Pharmacology of Histamine Receptors

Pharmacology of Histamine

• Histamine is a basic amine found in tissues, especially those exposed to the external environment (lungs, skin, gastrointestinal tract).
• Histamine is released by mast cells during inflammatory or allergic reactions.
• It's metabolized by histaminase and/or methylating enzymes.
• Histamine synthesis involves L-histidine decarboxylase.

Histamine Receptors

• Four types of histamine receptors (H1-H4) are G protein-coupled receptors (GPCRs).
• H1 receptors are associated with calcium influx.
• H2 receptors increase cAMP levels, linked to parietal cell acid secretion.
• All four types are involved in inflammatory responses.

Physiological Actions of Histamine

H1 Receptor-Mediated Actions

• Causes contraction of most smooth muscles (except blood vessels).
• Leads to vasodilation, bronchoconstriction, and increased vascular permeability.
• Stimulates sensory nerve fibers, causing itching in the skin.
• Involved in wakefulness (H1) and sleep pathways (H3).

H2 Receptor-Mediated Actions

• Stimulates gastric acid secretion (implicated in peptic ulcers).
• Influences cardiac stimulation.

Antihistamines

• H1-receptor antagonists and inverse agonists used to treat inflammation and allergies.
• Antihistamines are categorized as first-generation (e.g., chlorphenamine, sedating) and second-generation (e.g., cetirizine, non-sedating).
• Antihistamine formulations can vary (e.g., nasal sprays, oral medications, eye drops).

Clinical Uses of Antihistamines

• Allergic reactions: allergic rhinitis, urticaria, insect bites, and conjunctivitis treated with non-sedating antihistamines (e.g., fexofenadine, cetirizine).
• Treating allergic reactions (nasal and eye) or drug hypersensitivity reactions as an adjuvant to adrenaline.
• Prevent motion sickness, especially labyrinth disorders (e.g., promethazine).

H3 Receptor Antagonists

• Pitolisant is a first-line treatment for excessive daytime sleepiness (EDS) in narcoleptic patients.
• Blocking H3 receptors increases histamine synthesis and release, promoting wakefulness.

Adverse Effects of Antihistamines

• First-generation antihistamines have peripheral anticholinergic effects.
• Anticholinergic syndrome is a common adverse effect of first-generation antihistamine overdose.
• Second-generation antihistamines have lower sedative effects.
• Contraindications include alcohol, anticholinergics, digestive obstruction, and glaucoma (for 1st and 2nd gen.).
• Interactions can occur with inhibitors of CYP3A4 (e.g., 2nd generation).
• Potential for sedation, anticholinergic effects (dry mouth, blurred vision), digestive issues.
• Second-generation drugs may cause cardiac toxicity and arrhythmias if taken with grapefruit juice or inhibitors of P450 liver enzymes.
• Potential for photosensitivity reactions.