20-60 mg orally
20-60 mg orally
Induction; 9 mg orally Maintenance: 6 mg orally 15-60 mg orally or IV
300 mg IV in three divided doses 100 mg rectally at bedtime 90 mg recta I ly once or twice daily 25-50 my recially twice daily 25-50 mg rectal ly twice daily
The use of nonsulfapyridine-based aminosalicylates has led to greater tolerability. Although the adverse effects are similar to those of sulfasalazine, they occur at a much lower rate. Olsalazine, in particular, is associated with a higher incidence of secretory diarrhea. These agents can also be used safely in patients with a reported sulfonamide allergy.
Corticosteroids have potent anti-inflammatory properties and are used in active IBD to suppress inflammation rapidly. They may be administered systemically or delivered locally to the site of action by altering the drug formulation (Table 19-2). Because these drugs usually improve symptoms and disease severity rapidly, they should be restricted to short-term management of active disease. Long-term use of systemic corticosteroids is associated with significant adverse effects, including cataracts, skin at-
risk of infection, among others.
Budesonide is a high-potency glucocorticoid used in CD that has low systemic
bioavailability when administered orally. The formulation releases budesonide in the terminal ileum for treatment of disease involving the ileum or ascending colon. Due to its reduced bioavailability, budesonide may2prevent some long-term adverse effects in patients who have steroid-dependent IBD. 3,24
Agents targeting the excessive immune response or cytokines involved in IBD are potential treatment options (Table 19-3). Azathioprine and its active metabolite 6-mercaptopurine (6-MP) are inhibitors of purine biosynthesis and reduce IBD-asso-
ciated GI inflammation. They are most useful for maintaining remission of IBD or
reducing the need for long-term use of corticosteroids. ' Use in active disease is limited by their slow onset of action, which may be as long as 3 to 12 months. Adverse effects associated with azathioprine and 6-MP include hypersensitivity reactions res-
ulting in pancreatitis, fever, rash, hepatitis, and leukopenia. ' ' Patients should be tested for activity of thiopurine methyltransferase, the major enzyme responsible for metabolism of azathioprine. Deficiency or reduced activity of thiopurine methyltransferase may result in excess toxicity from azathioprine and 6-MP.
Table 19-3 Immunosuppressant and Biologic Agents for Treatment of IBD
Azathioprine 6 Mercaptopurine Methotrexate
1.5-2.5 mg/kg/day orally
1.5-2.5 mg/kg/day orally
15-25 mg weekly (IM/SC/ orally)
4 mg/kg/day IV continuous infusion
Induction; 5 mg/kg IV at 0.2, and 6 weeks; 10 mg/kg per dose IV for nonresponders
Maintenance: 5 mg/kg IV every 8 weeks
Induction: 160 mg SC day 1 (given as four 40-mg injections in one day or as two 40-mg injections per day for two consecutive days), then 80 mg SC 2 weeks later (day 15)
Maintenance: 40 mg SC every other week, starting on day 29 of therapy
Induction: 400 mg SC initially, then 400 mg SC at 2 and 4 weeks
Maintenance: 400 mg SC every 4 weeks if initial
Methotrexate is a folate antagonist used primarily for maintaining remission of CD. It maybe administered orally, subcutaneously, or IV and may result in a steroid-sparing effect in patients with steroid-dependent disease. , , Long-term methotrexate use may result in serious adverse effects, including hepatotoxicity, pulmonary fibrosis, and bone marrow suppression.
Cyclosporine is a cyclic polypeptide immunosuppressant typically used to prevent organ rejection in transplant patients. Its use is restricted to patients with fulminant or refractory symptoms in patients with active IBD. Significant toxicities associated with cyclosporine are nephrotoxicity, risk of infection, seizures, hypertension, and liv-
er function test abnormalities. ' Biologic Agents
Several biologic agents targeting TNF-a are used for treatment of IBD (Table 19-3). Reduction in TNF-a activity is associated with improvement in the underlying inflammatory process. Infliximab is the prototypical agent and is used in both UC and CD, whereas the other agents are approved for use only in CD. Due to its chimeric structure (i.e., part human, part mouse) antibodies to infliximab may develop, resulting in loss of efficacy over time. Newer biologic agents are humanized and have a lower propensity for antibody development.28
Disadvantages of anti-TNF biologic therapy include need for parenteral administration, significant drug cost, and potential for serious adverse effects. Adverse effects may include infusion-related reactions such as fever, chest pain, hypotension, and dyspnea. All of the TNF-a inhibitors have also been associated with reactivation of serious infections, particularly intracellular pathogens such as tuberculosis, as well as hepatitis B.16,22 These agents should not be used in patients with current infections, and patients should be screened for tuberculosis prior to initiating therapy. Exacerbation of heart failure is also a potential adverse effect, and biologic agents should be avoided in patients with advanced or decompensated heart failure. , ,
Natalizumab is a humanized monoclonal antibody that antagonizes integrin het-erodimers, prevents a4-mediated leukocyte adhesion to adhesion molecules, and prevents migration across the endothelium. 9 It has been associated with development of progressive multifocal leukoencephalopathy, and its use is restricted to patients with CD who have failed other therapies. Natalizumab should notbe used concomitantly with immunosuppressants or TNF-a inhibitors.
Antibiotics have been studied based on the rationale that they may interrupt the inflammatory response directed against endogenous bacterial flora. Metronidazole and ciprofloxacin have been the two most widely studied agents.30 Metronidazole may benefit some patients with pouchitis (inflammation of surgically created intestinal pouches) and patients with CD who have had ileal resection or have perianal fistulas. Ciprofloxacin has shown some efficacy in refractory active CD. Both drugs may cause diarrhea, and long-term use of metronidazole is associated with the development of peripheral neuropathy.
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