Alcohol-Related Drug Interactions

Detail-Document #240106 −This Detail-Document accompanies the related article published in−

PHARMACIST’S LETTER / PRESCRIBER’S LETTER January 2008 ~ Volume 24 ~ Number 240106

Alcohol-related Drug Interactions

Many drugs interact with alcohol resulting in undesirable outcomes. There are two types of alcohol- drug interactions: pharmacokinetic and pharmacodynamic. Pharmacokinetic interactions occur when alcohol alters the metabolism or excretion of the drug or vice versa. Pharmacodynamic interactions refer to the additive effects of alcohol and certain drugs, particularly in the central nervous system (CNS) (e.g., sedation) without affecting the pharmacokinetics of the drug. 2 Alcohol is primarily metabolized in the liver by several enzymes. The most important enzymes are aldehyde dehydrogenase and CYP2E1. In people consuming alcohol only occasionally, CYP2E1 metabolizes only a small fraction of the ingested alcohol. In contrast, chronic heavy drinking can increase CYP2E1 activity up to ten-fold, resulting in higher proportion of alcohol being metabolized by CYP2E1 rather than alcohol dehydrogenase. 5 Therefore, in some cases, the effect of alcohol on the interacting drug may be different depending on chronic or acute alcohol use. There are a number of classes of drugs that can potentially interact with alcohol (e.g., antibiotics, antidepressants, sedative/hypnotics, opioids, anticoagulants, etc). The included chart summarizes common alcohol-medication interactions including precautions and recommendations for alcohol consumption.

Abbreviations: CNS=central nervous system; GI=gastrointestinal; MAOIs=monoamine oxidase inhibitors; NSAIDs= nonsteroidal anti-inflammatory drugs. Drug/Drug Class a Effect(s) and Proposed Recommendations/ Mechanism(s) 1-5 Comments c,1-5 Analgesics (non-opioids) Aspirin, NSAIDs (e.g., • Increased risk of GI hemorrhage. • Warn patients of the increased ibuprofen, etc) • Aspirin or NSAIDs and alcohol risk for GI bleeding when each damage the gastric mucosal aspirin or NSAIDs are taken barrier. The combination can with alcohol, especially if result in additive or synergistic taken on an empty stomach. effects. • Tell patients to avoid taking aspirin within 8 to 10 hours of heavy alcohol use.

Acetaminophen • Chronic alcoholics are more • Warn patients who (Tylenol , Paracetamol , susceptible to acetaminophen- chronically consume several etc) induced hepatotoxicity. alcoholic drinks a day or more • Acute alcohol intoxication might to avoid taking large or reduce the formation of toxic prolonged doses of acetaminophen metabolites. acetaminophen. (Do not • Prolonged intake of large exceed 4 g/24 hr). amounts of alcohol may cause enzyme induction and enhance the formation of hepatotoxic metabolites of acetaminophen while lowering serum acetaminophen concentration.

More. . . Copyright © 2008 by Therapeutic Research Center - Posted Pharmacist’s Letter / Prescriber’s Letter ~ P.O. Box 8190, Stockton, CA 95208 ~ Phone: 209-472-2240 ~ Fax: 209-472-2249 www.pharmacistsletter.com ~ www.prescribersletter.com (Detail-Document #240106: Page 2 of 11)

Drug/Drug Class a Effect(s) and Proposed Recommendations/ Mechanism(s) 1-5 Comments c,1-5 Analgesics (Opioids) b Alfentanil • Chronic alcohol consumption • Consider higher doses of (Alfenta ) may increase the risk of alfentanil in patients who pharmacodynamic tolerance to regularly consume alcohol. alfentanil. • The exact mechanism of interaction is unknown.

Long-Acting Morphine • Increased morphine release rate • Tell patients to avoid alcohol (Kadian 6, Avinza 7) and absorption, which may lead and alcohol-containing drugs to potentially fatal doses. (NyQuil , etc). • Alcohol interacts with the • Alcohol is contraindicated extended-release mechanism and according to Canadian Kadian causes a dose dumping effect. monograph. 21 • In an in vitro study, alcohol was found to affect Kadian ’s extended release mechanism. However, in vivo studies done in the U.S. showed that dose dumping is not a problem.6

Long-Acting Oxymorphone • Enhanced CNS depression, • Tell patients to avoid alcohol (Opana ER 8) which can potentially result in and alcohol-containing drugs respiratory depression, (NyQuil , etc). hypotension, coma, and in some cases, death. 9 • An in vivo pharmacokinetic study showed an increased absorption of oxymorphone in the presence of alcohol.

Meperidine • Excessive CNS depression and • Tell patients to limit alcohol (Demerol ) impaired psychomotor intake to avoid excessive CNS performance. depression. • Alcohol may affect the • Monitor for excessive CNS distribution of meperidine, but depression if the combination the clinical importance of this is used. effect is not established.

More. . . Posted with permission Copyright © 2008 by Therapeutic Research Center CR07165 Pharmacist’s Letter / Prescriber’s Letter ~ P.O. Box 8190, Stockton, CA 95208 Phone: 209-472-2240 ~ Fax: 209-472-2249 www.pharmacistsletter.com ~ www.prescribersletter.com

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Drug/Drug Class a Effect(s) and Proposed Recommendations/ Mechanism(s) 1-5 Comments c,1-5 Analgesics (Opioids) b Con’t Methadone 22,23 • Excessive CNS depression and • Tell patients to avoid alcohol. (Dolophine ) impaired psychomotor • Monitor for excessive CNS performance. depression and signs and • The combination of methadone symptoms of respiratory and alcohol has been implicated depression if the combination in fatalities due to increased risk is used. for respiratory depression. • Acute alcohol ingestion can slow methadone metabolism, thereby increasing risk of methadone toxicity. • Due to methadone’s prolonged half-life, the risk of accidental overdose and potential for drug interactions is higher.

Propoxyphene • Overdoses of propoxyphene • Tell patients to avoid acute (Darvocet-N) combined with alcohol have been excessive alcohol intake. associated with fatal reactions. • Monitor for excessive CNS • Alcohol appears to increase depression if the combination propoxyphene bioavailability by is used. reducing its first-pass metabolism.

Antidepressants Tricyclic Antidepressants • Excessive CNS depression and • Warn patients taking tricyclic (e.g., amitriptyline, etc) impaired psychomotor antidepressants of enhanced performance. CNS depression, especially • Acute alcohol ingestion may within the first week of inhibit the first-pass hepatic treatment and with the more metabolism of tricyclic sedating tricyclics such as antidepressants. amitriptyline and doxepin. • Prolonged intake of large amounts of alcohol may stimulate the hepatic metabolism of tricyclic antidepressants. • Imipramine and desipramine elimination is increased in detoxified alcoholics.

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Drug/Drug Class a Effect(s) and Proposed Recommendations/ Mechanism(s) 1-5 Comments c,1-5 Antidepressants Con’t MAOIs • Severe hypertensive response • Tell patients to avoid alcohol. (e.g., phenelzine [ Nardil ], when taken with alcoholic • If alcohol is ingested, use isocarboxazid [ Marplan ], beverages containing tyramine. products that are unlikely to tranylcypromine [ Parnate ]) • No known mechanism for contain significant amounts of interaction between alcohol itself tyramine (e.g., vodka, white and MAOIs. wine) and ingest small • Some alcoholic beverages may amounts initially. contain considerable amounts of • Warn patients that the effects tyramine (e.g., some red wines of non-selective MAOIs may and beers), whose metabolism is persist for two weeks after severely impaired in the presence they are discontinued. of MAOIs.

Antidiabetics Sulfonylureas • Disulfiram-like reaction has been • Tell patients to avoid alcohol reported in patients on consumption in excess of an chlorpropamide who drank occasional drink to prevent alcohol. (Theoretical risk with hypoglycemia. other sulfonylureas.) The exact • Monitor for hypoglycemia if mechanism of interaction is the combination is used. unclear. • Counsel patients on • Acute alcohol use increases the sulfonylureas to avoid alcohol risk of severe hypoglycemia. if they experience flushing or • Alcohol may prolong glipizide’s headache. effect on blood glucose by delaying glipizide absorption and elimination. • Chronic alcohol ingestion may decrease the half-life of tolbutamide by decreasing absorption and increasing hepatic metabolism of tolbutamide. Insulin • Enhanced glucose-lowering • Tell patients to limit alcohol action of insulin. consumption and avoid • Enhanced release of insulin drinking on an empty following a glucose load and stomach. inhibition of gluconeogenesis. • Monitor for hypoglycemia if the combination is used.

Metformin 12,13 • Theoretically, an increased risk • Tell patients to limit alcohol (Glucophage, etc) for lactic acidosis. consumption. • Potentiate metformin effect on • Monitor for signs and lactate metabolism. symptoms of lactic acidosis if the combination is used.

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Drug/Drug Class a Effect(s) and Proposed Recommendations/ Mechanism(s) 1-5 Comments c,1-5 Antihistamines First generation • Enhanced CNS depression and • Tell patients to limit alcohol antihistamines (e.g., impaired psychomotor consumption. diphenhydramine, performance. • Monitor for signs and chlorpheniramine, • Interactions are more pronounced symptoms of CNS depression hydroxyzine, etc) in elderly patients. if the combination is used. • There are no documented cases with nonsedating antihistamines. Antihypertensives Alpha-1-adrenergic blockers • Hypotension, especially in • Tell patients to limit or avoid (prazosin) Asians. alcohol intake, especially in • Asians may be more susceptible patients who flush after because they are more likely than alcohol ingestion. whites to be deficient in aldehyde dehydrogenase. When such patients ingest alcohol, the vasodilatory alcohol metabolite acetaldehyde accumulates and reduces blood pressure. • Theoretically, a similar interaction with alcohol can occur with other alpha-1- adrenergic blockers (e.g., doxazosin, terazosin, etc). Verapamil • Increases alcohol concentrations • Warn patients of the potential (Calan , etc) and prolongs intoxication. for enhanced effects of • Verapamil appears to inhibit alcohol when combined with alcohol metabolism and it may verapamil. also decrease the first-pass metabolism of alcohol. Anti-infectives Cephalosporins • Disulfiram-like reactions. • Tell patients to avoid alcohol (cefoperazone [ Cefobid ], • These cephalosporins contain a while taking these cefotetan [ Cefotan ], Canada moiety that is structurally related cephalosporins and for 2 to 3 only : moxalactam [ Moxam ], to disulfiram and may inhibit days after discontinuing the cefamandole [ Mandol ]) aldehyde dehydrogenase, thereby drug. leading to accumulation of acetaldehyde, a metabolite of alcohol.

Doxycycline • Chronic alcohol ingestion may • Consider tetracycline in an reduce the serum concentration alcoholic patient when a of doxycycline. tetracycline is needed or • Chronic ingestion of large increase the doxycycline dose. amounts of alcohol can induce hepatic enzymes and increase doxycycline metabolism. More. . . Posted with permission Copyright © 2008 by Therapeutic Research Center CR07165 Pharmacist’s Letter / Prescriber’s Letter ~ P.O. Box 8190, Stockton, CA 95208 Phone: 209-472-2240 ~ Fax: 209-472-2249 www.pharmacistsletter.com ~ www.prescribersletter.com

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Drug/Drug Class a Effect(s) and Proposed Recommendations/ Mechanism(s) 1-5 Comments c,1-5 Anti-infectives Con’t Erythromycin • Alcohol appears to slow gastric • Warn patients of enhanced emptying, thereby delaying alcohol effects if the absorption of erythromycin (no combination is used. significant effect on efficacy noted). • Erythromycin may increase alcohol absorption when low doses of alcohol are administered.

Isoniazid • Increased risk of hepatotoxicity • Tell patients to limit or avoid in the presence of chronic alcohol. alcohol consumption on a daily • Alcoholic patients should be basis. monitored carefully for INH • The exact mechanism of hepatitis. interaction is unclear.

Ketoconazole • Disulfiram-like reaction. • Tell patients to limit or avoid (Nizoral , etc) • The exact mechanism of alcohol consumption. interaction is unclear. • Warn patients that alcohol consumption might cause flushing, headache, and nausea.

Metronidazole • Disulfiram-like reaction. • Tell patients to avoid alcohol (Flagyl ) • Metronidazole inhibits aldehyde or alcohol-containing drugs dehydrogenase, which leads to while taking metronidazole accumulation of acetaldehyde, a and for at least 1 day after metabolite of alcohol. stopping the drug. • Vaginal preparations have also • Monitor for flushing, nausea, been reported to interact with and vomiting if the alcohol. combination is used.

Tinidazole • Disulfiram-like reaction. • Manufacturer recommends (Tindamax ) • Tinidazole inhibits aldehyde avoiding alcohol or dehydrogenase, which leads to preparations with propylene accumulation of acetaldehyde, a glycol during tinidazole metabolite of alcohol. therapy and for 3 days following its discontinuation. • Monitor for flushing, nausea, and vomiting if the combination is used.

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Drug/Drug Class a Effect(s) and Proposed Recommendations/ Mechanism(s) 1-5 Comments c,1-5 Antipsychotics Phenothiazines • Excessive CNS depression and • Discourage alcohol intake. (e.g., chlorpromazine, impaired psychomotor • Warn patients receiving fluphenazine, performance. neuroleptics of the risk for prochlorperazine, etc) • Increased risk for extrapyramidal CNS depression and impaired symptoms. psychomotor performance. • Alcohol may lower the threshold of resistance to neurotoxic effects by depleting dopamine or calcium.

Atypical antipsychotics 16,17 • Excessive CNS depression and • Tell patients to avoid alcohol (quetiapine impaired psychomotor use beyond the occasional one [Seroquel ], aripiprazole performance. or two drinks. [Abilify ] , olanzapine • Enhanced orthostatic [Zyprexa ], risperidone hypotension when olanzapine [Risperdal ], ziprasidone and alcohol are taken together. [Geodon ], paliperidone [Invega ], clozapine [Clozaril ])

Sedatives-Hypnotics Barbiturates • Excessive CNS depression and • Tell patients to avoid alcohol (e.g., phenobarbital, impaired psychomotor since tolerance is pentobarbital, secobarbital, performance. unpredictable and deaths have etc) • There are reports of death been reported. associated with concomitant use • Monitor for excessive CNS of alcohol and barbiturates due to depression if the combination mechanisms other than excessive is used. CNS depression. • Acute intoxication with alcohol appears to inhibit pentobarbital metabolism, while chronic alcohol ingestion appears to enhance the hepatic metabolism of pentobarbital.

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Drug/Drug Class a Effect(s) and Proposed Recommendations/ Mechanism(s) 1-5 Comments c,1-5 Sedatives-Hypnotics Con’t Benzodiazepines • Excessive CNS depression and • Warn against moderate to (e.g., diazepam, lorazepam, impaired psychomotor large amounts of alcohol. etc) performance. • Small amount of alcohol • Alcohol has been reported to especially if taken with food increase aggression or amnesia probably causes little additive and/or reduce the anxiolytic CNS depression unless effects of some benzodiazepines. alertness is required (e.g., • Alcohol may increase the driving). absorption of diazepam and • Keep in mind that some reduce its hepatic metabolism. benzodiazepines (e.g., • Patients with alcoholic liver flurazepam, clonazepam, etc) disease may eliminate used at night for sedation are benzodiazepines more slowly still present in appreciable than those with normal liver amounts the next morning and function. the interaction continues. • Monitor for excessive CNS depression if the combination is used. Non-benzodiazepine • Increased risk of ‘sleep-driving’ • The manufacturers warn hypnotics 18-20 (i.e., driving not fully awake with against concurrent use with (zolpidem [ Ambien , etc], amnesia of the event). alcohol. zaleplon [ Sonata ], • The exact mechanism of eszopiclone [ Lunesta ], interaction is unknown. May be zopiclone [ Imovane , Canada due to additive CNS depressant only]) effect.

Chloral Hydrate • Excessive CNS depression and • Tell patients to limit alcohol impaired psychomotor intake. performance. • Monitor excessive CNS • In vitro studies showed that the depression if the combination metabolite of chloral hydrate, is used. trichloroalcohol, inhibits the • Disulfiram-reaction is rare, metabolism of alcohol. but has been reported. • Alcohol appears to stimulate the formation of trichloroalcohol and inhibit its conjugation with glucuronide.

Ramelteon • Enhanced CNS depression and • Manufacturer warns against (Rozerem ) impaired psychomotor concurrent use of ramelteon performance. and alcohol. 25 • The exact mechanism of interacation is unknown.

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Drug/Drug Class a Effect(s) and Proposed Recommendations/ Mechanism(s) 1-5 Comments c,1-5 Sedatives-Hypnotics Con’t Meprobamate • Excessive CNS depression and • Limit intake of alcohol to impaired psychomotor avoid excessive CNS performance. depression. • Acute use of alcohol appears to • Monitor for excessive CNS inhibit meprobamate metabolism, depression if the combination while chronic alcohol ingestion is used. appears to induce hepatic metabolism of meprobamate. Immunosuppressive Methotrexate • Increased risk of methotrexate- • Tell patients to avoid regular (Rheumatrex ) induced liver injury. consumption or excessive • Most cases involve regular use of amounts of alcohol. moderate to large amounts of • The manufacturer advises alcohol against initiating methotrexate • Exact mechanism of interaction in patients who drink alcohol is not known but may be due to excessively. 24 additive hepatotoxicity. Pimecrolimus 10 • Facial flushing. • Warn patients of increased (Elidel ) • The exact mechanism of risk of alcohol-induced facial interaction is unknown. flushing. • If flushing occurs, caution patients to avoid alcohol while using pimecrolimus.

Tacrolimus 11 • Facial flushing. • Warn patients of increased (Prograf ) • The exact mechanism of risk of alcohol-induced facial interaction is unknown. flushing. • If flushing occurs, caution patients to avoid alcohol while using tacrolimus. Other Agents Acitretin • Increased duration of teratogenic • Tell women of reproductive (Soriatane ) potential in women. potential to completely avoid • Alcohol increases the alcohol and alcohol- transesterification of acitretin to containing drugs while taking etretinate, a teratogen which can acitretin and for 2 months remain in the body for years. after the drug is stopped. Disulfiram • Flushing, hypotension, nausea, • Tell patients to avoid ANY (Antabuse ) tachycardia, vertigo, dyspnea, alcohol, alcohol-containing esophageal rupture, and blurred drugs, or propylene glycol. vision. • Deaths have also been reported. • Disulfiram inhibits aldehyde dehydrogenase which leads to accumulation of acetaldehyde, a metabolite of alcohol.

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Drug/Drug Class a Effect(s) and Proposed Recommendations/ Mechanism(s) 1-5 Comments c,1-5 Other Agents Con’t Metoclopramide • Additive sedative effects. • Warn patients of the potential (Reglan; Canada : Maxeran ) • Increases absorption rate of for an enhanced alcohol alcohol, probably by speeding effect. gastric emptying. • Monitor for excessive CNS depression if the combination is used. Nitroglycerin • Hypotension. • Tell patients to limit alcohol • Additive vasodilatory effects. intake. • Monitor for hypotension (e.g., lightheadedness, fainting) in patients receiving the combination. Phenytoin • Chronic alcohol abuse may • Monitor for a decreased (Dilantin , etc) reduce serum phenytoin anticonvulsant effect in heavy concentrations. drinkers. • Alcohol induces the hepatic metabolism of phenytoin. Procarbazine • Facial flushing. • Tell patients to avoid alcohol (Matulane ) • Procarbazine inhibits aldehyde if they develop facial flushing dehydrogenase in animal studies. with procarbazine. Propofol • Alcoholic patients may require • Be aware that higher doses of (Diprivan ) higher doses of propofol. propofol may be needed in • The exact mechanism of alcoholic patients. interaction is unknown. • In a small study (n=20), alcoholic patients required 30% higher doses of propofol to induce general anesthesia compared to nonalcoholics. Warfarin • Enhanced anticoagulant effects • Monitor INRs if patient has (Coumadin , etc) with acute alcohol intoxication. more than 3 alcoholic drinks a • Reduced anticoagulant effects in day or if there is a significant chronic alcoholics. change in the amount of • Acute excessive alcohol intake alcohol intake. may inhibit warfarin metabolism. • Warn patients of increased • Increase in warfarin metabolism risk of falls when under the with chronic heavy drinking is influence of alcohol, which likely due to alcohol- induced may result in bleeding stimulation of hepatic enzymes. injuries.

a. Note that only drug interactions that require actions to reduce risk are included. This list is not all- inclusive. b. Expect the combination of alcohol and any opioids to result in enhanced CNS depression. c. In general, experts consider moderate alcohol consumption to be one drink per day for adult women and two drinks a day for adult men.14,15,26 One drink is defined as a 12-oz beer, a 4-oz glass of wine, or a 1.5-oz glass of distilled spirits. 14

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Project Leader in preparation of this Detail- metformin-treated obese diabetics. Acta Med Document: Wan-Chih Tom, Pharm.D. Scand 1979;206:269-73. [Abstract]. 14. Buse JB, Ginsberg HN, Bakris GL, et al. Primary

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Cite this Detail-Document as follows: Alcohol-related drug interactions. Pharmacist’s Letter/Prescriber’s Letter 2008;24(1):240106.

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