2.2. Anti- ulcer drugs

Question 1

Peptic ulcer disease – area of damage to the inner lining of the stomach (gastric ulcer) or upper part of the duodenum (duodenal ulcer)

• More common in the duodenum than the stomach (4:1)
• Due to imbalance of protective factors or damage of gastrointestinal barrier
• Differences in presentation
  o Gastric ulcers – pain at ___________________
  o Duodenal ulcers – pain ___________________________

Gastrointestinal barrier – the integrity of the gastrointestinal mucosal barrier is important in maintaining a disease free state
- Protective factors lubricate ingested food and protect the stomach and duodenum from attack by acid and enzymes
o Mucous from gastric mucosa creates gastrointestinal mucosal barrier
o HCO3- ions trapped in mucous generate a pH of
6 to 7 at mucosal surface (pH of gastric lumen is pH 1 to 2)
o Locally produced ________________ stimulate mucous and bicarbonate production (paracrine action) and inhibit gastric acid secretion

- Other factors which are needed to convert food into a thick semi-liquid paste (chyme) have the potential to damage the mucosal barrier
o Acid secretion from \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_ in the gastric mucosa
o Pepsinogens (pepsin type 1) from the \_\_\_\_\_\_\_\_\_\_\_\_ which can erode the mucous layer

Pathogenesis of peptic ulcer disease – not well understood
- Certain factors which may cause damage to mucosal gastrointestinal barrier
o Increased acid and/or decreased bicarbonate production
o Decreased thickness of mucosal layer
o Increase in pepsin type I
o Decreased mucosal blood flow – _____________ contributes to gastric ulcers
o Infections with Helicobacter pylori (discovered 1982)
- Risk factors – genetic predisposition, stress, diet and smoking
- Prevalence – 1:10 population in developed countries

Answer 1

mealtimes when gastric acid is secreted;

relieved by a meal as pyloric sphincter closes, appears 2 to 3 hours after a meal;

prostaglandins;

parietal cells of the oxyntic glands;

chief cells;

mucosal ischemia

Question 2

Gastric acid secretion and control
- Gastric acid is secreted by parietal cells (oxyntic cells) – membrane of canaliculus of parietal cells have ________________ to increase surface area for acid secretion
- In parietal cells, vesicles contain ____________ pumps – able to pump H+ against a gradient of million to 1 (steepest in the body)
o When the parietal cell is activated, these vesicles move and coalesce with the _______________-allowing secretion of gastric acid to the lumen
- Vagus and enteric neurones release ACh – binds to AchM R on enterochromaffin cells and parietal cells
o Enterochromaffin cell – increases release of histamine
o Parietal cell – increases _______________, activating _________________

• Enterochromaffin cells produce histamine – binds to H2 R in parietal cells
  o Activates _____________ , converting more ATP to cAMP, in turn activating protein kinases
• Endocrine cells of mucosa produce gastrin – activates enterochromaffin cells to produce more histamine
  o Binds to parietal cells – calcium-protein kinase pathway
• Protein kinase activation – activation of parietal cell, vesicles with H-K ATPase pumps move and attach to the membrane , leading to more acid secretion
• Locally produced prostaglandin E2 binds to receptor on parietal cell – inhibits adenyl cyclase production of cAMP , reducing acid secretion

Answer 2

extensive invaginations;

H+-K+ ATPase;

luminal membrane ;

intracellular Ca2+ ;

protein kinases;

adenyl cyclase

Question 3

Antacids – neutralise gastric acid mainly salts of Na, Al and Mg e.g. GAVISCON

• Sodium bicarbonate has rapid effects whereas aluminum hydroxide and magnesium trisilicate have slower actions – used in combinations
• Neutralize acid – raises gastric pH and reduces ______________ activity
• Taken orally, primarily used for __________________ – may be effective in reducing duodenal ulcer recurrence rates

Answer 3

pepsin;

non-ulcer dyspepsia

Question 4

Proton pump inhibitors e.g. OMEPRAZOLE – inhibits basal and stimulated gastric acid secretion from the parietal cell by >90%
- PPIs are irreversible inhibitors of the H+-K+ ATPase – inactive at neutral pH
o A weak base – accumulates in the ___________________, concentrating its action there and prolongs its duration of action (2 to 3 days)
o Minimizes its effect on ion pumps elsewhere in the body – reducing side effects
- Uses of PPI – component of triple therapy, peptic ulcers resistant to H2 antagonists, ________________
- Orally active, administered as enteric coated slow-release formulations to prolong duration of action
- Unwanted effects are generally rare

Answer 4

canaliculi of parietal cells;

reflux oesophagitis

Question 5

Histamine type 2 receptor antagonists e.g. ___________ – inhibits gastric acid secretion by approximately 60% and are less effective at healing ulcers than PPIs

• Orally administered, well absorbed with rarely unwanted effects – allows healing of ulcers in weeks by preventing gastric acid secretion
  o However, >90% recurrence within 1 year after initial healing if the patient stops the drug
• Anti-muscarinic agents – little use as anti-ulcer drugs as there are other factors and pathways that can produce acid even if muscarinic receptors are blocked

Answer 5

CIMETIDINE, RANTIDINE

Question 6

Cytoprotective drugs – enhance mucosal protection mechanisms and/or build a physical barrier over the ulcer
1. Sucralfate – a polymer containing _______________________
- Acquires a strong negative charge in an acid environment, binds to positively charged groups in large molecules (proteins, glycoproteins) resulting in gel-like
complexes on the lining of the gastric mucosa
o Coat and protect the ulcer, limit H+ diffusion and pepsin degradation of mucus – increases PG, mucous and HCO3- secretion and reduces the number of H. pylori
- Side effects – most orally administered drug remains in GI tract as it is a large compound and not absorbed, leading to _______________ (15%)
o Reduces absorption of some other drugs as it lines the stomach lumen e.g. antibiotics and digoxin

2. _______________ – acts like sucralfate and used in triple therapy (resistant cases)
3. Misoprostol – a stable ___________________, mimics the action of locally produced PG to maintain the gastroduodenal mucosal barrier
   - May be co-prescribed with ___________________ when used chronically e.g. aspirin
   o NSAIDs block COX enzyme required for PGE synthesis from arachidonic acid
   o Reduction in the natural factors that inhibit gastric acid secretion and stimulate mucus and HCO3- production (iatrogenic cause of ulcer)
   - Similarly in patients taking glucocorticoids e.g. prednisolone and dexamethasone
   - Unwanted effects – acts potently on smooth muscle, leading to diarrhoea, abdominal cramps, _______________ (contraindicated in pregnancy)

Answer 6

aluminium hydroxide and sucrose octa-sulphate;

constipation;

Bismuth chelate;

prostaglandin analogue

oral non-steroidal anti-inflammatory drugs (NSAIDs);

uterine contractions

Question 7

Antibiotics – to eliminate Helicobacter pylori (Gram negative bacterium)
- H. Pylori –
o Gram negative spirals
o Grows in \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_
o \_\_\_\_\_\_\_\_\_\_\_ positive

• Inclusion of antibiotics along with inhibitors of gastric acid secretion or cytoprotective agents in the treatment of peptic ulcers reduces relapse rates from >90% to <15% (Hentschel, E New England Journal of Medicine 1993, 328: 308-12)
  o Patients were treated with ranitidine for 6 to 10 weeks to attain healing of their ulcer
  o One group also received antibiotic treatment for 12 days, while the other received placebo
  o Endoscopy was performed at intervals after healing to determine recurrence of disease
• Rationale for using antibiotics – 50 to 80% of population worldwide are chronically infected (low grade infections cause gastritis)
  o 10 to 20% of which go on to develop peptic ulcer disease or neoplasia (mechanisms unknown - genetic/virulence of strain)
  o Almost 100% of patients with duodenal ulcer and 80 to 90% with gastric ulcer are infected with H. pylori - Current therapy aims for 90% eradication within 7 to 14 days

Answer 7

microaerophilic conditions;

Oxidase;

Question 8

Triple therapy is currently best practice in treating peptic ulcer disease – a single antibiotic is not sufficiently effective partly due to development of resistance.

Problems of triple therapy
o Compliance
o Development of resistance – vaccinations may soon be available
o Adverse response to alcohol, especially with metronidazole – as it interferes with alcohol metabolism)

What are the 3 examples of triple therapy?

Answer 8

Option 1

1) Metronidazole (active against anaerobic bacteria and protozoa) or amoxycillin (broad spectrum antibiotic) depending on pattern of local resistance
2) Clarithromycin – antibiotics with a macrolide structure; inhibits translocation of bacterial tRNA)
3) Proton pump inhibitor (PPI) – improves antibiotic efficiency possibly by increasing gastric pH which improves stability and absorption

Example 2

1) H2 receptor antagonists
2) Clarithromycin – antibiotics with a macrolide structure; inhibits translocation of bacterial tRNA)
3) Bismuth – heavy metals are antibacterial. Bismuth chelate itself managed to prolong remission in 30% cases

Example 3

1) Metronidazole
2) Amoxycillin
3) Bismuth – heavy metals are antibacterial. Bismuth chelate itself managed to prolong remission in 30% cases

Question 9

Gastroesophageal reflux disease (GERD)
- Stomach and duodenal contents reflux into the oesophagus (oesophagitis) – occasional and uncomplicated GERD
o Uncomplicated GERD can present with heartburn – self-medication with ______________________
- Chronically may progress to pre-malignant mucosal cells and potentially oesophageal adenocarcinoma
o Treat with PPIs (drugs of choice) or H2 antagonists (less effective)
o Combine with drugs that increase gastric motility and emptying of the stomach e.g. __________________

Answer 9

antacids and H2 antagonists;

DA2 receptor antagonists (metoclopramide)