Chloroquine

Chloroquine is a medication primarily used to prevent and treat malaria in areas where malaria remains sensitive to its effects. It is also occasionally used for amebiasis that is occurring outside the intestines, rheumatoid arthritis, and lupus erythematosus. Chloroquine was discovered in 1934 by Hans Andersag and became widely used in the late 1940s. It is on the World Health Organization's List of Essential Medicines, the safest and most effective medicines needed in a health system.

Chemical Properties and Mechanism of Action

Chloroquine is a 4-aminoquinoline compound with a complex chemical structure that includes a quinoline ring and an amino side chain. Its chemical formula is C18H26ClN3, and it is typically administered as chloroquine phosphate or chloroquine sulfate. The drug works by accumulating in the food vacuoles of Plasmodium species, the parasites responsible for malaria. It inhibits the polymerization of heme to hemozoin, leading to the accumulation of toxic heme, which is lethal to the parasite. Additionally, chloroquine has immunomodulatory effects, which make it useful in autoimmune diseases like rheumatoid arthritis and lupus.

Pharmacokinetics

Chloroquine is well-absorbed from the gastrointestinal tract, with bioavailability ranging from 75% to 90%. It is widely distributed in body tissues, including the liver, spleen, kidney, and lungs, and has a large volume of distribution. The drug is metabolized in the liver by cytochrome P450 enzymes, primarily CYP3A4, and its metabolites are excreted in the urine. The half-life of chloroquine is long, ranging from 20 to 60 days, which allows for once-weekly dosing for malaria prophylaxis.

Clinical Uses

1. Malaria: Chloroquine is used for the prevention and treatment of malaria caused by Plasmodium vivax, Plasmodium ovale, Plasmodium malariae, and some strains of Plasmodium falciparum. However, widespread resistance in P. falciparum has limited its use in many regions. For prophylaxis, it is typically taken once a week, starting 1-2 weeks before traveling to an endemic area and continuing for 4 weeks after leaving.

2. Amebiasis: Chloroquine is used as an adjunct to other treatments for extraintestinal amebiasis, particularly amebic liver abscess.

3. Rheumatoid Arthritis and Lupus Erythematosus: Chloroquine and its derivative hydroxychloroquine are used to manage symptoms of autoimmune diseases. They help reduce inflammation and modulate the immune response.

4. COVID-19: During the COVID-19 pandemic, chloroquine and hydroxychloroquine were investigated as potential treatments. However, subsequent studies found them to be ineffective and associated with significant risks, leading to their disuse for this purpose.

Adverse Effects

Chloroquine is generally well-tolerated, but it can cause a range of adverse effects, particularly with long-term use or high doses. Common side effects include gastrointestinal disturbances (nausea, vomiting, diarrhea), headache, dizziness, and blurred vision. More serious adverse effects include retinopathy, which can lead to permanent vision loss, cardiomyopathy, and myopathy. Chloroquine can also cause hypoglycemia, especially in patients with diabetes, and can exacerbate psoriasis.

Contraindications and Precautions

Chloroquine is contraindicated in patients with known hypersensitivity to 4-aminoquinoline compounds. It should be used with caution in patients with pre-existing retinal or visual field changes, myopathy, or neurological disorders. Due to its potential to cause QT prolongation, it should be avoided in patients with known heart conditions or those taking other QT-prolonging drugs. Regular ophthalmological examinations are recommended for patients on long-term therapy.

Resistance

Resistance to chloroquine has become a significant problem, particularly in P. falciparum. Resistance is primarily due to mutations in the PfCRT (Plasmodium falciparum chloroquine resistance transporter) gene, which reduces the drug's accumulation in the parasite's food vacuole. This has led to the use of alternative antimalarial drugs, such as artemisinin-based combination therapies (ACTs), in many parts of the world.

Historical and Social Impact

Chloroquine played a crucial role in the global fight against malaria, particularly in the mid-20th century. It was a key component of malaria eradication campaigns and significantly reduced malaria-related morbidity and mortality. However, the emergence of resistance has diminished its effectiveness, highlighting the need for ongoing research and development of new antimalarial drugs.

Conclusion

Chloroquine remains an important drug in the medical arsenal, particularly for malaria prophylaxis and treatment in areas without resistance. Its immunomodulatory effects also make it valuable in managing autoimmune diseases. However, its use must be carefully monitored due to the risk of serious adverse effects, and its role in malaria treatment is increasingly limited by resistance. Ongoing research into new antimalarial therapies and strategies to combat resistance is essential to continue the fight against malaria and other diseases for which chloroquine has been historically significant.