Chloroquine (formerly Aralen®) and its close relative Hydroxychloroquine (Plaquenil®) are in the news as potential treatments for COVID-19. Individuals are obtaining supplies of these drugs from both pharmaceutical and non-pharmaceutical sources, intending to use them either as prophylaxis and/or as treatment for COVID-19.
These drugs are quite toxic in overdose and poison centers across the country have much experience with them. There has already been one death reported from accidental overdose in a person who was self-treating with chloroquine phosphate marketed as an aquarium product. Approximately 1 teaspoonful of chloroquine phosphate powder was ingested.
This special alert DOES NOT address the potential efficacy and safety of these drugs against COVID-19. Instead, it reviews their known toxicology.
Chloroquine was developed as a substitute for natural quinine found in the bark of Cinchona trees. As the name implies, hydroxychloroquine has a similar structure with an added β-hydroxylated side chain. It is reportedly 40% less toxic than chloroquine in animal studies.
Hydroxychloroquine and chloroquine have been used for decades to treat malaria, but widespread resistance of the parasite has diminished this use. Chloroquine is now rarely prescribed.
On the other hand, hydroxychloroquine availability has continued because of its value as an immunomodulator in autoimmune diseases such as lupus and rheumatoid arthritis.
Current FDA approved indications do not include COVID-19, although off-label use of drugs by individual physicians is permitted.
MECHANSIM OF ACTION & MECHANISM OF TOXICITY
Mechanism of Therapeutic Action:
Hydroxychloroquine and chloroquine are weak bases and have similar pharmacologic effects. As antimalarials, they concentrate in acid vesicles of the parasite to increase pH and interfere with the polymerization of heme which leads to parasite death. They have also been shown to block the synthesis of DNA and RNA.
In autoimmune diseases, the drugs inhibit movement of neutrophils and eosinophils and impair complement dependent antibody response. The exact mechanism inducing this anti-inflammatory action is not understood. There are many theories regarding potential mechanisms in COVID-19 infected patients.
Mechanism of Toxicity:
The primary effect in acute overdose is cardiotoxicity. Both drugs produce a quinidine-like effect in which sodium channels are blocked as seen by widening of the QRS complex. This leads to impaired conduction and cardiac contractility, and possibly ventricular arrhythmia.
Interference with the rectifying potassium current can delay ventricular repolarization and prolong the QT interval, increasing the risk of Torsades. Risk is highest soon after ingestion during the time of high circulating drug levels, prior to distribution to the tissues.
In most cases, risk of severe CV toxicity resolves within 24 hours.
THERAPEUTIC DOSE COMPARED TO POTENTIALLY TOXIC DOSE
Chloroquine phosphate is available in 250 mg and 500 mg tablets (chloroquine base 150 mg and 300 mg). Hydroxychloroquine sulfate is available as 200 mg tablets (hydroxychloroquine base 155 mg).
CAUTION: Be certain whether the dose information you are using refers to the drug as a base or to the drug as its pharmaceutical salt.
Dosing is weekly for malaria suppression or prophylaxis. For example, adults get 500 mg of chloroquine phosphate once a week, or 400 mg of hydroxychloroquine sulfate once a week. Children get 8.3 mg/kg chloroquine phosphate (5 mg/kg as chloroquine base).
Acute malaria is treated with a short regimen of daily dosing. For example, adults get 1 gram chloroquine phosphate (600 mg chloroquine base) as the initial dose, followed by 500 mg chloroquine phosphate in 6 hours, 24 ours, and 48 hours. Children receive 16.6 mg chloroquine phosphate (10 mg/kg as chloroquine base) as an initial dose followed by 8.3 mg/kg chloroquine phosphate (5 mg/kg chloroquine base) in the same regimen as adults. Doses of hydroxychloroquine base are essentially the same.
Chronic dosing of hydroxychloroquine sulfate for lupus is 200 mg to 400 mg daily. For rheumatoid arthritis the initial dose is 400 mg to 600 mg once a day if the patient can tolerate this dose without side effects, and after remission the daily dose is reduced by half for maintenance.
Proposed regimens for hydroxychloroquine sulfate in COVID-19 vary, and include 400 mg BID on day one, then daily for 5 days; or 400 mg BID on day one, then 200mg BID for 4 days; or 600 mg BID on day one, then 400 mg daily on days 2-5 [link to CDC]. Clinical trials to assess regimens and response are ongoing.
||TYPICAL ADULT DOSE
||VOLUME OF DISTRIBUTION
||500 mg daily (short term)
||1 to 2 hr
||24 to 36 hr
||6 to 60 days (mean 20)
||200 to 800 L/kg
||200 to 400 mg daily
||N/A in chronic dosing
||N/A in chronic dosing
||32 to 50
Kinetics are noteworthy for rapid oral absorption and early time to peak blood concentration. Redistribution from the blood into the tissues occurs in the first 24 hours, which lowers the blood concentration and reduces acute toxicity. The terminal half-life is quite prolonged (3 to 6 weeks) due to tissue binding. Very large volume of distribution precludes dialysis as a removal method.
Potentially Toxic Dose:
These drugs have a narrow therapeutic range and can cause potentially fatal poisonings within hours.
In adults, ingestion of 5 grams of hydroxychloroquine sulfate (4 grams hydroxychloroquine base)
or 2.5 grams of chloroquine phosphate (1.5 grams chloroquine base) can cause life-threatening toxicity.
The fatal dose of chloroquine phosphate is estimated to be 50 to 80 mg/kg. This equates to only 7 to 12 tablets of prescription 500 mg chloroquine sulfate in a 70 kg adult.
Children seem to be very sensitive to the toxic effects both drugs. Any dose higher than a single maximum therapeutic dose is considered potentially toxic in children.
>10 mg/kg of hydroxychloroquine base (13 mg/kg of hydroxychloroquine sulfate)
>10 mg/kg of chloroquine base (16.6 mg/kg chloroquine phosphate)
A dose only 2 to 3 times the therapeutic dose may be fatal in children. This equates to only 1 or 2 prescription tablets of 500 mg chloroquine phosphate in toddlers.
SYMPTOMS OF TOXICITY
In a minor to moderate overdose, GI symptoms (nausea, vomiting, diarrhea) are typically present along with headache, agitation, visual and hearing disturbances, and neuromuscular excitability. In addition, CNS depression, seizures, and coma may develop.
Severe poisoning is dominated by depressed cardiac contractility, hypotension and slowed conduction seen as widened QRS, prolonged QT, blocks, and ventricular arrhythmias. Hypokalemia is typical and results from intracellular trapping of potassium inside cells. A triad of hypotension, hypokalemia, and QRS prolongation is very suspicious for chloroquine or hydroxychloroquine overdose.
MANAGEMENT OF TOXICITY
There is no antidote for hydroxychloroquine or chloroquine overdose; treatment is symptomatic and supportive care. Development of full-blown toxicity is rapid, with sudden cardiovascular collapse.
- Be prepared for early intubation and mechanical ventilation after significant ingestion because deterioration occurs suddenly.
- Provide aggressive supportive care including hemodynamic support with epinephrine for hypotension or circulatory collapse and ACLS management of dysrhythmias and QRS widening.
- Monitor electrolytes (especially potassium) closely every 4 hours during the first 24 hours in symptomatic patients. Replace electrolytes according to lab results; and maintain potassium in low to normal range. Serum potassium rebounds as toxicity resolves and an over-correction can result in hyperkalemia.
- High-dose diazepam (2 mg/kg IV over 30 minutes) has been suggested to modify cardiac toxicity and improve survival for dysrhythmias, QRS widening, hypotension, or circulatory collapse. If diazepam in not available in large quantity, other benzodiazepines in equivalently high doses can be used.
- Consider prophylactic administration in any adult with history of ingestion of 5 grams or more of hydroxychloroquine or chloroquine.
- Follow loading dose with the same dose of diazepam except spread out over 24 hours.
- There are three reported cases of successful use of lipid emulsion when used early for hydroxychloroquine overdose. Extracorporeal life support (VA ECMO) may be considered if available.
Patients suspected of ingestion should be observed for 6 hours post ingestion to monitor for development of toxic symptoms.
If you have any questions about the management of chloroquine/hydroxychloroquine overdose, please feel free to call the Missouri Poison Center at 1-800-222-1222. Our specially trained nurses, pharmacists, and toxicologist can provide the most up-to-date information regarding exposures and treatment.