Histamine

Histamine is a tissue amine derived from the word histos meaning “tissue”. It is present in animal tissues and certain plants (stinging nettle).

This autacoid is a mediator of hypersensitivity phenomenon and tissue injury reactions. It is stored in storage granules of mast cells (tissue phagocytes) and basophils. Tissues rich in histamine are skin, gastric and intestinal mucosa, lungs, liver and placenta.

Non-mast cell histamine occurs in the brain, epidermis, gastric mucosa and growing region. The turnover of mast cell histamine is slow, while that of non-mast cell is fast. Histamine is also present in blood, most body secretions, venom and pathological fluids.

Release of histamine

Histamine is released from mast cells in response to IgE-mediated allergic reactions secondary to presentation of an antigen and is one of the principal mediators of hay fever, allergic rhinitis, urticaria and angioedema.

• Histamine is released during the following situations-
  1. Allergic reactions
  2. Cellular injury that may be caused by mechanical, thermal or radiation stimulus
  3. Administration of certain drugs / compounds  like morphine, d-tubocurarine, succinylcholine, contrast medium, vancomycin, 48/80 etc.

Histamines receptors

Three receptors have been identified as responsible for the pharmacological effects of histamine. They are H₁, H₂ and H₃ receptors. H₁ receptors are present in the bronchial, intestinal smooth muscles and CNS. They are also present in the vascular smooth muscles. This receptor mediates endothelial cell and smooth muscle responses to histamine.

Activation of peripheral H₁ receptors causes bronchoconstriction, vasodilatation, increased vascular permeability and stimulation of sensory nerve endings. The effector system for the H₁ receptor appears to be activation of phospholipase C, production of inositol-1,4,5-trisphosphate and increased intracellular Ca²⁺. 

H₂ receptors are present in the gastrointestinal tract and control gastric acid secretion. They are also present in the vascular smooth muscles. Activation of H₂ receptors stimulates adenylyl cyclase and increases the intracellular concentration of cAMP. This receptor increases gastric acid secretion by the parietal cell.

H₂ receptors on vascular smooth muscle cells make a minor contribution to the vasodilatation caused by histamine release (slower in onset but more sustained).

H₃ receptors are considered as auto receptors as they are responsible for the feed back regulation of histamine synthesis and release in many organ systems. They are also found on certain human autonomic nerve terminal, in arterial tissue and CNS.

Pharmacological action of Histamines

1. On blood vessels
   • On the blood vessels the actions of histamine are mediated by both H₁ and H₂ receptors.
   • Dilatation of small blood vessels including arterioles, capillaries and venules occurs.
   • On subcutaneous administration flushing, heat, increased heart rate and cardiac output with little or no fall of blood pressure is observed.
   • After rapid intravenous administration, a fall of blood pressure is noticed which is mediated by both H₁ and H₂ receptors.
   • H₁ receptors are responsible for an early short acting effect and H₂ receptors are responsible for a slow but more persistent effect on blood pressure.
   • However, with small doses, only the H₁ receptors are stimulated.
   • The effects of histamine on blood pressure can only be completely reversed, by giving both H₁ and H₂ blockers.
   • Dilatation of cranial blood vessels cause pulsatile headcahe.
   • Vasodilatation caused by histamine is partly due to EDRF.
   • Larger arteries and veins are constricted.
   • Histamine also causes increased capillary permeability due to separation of endothelial cells and exudation of plasma.
   • On intra dermal injection histamine causes a triple response of Lewis, which consists of flush, flare and wheal.
   • Red spot or flush is due to intense capillary dilatation
   • Flare – Redness in the surrounding area is due to arteriolar dilatation mediated by axon reflex.
   • Wheal is an elevated area due to exudation of fluid from the capillaries and venules.
2. On heart
   • Direct effects of histamine on the heart are not prominent. But, the isolated heart is stimulated.
3. On visceral smooth muscle
   • It causes bronchoconstriction.
   • Asthmatic individuals are highly sensitive to histamine.
   • Gastrointestinal motility is increased.
   • In larger doses it causes abdominal cramps and colic by increasing intestinal contractions.
   • Effect on uterine smooth muscle differs from species to species.
4. On glands
   • It causes a marked increase in gastric secretion – primarily of acid and also of pepsin. 
   • This action is exerted on the parietal cells through H₂ receptors.
   • The response to histamine with gastric, salivary, pancreatic, bronchial and lacrimal is variable. 
5. On sensory nerve endings
   • Itching occurs when histamine is injected and higher concentrations injected deeply cause pain.
   • It stimulates the nerve endings to produce these effects.
6. On autonomic ganglia and adrenal medulla
   • Histamine causes a stimulation of autonomic ganglia and adrenal medulla.
   • This in turn induces release of adrenaline and rise of blood pressure.
7. On central nervous system
   • Histamine does not cross the blood brain barrier and hence no central effects are seen normally.
   • However, it appears to be a neurotransmitter where it may regulate wakefulness and appetite.

Pathophysiological roles of Histamine

1. Gastric secretion
   • Histamine has a dominant physiological role in mediating secretion of hydrochloric acid in the stomach through the H₂ receptors.
   • H₂ blockers block acid secretion and also diminish the secretion in response to acetylcholine and gastrin.
2. Allergic phenomema
   • Histamine is one of the mediators of allergy and plays a role in causing urticaria, angioedema, bronchoconstriction and anaphylactic shock.
3. Transmitter
   • Histamine is believed to be a transmitter also in CNS, which initiates the sensation of itch and pain at the sensory nerves.
4. Inflammation
   • Histamine has been implicated as a mediator of vasodilatation and other changes that occur during inflammation.
5. Tissue growth and repair
   • Histamine is suggested to play an important role in tissue growth and repair.
6. Headache
   • Histamine has been implicated in certain vascular headaches.