Why Enalapril Causes Angioedema
Enalapril causes angioedema by blocking the angiotensin-converting enzyme (ACE), which normally degrades bradykinin and substance P—when these vasoactive peptides accumulate due to impaired breakdown, they increase vascular permeability and cause plasma extravasation into deeper tissue layers, resulting in non-urticarial swelling. 1, 2
Mechanism of ACE Inhibitor-Induced Angioedema
The pathophysiology involves a specific enzymatic blockade rather than an allergic reaction:
- ACE (also called kininase II) normally cleaves and inactivates bradykinin and substance P, which are potent vasoactive peptides 1
- When enalapril inhibits ACE, bradykinin degradation is prolonged, leading to elevated plasma bradykinin levels that have been directly measured in affected patients 1, 3
- Bradykinin acts on bradykinin B2 receptors to increase vascular permeability and stimulates release of substance P, causing vasodilation and fluid extravasation into tissues 3
- This is NOT a histamine-mediated allergic reaction, which explains why antihistamines, corticosteroids, and epinephrine are not reliably effective 1, 4, 5
Why This Is a Class Effect
- All ACE inhibitors share this mechanism, so patients who develop angioedema with enalapril will typically react to any other ACE inhibitor 1
- The FDA label explicitly states that ACE inhibitors affect the metabolism of eicosanoids and polypeptides, including endogenous bradykinin, making patients susceptible to this adverse reaction 2
- Individual susceptibility may be determined by the level or activity of other bradykinin-degrading enzymes in a given patient, explaining why only 0.1-0.7% of patients develop this complication 1, 6
Clinical Characteristics That Distinguish This Mechanism
The bradykinin-mediated mechanism produces distinct clinical features:
- Swelling occurs in deeper submucosal tissues rather than superficial skin, affecting face, lips, tongue, pharynx, larynx, and occasionally bowel and extremities 1, 7
- Urticaria is typically absent, helping differentiate this from histamine-mediated allergic angioedema 1, 5
- Timing is unpredictable—60% of cases occur within the first month, but onset can occur even after many years of continuous therapy 1, 4
- Swelling can persist for up to 6 weeks after discontinuation because bradykinin metabolism takes time to normalize 4, 8
Why Neprilysin Inhibitors Increase Risk
- Neprilysin is another enzyme that breaks down bradykinin, so combining neprilysin inhibitors with ACE inhibitors creates synergistic bradykinin accumulation 1, 4
- Omapatrilat (combined ACE inhibitor and neprilysin inhibitor) caused a 3-fold increased risk of angioedema compared to enalapril alone, leading to termination of its development 1
- A mandatory 36-hour washout period is required when switching between ACE inhibitors and neprilysin inhibitors to allow bradykinin metabolism to recover 1, 4
Risk Factors for Developing This Complication
Certain populations have higher susceptibility to bradykinin accumulation:
- African Americans have substantially higher risk than white patients 1, 4, 8
- Women, smokers, and older individuals are at increased risk 1, 4, 6, 3
- Patients with history of drug rash or seasonal allergies have elevated risk 3
- Diabetic patients have lower risk than non-diabetics 1
- Concurrent DPP-IV inhibitor use increases angioedema risk 4