What medications, excluding Angiotensin-Converting Enzyme (ACE) inhibitors and Angiotensin Receptor Blockers (ARBs), cause angioedema?

From the Guidelines

Medications that can cause angioedema outside of ACE inhibitors and ARBs include NSAIDs, antibiotics, opioids, certain chemotherapy drugs, statins, fibrates, proton pump inhibitors, contrast media, antidepressants, hormonal medications, allopurinol, and antiepileptic medications. These medications can trigger angioedema through various mechanisms, including direct mast cell activation leading to histamine release or alterations in bradykinin metabolism 1. According to the 2022 guidelines on chronic spontaneous urticaria, angiotensin II type 1 receptor blockers, dipeptidyl peptidase IV inhibitors, and neprilysin inhibitors have also been described as inducing angioedema, although less frequently than ACE inhibitors 1.

Key points to consider:

• NSAIDs, such as aspirin, ibuprofen, and naproxen, can cause angioedema by inhibiting the enzyme cyclooxygenase, leading to an imbalance in prostaglandin and leukotriene production 1.
• Antibiotics, particularly penicillins, cephalosporins, and sulfonamides, can trigger angioedema through an allergic reaction, which can be severe and life-threatening 1.
• Opioids, like codeine and morphine, can cause angioedema by releasing histamine from mast cells, leading to increased vascular permeability and swelling 1.
• Certain chemotherapy drugs, such as taxanes and platinum-based agents, can induce angioedema as a side effect, possibly due to their ability to activate mast cells and release histamine 1.
• Statins, fibrates, and proton pump inhibitors have been implicated in causing angioedema, although the exact mechanism is unclear 1.
• Contrast media used in imaging studies can trigger angioedema, possibly due to their ability to activate the complement system and release histamine 1.
• Antidepressants, especially SSRIs, and hormonal medications, including estrogens and oral contraceptives, can cause angioedema, possibly due to their ability to alter serotonin and histamine levels 1.
• Allopurinol, used for gout treatment, and some antiepileptic medications, like phenytoin and carbamazepine, are additional culprits that can trigger angioedema 1.

It is essential for patients with a history of angioedema to maintain a detailed list of medications that have triggered reactions and wear medical alert identification. The onset of angioedema can range from minutes to hours after medication exposure, and symptoms may persist for 24-72 hours even after discontinuing the offending agent 1.

From the FDA Drug Label

Warnings ... Allergy alert: Aspirin may cause a severe allergic reaction which may include: hives, facial swelling, asthma(wheezing), shock

• Angioedema can be considered a type of facial swelling, which is listed as a potential symptom of a severe allergic reaction to aspirin.
• The medication that may cause angioedema outside of ACE and ARBs is aspirin 2.

From the Research

Medications Causing Angioedema

Medications that can cause angioedema outside of ACE inhibitors and ARBs include:

• Nonsteroidal anti-inflammatory drugs (NSAIDs) 3
• Beta-lactam antibiotics 4, 3
• Non-beta lactam antibiotics 3
• Dipeptidyl peptidase IV inhibitors, a class of oral diabetic agents 5
• Neprilysin inhibitors, a class of cardiac medications, which includes sacubitril 5

Mechanisms of Angioedema

These medications can cause angioedema through various mechanisms, including:

• Histamine-mediated reactions 3
• Bradykinin-mediated reactions 4, 5
• Leukotriene-mediated reactions 3

Treatment of Angioedema

The mainstay of treatment for nonallergic drug-induced angioedema is cessation of the offending agent 3