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A Review on Pharmacokinetic and Pharmacodynamic Drug Interactions of Adrenergic β-blockers with Clinically Relevant Drugs-An Overview.
Maideen, NMP, Rajkapoor, B, Muthusamy, S, Ramanathan, S, Thangadurai, SA, Sughir, AA
Current drug metabolism. 2021;(9):672-682
Abstract
Adrenergic β-blockers are used to treat many conditions, including hypertension, cardiac arrhythmias, heart failure, angina pectoris, migraine, and tremors. The majority of the β-blockers including Propranolol, Metoprolol, Acebutolol, Alprenolol, Betaxolol, Carvedilol, Nebivolol and Oxprenolol are metabolised majorly by CYP2D6, and Bisoprolol is primarily metabolised by CYP3A4 enzymes. The drugs inhibiting or inducing them may alter the pharmacokinetics of those β-blockers. The plasma concentrations of Propranolol might be elevated by the concomitant use of drugs, such as SSRIs (Fluoxetine, Paroxetine), SNRIs (Duloxetine) and Cimetidine, while the plasma concentrations of Metoprolol increased by the concurrent use of SSRIs (Fluoxetine, Paroxetine), Amiodarone, Celecoxib, Cimetidine, Terbinafine, and Diphenhydramine. β-blockers can also interact pharmacodynamically with drugs, including fluoroquinolones, antidiabetic agents and NSAIDs. In addition, β-blockers may interact with herbs, such as curcumin, Ginkgo biloba, Schisandra chinensis, green tea, guggul, hawthorn, St. John's wort and Yohimbine. This article focuses on clinically relevant drug interactions of β-blockers with commonly prescribed medications. In addition to Pharmacokinetics and Pharmacodynamics of the drug interactions, recommendations for clinical practice are highlighted. The prescribers and the pharmacists are needed to be aware of the drugs interacting with β-blockers to prevent possible adverse drug interactions.
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Hyperkalemia with RAAS inhibition: Mechanism, clinical significance, and management.
Hundemer, GL, Sood, MM
Pharmacological research. 2021;:105835
Abstract
Renin-angiotensin-aldosterone system (RAAS) inhibitors are evidence-based treatments for a number of conditions including hypertension, diabetes mellitus, chronic kidney disease, and congestive heart failure. Among the most common adverse effects of RAAS inhibitors is hyperkalemia which results from either reduced secretion of aldosterone or increased resistance to aldosterone. Many of the conditions for which RAAS inhibitors are recommended further amplify the risk for hyperkalemia in and of themselves. RAAS inhibitor-related hyperkalemia is associated with an increased risk for cardiovascular events, hospitalizations, and death. Yet discontinuation of RAAS inhibitors for patients with chronic kidney disease and congestive heart failure is also associated with an increased risk for cardiovascular events, hospitalizations, and death. Therefore, clinicians are often left to struggle with the dilemma of the best management approach to RAAS inhibitor-related hyperkalemia. The ideal solution involves pharmacotherapies that are safe and effective in mitigating hyperkalemia and allow patients to continue to receive the beneficial effects from RAAS inhibitors. In this regard, modern pharmacologic agents such as patiromer and zirconium cyclosilicate are providing a mechanism whereby physicians are better equipped to maintain their patients on RAAS inhibitors.
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Adjunctive treatments for the management of septic shock - a narrative review of the current evidence.
Donovan, K, Shah, A, Day, J, McKechnie, SR
Anaesthesia. 2021;(9):1245-1258
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Abstract
Septic shock is a leading cause of death and morbidity worldwide. The cornerstones of management include prompt identification of sepsis, early initiation of antibiotic therapy, adequate fluid resuscitation and organ support. Over the past two decades, there have been considerable improvements in our understanding of the pathophysiology of sepsis and the host response, including regulation of inflammation, endothelial disruption and impaired immunity. This has offered opportunities for innovative adjunctive treatments such as vitamin C, corticosteroids and beta-blockers. Some of these approaches have shown promising results in early phase trials in humans, while others, such as corticosteroids, have been tested in large, international, multicentre randomised controlled trials. Contemporary guidelines make a weak recommendation for the use of corticosteroids to reduce mortality in sepsis and septic shock. Vitamin C, despite showing initial promise in observational studies, has so far not been shown to be clinically effective in randomised trials. Beta-blocker therapy may have beneficial cardiac and non-cardiac effects in septic shock, but there is currently insufficient evidence to recommend their use for this condition. The results of ongoing randomised trials are awaited. Crucial to reducing heterogeneity in the trials of new sepsis treatments will be the concept of enrichment, which refers to the purposive selection of patients with clinical and biological characteristics that are likely to be responsive to the intervention being tested.
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Redefining β-blocker response in heart failure patients with sinus rhythm and atrial fibrillation: a machine learning cluster analysis.
Karwath, A, Bunting, KV, Gill, SK, Tica, O, Pendleton, S, Aziz, F, Barsky, AD, Chernbumroong, S, Duan, J, Mobley, AR, et al
Lancet (London, England). 2021;(10309):1427-1435
Abstract
BACKGROUND Mortality remains unacceptably high in patients with heart failure and reduced left ventricular ejection fraction (LVEF) despite advances in therapeutics. We hypothesised that a novel artificial intelligence approach could better assess multiple and higher-dimension interactions of comorbidities, and define clusters of β-blocker efficacy in patients with sinus rhythm and atrial fibrillation. METHODS Neural network-based variational autoencoders and hierarchical clustering were applied to pooled individual patient data from nine double-blind, randomised, placebo-controlled trials of β blockers. All-cause mortality during median 1·3 years of follow-up was assessed by intention to treat, stratified by electrocardiographic heart rhythm. The number of clusters and dimensions was determined objectively, with results validated using a leave-one-trial-out approach. This study was prospectively registered with ClinicalTrials.gov (NCT00832442) and the PROSPERO database of systematic reviews (CRD42014010012). FINDINGS 15 659 patients with heart failure and LVEF of less than 50% were included, with median age 65 years (IQR 56-72) and LVEF 27% (IQR 21-33). 3708 (24%) patients were women. In sinus rhythm (n=12 822), most clusters demonstrated a consistent overall mortality benefit from β blockers, with odds ratios (ORs) ranging from 0·54 to 0·74. One cluster in sinus rhythm of older patients with less severe symptoms showed no significant efficacy (OR 0·86, 95% CI 0·67-1·10; p=0·22). In atrial fibrillation (n=2837), four of five clusters were consistent with the overall neutral effect of β blockers versus placebo (OR 0·92, 0·77-1·10; p=0·37). One cluster of younger atrial fibrillation patients at lower mortality risk but similar LVEF to average had a statistically significant reduction in mortality with β blockers (OR 0·57, 0·35-0·93; p=0·023). The robustness and consistency of clustering was confirmed for all models (p<0·0001 vs random), and cluster membership was externally validated across the nine independent trials. INTERPRETATION An artificial intelligence-based clustering approach was able to distinguish prognostic response from β blockers in patients with heart failure and reduced LVEF. This included patients in sinus rhythm with suboptimal efficacy, as well as a cluster of patients with atrial fibrillation where β blockers did reduce mortality. FUNDING Medical Research Council, UK, and EU/EFPIA Innovative Medicines Initiative BigData@Heart.
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Managing Hypertension Using Combination Therapy.
Smith, DK, Lennon, RP, Carlsgaard, PB
American family physician. 2020;(6):341-349
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Abstract
More than 70% of adults treated for primary hypertension will eventually require at least two antihypertensive agents, either initially as combination therapy or as add-on therapy if monotherapy and lifestyle modifications do not achieve adequate blood pressure control. Four main classes of medications are used in combination therapy for the treatment of hypertension: thiazide diuretics, calcium channel blockers, angiotensin-converting enzyme inhibitors (ACEIs), and angiotensin receptor blockers (ARBs). ACEIs and ARBs should not be used simultaneously. In black patients, at least one agent should be a thiazide diuretic or a calcium channel blocker. Patients with heart failure with reduced ejection fraction should be treated initially with a beta blocker and an ACEI or ARB (or an angiotensin receptor-neprilysin inhibitor), followed by add-on therapy with a mineralocorticoid receptor antagonist and a diuretic based on volume status. Treatment for patients with chronic kidney disease and proteinuria should include an ACEI or ARB plus a thiazide diuretic or a calcium channel blocker. Patients with diabetes mellitus should be treated similarly to those without diabetes unless proteinuria is present, in which case combination therapy should include an ACEI or ARB.
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Association of Weight-Adjusted Caffeine and β-Blocker Use With Ophthalmology Fellow Performance During Simulated Vitreoretinal Microsurgery.
Roizenblatt, M, Dias Gomes Barrios Marin, V, Grupenmacher, AT, Muralha, F, Faber, J, Jiramongkolchai, K, Gehlbach, PL, Farah, ME, Belfort, R, Maia, M
JAMA ophthalmology. 2020;(8):819-825
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IMPORTANCE Vitreoretinal surgery can be technically challenging and is limited by physiologic characteristics of the surgeon. Factors that improve accuracy and precision of the vitreoretinal surgeon are invaluable to surgical performance. OBJECTIVES To establish weight-adjusted cutoffs for caffeine and β-blocker (propranolol) intake and to determine their interactions in association with the performance of novice vitreoretinal microsurgeons. DESIGN, SETTINGS, AND PARTICIPANTS This single-blind cross-sectional study of 15 vitreoretinal surgeons who had less than 2 years of surgical experience was conducted from September 19, 2018, to September 25, 2019, at a dry-laboratory setting. Five simulations were performed daily for 2 days. On day 1, performance was assessed after sequential exposure to placebo, low-dose caffeine (2.5 mg/kg), high-dose caffeine (5.0 mg/kg), and high-dose propranolol (0.6 mg/kg). On day 2, performance was assessed after sequential exposure to placebo, low-dose propranolol (0.2 mg/kg), high-dose propranolol (0.6 mg/kg), and high-dose caffeine (5.0 mg/kg). INTERVENTIONS Surgical simulation tasks were repeated 30 minutes after masked ingestion of placebo, caffeine, or propranolol pills during the 2 days. MAIN OUTCOMES AND MEASURES An Eyesi surgical simulator was used to assess surgical performance, which included surgical score (range, 0 [worst] to 700 [best]), task completion time, intraocular trajectory, and tremor rate (range, 0 [worst] to 100 [best]). The nonparametric Friedman test followed by Dunn-Bonferroni post hoc test was applied for multiple comparisons. RESULTS Of 15 vitreoretinal surgeons, 9 (60%) were male, with a mean (SD) age of 29.6 (1.4) years and mean (SD) body mass index (calculated as weight in kilograms divided by height in meters squared) of 23.15 (2.9). Compared with low-dose propranolol, low-dose caffeine was associated with a worse total surgical score (557.0 vs 617.0; difference, -53.0; 95% CI, -99.3 to -6.7; P = .009), a lower antitremor maneuver score (55.0 vs 75.0; difference, -12.0; 95% CI, -21.2 to -2.8; P = .009), longer intraocular trajectory (2298.6 vs 2080.7 mm; difference, 179.3 mm; 95% CI, 1.2-357.3 mm; P = .048), and increased task completion time (14.9 minutes vs 12.7 minutes; difference, 2.3 minutes; 95% CI, 0.8-3.8 minutes; P = .048). Postcaffeine treatment with propranolol was associated with performance improvement; however, surgical performance remained inferior compared with low-dose propranolol alone for total surgical score (570.0 vs 617.0; difference, -51.0; 95% CI, -77.6 to -24.4; P = .01), tremor-specific score (50.0 vs 75.0; difference, -16.0; 95% CI, -31.8 to -0.2; P = .03), and intraocular trajectory (2265.9 mm vs 2080.7 mm; difference, 166.8 mm; 95% CI, 64.1-269.6 mm; P = .03). CONCLUSIONS AND RELEVANCE The findings suggest that performance of novice vitreoretinal surgeons was worse after receiving low-dose caffeine alone but improved after receiving low-dose propranolol alone. Their performance after receiving propranolol alone was better than after the combination of propranolol and caffeine. These results may be helpful for novice vitreoretinal surgeons to improve microsurgical performance.
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Hemodynamic Effects of Adding Simvastatin to Carvedilol for Primary Prophylaxis of Variceal Bleeding: A Randomized Controlled Trial.
Vijayaraghavan, R, Jindal, A, Arora, V, Choudhary, A, Kumar, G, Sarin, SK
The American journal of gastroenterology. 2020;(5):729-737
Abstract
INTRODUCTION Beta-blockers are the mainstay agents for portal pressure reduction and to modestly reduce hepatic venous pressure gradient (HVPG). We studied whether addition of simvastatin to carvedilol in cirrhotic patients for primary prophylaxis improves the hemodynamic response. METHODS Cirrhotic patients with esophageal varices and with baseline HVPG > 12 mm Hg were prospectively randomized for primary prophylaxis to receive either carvedilol (group A, n = 110) or carvedilol plus simvastatin (group B, n = 110). Primary objective was to compare hemodynamic response (HVPG reduction of ≥20% or <12 mm Hg) at 3 months, and secondary objectives were to compare first bleed episodes, death, and adverse events. RESULTS The groups were comparable at baseline. The proportion of patients achieving HVPG response at 3 months was comparable between groups (group A-36/62 [58.1%], group B-36/59 [61%], P = 0.85). The degree of mean HVPG reduction (17.3% and 17.8%, respectively, P = 0.98) and hemodynamic response (odds ratio [OR]: 0.88; 95% confidence interval [CI]: 0.43-1.83, P = 0.74) was also not different between the groups. Patients who achieved target heart rate with no hypotensive episodes in either group showed better hemodynamic response (77.8% vs 59.2%, P = 0.04). Failure to achieve target heart rate (OR: 0.48; 95% CI: 0.22-1.06) and Child C cirrhosis (OR: 4.49; 95% CI: 1.20-16.8) predicted nonresponse. Three (3.7%) patients on simvastatin developed transient transaminitis and elevated creatine phosphokinase and improved with drug withdrawal. Two patients in each group bled (P = 0.99). Three patients and 1 patient, respectively, in group A and B died (P = 0.32), with sepsis being the cause of death. DISCUSSION Addition of simvastatin to carvedilol for 3 months for primary prophylaxis of variceal bleeding does not improve hemodynamic response over carvedilol monotherapy. Simvastatin usage should be closely monitored for adverse effects in Child C cirrhotic patients.
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[Treatment of coronary artery disease in renal insufficiency].
Lopau, K, Wanner, C
Der Internist. 2020;(4):362-367
Abstract
The treatment of chronic but stable coronary artery disease is based on the stages of chronic kidney disease (CKD) stages G1-2 and stages G3-G5, distinguishing between advanced kidney disease (stages G3-G5) and end-stage kidney disease (G5D) treated by dialysis. In Germany, national guidelines are followed for patients with normal kidney function in addition to the recommendations of Kidney Disease - Improving Global Outcomes (KDIGO) for CKD patients. These guidelines focus on standard of care and include treatment with aspirin, statins, beta-blockers, inhibitors of the renin-angiotensin system, and sodium glucose cotransporters for patients with cardiovascular disease. Revascularization strategies follow a more pragmatic approach for the fragile, comorbid, and aging patient population. Younger patients appear to benefit from surgical interventions. Treatment of acute events is currently administered independent of the patient's kidney function, but there is no consensus yet on the best strategy. The focus of our efforts should be, via more controlled studies, to avoid "navigating through the darkness" to reach the end of the tunnel.
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Influence of timolol, benzalkonium-preserved timolol, and benzalkonium-preserved brimonidine on oxidative stress biomarkers in the tear film.
Sedlak, L, Wojnar, W, Zych, M, Wyględowska-Promieńska, D
Cutaneous and ocular toxicology. 2020;(3):260-268
Abstract
PURPOSE The objective of this study was to investigate the influence of topical preservative-free timolol, benzalkonium chloride(BAC)-preserved timolol, BAC-preserved timolol, and BAC-preserved brimonidine on total protein concentration, advanced oxidation protein products (AOPP) content, total sulfhydryl groups content, the activity of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx), as well as Total Oxidant Status (TOS), Total Antioxidant Response, and Oxidative Stress Index (OSI) in the tear film. METHODS The patients were divided into four groups: group C (n = 25)-control group-subjects who did not use topical antiglaucoma medications, group T (n = 17)-patients using topical preservative-free timolol, group T + BAC (n = 24)-patients using topical BAC-preserved timolol, and group BR + BAC (n = 19)-patients using topical BAC-preserved brimonidine. RESULTS The SOD, CAT, and GPx activities as well as AOPP, TOS, and OSI were found to be higher in the tear film of patients treated with BAC-preserved topical timolol or brimonidine in comparison with patients treated with preservative-free timolol or patients who did not use antiglaucoma topical medications. CONCLUSIONS This indicates that using BAC-preserved topical medications increases oxidative stress in the tear film and may, in the long-term, contribute to the clinical presentation of dry eye disease.
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Beta-Blockers, Calcium Channel Blockers, and Mortality in Stable Coronary Artery Disease.
Cruz Rodriguez, JB, Alkhateeb, H
Current cardiology reports. 2020;(3):12
Abstract
PURPOSE OF REVIEW To examine the current clinical evidence behind the use of calcium channel blockers (CCB) and beta-blockers (BB) for the treatment of patients with stable coronary artery disease (SCAD) and their effect on mortality. RECENT FINDINGS Current evidence suggests that BB use as a first line antianginal medication is associated with lower 5-year all-cause mortality only in patients who had MI within a year. This could be driven due to their effects reducing the sympathetic neuro-hormonal activation of more acutely ill patients. The use of CCB as an antianginal therapy, although proven effective in multiple trials both as monotherapy and combined with other agents, has not shown mortality benefit. Both BB and CCB are effective antianginals, and the selection among them depends on the patient clinical presentation and comorbidities. BB are the only ones that have shown survival benefit in SCAD, particularly the first year post-MI.