|Systematic (IUPAC) name|
|Pregnancy cat.||D (Au), C (U.S.)|
|Legal status||POM (UK), ℞-only (U.S.)|
|Mol. mass||335.872 g/mol|
|(what is this?)|
Hydroxychloroquine is an antimalarial drug, sold under the trade names Plaquenil, Axemal (in India), Dolquine and Quensyl, also used to reduce inflammation in the treatment of rheumatoid arthritis (see disease-modifying antirheumatic drugs) and lupus. Hydroxychloroquine differs from chloroquine by the presence of a hydroxyl group at the end of the side chain: The N-ethyl substituent is beta-hydroxylated. It is available for oral administration as hydroxychloroquine sulfate (plaquenil) of which 200 mg contains 155 mg base in chiral form. Hydroxychloroquine has similar pharmacokinetics to chloroquine, with quick gastrointestinal absorption and is eliminated by the kidney. Cytochrome P450 enzymes (CYP 2D6, 2C8, 3A4 and 3A5) N-desethylated Hydroxychloroquine to Ndesethylhydroxychloroquine.
Hydroxychloroquine has been used for many years to treat malaria. It is also used to treat systemic lupus erythematosus, rheumatic disorders like rheumatoid arthritis and Sjögren's Syndrome, and porphyria cutanea tarda. 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.
Hydroxychloroquine is also 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.
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 failure, loss of hair, muscle paralysis, weakness or atrophy, nightmares, psoriasis, reading difficulties, tinnitus, skin inflammation and scaling, skin rash, vertigo and weight loss. Hydroxychloroquine can worsen existing cases of both psoriasis and porphyria.
One of the most serious side effects is a toxicity in the eye (generally with chronic use). The daily safe maximum dose for eye toxicity can be computed from one's height and weight using this calculator. Macular toxicity is related to the total cumulative dose rather than the daily dose. 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. 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 "bulls eye" macular lesion which is absent in early involvement.
A type of enzyme deficiency (enzyme G6PD) found most frequently in those of African descent can develop into severe anemia and should also be monitored. Children are more sensitive to hydroxychloroquine than are adults, and small doses can be potentially fatal.
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). It will transfer into breast milk and should be used with care by pregnant or nursing mothers.
Symptoms of overdose can occur within a half-hour of taking the medication. Overdose symptoms include convulsions, drowsiness, headache, heart problems or heart failure, difficulty breathing and vision problems.
Mechanism of action
Antimalarials are lipophilic weak bases and easily go through 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 cyto-plasmic 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. Recently a novel mechanism has been 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, this model involves the inhibition of hemozoin biocrystallization, which facilitates the aggregation of cytotoxic heme. Free cytotoxic heme accumulates in the parasites, causing their deaths.
- Kalia, S.; Dutz, J. P. (2007). "New concepts in antimalarial use and mode of action in dermatology". Dermatologic Therapy 20 (4): 160–174. doi:10.1111/j.1529-8019.2007.00131.x. PMID 17970883.
- Waller et al. Medical pharmacology and therapeutics (2nd ed.). p. 370.
- Steere AC, Angelis SM (October 2006). "Therapy for Lyme arthritis: strategies for the treatment of antibiotic-refractory arthritis". Arthritis Rheum. 54 (10): 3079–86. doi:10.1002/art.22131. PMID 17009226.
- Flach AJ (2007). "Improving the risk-benefit relationship and informed consent for patients treated with hydroxychloroquine". Transactions of the American Ophthalmological Society 105: 191–4; discussion 195–7. PMC 2258132. PMID 18427609.
- Marmor, MF; Kellner, U, Lai, TY, Lyons, JS, Mieler, WF, American Academy of, Ophthalmology (February 2011). "Revised recommendations on screening for chloroquine and hydroxychloroquine retinopathy". Ophthalmology 118 (2): 415–22. doi:10.1016/j.ophtha.2010.11.017. PMID 21292109.
- "Hydroxychloroquine (Oral Route) - MayoClinic.com". Retrieved 2008-10-30.
- Kaufmann, A. M.; Krise, J. P. (2007). "Lysosomal sequestration of amine-containing drugs: Analysis and therapeutic implications". Journal of Pharmaceutical Sciences 96 (4): 729–746. doi:10.1002/jps.20792. PMID 17117426.
- Ohkuma, S.; Poole, B. (1978). "Fluorescence probe measurement of the intralysosomal pH in living cells and the perturbation of pH by various agents". Proceedings of the National Academy of Sciences of the United States of America 75 (7): 3327–3331. doi:10.1073/pnas.75.7.3327. PMC 392768. PMID 28524.
- Ohkuma, S.; Chudzik, J.; Poole, B. (1986). "The effects of basic substances and acidic ionophores on the digestion of exogenous and endogenous proteins in mouse peritoneal macrophages". The Journal of cell biology 102 (3): 959–966. doi:10.1083/jcb.102.3.959. PMC 2114118. PMID 3949884.
- Oda, K.; Koriyama, Y.; Yamada, E.; Ikehara, Y. (1986). "Effects of weakly basic amines on proteolytic processing and terminal glycosylation of secretory proteins in cultured rat hepatocytes". The Biochemical journal 240 (3): 739–745. PMC 1147481. PMID 3493770.
- Hurst, N. P.; French, J. K.; Gorjatschko, L.; Betts, W. H. (1988). "Chloroquine and hydroxychloroquine inhibit multiple sites in metabolic pathways leading to neutrophil superoxide release". The Journal of rheumatology 15 (1): 23–27. PMID 2832600.
- Fox, R (1996). "Anti-malarial drugs: possible mechanisms of action in autoimmune disease and prospects for drug development.". Lupus. Jun;5 Suppl 1:S4-10.: S4–10. PMID 8803903.
- Takeda, K.; Kaisho, T.; Akira, S. (2003). "Toll-Likereceptors". Annual Review of Immunology 21: 335–376. doi:10.1146/annurev.immunol.21.120601.141126. PMID 12524386.
- HealthCentral medication information on Hydroxychloroquine
- Medicinenet article on Hydroxychloroquine