Side Effect Of Angiotensin-converting Enzyme Inhibitors Research Articles

ACE Inhibitors-Induced Skin Reaction: A Case Report

Angiotensin-converting enzyme (ACE) inhibitors are widely used as antihypertensives, remodeling agents in heart failure, to stop the progression of diabetic nephropathy, as well as for a variety of other clinical purposes. Some side effects of ACE inhibitors are well recognized such as dry cough, hypotension, hyperkaliemia, proteinuria, renal failure. Also, these substances are known to have a wide range of dermatological side effects in addition to their adverse effects on other systems. (1,2) We report the case of a 46-year-old man treated for dilated cardiomyopathy with severe left ventricle dysfunction, who developed a cutaneous reaction secondary to the introduction of an ACE inhibitor.

Comparative study of pharmacokinetics, pharmacodynamics and cost-effectiveness between first-line Angiotensin Converting Enzyme inhibitors in Saudi Arabia during 2023

Angiotensin-converting enzyme (ACE) inhibitors were discovered in 1980 and since then they are used in many conditions like stable chronic heart failure, myocardial infarction (MI) and diabetic nephropathy and developed to become a recommended first-line therapy for hypertension (HTN), yet very few comparative studies and head-to-head trials exist to date. Hence, this study aimed to clarify ACE inhibitors pharmacokinetics and pharmacodynamics differences, assess the cost-effectiveness of ACE inhibitors, elaborate safety and side effects of ACE inhibitors, discuss which ACE inhibitor is favorable for variety of cases, and to promote more comparison studies and head-to-head trials between ACE inhibitors. This review article used published studies of ACE inhibitors properties and extracted data from Saudi Food and Drug Administration. It was found that enalapril has the longest duration of action of all ACE inhibitors, lasting 35 to 38 hours. While perindopril has the highest bioavailability, 65-75%, compared to other ACE inhibitors. The price variance of ACE inhibitors was found as lisinopril with the lowest price (18.7–37.45 Saudi Riyals SAR) and zofenopril with the highest price ($192). Further, zofenopril, trandolapril, and quinapril are the medications that are unavailable in Saudi Arabia. Moreover, angioedema is one of the most dangerous side effects of ACE inhibitors, along with hyperkalemia, kidney issues, headaches, and cough. However, the side effects of all these drugs are similar. Hence, it was concluded that the future of ACE inhibitors might also involve improved safety profiles through the development of novel ACE inhibitors with fewer side effects or better tolerability.

S2797 First Case of Isolated Angioedema of the Bowel Caused by Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)

INTRODUCTION: Visceral angioedema (VA) has been widely reported as a side-effect of angiotensin-converting enzyme inhibitors (ACEI). We report the first case of VA from NSAIDs. CASE DESCRIPTION/METHODS: An 80 y/o F with history of multiple abdominal surgeries, hypertension on lisinopril, and lumbago on aspirin 325 mg twice daily presented with acute epigastric pain, nausea, and vomiting. A CT scan showed moderate thickening and dilation of the distal small bowel (SB), without transition point. Symptoms resolved within days with supportive measures. One month later, while asymptomatic, a non-contrast MRI for pancreatic cyst surveillance showed normal SB. Two weeks after the MRI, her abdominal symptoms recurred. CT scan revealed multiple dilated, edematous fluid-filled stretches of SB, without transition point. Symptoms resolved spontaneously within days. Two months later, symptoms returned, with CT showing similar edema in the colon wall (Figure 1). Due to sharp angulations from edematous bowel, only a gastroscope could traverse the colon, with normal appearance of mucosa from the anus to the hepatic flexure. No SB evaluation was attempted due to SB edema. She improved after conservative management. She discontinued her lisinopril. One month later, symptoms recurred, with CT scan showing worsened bowel wall edema from prior CT (Figure 2). Labs were unremarkable for serum complement C4, C1 esterase inhibitor functional assay, extended stool pathogen panel, complete blood count, monoclonal gammopathy screen, and serum cytomegalovirus DNA. Aspirin was stopped. Symptoms abated within 24 hours. Five weeks later, while asymptomatic, her CT showed normalization of bowel wall (Figure 3). In no episode did the patient experience constitutional symptoms, dermatologic changes, dyspnea/wheezing, diarrhea, melena, or hematochezia. She had no new exposure to medications, travel, or dietary changes. In all cases where intravenous contrast was used, splanchnic vessels were patent. DISCUSSION: Episodic bowel obstructive symptoms associated with bowel thickening—and interval clinical improvement paralleling radiologic improvement of bowel thickening—illustrate the cadence of VA. As the VA occurred one month after stopping her ACEI, and symptoms resolved after stopping NSAIDs, it was likely triggered by her NSAID use. The shared pathogenesis and presentation of angioedema and enteropathy caused by NSAIDs provide a rationale for NSAID-induced VA. In patients without resolution of VA after stopping ACEI, NSAID cessation is the next step.Figure 1.: Computed tomography scan of the abdomen with intravenous contrast showed diffuse wall thickening of the descending and rectosigmoid colon. No transition point observed. Wall thickening, edema, and increased mucosal enhancement of multiple loops of the ileum and distal jejunum were observed, as well.Figure 2.: Computed tomography scan of the abdomen with intravenous contrast showed worsened evaluation compared to the previous scan. Diffuse wall thickening of the descending and rectosigmoid colon can be seen. No transition point can be seen. Wall thickening, edema, and increased mucosal enhancement of multiple loops of the ileum and distal jejunum were observed as well.Figure 3.: Five weeks after discontinuing her twice-daily aspirin, the patient underwent computed tomography scan with oral contrast (no intravenous contrast used), which showed interval resolution of the small bowel and colon wall thickening.

2644 ACE Inhibitor-Induced Visceral Angioedema - A Rare Phenomenon

INTRODUCTION: Angiotensin Converting enzyme (ACE) inhibitors are widely used to treat hypertension and congestive heart failure. Common adverse reactions include cough, hypotension and dizziness. Angioedema is a rare reaction that occurs in less than 1% of patients. Most cases of angioedema are involving the lips, tongue, face and airway. More rarely, visceral angioedema can also occur with jejunal involvement. CASE DESCRIPTION/METHODS: A 24-year-old female with recently diagnosed hypertension treated with lisinopril presented for evaluation of abdominal pain, vomiting, and diarrhea. On examination, she had moderate epigastric tenderness with normal bowel sounds and no organomegaly. Labs revealed white blood cells 20 k/mm3, elevated C-reactive protein 34.2 mg/L and normal erythrocyte sedimentation rate 7 mm/hr. Complement levels including C1 esterase inhibitor, C1q and C4 were found to be normal. Stool culture also remained negative. Computed tomography (CT) of the abdomen revealed moderate ascites, marked mucosal thickening of jejunal and ileal loops with adjacent mesenteric edema (Figure 1). Magnetic Resonance Enterography did not reveal any pathological process. A paracentesis was performed with the ascetic fluid analysis revealing a low serum-ascites albumin gradient without infection. Endoscopy with small bowel enteroscopy revealed normal duodenum and jejunum (Figure 2). Jejunal biopsy returned negative for an infectious or inflammatory process. Due to negative diagnostic workup, a diagnosis of ACE inhibitor-induced visceral angioedema was suspected. Patients symptoms quickly improved 24 hours after cessation of lisinopril and she was discharged home. On follow up 4 weeks later, the patient remained symptom-free. DISCUSSION: Visceral angioedema is a rare side effect of ACE inhibitors most commonly affecting the small bowel. The jejunum is most often affected followed by ileum and duodenum. High levels of bradykinin can cause increased vascular permeability within the bowel mucous membrane causing edema. Symptoms commonly include abdominal pain, anorexia, vomiting and diarrhea. Symptoms typically begin 72 hours after starting the ACE inhibitor. Imaging studies show circumferential small bowel thickening with mesenteric edema and ascites. Endoscopic examination is usually normal. Diagnosis is made by exclusion of other etiologies and improvement of symptoms within 48 hours of drug cessation. Treatment includes discontinuation of the offending drug and supportive therapy until symptoms are resolved.

Angiotensin-converting enzyme inhibitor-induced angioedema: A review of the literature.

According to the National Health and Nutrition Examination Survey 2012, one third of antihypertensive prescriptions in the United States in the past decade were for angiotensin-converting enzyme inhibitors (ACEIs). An important and serious side effect of ACEIs is angioedema caused by a reduction in bradykinin degradation. In a national medical chart abstraction study conducted at the US Veterans Affairs Health Care System in 2008, 0.20% of ACEI initiators developed angioedema while on the medication. The angiotensin-converting enzyme is a part of the renin-angiotensin system that converts angiotensin I to angiotensin II. It is additionally responsible for the degradation of bradykinin, which is generated from high molecular weight kininogen by kallikrein. Via bradykinin 2 receptors, bradykinin affects vascular permeability and stimulates the release of substance P, which is a peptide that causes vasodilation and fluid extravasation into tissues. Inhibition of the angiotensin-converting enzyme and subsequent blockade of bradykinin degradation is thought to be a likely explanation for ACEI-induced angioedema. Studies have shown that blacks, women, and smokers are at an increased risk for ACEI-induced angioedema. A 2005 study identified black race, history of drug rash, age older than 65years, and seasonal allergies as independent risk factors for angioedema related to enalapril. Angioedema may occur at any time during treatment with ACEIs and may continue after the medication is discontinued. The degree of ACEI-angiotensin receptor blocker angioedema cross-reactivity is difficult to determine from the literature. However, multiple studies have reported relatively low rates of native angioedema with angiotensin receptor blockers (approximately half that of ACEIs, or 0.1%) and a low incidence of cross-reactivity (<10%). Common treatments for angioedema, such as antihistamines and glucocorticoids, have not been shown to be effective in ACEI-induced angioedema. However, medications that have been used for acute treatment of hereditary angioedema and target the factors that cause ACEI-mediated angioedema are being explored.

Comparison of Clinical Factors Between Patients With Angiotensin-Converting Enzyme Inhibitor-Induced Angioedema and Cough.

Angioedema is a rare and serious adverse drug reaction (ADR) to angiotensin-converting enzyme (ACE) inhibitor treatment. Dry cough is a common side effect of ACE inhibitors and has been identified as a possible risk factor for angioedema. We compared characteristics between patients with ACE inhibitor-induced angioedema and cough with the aim of identifying risk factors that differ between these adverse events. Data on patients with angioedema or cough induced by ACE inhibitors were collected from the Swedish database of spontaneously reported ADRs or from collaborating clinicians. Wilcoxon rank sum test, Fisher's exact test, and odds ratios (ORs) with 95% CIs were used to test for between-group differences. The significance threshold was set to P <0.00128 to correct for multiple comparisons. Clinical characteristics were compared between 168 patients with angioedema and 121 with cough only. Smoking and concomitant selective calcium channel blocker treatment were more frequent among patients with angioedema than cough: OR = 4.3, 95% CI = 2.1-8.9, P = 2.2 × 10-5, and OR = 3.7, 95% CI = 2.0-7.0, P = 1.7 × 10-5. Angioedema cases were seen more often in male patients (OR = 2.2, 95% CI = 1.4-3.6, P = 1.3 × 10-4) and had longer time to onset and higher doses than those with cough ( P = 3.2 × 10-10 and P = 2.6 × 10-4). A multiple model containing the variables smoking, concurrent calcium channel blocker treatment, male sex, and time to onset accounted for 26% of the variance between the groups. Smoking, comedication with selective calcium channel blockers, male sex, and longer treatment time were associated with ACE inhibitor-induced angioedema rather than cough.

A Novel Design of Combining the Angiotensin Converting Enzyme (ACE) Inhibitor Captopril with the Angiotensin Receptor Blocker (ARB) Losartan Using Homo Coupling via PEG Diacid Linker

Cardiovascular disease is the leading cause of death in American adults. Furthermore, the incidence of congestive heart failure is on the rise as a major cause of hospitalization and mortality in this population. Angiotensin Converting Enzyme (ACE) inhibitors prevent the production of angiotensin II, which has been shown to reduce mortality in patients with congestive heart failure. Angiotensin II receptor blockers (ARB) were developed as a direct inhibitor of angiotensin II. ARBs have been shown to be effective in the treatment of patients with systolic heart failure but do not cause chronic coughing which is a common side effect of ACE inhibitors. In theory, a compound that has the combined effect of an ACE inhibitor and an ARB should be more effective in treating heart failure patients than either agents alone. Therefore, the purpose of this manuscript is to design and discuss the benefits of a new molecule, which combines captopril, an ACE inhibitor, with losartan, an ARB. In this experiment Captopril and Losartan were modified and synthesized separately and combined by homo or mono coupling. This was achieved by taking advantage of PEG (Polyethylene glycol) as a linker. It is expected that this molecule will have the combined modes of action of both ACEs and ARBs. Benefits from combination therapy include; increased efficacy, reduced adverse effects, convenience, compliance, and prolonged duration. Consequently, this combined molecule is expected to block the production of angiotensin II more efficiently and effectively. Although captopril and losartan work in the same system by blocking the effect of angiotensin II they have different action sites and mechanisms some patents are also discussed. Losartan blocks the AT1 receptor which is expressed on the cell surface, while captopril inhibits ACE, preventing production of angiotensin II, which is present in both the plasma and on the cell surface, especially on endothelial and smooth muscle cells.

Ramipril

Ramipril

Misdiagnosis and mistreatment of a common side‐effect – angiotensin‐converting enzyme inhibitor‐induced cough

Angiotensin-converting enzyme inhibitors (ACEi) are frequently prescribed for various cardiovascular and renal diseases. A common side-effect of these drugs is a persistent dry cough. Physicians who fail to recognize a dry cough to be ACEi-related may attempt to treat it with antitussive agents instead of recommended ACEi substitution. Prescription behaviour in the general population considering treatment of the side-effect with antitussive agents has not been studied before. Drug dispensing data between 2000 and 2007 were retrieved from the IADB.nl database. A prescription sequence symmetry analysis was used to determine whether antitussive agents were prescribed more often following ACEi initiation than the other way around. A logistic regression model was fitted to determine predictors. We identified 27 446 incident users of ACEi therapy. One thousand and fifty-four patients were incident users of both ACEi and antitussives within a half-year time span. There was an excess of patients being prescribed antitussive agents after ACEi initiation (703 vs. 351), adjusted sequence ratio 2.2 [confidence interval (CI) 1.9, 2.4]. Female patients were more likely to be prescribed antitussive agents following ACEi therapy initiation, odds ratio 1.4 (CI 1.1, 1.9), age and co-medications were not significant predictors. There was a significant and clinically relevant excess of patients receiving antitussives after ACEi initiation. The results suggest that cough as a side-effect of ACEi is not recognized as being ACEi-related or is symptomatically treated with antitussive agents instead of ACEi substitution. The estimated frequency of antitussive treatment of ACEi-induced dry cough is 15%.

Angioedema may not be a class side-effect of the angiotensin-converting-enzyme inhibitors

Sir, Angioedema is a well-documented and potentially life-threatening side-effect of treatment with angiotensin-converting-enzyme (ACE) inhibitors, occurring in 0.1–0.2% of patients treated with these drugs.1 Given the growing number of patients with hypertension or heart failure treated with these drugs, and the long duration of treatment, the frequency of this complication is probably set to rise. Although most cases of angioedema occur within the first week of treatment, recent reports indicate that late-onset angioedema may be more prevalent than initially thought. This side-effect of ACE inhibitors is not an allergic reaction and can occur after many years …

Section 7: Heart Failure in Patients With Left Ventricular Systolic Dysfunction

Section 7: Heart Failure in Patients With Left Ventricular Systolic Dysfunction

Bradykinin B(2) receptor gene polymorphism is associated with angiotensin-converting enzyme inhibitor-related cough.

The appearance of cough in association with angiotensin-converting enzyme (ACE) inhibitors is thought to be related to bradykinin, and it has been speculated that the elicitation of adverse effects is genetically predetermined. Several polymorphisms of the human bradykinin B(2) receptor gene may be involved in ACE inhibitor-related cough. To investigate this possibility, we identified the -58 thymine (T)/cytosine (C) polymorphism in subjects with ACE inhibitor-related cough. We classified the study population into 4 groups: subjects with and without cough that were treated with ACE inhibitors (n=30/30), nontreated essential hypertensive subjects (n=100), and normotensive subjects (n=100). The -58T/C was genotyped by the polymerase chain reaction single-strand conformation polymorphism method. The frequencies of the CC genotype and C allele of -58T/C were significantly higher in the nontreated hypertensive subjects than in the normotensive subjects. Conversely, the frequencies of the TT genotype and T allele were significantly higher in the subjects with cough than in the subjects without cough. These tendencies were more pronounced in females. Among the promoter assays of the human bradykinin B(2) receptor, -58T was found to have a higher transcription rate than that of -58C. This finding seems to suggest that the transcriptional activity of promoter might be involved in the appearance of ACE inhibitor-related cough. A genetic variant of the bradykinin receptor is involved in the elicitation of ACE inhibitor-related cough. It may be possible to predict the side effects of ACE inhibitors in advance.

Proceedings of the Symposium ‘Angiotensin AT1 Receptors: From Molecular Physiology to Therapeutics’: EXPERIENCE WITH ANGIOTENSIN II ANTAGONISTS IN HYPERTENSIVE PATIENTS

1. The availability of orally active specific angiotensin receptor antagonists (AT(1) antagonists) has opened new therapeutic choices and provided probes to test the specific role of the renin-angiotensin system in the pathogenesis of cardiovascular disease. 2. The data available so far suggest that the antihypertensive efficacy of angiotensin receptor antagonists is comparable to that of angiotensin-converting enzyme (ACE) inhibitors. This provides further evidence that this latter class of drugs exerts its effect mainly through blockade of the renin-angiotensin enzymatic cascade. As expected, the association of a diuretic exerts an equally strong additive effect to the antihypertensive efficacy of both classes of drugs. 3. The most common side effect of ACE inhibitors, dry cough, does not occur with AT(1) antagonists, which confirms the long-held view that this untoward effect of the ACE inhibitors is due to renin-angiotensin-independent mechanisms. 4. Long-term studies with morbidity/mortality outcome results are needed, before a definite position can be assigned to this newcomer in the orchestra of modern antihypertensive drugs. Notwithstanding, this new class of agents already represents an exciting new addition to our therapeutic armamentarium.

Clinical Evaluation of Delapril in Japan

Delapril, a new angiotensin converting enzyme (ACE) inhibitor discovered in the laboratory of Takeda Chemical Industries, Ltd., is the result of drug design based on the structure-activity relationships of ACE inhibitors. Delapril is an antihypertensive agent with a relatively long duration of action and no SH moiety in its structure. Following administration, it is converted into two active metabolites. Delapril effectively lowered blood pressure in 73% of 1,008 patients with hypertension during clinical trials in Japan. Efficacy rates were 73% for essential hypertension, 85% for renal hypertension, and 80% for renovascular hypertension. Excellent hypotensive response was observed in all age groups, from young to elderly patients. Side effects during administration of delapril, based on subjective evidence, were reported in 80 out of the 1,008 cases (7.9%). The main symptoms included orthostatic dizziness (1.7%), dizziness (1.3%), and nausea (1.1%). Dry cough, which has attracted attention in recent years as a side effect of ACE inhibitors, was reported at a low incidence of 1.1%. In a double-blind, controlled study in patients with mild to moderate essential hypertension in which captopril served as a positive control, delapril showed superior hypotensive effect and greater safety. Data derived from the Japan Study Group on Delapril indicate that this ACE inhibitor has excellent hypotensive effects and a high level of safety. It is suitable as a first-line drug in both monotherapy and combined therapy.

Clinical pharmacology of the ACE inhibitors.

The central role of the renin-angiotensin-aldosterone system in the regulation of fluid balance and haemodynamics was not fully appreciated until the discovery and clinical application of inhibitors of the angiotensin-converting enzyme (ACE). Captopril, the first orally active compound has proved to be highly effective in mild, intermediate and severe hypertension and in congestive heart failure. This is also true for enalapril, the first of the second generation (non-sulfhydryl) of ACE inhibitors. Both compounds combine a high degree of clinical efficacy with a low rate of side effects, and both are eliminated via renal excretion. Thus, reduced doses are required in renal failure. Captopril has a shorter half-life and requires more frequent dosing than enalapril. Whether long-acting ACE inhibitors carry distinct advantages or disadvantages compared with short-acting ones is not clear, but both possibilities must be considered. Among many new ACE inhibitors being developed, compounds eliminated via hepatic routes, such as fosfenopril and zofenopril, may prove advantageous in renal failure. Very long-acting ones, such as lisinopril, a potent ACE inhibitor already shown to be clinically effective, may add value to this group of therapeutic agents. Drug compliance may be easily tested by measuring ACE activity in serum from patients treated with stable ACE inhibitors, such as enalapril and lisinopril, which is an obvious advantage compared with other antihypertensive compounds. The presence of ACE in sites not associated with regulation of fluid balance or blood pressure, such as macrophages and reproductive organs, and the possibility that new functions of ACE may be discovered, call for vigilance regarding possible long term side effects of ACE inhibitors.