Lecture 33

Question 1

What are the two main group of drugs that inhibit gastric acid secretion?

Answer 1

1) H2 receptor antagonist (burimamide).

2) Proton pump inhibitors.

Question 2

What is histamine involved in?

Answer 2

Both acid secretion and allergic reaction.

Question 3

Describe the H1 receptor?

Answer 3

On smooth muscle and endothelial cells. Involved in allergy.
N.B. Anti-histamines are H1 receptor antagonists.

Question 4

Describe H2 receptor?

Answer 4

On parietal cells. Involved in gastric acid.

Question 5

Describe H2 receptor antagonists?

Answer 5

• These compete with histamine (agonist) for the binding site i.e. competitive antagonist.
• These can be “overcome” by strong agonist effect.
• Increasing doses - less additive effect.
• Rapid action (within 30 minutes), duration is 6-8 hours.
• Tolerance (tachyphylaxis): first does is most effective.

Question 6

What are the problems with H2 antagonists?

Answer 6

1) Not effective for many patients with heartburn.
2) Unable to heal moderate-severe reflex oesophagitis.
3) Need for multiple doses - four times per day for severe symptoms.
4) Maximum acid suppression - 50%.
5) Ok for peptic ulcer (given as sing;e night-time dose) but recurrence on stopping.

Question 7

Describe proton pumps?

Answer 7

They’re located on the gastric parietal cells and are responsible for acid secretion.

Question 8

Describe proton pump inhibitors?

Answer 8

1) Omeprazole is absorbed into the blood -> parietal cell.
2) Passes across parietal cell to canaliculi.
3) In canaliculi, converted to active sulphonamide in presence of acid.
4) Reacts with sulphydryl group of cysteine (amino acid) at proton pump.

Question 9

What do proton pump inhibitors do?

Answer 9

They provide irreversible blockage of activated proton pump.

Question 10

What is the duration of omeprazole?

Answer 10

Long duration - only need to take it once daily or twice as some duration is

Question 11

Can inhibition be overcome in omeprazole?

Answer 11

Blockage cannot be overridden by increased stimulation from histamine, gastrin or ACh.
>90% acid suppression in most people.

Question 12

What are the potential problems with long-term acid suppression?

Answer 12

1) Bacterial overgrowth of the stomach.
2) Malabsorption - acid helpful for absorption B12, Fe and Ca.
3) Potential formation of carcinogenic compounds.
4) acid required to sterilise food - small risk of enteric infections.
5) ECL hyperplasia secondary to high gastrin (compensatory response).

Question 13

What are the practical tips for H2 Receptor antagonists?

Answer 13

1) They’re good for “if required” dosing because of rapid onset and good first does effect.
2) Most effective in reducing nocturnal acid secretion.
3) Not as good for todd-stimulated acid-secretion.

Question 14

What are the practical tips for proton pump inhibitors?

Answer 14

1) Several days for maximal effect.
2) Good for maintenance treatment.
3) Prevention of degradation by gastric acid (enteric coated).
4) A meal to stimulate proton pumps - give 30 minutes before meal.

Question 15

What are the use of proton pump inhibitors?

Answer 15

1) Gastro-oesophageal reflux disease.
2) Not required as much for ulcer disease.
3) Required in ulcer disease causes by non-steroidal anti-inflammatory drugs (NSAIDs).
4) Useful for acute ulcer bleeding:
- Possible mechanism: decreases activity of pepsin when pH>5.
- Pepsin may dissolve fibrin clot in a vessel in the ulcer base.

Question 16

Describe the effect of the gut on drug delivery?

Answer 16

1) Acid degradation - some drugs may need to be enteric coated/delayed release.
2) Acid enhanced absorption - itraconazole.
3) Effect of rate of gastric emptying - matching insulin and meals.
4) Hepatic enzyme function - cytochrome p450 pathway.
5) Enterohepatic circulation/biliary secretion.

Question 17

Describe Case 1?

Answer 17

• 50yo man with chronic pancreatitis from long history of excessive alcohol.
• Develops steatorrhoea.
• Diagnosed with fat malabsorption from pancreatic exocrine insufficiency.
• Plan is to have supplement pancreatic enzymes.

Question 18

What are the problems with replacing pancreatic enzymes in chronic pancreatitis?

Answer 18

1) Large volume of enzyme required to replace normal function.
2) degradation by gastric acid.
3) Need for neutral pH in the duodenum.
4) Release in the proximal small bowel.

Question 19

What are the partial solutions with replacing pancreatic enzymes in chronic pancreatitis?

Answer 19

1) enteric coated capsules - problems with size and delayed release.
2) Non-enteric coated but also giving a proton pump inhibitor.

Question 20

Describe Case 2?

Answer 20

• 20yo man with bloody diarrhoea for 6 months, presents for colonoscopy.
• Diagnosed with mild ulcerative colitis affecting left and transverse colon.
• Plan is to start 5-aminosalicylic acid.

Question 21

What are the problems with giving anti-inflammatory medication (5-aminosalicytic acid 5-ASA) to the inflamed part of the SI or LI?

Answer 21

1) 5-ASA is the active drug used to treat IBD but is degraded by gastric acid.
2) 5-ASA needs to be delivered in highest concentration to areas of inflammation - mostly colon and terminal ileum.

Question 22

What are the possible solutions for giving anti-inflammatory medication (5-aminosalicytic acid 5-ASA) to the inflamed part of the SI or LI?

Answer 22

1) Join two 5-ASA molecules together with an ago bond - needs colonic bacteria to cleave bond.
2) Enteric coated - resists gastric breakdown.
3) pH-dependent release (neutral/alkaline pH).
4) Time-dependent release.

Question 23

What is sulphasalazine?

Answer 23

Made up of two 5-ASA linked to sulphapyridine, allows to travel to colon before being degraded by bacteria.
Uses colonic bacteria to be released at appropriate site.

Question 24

What are the limitations of sulphasalazine?

Answer 24

1) Adverse effects (hypersensitivity or intolerance in 20% of patients) - caused by “sulphur” part (sulphapyridine).
2) Only acts in colonic disease.
3) Higher doses may be more effective but cause severe adverse effects in most patients.

Question 25

Describe Case 3?

Answer 25

• 36yo woman takes ibuprofen for 6 weeks for sprained ankle.
• Presents with melaena and had gastroscopy.
• Diagnosed with gastric ulcers.
• Plan is to stop ibuprofen and start omeprazole.

Question 26

What is the problem with anti-inflammatory drugs?

Answer 26

1) NSAIDs very common treatment for arthritis and musculoskeletal pain - frequent cause of hospital admission even though risk per prescription is low.
2) NSAIDs can cause gastrointestinal bleeding from gastric ulceration.

Question 27

How do NSAIDs effect gastric mucosa?

Answer 27

Cause mucosal injury mainly via systemic (rather than topical) effects.

Question 28

What is the mechanism of NSAIDs causing mucosal injury?

Answer 28

Inhibit COX-1.

Question 29

What does COX-1 do?

Answer 29

COX-1 is an enzyme that is important in synthesis of prostaglandins.
These prostaglandins include those with inflammatory activity and cytoprotective activity (coat stomach lining with mucus and aid platelet aggregation).

Question 30

How do you reduce risk of GI bleeding from NSAIDs?

Answer 30

1) Stop NSAIDs - is the drug required?
2) Are there alternatives to NSAIDs?
3) Use lowest possible does.
4) Use a “protective” drug: proton pump inhibitor.
5) COX-2 inhibitors.

Question 31

Describe COX-2 inhibitors?

Answer 31

1) Newer drugs.
2) COX-2 is only involved in formation of inflammatory prostaglandins.
3) Inhibition of COX-2 has reduced effect on cytoprotective prostaglandins.
4) Reduced risk of bleeding (50%) but more expensive and increased risk of myocardial infarction.