Chloroquin Chemische Eigenschaften,Einsatz,Produktion Methoden
Beschreibung
Chloroquine is the most effective of the hundreds of 4-aminoquinolines synthesized and tested
during World War II as potential antimalarials. Structure–activity relationships demonstrated that
the chloro at the 8-position increased activity, whereas alkylation at C-3 and C-8 diminished
activity. The replacement of one of its N-ethyl groups with an hydroxyethyl produced hydroxychloroquine, a compound with reduced toxicity that is rarely used today except in cases of
rheumatoid arthritis.
Chemische Eigenschaften
solid
Verwenden
Chloroquine used in the treatment of malaria and MDR-strains. It is a COVID19-related research product.
Indications
Chloroquine (Aralen) is one of several 4-aminoquinoline
derivatives that display antimalarial activity.
Chloroquine is particularly effective against intraerythrocytic
forms because it is concentrated within the parasitized
erythrocyte. This preferential drug accumulation
appears to occur as a result of specific uptake
mechanisms in the parasite. Chloroquine appears to
work by intercalation with DNA, inhibition of heme
polymerase or by interaction with Ca++–calmodulinmediated
mechanisms. It also accumulates in the parasite’s
food vacuoles, where it inhibits peptide formation
and phospholipases, leading to parasite death.
Definition
ChEBI: An aminoquinoline that is quinoline which is substituted at position 4 by a [5-(diethylamino)pentan-2-yl]amino group at at position 7 by chlorine. It is used for the treatment of malaria, hepatic amoebiasis, lupus erythematosus, light-sensitive skin erupti
ns, and rheumatoid arthritis.
Weltgesundheitsorganisation (WHO)
Chloroquine, a 4-aminoquinoline derivative, was introduced in the
1940s for the treatment and prophylaxis of malaria. It was subsequently found to be
effective in higher and prolonged dosage in the treatment of lupus erythematosus,
rheumatoid arthritis and nephritis. In the early 1970s its use in these latter conditions was largely discontinued when it was found that prolonged daily
administration at high dosage was associated with cases of retinopathy resulting
from local deposition of the compound. Chloroquine however remains a valuable
drug. It can be used continuously at the dosages required for malaria prophylaxis
for as long as five years without risk of undue accumulation and it is included in
the WHO Model List of Essential Drugs for both its antimalarial and antiamoebic
activity.
(Reference: (WHTAC1) The Use of Essential Drugs, 2nd Report of the WHO Expert
Committee, 722, , 1985)
Antimicrobial activity
Chloroquine accumulates 300-fold in infected erythrocytes
and acts against the early erythrocytic stages of all four species
of Plasmodium that cause human malaria. It is also active
against the gametocytes of P. vivax, P. ovale and P. malariae,
but not against the hepatic stages or mature erythrocytic
schizonts
and merozoites.
Acquired resistance
Resistance of P. falciparum is widespread and has become a
major problem. The mechanism appears to be either decreased
uptake or increased efflux of the drug by the parasite,
or both.
Changes in genes encoding a P-glycoprotein homolog, Pfmdr1,
and another putative transporter, Pfcrt, are associated with resistance.
Reversal of resistance with, for example, verapamil or
probenecid has been demonstrated in experimental models, but
human trials have been disappointing. Chloroquine-resistant P.
vivax has been reported in South America and South East Asia.
Hazard
Toxic by ingestion. Questionable carcinogen.
Pharmazeutische Anwendungen
A synthetic 4-aminoquinoline, formulated as the phosphate
or sulfate for oral administration and as the hydrochloride or
sulfate for parenteral use. The salts are soluble in water.
Mechanism of action
The absorption of chloroquine from the gastrointestinal
tract is rapid and complete. The drug is distributed
widely and is extensively bound to body tissues,
with the liver containing 500 times the blood concentration.
Such binding is reflected in a large volume of distribution
(Vd). Desethylchloroquine is the major
metabolite formed following hepatic metabolism, and
both the parent compound and its metabolites are
slowly eliminated by renal excretion.The half-life of the
drug is 6 to 7 days.
Pharmakokinetik
Oral absorption: 80–90%
C
max 300 mg oral: 0.25 mg/L after 1–6 h
Plasma half-life: c. 9 days (mean)
Volume of distribution: 200 L/kg
Plasma protein binding: 50–70%
There is extensive tissue binding and a high affinity for melanin-
containing tissues. Chloroquine is extensively metabolized
to a biologically active monodesethyl derivative that
forms about 20% of the plasma level of the drug. The mean
elimination half-life results from an initial phase (3–6 days),
a slow phase (12–14 days) and a terminal phase (40 days).
Renal clearance is about 50% of the dose.
Clinical Use
The drug is effective against all four types of malaria
with the exception of chloroquine-resistant P. falciparum.
Chloroquine destroys the blood stages of the infection
and therefore ameliorates the clinical symptoms
seen in P. malariae, P. vivax, P. ovale, and sensitive P. falciparum
forms of malaria. The disease will return in P.
vivax and P. ovale malaria, however, unless the liver
stages are sequentially treated with primaquine after
the administration of chloroquine. Chloroquine also can
be used prophylactically in areas where resistance does
not exist. In addition to its use as an antimalarial,
chloroquine has been used in the treatment of rheumatoid
arthritis and lupus erythematosus,
extraintestinal amebiasis, and photoallergic reactions.
Nebenwirkungen
Minor side effects such as dizziness, headache, rashes, nausea
and diarrhea are common. Pruritus occurs in up to 20%
of Africans taking chloroquine. Long-term treatment can
induce CNS effects and cumulative dosing over many years
may cause retinopathy. Rarely, photosensitization, tinnitus
and deafness have occurred.
Environmental Fate
The exact mechanism of action of CQ and HCQ is not
completely understood but involves inhibition of DNA and
RNA polymerase. They are also direct myocardial depressants
that impair cardiac conduction through membrane stabilization.
It is unclear how they work in autoimmune diseases.
Chloroquin Upstream-Materialien And Downstream Produkte
Upstream-Materialien
Downstream Produkte