Peptic Ulcers

PHRM 304

Peptic ulcer
A peptic ulcer, also known as PUD or peptic ulcer disease, is an ulcer (defined as mucosal erosions equal to or greater than 0.5 cm). As many as 70-90% of ulcers are associated with Helicobacter pylori, a spiral-shaped bacterium that lives in the acidic environment of the stomach.

Peptic ulcer
Ulcers can also be caused or worsened by drugs such as aspirin, Clopidogrel, ibuprofen, and other NSAIDs.

Peptic ulcers

Physiology of gastric acid secretion

- Gastric acid (HCl) is produced by parietal cells of the oxyntic gland in the gastric mucosa.

- Produces 2-3 liters of gastric juice per day.

-Maintains stomach at a pH of 1 to 4. - Chief cell produce pepsinogen which is converted to pepsin by HCl.

Gastric (oxyntic) gland

Enterochromaffin-like (ECL) Cell

Enterochromaffin-like cells (ECL cells) in the gastric mucosa produce, store & release histamine activated by acetylcholine (M1 receptors), gastrin (CCK2 receptors). Acetylcholine and gastrin release activated by food stimulation and also by some secretagogues: Caffeine and theophylline Peptides Spices Alcohol Aspirin

Parietal cell
Parietal cells produce gastric acid (hydrochloric acid) in response to histamine (via H2 receptors), acetylcholine (M3 receptors) and gastrin (CCK2 receptors). The histamine receptors act by increasing intracellular cAMP, whereas the muscarinic and gastrin receptors increase intracellular Ca2+ levels.

Parietal cells contain a hydrogen ion pump (proton pump), a unique H+/K+ ATPase system that secretes H+ in exchange for the uptake of the K+ ion. The HCl acid is formed at the lumen of the canaliculi and then conducted through openings to the gastric lumen.

Gastric lumen

Fig: Canaliculi in parietal cell

Canalicui
A canaliculus is an adaptation found on gastric parietal cells. It is a deep infolding, or little channel, which serves to increase the surface area, e.g. for secretion. The membrane of parietal cells is dynamic; the numbers of canaliculi rise and fall according to secretory need.

Resting

Secreting

CCK2

Parasympathetic fiber Acetylcholine +

G cell in blood release Gastrin + CCK2

M1 ECL cells

Histamine

M3
1

2 3 CCK2 Parietal cell

1. Acetylcholine receptor 2. H2 receptor 3. Gastrin receptor

Hydrochloric acid

Fig: Factors influence gastric acid secretion

Fig: Factors influence gastric acid secretion

Mechanism of Action

Physiology of acid secretion

The parietal cell contains receptors for gastrin (CCK2), histamine (H2), and acetylcholine (muscarinic, M3). When acetylcholine or gastrin bind to the parietal cell receptors, they cause an increase in cytosolic calcium, which in turn stimulates protein kinases that stimulate acid secretion from a H+/K+ ATPase (the proton pump) on the canalicular surface.

In close proximity to the parietal cells are gut endocrine cells called enterochromaffin-like (ECL) cells. ECL cells have receptors for gastrin (CCK2) and acetylcholine (probably M1) and are the major source for histamine release. Histamine binds to the H2 receptor on the parietal cell, resulting in activation of adenylyl cyclase, which increases intracellular cyclic adenosine monophosphate (cAMP). cAMP activates protein kinases that stimulate acid secretion by the H+/K+ ATPase. In humans, it is believed that the major effect of gastrin upon acid secretion is mediated indirectly through the release of histamine from ECL cells rather than through direct parietal cell stimulation.

Drugs used in peptic ulcers

- Antacids
Neutralize pathology. secreted acid. No effect on underlying

- Inhibitors of gastric acid production

H2 receptor antagonists Proton pump inhibitors Muscarinic receptor antagonists Gastrin receptor antagonist

- Mucosal protectant
Decrease HCl & pepsin secretion & increase mucous production.

- Anti-Helicobacter pylori. drugs

Antacids: hydroxide

Aluminum

hydroxide,

Magnesium

H2 receptor antagonists: Cimetidine, Ranitidine

Muscarinic receptor antagonists: Atropine (M3 receptor), pirenzipine (M1 receptor)

Proton pump inhibitor: Omeprazole Gastrin receptor antagonist: Proglumide Mucosal protectants: Misoprostol (prostaglandin analogues)

Anti-Helicobacter pylori. Drugs: Antibiotics (commonly use triple therapy: one proton pump inhibitor-lansoprazole and two antibioticsamoxicillin and clarithromycin) These options are also effective:

Figure: A schematic illustration of the secretion of hydrochloric acid by the gastric parietal cell.

Histamine
Histamine is a hydrophilic molecule comprising an imidazole ring with a ethylamine side-chain.

Histamine exists as monocation at blood pH (7.4) Under physiological conditions, the aliphatic amino group (having a pKa around 9.4) will be protonated, whereas the second nitrogen of the imidazole ring (pKa 5.8) will not be protonated.

Interaction of histamine with receptor:

1. Electrostatic attraction between protonated N of histamine side chain and receptor (-ve charge site)

2. H-bonding between imidazole N and receptor

3. H-bonding receptor between imidazole N-H and

In aqueous solution histamine exists in two tautomeric forms, N-H-histamine and N-Hhistamine.