Pharmaceutical Agents Known to Produce Disulfiram-Like Reaction: Effects on Hepatic Ethanol Metabolism and Brain Monoamines

Abstract

Several pharmaceutical agents produce ethanol intolerance, which is often depicted as disulfiram-like reaction. As in the case with disulfiram, the underlying mechanism is believed to be the accumulation of acetaldehyde in the blood, due to inhibition of the hepatic aldehyde dehydrogenases. In the present study, chloramphenicol, furazolidone, metronidazole, and quinacrine, which are reported to produce a disulfiram-like reaction, as well as disulfiram, were administered to Wistar rats and the hepatic activities of alcohol and aldehyde dehydrogenases (1A1 and 2) were determined. The expression of aldehyde dehydrogenase 2 was further assessed by Western blot analysis, while the levels of brain monoamines were also analyzed. Finally, blood acetaldehyde was evaluated after ethanol administration in rats pretreated with disulfiram, chloramphenicol, or quinacrine. The activity of aldehyde dehydrogenase 2 was inhibited by disulfiram, chloramphenicol, and furazolidone, but not by metronidazole or quinacrine. In addition, although well known for metronidazole, quinacrine also did not increase blood acetaldehyde after ethanol administration. The protein expression of aldehyde dehydrogenase 2 was not affected at all. Interestingly, all substances used, except disulfiram, increased the levels of brain serotonin. According to our findings, metronidazole and quinacrine do not produce a typical disulfiram-like reaction, because they do not inhibit hepatic aldehyde dehydrogenase nor increase blood acetaldehyde. Moreover, all tested agents share the common property to enhance brain serotonin, whereas a respective effect of ethanol is well established. Therefore, the ethanol intolerance produced by these agents, either aldehyde dehydrogenase is inhibited or not, could be the result of a "toxic serotonin syndrome," as in the case of the concomitant use of serotonin-active medications.

Er det virkelig farlig å kombinere metronidazol og alkohol?

“…På bakgrunn av dette ble det blant annet spekulert i om histaminfrigjøring kunne skje på bakgrunn av økt acetaldehydkonsentrasjon i tarmen (12). I den nyeste studien ble det funnet at metronidazol hemmer alkoholdehydrogenase (ADH) i noen grad (13). Dette var ikke tilfellet i de tidligere studiene.…”

The Alcohol Intolerance Produced by Isoniazid Is Not Due to a Disulfiram-Like Reaction Despite Aldehyde Dehydrogenase Inhibition

“…The inhibition of the metabolism of acetaldehyde by these drugs, which theoretically leads to increased blood acetaldehyde levels, has been suggested as the main explanation for this syndrome, albeit it has not been confirmed in all cases. As a matter of fact, in a previous work of our laboratory team, we showed that a number of pharmaceutical agents believed to produce a DIS-like reaction neither inhibit ALDH of the liver nor increase blood acetaldehyde in the Wistar rat [5] .…”

Alcohol-Medication Interactions: The Acetaldehyde Syndrome

“…The inhibition of the activity of aldehyde dehydrogenase by furazolidone and chloramphenicol in rats has been shown [5,48].…”

“…Certain anti-infectives, as cephalosporins [3], nitroimidazoles [4] and furazolidone [5], dermatological preparations, as tacrolimus and pimecrolimus [6], as well as chlorpropamide [7] and nilutamide [8] are known to produce disulfiram-like reactions. Although disulfiram-alcohol and disulfiram-like reactions are usually mild or moderate (facial flushing, weakness, headache, tachycardia, nausea, vomiting, sweating, vertigo, hypotension) [9,10], they can trigger severe and potentially fatal events such as lifethreatening arterial hypotension, shock and myocardial infarction [11][12][13][14][15][16][17][18][19][20].…”