What drugs are associated with angioedema?

Drugs Associated with Angioedema

ACE inhibitors are the most clinically significant drug class causing angioedema, accounting for approximately one-third of all emergency department visits for angioedema, with an incidence of 0.1-0.7% and potential for fatal airway obstruction. 1, 2

High-Risk Drug Classes

ACE Inhibitors (Highest Risk)

• All ACE inhibitors carry a class-wide risk of angioedema that can occur at any time during treatment, including after years of stable therapy 1, 3
• Specific agents documented include:
  • Lisinopril 1, 4, 5
  • Enalapril 3, 5
  • Captopril 6, 5
• Fatal cases have been reported, particularly when laryngeal edema progresses to complete airway obstruction 4
• The mechanism involves inhibition of bradykinin degradation by ACE (kininase II), leading to vasodilation and plasma extravasation 2

Angiotensin Receptor-Neprilysin Inhibitors (ARNIs)

• ARNIs are absolutely contraindicated in patients with any history of angioedema 7
• Sacubitril/valsartan (the approved ARNI) carries a low-frequency but serious risk of angioedema 7
• Omapatrilat (combined neprilysin and ACE inhibitor) demonstrated a 3-fold increased risk of angioedema compared to enalapril, leading to termination of its clinical development 7
• The mechanism involves dual inhibition of both ACE and neprilysin, both of which break down bradykinin 7
• ARNIs must not be administered within 36 hours of switching from or to an ACE inhibitor 7

Angiotensin Receptor Blockers (ARBs) - Lower but Non-Zero Risk

• ARBs have a substantially lower incidence of angioedema compared to ACE inhibitors but the risk is not zero 8, 9, 6
• Cross-reactivity angioedema occurs in 2-17% of patients when switching from an ACE inhibitor to an ARB 8
• Specific agents mentioned include:
  • Losartan 8
  • Telmisartan 9
  • Valsartan 9
  • Candesartan 9
• A mandatory 6-week washout period is required after discontinuing an ACE inhibitor before initiating any ARB 8, 9

Other Medications

• Fibrinolytic agents have been associated with severe angioedema 6
• Estrogens should be avoided in patients with C1-INH deficiency 6
• NSAIDs can cause angioedema 6
• Scattered reports exist for other antihypertensive drugs and psychotropic medications 6

High-Risk Patient Populations

The following patient characteristics significantly increase angioedema risk with ACE inhibitors:

• African American/Black patients (highest risk group) 7, 2
• Smokers (particularly at risk) 7, 2
• Women 2
• Older individuals 2
• Patients with prior history of idiopathic angioedema (extremely high risk and should be treated with extreme caution) 3, 10
• History of drug rash or seasonal allergies 2
• Patients on immunosuppressive therapy 2

Critical Clinical Pitfalls

Timing Misconceptions

• Angioedema can occur at any time during ACE inhibitor therapy, not just during initial dosing 1, 3
• Long-term stable therapy does not eliminate risk 1
• Long-acting ACE inhibitors (lisinopril, enalapril) appear to cause more severe angioedema requiring intubation compared to short-acting agents (captopril) 5

Diagnostic Challenges

• Intestinal angioedema presents with abdominal pain (with or without nausea/vomiting) and may occur without facial angioedema or abnormal C1-esterase levels 3
• Diagnosis requires abdominal CT scan, ultrasound, or surgical exploration 3
• The relationship to ACE inhibitors is often missed and underestimated because the mechanism is not allergic or idiosyncratic 6

Re-challenge Risk

• Patients with ACE inhibitor-induced angioedema should never be re-challenged with any ACE inhibitor due to high recurrence risk 9, 2
• One patient with mild captopril-induced angioedema subsequently required intubation when switched to enalapril, demonstrating that prior mild reactions do not predict future severity 5

Management Implications

Immediate Actions

• Discontinue the offending agent immediately 6
• Epinephrine, antihistamines, and corticosteroids are commonly used but lack controlled trial evidence for efficacy 6, 4
• Emergency cricothyroidotomy or tracheostomy may be necessary for life-threatening airway obstruction 6, 4
• Severe laryngeal edema can progress rapidly to complete laryngospasm and airway obstruction despite aggressive medical management 4

Long-term Considerations

• Complete resolution of the predisposition to recurrent angioedema may take up to 6 weeks after drug discontinuation 8, 9, 11
• Acute symptoms typically subside within 1-2 weeks 11
• If angioedema persists beyond 2 weeks or worsens after discontinuation, investigate alternative causes including hereditary angioedema or acquired C1 inhibitor deficiency 11