S2: Gastric Acid Secretion: Disorders Flashcards
What does malformation of GIT lead to?
GIT (gastro-intestinal tract) is involved in absorption of nutrients, salts, water and elimination of undigested waste.
Therefore malformation leads to decreased nutrient status (malnutrition).
Mechanism of peptic ulcer formation
- Breakage of mucosal barrier if there is an imbalance between protective factors and damaging factors (HCl) which causes factors
- Exposure of tissues to erosive effects of HCl and Pepsin
Common sites of peptic ulcers
- Oesophagus (distal - especially barretts)
- Stomach (junction atrum and body)
- Duodenum (areas usually exposed to HCl and pepsin and as its not as well protected and the food going here is very acidic)
- Meckel’s diverticulum (cells here are thinner)
Ulcers can be renamed depending on where they are e.g.gastric or duodenal ulcers
Factors responsible for gastric acid secretion are therefore damaging factors for peptic ulcers.
List them
- Histamine
- Ach
- Gastrin
- Alcohol, smoking, caffeine, NSAIDs etc.
- Food
- Helicobacter pylori
- Hyperparathyroidism
Stress may also play a role, possibly aggravating existing ulcers. Bile acids are also irritants and genetics may play a part in ulcer formation.
Factors predisposing an individual to peptic ulceration
- Gastric and duodenal infection with H.pylori is a major risk factor
- Peptic ulcers acquired in childhood
- Environmental and host factors can determine the distribution and colonisation of H.pylori in the stomach
- Smoking, genetic factors, stress can all promote acid/pepsin secretion which impairs the mucosal defence mechanisms leading to a peptic ulcers
- NSAIDs also impair mucosal defence mechanisms by removing PGE2 (gastro-protective effects, increase mucus secretion and bicarb secretion) and thromboxane A2 (involved in healing).
What is the function of HCl?
- Help kill aerobic microorganisms and reduce risk of infection of the gastric mucosa
- Role in pepsinogen activation
- Stimulate release of bile and pancreatic juice release
List factors that prevent infection of gastric mucosa and
protective factors that Prevent Autodigestion of the Stomach
The gut is exposed to a very hostile environment, the gastric juices contain about 150mM HCl as well as the presence of pepsin.
- HCl
- Secretion of an alkaline mucus and HCO3-
- Peristalsis/fluid movement
- Seamless epithelium with tight junctions
- Fast cell turnover
- IgA secretions at mucosal surfaces
- Peyer’s patches
- Protein content of food
- Replacement of damaged cells within gastric pits
- Prostaglandins (E and I) which inhibit acid secretion and enhance blood flow
Classify bacteria
Coccus (round) Bacillus (rod shaped) Spirochetes (Spiral) Diplo (pair) Strepto (chain)
What type of bacteria for H.Pylori?
Gram negative spiral shaped aerobic bacterium
Describe the virulence factors of H.Pylori
H. Pylori is highly pathogenic with many virulence factors:
- Motility: It penetrates the gastric mucosa/mucus (like a corkscrew) so it is able to survive under the harsh conditions of the stomach down close to epithelium where pH is around 7
- Produces urease which converts urea to ammonia which buffers gastric
- Cytotoxin-associated antigen (CagA), this inserts pathogenicity islands inside the host and this confers ulcer-forming potential (cause apoptosis of cells and affect tight junctions)
- Vacuolating toxin A (VacA) this alters the trafficking of intracellular proteins in gastric mucosal cells
- CagA and VacA also alter immune cells like T cells and macrophages.
- Enzyme called mucinase, this enzyme degrades the mucus membrane overlying the epithelial cells.
- A large number of outer membrane proteins such as adhesins (BabA), phospholipases, porins, iron transporters and flagellum-associate proteins. These all help the bacteria.
Mechanism of H.Pylori
The H. pylori bores its way through the mucosa and then attaches to the epithelium using some virulence factors (CagA and VacA)
While there it releases ureases to convert urea to ammonia which neutralises any acidity that is in this area or being secreted.
Therefore any bacteria around can come and survive nicely in this area. The epithelium starts bleeding and being inflamed due to HCl and pepsin exposure and toxins. Inflammatory cells turn up and their effects can be damaging.
Also, H. pylori infection dysregulates gastrin secretion and decreases D and G cells (but decreases D cells more) increasing HCl secretion. It can also cause problems with the neutrophils and macrophages leading them to not function properly.
Diagnostic tests for peptic ulcers
Endoscopy (oesophagogastroduodenoscopy, EGD):
- Histological examination of an EGD biopsy
Test for the presence of H. pylori:
- Stool antigen test
Evaluate urease activity:
-Urea breathe test (can measure C14 isotope in CO2 exhaled after given a urea tablet that contains C14 so can collect the gas and see how much is being produced, this could indicate H.pylori if there are high levels)
Symptoms of peptic ulcers
- Anaemia
- Black, tarry stools
- Chest discomfort
- Vomiting
- Chest discomfort
- Weight loss
Main factors for chronic peptic ulcers
- Hyperacidity
- Reflux of duodenal contents
- H. pylori
- NSAIDs
- Genetic factors
- Sex, being male
Factors for acute peptic ulcers
Less frequent than chronic peptic ulcers
These develop from areas of corrosive gastritis (oesophagus, stomach, proximal duodenum)
- Severe stress or shock (such as burns, trauma)
Acute hypoxia of the surface epithelium may also cause acute ulcers (ischaemia of the gastric mucosa).
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Outcome of chronic and acute peptic ulcers
Acute = severe bleeding, complete healing, or could lead to a chronic peptic ulcer.
Chronic = if we treat we can get complete healing with replacement of tissue and possibly scarring.
Complications of peptic ulcers
- Haemorrhage (GI bleeding)
- Perforation (peritonitis) and penetration causing leakage of luminal contents
- Narrowing of pyloric canal due to strictures
- Malignant changes become 3-6x more likely with H. pylori infection
Give examples of H2 (histamine) receptor antagonists
cimetidine, ranitidine, famotidine, nizartidine.
How do H2 (histamine) receptor antagonists work?
H2 receptor antagonists block the histamine receptor. Histamine promotes acid release, so if we block it with an agent, we will inhibit stimulation of gastric acid release.
As well as inhibiting histamine, it also inhibits Ach and gastrin stimulated acid secretion. This is useful because these mediators, histamine, Ach and gastrin can syngergise to promote acid secretion, but if we take H2 receptor antagonists we can block acid secretion mediated by all of these.
- It can decrease basal (when we see it, smell etc.) and food-stimulated acid secretion by 90%
Clinical uses of H2 receptor antagonists
- Peptic ulcer
- Reflux oesophagitis
What do clinical trials on H2 receptor antagonist suggest?
The clinical trials on H2 receptor antagonists suggest they promote healing of duodenal ulcers but if you stop treatment you get a relapse because it is not solving the root cause of the problem (because the root cause could be H. Pylori!)
Side effects of H2 receptor antagonist
These may occur with long term use but are rare:
- Diarrhoea
- Muscle Cramps
- Transient Rashes
- Hypergastrinaemia (as H2 antagonist may also block D cells)
Cimetidine may cause gynaecomastia in men and inhibits P450 enzymes which will decrease metabolism of a number of drugs that are metabolised by P450 enzymes which would increase their concentration in plasma which could have other effects.
How do we know which drug is best (for inhibiting HCl secretion)?
We plot the % of acid inhibition against the concentration of drug,
e.g. we can see cimetidine is shifted to the right compared to rantidine. We look at the drug which has the lowest IC50, this is the concentration that produces 50% response.
We can see that ranitidine produces a 50% response at a lower dosage (has a lower IC50), this means it is much more potent.
Clinical uses of Proton Pump Inhibitors
- For peptic ulcers, reflux oesophagitis, as a component of therapy for H. pylori
- Can also be used in treatment of Zollinger- Ellison syndrome
These are drug of choice especially if hypersecretion occurs e.g. Zollinger- Ellison syndrome (tumour producing gastrin)
How do Proton Pump Inhibitors work?
The mechanism of proton pump inhibitors is that they are weak bases, so are inactive at neutral pH but then when pH lowers they irreversibly inhibit the H+/K+ ATPase pump. It decreases basal and food-stimulated gastric acid secretion.
With this it doesn’t matter where stimulation is coming from, as the actual pump is blocked.
The effects are also long lasting and doesn’t seem to matter if you take a low or high dosage.
Side effects of proton pump inhibitors
Headache, diarrhoea, mental confusion, rashes, somnolence, impotence, gynaecomastia, dizziness
What is a drug that protects gastric mucosa?
Prostaglandins (PGE2 and PGI2) we know are gastroprotective.
So we could produce analogues of it, e.g. misoprostol (a stable analogue of PGE1)
The mode of action of misoprotosol is that it inhibits basal and food stimulated acid secretion, it also inhibits histamine and caffeine induced gastric secretion.
It also increases mucosal blood flow and can augment the secretion of HCO3- and mucus.
So it works very similar to the real prostaglandin!
