Introduction
Plaquenil (hydroxychloroquine sulfate) is an antimalarial and immunomodulatory agent belonging to the 4-aminoquinoline class. Originally developed for malaria prophylaxis and treatment, it has become a cornerstone therapy for autoimmune conditions such as rheumatoid arthritis and systemic lupus erythematosus. Its unique mechanism of action and generally favorable safety profile have made it a widely prescribed medication in rheumatology and dermatology.
Mechanism of Action
Hydroxychloroquine exerts its effects through multiple mechanisms. It accumulates in acidic intracellular compartments like lysosomes, raising their pH and interfering with antigen processing and presentation. This disrupts autoantigen presentation to T-cells and inhibits Toll-like receptor signaling. The drug also interferes with cytokine production (particularly IL-1, IL-6, and TNF-α), phospholipase A2 activity, and neutrophil chemotaxis. In malaria, it concentrates in parasitic food vacuoles, inhibiting heme polymerase and leading to toxic heme accumulation.
Indications
FDA-approved indications:- Acute and chronic malaria (treatment and prophylaxis)
- Rheumatoid arthritis
- Systemic lupus erythematosus
- Chronic discoid lupus erythematosus
- Sjögren's syndrome
- Porphyria cutanea tarda
- Palindromic rheumatism
- Q fever
- Solar urticaria
- Sarcoidosis-associated hypercalcemia
Dosage and Administration
Rheumatoid arthritis and lupus:- Initial dose: 400-600 mg daily (as single or divided doses)
- Maintenance: 200-400 mg daily
- Maximum dose: ≤5 mg/kg actual body weight daily to reduce retinopathy risk
- 400 mg once weekly starting 1-2 weeks before exposure and continuing for 4 weeks after leaving endemic area
- 800 mg initially, followed by 400 mg at 6, 24, and 48 hours
- Renal impairment: Dose reduction required for CrCl <30 mL/min
- Hepatic impairment: Use with caution
- Geriatric: Consider reduced dosing due to decreased renal function
- Pediatric: 5 mg/kg actual body weight daily (max 400 mg/day)
Pharmacokinetics
Absorption: Rapid and complete (∼74%) with oral administration, bioavailability unaffected by food Distribution: Extensive tissue binding with large volume of distribution (Vd: 43,000 L); crosses placenta and enters breast milk Metabolism: Hepatic metabolism via CYP2D6, CYP3A4, CYP2C8 to active metabolites Elimination: Renal elimination (23-25% as unchanged drug); half-life ∼40 days due to extensive tissue bindingContraindications
- Known hypersensitivity to 4-aminoquinoline compounds
- Pre-existing macular changes or visual field defects
- Concomitant use of drugs with known risk of retinal toxicity
- G6PD deficiency (for malaria treatment)
- Severe hepatic impairment
Warnings and Precautions
Boxed Warning: Risk of retinal damage with long-term use Cardiac: May prolong QT interval and increase risk of torsades de pointes Neurologic: May exacerbate psoriasis and porphyria Hematologic: May cause hemolysis in G6PD-deficient patients Dermatologic: May cause severe skin reactions including Stevens-Johnson syndrome Psychiatric: May exacerbate psychiatric disorders Muscular: May cause skeletal muscle weakness or neuropathyDrug Interactions
Major interactions:- Digoxin: Hydroxychloroquine may increase digoxin levels
- Diabetes medications: May enhance effects of insulin and oral hypoglycemics
- QT-prolonging agents: Increased risk of torsades de pointes (antiarrhythmics, macrolides, antipsychotics)
- Mefloquine: Increased seizure risk
- CYP2D6 substrates: May inhibit metabolism of beta-blockers, antidepressants, antipsychotics
- Antacids: Reduced absorption (separate administration by ≥4 hours)
Adverse Effects
Common (>10%):- Nausea, vomiting, diarrhea
- Abdominal cramps
- Headache
- Dizziness
- Pruritus
- Skin pigmentation changes
- Irreversible retinal toxicity
- Cardiomyopathy with heart failure
- Severe hypoglycemia
- Bone marrow suppression
- Severe skin reactions
- Ototoxicity
- Skeletal muscle myopathy
- Neuropsychiatric events
Monitoring Parameters
Baseline:- Complete ophthalmologic exam including visual fields and SD-OCT
- CBC with differential
- Comprehensive metabolic panel
- G6PD testing (if indicated)
- ECG (if cardiac risk factors present)
- Annual ophthalmologic exam after 5 years of use (earlier if high-risk factors)
- Routine CBC and renal/liver function tests
- Blood glucose monitoring in diabetics
- Cardiac monitoring if symptoms develop
- Neurologic assessment if symptoms occur
Patient Education
- Take with food or milk to reduce gastrointestinal upset
- Do not crush or break tablets
- Regular eye exams are essential - report any visual changes immediately
- Inform all healthcare providers about Plaquenil use
- Use sun protection due to potential photosensitivity
- Report muscle weakness, unusual bleeding, bruising, or infections
- Diabetic patients should monitor blood glucose closely
- Do not stop medication abruptly without consulting prescriber
- Store at room temperature away from moisture
References
1. Marmor MF, et al. Recommendations on Screening for Chloroquine and Hydroxychloroquine Retinopathy (2016 Revision). Ophthalmology. 2016;123(6):1386-1394. 2. Furst DE, et al. Pharmacokinetics of hydroxychloroquine and chloroquine during treatment of rheumatic diseases. Lupus. 1996;5 Suppl 1:S11-15. 3. Ruiz-Irastorza G, et al. Clinical efficacy and side effects of antimalarials in systemic lupus erythematosus: a systematic review. Ann Rheum Dis. 2010;69(1):20-28. 4. FDA Prescribing Information: Plaquenil (hydroxychloroquine sulfate) tablets. 5. Jorge AM, et al. Hydroxychloroquine retinopathy - implications of research advances for rheumatology care. Nat Rev Rheumatol. 2018;14(12):693-703. 6. Schrezenmeier E, Dörner T. Mechanisms of action of hydroxychloroquine and chloroquine: implications for rheumatology. Nat Rev Rheumatol. 2020;16(3):155-166.