Hydroxychloroquine

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Hydroxychloroquine
Systematic (IUPAC) name
(RS)-2-[{4-[(7-chloroquinolin-4-yl)amino]pentyl}(ethyl)amino]ethanol
Clinical data
Trade namesPlaquenil
AHFS/Drugs.commonograph
MedlinePlusa601240
Pregnancy cat.D (Au), C (U.S.)
Legal statusPOM (UK), ℞-only (U.S.)
RoutesOral
Pharmacokinetic data
Half-life1–2 months
ExcretionRenal
Identifiers
CAS number118-42-3 YesY
ATC codeP01BA02
PubChemCID 3652
DrugBankDB01611
ChemSpider3526 YesY
UNII4QWG6N8QKH YesY
KEGGD08050 YesY
ChEMBLCHEMBL1535 YesY
Chemical data
FormulaC18H26ClN3O 
Mol. mass335.872 g/mol
 YesY (what is this?)  (verify)
 
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Hydroxychloroquine
Systematic (IUPAC) name
(RS)-2-[{4-[(7-chloroquinolin-4-yl)amino]pentyl}(ethyl)amino]ethanol
Clinical data
Trade namesPlaquenil
AHFS/Drugs.commonograph
MedlinePlusa601240
Pregnancy cat.D (Au), C (U.S.)
Legal statusPOM (UK), ℞-only (U.S.)
RoutesOral
Pharmacokinetic data
Half-life1–2 months
ExcretionRenal
Identifiers
CAS number118-42-3 YesY
ATC codeP01BA02
PubChemCID 3652
DrugBankDB01611
ChemSpider3526 YesY
UNII4QWG6N8QKH YesY
KEGGD08050 YesY
ChEMBLCHEMBL1535 YesY
Chemical data
FormulaC18H26ClN3O 
Mol. mass335.872 g/mol
 YesY (what is this?)  (verify)

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.[1][2]

Contents

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,[3] 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.[4] Alteration in pH causes inhibition of lysosomal acidic proteases causing a diminished proteolysis effect.[5] Higher pH within lysosomes causes decreased intracellular processing, glycosylation, and secretion of proteins with many immunologic and nonimmunologic consequences.[6] These effects are believed to be the cause of a decreased immune cell functioning such as chemotaxis, phagocytosis and superoxide production by neutrophils.[7] 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.[8]

Classification and use

Hydroxychloroquine is classified as an anti-malarial medication and is one of a number of drugs that have been used for many years in the treatment of malaria. It is also useful in treating systemic lupus erythematosus, rheumatic disorders like rheumatoid arthritis and Sjögren's Syndrome, and porphyria cutanea tarda. While hydroxychloroquine has been known for some time to increase[9] lysosomal pH in antigen presenting cells, its mechanism of action in inflammatory conditions has been recently elucidated and involves blocking the activation of 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, thereby mitigating the inflammatory process.

Hydroxychloroquine is also widely used in the treatment of post-Lyme arthritis that can be induced by Lyme disease. The action of the drug may involve both an anti-spirochaete activity and an anti-inflammatory activity, similar to the treatment of rheumatoid arthritis.[10]

Dosage

Malaria

For prevention of malaria the usual adult dose is 400 milligrams per seven days, on the same day, begun two weeks prior to exposure, or two 400 milligrams doses taken six hours apart. Suppressive therapy continues for eight weeks after leaving the transmission area. For acute malaria the recommendation is either a single 800 milligram dose or 800 milligrams followed by 400 milligrams six to eight hours later, and 400 milligrams once per day for two consecutive days. The children's dose will depend on the weight of the child but should be supervised by a doctor.

Lupus erythematosus

The adult starting dose is 6.5 mg/kg daily, for several weeks or months, depending on the reaction. This may be reduced to for maintenance. With systemic lupus, it is especially useful in relieving skin inflammation, hair loss, oral sores, fatigue and joint pain as well as preventing relapse.

Rheumatoid arthritis

The adult starting dose is 400 to 600 milligrams per day with food or milk; with improvement (between four to twelve weeks) the maintenance dose is 200 to 400 milligrams daily. Hydroxychloroquine has not been proven safe for the treatment of juvenile arthritis.

Side effects

Side effects are difficult to anticipate, and should be reported to a doctor immediately if new symptoms develop or old symptoms change in intensity. Generally side effects are not common, but can include (for short-term treatment of acute malaria) abdominal cramps, diarrhea, heart problems, reduced appetite, headache, nausea and vomiting. The symptoms for prolonged treatment of lupus or arthritis include the acute symptoms, plus altered eye pigmentation, acne, anemia, bleaching of hair, blisters in mouth and eyes, blood disorders, convulsions, significant 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.

The most common side effects are a mild nausea and occasional stomach cramps with mild diarrhea.

Eyes

One of the most serious side effects is a toxicity in the eye (generally with chronic use).[11] The daily safe maximum dose for eye toxicity can be computed from one's height and weight using this calculator. It should be noted that 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.[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 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. Established maculopathy is characterized by moderate reduction of visual acuity and an obvious "bulls eye" macular lesion. End stage maculopathy is characterized by severe reduction in visual acuity and severe atrophy of the retinal pigment epithelium.

Interactions

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.[13] 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.

Overdose symptoms

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.

References

  1. ^ New concepts in antimalarial use and mode of action in dermatology. Dermatol Ther. 2007 Jul-Aug;20(4):160-74. PMID 17970883
  2. ^ Pharmacogenetics of disease-modifying anti-rheumatic drugs. Best Pract Res Clin Rheumatol 2004:18: 233–247.
  3. ^ Lysosomal sequestration of amine-containing drugs: analysis and therapeutic implications. J Pharm Sci 2007:96: 729–746.
  4. ^ Fluorescence probe measurement of the intralysosomal pH in living cells and the perturbation of pH by various agents. Proc Natl Acad Sci USA 1978:75:3327–3331.
  5. ^ The effects of basic substances and acidic ionophores on the digestion of exogenous and endogenous proteins in mouse peritoneal macrophages. J Cell Biol 1986:102: 959–966.
  6. ^ Effects of weakly basic amines on proteolytic processing and terminal glycosylation of secretory proteins in cultured rat hepatocytes. Biochem J 1986:240: 739–745.
  7. ^ Chloroquine and hydroxychloroquine inhibit multiple sites in metabolic pathways leading to neutrophil superoxide release. J Rheumatol 1988:15: 23–27
  8. ^ Toll-like receptors. Annu Rev Immunol 2003:21: 335–376.
  9. ^ Waller et al. 2nd ed.'medical pharmacology and therapeutics'pg 370
  10. ^ 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. 
  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. //www.ncbi.nlm.nih.gov/pmc/articles/PMC2258132/. 
  12. ^ Marmor, MF; Kellner, U, Lai, TY, Lyons, JS, Mieler, WF, American Academy of, Ophthalmology (2011 Feb). "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. ^ "Hydroxychloroquine (Oral Route) - MayoClinic.com". http://www.mayoclinic.com/health/drug-information/DR600761. Retrieved 2008-10-30. 

External links