Ulcerative colitis drug therapy

Ardizzone S, Porro GB. Comparative tolerability of therapies for ulcerative colitis. Drug Saf 2002 25 561-582. 

Promoting an Optimal Response to Therapy The patient receiving a sulfonamide drug almost always lias an active infection. Some patients may be receiving one of Hiese drugs to prevent an infection (prophylaxis) or as part of Hie management of a disease such as ulcerative colitis. 

Parenteral Anticoagulant-induced prothrombin deficiency hypoprothrombinemia secondary to conditions limiting absorption or synthesis of vitamin K (eg, obstructive jaundice, biliary fistula, sprue, ulcerative colitis, celiac disease, intestinal resection, cystic fibrosis of the pancreas, regional enteritis) drug-induced hypoprothrombinemias due to interference with vitamin K metabolism (eg, antibiotics, salicylates) prophylaxis and therapy of hemorrhagic disease of the newborn. 

A 17-year-old boy with a history of sulfa allergy is diagnosed with left-side ulcerative colitis after a 3-week history of bloody diarrhea and tenesmus. On examination he is afebrile and has no abdominal tenderness. The appropriate drug therapy to institute initially is which of the following ... 

Therapeutic pyramid approach to inflammatory bowel diseases. Treatment choice is predicated on both the severity of the illness and the responsiveness to therapy. Agents at the bottom of the pyramid are less efficacious but carry a lower risk of serious adverse effects. Drugs may be used alone or in various combinations. Patients with mild disease may be treated with 5-aminosalicylates (with ulcerative colitis or Crohn s colitis), topical corticosteroids (ulcerative colitis), antibiotics (Crohn s colitis or Crohn s perianal disease), or budesonide (Crohn s ileitis). Patients with moderate disease or patients who fail initial therapy for mild disease may be treated with oral corticosteroids to promote disease remission immunomodulators (azathioprine, mercaptopurine, methotrexate) to promote or maintain disease remission or anti-TNF antibodies. Patients with moderate disease who fail other therapies or patients with severe disease may require intravenous corticosteroids, anti-TNF antibodies, or surgery. Natalizumab is reserved for patients with severe Crohn s disease who have failed immunomodulators and TNF antagonists. Cyclosporine is used primarily for patients with severe ulcerative colitis who have failed a course of intravenous corticosteroids. TNF, tumor necrosis factor. 

ASA drugs induce and maintain remission in ulcerative colitis and are considered to be the first-line agents for treatment of mild to moderate active ulcerative colitis. Their efficacy in Crohn s disease is unproven, although many clinicians use 5-ASA agents as first-line therapy for mild to moderate disease involving the colon or distal ileum. 

The effectiveness of 5-ASA therapy depends in part on achieving high drug concentration at the site of active disease. Thus, 5-ASA suppositories or enemas are useful in patients with ulcerative colitis or Crohn s disease confined to the rectum (proctitis) or distal colon (proctosigmoiditis). In patients with ulcerative colitis or Crohn s colitis that extends to the proximal colon, both the azo compounds and mesalamine formulations are useful. For the treatment of Crohn s disease involving the small bowel, mesalamine compounds, which release 5-ASA in the small intestine, have a theoretic advantage over the azo compounds. 

The main drugs used in the treatment of ulcerative colitis and Crohn s disease are the aminosalicylates and corticosteroids. Their mode of action is obscure. Other immunosuppressives also have a role and recent studies into the mechanisms of inflammation are leading to the introduction of novel therapies to inhibit the inflammatory process. 

Ciclosporin may induce remission in some patients with severe ulcerative colitis unresponsive to corticosteroid. The drug is given in a dose of 2-4 mg/kg i.v. until remission is attained. Renal function should be monitored closely as ciclosporin is nephrotoxic (see p. 620). For maintenance therapy azathioprine (see below) is often substituted. Ciclosporin use only delays surgery for many patients after 1 year 50% will have relapsed and undergone colectomy. 

In contrast to ulcerative colitis, about 50% of patients with Crohn s colitis will respond to metronidazole given for up to 3 months, although adverse effects including alcohol intolerance, and peripheral neuropathy from such prolonged therapy often limit its use. The drug is also helpful in controlling perianal and small bowel disease and it decreases the incidence of anastamotic recurrence after surgery. Other antimicrobials, particularly ciprofloxacin may also be effective. 

Ulcerative Colitis. The use of immunosuppressive drugs (6-mercapto-purine, busulfan, 6-thioguanosine, azathioprei ) in experimental therapy of ulcerative colitis has been reported. -106 Results have been encouraging in the small group of patients tested but potentially serious side effects were observed due to the high doses that were required. Disappointing features are the failure to achieve a cvire and the severity of relapse on suspension of treatment. 

Most patients with active ulcerative colitis have mild to moderate disease and do not require parenteral medications (Fig. 34-2). The first line of drug therapy for these patients is oral sulfasalazine or an oral mesalamine derivative, or topical mesalamine or steroids for distal... 

Steroids have a place in the treatment of moderate to severe ulcerative colitis that is unresponsive to maximal doses of oral and topical mesalamine derivatives. Oral steroids (usually up to 1 mg/kg per day of prednisone equivalent) may be used for patients who do not have an adequate response to sulfasalazine or mesalamine. Overall, steroids and sulfasalazine appear to be equally efficacious however, the response to steroids may be evident sooner. Oral steroids should not be used as initial therapy for mild to moderate ulcerative colitis, mainly because of the known risks of steroid use. If steroids are used to attain remission, tapered drug withdrawal should be accomplished to minimize long-term steroid exposure. 

Rectally administered steroids or mesalamine can be used as initial therapy for patients with ulcerative proctitis or distal colitis. Rectal agents are also beneficial for treatment of tenesmus. With these agents, local actions are believed to be responsible for drug effects. Rectal steroids are effective in the treatment of active, distal ulcerative colitis. However, rectal mesalamine is more effective than rectal steroids for inducing remission. ... 

FIGURE 36-2. Recommendations for treating chronic diarrhea. Follow these steps (1) Perform a careful history and physical examination. (2) The possible causes of chronic diarrhea are many. These can be classified into intestinal infections (bacterial or protozoal), inflammatory disease (Crohn s disease or ulcerative colitis), malabsorption (lactose intolerance), secretory hormonal tumor (intestinal carcinoid tumor or VIPoma), drug (antacid), factitious (laxative abuse), or motility disturbance (diabetes mellitus, irritable bowel syndrome, or hyperthyroidism). (3) If the diagnosis is uncertain, selected appropriate diagnostic studies should be ordered. (4) Once diagnosed, treatment is planned for the underlying cause with symptomatic antidiarrheal therapy. (5) If no specific cause can be identified, symptomatic therapy is prescribed. 

Azathioprine is indicated in renal homotransplantation (five-year patient survival rate of 35%) in rheumatoid arthritis (for patients with severe, active, and erosive disease not responding to conventional therapies) and in chronic ulcerative colitis, myasthenia gravis, and Behcet s syndrome (adverse effects may offset its limited value). As with other cytotoxic drugs, azathioprine can affect rapidly growing cells, resulting in leukopenia, thrombocytopenia, and gastrointestinal toxicity. In addition, hepatotoxicity (cholestasis) has been reported. Many of the general problems of immunosuppression, such as increased risk of infections, can also occur. 

Despite the fact that ulcerative colitis does not appear to have a Tul-type immune response mediated through TNF-a, some studies have shown a beneficial effect of TNF-a modulation in this disorder as well. Clearly, this area of IBD therapy is evolving rapidly as new drugs emerge and clinical experience increases. 

CHEMISTRY, MECHANISM OF ACTION, AND PHARMACOLOGICAL PROPERTIES 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. Sulfasalazine represents one of the first examples of an oral drug that is delivered effectively 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 now regarded as the therapeutic agent, with little, if any, contribution by sulfapyridine. 

Sulfasalazine is used for the treatment of mild to moderate ulcerative colitis as adjunct therapy in the treatment of severe ulcerative colitis, for the treatment of Crohn s disease, and for the treatment of rheumatoid arthritis or ankylosing spondylitis. Contraindications include hypersensitivity to sulfa drugs, salicylates, intestinal or urinary obstruction, and porphyria. 

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