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Ciprofloxacin is occasionally used for prophylaxis against travellers’ diarrhoea, but routine use is not recommended due to consequent encouragement of bacterial resistance. Lactobacillus preparations have not been shown to be effective. Early treatment of diarrhoea with ciprofloxacin will control the great majority of cases and this, together with oral replacement of salts and water, is the currently preferred approach. PSEUDOMEMBRANOUS COLITIS Broad-spectrum antibacterial drug therapy is sometimes associated with superinfection of the intestine with toxin-producing Clostridium difficile. Debilitated and immunosuppressed patients are at particular risk. The infection can be transmitted from person to person. Withdrawal of the antibacterial drug and the introduction of oral metronidazole or vancomycin should be instituted. IRRITABLE BOWEL SYNDROME This motility disorder of the gut affects approximately 10% of the population. Although the symptoms are mostly colonic, patients with the syndrome have abnormal motility throughout the gut and this may be precipitated by dietary items, such as alcohol or wheat flour. The important management principles are first to exclude a serious cause for the symptoms and then to determine whether exclusion of certain foods or alcohol would be worthwhile. An increase in dietary fibre over the course of several weeks may also reduce the symptoms. Psychological factors may be important precipitants and counselling may be helpful. Drug treatment is symptomatic and often disappointing. • Anticholinergic drugs, such as hyoscine, have been used for many years, although evidence of their efficacy is lacking. The oral use of better absorbed anticholinergics, such as atropine, is limited by their side effects. • Mebeverine (135 mg before meals three times daily) directly relaxes intestinal smooth muscle without anticholinergic effects. Its efficacy is marginal. • Peppermint oil relaxes intestinal smooth muscle and is given in an enteric-coated capsule which releases its contents in the distal small bowel. It is given before meals three times daily. • Antidiarrhoeal drugs, such as loperamide, reduce associated diarrhoea. • Psychotropic drugs, such as antipsychotics and antidepressants with anticholinergic properties, have also been effective in some patients. In general, however, they should be avoided for such a chronic and benign condition because of their serious adverse effects (see Chapters 19 and 20). PANCREATIC INSUFFICIENCY PANCREATIC INSUFFICIENCY 259 It is important to remember that, amongst the many causes of pancreatitis, certain drugs can very occasionally be an aetiological factor (Table 34.5). Exocrine pancreatic insufficiency is an important cause of steatorrhoea. The pancreas has a large functional reserve and malabsorption does not usually occur until enzyme output is reduced to 10% or less of normal. This type of malabsorption is usually treated by replacement therapy with pancreatic extracts (usually of porcine origin). Unfortunately, although useful, these preparations rarely abolish steatorrhoea. A number of preparations are available, but the enzyme activity varies between preparations – one with a high lipase activity is most likely to reduce steatorrhoea. Unfortunately, less than 10% of the lipase activity and 25% of the tryptic activity is recoverable from the duodenum regardless of the dose schedule. This limited effectiveness of oral enzymes is partly due to acid–peptic inactivation in the stomach and duodenum. H 2-antagonists decrease both acidity and volume of secretion and retard the inactivation of exogenous pancreatic enzymes. They are given as an adjunct to these preparations. Supplements of pancreatin are given to compensate for reduced or absent exocrine secretion in cystic fibrosis, pancreatectomy, total gastrectomy and chronic pancreatitis. Pancreatin is inactivated by gastric acid and therefore preparations are best taken with or immediately before or after food. Gastric acid secretion can be reduced by giving an H 2-blocker about one hour beforehand, or antacids may be given concurrently to reduce acidity. Pancreatin is inactivated by heat and, if mixed with liquids or food, excessive heat should be avoided. The dose is adjusted according to size, number and consistency of stools such that the patient thrives. Pancreatin can irritate the perioral skin and buccal mucosa if it is retained in the mouth and excessive doses can cause perianal irritation. The most frequent side effects are gastrointestinal ones including nausea, vomiting and abdominal discomfort. Hyperuricaemia and hyperuricuria have been associated with very high doses of the drug. Table 34.5: Drugs that are associated with pancreatitis (this is uncommon) Asparaginase Oestrogens Azathioprine Pentamidine Corticosteroids Sodium valporate Dideoxyinosine (DDI) Sulphonamides and Ethanol sulfasalazine Tetracycline Thiazides

260 ALIMENTARY SYSTEM AND LIVER LIVER DISEASE PRINCIPLES UNDERLYING DRUG TREATMENT OF HEPATIC ENCEPHALOPATHY AND LIVER FAILURE In severe liver dysfunction, neuropsychiatric changes occur and can progress to coma. The mechanism which produces these changes is not established, but it is known that in hepatic coma and pre-coma, the blood ammonia concentration increases. In many patients, the time-course of encephalopathy parallels the rise in blood ammonia concentrations. Orally administered nitrogenous compounds (e.g. protein, amino acids, ammonium chloride) yield ammonia in the gut, raise blood ammonia concentrations and provoke encephalopathy. The liver is the only organ that extracts ammonia from the blood and converts it to urea. Bacterial degradation products of nitrogenous material within the gut enter the systemic circulation because of a failure of first-pass hepatic extraction (due to hepatocellular damage), or due to bypass of the hepatocytes by collateral circulation or intrahepatic shunting. Another source is urea, which undergoes enterohepatic circulation and yields approximately 3.5 g/day of ammonia (see Figure 34.3). Ammonia diffuses into the blood across the large intestine epithelium, where it is trapped by becoming ionized due to the lower pH of blood compared to colonic contents. Ammonia is not the only toxin involved, as perhaps 20% of patients with encephalopathy have normal blood ammonia concentrations, and methionine can provoke encephalopathy without causing a significant rise in blood ammonia concentration. Furthermore, ammonia toxicity affects the cortex but not the brainstem, which is also involved in encephalopathy. Other toxins of potential relevance include the following: • Intestinal bacterial decarboxylation produces hydroxyphenyl amines, such as octopamine (from tyramine), which could replace normal transmitters at nerve endings in the central and peripheral nervous systems, thus acting as ‘false transmitters’ and changing the balance of inhibition and excitation at central synapses. Other nitrogenous substrates LIVER Systemic circulation Hepatic portal vein Urea Urine Protein Ammonia • Changes in fatty acid metabolism increase plasma free fatty acids, some of which have anaesthetic properties. In addition, these determine the availability of tryptophan to the brain and hence have an effect on 5-hydroxytryptamine synthesis. Glutathione synthesis is impaired in severe liver disease. Cellular damage due to free radical excess can produce multiorgan dysfunction. Intravenous administration of acetylcysteine is used prophylactically in some centres to enhance glutathione synthesis and thereby reduce oxidant (free radical) stresses by scavenging these reactive entities. Treatment of hepatic encephalopathy includes the following measures: • dietary protein restriction to as little as 20 g/day, while ensuring an adequate intake of essential amino acids; • emptying the lower bowel by means of enemas and purgatives to reduce the bacterial production of ammonia; • oral or rectal administration of non-absorbable antibiotics, such as neomycin, to reduce the bacterial population of the large bowel. Neomycin, 1–2 g four times daily, is often used. It should be remembered, if the patient also has renal impairment, that neomycin may accumulate and produce toxicity; • oral lactulose improves encephalopathy. This disaccharide is not a normal dietary constituent and humans do not possess a lactulase enzyme, so lactulose is neither digested nor absorbed but reaches the colon unchanged, where the bacterial flora breaks it down to form lactate, acetate and other acid products. These trap ammonia and other toxins within the intestinal lumen by reducing its pH, and in addition they act as a cathartic and reduce ammonia absorption by reducing the colonic transit time; • bleeding may occur due to interference with clotting factor synthesis or thrombocytopenia. Vitamin K is given and fresh frozen plasma or platelets are used as required. H 2 antagonists (e.g. ranitidine) or proton-pump inhibitors (e.g. omeprazole) are often used to prevent gastric erosions and bleeding; • sedatives should be avoided as patients with liver disease are extremely sensitive to such drugs. If sedation is essential (e.g. because of agitation due to alcohol Gut bacteria Bacterial urease Urea GUT Figure 34.3: Enterohepatic circulation of urea and ammonia.