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PubMed1999

Angioedema due to angiotensin-converting enzyme inhibitors.

Angiotensin-converting enzyme (ACE) inhibitor associated angioedema was detected in 39 subjects (17%) of 231 consecutive patients examined in the last 5 years at our out-patient clinic for symptoms of angioedema without urticaria. In these patients, angioedema was most commonly localized to the face. The duration of ACE-inhibitor treatment at the onset of angioedema ranged from 1 day to 8 years with a median of 6 months. The time elapsed between onset of angioedema and withdrawal of ACE-inhibitor ranged from 1 day to 10 years with a median of 10 months. Delayed diagnosis is explained by the unusual characteristics of this adverse reaction: angioedema may start years after beginning the treatment and then it recurs irregularly. In fact, ACE-inhibitors seem to facilitate angioedema in predisposed subjects, rather than causing it with an allergic or idiosyncratic mechanism. Thus, while Cl-inhibitor levels are usually normal in subjects developing ACE-inhibitor-dependent angioedema, we found that ACE-inhibitors caused angioedema in Cl-inhibitor-deficient patients. Because the main inactivator of bradykinin is kininase II, which is identical with ACE, it is believed that bradykinin mediates ACE-inhibitor-dependent angioedema. We had the possibility to examine the plasma bradykinin levels in one ACE-inhibitor-treated patient during an angioedema attack and we found very high levels, but we did not find an increase of break-down products of high-molecular-weight-kininogen as observed during acute attacks in hereditary angioedema. Bradykinin fell to normal levels during remission after withdrawal of the drug. These observations indicate that in ACE-inhibitor-induced angioedema, contrary to hereditary angioedema, the reduction of bradykinin catabolic rate plays a predominant role.

Adolescent↗
PubMed2003

Bradykinin and the pathophysiology of angioedema.

Angioedema has different causes and different clinical presentations. Some types of angioedema may be mediated by bradykinin. We measured plasma levels of bradykinin-(1-9)nonapeptide by radioimmunoassay after high-performance liquid chromatography in patients with different types of angioedema during acute attacks and/or in remission, i.e. hereditary C1-inhibitor deficiency, angiotensin converting enzyme (ACE) inhibitor treatment, idiopathic non histaminergic and responders to antihistamines. Eleven patients with the deficiency of C1-inhibitor had very high levels of bradykinin during acute attacks of angioedema (18.0-90.0 pM) (normal range 0.2-7.1 pM). In three patients with history of ACE inhibitor-related angioedema, plasma bradykinin was high during ACE inhibitor treatment (62.0, 8.9 and 27.0 pM) and in a fourth patient was 47.0 pM during an acute attack and decreased by 93% to 3.2 pM after withdrawal of the ACE inhibitor. The patient with idiopathic angioedema, during an acute attack involving the right arm, had high levels of bradykinin in the venous blood refluent from the angioedematous arm (20.0 pM) while in the contralateral arm bradykinin levels were normal (6.6 pM), similarly to what we previously observed in cases of brachial angioedema due to C1-inhibitor deficiency. The four patients with angioedema responsive to antihistamines had normal levels of bradykinin even during acute attacks (5.7, 3.4, 4.7 and 1.2 pM). In one of these patients who had a brachial angioedema, bradykinin levels were normal in the venous blood refluent from both arms. Bradykinin is involved in hereditary C1-inhibitor deficiency angioedema, in ACE inhibitor-related angioedema, and in idiopathic non-histaminergic angioedema, while bradykinin is not related to allergen-dependent or idiopathic angioedema that are responsive to antihistamines.

Angioedema↗
PubMed2004

Angioedema associated with angiotensin-converting enzyme inhibitor use: outcome after switching to a different treatment.

BACKGROUND: Angiotensin-converting enzyme (ACE) inhibitors are associated with angioedema episodes that are potentially life-threatening. Few data are available on the outcome of patients reporting this adverse effect when they are switched to another drug. Scattered reports of angioedema associated with angiotensin II receptor blocker (ARB) use question the safety of using these drugs in patients with ACE inhibitor-related angioedema. We describe 64 consecutive patients with ACE inhibitor-related angioedema, the outcome after discontinuing this treatment, and the safety of using ARBs. METHODS: Retrospective analysis of 64 consecutive patients (January 1993 to June 2002) presenting with angioedema onset while receiving treatment with an ACE inhibitor. RESULTS: Patients were recommended to stop ACE inhibitor use, substituting it upon advice of the physician. Fifty-four patients were available for follow-up (median follow-up, 11 months; range, 1-80 months): 26 had switched to an ARB, 14 to a calcium antagonist, and 14 to other antihypertensive drugs. Angioedema disappeared or drastically reduced upon withdrawal of the ACE inhibitor in 46 patients (85%). For the remaining 8 patients, angioedema was due to a cause other than ACE inhibitor use in 2; angioedema persisted independent of the treatment and without apparent cause (idiopathic angioedema) in 4; angioedema persisted after switching to an ARB and disappeared upon its withdrawal in 2. CONCLUSIONS: Stopping ACE inhibitor use without further assessments is a successful measure in the large majority of patients developing angioedema while taking this drug. Only a small percentage of patients with ACE inhibitor-related angioedema continue with this symptom when switched to an ARB.

Aged↗
PubMed1997

Recurrent angiotensin-converting enzyme inhibitor--associated angioedema.

CONTEXT: Angiotensin-converting enzyme (ACE) inhibitors are associated with an increased risk of angioedema, but the risk of recurrent angioedema if treatment is continued is not known. OBJECTIVE: To test the hypothesis that the association between ACE inhibitor use and angioedema may not be recognized and to determine characteristics of angioedema associated with continued use of ACE inhibitors. DESIGN: Retrospective cohort study. SETTING: Tennessee Medicaid program. PATIENTS: Medicaid enrollees aged 15 years or older who used an ACE inhibitor and had a first documented episode of angioedema between 1986 and 1992 were followed up for recurrent episodes through June 1993. MEASUREMENTS AND MAIN RESULTS: We previously identified 82 patients with a first confirmed diagnosis of angioedema during 51 752 person-years of ACE inhibitor use in this population (1.6 per 1000 person-years). Among these 82 patients, there were 16 outpatient recurrences of angioedema among 13 patients during 189 patient-years of follow-up (8.5 per 100 patient-years). The rate of angioedema was much higher in users of ACE inhibitors with continued exposure (18.7 per 100 patient-years) than in those whose use of the drug was discontinued (1.8 per 100 patient-years) (P=.001). Review of the medical records for patients taking ACE inhibitors who had recurrent angioedema revealed that physicians attributed angioedema to a number of causes not related to ACE inhibitor use, even after multiple recurrences. CONCLUSION: Continuing use of ACE inhibitors in spite of angioedema results in a markedly increased rate of angioedema recurrence with serious morbidity.

Adolescent↗
PubMed2005

Angioedema.

UNLABELLED: Although first described more than 130 years ago, the pathophysiology, origin, and management of the several types of angioedema are poorly understood by most dermatologists. Although clinically similar, angioedema can be caused by either mast cell degranulation or activation of kinin formation. In the former category, allergic and nonsteroidal anti-inflammatory drug-induced angioedema are frequently accompanied by urticaria. Idiopathic chronic angioedema is also usually accompanied by urticaria, but can occur without hives. In either case, an autoimmune process leading to dermal mast cell degranulation occurs in some patients. In these patients, histamine-releasing IgG anti-FcepsilonR1 autoantibodies are believed to be the cause of the disease, removal or suppression by immunomodulation being followed by remission. Angiotensin-converting enzyme inhibitor-induced angioedema is unaccompanied by hives, and is caused by the inhibition of enzymatic degradation of tissue bradykinin. Hereditary angioedema, caused by unchecked tissue bradykinin formation, is recognized biochemically by a low plasma C'4 and low quantitative or functional C'1 inhibitor. Progress has now been made in understanding the molecular genetic basis of the two isoforms of this dominantly inherited disease. Recently, a third type of hereditary angioedema has been defined by several groups. Occurring exclusively in women, it is not associated with detectable abnormalities of the complement system. Angioedema caused by a C'1 esterase inhibitor deficiency can also be acquired in several clinical settings, including lymphoma and autoimmune connective tissue disease. It can also occur as a consequence of specific anti-C'1 esterase autoantibodies in some patients. We have reviewed the clinical features, diagnosis, and management of these different subtypes of angioedema. LEARNING OBJECTIVE: After completing this learning activity, participants should be aware of the classification, causes, and differential diagnosis of angioedema, the molecular basis of hereditary and non-hereditary forms of angioedema, and be able to formulate a pathophysiology-based treatment strategy for each of the subtypes of angioedema.

Acute Disease↗
PubMed2005

Pattern of hospitalizations for angioedema in New York between 1990 and 2003.

BACKGROUND: The epidemiologic characteristics of angioedema have not been well described in the United States, especially regarding hospitalization patterns. This fact is particularly relevant given the increased use of angiotensin-converting enzyme inhibitors, a known cause of angioedema. OBJECTIVE: To profile hospital admissions for angioedema in New York State with respect to age, sex, race, comorbidities, and year. METHODS: A database of all acute hospitalizations in New York State was examined between 1990 and 2003. Patient admissions that had the principal admission diagnoses of angioedema and other acute allergic disorders (anaphylaxis, urticaria, or allergy unspecified) were extracted. Characteristics of angioedema admissions were tabulated and compared with those of other acute allergic disease admissions with respect to demographic variables and comorbidities. RESULTS: There were 6,775 hospitalizations for angioedema during the study period. The number of angioedema hospitalizations increased progressively from 293 in 1990 to 636 in 2003, which exceeded the number of hospitalizations for anaphylaxis that year. African Americans constituted 42% of the angioedema admissions despite being less than 16% of the state population. The increase in hospitalizations for angioedema was most marked in patients with a diagnosis of hypertension, and for each study year, patients admitted with angioedema were consistently older than those admitted with other allergic disorders. CONCLUSIONS: Angioedema has become the most common nonasthmatic acute allergic disorder that results in hospitalization in New York State. The predilection for angioedema occurring in patients with hypertension suggests that angiotensin-converting enzyme inhibitor use may play a role in this trend.

Adolescent↗
PubMed1996

Angiotensin converting enzyme inhibitor-associated angioedema: higher risk in blacks than whites.

We compared the incidence of angioedema during exposure to angiotensin converting enzyme inhibitors (ACEIs) in blacks with that in whites in a retrospective cohort study of Medicaid recipients from Michigan, Ohio and Tennessee during 1986- 1992. Medicaid administrative files were used to identify filled prescriptions for ACEIs and calcium channel blockers (CCBs), and to identify first episodes of angioedema that occurred during exposure to an ACEI or CCB. There were 48,776 black and 106,482 white patients with 43,989 and 114,448 person-years of exposure to an ACEI, respectively. For comparison, there were 49,004 black and 110,129 white patients with 43,064 and 117,684 person-years of exposure to a CCB, respectively. The incidence of angioedema in blacks ranged from 3.3 to 4.6 per 1000 person-years of ACEI exposure--three to four times higher than that for whites in each state. Controlling for a slightly greater incidence of angioedema in blacks and other covariates, black users of ACEIs had a 3.1-fold greater incidence than white users. First exposure to ACEIs was associated with a higher risk of angioedema than chronic exposure in blacks, but not whites. Among blacks, the rate of angioedema during the first 30 days of exposure was 11.4 times greater (95% confidence interval [CI], 3.5 to 37.0) among ACEI users than CCB users; for those with at least 1 year of exposure, the rate was 4.5 times higher (95% CI, 2.6 to 8.0). Among whites, the increased risk of angioedema was more modest (rate ratio 1.7, 95% CI, 1.3 to 2.4 compared to CCB users) and did not differ by duration of ACEI use. In an analysis of angioedema cases and randomly selected controls in a subset of the full cohort, the greater risk of ACEI-associated angioedema in blacks was not explained by concurrent exposure to diuretics or antibiotics. Blacks may be at greater risk of angioedema when taking ACEIs than whites. Further study is necessary to confirm these findings, to examine effects of underlying disease on angioedema incidence, and to describe any racial differences in the severity of angioedema occurring with ACEIs.

Journal Article↗
PubMed2005

Life-threatening orolingual angioedema during thrombolysis in acute ischemic stroke.

BACKGROUND: Orolingual angioedema can occur during thrombolysis with alteplase in stroke patients. However, data about its frequency, severity and the significance of concurrent use of angiotensin-converting-enzyme inhibitors (ACEi) are sparse. OBJECTIVE: (1), to alert to the potentially life-threatening complication of orolingual angioedema. (2), to present CT-scans of the tongue which exclude lingual hematoma. (3), to estimate the frequency of orolingual angioedema. (4), to evaluate the risk associated with the concurrent use of ACEi. METHODS: Single center, databank-based observational study on 120 consecutive patients with i. v. alteplase for acute stroke. Meta-analysis of all stroke studies on alteplase-associated angioedema, which provided detailed information about the use of ACE-inhibitors. Across studies, the Peto odds ratio of orolingual angioedema for "concurrent use of ACEi" was calculated. RESULTS: Orolingual angioedema occurred in 2 of 120 patients (1.7%, 95% CI 0.2-5.9 %). Angioedema was mild in one, but rapidly progressive in another patient. Impending asphyxia prompted immediate intubation. CT showed orolingual swelling but no bleeding. One of 19 (5%) patients taking ACEi had orolingual angioedema, compared to 1 of 101 (1%) patients without ACEi. Medline search identified one further study about the occurrence of alteplase-associated angioedema in stroke patients stratified to the use of ACEi. Peto odds ratio of 37 (95 % CI 8-171) indicated an increased risk of alteplasetriggered angioedema for patients with ACEi (p <0.001). CONCLUSION: Orolingual angioedema is a potentially life-threatening complication of alteplase treatment in stroke patients, especially in those with ACEi. Orolingual hematoma as differential diagnosis can be excluded by CT-scan.

Acute Disease↗
PubMed2005

Increased C-reactive protein in ACE-inhibitor-induced angioedema.

AIMS: This study was designed to identify new factors which may contribute to angiotensin-converting-enzyme-inhibitor (ACEI)-induced angioedema. METHODS: In a retrospective cohort study we examined 25 patients who used an ACEI and presented at our emergency room with acute angioedema as well as 18 patients with unknown cause of angioedema and a total of 21 patients on ACEI-therapy without previous angioedema. We measured markers of inflammation such as acute-phase proteins (C-reactive protein, fibrinogen), leukocyte count and body temperature. RESULTS: The mean interval between initiation of ACEI treatment and first manifestation of angioedema was 35.8 +/- 5.3 months. During symptomatic angioedema, mean plasma levels of C-reactive protein and fibrinogen were significantly increased by 7.3-fold and 1.5-fold, respectively, while leukocyte count and body temperature were normal. These changes disappeared after successful treatment of angioedema and were not found in patients with angioedema of unknown cause and those receiving ACEI without having experienced angioedema. CONCLUSION: Our findings demonstrate for the first time that ACEI-induced angioedema is associated with strongly increased plasma levels of CRP. We suggest that CRP is involved in the pathophysiology of ACEI-induced angioedema.

Aged↗
PubMed2001

Drug-induced angioedema without urticaria.

Angioedema without urticaria is a clinical syndrome characterised by self-limiting local swellings involving the deeper cutaneous and mucosa tissue layers. Most occurrences of angioedema respond to treatment with a histamine H1 receptor blocker (antihistamine) because they are an allergic or parallergic reaction. A small number of cases do not respond to antihistamine treatment. Such cases tend to occur in patients with deficiency or dysfunction of the inhibitor of the first component of the complement (C1-INH), but more rarely can occur in patients with other conditions and as an adverse drug reaction. Angioedema is well documented in patients taking ACE inhibitors. Considering that 35 to 40 million patients are treated worldwide with ACE inhibitors, this drug class could account for several hundred deaths per year from laryngeal oedema. ACE inhibitors certainly do not mediate angioedema through an allergic or idiosyncratic reaction. For this reason the relationship with this drug is often missed and consequently quite underestimated. Rare instances of angioedema have also been reported with angiotensin II receptor antagonists. This adverse effect seems to occur less frequently with angiotensin II receptor antagonists than with ACE inhibitors. However, we do not know whether this adverse effect has the same mechanism with the 2 classes of medications. Some cases of severe angioedema have been recently reported after treatment with fibrinolytic agents. Scattered reports suggest the possibility of angioedema associated with the use of estrogens, antihypertensive drugs other than ACE inhibitors, and psychotropic drugs. Angioedema can also occur with nonsteroidal anti-inflammatory drugs. Prevention of angioedema relies first on the patient history. Estrogen and ACE inhibitors should be avoided in a patient with congenital or acquired C1-INH deficiency. In the case of ACE inhibitors, the appearance of angioedema following long term treatment does not lessen the probability that such an agent could be the cause. The most important action to take in a patient with suspected drug-induced angioedema is to discontinue the pharmacological agent. Epinephrine (adrenaline), diphenydramine and intravenous methylprednisolone have been proposed for the medical management of airway obstruction, but so far no controlled studies have demonstrated their efficacy. If the acute airway obstruction leads to life-threatening respiratory compromise an emergency cricothyroidotomy must be performed.

Angioedema↗
PubMedDate not supplied

Angioedema in heart failure: occurrence with ACE inhibitors and safety of angiotensin receptor blocker therapy.

Angioedema is a well-known side effect of treatment with an angiotensin-converting enzyme (ACE) inhibitor and one that we have been willing to accept in view of the incidence of the problem and the clear benefits of this class of agents in numerous clinical situations. Angioedema is also seen with angiotensin receptor blocker (ARB) therapy but much less frequently than with ACE inhibitors. The mechanism for angioedema with ARB therapy remains poorly defined. ACE inhibitor-related angioedema occurs more commonly in black patients. The basis for an increased risk of angioedema in black patients remains unclear. Angioedema can be life-threatening but more times than not it can be managed with conservative treatment measures including specifically the discontinuation of the medication and/or administration of an antihistamine and/or epinephrine. Occasionally, maneuvers to protect the integrity of the airway may be needed. In a heart failure patient having previously experienced ACE inhibitor-related angioedema, ARBs should be used cautiously since angioedema has been reported with ARB therapy in heart failure patients. The need to reduce renin-angiotensin aldosterone system activity in a heart failure patient would seem to justify the small risk of angioedema with ARB therapy in a patient having previously experienced ACE inhibitor-related angioedema.

Angioedema↗
PubMed2002

Angioedema. Pathogenesis, differential diagnosis, and treatment.

Angioedema is a constellation of syndromes that present a great challenge to the clinician. The term "angioedema" describes the localized, transient, episodic edema of the deeper layers of the skin or of the mucosa of the gastrointestinal tract. Although angioedema may affect any part of the body, the skin and gastrointestinal tract are involved most commonly by far. Episodic abdominal pain arising from angioedema affecting any intra-abdominal organ may occur without skin angioedema; therefore, angioedema must be included in the differential diagnosis of intermittent, unexplained abdominal pain. Angioedema is caused by extravasation of plasma in the affected areas, which at times is accompanied by nonspecific, minimal cellular infiltrate. The most commonly identified causes of angioedema are medications, allergens, and physical agents, but most angioedema is idiopathic. Rare forms of angioedema associated with either hereditary or acquired faulty activation of the complement and kallikrein-kinin systems have been extensively described. Taking a comprehensive personal and family history, performing a physical examination, and compulsively monitoring the response to therapy are the most rewarding and cost-effective diagnostic and treatment tools. Diligent and knowledgeable follow-up by the attending physician spares patients costly and unnecessary tests as well as harmful treatment. The most effective treatment depends on the identification of the causative mechanism and--especially when the mechanism is not identified--on the clinician's knowledge and experience with innovative therapeutic regimens.

Angioedema↗
PubMed1997

Examination of baseline levels of carboxypeptidase N and complement components as potential predictors of angioedema associated with the use of an angiotensin-converting enzyme inhibitor.

OBJECTIVE: To determine if mean levels of complement components and carboxypeptidase N differed when comparing patients who exhibited angioedema following angiotensin-converting enzyme inhibitor therapy to those who received angiotensin-converting enzyme inhibitor therapy but did not have angioedema. DESIGN: Case-control study nested within an 8-week, open-label study of the use of quinapril hydrochloride for hypertension in 12275 patients. SETTING: Multicenter, with sites throughout the United States. PATIENTS: Of the 36 patients with angioedema described, 22 participated in the study. They were matched to 48 controls by age, sex, race, length of follow-up, and geographical region. INTERVENTION: All patients received quinapril therapy prior to participation in this case-control study. MAIN OUTCOME MEASURES: Levels of carboxypeptidase N, total hemolytic complement, C1 esterase inhibitor, and C4, along with questionnaire data, including a history of angioedema-like episodes and family history of angioedema. RESULTS: The 22 patients had significantly lower mean levels of carboxypeptidase N (kininase I) (P = .03) and C1 esterase inhibitor (P = .04) compared with the 48 matched controls, but all mean values were within normal laboratory ranges. A history of prior angioedema-like episodes was associated with an approximate 6-fold increase in the subsequent risk of angioedema following angiotensin-converting enzyme inhibitor therapy. CONCLUSIONS: Small differences in levels of carboxypeptidase N or C1 esterase inhibitor may contribute to an increased risk of angioedema with angiotensin-converting enzyme inhibitor therapy. Given the large overlap in the distributions of carboxypeptidase N and C1 esterase inhibitor levels, prior testing could not be used to evaluate angioedema risk for an individual patient considering angiotensin-converting enzyme inhibitor therapy. A history of prior angioedema-like episodes was associated with increased risk, but this result should be interpreted with caution because of possible recall bias.

Angioedema↗
PubMed2006

Evaluation and management of angioedema of the head and neck.

PURPOSE OF REVIEW: Sudden occurrence of subcutaneous or submucosal swelling, the so-called angioedema, is an established and potentially life-threatening condition. Several forms of angioedema show a great variety of tissue localizations and different underlying mechanisms such as genetic mutations, allergic reactions and nonallergic reactions exist. Unfortunately, angioedema is often unrecognized and/or incorrectly treated. To change this situation, a better understanding of angioedema and possible therapeutic approaches appears necessary. RECENT FINDINGS: Recent investigations have shed new light on the pathomechanism of nonallergic drug-induced angioedema and new therapeutic options targeting the kallikrein-kinin system have become available for patients in clinical trials. Furthermore, extensive clinical evaluations of commonly used inhibitors of the renin-angiotensin system have provided reliable data on the incidence of angioedema induced by these drugs. Accordingly, several thousand patients worldwide experience severe fatal attacks although timely medical care would have saved their lives. SUMMARY: Current data suggest that the nonapetide bradykinin plays a crucial role in the pathogenesis of most forms of nonallergic angioedema, while histamine acts as the main biogenic mediator in allergic angioedema. Thus, correct diagnosis is crucial for effective treatment. Standard antiallergic drugs such as glucocorticoids and antihistamines are most probably ineffective in nonallergic angioedema forms.

Angioedema↗
PubMed2005

Incidence and characteristics of angioedema associated with enalapril.

BACKGROUND: Angioedema is a rare but potentially serious adverse event of angiotensin-converting enzyme inhibitor therapy. However, no prospective, controlled studies have reported on its incidence and clinical characteristics. METHODS: We studied the occurrence of angioedema in a randomized, double-blind, controlled trial of 12 557 persons with hypertension treated with enalapril maleate, 5 to 40 mg/d, using a prospective ascertainment and adjudication of angioedema by an expert committee. RESULTS: Angioedema occurred in 86 (0.68%) of the subjects. Stepwise logistic regression identified black race (odds ratio [OR], 2.88; 95% confidence interval [CI], 1.72-4.82), history of drug rash (OR, 3.78; 95% CI, 1.80-7.92), age greater than 65 years (OR, 1.60; 95% CI, 1.02-2.53), and seasonal allergies (OR, 1.79; 95% CI, 1.06-3.00) as independent risk factors for angioedema. The incidence of angioedema was higher after initiation of therapy (3.6/1000 patients per month) and declined to 0.4/1000 patients per month. Treatment was not given in 44 (51%) of the cases; antihistamines were administered in 35 (41%); corticosteroids, in 20 (23%); and epinephrine, in 1 (1%). Two patients were hospitalized but none had airway compromise. CONCLUSIONS: Enalapril-related angioedema is uncommon. Although it is most likely to occur early after initiation of therapy, it may occur at any time. It is more likely to occur in black patients, those older than 65 years, and those with a history of drug rash or seasonal allergies. Fatal angioedema or angioedema requiring airway protection did not occur in this study.

Adult↗
PubMed2002

Dipeptidyl peptidase IV activity in patients with ACE-inhibitor-associated angioedema.

Bradykinin and substance P have been implicated as mediators in angiotensin-converting enzyme inhibitor (ACEI)-associated angioedema. Studies investigating the metabolism of bradykinin in sera from patients with a history of ACEI-associated angioedema and controls suggest that there is a defect in a non-ACE, non-kininase I pathway of bradykinin degradation, such as the aminopeptidase P (APP)/dipeptidyl peptidase IV (DPPIV) pathway. This study tested the hypothesis that serum APP or DPPIV activity is decreased in patients with ACEI-associated angioedema. APP and DPPIV activity were measured in sera collected from patients during ACEI-associated angioedema, from patients with a remote history of ACEI-associated angioedema, and from normotensive and untreated hypertensive controls. The effects of acute and chronic ACEI and corticosteroid treatment on serum DPPIV activity were also assessed. DPPIV activity was similar in normotensive volunteers (37.8 +/- 6.3 nmol/mL per min), in untreated hypertensive subjects who had been exposed previously to ACEI without angioedema (36.2 +/- 4.3 nmol/mL per min), in hypertensive patients with a remote history of angioedema (35.1 +/-8.5 nmol/mL per min), and in chronically ACEI-treated hypertensive subjects (36.1 +/- 5.6 nmol/mL per min). DPPIV activity decreased with increasing age (R(2)=0.10, P=0.016). Subject group significantly affected DPPIV activity (F=6.208, P=0.016) such that DPPIV activity was significantly lower in patients with ACEI-associated angioedema (26.9 +/- 4.1 nmol/mL per min) than in normotensive controls, in previously ACEI-exposed untreated hypertensive volunteers, or in ACEI-treated hypertensive volunteers, even after controlling for age. There was no effect of acute ACE inhibition or corticosteroids on DPPIV activity. With respect to APP activity, there was no difference between groups. These results suggest that DPPIV activity is depressed in individuals with hypertension during acute ACEI-associated angioedema.

Adult↗
PubMedDate not supplied

Valsartan-induced angioedema.

OBJECTIVE: To report a case of dose-dependent angioedema secondary to the use of the angiotensin-receptor blocker (ARB) valsartan. CASE SUMMARY: A 64-year-old Hispanic woman presented with swelling of the lips shortly after an increase in her valsartan dose for uncontrolled hypertension. Other potential causes were not identified. The angioedema subsequently resided after a dosage reduction and observation. Use of the Naranjo probability scale indicated a probable relationship between the angioedema and valsartan therapy in this patient. DISCUSSION: Drug-induced angioedema is often associated with the use of angiotensin-converting enzyme (ACE) inhibitors and is probably secondary to their effects on bradykinin levels. ARBs are thought to produce few, if any, cases of angioedema if excess bradykinin levels are the root cause of angioedema secondary to ACE inhibitor use. Several potential ARB-induced cases of angioedema have been reported. The exact mechanism of angioedema induced by drugs in both of these classes is unknown. Animal data suggest that there may be a relationship between ARB use and increased tissue bradykinin levels secondary to stimulation of angiotensin II AT2 receptors. CONCLUSIONS: This is the third reported case of valsartan-induced angioedema and the first thought to be dose dependent. Practitioners should be aware of this potential adverse effect of valsartan, although the underlying cause is still not known.

Angioedema↗
PubMed1998

ACE inhibitor-induced angioedema. Incidence, prevention and management.

Available information from 1980 to 1997 on angiotensin converting enzyme (ACE) inhibitor-induced angioedema and its underlying mechanisms are summarised and discussed. The incidence of angioedema is low (0.1 to 0.2%) but can be considered as a potentially life-threatening adverse effect of ACE inhibitor therapy. This adverse effect of ACE inhibitors, irrespective of the chemical structure, can occur early in treatment as well as after prolonged exposure for up to several years. The estimate incidence is quite underestimated. The actual incidence can be far higher because of poorly recognised presentation of angioedema as a consequence of its late onset in combination with usually long term therapy. Also, a spontaneous reporting bias can contribute to an actual higher incidence of this phenomenon. The incidence can be even higher (up to 3-fold) in certain risk groups, for instance Black Americans. Treatment includes immediate withdrawal of the ACE inhibitor and acute symptomatic supportive therapy followed by immediate (and long term) alternative therapy with other classes of drugs to manage hypertension and/or heart failure. Preclinical and clinical studies for the elucidation of the underlying mechanism(s) of ACE inhibitor-associated angioedema have not generated definite conclusions. It is suggested that immunological processes and several mediator systems (bradykinin, histamine, substance P and prostaglandins) are involved in the pathogenesis of angioedema. A great part of all reviewed reports suggest a relationship between ACE inhibitor-induced angioedema and increased levels of (tissue) bradykinin. However, no conclusive evidence of the role of bradykinin in angioedema has been found and an exclusive role of bradykinin seems unlikely. So far, no clear-cut evidence for an immune-mediated pathogenesis has been found. In addition, ACE gene polymorphism and some enzyme deficiencies are proposed to be involved in ACE inhibitor-induced angioedema. Progress in pharmacogenetic and molecular biological research should throw more light on a possible genetic component in the pathogenesis of ACE inhibitor-associated angioedema.

Angioedema↗