Toxicity of chloroquine and hydroxychloroquine following therapeutic use or overdose. 2021

Cassandra Doyno, and Diana M Sobieraj, and William L Baker
Department of Pharmacy Practice, University of Connecticut School of Pharmacy, Storrs, CT, USA.

While chloroquine, a derivative of quinine, has been used as an antimalarial for 70 years, hydroxychloroquine is now used to treat conditions such as rheumatoid arthritis and systemic lupus erythematosus. In 2020, hydroxychloroquine (and to a lesser extent chloroquine) also received attention as a possible treatment for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). During investigation for treating coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2, concerns for serious adverse events arose. We review the toxicity associated with hydroxychloroquine and chloroquine use both short-term and long-term and in overdose. Medline (via OVID) was searched from its inception through June 7 2020 using the following as either MeSH or keyword terms: ("Chloroquine/" or "Hydroxychloroquine/") AND ("Adverse Drug Event/" or "Toxicities, Drug/" or "Toxic.mp." or "Toxicity.mp." or "Overdose.mp."). We limited resultant articles to those published in English and reporting on Human subjects. This search yielded 330 articles, of which 57 were included. Articles were excluded due to lack of relevance, not reporting desired outcomes, or being duplicative in their content. Twenty-five additional articles were identified through screening references of included articles. To identify toxicities in individuals treated with hydroxychloroquine or chloroquine with COVID-19, we searched PubMed on June 10th, 2020: ("Chloroquine" or "Hydroxychloroquine") AND ("Coronavirus" or "COVID-19" or "SARS-CoV-2"). This search resulted in 638 articles. We reviewed articles for reporting of adverse events or toxicities. Most citations were excluded because they did not include original investigations or extrapolated data from subjects that did not have COVID-19; 34 citations were relevant. For the drug-interactions section, relevant classes and agents were identified through a screen of the https://www.covid19-druginteractions.org/ website. We then conducted targeted searches of PubMed up to June 7th 2020 combining "chloroquine" and "hydroxychloroquine" with terms for specific drug classes and drugs identified from the drug-interaction site as potentially relevant. We found 29 relevant articles. Gastrointestinal: Gastrointestinal toxicities are the most common to occur following initiation of chloroquine or hydroxychloroquine. Nausea, vomiting, and diarrhea account for most reported intolerances. Glucose abnormalities: Alterations in blood glucose concentrations may occur with hydroxychloroquine but are rare with standard therapeutic use. Cardiotoxicity: Short-term use can produce conduction abnormalities. Evidence from COVID-19 treatment suggests QT/QTc prolongation is of concern, particularly when used in combination with azithromycin, although disagreement exists across studies. Dermatologic: Drug eruptions or rashes, followed by cutaneous hyperpigmentation, pruritis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, may occur within days to weeks of exposure but usually resolve with the discontinuation of therapy. Neuropsychiatric: Reported symptoms include confusion, disorientation, and hallucination within 24-48 h of drug initiation. Other toxicities: Hemolysis and anemia may occur in patients with glucose-6-phosphate dehydrogenase. Chloroquine treatment of COVID-19 was associated with elevation in creatine kinase and creatine kinase-MB activities with more events in the higher-dose group. Retinopathy: Retinopathy is the major dose-limiting toxicity associated with long-term use; the risk is higher with increasing age, dose, and duration of usage. Cardiotoxicity: Long-term use has been associated with conduction abnormalities, cardiomyopathy, and valvular disorders. Neurotoxicity: Rarely myositis and muscle weakness, extremity weakness, and pseudoparkinsonism have been reported. Symptoms in overdose manifest rapidly (minutes to hours) and cardiotoxicity such as cardiovascular shock and collapse are most prominent. Neurotoxic effects such as psychosis and seizure may also occur. Hydroxychloroquine is a generally well-tolerated medication. Short-term (days to weeks) toxicity includes gastrointestinal effects and rarely glucose abnormalities, dermatologic reactions, and neuropsychiatric events. Cardiotoxicity became of increased concern with its use in COVID-19 patients. Long-term (years) toxicities include retinopathy, neuromyotoxicity, and cardiotoxicity (conduction abnormalities, cardiomyopathy). Deaths from overdoses most often result from cardiovascular collapse.

UI MeSH Term Description Entries
D011605 Psychoses, Substance-Induced Psychotic organic mental disorders resulting from the toxic effect of drugs and chemicals or other harmful substance. Psychoses, Drug,Psychoses, Toxic,Substance-Induced Psychoses,Toxic Psychoses,Drug Psychoses,Psychoses, Substance Induced,Substance Induced Psychoses
D012164 Retinal Diseases Diseases involving the RETINA. Disease, Retinal,Diseases, Retinal,Retinal Disease
D001786 Blood Glucose Glucose in blood. Blood Sugar,Glucose, Blood,Sugar, Blood
D002738 Chloroquine The prototypical antimalarial agent with a mechanism that is not well understood. It has also been used to treat rheumatoid arthritis, systemic lupus erythematosus, and in the systemic therapy of amebic liver abscesses. Aralen,Arechine,Arequin,Chingamin,Chlorochin,Chloroquine Sulfate,Chloroquine Sulphate,Khingamin,Nivaquine,Sulfate, Chloroquine,Sulphate, Chloroquine
D005767 Gastrointestinal Diseases Diseases in any segment of the GASTROINTESTINAL TRACT from ESOPHAGUS to RECTUM. Cholera Infantum,Gastrointestinal Disorders,Functional Gastrointestinal Disorders,Gastrointestinal Disorders, Functional,Disease, Gastrointestinal,Diseases, Gastrointestinal,Functional Gastrointestinal Disorder,Gastrointestinal Disease,Gastrointestinal Disorder,Gastrointestinal Disorder, Functional
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D006886 Hydroxychloroquine A chemotherapeutic agent that acts against erythrocytic forms of malarial parasites. Hydroxychloroquine appears to concentrate in food vacuoles of affected protozoa. It inhibits plasmodial heme polymerase. (From Gilman et al., Goodman and Gilman's The Pharmacological Basis of Therapeutics, 9th ed, p970) Hydroxychlorochin,Oxychlorochin,Oxychloroquine,Hydroxychloroquine Sulfate,Hydroxychloroquine Sulfate (1:1) Salt,Plaquenil
D000086402 SARS-CoV-2 A species of BETACORONAVIRUS causing atypical respiratory disease (COVID-19) in humans. The organism was first identified in 2019 in Wuhan, China. The natural host is the Chinese intermediate horseshoe bat, RHINOLOPHUS affinis. 2019 Novel Coronavirus,COVID-19 Virus,COVID19 Virus,Coronavirus Disease 2019 Virus,SARS Coronavirus 2,SARS-CoV-2 Virus,Severe Acute Respiratory Syndrome Coronavirus 2,Wuhan Coronavirus,Wuhan Seafood Market Pneumonia Virus,2019-nCoV,2019 Novel Coronaviruses,COVID 19 Virus,COVID-19 Viruses,COVID19 Viruses,Coronavirus 2, SARS,Coronavirus, 2019 Novel,Coronavirus, Wuhan,Novel Coronavirus, 2019,SARS CoV 2 Virus,SARS-CoV-2 Viruses,Virus, COVID-19,Virus, COVID19,Virus, SARS-CoV-2,Viruses, COVID19
D000093485 COVID-19 Drug Treatment The use of DRUGS to treat COVID19 or its symptoms. COVID-19 Drug Therapy,COVID19 Drug Therapy,COVID19 Drug Treatment,Coronavirus Disease 2019 Drug Treatment,Coronavirus Disease-19 Drug Treatment,COVID 19 Drug Therapy,COVID 19 Drug Treatment,COVID-19 Drug Therapies,COVID19 Drug Therapies,COVID19 Drug Treatments,Coronavirus Disease 19 Drug Treatment,Drug Therapy, COVID-19,Drug Therapy, COVID19,Therapy, COVID-19 Drug,Therapy, COVID19 Drug,Treatment, COVID-19 Drug
D012871 Skin Diseases Diseases involving the DERMIS or EPIDERMIS. Dermatoses,Skin and Subcutaneous Tissue Disorders,Dermatosis,Skin Disease

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