cortical centres affecting vomiting via descending pathways seems probable. There is some evidence that opioid pathways are involved in these actions. They are only moderately effective. Adverse effects Adverse effects include sedation, confusion, loss of coordination, dry mouth and hypotension. These effects are more prominent in older patients. MISCELLANEOUS AGENTS Large doses of glucocorticosteroids exert some anti-emetic action when used with cytotoxic drugs and the efficacy of the 5HT 3-antagonists has been shown to be improved when concomitant dexamethasone is given. Their mode of action is not known. Benzodiazepines given before treatment with cytotoxics reduce vomiting, although whether this is a specific antiemetic action or a reduction in anxiety is unknown. INFLAMMATORY BOWEL DISEASE Mediators of the inflammatory response in ulcerative colitis and Crohn’s disease include kinins and prostaglandins. The latter stimulate adenylyl cyclase, which induces active ion secretion and thus diarrhoea. Synthesis of prostaglandin E 2, thromboxane A 2 and prostacyclin by the gut increases during disease activity, but not during remission. The aminosalicylates influence the synthesis and metabolism of these eicosanoids, and influence the course of disease activity. Apart from correction of dehydration, nutritional and electrolyte imbalance (which in an acute exacerbation is potentially life-saving) and other non-specific treatment, glucocorticosteroids, aminosalicylates and immunosuppressive drugs are valuable. GLUCOCORTICOSTEROIDS Steroids modify every part of the inflammatory response and glucocorticosteroids (see Chapter 40) remain the standard by which other drugs are judged. Prednisolone and hydrocortisone given orally or intravenously are of proven value in the treatment of acute colitis or exacerbation of Crohn’s disease. Topical therapy in the form of a rectal drip, foam or enema of hydrocortisone or prednisolone is very effective in milder attacks of ulcerative colitis and Crohn’s colitis; some systemic absorption may occur. Diffuse inflammatory bowel disease or disease that does not respond to local therapy may require oral glucocorticosteroid treatment, e.g. prednisolone for four to eight weeks. Prednisolone is preferred to hydrocortisone as it has less mineralocorticoid effect at equipotent anti-inflammatory doses. Modified-release budesonide is licensed for Crohn’s disease affecting the ileum and the ascending colon; it causes fewer systemic side effects than oral prednisolone, due to extensive hepatic first-pass metabolism, but may be less effective. Glucocorticosteroids are not suitable for maintenance treatment because of side effects. AMINOSALICYLATES INFLAMMATORY BOWEL DISEASE 255 5-Aminosalicylic acid (5ASA) acts at many points in the inflammatory process and has a local effect on the colonic mucosa. However, as it is very readily absorbed from the small intestine, it has to be attached to another compound or coated in resin to ensure that it is released in the large bowel. Although these drugs are only effective for controlling mild to moderate ulcerative colitis when given orally, they are very effective for reducing the incidence of relapse per year from about 70 to 20%. The aminosalicylates are not effective in small-bowel Crohn’s disease. For rectosigmoid disease, suppository or enema preparations are as effective as systemic steroids. Drugs currently available in this group are sulfasalazine, mesalazine, balsalazide and olsalazine. Sulfasalazine remains the standard agent, but mesalazine, balsalazide and olsalazine avoid the unwanted effects of the sulphonamide carrier molecule (sulphapyridine) of sulfasalazine, while delivering 5ASA to the colon. Although usually well tolerated, the adverse effects of sulfasalazine are nausea, vomiting, epigastric discomfort, headache and rashes (including toxic dermal necrolysis). All of the adverse effects associated with sulphonamides can occur with sulfasalazine, and they are more pronounced in slow acetylators. Toxic effects on red cells are common (70% of cases) and in some cases lead to haemolysis, anisocytosis and methaemoglobinaemia. Sulfasalazine should be avoided in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Temporary oligospermia with decreased sperm motility and infertility occurs in up to 70% of males who are treated for over three years. Uncommon adverse effects include pancreatitis, hepatitis, fever, thrombocytopenia, agranulocytosis, Stevens–Johnson syndrome, neurotoxicity, photosensitization, a systemic lupus erythematosus (SLE)-like syndrome, myocarditis, pulmonary fibrosis, and renal effects including proteinuria, haematuria, orange urine and nephrotic syndrome. The newer agents are useful in patients who cannot tolerate sulfasalazine and in men who wish to remain fertile. Key points Aminosalicylates and blood dyscrasias • Any patient who is receiving aminosalicylates must be advised to report unexplained bleeding, bruising, purpura, sore throat, fever or malaise. • If the above symptoms occur, a blood count should be performed. • If there is suspicion of blood dyscrasia, stop aminosalicylates. • Aminosalicylates are associated with agranulocytosis, aplastic anaemia, leukopenia, neutropenia and thrombocytopenia.
256 ALIMENTARY SYSTEM AND LIVER IMMUNOSUPPRESSIVE DRUGS Although the exact pathogenetic mechanisms involved in inflammatory bowel disease remain unclear, there is abundant evidence that the immune system (both cellular and humoral) is activated in the intestine of patients with inflammatory bowel disease. This forms the rationale for the use of immunosuppressive agents in the group of patients who do not respond to therapy with aminosalicylates or glucocorticosteroids. General indications for their use include patients who have been on steroids for more than six months despite efforts to taper them off, those who have frequent relapses, those with chronic continuous disease activity and those with Crohn’s disease with recurrent fistulas. Patients with ulcerative colitis may benefit from a short course of ciclosporin (unlicensed indication). Patients with unresponsive or chronically active inflammatory bowel disease may benefit from azathioprine or mercaptopurine, or (in the case of Crohn’s disease) onceweekly methotrexate (these are all unlicensed indications). Infliximab, a monoclonal antibody that inhibits tumour nerosis factor � (see Chapters 16 and 26) is licensed for the management of severe active Crohn’s disease and moderate to severe ulcerative colitis in patients whose condition has not responded adequately to treatment with a glucocorticosteroid and a conventional immunosuppressant or who are intolerant of them. Infliximab is also licensed for the management of refractory fistulating Crohn’s disease. Maintenance therapy with infliximab should be considered for patients who respond to the initial induction course. OTHER THERAPIES Metronidazole may be beneficial for the treatment of active Crohn’s disease with perianal involvement, possibly through its antibacterial activity. It is usually given for a month, but no longer than three months because of concerns about developing peripheral neuropathy. Other antibacterials should be given if specifically indicated (e.g. sepsis associated with fistulas and perianal disease) and for managing bacterial overgrowth in the small bowel. Antimotility drugs such as codeine and loperamide (see below) and antispasmodic drugs may precipitate paralytic ileus and megacolon in active ulcerative colitis; treatment of the inflammation is more logical. Laxatives may be required in proctitis. Diarrhoea resulting from the loss of bile-salt absorption (e.g. in terminal ileal disease or bowel resection) may improve with colestyramine, which binds bile salts. Key points Inflammatory bowel disease The cause is unknown. There is local and sometimes systemic inflammation. • Correct dehydration, nutritional and electrolyte imbalance. • Drug therapy: aminosalicylates; glucocorticosteroids; other immunosuppressive agents. CONSTIPATION When constipation occurs, it is important first to exclude both local and systemic disease which may be responsible for the symptoms. Also, it is important to remember that many drugs can cause constipation (Table 34.4). In general, patients with constipation present in two ways: 1. Long-standing constipation in otherwise healthy people may be due to decreased colon motility or to dyschezia, or to a combination of both. It is usually sufficient to reassure the patient and to instruct them in the importance of reestablishing a regular bowel habit. This should be combined with an increased fluid intake and increased bulk in the diet. Bran is cheap andoften satisfactory. As an alternative, non-absorbed bulk substances such as methylcellulose, ispaghula or sterculia are helpful. The other laxatives described below should only be tried if these more ‘natural’ treatments fail. 2. Loaded colon or faecal impaction – sometimes it is necessary to evacuate the bowel before it is possible to start re-education, particularly in the elderly or those who are ill. In these cases, a laxative such as senna combined with glycerol suppositories is appropriate. Table 34.4: Drugs that can cause constipation Aluminium hydroxide Amiodarone Anticholinergics (older antihistamines) Diltiazem Disopyramide Diuretics Iron preparations Opioids Tricyclic antidepressants Verapamil LAXATIVES Laxatives are still widely although often inappropriately used by the public and in hospital. There is now a greater knowledge of intestinal pathophysiology, andof outstanding importance is the finding that the fibre content of the diet has a marked regulatory action on gut transit time and motility and on defecation performance. As a general rule, laxatives should be avoided. They are employed: • if straining at stool will cause damage (e.g. postoperatively, in patients with haemorrhoids or after myocardial infarction);