Hydroxychloroquine Pharmacology

Hydroxychloroquine is a 4-aminoquinoline antimalarial used as an immunomodulator in systemic lupus erythematosus, rheumatoid arthritis, Sjogren syndrome and antiphospholipid syndrome. It reduces lupus flares, organ damage and thrombosis, and is safe in pregnancy. It is the one drug nearly every patient with lupus should take unless contraindicated.

Mechanism. It raises lysosomal pH and inhibits toll-like receptor 7 and 9 signalling, antigen presentation and cytokine release. It also has weak antithrombotic and lipid-lowering effects.

Pharmacokinetics. Oral absorption about 75%; very long half-life (40 to 50 days); steady state takes 3 to 6 months; extensive tissue binding including melanin in the retina; renal and hepatic elimination.

Dosing.

• Adults: 200 to 400 mg daily, not over 5 mg/kg actual body weight daily (for example, 200 mg daily at 40 kg; 400 mg at 80 kg).
• Rheumatoid arthritis: 200 to 400 mg daily, alone for mild disease or in combination.
• Lupus: 200 to 400 mg daily; reduce after remission if appropriate but keep long-term therapy.
• Children: up to 5 mg/kg daily (maximum 400 mg).
• Reduce the dose in renal impairment (creatinine clearance under 30 mL/min) and review frequently.

Related drugs. Chloroquine (retinopathy at lower cumulative dose; seldom used for rheumatic disease); quinacrine for refractory cutaneous lupus (specialist).

Administration. Take with food to reduce nausea. Onset of benefit takes 8 to 12 weeks. Do not stop abruptly in lupus because flares may follow.

• First-line. All patients with systemic lupus erythematosus, unless contraindicated; mild rheumatoid arthritis; cutaneous lupus.
• Alternative. Combination with methotrexate and sulfasalazine in rheumatoid arthritis; Sjogren syndrome; discoid lupus.
• Specialist. Antiphospholipid syndrome (thrombosis prevention), pregnancy planning in lupus, palindromic rheumatism.
• Emergency. None.

Selection. Choose in mild disease, during pregnancy and in patients who need minimal immunosuppression. Do not rely on it for severe organ involvement, which needs stronger immunosuppression.

Contraindications. Known retinopathy or maculopathy; hypersensitivity to 4-aminoquinolines; myasthenia gravis (relative); QT prolongation risk; porphyria (relative); G6PD deficiency (caution, rare haemolysis).

Serious adverse effects.

• Retinopathy: irreversible, with risk rising after 5 years and over 5 mg/kg daily; presents as paracentral scotoma or bull’s eye lesion.
• QT prolongation and arrhythmia; cardiomyopathy and conduction defects with long use.
• Nausea, diarrhoea, rash, hyperpigmentation, headache; hypoglycaemia in diabetes; myopathy and neuropathy (rare).
• Skin photosensitivity and psoriasis exacerbation (rare).

Major interactions. QT-prolonging drugs (macrolides, fluoroquinolones, ondansetron, antipsychotics, artemether-lumefantrine); antacids and kaolin reduce absorption (separate by 4 hours); digoxin and ciclosporin levels rise; insulin and sulfonylurea effects increase.

Common prescribing errors.

• Dosing by ideal rather than actual body weight, or exceeding 5 mg/kg.
• No baseline eye examination.
• Stopping in pregnancy.
• Ignoring renal impairment.
• Combining with other QT-prolonging drugs without a baseline ECG.

Special groups.

• Pregnancy: continue; reduces flares and neonatal lupus risk.
• Breastfeeding: acceptable.
• Children: up to 5 mg/kg daily.
• Older adults: reduce dose with renal impairment; monitor eyes.
• Kidney: reduce dose under 30 mL/min.
• Liver: use with caution.
• East Africa: malaria endemicity means patients may use antimalarials concurrently, so check for double dosing with chloroquine and for QT prolongation with artemether-lumefantrine; baseline retinal screening may be limited, so record dose and duration and refer when able.

Monitoring. Baseline eye examination within the first year; annual retinal screening (optical coherence tomography and visual fields) after 5 years, or sooner with renal disease, tamoxifen use or doses over 5 mg/kg; ECG when taking other QT-prolonging drugs; blood count and liver tests periodically.

Referral and escalation. Any visual change or scotoma; syncope or palpitations; QT over 500 ms; severe skin reaction; unexpected lupus flare after stopping.

Comparison with alternative classes. Hydroxychloroquine is safe in pregnancy, needs minimal blood monitoring and reduces damage and mortality in lupus. It is less potent than methotrexate in rheumatoid arthritis, and retinopathy is its main long-term risk.