Hydroxychloroquine
Hydroxychloroquine, sold under the brand name Plaquenil among others, is a medication used to prevent and treat malaria in areas where malaria remains sensitive to chloroquine. Other uses include treatment of rheumatoid arthritis, lupus, and porphyria cutanea tarda. It is taken by mouth, often in the form of hydroxychloroquine sulfate.[3]
"HCQ" redirects here. For other uses, see HCQ (disambiguation).Clinical data
Common side effects may include vomiting, headache, blurred vision, and muscle weakness.[3] Severe side effects may include allergic reactions, retinopathy, and irregular heart rate.[3][4] Although all risk cannot be excluded, it remains a treatment for rheumatic disease during pregnancy.[5] Hydroxychloroquine is in the antimalarial and 4-aminoquinoline families of medication.[3]
Hydroxychloroquine was approved for medical use in the United States in 1955.[3] It is on the World Health Organization's List of Essential Medicines.[6] In 2021, it was the 116th most commonly prescribed medication in the United States, with more than 5 million prescriptions.[7][8]
Hydroxychloroquine has been studied for an ability to prevent and treat coronavirus disease 2019 (COVID-19), but clinical trials found it ineffective for this purpose and a possible risk of dangerous side effects.[9] Among studies that deemed hydroxychloroquine intake to cause harmful side effects, a publication by The Lancet was retracted due to data flaws.[10] The speculative use of hydroxychloroquine for COVID-19 threatens its availability for people with established indications.[11]
Medical uses
Hydroxychloroquine treats rheumatic disorders such as systemic lupus erythematosus, rheumatoid arthritis, and porphyria cutanea tarda, and certain infections such as Q fever and certain types of malaria.[3] It is considered the first-line treatment for systemic lupus erythematosus.[12] Certain types of malaria, resistant strains, and complicated cases require different or additional medication.[3]
It is widely used to treat primary Sjögren syndrome but does not appear to be effective.[13] Hydroxychloroquine is widely used in the treatment of post-Lyme arthritis. It may have both an anti-spirochete activity and an anti-inflammatory activity, similar to the treatment of rheumatoid arthritis.[14]
Contraindications
The US FDA drug label advises that hydroxychloroquine should not be prescribed to individuals with known hypersensitivity to 4-aminoquinoline compounds.[15] There are several other contraindications,[16][17] and caution is required if the person considered for treatment has certain heart conditions, diabetes, or psoriasis.
The drug transfers into breast milk.[1] There is no evidence that its use during pregnancy is harmful to the developing fetus and its use is not contraindicated in pregnancy.[11]
The concurrent use of hydroxychloroquine and the antibiotic azithromycin appears to increase the risk for certain serious side effects with short-term use, such as an increased risk of chest pain, congestive heart failure, and mortality from cardiovascular causes.[19] Care should be taken if combined with medication altering liver function as well as aurothioglucose (Solganal), cimetidine (Tagamet) or digoxin (Lanoxin). Hydroxychloroquine can increase plasma concentrations of penicillamine which may contribute to the development of severe side effects. It enhances hypoglycemic effects of insulin and oral hypoglycemic agents. Dose altering is recommended to prevent profound hypoglycemia. Antacids may decrease the absorption of hydroxychloroquine. Both neostigmine and pyridostigmine antagonize the action of hydroxychloroquine.[30]
While there may be a link between hydroxychloroquine and hemolytic anemia in those with glucose-6-phosphate dehydrogenase deficiency, this risk may be low in those of African descent.[31]
Specifically, the US Food and Drug Administration's (FDA) drug label for hydroxychloroquine lists the following drug interactions:[15]
Pharmacology
Pharmacokinetics
Hydroxychloroquine has similar pharmacokinetics to chloroquine, with rapid gastrointestinal absorption, large distribution volume,[32] and elimination by the kidneys; Tmax is 2–4.5 hours. Cytochrome P450 enzymes (CYP2D6, 2C8, 3A4 and 3A5) metabolize hydroxychloroquine to N-desethylhydroxychloroquine.[33] Both agents also inhibit CYP2D6 activity and may interact with other medications that depend on this enzyme.[11]
Pharmacodynamics
Antimalarials are lipophilic weak bases and easily pass plasma membranes. The free base form accumulates in lysosomes (acidic cytoplasmic vesicles) and is then protonated,[34] resulting in concentrations within lysosomes up to 1,000 times higher than in culture media. This increases the pH of the lysosome from four to six.[35] Alteration in pH causes inhibition of lysosomal acidic proteases causing a diminished proteolysis effect.[36] Higher pH within lysosomes causes decreased intracellular processing, glycosylation and secretion of proteins with many immunologic and nonimmunologic consequences.[37] These effects are believed to be the cause of a decreased immune cell functioning such as chemotaxis, phagocytosis and superoxide production by neutrophils.[38] Hydroxychloroquine is a weak diprotic base that can pass through the lipid cell membrane and preferentially concentrate in acidic cytoplasmic vesicles. The higher pH of these vesicles in macrophages or other antigen-presenting cells limits the association of autoantigenic (any) peptides with class II MHC molecules in the compartment for peptide loading and/or the subsequent processing and transport of the peptide-MHC complex to the cell membrane.[39]
Mechanism of action
Hydroxychloroquine increases[40] lysosomal pH in antigen-presenting cells[19] by two mechanisms: As a weak base, it is a proton acceptor and via this chemical interaction, its accumulation in lysozymes raises the intralysosomal pH, but this mechanism does not fully account for the effect of hydroxychloroquine on pH. Additionally, in parasites that are susceptible to hydroxychloroquine, it interferes with the endocytosis and proteolysis of hemoglobin and inhibits the activity of lysosomal enzymes, thereby raising the lysosomal pH by more than 2 orders of magnitude over the weak base effect alone.[41][42] In 2003, a novel mechanism was described wherein hydroxychloroquine inhibits stimulation of the toll-like receptor (TLR) 9 family receptors. TLRs are cellular receptors for microbial products that induce inflammatory responses through activation of the innate immune system.[43]
As with other quinoline antimalarial drugs, the antimalarial mechanism of action of quinine has not been fully resolved. The most accepted model is based on hydrochloroquinine and involves the inhibition of hemozoin biocrystallization, which facilitates the aggregation of cytotoxic heme. Free cytotoxic heme accumulates in the parasites, causing death.[44]
Hydroxychloroquine increases the risk of low blood sugar through several mechanisms. These include decreased clearance of the hormone insulin from the blood, increased insulin sensitivity, and increased release of insulin from the pancreas.[11]