Hydroxychloroquine

BRAND NAMES:

Plaquenil – Plaquenil 200 mg film-coated tablets are available with the composition of hydroxychloroquine sulfate, 200 mg equivalent to 155 mg hydroxychloroquine.

Sovuna - It's an oral tablet with hydrochloroquine as an active ingredient used in treating malaria.

MECHANISM OF ACTION:

The specific processes of hydroxychloroquine remain unclear. Hydroxychloroquine has been demonstrated to accumulate in the malaria parasite's lysosomes, increasing the pH of the vacuole. This function inhibits the parasite's capacity to proteolyse haemoglobin, inhibiting normal parasite development and reproduction. Hydroxychloroquine may inhibit parasite heme polymerase, which converts ferriprotoporphyrin Ⅸ from hemoglobin into beta-haematin. Hydroxychloroquine reduces heme polymerase activity without limiting FP release, resulting in the buildup of FP in a hazardous form.

Hydroxychloroquine accumulates in human organelles and elevates their pH, inhibiting antigen processing, preventing the alpha and beta chains of the major histocompatibility complex class Ⅱ from dimerizing, inhibiting antigen presentation, and reducing the inflammatory response. Elevated pH in vesicles may change the recycling of MHC complexes, resulting in only high-affinity complexes being presented on cell surfaces. Self-peptides bind to MHC complexes with low affinity, hence they are unlikely to be brought up to auto-immune T cells. Hydroxychloroquine also decreases the production of cytokines such as interleukin-1 and tumor necrosis factor, potentially by inhibiting Toll-like receptors.

Endosomes' elevated pH prevents virus particles from fusing and entering the cell. Hydroxychloroquine inhibits the terminal glycosylation of ACE2, the receptor SARS-CoV and SARS-CoV-2 used to enter the cell. Without glycosylation, ACE2 may bind less efficiently with the SARS-CoV-2 spike protein, further restricting viral entry.

PHARMACOKINETICS:

Absorption: Hydroxychloroquine has a bioavailability of 67–74%. The R and S enantiomers have similar bioavailability. A single 200 mg oral hydroxychloroquine in healthy male volunteers produced a whole blood hydroxychloroquine Cmax of 129.6 mg/ml and a Tmax of 3.3 hours. A single oral dosage of 200 mg hydroxychloroquine produced a mean absorption fraction of 0.74. 

Peak metabolite blood concentrations coincided with peak hydroxychloroquine levels. Peak blood concentrations ranged from 1161 mg/mL to 2436 mg/mL after the 155 mg infusion and 6 months after the 310 mg infusion. Pharmacokinetic characteristics did not alter significantly over the therapeutic dose range of 155 mg to 310 mg, confirming linear kinetics.

In patients with rheumatoid arthritis, the fraction of the dose absorbed varied greatly, and mean hydroxychloroquine levels were much greater in those with less disease activity.

Distribution: Hydroxychloroquine is broadly dispersed in tissues, accounting for 5522L in blood and 44,257L in plasma.

Metabolism: CYP3A4 N-dealkylates hydroxychloroquine to create desethylhydroxychloroquine, an active metabolite, as well as desethylchloroquine and bidesethylchloroquine, which are inactive. The most important metabolite is desethylhydroxychloroquine.

Excretion: The kidneys remove 40–50% of hydroxychloroquine; however, only 16–21% of the dose is excreted unchanged in urine. The skin sheds 5% of the dosage, whereas the bowels dispose of 24-2.

PHARMACODYNAMICS:

Hydroxychloroquine alters the function of lysosomes in humans and plasmodia. Changing the pH of the lysosomes diminishes low-affinity self-antigen presentation in autoimmune disorders and inhibits plasmodia's capacity to proteolyze hemoglobin for energy. Hydroxychloroquine has a lengthy duration of action and can be administered weekly for some indications. Hydroxychloroquine can cause severe hypoglycemia, so diabetic individuals should monitor their blood glucose levels. Hydroxychloroquine is effective against the erythrocytic forms of chloroquine-sensitive strains of Plasmodium falciparum, P. malaria, P. vivax, and P. ovale. Hydroxychloroquine has little effect on gametocytes or exoerythrocytic forms, such as P. vivax and P. ovale's hypnozoite liver stage. Hydroxychloroquine is ineffective against malaria in areas where chloroquine resistance has been reported.

DOSAGE AND ADMINISTRATION:

The tablets contain 200 mg or 300 mg of hydroxychloroquine. The dose is given to adults and children as directed by a physician. It is an orally administered drug with a meal or glass of milk.

DRUG INTERACTIONS:

• Hydroxychloroquine may interact with anti-cancer drugs. -tamoxifen

• Heart related medicines: digoxin, amiodarone

• Anti-diabetic drugs-insulin

• Anti-malarial drug-halofantrine, mefloquine

• Antibiotics-moxifloxacin, azithromycin, penicillamine

• Immuno suppressants-ciclosporin

• Heartburn medicines: cimetidine

• Anti-psychotics-amisulpride,quetiapine

• Anticoagulants

CONTRAINDICATIONS:

Chloroquine has been proven safe to use during pregnancy and in children. Chloroquine has few but serious contraindications. There are reports of cases of death relating to chloroquine administered to patients with porphyria cutaneous tarda. Chloroquine should not be used in patients with retinal vision changes unless treating acute malaria. Chloroquine is also contraindicated in patients who suffer from a known hydroxychloroquine sensitivity.

SIDE EFFECTS:

Certain medicines should not be used together at all; in other cases, two different medicines may be used together even if an interaction might occur. Common side effects include

• Nausea

• Vomiting

• Diarrhea

• Headache

• Dizziness

• Rash

• Abdominal cramps

• Loss of appetite

• Hair loss

Serious side effects include

• QT prolongation

• Retinal toxicity to vision change

• Blood disorders

• Allergic reactions

• Kidney problems

OVERDOSE:

Symptoms of overdose include

• Drowsiness

• Dry mouth

• Increased thirst

• Loss of appetite

• Mood changes

• No pulse

• Tingling in the hands, feet, or lips

TOXICITY:

Chloroquine toxicity is rare but has been known to occur when unusually high doses of chloroquine are ingested or after chronic Ⅳ administration. Accidental ingestion has also occurred in children. When toxicity is present, the most common symptom is retinal toxicity. Treatment of chloroquine toxicity includes mechanical ventilation and administration of diazepam and epinephrine, although these methods have been proven methods of treatment in all cases.

STORAGE:

Keep at room temperature (20–25°C; 68–77°F), with permission to stray to 15–30°C (59–86°F).