Angiotensin-Converting Enzyme Inhibitor–Induced Angioedema Abduljabar A. Theyab, MD; David S. Lee, MD; Amor Khachemoune, MD Angiotensin-converting enzyme (ACE) inhibitors the cumulative risk for developing angioedema is frequently are prescribed for the management of believed to be higher due to the long-term nature cardiovascular disorders. In addition to their ther- of treatment with ACE inhibitors and the fact that apeutic potential, ACE inhibitors are associated angioedema can occur at any point during therapy.6 with numerous adverse effects, some of which More than 3 decades after the first description of may be lethal. Angioedema is an uncommon but ACE inhibitor–induced angioedema, more is now serious acute event that may affect any individual understood about its underlying pathophysiology and taking an ACE inhibitor. This review outlines the variable clinical manifestations. In this article, we advances in our understanding of the pathogen- review the historical context of this phenomenon, esis, clinical presentation, and management of proposed molecular mechanisms, and clinical con- this medical emergency. siderations in the diagnosis and management of this Cutis. 2013;91:30-35. potentially fatal entity (Table). CUTISHistory ngiotensin-converting enzyme (ACE) inhibi- Angioedema was first described in the literature by tors are among the most commonly pre- Milton7 in 1876. The term angioneurotic angioedema scribed drugs in modern medicine with more was coined in 1882 by Quincke.8 Almost a century A 1 9 than 40 million patients using them. Numerous later, Wilkin et al characterized the association of ACE inhibitors are currently available (eg, captopril, angioedema with ACE inhibitor use in 1980 in a case benazepril, fosinopril, enalapril, zofenopril, ramipril, series involving 22 patients who received captopril, quinaprilDo hydrochloride, perindopril Not erbumine, lisino- which atCopy the time was a newly marketed antihyper- pril), differing primarily in their duration of action tensive agent. They also were the first to propose a and rate of metabolism.2 Although ACE inhibitors kinin-mediated mechanism for the phenomenon,9 a have numerous benefits, multiple adverse effects have theory that now is widely cited. Since then, angio- been attributed to their use, the most common being edema has been reported as a side effect associated syncope/dizziness (2%–5%), dry cough (0.9%–2.9%), with nearly all other agents in the ACE inhibitor fam- and hypotension (0.7%–1.7%).3 ily.10 Given the relative rarity of this reaction and the Angioedema is a rare yet potentially life- proven benefits of therapy, ACE inhibitors continue threatening condition that has been linked to the use to be widely used in the management of hypertension, of different medications including ACE inhibitors. heart failure, and diabetic renal insufficiency. The reported incidence of ACE inhibitor–induced angioedema is between 0.1% and 0.68%4,5; however, Pathophysiology The pathophysiology of ACE inhibitor–induced angioedema is best understood in the context of the Dr. Theyab is from Ramadi College of Medicine, Al-Anbar University, drug’s well-characterized mechanism of action. When Iraq. Dr. Lee is from the Department of Dermatology, Los Angeles ACE activity is competitively inhibited, the result County University of Southern California Medical Center. is a decreased rate of conversion of angiotensin I Dr. Khachemoune is from the VA NY Harbor Healthcare to angiotensin II, which is a potent vasoconstric- System, Brooklyn. tor.11 Lower concentrations of angiotensin II result The authors report no conflict of interest. Correspondence: Amor Khachemoune, MD, Dermatology Service, in a reduction in downstream aldosterone secretion, VA NY Harbor Healthcare System, 800 Poly Pl, Brooklyn, NY 11203 contributing to the blood pressure–lowering effect of ([email protected]). ACE inhibitors. Additionally, inhibition of ACE, also 30 CUTIS® WWW.CUTIS.COM Copyright Cutis 2013. No part of this publication may be reproduced, stored, or transmitted without the prior written permission of the Publisher. ACE Inhibitor–Induced Angioedema class of antihypertensive agents also acts on the renin- Key Features of ACE Inhibitor– angiotensin-aldosterone axis but has no known effects Induced Angioedema on the kallikrein-kinin system, suggesting additional mechanisms in the pathogenesis of angioedema.14 Historical, Pathophysiological, and Substance P—Substance P is an important periph- Clinical Features eral and central nervous system neurotransmitter that has been implicated in the pathogenesis of • Can occur at any point in therapy angioedema. It also is an inflammatory mediator • Possible with any ACE inhibitor found in unmyelinated fibers of sensory nerves.15 • Pathogenesis is multifactorial though primarily Angiotensin-converting enzyme inhibitors have been related to elevated bradykinin shown to impede the hydrolysis of substance P, 16,17 • Most common initial signs are shortness of thereby permitting its accumulation. Furthermore, breath, lip and tongue swelling, and it has been observed in mice that bradykinin itself laryngeal edema enhances the release of tachykinins, such as sub- • Visceral angioedema may mimic an acute stance P, from sensory nerves, which further promotes 18 abdomen plasma extravasation. Decreased activity of aminopeptidase P and dipep- Short-term and Long-term tidyl peptidase IV, enzymes that are both involved in Management Strategies substance P degradation, also appears to play a role 19 • Immediately discontinue use of ACE inhibitor and in some patients. In a pedigree analysis by Duan 20 maintain airway patency et al, a single nucleotide polymorphism of the X-linked gene X-prolyl aminopeptidase 2, XPNPEP2 • Airway compromise may necessitate inpatient (the C-2399A variant), was associated with decreased hospital management activity of aminopeptidase P and a higher incidence • Promptly initiate alternative pharmacologic of ACE inhibitor–induced angioedema. therapy for primary condition Histamine—Histamine is an important amino acid • Counsel first-time angioedemaCUTIS patients about that is implicated in the wheal and flare of inflam- increased risk for angioedema with the use mation. Its vasodilatory activity also is potentiated of ARBs by ACE inhibitors.9,21 Although agents such as opi- Abbreviations: ACE, angiotensin-converting enzyme; ARB, ates (eg, morphine, codeine) and iodinated con- angiotensin II receptor blocker. trast media have been shown to cause angioedema by direct histamine release, bradykinins, which increase with ACE inhibitor administration, also can induce Do Nothistamine Copy release from mast cells.22 One small human study, however, reported no increases in histamine- known as kininase II, decreases the kininase-mediated induced wheal and flare reactions with the addition degradation of the potent vasodilatory nonapeptide of an ACE inhibitor.23 bradykinin. Although bradykinin has been impli- Complement System—An interaction between cated as the major mediator in ACE inhibitor–related ACE inhibitors and the complement system also angioedema, it is becoming clearer that several other has been proposed to play a role in the pathogen- factors contribute to its pathogenesis. esis of ACE inhibitor–related angioedema based on Bradykinin—Elevated bradykinin levels have observations made in murine models.24 It is widely long been presumed to play a central role in the understood that patients with hereditary angio- pathogenesis of ACE inhibitor–related angioedema.9 edema (HAE) are deficient in C1 esterase inhibi- Angiotensin-converting enzyme inhibitors limit the tor (C1-INH).25,26 Although no known studies to date degradation of bradykinin, permitting increased lev- have identified frankly decreased C1-INH levels in els of this nonapeptide. In turn, bradykinin promotes patients with ACE inhibitor–related angioedema, it increased vascular permeability and vasodilation. has been proposed that ACE inhibitors may render Angiotensin-converting enzyme inhibitors have been select patients functionally deficient in C1-INH, shown to enhance bradykinin’s hypotensive effects putting them at a higher risk for developing angio- by approximately 20- to 50-fold.12 These changes are edema.27,28 Moreover, multiple accounts of successful believed to permit local edema formation. treatment of ACE inhibitor–related angioedema with Interestingly, angiotensin II receptor block- exogenous C1-INH concentrates further support a ers (ARBs), such as losartan, also have been associated role for the complement system in the pathogenesis with angioedema, though with less frequency.13 This of this entity.29,30 WWW.CUTIS.COM VOLUME 91, JANUARY 2013 31 Copyright Cutis 2013. No part of this publication may be reproduced, stored, or transmitted without the prior written permission of the Publisher. ACE Inhibitor–Induced Angioedema Genetic Association—A genetic predisposition to 5 years later.6 On average, an angioedematous episode ACE inhibitor–induced angioedema is likely. One occurs 14 months after starting an ACE inhibitor. large study described intrafamilial similarities in With long-term use, the cumulative 10-year risk for plasma ACE levels, suggesting heritable patterns developing ACE inhibitor–induced angioedema is of renin-angiotensin-aldosterone axis regulation.31 estimated to be as high as 1%.42 Because patients with HAE are more susceptible to Multiple risk factors have been associated with developing angioedema while taking an ACE inhibi- ACE inhibitor–induced