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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 rheumatoid arthritis. Drugs in this class include chloroquine phosphate (Aralen), amodiaquine hydrochloride (Camoquin), hydroxychloroquine sulfate (Plaquenil), mefloquine (Lariam), primaquine phosphate, and quinacrine hydrochloride (Atabrine). Chloroquine overdose is common, especially in countries where malaria is prevalent, and the mortality rate is 10–30%. Quinine toxicity is described in Quinine.

  1. Mechanism of toxicity

    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 [Vd] = 150–250 L/kg) and are eliminated very slowly from the body. The terminal half-life of chloroquine is 2 months, and that of hydroxychloroquine is 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–61).

  2. Toxic dose. The therapeutic dose of chloroquine phosphate is 500 mg once a week for malaria prophylaxis or 2.5 g over 2 days for 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.

  3. Clinical presentation

    1. Mild to moderate chloroquine overdose results in dizziness, nausea and vomiting, abdominal pain, headache and visual 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 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 (See Methemoglobinemia) or hemolysis; chronic treatment can cause ototoxicity and retinopathy.

    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.

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

    1. Specific levels. Chloroquine is usually not detected on comprehensive toxicology screening. Quantitative levels can be measured in blood but ...

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