Hydroxychloroquine
Clinical data | |
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Trade names | Plaquenil, others |
Other names | HCQ |
AHFS/Drugs.com | Monograph |
MedlinePlus | a601240 |
License data | |
Pregnancy category |
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Routes of administration | By mouth (tablets) |
ATC code | |
Legal status | |
Legal status | |
Pharmacokinetic data | |
Bioavailability | Variable (74% on average) |
Protein binding | 45% |
Metabolism | Liver |
Elimination half-life | 32–50 days |
Excretion | Mostly kidney (23–25% as unchanged drug), also biliary (<10%) |
Identifiers | |
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JSmol) | |
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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]
Common side effects may include
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
Medical uses
Hydroxychloroquine treats rheumatic disorders such as
It is widely used to treat primary
Contraindications
The US FDA drug label advises that hydroxychloroquine should not be prescribed to individuals with known
Adverse effects
Hydroxychloroquine has a narrow therapeutic index, meaning there is little difference between toxic and therapeutic doses.
For short-term treatment of acute malaria, adverse effects can include abdominal cramps, diarrhea, heart problems, reduced appetite, headache, nausea and vomiting.[3] Other adverse effects noted with short-term use of Hydroxychloroquine include low blood sugar and QT interval prolongation.[19] Idiosyncratic hypersensitivity reactions have occurred.[11]
For prolonged treatment of lupus or rheumatoid arthritis, adverse effects include the acute symptoms, plus altered eye pigmentation, acne, anemia, bleaching of hair, blisters in mouth and eyes, blood disorders, cardiomyopathy,[19] convulsions, vision difficulties, diminished reflexes, emotional changes, excessive coloring of the skin, hearing loss, hives, itching, liver problems or liver failure, loss of hair, muscle paralysis, weakness or atrophy, nightmares, psoriasis, reading difficulties, tinnitus, skin inflammation and scaling, skin rash, vertigo, weight loss, and occasionally urinary incontinence.[3] Hydroxychloroquine can worsen existing cases of both psoriasis and porphyria.[3]
Children may be especially vulnerable to developing adverse effects from hydroxychloroquine overdoses.[3]
Eyes
One of the most serious side effects is retinopathy (generally with chronic use).
Toxicity from hydroxychloroquine may be seen in two distinct areas of the eye: the cornea and the macula. The cornea may become affected (relatively commonly) by an innocuous cornea verticillata or vortex keratopathy and is characterized by whorl-like corneal epithelial deposits. These changes bear no relationship to dosage and are usually reversible on cessation of hydroxychloroquine.
The macular changes are potentially serious. Advanced retinopathy is characterized by reduction of visual acuity and a "bull's eye" macular lesion which is absent in early involvement.
Overdose
Overdoses of hydroxychloroquine are extremely rare, but extremely toxic.[11] Eight people are known to have overdosed since the drug's introduction in the mid-1950s, of which three have died.[23][24] Chloroquine has a risk of death in overdose in adults of about 20%, while hydroxychloroquine is estimated to be two or threefold less toxic.[25]
Serious signs and symptoms of overdose generally occur within an hour of ingestion.
Treatment recommendations include early
Detection
Hydroxychloroquine may be quantified in plasma or serum to confirm a diagnosis of poisoning in hospitalized victims or in whole blood to assist in a forensic investigation of a case of sudden or unexpected death. Plasma or serum concentrations are usually in a range of 0.1-1.6 mg/L during therapy and 6–20 mg/L in cases of clinical intoxication, while blood levels of 20–100 mg/L have been observed in deaths due to acute overdosage.[29]
Interactions
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
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]
- Digoxin (wherein it may result in increased serum digoxin levels)
- Insulin or anti-diabetic medication(wherein it may enhance the effects of a hypoglycemic treatment)
- Drugs that prolong the QT interval such as methadone, and other arrhythmogenic drugs, as hydroxychloroquine prolongs the QT interval and may increase the risk of inducing serious abnormal heart rhythms (ventricular arrhythmias) if used concurrently.[4]
- Mefloquine and other drugs known to lower the seizure threshold (co-administration with other antimalarials known to lower the convulsion threshold may increase risk of convulsions)
- Antiepileptics(concurrent use may impair the antiepileptic activity)
- Methotrexate (combined use is unstudied and may increase the frequency of side effects)
- Cyclosporin(wherein an increased plasma cyclosporin level was reported when used together).
Pharmacology
Pharmacokinetics
Hydroxychloroquine has similar
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
History
After World War I, the German government sought alternatives to
Chemical synthesis
The first synthesis of hydroxychloroquine was disclosed in a patent filed by
Manufacturing
It is frequently sold as a sulfate salt known as hydroxychloroquine sulfate.[3] In the sulfate salt form, 200 mg is equal to 155 mg of the pure form.[3]
Brand names of hydroxychloroquine include Plaquenil, Hydroquin, Axemal (in India), Dolquine, Quensyl, and Quinoric.[50]
COVID-19
Cleavage of the SARS-CoV-2 S2 spike protein required for viral entry into cells can be accomplished by proteases TMPRSS2 located on the cell membrane, or by cathepsins (primarily cathepsin L) in endolysosomes.[62] Hydroxychloroquine inhibits the action of cathepsin L in endolysosomes, but because cathepsin L cleavage is minor compared to TMPRSS2 cleavage, hydroxychloroquine does little to inhibit SARS-CoV-2 infection.[62]
Several countries initially used chloroquine or hydroxychloroquine for treatment of persons hospitalized with COVID-19 (as of March 2020), though the drug was not formally approved through clinical trials.
Their use was withdrawn as a possible treatment for COVID-19 infection when it proved to have no benefit for hospitalized patients with severe COVID-19 illness in the international Solidarity trial and UK RECOVERY Trial.[68][69] On 15 June 2020, the FDA revoked its emergency use authorization, stating that it was "no longer reasonable to believe" that the drug was effective against COVID-19 or that its benefits outweighed "known and potential risks".[70][71][72] In fall of 2020, the National Institutes of Health issued treatment guidelines recommending against the use of hydroxychloroquine for COVID-19 except as part of a clinical trial.[51]
In 2021, hydroxychloroquine was part of the recommended treatment for mild cases in India.[73]
In 2020, the speculative use of hydroxychloroquine for COVID-19 threatened its availability for people with established indications (malaria and auto-immune diseases).[55]References
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