peptic ulcers

Question 1

What are the two types of peptic ulcer

Answer 1

 A peptic ulcer = an area of damage to the inner lining of the stomach (gastric ulcer) or the upper part of the duodenum (duodenal ulcer).

Question 2

Compare the time course between the onset of symptoms in gastric and duodenal ulcers

Answer 2

o These ulcers can be distinguished based on timing of symptoms:
 Gastric ulcer – pain at mealtimes when the acid is secreted.
 Duodenal ulcer – pain relieved by a meal as the pyloric sphincter closes (pain starts after 2-3 hours).
o Duodenal: Gastric ulcers = 4: 1.

Question 3

What is a typical presentation of peptic ulcers

Answer 3

Epigastric pain, burning sensation that occurs after meals

Question 4

Outline the investigations that you would perform to diagnose H.Pylori infection

Answer 4

Carbon-urea breath test – positive
Stool antigen test – positive
H Pylori positive peptic ulcer

Question 5

Describe the basis of the carbon-urea breath test

Answer 5

Give a urate mixture that contains a distinctive isotope of carbon
H. pylori has enzymes that can break down the urate mixture and liberate the carbon isotope
This carbon isotope is then incorporated into carbon dioxide and is breathed out – this can then be detected to confirm high levels of H. pylori

Question 6

Outline the pathophysiology of a H.Pylori infection

Answer 6

Helicobacter pylori (H pylori)
Dissolves mucus layer in the gastric antrum
Causes epithelial cell death (due to loss of mucus protective layer which makes them more exposed to the acidity of the stomach).
Increased acidity  peptic ulcer

Stomach receives a large proportion of the cardiac output- thus there is a risk of severe G.I bleeding with severe stomach ulceration- this is a medical emergency.

Question 7

What is important to remember about the extent of the damage caused by H.Pylori

Answer 7

Dissolves the mucus layer in ‘pockets’

The whole mucuc lining isn’t obliterated- just a small portion to cause an ulcer.

Question 8

Summarise the treatment plan for a patient who is suspected of having a H.Pylori infection which is causing a peptic ulcer

Answer 8

Amoxicillin (penicillin) & Clarithromycin (macrolide)/Metronidazole (good gram negative antibiotic)– Antibiotics
Proton Pump Inhibitor (PPI) – reduces acid production (see later)

So two antibiotics + PPI- triple therapy

Question 9

What are the risk factors for acquiring H.Pylori

Answer 9

 Risk factors for acquiring H. pylori are unknown and the methods of transmission are uncertain but could be:
o Socioeconomic conditions.
o Contact with animals and contaminated faeces.

Question 10

Describe the key features of H.Pylori

Answer 10

Gram negative, motile, microaerophilic bacterium
Resides in human GI tract – exclusively colonising gastric-type epithelium (present commensally in 70-80% of individuals)

The fact that it is motile is important- can move around the stomach and gut to cause more ulcers.

Question 11

Describe how H.Pylori can result in ulcer formation

Answer 11

Increased gastric acid formation –  gastrin or  somatostatin

Gastric metaplasia – cell transformation due to excessive acid exposure

Downregulation of defence factors -  epidermal growth factor &  bicarbonate production

Question 12

Describe the virulence of H.Pylori

Answer 12

Urease – catalyses urea into ammonium chloride & monochloramine  damage epithelial cells

Urease – antigenic  evokes immune response- inflammation
Hence urease can cause damage both directly and indirectly

Certain virulent strains produce CagA (antigenic) or VacA (cytotoxic) – more intense tissue inflammation
These are exotoxins
CagA- antigenic and so stimulates inflammatory immune response
VacA- cytotoxic- damages cells directly.

Question 13

What is important to remember about the different strains of H.Pylori

Answer 13

Not all of them produce exotoxins,

Question 14

Describe the epidemiology of H.Pylori infections

Answer 14

 Aim is to eliminate H. pylori which infects a lot of people (50-80% are worldwide chronically infected).
o ~100% of duodenal ulcers and 80-90% of gastric ulcers are infected with H. pylori.

Question 15

Describe two ways in which H.Pylori can cause epithelial cell death

Answer 15

Causes epithelial cell death: exotoxins & inflammation

Increased acidity  peptic ulcer

Question 16

Describe the second line therapy in chronic infections with H.pylori

Answer 16

quinolone and tetracycline Abx instead of penicillins, especially in chronic infections; bismuth therapy is a chelating agent that can be used (or sucralfate)
Also give a PPI (omeprazole)- 4-12 weeks

Question 17

Describe the K+/H+ ATPase pump in the stomach

Answer 17

Expressed on secretory vesicles within parietal cells

 [Ca2+]i  — cAMP — translocation of secretory vesicles to parietal cell apical surface  H+ secretion

Question 18

What two things can increase the expression of K+/H+ ATPase pumps

Answer 18

Ca2+
cAMP (via Gs receptors) -will then stimulated protein kinases to bring about changes (i.e translocation for more proton pumps into apical membrane).

Question 19

Describe the role of proton pumps in ulcer formation

Answer 19

Increased activity of proton pump –  H+ secretion  reduction gastric pH

Question 20

Summarise the actions of bismuth and sucralfate

Answer 20

Create an acidic environment around the stomach- less access for bacteria- they also reduce inflammation around gastric epithelium.

Question 21

How does sucralfate work

Answer 21

Sucralfate is a complex of aluminium hydroxide and sulfated sucrose, which releases aluminium in the presence of acid. The residual complex carries a strong negative charge and binds to cationic groups in proteins, glycoproteins, etc. 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.
Can also protect H.Pylori

Question 22

What can reduce the efficacy of sucralfate

Answer 22

Because it requires an acid environment for activation, antacids given concurrently or prior to its administration will reduce its efficacy.

Question 23

What does sucralfate consist of

Answer 23

It is a polymer containing aluminium hydroxide and sucrose octa-sulfate

Question 24

How does the bismuth chelate/Pepto-Bismol work

Answer 24

The same as sucralfate

Question 25

What are the unwanted effects of sucralfate

Answer 25

Most of the orally administered sucralfate remains in the GI tract and this may cause constipation or reduced absorption of other drugs (digoxin and antibiotics including tetracycline).

Question 26

What are the two intramural plexuses that make up the enteric nervous system

Answer 26

There are two principal intramural plexuses in the tract: the myenteric plexus (Auerbach’s plexus) lies between the outer, longitudinal and the middle, circular muscle layers, and the submucous plexus (Meissner’s plexus) lies on the lumenal side of the circular muscle layer.

Question 27

What makes up the enteric nervous system

Answer 27

These plexuses are interconnected and their ganglion cells receive preganglionic parasympathetic fibres from the vagus. These are mostly cholinergic and excitatory, although a few are inhibitory. Incoming sympathetic fibres are largely postganglionic. In addition to innervating blood vessels, smooth muscle and some glandular cells directly, some sympathetic fibres terminate in these plexuses, where they inhibit acetylcholine secretion

Question 28

Describe the protective factors of the G.I barrier

Answer 28

§ Protective factors of the gastrointestinal barrier – lubricate the food and protect the mucosal surface:
o Mucus from gastric mucosa creates a gastrointestinal mucosal barrier.
o HCO3- ions are trapped in the mucous and generate a protective pH of 6-7 at the mucosal surface.
o Locally produced prostaglandins stimulate mucus and bicarbonate production (paracrine action), inhibit gastric acid secretion and facilitate a good blood supply to the stomach.

Question 29

Describe some factors that could damage the mucosal barrier

Answer 29

§ Some factors that convert the food into chyme can damage the mucosal barrier:
o Parietal cells – acid secretion from parietal cells of the oxyntic glands in the gastric mucosa.
o Chief cells – pepsinogens which erode the mucous layer.

Question 30

Describe some risk factors for peptic ulcers

Answer 30

§ Factors that contribute to mucosal damage:
o Increased acid or decreased HCO3-.
o Decreased thickness of mucosal layer.
o Increase in pepsin type 1.
o Decreased mucosal blood flow.
o Infections with H. pylori.
o Risk factors – genetics, stress, diet (alcohol, smoking

Question 31

Ultimately, what are the aims of treatment of peptic ulcers

Answer 31

§ Prevalence – 1: 10 population of developed countries.

§ Aims of treatment – eliminate cause of damage, promote healing

Question 32

Explain the basis of triple therapy

Answer 32

o Antibiotics – more than one type as there is some small resistance.
o Drugs that reduce gastric acid secretion.
o Drugs that promote healing.

So it targets all the pathways involved in the pathogenesis of gastric ulcers.

§ Inclusion of antibiotics along with inhibitors of gastric acid secretion or cyto-protective agents in the treatment of peptic ulcers reduces relapse rates from >90% to <15%.

Question 33

In the developed world, what are the most common causes of peptic ulcer

Answer 33

70-80%- H.Pylori

The rest- NSAID use

Question 34

Describe how NSAIDs can lead to ulcer formation

Answer 34

Directly cytotoxic
Reduces mucus production
Increases likelihood of bleeding
Increased acidity —  peptic ulcer

Question 35

Outline the treatment for NSAID peptic ulcers

Answer 35

Removal of NSAID (if possible)
Proton Pump Inhibitor or histamine H2 receptor antagonist (Ranitidine) – 4-8 weeks
H2 receptor increases acid secretion

Question 36

Describe the controls of acid secretion

Answer 36

1. Presence/smell of food can trigger acid production.
2. In the fundus, there are acid-secreting parietal cells.
   a. PNS can act on H-cells to stimulate histamine production.
3. In the antrum, amino-acids can trigger the G cells to secrete gastrin.
   a. Gastrin triggers more histamine release or can simply trigger more acid production directly (CCKB receptors).

Question 37

List some drugs which can inhibit gastric acid secretion

Answer 37

§ Inhibitors of gastric acid secretion include:
o Proton pump inhibitors. Omeprazole
o H2 receptor antagonists. Cimetidine, Ranitidine.
o Anti-muscarinics.

Question 38

Where are the cells which secrete protective bicarbonate located

Answer 38

Superficial epithelial cells provide the protective bicarbonate secretion which mixes with the mucus to protect.

Question 39

Describe the effects of PPIs and describe why they have little impact on other proton pumps in the body

Answer 39

Inhibits basal and stimulated gastric acid secretion from the parietal cells by >90%

o Becomes inactive at neutral pH – limits the action on other PPs around the body.
o Accumulates at the canaliculi as it is a weak base – concentrates action at the canaliculi.

Question 40

Describe the pharmacokinetics and side effects of omeprazole

Answer 40

§ Pharmacokinetics:
o Oral and administered in an enteric coating.
§ Side effects – rare due to short term use:
o Long term and/or high dose à enteric infections (C. diff), community acquired pneumonia, hip fracture.

Question 41

Describe H2 receptor antagonists

Answer 41

§ Inhibits gastric acid secretion by parietal cells by ~60% (less effective than PPIs).
§ MoA – competitive H2-receptor antagonists.

Question 42

Describe the pharmacokinetics and side effects of H2 receptor antagonists

Answer 42

§ Pharmacokinetics:
o Oral, well-absorbed. Ranitidine longer acting than cimetidine.
§ Side effects:
o Rare – headaches and dizziness.
o Fewer side effects with Ranitidine (available OTC).
§ Relapses are likely after withdrawal from treatment (>90% recurrence within 1 year after healing).
o Hence is part of triple therapy.

Question 43

Describe anti-muscarinics

Answer 43

Inhibitors of Gastric Acid Secretion: Anti-muscarinic drugs

§ Little use as anti-ulcer drugs, more effective in combination therapies.

Question 44

What are the cytoprotective drugs used in the treatment of peptic ulcers and summarise their function

Answer 44

Sucralfate, Bismuth chelate, Misoprostol

§ These drugs enhance mucosal protection and/or build a physical barrier over the ulcer.

Question 45

Describe misoprostol

Answer 45

§ Misoprostol – prostaglandin analogue (PGE1)
o Orally active.
o MoA – mimics action of prostaglandins to maintain mucosal barrier.
o Use – co-prescribed with NSAIDs when used chronically as NSAIDs block the COX enzymes required for PG synthesis from arachidonic acid.
o Side effects – diarrhoea, abdominal cramps, uterine contractions (don’t give in pregnancy).

Question 46

What are antacids

Answer 46

Salts of Na+, Al3+, Mg2+
§ Sodium bicarbonate has rapid effects whilst aluminium hydroxide and magnesium trisilicate have slower actions.
§ MoA – neutralise acid, raise gastric pH, reduce pepsin activity.
o May be effective in reducing duodenal recurrence rates.
§ Administer orally – primarily used for non-ulcer dyspepsia (OTC) e.g. rennie.

Question 47

Describe gastric acid regulation (at the level of the parietal cell)

Answer 47

Acetylcholine (ACh) released from neurones (vagus / enteric) acts on muscarinic (M3) receptors - increased  [Ca2+]i
Prostaglandins (PGs) released from local cells act on EP3 receptors - ↓ cAMP (this is why NSAIDs can cause gastric ulcers- they reduce the synthesis of prostaglandins)
Histamine released from enterochromaffin-like cells (ECL) act on H2 receptors - increasedcAMP
Gastrin released from G-cells, acts on cholecystokinin B receptors - increased [Ca2+]i

Question 48

Describe somatostains

Answer 48

Somatostatin – peptide that inhibits G-cells, ECL cells and parietal cells

Made by D cells

ACh release from vagus nerve can also inhibit somatostatin release

Question 49

Describe the problems with triple therapy

Answer 49

§ Problems with triple therapy:
o Compliance.
o Antibiotic resistance.
o Adverse response to alcohol (metronidazole- interferes with alcohol metabolism).

Question 50

What is the aim of antibiotic treatment with regard to peptic ulcers

Answer 50

90% eradication of H. pylori within 7-14 days

Question 51

Describe GERD and how it is treated

Answer 51

§ Patients experience heart burn.
§ OTC medication – antacids and H2-antagonists.
§ Chronic GORD à Barrett’s oesophagus.
o Drug – PPIs or H2-antagonists (are less effective but useful in patients resistant to PPIs).
§ Can combine the above drugs with drugs that increase gastric motility (e.g. D2 receptor antagonists – e.g. metoclopramide)

Question 52

Why is it important to treat GERD

Answer 52

Chronic GERD can progress to pre-malignant mucosal cells that can potentially lead to oesophageal adenocarcinoma