Mechanism of Action: Chloroquine and hydroxychloroquine are nonbiologic drugs mainly used for malaria (see Chapter 52) and in the rheumatic diseases as csDMARDs. The following mechanisms have been proposed: suppression of T-lymphocyte responses to mitogens, inhibition of leukocyte chemotaxis, stabilization of lysosomal enzymes, processing through the Fc-receptor, inhibition of DNA and RNA synthesis, and the trapping of free radicals.
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Pharmacokinetics: Antimalarials are rapidly absorbed and 50% protein-bound in the plasma. They are very extensively tissue-bound, particularly in melanin-containing tissues such as the eyes. The drugs are deaminated in the liver and have blood elimination half-lives of up to 45 days.
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Indications: Antimalarials are approved for RA, but they are not considered very effective DMARDs. Dose-loading may increase rate of response. There is no evidence that these compounds alter bony damage in RA at their usual dosages (up to 6.4 mg/kg per day for hydroxychloroquine or 200 mg/d for chloroquine). It usually takes 3–6 months to obtain a response. Antimalarials are used very commonly in SLE because they decrease mortality and the skin manifestations, serositis, and joint pains of this disease. They have also been used in Sjögren’s syndrome.
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Adverse Effects: Although ocular toxicity (see Chapter 52) may occur at dosages greater than 250 mg/d for chloroquine and greater than 6.4 mg/kg/d for hydroxychloroquine, it rarely occurs at lower doses. Nevertheless, ophthalmologic monitoring every 12 months is advised. Other toxicities include dyspepsia, nausea, vomiting, abdominal pain, rashes, and nightmares. These drugs appear to be relatively safe in pregnancy.
1. Mechanism of Action: Cyclophosphamide is a csDMARD. Its major active metabolite is phosphoramide mustard, which cross-links DNA to prevent cell replication. It suppresses T-cell and B-cell function by 30–40%; T-cell suppression correlates with clinical response in the rheumatic diseases. Its pharmacokinetics and toxicities are discussed in Chapter 54.
2. Indications: Cyclophosphamide is used regularly at 2 mg/ kg per day to treat SLE, vasculitis, Wegener’s granulomatosis, and other severe rheumatic diseases although mycophenolate is now often used for SLE and rituximab is often used for some forms of vasculitis (see below).
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Mechanism of Action: Cyclosporine is a peptide antibiotic but is considered a csDMARD. Through regulation of gene transcription, it inhibits IL-1 and IL-2 receptor production and secondarily inhibits macrophage–T-cell interaction and T-cell responsiveness (see Chapter 55). T-cell–dependent B-cell function is also affected.
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Pharmacokinetics: Cyclosporine absorption is incomplete and somewhat erratic, although a microemulsion formulation improves its consistency and provides 20–30% bioavailability. Grapefruit juice increases cyclosporine bioavailability by as much as 62%. Cyclosporine is metabolized by CYP3A and consequently is subject to a large number of drug interactions (see Chapters 55 and 66).
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