HCQS

Indications

• Malaria (treatment and prophylaxis)
• Rheumatoid arthritis
• Systemic lupus erythematosus
• Chronic discoid lupus erythematosus
• Porphyria cutanea tarda

Dosage

Adults: For malaria: 800 mg as a loading dose, followed by 400 mg at 6, 24

Mechanism of action

The exact mechanisms of hydroxychloroquine are unknown. It accumulates in the lysosomes of malaria parasites, raising the pH of the vacuole and interfering with proteolysis of hemoglobin, thus inhibiting the growth and replication of the parasite. It also inhibits the action of parasitic heme polymerase and alters antigen processing in human cells, leading to a reduced inflammatory response. Hydroxychloroquine further decreases the release of pro-inflammatory cytokines and prevents virus particles from utilizing their entry pathways.

Pharmacodynamics

Hydroxychloroquine modifies lysosomal function, reducing the presentation of low-affinity self-antigens in autoimmune diseases and impairing the proteolytic capability of malaria parasites. It has a long duration of action, allowing for weekly dosing in some cases. In terms of malaria, it is effective against erythrocytic forms of chloroquine-sensitive P. falciparum, P. malariae, P. vivax, and P. ovale, but not against gametocytes or exoerythrocytic forms.

Pharmacokinetics

Hydroxychloroquine is well-absorbed from the gastrointestinal tract, with peak plasma concentrations occurring within 1 to 4 hours post-administration. It has a large volume of distribution, primarily due to its accumulation in tissues, including the liver, lungs, and skin. The drug is metabolized in the liver and has a long half-life, allowing for sustained therapeutic effects. It is excreted primarily in urine as unchanged drug and metabolites.

Adverse effects

• Nausea
• Vomiting
• Diarrhea
• Abdominal pain
• Headache
• Dizziness
• Visual disturbances
• Skin rash
• Hemolysis in G6PD deficiency
• Cardiomyopathy
• Retinopathy

Interactions

• hydroxychloroquine+penicillamine: Severe (increases risk of haematological toxicity)
• hydroxychloroquine+agalsidase alfa: Unknown (decreases effects)
• hydroxychloroquine+agalsidase beta: Unknown (decreases exposure)
• hydroxychloroquine+oral cholera vaccine: Unknown (decreases efficacy)
• lanthanum+hydroxychloroquine: Unknown (decreases absorption)
• macrolides+hydroxychloroquine: Unknown (increases risk of serious cardiovascular adverse effects)
• hydroxychloroquine+remdesivir: Unknown (decreases effects)
• hydroxychloroquine+laronidase: Unknown (decreases exposure)

Precautions

• Monitor for retinal toxicity during long-term use
• Use with caution in patients with pre-existing liver disease
• Consider potential for hypoglycemia in diabetic patients
• Assess G6PD status before initiating therapy

Pregnancy

Hydroxychloroquine should only be used during pregnancy if the potential benefit justifies the potential risk to the fetus. It is classified as category C.

Breast-feeding

Hydroxychloroquine is excreted in breast milk. Caution is advised when administering to nursing mothers.

Storage

Store in a cool, dry place away from direct light. Keep out of reach of children.

Formulations

• Tablets: 200 mg

Indications

• Active rheumatoid arthritis
• Systemic lupus erythematosus
• Discoid lupus erythematosus
• Dermatological conditions triggered or exacerbated by sunlight
• Symptomatic relief of mild to moderate osteoarthritis

Dosage

Children: For refractory polyarticular juvenile idiopathic

Adults: 1250 mg once daily, review treatment if no benefit after 2–3 months.

Mechanism of action

Hydroxychloroquine exerts its therapeutic effects by interfering with the communication between immune cells, particularly T-lymphocytes. It inhibits the activation of these cells, thereby reducing the inflammatory processes associated with autoimmune diseases. Additionally, hydroxychloroquine may inhibit the production of pro-inflammatory cytokines, contributing to its anti-inflammatory effects.

Pharmacodynamics

Hydroxychloroquine has immunomodulatory and anti-inflammatory properties. It affects the function of several immune cells, including macrophages and T-lymphocytes, and inhibits the activation and proliferation of these cells in response to antigens. This leads to a decreased production of antibodies and cytokines, which are critical in the pathophysiology of autoimmune diseases. The drug's effects can take several weeks to months to manifest fully.

Pharmacokinetics

Hydroxychloroquine is well absorbed from the gastrointestinal tract, with peak plasma concentrations typically reached within 2 to 6 hours after oral administration. The drug has a large volume of distribution and is highly protein-bound. It is metabolized in the liver and has a long half-life, allowing for once-daily dosing. Hydroxychloroquine is eliminated primarily through the kidneys, and renal impairment may necessitate dosage adjustments. Monitoring of blood glucose is also recommended in patients with impaired glucose tolerance due to potential effects on glucose metabolism.

Contra-indications

• Hypersensitivity to hydroxychloroquine or any of its components
• Retinal or visual field changes attributable to 4-aminoquinoline compounds
• Porphyria

Adverse effects

• Common: gastrointestinal discomfort, headache, nausea, diarrhea, fatigue, constipation
• Uncommon: flushing, skin reactions, dizziness, corneal edema, alopecia
• Rare: psychiatric reactions, including suicidal behavior, agranulocytosis, vision disorders

Interactions

• Increased risk of cardiovascular events when used with macrolide antibiotics, especially azithromycin
• Potential for enhanced effects of other antimalarials and DMARDs
• May increase risk of hypoglycemia when used with antidiabetic drugs

Precautions

• Caution in patients with a history of seizures
• Monitor blood glucose concentration in patients with impaired glucose tolerance
• Regular eye examinations recommended due to risk of retinopathy
• Caution in patients with predisposition to cardiovascular disease

Pregnancy

Hydroxychloroquine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Limited data suggests possible adverse effects on fetal development.

Breast-feeding

Hydroxychloroquine is excreted in breast milk but is generally considered safe for use during breastfeeding. Monitoring of the infant is recommended.

Storage

Store in a cool, dry place, away from direct light. Keep out of reach of children.

Formulations

• Tablets: 200 mg hydroxychloroquine sulfate
• Oral solution: 250 mg per 5 mL

Mechanism of action

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, an enzyme that uses ferriprotoporphyrin IX (FP) released from hemoglobin as a substrate to form beta-hematin. By reducing the activity of heme polymerase without inhibiting the release of FP, hydroxychloroquine leads to the accumulation of FP in a toxic form. 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.

Pharmacodynamics

Hydroxychloroquine affects the function of lysosomes in humans as well as plasmodia. Altering the pH of the lysosomes reduces low-affinity self-antigen presentation in autoimmune diseases and interferes with the ability of plasmodia to proteolyze 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 active against the erythrocytic forms of chloroquine-sensitive strains of P. falciparum, P. malariae, P. vivax, and P. ovale. Hydroxychloroquine is not active against the gametocytes and exoerythrocytic forms including the hypnozoite liver stage forms of P. vivax and P. ovale. Hydroxychloroquine is not effective against malaria in areas where chloroquine resistance has been reported.