Antimalarial Agents

The major antimalarials used commonly in dermatology include chloroquine (aralen), hydroxychloroquine (plaquenil), and to a lesser extent, quinacrine (no longer available in the U.S.); all three drugs are useful because of their anti-inflammatory effects, especially in connective tissue disorders and photosensitivity diseases (see Chapter 39).

The mechanism of action of the immunological and anti-inflammatory effects of antimalarials include inhibition of phospholipase A2, 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 hydroxychloro-quine 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.

therapeutic uses FDA-approved dermatological uses of hydroxychloroquine include treatment of discoid and systemic lupus erythematosus. Unapproved but first-line uses include treatment of dermatomyositis, porphyria cutanea tarda, polymorphous light eruption, sarcoidosis, eosinophilic fasciitis, lymphocytic infiltrate of Jessner, lymphocytoma cutis, solar urticaria, granuloma annulare, and some forms of panniculitis.

Usual doses of antimalarials are hydroxychloroquine, 200 mg twice a day; chloroquine, 250-500 mg/day; and quinacrine, 100-200 mg/day. Usually, hydroxychloroquine is started first, and if no improvement is noted in 3 months, quinacrine is added. Alternatively, chloroquine is used as a single agent. Dosing should be adjusted for low-weight individuals so that chloroquine dosing is 2.5 mg/kg/day and hydroxychloroquine is 6.5 mg/kg/day. Antimalarial agents are the treatment of choice for widespread forms of cutaneous lupus that do not respond to topical glucocorticoids and sunscreens. Clinical improvement may be delayed for several months.

Porphyria cutanea tarda, characterized by fluid-filled vesicles and bullae on sun-exposed areas, can be either genetic or associated with alcohol abuse or hepatitis C. Although the associated iron overload is treated with phlebotomy, the dermatologic manifestations sometimes are treated with antimalarial agents. These patients require reduced doses because of the potential for hepatotoxic-ity, as manifested by elevated transaminase levels, and the rapid excretion of large amounts of uro-porphyrins in the urine that can occur with usual doses. Low-dose twice-weekly administration is effective and avoids these side effects.

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.

Quinacrine does not cause retinopathy. Eye examinations every 6 months or even yearly after a baseline examination probably are sufficient, provided dosing guidelines are followed. Although caution is required, there is evidence that antimalarial agents probably are safe in pregnancy and in children. Rare hematological side effects include agranulocytosis, aplastic anemia, and hemolysis in patients with glucose-6-phosphatase deficiency. Liver function tests and complete blood counts should be performed monthly at the start of therapy and at least every 4-6 months throughout treatment.

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