J Am Board Fam Pract: first published as 10.3122/jabfm.10.5.370 on 1 September 1997. Downloaded from BRIEF REPORTS Angioedema After Long-Term Use of an Angiotensin-Converting Enzyme Inhibitor Adriana]. Pavietic, MD Angioedema is an uncommon adverse effect of cyclobenzaprine, her angioedema was initially be­ angiotensin-converting enzyme (ACE) inhib­ lieved to be an allergic reaction to this drug, and itors. Its frequency ranges from 0.1 percent in pa­ it was discontinued. She was also given 125 mg of tients on captopril, lisinopril, and quinapril to 0.5 methylprednisolone intramuscularly. Her an­ percent in patients on benazepril. l Most cases are gioedema did not improve, and she returned to mild and occur within the first week of treat­ the clinic the following day. She was seen by an­ ment. 2-4 Recent reports indicate that late-onset other physician, who discontinued lisinopril, and angioedema might be more prevalent than ini­ her symptoms resolved within 24 hours. Mter her tially thought, and fatal cases have been de­ ACE inhibitor was discontinued, she experienced scribed.5-11 Many physicians are not familiar with more symptoms and an increased frequency of late-onset angioedema associated with ACE in­ palpitations, but she had no change in exercise hibitors, and a delayed diagnosis can have poten­ tolerance. A cardiologist was consulted, who pre­ tially serious consequences.5,8-II scribed the angiotensin II receptor antagonist losartan (initially at dosages of 25 mg/d and then Case Report 50 mg/d). The patient was advised to report any A 57-year-old African-American woman with symptoms or signs of angioedema immediately copyright. class 3 congestive heart failure caused by severe and to discontinue losartan if they occurred. mitral regurgitation came to the family medicine No side effects were observed after 18 months clinic with "swollen face and lips" of several of treatment. The patient's condition initially im­ hours' duration. She denied any breathing or proved with losartan therapy (decreased fre­ swallowing difficulties. Her medical history was quency of palpitations), but her congestive heart negative for allergies and angioedema. Her med­ failure gradually worsened, manifested as de­ ications included lisinopril 20 mg/d, digoxin 0.25 creasing exercise tolerance. An experimental in­ http://www.jabfm.org/ mg/d, furosemide 40 mg/d and cyclobenzaprine otropic drug was added to her regimen in March 10 mg at night, as needed. She had been taking 1996, 6 months after losartan therapy was initi­ lisinopril for 6 years without any problems. The ated. She is currently doing poorly and consider­ patient had been intermittently given cyclobenza­ ing cardiac transplantation. prine for recurrent low-back pain and never expe­ rienced any side effects. She had been off cy­ Discussion clobenzaprine for the past few months and had ACE inhibitors are prescribed widely for patients on 28 September 2021 by guest. Protected taken one 10-mg tablet the night before her who suffer from hypertension, congestive heart symptoms occurred. failure, and diabetes. These medications have a She had edema of her lower face and lips, but favorable side-effect profile and are generally well no evidence of tongue swelling or respiratory tolerated. Most physicians are familiar with early­ compromise. Because she had recently restarted onset angioedema, which occurs within the first weeks of therapy. In 1992 Israili and HalP re­ viewed the literature on cough and angioedema Submitted, revised, Marcb 7, 1997. related to ACE inhibitors. Their conclusion was From the Department of Family Medicine, University of Ne­ that "angioneurotic edema usually occurs within braska Medical Center, Omaha. Address reprint requests to Adri­ ana]. Pavletic, MD, Department of Family Medicine, University hours or at most 1 week after starting the ACE of Nebraska Medical Center, 600 South 42nd St, Omaha, NE inhibitor; however, in one report, it developed af­ 68198-3075. ter long-term therapy with an ACE inhibitor." 370 }ABFP Sept.-Oct. 1997 Vol. 10No. 5 J Am Board Fam Pract: first published as 10.3122/jabfm.10.5.370 on 1 September 1997. Downloaded from Although diagnosing early-onset angioedema complexes, physical stimuli, or agents that pro­ should not pose a problem, many physicians are mote histamine release. 13 not familiar with late-onset angioedema, and it ACE-inhibitor-associated angioedema is not an frequently goes unrecognized.5,8-11 In only one of allergic reaction. In most patients the disorder nine cases of angioedema associated with ACE occurs after starting ACE inhibitor therapy or af­ inhibitors treated at public hospitals in New ter switching from one ACE inhibitor to another Zealand was the patient advised to discontinue during a period that is too short for specific anti­ the ACE inhibitor. 11 In the present case, the diag­ bodies to develop.z Additional evidence against nosis was also initially missed because of a lack of an allergic basis for this side effect is that the any temporal relation between the ACE inhibitor structurally unrelated ACE inhibitors induce sim­ and angioedema. Moreover, the cause of the ilar reactions. I4 The exact pathophysiologic edema was somewhat clouded because the patient mechanism of this rare side effect is unknown, restarted cyclobenzaprine the night before her but it is believed to be nonimmunogenic and re­ symptoms occurred. lated to increased levels of bradykinins as a result The patient was seen the following day by a of inhibition of bradykinin degradation.z-4 Angio­ family practice resident who, during her recent tensin-converting enzyme, also known as kini­ otolaryngology rotation, had become familiar nase II, degrades bradykinin. Consequently, in­ with late-onset angioedema associated With ACE hibition of ACE is thought to increase the inhibitor therapy. If she had not read Litman's ar­ concentration of bradykinin in tissues. IZ Only a ticle on late-onset angioedema,4 she would also very small number of patients develop this side have thought that the cyclobenzaprine was re­ effect, however, probably because of a combi­ sponsible. Although angioedema is listed as a nation of poorly understood host and environ­ possible side effect, there is no published medical mental factors. IZ Patients who have a history of literature on cyclobenzaprine-associated angio­ sporadic and hereditary angioedema might be at edema. Both the patient and her physician were increased risk for this complication and should copyright. convinced that the patient's angioedema was due not be given ACE inhibitors. I5,I6 African-Ameri­ to lisinopril, not cyclobenzaprine, as initially sus­ cans can also be at increased risk. 17 pected. This belief was confirmed when the pa­ The clinical manifestation is highly variable. tient resumed cyclobenzaprine therapy without Jason6 reported a case of a 70-year-old African­ any problems. American man who had been taking captopril for It is possible that the diagnosis was presump­ 2 years when he developed obstructive angio­ tive, because the patient was not rechallenged edema over 3.5 hours. Oral intubation was unsuc­ http://www.jabfm.org/ with lisinopril. Rechallenging might have been of cessful, and a difficult tracheostomy was too late no diagnostic value given that ACE-inhibitor­ to save the patient. In other instances symptoms associated angioedema is not an allergic reaction. are mild and can regress spontaneously while the That means that a negative result (ie, no symp­ patient continues the medication, thus erro­ toms after rechallenging) does not rule out a neously prompting an alternative diagnosisJ-9 1f cause-effect relation between ACE inhibitor and the diagnosis is missed, recurrent and more se­ angioedema, because angioedema can recur at vere episodes can occur with potentially serious on 28 September 2021 by guest. Protected any time after restarting the therapy. In a worst­ consequences.5,9 Litman et al 5 described 2 cases case scenario rechallenging could have caused a of life-threatening angioedema associated with severe, potentially fatal reaction. enalapril that required tracheostomy. One of the Angioedema can be sporadic (also known as id­ patients, who had experienced four previous iopathic) or hereditary. The sporadic subtype is episodes of tongue swelling, had been seen by the most common, with a 5 to 10 percent lifetime several physicians and given steroids and antihist­ risk for the general population. IO,I2 The heredi­ amines with relief of symptoms. Because of the tary form, which can be either allergic or nonal­ lack of a temporal relation, the enalapril had lergic, is much less common, with only 198 pa­ never been discontinued. tients described in the literature through 1983.2 Finley et al lO described the case of a patient Angioedema can occur with drug ingestion, C 1 who sought care from qualified emergency physi­ esterase-inhibitor deficiency, circulating immune cians for angioedema 18 times during a 3-year pe- Angioedema and Use of ACE Inhibitors 371 J Am Board Fam Pract: first published as 10.3122/jabfm.10.5.370 on 1 September 1997. Downloaded from riod before the correct diagnosis was made. An­ tions for these drugs and the longer duration of other case report described a patient who had an the treatment. Accordingly, ACE inhihitors 18-month history of recurrent swelling (at least should be considered in the differential diagnosis 15 or 20 episodes) involving the left side of her of unexplained swelling of the face, lips, or face. This patient was examined hy several spe­ tongue or acute or recurrent ahdominal com­ cialists and underwent many diagnostic tests, in­ plaints in patients who are Oil ACE inhihitor cluding magnetic resonance imaging, before her therapy. problem was correctly diagnosed as angioedema associated with an ACE inhibitor.H References Unusual cases involving the gastrointestinal 1. Drug facts and comparisons. St. Louis, Mo: Facts tract have been reported.