CHLOROQUINE

Absorption

Chloroquine oral solution has a bioavailability of 52-102% and oral tablets have a bioavailability of 67-114%. Intravenous chloroquine reaches a Cmax of 650-1300μg/L and oral chloroquine reaches a Cmax of 65-128μg/L with a Tmax of 0.5h.

Toxicity

Patients experiencing an overdose may present with headache, drowsiness, visual disturbances, nausea, vomiting, cardiovascular collapse, shock, convulsions, respiratory arrest, cardiac arrest, and hypokalemia. Overdose should be managed with symptomatic and supportive treatment which may include prompt emesis, gastric lavage, and activated charcoal.

Description

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.

Chemical properties

solid

The Uses of CHLOROQUINE

Medicine (antimalarial). Usually dispensed as the phosphate.

The Uses of CHLOROQUINE

Chloroquine used in the treatment of malaria and MDR-strains. It is a COVID19-related research product.

The Uses of CHLOROQUINE

CQ and HCQ are both used as anti-inflammatory and antimalarial drugs.

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.

Indications

Chloroquine may be the drug of choice, but only in areas where chloroquine-sensitive P. falciparum organisms are present. Chloroquine prophylaxis is no longer effective for travel to many regions. Daily atovaquone–proguanil appears to be the first choice for chemoprophylaxis for travel to areas of chloroquine resistance. Prophylactic drugs, such as chloroquine or mefloquine, should be started 2 to 4 weeks prior to travel and continued for 6 to 8 weeks after leaving the endemic areas. The atovaquone–proguanil combination is the exception in that it is started 1 to 2 days prior to departure and is continued 1 week after return.

Indications

Chloroquine is indicated to treat infections of P. vivax, P. malariae, P. ovale, and susceptible strains of P. falciparum. It is also used to treat extraintestinal amebiasis.
Chloroquine is also used off label for the treatment of rheumatic diseases, as well as treatment and prophylaxis of Zika virus. Chloroquine is currently undergoing clinical trials for the treatment of COVID-19.

Background

Chloroquine is an aminoquinolone derivative first developed in the 1940s for the treatment of malaria. It was the drug of choice to treat malaria until the development of newer antimalarials such as pyrimethamine, artemisinin, and mefloquine. Chloroquine and its derivative hydroxychloroquine have since been repurposed for the treatment of a number of other conditions including HIV, systemic lupus erythematosus, and rheumatoid arthritis.
The FDA emergency use authorization for hydroxychloroquine and chloroquine in the treatment of COVID-19 was revoked on 15 June 2020.
Chloroquine was granted FDA Approval on 31 October 1949.

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.

brand name

Aralen hcl;Aralin (diphosphate);Artrochin;Avloclor (diphosphate);Endamal;Erestol;Hiliopar;Instana;Lagaquin;Letaquine;Malaraquin;Malarex (diphosphate);Malariron (diphosphate);Malquin;Miniquine;Nivaquine b';Nivembin;Norolon;Pfizerquin;Resichin;Resochin (diphosphate);Rivoquin;Salestol;Scaniquine (diphosphate);Serviquin;Siragon.

World Health Organization (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.

Pharmaceutical Applications

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.

Pharmacology

Chloroquine is the drug of choice for preventing and treating acute forms of malaria caused by P. vivax, P. malariae, P. ovale, as well as sensitive forms of P. falciparum. The mechanism of its action is not completely clear, although there are several hypotheses explaining its antimalarial activity. Chloroquine and its analogs inhibit synthesis of nucleic acids of the parasite by affecting the matrix function of DNA. This happens by preliminary binding of the drug through hydrogen bonds with the purine fragments, and subsequent introduction of the chloroquine molecule between the orderly arranged base pairs into the spirals of the DNA of the parasite. Thus chloroquine prevents transcription and translation, which significantly limits the synthesis of DNA and RNA in the parasite. The selective toxicity of chloroquine in particular with respect to malarial plasmodia is also attributed to the ability of the parasitized red blood cells to concentrate the drug in amounts approximately 25 times greater than in normal erythrocytes.
There is also a different hypothesis. Chloroquine has a high affinity for tissues of the parasite and is concentrated in its cytoplasm. As a weak base, it increases the pH of the intracellular lysosome and endosome. A more acidic medium in these organelles is needed for the parasite to affect mammalian cells. As a result, chloroquine inhibits growth and development of parasites.
Thus the main quality of chloroquine that exceeds all other antimalarial drug is its effect on erythrocytic schizonts (hematoschizotropic action). However, chloroquine also possesses amebicidal action. It has also been observed to have immunodepressive and antiarrhythmic properties.
It is used for all types of malaria, for chemotherapy, as well as for non-gastric amebiasis, and amebic abscesses of the liver. Synonyms of this drug are nivaquine, quingamine, delagil, resoquine, atroquine, and others.

Pharmacokinetics

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.

Pharmacokinetics

Chloroquine inhibits the action of heme polymerase, which causes the buildup of toxic heme in Plasmodium species. It has a long duration of action as the half life is 20-60 days. Patients should be counselled regarding the risk of retinopathy with long term usage or high dosage, muscle weakness, and toxicity in children.

Clinical Use

Prophylaxis and treatment of all types of malaria
Hepatic amebiasis (in sequential combination with dehydroemetine)
A combination with azithromycin has been suggested for intermittent preventive treatment.

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.

Side Effects

Dizziness, headache, itching (especially in darkskinned people), skin rash, vomiting, and blurring of vision may occur following low doses of chloroquine. In higher dosages these symptoms are more common, and exacerbation or unmasking of lupus erythematosus or discoid lupus, as well as toxic effects in skin, blood, and eyes can occur. Since the drug concentrates in melanincontaining structures, prolonged administration of high doses can lead to blindness. Chloroquine should not be used in the presence of retinal or visual field changes.

Side Effects

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.

Synthesis

Chloroquine, 7-chloro-4-(4-diethylamino-1-methylbutylamino)-quinoline (37.1.3), is made by reacting 4,7-dichloroquinoline (37.1.1.1) with 4-diethylamino- 1-methylbutylamine (37.1.1.2) at 180 °C.

In order to realize the synthesis, the necessary 4,7-dichloroquinoline (37.1.1.1) is prepared in several ways from 3-chloroaniline. One of these ways consists of reacting 3-chloroaniline with ethoxymethylenmalonic ester to make (3-choroanilino)-methylenemalonic ester (37.1.1.4), which then undergoes high-temperature heterocyclization to make the ethyl ester of 7-chloro-4-hydroxyquinolin-3-carboxylic acid (37.1.1.5). Hydrolyzing this with sodium hydroxide gives 7-chloro-4-hydroxyquinolin-3-decarboxylic acid (37.1.1.6), which when heated at 250–270 ° C is decarboxylated, forming 7-chloro-4-hydroxyquinoline (37.1.1.7). Treating this with phosphorus oxychloride gives one of the desired components for synthesis of chloroquine – 4,7-dichloroquinoline (37.1.1.1).
The second method of preparing of 4,7-dichloroquinoline (37.1.1.1) consists of reacting 3-chloroaniline with the diethyl ester of oxaloacetic acid in the presence of acetic acid to give the corresponding enamine (37.1.1.8), which when heated to 250 ° C undergoes heterocyclization to the ethyl ester of 7-chloro-4-hydrozyquinolin-2-carboxylic acid (37.1.1.9) accompanied with a small amount of 5-chloro-4-hydroxyquinolin-2-carboxylic acid (37.1.1.10), which is separated from the main product by crystallization from acetic acid. Alkaline hydrolysis of the ethyl ester of the 7-chloro-4-hydroxyquinolin-2-carboxylic acid (37.1.1.9) and subsequent high-temperature decarboxylation of the resulting acid (37.1.1.11) gives 7-chloro-4-hydroxyquinolin (37.1.1.7). Reacting this with phosphorus oxychloride using the scheme described above gives 4,7-dichloroquineoline (37.1.1.1).

Finally, the third of the suggested variants for making 4,7-dichloroquinoline (37.1.1.1) consists of reacting 3-chloroaniline with the ethyl ester of formylacetic acid to make the enamine (37.1.1.12), which on heating directly cyclizes to 7-chloro-4-hydroxyquinoline (37.1.1.7). Reacting this with phophorus oxychloride according to the scheme already described gives 4,7-dichloroquinoline (37.1.1.1).

The second component necessary for synthesizing of the chloroquine is 4-diethylamino- 1-methylbutylamine (37.1.1.2), is also made in various ways. Alkylating acetoacetic ester with 2-diethylaminoethylchloride gives 2-diethylaminoethylacetoacetic acid ester (37.1.1.13), which upon acidic hydrolysis (using hydrochloric acid) and simultaneous decarboxylation makes 1-diethylamino-4-pentanone (37.1.1.14). Reductive amination of this compound with hydrogen and ammonia using Raney nickel as a catalyst gives 4-diethylamino-1-methylbutylamine (37.1.1.2).

Drug interactions

Potentially hazardous interactions with other drugs
Anti-arrhythmics: increased risk of ventricular arrhythmias with amiodarone - avoid.
Antibacterials: increased risk of ventricular arrhythmias with moxifloxacin - avoid; concentration of praziquantel reduced - consider increasing praziquantel dose.
Anti-depressants: possible increased risk of ventricular arrhythmias with citalopram and escitalopram.
Antiepileptics: antagonism of anticonvulsant effect.
Antimalarials: increased risk of convulsions with mefloquine; avoid with artemether/lumefantrine.
Antipsychotics: increased risk of ventricular arrhythmias with droperidol - avoid.
Ciclosporin: increases ciclosporin concentration - increased risk of toxicity.
Cytotoxics: possible increased risk of ventricular arrhythmias with bosutinib, ceritinib and panobinostat.
Digoxin: possibly increased concentration of digoxin.
Lanthanum: absorption possibly reduced by lanthanum, give at least 2 hours apart.

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.

Metabolism

Chloroquine is extensively metabolised in the liver, mainly to monodesethylchloroquine with smaller amounts of bisdesethylchloroquine (didesethylchloroquinine) and other metabolites being formed. Monodesethylchloroquine has been reported to have some activity against Plasmodium falciparum
Chloroquine and its metabolites are excreted in the urine, with about half of a dose appearing as unchanged drug and about 10% as the monodesethyl metabolite.
Chloroquine may be detected in urine for several months.

Metabolism

Chloroquine is N-dealkylated primarily by CYP2C8 and CYP3A4 to N-desethylchloroquine. It is N-dealkylated to a lesser extent by CYP3A5, CYP2D6, and to an ever lesser extent by CYP1A1. N-desethylchloroquine can be further N-dealkylated to N-bidesethylchloroquine, which is further N-dealkylated to 7-chloro-4-aminoquinoline.

Toxicity evaluation

CQ is a white or slightly white odorless crystalline powder. It has a melting point from 87 to 92
C. CQ is slightly soluble in water, and also in chloroform, ether, and dilute acids. Solutions of chloroquine phosphate and hydroxychloroquine sulfate have a pH of 4.5.