CHLOROQUINE AND RELATED DRUGS

Classification | Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

Specific Substances

1) Chlorochin
2) Chlorochina
3) Chloroquin
4) Chloroquinum
5) Clorochina
6) Cloroquina
7) Klorokiini
8) Klorokin
9) CAS 54-05-7

1) Hidroxicloroquina
2) Hydroxychloroquine sulfate
3) Hydroxychloroquine sulphate
4) Win-1258-2
5) CAS 118-42-3 (hydroxychloroquine)
6) CAS 747-36-4 (hydroxychloroquine sulfate)

Available Forms Sources

1) Chloroquine phosphate is available as 250 and 500 mg tablets (Prod Info ARALEN(R) oral tablets, 2013; Prod Info chloroquine phosphate oral tablets, 2009).
2) Hydroxychloroquine sulfate is available as 200 mg tablets (Prod Info PLAQUENIL(R) oral tablets, 2009).
3) ILLICIT DRUGS: Chloroquine has been reported as an adulterant in heroin samples off the street. A patient who had ingested heroin which was estimated to contain 10% chloroquine was admitted with clinical signs of malaise and sweating (O'Gorman et al, 1987).

1) CHLOROQUINE: Chloroquine phosphate is used for suppression and treatment of acute attacks of malaria due to P. vivax, P. malariae, P. ovale, and susceptible strains of P. falciparum. It is also used to treat patients with extraintestinal amebiasis (Prod Info ARALEN(R) oral tablets, 2013).
2) HYDROXYCHLOROQUINE: Hydroxychloroquine is used for suppression and treatment of acute attacks of malaria due to P vivax, P malariae and P falciparum. It is also used to treat both chronic discoid and systemic lupus erythematosus and acute and chronic rheumatoid arthritis (Prod Info PLAQUENIL(R) oral tablets, 2009).

Overview

Life Support

Clinical Effects

0.2.1)

A) USES: Chloroquine is primarily used for prophylaxis or treatment of malaria. Chloroquine and hydroxychloroquine are the only drugs included within this management that are available in the United States; they are also used in the treatment of rheumatoid arthritis and extraintestinal amebiasis. Other related drugs in the aminoquinoline family include amodiaquine hydrochloride, broxyquinoline, cycloquine, diidohydroxyquin, mefloquine, mepacrine, pamaquin, pentaquine, primaquine phosphate, plasmocid, and quinacrine hydrochloride. Refer to the individual managements of MEFLOQUINE and PRIMAQUINE for further information.
B) PHARMACOLOGY: Chloroquine and its 4-aminoquinoline congeners block the synthesis of DNA and RNA. Hydroxychloroquine has the same mechanism of action, though it is less potent.
C) TOXICOLOGY: In overdose, chloroquine has quinidine-like effects, depressing cardiac contractility and impairing conduction. Hypokalemia is due to the shifting of potassium from extracellular to intracellular compartments.
D) EPIDEMIOLOGY: Chloroquine overdose is rare in the United States, but it is common in areas where malaria is endemic. Mortality is reported as 10% to 30% in overdose.
E) WITH THERAPEUTIC USE

1) CHLOROQUINE: Nausea, diarrhea and gastritis, skin changes (ie, pruritus and skin eruptions), and visual changes, including blurry vision and impaired night vision. Difficulty hearing and ringing in the ears may occur. Mood changes may occur at therapeutic dosing.
2) AMODIAQUINE: Amodiaquine can cause severe and fatal neutropenia with therapeutic dosing.

F) WITH POISONING/EXPOSURE

1) MILD TO MODERATE TOXICITY: Mild to moderate overdose of chloroquine can result in gastrointestinal effects (ie, nausea, vomiting, and abdominal pain), headache, visual disturbances that can result in permanent blindness, hearing disturbances that can result in deafness, and neuromuscular excitability.
2) SEVERE TOXICITY: Large overdoses of chloroquine or hydroxychloroquine can be rapidly fatal. After a large ingestion, life-threatening symptoms may develop within 1 to 2 hours. Clinical manifestations include depressed myocardial contractility, hypotension, heart block, ventricular dysrhythmias, and sinoatrial arrest. Seizures, coma, and cardiac or respiratory arrest may occur. Quinidine-like cardiotoxicity may cause QRS or QT prolongation on the ECG. Dysrhythmias may include ventricular tachycardia and fibrillation, torsade de pointes, bradycardia, or tachycardia. Severe hypokalemia commonly occurs in severe toxicity. Death is usually due to myocardial depression and dysrhythmias. A triad of hypotension, hypokalemia, and QRS prolongation should make one highly suspicious of chloroquine overdose.
3) CHRONIC TOXICITY: Chloroquine has been reported to cause vertigo, malaise, anorexia, headache, retinopathy, atrioventricular conduction defects, and, rarely, hemolytic anemia with chronic use. Chloroquine has been implicated in isolated acute psychosis with chronic use, especially in children.

0.2.3)

A) WITH POISONING/EXPOSURE

1) Hypotension, shock, bradycardia, tachycardia, cardiac arrest, tachypnea, respiratory arrest, and death may occur rapidly within 1 to 2 hours.

0.2.5)

A) WITH THERAPEUTIC USE

1) Biventricular hypertrophy and atrioventricular block have been reported with chronic therapeutic use or abuse of chloroquine.

B) WITH POISONING/EXPOSURE

1) Cardiac arrest, cardiogenic shock, dysrhythmias (ventricular tachycardia and fibrillation, torsade de pointes, bradycardia and tachycardia), and ECG changes (widened QRS and/or prolonged QT interval) have been reported with acute chloroquine and hydroxychloroquine overdose.
2) Biventricular hypertrophy and atrioventricular block have been reported with chronic therapeutic use or abuse of chloroquine.

0.2.6)

A) WITH POISONING/EXPOSURE

1) Tachypnea, pulmonary edema, acute respiratory distress, respiratory arrest, and death have occurred within 1 to 2 hours of ingestion of an overdose of chloroquine.

0.2.7)

A) WITH THERAPEUTIC USE

1) Occasionally vertigo, malaise, headache, and visual blurring may develop. Higher dosages may result in toxic psychosis with hallucinations and peripheral neuropathy. Neuromyopathy with granular depositions in muscle fibers has been reported.
2) Psychosis as the sole adverse effect has been reported often with therapeutic use of chloroquine, especially in children. Psychiatric disturbances may appear as early as within 24 hours of the first dose, or as late as days after the final dose.

B) WITH POISONING/EXPOSURE

1) Visual disturbances, hyperexcitability, agitation, seizures, drowsiness, coma, respiratory arrest, and death within an interval as short as 1 to 2 hours has been reported. Cerebral edema may occur.

0.2.8)

A) WITH THERAPEUTIC USE

1) Nausea, vomiting, diarrhea, and hemorrhagic gastritis have been reported with therapeutic use or overdose.

0.2.12)

A) WITH POISONING/EXPOSURE

1) Severe hypokalemia (1 to 2 mmol/L) is frequent in severe intoxication.

0.2.13)

A) WITH POISONING/EXPOSURE

1) Methemoglobinemia has been reported rarely after overdose. Disseminated intravascular coagulation may occur following massive overdose. Hemolytic anemia may occur in patients with glucose-6-phosphate dehydrogenase deficiency.

0.2.14)

A) WITH THERAPEUTIC USE

1) Skin eruptions, pruritus, and urticaria may occur with therapeutic use.

0.2.20)

A) Chloroquine and quinacrine are classified as FDA pregnancy category C. Chloroquine and other 4-aminoquinolones cross the placenta. Stillbirths and spontaneous abortions occurred after taking chloroquine or hydroxychloroquine. In animal data, chloroquine has also been shown to cross the placenta and remain in the fetal eyes of mice for 5 months after the drug was eliminated from the rest of the body. Hydroxychloroquine has been shown to be excreted in human milk in small amounts. There were no adverse effects in infants whose mothers were treated with hydroxychloroquine during breastfeeding.

Laboratory Monitoring

Treatment Overview

0.4.2)

A) MANAGEMENT OF MILD TO MODERATE TOXICITY

1) All patients with symptoms of aminoquinoline toxicity should be evaluated by a health care professional. The offending agent should be discontinued. In the case of neuropsychiatric symptoms, supportive pharmacotherapy such as antipsychotic medications or benzodiazepines may be given. Analgesics and antiemetics may be administered for headache and gastrointestinal symptoms as needed.

B) MANAGEMENT OF SEVERE TOXICITY

1) Patients may deteriorate and die within 1 to 2 hours of a large ingestion, usually due to myocardial depression and dysrhythmias. Aggressive symptomatic and supportive care are the mainstays of treatment. Patients with severe toxicity should be intubated and sedated with high doses of benzodiazepines, and circulatory support should be provided with fluids and vasopressors (eg, epinephrine). Consider intravenous lipid therapy early for patients with ventricular dysrhythmias or hypotension. Orotracheal intubation for airway protection should be performed early in cases of severe psychomotor agitation, repeated seizure activity, coma, or evidence of severe quinidine-like cardiotoxicity. Although the mechanism remains unclear, high dose diazepam at 2 mg/kg over 30 minutes after intubation has been shown to reduce mortality in animals and lessen cardiotoxicity in humans. Along with high dose diazepam and mechanical ventilation, epinephrine has been found to be useful in treating hypotension in chloroquine-poisoned patients. Doses of epinephrine may be started at 0.25 mcg/kg/min, increasing by increments of 0.25 mcg/kg/min until adequate blood pressure is obtained. One study showed marked improvement in survival in patients with severe chloroquine toxicity if early endotracheal intubation was performed and high dose IV diazepam and epinephrine were administered. Hypokalemia should be corrected carefully. Massive hemolysis may need to be treated with blood transfusions and supportive care, with careful monitoring for hyperkalemia and rhabdomyolysis.

C) DECONTAMINATION

1) PREHOSPITAL: Activated charcoal should be avoided in the prehospital setting because of the high risk of abrupt onset seizure or coma and subsequent aspiration.
2) HOSPITAL: Consider decontamination if a patient presents shortly after an oral overdose and is not yet manifesting symptoms of toxicity. Activated charcoal is generally not recommended in patients that are manifesting signs of toxicity as they may abruptly become comatose or seize and aspirate. If the airway is protected with orotracheal intubation, charcoal may be given. Gastric lavage may be considered in patients who are intubated and have recently (generally within 1 hour) ingested a life-threatening amount of chloroquine (2.25 g or more) as it is a life-threatening overdose with no specific antidote.

D) AIRWAY MANAGEMENT

1) Perform early in patients with severe intoxication (ie, coma, seizures, severe agitation, signs of quinidine-like cardiotoxicity).

E) ANTIDOTE

1) There is no specific antidote.

F) PSYCHOMOTOR AGITATION

1) Sedate patient with benzodiazepines as necessary; large doses may be required.

G) TACHYCARDIA

1) Tachycardia may occur from the development of agitation or hypotension. Treat the underlying cause.

H) CONDUCTION DISORDER OF THE HEART

1) QRS widening or ventricular tachycardia may respond to sodium bicarbonate. Serum alkalinization may be effective in the treatment of conduction disturbances due to quinidine-like drugs. A reasonable starting dose is 1 to 2 mEq/kg bolus, repeated as needed. Endpoints include resolution of dysrhythmias, narrowing of QRS complex, and a blood pH of 7.45 to 7.55. Epinephrine and high dose diazepam are indicated in patients with dysrhythmias, QRS widening, hypotension, or circulatory collapse. After endotracheal intubation, high dose diazepam at 2 mg/kg given over 30 minutes, along with epinephrine 0.25 mcg/kg/min, titrating to effect, has been shown to ameliorate quinidine-like cardiotoxicity in severely chloroquine-poisoned patients. Electrolytes should be optimized. Use lidocaine if sodium bicarbonate and epinephrine are not successful. Quinidine, disopyramide, and procainamide are CONTRAINDICATED as their effects on myocardial conduction are similar to that of chloroquine and related agents.

I) FAT EMULSION

1) Patients who develop significant cardiovascular toxicity may be treated with intravenous lipids. Administer 1.5 mL/kg of 20% lipid emulsion over 2 to 3 minutes as an IV bolus, followed by an infusion of 0.25 mL/kg/min. Evaluate the patient's response after 3 minutes at this infusion rate. The infusion rate may be decreased to 0.025 mL/kg/min (ie, 1/10 the initial rate) in patients with a significant response. This recommendation has been proposed because of possible adverse effects from very high cumulative rates of lipid infusion. Monitor blood pressure, heart rate, and other hemodynamic parameters every 15 minutes during the infusion. If there is an initial response to the bolus followed by the re-emergence of hemodynamic instability during the lowest-dose infusion, the infusion rate may be increased back to 0.25 mL/kg/min or, in severe cases, the bolus could be repeated. A maximum dose of 10 mL/kg has been recommended by some sources. Where possible, lipid resuscitation therapy should be terminated after 1 hour or less, if the patient's clinical status permits. In cases where the patient's stability is dependent on continued lipid infusion, longer treatment may be appropriate.

J) HYPOTHERMIA

1) Hypothermia can result from cardiovascular collapse in severe cases of poisoning. Treatment is external and internal rewarming if necessary, and aggressive resuscitation.

K) SEIZURES

1) Treatment includes endotracheal intubation and intravenous benzodiazepine (diazepam 2 mg/kg as an IV infusion over 30 minutes) followed by propofol or barbiturates if seizures persist. If seizures recur, intubate and paralyze the patient, with continuous EEG monitoring, and induce a barbiturate coma.

L) HYPOTENSIVE EPISODE

1) Severe hypotension may occur as a late and ominous finding as a result of myocardial depression. Initial treatment should be an intravenous normal saline bolus, if patient can tolerate the fluid load, then vasopressors to raise mean arterial pressure. Along with high dose diazepam and mechanical ventilation, epinephrine has been found to be useful in treating hypotension and myocardial depression in chloroquine-poisoned patients. Doses of epinephrine may be started at 0.25 mcg/kg/min, increasing by increments of 0.25 mcg/kg/min until adequate blood pressure is obtained.

M) HEMOLYSIS

1) Hemolysis may be treated with hydration and blood transfusion if needed. Monitor for and treat hyperkalemia and renal failure. Hydrate well with intravenous fluids.

N) HYPOKALEMIA

1) Correct hypokalemia cautiously as it is due to the shifting of potassium intracellularly, and aggressive correction may later cause hyperkalemia. Administer small doses of IV potassium with continuous ECG monitoring.

O) METHEMOGLOBINEMIA

1) Initiate oxygen therapy. Treat with methylene blue if patient is symptomatic (usually at methemoglobin concentrations greater than 20% to 30% or at lower concentrations in patients with anemia, underlying pulmonary or cardiovascular disease). METHYLENE BLUE: INITIAL DOSE/ADULT OR CHILD: 1 mg/kg IV over 5 to 30 minutes; a repeat dose of up to 1 mg/kg may be given 1 hour after the first dose if methemoglobin levels remain greater than 30% or if signs and symptoms persist. NOTE: Methylene blue is available as follows: 50 mg/10 mL (5 mg/mL or 0.5% solution) single-dose ampules and 10 mg/1 mL (1% solution) vials. Additional doses may sometimes be required. Improvement is usually noted shortly after administration if diagnosis is correct. Consider other diagnoses or treatment options if no improvement has been observed after several doses. If intravenous access cannot be established, methylene blue may also be given by intraosseous infusion. Methylene blue should not be given by subcutaneous or intrathecal injection. NEONATES: DOSE: 0.3 to 1 mg/kg.

P) ENHANCED ELIMINATION PROCEDURE

1) Hemodialysis and hemoperfusion have no role in the management of chloroquine toxicity because of extensive tissue distribution.

Q) PATIENT DISPOSITION

1) HOME CRITERIA: Only asymptomatic adults with small, inadvertent ingestions can be monitored at home.
2) OBSERVATION CRITERIA: Patients with deliberate ingestions, symptomatic patients, or children with inadvertent ingestions should be sent to a health care facility for observation for at least 4 hours as symptoms of severe toxicity will likely develop within this time period. Symptomatic patients should be observed for 24 hours.
3) ADMISSION CRITERIA: Patients with significant persistent central nervous stimulation and/or abnormal vital signs should be admitted. Patients with coma, seizures, dysrhythmias, or any other life-threatening result of toxicity or intubated patients should be admitted to an intensive care setting.
4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear. Consider ophthalmology consult for visual disturbances and otolaryngology consult for hearing disturbances.

R) PITFALLS

1) Not aggressively managing the patient's airway, breathing, and circulation. Not recognizing chloroquine toxicity and, thus, not initiating treatment with high dose diazepam and epinephrine.

S) PHARMACOKINETICS

1) Chloroquine and related drugs are highly tissue bound with a very high volume of distribution ranging from approximately 115 to 285 L/kg. Metabolism is primarily hepatic. Excretion of chloroquine is approximately 50% in urine and 10% in feces. Drug elimination is very slow. The terminal half-life of chloroquine is 278 hours and, for hydroxychloroquine, it is 40 days.

T) TOXICOKINETICS

1) The terminal elimination half-life of chloroquine was 60 days following an overdose ingestion of 7.5 grams.

U) DIFFERENTIAL DIAGNOSIS

1) CNS infection or sepsis, intracerebral hemorrhage, manic or psychotic episode due to psychiatric illness, ethanol/benzodiazepine/barbiturate withdrawal, hypoglycemia, hypoxia, or cocaine or other stimulant intoxication. Overdose with other sodium channel blocking agent (ie, tricyclic antidepressants).

Range Of Toxicity

Clinical Effects

Summary Of Exposure

Vital Signs

3.3.1)

A) WITH POISONING/EXPOSURE

1) Hypotension, shock, bradycardia, tachycardia, cardiac arrest, tachypnea, respiratory arrest, and death may occur rapidly within 1 to 2 hours.

3.3.2)

A) WITH POISONING/EXPOSURE

1) DYSPNEA: In one retrospective study of 286 chloroquine poisonings, respiratory effects commonly reported included dyspnea and polypnea progressing to a sudden-onset apnea and an intense peripheral cyanosis (N'Dri et al, 1976).

3.3.3)

A) WITH POISONING/EXPOSURE

1) HYPOTHERMIA: Mild hypothermia may develop, particularly in patients with severe cardiovascular toxicity (Wilkinson et al, 1993; Bauer et al, 1991; McKenzie, 1996).

3.3.4)

A) WITH POISONING/EXPOSURE

1) HYPOTENSION is common after significant overdose (Ling Ngan Wong et al, 2008; Wilkinson et al, 1993; Collee et al, 1992; Hantson et al, 1991; Stiff et al, 1991; Meeran & Jacobs, 1993).

a) CASE REPORT: Persistent hypotension necessitating the use of IV dopamine occurred in a 20-month-old girl following an accidental ingestion of approximately 800 mg of chloroquine (CDC, 1988).

Heent

3.4.3)

A) WITH THERAPEUTIC USE

1) CHRONIC THERAPEUTIC USE was evaluated in a prospective case series of 35 patients with bilateral irreversible chloroquine retinopathy. Diagnosis was made by an ophthalmologist using direct ophthalmoscopy. The patients had taken chloroquine for a mean duration of 6.9 years; the only other drug ingested was hydroxychloroquine. Thirty out of 35 of these patients were taking a therapeutic chloroquine dose of 250 mg/day or less (Easterbrook, 1987).
2) DIAGNOSTIC METHODS: A retrospective study of 83 patients suspected of having chloroquine retinopathy compared the diagnostic efficacy of fluorescein angiography with color fundus photography or ophthalmoscopy (Cruess et al, 1985).

a) Retinal toxicity was identified in 7.6% of patients when both methods were used for diagnosis. When only angiography was used, only 1.5% of the same patients were identified; when only photography was used 6.1% of these patients were identified. Photography was more sensitive than angiography in diagnosing retinopathy in these patients.

3) CORNEAL CHANGES: Prolonged administration of these drugs may cause ocular toxicity manifested as corneal and irreversible retinal changes (Rubin et al, 1963).
4) HYDROXYCHLOROQUINE: In a retrospective chart review, chronic therapy with hydroxychloroquine was found to be less toxic to the retina than chloroquine therapy (Block, 1998).

B) WITH POISONING/EXPOSURE

1) DIPLOPIA: Visual disturbances, including visual blurring and diplopia, (Frisk-Holmberg et al, 1983) have been reported following overdose.
2) CHLOROQUINE RETINOPATHY SYNDROME includes the following effects:

a) Effects include pigmentary stippling, mottling, a "bull's eye" pattern of macular hyperpigmentation, attenuation of the retinal arteries, pale optic discs, disturbance of color vision, and loss of central vision scotoma, and visual field defects (Magulike et al, 1993; Falcone et al, 1993; Mazzuca et al, 1994; Vu et al, 1999).

Cardiovascular

3.5.1)

A) WITH THERAPEUTIC USE

1) Biventricular hypertrophy and atrioventricular block have been reported with chronic therapeutic use or abuse of chloroquine.

B) WITH POISONING/EXPOSURE

3.5.2)

A) CARDIOVASCULAR FINDING

1) WITH POISONING/EXPOSURE

a) Chloroquine overdose has resulted in life-threatening cardiotoxic effects. The primary effects include hypotension, vasodilation, ECG abnormalities (prolonged PR, QRS, and QT interval), ventricular dysrhythmias, and cardiovascular collapse.

B) CARDIAC ARREST

1) WITH POISONING/EXPOSURE

a) Cardiac arrest may occur rapidly, within 1 to 2 hours following ingestion (CDC, 1988; DiMaio & Henry, 1974; Weniger, 1979; Koppel et al, 1988; McCarthy & Swabe, 1996; McKenzie, 1996; Reddy & Sinna, 2000).
b) CHLOROQUINE

1) CASE REPORT: A 37-year-old-woman experienced 2 episodes of cardiac arrest following an apparent intentional ingestion of chloroquine (amount unknown). She lost consciousness 20 minutes after she presented to a clinic with nausea, restlessness, and agitation. A cardiac rhythm of pulseless ventricular tachycardia was recorded. She was resuscitated after 45 minutes of advanced cardiac life support, intubated, and admitted to the ICU. Laboratory analysis showed hypokalemia and hypernatremia with normal cardiac enzymes. Treatment included therapeutic hypothermia, mechanical ventilation, and IV potassium. In the ICU, her Glasgow Coma Scale score remained 3, and an ECG showed sinus tachycardia with a QTc of 372 ms. Subsequently, she developed torsades de pointes followed by cardiac arrest. Return of spontaneous circulation was achieved after 30 minutes of resuscitation. The following day, a toxic chloroquine blood level of 71.9 mcmol/L was confirmed, along with low levels of naproxen. She was treated with IV diazepam and adrenaline. She remained hemodynamically stable for 96 hours, but the chloroquine level remained elevated at 50 mcmol/L. She developed hospital acquired pneumonia and died 10 days after admission (Phipps et al, 2011).

C) HYPOTENSIVE EPISODE

1) WITH POISONING/EXPOSURE

a) Hypotension is frequent and may progress rapidly to cardiogenic shock with increased central venous pressure following chloroquine or hydroxychloroquine overdose (Haesendonck et al, 2012; Yanturali et al, 2004; Messant et al, 2004; Palatnick et al, 1997; Wilkinson et al, 1993; Meeran & Jacobs, 1993; Collee et al, 1992; Bauer et al, 1991; Hantson et al, 1991; Hantson et al, 1991; Stiff et al, 1991)
b) CHLOROQUINE

1) INCIDENCE: In a series of 51 cases of chloroquine poisoning, 12 patients (24%) developed a systolic blood pressure less than 90 mmHg (Riou et al, 1988).
2) PROGNOSIS: In a series of 51 cases of chloroquine poisoning, systolic blood pressure less than 90 mmHg had a sensitivity of 1.0 and a specificity of 0.95 in predicting death before reaching the hospital (Riou et al, 1988). None of these patients were treated with prehospital mechanical ventilation, epinephrine or diazepam.
3) CASE REPORT: A 25-year-old woman ingested a presumed 10 g of chloroquine (plasma level on admission was 39 mcmol/L; lethal level thought to be above 25 mcmol/L), and was admitted with a blood pressure of 80/54, first degree AV block, CNS depression and hypokalemia. The patient recovered with no sequelae following aggressive supportive care. The authors suggested that early medical treatment resulted in the patient's positive outcome (Messant et al, 2004).

c) HYDROXYCHLOROQUINE

1) CASE REPORT: A 17-year-old girl ingested 22 g of hydroxychloroquine and developed profound hypotension (56/23 mmHg) within several hours of exposure. The patient required fluid resuscitation and a dopamine drip. Although her blood pressure normalized, cardiac toxicity progressed to include pulseless VT. Following supportive care the patient made a complete recovery (Yanturali et al, 2004).
2) CASE REPORT: Following an overdose of 20 g of hydroxychloroquine, an 18-year-old woman experienced hypotension and ventricular tachydysrhythmias similar to a chloroquine overdose. Initial BP was 100/50 mmHg, which dropped precipitously to 67/34 within 15 minutes. The patient received volume replacement and epinephrine and was successfully extubated 24 hours postingestion (Jordan et al, 1999).
3) CASE REPORT: A 49-year-old man developed hypotension (80/40 mmHg) and bradycardia (52 bpm) approximately 1 hour after intentionally ingesting 8 g of hydroxychloroquine. The patient recovered following supportive care (Ling Ngan Wong et al, 2008).

D) VENTRICULAR ARRHYTHMIA

1) WITH THERAPEUTIC USE

a) CASE REPORT: A 67-year-old woman with systemic lupus erythematosus treated with prednisolone and hydroxychloroquine presented with recurrent syncope. ECG showed multiple PVCs and a prolonged QT of 600 msec. She developed pulseless torsade de pointes and was defibrillated three times and treated with lidocaine with return of sinus rhythm. Troponin was normal and cardiac echo was unchanged from before (ejection fraction 76%, small apical aneurysm and old anteroseptal infarction, small muscular VSD). She had recurrent VT and was treated with magnesium and isoproterenol with suppression of dysrhythmias after 4 days; QT was still prolonged at 500 msec. She was discharged after 3 weeks without dysrhythmias of anti-arrhythmic drugs (Chen et al, 2006).

2) WITH POISONING/EXPOSURE

a) ONSET: Ventricular tachycardia (CDC, 1988) and fibrillation (Bauer et al, 1991) may not occur until 24 to 48 hours following ingestion. Atrioventricular dysrhythmias were seen 2.5 hours after an alleged ingestion of 12 g of hydroxychloroquine (Villalobos, 1991). Torsade and broadened QRS-complexes following cardiopulmonary resuscitation were reported in a teenager who ingested 50 tablets of chloroquine (Muhm et al, 1996).
b) CASE REPORTS

1) In a 13-year-old boy, ventricular fibrillation occurred within 1 to 2 hours after ingestion of 600 to 750 mg of chloroquine base (Collee et al, 1992).
2) A previously healthy 20-year-old woman who ingested approximately 9 g of chloroquine experienced multiple episodes of ventricular tachycardia and ventricular fibrillation despite aggressive therapy with fluid replacement, lidocaine, and overdrive pacing. She expired 26 hours after admission of intractable hypotension, refractory to epinephrine (Henderson et al, 1994).
3) A 67-year-old woman developed torsade de pointes due to subacute chloroquine poisoning from self medication for a fever. ECG after conversion to sinus rhythm with isoproterenol showed a prolonged QT interval, QRS duration of 0.11 seconds and diffuse ST changes; serum potassium was 3.2 mEq/L (Demaziere et al, 1995).
4) A 25-year-old healthy woman developed ventricular fibrillation and subsequently ventricular ectopy resulting in hemodynamic compromise 18 hours after ingesting 2.7 g chloroquine; lidocaine terminated the dysrhythmias. She was discharged on day 14 in stable condition (Reddy & Sinna, 2000).
5) A 24-year-old man was unresponsive, hypotensive, and developed ventricular fibrillation after suspected ingestion of several medications, including 58 250-mg chloroquine tablets, 20 7.5-mg midazolam, 5 10-mg domperidone tablets, and 10 4-mg ondansetron tablets. Resuscitation was initiated in the field, and on arrival to the emergency department, pulseless electrical activity was noted. Initial therapy included decontamination with activated charcoal, administration of albumin 5%, and initiation of intravenous lipid emulsion 20%. The patient was successfully cardioverted and his blood pressure normalized; however, an arterial blood sample showed inadequate oxygenation with 100% oxygen administration. Despite continued supportive measures, including veno-arterial extracorporeal membrane oxygenation, and gradual stabilization of his hemodynamic status, the patient was declared brain dead approximately 5 days postingestion (Haesendonck et al, 2012).

c) CASE SERIES

1) In a retrospective series, torsade de pointes developed in 2 of 11 patients who ingested more than 5 g of chloroquine (Riou et al, 1988).

d) HYDROXYCHLOROQUINE

1) An 18-year-old developed nonsustained multiform ventricular tachycardia 9 hours after ingesting 20 g of (plasma level 9.87 mg/L) hydroxychloroquine. The dysrhythmias were associated with severe hypokalemia (serum potassium 1.8 mmol/L), which was corrected with multiple boluses of potassium. The patient was stabilized over a 24-hour period postingestion (Jordan et al, 1999).

e) A 22-year-old woman developed hypotension, life-threatening ventricular dysrhythmias, and mild hypokalemia after ingesting 22 g of hydroxychloroquine. She recovered with intensive supportive care(Yanturali, 2004).

E) BRADYCARDIA

1) WITH THERAPEUTIC USE

a) HYDROXYCHLOROQUINE

1) Hydroxychloroquine has also been reported to cause bradycardia along with premature ventricular beats and a prolonged QT following therapeutic use in an elderly patient. It is believed to cause toxicity by impairing conductivity and decreasing excitability (Wang, 1995).

2) WITH POISONING/EXPOSURE

a) CHLOROQUINE

1) Profound bradycardia with ventricular escape rhythms has been reported in patients with toxic chloroquine concentrations (Michael & Aiwazzadeh, 1970).
2) CASE REPORT: Sinus bradycardia (rate 50/minute) with a widened QRS complex progressing to asystole developed in a 30-year-old woman after chloroquine overdose (Stiff et al, 1991).

b) HYDROXYCHLOROQUINE

1) CASE REPORT: A 49-year-old man developed hypotension (80/40 mmHg) and bradycardia (52 bpm) approximately 1 hour after intentionally ingesting 8 g of hydroxychloroquine. The patient recovered following supportive care (Ling Ngan Wong et al, 2008).

F) BUNDLE BRANCH BLOCK

1) WITH POISONING/EXPOSURE

a) Widening of the QRS (greater than 0.10 sec) occurs in severe poisoning (Stiff et al, 1991; Hantson et al, 1991; Bauer et al, 1991; Collee et al, 1992; Wilkinson et al, 1993; Meeran & Jacobs, 1993).
b) INCIDENCE: In a series of 51 cases of chloroquine poisoning, 13 patients (26%) developed QRS prolongation greater than 0.10 seconds (Riou et al, 1988).
c) PROGNOSIS: In a series of 51 cases of chloroquine poisoning, QRS duration of 0.12 seconds longer had a sensitivity of 1.0 and a specificity of 0.98 in predicting death before reaching the hospital (Riou et al, 1988). None of these patients were treated with prehospital mechanical ventilation, epinephrine or diazepam.

G) ELECTROCARDIOGRAM ABNORMAL

1) WITH POISONING/EXPOSURE

a) CHLOROQUINE

1) SUMMARY: The major effects are progressive prolongation of PR, QRS, and QT intervals; inversion and depression of T waves; and ventricular dysrhythmias
2) REPOLARIZATION ABNORMALITIES: Prolonged QT interval, prominent U waves, and depressed ST segments may be noted (N'Dri et al, 1976; Croes et al, 1991).
3) CONDUCTION ABNORMALITIES: Prolongation of the PR interval has also been reported (Wilkinson et al, 1993).

b) HYDROXYCHLOROQUINE

1) CASE REPORT: A 17-year-old girl developed a prolonged QT interval (600 ms) and episodes of bigeminal ventricular ectopic beats, non-sustained tachycardia and pulseless VT (approximately 6 hours after ingestion) following an intentional ingestion of 22 g hydroxychloroquine. Following aggressive supportive care the patient made a complete recovery (Yanturali et al, 2004).
2) CASE REPORT: QTc interval prolongation (492 ms) was reported in a 49-year-old man following an intentional ingestion of 8 g of hydroxychloroquine (Ling Ngan Wong et al, 2008).

H) TACHYARRHYTHMIA

1) WITH POISONING/EXPOSURE

a) INCIDENCE: In one retrospective study of 286 chloroquine poisonings, 80% of the patients had an initial moderate (100 to 120 beats/minute) tachycardia (N'Dri et al, 1976).
b) CASE REPORT: A 39-year-old woman became tachycardic after ingesting 2.5 g chloroquine, 100 mg Maloprim, some Sudafed tablets, and some antismoking and slimming tablets. Her blood chloroquine level was 6 micromoles/L, and methemoglobin level was 30% (Rajah, 1990).

I) ATRIOVENTRICULAR BLOCK

1) WITH POISONING/EXPOSURE

a) CHRONIC TOXICITY

1) SUMMARY: Atrioventricular block occurs commonly in patients who chronically abuse chloroquine. Toxicity can also occur following long-term therapeutic use (Guedira et al, 1998; Veinot et al, 1998; Reuss-Borst et al, 1999).
2) INCIDENCE: Twelve of thirty African patients with heart block gave a history of chloroquine abuse in one study (Ihenacho & Magulike, 1989). In another study 13 of 26 Nigerian patients with heart block gave a history of supratherapeutic long term use of chloroquine (Magulike et al, 1993). Patients presenting with AV block in malarial areas should be questioned about chloroquine use (Ihenacho & Magulike, 1989; Anon, 1990).
3) CASE SERIES: Five out of 112 patients with lupus who were on long-term therapeutic doses of chloroquine later developed atrioventricular block. None of these patients had a history notable for cardiac risk factors; three of the five had discoid rather than systemic lupus (Piette et al, 1987).
4) COMPLETE HEART BLOCK: Chronic chloroquine therapy has resulted in complete heart block necessitating permanent pacemaker insertion in two adults (Guedira et al, 1998; Veinot et al, 1998). In one case evidence of chloroquine toxicity was present prior to development of heart block, but the patient chose to ignore recommendations of his physician to discontinue therapy.

J) CARDIOMEGALY

1) WITH THERAPEUTIC USE

a) CHRONIC TOXICITY

1) VENTRICULAR HYPERTROPHY: Biventricular hypertrophy was reported in 2 patients during treatment of systemic lupus erythematosus (McAllister et al, 1987).

K) CARDIOMYOPATHY

1) WITH POISONING/EXPOSURE

a) CHRONIC TOXICITY

1) Chronic chloroquine use has been associated with cardiomyopathy (Ferrans et al, 1993). Chronic therapy with hydroxychloroquine has also been associated with the development of cardiomyopathy (Richards, 1998).
2) CASE REPORT: A 59-year-old woman with discoid lupus erythematosus treated with chloroquine for 25 years developed congestive heart failure secondary to a restrictive cardiomyopathy (Cubero et al, 1993).

Respiratory

3.6.1)

A) WITH POISONING/EXPOSURE

1) Tachypnea, pulmonary edema, acute respiratory distress, respiratory arrest, and death have occurred within 1 to 2 hours of ingestion of an overdose of chloroquine.

3.6.2)

A) APNEA

1) WITH POISONING/EXPOSURE

a) Respiratory arrest and death have occurred within an interval as short as 1 to 2 hours following overdose (CDC, 1988). Respiratory arrest is usually secondary to a circulatory arrest or to a severe shock.
b) CASE REPORT: Acute respiratory distress was reported in an acute chloroquine overdose patient following a rapid diazepam injection(Vitris & Aubert, 1983).

B) ACUTE LUNG INJURY

1) WITH POISONING/EXPOSURE

a) Pulmonary edema and congestion have also been reported (Weingarten & Cherry, 1981).
b) CASE REPORT: Pulmonary edema developed secondary to cardiogenic shock in a 20-year-old woman after ingestion of 6 g of chloroquine (Bauer et al, 1991).

C) HYPERVENTILATION

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 39-year-old woman became tachypneic after ingesting 2.5 g chloroquine, 100 mg maloprim, some sudafed tablets, and some antismoking and slimming tablets (Rajah, 1990). Her blood chloroquine level was 6 micromoles/L, and methemoglobin level was 30%.
b) CASE SERIES: In one retrospective study of 286 chloroquine poisonings, respiratory signs commonly reported included dyspnea and polypnea progressing to a sudden-onset apnea and an intense peripheral cyanosis (N'Dri et al, 1976).

D) RESPIRATORY FAILURE

1) WITH THERAPEUTIC USE

a) CASE REPORT: An 88-year-old woman developed respiratory failure secondary to chloroquine-induced toxic myopathy (Siddiqui et al, 2007).

Neurologic

3.7.1)

A) WITH THERAPEUTIC USE

B) WITH POISONING/EXPOSURE

3.7.2)

A) CENTRAL STIMULANT ADVERSE REACTION

1) WITH POISONING/EXPOSURE

a) Following overdose, visual disturbances, hyperexcitability and agitation, seizures within an interval as short as 1 to 2 hours have been reported (CDC, 1988; N'Dri et al, 1976; Rajah, 1990; Torrey, 1968).

B) CENTRAL NERVOUS SYSTEM DEFICIT

1) WITH POISONING/EXPOSURE

a) CNS depression and coma can develop in patients with severe poisoning (Phipps et al, 2011; Haesendonck et al, 2012; Messant et al, 2004; Bauer et al, 1991; McKenzie, 1996).
b) CASE REPORT: A 49-year-old man presented to the emergency department with nausea and vomiting, generalized weakness, and drowsiness one hour after intentionally ingesting 8 g of hydroxychloroquine. During the physical exam, the patient developed hypotension and bradycardia and became comatose (Glasgow Coma Scale {GCS} score of 3). Following supportive care, the patient's condition improved (GCS 14) and he was subsequently discharged approximately 10 days post-ingestion (Ling Ngan Wong et al, 2008).
c) CHLOROQUINE

1) CASE REPORT: A 37-year-old-woman lost consciousness 20 minutes after presenting to a clinic with nausea, restlessness, and agitation following an apparent intentional ingestion of chloroquine (amount unknown). Subsequently, she experienced an episode of pulseless ventricular tachycardia, was resuscitated, intubated, and admitted to the ICU. A toxic chloroquine blood level of 71.9 mcmol/L was detected the day after presentation. She experienced a second episode of cardiac arrest and resuscitation after admission to the ICU and neurologic exam showed a Glasgow Coma Scale score of 3 with negative corneal and oculocephalic reflexes. Despite aggressive treatment including mechanical ventilation, she developed hospital acquired pneumonia and died 10 days after admission to the ICU (Phipps et al, 2011).

C) SEIZURE

1) WITH THERAPEUTIC USE

a) Nonconvulsive status epilepticus was reported in a 68-year-old woman after 12 days of prophylactic (antimalarial) chloroquine therapy (Mulhauser et al, 1995). The patient presented with episodes of odd behavior and stammering. Symptoms resolved with drug cessation and a repeat EEG 6 months later was normal.

2) WITH POISONING/EXPOSURE

a) Seizures are common following overdose and may be difficult to control.
b) CASE SERIES

1) In a case series of chloroquine-induced psychiatric complications, all patients who developed seizures, all had symptoms of toxicity (eg, vomiting, diarrhea, abdominal cramps) prior to seizing (Bhatia & Malik, 1995).

c) CASE REPORTS

1) A 30-year-old woman developed a grand mal seizure, bradycardia, hypotension, and QRS widening followed by asystolic cardiac arrest after chloroquine overdose (Stiff et al, 1991).
2) A previously healthy 20-year-old woman who ingested approximately 9 g of chloroquine experienced multiple generalized seizures beginning about 12 hours after hospital admission and continuing until her death, 14 hours later. The seizures were resistant to therapy with phenytoin and an IV infusion of clonazepam (Henderson et al, 1994).
3) A 25-year-old healthy woman initially had generalized seizures and then developed repeated seizures after ingesting 2.7 g chloroquine; diazepam and phenytoin were required to treat the seizures. The patient had a complete recovery (Reddy & Sinna, 2000).

D) CEREBRAL EDEMA

1) WITH POISONING/EXPOSURE

a) SUMMARY: Cerebral edema has been reported following chloroquine exposure (Havens et al, 1988; McCarthy & Swabe, 1996) and has occurred as early as 96 hours after ingestion (McCarthy & Swabe, 1996).
b) CASE REPORTS

1) A head CT scan showed diffuse cerebral edema on day 8 of hospitalization in a 17-month-old, 14 kg boy who ingested eight 500 mg tablets (4 g) of chloroquine. Cardiovascular collapse occurred approximately 35 minutes after ingestion and adequate circulation was restored after 60 to 90 minutes (Havens et al, 1988).
2) Cerebral edema and anoxic cortical reactions have been observed on autopsy (Weingarten & Cherry, 1981).

E) ELECTROENCEPHALOGRAM ABNORMAL

1) WITH POISONING/EXPOSURE

a) CASE REPORT: EEGs done at 24 and 48 hours postingestion in a 17-month-old boy who ingested 4 g of chloroquine revealed intense beta activity while on high-dose diazepam (suggesting preservation of cortical neuronal activity) and watershed spike activity (indicating mild to moderate hypoperfusion injury) (Havens et al, 1988).

F) NEUROPATHY

1) WITH THERAPEUTIC USE

a) Following usual therapeutic doses vertigo, malaise, anorexia, headache, visual blurring, pruritus and urticaria have been reported. Higher dosages may result in toxic psychosis with hallucinations (Good & Shader, 1982) and peripheral neuropathy (Estes et al, 1987). Neuromyopathy with granular depositions in muscle fibers has been reported with therapeutic use of chloroquine (Parodi et al, 1985), and has also been reported following therapy with hydroxychloroquine (Stein et al, 2000).
b) STUDY: A dose of mefloquine hydrochloride (15 mg/kg) was administered to 7 healthy adult volunteers. All subjects had some neurologic effects within 6 hours of the dose; effects included lightheadedness, nausea, inability to concentrate, dizziness, and vertigo. Reactions did not correlate with dose and were transient (Patchen et al, 1989).

G) EXTRAPYRAMIDAL SIGN

1) WITH THERAPEUTIC USE

a) CASE REPORT: A 30-year-old woman on metronidazole therapy developed an acute dystonic reaction after her first dose of chloroquine (Achumba et al, 1988).

H) TOXIC ENCEPHALOPATHY

1) WITH THERAPEUTIC USE

a) PEDIATRIC

1) PSYCHOSIS: Six cases of chloroquine psychosis were reported in children (ages 7 to 12 years) who received 1 to 1.8 g of chloroquine for malaria (Bhatia et al, 1988). Premonitory features of psychosis included: agitation, confusion, and incoherent talk progressing to visual and auditory hallucinations and delusions.
2) PSYCHOSIS: Two cases of psychosis were reported in children given therapeutic doses of chloroquine (Agrawal & Agrawal, 1988).
3) HALLUCINATIONS: A 14-year-old girl who received a total of 1,300 mg of chloroquine therapeutically over 7 days developed delusions and hallucinations 4 days after stopping therapy. The effects persisted for one week; there was no history of previous psychiatric disturbances (James et al, 1987).
4) DELIRIUM, vertigo, aggression, and hallucinations were reported in four children (ages 3.5 to 10 years), who received chloroquine therapeutically. Signs resolved in all four with the discontinuation of chloroquine and addition of benzodiazepines (Garg et al, 1990).
5) CAPGRAS' SYNDROME, or the misguided belief that a familiar person has been replaced by an imposter, was reported in the case of an 8-year-old girl who was treated with therapeutic chloroquine for three days (Bhatia et al, 1988a).

b) ADULT

1) MEMORY LOSS: Three hours after taking a single 300 mg dose of chloroquine, a 62-year-old healthy man began to feel ill lost his immediate recall memory. Cerebral CT scan and EEG were normal. Effects resolved without further treatment within 24 hours (Cras & Martin, 1990).
2) MANIA: A 33-year-old man with no history of psychiatric disturbance developed hypomania (overactivity, irritability, racing thoughts with delusions of reference and grandeur) after beginning chloroquine prophylaxis (Lovestone, 1991).

2) WITH POISONING/EXPOSURE

a) CASE REPORT/PEDIATRIC: A 7-year-old girl presented with restlessness and excessive talking approximately 5 days after beginning chloroquine therapy. The child had been prescribed 10 mg/kg of chloroquine (base 150 mg) as the initial dose followed by 5 mg/kg at 6, 24, and 48 hours, but instead received a total dose of 1.5 g on the first day. The total dose received was approximately 100 mg/kg of the base as compared with the prescribed total therapeutic dose of 25 mg/kg. Following discontinuation of chloroquine, the patient recovered without sequelae (Zaki et al, 2009).

Gastrointestinal

3.8.1)

A) WITH THERAPEUTIC USE

1) Nausea, vomiting, diarrhea, and hemorrhagic gastritis have been reported with therapeutic use or overdose.

3.8.2)

A) NAUSEA AND VOMITING

1) WITH THERAPEUTIC USE

a) Nausea and vomiting may develop with therapeutic use (Wilkinson et al, 1993; Weingarten & Cherry, 1981).

2) WITH POISONING/EXPOSURE

a) Nausea and vomiting can occur after overdose with these agents (Phipps et al, 2011; Ling Ngan Wong et al, 2008; Wilkinson et al, 1993; Weingarten & Cherry, 1981).

B) GASTRIC HEMORRHAGE

1) WITH THERAPEUTIC USE

a) CASE REPORT: Two adult males both developed multiple gastric erosions and experienced hematemesis approximately 30 hours after taking 600 mg of chloroquine base each for therapeutic purposes (Bhasin & Chhina, 1989).
b) CASE SERIES: In a study of 18 patients with malaria, gastric erosions developed 24 to 36 hours after administration of 600 mg of chloroquine in four patients (Bhasin et al, 1991). Erosions only occurred if chloroquine was given while patients were febrile.

C) DIARRHEA

1) WITH THERAPEUTIC USE

a) Diarrhea has been noted (Weingarten & Cherry, 1981)

Hepatic

3.9.2)

A) HEPATIC NECROSIS

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Autopsy results on a previously healthy 20-year-old woman who ingested approximately 9 g of chloroquine revealed early centrilobular hepatic necrosis (Henderson et al, 1994).

B) HEPATIC FAILURE

1) WITH THERAPEUTIC USE

a) CASE REPORT: Two women with autoimmune disorders developed fatal fulminant hepatic failure 2 weeks after beginning therapy with hydroxychloroquine (Makin et al, 1994).

C) TOXIC HEPATITIS

1) WITH THERAPEUTIC USE

a) CASE SERIES/AMODIAQUINE: A retrospective case series identified 7 patients who developed hepatitis after taking amodiaquine for malaria prophylaxis for up to 15 weeks. Abnormal laboratory findings included an elevated ALT and prothrombin time and thrombocytopenia. Three of these patients were seriously ill; jaundice persisted for 3 to 6 months and liver function tests were still abnormal 7 to 27 months after the onset of hepatitis (Larrey et al, 1986).

D) TOXIC LIVER DISEASE

1) WITH THERAPEUTIC USE

a) CASE SERIES/AMODIAQUINE: Five patients developed signs and symptoms of hepatotoxicity (eg, cholestasis, elevated liver enzyme concentrations) and severe agranulocytosis after taking amodiaquine chronically. The total dose in all 5 patients ranged from 1.8 to 6 g, given over 34 to 63 days. One of the patients died due to complications from the agranulocytosis. Autopsy of the patient revealed mild centrilobular cholestasis and mononuclear infiltration mixed with few neutrophilic granulocytes within the portal tracts (Neftel et al, 1986).

Genitourinary

3.10.2)

A) NEPHRITIS

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Subclinical nephritis with intermittent hematuria and normal serum creatinine occurred in a 17-month-old boy who ingested 4 g of chloroquine (Havens et al, 1988).

Acid-Base

3.11.2)

A) ACIDOSIS

1) WITH POISONING/EXPOSURE

a) Metabolic acidosis is common in patients who develop seizures or cardiovascular instability (Hantson et al, 1991; Bauer et al, 1991; Clemessy et al, 1995).
b) CASE REPORT: Metabolic acidosis (pH 7.17, HCO3 14.4 mmol/L, pO2 11.8 kPa, pCO2 5.4 kPa) occurred in a 49-year-old man who intentionally ingested 8 g of hydroxychloroquine (Ling Ngan Wong et al, 2008).

Hematologic

3.13.1)

A) WITH POISONING/EXPOSURE

3.13.2)

A) HEMOLYTIC ANEMIA

1) WITH THERAPEUTIC USE

a) The 8-aminoquinolines may cause hemolytic anemia, particularly in patients with glucose-6-phosphate dehydrogenase deficiency.

B) METHEMOGLOBINEMIA

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 39-year-old woman developed a methemoglobin level of 30% after ingesting 2.5 g chloroquine, 100 mg Maloprim, some Sudafed tablets, and some antismoking and slimming tablets (Rajah, 1990).

C) LEUKOPENIA

1) WITH POISONING/EXPOSURE

a) CASE SERIES: A study of 25 Nigerian patients with chronic ingestion of supratherapeutic doses of chloroquine (at least 3,000 mg in 7 days) revealed neutropenia as compared with controls (Nwobodo & Obi, 1993). Neutropenia resolved within one month of discontinuation of therapy.

D) DISSEMINATED INTRAVASCULAR COAGULATION

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Progressive multiorgan failure including disseminated intravascular coagulation developed in a 14-year-old following ingestion of 50 chloroquine tablets. Death occurred 9 hours after exposure. It is suggested that after a massive overdose, coagulation and fibrinolytic functions may be affected (Muhm et al, 1996).

E) AGRANULOCYTOSIS

1) WITH THERAPEUTIC USE

a) CASE SERIES/AMODIAQUINE: Severe agranulocytosis was reported in 7 patients who had been taking amodiaquine. The total dose in all 7 patients ranged from 1.8 to 6 g, given over 34 to 63 days. In 3 patients, the neutrophil counts ranged from 72 x 10(6) to 8 x 10(6)/L, and in 4 patients, neutrophils were not detected. Five of the patients also presented with evidence of hepatic insufficiency. Of the 7 patients, 2 died of complications from agranulocytosis (development of pseudomonas septicemia) and 1 patient died from recurrent pulmonary embolism that was present when the patient became agranulocytic (Neftel et al, 1986).

Dermatologic

3.14.1)

A) WITH THERAPEUTIC USE

1) Skin eruptions, pruritus, and urticaria may occur with therapeutic use.

3.14.2)

A) ITCHING OF SKIN

1) WITH THERAPEUTIC USE

a) High doses may result in skin eruptions, pruritus, and urticaria.

B) LYELL'S TOXIC EPIDERMAL NECROLYSIS, SUBEPIDERMAL TYPE

1) WITH THERAPEUTIC USE

a) CASE REPORT: A 68-year-old developed toxic epidermal necrolysis after taking the fourth weekly 500 mg dose of chloroquine for malaria prophylaxis (Boffa & Chalmers, 1994).

C) HAIR DISCOLORATION

1) WITH POISONING/EXPOSURE

a) CASE REPORT: An 11-year-old boy developed a 1cm strip of white depigmentation of his scalp hair, as well as depigmentation of his eyelashes, eyebrows, and body hair after taking 1250 mg/day of chloroquine for 4 weeks instead of the prescribed dose of 250 mg/day. After changing to the correct dose of 250 mg/day, the patient's hair growth returned to normal pigmentation (Di Giacomo et al, 2009).

Musculoskeletal

3.15.2)

A) TOXIC MYOPATHY

1) WITH THERAPEUTIC USE

a) CASE REPORT: An 88-year-old woman presented with a 5-month history of dyspnea and weakness. At the time of presentation, her medications included methotrexate, prednisone (10 mg/day), glyburide, enalapril, and hydroxychloroquine (300 mg twice daily). She had been taking hydroxychloroquine for the last 5 years. Physical exam showed bilateral breath sounds, and upper and lower extremity weakness with diminished reflexes symmetrically. Laboratory data revealed normal creatine kinase levels. Arterial blood gas showed pH 7.37, pCO2 63 mmHg and pO2 33 mmHg. Pulmonary function tests demonstrated severe respiratory insufficiency (negative inspiratory force -15 cmH2O, FVC 0.56 L (24% predicted), FEV1 0.29 L (19% predicted). Electromyography indicated myositis and a skeletal muscle biopsy showed necrotizing vacuolar myopathy with curvilinear bodies, indicative of chloroquine myopathy. Hydroxychloroquine therapy was discontinued; however, her respiratory insufficiency continued. Despite supportive care, the patient subsequently died (Siddiqui et al, 2007).

Endocrine

3.16.2)

A) HYPOGLYCEMIA

1) WITH THERAPEUTIC USE

a) CASE REPORT: A 56-year-old woman with psoriatic arthritis and vagotomy and pyloroplasty developed symptomatic hypoglycemia after beginning chloroquine. Symptoms resolved when chloroquine was discontinued and recurred when it was resumed (Abu-Shakra & Lee, 1994).

Reproductive

3.20.1)

3.20.2)

A) ABORTION

1) CASE SERIES: A case series described 24 women with 27 pregnancies who took chloroquine (16) or hydroxychloroquine (8) during the first trimester of pregnancy. Of these 24 women, 11 had systemic lupus erythematosus, 3 had rheumatoid arthritis, and 4 were taking malaria prophylaxis. Most were taking other antiinflammatory drugs also. Of the 27 pregnancies 14 resulted in normal term infants, 6 were electively aborted, 3 were still births (at 28, 11 and 12 weeks) and 4 resulted in spontaneous abortions (between 12 and 15 weeks) (Levy et al, 1991).

B) LACK OF EFFECT

1) One hundred thirty-three pregnancies in women treated with hydroxychloroquine for systemic lupus erythematosus, Sjogren syndrome, and other connective tissue disorders were described, comparing the outcomes with a control group of 70 consecutive pregnancies. In the treated group, 90 women received hydroxychloroquine for at least 6 months prior to pregnancy, and continued treatment throughout gestation. Hydroxychloroquine 200 mg twice a day was administered in 122 pregnancies and once a day in 11 cases. Other medications used in both groups included prednisone, aspirin, low molecular weight heparin, azathioprine, and intravenous immunoglobulin. In the women treated with hydroxychloroquine, 133 pregnancies resulted in 117 live births. Three cases of malformations were documented: hypospadias, craniostenosis, and cardiac malformation. In the control group, 4 cases of malformations were documented. These results are equivalent to what would be expected in the general population. No differences in EKG findings were observed between the 2 groups. All pregnancies were evaluated for follow up, even those resulting in therapeutic abortion. At a mean age of 26 months, no visual, auditory, growth or developmental abnormalities were noted in the exposed infants (Costedoat-Chalumeau et al, 2003).
2) No visual acuity defects or ophthalmologic abnormalities were detected among 21 children exposed to full therapeutic doses of either hydroxychloroquine (n=14) or chloroquine (n=7) in utero. The average daily maternal doses were hydroxychloroquine 317 mg and chloroquine 332 mg used during treatment of either lupus or rheumatoid arthritis. Fourteen infants were exposed throughout the full 9 months gestation; only two pregnancies had no first trimester exposure. The average age at eye examination was 2.8 years (range, 0.2 to 10 years) (Klinger et al, 2001).
3) Among 10 infants born to women who received hydroxychloroquine from an average 11 weeks gestational age, follow-up examinations at between 1.5 to 3 years showed no health compromise. Height and weight were above the 50th percentile, cognitive development was normal, and no auditory or ophthalmic defects were noted (Levy et al, 2001).
4) The frequency of congenital anomalies was no higher than expected among 23 infants born to women with systemic lupus erythematosus who were treated with hydroxychloroquine during the first trimester of pregnancy (Buchanan et al, 1996). No congenital anomalies were seen among 12 children of women with systemic lupus erythematosus who were treated with hydroxychloroquine throughout pregnancy in one case series (Parke, 1988; Parke & West, 1996) or among five children of women who were treated with hydroxychloroquine for rheumatoid arthritis during the first and second trimesters in another series (Feldkamp & Carey, 1993).

C) ANIMAL STUDIES

1) MICE: Chloroquine has also been shown to cross the placenta and remain in the fetal eyes of mice for 5 months after the drug was eliminated from the rest of the body (Prod Info ARALEN(R) oral tablets, 2013; Prod Info PLAQUENIL(R) oral tablets, 2009).

3.20.3)

A) PLACENTAL BARRIER

1) A small study (n=11) indicated that hydroxychloroquine crosses the placenta. At delivery, mean concentrations of hydroxychloroquine in maternal blood and cord blood were not significantly different (893 nanograms (ng)/mL vs 894 ng/mL; p=0.01). Mother and child had similar hydroxychloroquine concentrations, and the fetal:maternal ratio was 1.04. Consecutive pregnant women received hydroxychloroquine 200 mg either once (n=3) or twice daily (n=8); all had received hydroxychloroquine for at least 6 months prior to pregnancy as treatment for systemic lupus erythematosus (7), Sjogren syndrome (1), or mixed/unclassified connective tissue disease (3). There were no malformations or abnormalities in the 11 live births (Costedoat-Chalumeau et al, 2002). Chloroquine and other 4-aminoquinolones cross the placenta. When given weekly in chemoprophylactic doses, chloroquine has not been shown to cause adverse effects in the fetus. However, chloroquine may accumulate in the melanin of the fetus' eyes. Since the risk is not well documented in pregnancy, chloroquine should not be used except in the suppression or treatment of malaria or hepatic amoebiasis where the risk to mother and fetus outweigh the possible adverse effects (Kasilo OMJ, 1991).

B) ABORTION

1) Chloroquine is wrongly believed to be an effective abortifacient by the public in some areas of the world. In one study in Zimbabwe, 9 of 22 total cases of chloroquine suicide were abortion attempts (Kasilo OMJ, 1991). In one study, it was noted that, of 80 suicide attempts in France using chloroquine, 67 were women; apparently 4 of these were clear cases of attempted abortion (all of which failed) (Vitris & Aubert, 1983). Another study also noted a preponderance of women among chloroquine overdoses (241 out of 286) (N'Dri et al, 1976).
2) Twenty-four women with 27 pregnancies who took chloroquine (n=16) or hydroxychloroquine (n=8) during the first trimester of pregnancy were described. Of these 24 women, 11 had systemic lupus erythematosus, 3 had rheumatoid arthritis, and 4 were taking malaria prophylaxis. Most were taking other antiinflammatory drugs concomitantly. Of the 27 pregnancies, 14 resulted in normal term infants, 6 were electively aborted, 3 were still births (at 28, 11, and 12 weeks) and 4 resulted in spontaneous abortions (between 12 and 15 weeks) (Levy et al, 1991a).

C) PREGNANCY CATEGORY

1) The manufacturers have classified CHLOROQUINE and QUINACRINE as FDA pregnancy category C (Briggs et al, 1998).

D) LACK OF EFFECT

1) PRENATAL EXPOSURE

a) OTOTOXICITY

1) In a small case-control study of 19 children, in utero exposure to chloroquine was evaluated to assess the potential risk for ototoxicity. In the exposed group (n=9), all of the mothers were taking chloroquine during some portion of their first trimester, and the mean duration of therapy was 6.1 (+/- 2.9) months. Pure tone audiometry was performed, with high and low frequency threshold measured. The results were similar in both groups. The findings indicated that in utero exposure to chloroquine did not induce hearing impairment (Borba et al, 2004).

3.20.4)

A) BREAST MILK

1) Chloroquine is excreted in human breast milk (Briggs et al, 1998a). The maximum dose infants received from breastfeeding following a single oral dose of chloroquine in malaria chemotherapy was around 0.7% of the maternal start dose (Prod Info ARALEN(R) oral tablets, 2013).
2) Hydroxychloroquine has been found in low amounts in breast milk, and several studies have reported no adverse effects of this drug in infants exposed during the lactation period. Although the benefits of breastfeeding outweigh the theoretical risk to the infant, the nursing infant should always be monitored for adverse effects (Motta et al, 2005).
3) Hydroxychloroquine was excreted into breast milk in 2 of 2 mothers. Hydroxychloroquine concentrations were 344 and 1424 nanograms/mL, respectively, with milk to whole blood ratios of 0.48 and 0.85, respectively (Costedoat-Chalumeau et al, 2002a) .

B) LACK OF EFFECT

1) Eye examinations showed no ocular complications in 8 infants of mothers who were taking hydroxychloroquine during the breastfeeding period. While the elimination is slow and there is a potential risk for accumulation in the infant, lupus experts hold that hydroxychloroquine may be continued while breastfeeding (Temprano et al, 2005).
2) No adverse events were reported in 13 babies who were breastfed by mothers being treated with hydroxychloroquine for rheumatic diseases were examined for visual function and neurodevelopmental outcome, suggesting that hydroxychloroquine treatment during gestation and lactation appears to be safe (Motta et al, 2005).

Laboratory Monitoring

Monitoring Parameters Levels

4.1.1)

A) Chloroquine concentrations are not readily available or useful to guide therapy.
B) Monitor vital signs and mental status.
C) Obtain an ECG and institute continuous cardiac monitoring in all patients.
D) Monitor serum electrolytes, particularly potassium, renal function, and glucose.
E) Consider head CT and lumbar puncture to rule out intracranial mass, bleeding, or infection if the diagnosis is unclear.
F) CPK should be obtained if the patient has had psychomotor agitation or seizure activity.

4.1.2)

A) BLOOD/SERUM CHEMISTRY

1) Chloroquine concentrations are not readily available or useful to guide therapy.
2) Monitor serum electrolytes, particularly potassium, renal function, and glucose.
3) CPK should be obtained if the patient has had psychomotor agitation or seizure activity.

B) HEMATOLOGIC

1) Monitor methemoglobin levels in cyanotic patients.

4.1.4)

A) OTHER

1) MONITORING

a) Monitor vital signs and mental status.
b) Obtain an ECG and institute continuous cardiac monitoring in all patients.
c) Consider head CT and lumbar puncture to rule out intracranial mass, bleeding, or infection if the diagnosis is unclear.

2) OPHTHALMOLOGY EXAM

a) Ocular toxicity has been associated with chloroquine therapy.

1) Ophthalmological exam and color vision testing (which are designed to detect both B-Y {blue-yellow} and protan defects) have been described in the evaluation of chloroquine-related retinal toxicity (Vu et al, 1999).

Radiographic Studies

1) GALLIUM-67 IMAGING: Has been reported in a child with chloroquine poisoning. Areas of significant gallium uptake were demonstrated in the renal cortices and the myocardium; this distribution pattern is similar to the known distribution of chloroquine (Havens et al, 1989).

Methods

1) It has been reported that the blood fraction used for measuring chloroquine blood concentrations is important since varied results have been noted when plasma, erythrocytes, and whole blood were analyzed.
2) To insure accurate interpretation of chloroquine assays, blood should be collected in EDTA, centrifuged within two hours and the plasma should be frozen at -20 to -40 C (Verdier et al, 1983).
3) Chloroquine concentration in the plasma is only 10 to 15% of that in the whole blood, therefore, high plasma concentrations may result if the plasma is not cell free. Chloroquine concentrations determined in serum are higher than those in plasma.

1) High pressure liquid chromatography is a preferred method for the measurement of chloroquine concentrations since apparent drug and its main metabolite can be assayed separately (Gustafsson et al, 1983).
2) Biological specimens have been analyzed using UV spectroscopy, thin-layer chromatography, gas chromatography/mass spectrometry (Kemmenoe, 1990).
3) An ELISA has been developed for detecting chloroquine and its metabolites in blood, urine, and breast milk. It has not been compared to HPLC, and it may not be readily available (Witte et al, 1990).
4) A ion-pair HPLC method with UV detection has been described to determine concentrations of chloroquine and metabolites in biological specimens (Houze et al, 1992).
5) A gas chromatographic method for determining the concentration of chloroquine in hair has been described (Runne et al, 1992). Determining concentration in sequential hair segments allowed assessment for the amount of drug taken and the time of initiation and cessation of therapy.
6) Keller et al (1998) described a GC/MS method that analyzes and determines chloroquine concentrations in body fluids which is reported as rapid, sensitive, and reliable (Keller et al, 1998).

Treatment

Life Support

Patient Disposition

6.3.1)

6.3.1.1) ADMISSION CRITERIA/ORAL

A) Patients with significant persistent central nervous stimulation and/or abnormal vital signs should be admitted. Patients with coma, seizures, dysrhythmias, or any other life-threatening result of toxicity or intubated patients should be admitted to an intensive care setting.

6.3.1.2) HOME CRITERIA/ORAL

A) Only asymptomatic adults with small, inadvertent ingestions can be monitored at home.
B) Because the margin of safety of chloroquine is so low in children and 2 to 3 times the therapeutic dose has been reported to be fatal within 2.5 hours (Cann & Verhulst, 1961), any child ingesting more than a therapeutic daily dose should be referred to a health care facility for decontamination, treatment and monitoring.

6.3.1.3) CONSULT CRITERIA/ORAL

A) Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear. Consider ophthalmology consult for visual disturbances and otolaryngology consult for hearing disturbances.

6.3.1.5) OBSERVATION CRITERIA/ORAL

A) Patients with deliberate ingestions, symptomatic patients, or children with inadvertent ingestions should be sent to a health care facility for observation for at least 4 hours as symptoms of severe toxicity will likely develop within this time period. Symptomatic patients should be observed for 24 hours.

Monitoring

Oral Exposure

6.5.1)

A) Activated charcoal should be avoided in the prehospital setting because of the high risk of abrupt onset seizure or coma and subsequent aspiration.

6.5.2)

A) ACTIVATED CHARCOAL

1) SUMMARY: Consider decontamination if a patient presents shortly after an oral overdose and is not yet manifesting symptoms of toxicity. Activated charcoal is generally not recommended in patients that are manifesting signs of toxicity as they may abruptly become comatose or seize and aspirate. If the airway is protected with orotracheal intubation, charcoal may be given.
2) CHARCOAL ADMINISTRATION

a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.

3) CHARCOAL DOSE

a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).

1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).

b) ADVERSE EFFECTS/CONTRAINDICATIONS

1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).

4) In 6 healthy volunteers, administration of activated charcoal (25 g) totally prevented absorption of chloroquine 500 mg. The activated charcoal was given within 5 minutes of the dose of chloroquine. Activated charcoal 25 g has adequate capacity to bind up to 5 g of chloroquine (Neuvonen et al, 1992; Kivisto & Neuvonen, 1993).

B) GASTRIC LAVAGE

1) The efficacy of gastric lavage varies greatly. In a kinetic study of 7 cases, gastric lavage removed a mean 7 percent of the amount ingested with a range between 0 and 23 percent (Jaeger et al, 1987a). Because of the close dose dependent toxicity of chloroquine, gastric lavage may be useful. But it must only be performed after intubation and ventilation because cardiac and respiratory arrest may occur suddenly and early.
2) Consider gastric lavage in patients who have recently (generally within 1 hour) ingested a life-threatening amount of chloroquine (2.25 g or more) as it is a life-threatening overdose with no specific antidote.
3) INDICATIONS: Consider gastric lavage with a large-bore orogastric tube (ADULT: 36 to 40 French or 30 English gauge tube {external diameter 12 to 13.3 mm}; CHILD: 24 to 28 French {diameter 7.8 to 9.3 mm}) after a potentially life threatening ingestion if it can be performed soon after ingestion (generally within 60 minutes).

a) Consider lavage more than 60 minutes after ingestion of sustained-release formulations and substances known to form bezoars or concretions.

4) PRECAUTIONS:

a) SEIZURE CONTROL: Is mandatory prior to gastric lavage.
b) AIRWAY PROTECTION: Place patients in the head down left lateral decubitus position, with suction available. Patients with depressed mental status should be intubated with a cuffed endotracheal tube prior to lavage.

5) LAVAGE FLUID:

a) Use small aliquots of liquid. Lavage with 200 to 300 milliliters warm tap water (preferably 38 degrees Celsius) or saline per wash (in older children or adults) and 10 milliliters/kilogram body weight of normal saline in young children(Vale et al, 2004) and repeat until lavage return is clear.
b) The volume of lavage return should approximate amount of fluid given to avoid fluid-electrolyte imbalance.
c) CAUTION: Water should be avoided in young children because of the risk of electrolyte imbalance and water intoxication. Warm fluids avoid the risk of hypothermia in very young children and the elderly.

6) COMPLICATIONS:

a) Complications of gastric lavage have included: aspiration pneumonia, hypoxia, hypercapnia, mechanical injury to the throat, esophagus, or stomach, fluid and electrolyte imbalance (Vale, 1997). Combative patients may be at greater risk for complications (Caravati et al, 2001).
b) Gastric lavage can cause significant morbidity; it should NOT be performed routinely in all poisoned patients (Vale, 1997).

7) CONTRAINDICATIONS:

a) Loss of airway protective reflexes or decreased level of consciousness if patient is not intubated, following ingestion of corrosive substances, hydrocarbons (high aspiration potential), patients at risk of hemorrhage or gastrointestinal perforation, or trivial or non-toxic ingestion.

6.5.3)

A) AIRWAY MANAGEMENT

1) INDICATIONS

a) Early intubation and mechanical ventilation are recommended in patients with significant ingestions, hypotension, QRS widening, seizures, CNS depression or dysrhythmias.
b) Thiopental should be AVOIDED for intubation, as it may increase mortality. In a retrospective study of 167 patients with chloroquine overdose, 25 developed cardiac arrest in the prehospital setting. In 7 of these patients, cardiac arrest occurred immediately after injection of thiopental to facilitate orotracheal intubation (Clemessy et al, 1996).

2) STUDY

a) Riou et al (1988b) reported that 10 of 11 patients who ingested more than 5 grams of chloroquine and were treated with intubation, mechanical ventilation, diazepam and epinephrine survived compared to 1 of 51 retrospective controls who ingested comparable dosages (Riou et al, 1988).

B) MONITORING OF PATIENT

1) Chloroquine concentrations are not readily available or useful to guide therapy.
2) Monitor vital signs and mental status.
3) Obtain an ECG and institute continuous cardiac monitoring in all patients.
4) Monitor serum electrolytes, particularly potassium, renal function, and glucose.
5) Consider head CT and lumbar puncture to rule out intracranial mass, bleeding, or infection.
6) CPK should be obtained if the patient has had psychomotor agitation or seizure activity.

C) EPINEPHRINE

1) INDICATIONS

a) Epinephrine is indicated in patients with dysrhythmias, QRS widening, hypotension or circulatory collapse; consider if more than 5 grams ingested by history in an adult.

2) DOSE

a) Begin infusion at 0.25 micrograms/kilogram/minute; titrate to maintain systolic blood pressure greater than 100 mmHg (Riou et al, 1988).

3) STUDIES

D) DIAZEPAM

1) INDICATIONS

a) Diazepam is indicated in patients with seizures, dysrhythmias, QRS widening, hypotension or circulatory collapse; consider if more than 5 grams ingested by history in an adult.

2) DOSE

a) LOADING DOSE: 2 milligrams/kilogram as an infusion over 30 minutes (Riou et al, 1988).
b) MAINTENANCE DOSE: Further administration of diazepam depends on effects and amount ingested. If cardiotoxic effects are present or if the amount ingested is greater than 5 grams in an adult or 30 milligrams/kilogram in a child, a continuous infusion of diazepam may be given at a dose of 1 to 2 milligrams/kilogram/day or more as needed over a period of 2 to 4 days (Riou et al, 1988). Recurrence of cardiac toxicity may respond to additional intravenous injections.

3) STUDIES

a) HUMAN: Riou et al (1988b) reported that 10 of 11 patients who ingested more than 5 grams of chloroquine and were treated with intubation, mechanical ventilation, diazepam and epinephrine survived compared to 1 of 51 retrospective controls who ingested comparable dosages (Riou et al, 1988).
b) CASE REPORT/HYDROXYCHLOROQUINE: A 24-year-old man ingested 12 grams of hydroxychloroquine in a suicide attempt and developed hypotension with sinus tachycardia and respiratory depression and symptoms were successfully reversed with diazepam 80 milligrams (1 milligram/kilogram) and supportive therapy with isoproterenol (Pruchnicki et al, 1996).
c) ANIMAL: Diazepam decreased the mortality rate in experimental chloroquine poisoning in rats (Crouzette et al, 1983) and toxicity associated with sublethal dose of chloroquine in pigs (Riou et al, 1988b).
d) ANIMAL: Koudogbo et al (1986) administered 330 milligrams chloroquine orally per kilogram body weight to rats (Koudogbo et al, 1986). Three hours later, a group of these rats then were given 20 milligrams diazepam per kilogram body weight intraperitoneally. Significantly less chloroquine was bound to myocardial tissue in the group which received the diazepam.

1) The authors propose that diazepam actually causes a release of chloroquine from myocardial binding sites. The dose of diazepam used was very high, and extrapolated directly to a 70-kilogram human would require a dose of 1400 milligrams diazepam.

e) ANIMAL: Riou et al (1988b) found that administration of diazepam to chloroquine-intoxicated pigs improved cardiovascular status by increasing heart rate and both systolic and diastolic blood pressure (Riou et al, 1988b).

4) MECHANISM

a) Diazepam may exert an antagonist action against chloroquine cardiotoxicity (Barriot et al, 1986; Bondurand et al, 1980; Bouvier et al, 1986; Charbonneau et al, 1986; Crouzette et al, 1983; Havens et al, 1988; Hoang et al, 1982; Riou et al, 1986; Riou et al, 1988b) McKenzie, 1996).
b) The role of diazepam in chloroquine poisoning has long been under study. Diazepam apparently competes for cardiac chloroquine fixation sites (Charbonneau et al, 1986; Rajah, 1990).

E) HYPOTENSIVE EPISODE

1) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and place in Trendelenburg position. If hypotension persists, administer epinephrine, isoproterenol, dopamine and/or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.
2) EPINEPHRINE

a) Begin infusion at 0.25 micrograms/kilogram/minute; titrate to maintain systolic blood pressure greater than 100 mmHg (Riou et al, 1988).

3) DOPAMINE

a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).

4) NOREPINEPHRINE

a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
b) DOSE

1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).

5) Isoproterenol has been reported to be effective in the treatment of shock due to drugs with quinidine-like effects (Jaeger et al, 1981; O'Keeffe et al, 1979).
6) ISOPROTERENOL INDICATIONS

a) Used for temporary control of hemodynamically significant bradycardia in a patient with a pulse; generally other modalities (atropine, dopamine, epinephrine, dobutamine, pacing) should be used first because of the tendency to develop ischemia and dysrhythmias with isoproterenol (Neumar et al, 2010).
b) ADULT DOSE: Infuse 2 micrograms per minute, gradually titrating to 10 micrograms per minute as needed to desired response (Neumar et al, 2010).
c) CAUTION: Decrease infusion rate or discontinue infusion if ventricular dysrhythmias develop(Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
d) PEDIATRIC DOSE: Not well studied. Initial infusion of 0.1 mcg/kg/min titrated as needed, usual range is 0.1 mcg/kg/min to 1 mcg/kg/min (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).

7) AMRINONE

a) CASE REPORT: A 17-year-old who had ingested 8 grams chloroquine presented in cardiac arrest. Cardiogenic shock was refractory to epinephrine, dopamine, and sodium lactate.
b) Amrinone was then administered as follows: a bolus dose of 75 milligrams was given over 5 minutes, followed by a continuous infusion at a rate of 16.6 micrograms/kilogram/minute. Within 20 minutes, arterial blood pressure and heart rate significantly increased and improvement in cardiac wall motility was seen on echocardiogram.
c) After stabilization, the patient received hemoperfusion and was weaned from inotropic drugs by the fourth day with no subsequent cardiovascular sequelae (Hantson et al, 1991).

F) TACHYCARDIA

1) Tachycardia may occur from the development of agitation or hypotension. Treat the underlying cause.

G) VENTRICULAR ARRHYTHMIA

1) QRS widening or ventricular tachycardia may respond to sodium bicarbonate. Serum alkalinization may be effective in the treatment of conduction disturbances due to quinidine-like drugs. A reasonable starting dose is 1 to 2 mEq/kg bolus, repeated as needed. Endpoints include resolution of dysrhythmias, narrowing of QRS complex, and a blood pH of 7.45 to 7.55. Epinephrine and high dose diazepam are indicated in patients with dysrhythmias, QRS widening, hypotension, or circulatory collapse. After endotracheal intubation, high dose diazepam at 2 mg/kg given over 30 minutes, along with epinephrine 0.25 mcg/kg/min, titrating to effect, has been shown to ameliorate quinidine-like cardiotoxicity in severely chloroquine-poisoned patients. Electrolytes should be optimized. Use lidocaine if sodium bicarbonate and epinephrine are not successful.
2) CONTRAINDICATIONS: Quinidine, disopyramide, and procainamide are contraindicated as their effects on myocardial conduction are similar to that of chloroquine and related agents.
3) LIDOCAINE

a) LIDOCAINE/DOSE

1) ADULT: 1 to 1.5 milligrams/kilogram via intravenous push. For refractory VT/VF an additional bolus of 0.5 to 0.75 milligram/kilogram can be given at 5 to 10 minute intervals to a maximum dose of 3 milligrams/kilogram (Neumar et al, 2010). Only bolus therapy is recommended during cardiac arrest.

a) Once circulation has been restored begin a maintenance infusion of 1 to 4 milligrams per minute. If dysrhythmias recur during infusion repeat 0.5 milligram/kilogram bolus and increase the infusion rate incrementally (maximal infusion rate is 4 milligrams/minute) (Neumar et al, 2010).

2) CHILD: 1 milligram/kilogram initial bolus IV/IO; followed by a continuous infusion of 20 to 50 micrograms/kilogram/minute (de Caen et al, 2015).

b) LIDOCAINE/MAJOR ADVERSE REACTIONS

1) Paresthesias; muscle twitching; confusion; slurred speech; seizures; respiratory depression or arrest; bradycardia; coma. May cause significant AV block or worsen pre-existing block. Prophylactic pacemaker may be required in the face of bifascicular, second degree, or third degree heart block (Prod Info Lidocaine HCl intravenous injection solution, 2006; Neumar et al, 2010).

c) LIDOCAINE/MONITORING PARAMETERS

1) Monitor ECG continuously; plasma concentrations as indicated (Prod Info Lidocaine HCl intravenous injection solution, 2006).

H) FAT EMULSION

1) Intravenous lipid emulsion (ILE) has been effective in reversing severe cardiovascular toxicity from local anesthetic overdose in animal studies and human case reports. Several animal studies and human case reports have also evaluated the use of ILE for patients following exposure to other drugs. Although the results of these studies are mixed, there is increasing evidence that it can rapidly reverse cardiovascular toxicity and improve mental function for a wide variety of lipid soluble drugs. It may be reasonable to consider ILE in patients with severe symptoms who are failing standard resuscitative measures (Lavonas et al, 2015).
2) The American College of Medical Toxicology has issued the following guidelines for lipid resuscitation therapy (LRT) in the management of overdose in cases involving a highly lipid soluble xenobiotic where the patient is hemodynamically unstable, unresponsive to standard resuscitation measures (ie, fluid replacement, inotropes and pressors). The decision to use LRT is based on the judgement of the treating physician. When possible, it is recommended these therapies be administered with the consultation of a medical toxicologist (American College of Medical Toxicology, 2016; American College of Medical Toxicology, 2011):

a) Initial intravenous bolus of 1.5 mL/kg 20% lipid emulsion (eg, Intralipid) over 2 to 3 minutes. Asystolic patients or patients with pulseless electrical activity may have a repeat dose, if there is no response to the initial bolus.
b) Follow with an intravenous infusion of 0.25 mL/kg/min of 20% lipid emulsion (eg, Intralipid). Evaluate the patient's response after 3 minutes at this infusion rate. The infusion rate may be decreased to 0.025 mL/kg/min (ie, 1/10 the initial rate) in patients with a significant response. This recommendation has been proposed because of possible adverse effects from very high cumulative rates of lipid infusion. Monitor blood pressure, heart rate, and other hemodynamic parameters every 15 minutes during the infusion.
c) If there is an initial response to the bolus followed by the re-emergence of hemodynamic instability during the lowest-dose infusion, the infusion rate may be increased back to 0.25 mL/kg/min or, in severe cases, the bolus could be repeated. A maximum dose of 10 mL/kg has been recommended by some sources.
d) Where possible, LRT should be terminated after 1 hour or less, if the patient's clinical status permits. In cases where the patient's stability is dependent on continued lipid infusion, longer treatment may be appropriate.

3) CASE REPORT: A 24-year-old man was unresponsive, hypotensive, and developed ventricular fibrillation after suspected ingestion of several medications, including 58 250-mg chloroquine tablets, 20 7.5-mg midazolam, 5 10-mg domperidone tablets, and 10 4-mg ondansetron tablets. Resuscitation was initiated in the field and continued for an hour because of difficulty removing him from his apartment. On arrival to the emergency department, pulseless electrical activity was noted. Initial therapy included decontamination with activated charcoal, administration of albumin 5%, and initiation of intravenous lipid emulsion 20% with a bolus dose of 1.5 mL/kg followed by a continuous infusion of 0.25 mL/kg/min. Shortly thereafter he developed a shockable rhythm. The patient was successfully cardioverted and his blood pressure normalized; however, an arterial blood sample showed inadequate oxygenation with 100% oxygen administration. Despite continued supportive measures, including veno-arterial extracorporeal membrane oxygenation, and gradual stabilization of his hemodynamic status, the patient was declared brain dead approximately 5 days post-ingestion (Haesendonck et al, 2012).

I) TORSADES DE POINTES

1) SUMMARY

a) Withdraw the causative agent. Hemodynamically unstable patients with Torsades de pointes (TdP) require electrical cardioversion. Emergent treatment with magnesium (first-line agent) or atrial overdrive pacing is indicated. Detect and correct underlying electrolyte abnormalities (ie, hypomagnesemia, hypokalemia, hypocalcemia). Correct hypoxia, if present (Drew et al, 2010; Neumar et al, 2010; Keren et al, 1981; Smith & Gallagher, 1980).
b) Polymorphic VT associated with acquired long QT syndrome may be treated with IV magnesium. Overdrive pacing or isoproterenol may be successful in terminating TdP, particularly when accompanied by bradycardia or if TdP appears to be precipitated by pauses in rhythm (Neumar et al, 2010). In patients with polymorphic VT with a normal QT interval, magnesium is unlikely to be effective (Link et al, 2015).

2) MAGNESIUM SULFATE

a) Magnesium is recommended (first-line agent) for the prevention and treatment of drug-induced torsades de pointes (TdP) even if the serum magnesium concentration is normal. QTc intervals greater than 500 milliseconds after a potential drug overdose may correlate with the development of TdP (Charlton et al, 2010; Drew et al, 2010). ADULT DOSE: No clearly established guidelines exist; an optimal dosing regimen has not been established. Administer 1 to 2 grams diluted in 10 milliliters D5W IV/IO over 15 minutes (Neumar et al, 2010). Followed if needed by a second 2 gram bolus and an infusion of 0.5 to 1 gram (4 to 8 mEq) per hour in patients not responding to the initial bolus or with recurrence of dysrhythmias (American Heart Association, 2005; Perticone et al, 1997). Rate of infusion may be increased if dysrhythmias recur. For persistent refractory dysrhythmias, a continuous infusion of up to 3 to 10 milligrams/minute in adults may be given (Charlton et al, 2010).
b) PEDIATRIC DOSE: 25 to 50 milligrams/kilogram diluted to 10 milligrams/milliliter for intravenous infusion over 5 to 15 minutes up to 2 g (Charlton et al, 2010).
c) PRECAUTIONS: Use with caution in patients with renal insufficiency.
d) MAJOR ADVERSE EFFECTS: High doses may cause hypotension, respiratory depression, and CNS toxicity (Neumar et al, 2010). Toxicity may be observed at magnesium levels of 3.5 to 4.0 mEq/L or greater (Charlton et al, 2010).
e) MONITORING PARAMETERS: Monitor heart rate and rhythm, blood pressure, respiratory rate, motor strength, deep tendon reflexes, serum magnesium, phosphorus, and calcium concentrations (Prod Info magnesium sulfate heptahydrate IV, IM injection, solution, 2009).

3) OVERDRIVE PACING

a) Institute electrical overdrive pacing at a rate of 130 to 150 beats per minute, and decrease as tolerated. Rates of 100 to 120 beats per minute may terminate torsades (American Heart Association, 2005). Pacing can be used to suppress self-limited runs of TdP that may progress to unstable or refractory TdP, or for override refractory, persistent TdP before the potential development of ventricular fibrillation (Charlton et al, 2010). In a case series overdrive pacing was successful in terminating TdP associated with bradycardia and drug-induced QT prolongation (Neumar et al, 2010).

4) POTASSIUM REPLETION

a) Potassium supplementation, even if serum potassium is normal, has been recommended by many experts (Charlton et al, 2010; American Heart Association, 2005). Supplementation to supratherapeutic potassium concentrations of 4.5 to 5 mmol/L has been suggested, although there is little evidence to determine the optimal range in dysrhythmia (Drew et al, 2010; Charlton et al, 2010).

5) ISOPROTERENOL

a) Isoproterenol has been successful in aborting torsades de pointes that was resistant to magnesium therapy in a patient in whom transvenous overdrive pacing was not an option (Charlton et al, 2010) and has been successfully used to treat torsades de pointes associated with bradycardia and drug induced QT prolongation (Keren et al, 1981; Neumar et al, 2010). Isoproterenol may have a limited role in pharmacologic overdrive pacing in select patients with drug-induced torsades de pointes and acquired long QT syndrome (Charlton et al, 2010; Neumar et al, 2010). Isoproterenol should be avoided in patients with polymorphic VT associated with familial long QT syndrome (Neumar et al, 2010).
b) DOSE: ADULT: 2 to 10 micrograms/minute via a continuous monitored intravenous infusion; titrate to heart rate and rhythm response (Neumar et al, 2010).
c) PRECAUTIONS: Correct hypovolemia before using; contraindicated in patients with acute cardiac ischemia (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).

1) Contraindicated in patients with preexisting dysrhythmias; tachycardia or heart block due to digitalis toxicity; ventricular dysrhythmias that require inotropic therapy; and angina. Use with caution in patients with coronary insufficiency (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).

d) MAJOR ADVERSE EFFECTS: Tachycardia, cardiac dysrhythmias, palpitations, hypotension or hypertension, nervousness, headache, dizziness, and dyspnea (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
e) MONITORING PARAMETERS: Monitor heart rate and rhythm, blood pressure, respirations and central venous pressure to guide volume replacement (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).

6) OTHER DRUGS

a) Mexiletine, verapamil, propranolol, and labetalol have also been used to treat TdP, but results have been inconsistent (Khan & Gowda, 2004).

7) AVOID

a) Avoid class Ia antidysrhythmics (eg, quinidine, disopyramide, procainamide, aprindine), class Ic (eg, flecainide, encainide, propafenone) and most class III antidysrhythmics (eg, N-acetylprocainamide, sotalol) since they may further prolong the QT interval and have been associated with TdP.

J) PSYCHOMOTOR AGITATION

1) INDICATION

a) If patient is severely agitated, sedate with IV benzodiazepines.

2) DIAZEPAM DOSE

a) ADULT: 5 to 10 mg IV initially, repeat every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
b) CHILD: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).

3) LORAZEPAM DOSE

a) ADULT: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed (Manno, 2003).
b) CHILD: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).

4) Extremely large doses of benzodiazepines may be required in patients with severe intoxication in order to obtain adequate sedation. Titrate dose to clinical response and monitor for hypotension, CNS and respiratory depression, and the need for endotracheal intubation.

K) HYPOKALEMIA

1) Initial hypokalemia should be corrected cautiously because potassium and quinidine-like drugs have a synergistic cardiotoxic effect, and intensive administration of potassium may lead to a sudden hyperkalemia (Megarbane et al, 2005; Jaeger et al, 1987a; Lofaso et al, 1987).
2) Administer potassium continuously with frequent monitoring of serum potassium levels. Add 50 milliequivalents potassium chloride to 500 milliliters D5W and do not exceed infusion of more than 10 to 15 milliequivalents potassium chloride per hour.

L) SEIZURE

1) Diazepam is the initial drug of choice for the treatment of seizures. At the doses used for the treatment of chloroquine cardiotoxicity seizures may not be controlled and other anticonvulsant drugs may be necessary.
2) SUMMARY

a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).

3) DIAZEPAM

a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .

4) NO INTRAVENOUS ACCESS

a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).

5) LORAZEPAM

a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2010; Chin et al, 2008).

6) PHENOBARBITAL

a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).

7) OTHER AGENTS

a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):

1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).

8) RECURRING SEIZURES

a) If seizures are not controlled by the above measures, patients will require endotracheal intubation, mechanical ventilation, continuous EEG monitoring, a continuous infusion of an anticonvulsant, and may require neuromuscular paralysis and vasopressor support. Consider continuous infusions of the following agents:

1) MIDAZOLAM: ADULT DOSE: An initial dose of 0.2 mg/kg slow bolus, at an infusion rate of 2 mg/minute; maintenance doses of 0.05 to 2 mg/kg/hour continuous infusion dosing, titrated to EEG (Brophy et al, 2012). PEDIATRIC DOSE: 0.1 to 0.3 mg/kg followed by a continuous infusion starting at 1 mcg/kg/minute, titrated upwards every 5 minutes as needed (Loddenkemper & Goodkin, 2011).
2) PROPOFOL: ADULT DOSE: Start at 20 mcg/kg/min with 1 to 2 mg/kg loading dose; maintenance doses of 30 to 200 mcg/kg/minute continuous infusion dosing, titrated to EEG; caution with high doses greater than 80 mcg/kg/minute in adults for extended periods of time (ie, longer than 48 hours) (Brophy et al, 2012); PEDIATRIC DOSE: IV loading dose of up to 2 mg/kg; maintenance doses of 2 to 5 mg/kg/hour may be used in older adolescents; avoid doses of 5 mg/kg/hour over prolonged periods because of propofol infusion syndrome (Loddenkemper & Goodkin, 2011); caution with high doses greater than 65 mcg/kg/min in children for extended periods of time; contraindicated in small children (Brophy et al, 2012).
3) PENTOBARBITAL: ADULT DOSE: A loading dose of 5 to 15 mg/kg at an infusion rate of 50 mg/minute or lower; may administer additional 5 to 10 mg/kg. Maintenance dose of 0.5 to 5 mg/kg/hour continuous infusion dosing, titrated to EEG (Brophy et al, 2012). PEDIATRIC DOSE: A loading dose of 3 to 15 mg/kg followed by a maintenance dose of 1 to 5 mg/kg/hour (Loddenkemper & Goodkin, 2011).
4) THIOPENTAL: ADULT DOSE: 2 to 7 mg/kg, at an infusion rate of 50 mg/minute or lower. Maintenance dose of 0.5 to 5 mg/kg/hour continuous infusing dosing, titrated to EEG (Brophy et al, 2012)

b) Endotracheal intubation, mechanical ventilation, and vasopressors will be required (Brophy et al, 2012) and consultation with a neurologist is strongly advised.
c) Neuromuscular paralysis (eg, rocuronium bromide, a short-acting nondepolarizing agent) may be required to avoid hyperthermia, severe acidosis, and rhabdomyolysis. If rhabdomyolysis is possible, avoid succinylcholine chloride, because of the risk of hyperkalemic-induced cardiac dysrhythmias. Continuous EEG monitoring is mandatory if neuromuscular paralysis is used (Manno, 2003).

M) METHEMOGLOBINEMIA

1) SUMMARY

a) Determine the methemoglobin concentration and evaluate the patient for clinical effects of methemoglobinemia (ie, dyspnea, headache, fatigue, CNS depression, tachycardia, metabolic acidosis). Treat patients with symptomatic methemoglobinemia with methylene blue (this usually occurs at methemoglobin concentrations above 20% to 30%, but may occur at lower methemoglobin concentrations in patients with anemia, or underlying pulmonary or cardiovascular disorders). Administer oxygen while preparing for methylene blue therapy.

2) METHYLENE BLUE

a) INITIAL DOSE/ADULT OR CHILD: 1 mg/kg IV over 5 to 30 minutes; a repeat dose of up to 1 mg/kg may be given 1 hour after the first dose if methemoglobin levels remain greater than 30% or if signs and symptoms persist. NOTE: Methylene blue is available as follows: 50 mg/10 mL (5 mg/mL or 0.5% solution) single-dose ampules (Prod Info PROVAYBLUE(TM) intravenous injection, 2016) and 10 mg/1 mL (1% solution) vials (Prod Info methylene blue 1% intravenous injection, 2011). REPEAT DOSES: Additional doses may be required, especially for substances with prolonged absorption, slow elimination, or those that form metabolites that produce methemoglobin. NOTE: Large doses of methylene blue may cause methemoglobinemia or hemolysis (Howland, 2006). Improvement is usually noted shortly after administration if diagnosis is correct. Consider other diagnoses or treatment options if no improvement has been observed after several doses. If intravenous access cannot be established, methylene blue may also be given by intraosseous infusion. Methylene blue should not be given by subcutaneous or intrathecal injection (Prod Info methylene blue 1% intravenous injection, 2011; Herman et al, 1999). NEONATES: DOSE: 0.3 to 1 mg/kg (Hjelt et al, 1995).
b) CONTRAINDICATIONS: G-6-PD deficiency (methylene blue may cause hemolysis), known hypersensitivity to methylene blue, methemoglobin reductase deficiency (Shepherd & Keyes, 2004)
c) FAILURE: Failure of methylene blue therapy suggests: inadequate dose of methylene blue, inadequate decontamination, NADPH dependent methemoglobin reductase deficiency, hemoglobin M disease, sulfhemoglobinemia, or G-6-PD deficiency. Methylene blue is reduced by methemoglobin reductase and nicotinamide adenosine dinucleotide phosphate (NADPH) to leukomethylene blue. This in turn reduces methemoglobin. Red blood cells of patients with G-6-PD deficiency do not produce enough NADPH to convert methylene blue to leukomethylene blue (do Nascimento et al, 2008).
d) DRUG INTERACTION: Concomitant use of methylene blue with serotonergic drugs, including serotonin reuptake inhibitors (SRIs), selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), norepinephrine-dopamine reuptake inhibitors (NDRIs), triptans, and ergot alkaloids may increase the risk of potentially fatal serotonin syndrome (U.S. Food and Drug Administration, 2011; Stanford et al, 2010; Prod Info methylene blue 1% IV injection, 2011).

3) TOLUIDINE BLUE OR TOLONIUM CHLORIDE (GERMANY)

a) DOSE: 2 to 4 mg/kg intravenously over 5 minutes. Dose may be repeated in 30 minutes (Nemec, 2011; Lindenmann et al, 2006; Kiese et al, 1972).
b) SIDE EFFECTS: Hypotension with rapid intravenous administration. Vomiting, diarrhea, excessive sweating, hypotension, dysrhythmias, hemolysis, agranulocytosis and acute renal insufficiency after overdose (Dunipace et al, 1992; Hix & Wilson, 1987; Winek et al, 1969; Teunis et al, 1970; Marquez & Todd, 1959).
c) CONTRAINDICATIONS: G-6-PD deficiency; may cause hemolysis.

N) HYPOTHERMIA

1) Hypothermia can result from cardiovascular collapse in severe cases of poisoning. Treatment is external and internal rewarming if necessary, and aggressive resuscitation.

O) HEMOLYSIS

1) Hemolysis may be treated with hydration and blood transfusion if needed. Monitor for and treat hyperkalemia and renal failure. Hydrate well with intravenous fluids.

Enhanced Elimination

1) SUMMARY

a) Chloroquine is well adsorbed by charcoal. However chloroquine has a large volume of distribution and is rapidly distributed intracellularly; therefore the amount removed by hemoperfusion is not large.

2) CASE REPORTS

a) In a case reported, only 5% of the amount ingested was removed by 6 hours of hemoperfusion (Heath et al, 1982).
b) LACK OF EFFECT: A 52-year-old woman ingested a calculated total of 8.4 g of chloroquine (whole blood concentration at admission was 57.5 mcmol/L), and was started on hemoperfusion 3.5 hours after ingestion following hemodynamic and respiratory stabilization. Hemoperfusion was maintained for 5.5 hours (column was changed after 2.5 hours), but the total amount of chloroquine removed by hemoperfusion was only 480 mg (5.3% of the total ingested). The authors concluded that hemoperfusion was NOT effective following severe poisoning even if therapy was begun shortly after intoxication (Boereboom et al, 2000).

1) Peritoneal dialysis and hemodialysis are of little value in removing drug from the body. Animal studies found that hemodialysis removed less than 5 percent of administered chloroquine, probably due to chloroquine being rapidly distributed intracellularly (Van Stone, 1976).
2) In human overdoses, hemodialysis and peritoneal dialysis proved to be ineffective (Jaeger et al, 1987a) due to extensive chloroquine binding in tissue (McKenzie, 1996).
3) Dialysis may be considered if the patient presents early and chloroquine is likely to be in blood. However, failure may still occur because chloroquine rapidly becomes intracellular after administration (Rajah, 1990).

1) Elimination of chloroquine in urine is more dependent on the hemodynamic status than on the infusion of osmotic solutions. The low amount of chloroquine eliminated in urine does not justify forced diuresis (Jaeger et al, 1987a).

1) Two episodes of plasmapheresis were done within a 12-hour period in a patient who was thought to have ingested 12 grams of hydroxychloroquine (HCQ). HCQ levels were not altered during the first episode and dropped from 3 milligrams/liter to 2.1 milligrams/liter after the second. Because only 20 to 30 milligrams of the 12 grams ingested were removed, and the clinical condition was not significantly changed, plasmapheresis does NOT appear to be of benefit (Villalobos, 1991).

1) Repeated doses of oral activated charcoal had no effect on the rate of elimination of chloroquine after subcutaneous administration in rats (Laine et al, 1992).

Abstracts

Case Reports

1) CHLOROQUINE: A previously healthy 20-year-old woman ingested approximately 9 g of chloroquine. On admission to the emergency department, ECG revealed a ventricular tachycardia and no demonstrable cardiac output. Resuscitation restored sinus rhythm; however, systolic blood pressure was 80 mmHg. Serum potassium level at 2.5 hours post-admission was 1.6 mmol/L. Serum chloroquine levels was determined to be 11.5 mg/L.

a) Therapy consisted of mechanical ventilation, activated charcoal, and intravenous diazepam, potassium, and magnesium sulfate. Over the next 12 hours her systolic blood pressure dropped and her central venous pressure was 25 mmHg. Multiple generalized seizures ensued over the next 12 hours, which appeared to be resistant to phenytoin and an IV infusion of clonazepam. The patient experienced multiple episodes of ventricular tachycardia and fibrillation, and expired due to intractable hypotension, refractory to epinephrine.
b) Autopsy results revealed cardiomegaly and early centrilobular hepatic necrosis. No other drugs were revealed on toxicological serum testing (Henderson et al, 1994).

2) HYDROXYCHLOROQUINE: A 30-year-old woman developed hypotension and hypokalemia after ingesting an unknown amount of hydroxychloroquine. She recovered uneventfully after treatment with diazepam, dopamine, and crystalloid infusion (Palatnick et al, 1997).

Range Of Toxicity

Therapeutic Dose

7.2.1)

A) SPECIFIC SUBSTANCE

1) CHLOROQUINE

a) SUMMARY: The dosage of chloroquine phosphate is often expressed in terms of equivalent chloroquine base. Each 500 mg tablet of chloroquine phosphate contains the equivalent of 300 mg chloroquine base (Prod Info ARALEN(R) oral tablets, 2013).
b) MALARIA: Suppression: The usual recommended dose is 500 mg (= 300 mg base) per week, administered on the same day of each week (Prod Info ARALEN(R) oral tablets, 2013).

1) Suppressive therapy should begin 2 weeks before and continue for 8 weeks after last exposure to endemic area. If therapy cannot begin 2 weeks before exposure, the initial loading dose may be doubled to 1000 mg (=600 mg base), administered in 2 divided doses, each dose given 6 hours apart (Prod Info ARALEN(R) oral tablets, 2013).

c) MALARIA: Treatment of acute attacks: The usual recommended initial dose is 1 g (= 600 mg base) orally followed by an additional 500 mg (= 300 mg base) after six to eight hours and a single dose of 500 mg (= 300 mg base) on each of two consecutive days. This is equivalent to a total dose of 2.5 g chloroquine phosphate or 1.5 g base in three days (Prod Info ARALEN(R) oral tablets, 2013).
d) PLASMODIUM INFECTIONS/INTRAVENOUS INFUSION: Slow intravenous infusion of chloroquine was used therapeutically in 5 adult males with Plasmodium infections. Dosage was 15 milligrams/kilogram over four hours. Further doses of 5 milligrams/kilogram were given at 12, 24, 36, and 60 hours. No adverse effects or significant blood pressure changes were noted in any of the patients (Edwards et al, 1987).
e) EXTRAINTESTINAL AMEBIASIS: In combination with an effective intestinal amebicide, the usual recommended dose is 1 g (=600 mg base) administered orally daily for 2 days, followed by 500 mg (=300 mg base) administered orally once daily for at least 2 to 3 weeks (Prod Info ARALEN(R) oral tablets, 2013).

2) HYDROXYCHLOROQUINE

a) SUMMARY: One tablet of 200 mg hydroxychloroquine sulfate is equivalent to 155 mg hydroxychloroquine base (Prod Info PLAQUENIL(R) oral tablets, 2009).
b) MALARIA: Suppression: The usual recommended dose is 400 mg (=310 mg base) orally per week, administered on the same day of each week (Prod Info PLAQUENIL(R) oral tablets, 2009)

1) In general, suppressive therapy should begin 2 weeks prior to exposure; however, If therapy cannot begin 2 weeks before exposure, the initial dose may be doubled to 800 mg (=620 mg base), administered in two divided doses, each dose given 6 hours apart. Suppressive therapy should continue for 8 weeks after leaving the endemic area (Prod Info PLAQUENIL(R) oral tablets, 2009).

c) MALARIA: Treatment of acute attacks: The usual recommended initial dose is 800 mg (=620 mg base) orally followed by an additional 400 mg (= 310 mg base) after six to eight hours and a single dose of 400 mg (= 310 mg base) on each of two consecutive days. This is equivalent to a total dose of 2 g hydroxychloroquine sulfate or 1.55 g base in three days (Prod Info PLAQUENIL(R) oral tablets, 2009).

1) An alternative dosing regimen is oral administration of a single 800 mg dose (=620 mg base) (Prod Info PLAQUENIL(R) oral tablets, 2009).

d) LUPUS ERYTHEMATOSUS: The recommended initial dose is 400 mg (=310 mg base) administered orally once or twice daily over a period of several weeks or months. For prolonged maintenance therapy, the recommended dose is 200 to 400 mg (=155 to 310 mg base) administered orally once daily (Prod Info PLAQUENIL(R) oral tablets, 2009).
e) RHEUMATOID ARTHRITIS: The usual recommended initial dose is 400 to 600 mg (=310 to 465 mg base) administered orally once daily for 4 to 12 weeks. For maintenance therapy, the usual recommended dose is 200 to 400 mg (=155 to 310 mg base) administered orally once daily (Prod Info PLAQUENIL(R) oral tablets, 2009).

7.2.2)

A) SPECIFIC SUBSTANCE

1) CHLOROQUINE

a) MALARIA: Suppression: 5 mg base/kg/dose to be given weekly, up to 300 mg base/dose. Therapy should begin 2 weeks prior to exposure and continue for 8 weeks after leaving the endemic area (Prod Info ARALEN(R) oral tablets, 2013).

1) If therapy cannot begin 2 weeks before exposure, the initial loading dose may be doubled to 10 mg base/kg, administered in 2 divided doses, each dose given 6 hours apart (Prod Info ARALEN(R) oral tablets, 2013).

b) MALARIA: Treatment of acute attacks: 10 mg base/kg/dose orally, up to 600 mg base/dose, for one dose, followed by 5 mg base/kg/dose (not to exceed 300 mg base/dose) 6 hours, 24 hours, and 36 hours after the first dose (for a total of 4 doses) (Prod Info ARALEN(R) oral tablets, 2013)

2) HYDROXYCHLOROQUINE

a) MALARIA: Suppression: 5 mg base/kg/dose to be given weekly, up to 310 mg base/dose. Therapy should begin 2 weeks prior to exposure and continue for 8 weeks after leaving the endemic area (Prod Info PLAQUENIL(R) oral tablets, 2009).

b) MALARIA: Treatment of acute attacks: 10 mg base/kg/dose orally, up to 620 mg base/dose, for one dose, followed by 5 mg base/kg/dose (not to exceed 310 mg base/dose) 6 hours, 18 hours, and 24 hours after the first dose (for a total of 4 doses) (Prod Info PLAQUENIL(R) oral tablets, 2009).

Minimum Lethal Exposure

1) CHLOROQUINE has a low margin of safety. As low as 2.25 to 3 grams absorbed orally has been reported in the literature to be fatal in an adult. The most commonly reported lethal dose for adults is 3 to 4 grams (Guillion & LeBonniec, 1982).
2) A lethal dose in man is estimated at 30 to 50 milligrams/kilogram chloroquine base (Frisk-Holmberg et al, 1983; Britton & Kevau, 1978)
3) MORTALITY RATES were not significantly higher in patients who ingested greater than 5 grams of chloroquine (9.3%) in a retrospective study of 167 chloroquine poisonings; overall mortality was 8.4% (Clemessy et al, 1996).
4) In children 2 to 3 times the therapeutic dose has been reported to be fatal within 2.5 hours (Cann & Verhulst, 1961). Fatal doses in children have been reported as low as 500 milligrams(Smith & Klein-Schwartz, 2005).

1) INFANT

a) A 12-month-old was apneic with occasional gasping respirations, a pulse of 20, and no obtainable blood pressure on arrival to a health care facility 30 minutes after ingestion of one tablet of Aralen (chloroquine base 300 milligrams and primaquine base 45 milligrams) and sucking or licking the coating off 12 other tablets. She was resuscitated and given supportive care until a repeat brainstem audio-evoked response, EEG, and neurologic examination were consistent with brain death on the second hospital day (Kelly et al, 1990). The serum chloroquine concentration was 4.4 milligrams/liter.

2) PEDIATRIC

a) A fatal intoxication occurred in a 3-year-old boy who ingested 300 milligrams (Clyde, 1966).
b) In a similar case, a 3-year-old ingested 750 to 1000 milligrams and died (Cann & Verhulst, 1961).
c) Two other pediatric fatalities occurred, one within 2.5 hours of a 1 gram ingestion in a 3-year-old, and within 2 hours in a 14-month-old who ingested 1 to 2 grams (Markowitz & McGinley, 1964).
d) In a review of pediatric chloroquine exposures, death or cardiovascular collapse with permanent neurologic sequelae were reported in infants and toddlers after doses ranging from 300 mg to 4 grams (27 mg/kg to 286 mg/kg)(Smith & Klein-Schwartz, 2005).

3) ADULT

a) A fatal outcome occurred in a 42-year-old man after an intravenous injection of 250 milligrams chloroquine (Abu-Aisha et al, 1979).
b) A 24-year-old man was unresponsive, hypotensive, and developed ventricular fibrillation after suspected ingestion of several medications, including 58 250-mg chloroquine tablets, 20 7.5-mg midazolam, 5 10-mg domperidone tablets, and 10 4-mg ondansetron tablets. Resuscitation was initiated in the field, and on arrival to the emergency department, pulseless electrical activity was noted. Initial therapy included decontamination with activated charcoal, administration of albumin 5%, and initiation of intravenous lipid emulsion 20%. The patient was successfully cardioverted and his blood pressure normalized; however, an arterial blood sample showed inadequate oxygenation with 100% oxygen administration. Despite continued supportive measures, including veno-arterial extracorporeal membrane oxygenation, and gradual stabilization of his hemodynamic status, the patient was declared brain dead approximately 5 days post-ingestion (Haesendonck et al, 2012).

Maximum Tolerated Exposure

1) A neurotoxic-GI syndrome has been described in Japan and other countries. It has been seen mostly with halogenated hydroxyquinolines like iodochlorhydroxyquin (ICH). At doses of less than 750 milligrams/day of ICH there was little risk. In doses of 750 to 1500 milligrams/day for under 14 days, the risk is less than 1 percent. If this dose is taken for more than 2 weeks the risks increase to 35 percent. As little as 1800 milligrams/day for 5 days may precipitate symptoms of peripheral neuropathy or myelopathy, dysesthesia or optic atrophy and death (Oakley, 1973).

1) CHLOROQUINE

a) Chloroquine toxicity is dose dependent. The following has been observed in adults (Vitris & Aubert, 1983; Reddy & Sinna, 2000):

1) Dose ingested greater than 4 grams - neurological, cardiovascular and ECG disturbances, serum chloroquine level greater than 5 milligrams/liter at the 4th hour.
2) Dose ingested 2 to 4 grams - neurological symptoms and ECG abnormalities, serum chloroquine level of 2.5 to 5 milligrams/liter.
3) Dose ingested less than 2 grams - no clinical symptoms, serum chloroquine level less than 2.5 milligrams/liter.
4) However, in a 13-year-old boy, ventricular fibrillation occurred after ingestion of 600 to 750 milligrams of chloroquine base, resulting in a plasma concentration of 1.6 milligrams/liter (Collee et al, 1992).

b) CASE REPORT: A 25-year-old woman ingested a presumed 10 g chloroquine and had a plasma level of 39 mcmol/L (presumed lethal level is thought to be above 25 mcmol/L). Manifestations included coma, hypotension, wide QRS complexes, first degree AV block and hypokalemia. The patient recovered completely following aggressive, supportive care and was transferred within 72 hours for further psychiatric care. The authors suggested that early medical treatment resulted in the patient's positive outcome (Messant et al, 2004).

2) HYDROXYCHLOROQUINE

a) CASE REPORT: A 17-year-old girl with a history of rheumatoid arthritis, ingested 22 g of hydroxychloroquine (a serum level was not available) and developed significant cardiac toxicity within several hours of exposure. Symptoms included hypotension (54/23 mmHg on admission), prolonged QT interval (600 ms), and monomorphic pulseless VT, which occurred approximately 6 hours after ingestion and resolved with defibrillation. Following supportive care, the patient remained stable and was discharged within several days with no permanent sequelae (Yanturali et al, 2004).
b) CASE REPORT: A 24-year-old man ingested 12 g hydroxychloroquine in a suicide attempt and developed hypotension with sinus tachycardia and a widened QRS (0.160 sec) and respiratory depression (Pruchnicki et al, 1996). The patient was successfully treated with isoproterenol and diazepam 80 mg (1 mg/kg). No permanent sequelae was reported.
c) CASE REPORT: A 29-year-old developed vomiting and ventricular tachycardia after ingesting 4 grams, but survived(Marquardt & Albertson, 2001).
d) CASE REPORT: A 49-year-old man developed hypotension, bradycardia, metabolic acidosis, QTc interval prolongation, and coma after intentionally ingesting 8 grams of hydroxychloroquine. Following supportive care, the patient made a complete recovery (Ling Ngan Wong et al, 2008).

Serum Plasma Blood Concentrations

7.5.1)

A) THERAPEUTIC CONCENTRATION LEVELS

1) GENERAL

a) Therapeutic plasma levels for chloroquine and other 4-aminoquinolines have been reported following 500 mg (300 mg base)/week doses and range from 20 to 40 mcg/L to 150 to 250 mcg/L.

7.5.2)

A) TOXIC CONCENTRATION LEVELS

1) CHLOROQUINE

a) In one retrospective review of 167 patients, it was determined that although mortality could NOT be correlated with amount ingested, mortality rate did correlate with blood chloroquine concentrations (Clemessy et al, 1996). In another review of 91 cases of chloroquine poisoning, no patient survived in whom blood concentrations were greater than 7.997 mg/L (25 mcmol/L) (Riou et al, 1988).
b) The occurrence of side effects in patients under chloroquine therapy is related to chloroquine serum levels. No side effects occurred in patients with serum levels less than 0.4 mg/L whereas 80% of the patients with a level higher than 0.8 mg/L had side effects (Frisk-Holmberg et al, 1979).
c) The following findings have been observed in association with chloroquine ingestion:

1) Dose ingested greater than 4 g: Neurological, cardiovascular and ECG disturbances, serum chloroquine level greater than 5 mg/L at the 4th hour (Vitris & Aubert, 1983).
2) Dose ingested 2 to 4 g: Neurological symptoms and ECG abnormalities, serum chloroquine level of 2.5 to 5 mg/L (Vitris & Aubert, 1983).
3) Patients ingesting more than 5 g of chloroquine and combined treatment with epinephrine, rapid intubation, and diazepam begun at home survived with blood chloroquine concentrations ranging from 40 to 80 mcmol/L (Riou et al, 1988).
4) However, in a 13-year-old boy, ventricular fibrillation occurred after ingestion of 600 to 750 mg of chloroquine base, resulting in a plasma concentration of 1.6 mg/L (Collee et al, 1992).

d) CASE REPORTS

1) A 37-year-old woman who presented to a clinic with nausea, restlessness, and agitation. She lost consciousness 20 minutes after presentation and experienced 2 episodes of cardiac arrest. A toxic chloroquine blood level of 71.9 mcmol/L was detected the day after presentation. With aggressive treatment her cardiac dysrhythmias were stabilized, but her prognosis was poor with persistent neurologic effects (ie, Glasgow coma score 3) and an elevated chloroquine level of 50 mcmol/L at 96 hours. She developed hospital acquired pneumonia and died 10 days after admission; postmortem chloroquine level was 50 mcmol/L (Phipps et al, 2011).
2) Despite severe intoxication, a 52-year-old woman recovered from a total calculated ingestion of 8.4 g chloroquine with an initial whole blood concentration of 57.5 mcmol/L (Boereboom et al, 2000).
3) A 20-year-old woman who ingested 6 g chloroquine and developed severe toxicity had a blood chloroquine level of 36 mcg/mL (112 mcmol/L) on admission (Bauer et al, 1991). Similar plasma concentrations were reported in a 14-year-old who died 9 hours after ingesting 50 chloroquine tablets. Postmortem analyses indicated the brain had the highest concentration of drug (Muhm et al, 1996).
4) POST MORTEM LEVELS in 2 cases were 18.7 and 0.28 mg/dL in blood (Obafunwa et al, 1994).

2) HYDROXYCHLOROQUINE

a) CASE REPORT: A blood hydroxychloroquine level of 35.2 mcmol/L was observed in a 19-year-old woman with severe hypokalemia after ingesting 6 g of hydroxychloroquine. Following supportive therapy, she recovered completely without further sequelae (Megarbane et al, 2005).

Summary

Pharmacology Toxicology

Pharmacologic Mechanism

General Bibliography

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CHLOROQUINE AND RELATED DRUGS

Classification | Detailed evidence-based information

Therapeutic Toxic Class

Specific Substances

Available Forms Sources

Life Support

Clinical Effects

Laboratory Monitoring

Treatment Overview

Range Of Toxicity

Summary Of Exposure

Vital Signs

Heent

Cardiovascular

Respiratory

Neurologic

Gastrointestinal

Hepatic

Genitourinary

Acid-Base

Hematologic

Dermatologic

Musculoskeletal

Endocrine

Reproductive

Monitoring Parameters Levels

Radiographic Studies

Methods

Life Support

Patient Disposition

Monitoring

Oral Exposure

Enhanced Elimination

Case Reports

Therapeutic Dose

Minimum Lethal Exposure

Maximum Tolerated Exposure

Serum Plasma Blood Concentrations

Summary

Pharmacologic Mechanism

Toxicologic Mechanism

General Bibliography