OBJECTIVESOn successful completion of this exercise you will:
PREPARATION FOR THIS SESSION
In order to understand how peptic ulceration occurs and may be treated, it is necessary to have an overview of the mechanisms by which gastric acid secretion is controlled. In the Biomedical Sciences ICU you investigated the role of histamine in the stimulation of gastric acid secretion.
You may find it useful to bring the material from Biomembranes Work Session 4 to this class. You will also need Kumar & Clark, and a biochemistry textbook, e.g. Smith, Marks & Lieberman, Stryer, Lehninger.
Before this class, you need to revise:
A copy of the Flow Diagram used in the Biomedical Sciences ICU is reproduced here. During your revision, annotate the flow diagram to remind yourself where cimetidine exerts its effect. Read the introduction to this session and include the inhibitory G protein pathway on your flow diagram.
At the end of this Work Session, you will be given a sheet of short answer questions to complete. This is a formative exercise, in preparation for the summative assessment in Week 25. Answer the questions on the sheet provided and show to your demonstrator at Work Session 2 (Tuesday 26th April).
Acid secretion from the parietal cell may be modulated by a number of different mechanisms. Gastrin, histamine and acetylcholine, as you already know, all stimulate acid secretion, via a range of pathways, as summarised in the diagram below. However, a mechanism also exists to inhibit acid secretion. This is mediated by prostaglandin E2 (PGE2), which binds to a specific receptor on the parietal cell surface, and activates an inhibitory G protein (GI). The inhibitory G protein inhibits activation of adenylate cyclase, and so decreases gastric acid production. Annotate your flow diagram to include this pathway.
Figure 1: Control of gastric acid secretion.
Duodenal and gastric ulceration is extremely common, affecting more than 10% of the population at some time in their lives. Two main causes have been identified for this condition:
NSAIDs such as aspirin and ibuprofen are common medicines found in millions of homes. They are used as minor painkillers and for the relief of inflammation. They are also regularly used in the treatment of chronic inflammatory conditions such as arthritis. Aspirin also has a role in the treatment of blood clotting disorders, and is used in the treatment and prevention of myocardial infarction (heart attacks) and strokes. However, these drugs may have very serious side-effects, in particular gastric bleeding. 10 -25% of patients on long term NSAID therapy will suffer from gastro-intestinal problems. A recent report suggests that they may cause up to 2000 deaths a year in the UK. This effect is not simply the result of irritation of the stomach by the drug itself, since rectal administration does not prevent gastric complications.
Recent trials have suggested that, while effective in reducing gastro-intestinal side effects, COX-2 inhibitors may increase the risk of coronary heart disease. Rofecoxib (Vioxx) was withdrawn from use in Autumn 2004, and concerns have been raised over the safety of celecoxib (Celebrex). The American Food and Drug Administration decided in March 2005 not to withdraw these drugs from the market at present, but advised use with caution. For further reading see Lancet article
Class of drug
Mode of action
Proton pump inhibitors
If you are interested in these topics, you might like to look at the following references:
Suerbaum, S & Michetti, P (2002) Helicobacter pylori infection N Engl J Med 347: 1175-1186
Seager, JM & Hawkey, CJ (2001) Indigestion and non-steroidal anti-inflammatory drugs BMJ 323: 1236-1239
Desperate measure: the illicit use of an ulcer drug for abortions is leaving a terrible legacy New Scientist (2001) 171:18
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