Cross-tolerance with ethanol

Many CNS depressants have some liability for dependence. This is typically greater with barbiturates, but lesser with benzodiazepines, and perhaps nonexistent in many antiseizure medications. CNS depressants produce tolerance when administered chronically, where increasingly larger doses are required to sustain the same level of effect. Further, a cross-tolerance often develops, where the tolerance is generalized to other CNS depressants. For example, a person with an ethanol tolerance will also display some tolerance to barbiturates. The therapeutic index tends to decrease as tolerance increases, so that the difference between an effective and toxic dose diminishes. Thus, tolerance to CNS depressants is accompanied by a smaller safety margin. 

Tolerance—decreased responsiveness to a drug following repeated exposure—is a common feature of sedative-hypnotic use. It may result in the need for an increase in the dose required to maintain symptomatic improvement or to promote sleep. It is important to recognize that partial cross-tolerance occurs between the sedative-hypnotics described here and also with ethanol (see Chapter 23)—a feature of some clinical importance, as explained below. The mechanisms responsible for tolerance to sedative-hypnotics are not well understood. An increase in the rate of drug metabolism (metabolic tolerance) may be partly responsible in the case of chronic administration of barbiturates, but changes in responsiveness of the central nervous system (pharmacodynamic tolerance) are of greater importance for most sedative-hypnotics. In the case of benzodiazepines, the development of tolerance in animals has been associated with down-regulation of brain benzodiazepine receptors. Tolerance has been reported to occur with the extended use of zolpidem. Minimal tolerance was observed with the use of zaleplon over a 5-week period and eszopiclone over a 6-month period. 

Chronic use leads to tolerance (cross with other S-H drugs), possibly via down-regulation of BZ receptors. Psychological and physical dependence occurs, but abuse liability and withdrawal signs are less intense than with ethanol or barbiturates. Rebound REM sleep, insomnia, and anxiety are common on discontinuance. 

The cross-sectional flow velocity through the resin columns was maintained at 10 cm/min. The columns were each rinsed with 2.5 bed volumes of 1 M HC1 followed by 2.5 bed volumes of distilled water to remove metallic oxides and other inorganic constituents. Finally, the organic components were eluted with 2.5 bed volumes of 95 ethanol. Ethanol was selected as the eluent because it seemed to be the best choice as a solvent tolerated by animals used in proposed biological tests. 

Carbomer gels (see Table 23.17) tolerate the addition of ethanol or isopropyl alcohol without losing the gel structure, although the extent depends on the type of neutralising substance (see further Sect. 23.7.3). They have a Umited compatibility with salts and cations depending oti their concentration the viscosity may be decreased. Zinc oxide disturbs the gel structure by cross-linking the polymer. If any addition causes the pH to decrease under 6, the gel structure will be lost as well. 

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