Chloroquine

Chloroquine is a medication primarily used to prevent

and treat malaria in areas where malaria remains sensitive
Chloroquine
to its effects.[1] Certain types of malaria, resistant strains,
and complicated cases typically require different or
additional medication.[1] Chloroquine is also occasionally
used for amebiasis that is occurring outside the intestines,
rheumatoid arthritis, and lupus erythematosus.[1] While it
has not been formally studied in pregnancy, it appears
safe.[1][2] It was studied to treat COVID-19 early in the
pandemic, but these studies were largely halted in the
summer of 2020, and is not recommended for this
purpose.[3] It is taken by mouth.[1]

Common side effects include muscle problems, loss of

appetite, diarrhea, and skin rash.[1] Serious side effects
include problems with vision, muscle damage, seizures,
and low blood cell levels.[1][4] Chloroquine is a member
of the drug class 4-aminoquinoline.[1] As an antimalarial,
it works against the asexual form of the malaria parasite Clinical data
in the stage of its life cycle within the red blood cell.[1] Pronunciation /ˈklɔːrəkwiːn/
How it works in rheumatoid arthritis and lupus Trade names Aralen, other
erythematosus is unclear.[1]
Other names Chloroquine phosphate
Chloroquine was discovered in 1934 by Hans AHFS/Drugs.com Monograph (https://www.
Andersag.[5][6] It is on the World Health Organization's drugs.com/monograph/ch
List of Essential Medicines.[7] It is available as a generic loroquine-phosphate.htm
medication.[1] l)
License data US DailyMed: Chloroquine
(https://dailymed.nlm.nih.
Contents gov/dailymed/search.cf
Medical uses m?labeltype=all&query=C
Malaria hloroquine)
Amebiasis US FDA: Chloroquine (htt
Rheumatic disease ps://www.accessdata.fda.
Side effects gov/scripts/cder/drugsatfd
Pregnancy a/index.cfm?fuseaction=S
Elderly earch.SearchAction&Sear
chTerm=Chloroquine&Se
Drug interactions
archType=BasicSearch)
Overdose
Routes of by mouth
Pharmacology administration
Mechanism of action ATC code P01BA01 (WHO (https://w
 Malaria ww.whocc.no/atc_ddd_ind
Antiviral ex/?code=P01BA01))
Other Legal status
History Legal status UK: P (Pharmacy
Chemical synthesis medicines)
Society and culture US: ℞-only
Formulations
In general:
Names
℞ (Prescription only)
Other animals
Pharmacokinetic data
Research
Metabolism Liver
COVID-19
Elimination 1-2 months
Other half-life
References Identifiers
External links IUPAC name
(RS)-N'-(7-chloroquinolin-4-yl)-N,N-diethyl-pe
ntane-1,4-diamine
Medical uses
CAS Number 54-05-7 (https://commonc
hemistry.cas.org/detail?ca
Malaria s_rn=54-05-7)
PubChem CID 2719 (https://pubchem.nc
Chloroquine has been used in the treatment and
prevention of malaria from Plasmodium vivax, P. ovale, bi.nlm.nih.gov/compound/
and P. malariae. It is generally not used for Plasmodium 2719)
falciparum as there is widespread resistance to it.[9][10] IUPHAR/BPS 5535 (http://www.guidetop
Chloroquine has been extensively used in mass drug harmacology.org/GRAC/Li
administrations, which may have contributed to the gandDisplayForward?liga
emergence and spread of resistance. It is recommended to ndId=5535)
check if chloroquine is still effective in the region prior to DrugBank DB00608 (https://www.dru
using it.[11] In areas where resistance is present, other
gbank.ca/drugs/DB0060
antimalarials, such as mefloquine or atovaquone, may be
8)
used instead. The Centers for Disease Control and
Prevention recommend against treatment of malaria with ChemSpider 2618 (https://www.chems
chloroquine alone due to more effective pider.com/Chemical-Struc
combinations.[12] ture.2618.html)
UNII 886U3H6UFF (https://pre
Amebiasis cision.fda.gov/uniisearch/
srs/unii/886U3H6UFF)
In treatment of amoebic liver abscess, chloroquine may
KEGG D02366 (https://www.keg
be used instead of or in addition to other medications in
the event of failure of improvement with metronidazole g.jp/entry/D02366)
or another nitroimidazole within 5 days or intolerance to ChEBI CHEBI:3638 (https://www.
metronidazole or a nitroimidazole.[13]
ebi.ac.uk/chebi/searchId.
do?chebiId=CHEBI:3638)
Rheumatic disease
ChEMBL
As it mildly suppresses the immune system, chloroquine ChEMBL76 (https://www.e
is used in some autoimmune disorders, such as bi.ac.uk/chembldb/index.p
rheumatoid arthritis and has an off label indication for hp/compound/inspect/Ch
lupus erythematosus.[1] EMBL76)
NIAID ChemDB 000733 (https://chemdb.n
Side effects iaid.nih.gov/CompoundDe
tails.aspx?AIDSNO=0007
Side effects include blurred vision, nausea, vomiting,
33)
abdominal cramps, headache, diarrhea, swelling
legs/ankles, shortness of breath, pale lips/nails/skin, CompTox DTXSID2040446 (https://
muscle weakness, easy bruising/bleeding, hearing and Dashboard (EPA)
comptox.epa.gov/dashbo
mental problems.[14][15] ard/chemical/details/DTX
SID2040446)
Unwanted/uncontrolled movements (including
tongue and face twitching) [14] ECHA InfoCard 100.000.175 (https://ech
Deafness or tinnitus.[14] a.europa.eu/substance-in
formation/-/substanceinfo/
Nausea, vomiting, diarrhea, abdominal
cramps[15] 100.000.175)

Headache.[14] Chemical and physical data

Mental/mood changes (such as confusion, Formula C18H26ClN3
personality changes, unusual Molar mass 319.88 g·mol−1
thoughts/behavior, depression, feeling being
watched, hallucinating)[14][15] 3D model Interactive image (https://
(JSmol)
Signs of serious infection (such as high fever, chemapps.stolaf.edu/jmo
severe chills, persistent sore throat)[14] l/jmol.php?model=Clc1cc
Skin itchiness, skin color changes, hair loss, 2nccc%28c2cc1%29NC%
and skin rashes.[15][16] 28C%29CCCN%28CC%2
9CC)
Chloroquine-induced itching is very
common among black Africans (70%), but SMILES
much less common in other races. It Clc1cc2nccc(c2cc1)NC(C)CCCN(CC)CC
increases with age, and is so severe as to
InChI
stop compliance with drug therapy. It is
increased during malaria fever; its severity InChI=1S/C18H26ClN3/c1-4-22(5-2)12-6-7-1
4(3)21-17-10-11-20-18-13-15(19)8-9-16(1
is correlated to the malaria parasite load in
7)18/h8-11,13-14H,4-7,12H2,1-3H3,(H,20,
blood. Some evidence indicates it has a
21)
genetic basis and is related to chloroquine
action with opiate receptors centrally or Key:WHTVZRBIWZFKQO-UHFFFAOYSA-N
peripherally.[17] (verify)
Unpleasant metallic taste
This could be avoided by "taste-masked and controlled release" formulations such as
multiple emulsions.[18]
Chloroquine retinopathy
Electrocardiographic changes[19]
This manifests itself as either conduction disturbances (bundle-branch block,
atrioventricular block) or Cardiomyopathy – often with hypertrophy, restrictive physiology,
and congestive heart failure. The changes may be irreversible. Only two cases have
been reported requiring heart transplantation, suggesting this particular risk is very low.
 Electron microscopy of cardiac
biopsies show pathognomonic
cytoplasmic inclusion bodies.
Pancytopenia, aplastic anemia,
reversible agranulocytosis, low blood
platelets, neutropenia.[20]

Pregnancy
Distribution of malaria in the world:[8]
Chloroquine has not been shown to have any ♦ Elevated occurrence of chloroquine- or multi-resistant
harmful effects on the fetus when used in the malaria
recommended doses for malarial ♦ Occurrence of chloroquine-resistant malaria
prophylaxis.[21] Small amounts of chloroquine ♦ No Plasmodium falciparum or chloroquine-resistance
are excreted in the breast milk of lactating ♦ No malaria
women. However, this drug can be safely
prescribed to infants, the effects are not
harmful. Studies with mice show that radioactively tagged chloroquine passed through the placenta rapidly
and accumulated in the fetal eyes which remained present five months after the drug was cleared from the
rest of the body.[20][22] Women who are pregnant or planning on getting pregnant are still advised against
traveling to malaria-risk regions.[21]

Elderly

There is not enough evidence to determine whether chloroquine is safe to be given to people aged 65 and
older. Since it is cleared by the kidneys, toxicity should be monitored carefully in people with poor kidney
functions.[20]

Drug interactions
Chloroquine has a number of drug–drug interactions that might be of clinical concern:

Ampicillin- levels may be reduced by chloroquine;[20]

Antacids- may reduce absorption of chloroquine;[20]
Cimetidine- may inhibit metabolism of chloroquine; increasing levels of chloroquine in the
body;[20]
Cyclosporine- levels may be increased by chloroquine;[20] and
Mefloquine- may increase risk of convulsions.[20]

Overdose
Chloroquine, in overdose, has a risk of death of about 20%.[23] It is rapidly absorbed from the gut with an
onset of symptoms generally within an hour.[24] Symptoms of overdose may include sleepiness, vision
changes, seizures, stopping of breathing, and heart problems such as ventricular fibrillation and low blood
pressure.[23][24] Low blood potassium may also occur.[23]

While the usual dose of chloroquine used in treatment is 10 mg/kg, toxicity begins to occur at 20 mg/kg,
and death may occur at 30 mg/kg.[23] In children as little as a single tablet can cause problems.[24]
Treatment recommendations include early mechanical ventilation, cardiac monitoring, and activated
charcoal.[23] Intravenous fluids and vasopressors may be required with epinephrine being the vasopressor of
choice.[23] Seizures may be treated with benzodiazepines.[23] Intravenous potassium chloride may be
required, however this may result in high blood potassium later in the course of the disease.[23] Dialysis has
not been found to be useful.[23]

Pharmacology
Absorption of chloroquine is rapid and primarily happens in the gastrointestinal tract.[25] It is widely
distributed in body tissues.[26] Protein binding in plasma ranges from 46% to 79%.[27] Its metabolism is
partially hepatic, giving rise to its main metabolite, desethylchloroquine.[28] Its excretion is ≥50% as
unchanged drug in urine, where acidification of urine increases its elimination. It has a very high volume of
distribution, as it diffuses into the body's adipose tissue.

Accumulation of the drug may result in deposits that can lead to blurred vision and blindness. It and related
quinines have been associated with cases of retinal toxicity, particularly when provided at higher doses for
longer times. With long-term doses, routine visits to an ophthalmologist are recommended.

Chloroquine is also a lysosomotropic agent, meaning it accumulates preferentially in the lysosomes of cells
in the body. The pKa for the quinoline nitrogen of chloroquine is 8.5, meaning it is about 10% deprotonated
at physiological pH (per the Henderson-Hasselbalch equation). This decreases to about 0.2% at a lysosomal
pH of 4.6. Because the deprotonated form is more membrane-permeable than the protonated form, a
quantitative "trapping" of the compound in lysosomes results.

Mechanism of action

Malaria

The lysosomotropic character of chloroquine is believed to account for much of its antimalarial activity; the
drug concentrates in the acidic food vacuole of the parasite and interferes with essential processes. Its
lysosomotropic properties further allow for its use for in vitro experiments pertaining to intracellular lipid
related diseases,[29][30] autophagy, and apoptosis.[31]

Inside red blood cells, the malarial parasite, which is then in its asexual lifecycle stage, must degrade
hemoglobin to acquire essential amino acids, which the parasite requires to construct its own protein and for
energy metabolism. Digestion is carried out in a vacuole of the parasitic cell.

Hemoglobin is composed of a protein unit (digested by the parasite) and a heme unit (not used by the
parasite). During this process, the parasite releases the toxic and soluble molecule heme. The heme moiety
consists of a porphyrin ring called Fe(II)-protoporphyrin IX (FP). To avoid destruction by this molecule, the
parasite biocrystallizes heme to form hemozoin, a nontoxic molecule. Hemozoin collects in the digestive
vacuole as insoluble crystals.

Chloroquine enters the red blood cell by simple diffusion, inhibiting the parasite cell and digestive vacuole.
Chloroquine then becomes protonated (to CQ2+), as the digestive vacuole is known to be acidic (pH 4.7);
chloroquine then cannot leave by diffusion. Chloroquine caps hemozoin molecules to prevent further
biocrystallization of heme, thus leading to heme buildup. Chloroquine binds to heme (or FP) to form the FP-
chloroquine complex; this complex is highly toxic to the cell and disrupts membrane function. Action of the
toxic FP-chloroquine and FP results in cell lysis and ultimately parasite cell autodigestion.[32] Parasites that
do not form hemozoin are therefore resistant to chloroquine.[33]
Resistance in malaria

Since the first documentation of P. falciparum

chloroquine resistance in the 1950s, resistant strains
have appeared throughout East and West Africa,
Southeast Asia, and South America. The effectiveness
of chloroquine against P. falciparum has declined as
resistant strains of the parasite evolved.

Resistant parasites are able to rapidly remove

chloroquine from the digestive vacuole using a
transmembrane pump. Chloroquine-resistant parasites
pump chloroquine out at 40 times the rate of
chloroquine-sensitive parasites; the pump is coded by
the P. falciparum chloroquine resistance transporter
(PfCRT) gene.[34] The natural function of the
chloroquine pump is to transport peptides: mutations to
the pump that allow it to pump chloroquine out impairs
its function as a peptide pump and comes at a cost to
the parasite, making it less fit.[35]

Resistant parasites also frequently have mutation in the

ABC transporter P. falciparum multidrug resistance
(PfMDR1) gene, although these mutations are thought
to be of secondary importance compared to PfCRT. An
altered chloroquine-transporter protein, CG2 has been
associated with chloroquine resistance, but other
mechanisms of resistance also appear to be
involved.[36]

Verapamil, a Ca2+ channel blocker, has been found to

restore both the chloroquine concentration ability and
sensitivity to this drug. Other agents which have been
shown to reverse chloroquine resistance in malaria are
Medical quinolines
chlorpheniramine, gefitinib, imatinib, tariquidar and
zosuquidar.[37]

As of 2014 chloroquine is still effective against poultry malaria in

Thailand. Sohsuebngarm et al. 2014 test P. gallinaceum at
Chulalongkorn University and find the parasite is not
resistant.[38]: 1237 Sertraline, fluoxetine and paroxetine reverse
chloroquine resistance, making resistant biotypes susceptible if used
in a cotreatment.[39]
Hemozoin formation in P. falciparum:
many antimalarials are strong
Antiviral inhibitors of hemozoin crystal growth.

Chloroquine has antiviral effects against some viruses.[40] It

increases late endosomal and lysosomal pH, resulting in impaired release of the virus from the endosome or
lysosome – release of the virus requires a low pH. The virus is therefore unable to release its genetic
material into the cell and replicate.[41][42]
Chloroquine also seems to act as a zinc ionophore that allows extracellular zinc to enter the cell and inhibit
viral RNA-dependent RNA polymerase.[43][44]

Other

Chloroquine inhibits thiamine uptake.[45] It acts specifically on the transporter SLC19A3.

Against rheumatoid arthritis, it operates by inhibiting lymphocyte proliferation, phospholipase A2, antigen
presentation in dendritic cells, release of enzymes from lysosomes, release of reactive oxygen species from
macrophages, and production of IL-1.

History
In Peru, the indigenous people extracted the bark of the Cinchona tree (Cinchona officinalis)[46] and used
the extract to fight chills and fever in the seventeenth century. In 1633 this herbal medicine was introduced
in Europe, where it was given the same use and also began to be used against malaria. The quinoline
antimalarial drug quinine was isolated from the extract in 1820.[47]: 130–131

After World War I, the German government sought alternatives to quinine. Chloroquine, a synthetic
analogue with the same mechanism of action was discovered in 1934, by Hans Andersag and coworkers at
the Bayer laboratories, who named it Resochin.[48][49] It was ignored for a decade, because it was
considered too toxic for human use. Instead, in World War II, the German Africa Corps used the
chloroquine analogue 3-methyl-chloroquine, known as Sontochin. After Allied forces arrived in Tunis,
Sontochin fell into the hands of Americans, who sent the material back to the United States for analysis,
leading to renewed interest in chloroquine.[50][51] United States government-sponsored clinical trials for
antimalarial drug development showed unequivocally that chloroquine has a significant therapeutic value as
an antimalarial drug.[47]: 61–66 It was introduced into clinical practice in 1947 for the prophylactic treatment
of malaria.[52]

Chemical synthesis

The first synthesis of chloroquine was disclosed in a patent filed by IG Farben in 1937.[53] In the final step,
4,7-dichloroquinoline was reacted with 1-diethylamino-4-aminopentane.

By 1949, chloroquine manufacturing processes had been established to allow its widespread use.[54]

Society and culture

Formulations
Chloroquine comes in tablet form as the phosphate, sulfate, and
hydrochloride salts. Chloroquine is usually dispensed as the
phosphate.[55]

Names

Brand names include Chloroquine FNA, Resochin, Dawaquin, and

Lariago.[56]

Other animals
Chloroquine, in various chemical forms, is used to treat and control
surface growth of anemones and algae, and many protozoan
infections in aquariums,[57] e.g. the fish parasite Amyloodinium
ocellatum.[58] It is also used in poultry malaria.[38]: 1237

Research
Chloroquine was proposed as a treatment for SARS, with in vitro
tests inhibiting the SARS-CoV virus.[59][60] In October 2004, a
published report stated that chloroquine acts as an effective inhibitor
of the replication of the severe acute respiratory syndrome
coronavirus (SARS-CoV) in vitro.[59] In August 2005, a peer-
reviewed study confirmed and expanded upon the results.[61]
Resochin tablet package
Chloroquine was being considered in 2003, in pre-clinical models
as a potential agent against chikungunya fever.[62]

COVID-19

Chloroquine and hydroxychloroquine are anti-malarial medications

also used against some auto-immune diseases.[63] Chloroquine,
along with hydroxychloroquine, was an early experimental
treatment for COVID-19.[64] Neither drug prevents SARS-CoV-2
infection.[65][66][67][68][69]

Cleavage of the SARS-CoV-2 S2 spike protein required for viral

entry into cells can be accomplished by proteases TMPRSS2 A World Health Organization
located on the cell membrane, or by cathepsins (primarily cathepsin infographic that states that
L) in endolysosomes.[70] Hydroxychloroquine inhibits the action of hydroxychloroquine does not prevent
cathepsin L in endolysosomes, but because cathepsin L cleavage is illness or death from COVID-19.
minor compared to TMPRSS2 cleavage, hydroxychloroquine does
little to inhibit SARS-CoV-2 infection.[70]

Several countries initially used chloroquine or hydroxychloroquine for treatment of persons hospitalized
with COVID-19 (as of March 2020), though the drug was not formally approved through clinical
trials.[71][72] From April to June 2020, there was an emergency use authorization for their use in the United
States,[73] and was used off label for potential treatment of the disease.[74] On 24 April 2020, citing the risk
of "serious heart rhythm problems", the FDA posted a caution against using the drug for COVID-19
"outside of the hospital setting or a clinical trial".[75]

Their use was withdrawn as a possible treatment for COVID-19 infection when it proved to have no benefit
for hospitalized patients with severe COVID-19 illness in the international Solidarity trial and UK
RECOVERY Trial.[76][77] On 15 June 2020, the FDA revoked its emergency use authorization, stating that
it was "no longer reasonable to believe" that the drug was effective against COVID-19 or that its benefits
outweighed "known and potential risks".[78][79][80] In fall of 2020, the National Institutes of Health issued
treatment guidelines recommending against the use of hydroxychloroquine for COVID-19 except as part of
a clinical trial.[63]

In 2021, hydroxychloroquine was part of the recommended treatment for mild cases in India.[81]

Other

The radiosensitizing and chemosensitizing properties of chloroquine are being evaluated for anticancer
strategies in humans.[82][83] In biomedicinal science, chloroquine is used for in vitro experiments to inhibit
lysosomal degradation of protein products. Chloroquine and its modified forms have also been evaluated as
treatment options for inflammatory conditions like rheumatoid arthritis and inflammatory bowel disease.[84]

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External links
"Chloroquine" (https://druginfo.nlm.nih.gov/drugportal/name/chloroquine). Drug Information
Portal. U.S. National Library of Medicine.
"Medicines for the Prevention of Malaria While Traveling – Chloroquine (Aralen)" (https://ww
w.cdc.gov/malaria/resources/pdf/fsp/drugs/Chloroquine.pdf) (PDF) (Fact sheet). U.S. Centers
for Disease Control and Prevention (CDC).
The dictionary definition of chloroquine at Wiktionary

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