Histamine and Antihistamines

Histamine is a biogenic amine related to serotonin and dopamine. It is found in most tissues, with highest concentrations in the lungs, skin, gastrointestinal tract, and brain where it functions as a neurotransmitter. Histamine is produced by decarboxylation of the amino acid histidine (by histidine decarboxylase).

Two pools of histamine exist. The slow turnover pool is stored in granules within mast cells (tissue) and basophils (blood), synthesised ahead of time; replenishment takes several weeks after degranulation. The fast turnover pool is found in gastric enterochromaffin-like cells and histaminergic neurons, which do not store histamine but produce it by histidine decarboxylase following stimulation; gastric histamine turnover is rapid.

Histamine release from granules is triggered by a rise in intracellular calcium. Released histamine binds to histamine receptors — all of which are GPCRs. Four receptor subtypes: H1, H2, H3, and H4 (H4 is less clinically relevant).

H1 receptor — activates the phosphatidylinositol pathway (Gq): vasodilation (via NO release) → flushing, redness, decreased BP; increased vascular permeability → oedema; contraction of intestinal and bronchial smooth muscle (bronchoconstriction); sensitisation of afferent nerve terminals → itching and pain; wakefulness (CNS neurotransmitter). The classic allergic response to histamine is the triple response: wheal, flare, and itch.

H2 receptor — activates adenylyl cyclase (Gs, increased cAMP): stimulates gastric acid secretion from parietal cells; increases heart rate and cardiac output.

H3 receptor — presynaptic autoreceptor; modulates histamine and other neurotransmitter release in the CNS.

Antihistamines: H1 receptor antagonists are the primary anti-allergy agents. First-generation H1 antagonists (e.g. mepyramine, diphenhydramine/Benadryl, chlorpheniramine, promethazine): lipid-soluble; cross the BBB → sedation, tinnitus, dizziness, fatigue; have anticholinergic side effects (blurred vision, dry mouth, urinary retention). Second-generation H1 antagonists (e.g. fexofenadine/Telfast, loratadine/Claritin, cetirizine/Zyrtec): do not cross the BBB → non-sedating; minimal anticholinergic effects; more selective for H1; longer lasting. Used for allergic rhinitis, acute urticaria, hay fever, motion sickness (promethazine, meclozine — given 1h before travel; ADRs: drowsiness, atropine-like effects), anti-tussive (diphenhydramine — suppresses cough reflex by direct action on cough centre in medulla).

H2 receptor antagonists (e.g. cimetidine, ranitidine): inhibit gastric acid secretion (suppress 24h gastric acid secretion by ~70%); used for reflux oesophagitis and peptic ulcers. Tolerance develops within 3 days. Lower incidence of side effects (<3%: diarrhoea, headache, drowsiness). Note: pH alterations from H2 antagonists can alter absorption of some drugs (e.g. targeted cancer drugs like gefitinib). H2 antagonists have shorter duration of action than PPIs (but longer than antacids), creating a clinical niche where shorter duration is needed or when drug absorption must not be significantly affected by prolonged pH changes. Cimetidine has important CYP450 enzyme interactions.

Cromolyn (cromoglicate): an exception — inhibits histamine release from mast cells (mast cell stabiliser); does not directly antagonise H1 receptors. Used as a nasal spray (allergic rhinitis), eye drops (allergic conjunctivitis), or oral (ulcerative colitis).