CLINICAL PHARMACOLOGY 2003 (PART 32)

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CLINICAL PHARMACOLOGY 2003 (PART 32)

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Approximately one-third of the population in Western societies experiences regular dyspepsia, although more than half selfmedicate with over-the-counter antacid preparations and do not seek medical advice. Up to 50% of those who do will have demonstrable pathology, most commonly gastro-oesophageal reflux or peptic ulceration. The remainder, in whom no abnormality is found, are diagnosed as having nonulcer dyspepsia.The pathophysiology and treatment differ for each of these three conditions.

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SECTION 7 GASTRO- INTESTINAL SYSTEM
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31 Oesophagus, stomach and duodenum SYNOPSIS the gastric and duodenal mucosa from these sub- stances (Fig. 31.1). The exact mechanisms are still Approximately one-third of the population in poorly understood. A major cause of peptic ulcer Western societies experiences regular is use of nonsteroidal anti-inflammatory drugs dyspepsia, although more than half self- (NSAIDs), particularly in the elderly. medicate with over-the-counter antacid Treatment of peptic ulceration has traditionally preparations and do not seek medical advice. centred around measures to neutralise gastric acid, Up to 50% of those who do will have to inhibit its secretion, or to enhance mucosal demonstrable pathology, most commonly defences. More recently, recognition of the central gastro-oesophageal reflux or peptic ulceration. role of Helicobacter pylori has revolutionised treat- The remainder, in whom no abnormality is ment. Smoking is a major environmental factor and found, are diagnosed as having nonulcer patients who smoke should be advised to stop. dyspepsia.The pathophysiology and treatment differ for each of these three conditions. ACID SECRETION BYTHE STOMACH Drugs for peptic ulcer Gastric acid is secreted by the parietal cells in Neutralisation of secreted acid gastric mucosa. The basolateral membranes of these Reduction of acid secretion cells contain receptors for the three main stimulants Enhancing mucosal resistance of acid secretion, namely gastrin (from antral G Eradication of Helicobacter pylori cells), histamine (from enterochromaffin-like cells) NSAIDs and the stomach and acetylcholine (from vagal efferents). The action Gastro-oesophageal reflux and vomiting • Antiemesis and prokinetic drugs • Treatment of various forms of vomiting Protective Aggressive Prostaglandins Acid Mucus Pepsin Bicarbonate NSAIDs Mucosal blood flow Helicobacter pylori Peptic ulcer Peptic ulcer occurs when there is an imbalance between the damaging effects of gastric acid and pepsin, and the defence mechanisms, which protect Fig. 3 1 . 1 Factors involved in maintaining acid balance 625
31 OESOPHAGUS, STOMACH AND DUODENUM of all these is to stimulate the gastric acid (proton) bismuth have largely been abandoned for this pump, which is the final common pathway for acid purpose because of systemic toxicity. Preparations secretion. The pump is an H + /K + ATPase, and when containing calcium may cause rebound acid hyper- stimulated it translocates from cytoplasmic vesicles secretion and, with prolonged use hypercalcaemia to the secretory canaliculus of the parietal cell and alkalosis. This may rarely be associated with and uses energy, derived from hydrolysis of ATP, to renal failure (the 'milk-alkali syndrome'). Some transport H+ out of parietal cells in exchange for K+. bismuth preparations may be absorbed, causing Hydrogen ions combine with chloride ions to form encephalopathy and arthropathy; this is not a HC1, which is secreted into the gastric lumen. problem with bismuth chelate (see below). On average, patients with duodenal ulcer produce Antacids protect the gastric mucosa against acid about twice as much HC1 as normal subjects, but (by neutralisation) and pepsin (which is inactive there is much overlap, and about half the patients above pH 5, and which in addition is inactivated by with duodenal ulcer have acid outputs in the normal aluminium and magnesium). Continuous elevation range. Patients with gastric ulcer produce normal of pH by intermittent administration is limited by or reduced amounts of acid. gastric emptying. If the gastric contents are liquid, half will have left in about 30 minutes, whatever INHIBITION AND NEUTRALISATION their volume. OF GASTRIC ACID Antacids are generally used to relieve dyspeptic symptoms and they are taken intermittently when Healing of gastric and duodenal ulcers by anti- symptoms occur. Side effects and inconvenience secretory drugs and antacids is dependent upon: limit their use as ulcer healing agents. • the degree of gastric acid suppression and • the duration of treatment. INDIVIDUAL ANTACIDS Proton pump inhibitors, which are the most potent antisecretory drugs, heal the majority of Magnesium oxide and hydroxide react quickly peptic ulcers within 4 weeks whereas the less with gastric HC1, but cause diarrhoea, as do all powerful H2-receptor antagonists require up to magnesium salts (which are also used as purgatives). twice as long to achieve the same healing rate. Magnesium carbonate is rather less effective. Antacids modify intragastric pH only transiently, yet relatively small daily doses (around 120 mmol) Magnesium trisilicate reacts slowly, to form will heal ulcers if they are taken for long enough. magnesium chloride, which reacts with intestinal By the end of three months 85% of peptic ulcers secretions to form the carbonate: chloride is liberated will have healed, regardless of the treatment, but and reabsorbed. Systemic acid-base balance is thus the stronger agents provide much more rapid not significantly altered. symptom relief. In addition, numerous studies have shown a high rate of placebo response in ulcer Aluminium hydroxide reacts with HC1 to form healing. aluminium chloride; this in turn reacts with intestinal secretions to produce insoluble salts, especially phosphate. The chloride is released and reabsorbed so systemic acid-base balance is not Antacids altered. It tends to constipate. Sufficient aluminium may be absorbed from the intestine to create a risk Antacids are basic substances that reduce gastric of encephalopathy in patients with chronic renal acidity by neutralising HC1. The hydroxide is the failure. Hypophosphataemia and hypophosphaturia most common base but trisilicate, carbonate and may result from impaired absorption due to bicarbonate are also used. Therapeutic efficacy and phosphate binding. adverse effects depend also on the metallic ion with which the base is combined, and this is usually Sodium bicarbonate reacts with acid and relieves aluminium, magnesium or sodium. Calcium and pain within minutes. It is absorbed and causes 626
H, RECEPTOR ANTAGONISTS 3]_ alkalosis which in short-term use may not cause supplemented by magnesium hydroxide or car- symptoms. Sodium bicarbonate can release enough bonate. Sometimes magnesium trisilicate or alu- CO2 in the stomach to cause discomfort and belching, minium hydroxide is added, but these are often which may or may not have a psychotherapeutic used alone, though they are relatively slow-acting. effect, according to the circumstances. Excess sodium Disturbed bowel habit can be corrected by altering intake may be undesirable in patients with cardiac the proportions of magnesium salts, which cause or renal disease (see below). diarrhoea, and aluminium salts, which constipate. Tablets are more convenient for the patient at Alginic acid may be combined with an antacid to work but they act more slowly unless they are encourage adherence of the mixture to the mucosa, chewed; a liquid may be more acceptable for frequent e.g. for reflux oesophagitis. use. Patients will find their own optimal pattern of use. Dimeticone is sometimes included in antacid mixtures as an antifoaming agent to reduce flatulence. It is a silicone polymer that lowers surface tension and allows the small bubbles of froth to coalesce H2 receptor antagonists into large bubbles that can more easily be passed up from the stomach or down from the colon. It helps These drugs bind selectively and competitively to distended mountaineers to belch usefully at high the histamine H2 receptor on the basolateral altitudes. membrane of the parietal cell. As well as inhibiting gastric acid release from histamine they inhibit acetylcholine- and gastrin-mediated acid secretion. Adverse effects of antacid mixtures This inhibitory effect can be overcome, particularly Those that apply to individual antacids are described when gastrin levels are high, as occurs above but the following general points are also postprandially. In addition, tolerance may develop, relevant. probably as a result of down-regulation of Some antacid mixtures contain sodium, which receptors. Peptic ulcer healing with H2 receptor may not be readily apparent from the name of the antagonists correlates best with suppression of preparation. Thus they may be dangerous for nocturnal acid secretion and these drugs are often patients with cardiac or renal disease. For example, given in a single evening dose. The usual ulcer- a 10 ml dose of magnesium carbonate mixture or of healing course is 8 weeks. magnesium trisilicate mixture contains about 6 mmol of sodium (normal daily dietary intake is Cimetidine approx. 120 mmol of sodium). Aluminium- and raagnes/wra-containing antacids Cimetidine was the first H2 receptor antagonist to may interfere with the absorption of other drugs by be used in clinical practice. It is rapidly absorbed binding with them or by altering gastrointestinal from the gastrointestinal tract and its plasma t1/2 is 2 h. pH or transit time. Reduced biological availability of iron, digoxin, warfarin and some NSAIDs has Adverse effects and interactions are few in short- been ascribed to this type of interaction. It is term use. Minor complaints include headache, probably advisable not to co-administer antacids dizziness, constipation, diarrhoea, tiredness and with drugs that are intended for systemic effect by muscular pain. Bradycardia and cardiac conduction the oral route. defects may also occur. Cimetidine is a weak antiandrogen, and may cause gynaecomastia and sexual dysfunction in males. In the elderly Choice and use of antacids particularly, it may cause CNS disturbances No single antacid is satisfactory for all circum- including lethargy, confusion and hallucinations. stances and mixtures are often used. They may Cimetidine inhibits cytochromes P450, in particular contain sodium bicarbonate for quickest effect, CYP 1A2 and CYP 3A4 and there is potential for 627
31 OESOPHAGUS, STOMACH AND DUODENUM increased effect from any drug with a low diffusion but becomes ionised in the acid milieu therapeutic index that is inactivated by these around the secretory canaliculus, where it is isoenzymes, e.g. warfarin, phenytoin, lidocaine, trapped and concentrated. In this form it is a highly propranolol, 5-fluorouracil and theophylline. chemically reactive species which binds to sulphydryl groups on Na + /K + ATPase. This irreversibly inactivates the enzyme causing profound inhibition Ranitidine, famotidine, nizatidine of acid secretion: a single 20 mg dose reduces gastric acid output by 90% over 24 h. Omeprazole is The modes of action, uses and therapeutic efficacy degraded at low pH and must be given in enteric- of these histamine H2 receptor antagonists are coated granules. Systemic availability increases with essentially those of cimetidine. Differences from dose and also with time, due to decreased inactivation cimetidine lie chiefly in dose and profile of unwanted of the prodrug as gastric acidity is reduced. effects. Ranitidine (t1/2 2 h) is 50%, famotidine (tV2 3 h) is 25% and nizatidine (t1/2 1 h) is 10% metabolised, in each case the remainder being excreted unchanged Adverse effects include nausea, headache, diar- by the kidney. rhoea, constipation and rash but are uncommon. The drugs are well tolerated but headache, Omeprazole inhibits the 2C family of the cytochrome dizziness, reversible confusion, constipation and P450 system, decreasing the metabolism of warfarin, diarrhoea may occur. In addition, urticaria, sweat- diazepam, carbamazepine and phenytoin, and ing and somnolence are reported with nizatidine. enhancing the action of these drugs (but inhibition The drugs do not inhibit hepatic microsomal is less than with cimetidine). enzymes and do not block androgen receptors. Concern has arisen that long-term use of powerful H2 receptor antagonists are available as over-the- antisecretory drugs may increase the risk of gastric counter preparations in the UK, albeit of lower neoplasia. Differing mechanisms have been proposed. strength than those available on prescription. The When acid secretion is suppressed, gastrin is released potential danger is that patients with serious patho- as a normal homeostatic response. Gastrin stimulates logy such as gastric carcinoma will self-medicate, growth of the gastric epithelium, including the allowing their disease to progress. Pharmacists are enterochromaffin cells which could transform into trained to advise patients to consult their doctor if carcinoid tumours; some rats developed these they have recurrent symptoms or other worrying tumours after prolonged exposure to high doses of manifestations such as weight loss. omeprazole. Furthermore, prolonged hypochlorhy- dria favours colonisation of the stomach by bacteria, which have the potential to convert ingested nitrates Proton pump inhibitors into carcinogenic nitrosamines. Surveillance studies to date have not provided evidence that this is a real (PPIs) hazard, and it is certainly unlikely with short-term use, e.g. up to 8 weeks. This class of drugs inactivates the H + /K + ATPase Other theoretical concerns relate to reduced (proton pump) in parietal cells, which is the final absorption of vitamin B12 and increased susceptibility common pathway for acid production. Omeprazole to gastrointestinal infections as a result of prolonged was the first preparation to be used in clinical hypochlorhydria. There is as yet no real evidence practice and esomeprazole, lansoprazole, pantoprazole for these being a clinical problem. and rabeprazole were subsequently introduced. All Proton pump inhibitors are widely used and are similar in efficacy and mode of action. possible adverse effects from very long term exposure, e.g. resistant symptoms from gastro- oesophageal reflux disease, are not yet known. Omeprazole Antimuscarinic drugs, e.g. pirenzepine, formerly Omeprazole is a prodrug, in common with all PPIs. widely used to suppress acid secretion, are now It enters the parietal cell from the blood by nonionic obsolete. 628
ENHANCING MUCOSAL RESISTANCE 11 and protectively to the ulcer base. It also binds to Enhancing mucosal and inactivates pepsin and bile acids. Sucralfate has negligible acid neutralising capacity, which explains resistance why it is ineffective in gastro-oesophageal reflux disease (see below). Its therapeutic efficacy in healing Drugs can increase mucosal resistance by: gastric and duodenal ulcers is approximately equal to that of the histamine H2 receptor antagonists. • protecting the base of a peptic ulcer (bismuth chelate, sucralfate) Adverse effects. Sucralfate may cause constipation • 'cytoprotection' (misoprostol). but is otherwise well tolerated. The concentration of aluminium in the plasma may be elevated but this Bismuth chelate appears to be a problem only with long-term use by Tripotassium dicitratobismuthate, bismuth subcitrate, uraemic patients, especially those undergoing (De-Nol) This substance was originally thought to dialysis. As the drug is effective only in acid act mainly by chelating with protein in the ulcer conditions, an antacid should not be taken 30 min base to form a coating, which protects the ulcer before or after a dose of sucralfate. Sucralfate from the adverse influences of acid, pepsin and bile. interferes with absorption of co-administered Subsequently, bismuth chelate was found to possess ciprofloxacin, theophylline, digoxin, phenytoin and an additional valuable action, namely activity against amitriptyline, possibly by binding due to its strong Helicobacter pylori, especially when combined with negative charge. an antimicrobial (see below). Bismuth chelate is used for benign gastric and Misoprostol duodenal ulcer and has a therapeutic efficacy Endogenous prostaglandins contribute importantly approximately equivalent to histamine H2 receptor to the integrity of the gastrointestinal mucosa by a antagonists. Ulcers remain healed for longer after number of related mechanisms (see Chapter 15). bismuth chelate than after the histamine H2 Misoprostol is a synthetic analogue of prostaglandin receptor antagonists, and this may relate to the Ej which protects against the formation of gastric ability of the former but not the latter to eradicate and duodenal ulcers in patients who are taking Helicobacter pylori. NSAIDs, presumably by these 'cytoprotective' mechanisms (see below). The drug also heals Adverse effects. Bismuth chelate, particularly as a chronic gastric and duodenal ulcers unrelated to liquid formulation, darkens the tongue, teeth and NSAIDs, but here the mechanism appears related to stool; the effect is less likely with the tablet, which is its antisecretory properties rather than to a cyto- thus more acceptable. There is little systemic protective action. absorption of bismuth from the chelated preparation, but bismuth is excreted by the kidney and it is Adverse effects. Diarrhoea and abdominal pain, prudent to avoid giving the drug to patients with transient and dose-related, are the commonest. impaired renal function. Urinary elimination Women may experience gynaecological disturbances continues for months after bismuth is discontinued. such as vaginal spotting and dysmenorrhoea; the drug is contraindicated in pregnancy or for women Sucralfate planning to become pregnant, for the products of conception may be aborted. Indeed, women have This is a complex salt of sucrose sulphate and resorted to using misoprostol (illicitly) as an aluminium hydroxide. In the acid environment of abortifacient in parts of the world where provision the stomach, the aluminium moiety is released so of contraceptive services is poor.1 that the compound develops a strong negative charge and binds to positively charged protein Liquorice derivatives (carbenoxolone) and degly- molecules that transude from damaged mucosa. cyrrhizinised liquorice, formerly used for peptic The result is a viscous paste that adheres selectively ulcer, are now obsolete. 629
31 OESOPHAGUS, STOMACH AND DUODENUM HELICOBACTER PYLORI ERADICATION TREATMENT OF HELICOBACTER PYLORI INFECTION Colonisation of the stomach with Helicobacter pylori is seen in virtually all patients with duodenal ulcer Successful eradication of Helicobacter pylori infection and 70-80% of those with gastric ulcers;2 this close usually results in long-term remission of the ulcer association is not seen in ulcers complicating because reinfection rates are low, particularly in NSAID therapy. In patients with duodenal ulcer areas of low endemicity. The organism is sensitive there is an associated antral gastritis whereas with to metronidazole, amoxicillin, clarithromycin, tetracycline gastric ulcer, gastritis is more diffuse throughout and bismuth salts, but eradication is difficult because the stomach. It is not known how Helicobacter pylori of its location below the mucus layer. Numerous predisposes to peptic ulceration, but chronic regimens have been proposed but none can offer infection with the organism, which establishes itself more than 80-90% efficacy (see also Table 11.1). within and below the mucus layer, is associated Therapy with one or two drugs is ineffective and with hypergastrinaemia and hyperacidity. The current regimens comprise three or four drugs. The hypergastrinaemia may result from reduced antral efficacy of antimicrobials can be increased con- production of somatostatin, which inhibits gastrin siderably by mucosal protection with a proton formation. Production of ammonia by urease by pump inhibitor, ranitidine or bismuth citrate (in the Helicobacter pylori may also play a role. With more latter case, in addition to its antimicrobial action). It extensive gastritis there is a reduction in parietal is important that treatment be as short, simple and cell mass and decreased acid secretion. Although all palatable as possible to encourage compliance, patients colonised with Helicobacter pylori develop because failure to complete the course encourages gastritis, only about 20% have ulcers or other lesions, antimicrobial resistance. Regimens containing and host factors are likely to be important. bismuth compounds as the only mucosal protectant Other possible effects of long-term infection with are less popular because they involve dosing four Helicobacter pylori include gastric carcinoma and times daily and are unpalatable to some. Effective lymphoma, particularly of the MALT (Mucosa regimens include: Associated Lymphoid Tissue) type. Eradication of the organism may lead to resolution of the latter • Proton pump inhibitor or ranitidine bismuth tumour. citrate3 (as Ranitidine Bismutrex) b.d. + Helicobacter pylori can be detected histologically clarithromycin 500 mg b.d. + amoxycillin Ig b.d. from antral biopsies obtained at gastroscopy, or for 7 days. biochemically. In the CLO test an endoscopic • Proton pump inhibitor or ranitidine bismuth biopsy specimen is incubated in a medium contain- citrate b.d. + clarithromycin 500 mg b.d. + ing urea and an indicator which chages colour if metronidazole 400 mg b.d. for 7 days. ammonia is produced. Proton pump inhibitors and Metronidazole resistance is a particular problem, bismuth compounds suppress but do not eradicate with a prevalence of up to 80% in some countries, Helicobacter pylori, and results may be falsely nega- particularly sub-Saharan Africa. It probably reflects tive if any of these tests is carried out within a extensive use of this antimicrobial for pelvic and month of taking these drugs. other infections, and is more common in women. 1 Resistance to clarithromycin is less common but it Gonzales C H et al 1998 Lancet 351:1624-1627. 2 may reach 10-15% of some communities. First reported by B Marshall and R Warren (Lancet 19831: 1273 and 1273-1274). The association was initially greeted It is not usually necessary to check for successful with widespread disbelief and sometimes hostility. Warren eradication unless the patient continues to have reports: "I was just doing my day-to-day pathology. I like symptoms. Under these circumstances the urea looking for funny things and this day, I saw a funny thing breath test4 is a useful noninvasive technique. and started wondering." In a gastric biopsy he saw "numerous bacteria in close contact with the surface epithelium ... They appeared to be actively growing and not 3 a contaminant." The story of Helicobacter pylori had begun. A complex of ranitidine with bismuth and citrate from (Lancet 2001 345: 694.) which ranitidine and bismuth are released. 630
NSAIDs AND THE STOMACH 11 Antimicrobial regimens used in eradication are MECHANISM OF GASTRIC MUCOSAL not without risk for cases of antibiotic-associated TOXICITY (pseudomembraneous) colitis have resulted. Aspirin and the other NSAIDs exert their anti- inflammatory effect through inhibition of the enzyme A cautionary note. Helicobacter pylori infection is cyclo-oxygenase (COX) (see Chapter 15). This enzyme acquired in early childhood, probably by the is present in two isoforms. COX-1 is involved in the faecal-oral route. The prevailing wisdom that 'the formation of prostaglandins, which protect the only good Helicobacter pylori is a dead Helicobacter gastric mucosa, while COX-2 is induced in response pylori' is now tempered by the possibility that the to inflammatory stimuli and is involved in the organism (or at least certain subtypes) may perform formation of cell-damaging cytokines. Most NSAIDs a useful function. This view is based on evidence inhibit both isoforms so the beneficial anti-inflam- that gastro-oesophageal reflux symptoms may matory effect is offset by the potential for gastric sometimes be worsened, and response to proton mucosal injury by depletion of prostaglandins. The pump inhibitors diminished, after eradication of latter leads to deleterious effects including reduction Helicobacter pylori. More worrying is the increased of mucosal blood flow and a reduced capacity to incidence of carcinoma at the gastro-oesophageal secrete protective mucus and bicarbonate ion. Aspirin junction which correlates epidemiologically with is particularly potent in this respect, perhaps due to reduced prevalence of Helicobacter pylori infection. the fact that it inhibits COX irreversibly, unlike the other NSAIDs where inhibition is reversible and In summary, Helicobacter pylori eradication therapy concentration dependent. Gastrointestinal bleeding is: can complicate use of low-dose aspirin. • indicated for gastric and duodenal ulcer not NSAIDs are weak organic acids and the acid associated with NSAID use, and gastric milieu of the stomach facilitates their nonionic lymphoma (especially MALT lymphoma), diffusion into gastric mucosal cells. Here the • not indicated for reflux oesophagitis, and neutral intracellular pH causes the drugs to become • equivocal in value for nonulcer dyspepsia, after ionised and they accumulate in the mucosa because incidental detection, and for prophylaxis of they cannot diffuse out in this form. Nabumetone gastric cancer. differs from other NSAIDs in that it is nonacidic, and therefore is not so avidly concentrated in gastric mucosa, which may partially explain why NSAIDs and the stomach this drug has less tendency to produce peptic ulceration. Some 500 million prescriptions for NSAIDs are written each year in the UK, and 10-15% of patients TREATMENT OF NSAID-INDUCED develop dyspepsia whilst taking these drugs. PEPTIC ULCERS Gastric erosions develop in up to 80%, but these are usually self-limiting. Gastric or duodenal ulcers Withdrawal of NSAIDs and acid suppression with occur in 1-5%. The incidence increases sharply with standard doses of antisecretory drugs will allow age in those over 60, and the risk of ulcers and their prompt resolution of these ulcers, which should not complications is doubled in patients over 75 and recur unless the drugs are resumed. Many patients those with cardiac failure or a history of peptic are prescribed NSAIDs inappropriately when their ulceration or bleeding. Ibuprofen may be less prone symptoms could be controlled by paracetamol or to cause these problems than other NSAIDs. by local treatment. Topical NSAID creams applied over an affected joint may be helpful, but peptic ulcers can complicate therapy with NSAIDs 4 The urea breath test measures radiolabelled CO2 in expired administered as rectal suppositories. Prodrugs such air after ingestion of labelled urea, exploiting the fact that the as sulindac, which are metabolised to form anti- organism produces urease and can convert urea to ammonia. inflammatory derivatives, can also produce ulcers. 631
31 OESOPHAGUS, STOMACH AND DUODENUM PREVENTION OF NSAID-INDUCED correlate with symptoms. The other main com- PEPTIC ULCERS plications are acute or chronic bleeding, oesophageal stricture and Barrett's metaplasia, which carries an This is particularly relevant for the elderly and increased risk of oesophageal carcinoma. There is other high-risk patients (see above). The synthetic no evidence that Helicobacter pylori is involved in prostaglandin misoprostol in a dose of 800 micro- pathogenesis of GORD. grams daily in 2-4t divided doses reduces the incidence of gastric and duodenal ulceration and their complications by about 40% when co- MANAGEMENT OF GORD administered with NSAIDs. Abdominal pain and diarrhoea limit its use; halving the dose reduces the Patients should be advised to lose weight, if it is incidence of adverse effects, but at the expense of a appropriate, and smokers to quit, as nicotine relaxes reduced protective effect. The proton pump the gastro-oesophageal sphincter. Raising the head inhibitors, in healing doses, are similar in efficacy to of the bed by 15-20 cm helps to diminish nocturnal the higher dose of misoprostol. H2 receptor reflux. Patients should be advised to avoid heavy antagonists offer some protection against duodenal meals and situations predisposing to reflux (such as ulcers but none against gastric ulcers. lying down or prolonged bending within Evidence for the benefit of Helicobacter pylori 3 hours of a meal). Drugs that encourage reflux eradication is controversial. should be avoided if possible, e.g. those with antimuscarinic activity (tricyclic antidepressants), Selective inhibition of COX-2 has the objective of smooth muscle relaxants (nitrates and calcium preserving anti-inflammatory activity whilst channel blockers) or theophylline compounds. avoiding gastric mucosal toxicity. Rofecoxib, celecoxib and meloxicam vary in their selectivity for COX-2. Antacids are helpful in controlling mild reflux The incidence of peptic ulcers and their com- symptoms when taken regularly after meals with plications with rofecoxib is similar to that seen additional doses as needed. Preparations in which when proton pump inhibitors are co-administered an antacid is combined with alginate are particularly with nonselective NSAIDs. The adverse effect useful: the alginate produces a viscous floating gel, profile of these drugs remains fully to be evaluated. which blocks reflux and protectively coats the oesophagus. Acid suppression. H2-receptor antagonists in Gastro-oesophageal reflux conventional peptic ulcer healing doses are useful disease (GORD) in the short-term management of mild oesophagitis but are less effective in the longer term and on Transient gastro-oesophageal reflux occurs in almost maintenance treatment only one-third of patients everybody and it is only when episodes become will be in remission. Proton pump inhibitors are frequent, with prolonged exposure of the oesophageal currently the most effective drugs. Conventional mucosa to acid and pepsin, that problems develop. ulcer healing doses rapidly relieve reflux symptoms Factors contributing to pathological reflux include: and heal oesophagitis in the majority of patients. Sometimes higher doses are needed, particularly • Incompetence of the gastro-oesophageal for maintenance therapy. Over three-quarters of sphincter patients will still be in remission after 12 months' • Delayed oesophageal clearance of acid treatment with a proton pump inhibitor. • Delayed gastric emptying. The commonest symptom is heartburn, and as Pro-kinetic drugs. The antidopaminergic compounds many as 15% of people in Western populations metoclopramide and domperidone can alleviate GORD experience this regularly. Approximately 50% will symptoms by increasing the tone of the gastro- have oesophagitis, the severity of which does not oesophageal sphincter and stimulating gastric 632
VOM ITI NG 11 emptying (actions that are additional to their herbs which are commonly included in liqueurs central action as antiemetics, see below). and (in nonalcoholic solutions) for babies. The problem is not new. The Roman Emperor Claudius Approaches to treatment. The 'step-up' approach (AD 10-54) planned an edict to legitimise the involves starting with lifestyle modification (above) breaking of wind at table, either silently or noisily, and an antacid, progressing as necessary to a H2 after hearing about a man who was so modest that receptor antagonist and prokinetic drug, and a he endangered his health by an attempt to restrain proton pump inhibitor only in those who fail to himself [Suetonius (trans) R Graves]. respond to less powerful measures. The converse Bitters are substances taken before meals to ('step down') approach advocates rapid control of improve appetite. They have not been scientifically symptoms with a proton pump inhibitor followed investigated. They include gentian, nux vomica and by substitution with less potent treatments, which quinine. Preparations can be found in formularies are titrated against symptoms. Evidence suggests and at wine merchants (Dubonnet, Campari). that this latter approach may be more cost-effective. The incidence of Helicobacter pylori colonisation in patients with nonulcer dyspepsia is not sign- ificantly different from that in the general population and eradication of the organism provides, at best, Other oesophageal only one-quarter of patients with prolonged conditions symptomatic improvement (a proportion that is similar to the placebo response for this condition). Diffuse oesophageal spasm may be helped by isosorbide dinitrate 5 mg sublingually or 10 mg by mouth, or by nifedipine 10 mg sublingually or swallowed. Vomiting Achalasia, in which there is failure of relaxation of the lower oesophageal sphincter, may be relieved If the cause of vomiting cannot be promptly by balloon dilatation or by injection of botulinum removed, it can be prevented, or at least suppressed toxin at the gastro-oesophageal junction. by drugs. The pharmacology of vomiting was little studied until the world war of 1939-45, when motion NONULCER DYSPEPSIA sickness attained military importance as a possible Many patients with nonulcer dyspepsia have handicap for sea landings made in the face of abnormalities of gastric emptying and increased resistance. The British military authorities and the pain perception in the gastrointestinal tract, Medical Research Council therefore organised an suggesting that the condition is part of the investigation. Whenever there was a prospect of spectrum of irritable bowel syndrome (see Chapter sufficiently rough weather, about 70 soldiers were 32). Patients with predominant epigastric pain or sent to sea in small ships, again and again, after reflux symptoms may improve with simple antacids being dosed with a drug or a dummy tablet and taken as needed. More severe symptoms may having had their mouths inspected to detect require antisecretory drugs, particularly a proton noncompliance. The ships returned to land when pump inhibitor, although the response rate is lower up to 40% of the soldiers vomited. 'On the whole (40-50%) than in patients with documented the men enjoyed their trips;' some of them, however, pathology. Where the main symptom is bloating, a being soldiers, thought the tablets were given in prokinetic agent (metoclopramide or domperidone, order to make them vomit and some 'believed see below) is preferred. firmly in the efficacy of the dummy tablets'. It was Flatulent patients may benefit from carminatives, concluded that, of the remedies tested, hyoscine substances which are held to assist expulsion of gas (0.6 mg or 1.2 mg) was the most effective.5 from the stomach and intestines. Examples are: 5 dimethicone, peppermint, dill, anise and other Holling H E et al 1944 Lancet 1:127. 633
11 OESOPHAGUS, STOMACH AND DUODENUM SOME PHYSIOLOGY TABLE 31.1 Classification of antiemesis drugs Useful vomiting occurs as a protective mechanism Drug Site of action/comment for eliminating irritant or harmful substances from Dopamine D2 receptor the upper gastrointestinal tract. The act of emesis is antagonists controlled by the vomiting centre in the medulla. domperidone CTZ and gut metoclopramide CTZ and gut Close to it lie other visceral centres, including those haloperidol CTZ for respiration, salivation and vascular control, phenothiazines, e.g. Vomiting centre and CTZ which give rise to the prodromal sensations of chlorpromazine, prochlorperazine, vomiting. These centres are not anatomically discrete thiethylperazine but comprise interconnected networks within the 5-HT3 receptor antagonists nucleus of the tractus solitarius). The vomiting centre ondansetron CTZ and gut granisetron does not initiate, but rather it coordinates the act of tropisetron emesis on receiving stimuli from various sources, Antimuscarinics namely, hyoscine and some drugs also Vomiting centre and gut classed as histamine H, receptor • The chemoreceptor trigger zone (CTZ), a nearby antagonists, e.g. cyclizine, dimenhydrinate, promethazine area that is extremely sensitive to the action of Other agents drugs and other chemicals corticosteroids (dexamethasone, Gut (vomiting due to • The vestibular system methylprednisolone) cytotoxics) cannabinoids (nabilone) • The periphery, e.g. distension or irritation of the benzodiazepines (lorazepam) gut, myocardial infarction, biliary or renal stone • Cortical centres. The vomiting centre and the nucleus of the and in the gastrointestinal tract. Phenothiazines tractus solitarius contain many muscarinic and butyrophenones owe their antiemetic efficacy cholinergic and histamine H1 receptors, and the CTZ to blockade of dopamine D2 receptors but they readily is rich in dopamine D2 receptors; drugs that block penetrate the brain and may produce unwanted these receptors are effective antiemetics. The extrapyramidal effects by blocking D2 receptors in precise role and location of 5-HT3 receptors (see the basal ganglia; many also have antimuscarinic ondansetron, below) in relation to emesis remains effects. to be defined but both central and peripheral mechanisms may be involved. Metoclopramide Metoclopramide acts centrally by blocking dopamine ANTIEMESIS DRUGS D2 receptors in the CTZ, and peripherally by These may be classified as shown in Table 31.1. enhancing the action of acetylcholine at muscarinic Antiemetics that act on the vomiting centre have nerve endings in the gut. It raises the tone of the antimuscarinic (their principal mode) and anti- lower oesophageal sphincter, relaxes the pyloric histaminic action (hyoscine, promethazine); they antrum and duodenal cap and increases peristalsis alleviate vomiting from any cause. In contrast, drugs and emptying of the upper gut. The peripheral that act on the CTZ (haloperidol, ondansetron) are actions are utilised to empty the stomach before effective only for vomiting mediated by stimulation emergency anaesthesia and in labour. If an opioid of the chemoreceptors (by morphine, digoxin, has been given, metoclopramide may fail to cytotoxics, uraemia). The most efficacious drugs act overcome the opioid-induced inhibition of gastric at more than one site (Table 31.1). emptying and thus the risk of vomiting and Antimuscarinic drugs (including those classed inhaling gastric contents remains. The direct effects primarily as histamine Hx receptor antagonists) are on the gut are antagonised by antimuscarinic drugs. described in Chapters 21 and 29. Drugs with The action of metoclopramide is terminated by antimuscarinic activity probably act both centrally metabolism in the liver (t1/2 4 h). 634
TREATMENT FORVARIOUS FORMS OF SICKNESS 31 Uses. Metoclopramide is used for nausea and injection or infusion immediately prior to cancer vomiting associated with gastrointestinal disorders, chemotherapy (notably with cisplatin), followed by and with cytotoxic drugs and radiotherapy. It is oral administration for up to 5 days (t1/2 5 h). The also an effective antiemetic in migraine and is used drug appears to be well tolerated but constipation, as a prokinetic agent (see above). headache and a feeling of flushing in the head and epigastrium may occur. Gmnisetron and tropisetron Adverse reactions are characteristic of dopamine are similar. receptor antagonists and include extrapyramidal dystonia (torticollis, facial spasms, trismus, oculogyric Nabilone is a synthetic cannabinoid and has crises) which occurs more commonly in children properties similar to tetrahydrocannabinol (the and young adults, and in those who are concurrently active constituent of marijuana) which has an receiving other dopamine receptor antagonists, e.g. antiemetic action. It is used to relieve nausea or phenothiazine drugs. The antimuscarinic drug, vomiting caused by cytotoxic drugs. Adverse effects benzatropine, given i.v., rapidly abolishes the include: somnolence, dry mouth, decreased appetite, reaction. Long-term use of metoclopramide may dizziness, euphoria, dysphoria, postural hypotension, cause tardive dyskinesia in the elderly. confusion and psychosis. These may be reduced if Metoclopramide stimulates prolactin release and prochlorperazine is given concomitantly. may cause gynaecomastia and lactation. Rest- lessness and diarrhoea may also occur. Domperidone is a selective dopamine D2 receptor Treatment for various antagonist; unlike metoclopramide it does not possess an acetylcholine-like effect. The t1/, is 7 h. forms of sickness Dopamine does not readily penetrate the blood-brain barrier; this does not limit its therapeutic efficacy, MOTION SICKNESS for the CTZ is functionally outwith the barrier, but there is less risk of adverse effects in the central Motion sickness is more easily prevented than nervous system. Domperidone is used for nausea or cured. It is due chiefly to overstimulation of the vomiting associated with gastrointestinal disorders vestibular apparatus (and does not occur if the and with cytotoxic and other drug treatment. It can labyrinth is destroyed). Other factors also contribute. also be helpful in management of bloating in Visually, a moving horizon can be most disturbing, patients with nonulcer dyspepsia (see above). It as can the sensations induced by the gravitational may cause gynaecomastia and galactorrhoea. inertia of a full stomach when the body is in vertical movement. That the environment, whether close Ondansetron is a selective 5-HT3 receptor antagonist. and smelly or open and vivifying, is important, is a Drugs with this activity appear to be highly effective matter of common experience amongst all who against nausea and vomiting induced by cytotoxic have been on a rough sea. Psychological factors, agents and radiotherapy. Evidence suggests that including observation of the fate of one's companions, such anticancer treatment releases serotonin (5-HT) are also important. Tolerance to the motion occurs, from enterochromaffin cells in the gut mucosa generally over a period of days. (where resides > 80% of the serotonin in the body) Drugs that are used for motion sickness include which activates specific receptors in the gut and the antimuscarinic agents cinnarizine, cyclizine, central nervous system to cause emesis.6 The action dimenkydrinate, hyoscine and promethazine. of ondansetron is thus partly central and partly peripheral. Ondansetron may be given by i.v. For prophylaxis an antiemetic is best taken 1 h before exposure to the motion. About 70% protection may be expected by the right dose given at the right 6 Cubeddu L X et al 1990 New England Journal of Medicine time. Once motion sickness has started, oral 322:810. administration of drugs may fail, and the i.m., s.c. 635
31 OESOPHAGUS, STOMACH AND DUODENUM or rectal routes are required. Alternatively, hyoscine and routine prophylaxis seems warranted only where may be administered as a dermal patch, so avoiding the risk is high, e.g. those with a history of post- the enteral route. Prevention of symptoms may operative vomiting or of motion sickness, or where therefore be possible only at the expense of trouble- vomiting carries special hazard, e.g. eye surgery. some unwanted effects: sleepiness, dry mouth, blurred vision. VOMITING IN PREGNANCY This reaches a peak at 10-11 weeks and usually DRUG-INDUCED VOMITING resolves by 13-14 weeks of gestation. Nausea alone does not require treatment. Much can be achieved If reducing the dose or withdrawing the offending by reassurance that the problem is transient and a drug are not options then an attempt, often discussion of diet, e.g. taking food before getting up unsatisfactory, may be made to oppose it by another in the morning. Rarely, a decision is taken to use a drug. In general, chlorpromazine or another pheno- drug, and then a histamine H1 receptor antagonist thiazine or metodopramide is best. Opioid-induced or a phenothiazine, e.g. promethazine (see above) is vomiting responds to one of the drugs used for preferred. Although pyridoxine deficiency has not motion sickness (see above); cyclizine and morphine been shown to complicate simple pregnancy are combined as Cyclimorph. vomiting, it may occur in hyperemesis gravidarum which requires i.v. fluids and multivitamin supplement. VOMITING DUETO CYTOTOXIC DRUGS VERTIGO Prevention and alleviation of this distressing and often very severe symptom of some forms of cancer A great range of drugs has been recommended to treatment may allow an optimal chemotherapeutic treat vertigo and labyrinthine disorders but anti- regimen to be used, and avoid admitting the patient muscarinics and phenothiazines are generally to hospital. Cisplatin is notably emetic. Ondansetron preferred. Cyclizine or prochlorperazine may be (see above) is highly effective and dexamethasom is used to relieve an acute attack. Betahistine (a histamine also efficacious although its mode of action is analogue) is used in the hope of improving the unclear. Lorazepam, despite dose-limiting sedation blood circulation to the inner ear in Meniere's and dysphoria, is a useful adjunct and provides syndrome; also cinnarizine. amnesia which may limit the development of anticipatory vomiting. For severe vomiting due to cytotoxics, ondansetron plus dexamethasone with GUIDETO FURTHER READING or without lorazepam (all given i.v.) is the most effective combination and is well tolerated. Agreus L, Talley N 1997 Challenges in managing Metodopramide may be substituted for ondansetron dyspepsia in general practice. British Medical where a less emetic regimen is used, especially in Journal 315:1284-1288 older patients who are less susceptible to its Blaser M J 1998 Helicobacter pylori and gastric extrapyramidal reactions. diseases. British Medical Journal 316:1507-1510 Cohen S, Parkman H P 1995 Treatment of achalasia — from whalebone to botulinum toxin. New England VOMITING AFTER GENERAL Journal of Medicine 332: 815-816 ANAESTHESIA Costa S H, Vessey M P 1993 Misoprostol and illegal Postoperative vomiting is related to the duration of abortion in Rio de Janeiro, Brazil. Lancet 341: anaesthesia and has many causes. Metodopramide, a 1258-1261 5-HT3 receptor antagonist, e.g. ondansetron or a Danesh J, Pounder R E 2000 Eradication of Helicobacter butyrophenone, e.g. haloperidol or droperidol, may pylori and non-ulcer dyspepsia. Lancet 355: be used. The condition affects some 30% of patients 766-767 636
TREATMENT FORVARIOUS FORMS OF SICKNESS 31 De Boer W A, Tytgat G N J 2000 Treatment of Galmiche J P et al 1998 Treatment of gastro- Helicobacter pylori infection. British Medical Journal oesophageal reflux disease in adults. British 320: 31-34 Medical Journal 316:1720-1723 Fisher R S, Parkman H P 1998 Management of Grunberg S M, Hesketh P J 1994 Control of nonulcer dyspepsia. New England Journal of chemotherapy-induced emesis. New England Medicine 339:1376-1381 Journal of Medicine 329:1790 Fox J G, Wang T C 2001 Helicobacter pylori — not a Mittal R K, Balaban D H 1997 The esophagogastric good bug after all. New England Journal of junction. New England Journal of Medicine 336: Medicine 345: 829-832 924-932 637

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