Lipid emulsion treatment as an antidote for chloroquine and hydroxychloroquine toxicity

Chloroquine and hydroxychloroquine, which have anti-malarial and anti-inflammatory effects, are used for treating malaria, rheumatoid arthritis, and systemic lupus erythematosus [ ]. These drugs are quinine derivatives having similar cellular mechanisms behind their toxicities [ ]. Because a toxic dose of chloroquine, which is a Vaughan–Williams Class IA antiarrhythmic, inhibits cardiac sodium, potassium, and calcium channels, it induces QT prolongation, QRS widening, and atrioventricular blockade, leading to hypotension and shock [ ]. In addition, acute toxicity of chloroquine and hydroxychloroquine results in other side effects including nausea, vomiting, sensorineural hearing loss, seizure, respiratory depression, aplastic anemia, agranulocytosis, hepatitis, visual disturbance, corneal opacity, tinnitus, and hypokalemia [ ]. We have read the review article titled “Acute chloroquine and hydroxychloroquine toxicity: A review for emergency clinicians,” recently published in The American Journal of Emergency Medicine, with great interest [ ]. Della Porta et al. described lipid emulsion treatment as a novel treatment modality for the toxicity induced by chloroquine and hydroxychloroquine [ ]. Intralipid, an emulsion with 100% long-chain fatty acids, was initially introduced for parenteral nutrition in 1961. However, SMOFlipid, which comprises 30% soybean oil, 30% medium-chain triglyceride, 25% olive oil, and 15% fish oil, is widely used for parenteral nutrition because a high concentration of n-6 fatty acids such as linoleic acid contained in Intralipid increases inflammatory reactions and lipid peroxidation [ ]. Currently, Intralipid is mainly used for the treatment of cardiovascular collapse induced by the toxicity of local anesthetics, including bupivacaine [ ]. Lipofundin MLC/LCT comprising 50% long-chain triglyceride and 50% medium-chain triglyceride, and SMOFlipid are sometimes used for treating local anesthetic-induced systemic toxicity [ ]. Reportedly, lipid emulsion is effective in alleviating cardiovascular collapse induced by non-local anesthetic drugs with high lipid solubility (log [octanol/water partition coefficient] >2) [ ]. In addition, lipid emulsion has been reported to be effective in treating cardiovascular depression induced by the toxicity of chloroquine and hydroxychloroquine [ , , ]. Recently, it was observed that chloroquine and hydroxychloroquine, which were used as alternative drugs for the treatment of coronavirus disease 2019, were able to inhibit the severe acute respiratory syndrome coronavirus 2 in laboratory experiments [ ]. However, clinical trials found that chloroquine and hydroxychloroquine induced cardiac toxicity due to the inhibition of cardiac sodium and potassium channels, leading to dangerous ventricular arrhythmia, conduction blockade, and myocardial depression [ ]. The widely accepted underlying mechanism of lipid emulsion treatment as a nonspecific antidote is the lipid shuttle [ ]. The lipid shuttle mechanism states that lipid emulsion absorbs highly lipid-soluble drugs (for example, bupivacaine; log [octanol/water partition coefficient]: 3.41), and lipid emulsions containing lipid-soluble drugs are subsequently transported to the liver and adipose tissue, leading to enhanced redistribution [ , ]. In terms of responsiveness to lipid emulsion treatment as an antidote, the following pharmacologic characteristics of chloroquine and hydroxychloroquine may contribute to a positive response. First, the lipid solubility (log [octanol/water partition coefficient]) of chloroquine and hydroxychloroquine is 4.63 and 3.6, respectively, indicating that they are highly lipid soluble, similar to bupivacaine [ , ]. Second, similar to the inhibition of cardiac sodium and potassium channels induced by toxic doses of bupivacaine, the toxicity of chloroquine and hydroxychloroquine inhibits cardiac sodium and potassium channels, which leads to ventricular arrhythmia and cardiac depression [ , , ]. In addition, the lipid emulsion itself has a positive inotropic effect [ ]. Lipofundin MCT/LCT and Intralipid attenuated the cardiac sodium channel inhibition induced by bupivacaine [ ]. Linolenic acid (18:3n-3) and stearic acid, which are long-chain fatty acids in Intralipid, attenuated sodium channel blockade induced by bupivacaine in HEK-293 cells expressing cardiac sodium channels [ ]. Third, lipid emulsions attenuate bupivacaine-induced cardiotoxicity by inhibiting oxidative stress caused by bupivacaine [ ]. Furthermore, lipid emulsion attenuates doxorubicin-induced cardiotoxicity by inhibitingrun reactive oxygen species [ ]. Similar to bupivacaine, the toxicity of chloroquine was found to increase reactive oxygen species in a rat model of pressure overload hypertrophy and the glial cells of the inner ear, leading to oxidative stress [ , ]. Fourth, it was reported that the magnitude of drug concentration reduction induced by lipid emulsion was mainly dependent on the lipid solubility constant and partial volume of distribution [ ]. Chloroquine and hydroxychloroquine have a large volume of distribution of more than 100 L/kg [ ]. Thus, this high volume of distribution may contribute to a greater reduction in the plasma concentration of chloroquine and hydroxychloroquine by lipid emulsion. These pharmacologic characteristics may contribute to alleviating cardiovascular depression induced by toxic doses of chloroquine and hydroxychloroquine. However, further research is needed to examine the effect of lipid emulsion on the toxicity induced by chloroquine and hydroxychloroquine. Thus, lipid emulsion may be considered for treating cardiovascular depression caused by toxic doses of chloroquine and hydroxychloroquine, which is not responsive to supportive treatment including vasopressor, diazepam, fluid, sodium bicarbonate, and mechanical ventilation.