Pharmacy Times

Oral Medication Interactions with Ethanol

Author: Christian Hartman, PharmD, and Colleen Lowery, PharmD

Approximately 52% of Americans consumed one or more alcoholic drinks in the past month.1 At the same time, prescription drug use has increased to ~10 prescriptions per person in the United States.2 It is likely that many Americans will use both prescription medications and alcohol, creating the potential for drug?ethanol interactions. It is, therefore, advisable for pharmacists to review medications that may interact with ethanol to enhance patient counseling and to avoid untoward effects.

Mechanisms of interaction may involve ethanol metabolism. Once ingested, a small percentage of ethanol is metabolized in the stomach to acetaldehyde by alcohol dehydrogenase (ADH).3 The majority of ethanol is metabolized in the liver by ADH and the cytochrome P450 isoenzyme 2E1. Ethanol is a substrate of isoenzyme 2E1 and an inducer, primarily with long-term use (short-term use paradoxically produces enzyme inhibition).4,5 Potential mechanisms for drug interactions include changes in enzyme activity, changes in gastric emptying, and additive toxicities.

Pain Medications/Muscle Relaxants

The concomitant use of ethanol and narcotics causes additive depression of the central nervous system (CNS), with impairment of speech, sedation, and lethargy. In the case of propoxyphene, bioavailability is increased when it is used with ethanol, likely due to reduced first-pass metabolism. Nonnarcotic pain relievers, such as tramadol, also may produce additive CNS depression.

The interaction of acetaminophen with ethanol is likely due to the induction of CYP2E1 in chronic alcohol users.4 Enzyme induction increases production of the toxic metabolite N-acetyl-p-benzoquinoneimine (NAPQI) and may result in hepatic injury or failure.

The combination of nonsteroidal anti-inflammatory drugs (NSAIDs) and ethanol may cause gastritis or gastrointestinal bleeding through additive irritation.4 Acute renal failure also is possible, secondary to volume contraction with ethanol coupled with NSAID-induced changes in renal blood flow. An increase in bleeding time also can be seen.6

Muscle relaxants such as tizanidine and chlorzoxazone have additive CNS depression with ethanol. Chlorzoxazone is a CYP2E1 substrate, and its metabolism may be inhibited by acute ethanol consumption or induced by chronic consumption.3

Sedatives

The combined use of sedatives and ethanol causes additive CNS depression and possibly fatal respiratory depression. Barbiturate metabolism in the liver also may be inhibited in the presence of alcohol, potentiating the pharmacologic effect.

Antianxiety/Antidepressant Drugs

Ethanol inhibits benzodiazepine metabolism, although not all agents are equally affected.7 For example, agents metabolized by conjugation reactions (eg, lorazepam) have unchanged blood levels, whereas levels for agents metabolized by oxidation (eg, diazepam) are increased. The use of ethanol and benzodiazepines results in additive CNS depression. Other antianxiety agents, such as meprobamate, also may potentiate CNS depression with ethanol.8 The tyramine content of some wines precludes concomitant use of ethanol with monoamine oxidase inhibitors.

The use of ethanol and tricyclic antidepressants is likely to cause alterations in psychomotor function, including "blackouts." Reduced metabolism of imipramine and amitriptyline has been shown with chronic ethanol use.

Although data are lacking, product manufacturers warn against the use of ethanol with selective serotonin reuptake inhibitors as well as with venlafaxine and nefazodone.9-13 Ethanol, when administered with mirtazapine, increases psychomotor impairment.14 Bupropion lowers the seizure threshold and, in the setting of abrupt alcohol withdrawal, could produce an additive lowering of the seizure threshold.15

Antihypertensive Agents

Ethanol causes additive vasodilation with such agents as nitroglycerin, methyldopa, and hydralazine.6 In addition, verapamil has been shown to increase blood ethanol levels, presumably by interfering with metabolism.16 High concentrations of ethanol may reduce the rate of gastric emptying and increase propranolol absorption.4,17

Anticoagulants

Both ethanol and aspirin have gastrointestinal (GI) irritant effects, which may contribute to GI bleeding. Additive prolongation of bleeding time is likely. Aspirin also may inhibit ADH in the stomach, reducing the first-pass effect of ethanol.

The use of ethanol with warfarin produces variable effects on the international normalized ratio (INR). In chronic alcohol users, warfarin metabolism may be induced,4 resulting in a lower INR. Acute ethanol use may inhibit warfarin metabolism, increasing the INR.

Antidiabetic Agents

Ethanol is thought to reduce gluconeogenesis and may affect the safety of antidiabetic medications.4 Ethanol can cause prolonged hypoglycemia or disulfiram-like reactions (flushing, sweating palpitations, headache) when used in conjunction with sulfonylureas (eg, glyburide, glipizide). Hypoglycemic reactions also are possible in patients treated with insulin. Ethanol can enhance the inhibition of lactate metabolism by metformin.18

Gastrointestinal Agents

In some studies, the histamine 2-receptor antagonists cimetidine and ranitidine produced slightly elevated blood alcohol levels.4,19 Cisapride and erythromycin may increase the rate of ethanol absorption by reducing the gastric emptying time and first-pass metabolism by ADH.4

Antimicrobial Agents

Many antifungals and antibiotics?including cotrimoxazole, ketoconazole, and griseofulvin?have the potential to produce a disulfiram-like reaction with ethanol through an unknown mechanism.20 The combination of isoniazid and ethanol may cause disulfiram-like reactions, a reduced half-life with acute ethanol ingestion, and increased isoniazid metabolism with chronic ethanol ingestion.21 The potential for liver injury with isoniazid also is increased with ethanol use.4 Metronidazole combined with ethanol may cause a disulfiram-like reaction, although this interaction has been questioned.22 The area under the concentration-time curve of tetracycline may be increased with ethanol.4

Antihyperlipidemics

Ethanol consumption can increase lipid levels, causing a pharmacodynamic interaction with HMG-CoA reductase inhibitors and other cholesterol-lowering drugs. Liver impairment as a result of chronic ethanol use can contribute to reduced metabolism and increased toxicity with these agents. At least one study involving moderate alcohol consumption with fluvastatin found that fluvastatin metabolism and kinetics were altered, although no adverse effects were reported and efficacy was maintained.5,23

Other Drugs

Other agents that interact with ethanol include amprenavir,24,25 sodium oxybate,26 theophylline,4 acitretin,27 isotretinoin,4 procarbazine,28 methotrexate, antipsychotic agents, antihistamines, phenytoin, and carbamazepine.4

It is impossible to predict the individual patient response to the concomitant use of prescription drugs and ethanol. Avoidance of alcohol, especially in the setting of polypharmacy, is the best way to avoid interactions. Avoidance should be strongly recommended in patients with underlying disease states aggravated by ethanol, such as gout, hypertension, esophagitis, heart failure, osteoporosis, renal dysfunction, depression, and diabetes.4 If avoidance is not possible, consumption of a meal prior to ingestion of ethanol is advisable. The use of lower doses of potentially toxic agents (eg, acetaminophen) in chronic alcohol users may be necessary.

Dr. Hartman is medication safety officer at UMass Memorial Medical Center, Worcester, Mass. He also is a clinical assistant professor at Northeastern University and an adjunct assistant professor at Massachusetts College of Pharmacy. Dr. Lowery is a pharmacy practice resident at Brigham and Women's Hospital, Boston, Mass.

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