Chloroquine Stats & Data
Pharmacology
DrugBankDescription
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 **The FDA emergency use authorization for hydroxychloroquine and chloroquine in the treatment of COVID-19 was revoked on 15 June 2020.** Chloroquine was granted FDA Approval on 31 October 1949.
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.
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.
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.
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.
Indication
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.
Half-life
The half life of chloroquine is 20-60 days.
Protein Binding
Chloroquine is 46-74% bound to plasma proteins. (-)-chloroquine binds more strongly to alpha-1-acid glycoprotein and (+)-chloroquine binds more strongly to serum albumin.
Elimination
Chloroquine is predominantly eliminated in the urine. 50% of a dose is recovered in the urine as unchanged chloroquine, with 10% of the dose recovered in the urine as desethylchloroquine.
Volume of Distribution
The volume of distribution of chloroquine is 200-800L/kg.
Clearance
Chloroquine has a total plasma clearance of 0.35-1L/h/kg.