Histamine and Bradykinin Pharmacology · Module 1

Histamine Biology, Receptors, and Physiological Roles

Storage sites, receptor subtypes, signaling, and pathophysiological roles

Storage Sites

Immune

Mast Cells

Skin, airways, gut mucosa
Largest peripheral reservoir
IgE-mediated degranulation

Immune

Basophils

Circulating granulocytes
IgE-mediated release
Contribute to late-phase reactions

Gastric Mucosa

ECL Cells

Oxyntic gastric mucosa
Stimulated by gastrin and acetylcholine
Paracrine H2 activation of parietal cells

CNS

Histaminergic Neurons

Tuberomammillary nucleus
Promote wakefulness via H1
H1 blockade → sedation

Receptor Subtypes

Receptor	G Protein	Key Location	Primary Effect	Drug Target
H1	Gq	Vascular endothelium, bronchial smooth muscle, sensory neurons, central nervous system	Vasodilation, increased permeability, bronchoconstriction, pruritus, wakefulness	H1 antihistamines (first- and second-generation)
H2	Gs	Gastric parietal cells	Cyclic adenosine monophosphate → proton pump → acid secretion	H2 blockers (cimetidine, famotidine)
H3	Gi	Presynaptic neurons, central nervous system	Inhibits histamine synthesis and release (autoreceptor)	Pitolisant (narcolepsy)
H4	Gi	Immune cells	Eosinophil chemotaxis, immune modulation	No approved Step 1-level drug

Pathophysiological Roles

Skin — H1

Triple Response of Lewis

Redness: local arteriolar vasodilation
Wheal: plasma extravasation, increased vascular permeability
Flare: axon reflex — surrounding erythema
Itch: sensory C fiber H1 activation

Systemic

Anaphylaxis

Histamine: primary mediator of urticaria, angioedema, flushing
Multimediator: prostaglandins, leukotrienes, platelet-activating factor also released
Antihistamines are adjuncts only — do not reverse bronchospasm or hemodynamic collapse
Epinephrine is the only first-line treatment

High-Yield Rule — Angioedema Without Urticaria

Histamine-mediated angioedema occurs with urticaria. Bradykinin-mediated angioedema (hereditary angioedema, angiotensin converting enzyme inhibitor-induced) occurs without urticaria and does not respond to antihistamines, corticosteroids, or epinephrine. Requires bradykinin-specific therapy. See Module 4.