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Ron Weathermon, Pharm.D., and David W. Crabb, M.D.

Many can interact with alcohol, thereby altering the or effects of alcohol and/or the medication. Some of these interactions can occur even at moderate levels and result in adverse 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 (e.g., ). Pharmacokinetic interactions generally occur in the , where both alcohol and many medications are metabolized, frequently by the same . Numerous classes of prescription medications can interact with alcohol, including , ,

, , , H2 antagonists, muscle relaxants, nonnarcotic medications and anti-inflammatory agents, , and . In addition, many over-the-counter and medications can cause negative effects when taken with alcohol. KEY WORDS: moderate AOD use; prescription ; adverse drug ; ; metabolism; cytochromes; liver; alcohol ; antibiotics; antidepressants; blockaders; barbiturates; benzodiazepines; 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 effects of both alcohol and tion may directly influence some of medications, at least occasionally. As a sedative medications can enhance the 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- , 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 is defined as one 12-ounce can drinks1 per day). Researchers, physi- in the Departments of and of or of cooler, one 5-ounce glass of wine, or 1.5 ounces of distilled spirits and is cians, and must therefore and Molecular , 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 , primar- alcohol as well as other substances; distribution, and metabolism within ily the and the upper small some of those enzymes, including the body; the sites where potential intestine. Alcohol absorption occurs alcohol (ADH) and alcohol-medication interactions can slowly from the stomach but rapidly are described in occur; and possible adverse effects from the upper . 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 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 (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 alcohol levels (BALs) after oral alcohol ingestion and after intravenous administration of the same alcohol . 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 + detectable after consumption of low NAD NADH Inhibition of oxidation 2 alcohol doses that leave the stomach 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 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 and by two variants ingestion increases, the amount of alco- of the enzyme dehydrogenase (ALDH). Alcohol metabolism by hol eliminated by first-pass metabolism ADH generates a byproduct called reduced dinu- becomes an even smaller fraction of cleotide (NADH). Excessive NADH levels can inhibit production the total amount of alcohol consumed. (i.e., gluconeogenesis) and breakdown (i.e., oxidation) of fat 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 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 , 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 and certain medications people taking certain antibiotics that interactions in both women and older used to treat ulcers and (i.e., are active against colonic . people. Aside from this effect of gender H receptor antagonists, such as cime- 2 and age on BALs, researchers have not tidine [Tagamet®], [Axid®] reported any other major gender- or and [Zantac®])—experience Alcohol’s Distribution in the Body age-related differences in susceptibility reduced first-pass metabolism (Caballaria Alcohol that has not been eliminated to alcohol-medication interactions. et al. 1991; Roine et al. 1990). Similarly, by first-pass metabolism enters the However, this issue requires fur- medications that accelerate gastric systemic circulation and is distributed ther investigation. emptying (e.g., the stomach medica- throughout the body water (i.e., the tions [Reglan®] and blood and the watery fluid surround- [Propulsid®] and the antibi- Alcohol Metabolism in the Liver ing and inside the cells). Alcohol does otic ) may reduce first- not dissolve in fat tissues. The propor- The liver is the primary site of alcohol pass metabolism in the stomach. tion of body water and body fat differs metabolism. Alcohol circulating in the The contribution of bacteria living between men and women and between blood is transported to the liver, where in the (i.e., colon) to young and old people; women and it is broken down by several enzymes, gastrointestinal alcohol metabolism is older people generally have more body the most important of which are ADH still controversial. Laboratory experi- fat and less body water than do men and cytochrome P450 (figure 2). The ments have demonstrated that these and younger people. As a result, alco- activities of these enzymes may vary bacteria can metabolize alcohol. In hol distribution throughout the body from person to person, contributing addition, a breakdown product of alco- depends on a person’s gender and age. to the observed variations in alcohol hol (i.e., acetaldehyde) is generated in Differences in alcohol distribution elimination rates among individuals the colon after alcohol administration. patterns also the BALs achieved (Martin et al. 1985). Finally, studies in rats found that ani- with a given alcohol dose (Thomasson ADH converts alcohol into - mals treated with an to reduce 1995). Thus, women, whose lower body dehyde in a reaction called oxidation. the number of bacteria in the colon water creates a smaller fluid volume in Acetaldehyde, which is a toxic sub- 2Low alcohol doses are defined here as 0.3 g per which the alcohol is distributed, tend stance that may contribute to many kilogram body weight, equivalent to approximately to achieve higher BALs than do men of alcohol’s adverse effects, is broken two standard for a person weighing 70 kg. after consuming the same amount of down further by an enzyme called

42 Alcohol Research & Health Alcohol andWhat Medication Is Moderate Interactions Drinking?

(ALDH). are both embedded in the membrane 3) (Lieber 1994). The effect of lower (The function of ALDH is discussed of a cell component called the endoplas- levels of alcohol consumption on in more detail in the following sec- mic reticulum.3 In addition to alcohol, CYP2E1 activity is unknown. Because tion.) Several ADH variants (i.e., CYP2E1 can metabolize numerous CYP2E1 also metabolizes several medi- isozymes) exist, which differ in their compounds, including acetaldehyde, the cations, alcoholics, in whom CYP2E1 activity when studied in the labora- pain medication acetaminophen, the activity is enhanced, exhibit increased tory. In humans, however, the effect antibiotic , and the metabolic rates for those medications of different ADH isozymes on alcohol . Accordingly, CYP2E1 when they are sober. When those elimination is small (Thomasson 1995). plays an important role in many alco- alcoholics are intoxicated, however, Although different ADH variants are hol-medication interactions. the alcohol in their system competes associated with different risks of devel- In people consuming alcohol only with the medication for metabolism oping , no studies to date occasionally, CYP2E1 metabolizes by CYP2E1. As a result, the - have researched the effects of these only a small fraction of the ingested down of the medication is slowed. isozymes on a person’s susceptibility to alcohol. Chronic heavy drinking, With many medications, increased alcohol-medication interactions. however, can increase CYP2E1 activ- or decreased metabolic rates can have In contrast to ADH, the alcohol- ity up to tenfold, resulting in a sub- adverse or even fatal consequences. metabolizing enzyme cytochrome stantial increase in the proportion of With increased metabolic rates, the P450—also called microsomal alcohol that is metabolized by this medication’s concentration in the ethanol oxidizing system (MEOS) enzyme rather than by ADH (figure body may be too low or may decline (Lieber 1994)—plays a central role too fast for it to be effective. Con- in alcohol-medication interactions. versely, decreased metabolic rates Cytochrome P450 actually is a system 3The endoplasmic reticulum is an extensive net- may result in the accumulation of work of membrane-enclosed tubules within the consisting of two enzymes, one called cell that is involved in the production of higher drug concentrations over cytochrome P450 reductase and and fat molecules and in the transport of those longer periods of times, which may another one called CYP2E1, which molecules within the cell. result in harmful overdoses.

(A) In the absence of alcohol, CYP activity is relatively low. CYP breaks down the medication, and the Drug Drug resulting products (i.e., ) are excreted. CYP

(B) After moderate alcohol consumption, CYP metabo- lizes alcohol in addition to the medication. As a Alcohol result of competition for CYP between alcohol and Drug CYP Drug metabolite ( ) Excretion ( ) the medication, the medication’s metabolism is reduced, and the production of metabolites as well as their excretion declines, resulting in higher medi- Interaction with alcohol in CNS cation levels in the body. In addition, interactions between alcohol and the medication may occur in the (CNS).

(C) In chronic heavy drinkers who are sober, CYP activity ( ) ( ) is enhanced. As a result, the breakdown of medications Drug Drug metabolite Excretion metabolized by CYP increases, and metabolite levels as well as their excretion are elevated, possibly CYP Drug metabolite resulting in insufficient medication levels in the body. Furthermore, toxic metabolites may accumulate.

(D) In chronic heavy drinkers who are intoxicated, CYP is activated, but most of the enzyme is involved in alcohol Alcohol metabolism. Consequently, the CYP-dependent Drug CYP Drug metabolite ( ) Excretion ( ) metabolism of other medications is reduced, and metabolite levels and their excretion decline. Alcohol- medication interactions also can occur in the CNS. Interaction with alcohol in CNS

Figure 3 Potential alcohol-medication interactions involving cytochrome P450 enzymes (CYP) in the liver.

Vol. 23, No. 1, 1999 43 Wide variation exists among people Caucasians. After consuming alcohol, when they consume alcohol. These in both CYP2E1 activity and metabolic many Asian people experience an observations imply that ALDH2 rates for medications broken down by unpleasant “” reaction that plays a crucial role in maintaining low this enzyme (e.g., acetaminophen and can include facial flushing, , acetaldehyde levels during alcohol chlorzoxasone, a medication used to and . These symptoms are metabolism. Consequently, even inad- relieve muscle pain). Some of this vari- caused by acetaldehyde accumulation vertent alcohol administration to peo- ation may be genetically determined, in the body. Thus, following alcohol ple of Asian heritage (who may have although the specific underlying mecha- consumption, acetaldehyde levels in inherited an inactive ALDH2 gene) nism is unknown (Carriere et al. people susceptible to the flushing can cause unpleasant reactions. Thus, 1996). A person’s CYP2E1 activity reaction may be 10 to 20 times higher the potential flushing response should level, however, could influence his or than in people who do not experience be an important concern for physi- her susceptibility to alcohol-medication flushing. Researchers have noted that cians and patients, because many interactions involving this enzyme. For approximately 40 percent of Asians prescription and OTC medications example, in a person with innately low lack ALDH2 activity because they contain substantial amounts of alco- metabolic rates, a further decrease in have inherited one or two copies of hol (see table 1). Physicians and phar- metabolism when alcohol is consumed an inactive variant of the gene that macists therefore must be alert to the would affect medication levels (and produces ALDH2 (Goedde et al. possibility that Asian patients may be thus the potential for adverse effects 1989). Most of these individuals flush intolerant of these medications. or interactions with alcohol) to a greater extent than in a person with innately high metabolic rates. Table 1 Alcohol Content of Prescription and Over-the-Counter Medications In addition to CYP2E1, at least two other cytochrome enzymes that Product Alcohol Content (%) metabolize various medications (i.e., CYP3A4 and CYP1A2) also can Betadine (, gargle) 8.8 break down alcohol (Salmela et al. Cepacol (mouthwash, gargle) 14.0 1998). Moreover, the amounts of var- Cheracol 12.5 ious enyzmes of the cytochrome Chlortrimeton 7.0 Oral 2.8 CYP3A family (including CYP3A4) Cyclosporine Oral Solution 9.5Ð12.5 can increase from alcohol consump- 5.0 tion (Niemela et al. 1998). Thus, DentSure (denture rinse, ) 14.4 potential interactions also exist Dr. Tichenor’s 70* between alcohol and medications 10.0 metabolized by these cytochromes. Entex 5.0 11.5 Intensol () 19.0 Acetaldehyde Metabolism in the Liver 26.9 As mentioned in the previous section, Listerine Cool Mint or Freshburst 21.6 Lomotil Liquid 15.0 alcohol breakdown by ADH generates Mellaril/Thioridiazine 3.0Ð4.2 acetaldehyde, which, in turn, is metab- Mentadent Mouthwash 10.0 olized further by ALDH. Two major Oral-B Anti-Plaque Rinse 8.0 types of ALDH (i.e., ALDH1 and Plax-Advanced 8.7 ALDH2) exist, which are located in Peri-colace 10.0 different regions of the cell. ALDH1 Phenobarbital Elixir 14.0 requires relatively high acetaldehyde /Phenergan 7.0 concentrations in the cell to be active, Ranitidine 7.5 whereas ALDH2 is active at extremely Scope, Baking Soda 9.9 low acetaldehyde levels. Accordingly, Scope, Cool Peppermint 14.0 Senokot Syrup 7.0 ALDH2 may play a particularly impor- Targon Smokers’ Mouth Wash, Clean 15.6* tant role in acetaldehyde breakdown Targon Smokers’ Mouth Wash, Original 16.0* after moderate alcohol consumption. Tavist Oral Solution 5.5 The significance of ALDH2 activity Elixir 20.0 in alcohol and acetaldehyde metabolism Viadent Oral Rinse 10.0 is further supported by an inborn *Specifically (SDA) 38B content. variation in alcohol metabolism that SOURCE: Knodel, L.C., ed. Nonprescription Products: Formulations and Features. 1998Ð1999. Washington, occurs primarily in people of Asian DC: American Pharmaceutical Association, 1999. heritage but which is rare among

44 Alcohol Research & Health Alcohol andWhat Medication Is Moderate Interactions Drinking?

Several medications can inhibit even consequences. For example, flushing is ulate the generation of fat molecules active ALDH molecules (both ALDH1 associated with a widening (i.e., dilation) and interfere with the ability of other and ALDH2), thereby inducing a flush- of the blood vessels, low blood pressure, liver enzymes to break down fat mole- ing reaction in all people who consume and rapid heartbeat, all of which can cules and produce the glucose. alcohol after taking those medications. be dangerous in patients with coronary Through these metabolic changes, In fact, this medication effect is artery disease. Patients taking medica- alcohol metabolism can substantially exploited in alcoholism treatment. The tions that can induce -like affect the body’s general metabolism medication disulfiram (Antabuse®), reactions therefore should be advised and functioning. Furthermore, elevated which inhibits mainly ALDH1 but also not to drink alcohol. NADH levels may prevent the liver ALDH2, is given to alcoholics trying from generating UDP-, to quit drinking. If the alcoholic drinks Alcohol’s Effects on Liver Metabolism a substance that must be attached to alcohol after taking disulfiram, he or she various medications before they can be will experience a severe flushing reaction. In addition to influencing the meta- excreted from the body. The experience of such an unpleasant bolism of many medications by acti- is an antioxidant, an reaction, or even the expectation that vating cytochrome P450 enzymes in agent that prevents certain highly reac- this reaction will occur if alcohol is con- the liver, alcohol and its metabolism tive, -containing molecules (i.e., sumed, can help many alcoholics achieve cause other changes in the liver’s ability reactive oxygen species) from damag- and maintain . Moderate to eliminate various substances from ing the cells. Both alcohol metabolism drinkers are not likely to be treated the body. Thus, alcohol metabolism and the metabolism of certain medi- with disulfiram; however, many other affects the liver’s state and glu- cations can generate reactive oxygen medications (and certain toxic sub- tathione levels. The term “redox state” species, thereby inducing a state called stances) also can induce disulfiram-like refers to the concentrations of two oxidative in the cells. At the same reactions when combined with alcohol substances in the cells—nicotinamide time, heavy alcohol consumption (see table 2). For example, the com- adenine dinucleotide (NAD+) and reduces the amount of glutathione in monly prescribed medication reduced NAD+ (NADH)—that are liver cells, particularly in the mitochon- and the antibiotics needed for the functioning of many dria (i.e., the cell components where and can induce enzymes. Alcohol metabolism by ADH most of the cell’s energy is generated). disulfiram-like reactions, even after inges- results in the conversion of NAD+ Consequently, the cell’s protective tion of only small alcohol amounts. into NADH, thereby increasing the mechanisms against oxidative stress are These reactions not only are unpleasant liver’s NADH levels (see figure 2). impaired, and cell may result. but also can result in serious medical Elevated NADH levels, in turn, stim- Furthermore, reduced glutathione levels increase the liver’s susceptibility to damage caused by toxic breakdown Table 2 Commonly Used Medications That Cause Disulfiram-Like Reactions (i.e., products of some medications (e.g., Flushing, Nausea, Vomiting, Sweating) After Alcohol Consumption acetaminophen and isoniazid).

Type of Medication Generic Names Names (NSAIDs) various Common Alcohol- Medication Interactions

Antibiotics Mandol Cefobid Mechanisms of Alcohol-Medication Cefotetan Cefotan Interactions various Fulvicin, Grifulvin,Grisactin Interactions between alcohol and a med- Isoniazid Nydrazid, Rifamate, Rifater ication can occur in a variety of situa- Metronidazole Flagyl tions that differ based on the timing Furadantin, Macrodantin of alcohol and medication consump- Bactrim, Septra tion. For example, such interactions Sulfisoxazole Pediazole can occur in people who consume alco- hol with a meal shortly before or after Cardiovascular medications dinitrate Dilatrate, Isordil, Sorbitrate taking a medication or who take pain () Nitro-Bid, Nitrostat medications after drinking to prevent a . Alcohol-medication inter- Diabetes medications Chlorpropamide Diabinese () Glyburide DiaBeta, Glynase, Micronase actions fall into two general categories: generic pharmacokinetic and pharmacodynamic. generic Pharmacokinetic interactions are those in which the presence of alcohol directly

Vol. 23, No. 1, 1999 45 Table 3 Interactions Between Alcohol and Various Classes of Medications

Drug Class (Conditions for which they are used) Generic Name Brand Name Availability Type of Interaction Analgesics Aspirin various Rx and OTC ¥Aspirin increases gastric emptying, leading to (pain relief) Acetaminophen e.g., faster alcohol absorption in the small intestine; may also inhibit gastric ADH. ¥Alcohol enhances acetaminophen metabolism into a toxic product, potentially causing liver damage.

Antibiotics Erythromycin various Rx ¥Erythromycin may increase gastric emptying, (microbial ) Isoniazid Nydrazid, leading to faster alcohol absorption in the Rifamate, Rifater small intestine. ¥Alcohol increases the risk of isoniazid-related .

Anticonvulsants Dilantin Rx ¥Chronic alcohol consumption induces ( disorders) phenytoin breakdown.

Antihistamines e.g., Rx and OTC ¥Alcohol enhances the effects of these agents (, colds) Chlorpheniramine various on the central nervous system (CNS), such as drowsiness, sedation, and decreased motor skills. Atarax, Vistaril ¥The interactions are more pronounced in Promethazine Phenergan elderly people. Cyproheptadine Periactin ¥No documented interactions exist with nonsedating antihistamines (i.e., certrizine, hismanal, loratidine).

Anticoagulants Warfarin Coumadin Rx ¥ alcohol intake may increase anticoagulation (prevention of blood clots) by decreasing warfarin metabolism; chronic alcohol ingestion decreases anticoagulation by increasing warfarin metabolism.

Antidiabetic agents Chlorpropamide Diabinese Rx ¥Alcohol consumption by diabetic patients taking (blood sugar Glucotrol these medications increases the risk of lower- regulation) Glyburide DiaBeta, Glynase, than-normal blood sugar levels (i.e., ). Micronase ¥Chlorpropamide, glyburide, and tolbutamide can Tolbutamide Orinase cause disulfiram-like interactions after alcohol Glucophage ingestion. ¥Metformin may cause increased levels of in the blood after alcohol consumption.

Barbiturates Phenobarbital various Rx ¥Chronic alcohol intake increases barbiturate (, pain relief) metabolism by cytochrome P450. ¥Alcohol enhances the sedative and effects on the CNS.

Benzodiazepines Xanax Rx ¥Alcohol enhances the effects of these agents (sedative agents) Librium on the CNS, such as drowsiness, sedation, and Klonopin decreased motor skills. Tranxene Diazepam Valium Ativan Versed Serax Restoril Halcion

46 Alcohol Research & Health Alcohol andWhat Medication Is Moderate Interactions Drinking?

continued

Drug Class (Conditions for which they are used) Generic Name Brand Name Availability Type of Interaction

Histamine H2 Cimetidine Tagamet Rx and OTC ¥The agents inhibit ADH in the stomach, thereby receptor antagonists Nizatidine Axid reducing alcohol first-pass metabolism (see (ulcers, ) Ranitidine Zantac figure 1), as well as increase gastric emptying. As a result, BALs are higher than expected for a given alcohol dose; this effect increases over time.

Immune modulators Rheumatrex Rx ¥Immune modulators (i.e., medications that affect () immune cell function) are associated with a risk of liver damage, which is increased in combination with alcohol.

Muscle relaxants Soma Rx ¥Alcohol consumption enhances impairment Flexeril of physical abilities (e.g., driving) and increases sedation. ¥Carisoprodol produces an -like high when taken with alcohol; it is metabolized to and sometimes abused as a street drug.

NSAIDs e.g., Motrin Rx and OTC ¥Alcohol consumption increases the (pain relief and various associated risk of gastrointestinal . ) Nalfon Orudis Naprosyn Voltaren

Opioids (pain relief) various Rx ¥Alcohol enhances the effects of these Dilaudid agents on the CNS, such as drowsiness, generic sedation, and decreased motor skills. various Meperidine e.g., Demerol Propoxyphene Darvon, Wygesic

Sedatives and Noctec Rx ¥Alcohol inhibits the metabolism of these Meprobamate Equanil, Miltown agents and produces a effect on the CNS that includes sleepiness, disorientation, incoherence, and .

Tricyclic Elavil, EndepRx ¥Alcohol consumption increases the risk of antidepressants Anafranil sedation and a sudden drop in blood () Norpramin pressure when a person stands up (i.e., Adapin, Sinequan orthostatic ). Tofranil Aventyl, Pamelor Surmontil

Herbal medications various OTC ¥Alcohol may accentuate the drowsiness that ( aids) preparations is associated with these herbal preparations.

ADH = alcohol dehydrogenase; BAL = blood alcohol level; NSAIDs = anti-inflammatory ; OTC = over the counter; Rx = prescription.

Vol. 23, No. 1, 1999 47 interferes with the normal metabolism tial for the occurrence and relevance grew from research findings indicat- of the medication. This interference of alcohol-medication interactions in ing that heavy alcohol use can impair can take two forms, as follows: moderate drinkers may differ, however, the function of certain immune cells between pharmacokinetic and pharma- and that alcoholics are predisposed to • The breakdown and excretion of codynamic interactions. The number certain infections. These effects, how- the affected medications are of potential pharmacokinetic interac- ever, are unlikely to occur in moder- delayed, because the medications tions with alcohol is great, because the ate drinkers. must compete with alcohol for various cytochrome P450 enzymes meta- breakdown by cytochrome P450. bolize many medications.4 However, Antidepressants. Several classes of This type of interaction has been many of the pharmacokinetic interac- medications exist, described mostly for metabolic tions discussed here were first discov- including antidepressants reactions involving CYP2E1, but it ered in heavy drinkers or alcoholics or (TCAs), selective also may involve CYP3A4 and were studied in animals given large inhibitors (SSRIs), monoamine oxi- CYP1A2 (Salmela et al. 1998). alcohol doses in their diet. Although dase (MAO) inhibitors, and atypical the potential for such effects certainly antidepressants. These classes differ in • The metabolism of the affected exists even after low alcohol consump- their in that medications is accelerated, because tion, researchers have not yet demon- they affect different chemicals. alcohol enhances the activity of strated the occurrence and relevance All types of antidepressants, however, medication-metabolizing cyto- of those effects in moderate drinkers. have some sedative as well as some chromes. When alcohol is not pre- Conversely, pharmacodynamic inter- stimulating activity. sent simultaneously to compete for actions can occur with intermittent TCAs with a higher ratio of sedative- the cytochromes, increased cyto- alcohol consumption and even after a to- activity (i.e., amitripty- chrome activity results in an increased single episode of drinking. Accordingly, line, doxepin, , and elimination rate for medications that those interactions clearly pertain to trimipramine) will cause the most these enzymes metabolize. moderate drinkers. sedation. Alcohol increases the TCAs’ sedative effects through pharmacody- Pharmacodynamic alcohol-medication Antibiotics. The package inserts for namic interactions. In addition, alcohol interactions do not involve enzyme most antibiotics include a warning for consumption can cause pharmacokinetic inhibition or activation, but rather patients to avoid using alcohol with interactions with TCAs. For example, refer to the additive effects of alcohol those medications. The rationale for alcohol appears to interfere with the and certain medications. In this type these warnings is not entirely clear, first-pass metabolism of amitriptyline of interaction, which occurs most however, because only a few antibi- in the liver, resulting in increased ami- commonly in the central nervous sys- otics appear to interact with alcohol. triptyline levels in the blood. In addi- tem (CNS), alcohol alters the effects For example, although some antibi- tion, alcohol-induced liver disease of the medication without changing otics induce flushing, most antibiotics further impairs amitriptyline break- the medication’s concentration in the do not. The antibiotic erythromycin down and causes significantly increased blood. With some medications (e.g., may increase alcohol absorption in levels of active medication in the body barbiturates and sedative medications the intestine (and, consequently, (i.e., increased ). High called benzodiazepines), alcohol acts increase BALs) by accelerating gastric TCA levels, in turn, can lead to convul- on the same molecules inside or on emptying. Furthermore, people tak- sions and disturbances in heart rhythm. the surface of the cell as does the med- ing the antituberculosis drug isoniazid SSRIs (i.e., , , ication. These interactions may be should abstain from alcohol, because , and ), which are synergistic—that is, the effects of the isoniazid can cause liver damage, currently the most widely used anti- combined medications exceed the sum which may be exacerbated by daily , are much less sedating of the effects of the individual medica- alcohol consumption. Aside from than are TCAs. In addition, no serious tions. With other medications (e.g., these effects, however, moderate alco- interactions appear to occur when antihistamines and antidepressants) hol consumption probably does not these agents are consumed with - alcohol enhances the sedative effects interfere with antibiotic effectiveness. erate alcohol doses (Matilla 1990). In of those medications but acts through Possibly, concerns regarding the con- fact, SSRIs have the best safety profile different mechanisms from those agents. current use of alcohol and antibiotics of all antidepressants, even when com- bined in large quantities with alcohol (e.g., in and overdose situations). Specific Alcohol-Medication 4An Internet Web site (www.accp.com/p450.html) Interactions Conversely, people taking MAO catalogs the classes of cytochrome P450 molecules inhibitors or atypical antidepressants that can metabolize various medications. This This section describes different classes resource can help identify medications metabo- can experience adverse consequences of medications and their interactions lized by CYP2E1 that may potentially interact when simultaneously consuming alco- with alcohol (see table 3). The poten- with alcohol. hol. Thus, MAO inhibitors (e.g.,

48 Alcohol Research & Health Alcohol andWhat Medication Is Moderate Interactions Drinking?

and ) can the medication’s sedative . date (Simmons and Cupp 1998). induce severe high blood pressure if Patients taking barbiturates therefore In addition, the metabolism of certain they are consumed together with a should be warned not to perform tasks BZDs involves cytochrome P450, substance called , which is that require alertness, such as driving or leading to the alcohol-induced changes present in . Accordingly, peo- operating heavy machinery, particularly in metabolism described earlier in ple taking MAO inhibitors should be after simultaneous alcohol consumption. this article. warned against drinking red wine. The In addition to the pharmacodynamic atypical antidepressants (i.e., interactions, pharmacokinetic interac- Histamine H2 Receptor Antagonists and ) may cause enhanced tions between alcohol and phenobar- (H2RAs). As mentioned earlier in this sedation when used with alcohol. bital exist, because alcohol inhibits the article, H2RAs (e.g., cimetidine, rani- medication’s breakdown in the liver. tidine, nizatidine, and ), Antihistamines. These medications, This inhibition results in a slower meta- which reduce gastric acid secretion, which are available both by prescription bolism and, possibly, higher blood are used in the treatment of ulcers and OTC, are used in the management and heartburn. These agents reduce of allergies and colds. Antihistamines ADH activity in the stomach mucosa may cause drowsiness, sedation, and (Caballeria et al. 1991), and cimeti- low blood pressure (i.e., hypotension), Pharmacodynamic dine also may increase the rate of - especially in elderly patients (Dufour tric emptying. As a result, alcohol et al. 1992). Through pharmacody- interactions can consumed with cimetidine undergoes namic interactions, alcohol can substan- less first-pass metabolism, resulting in tially enhance the sedating effects of occur with increased BALs. For example, in a these agents and may thereby increase, intermittent alcohol study of people who consumed three for example, a person’s risk of falling or four standard drinks over 135 min- or impair his or her ability to drive or consumption and utes while taking cimetidine, BALs operate other types of machinery. As a even after a single higher and remained elevated for result of these potential interactions, a longer period of time than in people warning labels on OTC antihistamines episode of drinking. not taking cimetidine (Lieber 1997; caution patients about the possibility Gupta et al. 1995). Not all H2RAs, of increased drowsiness when consum- however, exert the same effect on BALs ing the medication with alcohol. Newer when taken with alcohol. Thus, cime- antihistamines (i.e., certrizine and levels of phenobarbital. Conversely, tidine and ranitidine have the most loratidine) have been developed to barbiturates increase total cytochrome pronounced effect, nizatidine has an minimize drowsiness and sedation P450 activity in the liver and accelerate intermediate effect, and famotidine while still providing effective alcohol elimination from the blood appears to have no effect (i.e., appears relief. However, these newer medica- (Bode et al. 1979). This acceleration not to interact with alcohol).5 In addi- tions may still be associated with an of alcohol elimination probably does tion, because women generally appear increased risk of hypotension and falls not have any . to have lower first-pass metabolism of among the elderly, particularly when alcohol, they may be at less risk for combined with alcohol. Consequently, Benzodiazepines. Like barbiturates, adverse interactions with H2RAs. patients taking nonsedating antihis- benzodiazepines (BZDs) are classified tamines still should be warned against as sedative-hypnotic agents and act Muscle Relaxants. Several muscle relax- using alcohol. through the same brain molecules as do ants (e.g., carisoprodol, cyclobenzaprine, barbiturates. Accordingly, as with - and ), when taken with alcohol, Barbiturates. These medications are biturates, concurrent consumption of may produce a certain -like sedative or sleep-inducing (i.e., hyp- BZDs and moderate amounts of alcohol reaction that includes extreme weakness, notic) agents that are frequently used can cause synergistic sedative effects, , agitation, , and for anesthesia. Phenobarbital, which leading to substantial CNS impairment. confusion. For example, carisoprodol is probably the most commonly pre- It is worth noting that both barbitu- is a commonly abused and readily scribed barbiturate in modern prac- rates and benzodiazepines can impair available prescription medication that tice, also is used in the treatment of , as can alcohol. Consequently, is sold as a street drug. Its metabolism seizure disorders. Phenobarbital acti- the combination of these medications in the liver generates an -reducing vates some of the same molecules in with alcohol would exacerbate this agent that was previously marketed as the CNS as does alcohol, resulting in memory-impairing effect. In fact, this pharmacodynamic interactions between effect sometimes is exploited by mix- 5Another class of medications, which prevent gastric the two substances. Consequently, ing alcoholic beverages with BZDs, acid production through a different mechanism alcohol consumption while taking such as the rapid-acting from the H2RAs (i.e., and lansoprazole), phenobarbital synergistically enhances (Rohypnol®), an agent implicated in also do not appear to interact with alcohol.

Vol. 23, No. 1, 1999 49 a (meprobamate). minophen can increase the risk of can be particularly harmful when The of carisoprodol with beer acetaminophen-related toxic effects combined with alcohol because they is popular among street abusers for on the liver. Acetaminophen break- provide “hidden” doses of acetamin- creating a quick state of euphoria. down by CYP2E1 (and possibly ophen. As described in the previous CYP3A) results in the formation of a section, alcohol consumption may Nonnarcotic Pain Medications toxic product that can cause poten- result in the accumulation of toxic and Anti-Inflammatory Agents. tially -threatening liver damage. As breakdown products of acetamino- mentioned earlier, heavy alcohol use phen. Therefore, patients using Many people frequently use nonnarcotic enhances CYP2E1 activity. In turn, -acetaminophen combination pain medications and anti-inflamma- enhanced CYP2E1 activity increases products should be cautioned about tory agents (e.g., aspirin, acetaminophen, the formation of the toxic acetamino- restricting the total amount of acetamin- or ibuprofen) for and other phen product. To prevent liver damage, ophen they ingest daily (i.e., they minor aches and . In addition, patients generally should not exceed should not take regular acetaminophen arthritis and other disorders of the mus- the maximum doses recommended by in addition to the combination product). cles and are among the most the manufacturers (i.e., 4 grams, or common problems for which older up to eight extra-strength tablets of Warfarin. The warfarin people consult physicians (Adams 1995). acetaminophen per day). In people is used for the prevention of blood Nonsteroidal anti-inflammatory drugs who drink heavily or who are clots in patients with irregular heart (NSAIDs) (e.g., ibuprofen, naproxen, (which also increases CYP2E1 activ- rhythms or artificial heart valves; it is indomethacin, and diclofenac) and ity), however, liver may occur also used to treat clots that form in aspirin are commonly prescribed or at doses as low as 2 to 4 grams per extremities such as legs, arms, or some- recommended for the treatment of day. The specific drinking levels at times the lungs. Its anticoagulant these disorders and are purchased which acetaminophen toxicity is effect is acutely altered by even small OTC in huge amounts. Several poten- enhanced are still unknown. Because amounts of alcohol. In people taking tial interactions exist between alcohol acetaminophen is easily available warfarin and ingesting a few drinks in and these agents, as follows: OTC, however, labels on the packages one sitting, anticlotting effects may be warn people about the potentially stronger than necessary for medical • NSAIDs have been implicated in dangerous alcohol-acetaminophen purposes, placing these people at risk an increased risk of ulcers and gas- combination. Furthermore, people for increased bleeding. This excessive trointestinal bleeding in elderly should be aware that combination warfarin activity results from alcohol- people. Alcohol may exacerbate , cold, and flu medications may related inhibition of warfarin metab- that risk by enhancing the ability contain aspirin, acetaminophen, or olism by cytochrome P450 in the liver of these medications to damage the ibuprofen, all of which might con- (Lieber 1994). Conversely, in people stomach mucosa (Adams 1995).6 tribute to serious health consequences who chronically drink alcohol, long- when combined with alcohol. term alcohol consumption activates • Aspirin, indomethacin, and ibupro- cytochrome P450 and, consequently, fen cause prolonged bleeding by Opioids. Opioids are agents with warfarin metabolism. As a result, war- inhibiting the function of certain -like effects (e.g., sedation, pain farin is broken down faster than nor- blood cells involved in blood clot relief, and euphoria) that are used as mal, and higher warfarin doses are formation. This effect also appears pain medications. Alcohol accentuates required to achieve the desired antico- to be enhanced by concurrent alco- the opioids’ sedating effects. Accord- agulant effect. Thus, alcohol con- hol use (Deykin et al. 1982). ingly, all patients receiving narcotic sumption can result in dangerously prescriptions should be warned about high or insufficient warfarin activity, • Aspirin has been shown to increase the drowsiness caused by these agents depending on the patient’s drinking BALs after small alcohol doses, and the additive effects of alcohol. pattern. Therefore, patients taking possibly by inhibiting first-pass Overdoses of alcohol and opioids are warfarin generally should avoid alcohol. metabolism (Roine et al. 1990). potentially lethal because they can reduce the cough and An important pharmacokinetic functions; as a result, the patients are Moderate Alcohol interaction between alcohol and aceta- at risk of getting , fluids, or other Consumption and OTC objects stuck in their airways or of or Herbal Medications being unable to breathe. 6Moderate alcohol use by itself, however, does not Certain opioid pain medications Use of OTC medications is widespread appear to be associated with an increased risk of (e.g., codeine, propoxyphene, and among the general population. Accord- ulcers or gastrointestinal bleeding and also is unlikely to cause a certain type of inflammation ) are manufactured as ing to a recent survey, 85 percent of of the stomach lining (i.e., hemorrhagic ) combination products containing adults ages 18 and older have used that has been observed after heavy alcohol use. acetaminophen. These combinations OTC pain relievers at least once, and

50 Alcohol Research & Health Alcohol andWhat Medication Is Moderate Interactions Drinking?

up to 34 percent use OTC pain reliev- an alcohol content of 0.5 percent benzodiazepines and alcohol and the ers on a weekly basis, often without or less). interaction of alcohol with warfarin. consulting a . Furthermore, Given the variety and complexity of a recent scientific panel convened by • For children ages 6 to 12, the alco- observed interactions between alcohol the American Pharmaceutical Associa- hol content should range between and numerous medications, it is diffi- tion (1997) reported that although 0.5 and 5 percent. cult to recommend an alcohol con- adults frequently use OTC medica- sumption level that can be considered tions, many consumers fail to read the • For people over age 12, the alcohol safe when taking medications. As a product warning labels. Finally, con- content should not exceed 5 to 10 rule, people taking either prescription sumers frequently are unaware of the percent. or OTC medications should always type of medication they take (e.g., read the product warning labels to NSAID or ). For example, These levels represent only guide- determine whether possible interactions only one in three adults are familiar lines, however, and are not enforced exist. Similarly, health care providers with the product names acetaminophen, by the FDA. The manufacturers of should be alert to the potential for aspirin, or ibuprofen and are able to OTC products have agreed to main- moderate alcohol use to either enhance link these product names to specific tain certain standards to keep their medication effects or interfere with brand names. As a result, many con- products as close to these suggestions the desired therapeutic actions of a sumers are not fully aware of the as possible. Nevertheless, higher alco- medication. potential risks of taking these products, hol concentrations are considered particularly in combination with other acceptable in certain products, such as prescription medications or alcohol. herbal medications, because alcohol References Another factor contributing to an often is needed to and dissolve increasing risk of medication-medica- organic substances from . ADAMS, W.L. Interactions between alcohol and tion or alcohol-medication interac- Herbal medications currently are other drugs. International Journal of 30:1903–1923, 1995. tions is that many medications that widely used, and many people assume previously were available only by pre- that because these products are “natu- American Pharmaceutical Association. Navigating the Medication Marketplace: How Consumers scription (e.g., H2RAs and NSAIDs) ral,” they also are safe to use. This are gaining OTC status. OTC mar- assumption may not always be correct, Choose. Washington, DC: the Association, 1997. keting strategies, however, often lead however. For example, chamomile, BODE, J.C.; BODE, C.; AND THIELE, D. Alcohol the consumer to think that these echinacea, and valerian commonly are metabolism in man: Effect of intravenous infusion on blood ethanol elimination rate fol- medications are safe to use on an “as- used as sleep aids, and like prescrip- lowing stimulation by phenobarbital treatment or needed” basis, even though they can tion and OTC products that cause chronic alcohol consumption. Klinische be potentially dangerous when used sedation, these herbal products may Wochenschrift 57:125–130, 1979. with alcohol. For example, the mes- produce enhanced sedative effects in CABALLERIA, J.; BARAONA, E.; DEULOFEU, R.; sage that “acid blocker” medications the CNS when combined with alco- HERNANDEZ-MUNOZ, R.; RODES, J.; AND LIEBER, can be used before or during a spicy hol. In addition, liver caused C.S. Effects of H-2 receptor antagonists on gastric meal to prevent heartburn symptoms by various natural products have now alcohol dehydrogenase activity. Digestive Disease may lead consumers to believe that been identified (Heathcote and Wanless Sciences 36:1673–1679, 1991. this practice is also acceptable when 1995), and their combination with CARRIERE, V.; VERTHOU, F.; BAIRD, S.; BELLOC, they drink alcohol with their meal. alcohol may enhance potential adverse C.; BEAUNE, P.; AND DE WAZIERS, I. Not only the combination of alcohol effects. To date, limited documentation cytochrome P450 2E1 (CYP2E1): From genotype and OTC products but also the amount of such interactions exists because of a to phenotype. Pharmacogenetics 6:203–211, 1996. of alcohol contained in various OTC lack of scientific studies on this subject DEYKIN, D.; JANSON, P.; AND MCMAHON, L. products can be dangerous (see table 1). (Miller 1998). Ethanol potentiation of aspirin-induced prolon- Alcohol concentrations in these products gation of the bleeding time. New England Journal of Medicine 306:852–854, 1982. can be substantial; and cough tend to have the highest Conclusions DUFOUR, M.C.; ARCHER, L.; AND GORDIS, E. alcohol contents. In an effort to control Alcohol and the elderly. Clinical Geriatric Medicine the alcohol amounts in these products Alcohol’s effects on the metabolism 8:127–141, 1992. and promote safety, the and and activities of various medications GOEDDE, H.W.; SINGH, S.; AGARWAL, D.P.; FRITZE, G.; STAPEL, K.; AND PAIK, Y.K. Genotyping of Drug Administration’s (FDA’s) OTC- have been well documented in chronic mitochondrial aldehyde dehydrogenase in blood drugs advisory committee has adopted heavy drinkers. The effects of moderate samples using allele-specific oligonucleotides: the following limits on the amount of alcohol consumption, however, have Comparison with phenotyping in hair roots. alcohol considered appropriate: not been studied as thoroughly. Those Human Genetics 81:305–307, 1989. effects most likely to be clinically sig- GUPTA, A.M.; BARAONA, E.; AND LIEBER, C.S. • For children under age 6, products nificant are the risk of over-sedation Significant increase of blood alcohol by cimetidine should be “alcohol free” (i.e., have resulting from the combination of after repetitive drinking of small alcohol doses.

Vol. 23, No. 1, 1999 51 Alcohol’s Influences on Various Disease States

any people who are being treated for chronic a further drop in blood sugar levels. This response is health problems, such as diabetes and high particularly critical in diabetics taking medications Mblood pressure (i.e., ), consume that can cause hypoglycemia. Consequently, these alcohol, whether occasionally or regularly. As described patients should be advised to drink alcohol only with in the main article, alcohol consumption, even at mod- or shortly after meals. erate levels, may interfere with the activities of many Diabetics who consume alcohol also must be alert medications prescribed for such conditions. In addi- to the fact that the symptoms of mild intoxication tion, however, alcohol use may contribute to or exac- closely resemble those of hypoglycemia. Accordingly, erbate certain medical conditions. diabetics should check their blood glucose levels when- ever they are uncertain about whether their symptoms Diabetes are caused by hypoglycemia or (for additional recommendations for diabetics who In people with diabetes, control of the levels of the consume alcohol, see the textbox). Finally, patients sugar glucose in the blood is severely impaired, either using certain diabetes medications (e.g., chlorpropamide) because these people lack the , which should be cautioned that the medications can cause a plays a central role in blood sugar regulation, or disulfiram-like reaction when alcohol is consumed. because their body does not respond appropriately to the insulin they produce. Alcohol consumption in dia- Hyperlipidemia betics can result either in higher-than-normal blood sugar levels (i.e., ) or in lower-than-nor- In people with hyperlipidemia, the levels of fat mal blood sugar levels (i.e., hypoglycemia), depending molecules in the blood—particularly molecules called on the patient’s nutritional status (Emanuele et al. —are higher than normal. This condition 1998). Thus, long-term (i.e., chronic) alcohol consump- can be associated with an increased risk of various health tion in well-nourished diabetics can lead to hyper- problems, the most serious of which is cardiovascular glycemia. Conversely, alcohol consumption in diabetics disease. Alcohol consumption may exacerbate hyper- who have not eaten for a while and whose glucose lipidemia, because the same metabolic alcohol effects resources are exhausted (i.e., who are in a fasting state) that inhibit gluconeogenesis also inhibit fat metabolism. can induce hypoglycemia. Both hyperglycemia and As a result, the production of certain molecules called hypoglycemia can have serious health consequences. very low lipoprotein (VLDL) particles is Diabetes medications that substitute for or stimulate increased. Thus, people with elevated lev- the body’s own insulin production (e.g., insulin or sul- els in the blood should probably abstain from alcohol fonylureas) also may lead to hypoglycemia. to determine if alcohol consumption is contributing Alcohol-induced hypoglycemia occurs in the fasted to their elevated lipid levels. state, when the diabetic’s blood sugar levels are already low and the body depends on the production of new Hypertension glucose molecules (i.e., gluconeogenesis) to maintain sufficient blood glucose levels. Gluconeogenesis, Elevated blood pressure is a for cardiovas- which occurs in the liver, requires certain compounds cular disease, including heart attacks. Alcohol is whose levels are regulated by a substance called reduced known to cause a dose-dependent elevation in blood nicotinamide adenine dinucleotide (NADH). Alcohol pressure (Beilin 1995). Researchers do not yet know metabolism in the liver generates excessive NADH exactly what levels of alcohol consumption cause levels and thus reduces the levels of the compounds hypertension (for more information, see the article needed for gluconeogenesis, thereby contributing to by Klatsky, pp. 15–23). However, all patients who

52 Alcohol Research & Health Alcohol andWhat Medication Is Moderate Interactions Drinking?

are diagnosed with high blood pressure should be hol consumption in combination with those medi- questioned regarding their alcohol intake before cations may cause lower-than-normal blood pres- being started on antihypertensive . In some sure. These important potential risks associated of those patients, cessation of drinking alone may with even moderate alcohol consumption (i.e., one reduce blood pressure and thus obviate the need for or two standard drinks1 per day) must be consid- pharmacological treatment. Furthermore, patients ered when discussing the cardiovascular benefits taking certain kinds of cardiac medications (e.g., associated with moderate drinking (e.g., reduced isosorbide [Isordil and Ismo], [Hytrin], risk of heart attacks and certain kinds of .) [Cardura]) should be warned that alco- C Preventing Alcohol-Induced Infection with the , which can result Hypoglycemia in serious and even fatal liver damage, is common in the and around the world. The only Alcohol-consuming diabetic patients should effective treatment to date involves a substance called consider the following general suggestions interferon-α, often in combination with an agent for preventing alcohol-induced hypoglycemia: called , and has a cure rate of approximately 40 percent. Heavy alcohol use in patients infected • Never consume alcohol without food with hepatitis C accelerates the rate of liver damage or while in a fasting state. and increases the risk of . Moreover, heavy alcohol use appears to reduce the number of hepati- • Consume only moderate amounts of tis C-infected people who respond to treatment with alcohol (i.e., one or two of beer, interferon-α. Researchers do not yet know how glasses of wine, or mixed drinks at one alcohol consumption exacerbates disease progression sitting), and drink no more than once and interferes with treatment. Nevertheless, people or twice weekly. infected with the hepatitis C virus probably should avoid using alcohol, particularly during interferon-α • Allow 1.5 to 2 hours between drinks. treatment.

• Avoid sugar-containing drinks, and —Ron Weathermon and David W. Crabb consume only light beer, dry wine, or drinks mixed with diet sodas. References

• Check blood sugar levels if unsure BEILIN, L.J. Alcohol and hypertension. Clinical and Experimental whether certain body sensations (e.g., and Physiology 22:185–188, 1995. light-headedness) result from hypo- glycemia or alcohol effects. EMANUELE, N.V.; SWADE, T.F.; AND EMANUELE, M.A. Consequences of alcohol use in diabetics. Alcohol Health & Research World 22(3):211–219, 1998. • Be on the alert for alcohol hidden in prescription and over-the-counter 1A is defined as one 12-ounce can of beer or bottle of medications. 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.

Vol. 23, No. 1, 1999 53 Alcoholism: Clinical and Experimental Research gastric. Alcoholism: Clinical and Experimental tration decreases enhanced ethanol elimination in 19:1083–1087, 1995. Research 17:1337–1344, 1993. ethanol-fed rats. Alcohol and Alcoholism 34:48–54, 1999. HEATHCOTE, J., AND WANLESS, I.R. : MATILLA, M.J. Alcohol and drug interactions. Newer aspects of pathogenesis and treatment. Annals of Medicine 22:363–369, 1990. ROINE, R.; GENTRY, R.T.; HERNANDEZ-MUNOZ, Gastroenterologist 3(2):119–129, 1995. R.; BARAONA, E.; AND LIEBER, C.S. Aspirin MARTIN, N.G.; PERL, J.; OAKESHOTT, J.G.; GIBSON, increases blood alcohol concentration in humans LEVITT, M.D., AND LEVITT, D.G. Use of a two- J.B.; STARMER, G.A.; AND WILKS, A.V. A twin after ingestion of ethanol. Journal of the American compartment model to assess the pharmacokinet- study of ethanol metabolism. Behavior Genetics Medical Association 264:2406–2408, 1990. ics of human ethanol metabolism. Alcoholism: 15:93–109, 1985. SALMELA, K.S.; KESSOVA, I.G.; TSYRLOV, I.B.; Clinical and Experimental Research 22:1680– MILLER, L.G. Herbal medicinals. Archives of AND LIEBER, C.S. Respective roles of human 1688, 1998. Internal Medicine 158:2200–2211, 1998. cytochrome P-4502E1, 1A2, and 3A4 in the hep- atic microsomal ethanol oxidizing system. LIEBER, C.S. Alcohol and the liver: 1994 update. NIEMELA, O.; PARKKILA, S.; PASANEN, M.; IIMUR, Alcoholism: Clinical and Experimental Research 106:1085–1105, 1994. Y.; BRADFORD, B.; AND THURMAN, R.G. Early 22:2125–2132, 1998. alcoholic liver injury: Formation of LIEBER, C.S. Gastric ethanol metabolism and gas- adducts with acetaldehyde and lipid peroxidation SIMMONS, M.M., AND CUPP, M.J. Use and tritis: Interactions with other drugs, products, and expression of CYP2E1 and CYP3A. of flunitrazepam. Annals of Pharmacotherapy pylori, and antibiotic therapy. Alcoholism: Clinical Alcoholism: Clinical and Experimental Research 32:117–119, 1998. and Experimental Research 21:1360–1366, 1997. 22:2118–2124, 1998. THOMASSON, H.R. Gender differences in alcohol LIM, R.T., JR.; GENTRY, R.T.; ITO, D.; NOSOVA, T.; JOKELAINEN, K.; KAIHOVAARA, P.; metabolism. Physiological responses to ethanol. YOKOYAMA, H.; BARAONA, E.; AND LIEBER, C.S. VAKEVAINEN, S.; RAUTIO, M.; JOUSIMIES-SOMER, Recent Developments in Alcoholism 12:163–179, First-pass metabolism of ethanol is predominantly H.; AND SALASPURO, M. adminis- 1995.

Visit NIAAA in 1999!

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54 Alcohol Research & Health