Angiotensin‐converting enzyme inhibitor–induced angioedema: A review of the literature

Abstract

According to the National Health and Nutrition Examination Survey 2012, one third of antihypertensive prescriptions in the United States in the past decade were for angiotensin-converting enzyme inhibitors (ACEIs). An important and serious side effect of ACEIs is angioedema caused by a reduction in bradykinin degradation. In a national medical chart abstraction study conducted at the US Veterans Affairs Health Care System in 2008, 0.20% of ACEI initiators developed angioedema while on the medication. The angiotensin-converting enzyme is a part of the renin-angiotensin system that converts angiotensin I to angiotensin II. It is additionally responsible for the degradation of bradykinin, which is generated from high molecular weight kininogen by kallikrein. Via bradykinin 2 receptors, bradykinin affects vascular permeability and stimulates the release of substance P, which is a peptide that causes vasodilation and fluid extravasation into tissues. Inhibition of the angiotensin-converting enzyme and subsequent blockade of bradykinin degradation is thought to be a likely explanation for ACEI-induced angioedema. Studies have shown that blacks, women, and smokers are at an increased risk for ACEI-induced angioedema. A 2005 study identified black race, history of drug rash, age older than 65 years, and seasonal allergies as independent risk factors for angioedema related to enalapril. Angioedema may occur at any time during treatment with ACEIs and may continue after the medication is discontinued. The degree of ACEI-angiotensin receptor blocker angioedema cross-reactivity is difficult to determine from the literature. However, multiple studies have reported relatively low rates of native angioedema with angiotensin receptor blockers (approximately half that of ACEIs, or 0.1%) and a low incidence of cross-reactivity (<10%).Common treatments for angioedema, such as antihistamines and glucocorticoids, have not been shown to be effective in ACEI-induced angioedema. However, medications that have been used for acute treatment of hereditary angioedema and target the factors that cause ACEI-mediated angioedema are being explored.

Comprehensive review of cardiovascular toxicity of drugs and related agents

“…The symptoms typically last for 24–72 hr, followed by spontaneous remission. The incidence of ACEi‐induced angioedema is relatively low (approximately 0.2–0.7%) with higher chance in older patients and in females as compared to males . Importantly, African Americans are four to five times more likely than Caucasians to experience angioedema.…”

“…Common treatments for histamine‐mediated angioedema (such as antihistamines and glucocorticoids) are not effective in this setting. A risk of angioedema has been also described for angiotensin receptor blockers, but seems to be significantly lower (0.1%) with a low incidence of cross‐reactivity (<10%) . The mechanisms are thus much less clear.…”

“…It is typically associated with ACE inhibitor therapy, where it is attributed to excessive effects induced by bradykinin, which is physiologically degraded by the ACE enzyme. 485,486 Angioedema often affects soft tissue of the head such as lips, face, tongue, periorbital tissue and may cause obstruction of oropharyngeal airways that can be dangerous. 487 Swelling is accompanied by characteristic erythema (without itching) and pain/discomfort.…”

Direct activation of tachykinin receptors within baroreflex afferent pathway and neurocontrol of blood pressure regulation

“…The modulating roles of SP in baroreflex have been well reviewed . Recent observations have shown that SP may play a major role in the secondary injury process following traumatic brain injury, particularly with respect to neuro‐inflammation, increased blood‐brain‐barrier permeability, and tissue edema due mainly to SP release‐mediated vasodilation and fluid extravasation into the tissues . This secondary pathophysiological process may subsequently change the blood pressure to noxious level.…”

The Influence of ACE Inhibition on C1-Inhibitor: A Biomarker for ACE Inhibitor-Induced Angioedema?

“…AE manifestation in the upper airway region can be life-threatening due to its unpredictable clinical course. ACE is one of the main degradation enzymes of bradykinin – therefore, it is assumed that the iatrogenic inhibition of ACE leads to an increase in bradykinin levels [7]. Bradykinin in turn signals mainly via the constitutively expressed bradykinin receptor B 2 (B2R) and leads to vasodilatation and increases vascular permeability [8].…”