Hydroxychloroquine

Hydroxychloroquine (HCQ), sold under the brand name Plaquenil among others, is a medication used for the prevention and treatment of certain types of malaria.[1] Specifically it is used for chloroquine-sensitive malaria.[2] Other uses include treatment of rheumatoid arthritis, lupus, and porphyria cutanea tarda.[1] It is taken by mouth.[1]

Hydroxychloroquine
Clinical data
Trade namesPlaquenil, others
AHFS/Drugs.comMonograph
MedlinePlusa601240
License data
Pregnancy
category
  • AU: D
  • US: C (Risk not ruled out)
    Routes of
    administration    		By mouth (tablets)
    ATC code
    Legal status
    Legal status
    • AU: S4 (Prescription only)
    • UK: POM (Prescription only)
    • US: ℞-only
    Pharmacokinetic data
    BioavailabilityVariable (74% on average); Tmax = 2–4.5 hours
    Protein binding45%
    MetabolismLiver
    Elimination half-life32–50 days
    ExcretionMostly Kidney (23–25% as unchanged drug), also biliary (<10%)
    Identifiers
    CAS Number
    PubChem CID
    IUPHAR/BPS
    DrugBank
    ChemSpider
    UNII
    KEGG
    ChEBI
    ChEMBL
    CompTox Dashboard (EPA)
    ECHA InfoCard100.003.864
    Chemical and physical data
    FormulaC18H26ClN3O
    Molar mass335.872 g/mol g·mol−1
    3D model (JSmol)
     NY (what is this?)  (verify)

    Common side effects include vomiting, headache, changes in vision and muscle weakness.[1] Severe side effects may include allergic reactions.[1] It appears to be safe in pregnancy but this use has not been well studied.[3] Hydroxychloroquine is in the antimalarial and 4-aminoquinoline families of medication.[1]

    Hydroxychloroquine was approved for medical use in the United States in 1955.[1] It is on the World Health Organization's List of Essential Medicines, the safest and most effective medicines needed in a health system.[4] The wholesale cost in the developing world is about $5.40 to 7.44 per month.[5] In the United Kingdom this dose costs the NHS about £5.15.[6] In the United States the wholesale cost of a month of treatment is about US$25 as of 2019.[7] In 2016 it was the 135th most prescribed medication in the United States with more than 4 million prescriptions.[8]

    Medical use

    Hydroxychloroquine treats malaria, systemic lupus erythematosus, rheumatic disorders like rheumatoid arthritis, porphyria cutanea tarda, and Q fever.[1]

    In 2014, its efficacy to treat Sjögren syndrome was questioned in a double-blind study involving 120 patients over a 48-week period.[9]

    Hydroxychloroquine is widely used in the treatment of post-Lyme arthritis. It may have both an anti-spirochaete activity and an anti-inflammatory activity, similar to the treatment of rheumatoid arthritis.[10]

    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, anaemia, 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 urinary incontinence. Hydroxychloroquine can worsen existing cases of both psoriasis and porphyria.

    Eyes
    Main article: Chloroquine retinopathy

    One of the most serious side effects is a toxicity in the eye (generally with chronic use).[11] 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.[12]

    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.

    Interactions

    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.[13]

    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.[14]

    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.

    Pharmacology

    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.[15]

    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,[16] 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.[17] Alteration in pH causes inhibition of lysosomal acidic proteases causing a diminished proteolysis effect.[18] Higher pH within lysosomes causes decreased intracellular processing, glycosylation and secretion of proteins with many immunologic and nonimmunologic consequences.[19] These effects are believed to be the cause of a decreased immune cell functioning such as chemotaxis, phagocytosis and superoxide production by neutrophils.[20] 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.[21]

    Mechanism of action

    Hydroxychloroquine increases[22] lysosomal pH in antigen-presenting cells. In inflammatory conditions, it blocks toll-like receptors on plasmacytoid dendritic cells (PDCs). Hydroxychloroquine, by decreasing TLR signaling, reduces the activation of dendritic cells and the inflammatory process. Toll-like receptor 9 (TLR 9) recognizes DNA-containing immune complexes and leads to the production of interferon and causes the dendritic cells to mature and present antigen to T cells, therefore reducing anti-DNA auto-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.[23]

    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 of hydroxychloroquine include Plaquenil, Hydroquin, Axemal (in India), Dolquine, Quensyl, Quinoric.[24]

    References
    1. "Hydroxychloroquine Sulfate". The American Society of Health-System Pharmacists. Archived from the original on 29 December 2016. Retrieved 8 December 2016.
    2. Hamilton, Richart (2015). Tarascon Pocket Pharmacopoeia 2015 Deluxe Lab-Coat Edition. Jones & Bartlett Learning. p. 463. ISBN 9781284057560.
    3. "Hydroxychloroquine Use During Pregnancy | Drugs.com". www.drugs.com. Archived from the original on 29 December 2016. Retrieved 29 December 2016.
    4. World Health Organization (2019). "World Health Organization model list of essential medicines: 21st list 2019". World Health Organization (WHO). hdl:10665/325771. Cite journal requires |journal= (help)
    5. "Hydroxychloroquine Sulfate". International Drug Price Indicator Guide. Retrieved 8 December 2016.
    6. British national formulary: BNF 69 (69 ed.). British Medical Association. 2015. p. 730. ISBN 9780857111562.
    7. "NADAC as of 2019-08-07 | Data.Medicaid.gov". Centers for Medicare and Medicaid Services. Retrieved 9 August 2019.
    8. "The Top 300 of 2019". clincalc.com. Retrieved 22 December 2018.
    9. Effects of Hydroxychloroquine on Symptomatic Improvement in Primary Sjögren Syndrome, Gottenberg, et al. (2014) "Archived copy". Archived from the original on 11 July 2015. Retrieved 10 July 2015.CS1 maint: archived copy as title (link)
    10. Steere, AC; Angelis, SM (October 2006). "Therapy for Lyme Arthritis: Strategies for the Treatment of Antibiotic-refractory Arthritis". Arthritis and Rheumatism. 54 (10): 3079–86. doi:10.1002/art.22131. PMID 17009226.
    11. 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.
    12. Marmor, MF; Kellner, U; Lai, TYY; Lyons, JS; Mieler, WF (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.
    13. "Russian Register of Medicines: Plaquenil (hydroxychloroquine) Film-coated Tablets for Oral Use. Prescribing Information" (in Russian). Sanofi-Synthelabo. Archived from the original on 16 August 2016. Retrieved 14 July 2016.
    14. Mohammad, Samya; Clowse, Megan E. B.; Eudy, Amanda M.; Criscione-Schreiber, Lisa G. (March 2018). "Examination of Hydroxychloroquine Use and Hemolytic Anemia in G6PDH-Deficient Patients". Arthritis Care & Research. 70 (3): 481–485. doi:10.1002/acr.23296. ISSN 2151-4658. PMID 28556555.
    15. Kalia, S; Dutz, JP (2007). "New Concepts in Antimalarial Use and Mode of Action in Dermatology". Dermatologic Therapy. 20 (4): 160–74. doi:10.1111/j.1529-8019.2007.00131.x. PMID 17970883.
    16. Kaufmann, AM; Krise, JP (2007). "Lysosomal Sequestration of Amine-containing Drugs: Analysis and Therapeutic Implications". Journal of Pharmaceutical Sciences. 96 (4): 729–46. doi:10.1002/jps.20792. PMID 17117426.
    17. 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): 3327–31. doi:10.1073/pnas.75.7.3327. PMC 392768. PMID 28524.
    18. 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): 959–66. doi:10.1083/jcb.102.3.959. PMC 2114118. PMID 3949884.
    19. 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): 739–45. doi:10.1042/bj2400739. PMC 1147481. PMID 3493770.
    20. Hurst, NP; French, JK; Gorjatschko, L; Betts, WH (1988). "Chloroquine and Hydroxychloroquine Inhibit Multiple Sites in Metabolic Pathways Leading to Neutrophil Superoxide Release". The Journal of Rheumatology. 15 (1): 23–7. PMID 2832600.
    21. Fox, R (1996). "Anti-malarial Drugs: Possible Mechanisms of Action in Autoimmune Disease and Prospects for Drug Development". Lupus. 5: S4–10. doi:10.1177/096120339600500103. PMID 8803903.
    22. Waller; et al. Medical Pharmacology and Therapeutics (2nd ed.). p. 370.
    23. Takeda, K; Kaisho, T; Akira, S (2003). "Toll-Like Receptors". Annual Review of Immunology. 21: 335–76. doi:10.1146/annurev.immunol.21.120601.141126. PMID 12524386.
    24. "Hydroxychloroquine trade names". Drugs-About.com. Retrieved 18 June 2019.
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