LARAQUIN TABLETS

Indications

• Treatment of malaria caused by Plasmodium falciparum
• Prophylaxis of malaria in areas with chloroquine-sensitive strains
• Potential use in autoimmune diseases such as rheumatoid arthritis and lupus erythematosus

Dosage

Children: Refer

Adults: For the treatment of malaria, the usual adult dose is 600 mg (base) initially, followed by 300 mg at 6-8 hours, and then 300 mg on the second and third days. For prophylaxis, 300 mg weekly is recommended for adults.

Mechanism of action

Chloroquine inhibits the action of heme polymerase in malarial trophozoites, preventing the conversion of heme to hemazoin, leading to the accumulation of toxic heme and killing the parasite. It diffuses through cell membranes and into endosomes, lysosomes, and Golgi vesicles, where it becomes protonated, raising the pH and interfering with the parasite's metabolism. Additionally, chloroquine affects the glycosylation of ACE2, potentially impacting viral entry mechanisms.

Pharmacodynamics

Chloroquine inhibits heme polymerase, causing toxic heme accumulation in Plasmodium species. It has a long duration of action, with a half-life of 20-60 days. Long-term use or high doses can lead to retinopathy, muscle weakness, and increased toxicity risk in children.

Pharmacokinetics

Chloroquine is rapidly absorbed from the gastrointestinal tract, with peak plasma concentrations occurring within 1-3 hours. It has a large volume of distribution and is extensively bound to plasma proteins. The drug is metabolized in the liver and eliminated primarily via the kidneys. The half-life ranges from 20 to 60 days, contributing to its prolonged effects.

Contra-indications

• Known hypersensitivity to chloroquine or any of its components
• Pre-existing retinal or visual field abnormalities
• Porphyria

Adverse effects

• Abdominal pain
• Anxiety
• Cardiomyopathy
• Dizziness
• Drowsiness
• Hallucination
• Headache
• Nausea
• Photosensitivity reactions
• QT interval prolongation
• Skin reactions
• Thrombocytopenia
• Vomiting

Interactions

• Agalsidase alpha: Severe interaction (decreases effects)
• Agalsidase beta: Severe interaction (decreases effects)
• Penicillamine: Severe interaction (increases risk of haematological toxicity)
• Rabies vaccine: Severe interaction (decreases efficacy)
• Remdesivir: Severe interaction (decreases effects)
• Praziquantel: Moderate interaction (decreases exposure)
• Oral antacids: Unknown interaction (decreases absorption)
• Oral cholera vaccine: Unknown interaction (decreases efficacy)
• Lanthanum: Unknown interaction (decreases absorption)

Precautions

• Caution in patients with hepatic impairment
• Caution in patients with renal impairment
• Monitoring of ECG and plasma potassium concentration is advised in patients with underlying cardiovascular conditions
• Use with caution in patients with a history of seizures
• Patients should be monitored for signs of retinopathy with long-term use

Pregnancy

Chloroquine is teratogenic in animal studies, and the manufacturer advises use only if other antimalarials cannot be used.

Breast-feeding

The manufacturer advises avoiding chloroquine during breastfeeding as it is present in milk in animal studies.

Storage

Store in a cool, dry place, away from light. Keep out of reach of children.

Formulations

• Chloroquine phosphate 250 mg tablets
• Chloroquine syrup 50 mg/5 mL

Mechanism of action

Chloroquine inhibits the action of heme polymerase in malarial trophozoites, preventing the conversion of heme to hemazoin. _Plasmodium_ species continue to accumulate toxic heme, killing the parasite. Chloroquine passively diffuses through cell membranes and into endosomes, lysosomes, and Golgi vesicles; where it becomes protonated, trapping the chloroquine in the organelle and raising the surrounding pH. The raised pH in endosomes, prevent virus particles from utilizing their activity for fusion and entry into the cell. Chloroquine does not affect the level of ACE2 expression on cell surfaces, but inhibits terminal glycosylation of ACE2, the receptor that SARS-CoV and SARS-CoV-2 target for cell entry. ACE2 that is not in the glycosylated state may less efficiently interact with the SARS-CoV-2 spike protein, further inhibiting viral entry. The exact mechanism of antimalarial activity of chloroquine has not been determined. The 4-aminoquinoline derivatives appear to bind to nucleoproteins and interfere with protein synthesis in susceptible organisms; the drugs intercalate readily into double-stranded DNA and inhibit both DNA and RNA polymerase. In addition, studies using chloroquine indicate that the drug apparently concentrates in parasite digestive vacuoles, increases the pH of the vacuoles, and interferes with the parasite's ability to metabolize and utilize erythrocyte hemoglobin. Plasmodial forms that do not have digestive vacuoles and do not utilize hemoglobin, such as exoerythrocytic forms, are not affected by chloroquine. The 4-aminoquinoline derivatives, including chloroquine, also have anti-inflammatory activity; however, the mechanism(s) of action of the drugs in the treatment of rheumatoid arthritis and lupus erythematosus has not been determined. Chloroquine reportedly antagonizes histamine in vitro, has antiserotonin effects, and inhibits prostaglandin effects in mammalian cells presumably by inhibiting conversion of arachidonic acid to prostaglandin F2. In vitro studies indicate that chloroquine also inhibits chemotaxis of polymorphonuclear leukocytes, macrophages, and eosinophils. Antiprotozoal-Malaria: /Mechanism of action/ may be based on ability of chloroquine to bind and alter the properties of DNA. Chloroquine also is taken up into the acidic food vacuoles of the parasite in the erythrocyte. It increases the pH of the acid vesicles, interfering with vesicle functions and possibly inhibiting phospholipid metabolism. In suppressive treatment, chloroquine inhibits the erythrocytic stage of development of plasmodia. In acute attacks of malaria, chloroquine interrupts erythrocytic schizogony of the parasite. its ability to concentrate in parasitized erythrocytes may account for its selective toxicity against the erythrocytic stages of plasmodial infection. Antirheumatic-Chloroquine is though to act as a mild immunosuppressant, inhibiting the production of rheumatoid factor and acute phase reactants. It also accumulates in white blood cells, stabilizing lysosomal membranes and inhibiting the activity of many enzymes, including collagenase and the proteases that cause cartilage breakdown.

Pharmacodynamics

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.