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. 1H- 20 Jacobs et aP8 de and Comparisons; 1995:165f. scribed a patient who had recurrent episodes of 2. Slater EE, Merrill DD, Guess HA, Roylance PJ, abdominal pain that was initially diagnosed as Cooper WD, Inman WH, et al. Clinical profile of Crohn disease. The patient failed to respond to a angioedema associated with angiotensin-converting enzyme inhibition. JAMA 1988;260:967 -70. course of prednisone and sulfasalazine. Her symptoms resolved after discontinuing the 3. Israili ZH, Hall WD. Cough and angioneurotic edema associated with angiotensin-converting en enalapril. ACE inhibitors have recently been im zyme inhibitor therapy. A review of the literature plicated as a potential cause of acute pancreatitis, and pathophysiology. Ann Intern Med 1992; 117: with reports of cases associated with lisinopril, 234-42. captopril, and enalapril. 21 ,22 Angioedema of pan 4. Hedner T, Samuelsson 0, Lunde H, Lindholm L, creatic tissue can result in obstruction of the duc Andren L, Wiholm BE. Angio-oedema in relation to tal system and lead to pancreatitis.23 ,24 treatment with angiotensin-converting enzyme in The mainstay of therapy is to stop taking the hibitors. BMJ 1992;304:941-6. offending drug. In mild cases such as the one de 5. Litman RS, Sher WH, Hausman SA. Life-threaten ing acute airway obstruction due to enalapril in copyright. scribed here, which involved the face and lips duced angioedema. Immunol Allergy Pract 1992; 14: without respiratory compromise, discontinuing 21-4. the drug is usually sufficient. More severe cases 6. Jason DR. Fatal angioedema associated with capto involving the tongue or causing respiratory com pril.] Forensic Sci 1992;37:1418-21. promise are treated with epinephrine, diphenhy 7. Venable RJ. Angioedema after long-term enalapril dramine, and steroids.2-4 Occasionally airway use.] Fam Pract 1992;34:201-4. protection is necessary and is sometimes difficult 8. Frontera Y, Piecuch JF. Multiple episodes of angio to accomplish.2-7 edema associated with lisinopril, an ACE inhibitor. http://www.jabfm.org/ ACE receptor antagonists lack the bradykinin J Am Dent Assoc 1995;126:217 -20. potentiating capacity and can be prescribed as al 9. Chin HL, Buchan DA. Severe angioedema after ternative therapy for patients who cannot tolerate long-term use of an angiotensin-converting enzyme inhibitor. Ann Intern Med 1990;112:312-3. ACE inhibitors, as implied by Goodfriend et aJ.25 to. Finley C], Silverman MA, Nunez AE. Angiotensin Angioedema has been reported with losartan, converting enzyme inhibitor-induced angioedema: however.26 In the present case, the benefits were still unrecognized. AnI] Emerg Med 1992;10:550-2. on 28 September 2021 by guest. Protected believed to outweigh the risks of treatment, and 11. Weiner JM. Failure to recognize the association of the patient was counseled on the possibility of an life-threatening angio-oedema and angiotensin-con gioedema. Losartan has not yet been approved verting enzyme inhibitor therapy. Aust N Z J Med for treatment of congestive heart failure, al 1995;25:241-2. though it is currently being evaluated in patients 12. O'Mara NB, O'Mara EM Jr. Delayed onset of an who previously had angioedema from an ACE in gioedema with angiotensin-converting enzyme in hibitors: case report and review of literature. Phar hibitor. l ] Early studies in patients with congestive macotherapy 1996; 16:675-9. heart failure suggest that losartan exerts the same 13. Megerian CA, Arnold]E, Berger M. Angioedema: 5 hemodynamic effects as do ACE inhibitors, re years' experience, with a review of the disorder's pre ducing afterload and increasing cardiac outputP sentation and treatment. Laryngoscope 1992; 102: The number of patients who have an adverse 256-60. reaction to ACE inhibitors will increase, given 14. Fine RM. The Fine Page: angiotensin-converting the growing numbers who are receiving prescrip- enzyme angioedema. Int] DermatoI1993;32:95-6.
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