Hydroxychloroquine

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Hydroxychloroquine
Hydroxychloroquine.svg
Clinical data
Trade names Plaquenil, others
AHFS/Drugs.com Monograph
MedlinePlus a601240
Pregnancy
category
  • AU: D
  • US: C (Risk not ruled out)
Routes of
administration
By mouth (tablets)
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability Variable (74% on average); Tmax = 2–4.5 hours
Protein binding 45%
Metabolism Liver
Biological half-life 32–50 days
Excretion Mostly Kidney (23–25% as unchanged drug), also biliary (<10%)
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
ECHA InfoCard 100.003.864
Chemical and physical data
Formula C18H26ClN3O
Molar mass 335.872 g/mol
3D model (Jmol)
 NYesY (what is this?)  (verify)

Hydroxychloroquine (HCQ), sold under the brand names 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 rheumatoid arthritis, lupus, and porphyria cutanea tarda. It is taken by mouth.[1]

Common side effects include vomiting, headache, changes in vision and muscle weakness. 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 most effective and safe medicines needed in a health system.[4] The wholesale cost in the developing world is about 5.40 to 7.44 USD per month.[5] In the United Kingdom this dose costs the NHS about 5.15 pounds.[6] In the United States a month of treatment costs less than 25 USD.[2]

Medical use[edit]

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

In 2014 its efficacy to treat Sjögren's syndrome was questioned in a double-blind study involving 120 patients over a 48-week period.[7]

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.[8]

Adverse effects[edit]

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[edit]

One of the most serious side effects is a toxicity in the eye (generally with chronic use).[9] 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.[10]

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[edit]

A type of enzyme deficiency (enzyme G6PD) found most frequently in those of African descent can develop into severe anemia and requires monitoring.[11] 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.[12]

Overdose[edit]

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[edit]

Pharmacokinetics[edit]

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.[13]

Pharmacodynamics[edit]

Antimalarials are lipophilic weak bases and easily pass plasma membranes. The free base form accumulates in lysosomes (acidic cytoplasmic vesicles) and is then protonated,[14] 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.[15] Alteration in pH causes inhibition of lysosomal acidic proteases causing a diminished proteolysis effect.[16] Higher pH within lysosomes causes decreased intracellular processing, glycosylation and secretion of proteins with many immunologic and nonimmunologic consequences.[17] These effects are believed to be the cause of a decreased immune cell functioning such as chemotaxis, phagocytosis and superoxide production by neutrophils.[18] 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.[19]

Mechanism of action[edit]

Hydroxychloroquine increases[20] lysosomal pH in antigen-presenting cells. In inflammatory conditions, it blocks toll-like receptors on plasmacytoid dendritic cells (PDCs).[citation needed] 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.[21]

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.[citation needed]

Brand names[edit]

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

References[edit]

  1. ^ a b c d e "Hydroxychloroquine Sulfate". The American Society of Health-System Pharmacists. Retrieved 8 December 2016. 
  2. ^ a b 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. Retrieved 29 December 2016. 
  4. ^ "WHO Model List of Essential Medicines (19th List)" (PDF). World Health Organization. April 2015. Retrieved 8 December 2016. 
  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. ^ Effects of Hydroxychloroquine on Symptomatic Improvement in Primary Sjögren Syndrome, Gottenberg, et al. (2014) http://jama.jamanetwork.com/article.aspx?articleID=1887760
  8. ^ AC, Steere; SM, Angelis (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. 
  9. ^ 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 2258132Freely accessible. PMID 18427609. 
  10. ^ 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. 
  11. ^ "Hydroxychloroquine (Oral Route) - MayoClinic.com". Retrieved 2008-10-30. 
  12. ^ "Russian Register of Medicines: Plaquenil (hydroxychloroquine) Film-coated Tablets for Oral Use. Prescribing Information" (in Russian). Sanofi-Synthelabo. Retrieved 14 July 2016. 
  13. ^ 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. 
  14. ^ 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. 
  15. ^ 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 392768Freely accessible. PMID 28524. 
  16. ^ 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 2114118Freely accessible. PMID 3949884. 
  17. ^ 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 1147481Freely accessible. PMID 3493770. 
  18. ^ 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. 
  19. ^ 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. 
  20. ^ Waller; et al. Medical Pharmacology and Therapeutics (2nd ed.). p. 370. 
  21. ^ 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. 

External links[edit]