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Toxicity, Disulfiram: Treatment & Medication
Updated: Aug 20, 2008
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Treatment
Prehospital Care
For patients with possible disulfiram-ethanol reaction, the following should be performed:
- Provide supplemental oxygen, obtain intravenous access, and place all patients on a monitor. Administer thiamine, glucose, and naloxone to patients with altered mental status, as needed.
- Intravenous fluids should be instituted if hypotension, tachycardia, or severe vomiting is present.
- Patients with coma or a severely altered mental status should be intubated for airway protection. The frequent occurrence of vomiting secondary to DER places these patients at high risk for aspiration.
Emergency Department Care
ED treatment of disulfiram-ethanol reaction (DER) is primarily supportive. No specific antidote has been tested for efficacy in the treatment of DER or acute disulfiram overdose, though fomepizole has the theoretical benefit of blocking ethanol metabolism to acetaldehyde and may be a useful therapy in patients presenting with DER. Patients with a severely altered mental status or coma should be intubated for airway protection. The risk of aspiration in patients with DER is high.
- Mild sedation with benzodiazepines may be useful in the agitated patient, and benzodiazepines may be used to treat seizures. However, sedation of patients with intractable vomiting increases the risk of aspiration and its sequelae and should be approached with caution. Benzodiazepines also have the potential to exacerbate hypotension.
- In cases of intractable vomiting, phenothiazine use must be considered cautiously because their alpha-blockade effect may worsen or induce hypotension. Metoclopramide, ondansetron, or granisetron are considered the antiemetics of choice in these cases.
- Intravenous fluids should be given to patients experiencing a DER to replace volume losses from emesis and third spacing of intravascular fluid.
- Intravenous fluids and vasopressors are indicated to support blood pressure and treat patients who are in shock.
- Decontamination procedures are not likely to be beneficial once the reaction begins. Consider gastric emptying only in the hospital setting with cases of massive ethanol ingestion in which a patent and protected airway can be maintained.
- Inducing emesis with ipecac syrup is not recommended. Ipecac syrup contains ethanol, which could precipitate DER. Emesis may delay administration of activated charcoal, worsen the nausea and vomiting associated with disulfiram toxicity, and increase the likelihood of pulmonary aspiration if seizures and coma suddenly occur.
- In acute disulfiram overdose, consider the use of activated charcoal, if available and if the patient is alert and able to drink it safely. Use of multiple dose activated charcoal (MDAC) may be beneficial.
- Multiple dose activated charcoal can increase the rate of elimination of disulfiram and its metabolites that undergo enterohepatic recirculation. Activated charcoal is not indicated for disulfiramlike syndromes, and it is not indicated for the treatment of DER.
- The risk-benefit of administering charcoal to a patient with altered mental status and a high likelihood of vomiting and potential aspiration must be carefully weighed.
- In severe DER, hemodialysis may be indicated to enhance the elimination of ethanol and acetaldehyde. Neither hemodialysis nor hemoperfusion has been beneficial for treatment of acute disulfiram overdose.
- Some authors have suggested that fomepizole (Antizol) may be beneficial in cases of severe DER. Fomepizole is a potent inhibitor of alcohol dehydrogenase that may limit the metabolism of ethanol by this enzyme and thereby prevent further accumulation of acetaldehyde. No studies have examined the utility of fomepizole in this context; however, a theoretical benefit exists in patients taking disulfiram who present with DER after a large ethanol ingestion.
Consultations
- Consult with the local poison control center or a medical toxicologist.
Medication
The goals of pharmacotherapy are to reduce morbidity and to prevent complications.
GI decontaminant
These agents are empirically used to minimize systemic absorption of the toxin.
Activated charcoal (Liqui-Char)
Most useful if administered within 90 min of ingestion. Repeat doses may be used, especially with ingestion of sustained-release agents. Limited outcome studies exist, especially when administration is more than 1 h postingestion.
Administration of charcoal by itself (in aqueous solution), as opposed to coadministration with a cathartic, is becoming the current practice standard. This is because studies have not shown benefit from cathartics, and, while most drugs and toxins are absorbed within 30-90 min, laxatives take hours to work. Dangerous fluid and electrolyte shifts have occurred when cathartics are used in small children.
When ingested dose is known, charcoal may be administered at 10 times ingested dose of agent, over 1 or 2 doses.
Adult
1 g/kg PO/NG (50-75 g usual dose); may administer 0.5 g/kg PO/NG as repeat dose if desired
Cathartic not recommended
Pediatric
Administer as in adults (12.5-25 g usual dose)
Cathartic not recommended
May inactivate ipecac syrup if used concomitantly; effectiveness of other medications decreases with coadministration; decreased levels occur with coadministration of sherbet, milk, or ice cream
Documented hypersensitivity; poisoning or overdose of mineral acids and alkalies; unprotected airway with absent gag reflex or compromised ability to protect airway due to CNS depression expected
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Protect airway before administration in patients with absent gag reflex or a depressed level of consciousness; when considering repeat dosing, monitor for active bowel sounds to minimize risk of charcoal ileus
Cardiovascular agents
Treat hypotensive patients with IV crystalloid (eg, 0.9 NS or LR). If pressors are indicated, norepinephrine (Levophed) is DOC (over dopamine) because of catecholamine depletion.
Norepinephrine (Levophed)
Used in protracted hypotension following adequate fluid-volume replacement. Stimulates beta1- and alpha-adrenergic receptors, which, in turn, increases cardiac muscle contractility, heart rate, and vasoconstriction. As a result, systemic blood pressure and coronary blood flow increase.
After obtaining a response, adjust rate of flow to and maintain at a low normal blood pressure (eg, 80-100 mm Hg systolic), sufficient to perfuse vital organs.
Adult
4-8 mcg/min IV initial; titrate prn q5-10min
Pediatric
1-2 mcg/min IV or 0.1 mcg/kg/min IV initial; titrate prn
Arrhythmogenic in aromatic and halogenated hydrocarbon exposures; atropine may enhance the pressor response by blocking reflex bradycardia caused by norepinephrine
Documented hypersensitivity; peripheral or mesenteric vascular thrombosis because ischemia may be increased and area of the infarct extended
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Correct blood-volume depletion, if possible, before therapy; extravasation may cause severe tissue necrosis and, thus, should be administered into a large vein; caution in occlusive vascular disease
Antihistamines
Antihistamine improves the flushing response in DER. Diphenhydramine (H1 blocker) and cimetidine or ranitidine (H2 blockers) may be beneficial. NSAIDs (eg, Toradol) may ameliorate flushing response by blocking the synthesis of prostaglandins.
Diphenhydramine (Benadryl)
H1-receptor blocker with antiparkinsonism, antiemetic, and anticholinergic response.
Used for symptomatic relief of symptoms caused by histamine released in response to allergens.
Adult
25-50 mg PO/IV/IM q6-8h
Pediatric
5 mg/kg/d PO/IV/IM in divided qid (0.5-1 mg/kg/dose)
Potentiates effect of CNS depressants; because of alcohol content, do not administer syrup dosage form to patient taking medications that can cause disulfiramlike reactions
Documented hypersensitivity; MAOIs
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
May exacerbate angle-closure glaucoma, hyperthyroidism, peptic ulcer, and urinary tract obstruction; adverse effects include sedation and paradoxical excitation
Cimetidine (Tagamet)
H2 antagonist that, when combined with an H1 type, may be useful for treating itching and flushing in anaphylaxis, pruritus, urticaria, and contact dermatitis that do not respond to H1 antagonists alone. Use in addition to H1 antihistamines.
Adult
300 mg IV/IM q6h, continuous infusion 37.5 mg/h (900 mg/d), 400 mg PO bid, or 400-800 mg qhs
Pediatric
40-60 mg/kg/d IV/IM
Can increase blood levels of theophylline, warfarin, tricyclic antidepressants, triamterene, phenytoin, quinidine, propranolol, metronidazole, procainamide, and lidocaine
Documented hypersensitivity
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Elderly persons may experience confusion; may cause impotence and gynecomastia in young males; may increase levels of many drugs; adjust dose or discontinue treatment if changes in renal function occur
Ranitidine (Zantac)
H2 antagonist that, when combined with an H1 type, may be useful in treating allergic reactions that do not respond to H1 antagonists alone.
Adult
50 mg IV q6-8h, continuous infusion at 6.25 mg/h, 150 mg PO bid, or 300 mg qhs
Pediatric
5-10 mg/kg/d
May decrease effects of ketoconazole and itraconazole; may alter serum levels of ferrous sulfate, diazepam, nondepolarizing muscle relaxants, and oxaprozin
Documented hypersensitivity
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Caution in renal or liver impairment; if changes in renal function occur during therapy, consider adjusting dose or discontinuing treatment
Pharmacologic Antidotes
NSAIDs may benefit by reducing the severity of the flushing response. Pyridoxine (vitamin B-6) may be useful in patients who demonstrate evidence of neurological toxicity or intractable seizures.
Ketorolac (Toradol)
Inhibits prostaglandin synthesis by decreasing the activity of cyclooxygenase, which results in decreased formation of prostaglandin precursors.
Adult
Load 30-60 mg IV/IM, then 15-30 mg IV/IM q6-8h (60-120 mg/d) or 10-20 mg PO first dose, then 10 mg PO q4-6h, not to exceed 40 mg/d
>65 y: Use lower doses within dosing range; do not exceed 2 wk duration of therapy
Pediatric
Not established
Coadministration with aspirin increases risk of inducing serious NSAID-related adverse effects; probenecid may increase concentrations and, possibly, toxicity of NSAIDs; may decrease effect of hydralazine, captopril, and beta-blockers; may decrease diuretic effects of furosemide and thiazides; monitor PT closely (instruct patients to watch for signs of bleeding); may increase risk of methotrexate toxicity; phenytoin levels may be increased when administered concurrently
Documented hypersensitivity; peptic ulcer disease; recent GI bleeding or perforation; renal insufficiency; high risk of bleeding; do not administer into CNS
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Acute renal insufficiency, hyperkalemia, hyponatremia, interstitial nephritis, and renal papillary necrosis may occur; increases risk of acute renal failure in patients with preexisting renal disease or compromised renal perfusion; low WBC counts (rare), usually return to normal during ongoing therapy; discontinue therapy if leukopenia, granulocytopenia, or thrombocytopenia persists
Pyridoxine (Nestrex)
Used in the treatment of pyridoxine-dependent seizures. Involved in synthesis of GABA within CNS.
Adult
1 g IV initial; repeat prn
Pediatric
500 mg IV initial; repeat prn
May decrease levodopa, phenytoin, and phenobarbital serum levels; may act synergistically with benzodiazepines
Documented hypersensitivity
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
>200 mg/d may precipitate withdrawal effects when medication discontinued
Antiemetics
These agents are useful in cases of vomiting to mitigate symptoms and to avoid volume depletion.
Metoclopramide (Reglan)
A promotility agent that increases gastric contractions, relaxes the pyloric sphincter and duodenal bulb, and increases peristalsis in the duodenum and jejunum. Exact mechanism is unknown, but metoclopramide may increase gastric emptying and decrease intestinal transit time by sensitizing tissues to the effects of acetylcholine. Has little or no effect on gastric, biliary, or pancreatic secretions, or on colon or gallbladder motility.
Adult
10 mg IV/IM q2-3h prn
Pediatric
0.4-0.8 mg/kg/d PO/IV/IM divided qid; not to exceed to 5 mg/dose
Sedative effects may be potentiated by CNS depressants such as ethanol and benzodiazepines; promotility effects of metoclopramide are antagonized by anticholinergic and opioid drugs; decreased gastric transit time may decrease absorption of drugs (eg, digoxin) or increase absorption of drugs from small intestine (eg, acetaminophen, tetracycline, ethanol, levodopa); caution in patients taking MAOIs because of increased catecholamine release caused by metoclopramide
Documented hypersensitivity; GI hemorrhage, perforation, or obstruction; pheochromocytoma
Relative contraindications include seizure disorder or presence of other drugs likely to cause extrapyramidal symptoms or NMS
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Associated with suicidal ideation in patients with history of depression; dystonic reactions may be observed; neuroleptic malignant syndrome reported; long-term use, particularly in elderly persons, may be associated with tardive dyskinesia; since metoclopramide may induce release of catecholamines and is associated with transient rise in plasma aldosterone may cause hypertension or volume overload in patients with history of hypertension, cirrhosis, or CHF; metoclopramide is largely excreted renally, and dose should be lowered in patients with renal impairment
Ondansetron (Zofran)
Selective antagonist of serotonin 5HT3 receptors generally used to control chemotherapy-associated and postoperative nausea and vomiting. Precise mechanism of action is not known; however, ondansetron is thought to block either vagal stimulation of serotonin release in the central chemoreceptor trigger zone of the area postrema, or a vagally mediated vomiting reflex caused by release of serotonin from enterochromaffin cells of small intestine and stimulation of peripheral 5HT3 receptors, or both.
Adult
4 mg IV over 30 sec to 5 min
Pediatric
4-12 years: 100 mcg/kg IV over 30 sec to 5 min
>40 kg: 4 mg IV
Ondansetron is metabolized by hepatic cytochrome P-450 enzymes (CYP3A4, CYP2D6, CYP1A2); clearance is significantly increased by potent inducers of CYP3A4 (carbamazepine, phenytoin, rifampicin), but no dosage adjustments have been recommended for patients on these medications
Patients with previous hypersensitivity reactions to ondansetron or other 5HT3 antagonists
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Safety and clearance of ondansetron in patients with hepatic failure not studied, and its safety has not been studied in pregnancy or in children <3 y; increases large bowel transit time and should be used with caution in patients with possible subacute small-bowel obstruction; most frequently reported adverse effects are headache, constipation, and flushing; rare cases of tachycardia, bradycardia, hypotension, syncope, seizure, angina, and ECG abnormalities reported
Granisetron (Kytril)
An antinauseant and antiemetic available in PO and IV forms for use in severe postoperative and chemotherapy/radiation therapy-induced nausea. Granisetron is a selective antagonist of serotonin 5HT3 receptors. Precise mechanism of action not known; however, thought to block either vagal stimulation of serotonin release in central chemoreceptor trigger zone of area postrema, or a vagally mediated vomiting reflex caused by release of serotonin from enterochromaffin cells of small intestine and stimulation of peripheral 5HT3 receptors.
Adult
10 mcg/kg IV over 5 min
Pediatric
Not established
CYP-450 3A substrate, inducers (eg, phenobarbital) may decrease effect, while inhibitors (eg, erythromycin, clarithromycin) may increase toxicity
Documented hypersensitivity
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Caution in liver disease
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| Differential Diagnoses & Workup: Toxicity, Disulfiram |
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References
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Further Reading
Keywords
disulfiram toxicity, disulfiram, disulfiram poisoning, disulfiram exposure, alcohol treatment, Antabuse, acetaldehyde syndrome, disulfiram-ethanol reaction, DER, tetraethylthiuram disulfide, TETD, management of alcoholism, deterrent to ethanol abuse
