8 Gastrointestinal system

• Understand the function of the gastrointestinal system

• Know which drugs affect gastrointestinal function

• Be aware of drug indications, contraindications and adverse reactions.

The stomach

Basic concepts

The stomach not only acts as a sac to store food, but also helps in its breakdown both mechanically and chemically (through hydrochloric acid and digestive enzymes). Peptic ulceration and gastro-oesophageal reflux disease (GORD) are two of the common problems that can occur in the stomach.

Peptic ulceration

The gastric epithelium secretes several substances – hydrochloric acid (HCl) (parietal cells), digestive enzymes (peptic cells) and mucus (mucus-secreting cells). The acid and enzymes convert food into a thick semi-liquid paste called chyme. The mucus protects the stomach from its own corrosive secretions.

Peptic ulceration results from a breach in the mucosa lining the alimentary tract caused by acid and enzyme attack. Unprotected mucosa rapidly undergoes autodigestion leading to a range of damage – inflammation or gastritis, necrosis, haemorrhage, and even perforation as the erosion deepens.

Gastric and duodenal ulcers differ in their location, epidemiology, incidence and aetiology but present with similar symptoms and treatment is based on similar principles. Peptic ulcer disease is chronic, recurrent and common, affecting at least 10% of the population in developed countries. Helicobacter pylori plays a role in the pathogenesis of a significant proportion of peptic ulcer disease.

Communication

Mr Springfields is a 40-year-old city worker, who presents to accident and emergency with epigastric pain relieved by eating, smelling heavily of alcohol and smoke. He has vomited dark-coloured blood and this is evident on his shirt. He admits to melaena and recent weight loss. Mr Springfields has a 20-pack year smoking history and a 1-year past medical history of back pain, for which he takes ibuprofen. He is pale and tachycardic, with a blood pressure of 110/65 mmHg. Upper gastrointestinal flexible endoscopy reveals a shallow ulcer overlying a blood clot. Biopsy is taken to test for H. pylori and returns positive. His management includes being given oxygen and blood transfusions. He is also given H. pylori eradication therapy (a proton pump inhibitor and antibiotics) consisting of omeprazole, amoxicillin and metronidazole.

Protective factors

The mucosal defences against acid/enzyme attack consist of:

• The mucous barrier (approximately 500 mm thick), a mucous matrix into which bicarbonate ions are secreted, producing a buffering gradient.

• The surface epithelium, which requires prostaglandins E₂ and I₂, synthesized by the gastric mucosa. These are thought to exert a cytoprotective action by increasing mucosal blood flow.

The regulation of acid secretion by parietal cells is especially important in peptic ulceration and constitutes a major target for drug action (Fig. 8.1). Acid is secreted from gastric parietal cells by a unique proton pump that catalyses the exchange of intracellular H⁺ for extracellular K⁺. The secretion of HCl is controlled by the activation of three main receptors on the basolateral membrane of the parietal cell. These are:

• Gastrin receptors, which respond to gastrin secreted by the G cells of the stomach antrum

• Histamine (H₂) receptors, which respond to histamine secreted from the enterochromaffin-like paracrine cells that are adjacent to the parietal cell

• Muscarinic (M₁, M₃) receptors on the parietal cell, which respond to acetylcholine (ACh) released from neurons innervating the parietal cell.

Fig. 8.1 Acid secretion from parietal cells is reduced by muscarinic antagonists, histamine (H₂) antagonists and the proton pump inhibitors. Gastrin (G) and acetylcholine (Ach) stimulate the parietal cell directly to increase acid secretion and also stimulate enterochromaffin-like cells to secrete histamine, which then acts upon the H₂ receptors of the parietal cell. Antacids raise the luminal pH by neutralizing hydrogen ions. Mucosal strengtheners adhere to and protect ulcer craters and may kill Helicobacter pylori.

(Redrawn from Page et al. 2006.)

Although the parietal cells possess muscarinic and gastrin receptors, both ACh and gastrin mainly exert their acid secretory effect indirectly, by stimulating nearby enterochromaffin-like cells to release histamine. Histamine then acts locally on the parietal cells where activation of the H₂ receptor results in the stimulation of adenylyl cyclase and the subsequent secretion of acid. Excessive production of gastrin from a rare tumour, a gastrinoma, can result in excess acid production, and in peptic ulceration, a condition known as Zollinger–Ellison syndrome.

Gastro-oesophageal reflux

Stomach contents are normally prevented from re-entering the oesophagus by the lower oesophageal sphincter (LOS). Loss of tone of the LOS, or a rise in intra-abdominal pressure are the commonest causes of GORD, of which heartburn is the major symptom. Conservative treatment options include weight loss and raising the head of the patient’s bed. Precipitating factors should be avoided, as should excess smoking and alcohol. The drugs used in GORD are the same as for other acid-related disorders (Fig. 8.2).

Fig. 8.2 Treatment of gastro-oesophageal reflux disease: a stepwise approach.

(Adapted from Haslett et al. Davidson’s Principles and Practice of Medicine, 18th edition, Churchill Livingstone, Edinburgh, 1999.)

Prevention and treatment of acid-related disease

Drugs that are effective in the treatment of peptic ulcers either reduce/neutralize gastric acid secretion or increase mucosal resistance to acid-pepsin attack. Peptic ulcers thus treated will heal rapidly, but recurrence is common unless H. pylori is eliminated.

Reduction of acid secretion

Proton pump inhibitors (PPI)

Omeprazole and lansoprazole are examples of PPIs.

Mechanism of action

PPIs cause irreversible inhibition of H⁺/K⁺ ATPase that is responsible for H⁺ secretion from parietal cells (see Fig. 8.1). They are inactive prodrugs and are converted at acidic pH to sulphonamide, which combines covalently and thus irreversibly with -SH groups on H⁺/K⁺ ATPase. This inhibition is highly specific and localized.

Mucosal strengtheners

Misoprostol

Mechanism of action

Misoprostol is a synthetic analogue of prostaglandin E. It imitates the action of endogenous prostaglandins (PGE₂ and PGI₂) in maintaining the integrity of the gastroduodenal mucosal barrier, and promotes healing (Fig. 8.1).

Route of administration

Oral.

Indications

Ulcer healing and ulcer prophylaxis with non-steroidal anti-inflammatory drug (NSAID) use.

Contraindications

Misoprostol should not be given to people with hypotension, or to women who are pregnant or breastfeeding.

Adverse effects

Diarrhoea, abdominal pain.

Therapeutic notes

Misoprostol is most effective at correcting the deficit caused by NSAIDs that inhibit cyclooxygenase-1 and reduce prostaglandin synthesis (Ch. 10). Misoprostol can prevent NSAID-associated ulcers, and therefore is particularly useful in elderly people in whom NSAIDs cannot be withdrawn.

Chelates

Bismuth chelate and sucralfate appear to help protect the gastric mucosa by several means, including inhibiting the action of pepsin, promoting synthesis of protective prostaglandins and stimulating the secretion of bicarbonate. They are administered orally and are generally well tolerated.

Alginates

Alginate-containing antacids are administered orally, and form an impenetrable raft which floats on the surface of the gastric contents. This layer prevents gastric acid from refluxing into the oesophagus, and is therefore most useful in GORD. This class of drug is very well tolerated, but does not have any effect on acid secretion, or on preventing or healing of peptic ulcers.

Helicobacter pylori eradication regimens

H. pylori plays a significant role in the pathogenesis of peptic ulcer disease. It does not cause ulcers in everyone it infects (50–80% of the population) but, of those who develop ulcers, 90% can be found to have an H. pylori infection in their antrum.

Treatment of peptic ulcer disease should include eradication of H. pylori. The rate of recurrence of duodenal ulcer after healing can be as high as 80% within 1 year when H. pylori eradication is not part of the treatment, but less than 5% when H. pylori is eradicated.

The ideal treatment for H. pylori eradication is not yet clear. Current regimens under evaluation include:

• The ‘classic’ triple therapy – 1 or 2 weeks’ treatment with omeprazole, metronidazole and amoxicillin or clarithromycin. This eliminates H. pylori in 90% of patients but adverse effects, compliance and resistance can be problematic.

• Quadruple therapy – Omeprazole, two antibiotics and bismuth chelate.

Hints and Tips

Peptic ulcer disease is very common, and potentially life-threatening. Always check with patients if they have an ulcer or ulcer-like symptoms before prescribing NSAIDs.

Nausea and vomiting

Basic concepts

The commoner causes for nausea and vomiting are shown in Figure 8.3. The act of vomiting is coordinated in the vomiting centre within the brainstem. This centre receives neuronal input from several sources, though fibres from the chemoreceptor trigger zone (CTZ) of the fourth ventricle appear fundamental in bringing about emesis. The CTZ lies outside the blood–brain barrier, and is sensitive to many stimuli, such as drugs and endogenous and potentially exogenous chemical mediators. The CTZ contains numerous dopamine receptors, which partially explains why anti-Parkinsonian drugs (dopaminergic drugs) often induce nausea and vomiting, whereas some antidopaminergic drugs are used as antiemetics.