Authors

• Tanja Batinac — University Hospital Centre Rijeka, Rijeka, Croatia — ORCID: 0000-0002-3482-1937
• Željko Plazonić — University Hospital Centre Rijeka, Rijeka, Croatia — ORCID: 0000-0002-3769-9754
• Marija Bukvić — University Hospital Centre Rijeka, Rijeka, Croatia — ORCID: 0000-0003-0625-8056

Abstract

Rennin angiotensin system (RAS) blockers are commonly used drugs with proven benefits for cardiovascular and renal diseases. There are four classes of drugs acting on the angiotensin system, the most commonly used being angiotensin converting enzyme inhibitors (ACEI) followed by angiotensin receptor blockers (ARB). These drugs are generally considered safe and effective in the majority of patients, but in some cases adverse drug reactions may occur (ADRs). Angioedema resulting from RAS blocker treatment is a rare but potentially life-threatening event, and we should keep in mind that in recent years the exponential growth of the use if RAS blockers has been evident worldwide, resulting in increased prevalence of angioedema induced by RAS blockers in these patients.

Keywords

adverse drug reaction, angioedema, angiotensin converting enzyme inhibitors, renin angiotensin system blockers

DOI

Full Text

## Introduction Renin angiotensin system (RAS) blockers are commonly used drugs with proven effectiveness for cardiovascular and renal diseases such as heart failure, hypertension, post myocardial infarction, and kidney diseases (1). Today, there are four classes of drugs acting on the angiotensin system including: angiotensin converting enzyme inhibitors (ACEI), angiotensin receptor blockers (ARB), aldosterone agonists (AA), and direct renin inhibitors (DRI), but the most commonly used are ACEI. These drugs are generally considered safe and effective in the majority of patients, but in some cases adverse drug reactions may occur (ADRs). The most common ADR is persistent dry cough that occurs in about 9% of patients treated with ACEI and in about 2% treated with ARB (2). Rarely, patients develop potentially life-threatening angioedema usually affecting the head and neck regions and occurring in 0.1-2.5% of treated patients according to data reported from different studies (3-5). ## Clinical presentation and diagnosis Angioedema or Quincke’s edema is an abrupt, transient, localized swelling of the deep reticular dermis or subcutaneous or submucosal tissues (6). It is caused by vasodilatation and increased endothelial permeability, resulting in extravasation of fluid into the interstitial compartment (6, 7). Angioedema caused by RAS blockers is non-allergic in nature and more frequently affects the head and neck regions and the viscera only occasionally. It develops in the area of loose connective tissue over 4-6 h and usually resolves within 24-48 h. The swelling may be asymmetrical and most often affects the face, lips, tongue, and upper airways (6, 8). In some cases, clinically significant obstruction of the upper airway can be life-threatening and sometimes even fatal (6, 8). Patients develop symptoms such as a lump in the throat, hoarse voice, and difficulties breathing or swallowing as a signs of impending airway obstruction (6, 9). Angioedema induced by ARS blockers occasionally presents with urticaria or edema affecting gastrointestinal, genital, or regions other than the head and neck region (8, 10, 11). There is no specific test for the diagnosis of angioedema triggered by drugs acting on the angiotensin system, and no means to predict the risk that a patient will develop angioedema after initiating treatment. The diagnosis in the acute phase is clinical and anamnestic, including exclusion of other causes of angioedema. Other types of angioedema include: hereditary or acquired (mediated by bradykinin or vasoactive molecules), allergic or pseudoallergic (dependent on mast cell degranulation), and idiopathic angioedema (6, 8, 9, 12, 13). Angioedema generally occurs within the first 1-3 months of therapy, but symptoms may appear months, years, or even decades after treatment initiation (3, 4, 14, 15). This makes diagnosis of RAS blockers-induced angioedema quite difficult. After drug withdrawal, the tendency to develop angioedema usually decreases but may persist for months and even years (16, 17). This is not in accordance with the standard criteria for assessment for acutely occurring ADRs. It has been suggested that reoccurrence of angioedema after discontinuation of the incriminated drug reflects exacerbation of an intrinsic underlying susceptibility to angioedema of unclear etiology. Angioedema developing during ACEI treatment is more frequent than in other RAS blockers (4, 8). However, patients who have experienced ACEI angioedema can also develop angioedema when switched to ARB treatment, in about 4% of patients. Recent meta-analyses suggested that a previous episode of ACEI angioedema predisposes patients to develop ARB-induced angioedema (18, 19). ## Risk factors Several risk factors have been identified in triggering angioedema during ACEI treatment (6, 20), but the knowledge about risk factors contributing to angioedema induced by ARBs or other RAS blockers is poor, generally due to its rarity (21). Major risk factors include race (African ancestors), age over 65 years, smoking (22), female sex, history of hereditary, acquired, or idiopathic angioedema, use of certain drugs (aspirin, non-steroidal anti-inflammatory drugs, beta-lactam antibiotics, dipeptidyl peptidase IV inhibitors, immunosuppressants), respiratory tissue trauma, history of drug rash and seasonal allergies, coronary artery disease, and chronic heart failure (3, 4, 9, 22, 23). ## Pathophysiological mechanism Although the precise pathophysiological mechanism responsible for angioedema developing during RAS blockers treatment has not been elucidated, it is believed to be mediated by bradykinin levels and other vasodilating molecules (6, 9, 12). Initially, only ACEI were considered responsible due to their ability to directly increase bradykinin activity, but soon after introducing ARB and DRI into clinical practice it became evident that these drugs could also trigger angioedema (24, 25). Angiotensin converting enzyme (ACE) has two active sites able to degrade bradykinin to inactive metabolites and convert angiotensin I to angiotensin II. Inhibition of ACE by ACEI decreases the degradation of bradykinin and formation of angiotensin II. There are alternative bradykinin inactivation pathways that can be deficient due to genetic variants, leading to accumulation of bradykinin (9). Since only a minority of patients develops angioedema, it is believed that these drugs may facilitate angioedema in genetically predisposed individuals. Recently, several genetic polymorphisms have been associated with increased risk of angioedema due to the deficiency of several enzymes involved in the degradation of bradykinin, especially when ACE is inhibited. Variants have been detected in the gene encoding aminopeptidase P and the metallo-endopeptidase gene involved in bradykinin degradation to inactive metabolites (26-28). Contrary to ACEI, ARBs have no direct influence on ACE or bradykinin degradation. It is believed that ARBs increase bradykinin levels through indirect inhibition of ACE and metallo-endopeptidase (29), due to increased levels of circulating angiotensin II available for binding to the angiotensin type 2 receptor, as a result the type 1 receptor being blocked (30). ## Treatment The therapeutic management of angioedema in patients treated by RAS blockers starts by stopping the suspected drug once the diagnosis is suspected. The patient is advised not to take any drug of the same class again. Cross-reactivity is an important concern when prescribing RAS blockers. A patient who developed angioedema during ACEI treatment has an average 10% risk of developing it again if taking an angiotensin II agonist, such as sartans (31, 32). Thus, it has been suggested that switching an intolerant patient from one RAS blocker to the other should be considered only when the benefit strongly outweighs the risk. In addition, close monitoring must be implemented after switching. DRI, like aliskiren, appeared as an alternative for these patients, but recently it has also been associated with angioedema (25). Antihistamines, corticosteroids, and epinephrine, commonly used drugs in treatment of angioedema, have little or no effect on bradykinin-induced angioedema. Considering the pathophysiological phenomenon of angioedema triggered by RAS blockers, the molecule that seems to be the treatment of choice is icatibant (Fyrazyl®, Shire Orphan Therapies Inc., St. Helier, Jersey, USA). This is a blocker of B2 receptors, shown to be effective in the first hour after administration (33). The effectiveness of C1 esterase inhibitor concentrate (Berinert®) makes it the treatment of choice in hereditary or acquired angioedema, as has been demonstrated in case reports of angioedema triggered by RAS blockers (34). The effectiveness of Ecallantide®, an inhibitor of plasma kallikrein, has not yet been studied. Fresh frozen plasma contains natural angiotensin converting enzymes (ACE) and C1 esterase inhibitors. It is considered for treatment when other therapeutic options are unavailable, since it has been shown to effectively and rapidly treat angioedema due to ACEI (35). ## Conclusion Until more data is available, due to the increased popularity of RAS blockers attempts should be made to improve awareness and educate clinicians about possible ADR caused by these drugs. Even though angioedema resulting from RAS blocker treatment is a rare event, we should keep in mind that in recent years the exponential growth of the usage of RAS blockers has been evident worldwide resulting in increased prevalence of angioedema induced by RAS blockers along with an increase in hospitalization, health care resource consumption, and potential loss of lives (36).

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