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
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.
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
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
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
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.
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
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
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
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 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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