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Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Antagonists

Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Antagonists The use of angiotensin-converting enzyme inhibitors (ACEIs) has been implicated in many cases of angioedema, but, given the potential mechanism of this complication, it was not expected to be caused by angiotensin II receptor blockers (ARBs). However, in the past few years, scattered reports of angioedema associated with ARBs have appeared in the medical literature. We performed a retrospective chart review from January 1, 1998, through June 30, 2003, and a review of the literature. During this time, we managed head and neck angioedema induced by ACEIs (n = 27) and ARBs (n = 4) in 31 patients. All of them had significant mucosal swelling, and in some of them dyspnea and dysphagia coexisted. The most frequently involved areas were the oral tongue (13 cases), uvula and soft palate (5 cases), and larynx, mouth floor, and lips (3 cases each). Angioedema may be a more common complication of ACEI and/or ARB use than originally thought. This complication may occur after long-term use of these drugs. We advise that ARBs not be prescribed to patients with a history of angioedema, particularly that due to the use of ACEIs.Angioedema, also known as angioneurotic or Quincke edema, is a potentially life-threatening condition that is characterized by indurated, well-demarcated, nonpruritic, and often erythematous swelling of sudden onset. Usually 1 or more areas of the head and neck are involved.Hereditary angioedema is a clinical entity that has been attributed to deficiency or dysfunction of the C1 esterase inhibitor.Acquired angioedema could be secondary to several factors, among which use of angiotensin-converting enzyme inhibitors (ACEIs) is considered to be one of the most common causes, and is thought to result in 25% to 35% of all cases.The ACE, also known as kininase II, metabolizes bradykinin, a potent vasodilating substance, and converts angiotensin I to angiotensin II, a powerful vasoconstrictive agent. Angiotensin-converting enzyme inhibitors decrease angiotensin II and aldosterone levels on the one hand, and increase the level of bradykinin and prolong its action on the other hand. This combination of mechanisms is thought to be the cause of fluid extravasation into the subcutaneous tissues, which produces angioedema.Angiotensin II receptor blockers (ARBs) block the binding of angiotensin II receptors, thus inhibiting the known actions of angiotensin II that are associated with hypertension.Angiotensin II receptor blockers do not affect ACE, and theoretically bradykinin should remain unaffected.In this report, we present our experience of 5½ years during which we have diagnosed and treated head and neck angioedema caused by the use of ACEIs and/or ARBs in 31 patients.METHODSIn the period from January 1, 1998, through June 30, 2003, 31 patients were consulted or referred to our emergency department because of angioedema after treatment with ACEIs (27 patients) or ARBs (4 patients). All of them had significant mucosal swelling, and dyspnea and dysphagia coexisted in some of them. Table 1shows the implicated drugs. Nineteen patients were taking ACEIs; 8, ACEIs in combination with a diuretic (hydrochlorothiazide); and 4, ARBs. The group included 17 men and 14 women, with ages ranging from 42 to 81 years (mean age, 64 years). The most frequently involved areas were the oral tongue (13 cases), uvula and soft palate (5 cases), and larynx, mouth floor, and lips (3 cases each). Some cases involved more than 1 area. All patients were hospitalized from 2 to 9 days (mean time, 4 days), one of them in the intensive care unit and the others in the ear, nose, and throat ward.Table 1. ACEIs and ARBs That Caused AngioedemaDrug NameNo. of PatientsCaptopril7Lisinopril5Enalapril maleate4Quinapril hydrochloride2Ramipril1Captopril with hydrochlorothiazide3Lisinopril with hydrochlorothiazide3Enalapril with hydrochlorothiazide2Losartan potassium2Candesartan cilexetil1Valsartan1Abbreviations: ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker.A detailed history was obtained from all patients and was considered the most important step in the diagnosis of angioedema secondary to ACEIs or ARBs. When hereditary or allergic angioedema was suspected, measurements of C1 esterase inhibitor, total complement, C4 complement, and total and specific immunoglobulin IgE levels and specific skin-prick tests were ordered. Most of the patients were taking numerous medications because of various medical diseases; therefore the involvement of an internist was sought. We herein report 3 representative cases.REPORT OF CASESCASE 1A 67-year-old man weighing 88 kg was referred to our department from another hospital with severe edema of the tongue and floor of the mouth. Results of the clinical examination revealed a severely enlarged tongue obstructing the upper airway. The floor of his mouth had symmetrical swelling that pushed the edematous tongue to the palate. The patient was in mild respiratory distress. Results of a flexible fiberoptic examination through the nose revealed a watery edema of his base tongue and visualized a normal larynx.His medical history was remarkable for hypertension and mild type 2 diabetes mellitus. His hypertension was previously treated with lisinopril, 20 mg/d, which had been changed to losartan potassium, 50 mg/d, 2 months earlier.On general physical examination, his blood pressure was 145/80 mm Hg and pulse rate was 85/min. The patient was given a 0.4-mg dose of subcutaneous epinephrine hydrochloride and a 125-mg intravenous methylprednisolone sodium succinate bolus once. Intravenous methylprednisolone sodium succinate therapy was continued (1mg/kg of body weight divided in 3 doses per day) for 2 days, and then orally for 5 more days.After a detailed history was obtained, it was found that the patient had had 3 episodes of angioedema during his treatment with lisinopril, which were treated symptomatically elsewhere. The current episode, which was the most severe, was the first after lisinopril was changed to losartan therapy. The patient had never had an episode of angioedema before the initiation of the ACEI therapy 18 months earlier. During his hospitalization, his vital signs were monitored closely.The patient was discharged 3 days later and was instructed to stop taking ACEIs and ARBs. A list of medications containing ACEIs and ARBs was given to the patient. After consultation with his general practitioner, the treatment was changed to felodipine, and, as of this report, the patient has been free of episodes for 1 year.CASE 2A 61-year-old woman weighing 64 kg presented to the emergency department complaining of dysphagia and foreign-body sensation in her pharynx. There was no respiratory distress. Results of the ear, nose, and throat examination revealed a severe watery edema of her soft palate and uvula. Indirect laryngoscopy could not be performed because of the swelling. A flexible fiberoptic examination confirmed the edema of the soft palate, whereas the pharynx and larynx were normal. Her medical history was remarkable for hypertension treated by valsartan, 80 mg/d, for the past 7 months. She had experienced a similar but milder episode 2 months earlier, which was thought to be an allergic reaction and had been treated with oral corticosteroids by her general practitioner.The patient was given a single 125-mg intravenous bolus of methylprednisolone. Corticosteroids were administered for 6 days, initially intravenously and then orally. The edema improved 6 hours later and completely resolved in 48 hours. The patient had never had an episode of angioedema before the initiation of valsartan therapy. A close monitoring of her blood pressure and pulse rate (at admission, 165/90 mm Hg and 88/min, respectively) was recommended with a change of valsartan to antihypertensive medications other than ACEIs or ARBs. Written instructions against the use of ACEIs or ARBs were given to the patient. During her 15-month follow-up, she was free of symptoms.CASE 3A 62-year-old woman weighing 80 kg and with hypertension and stable angina pectoris was referred to our service with acute dyspnea. She had been taking atenolol, 100 mg/d, and aspirin, 100 mg/d, for the previous 5 years. Twice-daily captopril, 25 mg, and hydrochlorothiazide, 12.5 mg, had been added to her treatment for the past 3 months. Flexible endoscopy showed edema of the supraglottic larynx and the base of her tongue. The mobility of the vocal cords was normal. The patient was given a 16-mg intravenous bolus of dexamethasone sodium phosphate and a 50-mg intramuscular dose of hydroxyzine hydrochloride. Oxygen supplementation was also given by means of a facial mask, but 2 hours later there was no improvement. The patient was transferred urgently to the ear, nose, and throat surgical suite, where an emergency tracheotomy with the patient under local anesthesia was prepared. An attempt of nasotracheal intubation by using a flexible bronchoscope for guidance was successful. The patient was hospitalized in the intensive care unit under close monitoring of her vital signs, and she received corticosteroids and antihistamines. Epinephrine was not administered because of the use of the β-blocker. Three days later, flexible endoscopy showed resolution of the edema, and the patient underwent uneventful extubation.The patient had not had similar episodes in the past, nor did she have a history of allergy. Results of laboratory examinations, including measurement of total and specific immunoglobulins IgE, total complement, and C1 esterase inhibitor levels, were found to be within the reference ranges. The patient was discharged 4 days later receiving oral corticosteroid therapy, which was gradually tapered. After consulting her cardiologist, her antihypertensive treatment was changed, and captopril was replaced by a calcium channel antagonist (amlodipine besylate, 5 mg/d). A list of the medications containing ACEIs or ARBs was given to the patient. During her 24-month follow-up, she was free of symptoms.COMMENTAngiotensin-converting enzyme inhibitors are widely used for the treatment of hypertension, congestive heart failure, and diabetic nephropathy. The most common adverse effects are hypotension, renal dysfunction, hyperkalemia, and nonproductive cough (0%-39%).Hepatotoxicity, dysgeusia, teratogenesis, rash, proteinuria, neutropenia, and angioedema occur rarely (0.1%-1%).Angioedema is divided into the following 2 categories: hereditary (congenital) and acquired (Table 2).Antiotensin-converting enzyme inhibitors reduce the function of ACE, which in turn alters the conversion of angiotensin I to angiotensin II (a powerful vasoconstrictive agent) and inactivates bradykinin. The latter may cause local increases in levels of bradykinin, which is a potent vasodilator and increases vascular permeability. Most of the authors support these biochemical events as the cause of this form of angioedema.Angioedema secondary to ACEI therapy may appear from several hours to 2 years after initiation of treatment.Table 2. Types of AngioedemaCongenital Hereditary angioedema  C1 esterase inhibitor deficiency (85%)  C1 esterase inhibitor dysfunction (15%)AcquiredC1 esterase inhibitor deficiency  B-cell lymphoma  Connective tissue diseases  Development of C1 esterase inhibitor autoantibodies Allergic type 1 hypersensitivity  Parasites, food additives, drugs Chemical histamine releasers  Morphine, codeine, iodinated contrast mediaPhysical stimuli  Extremes of temperature, sunlight, vibrationAngiotensin-converting enzyme inhibitorsAngiotensin II receptor blockersMiscellaneous (rare) Systemic capillary leak syndrome Urticaria pigmentosaIdiopathicIn contrast, the ARBs theoretically do not increase bradykinin levels, because they act by blocking the effect of angiotensin II at the level of the angiotensin II receptors.Angioedema as a complication of ACEI therapy is becoming widely recognized. On the other hand, this complication is not well recognized with the use of ARBs. In recent years, isolated case reports of angioedema associated with ARBs have been published.The mechanism by which ARBs cause angioedema is unclear. There are speculations that patients with acquired angioedema may have a relative deficiency of the C1 esterase inhibitor, which is worsened by any alteration in the renin-angiotensin pathway, or that a deficiency of kininase I, which is another important enzyme for bradykinin degradation, could be implicated in cases of acquired angioedema.The initial therapeutic step is to secure the patency of the upper airway. Depending on the severity of the obstruction and the physician’s experience, medications, standard intubation, intubation with the use of a flexible bronchoscope, cricothyroidotomy, or tracheotomy may be used.Patients should be carefully monitored, as they usually have hypertension, heart disease, and other internal medicine illnesses that make the use of epinephrine or high doses of corticosteroids hazardous.We emphasize that the mechanism causing angioedema secondary to ACEI therapy is not the same mechanism causing allergic angioedema, and that ACEIs have a prolonged half-life. As a consequence, the standard treatment for allergic reactions (epinephrine, corticosteroids, and antihistamines) may not be as effective. Corticosteroids should also be used for a prolonged period to avoid recurrence. In Table 3, a comprehensive emergency treatment of acute angioneurotic edema of the upper aerodigestive tract is presented.Table 3. Comprehensive Emergency Management of Acute Angioneurotic Edema of the Aerodigestive Tract1. Secure patency of the upper airway2. Discontinue medication and perform clinical observation and examination3. Monitor circulatory system; perform electrocardiography and pulse oximetry4. Administer subcutaneous epinephrine (be aware of tachycardia, arrhythmia, or use of β-blockers)5. Administer oxygen, 3-6 L/min, depending on pulse oximetrical saturation6. Perform emergency blood tests7. Administer corticosteroids8. Administer antihistamine drugs9. Administer inhaled racemic epinephrine (be aware of tachycardia, arrhythmia, or use of β-blockers)10. Administer intravenous C1 esterase inhibitor in rare cases of a known lack of C1 esterase inhibitorIn everyday practice, angioedema secondary to ACEI or ARB therapy is usually diagnosed after several episodes. The reason is that the initial episodes are underestimated and the involved physicians (general practitioners, cardiologists, internists, and otolaryngologists) may not be aware of the association.By presenting our experience in the diagnosis and treatment of angioedema secondary to ACEI or ARB therapy in 31 patients, we emphasize that angioedema may be more common than was believed, that it may occur after long-term use of these agents, and that clinicians should exercise caution and avoid ARBs in patients with a history of angioedema, particularly that secondary to ACEI therapy.Correspondence:Dionysios E. Kyrmizakis, MD, DDS, Department of Ear, Nose, and Throat, University Hospital, 25 Papanastasiou St, Heraklion, Crete 71306, Greece (dkyrmiz@yahoo.com).Submitted for Publication:July 8, 2004; final revision received August 23, 2004; accepted August 26, 2004.REFERENCESRAgahVBandiKKGuntupalliAngioedema: the role of ACE inhibitors and factors associated with poor clinical outcome.Intensive Care Med1997237937969290997DEKyrmizakisCEPapadakisEJFountoulakisADLioliosJGSkoulasTongue angioedema after long-term use of ACE inhibitors.Am J Otolaryngol1998193943969839915VHDonaldsonRREvansA biochemical abnormality in hereditary angioneurotic edema: absence of serum inhibitor C1 esterase.Am J Med196335374414046003JPPracyJAMcGashanRMWalshMJGleesonAngioedema secondary to angiotensin-converting inhibitors.J Laryngol Otol19941086966987930926AACarrLMPrisantLosartan: first of a new class of angiotensin antagonists for the management of hypertension.J Clin Pharmacol1996363128932538AGChiuEJKrwiakZEDeebAngioedema associated with angiotensin II receptor antagonists: challenging our knowledge of angioedema and its etiology.Laryngoscope20011111729173111801934ZHIsrailiWDHallCough and angioneurotic edema associated with angiotensin-converting enzyme inhibitor therapy: a review of the literature and pathophysiology.Ann Intern Med19921172342421616218RAbdiVMDongCJLeeKANtosoAngiotensin II receptor blocker–associated angioedema: on the heels of ACE inhibitor angioedema.Pharmacotherapy2002221173117512222553KSLoAngioedema associated with candesartan.Pharmacotherapy2002221176117912222554PKSharmaJJYiumAngioedema associated with angiotensin II receptor antagonist losartan.South Med J1997905525539160080EESlaterDDMerrillHAGuessClinical profile of angioedema associated with angiotensin converting enzyme inhibition.JAMA19882609679702840522MTischLLamplAGrohHMaierAngioneurotic edemas of the upper aerodigestive tract after ACE-inhibitor treatment.Eur Arch Otorhinolaryngol200225941942112235515 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png JAMA Otolaryngology - Head & Neck Surgery American Medical Association

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Publisher
American Medical Association
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Copyright 2004 American Medical Association. All Rights Reserved. Applicable FARS/DFARS Restrictions Apply to Government Use.
ISSN
2168-6181
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2168-619X
DOI
10.1001/archotol.130.12.1416
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15611402
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Abstract

The use of angiotensin-converting enzyme inhibitors (ACEIs) has been implicated in many cases of angioedema, but, given the potential mechanism of this complication, it was not expected to be caused by angiotensin II receptor blockers (ARBs). However, in the past few years, scattered reports of angioedema associated with ARBs have appeared in the medical literature. We performed a retrospective chart review from January 1, 1998, through June 30, 2003, and a review of the literature. During this time, we managed head and neck angioedema induced by ACEIs (n = 27) and ARBs (n = 4) in 31 patients. All of them had significant mucosal swelling, and in some of them dyspnea and dysphagia coexisted. The most frequently involved areas were the oral tongue (13 cases), uvula and soft palate (5 cases), and larynx, mouth floor, and lips (3 cases each). Angioedema may be a more common complication of ACEI and/or ARB use than originally thought. This complication may occur after long-term use of these drugs. We advise that ARBs not be prescribed to patients with a history of angioedema, particularly that due to the use of ACEIs.Angioedema, also known as angioneurotic or Quincke edema, is a potentially life-threatening condition that is characterized by indurated, well-demarcated, nonpruritic, and often erythematous swelling of sudden onset. Usually 1 or more areas of the head and neck are involved.Hereditary angioedema is a clinical entity that has been attributed to deficiency or dysfunction of the C1 esterase inhibitor.Acquired angioedema could be secondary to several factors, among which use of angiotensin-converting enzyme inhibitors (ACEIs) is considered to be one of the most common causes, and is thought to result in 25% to 35% of all cases.The ACE, also known as kininase II, metabolizes bradykinin, a potent vasodilating substance, and converts angiotensin I to angiotensin II, a powerful vasoconstrictive agent. Angiotensin-converting enzyme inhibitors decrease angiotensin II and aldosterone levels on the one hand, and increase the level of bradykinin and prolong its action on the other hand. This combination of mechanisms is thought to be the cause of fluid extravasation into the subcutaneous tissues, which produces angioedema.Angiotensin II receptor blockers (ARBs) block the binding of angiotensin II receptors, thus inhibiting the known actions of angiotensin II that are associated with hypertension.Angiotensin II receptor blockers do not affect ACE, and theoretically bradykinin should remain unaffected.In this report, we present our experience of 5½ years during which we have diagnosed and treated head and neck angioedema caused by the use of ACEIs and/or ARBs in 31 patients.METHODSIn the period from January 1, 1998, through June 30, 2003, 31 patients were consulted or referred to our emergency department because of angioedema after treatment with ACEIs (27 patients) or ARBs (4 patients). All of them had significant mucosal swelling, and dyspnea and dysphagia coexisted in some of them. Table 1shows the implicated drugs. Nineteen patients were taking ACEIs; 8, ACEIs in combination with a diuretic (hydrochlorothiazide); and 4, ARBs. The group included 17 men and 14 women, with ages ranging from 42 to 81 years (mean age, 64 years). The most frequently involved areas were the oral tongue (13 cases), uvula and soft palate (5 cases), and larynx, mouth floor, and lips (3 cases each). Some cases involved more than 1 area. All patients were hospitalized from 2 to 9 days (mean time, 4 days), one of them in the intensive care unit and the others in the ear, nose, and throat ward.Table 1. ACEIs and ARBs That Caused AngioedemaDrug NameNo. of PatientsCaptopril7Lisinopril5Enalapril maleate4Quinapril hydrochloride2Ramipril1Captopril with hydrochlorothiazide3Lisinopril with hydrochlorothiazide3Enalapril with hydrochlorothiazide2Losartan potassium2Candesartan cilexetil1Valsartan1Abbreviations: ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker.A detailed history was obtained from all patients and was considered the most important step in the diagnosis of angioedema secondary to ACEIs or ARBs. When hereditary or allergic angioedema was suspected, measurements of C1 esterase inhibitor, total complement, C4 complement, and total and specific immunoglobulin IgE levels and specific skin-prick tests were ordered. Most of the patients were taking numerous medications because of various medical diseases; therefore the involvement of an internist was sought. We herein report 3 representative cases.REPORT OF CASESCASE 1A 67-year-old man weighing 88 kg was referred to our department from another hospital with severe edema of the tongue and floor of the mouth. Results of the clinical examination revealed a severely enlarged tongue obstructing the upper airway. The floor of his mouth had symmetrical swelling that pushed the edematous tongue to the palate. The patient was in mild respiratory distress. Results of a flexible fiberoptic examination through the nose revealed a watery edema of his base tongue and visualized a normal larynx.His medical history was remarkable for hypertension and mild type 2 diabetes mellitus. His hypertension was previously treated with lisinopril, 20 mg/d, which had been changed to losartan potassium, 50 mg/d, 2 months earlier.On general physical examination, his blood pressure was 145/80 mm Hg and pulse rate was 85/min. The patient was given a 0.4-mg dose of subcutaneous epinephrine hydrochloride and a 125-mg intravenous methylprednisolone sodium succinate bolus once. Intravenous methylprednisolone sodium succinate therapy was continued (1mg/kg of body weight divided in 3 doses per day) for 2 days, and then orally for 5 more days.After a detailed history was obtained, it was found that the patient had had 3 episodes of angioedema during his treatment with lisinopril, which were treated symptomatically elsewhere. The current episode, which was the most severe, was the first after lisinopril was changed to losartan therapy. The patient had never had an episode of angioedema before the initiation of the ACEI therapy 18 months earlier. During his hospitalization, his vital signs were monitored closely.The patient was discharged 3 days later and was instructed to stop taking ACEIs and ARBs. A list of medications containing ACEIs and ARBs was given to the patient. After consultation with his general practitioner, the treatment was changed to felodipine, and, as of this report, the patient has been free of episodes for 1 year.CASE 2A 61-year-old woman weighing 64 kg presented to the emergency department complaining of dysphagia and foreign-body sensation in her pharynx. There was no respiratory distress. Results of the ear, nose, and throat examination revealed a severe watery edema of her soft palate and uvula. Indirect laryngoscopy could not be performed because of the swelling. A flexible fiberoptic examination confirmed the edema of the soft palate, whereas the pharynx and larynx were normal. Her medical history was remarkable for hypertension treated by valsartan, 80 mg/d, for the past 7 months. She had experienced a similar but milder episode 2 months earlier, which was thought to be an allergic reaction and had been treated with oral corticosteroids by her general practitioner.The patient was given a single 125-mg intravenous bolus of methylprednisolone. Corticosteroids were administered for 6 days, initially intravenously and then orally. The edema improved 6 hours later and completely resolved in 48 hours. The patient had never had an episode of angioedema before the initiation of valsartan therapy. A close monitoring of her blood pressure and pulse rate (at admission, 165/90 mm Hg and 88/min, respectively) was recommended with a change of valsartan to antihypertensive medications other than ACEIs or ARBs. Written instructions against the use of ACEIs or ARBs were given to the patient. During her 15-month follow-up, she was free of symptoms.CASE 3A 62-year-old woman weighing 80 kg and with hypertension and stable angina pectoris was referred to our service with acute dyspnea. She had been taking atenolol, 100 mg/d, and aspirin, 100 mg/d, for the previous 5 years. Twice-daily captopril, 25 mg, and hydrochlorothiazide, 12.5 mg, had been added to her treatment for the past 3 months. Flexible endoscopy showed edema of the supraglottic larynx and the base of her tongue. The mobility of the vocal cords was normal. The patient was given a 16-mg intravenous bolus of dexamethasone sodium phosphate and a 50-mg intramuscular dose of hydroxyzine hydrochloride. Oxygen supplementation was also given by means of a facial mask, but 2 hours later there was no improvement. The patient was transferred urgently to the ear, nose, and throat surgical suite, where an emergency tracheotomy with the patient under local anesthesia was prepared. An attempt of nasotracheal intubation by using a flexible bronchoscope for guidance was successful. The patient was hospitalized in the intensive care unit under close monitoring of her vital signs, and she received corticosteroids and antihistamines. Epinephrine was not administered because of the use of the β-blocker. Three days later, flexible endoscopy showed resolution of the edema, and the patient underwent uneventful extubation.The patient had not had similar episodes in the past, nor did she have a history of allergy. Results of laboratory examinations, including measurement of total and specific immunoglobulins IgE, total complement, and C1 esterase inhibitor levels, were found to be within the reference ranges. The patient was discharged 4 days later receiving oral corticosteroid therapy, which was gradually tapered. After consulting her cardiologist, her antihypertensive treatment was changed, and captopril was replaced by a calcium channel antagonist (amlodipine besylate, 5 mg/d). A list of the medications containing ACEIs or ARBs was given to the patient. During her 24-month follow-up, she was free of symptoms.COMMENTAngiotensin-converting enzyme inhibitors are widely used for the treatment of hypertension, congestive heart failure, and diabetic nephropathy. The most common adverse effects are hypotension, renal dysfunction, hyperkalemia, and nonproductive cough (0%-39%).Hepatotoxicity, dysgeusia, teratogenesis, rash, proteinuria, neutropenia, and angioedema occur rarely (0.1%-1%).Angioedema is divided into the following 2 categories: hereditary (congenital) and acquired (Table 2).Antiotensin-converting enzyme inhibitors reduce the function of ACE, which in turn alters the conversion of angiotensin I to angiotensin II (a powerful vasoconstrictive agent) and inactivates bradykinin. The latter may cause local increases in levels of bradykinin, which is a potent vasodilator and increases vascular permeability. Most of the authors support these biochemical events as the cause of this form of angioedema.Angioedema secondary to ACEI therapy may appear from several hours to 2 years after initiation of treatment.Table 2. Types of AngioedemaCongenital Hereditary angioedema  C1 esterase inhibitor deficiency (85%)  C1 esterase inhibitor dysfunction (15%)AcquiredC1 esterase inhibitor deficiency  B-cell lymphoma  Connective tissue diseases  Development of C1 esterase inhibitor autoantibodies Allergic type 1 hypersensitivity  Parasites, food additives, drugs Chemical histamine releasers  Morphine, codeine, iodinated contrast mediaPhysical stimuli  Extremes of temperature, sunlight, vibrationAngiotensin-converting enzyme inhibitorsAngiotensin II receptor blockersMiscellaneous (rare) Systemic capillary leak syndrome Urticaria pigmentosaIdiopathicIn contrast, the ARBs theoretically do not increase bradykinin levels, because they act by blocking the effect of angiotensin II at the level of the angiotensin II receptors.Angioedema as a complication of ACEI therapy is becoming widely recognized. On the other hand, this complication is not well recognized with the use of ARBs. In recent years, isolated case reports of angioedema associated with ARBs have been published.The mechanism by which ARBs cause angioedema is unclear. There are speculations that patients with acquired angioedema may have a relative deficiency of the C1 esterase inhibitor, which is worsened by any alteration in the renin-angiotensin pathway, or that a deficiency of kininase I, which is another important enzyme for bradykinin degradation, could be implicated in cases of acquired angioedema.The initial therapeutic step is to secure the patency of the upper airway. Depending on the severity of the obstruction and the physician’s experience, medications, standard intubation, intubation with the use of a flexible bronchoscope, cricothyroidotomy, or tracheotomy may be used.Patients should be carefully monitored, as they usually have hypertension, heart disease, and other internal medicine illnesses that make the use of epinephrine or high doses of corticosteroids hazardous.We emphasize that the mechanism causing angioedema secondary to ACEI therapy is not the same mechanism causing allergic angioedema, and that ACEIs have a prolonged half-life. As a consequence, the standard treatment for allergic reactions (epinephrine, corticosteroids, and antihistamines) may not be as effective. Corticosteroids should also be used for a prolonged period to avoid recurrence. In Table 3, a comprehensive emergency treatment of acute angioneurotic edema of the upper aerodigestive tract is presented.Table 3. Comprehensive Emergency Management of Acute Angioneurotic Edema of the Aerodigestive Tract1. Secure patency of the upper airway2. Discontinue medication and perform clinical observation and examination3. Monitor circulatory system; perform electrocardiography and pulse oximetry4. Administer subcutaneous epinephrine (be aware of tachycardia, arrhythmia, or use of β-blockers)5. Administer oxygen, 3-6 L/min, depending on pulse oximetrical saturation6. Perform emergency blood tests7. Administer corticosteroids8. Administer antihistamine drugs9. Administer inhaled racemic epinephrine (be aware of tachycardia, arrhythmia, or use of β-blockers)10. Administer intravenous C1 esterase inhibitor in rare cases of a known lack of C1 esterase inhibitorIn everyday practice, angioedema secondary to ACEI or ARB therapy is usually diagnosed after several episodes. The reason is that the initial episodes are underestimated and the involved physicians (general practitioners, cardiologists, internists, and otolaryngologists) may not be aware of the association.By presenting our experience in the diagnosis and treatment of angioedema secondary to ACEI or ARB therapy in 31 patients, we emphasize that angioedema may be more common than was believed, that it may occur after long-term use of these agents, and that clinicians should exercise caution and avoid ARBs in patients with a history of angioedema, particularly that secondary to ACEI therapy.Correspondence:Dionysios E. Kyrmizakis, MD, DDS, Department of Ear, Nose, and Throat, University Hospital, 25 Papanastasiou St, Heraklion, Crete 71306, Greece (dkyrmiz@yahoo.com).Submitted for Publication:July 8, 2004; final revision received August 23, 2004; accepted August 26, 2004.REFERENCESRAgahVBandiKKGuntupalliAngioedema: the role of ACE inhibitors and factors associated with poor clinical outcome.Intensive Care Med1997237937969290997DEKyrmizakisCEPapadakisEJFountoulakisADLioliosJGSkoulasTongue angioedema after long-term use of ACE inhibitors.Am J Otolaryngol1998193943969839915VHDonaldsonRREvansA biochemical abnormality in hereditary angioneurotic edema: absence of serum inhibitor C1 esterase.Am J Med196335374414046003JPPracyJAMcGashanRMWalshMJGleesonAngioedema secondary to angiotensin-converting inhibitors.J Laryngol Otol19941086966987930926AACarrLMPrisantLosartan: first of a new class of angiotensin antagonists for the management of hypertension.J Clin Pharmacol1996363128932538AGChiuEJKrwiakZEDeebAngioedema associated with angiotensin II receptor antagonists: challenging our knowledge of angioedema and its etiology.Laryngoscope20011111729173111801934ZHIsrailiWDHallCough and angioneurotic edema associated with angiotensin-converting enzyme inhibitor therapy: a review of the literature and pathophysiology.Ann Intern Med19921172342421616218RAbdiVMDongCJLeeKANtosoAngiotensin II receptor blocker–associated angioedema: on the heels of ACE inhibitor angioedema.Pharmacotherapy2002221173117512222553KSLoAngioedema associated with candesartan.Pharmacotherapy2002221176117912222554PKSharmaJJYiumAngioedema associated with angiotensin II receptor antagonist losartan.South Med J1997905525539160080EESlaterDDMerrillHAGuessClinical profile of angioedema associated with angiotensin converting enzyme inhibition.JAMA19882609679702840522MTischLLamplAGrohHMaierAngioneurotic edemas of the upper aerodigestive tract after ACE-inhibitor treatment.Eur Arch Otorhinolaryngol200225941942112235515

Journal

JAMA Otolaryngology - Head & Neck SurgeryAmerican Medical Association

Published: Dec 1, 2004

There are no references for this article.