22.04 General Considerations with the use of Alcohol.

As with many drugs acting on GABA receptors, sex differences occur with ethanol. Men are less sensitive to the intoxicating effects of ethanol than women, and driving regulations and drinking guidelines reflect this notable sex difference. For example, men are advised to drink no more than two standard drinks in the first hour to avoid going over the legal blood alcohol concentration (BAC) limit of 0.05%, while women are advised that more than one standard drink per hour will tip them over the limit. Studies have suggested that the sex differences may partly be due to the difference in ethanol’s ability to induce neurosteroid synthesis in the CNS.

Another important consideration with the use of alcohol is drug-drug interactions. Given the numerous sedative, anxiolytic and hypnotic substances acting on GABA_A receptors, combinations of these drugs with ethanol are dangerous, and have been exploited to induce amnesia and sedation in some social settings.

Finally, complications arising from the metabolism of ethanol must be considered in some populations. Ethanol is oxidised in the first instance via alcohol dehydrogenase (and at high doses, CYP2E1) to acetaldehyde, a highly toxic and unstable compound. Regular heavy consumption of ethanol during pregnancy has been shown to lead to birth defects, and one mechanism thought to be involved is via the toxic action of acetaldehyde on the developing embryo and foetus.

Acetaldehyde is further synthesized via mitochondrial acetaldehyde dehydrogenase to acetic acid. Individuals lacking the mitochondrial form of acetaldehyde dehydrogenase, relatively common in some Asian populations, may experience increased intoxication. Moreover, acetic acid is metabolized to acetyl CoA then to fatty acids in the liver. Prolonged overconsumption of alcohol may increase fatty acid synthesis in the liver, leading to steatosis.