peptic ulcers Flashcards

1
Q

What are the two types of peptic ulcer

A

 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).

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2
Q

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

A

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.

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3
Q

What is a typical presentation of peptic ulcers

A

Epigastric pain, burning sensation that occurs after meals

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4
Q

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

A

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

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5
Q

Describe the basis of the carbon-urea breath test

A

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

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6
Q

Outline the pathophysiology of a H.Pylori infection

A

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.

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7
Q

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

A

Dissolves the mucus layer in ‘pockets’

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

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8
Q

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

A

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

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9
Q

What are the risk factors for acquiring H.Pylori

A

 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.

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10
Q

Describe the key features of H.Pylori

A

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.

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11
Q

Describe how H.Pylori can result in ulcer formation

A

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

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12
Q

Describe the virulence of H.Pylori

A

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.

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13
Q

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

A

Not all of them produce exotoxins,

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14
Q

Describe the epidemiology of H.Pylori infections

A

 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.

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15
Q

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

A

Causes epithelial cell death: exotoxins & inflammation

Increased acidity  peptic ulcer

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16
Q

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

A

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

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17
Q

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

A

Expressed on secretory vesicles within parietal cells

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

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18
Q

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

A

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

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19
Q

Describe the role of proton pumps in ulcer formation

A

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

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20
Q

Summarise the actions of bismuth and sucralfate

A

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

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21
Q

How does sucralfate work

A

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

22
Q

What can reduce the efficacy of sucralfate

A

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

23
Q

What does sucralfate consist of

A

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

24
Q

How does the bismuth chelate/Pepto-Bismol work

A

The same as sucralfate

25
Q

What are the unwanted effects of sucralfate

A

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).

26
Q

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

A

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.

27
Q

What makes up the enteric nervous system

A

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

28
Q

Describe the protective factors of the G.I barrier

A

§ 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.

29
Q

Describe some factors that could damage the mucosal barrier

A

§ 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.

30
Q

Describe some risk factors for peptic ulcers

A

§ 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

31
Q

Ultimately, what are the aims of treatment of peptic ulcers

A

§ Prevalence – 1: 10 population of developed countries.

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

32
Q

Explain the basis of triple therapy

A

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%.

33
Q

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

A

70-80%- H.Pylori

The rest- NSAID use

34
Q

Describe how NSAIDs can lead to ulcer formation

A

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

35
Q

Outline the treatment for NSAID peptic ulcers

A

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

36
Q

Describe the controls of acid secretion

A
  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).
37
Q

List some drugs which can inhibit gastric acid secretion

A

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

38
Q

Where are the cells which secrete protective bicarbonate located

A

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

39
Q

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

A

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.

40
Q

Describe the pharmacokinetics and side effects of omeprazole

A

§ 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.

41
Q

Describe H2 receptor antagonists

A

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

42
Q

Describe the pharmacokinetics and side effects of H2 receptor antagonists

A

§ 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.

43
Q

Describe anti-muscarinics

A

Inhibitors of Gastric Acid Secretion: Anti-muscarinic drugs

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

44
Q

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

A

Sucralfate, Bismuth chelate, Misoprostol

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

45
Q

Describe misoprostol

A

§ 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).

46
Q

What are antacids

A

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.

47
Q

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

A

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

48
Q

Describe somatostains

A

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

49
Q

Describe the problems with triple therapy

A

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

50
Q

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

A

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

51
Q

Describe GERD and how it is treated

A

§ 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)

52
Q

Why is it important to treat GERD

A

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