Adverse Effect Of Angiotensin-converting Enzyme Inhibitors Research Articles

Benefits and adverse effects of ACE inhibitors in patients with heart failure with reduced ejection fraction: a systematic review and meta-analysis.

Angiotensin-converting enzyme (ACE) inhibitors are part of first-line treatment for reduced ejection fraction heart failure (HFrEF). The aim was to assess the benefits and adverse effects of ACE inhibitors in HFrEF with a focus on important patient outcomes. A systematic review of double-blind randomized clinical trials (RCTs) and comparison of ACE inhibitors versus placebo, in HFrEF patients published in French or English. Searches were undertaken of Medline, Cochrane Central, and Embase. The primary outcomes were all-cause mortality and adverse events. From 636 articles analysed, 11 were included (13,882 patients). For all-cause mortality (5 RCTs, 9277 patients), the number needed to treat (NNT) to avoid one death at 6months was 50 (33-107). The NNT to prevent one death at 12months (6 RCTs, 13,016 patients) was 63 (35-314). Under the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, the evidence was of moderate quality. The number needed to harm was 12 (10-15) for cough, 20 (14-31) for hypotension, 23 (17-36) for dizziness, 31 (23-47) for hyperkalaemia, and 49 (30-121) for increased creatinine levels. The quality of evidence was moderate for these criteria except for cough (low quality of evidence). This review focuses on clinical elements necessary in a shared decision-making process. In practice, general practitioners will be able to use these data to discuss ACE inhibitor treatment with HFrEF patients. This study was registered in the PROSPERO registry under the reference number CRD42018096930.

Isolated Abdominal Angioedema from an Angiotensin-Converting Enzyme-Inhibitor

Angiotensin-converting enzyme-inhibitors (ACE-Is) are a frequently prescribed medication as treatment of several conditions including but not limited to hypertension. Angioedema is the second most common (prevalence 0.1%-3%) adverse effect of ACE-Is,1 preceded only by cough (prevalence 10%-20%). ACE-I–associated angioedema can be life-threatening and typically occurs on the lips, tongue, pharynx, and larynx; however, some cases have a gastrointestinal presentation. This is a case of ACE-I–induced abdominal angioedema.

Involvement of the TRPV1 receptor in plasma extravasation in airways of rats treated with an angiotensin-converting enzyme inhibitor

Angiotensin-converting enzyme inhibitors (ACEIs) are widely used in the treatment of hypertension, congestive heart failure and renal disease, and are considered relatively safe and generally well-tolerated drugs. However, adverse effects of ACEIs have been reported, including non-productive cough and angioedema, which can lead to poor adherence to therapy. The mechanisms by which ACEIs promote adverse effects are not fully elucidated, although increased bradykinin plasma levels following ACEI therapy seem to play an important role. Since bradykinin can sensitise the transient potential vanilloid receptor 1 (TRPV1), we investigated the role of TRPV1 in plasma extravasation in the trachea and bronchi of rats treated with the ACEI captopril. We observed that intravenous (i.v.) administration of captopril did not cause plasma extravasation in the trachea or bronchi of spontaneously breathing rats, but induced plasma extravasation in the trachea and bronchi of artificially ventilated rats. The intratracheal (i.t.) instillation of capsaicin or bradykinin also induced an increase in plasma extravasation in the trachea and bronchi of artificially ventilated rats. As expected, capsaicin-induced plasma extravasation was inhibited by i.t. pretreatment with the TRPV1 selective antagonist capsazepine (CPZ) while bradykinin-induced plasma extravasation was reduced by i.t. pretreatment with the selective B2 receptor antagonist Icatibant, originally known as HOE 140 (HOE). Interestingly, bradykinin-induced plasma extravasation was also inhibited by CPZ. The pretreatment with HOE and CPZ, singly or in combination and at doses which do not cause inhibitory effects per se, significantly inhibited the plasma extravasation induced by captopril treatment in artificially ventilated rats. In addition, treatment with a high dose of capsaicin in newborn rats, which induces degeneration of TRPV1-expressing sensory neurons, abolished both capsaicin and captopril-induced plasma extravasation in artificially ventilated rats. In conclusion, our study identified that captopril treatment promoted sensitisation of TRPV1, via B2 receptor activation, inducing plasma extravasation in the airways of mechanically ventilated rats. The present findings add a new view about the role of TRPV1 in the plasma extravasation induced by captopril and could to contribute to the elucidation of mechanisms by which ACEI induces adverse effects on airways.

Measuring Patients' Knowledge About Adverse Effects of Angiotensin-Converting Enzyme Inhibitors.

Knowledge about adverse effects of medications is an important part of proper medication use and prerequisite for good treatment adherence. The aim of our study was to construct, develop, and test a new questionnaire for the measurement of patients' knowledge about adverse drug reactions of angiotensin-converting enzyme (ACE) inhibitors. The 8-item questionnaire was constructed to measure adverse reactions to ACE inhibitors. The questions were closed, with 7 offered answers, in the form of a Likert scale. It was tested for psychometric properties on patients who visited their general practitioners at state-owned health facilities in 5 Serbian cities: Belgrade, Kragujevac, Banja Luka, Gracanica, and Despotovac. The questionnaire was tested on 259 patients from general practice, taking an ACE inhibitor for more than 3 months. Experience with at least 1 adverse effect of ACE inhibitor was reported in 64 patients (24.7%), only 94 patients (36.3%) previously received any form of information about at least 1 adverse effect of ACE inhibitors from health workers, and only 42% expressed knowledge of any adverse events. The patients who were informed knew about the following adverse events as phrased in the official patient information leaflets: severe dizziness or light-headedness (44%); cough (37%); swelling of the hands, face, lips, or tongue (32%); indigestion (22%); headache (51%); and difficulty in breathing (15%). The questionnaire showed satisfactory internal consistency, with Cronbach α of 0.767, and individual scores correlated with general education of the patients. Factorial analysis revealed 2 domains (subscales): the first one with 5 questions is directed to adverse effects the patients may physically experience directly, whereas the second with 3 questions measures knowledge about adverse effects that could be experienced only indirectly, through conditions caused by the adverse effects. The questionnaire about knowledge of ACE inhibitors' adverse effects is a reliable and probably valid instrument for measuring patients' knowledge about adverse effects of ACE inhibitors.

Angioedema Related to Angiotensin Inhibitors

Angiotensin inhibitors have been extensively evaluated in clinical trials and have demonstrated significant reductions in morbidity and mortality following myocardial infarction and stroke, as well as in patients with heart failure or who are at risk of cardiovascular disease. Further, both angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are frequently prescribed for the treatment of hypertension and to preserve renal function in patients with diabetes mellitus and chronic kidney disease. Angioedema is a known, but rare, adverse effect of ACEIs and ARBs. Therefore, it is important for clinicians to have a thorough understanding of risks and benefits of prescribing these medications, particularly in patients with a history of angioedema. This review describes the literature evaluating the incidence and cross-reactivity of angioedema with ACEIs and ARBs in order to provide guidance for clinical decision making.

Small Bowel Angioedema Secondary to ACE-Inhibitor

Purpose: Angiotensin-converting enzyme (ACE) inhibitors are routinely used in antihypertensive therapy, chronic kidney disease and in congestive heart failure. Tens of millions of patients worldwide use this class of medications. Angioedema, which most commonly affects the oropharynx and airway, is a well known adverse effect of ACE inhibitors. 0.1-0.2% of patients on ACE-inhibitors develop angioedema. Twenty-one cases of visceral angioedema associated with ACE inhibitor use have been described in the literature. We present a case of small bowel angioedema secondary to ACE inhibitor use to increase awareness of this serious adverse effect. Case: 46 year old female with newly diagnosed hypertension presented to the emergency room with 4 days of severe, periumbilical abdominal pain. She also developed nausea, vomiting and mild diarrhea. No fevers, chills, rashes, tongue or facial swelling, shortness of breath, wheezing, urticaria, history of atopy, vasculitis, vasculopathy, autoimmune disease, or history of angioedema. No family history of angioedema. Her first dose of lisinopril and hydrochlorothiazide was 12 hours prior to developing pain. She was afebrile and vital signs were within normal limits. Her abdomen had normal bowel sounds and was firm, slightly distended, with tenderness to palpation in the mid-abdomen, particularly in the periumbilical region. She had guarding but no rebound. White blood cell count was slightly elevated with a normal differential. Hemoglobin, platelets, comprehensive metabolic panel, amylase and lipase were all normal. CT scan revealed diffuse thickening of the jejunum and ileum, consistent with angioedema, and ascites. She discontinued lisinopril and had resolution of her pain. C1 esterase level is pending. Discussion: Angioedema is an adverse effect of ACE inhibitors and may affect the GI tract without involvement of the oropharynx or airway. The most common presenting symptoms are diffuse abdominal pain and vomiting. Diagnosis is based on history and clinical findings. There is no specific test for confirmation. Treatment involves stopping the ACE inhibitor. Patients who develop angioedema from ACE inhibitors should not be given angiotensin II receptor blockers as they may also precipitate angioedema. Although the number of reported cases of visceral angioedema is small compared to the number of patients using ACE inhibitors, this may reflect under diagnosis. A high degree of suspicion is necessary to quickly make the diagnosis and stop the medication without subjecting the patient to unnecessary invasive diagnostic procedures.

Severe Paradoxical Hypertension With Angiotensin-Converting Enzyme Inhibitors: An Unusual Feature of Renal Artery Stenosis

To the Editor: Angiotensin-converting enzyme (ACE) inhibitors are frequently used in the treatment of hypertension, heart failure, and renal disease but may cause acute renal failure in patients with renal artery stenosis (RAS).1 We describe a novel adverse effect of ACE inhibitors in patients with advanced chronic kidney disease (CKD) and RAS. We observed 4 episodes of severe paradoxical hypertension in 3 patients with CKD (Table) and bilateral RAS, during initiation or titration of the ACE inhibitor ramipril (Tritace, Sanofi-Aventis). The etiology of CKD was atherosclerotic renovascular disease in each case. Bilateral, hemodynamically significant RAS had been demonstrated previously with both Doppler ultrasound and renal angiography in all 3 of the patients and magnetic resonance angiography in 2 patients. Blood pressure (BP) measurement using …

Angiotensin II receptor antagonists in chronic heart failure: where do they fit?

Heart failure is a common and disabling condition with a dismal prognosis. Inhibition of the renin-angiotensin-aldosterone system (RAAS) with angiotensin converting enzyme (ACE) inhibitors has proven to be a valuable therapeutic strategy in this condition, with well-proven morbidity and mortality benefits. Nonetheless, ACE inhibitors provide incomplete blockade of the RAAS and also inhibit the degradation of bradykinin. Although increased levels of bradykinin may have haemodynamic advantages by contributing to vasodilatation, they may also be largely responsible for some of the adverse effects of ACE inhibitors. Angiotensin II (Ang II) receptor antagonists offer more complete blockade of the RAAS without the potentiation of bradykinin, and it was therefore hoped that they would provide even greater benefits for patients with heart failure. So far, much of the initial promise of the Ang II receptor antagonists in heart failure has not been realised. There has been no conclusive demonstration of their superiority to ACE inhibitors in their effects on morbidity and mortality, and their equivalence to ACE inhibitors has not been proven. The Ang II receptor antagonists have, however, proven to be better tolerated than ACE inhibitors and they are therefore likely to be a reasonable alternative for those patients with heart failure who cannot tolerate ACE inhibition. Recent evidence has indicated that the Ang II type 1 receptor antagonist valsartan is of value when used in patients already receiving either an ACE inhibitor or a beta-blocker, but has also suggested that giving all three drugs together is deleterious. Further evidence about the value of Ang II receptor antagonists in heart failure may be provided by further studies, of which several are currently ongoing.

Amelioration of Enalapril-Induced Dry Cough by Changing Dosing Time from Morning to Evening; A Preliminary Trial.

Objective: To determine whether the severity and frequency of dry cough induced by enalapril, an angiotensin-converting enzyme (ACE) inhibitor, might be altered by changing its administration time.Methods: Twenty-one patients with hypertension and three with chronic heart failure received enalapril (5 mg) once daily in the morning for more than 2 weeks and complained of persistent, non-productive dry cough. After the severity and frequency of cough were evaluated using a questionnaire, enalapril (5 mg) was given once daily in the evening for more than 2 weeks. At the end of this period, patients were asked to specify any changes in their cough during the evening treatment regimen, according to the following 5-point response scale: 1 (much worse), 2 (moderately worse), 3 (no change), 4 (moderately improved) and 5 (much improved).Results: The severity of dry cough was attenuated [mean change (and 95% CI): 3.75 (3.37-4.13)] and the frequency was reduced [mean change: 3.79 (3.44-4.14)] after the administraiton time was changed to evening.Conclusion: Dry cough is the most common adverse effect of ACE inhibitors. The present findings suggest that a chronopharmacological approach might ameliorate enalapril-induced dry cough and, consequently, improve QOL in treated patients.

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.

Adverse effects of the angiotensin-converting enzyme inhibitors.

To review current literature relating to the adverse effects of the angiotensin-converting enzyme (ACE) inhibitors. Online drug information sources, including MEDLINE (1966-November 1994), Iowa Drug Information Service, and the Australian Medical Index (AMI), were used to identify relevant literature, including reviews. Data were extracted from studies described in the English-language literature dealing with the adverse effects of ACE inhibitors. Comprehensive reviews and relevant case reports also were included. Important adverse effects of ACE inhibitors include first-dose hypotension, renal dysfunction, hyperkalemia, and cough. Less common adverse effects include angioedema, hepatotoxicity. Skin rashes, and dysgeusia. ACE inhibitors also are associated with adverse fetal effects; thus, this class of drugs in contraindicated in pregnancy. Some adverse effects of ACE inhibitors are predictable on the basis of the fundamental pharmacology of this class of drugs. However, other effects are idiosyncratic in nature, although these reactions are generally much less common. Attention to the principles of risk assessment, risk immunization, and patient monitoring are important when ACE inhibitor therapy is used for any indication. Provided these steps are taken. ACE inhibitors are generally a safe and effective class of drugs.

Tolerability of enalapril in congestive heart failure

This report reviews the tolerability profile of enalapril, an angiotensin-converting enzyme (ACE) inhibitor, in the treatment of patients with congestive heart failure. Data have been collected from 546 patients treated with enalapril for up to 9 months in clinical trials other than the Cooperative North Scandinavian Enalapril Survival Study. Results in patients treated with enalapril (n = 193) or placebo (n = 195) in double-blind, controlled clinical trials show that the incidences of death, serious adverse experiences, and adverse experiences requiring discontinuation of double-blind therapy, as well as the overall incidence of such experiences, were similar in the 2 groups. However, certain adverse experiences that are related to the mechanism of action of ACE inhibitors were seen more often after enalapril than after placebo treatment. Dizziness and hypotension were the most frequent adverse experiences reported in patients with heart failure treated with enalapril. The most frequent laboratory adverse experiences were increases in blood urea nitrogen and serum creatinine levels. Hyperkalemia was also seen in patients receiving enalapril. It is possible to identify patients at risk of these experiences before initiating treatment with enalapril and to take certain measures (such as withholding or reducing the dose of diuretic drugs and discontinuing potassium supplements or potassium-sparing diuretic drugs) to reduce the likelihood that hypotension, increases in blood urea nitrogen and serum creatinine levels, or hyperkalemia will occur. Angioedema, a recognized adverse effect of ACE inhibitors, was not seen in the clinical trials reviewed here. Cough, another recognized adverse effect of these agents, was seen infrequently and rarely resulted in the discontinuation of enalapril. The data from the clinical trials of enalapril in patients with heart failure show that this drug is well tolerated.

Characterization of angiotensin converting enzyme (ACE) in the testis and assessment of the in vivo effects of the ACE inhibitor perindopril.

Angiotensin converting enzyme (ACE) was characterized by radioligand studies utilizing the potent ACE inhibitor 351A, a derivative of lisinopril. Ligand binding characteristics were similar for ACE derived from testis, lung, and kidney, despite known differences in structure between ACe from these sources. This observation suggests that the ACE active enzymatic site is similar in different tissues. The effect of the orally active ACE inhibitor perindopril was studied ex vivo in tissues of the rat after oral gavage. Radioligand bound to tissue ACE was reduced after perindopril treatment, in tissue homogenates of lung and kidney, but not testis. Autoradiographs of radioligand binding to tissue sections obtained ex vivo after oral perindopril showed inhibition of ACE in the aorta, lung, and kidney, but did not reveal any inhibition of ACE in the testis. ACE in small vessels of the testis was inhibited as in the aorta, while at the same time testicular ACE was unaffected. ACE in rat testis appears to have a similar enzymatic binding site to ACE from the lung and kidney. Perindopril inhibited ACE in the lung and kidney but did not affect ACE in the testis, suggesting the drug is limited in testicular penetration by the blood-testis barrier. This may explain the lack of any reports of adverse effects of ACE inhibitors on testicular function.