Mechanism of Action Flowcharts

H₁ receptor is constitutively active H₁ is a GPCR with baseline (constitutive) activity even without histamine. Antihistamines are inverse agonists — they don't just block histamine; they stabilise the inactive receptor conformation and reduce baseline signalling below zero.

Gq/11 → PLC → IP₃ + DAG pathway Histamine binding activates Gq/11 → PLC cleaves membrane PIP₂ into IP₃ (→ ER Ca²⁺ release) and DAG (→ PKC activation). Both branches drive the full allergic response: vasodilation, oedema, bronchoconstriction, itch.

Ca²⁺ is the master effector In endothelial cells: Ca²⁺ → eNOS → NO → vasodilation (flushing/erythema). In vascular endothelium: Ca²⁺ → RhoA/ROCK → gap junction formation → plasma leak → oedema/wheal. In smooth muscle: Ca²⁺ → actin–myosin → contraction (bronchospasm, colic).

Inverse agonist ≠ competitive antagonist A competitive antagonist blocks agonist binding but does not affect constitutive activity. An inverse agonist (like cetirizine, loratadine) additionally reduces the basal activity of the receptor below its unoccupied level — clinically important in chronic urticaria where spontaneous H₁ activation drives symptoms without exogenous histamine.

Why antihistamines don't stop all bronchoconstriction Histamine-mediated bronchoconstriction involves H₁ on bronchial smooth muscle. Antihistamines reduce this but are not sufficient as sole asthma therapy because other mediators (leukotrienes, prostaglandins, PAF) maintain bronchospasm independently of H₁.

Clinical translation ↓ itch, sneezing, rhinorrhoea (H₁ on sensory nerves and nasal mucosa) · ↓ urticaria wheal and flare (vascular H₁ block) · partial bronchospasm protection · no effect on H₂-mediated gastric acid secretion (different receptor, different G-protein).