Histamine and Its Functions

Overview of Histamine

• What is Histamine?

• Synthesized from L-histidine by L-histidine decarboxylase.

• Organic nitrogenous molecule involved in local immune reactions and inflammation.

• Plays a crucial role as a mediator of itching (pruritis) and functions as a monoamine neurotransmitter.

• Distribution of Histamine and Mechanism of Release

• Found in almost all mammalian cells, abundant in skin, lungs, and intestinal mucosa.

• Main cellular source: Mast cells; also found in basophils and specialized histaminocytes (ECL cells).

• Stored in secretory granules and released in response to various stimuli (e.g., tissue damage).

• Histamine Receptors

• Four main types: H1, H2, H3, H4; all are classic GPCRs involved in inflammation.

• H1 receptors: act on smooth muscle, endothelial cells, and sensory nerves.

• H2 receptors: present in parietal cells, vascular smooth muscle, and cardiac myocytes.

• H3 receptors: primarily in CNS; low peripheral expression.

• H4 receptors: found in basophils and bone marrow.

Mechanism of Release

• Histamine Release Mechanisms

• Promoted by innate (Toll-like receptors) and adaptive immune responses (IgE).

• Involved in Ca2+ dependent exocytosis leading to increased capillary permeability for white blood cells and proteins.

• Some drugs, like morphine, can enhance histamine release.

• Histamine Inactivation

• Inactivated by histaminase or imidazole N-methyltransferase.

• Turnover rate in mast cells and basophils is slow, while histaminocytes regenerate rapidly.

Physiological Effects of Histamine

• Smooth Muscle

• Contracts smooth muscle in ileum, bronchi, and uterus, facilitated by H1 receptors.

• Cardiovascular System

• Dilates arterioles causing increased permeability and enhances heart rate (H2 receptors).

• Gastric Secretions

• Stimulates gastric acid secretion through H2 receptors.

• CNS

• Histaminergic neurons influence arousal and wakefulness.

Triple Response to Histamine

• Described by Sir Thomas Lewis (1924).
• Flush: reddening due to vasodilation.
• Flare: stimulation of nerve fibers causing vasodilation.
• Wheal: localized edema due to increased permeability.

Histamine Drugs

• H1 Antagonists

• Used for allergic reactions, urticaria, and sedation.

• First-generation (sedating) vs. second-generation (non-sedating) drugs.

• Example drugs:

  • Cetirizine: Non-sedating, inverse agonist.
  • Promethazine: Sedating, also an anti-emetic.

• H2 Antagonists

• Used for treating peptic ulcers and gastroesophageal reflux.

• Example drugs:

  • Cimetidine: reduces acid secretion, side effects include dizziness and rash.

• H3 Antagonists

• Pitolisant used in narcolepsy; can promote wakefulness by blocking autoreceptors.

Clinical Applications

• H1 Antagonists

• Effectively treat allergic rhinitis and urticaria; provide 3-6 hours relief.

• Some formulations are also available as topical treatments or nasal sprays.

• Anti-emetic Effects

• Used in the treatment of motion sickness; target H1 receptors in the vestibular system.

• Sedative Effects

• Beneficial effects utilized in insomnia treatment using first-generation antihistamines.

Important Milestones in Histamine Research

• 1910: Dale & Laidlaw describe histamine physiological effects.
• 1937: Bovet discovers the first anti-histamine.
• 1983 & 2000: Discovery of H3 and H4 receptors.

Summary

• Histamine is a critical mediator in immune responses, involved in various physiological effects related to allergies, gastric secretion, and CNS functions.
• H1 antagonists are used primarily for allergies, while H2 antagonists treat peptic ulcers.
• Emerging interest in H3 antagonists for cognitive and regulatory functions.