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 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 theophyllinePeptidesSpicesAlcoholAspirin

Enterochromaffin-like (ECL) Cell

Parietal cellParietal 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.

Fig: Canaliculi in parietal cell

Gastric lumen

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.

Canalicui

Resting Secreting

CCK2

Acetylcholine+

Gastrin+

ECL cells

Histamine

Parietal cell

Hydrochloric acid

Parasympathetic fiber G cell in blood release

1

2

3

1. Acetylcholine receptor2. H2 receptor

3. Gastrin receptor Fig: Factors influence gastric acid secretion

M1

M3

CCK2

CCK2

Fig: Factors influence gastric acid secretion

Mechanism of Action

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.

Physiology of acid secretion

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 secreted acid. No effect on underlying pathology.

- Inhibitors of gastric acid production

H2 receptor antagonists

Proton pump inhibitors

Muscarinic receptor antagonists

Gastrin receptor antagonist

- Mucosal protectantDecrease HCl & pepsin secretion & increase

mucous production.

- Anti-Helicobacter pylori. drugs

Antacids: Aluminum hydroxide, Magnesium hydroxide

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 antibiotics- amoxicillin and clarithromycin)

These options are also effective:

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

HistamineHistamine 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 between imidazole N-H and receptor

In aqueous solution histamine exists in two tautomeric forms, Nπ-H-histamine and Nτ-H-histamine.