Pharmacology of gastric control Flashcards
Explain what peptic ulcers look like and what they are exposed to
- usually solitary lesions (one at a time)
- sores in areas of GI tract exposed to acid/peptic juices from stomach and duodenum
- shows spontaneous release and remission
- not common in oesophagus unless you have gastric reflux, most common in duodenum
What are the main ulcer symptoms?
Abdominal pain, typically: an epigastric burning sensation ofter nocturnal.
If duodenal - heartburn and bloating.
What are two complications of ulcers?
Penetration (into an organ): ulcer burrows into the pancreas or liver which opens into the peritoneal cavity. Contents of the GI tract then attack other organs.
Upper GI bleeding: ulcer erodes into an artery and the artery bleeds into stomach.
How do ulcers develop?
Lining of the stomach secretes many substances. With ulcers, we are interested in mucus, acid and bicarbonate.
Oxyntic gland is in the stomach and this is involved in secreting these substances from the different glandular cells. The parietal cells secrete mucus and a high concentration of HCl.
This is useful for digestion as it is a non-selective digestive agent and a disinfectant. Important for covering pepsinogen to pepsin. This tends to damage the mucosa of the stomach. The mucus is what protects the lining of the stomach, it mixes with the stomach and sits on the surface of the mucosa forming a barrier.
In an ulcer, mucosa protection is defective so the acid attacks the lining.
What 6 factors were thought to / do cause peptic ulcers?
- Acid hypersecretion which doesn’t
- Stress
- Smoking
- Non-steroidal anti-inflammatory drugs
- Helicobacter pylori
- Zollinger-Ellison syndrome
Explain the main cause of gastric and duodenal ulcers?
Gastric:
- Usually H pylori infection of the gastric corpus
- Low to normal levels of gastric acid
- Defect in gastric mucosal resistance
Duodenal:
- Usually H pylori infection of the gastric antrum
- Increased secretion of acid/pepsin, duodenum mucosa becomes like gastric mucosa
- H pylori can then affect the duodenum
- Gastric metaplasia in duodenum which can be infected by H pylori
What happens once infected with the bacteria?
When one is affected this the bacteria, this causes acute inflammation. Can lead to chronic gastritis either predominant in antrum (leading to duodenal ulcers) or in the corpus of stomach (infection changes the stomach cells so they become worse at producing mucus)
Give some details on H pylori
•A spiral shaped bacterium causing chronic gastritis
•Grows on surface of epithelial cells, beneath the layer of mucus
•Causes increased secretion of gastrin (promotes acid release) and pepsin, may produce toxins which damage the mucosa
•Incidence rises with age (eg 50% at 50yrs)
•Certain strains may be especially pathogenic:
Cag pathogenicity island: Genes coding for CagA (a cytoskeleton- disrupting protein) and a type IV secretion system which injects the cagA protein into epithelial cells.
What does H pylori secrete and how do we test for it?
Secretes a urease which converts endogenous urea to bicarbonate and CO2, thus protecting itself from gastric acid.
Can be tested by testing for antigen in stool samples or antibodies in blood.
What were the 4 steps which lead to the bacteria linked to ulcers?
- The specific organism should be shown to be present in all cases of animals suffering from a specific disease but should not be found in healthy animals.
- The specific micro-organism should be isolated from the diseased animal and grown in pure culture on artificial laboratory media.
- This freshly isolated micro-organism, when inoculated into a healthy laboratory animal, should cause the same disease seen in the original animal.
- The microorganism should be re-isolated in pure culture from the experimental infection.
What are the two ways of treating these ulcers?
Restore balance in mucosal defence system and acid
Treat infection
Parietal cells release acid through ATP driven —- potassium exchanger. This is regulates by histamine, rebased from ECL cells in —- —-.
This acts on H2 receptor in cells which —- the cAMP concentration causing the acid pump to turn on and pump out HCl. —- also has an affect, along with histamine, on the acid release (works via the ENS on stomach cells so release more histamine or to increase —- to help activate the acid pump). Another thing that affects the acid pump is gastrin (released by G cells in —- and gets into gastric mucosa via blood stream and then does the same thing with histamine and calcium).
proton
gastric mucosa
increases
Ach
calcium
pancreas
What does the mucosal defence system work by?
Explain this
Mucosal defence system works via prostaglandins. This acts on EP3 receptors on mucus releasing cells getting them to secrete mucus and HCO3-. Also acts on parietal cells to suppress HCl secretion. Prostoglandin is a vasodilator so dilates the arterioles and capillaries which then increases blood flow to dilate the acid secretion.
What do proton inhibitors and H2 receptor blocks do?
Block acid release
Explain how proton pump inhibitors block acid release
- Irreversibly block parietal cell H+/K+-ATPase.
- Inactive pro-drugs (drugs that metabolised into the real drug) at neural pH. Goes in parietal cells and the secrete it into the oxyntic gland where it can then become activated.
Accumulate in the oxyntic glands and are converted to sulfenamides at pH < 3
These react covalently with sulphydryl groups on the H+/K+ ATPase, causing prolonged and >90% inhibition of acid secretion - 1st line drug for ulcer healing
- Adverse effects: uncommon, but long term use can cause osteoporosis
However PPI withdrawal can cause rebound acid hypersecretion
