indication

For the suppressive treatment and for acute attacks of malaria due to P. vivax, P.malariae, P. ovale, and susceptible strains of P. falciparum, Second-line agent in treatment of Rheumatoid Arthritis

pharmacology

Chloroquine is the prototype anti malarial drug, most widely used to treat all types of malaria except for disease caused by chloroquine resistant Plasmodium falciparum. It is highly effective against erythrocytic forms of Plasmodium vivax, Plasmodium ovale and Plasmodium malariae, sensitive strains of Plasmodium falciparum and gametocytes of Plasmodium vivax. Being alkaline, the drug reaches high concentration within the food vacuoles of the parasite and raises its pH. It is found to induce rapid clumping of the pigment. Chloroquine inhibits the parasitic enzyme heme polymerase that converts the toxic heme into non-toxic hemazoin, thereby resulting in the accumulation of toxic heme within the parasite. It may also interfere with the biosynthesis of nucleic acids.

mechanism of action

The mechanism of plasmodicidal action of chloroquine is not completely certain. Like other quinoline derivatives, it is thought to inhibit heme polymerase activity. This results in accumulation of free heme, which is toxic to the parasites. nside red blood cells, the malarial parasite must degrade hemoglobin to acquire essential amino acids, which the parasite requires to construct its own protein and for energy metabolism. Digestion is carried out in a vacuole of the parasite cell. During this process, the parasite produces the toxic and soluble molecule heme. The heme moiety consists of a porphyrin ring called Fe(II)-protoporphyrin IX (FP). To avoid destruction by this molecule, the parasite biocrystallizes heme to form hemozoin, a non-toxic molecule. Hemozoin collects in the digestive vacuole as insoluble crystals. Chloroquine enters the red blood cell, inhabiting parasite cell, and digestive vacuole by simple diffusion. Chloroquine then becomes protonated (to CQ2+), as the digestive vacuole is known to be acidic (pH 4.7); chloroquine then cannot leave by diffusion. Chloroquine caps hemozoin molecules to prevent further biocrystallization of heme, thus leading to heme buildup. Chloroquine binds to heme (or FP) to form what is known as the FP-Chloroquine complex; this complex is highly toxic to the cell and disrupts membrane function. Action of the toxic FP-Chloroquine and FP results in cell lysis and ultimately parasite cell autodigestion. In essence, the parasite cell drowns in its own metabolic products.

biotransformation

Hepatic (partially)

absorption

Completely absorbed from gastrointestinal tract

half life

1-2 months

route of elimination

Excretion of chloroquine is quite slow, but is increased by acidification of the urine.

drug interactions

Aluminium: The antiacid decreases the absorption of chloroquine

Artemether: Chloroquine may increase the adverse effects of artemether. Combination therapy is contraindicated unless there are no other treatment options.

Atomoxetine: The CYP2D6 inhibitor could increase the effect and toxicity of atomoxetine

Attapulgite: The antiacid decreases the absorption of chloroquine

Calcium: The antiacid decreases the absorption of chloroquine

Cyclosporine: Chloroquine may increase the therapeutic and adverse effects of cyclosporine.

Dihydroxyaluminium: The antiacid decreases the absorption of chloroquine

Kaolin: The antiacid decreases the absorption of chloroquine

Lumefantrine: Chloroquine may increase the adverse effects of lumefantrine. Combination therapy is contraindicated unless there are no other treatment options.

Magnesium: The antiacid decreases the absorption of chloroquine

Magnesium oxide: The antiacid decreases the absorption of chloroquine

Mesoridazine: Increased risk of cardiotoxicity and arrhythmias

Praziquantel: Markedly lower praziquantel levels

Tamoxifen: Chloroquine may decrease the therapeutic effect of Tamoxifen by decreasing the production of active metabolites. Consider alternate therapy.

Tamsulosin: Chloroquine, a CYP2D6 inhibitor, may decrease the metabolism and clearance of Tamsulosin, a CYP2D6 substrate. Monitor for changes in therapeutic/adverse effects of Tamsulosin if Chloroquine is initiated, discontinued, or dose changed.

Telithromycin: Telithromycin may reduce clearance of Chloroquine. Consider alternate therapy or monitor for changes in the therapeutic/adverse effects of Chloroquine if Telithromycin is initiated, discontinued or dose changed.

Terbinafine: Terbinafine may reduce the metabolism and clearance of Chloroquine. Consider alternate therapy or monitor for therapeutic/adverse effects of Chloroquine if Terbinafine is initiated, discontinued or dose changed.

Thioridazine: Increased risk of cardiotoxicity and arrhythmias

Tramadol: Chloroquine may decrease the effect of Tramadol by decreasing active metabolite production.

Voriconazole: Voriconazole, a strong CYP3A4 inhibitor, may increase the serum concentration of chloroquine by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of chloroquine if voriconazole is initiated, discontinued or dose changed.