Hydroxychloroquine
Inhibition of lysosomal acidification
Generic Name
Inhibition of lysosomal acidification
Mechanism
- Inhibition of lysosomal acidification: Raises the pH in endosomes/lysosomes, impairing antigen processing and presentation.
- Immunomodulation: Suppresses toll‑interceptor signaling, decreases cytokine release (IL‑6, TNF‑α), and reduces NF‑κB activation.
- Antimalarial activity: Interferes with heme detoxification in *Plasmodium* parasites, forming inhibitory mepacrine complexes.
- Photo‑sensitization: Enhances phototoxic responses, leading to cutaneous adverse events.
Pharmacokinetics
- Absorption: Oral bioavailability ~70–80 %; peak plasma levels 3–4 h post‑dose.
- Distribution: Large volume of distribution (~7000 L). Extensive tissue uptake—skin, retina, liver, spleen, and brain.
- Protein binding: 30–40 % to plasma proteins; free fraction ~60 %.
- Metabolism: Hepatic via CYP2C8, CYP3A4, CYP2D6 to desethyl‑hydroxychloroquine and other metabolites.
- Elimination: Elimination half‑life 30–50 days (reached steady state in ~4–5 months). Excreted mainly in urine and feces; less than 1 % unchanged.
Indications
| Indication | Typical Regimen | |
| Slept… | 400 mg PO daily (or 200 mg BID) | |
| Rheumatoid arthritis | 200–400 mg PO daily | |
| Malaria prophylaxis (non‑chloroquine‑resistant strains) | 400 mg PO weekly | |
| Malaria treatment (severe disease) | 600 mg PO loading dose, then 200 mg PO BID | |
| COVID‑19 (off‑label) | 200 mg PO BID for up to 10 days (not recommended by major guidelines) |
Contraindications
- Known hypersensitivity to quinoline antimalarials.
- Retinal disease (fundus or macular pathology).
- Pre‑existing QTc >460 ms (women) or >440 ms (men).
- Congenital long QT syndrome or a history of torsades de pointes.
- Severe hepatic or renal impairment (dose adjustment or monitoring required).
- Pregnancy: Category D; use only if benefits outweigh risks (e.g., severe SLE flare).
- Children under 7 yrs: Avoid for malaria treatment (tubercular infection risk).
Dosing
- Adults:
- *SLE/Rheumatoid arthritis*: 200–400 mg PO daily (loading dose 400 mg BID for 2 weeks if rapid control needed).
- *Malaria prophylaxis*: 400 mg PO once weekly, 1 week before exposure, continue throughout and 4 weeks after exposure.
- *Malaria treatment*: IV/PO 600 mg loading, then 200 mg PO BID for 7–10 days.
- Pediatrics (5 kg – 30 kg): 200 mg PO BID for 3 days, then 200 mg PO q48 h (weight‑based mg/kg guidelines above).
- Pregnancy: 200 mg PO BID until delivery; monitor eye health.
Administration tips
• Take with food or milk to reduce GI upset.
• Avoid concurrent use with medications prolonging QT (e.g., azithromycin, levofloxacin).
• Monitor CBC, LFTs, CMP at baseline and every 2–3 months.
Adverse Effects
| Category | Examples |
| Gastro‑intestinal | Nausea, vomiting, abdominal pain, constipation, diarrhea |
| Dermatologic | Rash, pruritus, photo‑sensitivity, rare Stevens–Johnson syndrome |
| Ophthalmic | Retinopathy (macular pigmentary changes, bull’s‐eye, subretinal crystals), optic neuropathy |
| Neurologic | Headache, dizziness, ataxia, seizures, myopathy |
| Hematologic | Hemolytic anemia (especially G6PD deficiency), thrombocytopenia, leukopenia |
| Cardiac | QT prolongation, arrhythmias (torsades), bradycardia, conduction block |
| Renal | Fanconi syndrome (proximal tubular dysfunction) in chronic users |
| Serious | Severe visual loss, sudden sensorineural hearing loss (rare), life‑threatening anaphylaxis |
Monitoring
- Baseline: CBC, LFTs, renal panel, electrolytes, ECG (QTc), ophthalmologic exam (baseline and annually if >5 yrs use).
- During therapy:
- Every 3–6 months: CBC, CMP, LFTs.
- QTc: Every 6–12 months if on QT‑prolonging agents.
- Eye exam: annually after 5 yrs of use; sooner if visual changes.
- Pregnancy: serum drug levels not required; monitor obstetric complications.
Clinical Pearls
1. Long, silent half‑life: Discontinuation may take weeks; monitor for rebound disease activity.
2. Photo‑sensitivity: Counsel patients to use broad‑spectrum sunscreen (SPF ≥ 50) and avoid intense UV exposure.
3. Drug interactions:
• CYP3A4 inhibitors (ketoconazole, ritonavir) ↑ levels—dose reduce.
• CYP2C8 inhibitors (lithium) ↑ risk of neurotoxicity.
4. Malaria prophylaxis: In *Plasmodium falciparum*‑resistant areas, avoid use; choose atovaquone/proguanil or doxycycline.
5. Retinal screening algorithm: Use the Ophthalmic Screening Guidelines for Hydroxychloroquine (AAO) – baseline at initiation, annually after 5 yrs or sooner if symptoms.
6. COVID‑19 off‑label: Clinical trials have not demonstrated efficacy; avoid with risk of cardiac toxicity.
7. Pregnancy: If SLE flare is life‑threatening, hydrocortisone + hydroxychloroquine may be justified; otherwise, the drug should be stopped pre‑conception.
8. G6PD deficiency: Evaluate before initiation—risk of hemolysis is higher.
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• Key pharmacology keywords: hydroxychloroquine, lysosomal pH, immunomodulation, antimalarial, QT prolongation, retinopathy, CYP450, G6PD deficiency, pregnancy category D, COVID‑19 off‑label.