L19 Clinical Pharmacology Gut acid secretion

Overview

This lecture covers why gut acid secretion needs pharmacological modulation, the therapeutic targets along the parietal-cell acid-secretion pathway, and the drug classes that act on them (antacids, proton pump inhibitors, mucosal strengtheners, H2 antihistamines and muscarinic antagonists). It then applies these to two clinical settings: gastro-oesophageal reflux disease (GERD), with its severity staging and antisecretory regimens, and peptic ulcer, including NSAID-associated ulcer, Helicobacter pylori infection and its eradication regimens. A single recurring drug-target schematic anchors the lecture and is returned to before each drug class.

Gastric acid secretion: cells and signalling

Key points to know:

• Gastric gland structure, from lumen inwards: surface epithelium, mucous neck cells, oxyntic (parietal) cells, peptic (chief) cells.
• The oxyntic/parietal cell has canaliculi into which acid is secreted.
• Core signalling loop: gastrin (from G cells) acts on the ECL cell, the ECL cell releases histamine onto the parietal cell, and this drives acid secretion.
• Three stimulatory inputs converge on the parietal cell:
  • Gastrin on CCK2 receptors, acting through a Ca2+-dependent pathway.
  • Histamine from ECL cells on H2 receptors, acting through a cAMP-dependent pathway.
  • ACh from vagal/enteric neurons, acting on M1 receptors at the ganglion and M3 receptors on the parietal cell.
• All of these converge on the H+/K+-ATPase (the proton pump), which secretes H+ in exchange for K+; a separate K+/Cl- channel is present in the same membrane.
• Prostaglandin input is inhibitory: gastric mucosa makes PGE2 and PGI2 from C20 fatty acids; these act on EP3 receptors on parietal and superficial epithelial cells to lower cAMP, reducing acid and stimulating mucus/HCO3- secretion (cytoprotection).

The mucus layer

• A 500 µm protective barrier.
• A mucus gel containing secreted HCO3- (base).
• The HCO3- neutralises stomach acid so the inner mucosal layer stays at neutral pH 7 even though the gastric lumen is at pH 2.

Warning

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Drug targets on the schematic

The recurring “Gut Acid – Drug Targets” diagram maps each class onto the pathway:

• Muscarinic antagonists (including pirenzepine) block M1/M3 cholinergic input.
• H2 antagonists block histamine action at the H2 receptor.
• Proton pump inhibitors block the H+/K+-ATPase directly.
• Antacids neutralise H+ after it has been secreted.
• NSAIDs inhibit C20 fatty acid conversion to PGE2/PGI2, removing the protective prostaglandin signal.
• Misoprostol substitutes for those prostaglandins at EP3 receptors.
• Sucralfate and carbenoxolone act on the mucus layer.
• H. pylori, shown adjacent to the mucus layer, is targeted by bismuth, metronidazole, tetracycline, clarithromycin and amoxicillin.

Antacids

Antacids act in the lumen, neutralising secreted acid. Composition and acid-neutralizing capacity (ANC, milliequivalents per tablet or per 5 mL) of popular preparations, with Al(OH)3 / Mg(OH)2 / CaCO3 / simethicone in mg:

Tablets:

• Gelusil: 200 / 200 / 0 / 25, ANC 10.5
• Maalox Quick Dissolve: 0 / 0 / 600 / 0, ANC 12
• Mylanta Double Strength: 400 / 400 / 0 / 40, ANC 23
• Riopan Plus Double Strength: magaldrate 1080, simethicone 20, ANC 30
• Calcium Rich Rolaids: Mg(OH)2 80, CaCO3 412, ANC 11
• Tums EX: CaCO3 750, ANC 15

Liquids:

• Maalox TC: 600 / 300 / 0 / 0, ANC 28
• Milk of Magnesia: 0 / 400 / 0 / 0, ANC 14
• Mylanta Maximum Strength: 400 / 400 / 0 / 40, ANC 25
• Riopan: magaldrate 540, ANC 15

Notes from the table: magaldrate is a magnesium aluminium hydroxide complex. The current trend of reusing well-known brand names for new products containing a different active ingredient than expected is a source of confusion that can present a danger to patients.

Proton pump inhibitors

• The four PPIs shown are lansoprazole, omeprazole, rabeprazole and pantoprazole.
• Mechanism: omeprazole is converted, by H+ in the acidic secretory canaliculi of the parietal cell, to a sulfenamide intermediate, then to a sulfenic acid, which reacts covalently with a sulfhydryl (cysteine) group on the enzyme to form an enzyme-inhibitor complex, irreversibly inhibiting the proton pump. The other three PPIs undergo analogous conversions.
• Kinetics: half-life 0.5-2 hours, but duration of action 24-48 hours (irreversible inhibition uncouples duration from plasma half-life).

Mucosal strengtheners

Prostaglandin analogues (misoprostol)

• Gastric mucosa signals through PGE2 and prostacyclin (PGI2).
• These bind the EP3 receptor on parietal cells and stimulate Gi protein, decreasing intracellular cAMP and gastric acid secretion, and stimulating mucus secretion.
• Misoprostol is the synthetic analogue: 15-deoxy-16-hydroxy-16-methyl-PGE1.
• Dose-related inhibition: an oral dose of 100-200 μg inhibits basal acid secretion by 85-95% and food-stimulated acid secretion by 75-85%.
• Pharmacokinetics: rapidly absorbed orally; rapidly de-esterified to misoprostol acid, the principal active metabolite. A single dose inhibits acid production within 30 minutes, peaks at 60-90 minutes, and lasts up to 3 hours.
• Adverse effects: diarrhoea, with or without abdominal pain and cramps, in up to 30% of patients.

Important

Misoprostol is contraindicated in pregnancy because it increases uterine contractility.

Sucralfate

• Sucrose octasulfate conjugated to Al(OH)3.
• Under acidic conditions (pH <4) it cross-links to form a viscous polymer that adheres to cells for up to 6 hours.
• Because it is activated by acid, it should be taken on an empty stomach, and antacids should not be given within 30 minutes of a dose.
• Adverse effects: constipation is the most common (~2%); the viscous layer can inhibit absorption of other drugs.

Warning

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Histamine and H2 receptor antagonists

• Histamine’s major sources: mast cells (tissues), basophils (blood), enterochromaffin-like (ECL) cells (gut).
• It is formed by decarboxylation of L-histidine by histidine decarboxylase.
• It mediates multiple cell actions through histamine receptors H1-H4.
• H2 receptor antagonists: main use is to inhibit gastric acid secretion; they have CYP450 enzyme interactions.
• The agents shown, with histamine as the reference structure: cimetidine, ranitidine, famotidine, nizatidine.
• Tolerability: well tolerated. Adverse effects in <3%: diarrhoea, headache, drowsiness, fatigue, muscular pain, constipation. Less common effects (confusion, hallucinations, slurred speech, headaches) occur with intravenous administration or in elderly subjects.

Muscarinic antagonists

• Muscarinic receptors involved in acid secretion: M1 subtype at the ganglia, M3 subtype on the parietal cell.
• M1 muscarinic receptor antagonists reduce basal acid production by 40-50%. Pirenzepine is the example given.
• Limitations: relatively poor efficacy, and anticholinergic side effects including decreased motility and constipation.
• Rarely used.

GERD

Epidemiology and severity

• Prevalence of heartburn in Western populations, by symptom frequency (proportion, approximate means read from the plot): monthly ~0.25, weekly ~0.12, daily ~0.045.
• Los Angeles classification of oesophagitis:
  • Grade A: one or more mucosal breaks no longer than 5 mm, not extending between the tops of two mucosal folds.
  • Grade B: one or more mucosal breaks more than 5 mm long, not extending between the tops of two mucosal folds.
  • Grade C: one or more mucosal breaks continuous between the tops of two or more mucosal folds, but involving less than 75% of the circumference.
  • Grade D: one or more mucosal breaks involving at least 75% of the oesophageal circumference.

Staged medical management

Guidelines shown cover only drugs that suppress or neutralise acid.

• Stage I: sporadic uncomplicated heartburn, often with a known precipitating factor, often not the chief complaint, fewer than 2-3 episodes per week, no additional symptoms. Management: lifestyle modification (diet, positional changes, weight loss) plus antacids and/or H2 receptor antagonists as needed.
• Stage II: frequent symptoms with or without oesophagitis, more than 2-3 episodes per week. Management: proton pump inhibitors, which are more effective than H2 receptor antagonists.
• Stage III: chronic unrelenting symptoms, immediate relapse off therapy, oesophageal complications such as stricture or Barrett’s metaplasia. Management: a proton pump inhibitor once or twice daily.

Antisecretory regimens for treatment and maintenance of GERD

H2 receptor antagonists: cimetidine 400/800 mg bid; famotidine 20/40 mg bid; nizatidine 150/300 mg bid; ranitidine 150/300 mg bid.
Proton pump inhibitors: esomeprazole 20/40 mg daily or 40 mg bid; lansoprazole 30/60 mg daily or 30 mg bid; omeprazole 20/40 mg daily or 20 mg bid; pantoprazole 40/80 mg daily or 40 mg bid; rabeprazole 20/40 mg daily or 20 mg bid. (bid = twice daily; several of these doses are marked as unlabeled use.)

Peptic ulcer

Causes

1. High acid and peptic content
2. Irritation
3. Poor blood supply
4. Poor secretion of mucus
5. Infection, H. pylori

Ulcers are shown at the classic sites in the stomach, including marginal ulcer, with the cardia and pylorus labelled.

NSAIDs

• 2-4% of patients develop ulcer or bleeding with chronic NSAID use.
• The management point emphasised: stop NSAIDs.

Recommendations for treatment of gastroduodenal ulcers (active ulcer -> maintenance)

H2 receptor antagonists:

• Cimetidine 800 mg at bedtime or 400 mg twice daily -> 400 mg at bedtime
• Famotidine 40 mg at bedtime -> 20 mg at bedtime
• Nizatidine/ranitidine 300 mg after the evening meal or at bedtime, or 150 mg twice daily -> 150 mg at bedtime

Proton pump inhibitors:

• Lansoprazole 15 mg daily (duodenal ulcer; NSAID risk reduction) or 30 mg daily (gastric ulcer, including NSAID-associated)
• Omeprazole 20 mg daily
• Rabeprazole 20 mg daily

Prostaglandin analogues:

• Misoprostol 200 μg four times daily for NSAID-associated ulcer prevention. Only misoprostol 800 μg/day has been directly shown to reduce the risk of ulcer complications such as perforation, haemorrhage or obstruction.

Helicobacter pylori

Pathogenesis

The response to infection runs as: H. pylori adheres to the gastric mucosal epithelium -> release of inflammatory mediators -> activation and recruitment of immune cells, including activated T cells -> tissue damage and gastric ulcer. These are presented as two parallel arms, an inflammatory response and an immune response.

Historical evidence

Marshall et al., “Attempt to fulfil Koch’s postulates for pyloric campylobacter,” Medical Journal of Australia 1985;142:436-439. A volunteer with histologically normal gastric mucosa ingested pyloric campylobacter by mouth. A mild illness developed lasting 14 days. Histologically proven gastritis was present on the tenth day after ingestion but had largely resolved by the fourteenth. The authors describe the syndrome of acute pyloric campylobacter gastritis and propose that it may progress to a chronic infection predisposing to peptic ulceration.

Epidemiology

• An estimated 50-60% of the world population is infected.
• Person-to-person transmission: faecal-oral, oral-oral, gastro-oral.
• Increased risk of infection: younger age, underdeveloped countries, lower socioeconomic status.

Diagnostic tests

Determination of the presence of H. pylori by:

• Antibodies in blood, serum or saliva
• Antigen in stool
• Functional tests of the bacterium’s urease enzyme using carbon-labeled urea: $(N{H}_2{)}_{2}CO+H_{2}O\to C{O}_2+2N{H}_3$

The half-life of carbon-14 is 5,730 ± 40 years.

Eradication therapy

• Triple therapy, 14 days: [proton pump inhibitor + clarithromycin 500 mg + (metronidazole 500 mg or amoxicillin 1 g)] twice a day. Tetracycline 500 mg can be substituted for amoxicillin or metronidazole.
• Quadruple therapy, 14 days: proton pump inhibitor twice a day + metronidazole 500 mg three times daily + (bismuth subsalicylate 525 mg + tetracycline 500 mg four times daily); or H2 receptor antagonist twice a day + (bismuth subsalicylate 525 mg + metronidazole 250 mg + tetracycline 500 mg) four times daily.
• PPI dosages used: omeprazole 20 mg, lansoprazole 30 mg, rabeprazole 20 mg, pantoprazole 40 mg, esomeprazole 40 mg.
• H2 receptor antagonist dosages used: cimetidine 400 mg, famotidine 20 mg, nizatidine 150 mg, ranitidine 150 mg.

Matching acid suppression to the indication

The target intragastric pH differs by indication, and the hours per day spent at that pH determine which drug class suffices (approximate values read from the bar chart):

• pH >3, duodenal ulcer: untreated ~4 h, H2 receptor antagonist ~11 h, PPI ~17 h.
• pH >4, GERD: untreated ~2 h, H2 receptor antagonist ~6 h, PPI ~12 h.
• pH >5, H. pylori eradication: untreated ~1 h, H2 receptor antagonist ~4 h, PPI ~9 h.

A shaded band at roughly 18-24 hours is labelled “No Further Improvement”. The pattern to take away: the higher the pH threshold required, the fewer hours per day any drug achieves it, and PPIs outperform H2 antagonists at every threshold.

Self-test

1. Describe the signalling sequence by which gastrin ultimately increases parietal cell acid secretion.
2. List the three stimulatory receptor inputs to the parietal cell, naming the receptor and the second-messenger pathway for each.
3. Describe the composition and function of the gastric mucus layer, including its thickness and the pH values on either side of it.
4. Explain how omeprazole is converted to its active form and how it inhibits the proton pump.
5. Explain why PPIs have a duration of action of 24-48 hours despite a half-life of only 0.5-2 hours.
6. Describe the mechanism by which PGE2 and PGI2 reduce gastric acid secretion.
7. What percentage inhibition of basal and of food-stimulated acid secretion does an oral misoprostol dose of 100-200 μg produce?
8. Predict what happens to gastric mucosal protection when a patient takes a chronic NSAID, and give the step in the pathway that is blocked.
9. Describe the time course of a single misoprostol dose (onset, peak, duration).
10. State the single absolute contraindication to misoprostol given in the lecture and the reason for it.
11. Explain why sucralfate must be taken on an empty stomach and why antacids should be separated from it by at least 30 minutes.
12. List the three major sources of histamine in the body and the enzyme that forms it.
13. Distinguish the muscarinic receptor subtype at the autonomic ganglion from that on the parietal cell, and state how much M1 antagonists reduce basal acid production.
14. Explain why muscarinic antagonists are rarely used for acid suppression.
15. Distinguish LA grade B from LA grade C oesophagitis.
16. A patient reports heartburn about once a fortnight, always after a large meal, with no other symptoms. State the GERD stage and the recommended management.
17. A patient has chronic unrelenting reflux symptoms that relapse immediately off therapy, with an oesophageal stricture. State the GERD stage and the recommended management.
18. List the five causes of peptic ulcer given in the lecture.
19. What proportion of patients on chronic NSAIDs develop ulcer or bleeding, and what is the key management step?
20. State the misoprostol regimen for NSAID-associated ulcer prevention, and the daily dose that has actually been shown to reduce ulcer complications.
21. Describe the sequence of events in the mucosal response to H. pylori infection.
22. Describe the design and result of Marshall’s 1985 self-experiment and what it was proposed to show.
23. List the three routes of person-to-person H. pylori transmission and three factors that increase infection risk.
24. Explain the principle behind the urea breath test for H. pylori and write the reaction it depends on.
25. State a 14-day triple therapy regimen for H. pylori eradication.
26. Distinguish the target intragastric pH for duodenal ulcer healing, GERD and H. pylori eradication.
27. Integrative: a patient needs H. pylori eradication. Using the intragastric pH data, explain why a PPI rather than an H2 receptor antagonist forms the backbone of the regimen.

Answers

Reveal answers

1. Gastrin is released from G cells and acts on the ECL cell (via CCK2 receptors); the ECL cell releases histamine onto the parietal cell, which drives acid secretion through the H+/K+-ATPase. Gastrin also acts directly on parietal cell CCK2 receptors via a Ca2+-dependent pathway.
2. Gastrin on CCK2 receptors, Ca2+-dependent pathway; histamine on H2 receptors, cAMP-dependent pathway; ACh on M1 receptors at the ganglion and M3 receptors on the parietal cell. All converge on the H+/K+-ATPase.
3. A 500 µm protective barrier consisting of a mucus gel containing secreted HCO3-; the HCO3- neutralises stomach acid so the inner mucosal layer stays at pH 7 while the gastric lumen is at pH 2.
4. In the acidic secretory canaliculi of the parietal cell, H+ converts omeprazole to a sulfenamide, then to a sulfenic acid, which reacts covalently with a sulfhydryl (cysteine) group on the pump to form an enzyme-inhibitor complex, irreversibly inhibiting it.
5. Because inhibition is covalent and irreversible, the effect persists after the drug has been cleared; activity returns only with new pump synthesis rather than tracking plasma levels.
6. They bind EP3 receptors on parietal cells and stimulate Gi protein, decreasing intracellular cAMP and so decreasing acid secretion; they also stimulate mucus (and HCO3-) secretion from superficial epithelial cells.
7. Basal acid secretion 85-95%; food-stimulated acid secretion 75-85%.
8. NSAIDs inhibit conversion of C20 fatty acids to PGE2/PGI2, removing the prostaglandin signal at EP3 receptors; cAMP is no longer suppressed and mucus/HCO3- secretion (cytoprotection) falls, so acid rises and mucosal protection is lost. 2-4% of chronic NSAID users develop ulcer or bleeding.
9. Inhibits acid production within 30 minutes, peaks at 60-90 minutes, lasts up to 3 hours.
10. Pregnancy, because misoprostol increases uterine contractility.
11. Sucralfate is activated by acid: at pH <4 it cross-links into a viscous adherent polymer, so it needs an acidic empty stomach; antacids raise gastric pH and would prevent activation, hence the 30-minute separation.
12. Mast cells (tissues), basophils (blood), enterochromaffin-like cells (gut). Formed by decarboxylation of L-histidine by histidine decarboxylase.
13. Ganglia carry the M1 subtype, the parietal cell the M3 subtype. M1 antagonists reduce basal acid production by 40-50%.
14. Relatively poor efficacy plus anticholinergic side effects (decreased motility, constipation).
15. Grade B: one or more mucosal breaks more than 5 mm long that do not extend between the tops of two mucosal folds. Grade C: breaks continuous between the tops of two or more mucosal folds but involving less than 75% of the circumference.
16. Stage I (sporadic uncomplicated heartburn with a known precipitant, fewer than 2-3 episodes per week, no additional symptoms). Lifestyle modification including diet, positional changes and weight loss, plus antacids and/or H2 receptor antagonists as needed.
17. Stage III. A proton pump inhibitor either once or twice daily.
18. High acid and peptic content; irritation; poor blood supply; poor secretion of mucus; infection with H. pylori.
19. 2-4%; stop the NSAIDs.
20. Misoprostol 200 μg four times daily for NSAID-associated ulcer prevention; only 800 μg/day has been directly shown to reduce complications such as perforation, haemorrhage or obstruction.
21. H. pylori adheres to the mucosal epithelium, inflammatory mediators are released, immune cells are activated and recruited including activated T cells, and tissue damage follows, producing gastric ulcer; presented as parallel inflammatory and immune responses.
22. A volunteer with histologically normal gastric mucosa ingested pyloric campylobacter by mouth; a mild illness lasting 14 days followed, with histologically proven gastritis on day 10 that had largely resolved by day 14. It was proposed that this acute gastritis may progress to chronic infection predisposing to peptic ulceration, as an attempt to fulfil Koch’s postulates.
23. Faecal-oral, oral-oral, gastro-oral. Risk increased by younger age, underdeveloped countries, lower socioeconomic status.
24. It is a functional test of the bacterium’s urease enzyme using carbon-labeled urea: $(N{H}_2{)}_{2}CO+H_{2}O\to C{O}_2+2N{H}_3$, detecting the labelled CO2 produced. (Other tests: antibodies in blood, serum or saliva; antigen in stool.)
25. Fourteen days of [a proton pump inhibitor + clarithromycin 500 mg + (metronidazole 500 mg or amoxicillin 1 g)] twice a day; tetracycline 500 mg can substitute for amoxicillin or metronidazole.
26. Duodenal ulcer pH >3; GERD pH >4; H. pylori eradication pH >5.
27. Eradication needs the highest threshold, pH >5, which is achieved for the fewest hours per day of the three indications. At that threshold an untreated patient manages roughly 1 hour per day and an H2 receptor antagonist roughly 4 hours, whereas a PPI achieves roughly 9 hours, so only a PPI holds pH high enough for long enough to support eradication.