Devinder Singh Bansi, John Louis-Auguste
Synopsis
‘Dyspepsia’ is a non-specific term which encompasses a number of symptoms attributable to the upper gastrointestinal (GI) tract, and may include anything from acid reflux to abdominal bloating. Approximately one third of the population in Western societies experiences regular dyspepsia, although the majority self-medicate with over-the-counter anti-acid 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 non-ulcer dyspepsia. Finally, nausea and vomiting are deeply unpleasant sensations with a number of causes and, fortunately, a number of effective therapies.
The oesophagus in health and disease
The normal oesophagus effortlessly transfers food and drink from the benign environment of the mouth through the gate of the lower oesophageal sphincter into the harsh acidic environment of the stomach. Transient gastro-oesophageal reflux occurs in almost everybody and it is only when episodes become frequent, with prolonged exposure of the oesophageal mucosa to acid and pepsin, that problems develop.
The physiological lower oesophageal sphincter (LOS), normally located at the gastro-oesophageal junction at the level of the diaphragm, allows solid and liquid boluses to pass into the stomach while preventing acidic gastric contents refluxing into the oesophagus. Intrinsic tonic contraction of the LOS is interrupted by normal transient lower oesophageal relaxation as well as coordinated relaxation when swallowing is initiated. Numerous neurohumoral intermediaries are involved in these processes, including parasympathetic efferents, acetylcholine (Ach), γ-aminobutyric acid (GABA) and glutamate. The integrity of the sphincter can be compromised by the presence of a hiatus hernia, which disrupts its anatomical and physiological components.
Excessive or inappropriate relaxation of the LOS results in gastro-oesophageal reflux disease, oesophagitis and oesophageal ulceration, stricturing resulting in mechanical obstruction and sometimes a secondary oesophageal dysmotility and spasm. Reduced oesophageal clearance of acid may also contribute. In susceptible individuals, acid reflux triggers columnar metaplasia of the native squamous epithelium (also known as Barrett's oesophagus). This is a pre-malignant condition for oesophageal adenocarcinoma.
Oesophageal dysmotility tends to produce symptoms of dysphagia to both solids and liquids, as opposed to mechanical obstruction which results in dysphagia to solids unless very advanced. A high sphincter tone and uncoordinated oesophageal contractions can cause dysphagia and pain. Achalasia is a motility disorder of unknown aetiology characterised by oesophageal hypomotility, a hypertonic LOS and a failure of relaxation of the LOS.
Gastric acid secretion and mucosal protection
In the normal upper GI tract, the destructive effects of gastric hydrochloric acid are balanced by a variety of mucosal protective mechanisms. Duodenal and gastric ulceration results from an imbalance between these two opposing forces. Helicobacter pylori infection and use of non-steroidal anti-inflammatory drugs (NSAIDs) play an important role in upsetting this fine balance. Other digestive enzymes such as pepsinogen/pepsin also contribute to the gastric phase of digestion but are qualitatively of less importance.
Gastric acid secretion
Acid secretion by parietal cells in the gastric mucosa is regulated by four main neurohumoral mediators.
Gastrin
Gastrin is a peptide hormone secreted by neuroendocrine G cells in response to a variety of physical and neurohumoral stimuli such as gastric distension, the presence of amino acids, vagal stimulation and histamine. Gastrin passes into the portal circulation, where it activates gastrin receptors on the basolateral aspect of the parietal cell, stimulating acid secretion. This inhibits further gastrin release. Gastrin also stimulates histamine release from enterochromaffin-like cells (ECL) cells (see below).
Acetylcholine (ACh)
ACh, secreted by parasympathetic vagal efferents, activates muscarinic M3 receptors on parietal cells and also on mast cell-like histamine secreting cells in the gastric mucosa. Both of these actions result in acid secretion.
Histamine
Histamine is secreted by enterochromaffin-like cells (mast cell-like cells in the gastric mucosa) at a basal rate, and secretion is augmented by gastrin and ACh from parasympathetic stimulation. Histamine secreted into the portal circulation stimulates H2 receptors on parietal cells, promoting acid secretion.
Prostaglandins
Locally produced prostaglandins E2 and I2 inhibit parietal cell acid secretion. Prostaglandins are produced by the cyclo-oxygenase enzyme. In the stomach, these prostaglandins are produced by the constitutively expressed COX-1 enzyme isoform.
The parietal cell integrates these pro- and anti-secretory signals. The final common pathway for acid secretion is the H+/K+-ATPase (the ‘proton pump’) located on the apical aspect of the parietal cell, which secretes hydrogen ions into the gastric lumen.
Mucosal protective mechanisms
Mucus and bicarbonate is secreted by cells in the gastric and duodenal mucosa and provides a protective relatively alkaline physical barrier against the otherwise destructive intragastric environment. Secretion is promoted by prostaglandins, which also inhibit gastric acid secretion. Numerous lifestyle factors adversely affect the mucosal barrier, including smoking and alcohol.
Helicobacter pylori (H. pylori): an occasionally silent killer
It is now known that a large majority of benign gastric and duodenal ulceration is due to H. pylori infection (following Marshall and Warren's Nobel prize-winning experiments1,2); most of the remainder can be attributed to NSAID use. Colonisation of the stomach with H. pylori is seen in virtually all patients with a duodenal ulcer and in 70–80% of those with gastric ulcers. H. pylori appears to stimulate increased acid secretion. All patients colonised with H. pylori develop gastritis, but only about 20% have ulcers or other lesions. As yet incompletely understood host factors and differences in strain of the organism are likely to explain this discrepancy.
H. pylori infection is carcinogenic and is the leading cause of gastric carcinoma. It is also highly associated with gastric MALT lymphoma. Eradication of the organism can lead to regression and even resolution of this latter malignancy.
Somewhat counterintuitively, H. pylori infection is not a cause of acid reflux disease, and in fact its eradication may precipitate or exacerbate acid reflux. Indeed, the recent surge in oeosphageal adenocarcinoma incidence in the West has been blamed by many on the now commonplace practice of searching for and eradicating H. pylori, although this has conversely resulted in a fall in the incidence of gastric cancer.
NSAIDs: enemies of the gut
Some 500 million prescriptions for NSAIDs are written each year in the UK, and 10–15% of patients develop dyspepsia while taking these drugs. Gastric erosions develop in up to 80%, but these are usually self-limiting. Gastric or duodenal ulcers occur in 1–5%. The incidence increases sharply with age in those over 60 years, and the risk of ulcers and their complications is doubled in patients aged more than 75 years and those with cardiac failure or a history of peptic ulceration or bleeding. All NSAIDs are ulcerogenic, but ibuprofen is less prone to cause these problems than other non-selective NSAIDs.
NSAIDs are weak organic acids and the acid milieu of the stomach facilitates their non-ionic diffusion into gastric mucosal cells. Here the neutral intracellular pH causes the drugs to become ionised and trapped in the mucosa because they cannot diffuse out in this form.
Aspirin and the other NSAIDs inhibit cyclo-oxygenase (COX) (see Ch. 16). In the stomach, the constitutively expressed COX-1 isoform is responsible for the production of the gastroprotective prostaglandins E2 and I2 (see above). Inhibition of the inducible COX-2 isoform (which is normally up-regulated in activated inflammatory cells) is responsible for NSAIDs’ anti-inflammatory properties. Most NSAIDs inhibit both isoforms unselectively, so the beneficial anti-inflammatory effect is offset by the potential for mucosal injury by depletion of protective prostaglandins. Aspirin is particularly potent in this respect, perhaps because it inhibits COX irreversibly, unlike the other NSAIDs where inhibition is reversible and concentration dependent.
Selective COX-2 inhibitors represent an attempt to provide beneficial anti-inflammatory effects without promoting ulceration. Unfortunately, there is evidence that unopposed COX-2 inhibition results in an increased risk of thrombotic events (including myocardial infarction and stroke); the UK Committee on Safety of Medicines therefore counsels against their use in preference to non-selective NSAIDs in the absence of a compelling indication, and cardiovascular risk should be assessed.
Drugs affecting oesophageal motility and the lower oesophageal sphincter
The D2 agonist drugs domperidone and metoclopramide (see below) can have a beneficial effect on reflux symptoms, firstly by enhancing gastric emptying and thus reducing the volume of acid available to reflux up the oesophagus, and secondly by increasing lower oesophageal sphincter (LOS) basal tone.
A number of drugs reduce tonic lower oesophageal sphincter tone or increase transient lower oesophageal sphincter relaxation and thus promote reflux, including nitrates, theophyllines, drugs with antimuscarinic activity or unwanted effects, and calcium channel antagonists. The pharmacology and pharmocokinetics of these drugs appear in detail elsewhere (see Index). These agents may occasionally be useful in alleviating the symptoms of oesophageal spasm, although the effect is usually disappointing. They are rarely potent enough to be of significant use in achalasia. Commonly used examples include nifedipine, diltiazem, and modified-release nitrates.
Newer therapies being explored in the treatment of GORD include GABA inhibition to reduce transient lower oesophageal sphincter relaxations. Baclofen (see p. 304) is clinically effective but has limiting CNS unwanted effects, and more tolerable compounds are being investigated. Other pharmacological targets which are showing potential in early clinical research include cannabinoid agonists.
Drugs to reduce or neutralise gastric acid
Proton pump inhibitors (PPIs)
Pharmacology
As can be deduced from the above, the most effective site of action for antisecretory drugs is the proton pump. Proton pump inhibitors are taken up by parietal cells from the portal circulation and are then excreted into the acid milieu around the secretory canaliculus. The resulting ionised form binds irreversibly to the proton pump, resulting in virtual total inhibition of acid secretion (Fig 32.1).
Fig. 32.1 Secretion of acid by the parietal cell.
Pharmacokinetics
PPIs are available in oral and intravenous formulations. Oral PPIs are degraded at low pH and must be given in enteric-coated forms. Systemic availability increases with dose and also with time, owing to decreased inactivation of the prodrug as gastric acidity is reduced. Maximum efficacy occurs after up to 5 days of therapy. Uninhibited Na+/K+-ATPase will regenerate when the PPI is discontinued; this may take 2–3 days
Adverse reactions and interactions
PPIs are as a rule well tolerated and serious adverse effects are unusual. Given their mechanism of action, there are theoretical concerns about cancer (due to the stimulatory effect of the hypergastrinaemia resulting from the loss of negative feedback), mineral deficiencies (due to loss of acid-related absorption of iron, calcium and B12, for example) and enteric infections (due to the loss of the antibacterial properties of a strongly acidic environment). Although an increased incidence of osteoporotic fractures and Clostridium difficile (C. diff) colitis has been noted in some observational studies, there has been no good evidence that these risks are significant, even after almost 20 years of clinical experience.
Examples of PPIs are omeprazole (10–20 mg daily), lansoprazole (15–30 mg daily) and pantoprazole. All are similar in pharmacokinetics, efficacy and adverse effect profile.
H2 receptor antagonists (H2RAs)
Pharmacology
H2RAs are less potent than the PPIs, as alternative pathways of parietal cell activation remain uninhibited. They competitively inhibit histamine binding at H2 receptors on the basolateral aspect of parietal cells, resulting in a reduction of gastric acid secretion. The inhibitory effect can be overcome with high gastrin levels, as occurs postprandially. Tolerance may develop, probably due to down-regulation of receptors.
Pharmacokinetics and dosage
H2RAs are given orally and are well absorbed. Since there is anecdotal evidence that peptic ulcer healing with H2-receptor antagonists correlates best with suppression of nocturnal acid secretion, many prefer to give these drugs as a single evening dose (e.g. ranitidine 150–300 mg).
Adverse effects and interactions
H2RAs are generally well tolerated. Adverse effects and interactions are few with short-term use. Cimetidine is a weak anti-androgen, and may cause gynaecomastia and sexual dysfunction in males. Cimetidine inhibits cytochromes P450 and there is potential for increased effect from any drug with a low therapeutic index that is inactivated by these isoenzymes, e.g. warfarin, phenytoin. Ranitidine and famotidine avoid these unwanted effects.
H2RAs are available as over-the-counter preparations in the UK, albeit of lower strength than those available on prescription. A potential danger is that patients with serious pathology such as gastric carcinoma will self-medicate, allowing their disease to progress. Pharmacists are trained to advise patients to consult their doctor if they have recurrent symptoms or other worrying manifestations such as weight loss.
Antacids
Antacids directly neutralise secreted acid and raise intragastric pH. They protect the gastric mucosa against acid (by neutralisation) and pepsin (which is inactive above pH 5, and which in addition is inactivated by aluminium and magnesium). Most commonly they are magnesium or aluminium salts. The hydroxide is the most common base, but trisilicate, carbonate and bicarbonate are also used.
Antacids relieve mild dyspeptic symptoms and they are taken intermittently when symptoms occur. Unwanted effects and inconvenience (see below) limit their regular use.
Individual antacids
Numerous antacid preparations are available over the counter. Some of the more common are described here.
Sodium bicarbonate reacts with acid and relieves pain within minutes. It is absorbed and causes a metabolic alkalosis. This is not of clinical significance if used on an intermittent, short-term basis but if given regularly over a period of time (days to weeks or longer) or in large doses will result in a potentially dangerous metabolic alkalosis. Sodium bicarbonate can release sufficient carbon dioxide in the stomach to cause discomfort and belching, which may have a beneficial psychotherapeutic effect.
Magnesium oxide and hydroxide react quickly, and magnesium trisilicate more slowly with gastric hydrochloric acid. All magnesium salts cause an osmotic diarrhoea.
Aluminium hydroxide reacts with hydrochloric acid to form aluminium chloride; this in turn reacts with intestinal secretions to produce insoluble salts, especially phosphate. It tends to constipate.
Some antacid mixtures contain sodium, which may not be readily apparent from the name of the preparation and thus may be dangerous for patients with cardiac, renal or liver disease. For example, a 10-mL dose of magnesium carbonate mixture or of magnesium trisilicate mixture contains about 6 mmol sodium (normal daily dietary intake is approximately 120 mmol sodium).
Aluminium- and magnesium-containing antacids may interfere with the absorption of other drugs by binding with them or by altering gastrointestinal pH or transit time. It is probably advisable not to co-administer antacids with drugs that are intended for systemic effect by the oral route.
Other targets for acid suppression
Gastrin inhibitors exist as experimental tools only as they are not effective acid suppressants. Antimuscarinic treatments for peptic ulceration are obsolete, but underlie the rationale for the surgical vagotomy which is now rarely performed.
Drugs to enhance mucosal protection
Sucralfate (SUCRose sulFATE and ALuminium hydroxide complex)
Sucralfate provides a physical barrier to gastric acid. It is activated by acid to produce a viscous gel, and will therefore be ineffective if given with therapies that inhibit acid release or raise gastric pH. In the acid environment of the stomach, the aluminium moiety is released so that the compound develops a strong negative charge and binds to positively charged protein molecules that transude from damaged mucosa. The result is a viscous paste that adheres selectively and protectively to the ulcer base. It also binds to and inactivates pepsin and bile acids, which has the added benefit of reducing mucus degradation. Its therapeutic efficacy in healing gastric and duodenal ulcers is approximately equal to that of the histamine H2-receptor antagonists.
Adverse effects and interactions
Sucralfate may cause constipation but is otherwise well tolerated. The concentration of aluminium in the plasma may be raised but this appears to be a problem only with long-term use by uraemic patients, especially those undergoing chronic intermittent haemodialysis. As the sucralfate is effective only in acid conditions, an antacid should not be taken 30 min before or after a dose. Sucralfate interferes with absorption of several drugs, including ciprofloxacin, theophylline, digoxin, phenytoin and amitriptyline, possibly by binding due to its strong negative charge.
Bismuth chelate (tripotassium dicitratobismuthate, bismuth sub-citrate)
This substance was thought to act by chelating with protein in the ulcer base to form a protective coating against adverse influences of acid, pepsin and bile. It may also promote protective prostaglandin, mucus and bicarbonate synthesis. Probably more importantly, bismuth chelate is now known to suppress Helicobacter pylori growth, especially when combined with an antimicrobial (see below). Bismuth chelate finds use for benign gastric and duodenal ulcer, and has a therapeutic efficacy approximately equivalent to that of histamine H2-receptor antagonists. Ulcers remain healed for a longer time after bismuth chelate than after H2-receptor antagonists, probably due to its ability to eradicate H. pylori.
Adverse effects
Bismuth chelate, particularly as a liquid formulation, darkens the tongue, teeth and stool; the effect is less likely with the tablet, which is thus more acceptable. Systemic absorption of bismuth from the chelated preparation is small but it does pass into the urine and it is prudent to avoid the drug for patients with impaired renal function. Urinary elimination continues for months after bismuth is discontinued. Bismuth toxicity causes encephalopathy.
Misoprostol
Misoprostol is a synthetic analogue of the protective prostaglandin E1 and therefore has the same antisecretory and cytoprotective properties. Traditionally it has been co-administered with NSAIDs to counteract the latter's effects on endogenous prostaglandin synthesis.
Adverse effects
Diarrhoea and abdominal pain, transient and dose related, are the commonest. Women may experience gynaecological disturbances such as vaginal spotting and dysmenorrhoea; the drug is contraindicated in pregnancy or for women planning to become pregnant, as the products of conception may be aborted. Indeed, women have resorted to using misoprostol (illicitly) as an abortifacient in parts of the world where provision of contraceptive services is poor.
Alginate
Alginate is a common and harmless component of antacids. It forms a viscous raft which forms a physical barrier between the gastric contents and the oesophageal, gastric and duodenal mucosa.
Pharmacological management
Gastro-oesophageal reflux
Lifestyle modification includes reduction in habits that promote acid reflux. Caffeine, alcohol, smoking and obesity relax the lower oesophageal sphincter and should be substituted or discontinued if possible. Avoid late evening meals to allow time for the stomach to empty before lying supine. Minor occasional symptoms are effectively managed with over-the-counter alginate-containing antacids.
The mainstay of medical treatment of acid reflux disease is the neutralisation or reduction of gastric acid production, and is therefore most easily achieved with PPIs, although H2RAs (e.g. ranitidine 150–300 mg daily) may be sufficient. Endoscopically proven oesophagitis may require 4–6 weeks of PPI therapy to heal (e.g. omeprazole 20 mg once daily; lansoprazole 30 mg once daily). If symptoms recur, the lowest effective antacid dose should be used to maintain remission. Doses may need to be doubled in severe or refractory cases. Prokinetic drugs such as domperidone 10–20 mg four times daily or metoclopramide 10 mg three times daily can improve symptoms, best in conjunction with an antisecretory agent.
Reflux-like symptoms unresponsive to PPI therapy are unlikely to be due to acid reflux and alternative causes require exploration. Biliary reflux can produce identical symptoms to acid reflux, and is unresponsive to PPI therapy due to its alkaline nature. It may respond to prokinetic therapy.
Eosinophilic oesophagitis
This is increasingly recognised as an important cause of oesophageal symptoms. It is a disorder of unknown aetiology characterised by substantial eosinophilic submucosal infiltrates in the absence of significant acid reflux and may be associated with other atopic conditions. Treatment options are limited, but topically applied corticosteroids (e.g. swallowing inhaled steroids) can be helpful in inducing and maintaining remission.
Oesophageal dysmotility
This can be notoriously difficult to treat satisfactorily. Prokinetic drugs can be tried in cases of confirmed oesophageal hypomotility; conversely, a calcium channel antagonist or a long-acting nitrate can be tried if the problem is predominantly one of spasm. Treatment of coexistent reflux may improve spasm secondary to reflux.
Pharmacological management of achalasia3 is best viewed as a temporary measure and drugs which reduce LOS tone rarely provide effective symptomatic improvement. Botulinum toxin, which inhibits cholinergic transmission by reducing ACh release from pre-synaptic motor neurones (see Ch. 22), can be injected endoscopically into the LOS and results in medium-term (3–6 months) relaxation of the LOS and symptomatic improvement. Endoscopic dilatation or surgical correction results in longer-term improvement. Relaxation of the LOS results in potentially free reflux of gastric acid contents and must therefore be accompanied by a PPI.
Peptic ulceration (Fig. 32.2)
For years, the treatment of peptic ulceration centred around measures to neutralise gastric acid, to inhibit its secretion or to enhance mucosal defences, but recognition of the central role of Helicobacter pylorirevolutionised the approach.
Fig. 32.2 Factors involved in pathogenesis of peptic ulcer.
Haemorrhage is one of the feared complications of peptic ulceration. The treatment of choice is endoscopic therapy, but PPIs, usually given as an intravenous infusion for 72 h to guarantee high and constant plasma levels, have a role as an adjunctive treatment. Reduction of gastric acid and raising of gastric pH results in clot stabilisation, thus promoting haemostasis.
Treatment of H. pylori
Consider H. pylori infection in all cases of peptic ulceration, as ulcer healing will be only transient if the organism remains. Indeed, eradication of H. pylori alone is generally sufficient to allow ulcer healing but is usually combined with a course of PPI therapy. Highly effective eradication regimens consist of a 1–2 week course of two antibiotics (typically amoxicillin with clarithromycin or clarithromycin with metronidazole) combined with a PPI. Treatment failures occur in ~ 5%, requiring more prolonged and complex regimens, usually containing bismuth chelate, although numerous antibacterial regimens have been shown to be effective.
Use of NSAIDs
If NSAID use is unavoidable in patients at high risk of developing serious side-effects, the risk of gastrotoxicity is reduced by about 40% with the co-administration of a PPI or misoprostol, although PPIs tend to be better tolerated. H2RAs do not offer effective protection against peptic ulceration in this scenario.
The use of COX-2 selective NSAIDs is limited by an increased incidence of adverse cardiovascular effects; furthermore the risk of gastrointestinal complications with a coxib alone is similar to that of a non-selective NSAID with a PPI. Although the use of COX-2 inhibitors is associated with a lower rate of unwanted gastrointestinal effects in the short term, the risk remains significantly greater than placebo. Concomitant use of aspirin negates the beneficial effect.
Ironically, there is increasing evidence that aspirin may reduce the incidence of adenocarcinoma in cases of Barrett's oesophagus. Clinical trials are assessing the risk/benefit ratio of this treatment.
Other disorders of acid secretion
The Zollinger–Ellison syndrome is a rare disorder due to a gastrin-secreting tumour which may arise anywhere in the GI tract, but most commonly in the pancreas, duodenum or stomach. High levels of serum gastrin cause hyperstimulation of parietal cells and hypersecretion of gastric acid, leading to multiple gastric and small bowel ulcers. Very high doses of PPI, up to 120 mg of omeprazole or greater per day, may be required to counteract this.
Nausea and vomiting
The physiology of nausea and vomiting is complex and incompletely understood. Vomiting can be protective, e.g. when it expels toxins (such as food poisoning and alcohol) from the GI tract. Suppressing nausea and vomiting is important in the management of other conditions including chemotherapy, general anaesthesia, morning sickness of pregnancy and when it accompanies other disease states (e.g. cardiac ischaemia, migraine).4
A number of stimuli are integrated in the chemoreceptor trigger zone (CTZ) and vomiting centre located in the floor of the fourth ventricle, including blood-borne molecules (especially toxins, peptides and drugs), sensory and psychological stimulation from higher centres, physical signals such as distension from the stomach and GI tract, other autonomic inputs, and vestibular feedback. Implicated neurotransmitter mediators include ACh (acting on muscarinic receptors), HA (H1 receptors), DA (D2 receptors), 5-HT (5-HT3 receptors) and Substance P (NK1 receptors).
Drugs used in nausea and vomiting
Antimuscarinics
Hyoscine is still the most common drug of its class used as an antiemetic. It suffers from all the side-effects of antimuscarinic agents.
H1-receptor antagonists
Examples include cyclizine, promethazine and cinnarizine. They do not have significant action at the CTZ. Drowsiness is a significant side-effect.
D2-receptor antagonists
These include the phenothiazines, also used as antipsychotics, such as chlorpromazine and haloperidol. They are powerful antiemetics but have relatively common and significant CNS side-effects including drowsiness and extrapyramidal movement disorders. Their pharmacology is discussed in detail in Chapter 20.
Metoclopramide and domperidone are D2-receptor antagonists without antipsychotic activity which have prokinetic properties, which can augment their antiemetic effect. They act centrally by blocking dopamine D2 receptors in the CTZ, and metoclopramide also acts peripherally by enhancing the action of acetylcholine at muscarinic nerve endings in the gut. They raise the tone of the lower oesophageal sphincter, relax the pyloric antrum and duodenal cap, and increase peristalsis and emptying of the upper gut. The peripheral actions are utilised to empty the stomach before emergency anaesthesia and in labour. Metoclopramide can cause the same side-effects as the phenothiazines. Domperidone does not readily cross the blood–brain barrier and consequently has fewer CNS effects.
5-HT3-receptor antagonists
Drugs such as ondansetron are powerful and well tolerated agents which act at the CTZ.
Corticosteroids
Corticosteroids are particularly useful in chemotherapy-associated nausea and vomiting. Their mechanism of action is unclear.
Newer therapies, at present only licensed in the context of chemotherapy-associated symptoms, include the cannabinoid receptor agonist nabilone and the neurokinin-1 antagonist aprepitant.
Choice of antiemetic
Muscarinic and H1 antagonists and the D2 antagonists domperidone and metoclopramide are useful for general use, including motion sickness. Promethazine is used frequently to treat morning sickness.
The 5-HT33 antagonists can be used in cases unresponsive to these first-line therapies, and are particularly useful in postoperative nausea and vomiting.
Corticosteroids are used primarily in the context of chemotherapy-associated nausea and vomiting, either alone or in conjunction with one or more of drugs such as a phenothiazine, 5-HT3 antagonist, nabilone or aprepitant.
Non-ulcer dyspepsia and functional disorders
Up to a third of patients presenting to secondary care with dyspeptic symptoms have no pathological cause identified and have ‘non-ulcer dyspepsia’. Management of these patients can be challenging and requires a comprehensive approach. Many patients with non-ulcer dyspepsia have abnormalities of gastric emptying and increased pain perception in the gastrointestinal tract, suggesting that the condition is part of the spectrum of irritable bowel syndrome (see Ch. 33).
Acid-predominant symptoms such as heartburn and epigastric discomfort may respond to anti-acid or anti-secretory therapy. Although a minority of patients may respond to H. pylori eradication, there is no evidence that there is a causative link and the response rate is not greater than that seen with placebo.
The sensation of bloating is poorly understood but may involve visceral afferent hypersensitivity and hypomotility. Motility-predominant symptoms such as bloating may respond to prokinetic drugs. Antispasmodics such as peppermint oil can help, as can tricyclic antidepressants in low-dose, as for neuropathic pain.
Guide to further reading
Armstrong D., Sifrim D. New pharmacologic approaches in gastroesophageal reflux disease. Gastroenterol. Clin. North Am.. 2010;39:393–418.
Camilleri M., Tack J.F. Current medical treatments of dyspepsia and irritable bowel syndrome. Gastroenterol. Clin. North Am.. 2010;39:481–493.
McColl K.E. Helicobacter pylori infection. N. Engl. J. Med.. 2010;362:1597–1604.
Moayyedi P., Talley N. Gastro-oesophageal reflux disease. Lancet. 2006;367:2086–2100.
National Institute for Health and Clinical Excellence (NICE). Dyspepsia: Managing Dyspepsia in Adults in Primary Care. London: NICE; 2004.
Richter J.E. Oesophageal motility disorders. Lancet. 2001;358:823–828.
Rotherberg M.E. Biology and treatment of eosinophilic esophagitis. Gastroenterology. 2009;137(4):1238–1249.
White P.F. Prevention of postoperative nausea and vomiting – a multimodal solution to a persistent problem. N. Engl. J. Med.. 2004;350:2511–2515.
Yang Y.X., Metz D.C. Safety of proton pump inhibitor exposure. Gastroenterology. 2010;139:1115–1127.
1 Marshall B J, Warren J R 1984 Unidentified curved bacillis in the stomach of patients with gastritis and peptic ulceration. Lancet i:1311–1315. (Marshall deliberately infected himself by drinking a solution swimming with the bacterium, as part of a successful and widely reported experiment to prove Koch's postulates.)
2 Pincock S 2005 Nobel Prize winners Robin Warren and Barry Marshall. Lancet 366:1429.
3 Characterised by incomplete relaxation of the lower oesophageal sphincter (LOS), increased LOS tone, lack of peristalsis in the oesophagus and consequent inability of smooth muscle to move food down the oesophagus.
4 The pharmacology of vomiting was little studied until the world war of 1939–1945, when motion sickness attained military importance as a possible handicap for sea landings made in the face of resistance. The British military authorities and the Medical Research Council therefore organised an investigation. Whenever there was a prospect of sufficiently rough weather, about 70 soldiers were sent to sea in small ships, again and again, after being dosed with a drug or a dummy tablet and having had their mouths inspected to detect non-compliance. The ships returned to land when up to 40% of the soldiers vomited. ‘On the whole the men enjoyed their trips’; some of them, however, being soldiers, thought the tablets were given in order to make them vomit and some ‘believed firmly in the efficacy of the dummy tablets’. It was concluded that, of the remedies tested, antimuscarinic drug hyoscine was the most effective. Holling H E, McArdle B, Trotter W R 1944 Prevention of seasickness by drugs. Lancet i:127.