Chloroquine and other aminoquinolines are used in the prophylaxis of or therapy for malaria and other parasitic diseases. Chloroquine and hydroxychloroquine also are used in the treatment of autoimmune diseases including rheumatoid arthritis. Antimalarial and related drugs include chloroquine phosphate, amodiaquine hydrochloride, hydroxychloroquine sulfate, mefloquine, primaquine phosphate, and quinacrine hydrochloride. Chloroquine overdose is common, especially in countries where malaria is prevalent, and the mortality rate is 10-30%. Quinine toxicity is described.

1. Chloroquine blocks the synthesis of DNA and RNA and also has some quinidine-like cardiotoxicity. Hydroxychloroquine has similar actions but is considerably less potent.
2. Primaquine and quinacrine are oxidizing agents and can cause methemoglobinemia or hemolytic anemia (especially in patients with glucose-6-phosphate dehydrogenase [G6PD] deficiency).
3. Pharmacokinetics. Chloroquine and related drugs are highly tissue-bound (volume of distribution 150-250 L/kg) and are eliminated very slowly from the body. The half-life of chloroquine and hydroxychloroquine are variable and long at 75-278 hours and 15.5-31 hours, respectively. But the terminal half-life of chloroquine maybe as long as 2 months, and that of hydroxychloroquine may be as long as 40 days. Primaquine, with a half-life of 3-8 hours, is extensively metabolized to an active metabolite that is eliminated much more slowly (half-life of 22-30 hours) and can accumulate with chronic dosing (see also Table II-63).

The therapeutic dose of chloroquine phosphate is 500 mg once a week for malaria prophylaxis or 2.5 g over 2 days for the treatment of malaria. Deaths have been reported in children after ingesting one or two tablets—doses as low as 300 mg; the lethal dose of chloroquine for an adult is estimated at 30-50 mg/kg.

1. Mild-to-moderate chloroquine overdose results in dizziness, nausea and vomiting, abdominal pain, headache and visual/retinal disturbances (sometimes including irreversible blindness), auditory disturbances (sometimes leading to deafness), agitation, and neuromuscular excitability. The use of chloroquine and proguanil in combination is common and is associated with GI and neuropsychiatric side effects, including acute psychosis.
2. Severe chloroquine overdose may cause convulsions, coma, shock, and respiratory or cardiac arrest. Quinidine-like severe cardiotoxicity may be seen, including sinoatrial arrest, depressed myocardial contractility, QRS- and/or QT-interval prolongation, heart block, and ventricular arrhythmias. Severe hypokalemia can occur with either chloroquine or hydroxychloroquine and may contribute to arrhythmias.
3. Primaquine and quinacrine intoxication commonly causes GI upset and may also cause severe methemoglobinemia or hemolysis (in patients with G6PD deficiency); chronic treatment can cause ototoxicity and retinopathy. Cardiovascular toxicity is not associated with primaquine.
4. Amodiaquine in therapeutic doses has caused severe and even fatal neutropenia.
5. Mefloquine in therapeutic use or overdose may cause headache, dizziness, vertigo, insomnia, visual and auditory hallucinations, panic attacks, severe depression, psychosis, confusion, and seizures. Neuropsychiatric side effects generally resolve within a few days after withdrawal of mefloquine and with supportive pharmacotherapy, but occasionally symptoms persist for several weeks.

The findings of gastritis, visual disturbances, and neuromuscular excitability, especially if accompanied by hypokalemia, hypotension, QRS- or QT-interval widening, or ventricular arrhythmias, should suggest chloroquine overdose. Hemolysis or methemoglobinemia suggests primaquine or quinacrine overdose.

1. Specific levels. Chloroquine is usually not detected on comprehensive toxicology screening. Quantitative levels can be measured in blood but are not generally available. Because chloroquine is concentrated intracellularly, whole-blood measurements are fivefold higher than serum or plasma levels.
   1. Plasma (trough) concentrations of 10-20 ng/mL (0.01-0.02 mg/L) are effective in the treatment of various types of malaria.
   2. Cardiotoxicity may be seen with serum levels of 1 mg/L (1,000 ng/mL); serum levels reported in fatal cases have ranged from 1 to 210 mg/L (average, 60 mg/L).
2. Other useful laboratory studies include electrolytes (particularly potassium levels), glucose, BUN, creatinine, creatine kinase, cardiac troponin, ECG, and ECG monitoring. With primaquine or quinacrine, also include CBC, free plasma hemoglobin, and methemoglobin.

1. Emergency and supportive measures
   1. Maintain an open airway and assist ventilation if necessary.
   2. Treat seizures, coma, hypotension, hypokalemia, and methemoglobinemia if they occur.
   3. Treat massive hemolysis with blood transfusions if needed and prevent hemoglobin deposition in the kidney tubules with intravenous fluids (as for rhabdomyolysis).
   4. Continuously monitor the ECG for at least 6-8 hours or until ECG normalizes.
2. Specific drugs and antidotes
   1. Treat cardiotoxicity as for quinidine poisoning with sodium bicarbonate, 1-2 mEq/kg IV.
   2. Potassium should be administered for severe hypokalemia but should be dosed with caution and with frequent serum potassium measurements, as hyperkalemia may exacerbate quinidine-like cardiotoxicity.
   3. If dopamine and norepinephrine are not effective, epinephrine infusion may be useful in treating hypotension via combined vasoconstrictor and inotropic actions. Dosing recommendations in one study were 0.25 mcg/kg/min, increased by increments of 0.25 mcg/kg/min until adequate blood pressure was obtained, along with administration of high-dose diazepam (see below) and mechanical ventilation.
   4. High-dose benzodiazepines such as diazepam (2 mg/kg) IV given over 30 minutes after endotracheal intubation and mechanical ventilation has been reported to reduce mortality in animals and to relieve cardiotoxicity in human chloroquine poisonings. The mechanism of action is unknown.
3. Decontamination. Administer activated charcoal orally if conditions are appropriate (see Table I-37). Perform gastric lavage for significant ingestions (eg, >30-50 mg/kg).
4. Enhanced elimination. Because of extensive tissue distribution, enhanced removal procedures are ineffective.