Histamine and bradykinin
Two mediators of swelling: histamine drives allergy and acid secretion; bradykinin drives ACE-inhibitor and hereditary angioedema.
Histamine and bradykinin both widen small vessels and make them leak, so both can cause swelling of the lips, tongue and airway. They are treated very differently, however: histamine-driven swelling responds to antihistamines, corticosteroids and adrenaline, while bradykinin-driven angioedema usually does not and needs other measures.
Histamine and its receptors
Allergen bound to IgE on mast cells makes them release histamine in seconds, together with other mediators. Some drugs (opioids such as morphine, vancomycin given too fast, contrast media) can release histamine without IgE.
- H1: itch, wheal and flare, sneezing, bronchoconstriction, vasodilation and leak
- H2: gastric acid secretion; also some vascular and heart effects
- H3: autoreceptor in the brain that limits histamine release
- H4: on immune cells; involved in itch and chemotaxis
Antihistamines
H1 antihistamines are inverse agonists that stabilise the inactive receptor. First-generation drugs (chlorphenamine, diphenhydramine) also block muscarinic receptors and enter the brain, causing sleepiness, dry mouth and confusion in older adults. Second-generation drugs (loratadine, cetirizine) treat allergic rhinitis and hives with less sedation. H2 blockers (famotidine) lower acid. In anaphylaxis antihistamines only ease the skin symptoms: intramuscular adrenaline is the treatment that reverses airway swelling and shock.
The kinin system
Kallikrein cleaves high-molecular-weight kininogen to release bradykinin, which acts on B2 receptors on the endothelium: vasodilation, leak, pain. C1 inhibitor normally holds kallikrein and part of the complement system in check. ACE, the same enzyme that makes angiotensin II, is also kininase II and destroys bradykinin; neprilysin is another route of breakdown.
Bradykinin angioedema
Bradykinin swelling is deep, not itchy, and comes without hives.
- ACE inhibitors: bradykinin builds up; angioedema can appear at any time during treatment, even after years; dry cough is another kinin-related effect
- Sacubitril (a neprilysin inhibitor) adds to the risk, so it is never combined with an ACE inhibitor and a washout period separates them
- ARBs do not block bradykinin breakdown directly and carry a lower risk
- Hereditary angioedema: SERPING1 variants lower C1 inhibitor, bradykinin rises and attacks can block the airway
- Treatment targets the kinin system: C1 inhibitor concentrate, the B2 receptor antagonist icatibant or kallikrein inhibitors; airway protection comes first
Test yourself
Think of the answer, then tap the question to see it.
Why do ACE inhibitors cause angioedema and cough?
ACE is also kininase II; blocking it lets bradykinin build up, which causes vascular leak (angioedema) and irritates the airway (cough).
Why are first-generation antihistamines more sedating?
They cross the blood–brain barrier and block central H1 receptors (and often muscarinic receptors); second-generation drugs cross much less.
What is missing or defective in hereditary angioedema?
C1 inhibitor, because of variants in the SERPING1 gene; uncontrolled kallikrein activity raises bradykinin.
In anaphylaxis, which drug reverses airway swelling and low blood pressure?
Intramuscular adrenaline (epinephrine); antihistamines only relieve skin symptoms.
Example drugs
- Loratadine
- Cetirizine
- Chlorphenamine
- Famotidine
- Epinephrine
- Enalapril
- Lisinopril
- Sacubitril/valsartan
- Icatibant
- C1 esterase inhibitor
- Tranexamic acid
Connections
Educational content on how drugs work; not a prescribing guide and no substitute for a health professional's advice. No doses are given.
Sources: Angioedema: MedlinePlus Medical Encyclopedia (MedlinePlus (U.S. National Library of Medicine), 2026); Hereditary angioedema: MedlinePlus Genetics (MedlinePlus (U.S. National Library of Medicine), 2026); Lisinopril: MedlinePlus Drug Information (MedlinePlus (U.S. National Library of Medicine), 2026).
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Representative model, for educational purposes only.