have any known nephrotoxic properties and are, from a kidney point of view, excellent choices for anesthetizing patients with preexisting renal disease. 

Saito, K Takayasu, T. Nishigami, J. Kondo, T. Ohtsuji, M et al. (1995). Determination of the volatile anesthetics halothane, enflurane, isoflurane and sevoflurane in biological specimens by pulse heating GC-MS. Journal of Amdytical toxicology, 19, 115-119... 

This conclusion has been confirmed in simulations of several solutes permeating different membranes. Benzene in DMPC at 310 K [9,10], oxygen in DPPC at 350 K [13], and several alkanes and fluoroalkanes in GMO at 310 K [16,19] all tend to accumulate in the middle of the bilayer. In contrast, a series of small, polar, anesthetically relevant molecules in GMO were found to reside mostly in the interfacial region [16,19]. Several examples are shown in Figure 4. The same preference was observed for a clinical anesthetic, halothane, in DPPC [15]. The tendency of structurally diverse, polar solutes to accumulate at the interface was also found in recent NMR studies. Polar anesthetics, such as 1-chloro-1,2,2-trifluorocyclobutane, halothane, isoflurane, enflurane, xenon and ethanol were all found to exhibit a preference for the water-phospholipid bilayer interface [38-42]. In contrast, nonpolar 1,2-dichlorohexafluorobutane partitions into the hydrocarbon core of the membrane [39,41]. 

Anesthetics General anesthetics Alkanols Halothane Enflurane Isoflurane Halogenated cyclobutanes Xenon... 

FIG. 1 Molecular structures of the drugs examined in the delivery study the general anesthetics, alkanols (I), halothane (II), enflurane (III), isoflurane (IV), halogenated cyclobutane (V) the local anesthetics, dibucaine hydrochloride (VI), procaine hydrochloride (VII), tetracaine hydrochloride (VIII), lidocaine hydrochloride (IX), benzyl alcohol (X) the endocrine disruptor, bisphenol A (XI), and alkylbenzenes, benzene (XII), toluene (XIII), ethylbenzene (XIV), and propylbenzene (XV). 

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