Mechanisms of gastric acid secretion & the pharmacological agents for gastric acid suppression

In this first part of the gastrointestinal pharmacology series, we will look at the mechanisms of gastric acid production, common gastric acid disorders and the pharmacotherapy of dyspepsia, GORD and PUD. The gastrointestinal drugs we will learn about include H₂ receptor antagonists and proton pump inhibitors.

The stomach produces enzymes and acid to aid digestion

The stomach has four regions. It is divided into the fundic, cardiac, body, and pyloric regions.

The stomach also has four tissue layers, namely the serosa, muscularis, submucosa and mucosa. The serosa is the outermost layer of the stomach. It consists of a thin layer of connective tissue that helps anchor the stomach in place. The innermost layer, the mucosa, is further subdivided into the surface epithelium, lamina propria, and muscularis mucosa. The mucosal layer is in contact with food as it enters the stomach and is responsible for secreting digestive enzymes and hydrochloric acid (HCl^–). The epithelium folds into the lamina propria, forming the gastric pits and glands, which contain the specialised cells such as surface mucous cells, parietal cells, chief cells and entero-endocrine cells.

The different cells in the gastric pits secrete different substances that contribute to the overall function of the stomach. Approximately ~2.5L of gastric juice is secreted daily and it consists of HCl-, pepsinogen, mucous and intrinsic factor. It is highly acidic (pH 1-2) which is important for the proteolytic digestion of food, conversion of pepsinogen to the active form of pepsin and killing of pathogens that prevent infection or sickness from occurring.

Hydrogen and chloride ions are actively pumped out from the parietal cell and into the lumen of the stomach. Gastric acid secretagogues (gastrin, histamine and acetylcholine) bind to receptors on parietal cells to stimulate the release of gastric acid. Gastrin binds to CCK₂ receptors whilst histamine binds to H₂ receptors and Ach binds to M₃ receptors. Gastrin and Ach act by inducing an increase in intracellular Ca²⁺ levels whilst histamine binding causes activation of adenyl cyclase. Overall, the receptor-mediated binding of the secretagogues results in the activation of an enzyme called the H⁺/K⁺ adenosine triphosphate (ATPase) proton pump. The proton pump uses energy derived from the cleavage of ATP to transport ions against a concentration gradient. It transports H⁺ out of the parietal cell in exchange for K⁺ ions.

The stomach is protected from the acidic environment of the lumen by a gel like barrier. Mucosal cells maintain a protective mucosal surface (pH 6-7) by secreting bicarbonate ions (HCO3-) and mucous. Prostaglandins are gastroprotective because receptor binding of PG_E2 and PG_I2 on parietal cells inhibit gastric acid production and stimulates HC03- and mucous secretion.  Somatostatin also inhibits gastric acid secretion.

The stomach is the site of common pathologies

Dyspepsia: Chronic or recurrent pain, burning or discomfort centred in the upper abdomen.

GORD: Gastro-oesophageal reflux disease (GORD) is present if symptoms are frequent (2 or more episodes per week) or severe enough to significantly impair quality of life, or if complications of gastro-oesophageal reflux are present.

Peptic Ulcer Disease: Peptic ulcer disease (PUD) includes gastric and duodenal ulcers. PUD is mostly caused by Helicobacter pylori (H. pylori) infection or nonsteroidal anti-inflammatory drug (NSAID) use. In a small number of patients with peptic ulcer disease, neither risk factor is present.

📺 Watch the following lecture on the mechanisms of gastric acid secretion (19 minutes)

Treatment options – Dyspepsia, GORD, PUD

The treatment of disorders relating to gastric acid secretion can be targeted in several ways. The drugs that are used act to inhibit the action of secretagogues. This may be by any of the following mechanisms:

• Neutralizing gastric acid: the use of basic salts to increase PH: Antacids
• Forming a protective barrier, coating ulcers and limiting acid diffusion: Cyto-protective agents (Sucralfate, bismuth)
• Increasing protective mucus, bicarbonate and prostaglandin: Cyto-protective agents and Misoprostol
• Reducing gastric acid secretion: H2 receptor antagonists, PPIs, Misoprostol

Our main focus will be the mechanisms of action of H2 receptor antagonists and Proton Pump Inhibitors.

• H2 receptor antagonists block the effects of Histamine
• PPIs inhibit proton pump activation by mediators Histamine, ACH and Gastrin

Other treatment considerations include testing for and treating H.pylori; cessation of causative agents (eg: NSAIDs) and several lifestyle modifications.

1. H₂ Receptor Antagonists

H₂ receptor antagonists competitively and reversibly block endogenous histamine from binding to the H₂ receptor on parietal cells. Consequently, there is a reduction in cAMP dependent protein kinase which is involved in the transport of H⁺/K⁺ ATPase from the cytoplasm to the cell membrane. H₂ receptor antagonists reduce gastric acid production by ~70% and are used to treat dyspepsia, GORD and PUD. Their duration of action is 12 hours, meaning dosing is twice daily. The drug names end in the suffix -tidine and examples include famotidine and nizatidine. 

2. Proton Pump Inhibitors

Proton pump inhibitors irreversibly bind to and inactivate the H⁺/K⁺ ATPase enzyme. Both basal and meal-stimulated gastric acid secretion is reduced. PPIs are the most potent inhibitors of acid secretion (reduced by ~85%) as they affect the terminal step in the acid secretory pathway.

Degrade rapidly in low pH (the stomach) so enteric coating allows absorption from the small intestine into the blood then the drug accumulates in the parietal cell canaliculi where it is activated to the metabolite- a thiophilic sulphenamide. The active metabolite interacts covalently with the H⁺/K⁺ ATPase pump involved in H+ ion transport.

PPIs have a long duration of action and a single daily dose of PPI can affect acid secretion for 2-3 days. This is because they bind irreversibly therefore a new H⁺/K⁺ ATPase must be synthesised.

The drug names of PPIs end in the suffix -razole and examples include esomeprazole, lansoprazole, omeprazole, pantoprazole and rabeprazole.

PPIs are generally well tolerated and adverse effects include headache and diarrhoea, hypomagnesaemia, reduced vitamin B₁₂ absorption and less commonly, interstitial nephritis.

Triple Therapy for Helicobacter pylori

H.pylori infection is prevalent in about 30% of adult Australians. H.pylori is a causal agent in the development of numerous conditions- duodenal and gastric ulcers, chronic gastritis and gastric cancer

It is diagnosed from a urea breath test. Diagnosis by urea breath test: patient given 13C-urea orally, the urease in H.pylori metabolises it to release 13CO2 and NH3, the amount of CO2 in the expired air is measure to confirm diagnosis. Diagnosis may also involve antibody testing, endoscopy or biopsy

Eradication of H.pylori involves triple therapy with two antibacterials and a PPI as the first line of treatment. Usually, this is amoxicillin + clarithromycin + PPI for 7- 14 days. In people who are hypersensitive to penicillin, amoxicillin is replaced by metronidazole.

The image below shows the contents of Nexium HP7 and was sourced from the NPS Medicinewise website. It can be found at https://www.nps.org.au/medicine-finder/nexium-hp7-combination-pack

Let’s compare the difference in effectiveness of H₂ receptor antagonists and PPIs. The image below shows the effects of H₂ receptor antagonists and proton pump inhibitors on the acid secretion pathway in parietal cells. H₂ receptor antagonists only block 1 of 3 pathways in which the production of gastric acid is stimulated. PPIs block the terminal step in the acid secretory pathway, making them more effective.

📺 Watch the following lecture on the pharmacological agents for gastric acid suppression (18 minutes)

Lecture Notes:

✍️Let’s do an activity