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What toxic effects of chloroquine or hydroxychloroquine are of concern?

posted on 7:18 PM, April 14, 2020

For all patients, gastrointestinal symptoms of nausea and abdominal pain may accompany dosing. The most important chronic toxicity is retinal toxicity with decreased visual acuity, night vision, and peripheral field loss. However, this generally requires doses in excess of 5mg/kg daily for several years, and would thus not be of concern during short-term use. For patients on chronic therapy (months-years), significant ototoxicity is a concern. During short-term therapy, alterations in high frequency hearing threshold and/or tinnitus, as well as nystagmus and vertigo, have been described. These latter symptoms have been largely reversible upon cessation of therapy.

Cardiac conduction disturbances (bundle branch block, atrioventricular block) and cardiomyopathy with congestive heart failure have been described in patients on chronic hydroxychloroquine and chloroquine therapy. While some of these findings are confounded by the age and underlying illnesses of patients on chronic therapy, cardiac toxicity attributable to acute use of these drugs is unquestioned. QT interval prolongation with increased risk for ventricular dysrhythmia and decreased cardiac contractility and vasodilation leading to hypotension are hallmarks of acute chloroquine and hydroxychloroquine overdose, uniformly accompanied by marked hypokalemia due to intracellular potassium shifts. The risk for cardiac toxicity in therapeutic use is increased at higher doses and in the presence of significant hepatic or renal impairment that would impair drug metabolism and elimination.

Underlying cardiac disease or active alcoholism and other conditions predisposing to electrolyte abnormalities (particularly of potassium, magnesium, and calcium) are likely to increase the risk of cardiac toxicity as well. In the setting of treatment of COVID-19, the potential for viral cardiomyopathy and the large number of medications potentially interfering with hepatic metabolism are additional concerns. A pre-publication (Borba 2020) interim safety analysis of 81 hospitalized patients randomized to either chloroquine 1200 mg daily for 10 days or 900 mg loading dose followed by 450 mg daily for 4 days (both groups also receiving azithromycin and ceftriaxone, and ~90% receiving oseltamivir [QTc interval-prolonging drug]) found a trend towards increase in QTc>500msec (19% vs 11%; p=0.51) and a statistically significant increased mortality (27% overall, with 39% in higher dose group vs 15% in lower dose group; p=0.03) by day 13, with no evidence of more rapid viral clearing (by day 4). The 5 patients over age 75 were all in the high dose group; 2 of the 22 deaths were in this older age group. Two patients in the high dose group developed ventricular tachycardia. The higher dose treatment arm was stopped and the study is ongoing. Although the ages of the two groups were not matched and the number of recognized QTc interval prolongation events (ECGs were not obtained in a standardized fashion) was not statistically significant, this interim analysis highlights that caution is necessary when prescribing these medications.

 

References:

Abbasi S, Tarter L, Farzaneh-Far R, Farzaneh-Far A. Hydroxychloroquine: a treatable cause of cardiomyopathy. J Am Coll Cardiol 2012;60(8):786. doi:10.1016/j.jacc.2011.12.060.

Borba M, de Almeida Val F, Sampaio VS, Alexandre MA, Melo GC, et al. Chlorquine diphosphate in two different dosages as adjunctive therapy of hospitalized patients with swevere respiratory syndrome in the context of conronavirus (SARS-CoV-2) infection: preliminary safety results of a randomized, double-blinded, phase IIb clinical trial (CloroCovid-19 Study). medRxiv BMJ 2020 Apr11. doi: https://doi.org/10.1101/2020.04.07.20056424

Chloroquine Sulfate. In: POISINDEX Managements [U.S. Pharmacopedia]. Rockville, MD: Thomson Micromedex. [cited 2020 April 3]. 

Fernandez AP. Updated recxommendations on the use of hydroxychloroquinein dermatological practice. J Am Acad Dermatol 2017;76:1176-1182

Keating RJ, Bhatia S, Amin S, Williams A, Sinak LJ, Edwards WD. Hydroxychloroquine-induced cardiotoxicity in a 39-year-old woman with systemic lupus erythematosus and systolic dysfunction. J Am Soc Echocardiogr 2005;18(9):981. PubMed PMID: 16153529.

Subramaniam V, Vaswani R. Assessment of short term chloroquine-induced ototoxicity in malaria patients. Global J Med Res – J Dentistry Otolaryngology 2015;15(2):00-00.

Tönnesmann E, Kandolf R, Lewalter T. Chloroquine cardiomyopathy - a review of the literature. Immunopharmacol Immunotoxicol 2013;35(3):434-42. doi:10.3109/08923973.2013.780078.

Yogasundaram H, Putko BN, Tien J, Paterson DI, Cujec B, Ringrose J, Oudit GY. Hydroxychloroquine-induced cardiomyopathy: case report, pathophysiology, diagnosis, and treatment. Can J Cardiol 2014;30(12):1706-15. doi: 10.1016/j.cjca.2014.08.016.