Hydroxychloroquine

Medical use

Hydroxychloroquine treats malaria, systemic lupus erythematosus, rheumatic disorders like rheumatoid arthritis and Sjögren's syndrome and porphyria cutanea tarda.

In 2014 its efficacy to treat Sjögren's syndrome was questioned in a double-blind study involving 120 patients over a 48-week period.

Hydroxychloroquine is widely used in the treatment of post-Lyme arthritis following Lyme disease. It may have both an anti-spirochaete activity and an anti-inflammatory activity, similar to the treatment of rheumatoid arthritis.

Adverse effects

The most common adverse effects are a mild nausea and occasional stomach cramps with mild diarrhea. The most serious adverse effects affect the eye.

For short-term treatment of acute malaria, adverse effects can include abdominal cramps, diarrhea, heart problems, reduced appetite, headache, nausea and vomiting.

For prolonged treatment of lupus or arthritis, adverse effects include the acute symptoms, plus altered eye pigmentation, acne, anemia, bleaching of hair, blisters in mouth and eyes, blood disorders, 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 incontinence. Hydroxychloroquine can worsen existing cases of both psoriasis and porphyria.

Eyes

One of the most serious side effects is a toxicity in the eye (generally with chronic use). People taking 400 mg of hydroxychloroquine or less per day generally have a negligible risk of macular toxicity, whereas the risk begins to go up when a person takes the medication over 5 years or has a cumulative dose of more than 1000 grams. The daily safe maximum dose for eye toxicity can be computed from one's height and weight using this calculator. Cumulative doses can also be calculated from this calculator. 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.

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 and are related to dosage and length of time taking hydroxychloroquine. Advanced retinopathy is characterized by reduction of visual acuity and a "bull's eye" macular lesion which is absent in early involvement.

Interactions

A type of enzyme deficiency (enzyme G6PD) found most frequently in those of African descent can develop into severe anemia and requires monitoring. Children are more sensitive to hydroxychloroquine: small doses can be potentially fatal.

The drug transfers into breast milk and should be used with care by pregnant or nursing mothers.

Hydroxychloroquine generally does not have significant interactions with other medications, but care should be taken if combined with medication altering liver function as well as aurothioglucose (Solganal), cimetidine (Tagamet) or digoxin (Lanoxin). HCQ 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 HCQ. Both neostigmine and pyridostigmine antagonize the action of hydroxychloroquine.

Overdose

Due to rapid absorption, symptoms of overdose can occur within a half an hour after ingestion. Overdose symptoms include convulsions, drowsiness, headache, heart problems or heart failure, difficulty breathing and vision problems.

Pharmacokinetics

Hydroxychloroquine has similar pharmacokinetics to chloroquine, with rapid gastrointestinal absorption and elimination by the kidneys. Cytochrome P450 enzymes (CYP2D6, 2C8, 3A4 and 3A5) metabolize hydroxychloroquine to N-desethylhydroxychloroquine.

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, resulting in concentrations within lysosomes up to 1000 times higher than in culture media. This increases the pH of the lysosome from 4 to 6. Alteration in pH causes inhibition of lysosomal acidic proteases causing a diminished proteolysis effect. Higher pH within lysosomes causes decreased intracellular processing, glycosylation and secretion of proteins with many immunologic and nonimmunologic consequences. These effects are believed to be the cause of a decreased immune cell functioning such as chemotaxis, phagocytosis and superoxide production by neutrophils. HCQ 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.

Mechanism of action

Hydroxychloroquine increases lysosomal pH in antigen-presenting cells. In inflammatory conditions, it blocks toll-like receptors on plasmacytoid dendritic cells (PDCs). Toll-like receptor 9 (TLR 9), which recognizes DNA-containing immune complexes, leads to the production of interferon and causes the dendritic cells to mature and present antigen to T cells. Hydroxychloroquine, by decreasing TLR signaling, reduces the activation of dendritic cells and the inflammatory process.

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.

As with other quinoline antimalarial drugs, the 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 their deaths.

Brand names

Brand names include Plaquenil, Axemal (in India), Dolquine and Quensyl.