CLINICAL PHARMACOLOGY 2003 (PART 33)

Chia sẻ: Big Big | Ngày: | Loại File: PDF | Số trang:12

Thêm vào BST

Báo xấu

92
lượt xem 9
download

Download Vui lòng tải xuống để xem tài liệu đầy đủ

Problems of constipation, diarrhoea and irritable bowel syndrome are common. Infective diarrhoeal diseases are a significant cause of morbidity and mortality worldwide, especially in infants and children.The management of these conditions is reviewed. • Constipation: mode of action and use of drugs • Diarrhoea (drug treatment importance of fluid and electrolyte replacement) • Inflammatory bowel disease • Irritable bowel syndrome STOOL BULKING AGENTS Dietary fibre comprises the cell walls and supporting structures of vegetables and fruits. Most of the fibre in our diet is in the form of nonstarch polysaccharides (NSP),1 which are not digestible by human enzymes. Fibre...

Chủ đề:

Bình luận(0) Đăng nhập để gửi bình luận!

Lưu

Nội dung Text: CLINICAL PHARMACOLOGY 2003 (PART 33)

32 Intestines SYNOPSIS STOOL BULKING AGENTS Problems of constipation, diarrhoea and Dietary fibre comprises the cell walls and supporting irritable bowel syndrome are common. structures of vegetables and fruits. Most of the fibre Infective diarrhoeal diseases are a significant in our diet is in the form of nonstarch poly- cause of morbidity and mortality worldwide, saccharides (NSP),1 which are not digestible by especially in infants and children.The human enzymes. Fibre may be soluble (pectins, guar, management of these conditions is reviewed. ispaghula) or insoluble (cellulose, hemicelluloses, • Constipation: mode of action and use of lignin). Insoluble fibre has less effect than soluble drugs fibre on the viscosity of gut contents but is a • Diarrhoea (drug treatment importance of stronger laxative because it resists digestion in the fluid and electrolyte replacement) small bowel and so enters the colon intact. In • Inflammatory bowel disease addition it has a vast capacity for retaining water; • Irritable bowel syndrome thus one gram of carrot fibre can hold 23 grams of water.2 It has been proposed that as humans have refined the carbohydrates in their diet over the centuries, so they have deprived themselves of fibre, the ensuing under-filling of the colon being an important cause of constipation, haemorrhoids and Constipation diverticular disease. Stool bulking agents, which add fibre to the diet, are the treatment of choice for The terms purgative, cathartic, laxative, aperient simple constipation. They act by increasing the and evacuant are synonymous. They are medicines volume and lowering the viscosity of intestinal that promote defaecation largely by reducing the contents to produce a soft bulky stool, which viscosity of the contents of the lower colon and are encourages normal reflex bowel activity. The mode classified as follows: of action of stool bulking agents is thus more • Stool bulking agents physiological than other types of laxative. They • Osmotic laxatives • Faecal softeners 1 The term 'unavailable complex carbohydrate' (UCC) is also • Stimulant laxatives. used and refers to NSP plus undigested ('resistant') starch. 2 McConnell A A et al 1974 J Sci Food Agric 25:1427. 639
32 INTESTINES should be taken with liberal quantities of fluid (at the treatment of hepatic encephalopathy (see least 2 litres daily). Chapter 33). Osmotic laxatives are frequently used to clear Individual preparations the colon for diagnostic procedures or surgery. Bran is the residue left when flour is made from Enemas containing phosphate or citrate effectively cereals; it contains between 25% and 50% of fibre. evacuate the distal colon and can be useful for The fibre content of a normal diet can be increased treating obstinate constipation in elderly or by eating wholemeal bread and bran cereals but debilitated patients. Oral preparations containing over-zealous supplementation may cause trouble- magnesium sulphate and citric acid (Citramag) or some wind (from bacterial fermentation in the colon). polyethylene glycol (Klean Prep) are used in Viscous (soluble) fibres, e.g. ispaghula, are effec- preparation for colonoscopy; they are made up tive and more palatable than bran. Ispaghula husk with water to create an isotonic solution and some contains mucilage and hemicelluloses which swell patients find the large volumes difficult to tolerate. rapidly in water. Methylcellulose takes up water to Isotonic mannitol was used for the same purpose in swell to a colloid about 25 times its original volume the early days of colonoscopy, but has since been and sterculia,3 similarly, swells when mixed with abandoned; hydrogen liberated by the action of water. colonic bacteria was the cause of several intestinal explosions triggered by the use of diathermy. The stimulant laxative sodium picosulphate OSMOTIC LAXATIVES (Picolax) is a frequently used alternative to These are but little absorbed and increase the bulk the osmotic preparations. Care should be used with and reduce viscosity of intestinal contents to promote all these preparations in the elderly; they can a fluid stool. induce dehydration, hypovolaemia and electrolyte disturbances. Some inorganic salts retain water in the intestinal lumen or, if given as hypertonic solution, withdraw FAECAL SOFTENERS (EMOLLIENTS) it from the body. When constipation is mild, magnesium hydroxide will suffice but magnesium The softening properties of these agents are useful sulphate (Epsom4 salts) is used when a more power- in the management of anal fissure (see below) and ful effect is needed. Both magnesium salts act in 2-4 h. haemorrhoids. The small amount of magnesium absorbed when Docusate sodium (dioctyl sodium sulphosuccinate) the sulphate is frequently used can be enough to softens faeces by lowering the surface tension of cause magnesium poisoning in patients with renal fluids in the bowel. This allows more water to impairment, the central nervous effects of which remain in the faeces. It appears also to have bowel somewhat resemble those of uraemia. Magnesium stimulant properties but these are relatively weak. sulphate 50% (hypertonic) is available as a single Docusate sodium acts in 1-2 days. Poloxamers, e.g. dose retention enema to reduce cerebrospinal fluid poloxalkol (poloxamer 188), act similarly and are pressure in neurosurgery. used in combination with other agents. Liquid paraffin is a chemically inert mineral oil Lactulose is a synthetic disaccharide. Taken orally, and is not digested. It promotes the passage of it is unaffected by small intestinal disaccharidases, softer faeces. It is often presented in emulsions with is not absorbed and thus acts as an osmotic laxative. magnesium hydroxide. Large doses may leak out of Tolerance may develop. Lactulose is also used in the anus causing both physical and social dis- comfort. Paraffin taken orally over long periods, 3 especially at night, may be aspirated and cause Named after Sterculinus, a god of ancient Rome, who presided over manuring of agricultural land. chronic lipoid pneumonia. An unusual case resulted 4 Epsom, a town near London, known for its now defunct from attempts by a patient, an amateur singer, to mineral spring water, and for horse racing. lubricate his larynx with liquid paraffin. Because of 640
MISUSE OF LAXATIVES 32 these disadvantages its use is declining and it Danthron is available as a standardised preparation should never be used long term as a laxative. in combination with the faecal softeners poloxamer 188 (co-danthramer) and docusate sodium (as co- danthrusate). It acts in 6-12 h. Evidence from rodent STIMULANT LAXATIVES studies indicates a possible carcinogenic risk and These drugs increase intestinal motility by various long-term exposure to danthron should be avoided. mechanisms; they may cause abdominal cramps, Drastic purgatives (castor oil, cascara, jalap,6 should used only with caution in pregnancy, and colocynth, phenolphthalein and podophyllum) are never where intestinal obstruction is suspected. obsolete. Bisacodyl stimulates sensory endings in the colon Suppositories and enemas by direct action from the lumen. It is effective orally in 6-10 h and, as a suppository, acts in 1 h. In geriatric Suppositories (bisacodyl, glycerin) may be used to patients, bisacodyl suppositories reduce the need obtain a bowel action in about 1 hour. Enemas for regular enemas. There are no important unwanted produce defaecation by softening faeces and effects. distending the bowel. They are used in preparation for surgery, radiological examination and endoscopy.7 Sodium picosulphate is similar and is also used to Preparations with sodium phosphate, which is evacuate the bowel for investigative procedures poorly absorbed and so retains water in the gut, are and surgery. generally used. Arachis oil is included in enemas to soften impacted faeces. Glycerol has a mild stimulant effect on the rectum when administered as a suppository. The anthraquinone group of laxatives includes Misuse of laxatives senna, danthron, cascara, rhubarb5 and aloes. In the small intestine soluble anthraquinone derivates are Dependence (abuse) may arise following laxative liberated and absorbed. These are excreted into the use during an illness or in pregnancy, or the colon and act there, along with those that have individual may have the mistaken notion that a escaped absorption, probably after being chemically daily bowel motion is essential for health, or that changed by bacterial action. Patients taking some anthraquinones may notice their urine coloured brown (if acid) or red (if alkaline). 6 In the 19th century 'young men proceeding to Africa' were Prolonged use can cause melanosis of the colon. advised to take pills named Livingstone's Rousers, Anthraquinone preparations made from crude consisting of rhubarb, jalap, calomel and quinine. British plant extracts are to be avoided as their lack of Medical Journal 1964 2:1583. 7 Enemas may arouse complex psychosocial/sexual impulses standardisation leads to erratic results. ranging from frequent use for imagined self-cleansing (colonic lavage) to the extraordinary case of the 'Illinois Senna, available as a biologically standardised enema bandit' (USA, 1966-75), a man who broke into women preparation, is widely used to relieve constipation students' accommodation and forcibly administered enemas. and to empty the bowel for investigative procedures His exploits were immortalised in song by Frank Zappa (© 1978 Zappa Family Trust. Reprinted by permission): and surgery. It acts in 8-12 h. "The Illinois Enema Bandit I heard he's on the loose I heard he's on the loose Lord, the pitiful screams 5 In the late 18th century Britain made approaches to trade Of all them college-educated women... with China which were met with indifference; it seems that Boy, he'd just be tyin' 'em up the mandarins held the belief that the British feared death (They'd be all bound down!) from constipation if deprived of rhubarb (Rheum palmatum), Just be pumpin' every one of 'em up with all the bag fulla one of China's exports. The Illinois Enema Bandit Juice...' 641
32 INTESTINES the bowels are only incompletely opened by nature, malnutrition among children in less developed and so indulge in regular purgation. This effectively countries; acute diarrhoea from gastroenteritis prevents the easy return of normal habits because causes 4-5 million deaths throughout the world the more powerful stimulant purges empty the annually. Drugs have a place in its management but whole colon, whereas normal defaecation empties the first priority of therapy is to preserve fluid and only the descending colon. Cessation of use after a electrolyte balance. few weeks is thus inevitably followed by a few days' constipation whilst sufficient material collects to restore the normal state; the delay may convince SOME PHYSIOLOGY the patient of the continued need for purgatives. In the normal adult, 7-8 litres of of water and Laxative dependence, which may be solely emotional electrolytes are secreted daily into the gastro- at first, may be followed by physical dependence, so intestinal tract. This, together with dietary fluid, is that the bowels will not open without a purgative. absorbed by epithelial cells in the small and large Prolonged abuse can damage gut nerves and lead bowel. Water follows the osmotic gradients which to an atonic colon. result from shifts of electrolytes across the intestinal It is easier to prevent laxative dependence than epithelium, and sodium and chloride transport to cure it; patients feel they understand their own mechanisms are central to the causation and bowels far better than anyone else possibly could, management of diarrhoea, especially that caused by an opinion they seldom extend to other organs, bacteria and viruses. The energy for the process is except perhaps the liver. In Britain, there is a belief provided by the activity of Na + /K + ATPase. that nurses have an intuitive understanding of the Absorption of sodium into the epithelium is bowels that is denied to doctors. effected by: Excessive use of stimulant purgatives8 may, especially in the old, lead to severe water and • Sodium-glucose-coupled entry. Glucose stimulates electrolyte depletion, even to hypokalaemic para- the absorption of sodium and the resulting water lysis, malabsorption and protein-losing enteropathy. flow also sweeps additional sodium and chloride Purgatives are dangerous if given to patients with along with it (solvent drag). This important undiagnosed abdominal pain, inflammatory bowel mechanism remains active in diarrhoea of disease or obstruction. Nor should they be used various aetiologies and improvement of sodium to empty the rectum of hardened faeces, for they and water absorption by glucose (and amino will fail and cause pain. Initial treatment should be acids) is the basis of oral rehydration regimens with enemas, but digital removal, generally (see below). Absorption of sodium and water in ordered by a senior and performed by a junior the colon is stimulated by short-chain fatty acids doctor, may occasionally be required. A bulking (see below, cereal-based ORT). agent or a faecal softener will help to prevent • Sodium-ion-coupled entry. Na+ and Cl~ enter the recurrence. epithelial cell, either as a pair or, as seems more likely, there is a double exchange: Na+ (extracellular) with H+ (intracellular) and Cl~ (extracellular) with 2OR- or 2HCO3- Diarrhoea (intracellular). Oral rehydration solutions (see below) contain sodium, chloride and Diarrhoea ranges from a mild and socially in- bicarbonate. convenient illness to a major cause of death and Secretion is the opposite process to that of absorp- 8 tion. In response to various stimuli, crypt cells The Roman Emperor Nero (AD 37-68) murdered his actively transport chloride into the gut lumen and severely constipated aunt by ordering the doctors to give her 'a laxative of fatal strength'. He 'seized her property before sodium and water follow. This stimulus-secretion she was quite dead and tore up the will so that nothing could coupling is modulated by cyclic AMP and GMP, escape him'. (Suetonius (trans) R Graves). calcium, prostaglandins and leukotrienes. 642
DIARRHOEA 32 Diarrhoea results from an imbalance between Several other formulations exist, some with less secretion and reabsorption of fluid and electrolytes; sodium (see national formularies).10 it has numerous causes, including infections with Rehydration therapy with commercial soft drinks enteric organisms (which may stimulate secretion alone will fail because their sodium content is too or damage absorption), inflammatory bowel disease low (usually less than 4 mmol/1). The glucose may and nutrient malabsorption due to disease. It also be replaced by another substrate such as glycine or commonly occurs as a manifestation of disordered rice powder. Indeed cereal-based ORS, relying on gut motility in the absence of demonstrable disease starch (to produce glucose) from many sources (see below). Rarely it is due to secretory tumours of (rice, wheat, corn, potato) have the advantage of the alimentary tract, e.g. carcinoid tumour or vipoma controlling diarrhoea much more effectively than (a tumour which secretes VIP, vasoactive intestinal the glucose-based preparations. This may be because peptide). undigested starch is fermented in the colon to short- chain fatty acids, which stimulate colonic sodium and Motility patterns in the bowel. An important factor water absorption. Thus almost every household in in diarrhoea may be loss of the normal segmenting the world can find the essential components of an contractions that delay passage of contents, so that effective oral rehydration mixture: cereals and salt. an occasional peristaltic wave has a greater propulsive Most cases can be adequately treated by assiduous effect. Segmental contractions of the smooth muscle attention to oral intake, but fluid and electrolyte in the bowel mix the intestinal contents. Patients depletion is especially dangerous in children and with diarrhoea commonly have less spontaneous intravenous fluid replacement in hospital may be segmenting activity in the sigmoid colon than do needed. Antimotility drugs are inappropriate for people with normal bowel habit, and patients with severe diarrhoea in young children; any marginal constipation have more. Antimotility drugs (see effect they may have is liable to be counterbalanced below) reduce diarrhoea by increasing segmentation by hazardous adverse effects (see below). and inhibiting peristalsis. FLUID AND ELECTROLYTE ANTIDIARRHOEAL DRUGS TREATMENT There are two types of drug which are often used in combination. Oral rehydration therapy (ORT) with glucose- electrolyte solution is sufficient to treat the vast majority of episodes of watery diarrhoea from acute Antimotility drugs gastroenteritis. As a simple, effective, cheap and These act on bowel muscle to delay the passage of readily administered therapy for a potentially lethal gut contents so allowing time for more water to be condition, ORT must rank as a major advance in absorbed. therapy. It is effective because glucose-coupled Codeine (t l / 2 3 h) activates opioid receptors on the sodium transport continues during diarrhoea and smooth muscle of the bowel to reduce peristalsis so enhances replacement of water and electrolyte and increase segmentation contractions. Tolerance losses in the stool. may develop with prolonged use, as may dependence Oral rehydration salts (ORS) The WHO/UNICEF (rarely). It should be avoided in patients with recommended formulation is: 9 Sodium chloride 3.5 g/1 Solutions with lower sodium content and thus reduced Potassium chloride 1.5 g/1 total osmolarity (250 mmol/1) are associated with less need for unscheduled intravenous fluid infusion, lower stool Sodium citrate 2.9 g/1 volume and less vomiting, and may now be preferred. Hahn Anhydrous glucose 20.0 g/1 S et al 2001 British Medical Journal 323: 81-85. 10 The higher sodium content of the WHO/UNICEF This provides sodium 90 mmol/1, potassium 20 formulation is based on sodium concentrations in diarrhoeal mmol/1, chloride 80 mmol/1, citrate 10 mmol/1, stools, but low-sodium, high-glucose formulations may be glucose 111 mmol/1 (total osmolarity 311 mmol/1).9 preferred for infants, whose faecal losses of sodium are less. 643
32, INTESTINES diverticular disease as it increases intraluminal Most cases are infective, and up to half of the pressure. diarrhoea that afflicts visitors to tropical and sub- Diphenoxylate (t1// 3 h) is structurally related to tropical countries is associated with enterotoxigenic pethidine and affects the bowel like codeine. The strains of Escherichia coli; other bacteria including drug is offered mixed with a trivial dose of atropine Shigella and Salmonella spp, viruses including the (to discourage abuse) as co-phenotrope (Lomotil). Norwalk family, and parasites (particularly Giardia The drug can cause nausea, vomiting, abdominal lamblia) have also been implicated. Recognition that pain and CNS depression. Following overdose with transmission is almost invariably by ingestion of Lomotil respiratory depression may be serious, and contaminated food and water points to the most can occur up to 16 h after ingestion because gastric effective way of reducing the risk. emptying is delayed. Acute watery diarrhoea in adults can usually be Loperamide (t1/, 10 h) is structurally similar to controlled by oral rehydration solutions and one of diphenoxylate. Its precise mode of action remains the antimotility drugs, although in mild cases the obscure but it impairs propulsion of gut contents by abdominal bloating produced by the latter may be effects on intestinal circular and longitudinal muscle less acceptable than the loose stools. While diarrhoea that are at least partly due to an action on opioid usually lasts only 2-3 days, this may still be socially receptors. Loperamide may cause nausea, vomiting inconvenient, and if symptomatic remedies fail, an and abdominal cramps. Its potential for abuse aminoquinolone, e.g. ciprofloxacin 500 mg b.d. will appears to be low. be effective. The use of antimicrobials for travellers' The actions of codeine, diphenoxylate and diarrhoea continues to evoke controversy (see below) loperamide are antagonised by naloxone. but most sufferers will appreciate the relief that even one or two tablets can bring. Warning. Antimotility drugs should not be used Prophylactic antimicrobial therapy has been for acute diarrhoea in children, especially babies, or shown to reduce the incidence of attacks of diarrhoea in patients with active inflammatory bowel disease, but its routine use carries the risk of hindering the for there is danger of causing paralytic ileus and, in diagnosis of serious infection. A wider issue is the babies, respiratory depression. possible development and spread of antibiotic- resistant organisms. Thus any benefits to the individual must be weighed against the risk to the Drugs that directly increase the viscosity community in the future. In most instances pro- of gut contents phylactic antimicrobials should not be used but Kaolin and chalk are adsorbent powders. Their ciprofloxacin (500 mg once daily) may be justified therapeutic efficacy is marginal as is shown by the for individuals who must remain well while travelling fact that they are often combined with an opioid. for short periods to high-risk areas. Bulk-forming agents such as ispaghula, methylcellulose and sterculia (see above) are useful for diarrhoea in SPECIFIC INFECTIVE DIARRHOEAS diverticular disease, and for reducing the fluidity of faeces in patients with ileostomy and colostomy. Chemotherapy is available for certain specific organisms, e.g. amoebiasis, giardiasis, typhoid fever (see Index). TRAVELLERS' DIARRHOEA So familiar is diarrhoea to travellers that it has DRUG-INDUCED DIARRHOEA acquired regional popular names: the Aztec 2-step, Montezuma's Revenge, Delhi Belly, Rangoon Runs, Antimicrobials are the commonest drugs that cause Tokyo Trots, Gyppy Tummy, Hong-Kong Dog, diarrhoea, probably due to alteration of bowel flora. Estomac Anglais and Casablanca Crud, all indicate It may range from a mild inconvenience to life- some of the areas deemed dangerous by visitors. threatening antibiotic-associated (pseudomembranous The Mexican name 'turista' indicates the principal colitis), due to colonisation of the bowel with sufferers. Clostridium difficile. The condition particularly affects 644
INFLAMMATORY BOWEL DISEASE 32 elderly patients in hospital. Clindamycin and third ULCERATIVE COLITIS generation cephalosporins are especially prone to cause this complication, whereas it is uncommon Aminosalicylates with the quinolone and aminoglycoside groups. Aminosalicylates maintain remission in patients Treatment is with vancomycin or metronidazole. with ulcerative colitis (relapses are reduced by a Magnesium-containing antacids may also produce factor of 3), and may also be used for treatment of diarrhoea, as may NSAIDs and lithium. an acute attack (corticosteroids may also be needed). Sulfasalazine (salicylazosulfapyridine, SECRETORY DIARRHOEAS Salazopyrin) consists of two compounds, sulpha- Octreotide, a synthetic peptide which shares amino pyridine and 5-aminosalicylic acid, joined by an acid homology with somatostatin (see p. 710), inhibits azo-bond. Sulfasalazine is poorly absorbed from the release of peptides that mediate certain alimentary the small intestine and colonic bacteria split the secretions, and may be used to relieve diarrhoea azo-bond to release the component parts. The due to carcinoid tumours and vipomas. therapeutically active moiety is 5-aminosalicylic acid (5-ASA). Sulphapyridine is well absorbed, is acetylated in the liver and excreted in the urine; it has no therapeutic action in colitis but contributes Inflammatory bowel to a mechanism for delivering 5-ASA to the colon. Sulfasalazine is also used as a disease-modifying disease agent in rheumatoid arthritis (see p. 292), the condition for which it was originally introduced in The pathogenesis of inflammatory bowel disease is the 1930s. It is available as a tablet, retention enema still poorly understood. Immune mechanisms are or suppository. probably involved, and potential antigens include Adverse effects are due largely to the sulph- intestinal bacteria and intestinal epithelium. onamide moiety and include headache, malaise, Abnormalities in inflammatory mediators have also anorexia, nausea and vomiting; these are dose- been described; it has been suggested that an related and commoner in slow acetylators (of the imbalance between proinflammatory and anti- sulphonamide). Allergic reactions include rash, fever inflammatory cytokines may determine susceptibility, and lymphadenitis; rarely leucopenia and agranulo- although the abnormalities observed could simply cytosis occur. Males may become infertile due to be secondary to the disease process. oligospermia and reduced sperm motility; this The main drugs used in the treatment of ulcerative reverses if salazopyrin is replaced with mesalazine. colitis and Crohn's disease are the aminosolicylates and corticosteroids. Their mode of action is obscure. Mesalazine. Patients intolerant of salazopyrin Other immunosuppressives also have a role and usually tolerate mesalazine, which is 5-ASA. recent studies into the mechanisms of inflammation Mesalazine is absorbed rapidly and completely in are leading to the introduction of novel therapies to the upper jejunum, and is presented in various inhibit the inflammatory process. formulations which delay its release. Asacol tablets In acute exacerbations of inflammatory bowel are coated in a resin, which dissolves only at a pH disease a gastrointestinal infection should always of 7 or higher, favouring its release in the ileum and be excluded by stool microscopy and culture, and colon. In contrast Pentasa has a slow-release but pH testing for Clostridium difficile toxin. Measures to independent coating so that 5-ASA is liberated correct anaemia, fluid and electrolyte abnormalities throughout the gastrointestinal tract. 5-ASA that and to improve the general nutritional state are also enters the blood is rapidly cleared by acetylation in important. Antidiarrhoeals should be used with the liver and renal excretion. In addition to oral extreme caution in active colitis and are contra- formulations, mesalazine is available as an enema. indicated if the disease is severe. They can lead to The profile of adverse effects includes nausea, toxic dilatation of the colon, with perforation. abdominal pain, watery diarrhoea (which can lead 645
32 INTESTINES to diagnostic confusion in patients with inflammatory prednisolone 60 mg/d). A response should start bowel disease) and interstitial nephritis. Renal within 10-14 d and if it does not the patient should function should be monitored regularly in patients be admitted to hospital for more intensive treatment taking 5-ASA, particularly preparations extensively including intravenous corticosteroid. Once re- released in the small intestine. mission has been attained the dose can be tailed down over a period of 6-8 weeks. It is important Two other 5-ASA preparations effectively delay not to do this too quickly; the rapidly tailing release of the active moiety until the preparation regimes used for treating asthma are not appropriate reaches the colon: Olsalazine is two molecules of 5- for inflammatory bowel disease. ASA acid linked by an azo-bond, while balsalazide Severe attacks of ulcerative colitis should be comprises one molecule of 5-ASA acid linked by an treated in hospital with intravenous corticosteroid. azo-bond to an inert carrier. 5-ASA is liberated after The main danger is toxic dilatation of the colon and cleavage of the azo-bonds by colonic bacteria. perforation, which can occur insidiously. Regular measurements of abdominal girth and straight x- ray of the abdomen are useful in monitoring response, Corticosteroids which should be seen within 72 h. If there is no improvement a trial of ciclosporin (see below) may Enemas and suppositories. When ulcerative colitis induce response. Treatment otherwise is by emergency is restricted to the left hemicolon, exacerbations that colectomy. do not respond to an aminosalicylate alone can often be controlled by steroid enemas. Properly Ciclosporin may induce remission in some patients administered, these will reach the splenic flexure, with severe ulcerative colitis unresponsive to cortico- and for this to occur the patient should be instructed steroid. The drug is given in a dose of 2-4 mg/kg i.v. to lie down for at least 30 minutes after insertion of until remission is attained. Renal function should the enema. The foam-based preparations appear to be monitored closely as ciclosporin is nephrotoxic coat the colonic mucosa more efficiently than the (see p. 620). For maintenance therapy azathioprine aqueous formulations. (see below) is often substituted. Ciclosporin use In patients with disease limited to the distal few only delays surgery for many patients; after 1 year centimetres of the rectum, steroid enemas may be 50% will have relapsed and undergone colectomy. ineffective because they will be delivered proximal Smoking aggravates Crohn's disease but to the inflamed segment. In this situation steroid (perversely) improves ulcerative colitis. Nicotine suppositories are often helpful. Patients with distal patches may provide benefit in ulcerative colitis but colitis are prone to faecal loading above the inflamed the effect is not sufficiently great to justify their segment and this can lead to overflow diarrhoea routine use in management. and worsening of inflammation. Faecal loading can be detected on straight abdominal x-ray and is Maintenance of remission treated with laxatives; this is safe provided the inflammatory process is restricted to the distal colon. Corticosteroids can be reduced slowly (see above) On no account should antidiarrhoeals be used as and maintenance therapy with an aminosalicylate these will exacerbate the problem. Adequate started. If the disease is corticosteroid dependent, quantities of dietary fibre and fluid should be azathioprine or another immunosuppressive agent encouraged, and stool bulking agents can also be may be used (see below). Surgery is indicated if helpful in protecting against faecal loading. medical therapy fails to control the disease or is associated with unacceptable adverse effects. Systemic corticosteroid. Moderately severe attacks of ulcerative colitis should be treated with systemic CROHN'S DISEASE corticosteroid, and oral preparations usually suffice. It is important to give enough drug to bring the Treatment depends on the site of disease. Manage- inflammatory process under control (starting dose ment of colonic Crohn's disease is very similar to 646
INFLAMMATORY BOWEL DISEASE 11 that of ulcerative colitis, with aminosalicylate and Maintenance of remission may require addition of corticosteroid. These drugs are of less value in azathioprine or another immunosuppressive drug maintaining remission in Crohn's disease than in (see below). Tobacco smoking definitely contributes ulcerative colitis, although they do help to reduce to relapse and should be strongly discouraged. recurrence of disease at sites of surgical anastamoses. Crohn's disease may be complicated by intestinal Topical enema preparations are less useful because strictures, fistulae and intra-abdominal abscesses. of the patchy distribution of inflammation and Surgery is often necessary but strictures may be rectal sparing. amenable to endoscopic balloon dilatation and In contrast to ulcerative colitis, about 50% of abscesses can be drained under radiographic control. patients with Crohn's colitis will respond to metronidazole given for up to 3 months, although Dietary therapy adverse effects including alcohol intolerance, and peripheral neuropathy from such prolonged therapy There is evidence that liquid diets based on amino- often limit its use. The drug is also helpful in acids (elemental diets) or oligopeptides for 4-6 weeks controlling perianal and small bowel disease and it are as effective as corticosteroids in controlling decreases the incidence of anastamotic recurrence Crohn's disease although relapse is common when after surgery. Other antimicrobials, particularly the treatment stops. Elemental preparations are not ciprofloxacin may also be effective. particularly palatable and they often have to be Crohn's disease of the small bowel classically administered through a nasogastric tube, which is affects the ileocaecal region, although any part of not popular with patients. They are worth trying in the gastrointestinal tract may be involved, from the steroid resistant cases, and are particularly favoured mouth downwards. Patients with small bowel in- by paediatricians who prefer to avoid adrenal steroid volvement are frequently malnourished and specialist because of its adverse effects on growth. dietetic input is essential; enteral or parenteral nutrition may be required. Osteoporosis is common, Antibodies to tumour necrosis factor particularly if corticosteroid consumption has been (TNF) high. Sulfasalazine, olsalazine and balsalazide are TNFoc causes activation of immune cells and release ineffective in small bowel Crohn's disease because of inflammatory mediators. The inhibitors of TNF, these drugs are designed to liberate 5-ASA in the infliximab and etanercept (see p. 293), have been colon. Mesalazine preparations release 5-ASA higher found to benefit Crohn's disease. A single dose of in the gut and control mild to moderate exacerbations anti-TNFa will induce remission in approximately of ileocaecal disease in approximately 50% of one-third of patients with Crohn's disease resistant patients, although high doses are needed (Asacol to conventional therapies, with improvement in a 2.4 g in divided doses, Pentasa 2 g b.d.). further third. A further dose after 8 weeks appears In more severe disease corticosteroids are needed to produce longer lasting remissions. This treatment to induce remission (prednisolone 60 mg/day until is also useful in treating Crohn's fistulae. Adverse remission induced, tailing the dose by 5 mg/week). reactions include headache, nausea and malaise; Approximately 75% of patients respond. Budesonide, repeat infusions after prolonged intervals (1-2 years) a potent topically active corticosteroid, is an may lead to hypersensitivity reactions. Its efficacy alternative which can be administered either orally and potential for adverse effects in the long term or as an enema. The oral preparation is presented as (including development of malignancy) remain to a delayed release formulation which delivers drug be established. There is no good evidence that anti- to the terminal ileum and ascending colon. Extensive TNFa antibodies are effective for ulcerative colitis. first pass metabolism in the liver limits its systemic availability and potential for adverse effects. Immunosuppressive drugs Budesonide is also useful as maintenance therapy of the 30% of patients with Crohn's disease who are Azathioprine is effective as a steroid sparing agent steroid dependent. in maintenance therapy of Crohn's disease. Use of 647
32 INTESTINES this drug in a dose of up to 2 mg/kg may allow and it occurs in many patients with microscopic corticosteroid to be withdrawn altogether. It is also colitis. Bile salts in the colon cause diarrhoea which is used for the same purpose in ulcerative colitis relieved by colestyramine. The dose required is although evidence for its efficacy in this disorder is titrated against symptoms, starting with 8 g bd. less persuasive. As the onset of action of azathioprine Colestyramine can also bind to many drugs and is delayed for about 8 weeks, it is not effective for reduce their bioavailability (see p. 131). inducing remission, and reduction in steroid dose in the first few weeks of azathioprine treatment may IRRITABLE BOWEL SYNDROME (IBS) lead to relapse. Azathioprine can cause bone marrow suppression and the blood count should be monitored This condition affects 20% of the population and is weekly for the first two months of therapy and every 2 the commonest reason for referral to a gastro- months thereafter for as long as the drug is taken. enterologist. It is manifested by a variety of Intolerance of azathioprine is shown by malaise, gastrointestinal symptoms including disordered abdominal discomfort and sometimes fever. Pan- bowel habit (constipation, diarrhoea or both), creatitis occurs in up to 5%. These effects are abdominal pain and bloating. Upper gastrointestinal usually due to the imidazole side chain of the symptoms manifest as nonulcer dyspepsia (see molecule, and mercaptopurine (which is azathioprine Chapter 31). All these symptoms occur in the absence without the side chain) may be better tolerated. The of demonstrable pathology in the gastrointestinal dose is 1-1.5 mg/kg. tract, although patients with IBS often have ab- normalities of gut motility. Another feature of the Ciclosporin. There is no good evidence that condition is visceral hypersensitivity; patients with ciclosporin is effective in Crohn's disease. IBS have lower thresholds for pain from colonic distension induced by inflating balloons placed in Methotrexate can be helpful in controlling relapses the bowel. A proportion of patients develop their of Crohn's disease unresponsive to corticosteroid or IBS symptoms after an episode of gastroenteritis azathioprine. It has also been used with benefit in and in many emotional stress is an important ulcerative colitis. Its short- and long-term use are precipitating factor. Associated psychopathology, limited by a wide profile of adverse effects with anxiety and sometimes depression, are common. including bone marrow suppression and The mainstay of treatment, after investigation pulmonary and hepatic fibrosis (see p. 291). when appropriate, is to reassure the patient of the entirely benign nature of the disorder and the good prognosis. Those with predominant constipation should be encouraged to increase the fluid and fibre Other conditions content of their diet. Unprocessed bran can lead to troublesome bloating and wind and a bulking agent such as ispaghula husk is often better tolerated. MICROSCOPIC COLITIS Diarrhoea can be treated with an antimotility This condition presents with diarrhoea: the colonic drug such as loperamide, the dose being adjusted to mucosa is macroscopically normal but histologically symptoms. Codeine phosphate is effective although shows either lymphocytic infiltration of the mucosa it may cause sedation. (lymphocytic colitis) or subendothelial fibrosis Antispasmodics (see below) are given for abdominal (collagenous colitis). Treatment with aminosalicylate pain, although there is little objective evidence for induces remission in about 50% and corticosteroid their efficacy from controlled clinical trials. The may also be needed. generation of evidence is complicated by the variable nature of IBS symptoms, the patients who suffer from them, and the high rate of placebo response in BILE SALT MALABSORPTION this condition. There are two main classes of Failure of the terminal ileum to reabsorb bile salts antispasmodic, the antimuscarinic drugs and drugs may result from Crohn's disease, or ileal resection, which are direct smooth muscle relaxants. 648
OTHER CONDITIONS 32 Antimuscarinic drugs ciprofloxacin and metronidazole, or ampicillin, gentamycin and metronidazole). These drugs block cholinergic transmission at parasympathetic postganglionic nerve endings and cause smooth muscle to relax. The synthetic anti- PROTECTION AGAINST COLON muscarinics dicydomine and propantheline are probably CARCINOMA the most useful in IBS, but therapeutic efficacy is Certain drugs may develop a protective role against often limited by other anticholinergic effects. The colonic cancer. The reasoning is based on the ob- drugs are contraindicated in patients with glaucoma servation that expression of the cyclo-oxygenase and prostatism, and should be avoided in patients isoenzyme COX-2 is increased in colon cancer with gastro-oesophageal reflux. tumours, and also in familial adenomatous polyposis, a premalignant condition. Evidence suggests that Other smooth muscle relaxants aspirin and other NSAIDs may exert a protective effect through inhibiting this enzyme; the protective Mebeverine is a reserpine derivative which has a dose of aspirin is probably higher than that used in direct effect on colonic muscle activity, especially, it cardiovascular disease and, clearly, any benefits appears, on colonic hypermotility. As it does not must be weighed against risks from complications, possess antimuscarinic activity, it does not exhibit notably gastrointestinal bleeding. Selective COX-2 the troublesome unwanted effects of that group of inhibitors may possess advantage in this situation. drugs. Alverine and peppermint oil also have direct smooth muscle relaxing activity. ANAL FISSURE A trial of low dose amitryptiline (10-25 mg at Anal fissures are often intensely painful due to night) is worthwhile in patients who do not respond sphincter spasm. Anaesthetic ointments and stool to antispasmodics, and associated depression will softening agents have been widely used, with surgery be helped by conventional doses of this or other (lateral internal sphinterotomy) for severely affected antidepressants. Relaxation therapy, hypnotherapy cases, but this procedure can cause incontinence and cognitive behaviour therapy have a place in from loss of sphincter control. An alternative is selected cases. topical application of nitrate which heals two-thirds of fissures. Preparations should be diluted to 0.2% DIVERTICULAR DISEASE as such use may be complicated by headache; tolerance can develop. Intrasphincteric injection of Diverticular disease affects 5-10% of Western people botulinum toxin has also been shown to be effective. over the age of 45; the incidence rises to 80% in those over 80. Colonic dysmotility with increased intracolonic pressure, and diets high in refined carbohydrate and low in fibre are important patho- genic factors. Some patients experience abdominal GUIDETO FURTHER READING pain from dysmotility whilst others remain asympto- matic. Infection of diverticula occurs in a minority, Almroth S, Latham M C 1995 Rational home giving potential for rupture or abscess formation. management of diarrhoea. Lancet 345: 709-711 Symptomatic diverticular disease often responds Eastwood M 1995 The dilemma of laxative abuse. to an increase in dietary fibre, and addition of a Lancet 346:1115 stool bulking agent. Antispasmodic drugs are Farrell R J, Reppercorn M A 2002 Ulcerative colitis. helpful in controlling the pain of colon spasm but Lancet 359: 331-340 antimotility drugs encourage stasis of bowel Ferzoco L B et al 1998 Acute diverticulitis. New contents, increase intracolonic pressure, and should England Journal of Medicine 338:1521-1526 be avoided. Diverticulitis requires treatment with Goyal R K, Hirano 11996 The enteric nervous system. broad spectrum antimicrobials for 7-10 days (e.g. New England Journal of Medicine 334:1106-1115 649
INTESTINES 32 Horwitz B J, Fisher R S 2001 The irritable bowel Rabbani G H 2000 The search for a better oral syndrome. New England Journal of Medicine 344: rehydration solution for cholera. New England 1846-1850 Journal of Medicine 342: 345-347 Janne P A, Mayer R J 2000 Chemoprevention of Schiller L R 2000 Pathogenesis and treatment of colorectal cancer. New England Journal of microscopic-colitis syndrome. Lancet 355: Medicine 342:1960-1968 1198-1199 Madoff R D 1998 Pharmacologic therapy for anal Talky N J, Spiller R 2002 Irritable bowel syndrome: a fissure. New England Journal of Medicine 338: 257 little understood organic bowel disease? Lancet Midgley R, Kerr D 1999 Colorectal cancer. Lancet 353: 360: 555-564 391-399 Wright N, Scott B 1997 Dietary treatment of active Podolsky D K 2002 Inflammatory bowel disease. New Crohn's disease. British Medical Journal 314: England Journal of Medicine 347: 417-430 454-455 650