Page 664 - Basic _ Clinical Pharmacology ( PDFDrive )

650 SECTION VI Drugs Used to Treat Diseases of the Blood, Inflammation, & Gout

Most patients respond to abatacept within 12–16 weeks after Controlled trials show efficacy in PA, reactive arthritis, polymyosi-
the initiation of the treatment; however, some patients can tis, SLE, maintenance of remission in vasculitis, and Behçet’s dis-
respond in as few as 2–4 weeks. A study showed equivalence ease. Azathioprine is also used in scleroderma; however, in one
between adalimumab (see TNF-α Blocking Agents) and study, it was found to be less effective than cyclophosphamide in
abatacept. controlling the progression of scleroderma lung disease. Another
3. Indications: Abatacept can be used as monotherapy or in com- registry study indicated possible usefulness in scleroderma lung
bination with methotrexate or other DMARDs in patients with disease. Thus it is not clear what place, if any, azathioprine has for
moderate to severe RA or severe PJIA. It has been tested in treating scleroderma.
combination with methotrexate in early rapidly progressing RA 4. Adverse Effects: Azathioprine’s toxicity includes bone marrow
and methotrexate-naïve patients. The combination was supe- suppression, GI disturbances, and some increase in infection
rior to methotrexate in achieving minimal disease activity as risk. As noted in Chapter 55, lymphomas may be increased
early as 2 months, significantly inhibiting radiographic progres- with azathioprine use. Rarely, fever, rash, and hepatotoxicity
sion at 1 year and improving patients’ physical function and signal acute allergic reactions.
symptoms. Such improvement is sustained or improved during
the second year. Another trial (ADJUST) tested the effective-
ness of abatacept in preventing progression to defined RA in CHLOROQUINE &
patients with undifferentiated inflammatory arthritis. The
results showed that numerically, RA developed in more patients HYDROXYCHLOROQUINE
treated with placebo than in those treated with abatacept over
1 year. Abatacept has been tested in other rheumatic diseases 1. Mechanism of Action: Chloroquine and hydroxychloroquine
like SLE, primary Sjögren’s syndrome, type 1 diabetes, inflam- are nonbiologic drugs mainly used for malaria (see Chapter 52)
matory bowel disease, and psoriasis vulgaris, but the most and in the rheumatic diseases as csDMARDs. The following
beneficial effects were seen in psoriatic arthritis (PsA) patients. mechanisms have been proposed: suppression of T-lymphocyte
4. Adverse Effects: There is a slightly increased risk of infection responses to mitogens, inhibition of leukocyte chemotaxis,
(as with other biologic DMARDs), predominantly of the upper stabilization of lysosomal enzymes, processing through the
respiratory or urinary tracts. Concomitant use with TNF-α Fc-receptor, inhibition of DNA and RNA synthesis, and the
antagonists or other biologics is not recommended due to the trapping of free radicals.
increased incidence of serious infection. All patients should be 2. Pharmacokinetics: Antimalarials are rapidly absorbed and
screened for latent tuberculosis and viral hepatitis before start- 50% protein-bound in the plasma. They are very extensively
ing this medication. Live vaccines should be avoided in patients tissue-bound, particularly in melanin-containing tissues such as
while taking abatacept and up to 3 months after discontinua- the eyes. The drugs are deaminated in the liver and have blood
tion. Infusion-related reactions and hypersensitivity reactions, elimination half-lives of up to 45 days.
including anaphylaxis, have been reported but are rare. Anti- 3. Indications: Antimalarials are approved for RA, but they are not
abatacept antibody formation is infrequent (<5%) and has no considered very effective DMARDs. Dose-loading may increase
effect on clinical outcomes. There is a possible increase in lym- rate of response. There is no evidence that these compounds alter
phomas but not other malignancies when using abatacept. 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
AZATHIOPRINE used very commonly in SLE because they decrease mortality and
the skin manifestations, serositis, and joint pains of this disease.
1. Mechanism of Action: Azathioprine is a csDMARD that acts They have also been used in Sjögren’s syndrome.
through its major metabolite, 6-thioguanine. 6-Thioguanine 4. Adverse Effects: Although ocular toxicity (see Chapter 52)
suppresses inosinic acid synthesis, B-cell and T-cell function, may occur at dosages greater than 250 mg/d for chloroquine
immunoglobulin production, and IL-2 secretion (see Chapter 55). and greater than 6.4 mg/kg/d for hydroxychloroquine, it rarely
2. Pharmacokinetics: Azathioprine can be given orally or paren- occurs at lower doses. Nevertheless, ophthalmologic monitor-
terally. Its metabolism is bimodal in humans, with rapid ing every 12 months is advised. Other toxicities include dyspep-
metabolizers clearing the drug four times faster than slow sia, nausea, vomiting, abdominal pain, rashes, and nightmares.
metabolizers. Production of 6-thioguanine is dependent on These drugs appear to be relatively safe in pregnancy.
thiopurine methyltransferase (TPMT), and patients with low
or absent TPMT activity (0.3% of the population) are at par-
ticularly high risk of myelosuppression by excess concentrations CYCLOPHOSPHAMIDE
of the parent drug, if dosage is not adjusted.
3. Indications: Azathioprine is approved for use in RA at 2 mg/kg 1. Mechanism of Action: Cyclophosphamide is a csDMARD. Its
per day. It is also used for the prevention of kidney transplant rejec- major active metabolite is phosphoramide mustard, which
tion in combination with other immune suppressants. cross-links DNA to prevent cell replication. It suppresses T-cell