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Home , ACE inhibitor, Angioedema

-Converting –Induced

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 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, , angioedema with ACE inhibitor use in 1980 in a case , , , , , series involving 22 patients who received captopril, quinaprilDo hydrochloride, 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 .2 Although ACE inhibitors -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 has been reported as a side effect associated syncope/dizziness (2%–5%), dry (0.9%–2.9%), with nearly all other agents in the ACE inhibitor fam- and (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 , of different including ACE inhibitors. 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, ’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 secretion, VA NY Harbor Healthcare System, 800 Poly Pl, Brooklyn, NY 11203 contributing to the pressure–lowering effect of ([email protected]). ACE inhibitors. Additionally, inhibition of ACE, also

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class of antihypertensive agents also acts on the - Key Features of ACE Inhibitor– angiotensin-aldosterone axis but has no known effects Induced Angioedema on the -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 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 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 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 management activity of aminopeptidase P and a higher incidence • Promptly initiate alternative pharmacologic of ACE inhibitor–induced angioedema. therapy for primary condition —Histamine is an important • 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, , 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- —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 . 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 , 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

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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 angioedema, including black tor, the use of ACE inhibitors should generally be , female gender, and increasing age.42,43 Historical avoided in these patients. In addition, carboxypep- risk factors such as HAE or idiopathic angioedema,44,45 tidase N, a metalloenzyme inhibitor of complement autoantibodies against C1-INH,46 or excessive emo- components and bradykinin whose deficiency has tional stress have been proposed in the literature. been associated with angioedema, has been found to Furthermore, iatrogenic risk factors such as recent be deficient in an autosomal-recessive pattern.32 head/neck surgery47 as well as the use of local anesthe- Trauma—External trauma may be an inciting sia,48 other antihypertensive agents, agents, or contributing factor in the pathogenesis of ACE and nonsteroidal anti-inflammatory drugs46 have been inhibitor–induced angioedema. Local trauma has suggested as potential triggers. been reported to trigger angioedema in patients on ACE inhibitors or with a history of HAE.33,34 It is ACE Inhibitor–Induced likely that mechanical to skin or mucosal cells Visceral Angioedema results in a release of vasoactive substances that, in Peripheral angioedema is commonly associated with conjunction with ACE inhibitor–related bradykinin ACE inhibitor use. Less frequently, ACE inhibitors elevation, promote local edema formation. can produce visceral angioedema, often mimicking the signs of an . The diagnosis easily Clinical Presentation, , and may be overlooked, and unless potential drug reactions Risk Factors are considered, patients may be subject to misguided Angioedema generally presents as an acute onset of workup and management. In addition to multiple sin- localized edema in the dermal,CUTIS subcutaneous, and gle case reports published on this entity,49-52 Dobbels mucosal tissues. Most frequently, angioedema occurs et al53 conducted the largest-known single-center case in the head and neck, including the face and perioral series that described 7 patients with intermittent acute and oral tissues.35 In severe cases, laryngeal edema abdominal attributable to the use of ACE inhibi- may develop, leading to potentially fatal airway tors. The authors concluded that ACE inhibitor– obstruction. A multicenter study of 220 patients related visceral angioedema likely is much more presenting to emergency departments with ACE common than has been indicated in the literature.53 inhibitor–inducedDo angioedema Notrevealed that the most Copy common presenting signs were , lip Management and Prevention and tongue swelling, and laryngeal edema.36 In cases of suspected ACE inhibitor–induced angio- Angiotensin-converting enzyme inhibitors have edema, immediate discontinuation of the drug and been implicated as causative agents in up to 25% of maintenance of adequate airway function are imper- angioedema cases presenting to emergency depart- ative. Isolated cutaneous edema can progress to ments.37 Multiple retrospective studies from the 1990s, laryngeal edema within minutes to hours; thus it is however, highlighted the relative underdiagnosis recommended that patients be observed for at least of this specific entity in the acute care setting.38-40 6 hours in the hospital.54 Patients with signs of com- Despite increased awareness of ACE inhibitors as a promised upper airway function (eg, tongue swelling, cause of angioedema, underdiagnosis remains a rel- , , accessory muscle use) are at high evant concern.41 risk for respiratory decompensation and may require One factor that may contribute to the underdi- emergency intubation. Depending on symptom sever- agnosis of an ACE inhibitor–related etiology is that ity, these patients should be admitted to either an acute-onset angioedema does not always correlate intensive care unit or a non–intensive care bed for with recent use of an ACE inhibitor. Patients often further monitoring. may present with a long history of ACE inhibitor use Additional supportive measures such as fluid with no history of reaction. In these cases, a physi- resuscitation may be indicated in hemodynamically cian may overlook the drug as a potential etiology; unstable patients. Adjunct therapies such as subcu- however, it is important to note that ACE inhibitor– taneous epinephrine injections, intravenous or intra- induced angioedema can occur any time from within muscular diphenhydramine hydrochloride, and oral several hours of initial administration to up to or intravenous also may be initiated;

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however, the efficacy of angioedema therapies other any , a detailed discussion of the benefits than discontinuation of ACE inhibitors has come and risks for ACE inhibitors should occur between into question by some clinicians, as no known the physician and the patient before administration controlled studies assessing these treatments have of the drug, and appropriate alternatives should be been conducted.55 considered when a patient is at risk for or has pre- Proper alternative treatment of the patient’s viously experienced angioedema while taking an underlying conditions (eg, hypertension, heart fail- ACE inhibitor. ure) should be promptly initiated and may include regimens such as beta-blockers, calcium channel REFERENCES blockers, hydrochloride, , or 1. Byrd JB, Adam A, Brown NJ. Angiotensin-converting ARBs. The use of ARBs also has been associated enzyme inhibitor-associated angioedema. Immunol with the development of angioedema. One sys- Clin North Am. 2006;26:725-737. temic review and meta-analysis by Haymore et al56 2. Katzung BG, Masters S, Trevor A, eds. Basic & Clinical found that in 71 patients with a history of ACE . 11th ed. New York, NY: McGraw-Hill; 2009. inhibitor–induced angioedema, the risk for devel- 3. Inman WH, Rawson NS, Wilton LV, et al. Postmarketing oping subsequent ARB-related angioedema was surveillance of enalapril. I: results of prescription-event between 2% and 17%. This important finding may monitoring. BMJ. 1988;297:826-829. aid clinicians in their discussions with patients 4. Slater EE, Merrill DD, Guess HA, et al. Clinical profile about alternative therapies after an episode of ACE of angioedema associated with angiotensin converting- inhibitor–induced angioedema. enzyme inhibition. JAMA. 1988;260:967-970. 5. Kostis JB, Packer M, Black HR, et al. On the Horizon and enalapril in patients with hypertension: the A newer drug that has been approved in both Europe Omapatrilat Cardiovascular Treatment vs. Enalapril and the United States for the management of heredi- (OCTAVE) trial. Am J Hypertens. 2004;17:103-111. tary angioedema is , a synthetic bradykinin 6. Cordes B. Angioedema of the head and neck. Presented B2 receptor antagonist that has shown promise based at: Veteran Affairs Medical Center Grand Rounds; on a study of patients with ACECUTIS inhibitor–induced December 22, 2005; Houston, TX. angioedema. Bas et al57 administered a single subcu- 7. Milton JL. On giant urticaria. Edinburgh Med J. taneous injection of icatibant to 8 patients on pre- 1876;22:513-526. Cited by: Cicardi M, Agostoni A. sentation to the . Compared . N Engl J Med. 1996;334: to a historical patient cohort, the severity of illness 1666-1667. and speed of recovery were markedly improved in the 8. Quincke H. Uber akutes umschreibenes hauto- group treated with icatibant.57 A number of larger- dem. Monatsschr Prakt Dermatol. 1882;1:129. scaleDo clinical trials to evaluate theNot efficacy of icatibant 9. WilkinCopy JK, Hammond JJ, Kirkendall WM. The captopril- in ACE inhibitor–induced angioedema are under way induced eruption. a possible mechanism: cutaneous kinin or in planning.58-60 potentiation. Arch Dermatol. 1980;116:902-905. Recombinant plasma kallikrein inhibitors and 10. Cicardi M, Zingale LC, Bergamaschini L, et al. Angio- purified and recombinant C1-INH also are newer edema associated with angiotensin-converting enzyme drugs for the prevention and treatment of HAE.61 inhibitor use: outcome after switching to a different treat- Further investigation is warranted to determine the ment. Arch Intern Med. 2004;164:910-913. efficacy of these drugs in the treatment of ACE 11. Jackson EK. Renin and angiotensin. In: Brunton LL, inhibitor–induced angioedema. Lazo JS, Parker KL, eds. Goodman & Gilman’s The Pharmacological Basis of Therapeutics. 11th ed. New York, Conclusion NY: McGraw-Hill; 2006:789-822. Angiotensin-converting enzyme inhibitors have 12. Bönner G, Preis S, Schunk U, et al. Hemodynamic effects become key agents in the management of cardio- of bradykinin on systemic and in vascular ; however, a rare but serious adverse healthy and hypertensive humans. J Cardiovasc Pharmacol. effect of these drugs is angioedema, which may afflict 1990;15(suppl 6):S46-S56. susceptible patients at any point during therapy. A 13. Burrell LM. A risk-benefit assessment of losartan potassium careful medical and family history should be taken for in the treatment of hypertension. Drug Saf. 1997;16:56-65. any patient who presents with the clinical features of 14. Sharma PK, Yium JJ. Angioedema associated with angio- angioedema. The most appropriate initial manage- tensin II receptor antagonist losartan. South Med J. ment of ACE inhibitor–induced angioedema is the 1997;90:552-553. discontinuation of the drug and maintenance of ade- 15. Foreman JC. Neuropeptides and the pathogenesis of quate ventilation until the edema resolves. As with allergy. Allergy. 1987;42:1-11.

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