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]
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 5million 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Among studies that deemed hydroxychloroquine intake to cause harmful side effects, a publication by The Lancet was retracted due to data flaws.[10] The speculative use of hydroxychloroquine for COVID-19 threatens its availability for people with established indications.[11]
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-Lymearthritis. 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.
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]
One of the most serious side effects is retinopathy (generally with chronic use).[3][20] People taking 400 mg of hydroxychloroquine or less per day generally have a negligible risk of
macular toxicity, whereas the risk begins to increase when a person takes the medication over five years or has a cumulative dose of more than 1000 grams. The daily safe maximum dose for eye toxicity can be estimated from a person's height and weight.[21] Macular toxicity is related to the total cumulative dose rather than the daily dose. Regular eye screening, even in the absence of visual symptoms, is recommended to begin when either of these risk factors occurs.[22]
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]
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
antibioticazithromycin 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]
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
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
hemozoinbiocrystallization, 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]
History
After World War I, the German government sought alternatives to
quinine as an anti-malarial. Chloroquine, a synthetic analogue with the same
mechanism of action was discovered in 1934, by
Hans Andersag and coworkers at the
Bayer laboratories.[45][46]: 130–131 This was introduced into clinical practice in 1947 for the prophylactic treatment of malaria.[47] Researchers subsequently attempted to discover
structural analogs with superior properties and one of these was hydroxychloroquine.[48]
Chemical synthesis
The first synthesis of hydroxychloroquine was disclosed in a patent filed by
Sterling Drug in 1949.[49] In the final step,
4,7-dichloroquinoline was reacted with a
primary amine which in turn had been made from the chloro-
ketone shown:
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]
Chloroquine and hydroxychloroquine are
anti-malarial medications also used against some
auto-immune diseases.[51] Chloroquine, along with hydroxychloroquine, was an early experimental treatment for
COVID-19.[52] Neither drug has been useful to prevent or treat SARS-CoV-2 infection.[53][54][55][56][57][58] Administration of chloroquine or hydroxychloroquine to COVID-19 patients has been associated with increased mortality and adverse effects, such as
QT prolongation.[59][60] Researchers estimate that off-label use of hydroxychloroquine in hospitals during the first phase of the pandemic caused 17,000 deaths worldwide.[61] The widespread administration of chloroquine or hydroxychloroquine, either as monotherapies or in conjunction with
azithromycin, has been associated with deleterious outcomes, including QT interval prolongation. As of 2024,[update] scientific evidence does not substantiate the efficacy of hydroxychloroquine, with or without the addition of azithromycin, in the therapeutic management of COVID-19.[59]
Cleavage of the SARS-CoV-2
S2spike protein required for viral entry into cells can be accomplished by
proteasesTMPRSS2 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.[63][64] From April to June 2020, there was an
emergency use authorization for their use in the United States,[65] and was used
off label for potential treatment of the disease.[66] On 24 April 2020, citing the risk of "serious heart rhythm problems", the FDA posted a caution against using the drug for COVID-19 "outside of the hospital setting or a clinical trial".[67]
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]
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