Retinal toxicity chloroquine

Eye. Several drugs have an affinity for the retinal pigment melanin and thus may accumulate in the eye. Chlorpromazine and other phe-nothiazines bind to melanin and accumulate in the uveal tract, where they may cause retino-toxicity. Chloroquine concentration in the eye can be approximately 100 times that found in the liver. 

Originally used in the treatment of malaria, the drugs chloroquine (Aralen) and hydroxychloroquine (Pla-quenil) have also been used to treat rheumatoid arthritis. In the past, these drugs have been used reluctantly because of the fear of retinal toxicity (see Adverse Side Effects ).25 There is now evidence, however, that these agents can be used safely, but they are only marginally effective when compared to other DMARDs. These drugs are therefore not usually the first choice, but they can be used in patients who cannot tolerate other DMARDs, or in combination with another DMARD (e.g., methotrexate) for more comprehensive treatment. 

Chloroquine Aralen Oral Up to 4 mg/kg of lean body weight per day. Periodic ophthalmic exams recommended to check for retinal toxicity. 

Comeal deposits of chloroquine may be asymptomatic or may cause halos around lights or photophobia. These are not a threat to vision and reverse when the dmg is stopped. Retinal toxicity is more serious, however, and may be irreversible. In the early stage it takes the form of visual field defects late retinopathy classically gives the picture of macular pigmentation surrounded by a ring of pigment (the bull s-eye macula). The functional defect can take the form of scotomas, photophobia, defective colour vision and decreased visual acuity resulting, in the extreme case, in blindness. 

Shroyer NF, Lewis RA, Lupski JR. Analysis of the ABCR (ABCA4) gene in 4-aminoquinoline retinopathy is retinal toxicity by chloroquine and hydroxychloroquine related to Stargardt disease Am J Ophthalmol 2001 131(6) 761-6. 

Dosage and duration of therapy depend on patient response, tolerance of side effects, and development of retinal toxicity, which is a potentially irreversible adverse reaction associated with long-term therapy, especially with chloroquine. Current recommended doses of antimalarials in SLE are hydroxychloroquine 200-400 mg/day and chloroquine 250-500 mg/day. After 1 or 2 years of treatment, gradual tapering of dosage can be attempted. Some patients may require only one or two tablets per week to suppress cutaneous manifestations. ... 

Side effects of these drugs include CNS effects (e.g., headache, nervousness, insomnia, and others), rashes, dermatitis, pigmentary changes of the skin and hair, gastrointestinal disturbance (e.g., nausea), and reversible ocular toxicities such as cycloplegia and corneal deposits. Potentially serions retinal toxicity is uncommon when the currently recommended doses are used and is least common with hydroxychloroquine. However, because of the possibility of permanent damage associated with the retinopathy, an ophthalmologic evaluation should be done at baseline and every 3 months when chloroquine is used and every 6 to 12 months when hydroxychloroquine is used. If retinal abnormalities are noted, antimalarial therapy should be discontinued or the dose reduced. ... 

The mechanism of action of the immunological and anti-inflammatory effects of antimalarials include inhibition of phospholipase A, inhibition of platelet aggregation, a range of lysosomal effects (e.g., an increase in pH, membrane stabilization, and inhibition of release and activity of lysosomal enzymes), inhibition of phagocytosis, an increase in intracellular pH in cytoplasmic vacuoles leading to decreased stimulation of autoimmune CD4 T cells, decreased cytokine release from lymphocytes and stimulated monocytes, inhibition of immune complex formation, and antioxidant activity. In patients with porphyria cutanea tarda, chloroquine and hydroxychloroquine bind to porphyrins and/or iron to facilitate their hepatic clearance. The ability to bind to melanin and other pigments may contribute to the retinal toxicity seen occasionally when anti-malarial agents are used. 

Chloroquine destroys schizonts in erythrocytes by interfering with DNA synthesis. The phosphate salts are active orally, whereas the hydrochloride salt is used for intravenous purposes. It accumulates in normal and parasitized erythrocytes. Overdosage has caused reversible corneal damage and permanent retinal damage. In toxic doses, chloroquine causes visual disturbances, hyperexcitability, convulsions, and heart block. It is an antimalarial of choice in all cases except chloroquine-resistant Plasmodium falciparum. In addition, it has a certain degree of effectiveness in amebiasis and in the late stages of rheumatoid arthritis. 

Figure 35-10 Peripheral retinal pigment epithelial hyperplasia characteristic of pseudoretinitis pigmentosa in 42-year-old man with chloroquine toxicity.

Eye. Toxic cataract can be due to chloroquine and related drugs, adrenal steroids (topical and systemic), phenothiazines and alkylating agents. Comeal opacities occur with phenothiazines and chloroquine. Retinal injury occurs with thioridazine (particularly, of the antipsychotics), chloroquine and indomethacin. 

Answer C. Ocular toxicity is characteristic of chloroquine and hydroxychloroquine. Corneal deposits are reversible, but retinal pigmentation can ultimately lead to blindness. Patients will complain about GI distress, visual dysfunction, ringing in the ears (note that tinnitus aiso occurs in salicylism), and itchy skin. Hydroxychloroquine also promotes oxidative stress that can lead to hemolysis in G6PD deficiency. DMARDs include gold salts (e.g., auranofin), methotrexate, and etanercept, but thioridazine is a phenothiazine used as an antipsychotic it lacks anti-inflammatory effect, but does cause retinal pigmentation. 

Quinoline antimalarials such as hydroxychloroquine (Fig. 5-6) and chloroquine have been found to have antiarthritic properties however, the onset of clinical improvement, as with penicillamine and gold, takes months. Irreversible retinopathy, including retinal opacity, can be encountered. Lesser toxicities include skin pigmentation and alopecia. Proposals to possible mechanisms of action are speculative at best. It should be emphasized that none of the slow-action antiarthritic agents discussed earlier should be considered as initial therapy in RA. The salicylates and other NSAIDs deserve this distinction. If results are unsatisfactory gold may be considered as the subsequent therapeutic step. Penicillamine would be a logical alternate, as would short-term steroids or cytotoxic agents. 

Toxicity At low doses, chloroquine causes gastrointestinal irritation, skin rash, and headaches. High doses may cause severe skin lesions, peripheral neuropathies, myocardial depression, retinal damage, auditory impairment, and toxic psychosis. Chloroquine may also precipitate porphyria attacks. 

Toimela T, Tahti H, Salminen L (1995) Retinal pigment epithelium cell culture as a model for evaluation of the toxicity of tamoxifen and chloroquine. Ophthalmic Research 27 Suppl 1 150-153. 

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