WORK SESSION 1: Peptic Ulcers

AIMS

• To further your understanding of the mechanisms controlling gastric acid secretion.
• To understand the mechanism of action of the three classes of drugs used in treating peptic ulceration.
• To be aware the role of H. pylori and NSAIDs in the causation of peptic ulcers.

OBJECTIVES

• Have revised and extended your knowledge of signal transduction.
• Appreciate the common causes of peptic ulceration.
• Know how H. pylori infection may be diagnosed and treated.
• Be able to explain why NSAIDs predispose patients to gastric ulceration.
• Be aware of the three classes of drug which may be used to treat ulcers.
• Have completed a flow chart which demonstrates the mechanisms responsible for control of gastric acid secretion, and the points in this process which may be affected by anti-ulcer drugs.

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:

• The role of G proteins as second messengers in histamine-induced acid secretion.
• How acid secretion from parietal cells occurs.
• The mechanism of action of H₂ blockers, e.g. cimetidine

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.

ASSESSMENT

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).

FLOW DIAGRAM

INTRODUCTION

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 (G_I). 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.

Causes of peptic ulceration

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:

• Infection with Helicobacter pylori
• Use of nonsteroidal anti-inflammatory drugs, e.g. aspirin

Section A:  H. PYLORI INFECTION

1. What sort of organism is H. pylori?
2. Which well known enzyme does it produce?
3. What reaction does this enzyme catalyse? How might the enzyme assist H. pylori in surviving the harsh environment of the stomach?
4. How common is H. pylori infection? What is the age and social distribution?
5. Describe the likely pathogenic process
6. Which gastrointestinal disorders are associated with H. pylori infection?
7. How is H. pylori infection diagnosed? Which patients should undergo endoscopy?
8. Describe briefly the three standard treatments for H. pylori infection. In addition to drug treatment, what lifestyle advice should be given to patients with peptic ulcers?
9. In researching the previous answer you will have found references to PPIs (proton pump inhibitors). What is the correct biochemical name for the proton pump? Annotate your flow diagram to show where PPIs act

• Additional information about h.pylori may be found on the Nobel Prize website.

Section B:  NON-STEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDS) - KILL OR CURE?

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.

• Aspirin irreversibly inhibits the enzyme cyclo-oxygenase (COX).

10. How does this lead to its therapeutic effects? Sketch the pathway affected.
11. Why might aspirin use tend to encourage the secretion of excess gastric acid?
12. Cyclo-oxygenase exists in two isoenzyme forms, COX 1 and COX 2. How do these two isoenzyme forms differ in location and activity?
13. Which of these two isoenzymes will be responsible for the inflammatory response?
14. Which is primarily responsible for effects on the gastric mucosa?
15. Why would COX 2 specific NSAIDS (e.g. Celecoxib) be preferable to aspirin for long term use?

    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

    
    
    NSAIDS may be prescribed in combination with misoprostol, e.g. Arthrotec (Diclofenac + misoprostol).
16. What type of compound is misoprostol?
17. How does misoprostol protect against gastric ulceration?
    Annotate your flow diagram to show where misoprostol acts
18. Among the Special Precautions listed for the prescription of Arthrotec it states:
    "Premenopausal women should use effective contraception". Why is this necessary?
19. Why might aspirin be particularly inclined to promote haemorrhage from peptic ulcers?