LECTURE 4

learning Outcomes:

1. Gastric Juice - Composition + function.

2. Mechanism of gastric acid secretion.

3. Systemic regulation of acid secretion.

4. cellular regulation of acid secretion.

5. peptic ulcers - too much acid.

Secretion of gastric juice: from gastric glands in fundus + body of stomach

Composition →

Parietal Cells: Secrete HCL + intrinsic factor

Chief cells: secrete: Pepsinogen + gastric lipases

HCl: Acidic environment, hostile to microbes, solubilisation of food.

• Activates pepsinogen to produce pepsin - enzyme that digests protein.

Gastric lipases: Enzyme removes one fatty acid from triacylglycerol → not as effective as lipase in pancreases that removes two chains.

Intrinsic factor: binds to vit B12 allowing absorption in the small intestine.

Mucus gland: secrete mucus →

• Protect stomach from acidic environment.

• Lubricates food. allowing it to move easily.

HCl secretion from the parietal cell →

• Process involves a proton pump that is energy-intensive due to the pH difference between the stomach lumen and the epithelial cells.

• The gradient of protons is significant, with more protons outside the cell than inside.

• Initially, carbon dioxide and water combine to form carbonic acid.

• Carbonic anhydrase then breaks it down into protons and bicarbonate ions.

• The protons are pumped out of the cell, driven by ATP and potassium ions leaking out of the cell.

• Bicarbonate ions diffuse out of the cell into the blood, exchanging with chloride ions coming in. This exchange results in a less acidic pH in the blood leaving the stomach compared to the blood entering the stomach.

• The chloride ions that entered the cell then leak out into the lumen, where they combine with protons to create hydrochloric acid.

Acid secretion is stimulated by:

• Acetylcholine binds to muscarinic receptors, gastrin binds to CCK2 receptors, and histamine binds to H2 receptors, it triggers changes in the parietal cell membrane.

• This results in an increase in the number of pumps in the membrane, allowing protons to be pumped out into the gastric fluid, thus increasing the surface area for secretion to occur.

Control of gastric acid secretion: Three phases

Phase 1 → Cephalic/Head Phase (stimulatory)

• When food enters the mouth or even just the smell, taste, or sound of food stimulates the brain to activate the parasympathetic pathways.

• This leads to the release of acetylcholine by the vagus nerve into the stomach, increasing the production of protons.

• Additionally, the vagus nerve releases gastrin-releasing peptide, which acts on G cells in the stomach to secrete gastrin.

• Gastrin then travels in the blood to the parietal cells, causing an increase in the secretion of acid.

Gastric Phase (Stimulatory/inhibitory phase):

• Has both a stimulatory and an inhibitory role.

• When there's food in the stomach, it activates stretch receptors due to the distention of the stomach.

• Peptides and amino acids released by protein digestion act on local enteric nerves, which then stimulate the vagus nerve to increase stomach acid production.

• The vagus nerve also stimulates gastric cells to produce gastrin, which acts on the parietal cells.

• Distension of the stomach wall and amino acids, particularly aromatic amino acids, also trigger the G cells to produce gastrin.

• Additionally, products like caffeine affect the parietal cells through bitter taste receptors, known as TAS2Rs.

• The feedback mechanism involves somatostatin hormone released by D cells to inhibit gastrin secretion when the pH decreases due to increased proton secretion.

• The food in the stomach acts as a buffer, limiting the negative feedback loop by mopping up protons and raising the pH as more food enters.

Intestinal phase (Inhibitory):

• Inhibitory mechanisms kick in as food enters the intestine, leading to a reduction in pH in the duodenum.

• This reduction, caused by fats and peptides, results in decreased X Plus secretion. Enteric gastric reflex, controlled by the enteric nervous system and somatostatin, acts as a negative feedback loop.

• Hormones like secretin and cholecystokinin inhibit gastrin and gastric acid secretion. Additionally, gastric inhibitory peptide, mainly involved in blood sugar control, also contributes to the inhibitory effect by reducing gastric acid secretion.

• The brain's nervous control involves gastric-releasing peptide stimulating gastric cells to produce gastrin, which then affects parietal cells and chief cells.

• Acetylcholine released by nerves from the dorsal vagal complex directly stimulates parietal cells, while G cells stimulate enterochromaffin-like cells to release histamine, which has a local effect on parietal cells.

Summary of signalling pathways:

- Gastrin acts on CCK2 or CCKB receptors and acetylcholine acts on the M3 receptor, both are G protein-linked receptors.

- Gastrin activates the GQ protein, stimulating phospholipase C, leading to an increase in IP3 and releasing calcium from the endoplasmic reticulum, resulting in an increase in intracellular calcium.

- The M3 receptor is linked to calcium channels, increasing calcium influx, which activates the proton pump.

- Histamine acts on H2 receptors, linked to the stimulatory G protein, increasing calcium through different pathways, activating adenylate cyclase, leading to cAMP production, activating protein kinase A, and enhancing proton pump activity.

- The inhibitory pathway involves somatostatin acting on the Gi protein, inhibiting adenylate cyclase, and prostaglandins, which help reduce acid response by stimulating the Gi protein.

Mucosal Protection:

- Mucosal protection is crucial in the stomach and duodenum due to the highly acidic environment.

- Mucus, made of glycoproteins and water, forms two layers: loose mucus and tight mucus, acting as a protective barrier against acid erosion.

- Loose mucus traps bicarbonate secretions to create a barrier against acid penetration.

- Surface epithelium in the stomach and Brunner's glands in the duodenum secrete bicarbonate to neutralize acid and trap it in the mucus layer.

- Secretions are stimulated by stomach irritation through short reflexes, the enteric nervous system, the stomach's own nervous system, and prostaglandins.

- The vagus nerve and secretin play a role in stimulating mucus production for protection; failure in this protection or excessive acid production can lead to severe consequences.

Ulcer = Acid/enzyme damage to stomach or intestinal wall

- Erosion of the stomach lining due to excessive acid or inadequate protection.

- Gastric ulcers affect around 10% of Europeans and North Americans, more common in females under 40, with various reasons for gender differences.

- Erosion of the mucosa can lead to bleeding into the GI tract and, if perforation occurs, can result in stomach contents entering the peritoneum, causing peritonitis and potentially sepsis.

- Treatment for gastric or duodenal ulcers used to require surgery until the 1970s; repair involves using part of the stomach, called the momentum, to cover the eroded area and prevent further damage.

Causes of ulcers:

• Bacterial infection: Heliobacter Pylori.

• Non - steroidal anti inflammatory drugs.

• Smoking

• Zollinger - Ellison syndrome (Gastrin secreting tumours)

• Excessive alcohol consumption.

• Anxiety/ stress

Most important cause of peptic ulcers → Heliobacter Pylori

• Gram negative Bacteria - inflammation of stomach lining.

• Slow growing in culture so difficult to identify.

• Also associated with stomach carcinoma

• Remains in gut fro life unless treated.

• Easily diagnosed using a blood test.

• Bacteria able to tolerate low Ph of stomach

• Metabolise urea, forming cloud of ammonia → protecting organism from acid.

• Inflammation in the antrum impairs somatostatin release = increases gastrin + acid secretion = perfect to increase stomach ulcers.

- Helicobacter pylori is a major cause of gastric ulcers, along with nonsteroidal anti-inflammatory drugs like ibuprofen and aspirin that interfere with prostaglandin production, affecting the protective mechanism.

- Smoking can lead to gastric ulcers by causing free radicals, increasing acid production, reducing prostaglandin production, mucosal blood flow, and healing properties.

- Zollinger-Ellison syndrome, associated with gastrin-secreting tumors, can increase acid production. Excessive alcohol consumption may also be linked to ulcers, possibly due to smoking habits.

- Anxiety and stress are potential factors in ulcer development, as stress may lead to self-medication with painkillers, including nonsteroidal anti-inflammatory drugs.

- Research on Helicobacter pylori increased in the 80s when Australian researcher Barry Marshall investigated its role in gastric ulcers.

Treatments in the past:

- In the 1940s, the primary treatment for gastric ulcers was vagotomy, cutting the vagus nerve. However, vagotomy had many side effects due to its involvement in stomach acid control, gut motility, and gallbladder contraction.

- Histamine receptor antagonists in the 1970s blocked histamine receptors, reducing stomach acid production.

Breakthrough: 1988 →

- In 1988, a major breakthrough was the development of proton pump inhibitors, with James Black being a key figure in this field, along with the identification of H. pylori leading to the use of antibiotics for ulcer treatment.

1975 →

- Histamine receptor antagonists, like cimetidine, were developed around 1975 by identifying compounds structurally related to histamine.

James Black, a key figure in this field, developed the specific H2-receptor antagonist cimetidine, which raised stomach pH and provided protection against gastric ulcers for up to 10 hours.

This class of drugs targets the H2 receptors on parietal cells, different from antihistamines used for allergies, which are H1 receptor antagonists.

GlaxoSmithKline later developed Zantac, a longer-acting and more effective drug for acid secretion.

1980 →

- The 1980s were crucial for developing potential new anti-asthma drugs targeting H2 and muscarinic receptors to block vagal stimulation effects.

- Research was also done on gastrin receptors, CCK receptor agonists, potassium leak channels, and chloride channels as potential targets. The discovery of proton pump inhibitors, like omeprazole, was accidental while searching for a gastrin antagonist.

- Omeprazole was a significant success as the first generation of proton pump inhibitors developed around 1989 by Astra and later AstraZeneca.

Mechanism:

• The enzyme inhibitor complex is designed in an enteric coated form to protect it in the stomach and ensure it passes through to the small intestine for absorption.

• This way, it can reach the parietal cells in the blood to have its effects. The second generation of proton pump inhibitors, like Nexium, has been developed to improve the drug.

• Clinical trials have indicated that Nexium is more effective than the previous mixture.

• To eradicate H. pylori and cure ulcers, a combination of two antibiotics is typically used. If a patient is allergic to penicillin, Clarithromycin replaces amoxicillin in the treatment.

• This combination is usually accompanied by a proton pump inhibitor and sometimes a bismuth compound, which has bactericidal effects.

• The challenge with long-term antibiotic use is the development of antibiotic resistance, so different antibiotic combinations are used to combat this issue.

• Patients might find it challenging to adhere to treatments involving multiple drugs. The proton pump inhibitor and bismuth compound help by raising the pH level, which can be beneficial since H. pylori grows faster at a higher pH.

• The bismuth compound also slows down acidification, aiding in the treatment process.