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Annals of Pharmacotherapy February 2000 vol. 34 no.

2 255-257

Do Ethanol and Metronidazole Interact to
Produce a Disulfiram-Like Reaction?

Caroline S Williams
Caroline S Williams BPharm, Senior Clinical Pharmacist, Pharmacy
Department, Winchester and Eastleigh NHS Trust, Winchester, England
Kevin R Woodcock⇑
Kevin R Woodcock MBBS MSc MRCP, Consultant Physician, Department of
Sexual Health, Winchester and Eastleigh NHS Trust
: Kevin R Woodcock MBBS MSc MRCP, Department of Sexual Health, Royal Hampshire
County Hospital, Romsey Rd., Winchester SO22 5DG, England, F A X 44 1962 825621, Email

OBJECTIVE: To obtain and evaluate evidence about the supposed disulfiram-like interaction
between metronidazole and ethanol.
DATA SOURCES: MEDLINE search from January 1964 to June 1999, using the terms
metronidazole, ethanol, and drug reaction.
DATA SYNTHESIS: The manufacturer's warnings include a disulfiram-like reaction between
metronidazole and ethanol. However, review of reports published between 1969 and 1982
produced no convincing evidence that this reaction exists. Six case reports involving eight
patients were evaluated.
CONCLUSIONS: Four of the eight cases were serious, including one death, but the authors
of all the reports presumed the metronidazole–ethanol reaction to be an established
pharmacologic fact. None provided evidence that could justify their conclusions.

Annals of Pharmacotherapy. 2002 Jun;36(6):971-4

Lack of disulfiram-like reaction with metronidazole and ethanol.
Visapää JP1, Tillonen JS, Kaihovaara PS, Salaspuro MP.
Author information
Metronidazole, an effective antianaerobic agent, has been reported to have aversive properties when
ingested with ethanol. This is thought to be due to the blocking of hepatic aldehyde dehydrogenase
(ALDH) enzyme followed by the accumulation of acetaldehyde in the blood. However, based on animal
studies and on only 10 human case reports, the existence of metronidazole-related disulfiram-like
reaction has recently been questioned.
To investigate the possible disulfiram-like properties of metronidazole and ethanol in human volunteers.
Of 12 healthy male volunteers in this double-blind study, one-half received metronidazole for 5 days and
the other half received placebo. All volunteers received ethanol 0.4 g/kg at the beginning of the study.
Repeated blood samples were taken every 20 minutes for 4 hours, and blood acetaldehyde and ethanol
concentrations were determined. Blood pressure, heart rate, and skin temperature were also measured
every 20 minutes for objective signs of a possible disulfiram-like reaction. Volunteers also completed a
questionnaire focusing on the subjective signs of disulfiram-like reaction.
Metronidazole did not raise blood acetaldehyde or have any objective or subjective adverse effects when
used together with ethanol.
This study shows that metronidazole does not have an effect on blood acetaldehyde
concentrations when ingested with ethanol and does not have any objective or subjective
disulfiram-like properties. However, it is possible that disulfiram-like reaction can occur in some
subgroups and by other mechanisms than the inhibition of hepatic ALDH.

PMID:12022894 [PubMed - indexed for MEDLINE]

Disulfiram Toxicity
Disulfiram (tetraethylthiuram disulfide [TETD]) has been used for more than 50 years as a deterrent to ethanol
abuse in the management of alcoholism. Approximately 200,000 alcoholics take disulfiram, or Antabuse,
regularly in the United States.
The first suggestion that disulfiram might be used in the treatment of alcoholism came in 1937 when an
American physician noted that workers in the rubber industry who were exposed to TETD developed a reaction
after drinking ethanol. A decade later, two Danish researchers at the Royal Danish School of Pharmacy in
Copenhagen made the same discovery. Jens Hald and Eric Jacobsen were experimenting with disulfiram as a
potential antihelminthic, and each took small doses to determine potential side effects in humans. Several days
later, they attended a cocktail party and both became ill. They concluded that the facial flushing and
tachycardia they experienced must be due to the disulfiram.
Soon thereafter, physicians began prescribing disulfiram as a deterrent to ethanol abuse. It has also been
proposed as a deterrent to cocaine abuse, and several studies have suggested improved retention rates in
treatment programs for cocaine-dependent individuals treated with disulfiram. A study found diminished "high"
or "rush" after intravenous cocaine administration to healthy volunteers pretreated with disulfiram, with no
change in cardiovascular parameters.[1]
The disulfiram-ethanol reaction (DER) is due to increased serum acetaldehyde concentrations generated by
the metabolism of ethanol by alcohol dehydrogenase in the liver. Normally, this acetaldehyde is cleared rapidly
by its metabolism to acetate via aldehyde dehydrogenase. [2] Disulfiram blocks this enzyme, irreversibly inhibiting
the oxidation of acetaldehyde and causing a marked increase in acetaldehyde concentrations after ethanol
consumption. The discomfort associated with this syndrome is intended to serve as a negative stimulus, but the
reaction may be severe enough to cause hypotension and death.

In considering disulfiram toxicity, a distinction must be made between the clinical manifestations of a disulfiramethanol reaction (DER) and the toxic effects of disulfiram itself. Direct disulfiram toxicity may be further divided
into acute poisoning versus chronic poisoning. The directly toxic effects of disulfiram include neurologic,
cutaneous, and hepatotoxic sequelae in addition to the disulfiram-ethanol reaction.
Disulfiram received US Food and Drug Administration (FDA) approval for use in the treatment of alcoholism in
1951. At that time, it was commonly prescribed in very high doses, up to 3,000 mg a day in some cases. This
resulted in a relatively high rate of extremely severe or fatal reactions. Today, much lower doses are used, and
the incidence of disulfiram toxicity has waned.

Ethanol is mainly metabolized in the liver to acetaldehyde by alcohol dehydrogenase (ADH). Acetaldehyde is
then oxidized to acetate by aldehyde dehydrogenase (ALDH). Disulfiram irreversibly inhibits the oxidation of
acetaldehyde by competing with the cofactor nicotinamide adenine dinucleotide (NAD) for binding sites on
ALDH (see the image below).

The pathway of ethanol metabolism. Disulfiram
reduces the rate of oxidation of acetaldehyde by competing with the cofactor nicotinamide adenine dinucleotide (NAD) for
binding sites on aldehyde dehydrogenase (ALDH).

Ultimately, disulfiram reduces the rate of oxidation of acetaldehyde, causing a 5- to 10-fold increase in the
concentration of acetaldehyde. An increased serum acetaldehyde concentration is thought to be responsible for
the unpleasant side effects associated with the disulfiram-ethanol reaction.
Disulfiram also directly inhibits hepatic microsomal enzymes (cytochrome P450), in particular CYP2E1. This
interferes with the metabolism of certain drugs, most notably that of warfarin, phenytoin, and theophylline.
Disulfiram may also decrease the clearance of some benzodiazepines (diazepam, oxazepam, and
chlordiazepoxide), caffeine, and some tricyclic antidepressants (desipramine and imipramine). The resulting
possible elevation of serum concentrations of these medications has the potential to cause a corresponding
Disulfiram is highly lipid soluble (accumulates in adipose tissue, crosses blood-brain barrier), highly proteinbound, and has 80% bioavailability after an oral dose of 350 mg. Approximately 5-20% is not metabolized and
is excreted unchanged in the feces; the remainder is metabolized to both toxic and nontoxic metabolites. The
elimination of disulfiram and its numerous metabolites is a very slow process. Approximately 20% of the drug
remains in the body for 1-2 weeks postingestion. Most of these metabolites are then eliminated through the
gastrointestinal (GI), renal, and respiratory routes. The prolonged effects of disulfiram occur not only because
the drug is slowly eliminated from the body but also because it irreversibly inhibits aldehyde dehydrogenase. In
order to regain the ability to metabolize acetaldehyde, the individual must therefore synthesize new stores of
the enzyme.
Disulfiram metabolites cause clinically important effects in the body (see the image below).

Disulfiram, prodrug for active metabolites.

The most important toxic metabolites are diethyldithiocarbamate (DDC) and its metabolite carbon disulfide
(CS2). DDC chelates copper, thus impairing the activity of dopamine beta-hydroxylase, an enzyme that
catalyzes the metabolism of dopamine to norepinephrine. In this way, DDC causes depletion of presynaptic
norepinephrine and accumulation of dopamine. Although hypotension from the disulfiram-ethanol reaction is
mainly attributable to the effects of acetaldehyde, depletion of the potent vasoconstrictor norepinephrine may
also be a contributing factor.
Dopamine agonism may be implicated in some of the altered behavior associated with disulfiram toxicity.
Although no studies have directly examined the effects of low doses of disulfiram on psychotic symptoms,
hypomania and psychosis have been documented in many reports among alcoholics taking high-dose
disulfiram (up to 2,000 mg/d). It is possible that disulfiram, like L-dopa and amphetamine, unmasks or
exacerbates preexisting psychotic symptoms in susceptible individuals by increasing central dopamine levels.
Neurotoxic effects associated with disulfiram include extrapyramidal symptoms, and lesions of the basal
ganglia have been described in patients after therapy with disulfiram. Potential mechanisms for disulfiramassociated neurotoxicity include abnormal CNS metal accumulation from the chelation of copper by DDC,
leading to free radical formation and neuronal oxidative stress. In addition, one study found that disulfiram and
DDC increase the release of glutamate from striato-cortical synaptic vesicles, both in vitro and in rats,
suggesting yet another possible mechanism for DDC-mediated neuronal damage. [3]
Other mechanisms implicated in DDC’s cytotoxic effects include its ability to chelate nickel, to interfere with
sulfhydryl groups in cytochrome P-450 enzymes, and to inhibit ADH and ALDH enzymes. Furthermore, DDC
inhibits superoxide dismutase, thereby impairing the ability to eliminate free radicals. DDC-induced
methemoglobinemia can also occur secondary to impairment (consumption) of glutathione-dependent
methemoglobin reduction.
Carbon disulfide (CS2), another disulfiram metabolite from DDC metabolism, has neurotoxic effects when
administered directly. Acute exposure to CS2 causes rapid onset of headache, confusion, nausea,
hallucinations, delirium, seizures, coma, and potentially death. CS 2 may cause seizures by interacting with
pyridoxal-5-phosphate, a cofactor in the production of GABA from glutamate, thereby depleting GABA levels in
the brain and leading to benzodiazepine-resistant seizures; this forms the basis for an important experimental
rat model of status epilepticus. In addition to its neurotoxic effects (neurobehavioral toxin), CS 2 is hepatotoxic,
inhibits cytochrome P-450, and is cardiotoxic.
The mechanism by which chronic disulfiram therapy produces hepatotoxicity is not well understood and may
involve hypersensitivity or immunologic reactions in addition to the direct cytotoxic effects of its metabolites.

Disulfiram toxicity has a particular classification with significant overlap. The first type of toxicity is the classic
disulfiram-ethanol reaction, known as the acetaldehyde syndrome. Secondly, disulfiram has its own associated
acute and chronic adverse drug reactions. Finally, disulfiram-like reactions are associated with many other
substances that have an ethanol-like mechanism of toxicity with disulfiram.

Disulfiram is usually prescribed at an initial dose of 500 mg/d for 1-2 weeks, followed by a
maintenance dose of 125-500 mg/d. Close monitoring for adverse reactions is required.
Disulfiram use is associated with adverse reactions at a rate of approximately 1 per 200-2000 each
year. Frequently reported aversive reactions are mainly hepatic, neurologic, dermatologic, and psychiatric.
Drowsiness is the most common side effect and occurs in up to 5% of patients. It generally resolves
after 2 weeks of treatment. Other side effects include dyspnea, sweating, alteration of taste, vasodilation,
impotence, amblyopia, dizziness, headache, ataxia, polyneuritis, psychosis, and hypertension.
Acute disulfiram overdose is uncommon. In adults, clinical manifestations after acute overdose are
rare with doses less than 3 g. Ingestion of 10-30 g may be lethal. Toxicity in children has been reported after
ingestion of 2.5 g of disulfiram. Symptoms of overdose in children are mostly neurologic.

Agents that may produce disulfiramlike reactions with ethanol include the following:

Industrial solvents ("degreasers' flush")
Mushrooms (eg, Coprinus atramentarius [inky cap], Clitocybe claviceps)
Antibiotics (eg, metronidazole, sulfonamides, some cephalosporins, nitrofurantoin, chloramphenicol)
Pesticides (eg, carbamates, monosulfiram [Tetmosol])
Chloral hydrate
Antifungals (griseofulvin)
the above may cause symptoms similar to to a disulfirum reaction so they must rule out all of these to
conclude tha it was a disulfirum like reaction

Differential Diagnoses

Allergic Contact Dermatitis


Ciguatera Toxicity

Delirium Tremens (DTs)

Disulfiramlike Mushroom Toxicity

Emergent Treatment of Gastroenteritis

Gyromitra Mushroom Toxicity

Hypovolemic Shock

Medication-Induced Dystonic Reactions


Shock, Cardiogenic


Tension Headache

Toxicity, Mushrooms

Toxicity, Mushrooms

Toxicity, Scombroid

Urinary Obstruction

Viral Hepatitis

Withdrawal Syndrome
All the above have symptoms similar to to a disulfirum reaction so they must rule out all of these to
conclude tha it was a disulfirum like reaction

Laboratory Studies
For suspected disulfiram toxicity, the following laboratory studies should be obtained:

Glucose level
Electrolyte levels
Renal function tests
Liver function tests
Ethanol level
Acetaminophen level
Arterial blood gas analysis
Methemoglobin level (%)

If these were not done then how did they conclude kuti it was a
disulfiram like reaction