Crohn Disease Medication

The goals of pharmacotherapy in patients with Crohn disease are to reduce morbidity, to prevent complications, and to maintain nutritional status.

Management of Diarrhea

Chronic diarrhea in Crohn disease responds well to antidiarrheal agents such as loperamide (2-4 mg), diphenoxylate with atropine (1 tab), and tincture of opium (8-15 gtt). Such agents may be administered up to 4 times daily, but they should not be given to patients with active colitis because of the risk of developing toxic megacolon.

Patients with terminal ileal disease may not absorb bile acids normally, which can lead to secretory diarrhea in the colon. These patients may benefit from bile acid sequestrants (eg, cholestyramine [2-4 g], colestipol [5 g] bid/tid ac).

Abdominal cramps may be reduced with propantheline (0.125 mg), dicyclomine (10-20 mg), or hyoscyamine (0.125 mg). These drugs should not be used if there is the possibility of a bowel obstruction.^{[3, 23]}

Management of Bowel Inflammation

For colon and small bowel inflammation, anti-inflammatory drugs or antibiotics are helpful. Sulfasalazine does not alleviate small bowel disease. Products such as mesalamine (Asacol, Rowasa, Canasa) that release 5-ASA in the distal small bowel secondary to pH changes are more useful in patients with small intestinal Crohn disease.

According to a systemic review, antituberculosis therapy, macrolides, fluoroquinolones, 5-nitroimidazoles, and rifaximin (alone or in combination) have been shown to induce remission in active Crohn disease and ulcerative colitis.^[58] Further trials of antibiotic therapy are necessary in order to determine the best course of single or combination antibiotic therapy.

Long-term maintenance with mesalamine (800 mg tid) may delay clinical relapse. Prednisone (Deltasone, Orasone) (40-60 mg/d) is generally helpful in acute inflammation.

Steroids are not indicated for maintenance therapy because of serious complications, such as aseptic necrosis of the hip, osteoporosis, cataract, diabetes, and hypertension. Accordingly, once remission is achieved, the agent is slowly tapered (5-10 mg q1-2wk). If steroid withdrawal proves difficult, immunosuppressants such as azathioprine (Imuran) (2 mg/kg/d) or its active metabolite, 6-MP, may be considered. Response is usually observed within 3-6 months. Mycophenolate mofetil (CellCept) 500 mg twice a day in 2 divided doses is well tolerated by patients and can be used to reduce the steroid dose.^{[3, 23]}

Management of Fistulae

Fistulae between bowel loops (eg, ileoileal, ileocecal, ileosigmoid) are usually benign and may not produce any major problems. Medical management is used to treat underlying infections and symptoms with oral metronidazole (Flagyl, 1 g/d) for at least 1-2 months. Infliximab is effective in patients who have refractory perianal and enterocutaneous fistulae. Current clinical practice is to use it as an intravenous (IV) infusion of 5 mg/kg at 0 weeks, 2 weeks, and 6 weeks, followed by maintenance IV infusions every 8 weeks. On average, the effect lasts for 12 weeks.

Class Summary

These agents are used to treat mild-to-moderate disease and to maintain remission. These agents have anti-inflammatory effects.

Mesalamine (Asacol, Rowasa, Canasa)

Products such as mesalamine (Asacol, Rowasa, Canasa) that release 5-ASA in the distal small bowel secondary to pH changes are more useful in patients with small intestinal Crohn disease. Long-term maintenance with mesalamine may delay clinical relapse. It is better tolerated and has less adverse effects than sulfasalazine.

Sulfasalazine (Azulfidine)

Sulfasalazine (Azulfidine) is useful mainly in colonic disease, because the active compound, 5- ASA, is released in the large bowel by bacterial degradation of the parent compound. Sulfasalazine does not alleviate small bowel disease. It acts locally in the colon to reduce the inflammatory response and systemically inhibits prostaglandin synthesis. Sulfasalazine does not have an additive effect or a steroid-sparing effect when used in conjunction with corticosteroids. In contrast to its action in ulcerative colitis, sulfasalazine does not seem to maintain remission in Crohn disease.

Class Summary

Corticosteroids are used to treat active moderate-to-severe disease. They are not indicated for maintenance therapy. Budesonide is available in an ileal controlled-release form and is used for the treatment of ileal and/or right-sided colonic disease. A short course of corticosteroid therapy is indicated in patients with severe systemic symptoms (eg, fever, nausea, weight loss) and in those whose condition does not respond to anti-inflammatory agents. Budesonide induces remission in active Crohn disease but is less effective than other standard glucocorticosteroids and is of no benefit in preventing relapse.^[59]

Prednisone (Deltasone, Orasone)

Prednisone exerts anti-inflammatory effects through decreased capillary permeability, impaired neutrophil chemotaxis, release of anti-inflammatory cytokines, decrease of production of eicosanoids, and stabilization of lysosomal membranes. Prednisone is generally helpful in acute inflammation.

Methylprednisolone (Asacol, Rowasa, Canasa)

Methylprednisolone exercises the anti-inflammatory effects through decreased capillary permeability, impaired neutrophil chemotaxis, release of anti-inflammatory cytokines, decreased production of eicosanoids, and stabilization of the lysosomal membrane.

Budesonide (Entocort EC)

Budesonide alters levels of inflammation in tissues by inhibiting multiple types of inflammatory cells and decreasing the production of cytokines and other mediators involved in inflammatory reactions.

Hydrocortisone (Cortenema, Anusol-HC)

Adrenocortical steroids act as potent inhibitors of inflammation. They may cause profound and varied metabolic effects, particularly in relation to salt, water, and glucose tolerance, in addition to their modification of the immune response of the body.

Class Summary

These agents are used to treat moderate-to-severe disease, to treat steroid-dependent or steroid-refractory disease, and to maintain remission.

6-Mercaptopurine (Purinethol)

6-Mercaptopurine and its prodrug azathioprine are purine analogues and they interfere with protein synthesis and nucleic acid metabolism and have cytotoxic effect on lymphoid cells. If steroid withdrawal proves difficult, immunosuppressants such as 6-mercaptopurine may be considered.

Azathioprine (Imuran)

Azathioprine antagonizes purine metabolism and inhibits synthesis of DNA, RNA, and proteins. It may decrease proliferation of immune cells, which lowers autoimmune activity.

Methotrexate (Folex PFS, Rheumatrex)

Methotrexate is a structural analogue to folic acid that inhibits binding of dihydrofolic acid to the enzyme dihydrofolate reductase. It impairs DNA synthesis, induces apoptosis, and reduces interleukin 1 production. Methotrexate is used for the treatment of moderate-to-severe disease and maintenance of remission. Its onset of action delayed. Methotrexate is effective in inducing and maintaining remission in chronic Crohn disease in adults and has been shown to be effective and well tolerated for maintenance of remission in children.

Tacrolimus (Prograf)

Tacrolimus is an immunomodulator produced by the bacteria Streptomyces tsukubaensis. The mechanism of action is similar to that of cyclosporine. It may be effective in treating Crohn disease.

Class Summary

These agents are used in the treatment of active disease or fistulizing disease unresponsive to other medical therapy.

Infliximab (Remicade)

Infliximab (Remicade) is a chimeric mouse-human monoclonal antibody against TNF-alpha that shows promise in Crohn disease treatment; it blocks TNF-alpha in the serum and at the cell surface, leading to the lysis of TNF-producing macrophages and T cells. Infliximab has been approved for the treatment of pediatric Crohn disease.

Adalimumab (Humira)

Adalimumab is a recombinant human IgG1 monoclonal antibody specific for human TNF. It binds specifically to TNF-alpha and blocks interaction with p55 and p75 cell-surface TNF receptors. This interferes with the cytokine driven inflammatory processes. It also lyses surface TNF-expressing cells in vitro in the presence of complement, but it does not bind to TNF-beta (lymphotoxin).

Certolizumab pegol (Cimzia)

Certolizumab pegol is a pegylated anti–TNF-alpha blocker, which results in disruption of the inflammatory process. It is indicated for moderate-to-severe Crohn disease in individuals whose condition has not responded to conventional therapies.

Natalizumab (Tysabri)

Natalizumab is a monoclonal antibody against the alpha4 integrin subunit that inhibits leukocyte adhesion and migration to areas of inflammation. It is indicated for moderate-to-severe Crohn disease patients who have had inadequate responses to other therapies.

Class Summary

These agents are used in the treatment of mild-to-moderate, fistulizing, and perianal disease. Antibiotics may change the microbial florae of the intestine and have a potential effect on the cell-mediated immune system.

Metronidazole (Flagyl)

Metronidazole is an imidazole ring–based antibiotic active against various anaerobic bacteria and protozoa. It is sometimes used in combination with other antimicrobial agents (except for in Clostridium difficile enterocolitis). It also possesses immunosuppressive and anti-inflammatory properties.

Ciprofloxacin (Cipro)

A fluoroquinolone, ciprofloxacin has activity against pseudomonads, streptococci, MRSA, Staphylococcus epidermidis, and most gram-negative organisms, but no activity against anaerobes. It inhibits bacterial DNA synthesis and, consequently, growth.

Class Summary

Chronic diarrhea in Crohn disease responds well to antidiarrheal agents such as loperamide (2-4 mg), diphenoxylate with atropine (1 tab), and tincture of opium (8-15 gtt). Such agents may be administered up to 4 times daily, but they should not be given to patients with active colitis because of the risk of developing toxic megacolon.

Loperamide (Imodium)

Loperamide, which is available over the counter, acts on intestinal muscles to inhibit peristalsis and to slow intestinal motility. It prolongs the movement of electrolytes and fluid through the bowel and increases the viscosity and loss of fluids and electrolytes. Loperamide improves stool frequency and consistency, reduces abdominal pain and fecal urgency, and may exacerbate constipation.

Diphenoxylate and atropine (Lomotil)

This drug combination consists of 2.5 mg of diphenoxylate, which is a constipating meperidine congener, and 0.025 mg of atropine to discourage abuse. The preparation inhibits excessive GI propulsion and motility, but it may exacerbate constipation.

Class Summary

Patients with terminal ileal disease may not absorb bile acids normally, which can lead to secretory diarrhea in the colon. These patients may benefit from bile acid sequestrants such as cholestyramine and colestipol.

Cholestyramine (Prevalite, Questran, Questran Lite)

Cholestyramine is used for diarrhea associated with the disease. It binds bile acids, thus reducing damage to the intestinal mucosa. It also reduces the induction of colonic fluid secretion. It forms a nonabsorbable complex with bile acids in the intestine, which, in turn, inhibits enterohepatic reuptake of intestinal bile salts.

Colestipol

Colestipol forms a soluble complex after binding to bile acid, increasing fecal loss of bile acid–bound low-density lipoprotein cholesterol.

Class Summary

Abdominal cramps may be reduced with propantheline, dicyclomine, or hyoscyamine. These drugs should not be used if there is the possibility of a bowel obstruction.

Dicyclomine (Bentyl)

Dicyclomine treats gastrointestinal motility disturbances. It blocks the action of acetylcholine at parasympathetic sites in secretory glands, smooth muscle, and the CNS. Adverse effects are dose dependent.

Hyoscyamine (Levsin)

Hyoscyamine blocks the action of acetylcholine at parasympathetic sites in smooth muscle, secretory glands, and the CNS, which, in turn, has antispasmodic effects. It decreases fecal urgency and pain.

Propantheline

Propantheline is a quaternary ammonium antimuscarinic with peripheral effects that are similar to atropine. It inhibits gastrointestinal motility and decreases gastric acid secretion.