Can hydrochlorothiazide (HCTZ) cause angioedema?

Hydrochlorothiazide and Angioedema

Yes, hydrochlorothiazide (HCTZ) can cause angioedema, though it is a rare adverse effect that is often underrecognized and can be life-threatening.

Evidence for HCTZ-Induced Angioedema

The association between HCTZ and angioedema is documented in case reports, though it is not as widely recognized as ACE inhibitor-induced angioedema:

• A definitive case report demonstrated HCTZ as the cause of recurrent angioedema in an 82-year-old woman with a documented sulfonamide antibiotic allergy, scoring 9 on the 10-point Naranjo adverse drug reaction probability scale (indicating a "definite" causal relationship) 1

• The patient experienced repeated episodes of angioedema with severe dysphagia and shortness of breath that only resolved after permanent discontinuation of HCTZ, with symptoms recurring upon rechallenge 1

• Another case report documented a 78-year-old woman who experienced severe hypersensitivity reactions to HCTZ mimicking septic shock, with symptoms beginning within hours of HCTZ administration 2

Clinical Presentation and Mechanism

HCTZ-induced angioedema typically presents as:

• Self-limiting local swellings involving deeper cutaneous and mucosal tissue layers 3
• Facial, lip, and tongue edema 4
• Potentially life-threatening laryngeal edema causing dysphagia and respiratory compromise 1

The mechanism differs from ACE inhibitor-induced angioedema (which involves bradykinin accumulation) 5. HCTZ is a sulfonamide-containing drug, and while true cross-reactivity between sulfonamide antibiotics and non-antibiotics is debated, allergic-like reactions can occur in patients with sulfonamide antibiotic allergies 1.

Critical Distinction from ACE Inhibitor Angioedema

ACE inhibitors are the most common drug cause of angioedema:

• ACE inhibitors cause angioedema in 0.1% to 0.5% of patients 6, 3
• The mechanism involves inhibition of bradykinin breakdown 5
• Can occur even after years of uneventful therapy 4, 6
• Accounts for potentially several hundred deaths per year from laryngeal edema worldwide 3

Important caveat: Many patients take combination products containing both an ACE inhibitor (or ARB) and HCTZ (e.g., lisinopril/HCTZ) 5, 4. When angioedema occurs in these patients, the ACE inhibitor is typically assumed to be the culprit, potentially masking HCTZ as a cause 1.

Management Algorithm

When angioedema occurs in a patient on HCTZ:

1. Immediately discontinue HCTZ - this is the only definitive treatment 3, 1

2. Assess airway urgency:

   • If dyspnea or stridor present: perform early endoscopically-controlled intubation or emergency cricothyroidotomy to prevent hypoxemia and death 6, 3
   • Laryngeal edema is the main cause of death in angioedema 4

3. Acute medical management (though efficacy not proven in controlled trials):

   • Epinephrine (subcutaneous and inhaled) 4, 3
   • Intravenous methylprednisolone 4, 6, 3
   • Diphenhydramine 4, 3

4. Do not rechallenge - permanent discontinuation is required 1

High-Risk Populations

Monitor closely in patients with:

• Known sulfonamide antibiotic allergies 2, 1
• History of drug allergies or predisposition to allergic reactions 2
• Concurrent ACE inhibitor or ARB therapy (though these cause angioedema through different mechanisms) 5, 4

Clinical Pitfall

The most critical error is failing to recognize HCTZ as a potential cause of angioedema, especially when it occurs after long-term uneventful use or in combination products with ACE inhibitors/ARBs 1. The relationship is often missed because angioedema is not commonly associated with thiazide diuretics in clinical practice, leading to continued exposure and potentially fatal outcomes 3.