The Gastrointestinal Tract - Digestive Physiology

The gastrointestinal tract  GASTRIC SECRETION The stomach secretes about 2.5 L of gastric juice daily. Hydrochloric acid (HCl) secreted by the parietal cells. The production of acid is important for promoting proteolytic digestion of foodstuffs, iron absorption and killing pat...

The gastrointestinal tract  GASTRIC SECRETION The stomach secretes about 2.5 L of gastric juice daily. Hydrochloric acid (HCl) secreted by the parietal cells. The production of acid is important for promoting proteolytic digestion of foodstuffs, iron absorption and killing pathogens. Mucus secreting cells also abound in the gastric mucosa.  Bicarbonate ions are secreted and trapped in the mucus, creating a gel- like protective barrier that maintains the mucosal surface at a pH of 6–7 in the face of a much more acidic environment (pH 1–2) in the lumen. Locally produced ‘cytoprotective’ prostaglandins stimulate the secretion of both mucus and bicarbonate.  Disturbances in these secretory and protective mechanisms are thought to be involved in the pathogenesis of peptic ulcer, and other types of gastric damage such as gastro- oesophageal reflux disease (GORD) and injury caused by non-steroidal anti-inflammatory drugs (NSAIDs). THE REGULATION OF ACID SECERETION BY PARIETAL CELLS Disturbances of acid secretion are important in the pathogenesis of peptic ulcer and constitute a particular target for drug action. The secretion of the parietal cells is an isotonic solution of HCl (150 mmol/L) with a pH less than 1, to produce this, Cl− is actively transported. This is accompanied by K+ secretion, which is then exchanged for H+ from within the cell by a K+-H+-ATPase (the ‘proton pump’).  Within the cell, carbonic anhydrase catalyses the combination of carbon dioxide and water to give carbonic acid, which dissociates into H+ and bicarbonate ions. The latter exchanges across the basal membrane of the parietal cell for Cl−. The principal mediators that directly or indirectly control :parietal cell acid output are histamine (a stimulatory local hormone) acetylcholine (a stimulatory neurotransmitter) prostaglandins E2 and I2 (local hormones that inhibit acid secretion) gastrin (a stimulatory peptide hormone) somatostatin (an inhibitory peptide hormone) HISTAMINE Neuroendocrine cells abound in the stomach and the dominant type are the ECL cells (enterochromaffinl ike cells). These are histamine-containing cells similar to mast cells, which lie close to the parietal cells. They sustain a steady basal release of histamine, which is further increased by gastrin and acetylcholine.  Histamine acts on parietal cell H2 receptors to elevate cAMP that activates the secretion of acid by the proton pump. ACETYLCHOLINE Acetylcholine, released , from postganglionic cholinergic neurons, stimulates specific muscarinic M3 receptors on the surface of the parietal cells , thereby elevating intracellular Ca2+ and stimulating acid secretion. PROSTAGLANDINS Most cells of the GI tract produce prostaglandins , the most important being PGE2 and I2. Prostaglandins exert ‘cytoprotective’ effects on many aspects of gastric function including increasing bicarbonate secretion , increasing the release of protective mucin , reducing gastric acid output, and preventing the vasoconstriction (and thus damage to the mucosa) that follows injury or insult.  Misoprostol is a synthetic prostaglandin that probably exploits many of these effects to bring about its therapeutic action. DRUGS USED TO INHIBIT OR NEUTRALISE GASTRIC ACID SECRETION The principal clinical indications for reducing acid secretion are peptic ulceration (both duodenal and gastric), GORD (in which gastric secretion causes damage to the oesophagus) and the Zollinger– Ellison syndrome (a rare hypersecretory condition caused by a gastrin-producing tumour).  If untreated, GORD can cause a dysplasia of the oesophageal epithelium which may progress to a potentially dangerous pre-cancerous condition called Barrett oesophagus. The reasons why peptic ulcers develop are not fully understood, Infection of the stomach mucosa with Helicobacter pylori – a Gram- negative bacillus that causes chronic gastritis – is now generally considered to be a major cause (especially of duodenal ulcer) and forms the usual basis for therapy. Many non-specific NSAIDs cause gastric bleeding and erosions by inhibiting cyclo-oxygenase I, the enzyme responsible for synthesis of protective prostaglandins. HISTAMINE H2 RECEPTOR ANTAGONISTS The discovery and development of histamine H2-blocking drugs was a major breakthrough in the treatment of gastric ulcers. H2 receptor antagonists competitively inhibit histamine actions at all H2 receptors, but their main clinical use is as inhibitors of gastric acid secretion.  They inhibit histamine- and gastrin- stimulated acid secretion. The main drugs used are cimetidine, ranitidine , nizatidine and famotidine. There is little difference between them. Pharmacokinetic aspects and unwanted effects The drugs are generally given orally and are well absorbed, although preparations for intramuscular and intravenous use are also available (except famotidine). Cimetidine sometimes causes gynaecomastia in men and, rarely, a decrease in sexual function. This is probably caused by a modest affinity for androgen receptors.  Cimetidine (but not other H2 receptor antagonists) also inhibits cytochrome P450, and can retard the metabolism (and thus potentiate the action) of a range of drugs including oral anticoagulants PROTON PUMP INHIBITORS The first proton pump inhibitor was omeprazole, which irreversibly inhibits the H+-K+-ATPase (the proton pump), the terminal step in the acid secretory pathway. Other proton pump inhibitors (all of which have a similar mode of activation and pharmacology) include esomeprazole (the [S] isomer of omeprazole), lansoprazole, pantoprazole and rabeprazole. Pharmacokinetic aspects and unwanted effects Oral administration is the most common route of administration, although some injectable preparations are available. Omeprazole is given orally, but as it degrades rapidly at low pH, it is administered as capsules containing enteric coated granules. Following absorption in the small intestine, it passes from the blood into the parietal cells and then into the canaliculi where it exerts its effects.  For maximum effect, PPIs should be taken 30 to 60 minutes before breakfast or the largest meal of the day. Although the plasma half-life of these agents is only a few hours, they have a long duration of action due to covalent bonding with the H+/K+- ATPase enzyme.  Unwanted effects The PPIs are generally well tolerated. Headache, diarrhoea (both sometimes severe) and rashes. Acid-suppression with proton pump inhibitors is associated with increased risk of Clostridium difficile diarrhoea, particularly in patients who are immunosuppressed or have been receiving antibiotics.  Omeprazole and esomeprazole may decrease the effectiveness of clopidogrel because they inhibit CYP2C19 and prevent the conversion of clopidogrel to its active metabolite. Concomitant use of these PPIs with clopidogrel is not recommended. PPIs may increase the risk of fractures, particularly if the duration of use is 1 year or greater.  Prolonged acid suppression with PPIs (and H2 receptor antagonists) may result in low vitamin B12 because acid is required for its absorption in a complex with intrinsic factor. Additional adverse effects may include hypomagnesemia and an increased incidence of pneumonia. ANTACIDS Antacids are the simplest way to treat the symptoms of excessive gastric acid secretion. They directly neutralise acid and this also has the effect of inhibiting the activity of peptic enzymes, which practically ceases at pH 5.  Most antacids in common use are salts of magnesium and aluminium. Magnesium salts cause diarrhoea and aluminium salts, constipation – so mixtures of these two can, happily, be used to preserve normal bowel function. TREATMENT OF HELICOBACTER PYLORI INFECTION H. pylori infection has been implicated as a causative factor in the production of gastric and, more particularly, duodenal ulcers, as well as a risk factor for gastric cancer. Certainly, eradication of H. pylori infection promotes rapid and long-term healing of ulcers, and it is routine practice to test for the organism in patients presenting with suggestive symptoms.  If the test is positive, then the organism can generally be eradicated with a 1- or 2-week regimen of ‘triple therapy’, comprising a proton pump inhibitor in combination with the antibacterials amoxicillin and metronidazole or clarithromycin other combinations are also used. Bismuth containing preparations are sometimes added DRUGS THAT PROTECT THE MUCOSA Some agents, termed cytoprotective, are said to enhance endogenous mucosal protection mechanisms and/or to provide a physical barrier over the surface of the ulcer. Bismuth chelate Bismuth chelate (tripotassium dicitratobismuthate) is sometimes used in combination regimens to treat H. pylori. It has toxic effects on the bacillus, and may also prevent its adherence to the mucosa. In addition to its antimicrobial actions, it increases secretion of mucus, and interacts with glycoproteins in necrotic mucosal tissue to coat and protect the ulcer.  Very little is absorbed, but if renal excretion is impaired, the raised plasma concentrations of bismuth can result in encephalopathy. Unwanted effects include nausea and vomiting, and blackening of the tongue and faeces. Sucralfate Sucralfate is a complex of aluminium hydroxide and sulfated sucrose It can form complex gels with mucus, an action that is thought to decrease the degradation of mucus by pepsin and to limit the diffusion of H+ ions.  Sucralfate can also inhibit the action of pepsin and stimulate secretion of mucus, bicarbonate and prostaglandins from the gastric mucosa. All these actions contribute to its mucosa-protecting action.  Sucralfate is given orally and about 30% is still present in the stomach 3 h after administration. It reduces the absorption of a number of other drugs, including fluoroquinolone antibiotics, theophylline, tetracycline, digoxin and amitriptyline.  Because it requires an acid environment for activation, antacids given concurrently or prior to its administration will reduce its efficacy. Although sucralfate is effective for the treatment of duodenal ulcers, its use is limited due to the need for multiple daily dosing, drug–drug interactions, and availability of more effective agents. Unwanted effects are few, the most common being constipation. Misoprostol Prostaglandins of the E and I series have a generally homeostatic protective action in the GI tract, and a deficiency in endogenous production (after ingestion of an NSAID, for example) may contribute to ulcer formation. Misoprostol is a stable analogue of prostaglandin E1.  It is given orally and is used to promote the healing of ulcers or to prevent the gastric damage that can occur with chronic use of NSAIDs. It exerts a direct action on the ECL cell (and possibly parietal cell), inhibiting the basal secretion of gastric acid as well as the stimulation of production seen in response to food.  It also increases mucosal blood flow and augments the secretion of mucus and bicarbonate. Unwanted effects include diarrhoea and abdominal cramps; uterine contractions can also occur, so the drug should not be given during pregnancy (unless deliberately to induce a therapeutic abortion) Clinical use of agents affecting gastric acidity Histamine H2 receptor antagonists (e.g. ranitidine): – peptic ulcer – reflux oesophagitis Proton pump inhibitors (e.g. omeprazole, lansoprazole): – peptic ulcer – reflux oesophagitis – as one component of therapy for Helicobacter pylori infection – Zollinger–Ellison syndrome (a rare condition caused by gastrin-secreting tumours) Antacids (e.g. magnesium trisilicate, aluminium hydroxide, alginates): – dyspepsia – symptomatic relief in peptic ulcer Bismuth chelate: – as one component of therapy for H. pylori infection