Hydroxychloroquine is a drug that was first used to prevent and treat malaria in areas where malaria is sensitive to chloroquine. Today, it is also prescribed to treat rheumatoid arthritis, lupus, and porphyria cutanea tarda. It is taken orally, often in the form of hydroxychloroquine sulfate.
Code ATC: P01BA02
Drug class: Antimalarial – Antiarthritic
Dosage form: Tablet
Available doses: 200 mg
Brand: Rakanil®
Uses: Malaria, rheumatoid arthritis, and lupus erythematosus
Pharmacodynamics of hydroxychloroquine
Hydroxychloroquine affects the function of lysosomes in humans as well as in Plasmodia. Altering the pH of lysosomes reduces the presentation of low-affinity self-antigens in autoimmune diseases and interferes with the ability of Plasmodia to proteolyze hemoglobin for their energy needs. Hydroxychloroquine has a long duration of action because it may be administered weekly for some indications. Hydroxychloroquine may cause severe hypoglycemia, 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.
Mechanism of action
Malaria
- The exact mechanism of action against Plasmodium is unknown.
- Hydroxychloroquine, like chloroquine, is a weak base and may exert its effect by concentrating in the acidic vesicles of the parasite and inhibiting heme polymerization.
- It can also inhibit certain enzymes through its effect on DNA.
Rheumatoid arthritis and lupus erythematosus
The mechanism of the anti-inflammatory and immunomodulatory effects of hydroxychloroquine is unknown.
| Purpose | Performance |
| Toll-like receptor 7 (TLR7) | antagonist |
| Toll-like receptor 9 (TLR9) | antagonist |
| DNA | Crosslinking/Alkylation |
| Angiotensin-converting enzyme 2 (ACE2) | Modulator |
Pharmacokinetics
Hydroxychloroquine absorption
Hydroxychloroquine has a bioavailability of 67 to 74%. The bioavailability of the R and S enantiomers does not appear to be significantly different.
Maximum plasma concentration: 129.6 ng/mL (single dose of 200 mg)
Time to peak plasma concentration: 3 to 4 hours
Volume of distribution
Hydroxychloroquine is widely distributed in tissues. Its volume of distribution from blood is 5522 liters and from plasma is 44257 liters. The S-enantiomer of hydroxychloroquine is 64% protein bound in plasma. 50% is bound to serum albumin and 29% to alpha-1-acid glycoprotein. The R-enantiomer is 37% protein bound in plasma. 29% is bound to serum albumin and 41% to alpha-1-acid glycoprotein. Overall, hydroxychloroquine is 50% protein bound in plasma.
Metabolism
Hydroxychloroquine is N-dealkylated by CYP3A4 to the active metabolite desethylhydroxychloroquine as well as the inactive metabolites desethylchloroquine and bisethylchloroquine. Desethylhydroxychloroquine is the major metabolite.
Excretion of hydroxychloroquine
40-50% of hydroxychloroquine is excreted through the kidneys, while only 16-21% of a dose is excreted unchanged in the urine. 5% of the administered dose is excreted through the skin and 24-25% through the feces.
Half-life
124 days (after a single 200 mg dose)
Clearance
The clearance of hydroxychloroquine is 96 mL/min. Renal clearance of the unchanged drug is approximately 16 to 30%.
Uses
- Malaria prevention, management and treatment
- Management of rheumatoid arthritis
- Management of lupus erythematosus (systemic and discoid)
- Sjögren’s Syndrome Management (Informal)
- Treatment of porphyria cutanea tarda (unofficial)
Contraindications for hydroxychloroquine
Sensitivity to hydroxychloroquine and its compounds, history of retinal disorders, long-term treatment in children
Warnings
- Hydroxychloroquine sulfate administration to patients with psoriasis may exacerbate severe psoriasis flare-ups. Avoid hydroxychloroquine sulfate in patients with psoriasis unless the benefits to the patient outweigh the potential risks.
- In people with diabetes, it may cause severe hypoglycemia, including loss of consciousness, which can be life-threatening in patients treated with or without antidiabetic medications. Check blood sugar and adjust treatment if necessary.
- Use caution in patients with liver disease or alcoholism or taking known hepatotoxic drugs. Dosage reduction may be necessary in patients with liver or kidney disease, as well as in those taking drugs that affect these organs.
- Antimalarial compounds should be used with caution in patients with liver disease or alcoholism or in combination with known hepatotoxic drugs. If patients are given long-term therapy, perform periodic blood cell counts. If any severe blood disorder (e.g., aplastic anemia, agranulocytosis, leukopenia, thrombocytopenia) appears that is not attributable to the disease being treated, discontinue therapy.
- Correct electrolyte imbalances prior to use; monitor cardiac function as clinically indicated during therapy. Discontinue therapy if cardiac toxicity is suspected or proven by tissue biopsy.
- Use with caution in patients with glucose-6-phosphate dehydrogenase (G-6-PD) deficiency.
Side effects of hydroxychloroquine
Blood and lymphatic system disorders: bone marrow failure, anemia, aplastic anemia, agranulocytosis, leukopenia, and thrombocytopenia
Cardiac disorders: cardiomyopathy, QT prolongation and ventricular arrhythmias, heart failure, atrioventricular block, and pulmonary hypertension
Ear disorders: vertigo, tinnitus, nystagmus, sensorineural hearing loss
Eye disorders: Irreversible retinopathy with retinal pigment changes, visual field defects, macular degeneration, decreased dark adaptation, corneal changes
Gastrointestinal disorders: nausea, vomiting, diarrhea, and abdominal pain
General disorders: fatigue
Hepatobiliary disorders: liver function tests are abnormal, acute liver failure is present
Immune system disorders: urticaria, angioedema, and bronchospasm
Metabolism and nutrition disorders: decreased appetite, hypoglycemia, and weight loss
Musculoskeletal and connective tissue disorders: Sensorimotor disorder, musculoskeletal myopathy or neuromyopathy leading to progressive weakness, decreased tendon reflexes, and abnormal nerve conduction
Nervous system disorders: headache, dizziness, seizures, ataxia, and disorders such as dystonia, dyskinesia, and tremor
Psychiatric disorders: irritability, nervousness, psychosis, suicidal ideation, depression, hallucinations, anxiety, restlessness, confusion, delusions, paranoia, mania, and sleep disorders (insomnia, night terrors, nightmares)
Skin and subcutaneous tissue disorders: rash, pruritus, pigmentation disorders of the skin and mucous membranes, hair discoloration, alopecia, and dermatitis bullous eruptions including erythema multiforme
Drug interactions
Contraindications
Lefamulin: Increases the level or effect of hydroxychloroquine sulfate by affecting the metabolism of the hepatic/intestinal CYP3A4 enzyme.
Serious interference
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