Bradykinin Metabolism and Drug-Induced Angioedema

Abstract

Bradykinin (BK) metabolism and its receptors play a central role in drug-induced angioedema (AE) without urticaria through increased vascular permeability. Many cardiovascular and diabetic drugs may cause BK-mediated AE. Angiotensin-converting enzyme inhibitors (ACEIs) and neprilysin inhibitors impair BK catabolism. Dipeptidyl peptidase-IV (DPP-IV) inhibitors reduce the breakdown of BK and substance P (SP). Moreover, angiotensin receptor blockers, thrombolytic agents, and statins may also induce BK-mediated AE. Understanding pathophysiological mechanisms is crucial for preventing and treating drug-induced AE.

Keywords: bradykinin metabolism; drug-induced angioedema.

Figure 1

Structure of BK and sites of cleavage by significant enzymes related to drug-induced AE. Note: The amino acid sequence of BK is Arginine (Arg)–Proline (Pro)–Proline (Pro)–Glycine (Gly)–Phenylalanine (Phe)–Serine (Ser)–Proline (Pro)–Phenylalanine (Phe)–Arginine (Arg). Figure adapted from [23] for a simplified presentation of the sites of cleavage of BK by different important enzymes, marked with red arrows for ACE (angiotensin-converting enzyme), APP (aminopeptidase P), NEP (neutral endopeptidase), CPN (carboxypeptidase N), and DPPIV (dipeptidyl peptidase IV).

Figure 2

Overall presentation of different causes of angioedema classified by pathophysiology mechanisms, focusing on bradikinergic or BK-mediated angioedema (BK-AE) and drug-induced forms [3,47,109]. * Hereditary angioedema (HAE) with C1-INH deficiency with low antigenic and functional C1-INH levels (HAE-1, 85% of cases), HAE due to C1-INH dysfunction (HAE-2, 10% of cases) characterized by normal or elevated antigenic but low functional C1-INH levels, and HAE with normal C1-INH (HAE-nC1-INH, 5% of cases) due to various gene mutations. ** Acquired forms of BK-AE include drug-induced AE, such as AE induced by angiotensin-converting enzyme inhibitors (ACEIs), AE due to acquired C1-INH deficiency (AAE-C1-INH), and acquired idiopathic non-histaminergic AE. *** Mast cell-mediated angioedema (MC-AE) includes allergic IgE-mediated reactions (such as AE with anaphylaxis), nonallergic non-IgE-mediated reactions (such as AE due to non-steroidal anti-inflammatory drugs or infections), AE in chronic inducible urticaria or chronic spontaneous urticaria (sometimes referred to as idiopathic histaminergic acquired AE). The diversity of mediators involved in MC-AE is reflected also by the fact that patients with chronic spontaneous urticaria may respond to treatment with omalizumab but not to H₁ antihistamines.

Figure 3

Metabolism of bradykinin (BK) and angioedema induced by cardiovascular and antidiabetic drugs: angiotesin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (sartans), neprilysin inhibitors, direct renin inhibitor (aliskiren), gliptins (DPP-IV inhibitors), and recombinant tissue plasminogen activators (rt-PAs), figure created and adapted after [23,57,87,111].