Goodman and Gilman Manual of Pharmacology and Therapeutics

Section VI
Drugs Affecting Gastrointestinal Function

chapter 47
Pharmacotherapy of Inflammatory Bowel Disease

Inflammatory bowel disease (IBD) is a spectrum of chronic, idiopathic, inflammatory intestinal conditions. IBD causes significant gastrointestinal (GI) symptoms that include diarrhea, abdominal pain, bleeding, anemia, and weight loss. IBD conventionally is divided into 2 major subtypes: ulcerative colitis and Crohn disease. Ulcerative colitis is characterized by confluent mucosal inflammation of the colon starting at the anal verge and extending proximally for a variable extent (e.g., proctitis, left-sided colitis, or pancolitis).Crohn disease, by contrast, is characterized by transmural inflammation of any part of the GI tract but most commonly the area adjacent to the ileocecal valve. The inflammation in Crohn disease is not necessarily confluent, frequently leaving “skip areas” of relatively normal mucosa. The transmural nature of the inflammation may lead to fibrosis and strictures or fistula formation.

PATHOGENESIS OF IBD. Crohn disease and ulcerative colitis are chronic idiopathic inflammatory disorders of the GI tract; a summary of proposed pathogenic events and potential sites of therapeutic intervention is shown in Figure 47–1. Crohn disease and ulcerative colitis result from distinct pathogenetic mechanisms. Histologically, the transmural lesions in Crohn disease exhibit marked infiltration of lymphocytes and macrophages, granuloma formation, and submucosal fibrosis, whereas the superficial lesions in ulcerative colitis have lymphocytic and neutrophilic infiltrates. Within the diseased bowel in Crohn disease, the cytokine profile includes increased levels of interleukin (IL)-12, IL-23, interferon-γ, and tumor necrosis factor-α (TNFα), findings characteristic of T-helper 1 (TH1)–mediated inflammatory processes. In contrast, the inflammatory response in ulcerative colitis resembles aspects of that mediated by the TH2 pathway. Understanding of the inflammatory processes has evolved with the description of regulatory T cells and pro-inflammatory TH17 cells, a novel T-cell population that expresses IL-23 receptor as a surface marker and produces, among others, the pro-inflammatory cytokines IL-17, IL-21, IL-22, and IL-26. TH17 cells seem to play a prominent role in intestinal inflammation, particularly in Crohn disease.


Figure 47–1 Proposed pathogenesis of inflammatory bowel disease and target sites for pharmacological intervention. Shown are the interactions among bacterial antigens in the intestinal lumen and immune cells in the intestinal wall. If the epithelial barrier is impaired, bacterial antigens can gain access to antigen-presenting cells (APC) such as dendritic cells in the lamina propria. These cells then present the antigen(s) to CD4+ lymphocytes and also secrete cytokines such interleukin (IL)-12 and IL-18, thereby inducing the differentiation of TH1 cells in Crohn’s disease (or, under the control of IL-4, type 2 helper T cells [TH2] in ulcerative colitis). The balance of pro-inflammatory and anti-inflammatory events is also governed by regulatory TH17 and TReg cells, both of which serve to limit immune and inflammatory responses in the GI tract. Transforming growth factor (TGF)β and IL-6 are important cytokines that drive the expansion of the regulatory T cell subsets. The TH1 cells produce a characteristic array of cytokines, including interferon (IFN) γ and TNFα, which in turn activate macrophages. Macrophages positively regulate TH1 cells by secreting additional cytokines, including IFNγ and TNFα. Recruitment of a variety of leukocytes is mediated by activation of resident immune cells including neutrophils. Cell adhesion molecules such as integrins are important in the infiltration of leukocytes and novel biological therapeutic strategies aimed at blocking leukocyte recruitment are effective at reducing inflammation. General immunosuppressants (e.g., glucocorticoids, thioguanine derivatives, methotrexate, and cyclosporine) affect multiple sites of inflammation. More site-specific intervention involve intestinal bacteria (antibiotics, prebiotics, and probiotics) and therapy directed at TNFα or IL-12.

PHARMACOTHERAPY FOR IBD. Medical therapy for IBD is problematic. Because no unique abnormality has been identified, therapy for IBD seeks to dampen the generalized inflammatory response. Regrettably, no agent can reliably accomplish this, and the response of an individual patient to a given medicine may be limited and unpredictable. Specific goals of pharmacotherapy in IBD include controlling acute exacerbations of the disease, maintaining remission, and treating specific complications such as fistulas. The major therapeutic options are considered below and summarized at chapter’s end by Table 47–1.

Table 47–1

Medications Commonly Used to Treat Inflammatory Bowel Disease



First-line therapy for mild to moderate ulcerative colitis generally involves mesalamine (5-aminosalicylic acid, or 5-ASA). The archetype for this class of medications is sulfasalazine (AZULFIDINE), which consists of 5-ASA linked to sulfapyridine by an azo bond (Figure 47–2).


Figure 47–2 Generation of mesalamine from the prodrug sulfasalazine. The red N atoms indicate the diazo linkage that is cleaved in the colon to generate the active moiety.

MECHANISM OF ACTION AND PHARMACOLOGICAL PROPERTIES. Sulfasalazine is an oral prodrug that effectively delivers 5-ASA to the distal GI tract. The azo linkage in sulfasalazine prevents absorption in the stomach and small intestine, and the individual components are not liberated for absorption until colonic bacteria cleave the bond. 5-ASA is the therapeutic moiety, with little, if any, contribution by sulfapyridine. Although 5-ASA is a salicylate, its therapeutic effect does not appear to be related to cyclooxygenase inhibition; indeed, traditional nonsteroidal anti-inflammatory drugs may exacerbate IBD. Many potential sites of action (effects on immune function and inflammation) have been demonstrated in vitro for either sulfasalazine or mesalamine (inhibition of the production of IL-1 and TNFα, inhibition of the lipoxygenase pathway, scavenging of free radicals and oxidants, and inhibition of NFκB, a transcription factor pivotal to production of inflammatory mediators), however, specific mechanisms of action have not been identified.

Although not active therapeutically, sulfapyridine causes many of the adverse effects observed in patients taking sulfasalazine. To preserve the therapeutic effect of 5-ASA without the adverse effects of sulfapyridine, several second-generation 5-ASA compounds have been developed (Figures 47–247–3, and 47–4). They are divided into 2 groups: prodrugs andcoated drugs. Prodrugs contain the same azo bond as sulfasalazine but replace the linked sulfapyridine with either another 5-ASA (olsalazine, DIPENTUM) or an inert compound (balsalazide, COLAZIDE). The alternative approaches employ either a delayed-release formulation (PENTASA) or a pH-sensitive coating (ASACOL; LIALDA/MEZAVANT). Delayed-release mesalamine is released throughout the small intestine and colon, whereas pH-sensitive mesalamine is released in the terminal ileum and colon. These different distributions of drug delivery have potential therapeutic implications.


Figure 47–3 Metabolic fates of the different oral formulations of mesalamine (5-ASA).


Figure 47–4 Sites of release of mesalamine (5-ASA) in the GI tract from different oral formulations.

Oral sulfasalazine is effective in patients with mild or moderately active ulcerative colitis, with response rates of 60-80%. The usual dose is 4 g/day in 4 divided doses with food; to avoid adverse effects, the dose is increased gradually from an initial dose of 500 mg twice a day. Doses as high as 6 g/day can be used but cause an increased incidence of side effects. For patients with severe colitis, sulfasalazine is of less certain value, even though it is often added as an adjunct to systemic glucocorticoids. The drug plays a useful role in preventing relapses once remission has been achieved. Because they lack the dose-related side effects of sulfapyridine, the newer formulations can be used to provide higher doses of mesalamine with some improvement in disease control. The usual doses to treat active disease are 800 mg 3 times a day for ASACOL and 1 g 4 times a day for PENTASA. Lower doses are used for maintenance (e.g., ASACOL, 800 mg twice a day). The efficacy of 5-ASA preparations (e.g., sulfasalazine) in Crohn disease is less striking, with modest benefit at best in controlled trials. The second-generation 5-ASA prodrugs (e.g., olsalazine and balsalazide) do not have a significant effect in small-bowel Crohn disease.

Topical preparations of mesalamine suspended in a wax matrix suppository (ROWASA) or in a suspension enema (CANASA) are effective in active proctitis and distal ulcerative colitis, respectively. They appear to be superior to topical hydrocortisone in this setting, with response rates of 75-90%. Mesalamine enemas (4 g/60 mL) should be used at bedtime and retained for at least 8 h; the suppository (500 mg) should be used 2 to 3 times a day with the objective of retaining it for at least 3 h. Response to local therapy with mesalamine may occur within 3-21 days; however, the usual course of therapy is from 3-6 weeks. Once remission has occurred, lower doses are used for maintenance.

ADME. About 20-30% of orally administered sulfasalazine is absorbed in the small intestine. Much of this is taken up by the liver and excreted unmetabolized in the bile; the rest (~10%) is excreted unchanged in the urine. The remaining 70% reaches the colon, where, if cleaved completely by bacterial enzymes, it generates 400 mg mesalamine for every gram of the parent compound. Thereafter, the individual components of sulfasalazine follow different metabolic pathways. Sulfapyridine is absorbed rapidly from the colon. It undergoes extensive hepatic metabolism, including acetylation and hydroxylation, conjugation with glucuronic acid, and excretion in the urine. The acetylation phenotype of the patient determines plasma levels of sulfapyridine and the probability of side effects; rapid acetylators have lower systemic levels of the drug and fewer adverse effects. Only 25% of mesalamine is absorbed from the colon, and most of the drug is excreted in the stool. The small amount that is absorbed is acetylated in the intestinal mucosal wall and liver and then excreted in the urine. Intraluminal concentrations of mesalamine therefore are very high (~1500 μg/mL).

The pH-sensitive coatings of ASACOL (EUDAGRIT) and LIALDA/MEZAVANT limit gastric and small intestinal absorption of 5-ASA. The pharmacokinetics of PENTASA differ somewhat. The ethylcellulose-coated microgranules are released in the upper GI tract as discrete prolonged-release units of mesalamine. Acetylated mesalamine can be detected in the circulation within an hour after ingestion, indicating some rapid absorption, but some intact microgranules also can be detected in the colon. Because it is released in the small bowel, a greater fraction of PENTASA is absorbed systemically compared with the other 5-ASA preparations.

ADVERSE EFFECTS. Side effects of sulfasalazine occur in 10-45% of patients with ulcerative colitis and are related primarily to the sulfa moiety. Some are dose related, including headache, nausea, and fatigue; these can be minimized by giving the medication with meals or by decreasing the dose. Allergic reactions include rash, fever, Stevens-Johnson syndrome, hepatitis, pneumonitis, hemolytic anemia, and bone marrow suppression. Sulfasalazine reversibly decreases the number and motility of sperm but does not impair female fertility. Sulfasalazine inhibits intestinal folate absorption and is usually administered with folate. The newer mesalamine formulations generally are well tolerated. Headache, dyspepsia, and skin rash are the most common. Diarrhea appears to be particularly common with olsalazine (occurring in 10-20% of patients). Nephrotoxicity, although rare, is a more serious concern. Mesalamine has been associated with interstitial nephritis; renal function should be monitored in all patients receiving these drugs. Both sulfasalazine and its metabolites cross the placenta but have not been shown to harm the fetus. The newer formulations also appear to be safe in pregnancy.


The effects of glucocorticoids on the inflammatory response are numerous (see Chapters 38 and 42). Glucocorticoids are indicated for moderate to severe IBD. Patients with IBD segregate into 3 general groups with respect to their response to glucocorticoids:

• Glucocorticoid-responsive patients improve clinically within 1-2 weeks and remain in remission as the steroids are tapered and then discontinued.

• Glucocorticoid-dependent patients respond to glucocorticoids but then experience a relapse of symptoms as the steroid dose is tapered.

• Glucocorticoid-unresponsive patients do not improve even with prolonged high-dose steroids.

Approximately 40% of patients are glucocorticoid responsive, 30-40% have only a partial response or become glucocorticoid dependent, and 15-20% of patients do not respond to therapy. Glucocorticoids sometimes are used for prolonged periods to control symptoms in corticosteroid-dependent patients. However, the failure to respond to steroids with prolonged remission (i.e., a disease relapse) should prompt consideration of alternative therapies, including immunosuppressive agents and anti-TNFα therapies. Glucocorticoids are not effective in maintaining remission in either ulcerative colitis or Crohn disease.

Initial doses in IBD are 40-60 mg of prednisone or equivalent per day; higher doses generally are no more effective. The glucocorticoid dose in IBD is tapered over weeks to months. Efforts should be made to minimize the duration of therapy. Glucocorticoids induce remission in most patients with either ulcerative colitis or Crohn disease. Most patients improve substantially within 5 days of initiating treatment; others require treatment for several weeks before remission occurs. For more severe cases, glucocorticoids such as methylprednisolone or hydrocortisone are given intravenously. Some experts believe that ACTH is more effective in patients who have not previously received any steroids.

Glucocorticoid enemas are useful mainly in patients whose disease is limited to the rectum and left colon. Hydrocortisone is available as a retention enema (100 mg/60 mL), and the usual dose is one 60-mL enema per night for 2 or 3 weeks. Patients with distal disease usually respond within 3-7 days. Absorption, although less than with oral preparations, is still substantial (up to 50-75%). Hydrocortisone also can be given once or twice daily as a 10% foam suspension (CORTIFOAM) that delivers 80 mg hydrocortisone per application; this formulation can be useful in patients with very short areas of distal proctitis and difficulty retaining fluid.

Budesonide (ENTOCORT ER) is an enteric-release form of a synthetic steroid that is used for ileocecal Crohn disease. It is proposed to deliver adequate steroid therapy to a specific portion of inflamed gut while minimizing systemic side effects owing to extensive first-pass hepatic metabolism to inactive derivatives. Topical therapy (e.g., enemas and suppositories) also is effective in treating colitis limited to the left side of the colon. Budesonide (9 mg/day for up to 8 weeks followed by 6 mg/day for maintenance of remission for up to 3 months) is effective in the acute management of mild-to-moderate exacerbations of Crohn disease.


Several drugs developed for cancer chemotherapy or as immunosuppressive agents in organ transplants have been adapted for treatment of IBD. Clinical experience has defined specific roles for each of these agents as mainstays in the pharmacotherapy of IBD. However, their potential for serious adverse effects mandates a careful assessment of risks and benefits in each patient.


The cytotoxic thiopurine derivatives mercaptopurine (6-MP, PURINETHOL) and azathioprine (IMURAN) (see Chapters 35 and 61) are used to treat patients with severe IBD or those who are steroid-resistant or steroid-dependent. These thiopurines impair purine biosynthesis and inhibit cell proliferation. Both are prodrugs: azathioprine is converted to mercaptopurine, which is subsequently metabolized to 6-thioguanine nucleotides, the putative active moieties (Figure 47–5).


Figure 47–5 Metabolism of azathioprine and 6-mercaptopurine. HGPRT, hypoxanthine–guanine phosphoribosyl transferase; TPMT, thiopurine methyltransferase; XO, xanthine oxidase. The activities of these enzymes vary among humans due to differential expression of genetic polymorphisms, explaining responses and side effects when azathioprine–mercaptopurine therapy is employed (see text for details).

These drugs generally are used interchangeably with appropriate dose adjustments, typically azathioprine (2-2.5 mg/kg) or mercaptopurine (1.5 mg/kg). Because of concerns about side effects, these drugs were used initially only in Crohn disease, which lacks a surgical curative option. They now are considered equally effective in Crohn disease and ulcerative colitis. These drugs effectively maintain remission in both diseases; they also may prevent or delay recurrence of Crohn disease after surgical resection. Finally, they are used successfully to treat fistulas in Crohn disease. The clinical response to azathioprine or mercaptopurine may take weeks to months, such that other drugs with a more rapid onset of action (e.g., mesalamine, glucocorticoids, or infliximab) are preferred in the acute setting.

In general, physicians who treat IBD believe that the long-term risks of azathioprine–mercaptopurine are lower than those of steroids. Thus, these purines are used in glucocorticoid-unresponsive or glucocorticoid-dependent disease and in patients who have had recurrent flares of disease requiring repeated courses of steroids. Additionally, patients who have not responded adequately to mesalamine but are not acutely ill may benefit by conversion from glucocorticoids to immunosuppressive drugs. Immunosuppressives therefore may be viewed as steroid-sparing agents.

Adverse effects of azathioprine–mercaptopurine can be divided into 3 general categories: idiosyncratic, dose related, and possible. Adverse effects occur at any time after initiation of treatment and can affect up to 10% of patients. The most serious idiosyncratic reaction is pancreatitis, which affects ~5% of patients treated with these drugs. Fever, rash, and arthralgias are seen occasionally, whereas nausea and vomiting are somewhat more frequent. The major dose-related adverse effect is bone marrow suppression, and circulating blood counts should be monitored closely when therapy is initiated and at less frequent intervals during maintenance therapy. Elevations in liver function tests also may be dose related. The serious adverse effect of cholestatic hepatitis is relatively rare. Immunosuppressive regimens given in the setting of cancer chemotherapy or organ transplants have been associated with an increased incidence of malignancy, particularly non-Hodgkin’s lymphoma.

METABOLISM AND PHARMACOGENETICS. Favorable responses to azathioprine–mercaptopurine are seen in up to two-thirds of patients. Mercaptopurine has 3 metabolic fates (see Figure 47–5):

• Conversion by xanthine oxidase to 6-thiouric acid

• Metabolism by thiopurine methyltransferase (TPMT) to 6-methyl-mercaptopurine (6-MMP)

• Conversion by hypoxanthine–guanine phosphoribosyl transferase (HGPRT) to 6-thioguanine nucleotides and other metabolites

The relative activities of these different pathways may explain, in part, individual variations in efficacy and adverse effects of these immunosuppressives.

The plasma t1/2 of mercaptopurine is limited by its relatively rapid (i.e., within 1-2 h) uptake into erythrocytes and other tissues. Following this uptake, differences in TPMT activity determine the drug’s fate. Approximately 80% of the U.S. population has what is considered “normal” metabolism, whereas 1 in 300 individuals has minimal TPMT activity. In the latter setting, mercaptopurine metabolism is shifted away from 6-methyl-mercaptopurine and driven toward 6-thioguanine nucleotides, which can severely suppress the bone marrow. About 10% of people have intermediate TPMT activity; given a similar dose, these individuals will tend to have higher 6-thioguanine levels than the normal metabolizers. Finally, ~10% of the population are rapid metabolizers. In these individuals, mercaptopurine is shunted away from 6-thioguanine nucleotides toward 6-MMP, which has been associated with abnormal liver function tests. In addition, relative to normal metabolizers, the 6-thioguanine levels of these rapid metabolizers are lower for an equivalent oral dose, possibly reducing therapeutic response. Pharmacogenetic typing can guide therapy (see Chapter 7).

Xanthine oxidase in the small intestine and liver converts mercaptopurine to thiouric acid, which is inactive as an immunosuppressant. Inhibition of xanthine oxidase by allopurinol diverts mercaptopurine to more active metabolites such as 6-thioguanine and increases both immunosuppressant and potential toxic effects. Thus, patients on mercaptopurine should be warned about potentially serious interactions with medications used to treat gout or hyperuricemia, and the dose should be decreased to 25% of the standard dose in subjects who are already taking allopurinol.


Methotrexate is reserved for patients whose IBD is either steroid-resistant or steroid-dependent. In Crohn disease, it both induces and maintains remission. Therapy of IBD with methotrexate differs somewhat from its use in other autoimmune diseases. Most importantly, higher doses (e.g., 15-25 mg/week) are given parenterally. The increased efficacy with parenteral administration may reflect the unpredictable intestinal absorption at higher doses of methotrexate.

Methotrexate inhibits dihydrofolate reductase, thereby blocking DNA synthesis and causing cell death (see Figure 61–4). The anti-inflammatory effects of methotrexate may involve mechanisms in addition to inhibition of dihydrofolate reductase.


Cyclosporine is an inhibitor of calcineurin and is a potent immunomodulator used most frequently after organ transplantation (see Figure 35–1 and text). It is effective in specific clinical settings in IBD, but the high frequency of significant adverse effects limits its use as a first-line medication. Cyclosporine is effective in patients with severe ulcerative colitis who have failed to respond adequately to glucocorticoid therapy.

Between 50% and 80% of these severely ill patients improve significantly (generally within 7 days) in response to intravenous cyclosporine (2-4 mg/kg per day), sometimes avoiding emergent colectomy. Careful monitoring of cyclosporine levels is necessary to maintain a therapeutic level in whole blood between 300 and 400 ng/mL. Oral cyclosporine is less effective as maintenance therapy in Crohn disease, perhaps because of its limited intestinal absorption. In this setting, long-term therapy with NEORAL or GENGRAF (formulations of cyclosporine with increased oral bioavailability) may be more effective. Cyclosporin can be used to treat fistulous complications of Crohn disease. A significant rapid response to intravenous cyclosporine has been observed; however, frequent relapses accompany oral cyclosporine therapy, and other medical strategies are required to maintain fistula closure. Thus, calcineurin inhibitors generally are used to treat specific problems over a short term while providing a bridge to longer-term therapy.

Other immunomodulators that are being evaluated in IBD include the calcineurin inhibitor tacrolimus (FK 506, PROGRAF), mycophenolate mofetil and mycophenolate (CELLCEPT, MYFORTIC), inhibitors of inosine monophosphate dehydrogenase to which lymphocytes are especially susceptible (see Chapter 35).



Infliximab (REMICADE, cA2) is a chimeric immunoglobulin (25% mouse, 75% human) that binds to and neutralizes TNFα, 1 of the principal cytokines mediating the TH1 immune response characteristic of Crohn disease (see Figure 47–1).

Although infliximab was designed specifically to target TNFα, it may have more complex actions. Infliximab binds membrane-bound TNFα and may cause lysis of these cells by antibody-dependent or cell-mediated cytotoxicity. Thus, infliximab may deplete specific populations of subepithelial inflammatory cells. These effects, together with its mean terminal plasma t1/2 of 8-10 days, may explain the prolonged clinical effects of infliximab. Infliximab (5 mg/kg infused intravenously at intervals of several weeks to months) decreases the frequency of acute flares in approximately two-thirds of patients with moderate to severe Crohn disease and also facilitates the closing of enterocutaneous fistulas associated with Crohn disease. Emerging evidence also supports its efficacy in maintaining remission and in preventing recurrence of fistulas. The combination of infliximab and azathioprine is more effective than infliximab alone in induction of remission and mucosal healing in steroid-resistant patients. Infliximab has also proven to be an effective treatment for refractory ulcerative colitis.

Both acute (fever, chills, urticaria, or even anaphylaxis) and subacute (serum sickness–like) reactions may develop after infliximab infusion. Antibodies to infliximab can decrease its clinical efficacy. Strategies to minimize the development of these antibodies (e.g., treatment with glucocorticoids or other immunosuppressives) may be critical to preserving infliximab efficacy. Infliximab therapy is associated with increased incidence of respiratory infections; of particular concern is potential reactivation of tuberculosis or other granulomatous infections with subsequent dissemination. The FDA recommends that candidates for infliximab therapy be tested for latent tuberculosis with purified protein derivative; patients testing positive should be treated prophylactically with isoniazid. Infliximab is contraindicated in patients with severe congestive heart failure. There is concern about a possible increased incidence of non-Hodgkin lymphoma, but a causal role has not been established. The significant cost of infliximab is an important consideration for some patients.

Adalimumab (HUMIRA) is a humanized recombinant human IgG1 monoclonal antibody against TNFα. It is effective in inducing remission in mild to moderate, severe, and fistulizing Crohn disease.

Certolizumab pegol (CIMZIA) is a pegylated humanized fragment antigen binding (Fab) that binds TNFα. It is approved in the U.S. for the treatment of Crohn disease. With both adalimumab and certolizumab pegol, immunogenicity appears to be less of a problem than that associated with infliximab.

Natalizumab (TYSABRI) is a humanized monoclonal antibody against α4-integrin (also known as VLA-4). Binding of the antibody to this adhesion molecule will reduce extravasation of certain leukocytes (e.g., lymphocytes), preventing them from migrating to sites of inflammation where they may exacerbate tissue injury.

Natalizumab is approved in the U.S. for induction and maintenance of remission of moderate to severe Crohn disease. Natalizumab is contraindicated for use with other immunomodulators; patients taking natalizumab for the treatment of Crohn disease should have their doses of corticosteroids reduced before starting natalizumab treatment.

Etanercept (ENBREL), an anti-TNFα agent, is a fusion protein of the ligand-binding portion of the TNFα receptor and the Fc portion of human IgG1. This construct binds to TNFα and blocks its biologic effects but is ineffective in Crohn disease.

Ulcerative Colitis

The role of anti-TNF therapies for steroid-refractory or steroid-dependent ulcerative colitis is less clear. Large controlled clinical trials have demonstrated that anti-TNF agents significantly reduce the severity of the inflammation. Unlike Crohn disease, ulcerative colitis is cured with surgery; thus, the cost and serious adverse events associated with anti-TNF therapy need to be balanced with the effectiveness of the drug at preventing the need for colectomy.


A balance normally exists in the GI tract among the mucosal epithelium, the normal gut flora, and the immune response. Colonic bacteria may either initiate or perpetuate the inflammation of IBD, and recent studies have implicated specific bacterial antigens in the pathogenesis of Crohn disease. Thus, certain bacterial strains may be either pro- (e.g.,Bacteroides) or anti-inflammatory (e.g., Lactobacillus), prompting attempts to manipulate the colonic flora in patients with IBD. Traditionally, antibiotics have been used most prominently in Crohn disease.

Antibiotics can be used as:

• Adjunctive treatment along with other medications for active IBD

• Treatment for a specific complication of Crohn disease

• Prophylaxis for recurrence in postoperative Crohn disease

Metronidazole, ciprofloxacin, and clarithromycin are the antibiotics used most frequently. Crohn disease-related complications that may benefit from antibiotic therapy include intra-abdominal abscess and inflammatory masses, perianal disease (including fistulas and perirectal abscesses), small-bowel bacterial overgrowth secondary to partial small-bowel obstruction, secondary infections with organisms such as Clostridium difficile, and postoperative complications. More recently, probiotics have been used to treat specific clinical situations in IBD. Probiotics are mixtures of putatively beneficial lyophilized bacteria given orally. Several studies have provided evidence for beneficial effects of probiotics in ulcerative colitis and pouchitis. However, the utility of probiotics as a primary therapy for IBD remains unclear.


Analgesic, anticholinergic, and antidiarrheal agents play supportive roles in reducing symptoms and improving quality of life. Oral iron, folate, and vitamin B12 should be administered as indicated. Loperamide or diphenoxylate (see Chapter 46) can be used to reduce the frequency of bowel movements and relieve rectal urgency in patients with mild disease; these agents are contraindicated in patients with severe disease because they may predispose to the development of toxic megacolon. Cholestyramine can be used to prevent bile salt–induced colonic secretion in patients who have undergone limited ileocolic resections. Anticholinergic agents (dicyclomine hydrochloride, etc.; Chapter 9) are used to reduce abdominal cramps, pain, and rectal urgency. As with the antidiarrheal agents, they are contraindicated in severe disease or when obstruction is suspected.


IBD is a chronic disease that affects women in their reproductive years. In general, decreased disease activity increases fertility and improves pregnancy outcomes. At the same time, limiting medication during pregnancy is always desired but sometimes conflicts with the goal of controlling the disease. Mesalamine and glucocorticoids are FDA Category B drugs that are used frequently in pregnancy and generally are considered safe, whereas methotrexate is clearly contraindicated in pregnant patients. There does not appear to be an increase in adverse outcomes in pregnant patients maintained on thiopurine-based immunosuppressives.


Table 47–1 summarizes the medications routinely used to treat IBD.