Hydroxychloroquine

335.88

335.87

204-249-8

DTXSID8023135

P01BA02|P - Antiparasitic products, insecticides and repellents

2933499090

48.4

3.85600

Solid

1.1438 (rough estimate)

90 °C

516.7±50.0 °C(Predicted)

266.3ºC

1.5790 (estimate)

2.61e-02 g/L

9.67None

9.67

180.2 Ų [M+H]+ [CCS Type: TW, Method: Major Mix IMS/Tof Calibration Kit (Waters)]

R22;R36

S26

Xn

P264, P270, P301+P312, P330, P501

H302

|Warning|H302 (100%): Harmful if swallowed [Warning Acute toxicity, oral]|P264, P270, P301+P312, P330, and P501|Aggregated GHS information provided by 39 companies from 1 notifications to the ECHA C&L Inventory.

Patients experiencing an overdose may present with headache, drowsiness, visual disturbances, cardiovascular collapse, convulsions, hypokalemia, rhythm and conduction disorders including QT prolongation, torsades de pointes, ventricular tachycardia, and ventricular fibrillation. This may progress to sudden respiratory and cardiac arrest. Overdose should be treated with immediate gastric lavage and activated charcoal at a dose of at least 5 times the hydroxychloroquine dose within 30 minutes. Parenteral diazepam may be given to treat cardiotoxicity, transfusion may reduce serum concentrations of drug, patients should be monitored for at least 6 hours, fluids should be given, and ammonium chloride should be given to acidify urine and promote urinary excretion. Patients may also be given epinephrine.

Hydroxychloroquine has not been associated with significant serum enzyme elevations during therapy of rheumatologic diseases. Furthermore, clinically apparent liver injury from hydroxychloroquine is rare. A single case series (two cases) of acute liver failure attributed to hydroxychloroquine was published twenty years ago, but case reports of clinically apparent liver injury have not appeared subsequently. Thus, acute liver injury with jaundice due to hydroxychloroquine must be very rare, if it occurs at all. In clinical trials of hydroxychloroquine for COVID-19 prevention and treatment, there were no reports of hepatotoxicity and rates of serum enzyme elevations during hydroxychloroquine treatment were low and similar to those in patients receiving placebo or comparator agents.

The S enantiomer of hydroxychloroquine is 64% protein bound in plasma. It is 50% bound to serum albumin and 29% bound to alpha-1-acid glycoprotein. The R enantiomer is 37% protein bound in plasma. It is 29% bound to serum albumin and 41% bound to alpha-1-acid glycoprotein. In total, hydroxychloroquine is 50% protein bound in plasma.

Hydroxychloroquine is indicated for the prophylaxis of malaria where chloroquine resistance is not reported, treatment of uncomplicated malaria (caused by _P. falciparum_, _P. malariae_, _P. ovale_, or _P. vivax_), chronic discoid lupus erythematosus, systemic lupus erythematosus, acute rheumatoid arthritis, and chronic rheumatoid arthritis.

Hydroxychloroquine is a derivative of chloroquine that has both antimalarial and antiinflammatory activities and is now most often used as an antirheumatologic agent in systemic lupus erythematosis and rheumatoid arthritis. Hydroxychloroquine therapy has not been associated with liver function abnormalities and is an extremely rare cause of clinically apparent acute liver injury.

Antirheumatic Agents

Hydroxychloroquine affects the function of lysozomes in humans as well as plasmodia. Altering the pH of the lysozomes reduces low affinity self antigen presentation in autoimmue diseases and interferes with the ability of plasmodia to proteolyse hemoglobin for their energy requirements. Hydroxychloroquine has a long duration of action as it may be taken on a weekly basis for some indications. Hydroxychloroquine may lead to severe hypoglycemia and so diabetic patients are advised to monitor their blood glucose levels. Hydroxychloroquine is not effective against malaria in areas where chloroquine resistance has been reported.

Agents used in the treatment of malaria. They are usually classified on the basis of their action against plasmodia at different stages in their life cycle in the human. (From AMA, Drug Evaluations Annual, 1992, p1585) (See all compounds classified as Antimalarials.)|Drugs that are used to treat RHEUMATOID ARTHRITIS. (See all compounds classified as Antirheumatic Agents.)|Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction. (See all compounds classified as Enzyme Inhibitors.)

Hydroxychloroquine is 67-74% bioavailable. Bioavailability of the R and S enantiomers were not significantly different. Following a 200mg oral dose, hydroxychloroquine reached a C_max of 129.6ng/mL with a T_max of 3.26h in the blood and a C_max of 50.3ng/mL with a T_max of 3.74h in the plasma. Following 155mg and 310mg intravenous doses, C_max in the blood ranged from 1161-2436ng/mL with an average of 1918ng/mL.|40-50% of hydroxychloroquine is excreted renally, while only 16-21% of a dose is excreted in the urine as unchanged drug. 5% of a dose is sloughed off in skin and 24-25% is eliminated through the feces.|Hydroxychloroquine has a volume of distribution of 5522L from blood and 44,257L from plasma.|The clearance of hydroxychloroquine is 96mL/min.

Hydroxychloroquine is N-dealkylated by CYP3A4 to the active metabolite desethylhydroxychloroquine, as well as the inactive metabolites desethylchloroquine and bidesethylchloroquine. Desethylhydroxychloroquine is the major metabolite.

Oral hydroxychloroquine has an absorption half life of 3-4 hours. A 200mg oral dose of hydroxychloroquine has a half life of 537 hours or 22.4 days in blood, and 2963 hours or 123.5 days in plasma. A 155mg intravenous dose has a half life of 40 days.

The exact mechanisms of hydroxychloroquine are unknown. It has been shown that hydroxychloroquine accumulates in the lysosomes of the malaria parasite, raising the pH of the vacuole. This activity interferes with the parasite's ability to proteolyse hemoglobin, preventing the normal growth and replication of the parasite. Hydroxychloroquine can also interfere with the action of parasitic heme polymerase, allowing for the accumulation of the toxic product beta-hematin. Hydroxychloroquine accumulation in human organelles also raise their pH, which inhibits antigen processing, prevents the alpha and beta chains of the major histocompatibility complex (MHC) class II from dimerizing, inhibits antigen presentation of the cell, and reduces the inflammatory response. Elevated pH in the vesicles may alter the recycling of MHC complexes so that only the high affinity complexes are presented on the cell surface. Self peptides bind to MHC complexes with low affinity and so they will be less likely to be presented to autoimmune T cells. Hydroxychloroquine also reduces the release of cytokines like interleukin-1 and tumor necrosis factor, possibly through inhibition of Toll-like receptors. The raised pH in endosomes, prevent virus particles (such as SARS-CoV and SARS-CoV-2) from utilizing their activity for fusion and entry into the cell. Hydroxychloroquine 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.

Hydroxychlorochin

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