The main physiological aspects of gastrointestinal (GI) tract function that are of pharmacological importance are gastric acid secretion, the motility of the bowel and the excretion of its contents; the main pathophysiological conditions of the GI tract are peptic ulcers, nausea and vomiting, diarrhoea, constipation, gallstones and chronic inflammatory bowel disease (ulcerative colitis, Crohn’s disease).
Gastric Secretion and Peptic Ulcer
Pathogenesis of peptic ulcer
In peptic ulceration the balance between mucosal-damaging processes (excessive secretion of acid and pepsin) and mucosal-protective mechanisms (secretion of bicarbonate and mucus) is altered. The bacillus Helicobacter pylori is likely to be a major cause of the swing towards mucosal damage by increasing gastrin secretion. Nonsteroidal anti-inflammatory drugs (NSAIDs) are an additional important cause of gastric ulceration.
Drugs used to treat peptic ulcer, with their mechanisms of action
The main approaches are (1) to reduce acid secretion (this is the most important), (2) to treat H. pylori infection and (3) to protect the gastric mucosa.
Drugs used to reduce acid secretion ( Fig. 21.1 )
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Histamine H 2 antagonists (e.g. cimetidine , ranitidine ) or proton pump inhibitors (e.g. omeprazole ) are the most effective agents.
Fig. 21.1
Control of acid secretion and drug actions.
ACh , Acetylcholine; NSAIDs , nonsteroidal anti-inflammatory drugs; PGE 2 , prostaglandin E 2 .
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Selective muscarinic M 1 antagonists (e.g. pirenzepine ) also reduce acid secretion, but less effectively than H 2 antagonists. (There are no clinically useful gastrin antagonists.)
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Antacids (e.g. magnesium trisilicate, aluminium hydroxide ) simply neutralize the acid in the stomach.
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Misoprostol , a prostaglandin (PGE) 2 analogue, not only reduces gastric acid secretion, but may also increase bicarbonate and mucus secretion by epithelial cells. Its main use is to counteract the damaging effects of NSAIDs on the gastric mucosa.
Drugs used to treat H. pylori infection
H. pylori infection is treated with a combination of a proton pump inhibitor or H 2 antagonist with two antibiotics ( amoxicillin is commonly used with either metronidazole or clarithromycin ). Bismuth chelate , which has an antibacterial action plus a mucosa-protective effect, can also be used.
Drugs used to protect the gastric mucosa
Sucralfate (a complex of aluminium hydroxide and sulphated sucrose) can form complex gels with mucus to enhance its protective effect on the mucosa. Bismuth chelate is also protective.
Pharmacokinetic aspects and unwanted actions
H 2 antagonists are readily absorbed after oral administration. Both cimetidine and ranitidine can inhibit renal tubular secretion of basic drugs. Cimetidine, importantly, can inhibit cytochrome P450 and so potentiate the actions of many drugs including oral anticoagulants, phenytoin and aminophylline. Omeprazole has a half-life of only 1 h but its concentration in the parietal cell canaliculus allows its action to persist for 2–3 days. Most of a sucralfate dose remains in the gut, where it can reduce the absorption of other drugs (e.g. digoxin, tetracycline and theophylline).
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5-hydroxytryptamine (5-HT 3 ) receptor antagonists (e.g. ondansetron ): Emesis caused by cancer chemotherapy agents (drugs of choice), postoperative and radiation-induced vomiting.
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Dopamine D 2 receptor antagonists (e.g. domperidone, phenothiazines ): Emesis caused by uraemia, radiation, gastrointestinal (GI) tract disorders, viral gastroenteritis.
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Muscarinic receptor antagonists (e.g. scopolamine ): motion sickness (drug of choice).
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Histamine H 1 receptor antagonists: cyclizine (motion sickness), cinnarizine (Ménière’s disease).
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Cannabinoids (e.g. nabilone): Emesis caused by cytotoxic drugs.
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