Histamine and Bradykinin Pharmacology · Module 4

Bradykinin Pharmacology and Angioedema

Kallikrein-kinin cascade, ACE inhibitor adverse effects, and hereditary angioedema treatment

Kallikrein-Kinin Cascade

Trigger

Factor XII activation

→

Enzyme

Plasma kallikrein

→

Substrate

HMW kininogen

→

Product

Bradykinin

→

Degraded by

ACE (kininase II)

Angiotensin Converting Enzyme Inhibitor Adverse Effects

Bradykinin Accumulation — Airways

ACE Inhibitor Cough

Bradykinin sensitizes bronchial C fibers via B2 receptor
Dry, nonproductive cough — onset days to weeks
Resolves on discontinuation
More common in East Asian patients
Fix: switch to angiotensin receptor blocker

Bradykinin Accumulation — Vasculature

ACE Inhibitor Angioedema

Bradykinin increases vascular permeability via B2 receptor
Face, lips, tongue, larynx — no urticaria
Higher risk in African American patients
Does NOT respond to epinephrine or antihistamines
Fix: stop ACE inhibitor permanently; switch to ARB

Histamine vs Bradykinin Angioedema

Feature	Histamine-Mediated	Bradykinin-Mediated
Urticaria	Yes — almost always	No — key distinguishing feature
Causes	Allergic reaction, food/drug allergy	ACE inhibitor; hereditary angioedema (C1 inhibitor deficiency)
Responds to epinephrine	Yes	No
Responds to antihistamines	Yes — adjunctive	No
Specific treatment	Epinephrine; antihistamines; corticosteroids	Icatibant; C1 inhibitor concentrate; stop ACE inhibitor

Hereditary Angioedema Treatment

Acute Attack

Icatibant

B2 receptor antagonist — blocks bradykinin action
Subcutaneous; can be self-administered
Drug of choice for acute attacks

Acute Attack / Prophylaxis

C1 Inhibitor Concentrate

Replaces deficient C1 inhibitor protein
Restores kallikrein control — stops bradykinin generation
Intravenous; also used as pre-procedure prophylaxis

Long-Term Prophylaxis

Lanadelumab

Monoclonal antibody against plasma kallikrein
Prevents bradykinin generation at its source
Subcutaneous every 2–4 weeks

Long-Term Prophylaxis (historical)

Danazol

Attenuated androgen — upregulates hepatic C1 inhibitor synthesis
Second-line; significant adverse effects (virilization, hepatotoxicity)
Largely replaced by lanadelumab

High-Yield Rule — Hereditary Angioedema

Hereditary angioedema is bradykinin-mediated, not histamine-mediated. Epinephrine, antihistamines, and corticosteroids do not work. Angioedema without urticaria + failure to respond to standard allergy treatment = consider bradykinin-mediated mechanism. Treat with icatibant or C1 inhibitor concentrate.