Peptic ulcers Flashcards
Neuronal control of the GI tract
Blood vessels, smooth muscle (pushes food through) and glands
Myenteric plexus and submucosal plexus
Acetylcholine and noradrenaline from these structures
Also GABA, serotonin, purines and nitric oxide
Peptides: VIP, cholecystokinin, etc.
Hormonal control of GI tract
Under endocrine and paracrine control
Endocrine hormones: released into bloodstream
Gastrin (G-cells): stimulates acid secretion in stomach
Cholecystokinin (duodenum): stimulates vagal afferents after fatty meal → helps movement of food through vagal system
Paracrine hormones: released locally
Histamine (ECL cells): stimulates acid release from nearby parietal cells
Secretin (duodenum): stimulates bicarbonate release from pancreas
Somatostatin (D-cells): inhibits gastrin and histamine release → acts as off mechanism for gastrin
Amylases
secreted from salivary glands and pancreas, act on starch
Lipases
Secreted from salivary glands, stomach and pancreas, act on triglycerides
Pepsin
secreted from stomach, acts on proteins
Trypsin and chymotrypsin
secreted from pancreas, acts on peptides
Disaccharidases
secreted from intestinal epithelium
sucrase - sucrose
maltase - maltose
lactase - lactose
Peptidases
secreted from the intestinal epithelium
endopeptidases
exopeptidases
GI secretions
volume and pH of secretions fluctuates throughout the GI tract
Stomach
made up of gastric pits - highly vascularised layers of muscle and tissue
gastric pits in mucosal layer → increase available surface area, increasing space available for secretion of key hormones and other digestive processes
parietal cells
chief cells
eneteroendocrine cell
Parietal cells
produce HCl for digestion
Chief cells
release enzymes needed for digestion of proteins
Foveolar cells
produce special type of mucus consisting of water, mucin and surfactants
G-cells
produce gastrin which enhances acid production by parietal cells
D-cells
produce somatostatin which inhibits acid production by parietal cells
ECL cells (enterochromaffin-like cells)
Produce histamine which enhances acid secretion from parietal cells
Secretagogues
Regulation of acid secretion
- Gastrin
- Histamine
- Acetylcholine
- Somatostatin
- Prostaglandins
-gastrin produced from G cells
-acts on ECL cells - CCK2R
-ECL cell produces histamine - H2R
-acts on parietal cell
-through symport and antiport mechanism, produces HCl
-efflux of H+ and Cl- ions to make HCl
-somatostatin acts on these cells via SST2R, inhibiting HCl prodduction
-ACh also stimulates HCl production
-prostaglandins also act on ECL cells
Mechanism of acid secretion
Antiport: HCO3- out vs Cl- in
Symport carrier: K+ out vs Cl- out
Proton pump (P): H+ out vs K+ in
Peptic ulcers
damage to GI tract
acid and protease secretions are not regulated properly and stomach lining not protected from the strong acid
inappropriate build up of stomach acid causes damage to cells
Causes of peptic ulcers
Stress
Diet
Alcohol
Obesity
H. Pylori
NSAIDs
Helicobacter pylori
Gram-negative bacterium
Infects upper GI tract of 50% of world’s population; >80% are asymptomatic
Carriers: 10-20% lifetime risk of gastric ulcer; 1-2% stomach cancer
Impact of NSAIDs
Non-steroidal anti-inflammatory drugs (NSAIDs) amongst the most commonly used drugs in history
Aspirin, ibuprofen, celecoxib, etc.
Exert effects via inhibition of COX1 and COX2, differential selectivity
Cytoprotective effects of PGE2 and PGI2 reversed by many NSAIDs
Long-term NSAID use causes gastric erosions, bleeding and pain
Antacids
Dyspepsia and symptomatic relief from peptic ulcers
Increase gastric pH to ~5 by direct acid neutralisation → due to overproduction of stomach acid
Inhibit conversion of pepsinogen to pepsin
Aluminium and magnesium salts
Al hydroxide: slow to dissolve, long duration, constipation
Mg hydroxide: rapid onset, laxative
Mg trisilicate: prolonged effect, adsorbs pepsin
-all form chloride salts in stomach
Alginates
Alginates: increase viscosity and adherence of mucus to reduce production of acid
H2 antagonists
Competitive inhibition of histamine effects at H2 receptors (different from H1 antagonists used in allergy)
Main effect is reduction of histamine (and gastrin) stimulated gastric acid secretion; also promote healing of peptic ulcers → inhibit production of gastric acid and protects cells from impact of gastric acids
Low dose forms available over-the-counter (e.g. cimetidine)
Proton pump inhibitors
Potent, selective and irreversible inhibition of the H+ K+ ATPase (or proton pump) - the body will only overcome this by producing more protein - less secretion of H+ and Cl-, would need to make more proton pumps
Terminal and common step in acid secretion from parietal cell; effective irrespective of secretagogue - not reliant on different gastric secretions throughout the mechanism
Prodrugs and weak bases: activated by low pH, accumulate in cannaliculi of parietal cell → able to accumulate where they need to - don’t want them to be degraded at wrong point
Proton pump inhibitors - examples
Main compounds: omeprazole (Losec®), lansoprazole (Loton®)
Omeprazole is enteric coated to protect it from degradation by acid
Half-life ~1h but effects last ~3 days; synthesis of new H+ K+ ATPase
Adverse effects relatively uncommon; headache, diarrhoea, rash
Treatment of H. pylori infection
Test for H. pylori – blood antibody, stool or breath test, endoscopic biopsy
If positive, treat with antibiotics and proton pump inhibitors:
Standard one-week triple therapy: clarithromycin, amoxicillin, omeprazole
Penicillin allergy: replace amoxicillin with metronidazole
Levofloxacin for clarithromycin-resistant strains
Bismuth chelate added – quadruple therapy – prevents bacillus adherence to mucosa
Triple therapy eradicates H. pylori and is curative but re-infection can occur
Misoprostol
stable synthetic analogue of PGE1
co-predcribed with NSAIDs during long-term use
direct action via EP2 receptor on ECL cells, possible additional effect on parietal cells
inhibits basal secretion of gastric acid and increased acid production in response to food
enhances mucus and bicarbonate production
can initiate uterine contractions - not used in pregnancy
