Peptic ulcers Flashcards by Millie Pates McAllister

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.

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Hormonal control of GI tract

Under endocrine and paracrine control

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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

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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

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Amylases

secreted from salivary glands and pancreas, act on starch

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Lipases

Secreted from salivary glands, stomach and pancreas, act on triglycerides

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Pepsin

secreted from stomach, acts on proteins

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Trypsin and chymotrypsin

secreted from pancreas, acts on peptides

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Disaccharidases

secreted from intestinal epithelium
sucrase - sucrose
maltase - maltose
lactase - lactose

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Peptidases

secreted from the intestinal epithelium
endopeptidases
exopeptidases

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GI secretions

volume and pH of secretions fluctuates throughout the GI tract

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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

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Parietal cells

produce HCl for digestion

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Chief cells

release enzymes needed for digestion of proteins

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Foveolar cells

produce special type of mucus consisting of water, mucin and surfactants

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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