Hydroxychloroquine
Encyclopedia
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 drug
s) 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. ,
(TLR) 9 family receptors. TLRs are cellular receptors for microbial products that induce inflammatory responses through activation of the innate immune system
as well as rheumatoid arthritis
and Sjögren's Syndrome
(all rheumatic disorders). While hydroxychloroquine has been known for some time to increase 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 thus 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.
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.
, 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.
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.
deficiency (enzyme
G6PD) found most frequently in those of Africa
n descent can develop into severe anemia
and should also be monitored. Children are more sensitive to hydroxychloroquine than adults are, 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.
Rheumatoid arthritis
Rheumatoid arthritis is a chronic, systemic inflammatory disorder that may affect many tissues and organs, but principally attacks synovial joints. The process produces an inflammatory response of the synovium secondary to hyperplasia of synovial cells, excess synovial fluid, and the development...
(see disease-modifying antirheumatic drug
Disease-modifying antirheumatic drug
Disease-modifying antirheumatic drugs is a category of otherwise unrelated drugs defined by their use in rheumatoid arthritis to slow down disease progression...
s) and lupus
Lupus erythematosus
Lupus erythematosus is a category for a collection of diseases with similar underlying problems with immunity . Symptoms of these diseases can affect many different body systems, including joints, skin, kidneys, blood cells, heart, and lungs...
. 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. ,
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 then protonated, in an ionized state., Resulting in concentrations within lysosomes up to 1000 times higher than in culture media, increasing 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 . Recently a novel mechanism has been describe whereas hydroxychloroquine inhibits stimulation of the toll-like receptorToll-like receptor
Toll-like receptors are a class of proteins that play a key role in the innate immune system. They are single, membrane-spanning, non-catalytic receptors that recognize structurally conserved molecules derived from microbes...
(TLR) 9 family receptors. TLRs are cellular receptors for microbial products that induce inflammatory responses through activation of the innate immune system
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 erythematosusLupus erythematosus
Lupus erythematosus is a category for a collection of diseases with similar underlying problems with immunity . Symptoms of these diseases can affect many different body systems, including joints, skin, kidneys, blood cells, heart, and lungs...
as well as rheumatoid arthritis
Rheumatoid arthritis
Rheumatoid arthritis is a chronic, systemic inflammatory disorder that may affect many tissues and organs, but principally attacks synovial joints. The process produces an inflammatory response of the synovium secondary to hyperplasia of synovial cells, excess synovial fluid, and the development...
and Sjögren's Syndrome
Sjögren's syndrome
Sjögren's syndrome , also known as "Mikulicz disease" and "Sicca syndrome", is a systemic autoimmune disease in which immune cells attack and destroy the exocrine glands that produce tears and saliva....
(all rheumatic disorders). While hydroxychloroquine has been known for some time to increase 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
Interferon
Interferons are proteins made and released by host cells in response to the presence of pathogens—such as viruses, bacteria, or parasites—or tumor cells. They allow communication between cells to trigger the protective defenses of the immune system that eradicate pathogens or tumors.IFNs belong to...
and causes the dendritic cells to mature and present antigen
Antigen
An antigen is a foreign molecule that, when introduced into the body, triggers the production of an antibody by the immune system. The immune system will then kill or neutralize the antigen that is recognized as a foreign and potentially harmful invader. These invaders can be molecules such as...
to T cells. Hydroxychloroquine, by decreasing TLR signaling, reduces the activation of dendritic cells thus mitigating the inflammatory process.
Hydroxychloroquine is also widely used in the treatment of post-Lyme arthritis
Arthritis
Arthritis is a form of joint disorder that involves inflammation of one or more joints....
that can be induced by Lyme disease
Lyme disease
Lyme disease, or Lyme borreliosis, is an emerging infectious disease caused by at least three species of bacteria belonging to the genus Borrelia. Borrelia burgdorferi sensu stricto is the main cause of Lyme disease in the United States, whereas Borrelia afzelii and Borrelia garinii cause most...
. The action of the drug may involve both an anti-spirochaete
Spirochaete
Spirochaetes belong to a phylum of distinctive Gram-negative bacteria, which have long, helically coiled cells...
activity and an anti-inflammatory activity, similar to the treatment of rheumatoid arthritis.
Malaria
For prevention of malariaMalaria
Malaria is a mosquito-borne infectious disease of humans and other animals caused by eukaryotic protists of the genus Plasmodium. The disease results from the multiplication of Plasmodium parasites within red blood cells, causing symptoms that typically include fever and headache, in severe cases...
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 atrophyMuscle atrophy
Muscle atrophy, or disuse atrophy, is defined as a decrease in the mass of the muscle; it can be a partial or complete wasting away of muscle. When a muscle atrophies, this leads to muscle weakness, since the ability to exert force is related to mass...
, nightmares, psoriasis
Psoriasis
Psoriasis is an autoimmune disease that appears on the skin. It occurs when the immune system mistakes the skin cells as a pathogen, and sends out faulty signals that speed up the growth cycle of skin cells. Psoriasis is not contagious. However, psoriasis has been linked to an increased risk of...
, reading difficulties, tinnitus
Tinnitus
Tinnitus |ringing]]") is the perception of sound within the human ear in the absence of corresponding external sound.Tinnitus is not a disease, but a symptom that can result from a wide range of underlying causes: abnormally loud sounds in the ear canal for even the briefest period , ear...
, skin inflammation and scaling, skin rash, vertigo, and weight loss. Hydroxychloroquine can worsen existing cases of both psoriasis
Psoriasis
Psoriasis is an autoimmune disease that appears on the skin. It occurs when the immune system mistakes the skin cells as a pathogen, and sends out faulty signals that speed up the growth cycle of skin cells. Psoriasis is not contagious. However, psoriasis has been linked to an increased risk of...
and porphyria
Porphyria
Porphyrias are a group of inherited or acquired disorders of certain enzymes in the heme bio-synthetic pathway . They are broadly classified as acute porphyrias and cutaneous porphyrias, based on the site of the overproduction and accumulation of the porphyrins...
.
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) 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 400mg 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 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 enzymeEnzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
deficiency (enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
G6PD) found most frequently in those of Africa
Africa
Africa is the world's second largest and second most populous continent, after Asia. At about 30.2 million km² including adjacent islands, it covers 6% of the Earth's total surface area and 20.4% of the total land area...
n descent can develop into severe anemia
Anemia
Anemia is a decrease in number of red blood cells or less than the normal quantity of hemoglobin in the blood. However, it can include decreased oxygen-binding ability of each hemoglobin molecule due to deformity or lack in numerical development as in some other types of hemoglobin...
and should also be monitored. Children are more sensitive to hydroxychloroquine than adults are, 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
Aurothioglucose
Aurothioglucose, also known as gold thioglucose, is a chemical compound with the formula AuSC6H11O5. This derivative of the sugar glucose is used to treat rheumatoid arthritis.-History:...
(Solganal), cimetidine
Cimetidine
Cimetidine INN is a histamine H2-receptor antagonist that inhibits the production of acid in the stomach. It is largely used in the treatment of heartburn and peptic ulcers. It is marketed by GlaxoSmithKline under the trade name Tagamet...
(Tagamet) or digoxin
Digoxin
Digoxin INN , also known as digitalis, is a purified cardiac glycoside and extracted from the foxglove plant, Digitalis lanata. Its corresponding aglycone is digoxigenin, and its acetyl derivative is acetyldigoxin...
(Lanoxin). It will transfer into breast milk
Breast milk
Breast milk, more specifically human milk, is the milk produced by the breasts of a human female for her infant offspring...
and should be used with care by pregnant or nursing mothers.