Can ACE inhibitors cause angioedema?

Last updated Feb. 10, 2025, by Lindsey Shapiro, PhD
Fact-checked by Joana Carvalho, PhD

Angiotensin-converting enzyme (ACE) inhibitors, a widely prescribed class of medications often used to treat high blood pressure, cardiovascular conditions, and kidney disease, are the most common known cause of drug-induced nonallergic angioedema.

Angioedema is characterized by swelling attacks in the deep layers of the skin or in the mucous membranes that line internal organs. There are several types of angioedema, each with its own underlying cause. When swelling is caused by adverse reactions to certain medications, it’s classified as drug-induced nonallergic angioedema.

While rare, angioedema is a potentially serious side effect of ACE inhibitors. Although it occurs in a minority of patients on these medications, it can be life-threatening. It is thus important to understand the connection between ACE inhibitors and angioedema and know how to recognize the signs of a possible angioedema attack so that appropriate treatment can be administered as soon as possible.

How ACE inhibitors cause angioedema

The symptoms of drug-induced nonallergic angioedema typically arise when certain medications cause elevations in a signaling molecule called bradykinin, which is involved in inflammation and blood pressure regulation. Bradykinin causes blood vessels to be more permeable, or leakier. This enables fluid to leak out of blood vessels and pool into surrounding tissues, resulting in swelling.

ACE inhibitors are a class of blood pressure-lowering medications that are commonly prescribed to treat high blood pressure, heart problems, stroke, and kidney disease.

They act on the renin-angiotensin system (RAS) that’s involved in regulating blood pressure. Specifically, they block the activity of ACE, an enzyme that normally promotes the conversion of angiotensin I to the blood pressure-increasing hormone angiotensin II. ACE is also directly involved in bradykinin degradation. ACE inhibitors thus prevent bradykinin breakdown, causing its levels to rise. That’s believed to be the reason why angioedema is one of the side effects of ACE inhibitors in the body.

ACE inhibitor-induced angioedema is considered to be a class-related side effect, meaning any ACE inhibitor has the potential to cause the swelling disorder. Many studies have shown a relationship between common ACE inhibitors such as lisinopril and angioedema. Examples of ACE inhibitors available in the U.S. that may potentially cause angioedema include:

benazepril (marketed as Lotensin and others)
captopril (available as generics)
enalapril (marketed as Vasotec and others)
fosinopril (available as generics)
lisinopril (marketed as Zestril and others)
quinapril (available as generics)
perindopril (available as generics)
ramipril (marketed as Altace).

High bradykinin also acts as the driver of other forms of angioedema, but the specific underlying cause for why this happens is different. For example, in hereditary angioedema (HAE), the presence of certain genetic mutations causes bradykinin levels to rise, while in acquired angioedema this happens as a result of other underlying diseases. In idiopathic angioedema, the underlying cause of swelling isn’t known, but bradykinin may be involved in some cases.

Acute allergic angioedema is primarily driven by an inflammatory molecule called histamine and is not considered to be a form of bradykinin-mediated angioedema. While medications can trigger both allergic and drug-induced nonallergic angioedema, the swelling in the latter is not caused by an allergic reaction.

Prevalence and risk factors in ACE inhibitor-induced angioedema

While ACE inhibitors are the most well-known cause of drug-induced nonallergic angioedema, the swelling disorder is still a rare adverse effect of these medications, and only a minority of patients using them will actually develop angioedema.

Angioedema has been reported to occur in as many as 2.5% of people who use ACE inhibitors. With the use of ACE inhibitors on the rise, up to 40% of emergency department visits due to angioedema each year are attributed to these medications.

Various risk factors have been associated with an increased susceptibility for ACE inhibitor-induced angioedema including:

Black or Hispanic race
female sex
older age, specifically older than 65 years
use of certain medications, including dipeptidyl peptidase 4 inhibitors, a class of medications used to treat type 2 diabetes
a history of smoking
a history of drug rash, a type of skin reaction to certain medications
a history of seasonal allergies
chronic heart failure or coronary artery disease.

Studies have also looked at whether there are genetic factors that underlie the susceptibility to ACE inhibitor-induced angioedema and which may explain racial disparities in the risk of developing the condition. A number of possible candidates have been identified. In particular, genetic variants in genes related to bradykinin degradation or signaling have been identified as possible risk factors, but research in this area is still ongoing.

Challenges in diagnosing ACE inhibitor-induced angioedema

Although angioedema most commonly develops soon after starting treatment with ACE inhibitors — often within the first week — it can develop at any time, including weeks, months, or even years after starting treatment. There have also been cases in which angioedema has recurred in patients even after they’ve stopped using the medication at issue.

The symptoms of ACE inhibitor-induced angioedema are often mild, but in some cases, they can lead to severe and life-threatening complications if the airways become affected. Patients should always seek medical care if they experience any possible signs of angioedema at any time during or after treatment with ACE inhibitors. Anyone having trouble breathing should immediately go to a hospital emergency department or emergency room.

Symptoms of ACE inhibitor-induced angioedema can vary, but may include problems specifically in the abdominal area, or across any part of the skin:

Swelling is a symptom, and is characterized by large, smooth welts that are generally not itchy or painful. Such swelling can occur anywhere on the body, but is commonly seen on the face, tongue, or lips, or at the throat.
Abdominal pain or other gastrointestinal symptoms related to swelling of the mucus membranes in the gut also can occur. This may mimic other gut conditions, such as irritable bowel syndrome.

It may be challenging for doctors to recognize ACE inhibitor-induced angioedema in the clinic. Some patients might experience multiple episodes before an accurate diagnosis is reached.

No lab tests are available to establish the diagnosis of ACE inhibitor-induced angioedema. If a person is showing signs of a swelling attack, doctors will usually rely on a clinical examination and medical history to rule out other possible causes of a person’s symptoms, including other types of angioedema.

An important first step in getting a correct diagnosis is to rule out angioedema caused by an allergic reaction. Unlike drug-induced nonallergic angioedema, acute allergic angioedema is typically accompanied by signs of an allergic reaction, such as hives, rash, or itching. Its symptoms also usually come on much quicker.

If a person’s symptoms don’t appear to be associated with allergies, and they have a history of taking an ACE inhibitor, drug-induced nonallergic angioedema may be considered. Later, a person may undergo additional blood tests to rule out HAE or acquired angioedema.

Management and treatment strategies for ACE inhibitor-induced angioedema

There aren’t any medications or other therapies specifically approved for treating ACE inhibitor-induced angioedema. The most important aspect of treatment is to discontinue the attack-provoking medication. There’s a growing body of evidence indicating that some treatments used for managing HAE swelling attacks might also be beneficial in ACE inhibitor-related angioedema, but this is still being explored.

Alternatives to ACE inhibitors may need to be started to control a person’s high blood pressure or other health conditions in the long run. Any such decision should be made in careful consultation with the patient’s doctors.

Immediate management

Short-term management of ACE inhibitor-induced angioedema attacks will depend on the location, extent, and severity of swelling a person is experiencing. Usually, the attacks are self-limiting and will resolve within a few days of stopping the medication without additional intervention.

However, if swelling is severe enough to affect the airways, this may require emergency interventions and airway management to restore breathing.

Importantly, medications usually used to treat swelling in acute allergic angioedema, such as antihistamines, corticosteroids, and epinephrine, have limited effectiveness in ACE inhibitor-induced angioedema because this type of angioedema is mediated by bradykinin rather than histamine. This is why it’s critical for doctors to rule out an allergic reaction as a cause of swelling to ensure the right treatment is being administered.

Stopping ACE inhibitors and finding alternatives

Once ACE inhibitors are discontinued, suitable alternatives for managing a person’s high blood pressure or other health conditions should also be started at a doctor’s discretion. There are alternatives that may be considered:

Angiotensin II receptor blockers or ARBs, such as losartan (sold as Cozaar and others) or valsartan (sold as Diovan and others), are the most commonly used alternative to ACE inhibitors.
The direct renin inhibitor aliskiren (sold as Tekturna) may also be used in some cases.

Can you use an ARB in someone with angioedema?

ARBs and direct renin inhibitors also target the RAS pathway, but do so in different ways than ACE inhibitors and are not believed to influence bradykinin levels. ARBs, the most common alternative to ACE inhibitors, have been linked to cases of drug-induced nonallergic angioedema, although substantially less often than ACE inhibitors. Direct renin inhibitors have also been rarely linked to the swelling disorder.

Some studies have found that people who previously had swelling attacks from ACE inhibitors may be at a higher risk of also developing them from ARBs, but not all studies have observed this association, and this does not necessarily mean that a person who has had episodes of angioedema related to ACE inhibitors should not use ARBs.

Patients should always talk with their doctors before starting any new medication, as clinicians can help in weighing the potential benefits for managing other health conditions against the risk of such drugs causing angioedema attacks.

Emerging treatment strategies

There are no therapies specifically approved for managing swelling attacks caused by ACE inhibitors. Accumulating evidence suggests that some medications used for the on-demand treatment of HAE attacks might also be beneficial for treating ACE inhibitor-related angioedema, given that bradykinin elevations underlie both forms of the disease.

HAE therapies that have shown benefit in people with ACE inhibitor-related angioedema include:

C1 inhibitor concentrates (e.g. Berinert and Ruconest), which deliver a version of the C1-INH protein that normally regulates bradykinin production
fresh frozen plasma, which provides C1-INH and other blood components to break down bradykinin
Firazyr (icatibant), which prevents bradykinin from interacting with the receptor it normally binds to trigger swelling
Kalbitor (ecallantide), which blocks the activity of an enzyme needed to produce bradykinin.

It’s important to note that these therapies are not specifically approved for treating ACE inhibitor-induced angioedema. Much of the existing evidence comes from case reports, and the possible benefits of these treatments have not been established in controlled clinical trials. Patients’ healthcare providers can help determine the best treatment approach in each particular case.

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