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.
Chloroquine is partially metabolized; the major metabolite is desethylchloroquine. Desethylchloroquine also has antiplasmodial activity, but is slightly less active than chloroquine. Bisdesethylchloroquine, which is a carboxylic acid derivative, and several other unidentified metabolites are also formed in small amounts.
Completely absorbed from gastrointestinal tract. Chloroquine is partially metabolized; the major metabolite is desethylchloroquine. Desethylchloroquine also has antiplasmodial activity, but is slightly less active than chloroquine. Bisdesethylchloroquine, which is a carboxylic acid derivative, and several other unidentified metabolites are also formed in small amounts (A625).
Route of Elimination: Excretion of chloroquine is quite slow, but is increased by acidification of the urine.
Half Life: 1-2 months
IDENTIFICATION: Chloroquine is a white or slightly yellow, odorless crystalline powder with a bitter taste. Very slightly soluble in water, soluble in chloroform, ether and dilute acids. Chloroquine diphosphate is a white, bitter, crystalline powder. Chloroquine sulfate is a white, odorless, bitter, crystalline powder. Hydroxychloride chloroquine is a colorless liquid. Uses: Indications: Malaria: Chloroquine is the drug of choice for the prophylaxis and treatment of malaria caused by Plasmodium vivax. P. ovale, P. malariae and sensitive P. falciparum. Amebiasis: Chloroquine is used for the treatment of extraintestinal amebiasis (usually in combination with amebicides). Treatment of discoid lupus erythematosis and rheumatoid arthritis (acute and chronic). Chloroquine may be used for the treatment of these conditions. Other less common indications are: amebic liver abscess, porphyria cutanea tarda, solar urticaria, chronic cutaneous vasculitis. HUMAN EXPOSURE: Main risks and target organs: The main toxic effects of chloroquine are related to its quinidine-like (membrane stabilizing) actions on the heart. Other acute effects are respiratory depression and severe gastro-intestinal irritation. Summary of clinical effects: Toxic manifestations appear rapidly within one to three hours after ingestion and include: Cardiac disturbances: circulatory arrest, shock, conduction disturbances, ventricular arrhythmias. Neurological symptoms: drowsiness, coma and sometimes convulsions. Visual disturbances not uncommon. Respiratory symptoms: apnea. Gastrointestinal symptoms: severe gastrointestinal irritation; nausea, vomiting, cramps, diarrhea. Children are specially sensitive to toxic effects. Dizziness, nausea, vomiting, diarrhea, headache, drowsiness, blurred vision, diplopia, blindness, convulsions, coma, hypotension, cardiogenic shock, cardiac arrest and impaired respiration are the characteristic features of chloroquine poisoning. Electrocardiography (ECG) may show decrease of T wave, widening of QRS, ventricular tachycardia and fibrillation. Hypokalemia is associated with severe poisoning. Contraindications: Hepatic and renal function impairment, blood disorders, gastrointestinal illnesses, glucose-6-phosphate dehydrogenase (G-6-PD) deficiency, severe neurological disorders, retinal or visual field changes. Chloroquine should not be used in association with gold salts or phenylbutazone. Routes of entry: Oral: Oral absorption is the most frequent cause of intoxication. Parenteral: Intoxication after parenteral administration is rare. A fatal outcome reported was after 250 mg IV chloroquine in a 42-year-old man. Absorption by route of exposure: Readily and almost completely absorbed from the gastrointestinal tract. Bioavailability is 89% for tablets. Peak plasma concentration is reached 1.5 to 3 hours after ingestion. Distribution by route of exposure: Protein binding: 5O to 65%. Chloroquine accumulates in high concentrations in kidney, liver, lung and spleen, and is strongly bound in melanin-containing cells (eye and skin). Red cell concentration is five to ten times the plasma concentration. Very low concentrations are found in the intestinal wall. Crosses the placenta. Biological half-life by route of exposure: Plasma terminal half-life is mean 278 hours or 70 to 120 hours. Shorter plasma elimination half-lives have been reported in children: 75 to 136 hours. Metabolism: Chloroquine undergoes metabolism by hepatic mechanisms. The main active metabolite is desethylchloroquine. Plasma half-life of desethylchloroquine is similar to chloroquine. Elimination by route of exposure: Chloroquine is eliminated very slowly. About 55% is excreted in urine and 19% in feces within 77 days following therapy with 310 mg for 14 days. Kidney: in urine about 70% is unchanged chloroquine and 23% is desethylchloroquine. It is excreted in breast milk. Toxicodynamics: The cardiotoxicity of chloroquine is related to it quinidine-like (membrane/stabilizing) effects. Chloroquine has a negative inotropic action, inhibits spontaneous diastolic depolarization, slows conduction, lengthens the effective refractory period and raises the electrical threshold. This results in depression of contractility, impairment of conductivity, decrease of excitability, but with possible abnormal stimulus re-entry mechanism. Hypokalemia: Acute hypokalemia may occur in acute poisoning. It is probably related to intracellular transport of potassium by a direct effect on cellular membrane permeability. Neurological symptoms: Neurological symptoms in acute overdose may be related to a direct toxic effect on CNS or to cerebral ischemia due to circulatory failure or respiratory insufficiency. The mechanism of the anti-inflammatory effect is not known. Toxicity: Human data: Chloroquine has a low margin of safety; the therapeutic, toxic and lethal doses are very close. Fatalities have been reported in children after chloroquine overdoses. Interactions: Chloroquine toxicity may be increased by all drugs with quinidine-like effects. Combination with hepatotoxic or dermatitis-causing medication should be avoided, as well as with heparin (risk of hemorrhage) and penicillamine. Eye: Keratopathy and retinopathy may occur when large doses of chloroquine are used for long periods. Changes occurring in the cornea are usually completely reversible on discontinuing treatment; changes in the retina, pigmentary degeneration of the retina, loss of vision, scotomas, optic nerve atrophy, field defects and blindness are irreversible. Retinopathy is considered to occur when the total cumulative dose ingested exceeds 100 g. Blurring of vision, diplopia may occur with short-term chloroquine therapy and are reversible. ANIMAL/PLANT STUDIES: The following progression of ECG changes was observed in dogs with experimental overdosage: severe tachycardia preceded by loss of voltage and widening of QRS, followed by sinus bradycardia, ventricular tachycardia, ventricular fibrillation and finally asystole.
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.
Despite use for more than 50 years, chloroquine has rarely been linked to serum aminotransferase elevations or to clinically apparent acute liver injury. In patients with acute porphyria and porphyria cutanea tarda, chloroquine can trigger an acute attack with fever and serum aminotransferase elevations, sometimes resulting in jaundice. Hydroxychloroquine does not cause this reaction and appears to have partial beneficial effects in porphyria. In clinical trials of chloroquine for COVID-19 prevention and treatment, there were no reports of hepatotoxicity, and rates of serum enzyme elevations during chloroquine treatment were low and similar to those in patients receiving placebo or standard of care.
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.
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.
Chloroquine is rapidly and almost completely absorbed from the GI tract following oral administration, and peak plasma concn of the drug are generally attained within 1-2 hr. Considerable interindividual variations in serum concn of chloroquine have been reported. Oral administration of 310 mg of chloroquine daily reportedly results in peak plasma concn of about 0.125 ug/mL. If 500 mg of chloroquine is administered once weekly, peak plasma concn of the drug reportedly range from 0.15-0.25 ug/mL and trough plasma concn reportedly range from 0.02-0.04 ug/mL. Results of one study indicate that chloroquine may exhibit nonlinear dose dependent pharmacokinetics. In this study, administration of a single 500 mg oral dose of chloroquine resulted in a peak serum concentration of 0.12 ug/mL, and administration of a single 1 g oral dose of the drug resulted in a peak serum concentration of 0.34 ug/mL.
