Describe the pharmacological function of histamine on induction of inflammation. Explain the mechanism of gastric acid secretion and antiulcer activity of H2 blockers

Histamine plays a crucial role in the induction of inflammation. It is a biogenic vasoactive amine that impacts the immune system, usually as proinflammatory factors

Induction of Inflammation

Histamine acts on four different histamine receptors: H1, H2, H3, and H4. The H1 & H4 receptor is responsible for most of the effects of histamine on the triple response as well as for the induction of inflammatory response.

Mechanism – (H1 Receptor) 

Histamine induces inflammation by binding to H1 receptors on blood vessels and other cells.

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This binding causes vasodilation and increased vascular permeability (leakiness of the blood vessels).

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This leads to increased blood flow and fluid accumulation (with inflammatory mediators) in the tissues (Exudation)

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Results in the redness, swelling, and that are characteristic of inflammation.

Mechanism by H4 Receptor

For instance, activation of H4 receptors by histamine stimulates the synthesis of IL-4 (interleukin 4) and IL-5 (interleukin 5) in human spinal cord, blood mast cells , which are inflammatory cytokines. 

  • we know interleukin 4 (produced by mast cells) is an important cytokine that plays an important role inducing stimulation of activated B cells and T cell's proliferation in inflammatory response. 
  • it also promotes airway inflammation. 

Gastric Acid Secretion:

ð The Gastric Acid secretion mechanism consists of several factors –

(a)   Neural Factors:

-        Vegus nerve stimulates the release of Gastrin from G cells. Gastrin binds with gastrin receptor of Parietal cells and release gastric acid.

-        Gastrin also helps in the release of Histamine from ECL (Enterochromaffin-like) cells by binding with Gastrin receptor of the respective cells.

-        Ach also released from parasympathetic nerve endings also stimulates in the secretion of Acid from parietal cells by binding with Muscarinic (M3) receptor. And also stimulates the secretion of Histamine from ECL cells.

 

(b)   Hormonal Factors: Histamine is the most potent stimulator of gastric acid secretion. It binds with H2 receptor of Parietal cells → increases the cAMP level thus increases the H+ release from parietal cells.



The release of gastric acid is driven by proton pump (H+/K+ - ATPase pump). This enzyme pumps H+ from the parietal cells to the lumen of stomach against the concentration gradient. H+ combines with Cl- ion and from HCl.


Anti-ulcer activity of H2 blocker:

 

A lesion in the lining of the digestive tract, typically in the stomach and duodenum caused by the digestive action of pepsin and digestive acid.

 

Pathophysiology of Peptic Ulcer

Peptic ulcer disease occurs due to an imbalance between mucosal defence factors (bicarbonate, mucin, prostaglandin, nitric oxide, and other peptides and growth factors) and injurious factors (acid and pepsin). a weakened mucosal defence and reduced bicarbonate production and increased gastric acid production is the main cause of peptic ulcer.

 

Activity of H2 blocker –

Histamine Binds with H2 receptor of Gastric Parietal cells and stimulate Gs pathway thereby increasing intracellular cyclic AMP and Gastric Acid secretion by (PKC dependent pathway).

*The H2 -receptor antagonists inhibit acid production by reversibly competing with histamine for binding to H2 receptor.

 


Prostaglandin E2 (PGE2) and prostacyclin (PGI2) are the major prostaglandins synthesized by the gastric mucosa. They bind to the EP3 receptor on parietal cells and stimulate the Gi pathway, thereby decreasing intracellular cyclic AMP and gastric acid secretion.

 

H2 blockers also enhances the bicarbonate protection upon the gastric mucosa thereby strengthening the mucosal defence factor.





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