Drugs for Hereditary Angioedema
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Direct answer
Hereditary angioedema swells without itching — and that one missing feature redirects the entire therapeutic logic. The disease is C1-inhibitor deficiency (type 1: low antigenic levels; type 2: dysfunctional protein), leaving bradykinin free to leak vessels; there is no urticaria, no pruritus, and no response to antihistamines, steroids or adrenaline. Screening shows low C4; diagnosis needs C1-INH antigenic and functional levels, with C1q normal in hereditary disease (low C1q suggests the acquired form). Acute attacks take icatibant (bradykinin B2 receptor antagonist, 30 mg subcutaneously), C1-inhibitor concentrate intravenously, or — where concentrates are unavailable, as across much of India — fresh frozen plasma. Long-term prophylaxis runs from lanadelumab (anti-plasma kallikrein, fortnightly) and oral berotralstat to danazol and tranexamic acid; ACE inhibitors are permanently contraindicated.
What you must remember
- The pathway: factor XII activation → plasma kallikrein → bradykinin → B2 receptor → vascular leak — this chain explains every drug choice and the ACE inhibitor danger.
- Acute attack: icatibant 30 mg SC (self-administered in most guidelines), C1-INH concentrate 20 U/kg IV, ecallantide (plasma kallikrein inhibitor, US); FFP is the resource-limited stand-in since it carries C1-INH.
- Prophylaxis, modern: lanadelumab 300 mg SC every 2 weeks (anti-plasma kallikrein monoclonal), berotralstat (oral daily kallikrein inhibitor), C1-INH subcutaneous.
- Prophylaxis, classic: danazol 200 mg (range 50–600 mg) daily — an attenuated androgen that raises hepatic C1-INH and C4 synthesis; virilisation, weight gain, hepatic adenomas (LFTs and liver ultrasound for life); tranexamic acid 1 g two-three times daily as the weaker, cheaper alternative.
- Diagnosis ladder: C4 low during and between attacks (the screening test), C1-INH antigenic low (type 1) or normal antigenic with low function (type 2), C1q normal; family history in about 75%.
- Permanent exclusions: ACE inhibitors (bradykinin degradation blocked) and oestrogens (worsen attacks) — for life, not just during treatment.
- Procedural cover: C1-INH concentrate or a danazol boost before dental or surgical work — laryngeal attacks after airway instrumentation are the feared event.
- Indian anchor: danazol plus FFP remains the affordable backbone; acquired C1-INH deficiency (lymphoproliferative or autoimmune, C1q low) is the differential the C1q level resolves.
The laryngeal attack and the diagnosis that explains it
A 24-year-old woman arrives with lip and tongue swelling and a tightening throat — no wheal, no itch, no response to adrenaline given in the ambulance. That trio is the diagnosis speaking: hereditary angioedema, confirmed later by C4 of 8 mg/dL (low), C1-INH antigenic low, C1q normal. The airway takes precedence — icatibant 30 mg subcutaneously, C1-INH concentrate 20 U/kg IV where available, intubation standby; adrenaline was always going to fail because there is no mast-cell mediator to block. Her triggers get named — minor trauma, dental work, oestrogen-containing pills (she stopped them that day), and an ACE inhibitor her previous doctor prescribed for hypertension, now permanently replaced. Long-term: danazol 200 mg daily, started with a frank conversation about virilisation, weight, and the liver scans she will keep for life; where cost allows, lanadelumab every fortnight offers cleaner chemistry with the same endpoint — no laryngeal attack. Every therapeutic sentence in this story traces back to one biochemistry line: without C1-INH, bradykinin runs unchecked.
Where students slip
The first slip is treating it like allergic angioedema — adrenaline, steroids and antihistamines do nothing here, and recognising their failure is itself diagnostic information; the viva question "why did adrenaline fail?" expects the bradykinin answer. The second is the screening test: C4, low even between attacks, is the cheap first clue, while C1q's level separates hereditary (normal) from acquired (low) disease. Third, ACE inhibitors in HAE are not merely unhelpful — they are contraindicated for life, because ACE degrades bradykinin; the same logic explains why the drug causes acquired angioedema in normal people. Fourth, danazol is quoted without its tax: attenuated androgen, hepatic adenoma risk, virilisation, lifelong monitoring — and pregnancy absolutely contraindicates it, at which point C1-INH concentrate becomes the prophylaxis of choice. Fifth, students forget procedural cover before dental extraction or intubation — the trigger list (trauma, oestrogens, ACE inhibitors, instrumentation) is half the clinical exam. Finally, tranexamic acid's role is antifibrinolytic dampening of the kallikrein-driven cascade — weaker, cheaper, and honest about both.
Frequently asked questions
Why do antihistamines and adrenaline fail in hereditary angioedema?
The mediator is bradykinin, not histamine — mast-cell-directed drugs have no target, which itself helps distinguish HAE clinically.
What is the screening test and how is hereditary distinguished from acquired disease?
C4 is low in both during and between attacks; C1q is normal in hereditary C1-INH deficiency and low in the acquired form.
How does icatibant work?
It is a selective bradykinin B2 receptor antagonist given 30 mg subcutaneously, blocking the vascular-leak signal at the end of the kallikrein-kinin pathway.
Why is danazol effective despite being an androgen?
Attenuated androgens increase hepatic synthesis of C1-INH and C4, raising functional inhibitor levels — with virilisation and hepatic adenoma risks requiring lifelong monitoring.
Which drugs are permanently contraindicated in HAE?
ACE inhibitors (they block bradykinin degradation) and oestrogens (they worsen attacks) — for life, independent of therapy.