Alcohol and Medication Interactions Ron Weathermon, Pharm.D., and David W. Crabb, M.D. Many medications can interact with alcohol, thereby altering the metabolism or effects of alcohol and/or the medication. Some of these interactions can occur even at moderate drinking levels and result in adverse health effects for the drinker. Two types of alcohol- medication interactions exist: (1) pharmacokinetic interactions, in which alcohol interferes with the metabolism of the medication, and (2) pharmacodynamic interactions, in which alcohol enhances the effects of the medication, particularly in the central nervous system (e.g., sedation). Pharmacokinetic interactions generally occur in the liver, where both alcohol and many medications are metabolized, frequently by the same enzymes. Numerous classes of prescription medications can interact with alcohol, including antibiotics, antidepressants, antihistamines, barbiturates, benzodiazepines, histamine H2 receptor antagonists, muscle relaxants, nonnarcotic pain medications and anti-inflammatory agents, opioids, and warfarin. In addition, many over-the-counter and herbal medications can cause negative effects when taken with alcohol. KEY WORDS: moderate AOD use; prescription drug; adverse drug interaction; drug metabolism; ethanol metabolism; cytochromes; liver; alcohol dehydrogenases; antibiotics; antidepressants; histamine H1 receptor blockaders; barbiturates; benzodiazepines; histamine H2 receptor blockaders; anti-inflammatory agents; opioids; warfarin; over-the-counter drug; literature review ost people who consume in potentially serious medical observations made with heavy drinkers. alcohol, whether in moderate consequences. For example, the In addition, moderate alcohol consump- Mor large quantities, also take sedative effects of both alcohol and tion may directly influence some of medications, at least occasionally. As a sedative medications can enhance the disease states for which medications result, many people ingest alcohol each other (i.e., the effects are addi- are taken (see sidebar, pp. 52–53, for while a medication is present in their tive), thereby seriously impairing a further discussion of alcohol’s influ- body or vice versa. A large number of person’s ability to drive or operate ences on various disease states). This medications—both those available other types of machinery. only by prescription and those avail- Most studies assessing alcohol- RON WEATHERMON, PHARM.D., is an able over the counter (OTC)—have medication interactions focus on the assistant professor at the School of the potential to interact with alcohol. effects of chronic heavy drinking. Pharmacy and Pharmaceutical Those interactions can alter the meta- Relatively limited information is avail- Sciences, Purdue University, bolism or activity of the medication able, however, on medication interac- Indianapolis, Indiana. and/or alcohol metabolism, resulting tions resulting from moderate alcohol consumption (i.e., one or two standard DAVID W. C RABB, M.D., is a professor 1A standard drink is defined as one 12-ounce can drinks1 per day). Researchers, physi- in the Departments of Medicine and of beer or bottle of wine cooler, one 5-ounce glass of wine, or 1.5 ounces of distilled spirits and is cians, and pharmacists must therefore Biochemistry and Molecular Biology, equivalent to approximately 0.5 ounce, or 12 infer potential medication interactions Indiana University School of Medicine, grams (g), of pure alcohol. at moderate drinking levels based on Indianapolis, Indiana. 40 Alcohol Research & Health Alcohol andWhat Medication Is Moderate Interactions Drinking? article discusses alcohol absorption, from the gastrointestinal tract, primar- alcohol as well as other substances; distribution, and metabolism within ily the stomach and the upper small some of those enzymes, including the body; the sites where potential intestine. Alcohol absorption occurs alcohol dehydrogenase (ADH) and alcohol-medication interactions can slowly from the stomach but rapidly cytochrome P450 are described in occur; and possible adverse effects from the upper small intestine. Once more detail in the section “Alcohol from various alcohol-medication absorbed, the alcohol is transported to Metabolism in the Liver.” combinations, including OTC or the liver through the portal vein. A The contribution of stomach (i.e., herbal products. portion of the ingested alcohol is gastric) enzymes to first-pass alcohol metabolized during its initial passage metabolism, however, is controversial. through the liver; the remainder of Whereas some researchers have pro- Alcohol Absorption, the ingested alcohol leaves the liver, posed that gastric enzymes play a major Distribution, and enters the general (i.e., systemic) cir- role in first-pass metabolism (Lim et Metabolism culation, and is distributed through- al. 1993), other investigators consider out the body’s tissues. the liver to be the primary site of first- Gastrointestinal Absorption Alcohol metabolism (or the meta- pass metabolism (Levitt and Levitt and Metabolism bolism of any other substance) that 1998). Furthermore, some gender dif- occurs in the gastrointestinal tract and ferences appear to exist in the overall When alcohol is ingested through the during the substance’s initial passage extent of, and in the contribution of, mouth, a small amount is immediately through the liver is called “first-pass gastric enzymes to first-pass meta- broken down (i.e., metabolized) in the metabolism” (see figure 1). For exam- bolism. For example, the extent of stomach. Most of the remaining alcohol ple, the mucosa lining the stomach first-pass metabolism is less in women is then absorbed into the bloodstream contains enzymes that can metabolize than in men and some studies also Panel A Panel B Liver Stomach Intravenous alcohol Alcohol to 50 systemic circulation 40 Portal Vein Oral alcohol 30 Alcohol 20 BAL (mg %) BAL Hepatic metabolism 10 of alcohol Intestine (possibly 0 blocked Transgastric metabolism 1 2 3 4 by some (possibly blocked by Hours medications) some medications) Alcohol absorption Increased gastric emptying into bloodstream (stimulated or inhibited by some medications) Figure 1 Schematic representation of first-pass metabolism. (A) Alcohol ingested through the mouth reaches the stomach, where a portion is metabolized by the enzyme alcohol dehydrogenase (ADH). The remaining alcohol enters the intestine, where most of the remainder is absorbed into the bloodstream and enters the portal vein that leads to the liver. In the liver, part of the alcohol is metabolized by ADH or cytochrome P450. The remaining alcohol enters the general (i.e., systemic) circulation and eventually is transported back to the liver and metabolized there. The metabolism of alcohol in the stomach or during the first passage through the liver after absorption from the intestine is called first-pass metabolism. (B) Changes in blood alcohol levels (BALs) after oral alcohol ingestion and after intravenous administration of the same alcohol dose. The difference in BALs achieved with both administration routes (i.e., the amount by which the BAL is lower after oral ingestion) represents that portion of the ingested alcohol that has been broken down by first-pass metabolism before reaching the systemic circulation. Vol. 23, No. 1, 1999 41 have found lower gastric ADH activity in women (Thomasson 1995). First-pass metabolism is readily Inhibition of gluconeogenesis + detectable after consumption of low NAD NADH Inhibition of fat oxidation 2 alcohol doses that leave the stomach Stimulation of fat synthesis slowly (e.g., because they have been ADH consumed with a meal). Thus, under such conditions of delayed gastric emp- ALDH2 Alcohol Acetaldehyde Acetate tying, more alcohol can be metabolized ALDH1 in the stomach or absorbed slowly from the stomach and transported to the liver for first-pass metabolism. CYPs In general, probably only a small frac- tion (perhaps 10 percent) of ingested alcohol is eliminated from the body Figure 2 Alcohol metabolism in the liver. Alcohol is broken down to acetaldehyde by first-pass metabolism after consump- either by alcohol dehydrogenase (ADH) or cytochrome P450 (CYP). The tion of low doses of alcohol. As alcohol acetaldehyde then is broken down to acetic acid and water by two variants ingestion increases, the amount of alco- of the enzyme aldehyde dehydrogenase (ALDH). Alcohol metabolism by hol eliminated by first-pass metabolism ADH generates a byproduct called reduced nicotinamide adenine dinu- becomes an even smaller fraction of cleotide (NADH). Excessive NADH levels can inhibit glucose production the total amount of alcohol consumed. (i.e., gluconeogenesis) and breakdown (i.e., oxidation) of fat molecules as Some researchers have suggested, how- well as stimulate production of fat molecules. ever, that some medications can block first-pass metabolism, resulting in showed a reduced alcohol elimination alcohol. The normal loss of lean body blood alcohol levels (BALs) that are rate compared with untreated rats weight and increase in body fat that higher than normal for a given alcohol (Nosova et al. 1999). If these research occurs with aging has a similar effect dose. For example, people taking med- findings also apply to humans, alco- on BALs. The potentially higher BALs ications that can inhibit ADH activity— hol elimination may be delayed in can exaggerate alcohol-medication such as aspirin and certain medications people taking certain antibiotics that interactions in both women and