Toxicity hydroxychloroquine/chloroquine

DIGOXIN CHLOROQUINE, HYDROXYCHLOROQUINE Chloroquine may t plasma concentrations of digoxin Uncertain at present Monitor digoxin levels watch for digoxin toxicity... 

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. 

Amodiaquin (10), 4-aminoquinoline which contains 3-diethylaminomethyl-4-hydroxyphenylamino and chloro groups, was synthesized and found to be more potent against P. falciparum than chloroquine. However it is more hepatotoxic than chloroquine and produces granulocytosis. One of the N-ethyl substituents of chloroquine is 0-hydroxyIated to produce hydroxychloroquine (11), which has similar efficient activity against falciparum malaria, and is less toxic than chloroquine. This compound is preferred over chloroquine in the treatment of rheumatoid arthritis and lupus erythematosus. 

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. 

Browning DJ. Hydroxychloroquine and chloroquine retinopathy screening for drug toxicity. AmJ Ophthalmol. 2002 133 649-656. 

Long-term chloroquine can cause cardiac comphca-tions, such as conduction disorders and cardiomyopathy (restrictive or hypertrophic), by structural alteration of the interventricular septum (4). Thirteen cases of cardiac toxicity associated with long-term chloroquine and hydroxychloroquine have been reported in patients with systemic autoimmune diseases. The cumulative doses were 600-2281 g for chloroquine and 292-4380 g for hydroxychloroquine. 

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. ... 

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. 

Quinacrine, which is tricyclic and highly lipophilic, will easily penetrate cell membranes but hardly diffuse through the hydrophilic vitreous cavity. It also forms a stable complex with melanin and will therefore be retained in the RPE. Quinacrine must be considered a potent photosensitizer in the retina due to the absorption maximum of this drug in the visible region of the spectrum (Table 10.1). The more hydrophilic compounds chloroquine and hydroxychloroquine will more easily be transported to the lens. They are known to accumulate in the eye and induce toxic reactions. Primaquine is not likely to be distributed to the eye to any extent due to low distribution volume and fast elimination. 

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. 

Several 4-aminoquinolines have now been tested and hydroxychloroquine sulphate (Plaquenil XLV, R =Et, R =CH2-CH2-OH), a closely related derivative of chloroquine, is known to possess antirheumatic properties similar to those of chloroquine . Amodiaquine (Camoquin, XLVl, R=NEt2) also possesses activity but seems to be too toxic for routine use . . . However, the closely-related amopyroquin (Propoquin, XLVI, R=pyrrolidino) appears to possess desirable clinical activity without serious toxicity . Drugs of the 4-aminoquinoline type in most frequent use are chloroquine phosphate, 250-500 mg daily, chloroquine sulphate, 200-400 mg daily, and hydroxychloroquine sulphate, 400-600 mg daily . A striking feature of this therapy is that beneficial effects are often not apparent until... 

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. 

TOXICITY AND MONITORING The toxic effects of antimalarial agents are described in Chapter 39. The incidence of retinopathy from chloroquine and hydroxychloroquine is low, as long as the doses are as described above and the medication is used for less than 10 years in patients with normal renal function. 

Chloroquine and hydroxychloroquine belonging to the class of 4-amino-quinoline anthmalarials are being used in clinical practice in the eure and treatment of rheumatoid arthritis sinee 1957. However, the two important disadvantageous faetors, namely slow onset of therapeutie effeet and significant ocular toxicity seemed to have shadowed the elinieal supremacy of these drugs. 

Chloroquine and other aminoquinolines are used in the prophylaxis or therapy of malaria and other parasitic diseases. Chloroquine and hydroxychloroquine are also used in the treatment of rheumatoid arthritis. Drugs in this class include chloroquine phosphate (Aralen ), amodiaquine hydrochloride (Camoquin ), hydroxychloroquine sulfate (Plaquenil ), mefloquine (Lariam" ), primaquine phosphate, and quinacrine hydrochloride (Atabrine ). Chloroquine overdose is common, especially in countries where malaria is prevalent, and the mortality rate is 10-30%. Quinine toxicity is described on p 326. 

Both antimalarial agents are administered orally with the usual dose for hydroxychloroquine 200 to 400 mg/day and chloroquine 250 to 750 mg/day. Parental administration is not recommended. Because of the higher toxicity reported with chloroquine, most physicians prefer hydroxychloroquine. A reduced dose of hydroxychloroquine is recommended for those with a low lean body mass. 

Both hydroxychloroquine and chloroquine are well absorbed when given orally (235). For hydroxychloroquine, the effectiveness and toxicity appear to be dose dependent (236). Both dmgs have prolonged half-lives of over six weeks (237). Both drugs bind strongly to pigmented tissues but also bind to other cells such as mononuclear cells. Potentially important kinetic interactions have been documented for D-peniciUamine and cimetidine (235). 

Chloroquine and hydroxychloroquine are well-recognised anfiparasitic drugs. However, they are also prescribed for the treatment of rheumatic diseases such as sysfemic lupus eryfhematosus [10 ]. Ocular and cardiac toxicities induced by chloroquine are discussed in a review [11 ]. 

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