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Chloroquine/Hydroxychloroquine(US: Aralen): Side Effects

Chloroquine is rapidly and almost completely absorbed from the intestinal tract, peak serum concentrations being reached in 1-6 hours (average 3 hours). It is extensively distributed and redistribution follows. It is slowly metabolized by side-chain de-ethylation. The half-life is 30-60 days. Elimination is mainly via the kidney. Malnutrition can slow down the rate of metabolism.

Comparative studies

Amodiaquine and chloroquine have been compared in an open, randomized trial in uncomplicated falciparum malaria in Nigerian children. The doses were amodiaquine 10 mg/kg/day for 3 days and chloroquine 10 mg/kg/day for 3 days. After 28 days, the cure rate was significantly higher with amodiaquine than chloroquine (95% versus 58%). The rates of adverse events, most commonly pruritus (10%) and gastrointestinal disturbances (3%), were similar in the two groups. Cross-resistance between the two aminoquinolines is common, and there are concerns regarding toxicity of amodiaquine with repeated use.

General adverse effects

There are relatively few adverse effects at the doses of chloroquine that are used for malaria prophylaxis and standard treatment doses. However, the use of higher doses than those recommended, for example because of problems with resistance, can cause problems. Infants are very easily overdosed. In the treatment of rheumatoid arthritis and lupus erythematosus, larger doses are used, often for long periods of time, and with this use the incidence of adverse effects is high. Neuromyopathy, neuritis, myopathy, and cardiac myopa-thy can cause serious problems. Retinopathy can lead to blindness. Chloroquine has a long half-life and accumulates in the tissues, including the brain. Concentrations in the brain can have a bearing on mental status and psychotic syndromes. Chloroquine interferes with the action of several enzymes, including alcohol dehydrogenase, and blocks the sulfhydryl-disulfide interchange reaction. Allergic reactions are generally limited to rashes and pruritus.

Chloroquine and Hydroxychloroquine: Organs and Systems

Long-Term Effects

Drug tolerance

Chloroquine-resistant falciparum malaria was first reported in 1960. As of 1996, chloroquine resistance became widespread throughout the world and in many areas there is multidrug resistance. Preventive administration of drugs such as chloroquine, primaquine, and pyrimethamine, as well as the use of various sulfonamide mixtures and combinations of sulfonamides with trimethoprim, has progressively lost its usefulness. Currently, hardly half a century after the therapeutic breakthroughs occurred, quinine is once more one of the most valuable drugs in the treatment of malaria and there is a desperate need for other effective drugs.

Alongside the well-known development of resistance by P. falciparum to chloroquine, the emergence of chloroquine-resistant Plasmodium vivax is now clear. An increased frequency of cerebral malaria appears to coincide with the growing emergence of the chloroquine-resistant strains in Francophone Africa.

Second-Generation Effects

Pregnancy

Chloroquine inactivates DNA, and crosses the placenta in animals. Caution has generally been advised with respect to the use of chloroquine and related compounds during pregnancy, but except for one (perhaps coincidental) case, there have been no reports of complications to mother or child from treatment with chloroquine during pregnancy.

An observational comparison in a rural Ghanaian hospital of 2083 pregnant women and 3084 historical controls showed no serious adverse events with chloroquine che-moprophylaxis (300 mg/week), but a high rate of pruritus. There was a decrease in anemia in pregnancy but no increase in perinatal mortality or birth weight in the chloroquine-treated mothers, although this was only in comparison with historical controls.

Susceptibility Factors

Genetic factors

Mutations in the ABCR gene (a photoreceptor-specific Adenosine and adenosine triphosphate-binding cassette transporter gene) have been associated with Stargardt disease, which has some features similar to chloroquine-induced retinopathy. In a case-control study of eight cases of chloroquine-induced retinopathy, five of the eight cases had mis-sense mutations in the ABCR gene, two of which have been associated with Stargardt disease. It may be that polymorphisms in the ABCR gene predispose to chloroquine-induced retinopathy.

Age

Small children have usually been considered as being relatively more sensitive to the effects of overdosage, but it has been calculated that on a mg/kg body weight basis, adults are in fact equally sensitive. Young children seem to be truly more susceptible to gastric irritation. Patients with a history of mania or epilepsy should be careful in taking chloroquine. The hypoxemic effects of chloroquine, reflecting cardiac and respiratory toxicity, pose a particular problem in the newborn, in whom existing malarial infection may not become clinically manifest until some months after birth.

Compared with adults, mortality in children after acute chloroquine poisoning is extremely high. Although the clinical presentation is mostly similar to that in adults (apnea, seizures, cardiac dysrhythmias), a single 300 mg chloroquine tablet was enough to kill a 12-month-old female infant.

Other features of the patient

Skin reactions to hydroxychloroquine occur more often in patients with dermatomyositis than in patients with systemic lupus erythematosus, as has been shown in a retrospective, age-, sex-, and race-matched case-control study in 78 patients. Twelve of 39 patients with dermatomyositis developed a skin reaction to hydroxychloroquine, compared with only one of 39 patients with lupus erythematosus.

Chloroquine and Hydroxychloroquine: Drug Administration

Chloroquine and Hydroxychloroquine: Drug-Drug Interactions

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