====== Histamine Physiology ======

Histamine is a biogenic amine involved in:

  * Immediate hypersensitivity reactions
  * Gastric acid secretion
  * Neurotransmission
  * Inflammatory signaling

This page covers synthesis, storage, release, and physiologic effects.

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===== Synthesis =====

Histamine is synthesized from the amino acid **histidine**.

Reaction:
  Histidine → (Histidine decarboxylase) → Histamine

  * Enzyme: Histidine decarboxylase
  * Requires pyridoxal phosphate (Vitamin B6)

Primary sites of synthesis:
  * Mast cells
  * Basophils
  * Enterochromaffin-like (ECL) cells of the stomach
  * Certain neurons in the CNS

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===== Storage =====

==== Mast Cells ====
  * Stored in cytoplasmic granules
  * Complexed with heparin and proteoglycans
  * Preformed mediator (ready for immediate release)

==== Basophils ====
  * Circulating granulocytes
  * Contain histamine granules similar to mast cells

==== Gastric ECL Cells ====
  * Release histamine to stimulate acid secretion

Histamine is NOT synthesized on demand in mast cells — it is preformed and stored.

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===== Release Mechanisms =====

==== 1) IgE-Mediated (Type I Hypersensitivity) ====

  * Allergen cross-links IgE bound to FcεRI receptors
  * Calcium influx
  * Rapid degranulation
  * Immediate mediator release

This produces:
  * Urticaria
  * Bronchoconstriction
  * Hypotension
  * Anaphylaxis

See: [[allergy:immunology:type_i_hypersensitivity|Type I Hypersensitivity]]

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==== 2) Non-IgE Mediated Mast Cell Activation ====

Certain agents directly trigger mast cell degranulation:

  * Opioids
  * Radiocontrast
  * Vancomycin (Red Man Syndrome)
  * Physical stimuli (cold, pressure)

This is sometimes called "pseudoallergic" activation.

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==== 3) Gastric Regulation ====

In the stomach:

  * Vagus nerve → Acetylcholine
  * Gastrin
  → Stimulate ECL cells
  → Histamine release
  → H2 receptor activation on parietal cells
  → ↑ Gastric acid secretion

See: [[gi:drugs:h2_blockers|H2 Blockers]]

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===== Histamine Receptors =====

There are four known histamine receptors:

^ Receptor ^ G-Protein Coupling ^ Primary Effect ^
| H1 | Gq | Vasodilation, permeability, bronchoconstriction |
| H2 | Gs | ↑ Gastric acid secretion |
| H3 | Gi | CNS neurotransmitter modulation |
| H4 | Gi | Immune cell chemotaxis |

See detailed signaling:
[[allergy:histamine:histamine_receptors|Histamine Receptor Signaling]]

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===== Physiologic Effects of H1 Activation =====

  * Endothelial contraction → Capillary leakage → Edema
  * Nitric oxide release → Vasodilation
  * Sensory nerve stimulation → Pruritus
  * Bronchial smooth muscle contraction → Wheezing
  * Increased mucus secretion

Clinical correlates:
  * Allergic rhinitis
  * Urticaria
  * Asthma
  * Anaphylaxis

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===== Early vs Late Phase Response =====

==== Early Phase (Minutes) ====
  * Histamine
  * Tryptase
  * Leukotrienes
  * Prostaglandins

==== Late Phase (Hours) ====
  * Eosinophils
  * Cytokines (IL-4, IL-5, IL-13)
  * Sustained inflammation

Histamine dominates early symptoms (itching, redness, sneezing).

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===== Metabolism =====

Histamine is rapidly metabolized by:

  * Histamine-N-methyltransferase (HNMT)
  * Diamine oxidase (DAO)

Short half-life in circulation.

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===== Clinical Relevance =====

Blocking histamine signaling forms the basis of:

  * [[allergy:drugs:loratadine|H1 Antihistamines]]
  * [[gi:drugs:famotidine|H2 Blockers]]
  * Anaphylaxis management ([[cardio:drugs:epinephrine|Epinephrine]])

Histamine explains:
  * Why allergic reactions are rapid
  * Why itching occurs
  * Why congestion develops
  * Why anaphylaxis causes vasodilation and shock

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===== Board Pearls =====

  * Histamine is preformed in mast cell granules.
  * H1 receptors signal through Gq → IP3 → Ca²⁺.
  * H2 receptors signal through Gs → cAMP.
  * Histamine causes both vasodilation AND increased vascular permeability.
  * Decongestants treat symptoms, not histamine release.