Chloroquine and hydroxychloroquine

Chloroquine and hydroxychloroquine are drugs derived from the quinoline molecule. Both are used as antimalarial blood schizonticides, and hydroxychloroquine is also frequently used as an antirheumatic. Their mechanism of action is not entirely understood. Despite their varying therapeutic dosage and toxicity, both drugs have similar clinical indications and side effects. One of their most serious side effects is retinal toxicity, referred to as 4AQ retinopathy or chloroquine retinopathy, which must be screened for in all cases of long-term use.

The precise mechanisms of action are unknown, but the following are the most widely accepted hypotheses:

• Antimalarial action: drug accumulation in the parasite's food vacuole: → inhibition of heme polymerization (and thus, detoxification) into hemozoin and formation of highly toxic heme-chloroquine complexes → lysis of membranes and death of the parasites ^[1]
• Antirheumatoid action: interference with antigen processing in macrophages and other APCs → ↓ formation of peptide-MHC protein complexes → ↓ immune response against autoantigenic peptides ^[2]

• Gastrointestinal ^[3][4]
  • Nausea with cramps (most common)
  • Anorexia
  • Vomiting
• Visual disturbances
  • Irreversible bilateral retinopathy: key fundoscopic feature is bull's eye maculopathy and paracentral scotomata
  • Blurred vision
  • Photophobia
• Dermatologic
  • Pruritus (most commonly seen in dark-skinned individuals ) ^[5]
  • Photosensitivity
  • Alopecia
  • Whitening of hair
• Neurologic
  • Myasthenia-like muscle weakness
  • Sensorineural deafness
  • Tinnitus
  • Cranial nerve palsies
• Cardiac: torsades de pointes (due to possible QT prolongation), can cause sudden death ^[6]
• Hematologic: e.g., thrombocytopenia, leukopenia
• Worsening of preexisting conditions: epilepsy, psoriasis, porphyria and preexisting retinal damage

Patients using long-term chloroquine/hydroxyhloroquine should have regular ophthalmological examinations.

We list the most important adverse effects. The selection is not exhaustive.

• Definition: a type of toxic retinopathy caused by long-term chloroquine and hydroxychloroquine use
• Pathogenesis: long-term chloroquine and hydroxychloroquine use ; (threshold dose ∼ 300 mg/d) → irreversible changes in the retinal pigment epithelium; often bilateral
• Clinical features
  • Decrease in visual acuity
  • Impaired color perception
• Diagnostics
  • Ophthalmoscopy: bull's eye maculopathy (annular changes of the retinal pigment epithelium with hyperpigmentation and hypopigmentation)
  • Fluorescence angiography: central hyperfluorescence
• Differential diagnosis: In advanced stage, symptoms are similar to those of retinitis pigmentosa.

• Malaria
  • Treatment and prophylaxis of malaria due to Plasmodium malariae, P. ovale, or P. vivax
  • Strains of P. falciparum are usually resistant
  • See “Treatment” in “Malaria”
• Rheumatic diseases: used in mild courses
  • Rheumatoid arthritis (basic therapy)
  • Systemic lupus erythematosus and discoid lupus erythematosus (without organ involvement)
• Porphyria cutanea tarda (in low doses)

• Attributed to the development of membrane efflux pumps, which decrease the intracellular concentration of the drug.
• Occurs especially in P. falciparum