Page 665 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 36 NSAIDs, Antirheumatic Drugs, Nonopioid Analgesics, & Drugs Used in Gout 651

and B-cell function by 30–40%; T-cell suppression correlates and is subject to enterohepatic recirculation. Cholestyramine
with clinical response in the rheumatic diseases. Its pharmaco- can enhance leflunomide excretion and increases total clearance
kinetics and toxicities are discussed in Chapter 54. by approximately 50%.
2. Indications: Cyclophosphamide is used regularly at 2 mg/ 3. Indications: Leflunomide is as effective as methotrexate in RA,
kg per day to treat SLE, vasculitis, Wegener’s granulomatosis, including inhibition of bony damage. In one study, combined
and other severe rheumatic diseases although mycophenolate is treatment with methotrexate and leflunomide resulted in a
now often used for SLE and rituximab is often used for some 46.2% ACR20 response compared with 19.5% in patients
forms of vasculitis (see below). receiving methotrexate alone.
4. Adverse Effects: Diarrhea occurs in approximately 25% of
patients given leflunomide, although only about 3–5% of
CYCLOSPORINE patients discontinue the drug because of this side effect.
Elevation in liver enzymes can occur. Both effects can
1. Mechanism of Action: Cyclosporine is a peptide antibiotic but be reduced by decreasing the dose of leflunomide. Other
is considered a csDMARD. Through regulation of gene tran- adverse effects associated with leflunomide are mild alope-
scription, it inhibits IL-1 and IL-2 receptor production and cia, weight gain, and increased blood pressure. Leukopenia
secondarily inhibits macrophage–T-cell interaction and T-cell and thrombocytopenia occur rarely. This drug is contrain-
responsiveness (see Chapter 55). T-cell–dependent B-cell func- dicated in pregnancy.
tion is also affected.
2. Pharmacokinetics: Cyclosporine absorption is incomplete and
somewhat erratic, although a microemulsion formulation METHOTREXATE
improves its consistency and provides 20–30% bioavailability.
Grapefruit juice increases cyclosporine bioavailability by as Methotrexate, a synthetic nonbiologic antimetabolite, is the
much as 62%. Cyclosporine is metabolized by CYP3A and first-line csDMARD for treating RA and is used in 50–70% of
consequently is subject to a large number of drug interactions patients. It is active in this condition at much lower doses than
(see Chapters 55 and 66). those needed in cancer chemotherapy (see Chapter 54).
3. Indications: Cyclosporine is approved for use in RA and 1. Mechanism of Action: Methotrexate’s principal mechanism of
retards the appearance of new bony erosions. Its usual dosage is action at the low doses used in the rheumatic diseases probably
3–5 mg/kg per day divided into two doses. Anecdotal reports relates to inhibition of amino-imidazolecarboxamide ribonu-
suggest that it may be useful in SLE, polymyositis and derma- cleotide (AICAR) transformylase and thymidylate synthetase.
tomyositis, Wegener’s granulomatosis, juvenile chronic arthritis, AICAR, which accumulates intracellularly, competitively
and refractory eye involvement in Behçet disease. inhibits AMP deaminase, leading to an accumulation of AMP.
4. Adverse Effects: Leukopenia, thrombocytopenia, and, to a The AMP is released and converted extracellularly to adenos-
lesser extent, anemia are predictable. High doses can be car- ine, which is a potent inhibitor of inflammation. As a result,
diotoxic and neurotoxic, and sterility may occur after chronic the inflammatory functions of neutrophils, macrophages,
dosing at antirheumatic doses, especially in women. Bladder dendritic cells, and lymphocytes are suppressed. Methotrexate
cancer is very rare but must be looked for, even 5 years after has secondary effects on polymorphonuclear chemotaxis.
cessation of use. There is some effect on dihydrofolate reductase and this affects
lymphocyte and macrophage function, but this is not its prin-
cipal mechanism of action. Methotrexate has direct inhibitory
LEFLUNOMIDE effects on proliferation and stimulates apoptosis in immune-
inflammatory cells. Additionally, it inhibits proinflammatory
1. Mechanism of Action: Leflunomide, another csDMARD, cytokines linked to rheumatoid synovitis.
undergoes rapid conversion, both in the intestine and in the 2. Pharmacokinetics: Methotrexate can be administered either
plasma, to its active metabolite, A77-1726. This metabolite orally or parentally (SC or IM). The drug is approximately
inhibits dihydroorotate dehydrogenase, leading to a decrease in 70% absorbed after oral administration (see Chapter 54).
ribonucleotide synthesis and the arrest of stimulated cells in the Although variable, bioavailability decreased further in one
G phase of cell growth. Consequently, leflunomide inhibits study when more than 25 mg weekly MTX was used. MTX
1
T-cell proliferation and reduces production of autoantibod- is metabolized to a less active hydroxylated product. Both
ies by B cells. Secondary effects include increases of IL-10 the parent compound and the metabolite are polygluta-
receptor mRNA, decreased IL-8 receptor type A mRNA, mated within cells where they stay for prolonged periods.
and decreased TNF-α–dependent nuclear factor kappa B Methotrexate’s serum half-life is usually only 6–9 hours.
(NF-κB) activation. Hydroxychloroquine can reduce the clearance or increase
2. Pharmacokinetics: Leflunomide is completely absorbed from the tubular reabsorption of methotrexate. Methotrexate is
the gut and has a mean plasma half-life of 19 days. Its active excreted principally in the urine, but up to 30% may be
metabolite, A77-1726, has approximately the same half-life excreted in bile.