Alcohol and Medication Interactions (2024)

Alcohol’s Influences on Various Disease States

Many people who are being treated for chronic health problems, such as diabetes and high blood pressure (i.e., hypertension), consume alcohol, whether occasionally or regularly. As described in the main article, alcohol consumption, even at moderate levels, may interfere with the activities of many medications prescribed for such conditions. In addition, however, alcohol use may contribute to or exacerbate certain medical conditions.

Diabetes

In people with diabetes, control of the levels of the sugar glucose in the blood is severely impaired, either because these people lack the hormone insulin, which plays a central role in blood sugar regulation, or because their body does not respond appropriately to the insulin they produce. Alcohol consumption in diabetics can result either in higher-than-normal blood sugar levels (i.e., hyperglycemia) or in lower-than-normal blood sugar levels (i.e., hypoglycemia), depending on the patient’s nutritional status (Emanuele et al. 1998). Thus, long-term (i.e., chronic) alcohol consumption in well-nourished diabetics can lead to hyper-glycemia. Conversely, alcohol consumption in diabetics who have not eaten for a while and whose glucose resources are exhausted (i.e., who are in a fasting state) can induce hypoglycemia. Both hyperglycemia and hypoglycemia can have serious health consequences. Diabetes medications that substitute for or stimulate the body’s own insulin production (e.g., insulin or sulfonylureas) also may lead to hypoglycemia.

Alcohol-induced hypoglycemia occurs in the fasted state, when the diabetic’s blood sugar levels are already low and the body depends on the production of new glucose molecules (i.e., gluconeogenesis) to maintain sufficient blood glucose levels. Gluconeogenesis, which occurs in the liver, requires certain compounds whose levels are regulated by a substance called reduced nicotinamide adenine dinucleotide (NADH). Alcohol metabolism in the liver generates excessive NADH levels and thus reduces the levels of the compounds needed for gluconeogenesis, thereby contributing to a further drop in blood sugar levels. This response is particularly critical in diabetics taking medications that can cause hypoglycemia. Consequently, these patients should be advised to drink alcohol only with or shortly after meals.

Diabetics who consume alcohol also must be alert to the fact that the symptoms of mild intoxication closely resemble those of hypoglycemia. Accordingly, diabetics should check their blood glucose levels whenever they are uncertain about whether their symptoms are caused by hypoglycemia or alcohol intoxication (for additional recommendations for diabetics who consume alcohol, see the textbox). Finally, patients using certain diabetes medications (e.g., chlorpropamide) should be cautioned that the medications can cause a disulfiram-like reaction when alcohol is consumed.

Hyperlipidemia

In people with hyperlipidemia, the levels of fat molecules in the blood—particularly molecules called triglycerides—are higher than normal. This condition can be associated with an increased risk of various health problems, the most serious of which is cardiovascular disease. Alcohol consumption may exacerbate hyperlipidemia, because the same metabolic alcohol effects that inhibit gluconeogenesis also inhibit fat metabolism. As a result, the production of certain molecules called very low density lipoprotein (VLDL) particles is increased. Thus, people with elevated triglyceride levels in the blood should probably abstain from alcohol to determine if alcohol consumption is contributing to their elevated lipid levels.

Hypertension

Elevated blood pressure is a risk factor for cardiovascular disease, including heart attacks. Alcohol is known to cause a dose-dependent elevation in blood pressure (Beilin 1995). Researchers do not yet know exactly what levels of alcohol consumption cause hypertension (for more information, see the article by Klatsky, pp. 15–23). However, all patients who are diagnosed with high blood pressure should be questioned regarding their alcohol intake before being started on antihypertensive therapy. In some of those patients, cessation of drinking alone may reduce blood pressure and thus obviate the need for pharmacological treatment. Furthermore, patients taking certain kinds of cardiac medications (e.g., isosorbide [Isordil^® and Ismo^®], terazosin [Hytrin^®], doxazosin [Cardura^®]) should be warned that alcohol consumption in combination with those medications may cause lower-than-normal blood pressure. These important potential risks associated with even moderate alcohol consumption (i.e., one or two standard drinks¹ per day) must be considered when discussing the cardiovascular benefits associated with moderate drinking (e.g., reduced risk of heart attacks and certain kinds of strokes.)

Hepatitis C Infection

Infection with the hepatitis C virus, which can result in serious and even fatal liver damage, is common in the United States and around the world. The only effective treatment to date involves a substance called interferon-α, often in combination with an agent called ribavirin, and has a cure rate of approximately 40 percent. Heavy alcohol use in patients infected with hepatitis C accelerates the rate of liver damage and increases the risk of cirrhosis. Moreover, heavy alcohol use appears to reduce the number of hepatitis C-infected people who respond to treatment with interferon-α. Researchers do not yet know how alcohol consumption exacerbates disease progression and interferes with treatment. Nevertheless, people infected with the hepatitis C virus probably should avoid using alcohol, particularly during interferon-α treatment.

— Ron Weathermon and David W. Crabb

¹A standard drink is defined as one 12-ounce can of beer or bottle of wine cooler, one 5-ounce glass of wine, or 1.5 ounces of distilled spirits and is equivalent to approximately 0.5 ounce, or 12 grams (g), of pure alcohol.

Gastrointestinal Absorption and Metabolism

When alcohol is ingested through the mouth, a small amount is immediately broken down (i.e., metabolized) in the stomach. Most of the remaining alcohol is then absorbed into the bloodstream from the gastrointestinal tract, primarily the stomach and the upper small intestine. Alcohol absorption occurs slowly from the stomach but rapidly from the upper small intestine. Once absorbed, the alcohol is transported to the liver through the portal vein. A portion of the ingested alcohol is metabolized during its initial passage through the liver; the remainder of the ingested alcohol leaves the liver, enters the general (i.e., systemic) circulation, and is distributed throughout the body’s tissues.

Alcohol metabolism (or the metabolism of any other substance) that occurs in the gastrointestinal tract and during the substance’s initial passage through the liver is called “ first-pass metabolism” (see figure 1). For example, the mucosa lining the stomach contains enzymes that can metabolize alcohol as well as other substances; some of those enzymes, including alcohol dehydrogenase (ADH) and cytochrome P450 are described in more detail in the section “Alcohol Metabolism in the Liver.”

The contribution of stomach (i.e., gastric) enzymes to first-pass alcohol metabolism, however, is controversial. Whereas some researchers have proposed that gastric enzymes play a major role in first-pass metabolism (Lim et al. 1993), other investigators consider the liver to be the primary site of first-pass metabolism (Levitt and Levitt 1998). Furthermore, some gender differences appear to exist in the overall extent of, and in the contribution of, gastric enzymes to first-pass metabolism. For example, the extent of first-pass metabolism is less in women than in men and some studies also have found lower gastric ADH activity in women (Thomasson 1995).

First-pass metabolism is readily detectable after consumption of low alcohol doses² that leave the stomach slowly (e.g., because they have been consumed with a meal). Thus, under such conditions of delayed gastric emptying, more alcohol can be metabolized in the stomach or absorbed slowly from the stomach and transported to the liver for first-pass metabolism.

In general, probably only a small fraction (perhaps 10 percent) of ingested alcohol is eliminated from the body by first-pass metabolism after consumption of low doses of alcohol. As alcohol ingestion increases, the amount of alcohol eliminated by first-pass metabolism becomes an even smaller fraction of the total amount of alcohol consumed. Some researchers have suggested, however, that some medications can block first-pass metabolism, resulting in blood alcohol levels (BALs) that are higher than normal for a given alcohol dose. For example, people taking medications that can inhibit ADH activity—such as aspirin and certain medications used to treat ulcers and heartburn (i.e., H₂ receptor antagonists, such as cimetidine [Tagamet^® ], nizatidine [Axid^® ] and ranitidine [Zantac^® ])—experience reduced first-pass metabolism (Caballaria et al. 1991; Roine et al. 1990). Similarly, medications that accelerate gastric emptying (e.g., the stomach medications metoclopramide [Reglan^® ] and cisapride [Propulsid^® ] and the antibiotic erythromycin) may reduce first-pass metabolism in the stomach.

The contribution of bacteria living in the large intestine (i.e., colon) to gastrointestinal alcohol metabolism is still controversial. Laboratory experiments have demonstrated that these bacteria can metabolize alcohol. In addition, a breakdown product of alcohol (i.e., acetaldehyde) is generated in the colon after alcohol administration. Finally, studies in rats found that animals treated with an antibiotic to reduce the number of bacteria in the colon showed a reduced alcohol elimination rate compared with untreated rats (Nosova et al. 1999). If these research findings also apply to humans, alcohol elimination may be delayed in people taking certain antibiotics that are active against colonic bacteria.

Alcohol’s Distribution in the Body

Alcohol that has not been eliminated by first-pass metabolism enters the systemic circulation and is distributed throughout the body water (i.e., the blood and the watery fluid surrounding and inside the cells). Alcohol does not dissolve in fat tissues. The proportion of body water and body fat differs between men and women and between young and old people; women and older people generally have more body fat and less body water than do men and younger people. As a result, alcohol distribution throughout the body depends on a person’s gender and age.

Differences in alcohol distribution patterns also affect the BALs achieved with a given alcohol dose (Thomasson 1995). Thus, women, whose lower body water creates a smaller fluid volume in which the alcohol is distributed, tend to achieve higher BALs than do men after consuming the same amount of alcohol. The normal loss of lean body weight and increase in body fat that occurs with aging has a similar effect on BALs. The potentially higher BALs can exaggerate alcohol-medication interactions in both women and older people. Aside from this effect of gender and age on BALs, researchers have not reported any other major gender- or age-related differences in susceptibility to alcohol-medication interactions. However, this issue still requires further investigation.

Alcohol Metabolism in the Liver

The liver is the primary site of alcohol metabolism. Alcohol circulating in the blood is transported to the liver, where it is broken down by several enzymes, the most important of which are ADH and cytochrome P450 (figure 2). The activities of these enzymes may vary from person to person, contributing to the observed variations in alcohol elimination rates among individuals (Martin et al. 1985).

ADH converts alcohol into acetaldehyde in a reaction called oxidation. Acetaldehyde, which is a toxic substance that may contribute to many of alcohol’s adverse effects, is broken down further by an enzyme called aldehyde dehydrogenase (ALDH). (The function of ALDH is discussed in more detail in the following section.) Several ADH variants (i.e., isozymes) exist, which differ in their activity when studied in the laboratory. In humans, however, the effect of different ADH isozymes on alcohol elimination is small (Thomasson 1995). Although different ADH variants are associated with different risks of developing alcoholism, no studies to date have researched the effects of these isozymes on a person’s susceptibility to alcohol-medication interactions.

In contrast to ADH, the alcohol-metabolizing enzyme cytochrome P450—also called microsomal ethanol oxidizing system (MEOS) (Lieber 1994)—plays a central role in alcohol-medication interactions. Cytochrome P450 actually is a system consisting of two enzymes, one called cytochrome P450 reductase and another one called CYP2E1, which are both embedded in the membrane of a cell component called the endoplasmic reticulum.³ In addition to alcohol, CYP2E1 can metabolize numerous compounds, including acetaldehyde, the pain medication acetaminophen, the antibiotic isoniazid, and the barbiturate phenobarbital. Accordingly, CYP2E1 plays an important role in many alcohol-medication interactions.

In people consuming alcohol only occasionally, CYP2E1 metabolizes only a small fraction of the ingested alcohol. Chronic heavy drinking, however, can increase CYP2E1 activity up to tenfold, resulting in a substantial increase in the proportion of alcohol that is metabolized by this enzyme rather than by ADH (figure 3) (Lieber 1994). The effect of lower levels of alcohol consumption on CYP2E1 activity is unknown. Because CYP2E1 also metabolizes several medications, alcoholics, in whom CYP2E1 activity is enhanced, exhibit increased metabolic rates for those medications when they are sober. When those alcoholics are intoxicated, however, the alcohol in their system competes with the medication for metabolism by CYP2E1. As a result, the breakdown of the medication is slowed. With many medications, increased or decreased metabolic rates can have adverse or even fatal consequences. With increased metabolic rates, the medication’s concentration in the body may be too low or may decline too fast for it to be effective. Conversely, decreased metabolic rates may result in the accumulation of higher drug concentrations over longer periods of times, which may result in harmful overdoses.

Wide variation exists among people in both CYP2E1 activity and metabolic rates for medications broken down by this enzyme (e.g., acetaminophen and chlorzoxasone, a medication used to relieve muscle pain). Some of this variation may be genetically determined, although the specific underlying mechanism is unknown (Carriere et al. 1996). A person’s CYP2E1 activity level, however, could influence his or her susceptibility to alcohol-medication interactions involving this enzyme. For example, in a person with innately low metabolic rates, a further decrease in metabolism when alcohol is consumed would affect medication levels (and thus the potential for adverse effects or interactions with alcohol) to a greater extent than in a person with innately high metabolic rates.

In addition to CYP2E1, at least two other cytochrome enzymes that metabolize various medications (i.e., CYP3A4 and CYP1A2) also can break down alcohol (Salmela et al. 1998). Moreover, the amounts of various enyzmes of the cytochrome CYP3A family (including CYP3A4) can increase from alcohol consumption (Niemela et al. 1998). Thus, potential interactions also exist between alcohol and medications metabolized by these cytochromes.

Acetaldehyde Metabolism in the Liver

As mentioned in the previous section, alcohol breakdown by ADH generates acetaldehyde, which, in turn, is metabolized further by ALDH. Two major types of ALDH (i.e., ALDH1 and ALDH2) exist, which are located in different regions of the cell. ALDH1 requires relatively high acetaldehyde concentrations in the cell to be active, whereas ALDH2 is active at extremely low acetaldehyde levels. Accordingly, ALDH2 may play a particularly important role in acetaldehyde breakdown after moderate alcohol consumption.

The significance of ALDH2 activity in alcohol and acetaldehyde metabolism is further supported by an inborn variation in alcohol metabolism that occurs primarily in people of Asian heritage but which is rare among Caucasians. After consuming alcohol, many Asian people experience an unpleasant “ flushing” reaction that can include facial flushing, nausea, and vomiting. These symptoms are caused by acetaldehyde accumulation in the body. Thus, following alcohol consumption, acetaldehyde levels in people susceptible to the flushing reaction may be 10 to 20 times higher than in people who do not experience flushing. Researchers have noted that approximately 40 percent of Asians lack ALDH2 activity because they have inherited one or two copies of an inactive variant of the gene that produces ALDH2 (Goedde et al. 1989). Most of these individuals flush when they consume alcohol. These observations imply that ALDH2 plays a crucial role in maintaining low acetaldehyde levels during alcohol metabolism. Consequently, even inadvertent alcohol administration to people of Asian heritage (who may have inherited an inactive ALDH2 gene) can cause unpleasant reactions. Thus, the potential flushing response should be an important concern for physicians and patients, because many prescription and OTC medications contain substantial amounts of alcohol (see table 1). Physicians and pharmacists therefore must be alert to the possibility that Asian patients may be intolerant of these medications.

Several medications can inhibit even active ALDH molecules (both ALDH1 and ALDH2), thereby inducing a flushing reaction in all people who consume alcohol after taking those medications. In fact, this medication effect is exploited in alcoholism treatment. The medication disulfiram (Antabuse^® ), which inhibits mainly ALDH1 but also ALDH2, is given to alcoholics trying to quit drinking. If the alcoholic drinks alcohol after taking disulfiram, he or she will experience a severe flushing reaction. The experience of such an unpleasant reaction, or even the expectation that this reaction will occur if alcohol is consumed, can help many alcoholics achieve and maintain abstinence. Moderate drinkers are not likely to be treated with disulfiram; however, many other medications (and certain toxic substances) also can induce disulfiram-like reactions when combined with alcohol (see table 2). For example, the commonly prescribed diabetes medication chlorpropamide and the antibiotics cefotetan and metronidazole can induce disulfiram-like reactions, even after ingestion of only small alcohol amounts. These reactions not only are unpleasant but also can result in serious medical consequences. For example, flushing is associated with a widening (i.e., dilation) of the blood vessels, low blood pressure, and rapid heartbeat, all of which can be dangerous in patients with coronary artery disease. Patients taking medications that can induce disulfiram-like reactions therefore should be advised not to drink alcohol.

Alcohol’s Effects on Liver Metabolism

In addition to influencing the metabolism of many medications by activating cytochrome P450 enzymes in the liver, alcohol and its metabolism cause other changes in the liver’s ability to eliminate various substances from the body. Thus, alcohol metabolism affects the liver’s redox state and glutathione levels. The term “redox state” refers to the concentrations of two substances in the cells—nicotinamide adenine dinucleotide (NAD⁺) and reduced NAD⁺ (NADH)—that are needed for the functioning of many enzymes. Alcohol metabolism by ADH results in the conversion of NAD⁺ into NADH, thereby increasing the liver’s NADH levels (see figure 2). Elevated NADH levels, in turn, stimulate the generation of fat molecules and interfere with the ability of other liver enzymes to break down fat molecules and produce the sugar glucose. Through these metabolic changes, alcohol metabolism can substantially affect the body’s general metabolism and functioning. Furthermore, elevated NADH levels may prevent the liver from generating UDP-glucuronic acid, a substance that must be attached to various medications before they can be excreted from the body.

Glutathione is an antioxidant, an agent that prevents certain highly reactive, oxygen-containing molecules (i.e., reactive oxygen species) from damaging the cells. Both alcohol metabolism and the metabolism of certain medications can generate reactive oxygen species, thereby inducing a state called oxidative stress in the cells. At the same time, heavy alcohol consumption reduces the amount of glutathione in liver cells, particularly in the mitochondria (i.e., the cell components where most of the cell’s energy is generated). Consequently, the cell’s protective mechanisms against oxidative stress are impaired, and cell death may result. Furthermore, reduced glutathione levels increase the liver’s susceptibility to damage caused by toxic breakdown products of some medications (e.g., acetaminophen and isoniazid).

Mechanisms of Alcohol-Medication Interactions

Interactions between alcohol and a medication can occur in a variety of situations that differ based on the timing of alcohol and medication consumption. For example, such interactions can occur in people who consume alcohol with a meal shortly before or after taking a medication or who take pain medications after drinking to prevent a hangover. Alcohol-medication interactions fall into two general categories: pharmaco*kinetic and pharmacodynamic. Pharmaco*kinetic interactions are those in which the presence of alcohol directly interferes with the normal metabolism of the medication. This interference can take two forms, as follows:

• The breakdown and excretion of the affected medications are delayed, because the medications must compete with alcohol for breakdown by cytochrome P450. This type of interaction has been described mostly for metabolic reactions involving CYP2E1, but it also may involve CYP3A4 and CYP1A2 (Salmela et al. 1998).

• The metabolism of the affected medications is accelerated, because alcohol enhances the activity of medication-metabolizing cytochromes. When alcohol is not present simultaneously to compete for the cytochromes, increased cytochrome activity results in an increased elimination rate for medications that these enzymes metabolize.

Pharmacodynamic alcohol-medication interactions do not involve enzyme inhibition or activation, but rather refer to the additive effects of alcohol and certain medications. In this type of interaction, which occurs most commonly in the central nervous system (CNS), alcohol alters the effects of the medication without changing the medication’s concentration in the blood. With some medications (e.g., barbiturates and sedative medications called benzodiazepines), alcohol acts on the same molecules inside or on the surface of the cell as does the medication. These interactions may be synergistic—that is, the effects of the combined medications exceed the sum of the effects of the individual medications. With other medications (e.g., antihistamines and antidepressants) alcohol enhances the sedative effects of those medications but acts through different mechanisms from those agents.

Specific Alcohol-Medication Interactions

This section describes different classes of medications and their interactions with alcohol (see table 3). The potential for the occurrence and relevance of alcohol-medication interactions in moderate drinkers may differ, however, between pharmaco*kinetic and pharmacodynamic interactions. The number of potential pharmaco*kinetic interactions with alcohol is great, because the various cytochrome P450 enzymes metabolize many medications.⁴ However, many of the pharmaco*kinetic interactions discussed here were first discovered in heavy drinkers or alcoholics or were studied in animals given large alcohol doses in their diet. Although the potential for such effects certainly exists even after low alcohol consumption, researchers have not yet demonstrated the occurrence and relevance of those effects in moderate drinkers. Conversely, pharmacodynamic interactions can occur with intermittent alcohol consumption and even after a single episode of drinking. Accordingly, those interactions clearly pertain to moderate drinkers.

Nonnarcotic Pain Medications and Anti-Inflammatory Agents

Many people frequently use nonnarcotic pain medications and anti-inflammatory agents (e.g., aspirin, acetaminophen, or ibuprofen) for headaches and other minor aches and pains. In addition, arthritis and other disorders of the muscles and bones are among the most common problems for which older people consult physicians (Adams 1995). Nonsteroidal anti-inflammatory drugs (NSAIDs) (e.g., ibuprofen, naproxen, indomethacin, and diclofenac) and aspirin are commonly prescribed or recommended for the treatment of these disorders and are purchased OTC in huge amounts. Several potential interactions exist between alcohol and these agents, as follows:

• NSAIDs have been implicated in an increased risk of ulcers and gastrointestinal bleeding in elderly people. Alcohol may exacerbate that risk by enhancing the ability of these medications to damage the stomach mucosa (Adams 1995).⁶

• Aspirin, indomethacin, and ibuprofen cause prolonged bleeding by inhibiting the function of certain blood cells involved in blood clot formation. This effect also appears to be enhanced by concurrent alcohol use (Deykin et al. 1982).

• Aspirin has been shown to increase BALs after small alcohol doses, possibly by inhibiting first-pass metabolism (Roine et al. 1990).

An important pharmaco*kinetic interaction between alcohol and acetaminophen can increase the risk of acetaminophen-related toxic effects on the liver. Acetaminophen breakdown by CYP2E1 (and possibly CYP3A) results in the formation of a toxic product that can cause potentially life-threatening liver damage. As mentioned earlier, heavy alcohol use enhances CYP2E1 activity. In turn, enhanced CYP2E1 activity increases the formation of the toxic acetaminophen product. To prevent liver damage, patients generally should not exceed the maximum doses recommended by the manufacturers (i.e., 4 grams, or up to eight extra-strength tablets of acetaminophen per day). In people who drink heavily or who are fasting (which also increases CYP2E1 activity), however, liver injury may occur at doses as low as 2 to 4 grams per day. The specific drinking levels at which acetaminophen toxicity is enhanced are still unknown. Because acetaminophen is easily available OTC, however, labels on the packages warn people about the potentially dangerous alcohol-acetaminophen combination. Furthermore, people should be aware that combination cough, cold, and flu medications may contain aspirin, acetaminophen, or ibuprofen, all of which might contribute to serious health consequences when combined with alcohol.

¹A standard drink is defined as one 12-ounce can of beer or bottle of wine cooler, one 5-ounce glass of wine, or 1.5 ounces of distilled spirits and is equivalent to approximately 0.5 ounce, or 12 grams (g), of pure alcohol.

²Low alcohol doses are defined here as 0.3 g per kilogram body weight, equivalent to approximately two standard drinks for a person weighing 70 kg.

³The endoplasmic reticulum is an extensive network of membrane-enclosed tubules within the cell that is involved in the production of proteins and fat molecules and in the transport of those molecules within the cell.

⁴An Internet Web site (www.accp.com/p450.html) catalogs the classes of cytochrome P450 molecules that can metabolize various medications. This resource can help identify medications metabolized by CYP2E1 that may potentially interact with alcohol.

⁵Another class of medications, which prevent gastric acid production through a different mechanism from the H₂RAs (i.e., omeprazole and lansoprazole), also do not appear to interact with alcohol.

⁶Moderate alcohol use by itself, however, does not appear to be associated with an increased risk of ulcers or gastrointestinal bleeding and also is unlikely to cause a certain type of inflammation of the stomach lining (i.e., hemorrhagic gastritis) that has been observed after heavy alcohol use.

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