COMPREHENSIVE OVERVIEW OF HISTAMINE AND ANTIHISTAMINE AGENTS

Histamine is an organic nitrogenous compound that plays a crucial role in various physiological processes, including immune responses, gastric acid secretion, and neurotransmission. It is synthesized from the amino acid histidine through a decarboxylation reaction catalyzed by the enzyme histidine decarboxylase (HDC). This process occurs primarily in mast cells and basophils, which are types of white blood cells involved in allergic reactions and inflammatory responses.

Locations of Synthesis:

• Mast Cells: These cells are predominantly found in connective tissues throughout the body, particularly near blood vessels and nerves. They store histamine in granules.
• Basophils: Similar to mast cells but circulate in the bloodstream; they also contain histamine.
• Enterochromaffin-like (ECL) Cells: Located in the gastric mucosa, these cells produce histamine to stimulate gastric acid secretion.

Storage: Histamine is stored primarily in granules within mast cells and basophils. In ECL cells, it is also stored within secretory vesicles. The storage form of histamine is bound to other molecules such as heparin or chondroitin sulfate, which helps prevent its premature release.

Catabolism: The breakdown of histamine occurs mainly through two enzymatic pathways:

1. Methylation: Histamine can be methylated by the enzyme histamine N-methyltransferase (HNMT) to form N-methylhistamine.
2. Oxidative Deamination: The primary pathway involves the action of diamine oxidase (DAO), which converts histamine into imidazole acetaldehyde. Both pathways ultimately lead to the formation of inactive metabolites that are excreted via urine.

Differences Between H1 and H2 Receptors

Histamine exerts its effects through four types of receptors: H1, H2, H3, and H4. Here we focus on H1 and H2 receptors:

• H1 Receptors:
  • Location: Found on smooth muscle cells (e.g., bronchial tissues), endothelial cells, and neurons.
  • Physiological Function: Activation of H1 receptors leads to vasodilation, increased vascular permeability (resulting in edema), bronchoconstriction, and stimulation of sensory nerves causing itching or pain.
  • Pathophysiological Role: In allergic reactions, excessive activation can contribute to symptoms like rhinitis or asthma.

  H2 Receptors:

  • Location: Primarily located on gastric parietal cells but also found in cardiac tissue and some immune cells.
  • Physiological Function: Activation of H2 receptors stimulates gastric acid secretion from parietal cells; it also has a role in cardiac function by increasing heart rate and contractility.
  • Pathophysiological Role: Overactivity can lead to conditions such as peptic ulcers due to excessive gastric acid production.

Triple Response of Lewis

The triple response of Lewis is a classic physiological response observed in the skin when it comes into contact with a noxious stimulus, such as an irritant or an allergen. It is named after Sir Thomas Lewis, a prominent Welsh physician and cardiologist who first described this phenomenon in the early 20th century. The triple response consists of three distinct stages: (1) the initial redness (erythema), (2) the flare (or spreading erythema), and (3) the wheal (or edema).

1. Initial Redness (Erythema)

The first stage of the triple response is the initial redness, also known as erythema. This occurs due to the dilation of superficial blood vessels in the skin, which increases blood flow to the affected area. The dilation is caused by the release of histamine and other vasoactive substances from mast cells in response to the noxious stimulus. As more blood flows into the capillaries, oxygenated hemoglobin in the red blood cells gives the skin a reddish appearance.

2. Flare (Spreading Erythema)

The second stage of the triple response is the flare, or spreading erythema. This is characterized by a spreading redness around the initial site of irritation. The flare occurs due to the release of axon reflexes, which are nerve impulses triggered by pain or itch sensation. These impulses travel along sensory nerve fibers and activate nearby blood vessels, causing them to dilate and create an area of redness around the original site of irritation.

3. Wheal (Edema)

The third and final stage of the triple response is the wheal, or edema. This stage involves localized swelling due to an increase in vascular permeability and fluid accumulation in the affected area. The fluid leakage from blood vessels results from histamine-mediated contraction of endothelial cells lining these vessels. Histamine also triggers local inflammation, leading to further immune cell recruitment and fluid accumulation. Wheal formation typically subsides within a few hours as the body clears out excess fluid and mediators responsible for these reactions.

In summary, the triple response of Lewis comprises three distinct stages: initial redness due to vasodilation, spreading redness due to axon reflexes, and localized swelling due to increased vascular permeability and fluid accumulation. This complex physiological response plays a crucial role in our body’s defense mechanisms against noxious stimuli and helps facilitate immune cell recruitment and clearance of harmful agents from affected areas.

Therapeutic Uses, Pharmacokinetic Properties, and Side Effects of H1 and H2 Antagonists

• H1 Antagonists (Antihistamines):
  • Primary Therapeutic Uses: Used to treat allergic reactions such as rhinitis, urticaria (hives), conjunctivitis; also used for motion sickness and insomnia.
  • Pharmacokinetic Properties:
    • First-generation antihistamines like diphenhydramine cross the blood-brain barrier causing sedation.
    • Second-generation antihistamines like loratadine have minimal central nervous system penetration reducing sedative effects.
  • Side Effects:
    • First-generation: Sedation, dry mouth (anticholinergic effect), dizziness.
    • Second-generation: Generally well-tolerated with fewer side effects; occasional headache or mild gastrointestinal disturbances.
• H2 Antagonists (H2 Blockers):
  • Primary Therapeutic Uses: Used to reduce gastric acid secretion for treating peptic ulcers, gastroesophageal reflux disease (GERD), Zollinger-Ellison syndrome.
  • Pharmacokinetic Properties:
    • Examples include cimetidine and ranitidine which are absorbed orally with varying half-lives allowing for different dosing schedules.
  • Side Effects:
    • Generally mild but can include headache, dizziness; cimetidine may cause gynecomastia or interfere with cytochrome P450 enzymes affecting drug metabolism.
• Antidegranulating Drugs (Mast Cell Stabilizers):
  • These drugs prevent mast cell degranulation thereby inhibiting histamine release.
  • Examples include cromolyn sodium used prophylactically for asthma management.
  • Side effects are minimal but can include throat irritation or cough when inhaled.