DESCRIPTION

Antiprotozoal medications include metronidazole (Flagyl, Protostat), chloroquine (Aralen), and hydroxychloroquine (Plaquenil).

FORMS AND USES

• Chloroquine
  • For malaria, the adult dose is 160 to 200 mg intramuscularly, then 1 g orally, followed by 500 mg orally in 6 hours, and 500 mg orally daily for 2 days.
  • For extraintestinal amebiasis, the adult loading dose is 1 g orally, followed by 500 mg daily for 2 to 3 weeks; the pediatric loading dose is 10 mg base/kg, orally, then 5 mg base/kg.
  • Hydroxychloroquine. For malaria, the adult dose is 620 mg of the base initially, followed by 310 mg in 6 to 8 hours and 310 mg/day for 2 days.
  • Metronidazole. For Trichomonas infection, intestinal amebiasis, and serious anaerobic infections, the adult dose is 375 to 1,000 mg, two to four times daily.

TOXIC DOSE

• Chloroquine has extreme potential toxicity; just three to four times the normal dose has caused death in either adults or children.
• Hydroxychloroquine may be fatal in an overdose above 10 g.
• Metronidazole. Although 2 to 3 g may cause mild symptoms, ingestion of 10 g rarely causes serious effects.

PATHOPHYSIOLOGY

Chloroquine is thought to act like class 1A antidysrhythmic agents by blocking the fast sodium channel, slowing phase zero of the action potential (depolarization), and depressing cardiac conduction velocity.

EPIDEMIOLOGY

• Poisoning by any of these agents is uncommon.
• Toxic effects are mild for metronidazole.

CAUSES

• A parenteral overdose is usually an iatrogenic error.
• An oral overdose is usually an intentional ingestion.
• Child neglect or abuse should be considered if the patient is less than 1 year of age, suicide attempt if the patient is over 6 years of age.

DRUG AND DISEASE INTERACTIONS

• Chloroquine and metronidazole levels are increased by cimetidine.
• Metronidazole potentiates the effect of oral anticoagulants.
• Phenytoin and phenobarbital increase clearance of metronidazole and result in reduced serum levels.
• Lithium levels may become toxic with use of metronidazole.

PREGNANCY AND LACTATION

• Metronidazole. US FDA Pregnancy Category B. Animal studies indicate no fetal risk and there are no controlled human studies, or animal studies show an adverse fetal effect but well-controlled studies in pregnant women do not.
• Chloroquine. US FDA Pregnancy Category D. Positive evidence of human fetal risk exists, but benefits in certain situations (e.g., life-threatening situations or serious diseases) may make use of the drug acceptable despite its risks.
• Metronidazole should be avoided in pregnant women.

Section Outline:

• DESCRIPTION
• FORMS AND USES
• TOXIC DOSE
• PATHOPHYSIOLOGY
• EPIDEMIOLOGY
• CAUSES
• DRUG AND DISEASE INTERACTIONS
• PREGNANCY AND LACTATION

DIFFERENTIAL DIAGNOSIS

• Chloroquine. Toxicologic causes of CNS depression, seizure, and ECG conduction abnormality include class I antidysrhythmic agents, antihistamines, cocaine, beta-receptor or calcium channel blockers, quinine, digoxin, phenothiazine, and cyclic antidepressants.
• Metronidazole. Other causes of a disulfiram-like reaction include a combination of disulfiram and alcohol or other medications.

SIGNS AND SYMPTOMS

Chloroquine

Respiratory depression, cardiovascular collapse, seizures, and death occur in a serious overdose.

Hydroxychloroquine

• Neurotoxicity may occur with subacute myelooptic neuropathy, potentially leading to loss of vision.
• A delayed-onset, retrograde amnesia is reported following acute overdose.

Metronidazole

Nausea, vomiting, and ataxia occur in overdose; a disulfiram-like reaction occurs with ethanol.

Vital Signs

Chloroquine may cause tachycardia and hypotension.

HEENT

• Chloroquine and hydroxychloroquine. Tinnitus, sensorineural hearing loss, scotomas, blurred/clouded vision, and retinopathy (with chronic treatment) may occur.
• Hydroxychloroquine. Symptoms include retinopathy, decreased vision, scotoma and blurred vision, as well as corneal edema and opacities.

Dermatologic

• Chloroquine. Eruptions similar to lichen planus and pigmentary changes of skin and mucous membranes may occur.
• Hydroxychloroquine. Bleaching of hair, alopecia, pruritus, and skin eruptions (urticarial, lichenoid, exfoliative, and others) may occur.

Cardiovascular

Chloroquine may cause a widened QRS interval, inversion and depression of T-waves, and ventricular dysrhythmias, and cardiac arrest may occur suddenly after a large ingestion.

Pulmonary

Chloroquine may cause respiratory depression and arrest in severe cases.

Gastrointestinal

• Chloroquine and hydroxychloroquine. Anorexia, nausea, vomiting, diarrhea, and abdominal cramps may occur.
• Metronidazole. Nausea, vomiting, metallic taste, abdominal pain, and occasionally constipation may occur.

Hepatic

• Liver injury may occur in chloroquine-poisoned patients with glucose-6-phosphate dehydrogenase deficiency or alcoholic liver disease.
• Hydroxychloroquine has been associated with fulminant hepatic failure.

Renal

Metronidazole can cause dysuria, cystitis, polyuria, and dark urine.

Hematologic

• Chloroquine and hydroxychloroquine. Hemolytic anemia and methemoglobinemia have been reported.
• Metronidazole. Neutropenia and, rarely, thrombocytopenia may occur.

Neurologic/Psychiatric

• Chloroquine. Headache, neuropathy, visual disturbance, and agitation are followed by seizures and coma.
• Hydroxychloroquine. CNS irritability, psychosis, headache, nystagmus, ataxia, and seizures may occur.
• Metronidazole. Drowsiness, vertigo, seizures, and peripheral neuropathy may develop.

Immunologic

All of the drugs in this chapter have been reported to produce allergic reactions.

PROCEDURES AND LABORATORY TESTS

Essential Tests

• Chloroquine. ECG and cardiac monitoring to detect QRS and QTc widening which often precede ventricular dysrhythmia.
• Chloroquine or metronidazole. Complete blood count may detect neutropenia or thrombocytopenia, which is usually mild and reversible with cessation of the drug.

Recommended Tests

• Serum electrolytes, BUN, creatinine levels are ordered to evaluate altered mental status or cardiac dysrhythmia.
• Serum acetaminophen and aspirin levels in an overdose setting are used to detect occult overdose with analgesic medications.
• An ophthalmologic evaluation is ordered for any visual symptoms.

Not Recommended Tests

Specific drug levels are not clinically helpful.

Section Outline:

• DIFFERENTIAL DIAGNOSIS
• SIGNS AND SYMPTOMS
  • Chloroquine
  • Hydroxychloroquine
  • Metronidazole
  • Vital Signs
  • HEENT
  • Dermatologic
  • Cardiovascular
  • Pulmonary
  • Gastrointestinal
  • Hepatic
  • Renal
  • Hematologic
  • Neurologic/Psychiatric
  • Immunologic
• PROCEDURES AND LABORATORY TESTS
  • Essential Tests
  • Recommended Tests
  • Not Recommended Tests

• Chloroquine. Treatment focuses on airway management, supportive care, and administration of benzodiazepines and epinephrine in serious cases.
• Metronidazole. Treatment focuses on supportive care and management of hematologic abnormalities.
• The dose and time of exposure should be determined for all substances involved.

DIRECTING PATIENT COURSE

The health-care professional should call the poison control center when:

• Any toxic effects develop.
• Toxic effects are not consistent with expected toxicity.
• A coingestant, drug interaction, or underlying disease presents an unusual problem.

The patient should be referred to a health-care facility when:

• Attempted suicide or homicide is possible.
• Patient or caregiver seems unreliable.
• Any toxic effects develop.
• A coingestant, drug interaction, or underlying disease presents an unusual problem.

Admission Considerations

• Inpatient management is warranted for chloroquine- or hydroxychloroquine-poisoned patients who develop hypotension, respiratory or CNS depression, seizure, or dysrhythmia.
• For metronidazole, hospital admission is appropriate for patients with toxic effects that do not resolve promptly.

DECONTAMINATION

Out of Hospital

• Chloroquine and hydroxychloroquine. Do not induce emesis.
• Metronidazole. Ipecac should be administered to induce emesis within 1 hour of ingestion for alert pediatric or adult patients, if health-care evaluation will be delayed.

In Hospital

• Gastric lavage should be performed in pediatric (tube size 24-32 French) or adult (tube size 36-42 French) patients for large ingestion presenting within 1 hour of ingestion or if life-threatening effects are present.
• One dose of activated charcoal (1-2 g/kg) should be administered without a cathartic if a potentially toxic amount has been ingested.

ANTIDOTES

There is no specific antidote for overdose with any of these agents.

ADJUNCTIVE TREATMENT

• Chloroquine-induced dysrhythmia, hypotension, or seizure or history of ingestion of more than 5 g. Therapy should include early endotracheal intubation and administration of high doses of epinephrine and diazepam.
  • Epinephrine. Infusion begins at 0.25 µg/ kg/min, with the rate increased to maintain systolic blood pressure at greater than 100 mm Hg.
  • Diazepam. The initial dose is 2 mg/kg infused over 30 minutes, followed by a continuous infusion of 1 to 2 mg/kg/day for 2 to 4 days depending on severity of toxicity; recurrence of cardiac dysrhythmia may respond to repeat diazepam bolus.
• Isolated seizures or altered mental status
  • No data are available except for the treatment described above for chloroquine.
  • Standard seizure management with more modest benzodiazepine doses may be used if these effects are isolated; however, it must be assured that the cardiac effects are absent.
• Not recommended therapies. No type of enhanced elimination is recommended.

Section Outline:

• DIRECTING PATIENT COURSE
  • Admission Considerations
• DECONTAMINATION
  • Out of Hospital
  • In Hospital
• ANTIDOTES
• ADJUNCTIVE TREATMENT

PATIENT MONITORING

• Chloroquine and hydroxychloroquine. Respiratory and hemodynamic function should be monitored in an ICU.
• Metronidazole. Blood counts should be monitored as indicated by the initial laboratory results.

EXPECTED COURSE AND PROGNOSIS

• Acute overdoses with metronidazole usually peak in the first few hours and quickly resolve.
• A patient with chloroquine overdose typically deteriorates within a couple of hours, and death may occur abruptly; recovery may require days.
• Chloroquine may produce permanent hearing loss or sequelae of hypoxia, depending on whether complications occur.
• Retinopathy of chloroquine and hydroxy-chloroquine may persist or worsen despite treatment.

DISCHARGE CRITERIA/INSTRUCTIONS

• From the emergency department
  • Chloroquine. It is unusual to discharge patients due to potentially lethal toxicity and narrow therapeutic ratio.
  • Hydroxychloroquine. Patients without CNS or cardiac effects for 8 hours may be discharged after decontamination and psychiatric evaluation, if needed.
  • Metronidazole. Patients may be discharged if toxicity does not develop over 2 to 4 hours, following gastrointestinal decontamination and psychiatric evaluation, if needed.
• From the hospital. Patients may be discharged after toxic effects have resolved or stabilized.

Section Outline:

• PATIENT MONITORING
• EXPECTED COURSE AND PROGNOSIS
• DISCHARGE CRITERIA/INSTRUCTIONS

Because chloroquine may produce rapid cardiovascular and CNS deterioration, the patient must be monitored very closely and receive early and aggressive care.

Poisoning by other antiinfectives: antiviral drugs.

RECOMMENDED READING

Frytak S, Moertel CG, Childs DS, et al. Neurologic toxicity associated with high-dose metronidazole therapy. Ann Intern Med 1978;88:361-362.

Riou B, Barriot P, Rimailho A, et al. Treatment of severe chloroquine poisoning. N Engl J Med 1988;318:1-6.

Author: Steven A. Seifert

Reviewer: Luke Yip