Hydroxychloroquine

Hydroxychloroquine is an antimalarial drug used to treat uncomplicated cases of malaria and for chemoprophylaxis in certain regions. Hydroxychloroquine also belongs to the group of so-called "disease modifying anti-rheumatic drugs" (DMARDs), which is why it is also used to treat rheumatoid arthritis and lupus erythematosus. It is taken by mouth, often in the form of hydroxychloroquine sulfate.

Hydroxychloroquine has also been studied for its suitability in the prevention and treatment of 2019 coronavirus disease (COVID-19). However, it proved ineffective for this indication in clinical trials.

History

After World War I, governments worldwide sought alternatives to quinine extracted from the cinchona tree, which until then was the only known antimalarial agent. In 1934, German researchers at Bayer discovered chloroquine, a synthetic analogue with the same mechanism of action. In 1947, in the search for other structural analogues with improved properties, the substance hydroxychloroquine was finally produced. It was approved for medical use in the United States in 1955 and is on the World Health Organization's list of essential medicines.

Pharmacodynamics

Hydroxychloroquine is generally effective against all 4 strains of the malaria-causing plasmodia. Strains in which resistance has developed are an exception. As with other quinoline malaria drugs, the antimalarial mechanism of action of hydroxychloroquine is not fully understood. The most common model is based on inhibition of the degradation of a specific metabolite of the pathogens. For energy production, the plasmodia degrade the blood pigment hemoglobin, which leads to the formation of the toxic intermediate ferriprotoporphyrin IX. This is normally further metabolized to the substance hemozoin. Hydroxychloroquine, however, prevents this last degradation step by binding to ferriprotoporphyrin IX, whereby the substance accumulates and the pathogen is ultimately killed.

In addition, due to its basic character, hydroxychloroquine affects the pH of lysosomes in the pathogen, inhibiting proteolysis and thereby growth and replication of the plasmodia.

The anti-inflammatory effect of the substance is probably due to inhibition of the immune system.

Pharmacokinetics

Orally ingested hydroxychloroquine has an absorption half-life of approximately 3-4 hours and is 67-74% orally bioavailable. Overall, the substance is 50% protein-bound in plasma. Hydroxychloroquine is degraded by the enzyme CYP3A4 in the liver by N-dealkylation. The majority of hydroxychloroquine is excreted in unchanged form or as a metabolite in the urine. Approximately 5% of the administered dose is excreted through the skin and 24-25% is excreted in the feces. The elimination half-life of hydroxychloroquine is extremely long and can sometimes exceed 500 hours.

Drug Interactions

The following drugs may interact in combination with hydroxychloroquine:

• Antacids may decrease the absorption of hydroxychloroquine.
• Both neostigmine and pyridostigmine antagonize the effect of hydroxychloroquine
• Digoxin (may lead to increased digoxin serum levels)
• Insulin or antidiabetic medications (may increase risk of hypoglycemia)
• Medicines that prolong the QT interval
• Antiepileptic drugs (concomitant use may interfere with antiepileptic effects)

Side effects

Hydroxychloroquine has a narrow therapeutic range, meaning there is little difference between toxic and therapeutic doses.

The most common adverse effects are

• Nausea
• Stomach cramps
• Diarrhea
• Weight loss
• General itching
• Headache

The most serious adverse effects involve the eye, and dose-dependent retinopathy may develop even after discontinuation of hydroxychloroquine.

Furthermore, serious neuropsychiatric side effects may occur. These include agitation, mania, sleep disturbances, hallucinations, psychosis, catatonia, paranoia, depression, and suicidal ideation.

In overdose, headache, drowsiness, visual disturbances, cardiovascular collapse, convulsions, hypokalemia, rhythm and conduction disturbances including QT prolongation, torsades de pointes arrhythmias, ventricular tachycardia, and ventricular fibrillation may occur.

There is no evidence that use during pregnancy is harmful to the developing fetus; therefore, use during pregnancy is not contraindicated.

Contraindications

• Myasthenia gravis
• glucose-6-phosphate dehydrogenase deficiency
• Maculopathy
• Retinopathy