Bisoprolol

Selective Beta-1 Adrenergic Receptor Antagonism

This compound is characterized as a cardioselective beta-1 adrenergic receptor antagonist. drugbank.compatsnap.comnih.gov This selectivity means it preferentially binds to and blocks beta-1 receptors, which are predominantly located in the heart, compared to beta-2 receptors, which are found in various tissues including the lungs and peripheral blood vessels. patsnap.comnih.govwikipedia.orgbihsoc.org By selectively blocking beta-1 receptors, this compound reduces the influence of the sympathetic nervous system on the heart. qingmupharm.com This cardioselectivity is considered significant as it may minimize effects on beta-2 receptors, potentially reducing side effects such as bronchoconstriction. patsnap.com Research indicates that this compound possesses a higher degree of beta-1 selectivity compared to other beta-blockers like atenolol and metoprolol. wikipedia.orgtandfonline.com

Competitive Inhibition of Catecholamine Binding (e.g., Epinephrine, Norepinephrine)

This compound acts as a competitive antagonist at beta-1 receptors. drugbank.comqingmupharm.com This means it competes with endogenous catecholamines, such as epinephrine (adrenaline) and norepinephrine (noradrenaline), for binding sites on the beta-1 receptor. qingmupharm.comnih.govwikipedia.org By binding to the receptor, this compound prevents these potent agonists from activating it. qingmupharm.comwikipedia.org Normally, the binding of epinephrine and norepinephrine to beta-1 receptors stimulates a cascade that increases heart rate and contractility. patsnap.comwikipedia.orgwikipedia.org this compound's competitive inhibition effectively reduces this adrenergic stimulation of the heart. wikipedia.orgqingmupharm.com

Modulation of G Protein-Coupled Receptor Signaling Cascades

Beta-1 adrenergic receptors are coupled to G proteins, specifically Gs proteins. wikipedia.orgqingmupharm.comcvphysiology.comcvpharmacology.com The binding of an agonist typically activates these G proteins, initiating intracellular signaling cascades. wikipedia.orgqingmupharm.comcvphysiology.com As an antagonist, this compound prevents the activation of these G proteins by catecholamines. qingmupharm.com

Impact on Adenylate Cyclase Activity

Activation of the Gs protein, downstream of beta-1 receptor activation by agonists, leads to the stimulation of the enzyme adenylyl cyclase (also known as adenylate cyclase). wikipedia.orgqingmupharm.comcvphysiology.comcvpharmacology.com Adenylyl cyclase is responsible for catalyzing the conversion of adenosine triphosphate (ATP) into cyclic adenosine monophosphate (cAMP). wikipedia.orgcvphysiology.comcvpharmacology.comgenome.jp this compound, by blocking the beta-1 receptor and preventing Gs protein activation, inhibits the stimulation of adenylyl cyclase activity that would normally be induced by catecholamines. qingmupharm.comcvphysiology.comcvpharmacology.com

Consequences for Cyclic AMP (cAMP) Production

The inhibition of adenylyl cyclase activity by this compound results in a reduction in the production of cyclic AMP (cAMP). patsnap.comqingmupharm.comcvphysiology.comcvpharmacology.com cAMP serves as a crucial second messenger in this signaling pathway. wikipedia.orgcvphysiology.comgenome.jp By lowering intracellular cAMP levels, this compound attenuates the downstream effects that would typically be triggered by elevated cAMP. wikipedia.orgcvphysiology.comcvpharmacology.com

Downstream Effects on Protein Kinase A (PKA) and Intracellular Calcium Dynamics

Reduced levels of cAMP have direct consequences for the activity of Protein Kinase A (PKA). wikipedia.orgqingmupharm.comcvphysiology.comgenome.jp cAMP is a key activator of PKA. wikipedia.orgcvphysiology.comgenome.jp Therefore, the decrease in cAMP production due to this compound leads to decreased activation of PKA. qingmupharm.comcvphysiology.com PKA is a crucial enzyme that phosphorylates various intracellular targets, including ion channels and calcium-handling proteins. wikipedia.orgcvphysiology.comgenome.jp

One significant target of PKA phosphorylation in cardiac myocytes is the L-type calcium channel in the cell membrane. wikipedia.orgcvphysiology.comcvpharmacology.com PKA-mediated phosphorylation increases the open probability of these channels, leading to increased influx of extracellular calcium into the cell. wikipedia.orgcvphysiology.comcvpharmacology.com PKA also phosphorylates proteins involved in calcium release from the sarcoplasmic reticulum, such as phospholamban, which enhances calcium availability for contraction. wikipedia.orgcvphysiology.com

Cardiac System Regulation

This compound's impact on the heart is characterized by a reduction in sympathetic drive, leading to decreased cardiac activity. This is achieved through its selective antagonism of beta-1 receptors located in myocardial tissue and the heart's conduction system. patsnap.comnih.govwikipedia.orgqingmupharm.com

This compound significantly reduces heart rate, a phenomenon known as a negative chronotropic effect. patsnap.comdrugbank.comnih.govwikipedia.orgqingmupharm.comroyalsocietypublishing.orghres.cadrugs.com This occurs because beta-1 receptors in the sinoatrial (SA) node, the heart's natural pacemaker, are blocked. wikipedia.orgqingmupharm.com The binding of catecholamines to these receptors normally increases the rate of electrical impulse generation, thereby increasing heart rate. By competitively blocking these receptors, this compound attenuates this sympathetic stimulation, leading to a slower heart rate at rest and during exercise. patsnap.comwikipedia.orgpatsnap.comqingmupharm.comhres.ca Electrophysiology studies have demonstrated that this compound decreases heart rate and increases sinus node recovery time. drugs.com

This compound also exerts a negative inotropic effect, decreasing the force of myocardial contraction. patsnap.comdrugbank.comnih.govwikipedia.orgqingmupharm.comroyalsocietypublishing.orgdroracle.aiwikipedia.org Beta-1 receptors are abundant in cardiac muscle cells (myocytes). nih.govwikipedia.org Activation of these receptors by catecholamines triggers a signaling cascade involving Gs protein and cyclic adenosine monophosphate (cAMP), which ultimately increases intracellular calcium levels and enhances contractility. wikipedia.orgqingmupharm.com this compound's blockade of beta-1 receptors inhibits this cascade, resulting in reduced calcium influx and consequently diminished contractility. wikipedia.orgqingmupharm.com

Negative Inotropic Effects: Decreased Myocardial Contractility

Renal System Interactions

Beyond its primary cardiac effects, this compound also influences the renal system, specifically impacting the renin-angiotensin-aldosterone system (RAAS). patsnap.comnih.govpatsnap.com

Inhibition of Renin Release from Juxtaglomerular Cells

Central Nervous System Contributions

While the precise mechanism of this compound's antihypertensive effects is not fully established, contributions from the central nervous system (CNS) are considered to play a role. droracle.aihres.cahres.cadrugbank.com

Diminution of Tonic Sympathetic Outflow from Vasomotor Centers

One proposed mechanism contributing to the antihypertensive action of this compound is the diminution of tonic sympathetic outflow from the vasomotor centers in the brain. droracle.aihres.cadroracle.aihres.cadrugbank.comnih.gov this compound is classified as having moderate lipophilicity, suggesting an intermediate potential for crossing the blood-brain barrier. wikipedia.org This property may facilitate its influence on central sympathetic activity, leading to a decrease in blood pressure and heart rate. drugbank.com

High Selectivity for Beta-1 Adrenergic Receptors in Therapeutic Range

This compound is a highly selective beta-1 adrenoceptor blocking agent. medsafe.govt.nzsandoz.com In the therapeutic dose range, it selectively inhibits the response to adrenergic stimuli by competitively blocking cardiac beta-1 adrenergic receptors, while exhibiting little effect on the beta-2 adrenergic receptors found in bronchial and vascular smooth muscle. hres.cahres.camedcentral.comdrugs.com Studies comparing the selectivity of various beta-blockers have demonstrated that this compound possesses a high degree of beta-1 selectivity. wikipedia.orgbpac.org.nznih.gov For instance, research using cloned human beta-1 and beta-2 receptors indicated that this compound had a 19-fold higher affinity for the beta-1 receptor compared to the beta-2 receptor, displaying a beta2/beta1 ratio of 19. nih.gov Other reports suggest a selectivity ranging from 11 to 15 times more selective for beta-1 over beta-2. wikipedia.org This high selectivity is considered greater than that of some other cardioselective beta-blockers like atenolol and metoprolol. wikipedia.orgbpac.org.nznih.gov

Table 1: Beta-1 Selectivity Ratios of this compound

Potential for Beta-2 Adrenergic Receptor Antagonism at Elevated Doses

While this compound demonstrates high beta-1 selectivity within its therapeutic range, this selectivity is not absolute. hres.cahres.camedcentral.comdrugs.com At higher doses, the selectivity for beta-1 adrenergic receptors diminishes, and this compound can also competitively inhibit beta-2 adrenoceptors. hres.cahres.cawikipedia.orgmedcentral.comdrugs.com These beta-2 receptors are predominantly located in the bronchial and vascular musculature. hres.cahres.camedcentral.comdrugs.combpac.org.nz Studies have indicated that at doses exceeding the typical therapeutic range, such as above 20 mg or particularly above 30 mg, there can be incipient impairment of bronchomotor function, indicative of beta-2 blockade. nih.gov Therefore, while highly selective at lower doses, the potential for beta-2 receptor antagonism increases with elevated this compound concentrations. medsafe.govt.nzsandoz.commedcentral.comdrugs.com

Table 2: Dose-Dependent Beta-2 Adrenergic Receptor Antagonism

Gastrointestinal Absorption Characteristics

This compound is absorbed almost completely from the gastrointestinal tract following oral administration. tevauk.commedicines.org.ukhpra.ie Studies using human intestinal epithelial cells suggest that the uptake of this compound can be pH-dependent and variable, potentially contributing to interindividual differences in pharmacokinetics. nih.govnih.gov

Extent of Systemic Bioavailability and First-Pass Metabolism

This compound exhibits high absolute bioavailability, reported to be approximately 80% to 90% after oral administration. tevauk.commedicines.org.ukhpra.iedrugs.comfda.govhres.cahres.cadrugs.comtg.org.aunih.gov This high bioavailability is attributed to minimal first-pass metabolism in the liver, which is reported to be about 10% to 20%. hpra.iedrugs.comfda.govhres.cahres.cadrugs.comtg.org.aunih.govhres.ca

Data on Bioavailability and First-Pass Metabolism:

Influence of Food Intake on Absorption Kinetics

The absorption of this compound is not significantly affected by the presence of food. hpra.iedrugs.comfda.govhres.cahres.cadrugs.comdrugbank.combepharco.com This allows for flexibility in administration, as it can be taken with or without meals. drugs.combepharco.com

Time to Peak Plasma Concentration and Steady-State Achievement

Peak plasma concentrations of this compound are typically attained within 2 to 4 hours after oral dosing. drugs.comfda.govhres.cahres.cahres.cadrugbank.com Steady-state plasma concentrations are generally achieved within approximately 5 days of once-daily administration. drugs.comhres.cadrugbank.comgeneesmiddeleninformatiebank.nl

Data on Peak Concentration and Steady State:

Lipophilicity and Blood-Brain Barrier Permeability

This compound is classified as a beta-blocker with moderate lipophilicity. wikipedia.orgwikipedia.org It is soluble in both lipids and water, a property that contributes to its balanced elimination. wikipedia.org Due to its moderate lipophilicity, this compound has an intermediate potential for crossing the blood-brain barrier (BBB). wikipedia.orgwikipedia.org While it can penetrate the brain, its passage is considered minimal compared to highly lipophilic beta-blockers like propranolol. nih.govresearchgate.netwho.int Studies suggest that this compound concentrations in cerebrospinal fluid may be comparable to those in plasma. researchgate.net The plasma protein binding of this compound is approximately 30% to 35%. tevauk.commedicines.org.ukhpra.iedrugs.comfda.govhres.cahres.canih.govgeneesmiddeleninformatiebank.nlwikipedia.org The volume of distribution is reported to be around 3.5 L/kg. tevauk.commedicines.org.ukdrugbank.comgeneesmiddeleninformatiebank.nlwikipedia.org

Data on Distribution:

Plasma Protein Binding Characteristics

This compound exhibits relatively low plasma protein binding. Studies indicate that approximately 30% of this compound in the bloodstream is bound to serum proteins. drugbank.comnih.govmedicines.org.uknih.govmedicines.org.ukfda.gov One source suggests the binding is approximately 35%. wikipedia.org This low level of protein binding suggests that a significant fraction of the drug remains unbound and available to exert its pharmacological effects and undergo elimination. Low plasma protein binding can also influence the potential for drug interactions based on protein binding displacement, although the kinetics of this compound are considered insensitive to protein-binding interactions due to this low binding percentage. nih.gov

Volume of Distribution

The volume of distribution (Vd) provides insight into how a drug is distributed throughout the body's tissues compared to the plasma. For this compound, the reported volume of distribution is approximately 3.5 L/kg. drugbank.comnih.govmedicines.org.ukmedicines.org.ukwikipedia.orgnih.gov This value suggests that this compound is distributed beyond the plasma volume into the tissues. This compound is known to cross the placenta. drugbank.com

Role of Hepatic Metabolism via Oxidative Pathways

Approximately 50% of an administered dose of this compound is metabolized by the liver. nih.govmedicines.org.ukmedicines.org.ukwikipedia.orghres.ca The hepatic metabolism of this compound occurs through oxidative metabolic pathways. drugbank.comnih.govhres.canih.govsemanticscholar.org Unlike some other drugs, this compound's metabolism does not involve subsequent conjugation reactions. drugbank.comhres.canih.govsemanticscholar.org This oxidative biotransformation converts this compound into more polar compounds, which facilitates their excretion, predominantly via the kidneys. drugbank.comnih.govhres.ca

Contribution of Cytochrome P450 Isoenzymes (e.g., CYP3A4, CYP2D6)

The hepatic metabolism of this compound is primarily mediated by the cytochrome P450 (CYP) enzyme system. The major isoenzyme involved in the metabolism of this compound is CYP3A4, which is responsible for approximately 95% of its metabolism. drugbank.comnih.govhres.cafrontiersin.org Cytochrome P450 2D6 (CYP2D6) plays a minor role in this process, contributing to approximately 5% of the metabolism. frontiersin.org Some sources generally state that this compound is metabolized by both CYP3A4 and CYP2D6, with CYP2D6 having a minor or not clinically significant role. nih.govwikipedia.orgnih.govsemanticscholar.orgdovepress.commeded101.com In vitro studies using recombinant human CYP isoforms have shown that both CYP2D6 and CYP3A4 catalyze the oxidation of this compound enantiomers. drugbank.com While CYP3A4-mediated metabolism of this compound appears to be non-stereoselective, CYP2D6 exhibits some stereoselectivity, metabolizing the (R)-(+)-bisoprolol enantiomer more readily than the (S)-(-)-bisoprolol enantiomer. drugbank.comdrugbank.com

Bimodal Elimination: Renal Excretion and Hepatic Clearance

This compound is characterized by a balanced, bimodal elimination process involving both renal excretion of the unchanged drug and hepatic metabolism to inactive metabolites. Approximately 50% of an administered dose is excreted unchanged in the urine. drugbank.comnih.govfda.govwikipedia.orgmedsafe.govt.nz The remaining 50% undergoes hepatic metabolism. drugbank.comnih.govwikipedia.orgmedsafe.govt.nz

Hepatic metabolism of this compound occurs primarily through oxidative pathways, predominantly mediated by the cytochrome P450 (CYP) enzyme CYP3A4 (95%), with a minor contribution from CYP2D6. drugbank.comnih.gov These metabolic processes result in the formation of polar, pharmacologically inactive metabolites. drugbank.comwikipedia.orgnih.gov These inactive metabolites are subsequently excreted by the kidneys. nih.govmedsafe.govt.nzresearchgate.net Less than 2% of an ingested dose is found to be excreted in the feces. drugbank.comfda.govwikipedia.org

Elimination Half-Life in General and Specific Populations

The plasma elimination half-life of this compound in healthy individuals typically ranges from 9 to 12 hours. fda.govwikipedia.orgmedsafe.govt.nzhres.cadrugs.com Some studies in healthy volunteers have reported a mean plasma half-life of approximately 10-12 hours or around 10 hours. drugbank.comnih.gov This half-life supports once-daily dosing, providing a 24-hour effect. medsafe.govt.nz

However, the elimination half-life can be altered in specific patient populations with impaired organ function. In patients with renal impairment, the half-life is prolonged. For instance, in patients with a mean creatinine clearance of 28 mL/min, the half-life was prolonged to 18.5 hours. nih.gov In subjects with creatinine clearance less than 40 mL/min, the plasma half-life is increased approximately threefold compared to healthy subjects. fda.govnih.govdrugs.com In uremic patients with creatinine clearance less than 5 mL/min, the elimination half-life was reported as 24.2 hours. nih.gov

Similarly, hepatic dysfunction can affect this compound elimination. In patients with cirrhosis of the liver, the elimination rate is more variable and significantly slower than in healthy subjects, with plasma half-life values ranging from 8.3 to 21.7 hours. fda.govhres.cadrugs.com In patients with liver cirrhosis, the half-life increased to 13.5 hours in one study. nih.gov

The elimination half-life may also be slightly longer in elderly patients, partly due to decreased renal function commonly observed in this population. fda.govhres.cadrugs.com In patients with chronic heart failure, the plasma elimination half-life has been reported to be prolonged (17 hours) compared to healthy volunteers (11 hours). researchgate.net

Here is a summary of the elimination half-life in different populations:

Total Body Clearance and Factors Influencing It

The total body clearance of this compound in healthy individuals is approximately 14.2 L/h or around 15 L/h. drugbank.comwikipedia.orgmedsafe.govt.nznih.gov This clearance represents the volume of plasma from which the drug is completely removed per unit of time.

Several factors can influence the total body clearance of this compound. As indicated by its bimodal elimination, both renal and hepatic function play significant roles. In patients with renal impairment, total body clearance is reduced. For instance, in patients with a mean creatinine clearance of 28 mL/min, total body clearance decreased to 7.8 L/h. nih.gov In uremic patients (creatinine clearance less than 5 mL/min), the total clearance was 5.0 L/h. nih.gov Hepatic dysfunction also reduces the clearance of this compound. drugbank.com In patients with liver cirrhosis, total body clearance decreased to 10.8 L/h. nih.gov

Population pharmacokinetic analyses have identified demographic factors that can influence this compound clearance. Age and body weight have been shown to be associated with variability in clearance. nih.govtandfonline.com Older age and lower body weight were most strongly associated with reduced this compound clearance in one study. tandfonline.com Plasma clearance has been related to age in patients with essential hypertension, to serum creatinine in patients with renal impairment, and to aspartate transaminase activity in patients with hepatic impairment. nih.gov Progressive increases in serum creatinine or aspartate transaminase activity are predicted to result in a reduction of clearance. nih.gov

Smoking status has also been suggested to have a significant effect on this compound clearance, possibly due to the induction of CYP3A4. tandfonline.com While the influence of sex on this compound pharmacokinetics has not been extensively studied, women have been reported to have higher drug exposure and lower clearance of metoprolol, another beta-blocker. tandfonline.com

The total clearance of this compound is approximately 15 L/h. wikipedia.orgmedsafe.govt.nzresearchgate.net

Here is a summary of total body clearance in different populations:

Factors influencing this compound clearance include:

Efficacy in Mild to Moderate Essential Hypertension

This compound has demonstrated efficacy in reducing blood pressure in patients with mild to moderate essential hypertension. merckgroup.comoatext.comnih.gov Studies have shown dose-dependent reductions in heart rate and blood pressure with once-daily administration of this compound in this patient population. merckgroup.com For instance, in double-blind randomized studies, doses ranging from 5 to 20 mg once daily resulted in dose-dependent blood pressure reductions measured at 3 and 24 hours post-administration. merckgroup.com A study involving a fixed-dose combination of this compound and amlodipine in patients with mild to moderate essential hypertension showed significant reductions in both systolic and diastolic blood pressure after 8 weeks of treatment. oatext.com Another study using 24-hour ambulatory blood pressure monitoring in patients with mild to moderate essential hypertension treated with a low-dose combination of this compound/hydrochlorothiazide also revealed significant reductions in 24-hour, daytime, and nighttime systolic and diastolic blood pressure. nih.gov

Long-Term Efficacy in Blood Pressure Reduction

This compound provides effective long-term treatment for hypertension, maintaining systolic and diastolic blood pressure reduction over periods of 2 to 3 years without losing efficacy. merckgroup.com Long-term studies analyzing age-dependent changes in blood pressure have indicated that this compound is equally effective across all age groups. merckgroup.com

Impact on Cardiovascular Mortality and Morbidity in Hypertensive Patients

Beta-blockers, including this compound, have been shown to reduce left ventricular hypertrophy, which is a risk factor for cardiovascular disease and stroke, and thus the risk of coronary events in hypertensive patients to a similar extent as other antihypertensive agents. merckgroup.com Evidence from placebo-controlled blood pressure-lowering trials highlights significant cardiovascular benefits of beta-blockers, including a reduction in major cardiovascular events, mortality, and all-cause mortality. japi.org These outcomes, supported by meta-analyses of randomized trials, validate the substantial role of beta-blockers in reducing cardiovascular risks and mortality in hypertensive patients. japi.org this compound has also shown benefits in lowering morbidity and mortality post-myocardial infarction and reducing the risks of stroke and coronary artery disease in patients with heart disease. nih.govjapi.org

Effects on All-Cause and Cardiovascular Mortality

Data Table: Efficacy of this compound in CIBIS-II Trial

Further studies have supported the efficacy of this compound on secondary endpoints and in patient subgroups. researchgate.net this compound also had important effects on cardiovascular morbidity, with lower all-cause hospitalizations and reduced hospital admissions for worsening heart failure observed in patients treated with this compound compared to placebo. researchgate.net A meta-analysis comparing carvedilol and this compound in Asian patients with HFrEF found no significant difference in all-cause mortality or hospitalization between the two drugs. pensoft.net

Improvements in Left Ventricular Function (e.g., Ejection Fraction)

Studies have shown that this compound can lead to improvements in left ventricular function, including an increase in ejection fraction (LVEF), in patients with heart failure. In a meta-analysis of placebo-controlled studies, the average improvement in LVEF with beta-blockers was 0.07, resulting in a net improvement of 0.05 compared to placebo groups. revespcardiol.org The BISOCOR study, an observational study, reported that mean LVEF increased from 0.29 at the start of treatment to 0.35 after 9 months of this compound therapy (P<.0001). revespcardiol.orgrevespcardiol.org Real-world evidence also highlights that this compound, when used with guideline-directed medical therapy (GDMT), significantly improved LVEF in patients with heart failure with reduced ejection fraction (HFrEF) or heart failure with mildly reduced ejection fraction (HFmrEF) recovering in the acute post-acute coronary syndrome (ACS) phase. japi.org

Impact on Heart Failure Hospitalization Rates

This compound has been shown to reduce the rate of hospitalizations due to worsening heart failure. In the CIBIS trial, the heart failure hospitalization rate was lower in patients assigned to this compound compared with placebo (61 vs 90, p < 0.01). nih.gov The CIBIS-II study also demonstrated a reduction in hospital admission for worsening heart failure (HR: 0.64 [0.53–0.79]) compared with placebo. nih.gov A meta-analysis of the CIBIS and CIBIS-II studies confirmed a significant reduction in cardiovascular hospitalizations. japi.org

Enhancement of Functional Status and Quality of Life Measures

This compound can lead to an enhancement of functional status in patients with heart failure. In the CIBIS trial, more patients in the this compound group improved their functional status compared to the placebo group. nih.gov Specifically, in CIBIS, 21% of patients in the this compound group improved their NYHA functional class compared to 15% in the placebo group (p = 0.03). nih.govacpjournals.org The BISOCOR study also observed a significant improvement in NYHA functional class. revespcardiol.org While some studies on quality of life measurements with beta-blockers have shown effects similar to placebo, a substudy of CIBIS-II using the Functional Status Questionnaire (FSQ) indicated a difference between the placebo and this compound groups in the single item question about "days in bed" (p = 0.018 in favor of this compound). nih.govresearchgate.net

Integration with Guideline-Directed Medical Therapy

This compound is a cornerstone of Guideline-Directed Medical Therapy (GDMT) for heart failure with reduced ejection fraction (HFrEF). droracle.ai It is recommended for all stable patients with current or previous symptoms of HFrEF, unless contraindicated, to reduce morbidity and mortality. droracle.ai Indian and International guidelines recommend beta-1 blocking beta-blockers such as this compound as one of the evidence-based selective beta-blockers in the first-line management of HFrEF. japi.org The use of beta-blockers, including this compound, has been shown to reduce mortality and morbidity in patients with HFrEF when given with other standard therapies like ACE inhibitors and diuretics. japi.org GDMT for HFrEF typically includes beta-blockers (such as this compound), ACE inhibitors or ARBs or ARNIs, and mineralocorticoid receptor antagonists (MRAs), with the recent addition of SGLT2 inhibitors as a fourth pillar. viamedica.plnih.gov

Reduction of Cardiovascular Risk in Ischemic Heart Disease

This compound is a mainstay of therapy in patients with HFrEF and CAD due to its prognostic benefit. japi.org Major guidelines recommend beta-blockade as first-line therapy for stable CAD and for secondary prevention after MI. tandfonline.com The benefits of beta-blockade post-acute MI are well-established, particularly when patients are hemodynamically stable. tandfonline.com Early beta-blockade (within 24 hours of presentation) in MI has been shown to improve patient outcomes. gavinpublishers.com While many studies on this compound post-MI were conducted in the pre-revascularization era, recent studies continue to explore its role. gavinpublishers.com A study involving patients with NSTEMI administered low-dose oral this compound within 24 hours of admission showed a reduced incidence of major adverse cardiovascular events (MACE). gavinpublishers.com Another study demonstrated the benefit of this compound in the secondary prevention of AMI regardless of the presence of heart failure. gavinpublishers.com However, a recent trial (REDUCE-AMI) in patients with AMI and preserved LVEF found that beta-blockade with metoprolol or this compound was not associated with decreased all-cause mortality or future AMI compared with usual care, suggesting the benefit in this specific subgroup in the modern era may be less clear. acc.org

Table 1: Summary of Key Findings for this compound in Heart Failure

Note: This table summarizes key findings from the provided text snippets and is not exhaustive of all study results.

Table 2: this compound in Post-Myocardial Infarction

Note: This table summarizes key findings from the provided text snippets.

Efficacy in Angina Pectoris Symptoms and Ischemic Episodes

This compound has shown effectiveness in reducing the symptoms of stable angina pectoris and the frequency of ischemic episodes. Studies have compared this compound to other anti-anginal medications, such as nifedipine. The Total Ischemic Burden this compound Study (TIBBS), a randomized double-blind multicenter trial, compared the effects of this compound (10 mg daily) and slow-release nifedipine (20 mg twice daily) in patients with stable angina pectoris who had more than two transient ischemic episodes during a 48-hour Holter monitoring period jacc.org.

Results from the TIBBS study indicated that this compound significantly reduced the mean number of transient ischemic episodes per 48 hours from 8.1 ± 0.6 to 3.2 ± 0.4. jacc.org. In comparison, nifedipine reduced episodes from 8.3 ± 0.5 to 5.9 ± 0.4 per 48 hours. jacc.org. The reduction in the total duration of ischemia was also significantly greater with this compound (from 99.3 ± 10.1 to 31.9 ± 5.5 min/48 h) compared to nifedipine (from 101 ± 9.1 to 72.6 ± 8.1 min/48 h). jacc.org. The differences between this compound and nifedipine in reducing both the number and duration of ischemic episodes were statistically significant (p < 0.0001). jacc.org. This compound also demonstrated a marked circadian effect, particularly reducing the morning peak of transient ischemic episodes. jacc.org.

A separate study comparing once-daily this compound (10 mg) with atenolol (100 mg) in patients with stable angina using a placebo-controlled double-blind randomized crossover protocol also assessed efficacy through exercise testing. Both this compound and atenolol significantly increased exercise time and time to 1 mm ST depression compared to placebo. nih.gov. This compound reduced the mean basal resting heart rate from 84 ± 4 bpm to 63 ± 2 bpm and significantly decreased the peak exercise heart rate. nih.gov.

Table 1: Efficacy in Reducing Ischemic Episodes (TIBBS Study)

Data derived from the TIBBS study jacc.org. Values are Mean ± SEM.

Influence on Mortality and Cardiovascular Events Post-MI

The role of beta-blockers, including this compound, in reducing mortality and cardiovascular events following myocardial infarction (MI) has been well-established, particularly in patients with reduced left ventricular ejection fraction (LVEF). jacc.orgaccjournal.org. Major randomized controlled trials from the pre-reperfusion era demonstrated a significant reduction in all-cause mortality with long-term beta-blocker therapy after MI. jacc.orgunil.ch.

Studies have shown that this compound is among the beta-blockers recommended for use in patients with MI and concomitant heart failure with reduced systolic function (LVEF ≤ 40%). accjournal.orgacc.org. These guidelines are based on evidence demonstrating that this compound, along with carvedilol and sustained-release metoprolol succinate, reduces the risk of death in this population. accjournal.org.

In high-risk patients undergoing major vascular surgery with evidence of myocardial ischemia, this compound significantly reduced long-term cardiac death and myocardial infarction over a follow-up period of up to 2 years. nih.gov. The incidence of cardiac events (cardiac death or myocardial infarction) during follow-up was 12% in the this compound group compared to 32% in the standard care group (P=0.025). nih.gov.

However, in the contemporary era with widespread early revascularization and optimal medical therapy, the benefit of routine beta-blockade in post-MI patients with preserved LVEF is less clear. unil.chacc.org. The REDUCE-AMI trial, a recent randomized study, found that beta-blockade with metoprolol or this compound in patients with MI and preserved LVEF was not associated with a decrease in all-cause mortality or future MI compared with usual care. acc.org. The primary outcome (composite of all-cause death or nonfatal MI) occurred in 7.9% of the beta-blocker group versus 8.3% in the usual care group (HR 0.96, 95% CI 0.79-1.16, p = 0.64). acc.org.

Timing of Initiation and its Impact on Outcomes in Acute Coronary Syndromes

However, some studies in the reperfusion era suggest that the benefits of immediate intravenous beta-blocker therapy within 24 hours after the onset of suspected AMI may be associated with an increased risk of cardiogenic shock. accjournal.org. Current recommendations often suggest initiating oral beta-blockers within the first 24 hours in patients with STEMI in the absence of contraindications, and for NSTEMI patients unless contraindications exist. accjournal.orgacc.org.

Antiarrhythmic Effects in Paroxysmal Atrial Fibrillation

Beta-blockers are known to have antiarrhythmic effects due to their suppression of sympathetic activity. nih.govjst.go.jpnih.gov. This compound, as a highly selective beta-1 blocker, has been evaluated for its antiarrhythmic effects in patients with paroxysmal atrial fibrillation (P-AF). jst.go.jpnih.gov.

A study evaluating the effects of this compound in patients with symptomatic diurnal P-AF reported subjective symptom improvement in 80% of patients and quality of life improvement in 76%. jst.go.jpnih.gov. Elimination of P-AF episodes in Holter electrocardiograms (ECGs) was observed in 62% of patients. jst.go.jpnih.gov. A long-term suppressive effect by this compound was observed in 84% of patients in this study. jst.go.jpnih.gov. The elimination rate of P-AF episodes in ECGs was higher in the diurnal P-AF group compared to the diurnal and nocturnal P-AF group. jst.go.jpnih.gov.

While this compound can help stabilize rhythm in patients with paroxysmal atrial fibrillation, it is not considered superior to other treatments for sustained AF. scot.nhs.uk.

Prevention of Post-Operative Atrial Fibrillation (e.g., after CABG)

Postoperative atrial fibrillation (POAF) is a common complication following cardiac surgery, particularly coronary artery bypass graft (CABG) surgery, and is associated with increased morbidity and hospital stay. najah.edu. Beta-blockers are widely regarded as preventive therapy for POAF. najah.edu.

Studies have investigated the efficacy of this compound in preventing POAF after CABG surgery. One study comparing this compound alone versus a combination of this compound and hydrocortisone for the prevention of AF after on-pump CABG surgery found a statistically significant decrease in the occurrence of atrial fibrillation in the combination group compared to the this compound alone group. .

Transdermal this compound has also been investigated for the prevention of POAF. A systematic review and meta-analysis found a decreased risk of postoperative atrial fibrillation or atrial tachyarrhythmias in patients treated with transdermal this compound (RR 0.43, 95% CI 0.27–0.67, p = 0.0002). nih.govresearchgate.net.

Impact on Heart Rate Control in Atrial Fibrillation

This compound is commonly used for ventricular rate control in patients with atrial fibrillation. nih.govrbht.nhs.uk. Beta-blockers are considered first-line therapy for controlling ventricular rate in AF, and they are preferred over digoxin for their effectiveness in limiting rate during exercise or increased sympathetic drive. scot.nhs.uk.

This compound works by blocking the effects of adrenaline and related hormones on the heart, thereby slowing down the heart rate. rbht.nhs.uknih.gov. This negative chronotropic effect is a key mechanism by which this compound controls ventricular rate in AF. nih.gov.

In a study analyzing heart rate and cardiac rhythm relationships with this compound benefit in chronic heart failure in the CIBIS II trial, heart rate reduction at 2 months was slightly lower in patients with atrial fibrillation compared to those in sinus rhythm. ahajournals.org. However, the amplitude of this difference (2 bpm) was not considered sufficient to fully explain the observed difference in this compound's effect on mortality between the two groups. ahajournals.org.

While this compound is effective for rate control, its benefit on survival in patients with heart failure and concomitant atrial fibrillation has been questioned in some studies, unlike its clear benefit in patients with heart failure in sinus rhythm. ahajournals.org.

Table 2: Incidence of Postoperative Atrial Fibrillation after CABG

Data derived from a study on POAF prevention after CABG ekb.eg.

Table 3: Antiarrhythmic Effects in Paroxysmal Atrial Fibrillation

Data derived from a study on this compound in paroxysmal AF jst.go.jpnih.gov.

Synergistic Effects with ACE Inhibitors and Diuretics in CHF

This compound is a cornerstone of guideline-directed medical therapy for stable chronic heart failure with reduced ejection fraction (HFrEF), typically used in combination with Angiotensin-Converting Enzyme (ACE) inhibitors and diuretics. This combination targets multiple pathophysiological mechanisms involved in CHF progression. ACE inhibitors block the renin-angiotensin-aldosterone system (RAAS), while diuretics help manage fluid overload. This compound, as a beta-blocker, counteracts the detrimental effects of sympathetic nervous system activation, reducing heart rate and improving left ventricular function. researchgate.netnih.gov

Major randomized controlled trials have demonstrated the significant benefits of adding this compound to a regimen including ACE inhibitors and diuretics in patients with stable chronic heart failure (NYHA class III or IV). The Cardiac Insufficiency this compound Study (CIBIS) and CIBIS II trials are prime examples. CIBIS II, involving 2647 patients, showed a significantly lower all-cause mortality in patients receiving this compound (11.8%) compared to placebo (17.3%). researchgate.netnih.gov A meta-analysis of CIBIS and CIBIS II, encompassing 3288 patients, indicated a 29% relative reduction in all-cause mortality with this compound. researchgate.netnih.gov Furthermore, CIBIS II reported significantly fewer cardiovascular deaths, hospital admissions for any reason, and combined cardiovascular deaths or hospitalizations in the this compound group. researchgate.netnih.gov The addition of this compound to standard therapy (ACE inhibitor and diuretic) has been shown to significantly improve survival and reduce the need for hospitalization in patients with stable, moderate to severe chronic heart failure. researchgate.netnih.gov

Data from CIBIS II trial illustrating the impact of this compound on key outcomes when added to standard therapy:

The CIBIS III trial investigated the optimal sequence of initiating treatment with this compound and Enalapril in stable, mild-to-moderate systolic CHF. While non-inferiority of the this compound-first strategy compared to Enalapril-first was not definitively proven in the per-protocol analysis, the results indicated that initiating treatment with this compound may be as safe and efficacious as starting with Enalapril. ahajournals.org Notably, the this compound-first strategy significantly reduced sudden death during the first year of treatment by 46% compared to the Enalapril-first strategy. oup.com

Analysis of Treatment Outcomes in Real-World Clinical Settings

Real-world clinical settings often involve patients with multiple comorbidities and complex medication regimens, which can differ from the controlled environments of clinical trials. Analyzing treatment outcomes in these settings provides valuable insights into the effectiveness and tolerability of this compound-based combination therapies in broader patient populations.

Data regarding specific real-world outcomes for this compound combinations with Cilnidipine were not prominently featured in the provided search results. However, the general principles of combination therapy in managing hypertension in real-world scenarios would apply, aiming for optimal blood pressure control and reduction of cardiovascular risk factors.

Worsening of Heart Failure Symptoms: Considerations and Patient Selection

Masking of Hypoglycemia Symptoms in Diabetic Patients: Mechanism and Clinical Implications

Beta-blockers, including this compound, can mask some of the typical adrenergic symptoms of hypoglycemia in diabetic patients, particularly those treated with insulin or oral hypoglycemic agents. wikipedia.orgnih.govdrugs.comayubmed.edu.pk The sympathetic nervous system plays a crucial role in the body's counter-regulatory response to low blood glucose, triggering symptoms like tremor, palpitations, and tachycardia via adrenergic receptors. drugs.comnih.gov

This compound, by blocking beta-1 adrenergic receptors, reduces the heart rate and contractility response to hypoglycemia-induced catecholamine release. patsnap.comdrugbank.com This blunting of the cardiovascular response can make it more difficult for patients to recognize the onset of hypoglycemia, potentially delaying intervention and increasing the risk of severe episodes. drugs.comayubmed.edu.pkfrontiersin.org

While this compound is cardioselective, the masking effect on hypoglycemia symptoms is a known consideration. wikipedia.orgnih.govfrontiersin.org However, other hypoglycemia symptoms not mediated by beta-adrenergic receptors, such as headache, dizziness, drowsiness, confusion, nausea, hunger, weakness, and perspiration, may remain unaffected. drugs.com Diabetic patients taking this compound should be advised of the potential for masked symptoms and the importance of regular blood glucose monitoring. nih.govdrugs.com

Effects on Lipid Profile (e.g., Triglycerides, HDL-C)

The effects of beta-blockers on lipid profiles, particularly triglycerides and high-density lipoprotein cholesterol (HDL-C), have been a subject of research. Non-selective beta-blockers are often associated with increases in triglycerides and decreases in HDL-C. researchgate.net

Studies investigating the impact of this compound on lipid profiles have yielded varying results, but generally suggest a more favorable or neutral effect compared to non-selective agents. Some research indicates that this compound may lead to small, non-significant decreases in triglycerides and increases in HDL cholesterol. researchgate.net For instance, one study involving hypertensive patients treated with this compound for eight weeks observed a 4.8% decrease in triglycerides and a 5.2% increase in HDL cholesterol, although these changes were not statistically significant. researchgate.net This increase in HDL cholesterol was primarily attributed to an increase in the atheroprotective HDL2 subfraction. researchgate.net

Another long-term study over 10 months noted a small but statistically significant increase in serum triglycerides from the start of the study period, but no significant changes in total cholesterol, LDL cholesterol, or HDL cholesterol within the study period itself. nih.gov

The less pronounced effect of this compound on lipid metabolism compared to non-selective beta-blockers is likely related to its higher beta-1 selectivity, minimizing interference with beta-2 receptor-mediated metabolic processes. medicines.org.uk

Here is a summary of lipid profile changes observed in a study:

Note: Specific baseline and post-treatment values were not consistently available across sources for a direct comparison table, but the percentage changes and significance levels were reported.

Fatigue and Asthenia

Fatigue and asthenia (a feeling of weakness or lack of energy) are commonly reported adverse effects associated with this compound use. nih.govmedicines.org.ukmims.comhres.casandoz.commims.comqingmupharm.com These symptoms are often mild and may be more prominent at the beginning of therapy, typically resolving within one to two weeks. medicines.org.uksandoz.com

The exact mechanisms underlying beta-blocker induced fatigue and asthenia are not fully elucidated but may involve several factors. The reduction in heart rate and cardiac output can lead to decreased oxygen delivery to tissues, potentially contributing to feelings of tiredness. patsnap.comdrugbank.com While this compound has moderate lipophilicity and can cross the blood-brain barrier, its potential for central nervous system effects is considered lower than highly lipophilic beta-blockers like propranolol. wikipedia.org However, some central effects cannot be entirely ruled out as a contributing factor to fatigue. drugbank.com

Gastrointestinal Disturbances

Gastrointestinal disturbances such as nausea, vomiting, constipation, and diarrhea have been reported with this compound. nih.govmims.commims.comqingmupharm.com These effects are generally considered common but are usually not severe. nih.govmims.com

The mechanisms behind these gastrointestinal side effects are not extensively detailed in available literature specific to this compound. However, beta-adrenergic receptors are present in the gastrointestinal tract and influence motility and secretions. While this compound primarily targets beta-1 receptors, some off-target effects on beta-2 receptors in the gut, particularly at higher doses, could theoretically contribute to altered gastrointestinal function. Additionally, systemic effects of the medication may indirectly influence the digestive system.

Neuropsychiatric Manifestations (e.g., Insomnia)

Neuropsychiatric effects, including insomnia, are potential adverse manifestations associated with beta-blocker therapy. drugs.comoup.com The occurrence and severity of these effects can be influenced by a beta-blocker's ability to cross the blood-brain barrier (BBB). wikipedia.orgnih.gov this compound is classified as a beta-blocker with moderate lipophilicity, suggesting an intermediate potential for penetrating the BBB. wikipedia.orgresearchgate.net This characteristic may contribute to a lower risk of central nervous system (CNS)-related side effects, such as neuropsychiatric manifestations, compared to highly lipophilic beta-blockers like propranolol. wikipedia.orgwho.int However, the risk may be greater than with beta-blockers exhibiting low lipophilicity, such as atenolol. wikipedia.org

One proposed mechanism for sleep disturbances, including insomnia and nightmares, associated with beta-blockers involves their interaction with adrenergic and serotonergic receptors, potentially suppressing rapid eye movement (REM) sleep. nih.gov Additionally, beta-blockers can influence the synthesis and secretion of melatonin, a key hormone regulating circadian rhythm and the sleep-wake cycle, by affecting beta-1 adrenergic receptors. nih.gov Reduction in melatonin levels due to beta-blockade may contribute to sleep disorders. nih.gov While neuropsychiatric adverse events such as insomnia may be caused by this compound, some research has not found an association between this compound use and depression. nih.gov

Other Beta-Blockers: Exacerbation of Bradycardia and Hypotension

The co-administration of this compound with other beta-blockers, regardless of their selectivity, can result in an exacerbation of pharmacodynamic effects. Both agents block beta-adrenergic receptors, leading to a cumulative reduction in heart rate (bradycardia) and blood pressure (hypotension). medscape.comdrugs.com This synergistic effect can increase the risk of symptomatic bradycardia, dizziness, and syncope. medscape.com

Non-Dihydropyridine Calcium Channel Blockers (e.g., Verapamil, Diltiazem): Myocardial Depression, Bradycardia, AV Block, Heart Failure

Non-dihydropyridine calcium channel blockers like Verapamil and Diltiazem exert their primary effects by blocking L-type calcium channels in the heart, particularly in the sinoatrial (SA) and atrioventricular (AV) nodes, and on myocardial cells. wikipedia.orgmims.com this compound, by blocking beta-1 receptors, also reduces heart rate and slows AV nodal conduction. mims.com When co-administered, the combined negative chronotropic (heart rate reduction) and dromotropic (AV conduction slowing) effects can be significantly enhanced, leading to severe bradycardia and high-grade AV block. medscape.comdrugs.comnih.gov Furthermore, both classes of drugs can have negative inotropic effects (reducing myocardial contractility), increasing the risk of myocardial depression and the precipitation or worsening of heart failure, particularly in patients with pre-existing ventricular dysfunction. nih.gov

Antiarrhythmic Drugs (e.g., Digoxin, Amiodarone, Sotalol): Increased Risk of Bradycardia

Concomitant use of this compound with certain antiarrhythmic drugs, such as Digoxin, Amiodarone, and Sotalol, can increase the risk of bradycardia and impaired AV conduction. Digoxin primarily affects the Na+/K+-ATPase pump, leading to increased intracellular calcium and enhanced contractility, but it also increases vagal tone, slowing heart rate and AV conduction. wikipedia.orgmims.com Amiodarone, a complex antiarrhythmic, has effects on multiple ion channels and also possesses beta-blocking and calcium channel blocking properties. wikipedia.orgprobes-drugs.orgmims.com Sotalol is a non-selective beta-blocker with additional potassium channel blocking properties (Class III antiarrhythmic effects). wikipedia.orgmims.cominvivochem.com The combination of this compound's beta-blocking effects with the electrophysiological effects of these antiarrhythmics can lead to additive or synergistic slowing of heart rate and AV nodal conduction, increasing the risk of symptomatic bradycardia and conduction disturbances. medscape.com

Clonidine: Rebound Hypertension upon Withdrawal

Clonidine is a centrally acting alpha-2 adrenergic agonist that reduces sympathetic outflow, leading to decreased heart rate, blood pressure, and peripheral vascular resistance. mims.com Abrupt discontinuation of clonidine can lead to a rapid increase in sympathetic activity, resulting in severe rebound hypertension. drugs.comnih.gov When this compound is co-administered with clonidine, the beta-blockade effect of this compound can leave the alpha-adrenergic receptors unopposed during clonidine withdrawal. This unopposed alpha-stimulation can exaggerate the vasoconstrictive response to the surge in catecholamines, leading to a more severe hypertensive crisis than would occur with clonidine withdrawal alone. drugs.com Therefore, if therapy needs to be discontinued, this compound should ideally be withdrawn gradually several days before the tapering of clonidine. drugs.comnih.govscbdd.com

Other Antihypertensives: Additive Hypotensive Effects

This compound can have additive hypotensive effects when used concurrently with other antihypertensive agents, including diuretics, ACE inhibitors, angiotensin II receptor blockers, and alpha-blockers. medscape.commedcentral.comdrugs.com This is primarily a pharmacodynamic interaction resulting from the combined mechanisms of blood pressure reduction. While often beneficial in achieving target blood pressure, this combination requires careful monitoring to avoid excessive hypotension, dizziness, and syncope. medscape.comdrugs.com

CYP3A4 Inducers (e.g., Rifampin): Increased this compound Clearance

Concomitant use of this compound with potent inducers of CYP3A4, such as rifampin, can lead to increased metabolic clearance of this compound. hres.canih.gov Rifampin is a well-known potent enzyme-inducing drug that strongly induces the expression of CYP3A4 in the liver. nih.gov This induction enhances the hepatic metabolism of this compound, resulting in a shortened elimination half-life and decreased plasma concentrations of the drug. hres.canih.gov Consequently, the therapeutic effect of this compound, such as its antihypertensive action, may be reduced. nih.gov While initial dose modifications may not always be necessary, caution is advised when administering compounds with enzymatic induction potential to patients receiving this compound therapy. hres.caucsf.edu

Impact of Cholinesterase Inhibitors (e.g., Donepezil)

Cholinesterase inhibitors, such as donepezil, can increase vagotonic effects on the sinoatrial and atrioventricular nodes, potentially leading to bradycardia and heart block. drugs.com When administered concomitantly with this compound, which also has bradycardic effects due to its beta-blocking activity, additive effects on heart rate and atrioventricular conduction can occur. nih.govdrugs.comdrugbank.com This pharmacodynamic interaction may increase the risk of bradycardia, falls, and syncope. nih.gov Caution is advised when using acetylcholinesterase inhibitors concurrently with bradycardic drugs like this compound. drugs.com

Effects on Serum Levels of Co-administered Drugs

Based on available information, pharmacokinetic studies have documented no clinically relevant adverse interactions with certain agents given concomitantly with this compound, including thiazide diuretics, digoxin, and cimetidine. hres.ca However, some sources indicate that this compound may decrease the excretion rate of certain drugs, potentially leading to higher serum levels. For instance, this compound may decrease the excretion rate of amikacin, auranofin, and aurothioglucose, which could result in increased serum concentrations of these drugs. drugbank.com Additionally, the serum concentration of avanafil can be increased when combined with this compound. drugbank.com Conversely, the serum concentration of this compound can be increased when combined with acetophenazine. drugbank.com

Nonsteroidal Anti-inflammatory Drugs (NSAIDs): Attenuation of Antihypertensive Effect

Nonsteroidal anti-inflammatory drugs (NSAIDs) may attenuate the antihypertensive effect of beta-blockers, including this compound. accord-healthcare.asiamedsafe.govt.nzdrugs.com The proposed mechanism for this interaction involves NSAID-induced inhibition of renal prostaglandin synthesis. drugs.com Prostaglandins play a role in regulating blood pressure, and their inhibition can result in unopposed pressor activity, leading to hypertension. drugs.com Furthermore, NSAIDs can cause fluid retention, which can also negatively impact blood pressure control. drugs.com Various studies have provided some evidence of reduced beta-blocker effects on hypertension or heart failure in patients receiving NSAIDs such as indomethacin, piroxicam, ibuprofen, and naproxen, or aspirin. drugs.comhres.ca This interaction is generally considered a monitor-level interaction, and closer blood pressure monitoring is recommended for patients receiving prolonged concomitant therapy with an NSAID and a beta-blocker. drugs.com The interaction is not typically expected with low doses or intermittent short-term administration of NSAIDs. drugs.com

Alcohol: Potential for Enhanced Adverse Effects

The consumption of alcohol while taking this compound may potentially lead to enhanced adverse effects. goodrx.comdrugs.commedindia.net this compound and ethanol (alcohol) may have additive effects in lowering blood pressure. drugs.com This can result in symptoms such as headache, dizziness, lightheadedness, fainting, and/or changes in pulse or heart rate. drugs.com These effects are more likely to occur at the beginning of treatment, following a dose increase, or when treatment is restarted after an interruption. drugs.com Alcohol can also potentially worsen this compound's side effects like dizziness and lightheadedness. goodrx.com Additionally, regular alcohol use can contribute to weight gain and high blood pressure, which could potentially worsen existing heart conditions. goodrx.com

Selected Herbal and Dietary Supplements

Information regarding interactions between this compound and herbal or dietary supplements is less extensively documented compared to prescription medications. However, some potential interactions have been noted based on the known pharmacological effects of certain supplements.

Certain dietary supplements may interfere with the effectiveness of this compound. goodrx.com These include supplements that can affect blood pressure and heart rate. goodrx.com

Some sources suggest avoiding supplements like ginseng, licorice root, and St. John's wort while taking this compound, as they may interfere with its effectiveness or raise the risk of side effects. goodrx.com Specifically, licorice root may increase the side effects of potassium-depleting diuretics, which are sometimes co-administered with this compound in combination products. peacehealth.org Pleurisy root, which contains cardiac glycosides, is also not recommended with heart medications like this compound due to potential additive effects similar to digitalis. peacehealth.orgmedindia.net

Herbs with diuretic effects, such as dandelion, uva ursi, juniper, buchu, cleavers, horsetail, and gravel root, should be avoided when taking diuretic medications alongside this compound, as they may enhance the diuretic effect and potentially lead to cardiovascular side effects. peacehealth.org

Potassium-rich foods and potassium supplements should be used with caution, as some beta-blockers can increase serum potassium levels. medscape.compeacehealth.org While this interaction is considered to have preliminary, weak, or contradictory scientific evidence, it is still a consideration. peacehealth.org

Caffeine, found in coffee and tea, may decrease the effectiveness of beta-blockers like this compound, and it is generally advisable to avoid consuming large amounts of caffeine while taking this compound. goodrx.commedindia.net

Salt substitutes, which often contain potassium, and foods rich in sodium, calcium, and magnesium may reduce or negate the blood pressure-lowering effect of this compound. medindia.net

It is important for patients to inform their healthcare providers about all herbal remedies, vitamins, or supplements they are taking due to the limited information available on these interactions and the potential for impact on this compound's effects. www.nhs.ukgoodrx.comwebmd.comsiloamhospitals.com

Beta-Adrenoceptor Gene Variants (e.g., ADRB1, ADRB2): Association with Efficacy and Tolerability

Polymorphisms in the beta-1 adrenergic receptor gene (ADRB1) and beta-2 adrenergic receptor gene (ADRB2) have been extensively studied for their potential influence on this compound response. ADRB1 is the primary target of this compound, a β₁-selective beta-blocker. nih.govresearchgate.netmdpi.com

Two common variants in ADRB1 are Ser49Gly (rs1801252) and Arg389Gly (rs1801253). nih.govresearchgate.net Studies investigating the association between these variants and this compound response have yielded some findings, although results can be contradictory. researchgate.netbmj.comrepositoriosalud.es

One study in patients with acute coronary syndrome (ACS) found that carriers of the Arg389Arg genotype of ADRB1 showed greater reductions in both systolic and diastolic blood pressure compared to Gly389 carriers after four weeks of this compound treatment. nih.govtandfonline.com Specifically, Arg389Arg carriers had mean reductions of -8.5% ± 7.8% in systolic blood pressure and -9.5% ± 9.7% in diastolic blood pressure, while Gly389 carriers had reductions of -0.76% ± 8.7% and -0.80% ± 11.5%, respectively. nih.govtandfonline.com This suggests that the Arg389Gly polymorphism may be a predictor of this compound response in ACS patients. nih.govtandfonline.com The Arg389 variant has been reported to contribute to greater activity of the β-1 adrenergic receptor compared to Gly389. kjim.org

However, other studies have not found a significant association for the Arg389Gly and Ser49Gly polymorphisms with this compound response. bmj.comugr.es A systematic review and meta-analysis concluded that while the ADRB1 Arg389Gly variant seems to have an influence on this compound efficacy, the results are inconclusive, and the meta-analysis did not find statistically significant results. bmj.comrepositoriosalud.es

Regarding ADRB2 polymorphisms, such as Gly16Arg (rs1042713) and Glu27Gln (rs1042714), some research suggests potential associations with response and tolerability to beta-blockers, including this compound, in ACS patients, particularly concerning hypotensive events. ugr.esresearchgate.net One observational study found that the presence of the G allele (Glu) of the ADRB2 gene (rs1042714) was associated with a protective effect against beta-blocker-induced hypotension. ugr.esresearchgate.net The ADRB2 (rs1042713) GG genotype might also prevent hypotensive events. ugr.esresearchgate.net However, SNPs in ADRB1 and certain CYP2D6 variants were not associated with primary events in this study. ugr.esresearchgate.net

Interactive Table 1: Association of ADRB1 Arg389Gly with Blood Pressure Response to this compound in ACS Patients

Influence of ACY3 Gene Polymorphisms on Blood Pressure Response

Polymorphisms in the aminoacylase III (ACY3) gene on chromosome 11 have also been investigated for their association with this compound's effect on blood pressure. The Genetics of Drug Responsiveness in Essential Hypertension (GENRES) study, a genome-wide association study (GWAS), identified three SNPs within the ACY3 gene (rs2514036, rs948445, and rs2514037) that showed associations with this compound response reaching genome-wide significance (P<5x10⁻⁸). nih.govnih.govahajournals.orgahajournals.org These SNPs map within the coding and regulatory regions of ACY3. nih.gov

Specifically, rs2514036 was strongly associated with ACY3 expression in various tissues. tandfonline.com Another SNP, rs4313593, in linkage disequilibrium with rs2514036, was associated with both systolic and diastolic blood pressure responses to this compound in the GENRES study. tandfonline.com

However, replication of these findings has been challenging. The associations observed with ACY3 polymorphisms in the GENRES study could not be replicated in the PEAR Study, which used atenolol, another beta-blocker. nih.govnih.govahajournals.orgahajournals.org Despite the initial genome-wide significant associations, the lack of replication in independent cohorts highlights the need for further research to confirm the clinical relevance of ACY3 gene polymorphisms in predicting this compound blood pressure response. nih.govnih.govahajournals.orgahajournals.org

Other Investigated Single Nucleotide Polymorphisms (SNPs) and their Clinical Relevance

Beyond the beta-adrenoceptor and ACY3 genes, other SNPs have been explored for their potential influence on this compound response. However, the evidence for associations with this compound specifically is often limited, inconclusive, or derived from studies combining results with other beta-blockers. researchgate.netbmj.comrepositoriosalud.es

Some studies have investigated SNPs in genes related to drug metabolism, such as CYP2D6 and CYP3A5, for their potential pharmacodynamic effects, although their primary influence is on pharmacokinetics. nih.govnih.gov As discussed in the pharmacokinetics section, the findings regarding the impact of these genes on this compound plasma concentrations and, consequently, potential pharmacodynamic effects are mixed. nih.govnih.govresearchgate.netresearchgate.net

A GWAS investigating this compound pharmacokinetics and pharmacodynamics identified a novel locus on chromosomal region 11p14.1, with the lead SNP being rs11029955, which was associated with 24-hour heart rate response to this compound in an independent cohort of hypertensive subjects. researchgate.netnih.govnih.gov This suggests that genetic variants in this region may play a role in the pharmacodynamic response to this compound, specifically heart rate reduction. researchgate.netnih.govnih.gov

CYP2D6 and CYP3A5 Polymorphisms: Impact on this compound Plasma Concentrations and Clearance

This compound is metabolized by cytochrome P450 (CYP) enzymes, primarily CYP3A4 and, to a lesser extent, CYP2D6. tandfonline.comnih.govconicet.gov.ar Approximately 50% of this compound is metabolized by the liver, while the other 50% is eliminated unchanged by the kidneys. tandfonline.comnih.govg-standaard.nl

Given the involvement of CYP2D6 in the metabolism of many beta-blockers, its polymorphisms have been studied in relation to this compound. CYP2D6 is highly polymorphic, with numerous alleles affecting enzyme activity. tandfonline.com Similarly, polymorphisms in CYP3A5, another enzyme involved in this compound metabolism, have been investigated. nih.govnih.gov

Studies on the impact of CYP2D6 and CYP3A5 polymorphisms on this compound pharmacokinetics have yielded conflicting results. Some studies have found no significant effect of common polymorphisms in CYP2D6 and the CYP3A5*3 polymorphism on this compound plasma concentrations or clearance. nih.govnih.govtandfonline.comg-standaard.nl For instance, one study in hypertensive Chinese patients found no significant association between CYP2D6 and CYP3A5 polymorphisms and peak or trough this compound plasma concentrations, although baseline body weight was significantly associated with plasma concentration. nih.govnih.govresearchgate.net Another study also reported no significant association of single CYP2D6 and CYP3A genotypes or metabolizer phenotypes with this compound clearance. tandfonline.com

However, other research suggests a potential association. One study indicated an association between CYP3A53, CYP2D64, and CYP2D6*2A variants and this compound peak concentration. researchgate.net Another study in patients from Saudi Arabia demonstrated an association between the variant rs1080985 of the CYP2D6 gene and the concentration of this compound in plasma. researchgate.net

Interactive Table 2: Association of CYP Polymorphisms with this compound Peak Concentration

Chromosomal Region 11p14.1 (CCDC34): Association with this compound Clearance and Heart Rate Response

A genome-wide association study (GWAS) identified a novel locus on chromosomal region 11p14.1 that is significantly associated with this compound pharmacokinetics. researchgate.netnih.govnih.gov The lead SNP in this region, rs11029955, mapped to the region of coiled-coil domain containing 34 (CCDC34), showed a strong association with this compound clearance. researchgate.netnih.govnih.gov

In a cohort of patients with acute coronary syndrome, rs11029955 was associated with this compound clearance (p=7.17×10⁻⁹). researchgate.netnih.govnih.gov Each copy of the minor allele of rs11029955 was associated with a 2.2 L/h increase in this compound clearance. researchgate.netnih.govnih.govresearchgate.net The mean estimated clearance in this population was 13.6 (10.0–18.0) L/h. researchgate.netnih.gov

Furthermore, this association was validated in an independent cohort of hypertensive subjects, where rs11029955 was associated with 24-hour heart rate response to 4-week treatment with this compound (p= 9.3×10⁻⁵). researchgate.netnih.govnih.gov This suggests that genetic variation in the 11p14.1 region, particularly around CCDC34, influences both the rate at which this compound is cleared from the body and the resulting pharmacodynamic effect on heart rate. researchgate.netnih.govnih.gov Another SNP, rs116702638, also on chromosome 11, showed association with clearance but not with heart rate response in the validation cohort. researchgate.netnih.govnih.gov

Interactive Table 3: Association of rs11029955 (CCDC34) with this compound Clearance and Heart Rate

Further studies are needed to fully understand the functional implications of these genetic variants in the 11p14.1 region and their precise role in this compound pharmacokinetics and pharmacodynamics. tandfonline.com

Influence of Smoking Status on this compound Clearance

Smoking status has been identified as a non-genetic factor that can impact this compound clearance. Studies have indicated that smoking is associated with increased this compound clearance. wikipedia.orgguidetopharmacology.orgmims.com This effect is potentially attributed to the induction of cytochrome P450 3A4 (CYP3A4) enzymes in the liver by components of cigarette smoke. wikipedia.orgmims.com

Impact of Total Daily Dose on Clearance in Specific Populations

The total daily dose of this compound can also influence its clearance, particularly in specific patient populations. In patients with acute coronary syndrome, the mean daily dose has been suggested to influence the variability in this compound clearance. wikipedia.orgmims.com This observation has led to the hypothesis of possible autoinduction of drug metabolism by higher total daily doses. wikipedia.orgmims.com

A study focusing on patients with chronic heart failure identified the total daily dose of this compound as a significant covariate affecting its clearance. A population pharmacokinetic model in this group demonstrated a relationship between this compound clearance and the total daily dose. The final regression model for clearance (CL) in this population was described as:

CL (L/h) = 4.68 + 0.859 * Total Daily Dose (mg)

This finding highlights that in patients with chronic heart failure, higher total daily doses are associated with increased clearance of this compound.

Here is a representative data illustration based on the regression model for this compound clearance in patients with chronic heart failure:

Note: Estimated clearance values are calculated using the regression model CL (L/h) = 4.68 + 0.859 * Total Daily Dose (mg) derived from a study in patients with chronic heart failure.

Alterations in Pharmacokinetic Parameters (e.g., Half-Life, Clearance)

Studies have demonstrated that renal impairment alters the pharmacokinetic parameters of this compound. In patients with renal impairment, the elimination half-life of this compound is prolonged compared to individuals with normal renal function drugbank.comnih.gov. One study reported an increase in half-life to 18.5 hours in patients with renal impairment, compared to 10.0 hours in healthy subjects nih.gov. In uremic patients with creatinine clearance less than 5 mL/min/1.73m², the elimination half-life was further prolonged to 24.2 hours nih.gov.

Total body clearance of this compound is also reduced in the presence of renal dysfunction drugbank.comnih.gov. In patients with renal impairment (mean creatinine clearance of 28 ± 5 mL/min/1.72m²), total body clearance decreased to 7.8 L/h from 14.2 L/h in healthy subjects nih.gov. For uremic patients (creatinine clearance < 5 mL/min/1.73m²), total clearance was reported as 5.0 L/h nih.gov. The increase in half-life in severe renal dysfunction has been observed to be by a factor of approximately 1.96 nih.govoup.comoup.com.

The following table summarizes the changes in pharmacokinetic parameters of this compound in healthy subjects and patients with renal impairment:

Considerations for Patients Undergoing Dialysis

Limited data suggest that this compound is not significantly removed by dialysis fda.govdroracle.ai. Therefore, drug replacement is generally not considered necessary in patients undergoing dialysis fda.govdroracle.ai. While some studies classify this compound as moderately dialyzable with a reported dialytic clearance, the extent of removal may not necessitate dose adjustments based solely on dialysis schedules droracle.aidroracle.aidovepress.comnih.gov. The 48-hour plasma levels in patients on dialysis have been noted to be similar to those in patients with severe renal dysfunction, suggesting that significant accumulation is unlikely even in end-stage renal failure nih.govoup.com.

Impact on this compound Clearance

Hepatic dysfunction has been shown to reduce the clearance of this compound drugbank.com. In patients with liver cirrhosis, the elimination of this compound is more variable and significantly slower compared to healthy subjects fda.govdrugs.comhres.ca. The plasma half-life in patients with liver cirrhosis has been reported to range from 8.3 to 21.7 hours fda.govdrugs.comhres.ca. A study in patients with liver cirrhosis observed an increased half-life of 13.5 hours and a decrease in total body clearance to 10.8 L/h, compared to healthy subjects nih.gov. Despite these changes, accumulation of this compound beyond a factor of 2 is considered unlikely in patients with impaired liver function nih.gov.

Age-Related Pharmacokinetic and Pharmacodynamic Changes

In elderly patients, the plasma elimination half-life of this compound may be slightly longer compared to younger patients, partly due to decreased renal function commonly observed in this population fda.govdrugs.comhres.ca. While some pharmacokinetic parameters such as half-life, AUC, and Cmax have been found to be greater in the elderly, plasma accumulation is generally low fda.govhres.cahres.ca. The pharmacokinetics of this compound are considered linear and independent of age fda.govgeneesmiddeleninformatiebank.nl.

Regarding pharmacodynamics, observed reductions in heart rate have been slightly greater in the elderly than in younger individuals and have shown a tendency to increase with increasing dose fda.govdrugs.comhres.cahres.cahres.ca. Despite potential age-related changes, response rates and mean decreases in blood pressure in elderly patients with hypertension have been similar to those in younger patients in some clinical studies fda.govdrugs.comhres.cahres.ca.

Prevalence of Polypharmacy and Drug Interaction Risk

Polypharmacy, defined as the concurrent use of multiple medications, is common, particularly in elderly patients with comorbidities mdpi.comfrontiersin.org. This increases the potential for drug-drug interactions (DDIs), which can lead to altered drug efficacy or increased risk of adverse events mdpi.com.

Studies have investigated the prevalence of potential DDIs involving this compound in various patient groups. In a study of hospitalized patients with acute coronary syndrome receiving at least two medications, potential drug-drug interactions involving this compound were identified, including combinations with Amlodipine, Empagliflozin, Aspirin, and Potassium Chloride ekb.eg. Another study focusing on cardiovascular drugs in geriatric patients with congestive heart failure found that this compound was the second most frequently prescribed drug, and potential interactions with furosemide and spironolactone were among the most frequent semanticscholar.org.

A large study analyzing drug dispensings in France between 2010 and 2015 identified "this compound + flecainide" as the most frequently involved drug pair in contraindicated co-dispensings, accounting for 38% of all identified cases frontiersin.org. This highlights the clinical significance of potential interactions, particularly with other cardiovascular medications. The risk of DDIs is a significant concern in patients on polypharmacy, and careful consideration of concomitant medications is crucial when prescribing this compound mdpi.com.

Distinct Pharmacokinetic Profile in Stable CHF

The pharmacokinetics of this compound in patients with stable chronic heart failure (CHF) can differ from those in healthy volunteers. Studies in patients with chronic heart failure, particularly those in NYHA stage III, have shown higher plasma levels and a prolonged half-life of this compound compared to healthy individuals medsafe.govt.nzsandoz.comhpra.iemagonlinelibrary.comcbg-meb.nl.

For instance, in patients with NYHA stage III CHF receiving a daily dose of 10 mg, the maximum plasma concentration at steady state was reported as 64 ± 21 ng/ml, and the half-life was 17 ± 5 hours medsafe.govt.nzsandoz.comhpra.iemagonlinelibrary.comcbg-meb.nl. This is longer than the typical elimination half-life of 10-12 hours observed in healthy individuals nih.govsandoz.commagonlinelibrary.comdrugbank.com. The reduced clearance of this compound in CHF patients may contribute to these higher plasma concentrations nih.gov.

While this compound is eliminated equally by hepatic metabolism and renal excretion, studies specifically investigating the pharmacokinetics in patients with stable CHF and concomitant impaired liver or renal function are limited medsafe.govt.nzsandoz.comhpra.iemagonlinelibrary.comcbg-meb.nl. However, some data suggest that in patients with severe renal impairment (creatinine clearance <10 mL/min), the exposure to this compound can increase twofold, and the half-life can extend to 24.2 hours researchgate.net.

Pharmacodynamic Considerations in Different NYHA Functional Classes

This compound's pharmacodynamic effects in chronic heart failure contribute to its therapeutic benefits. In acute administration to patients without CHF, this compound reduces heart rate, stroke volume, cardiac output, and oxygen consumption medsafe.govt.nzsandoz.comhpra.iemagonlinelibrary.com. With chronic administration, the initially elevated peripheral resistance decreases medsafe.govt.nzsandoz.comhpra.iemagonlinelibrary.com.

Clinical trials, such as the CIBIS II study, have provided valuable insights into the pharmacodynamics of this compound in different NYHA functional classes. The CIBIS II trial included a large proportion of patients in NYHA class III (83%) and NYHA class IV (17%) with stable symptomatic systolic heart failure sandoz.comhpra.iecbg-meb.nl. This study demonstrated a significant reduction in total mortality and a reduced number of heart failure episodes requiring hospital admission in the this compound group compared to placebo sandoz.comhpra.iecbg-meb.nl. Furthermore, a significant improvement in functional status according to the NYHA classification was observed sandoz.comhpra.iecbg-meb.nlnih.gov.

While the CIBIS II study included patients up to NYHA class IV, there is limited therapeutic experience with this compound treatment of heart failure in patients with NYHA class II heart failure in some contexts cbg-meb.nl. However, other studies have shown improvement in NYHA functional class with this compound treatment in CHF patients nih.gov.

Data Table: Pharmacokinetic Parameters of this compound in Different Populations

Pharmacokinetic Profile in Type 2 Diabetes Mellitus

The pharmacokinetics of this compound in patients with Type 2 Diabetes Mellitus (T2DM) have been investigated. While this compound is eliminated equally by hepatic metabolism and renal excretion, studies suggest that in patients with hypertension and T2DM, creatinine clearance can significantly influence the elimination of this compound prolekare.czresearchgate.netresearchgate.net.

A population pharmacokinetic study in adult patients with hypertension and T2DM found a wide range of this compound plasma concentrations (1–103 ng/mL) prolekare.czresearchgate.netnih.gov. The results indicated that creatinine clearance was the only assessed covariate that had a potential impact on the variability of this compound clearance researchgate.netnih.gov. This suggests that renal function should be routinely assessed in these patients, and dose adjustments may be necessary to prevent potential accumulation researchgate.netresearchgate.netnih.gov.