Amlodipine

Inhibition of Voltage-Dependent L-Type Calcium Channels

This compound functions as a calcium ion antagonist or slow-channel blocker, inhibiting the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle cells. fda.govmedchemexpress.com This inhibition primarily targets voltage-dependent L-type calcium channels. nih.govdrugbank.commedchemexpress.com By blocking these channels, this compound reduces the entry of extracellular calcium, which is crucial for the contractile processes in both cardiac and vascular smooth muscle. fda.gov The interaction of this compound with the L-type calcium channel receptor is characterized by a gradual rate of association and dissociation, contributing to its prolonged effect. fda.gov

Differential Effects on Vascular Smooth Muscle Cells versus Cardiac Muscle Cells

This compound demonstrates a greater inhibitory effect on calcium ion influx across cell membranes in vascular smooth muscle cells compared to cardiac muscle cells. drugbank.comfda.gov This selectivity for vascular smooth muscle is a key characteristic of dihydropyridine calcium channel blockers, including this compound. mdpi.comdrugbank.com This preferential targeting of vascular smooth muscle, particularly CaV1.2 channels, leads to reduced peripheral vascular resistance and vasodilation, with less impact on cardiac contractility at therapeutic doses. fda.govoup.comwikipedia.org Some research suggests this preferential targeting may be partly due to a splice variant of CaV1.2 channels found in smooth muscle that exhibits higher sensitivity to dihydropyridines. oup.com

Exploration of N-Type Calcium Channel Inhibition

While primarily known for its effects on L-type calcium channels, studies have also explored this compound's interaction with N-type calcium channels. Research indicates that this compound can have a blocking action on N-type calcium channels, similar in level to its effect on L-type channels in some experimental settings, such as in oocytes. frontiersin.org The action of this compound on N-type Ca2+ channels can be dependent on holding potential and extracellular pH. frontiersin.org However, other studies in human cardiac tissue suggest that L-type channels are not involved in calcium influx into cardiac sympathetic nerves during depolarization, and selective blockers of L-type channels like this compound were ineffective in inhibiting norepinephrine release triggered by N-type channels in this context. ahajournals.org Some newer generation calcium channel blockers, such as cilnidipine, are known to inhibit both L-type and N-type calcium channels, and studies have compared their effects to this compound, particularly in relation to sympathetic nerve activity and outcomes like proteinuria. medsci.orgnih.govijbcp.com

Impact on Intracellular Calcium Dynamics and Calcium Influx

This compound's primary mechanism involves inhibiting the initial influx of calcium through voltage-dependent L-type calcium channels, leading to reduced intracellular calcium levels in vascular smooth muscle cells. nih.govmedchemexpress.comwikipedia.orgnih.gov This reduction in intracellular calcium subsequently decreases vascular smooth muscle contractility, promoting relaxation and vasodilation. nih.gov In addition to inhibiting influx, some studies suggest this compound may also specifically alter calcium mobilization from internal stores, potentially by interacting with the sarcoplasmic reticulum, particularly in stimulated vascular smooth muscle cells. nih.govresearchgate.netphysiology.org This effect on intracellular calcium dynamics appears to be a specific property of this compound and may contribute to its inhibitory effect on vascular smooth muscle cell growth. physiology.org this compound has also been shown to diminish the increase in intracellular calcium concentration in response to certain stimuli in other cell types, such as THP-1 cells. ahajournals.org

Effects on Mitogen-Activated Protein Kinase (ERK 1/2) Activation

Research indicates that this compound can influence the Mitogen-Activated Protein Kinase (MAPK) pathway, specifically the ERK 1/2 cascade. In some cell types, such as basic fibroblast growth factor (bFGF)-stimulated vascular smooth muscle cells, this compound has been shown to reduce both calcium influx and ERK 1/2 activation. nih.govresearchgate.net This suggests a link between voltage-gated calcium influx and ERK 1/2 activation in these cells. nih.govresearchgate.net Furthermore, this compound has been observed to inhibit prosurvival ERK signaling in certain cancer cells, contributing to potential enhanced therapeutic responses when combined with chemotherapy. pnas.org Studies in other models, such as LPS-induced cardiomyocytes, have shown this compound activating the PI3K/Akt pathway, which can be linked to downstream signaling effects, although the direct interaction with ERK 1/2 in this specific context might vary. nih.govpharmgkb.org In Marfan mice models, this compound treatment was associated with accentuated activation of both canonical and noncanonical TGFβ-dependent signaling cascades, including enhanced activation of ERK1/2, suggesting complex interactions depending on the cellular and physiological context. elifesciences.org this compound has been shown to effectively inhibit the phosphorylation of c-Raf and ERK without affecting total ERK levels in certain cancer cell lines, suggesting an impact upstream in the Raf/ERK pathway. nih.gov

Potential Role in Nitric Oxide Production and Endothelial Function

This compound has been investigated for its potential to influence nitric oxide (NO) production and improve endothelial function. Endothelial cells are crucial for releasing NO, a molecule vital for vasodilation and possessing antithrombotic, antiatherosclerotic, and anti-inflammatory properties. oup.com Studies suggest that this compound can enhance NO production in endothelial cells. oup.comahajournals.org

In vitro studies using cultured endothelial cells have indicated that this compound can increase basal NO formation in a concentration-dependent manner. researchgate.net This effect appears to involve an increase in endothelial NO synthase (eNOS) protein expression. researchgate.net Furthermore, research suggests that this compound may potentiate vascular endothelial growth factor (VEGF)-induced NO release by preventing the binding of acylated eNOS complexes to caveolin-1, an inhibitor of eNOS. researchgate.net This modulation of the eNOS/caveolin-1 interaction could represent a mechanism by which this compound improves endothelial function. researchgate.net

Beyond increasing NO formation, this compound may also enhance NO bioavailability by prolonging its half-life through antioxidative properties. researchgate.net In vitro models have shown that this compound can attenuate the release of reactive oxygen species, which can degrade NO. researchgate.net

Clinical studies have also explored the effect of this compound on NO production in humans. One study in patients with essential hypertension found that treatment with this compound significantly increased exhaled NO output both at rest and during exercise. oup.com This augmented NO bioavailability may contribute to improved endothelial function in these patients. oup.com

Research into Vasoprotective Properties

Research indicates that this compound possesses vasoprotective properties. rndsystems.com These effects may be related to its anti-inflammatory and antioxidative roles. cardiologyresearchjournal.comnih.gov Studies have shown that this compound can inhibit oxidative damage by free radicals in both in vivo and in vitro settings. cardiologyresearchjournal.com It is proposed that this compound counters oxidative stress by inhibiting the formation of free radicals through the donation of protons to lipid peroxide molecules, thereby protecting the cell membrane's lipid bilayer. cardiologyresearchjournal.com

Furthermore, this compound has been shown to inhibit the proliferation of human vascular smooth muscle cells, an action that can be related to antiatherosclerotic effects. rndsystems.comecrjournal.com It may also modulate matrix metalloproteinases, contributing to its vascular actions. ecrjournal.com

Modulation of Atherosclerotic Progression in Coronary and Carotid Arteries

This compound treatment has been associated with an impairment in the progression of atherosclerosis at both coronary and carotid levels in some studies. ecrjournal.com

The Prospective Randomized Evaluation of the Vascular Effects of Norvasc Trial (PREVENT) investigated the effect of this compound on the progression of early coronary atherosclerosis in patients with documented coronary artery disease. nih.govresearchgate.net While the study did not show a significant effect on the angiographic progression of coronary atherosclerosis, it demonstrated a significant effect in slowing the progression of carotid artery atherosclerosis as measured by the change in intima-media thickness (IMT). nih.govresearchgate.net

The Comparison of this compound versus Enalapril to Limit Occurrences of Thrombosis (CAMELOT) study also included a substudy evaluating coronary atherosclerosis progression by intravascular ultrasound (IVUS). ecrjournal.com In this substudy, the percentage atheroma volume increased less in the this compound group compared to the placebo group. ecrjournal.com

This compound's anti-inflammatory actions may also contribute to its effects on atherosclerosis. Studies in animal models have suggested that this compound can attenuate arteriosclerosis through the inhibition of inflammatory disorders. physiology.orgnih.gov This may involve the inhibition of local factors such as monocyte chemoattractant protein-1 (MCP-1) and a decrease in its receptor CCR2 in circulating monocytes. physiology.orgnih.gov Inhibition of the MCP-1 to CCR2 pathway may represent anti-inflammatory actions of this compound beyond blood pressure lowering. physiology.orgnih.gov this compound has also been shown to reduce expressions of inflammatory markers such as p38 mitogen-activated protein kinase (p38 MAPK), nuclear factor-kappa B (NF-κB), tumor necrosis factor-alpha (TNF-α), and vascular cell adhesion molecule-1 (VCAM-1) in in vitro models. researchgate.net

The inhibition of monocyte adhesion to vascular endothelium is considered a crucial step in atherogenesis. ahajournals.org In vitro studies have demonstrated that this compound can inhibit the adhesion of monocytes to vascular endothelium, suggesting a potential mechanism for its antiatherosclerotic effect. ahajournals.org This effect may involve the modulation of protein kinase C- and RhoA-dependent mechanisms. ahajournals.org

Characteristics of Oral Absorption

Plasma Protein Binding Characteristics

Hepatic Metabolism by Cytochrome P450 System (CYP3A4 and CYP3A5)

This compound undergoes extensive metabolism in the liver, primarily converted to inactive metabolites. drugbank.comnih.govwikipedia.org The cytochrome P450 (CYP) enzyme system plays a crucial role in this metabolic process, with CYP3A4 and CYP3A5 identified as the principal enzymes involved in the dehydrogenation of this compound. nih.govspandidos-publications.comdovepress.comresearchgate.net CYP3A4 is considered the main contributor to this compound dehydrogenation. dovepress.com

Studies have indicated that the activity of CYP3A enzymes can vary significantly among individuals, potentially influencing the in vivo pharmacokinetics of this compound. spandidos-publications.com Genetic polymorphisms in CYP3A4 and CYP3A5 genes have been investigated for their effects on this compound pharmacokinetics and pharmacodynamics. While some research suggests that CYP3A4 genotypes may be associated with blood pressure response to this compound, other studies have found no significant impact of CYP3A4 and CYP3A5 genetic polymorphisms on the pharmacokinetics and pharmacodynamics of this compound in primary hypertensive patients. spandidos-publications.compharmgkb.org However, some studies in specific populations, such as healthy Korean males, have observed differences in this compound oral clearance depending on the CYP3A5 genotype, with CYP3A53/*3 carriers exhibiting lower plasma concentrations compared to CYP3A51 carriers, although without significant differences in blood pressure or pulse rate. researchgate.netpharmgkb.org

The extensive hepatic metabolism of this compound, largely mediated by CYP3A4 and CYP3A5, is a key determinant of its elimination profile.

Excretion Routes and Metabolite Profiles

This compound is extensively metabolized in the liver, with approximately 90% converted to inactive metabolites. drugbank.comnih.gov The primary route of excretion for this compound and its metabolites is renal elimination. wikipedia.orgresearchgate.netnih.gov Approximately 60% of an administered dose is recovered in the urine, predominantly in the form of inactive pyridine metabolites. drugbank.comnih.govwikipedia.orgnih.gov Only about 10% of the parent compound is excreted unchanged in the urine. drugbank.comnih.gov A smaller proportion of the drug, 20-25%, is excreted in the feces. wikipedia.org

Studies using 14C-labelled this compound in human volunteers have shown that renal elimination is the major route, with about 60% of the radioactivity recovered in urine. nih.gov Total recovered radioactivity in urine and feces amounted to 84%. nih.gov Analysis of urine has identified pyridine metabolites as the primary excreted forms, with minimal unchanged this compound present. nih.gov The major metabolite identified was 2-([4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl- 2-pyridyl]methoxy) acetic acid, representing a significant portion of the urinary radioactivity. nih.gov The metabolic pathway involves the oxidation of this compound to its pyridine analogue, followed by further metabolism through oxidative deamination, de-esterification, and aliphatic hydroxylation. nih.gov

Terminal Elimination Half-Life Dynamics

This compound is characterized by a prolonged terminal elimination half-life, which is a significant factor contributing to its once-daily dosing regimen and sustained therapeutic effect. nih.govresearchgate.netbmj.comcardiologyresearchjournal.comnih.govdroracle.aidrugs.com The plasma elimination of this compound is biphasic. drugbank.comnih.govresearchgate.net The terminal elimination half-life typically ranges from approximately 30 to 50 hours in healthy individuals. drugbank.comnih.govwikipedia.orgresearchgate.netnih.govdroracle.ai Some sources report the half-life to be between 40-60 hours or 35-50 hours. nih.govdroracle.ainih.gov

This extended half-life allows for stable plasma concentrations to be maintained over a 24-hour period with once-daily administration. droracle.aiconsensus.app Steady-state plasma levels are generally achieved after 7 to 8 days of consecutive daily dosing. drugbank.comnih.govwikipedia.org In a study involving repeated oral administration to volunteers, steady state was reached after seven doses, with a mean half-life of 45 hours. umb.edu.pl

Factors such as impaired hepatic function can influence the half-life of this compound, leading to a prolonged elimination. nih.govdroracle.ai For instance, the plasma elimination half-life is reported to be 56 hours in patients with impaired hepatic function. drugbank.com Elderly patients may also exhibit reduced clearance of this compound, with an increase in the area under the curve (AUC) of about 40-60%. drugbank.com Renal impairment, however, does not appear to significantly influence the pharmacokinetics of this compound. nih.govwikipedia.org

The long half-life is a key pharmacokinetic characteristic that supports the sustained antihypertensive effect of this compound and minimizes fluctuations in blood pressure throughout the dosing interval. nih.govnih.gov

Here is a table summarizing some half-life data:

Onset and Duration of Antihypertensive Effect

The onset of the antihypertensive effect of this compound after oral administration is gradual. nih.govconsensus.appnsw.gov.au Peak plasma concentrations are typically achieved between 6 and 12 hours post-dose. drugbank.comnih.govwikipedia.org Some sources specify peak plasma concentrations occurring around 6 to 8 hours after dosing. nih.govconsensus.app This slow absorption contributes to a gradual decrease in blood pressure. consensus.app

The duration of the antihypertensive effect is notably long, lasting for at least 24 hours following a single daily dose. wikipedia.orgcardiologyresearchjournal.comnih.govmedscape.com This prolonged duration is directly linked to its long elimination half-life. droracle.aiconsensus.app Steady-state plasma levels, and thus full antihypertensive effect, are generally reached after 7 to 8 days of daily dosing. drugbank.comnih.govwikipedia.orgnsw.gov.auclincalc.com After a single dose, blood pressure may decrease gradually over 4-8 hours and slowly return to baseline over 24-72 hours. nih.gov Discontinuation of this compound treatment results in a slow return of blood pressure to baseline over 7-10 days. nih.gov

Here is a table summarizing onset and duration data:

Impact on Peripheral Vascular Resistance and Blood Pressure Reduction

This compound is classified as a peripheral arterial vasodilator. wikipedia.org Its primary mechanism of action in reducing blood pressure involves the inhibition of calcium ion influx into vascular smooth muscle cells. wikipedia.org This inhibition leads to the relaxation of these muscle cells, resulting in vasodilation and a decrease in peripheral vascular resistance. wikipedia.org The reduction in peripheral vascular resistance is a direct contributor to the lowering of blood pressure. wikipedia.org

Clinical studies have demonstrated that this compound effectively lowers both supine and standing blood pressure in patients with hypertension. drugbank.comwikipedia.org this compound significantly reduces total vascular resistance without decreasing cardiac output. wikipedia.org In studies, this compound significantly reduced baseline blood pressure and total peripheral resistance. oup.com

Absence of Significant Reflex Tachycardia

A notable pharmacodynamic characteristic of this compound is the absence of significant reflex tachycardia at therapeutic doses. wikipedia.orgbmj.comdroracle.ainih.gov Reflex tachycardia is a compensatory increase in heart rate that can occur with rapid vasodilation induced by some antihypertensive agents. This compound's gradual onset of action and prolonged duration of effect contribute to a slow and sustained reduction in blood pressure, which typically does not trigger the baroreflex-mediated stimulation of the sympathetic nervous system that leads to reflex tachycardia. nih.govconsensus.appoup.com

Blood Pressure Variability Modulation

Blood pressure variability (BPV) refers to the fluctuations in blood pressure over different time scales, including beat-to-beat, short-term (over 24 hours), mid-term (day-to-day or week-to-week), and long-term (visit-to-visit) variability. Increased BPV, independent of average blood pressure levels, has been recognized as a significant risk factor for cardiovascular events and target organ damage. bjcardio.co.ukmdpi.com Research indicates that certain antihypertensive medications can influence BPV, and this compound, a long-acting dihydropyridine calcium channel blocker, has been specifically studied for its effects on this parameter. bjcardio.co.ukmdpi.comresearchgate.net

Clinical trials and observational studies have provided evidence suggesting that this compound can effectively reduce BPV. bjcardio.co.ukmdpi.comresearchgate.net This effect has been observed across different time scales, including short-term and long-term variability. mdpi.comconicet.gov.ar Studies have compared this compound's effects on BPV to other classes of antihypertensive drugs, such as angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), beta-blockers, and diuretics. bjcardio.co.ukmdpi.comconicet.gov.ar

Detailed research findings highlight this compound's favorable impact on BPV. The X-CELLENT study, a randomized, double-blind, placebo-controlled trial, analyzed 24-hour ambulatory blood pressure monitoring (ABPM) data in hypertensive patients treated with this compound, candesartan, or indapamide sustained release. ahajournals.org The study found that this compound treatment was associated with a significant decrease in systolic BPV over 24 hours, as well as during daytime and nighttime periods. ahajournals.org In contrast, candesartan showed no significant effect on short-term BPV, while indapamide sustained release reduced daytime and 24-hour systolic BPV but not nighttime variability. ahajournals.org

The reduction in BPV observed with this compound in the X-CELLENT study was found to be significantly associated with both the reduction in mean systolic blood pressure and the reduction in heart rate variability (HRV). ahajournals.org This suggests that this compound's effect on BPV may be partly attributable to its blood pressure lowering effect and its influence on autonomic nervous system regulation. ahajournals.orgahajournals.orgresearchgate.net

Long-term, visit-to-visit BPV has also been shown to be reduced by this compound. bjcardio.co.ukmdpi.com The ASCOT (Anglo-Scandinavian Cardiac Outcomes Trial) study, for instance, demonstrated that an this compound-based regimen resulted in lower in-treatment visit-to-visit systolic BPV compared to an atenolol-based regimen. bjcardio.co.ukahajournals.org This reduction in long-term BPV with this compound was associated with a lower risk of cardiovascular outcomes, particularly stroke. bjcardio.co.ukmdpi.comahajournals.org The long half-life of this compound is thought to contribute to its sustained blood pressure lowering effect and its ability to reduce visit-to-visit variability. mdpi.comb-cdn.net

Studies comparing this compound to other antihypertensive classes have consistently shown a more pronounced reduction in BPV with this compound. bjcardio.co.ukmdpi.comconicet.gov.ar Meta-analyses have also supported the favorable impact of calcium channel blockers, including this compound, on visit-to-visit blood pressure variability compared to other antihypertensives. mdpi.com

While the precise mechanisms by which this compound modulates BPV are still being investigated, potential factors include its long duration of action, its effect on arterial stiffness, its influence on the baroreflex sensitivity, and its modulation of autonomic nervous system activity. ahajournals.orgresearchgate.netahajournals.org

Here is a data table summarizing findings from the X-CELLENT study regarding the effect of different antihypertensive agents on systolic blood pressure variability:

Another study comparing high-dose this compound, high-dose valsartan, and low-dose combination of this compound and valsartan over 10 weeks also assessed their effects on 24-hour systolic BPV. nih.gov

Here is a data table based on the findings of this study:

*Note: These values represent the change in 24-hour systolic BPV from baseline after 10 weeks of treatment. nih.gov A significant decrease in 24-hour systolic BPV was observed in the this compound and combination groups compared to baseline. nih.gov

These findings underscore the role of this compound in modulating blood pressure variability, which is considered an important factor in reducing cardiovascular risk beyond just lowering average blood pressure. bjcardio.co.ukmdpi.comresearchgate.net

Monotherapy Efficacy in Mild to Moderate Hypertension

Clinical studies have investigated the effectiveness of this compound as a monotherapy for mild to moderate hypertension. In a single-blind, placebo-controlled study involving patients with baseline diastolic blood pressure between 90 and 115 mmHg, this compound treatment for four weeks resulted in a significant reduction in both mean systolic and diastolic blood pressure nih.gov. Specifically, mean systolic pressure decreased from 177 mmHg to 145 mmHg, and mean diastolic pressure decreased from 106 mmHg to 84 mmHg (p < 0.05) nih.gov. At the end of the study period, 95% of patients achieved a diastolic blood pressure of ≤ 90 mmHg nih.gov.

Another study in Asian populations with mild to moderate hypertension showed that titrating this compound from 5 mg/day to 10 mg/day significantly reduced systolic blood pressure dovepress.comnih.gov. A real-world observational study in India also demonstrated that this compound therapy, used as monotherapy or add-on therapy, provided significant reductions in both office and 24-hour ambulatory blood pressure measurements over eight weeks in patients with mild to moderate essential hypertension nih.gov.

Comparative Efficacy Studies with Other Antihypertensive Agents

Comparative studies have evaluated the efficacy of this compound against other classes of antihypertensive medications. Research indicates that this compound is superior to diltiazem and hydrochlorothiazide in reducing systolic and diastolic blood pressure in patients with mild or moderate hypertension nih.gov. A study comparing this compound and hydrochlorothiazide monotherapy in Nigerian patients with mild to moderate hypertension found that this compound was significantly more effective in reducing both systolic and diastolic blood pressure, with 80% of patients in the this compound group achieving normal blood pressure compared to 50% in the hydrochlorothiazide group bioline.org.br.

In a study comparing this compound with fosinopril (an ACE inhibitor), this compound achieved a greater reduction in both systolic and diastolic blood pressure ahajournals.org. Systolic blood pressure reduction was 10 mmHg with this compound versus 8 mmHg with fosinopril (P=0.029), and diastolic blood pressure reduction was 5 mmHg with this compound versus 3 mmHg with fosinopril (P=0.040) ahajournals.org.

A systematic review comparing ACE inhibitors and calcium channel blockers (including this compound) for hypertension management found that CCBs generally showed superior efficacy in blood pressure reduction and achieving target blood pressure compared to ACE inhibitors ijmdc.com. A study comparing this compound and candesartan cilexetil as monotherapy in mild to moderate essential hypertensives showed that while both reduced blood pressure, the combination of this compound and candesartan was more effective jhsmr.org. After 12 weeks, this compound monotherapy reduced systolic blood pressure by 11.7 mmHg and diastolic blood pressure by 6.2 mmHg, while candesartan reduced systolic blood pressure by 13.1 mmHg and diastolic blood pressure by 10.7 mmHg jhsmr.org. The combination therapy resulted in reductions of 19 mmHg (systolic) and 11.9 mmHg (diastolic) (p < 0.0001) jhsmr.org.

A comparison between this compound and cilnidipine in hypertensive patients showed that both drugs effectively lowered systolic and diastolic blood pressure over an 8-week period fortuneonline.org. At week 8, the this compound group had a mean SBP of 133.12 mmHg and DBP of 86.3 mmHg, while the cilnidipine group had a mean SBP of 130.09 mmHg and DBP of 84.86 mmHg fortuneonline.org.

Sustained 24-Hour Blood Pressure Control

This compound's long elimination half-life of 35-50 hours supports once-daily administration and contributes to sustained blood pressure control over a 24-hour period nih.govnih.govconsensus.app. Studies using 24-hour ambulatory blood pressure monitoring (ABPM) have confirmed that this compound effectively maintains blood pressure control throughout the day and night consensus.appconsensus.appjcardcritcare.org. A randomized trial demonstrated that this compound 5 mg once daily was effective in maintaining both diastolic and systolic blood pressure below baseline levels throughout a 24-hour observation period jcardcritcare.org. A real-world study also reported significant reductions from baseline in all 24-hour ABPM measurements after eight weeks of this compound therapy nih.gov.

Furthermore, this compound has been shown to minimize blood pressure variability (BPV), which is considered crucial in reducing the risk of cardiovascular events nih.govjcardcritcare.org. In a study comparing this compound, candesartan, and indapamide, this compound was associated with a significant decrease in systolic BPV over 24 hours, as well as during daytime and nighttime periods ahajournals.org. This reduction in BPV with this compound was significantly associated with the reduction in mean systolic blood pressure and heart rate variability ahajournals.org.

Regression of Left Ventricular Hypertrophy

Left ventricular hypertrophy (LVH) is a significant predictor of cardiovascular morbidity and mortality in hypertensive patients karger.com. Blood pressure lowering is associated with the reduction of LVH nih.govamegroups.org. Studies have investigated the effect of this compound on the regression of LVH.

A 20-week open-label study in patients with essential hypertension and LVH showed that this compound treatment resulted in a significant regression in LVH, with the left ventricular mass index (LVMI) decreasing from 169.0 g/m² to 140.6 g/m² (p < 0.01, n = 12) karger.com. This study also observed significant reductions in diastolic wall thickness of the interventricular septum and posterior wall karger.com.

A systematic review and meta-analysis including 23 studies involving 737 patients found that this compound treatment led to a significant reduction in LVMI nih.govamegroups.org. The mean difference between follow-up and baseline LVMI was -12.9 g/m² (95% CI: -15.4 to -10.4; P < 0.001) nih.gov. This decrease in LVMI was positively associated with the duration of follow-up and the baseline LVMI nih.gov. This compound treatment also significantly reduced the left ventricular posterior wall thickness nih.gov.

However, a comparative study evaluating valsartan versus this compound on LV mass in hypertensive patients with LVH found that valsartan significantly reduced LVMI after eight months (16% reduction), while this compound had a lesser effect (1.2% reduction) (p < 0.01 for the comparison) jacc.org.

Management of Chronic Stable Angina and Vasospastic Angina

Controlled clinical studies have confirmed the anti-anginal efficacy of this compound nih.gov. In patients with chronic stable angina, this compound has demonstrated significant improvements in exercise tolerance and a reduction in the frequency of angina attacks consensus.app. A study showed that this compound significantly increased exercise duration and decreased the frequency of angina attacks and nitroglycerin consumption after just 4 weeks of treatment consensus.app. These findings were supported by another study noting improvements in exercise parameters as early as 6 hours post-dose, with sustained effects at 24 hours consensus.app.

This compound has been shown to have comparable anti-anginal efficacy to the beta-blocker nadolol and the calcium antagonist diltiazem nih.gov. When added to the treatment regimen of patients with uncontrolled chronic stable angina despite treatment with nitrates, beta-blockers, or both, this compound produced improved anti-anginal efficacy nih.gov.

This compound has also been consistently effective in patients with vasospastic angina nih.govnih.gov. A randomized placebo-controlled trial in patients with documented vasospastic angina found that this compound treatment significantly decreased the rate of anginal episodes compared to placebo, and the intake of sublingual nitroglycerin tablets showed a similar trend jacc.org. A systematic review comparing various calcium antagonists on vasospastic angina concluded that this compound is potent in decreasing vasospastic angina symptoms bmj.com.

Studies have shown no evidence of tolerance to the anti-anginal effects of this compound in clinical trials involving treatment for up to 26 weeks nih.govnih.gov.

Table 1: Summary of this compound Efficacy in Hypertension and Angina

Effects on Coronary Revascularization and Hospitalizations for Angina

Clinical trials have investigated the effects of this compound on the need for coronary revascularization procedures and the incidence of hospitalizations due to angina. The Prospective Randomized Evaluation of the Vascular Effects of Norvasc Trial (PREVENT), which included 825 patients with angiographically documented coronary artery disease (CAD), suggested a favorable outcome with this compound regarding fewer hospitalizations for angina and revascularization procedures over a 3-year follow-up period. pfizer.comnih.gov Specifically, this compound use was associated with fewer cases of unstable angina and coronary revascularization. ahajournals.org In the PREVENT trial, this compound significantly reduced the rates of unstable angina (60 events in the this compound group versus 85 in the placebo group, HR 0.67 [0.48 to 0.93]) and coronary revascularizations (53 events in the this compound group versus 86 in the placebo group, HR 0.57 [0.41 to 0.81]). ahajournals.org These reductions in hospitalization for angina pectoris and revascularization were observed regardless of concomitant use of beta-blockers, nitrates, or lipid-lowering therapy. ahajournals.org The Coronary Angioplasty this compound Restenosis Study (CAPARES) also evaluated this compound's effect on clinical outcomes in patients undergoing percutaneous transluminal coronary angioplasty (PTCA), finding a reduced incidence of repeat PTCA and significantly reduced composite major adverse clinical events during the four-month follow-up after PTCA in patients treated with this compound. cardiologyresearchjournal.com

Research on Atherosclerosis Progression in Coronary and Carotid Arteries

Research has explored this compound's impact on the progression of atherosclerosis in both coronary and carotid arteries. The PREVENT trial assessed the development and progression of atherosclerotic lesions in patients with known CAD. nih.govbmj.com While the study did not show a significant effect on the primary objective of change in coronary luminal diameter as assessed by quantitative coronary angiography over 36 months, it demonstrated a statistically significant influence on carotid artery atherosclerosis progression (p=0.007). ahajournals.orgcardiologyresearchjournal.com In the PREVENT study, the placebo group experienced a 0.033-mm increase in carotid intima-media thickness (IMT) over 3 years, whereas the this compound group had a 0.0126-mm decrease, indicating a slowing of progression in the carotid arteries. ahajournals.org The Comparison of this compound versus Enalapril to Limit Occurrences of Thrombosis (CAMELOT) study, which included patients with angiographically documented coronary disease, also included a substudy using intravascular ultrasound (IVUS) to measure coronary atherosclerosis progression. ecrjournal.com After 24 months, IVUS showed progression in the placebo group, a trend toward progression in the enalapril group, but no progression in the this compound group. tandfonline.com

Stroke Prevention Research

Multiple studies and meta-analyses have examined this compound's role in stroke prevention. A meta-analysis of seven long-term outcome trials comparing this compound-based regimens with non-calcium channel blocker (non-CCB) antihypertensive therapies found that this compound-based regimens significantly decreased the risk of stroke (OR, 0.84; 95% CI, 0.79 to 0.90; p < 0.00001). researchgate.netnih.gov Another quantitative overview of outcome trials involving this compound or angiotensin receptor blockers (ARBs) in patients with hypertension, CAD, or diabetic nephropathy showed that this compound provided more protection against stroke than other antihypertensive drugs, including ARBs (-19%, P<0.0001) and placebo (-37%, P=0.06). ahajournals.orgnih.gov The Anglo-Scandinavian Cardiac Outcome Trial (ASCOT) also showed that an this compound-based regimen (this compound + perindopril) significantly reduced stroke by 23% compared to an atenolol-based regimen (atenolol + thiazide diuretic). europa.eu The VALUE trial, comparing valsartan and this compound in high-risk hypertensive patients, indicated that this compound was superior to valsartan in the prevention of stroke (15%; p=0.08), although the difference did not reach statistical significance. ecrjournal.comahajournals.org

Myocardial Infarction Reduction Studies

Studies have also assessed this compound's efficacy in reducing the incidence of myocardial infarction (MI). The meta-analysis of seven long-term outcome trials showed that the risk of myocardial infarction was significantly decreased with an this compound-based regimen compared with a non-CCB-based regimen (odds ratio [OR], 0.91; 95% confidence interval [CI], 0.84 to 0.99; p = 0.03). researchgate.netnih.gov The quantitative overview of trials involving this compound or ARBs also indicated that this compound provided more protection against myocardial infarction than other antihypertensive drugs, including ARBs (-7%, P=0.03) and placebo (-29%, P=0.04). ahajournals.orgnih.gov The VALUE trial reported that this compound was superior to valsartan in the prevention of myocardial infarction (19%; p=0.02). ecrjournal.comahajournals.org

Overall Cardiovascular Morbidity and Mortality Outcomes

Here is a summary of key cardiovascular outcomes from selected studies:

This compound in Renin-Angiotensin-Aldosterone System Inhibitor Combinations

Combinations of this compound with RAAS inhibitors, such as Angiotensin-Converting Enzyme (ACE) inhibitors or Angiotensin II Receptor Blockers (ARBs), are a common and effective strategy for managing hypertension. These combinations leverage complementary mechanisms of action to achieve greater blood pressure reductions and potentially provide additional cardiovascular benefits.

Clinical trials have demonstrated the superior efficacy of this compound combined with RAAS inhibitors compared to monotherapy with either agent. A meta-analysis of 17 randomized controlled trials involving 3291 patients showed that the combination of this compound and ACE inhibitors resulted in a greater reduction of both systolic blood pressure (SBP) and diastolic blood pressure (DBP) than this compound monotherapy. nih.govnih.gov Specifically, the weighted mean difference for SBP reduction was 5.72 mmHg (95% CI: 4.10-7.33), and for DBP reduction was 3.62 mmHg (95% CI: 2.39-4.85). nih.govnih.gov The combination treatment also led to a higher hypertension therapeutic control rate (SBP <140, DBP <90 mmHg) compared to monotherapy (relative risk: 1.36, 95% CI: 1.07-1.73). nih.govnih.gov

Studies involving this compound and ARB combinations have also shown favorable results. A meta-analysis including seven RCTs with a total of 3,909 subjects found that the on-target rate of hypertension treatment was significantly higher in the this compound + ARB group than in the this compound monotherapy group (RR = 1.59; 95% CI, 1.31–1.91; P<0.01). amegroups.cnamegroups.org The response rates for SBP and DBP were also significantly higher with the combination therapy. amegroups.org

The Avoiding Cardiovascular Events Through Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) trial provided significant evidence regarding the benefits of combining this compound with a RAAS inhibitor. This study compared the combination of benazepril (an ACE inhibitor) and this compound with benazepril and hydrochlorothiazide (a diuretic) in high-risk hypertensive patients. centreformedicinesoptimisation.co.ukahajournals.orgeshonline.org The trial was stopped early due to the superior cardiovascular outcomes observed in the benazepril-amlodipine group. centreformedicinesoptimisation.co.ukahajournals.orgeshonline.org Over a mean follow-up of 36 months, there were fewer primary-outcome events (a composite of death from CV causes, nonfatal myocardial infarction, nonfatal stroke, hospitalization for angina, resuscitation after sudden cardiac arrest, or coronary revascularization) in the benazepril–this compound group (9.6%) than in the benazepril–hydrochlorothiazide group (11.8%). centreformedicinesoptimisation.co.uk This represented a relative risk reduction of 19.6% (hazard ratio [HR], 0.80, 95% confidence interval [CI] 0.72 to 0.90; P<0.001) with benazepril-amlodipine therapy. centreformedicinesoptimisation.co.uk The benefits of the benazepril/amlodipine combination over benazepril/hydrochlorothiazide were observed in both diabetic and non-diabetic patients. oup.com

Another comparative trial demonstrated that a combination of this compound plus valsartan (an ARB) produced greater reductions in blood pressure compared with a combination of lisinopril (an ACE inhibitor) and hydrochlorothiazide. nih.gov The combination of this compound and an ARB has been shown to be well tolerated, including in patients with stage 2 hypertension and the elderly. nih.gov Fixed-dose combinations of this compound with ARBs like valsartan and olmesartan have demonstrated BP-lowering efficacy and tolerability in diverse patient populations, including those with difficult-to-control blood pressure. nih.gov

The rationale for combining this compound with RAAS inhibitors lies in their complementary mechanisms. This compound, a vasodilator, can sometimes lead to reflex activation of the RAAS. bmj.com Combining it with an ACE inhibitor or ARB counteracts this activation, leading to enhanced antihypertensive effects. bmj.com Beyond blood pressure lowering, laboratory and experimental studies have suggested that ARBs and CCBs may possess anti-inflammatory, antioxidant, antiproliferative, and prorelaxant effects, although the clinical implications of these effects require further clarification. nih.gov

Table 1: Summary of Efficacy Data for this compound in RAAS Inhibitor Combinations

This compound in Beta-Blocker Combinations

The combination of this compound, a calcium channel blocker, and a beta-blocker is another approach used in hypertension management, particularly when monotherapy is insufficient or in patients with coexisting conditions like angina. The rationale for this combination stems from their different mechanisms of action, which can lead to additive blood pressure lowering effects. Beta-blockers reduce heart rate and contractility, while this compound causes vasodilation.

Research has investigated the efficacy of combining this compound with beta-blockers. A randomized double-blind parallel group study assessed the efficacy of atenolol combined with this compound in patients with stage I-II essential hypertension not controlled by atenolol alone. nih.gov Twenty-four-hour arterial blood pressure monitoring demonstrated that the addition of this compound to atenolol resulted in a statistically significant reduction in blood pressure values compared with placebo in these patients. nih.gov The study indicated that the combination was effective in lowering blood pressure in patients who had not achieved adequate control with beta-blocker monotherapy. nih.gov

The Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) included a comparison between an this compound-based regimen (this compound with perindopril as required) and an atenolol-based regimen (atenolol with or without a diuretic) in hypertensive patients with at least three other cardiac risk factors. bmj.comcardiologyresearchjournal.com While this trial primarily compared different strategies, the this compound-based regimen, which often involved the addition of perindopril (an ACE inhibitor), showed superior outcomes in reducing all-cause mortality, CV mortality, coronary events, and strokes compared to the atenolol-based regimen. bmj.com Although this trial's this compound arm frequently included a RAAS inhibitor, it provides context for the role of this compound in combination strategies and suggests potential advantages over beta-blocker-based regimens in certain outcomes. bmj.comcardiologyresearchjournal.com

A population-based cohort study comparing clinical outcomes in hypertensive patients treated with this compound plus bisoprolol (a beta-blocker) versus this compound plus valsartan (an ARB) found similar efficacy outcomes regarding all-cause death, atherosclerotic cardiovascular disease (ASCVD) events, and heart failure between the two combinations over a mean follow-up of 4.34 years. researchgate.net However, the risk of hemorrhagic stroke was lower in the this compound plus bisoprolol group. researchgate.net

Table 2: Summary of Efficacy Data for this compound in Beta-Blocker Combinations

This compound in Diuretic Combinations

Combining this compound with a diuretic, particularly a thiazide diuretic, is another established strategy for managing hypertension. Diuretics reduce blood volume and complement the vasodilatory effects of this compound, leading to enhanced blood pressure lowering.

Clinical studies have evaluated the efficacy of this compound in combination with diuretics. A study comparing this compound monotherapy with hydrochlorothiazide monotherapy in elderly patients with ambulatory hypertension found that while this compound monotherapy induced significant reductions in both clinic and ambulatory blood pressure, hydrochlorothiazide monotherapy only significantly decreased clinic blood pressure. oup.com However, the addition of this compound to hydrochlorothiazide in patients inadequately controlled by monotherapy resulted in statistically significant reductions in both clinic and ambulatory blood pressure, comparable to those achieved with this compound monotherapy. oup.com

The ACCOMPLISH trial, as mentioned earlier, compared benazepril-amlodipine with benazepril-hydrochlorothiazide. centreformedicinesoptimisation.co.ukahajournals.orgeshonline.org While the focus was on the RAAS inhibitor combination, the benazepril-hydrochlorothiazide arm serves as a comparator involving a diuretic. The results showed that the benazepril-amlodipine combination was superior in reducing cardiovascular events despite similar blood pressure reductions in both groups in some analyses. centreformedicinesoptimisation.co.ukahajournals.orgeshonline.orgoup.com This suggests that while this compound-diuretic combinations are effective in lowering blood pressure, this compound-RAAS inhibitor combinations may offer additional cardiovascular protection in high-risk populations. centreformedicinesoptimisation.co.ukahajournals.orgeshonline.org

A study comparing this compound plus telmisartan (an ARB) and this compound plus amiloride/hydrochlorothiazide in patients with essential hypertension and at least one cardiovascular risk factor found that long-term combination therapy with both regimens was efficacious in reducing blood pressure levels with acceptable control rates. nih.gov The blood pressure reductions were similar between the two groups at the endpoint of 96 weeks. nih.gov

Research also indicates that in patients whose blood pressure is not controlled by the combination of this compound and lisinopril (an ACE inhibitor), the addition of a thiazide diuretic (bendrofluazide) causes a significant fall in blood pressure compared with placebo and a significantly greater fall than the addition of atenolol (a beta-blocker). ahajournals.org This suggests that a diuretic can be an effective third agent when an this compound-ACE inhibitor combination is insufficient. ahajournals.org The additive effect of a thiazide diuretic in the presence of both a dihydropyridine calcium antagonist and an ACE inhibitor is thought to be due to the ACE inhibitor preventing the compensatory rise in angiotensin II that might otherwise occur with diuretic use alongside a calcium channel blocker. ahajournals.org

Table 3: Summary of Efficacy Data for this compound in Diuretic Combinations

Interactions with Macrolide Antibiotics (Clarithromycin, Erythromycin)

Macrolide antibiotics, such as clarithromycin and erythromycin, are known inhibitors of CYP3A4. nih.govhse.ienih.gov Co-administration of this compound with these macrolides can lead to increased plasma levels of this compound due to reduced metabolism. droracle.ainih.govverywellhealth.com This interaction is particularly significant in older adults (65 years and older), who may be more susceptible to the effects of increased this compound exposure, such as hypotension and kidney problems. verywellhealth.com

A study involving older patients receiving a calcium channel blocker (including this compound) demonstrated a strong association between the use of erythromycin or clarithromycin and an increased risk of hospitalization for hypotension or shock. nih.govcmaj.ca Erythromycin was associated with an odds ratio (OR) of 5.8 (95% confidence interval [CI] 2.3–15.0) for hospitalization due to hypotension, while clarithromycin had a marginally lower but still significant risk (OR 3.7, 95% CI 2.3–6.1). cmaj.ca In contrast, azithromycin, another macrolide that does not significantly inhibit CYP3A4, showed no such association (OR 1.5, 95% CI 0.8–2.8). nih.govcmaj.ca

These findings highlight the clinical significance of the interaction between this compound and CYP3A4-inhibiting macrolides, suggesting that preferential use of azithromycin should be considered when a macrolide is required in patients already receiving a calcium channel blocker. nih.govcmaj.ca

Interactions with HIV Protease Inhibitors (e.g., Lopinavir/Ritonavir)

HIV protease inhibitors, particularly ritonavir, are potent inhibitors of CYP3A4 and are often used in combination with other antiretroviral drugs. wikipedia.orgebi.ac.ukmims.comwikipedia.org Co-administration of this compound with ritonavir-boosted regimens can lead to a significant increase in this compound plasma concentrations. droracle.ainih.gov

A population pharmacokinetic analysis in people living with HIV (PLWH) demonstrated that this compound apparent clearance was influenced by CYP3A4 inhibitors. nih.gov Model-based simulations from this study revealed that this compound AUC (area under the curve), a measure of drug exposure, increased by 96% when coadministered with CYP3A4 inhibitors, primarily driven by ritonavir-boosted darunavir. nih.gov This substantial increase in exposure necessitates careful monitoring and potential this compound dose adjustments when used concurrently with potent CYP3A4 inhibitors like those found in lopinavir/ritonavir combinations.

Implications for Other CYP3A4 Substrates, Inhibitors, and Inducers

As a CYP3A4 substrate and inhibitor, this compound's pharmacokinetics can be affected by other drugs that interact with this enzyme. droracle.aimdpi.comnih.gov

CYP3A4 Inhibitors: Other potent and moderate CYP3A4 inhibitors, such as certain antifungals (e.g., ketoconazole, itraconazole, fluconazole), diltiazem, and grapefruit juice, can increase this compound exposure, potentially leading to increased risk of toxicity and hypotension. droracle.aidrugs.comverywellhealth.com For instance, coadministration of a single 5 mg dose of this compound with diltiazem (a moderate CYP3A4 inhibitor) resulted in a nearly 60% increase in this compound peak plasma concentration and systemic exposure in elderly hypertensive patients. drugs.com

CYP3A4 Inducers: Conversely, potent CYP3A4 inducers like rifampin, phenytoin, carbamazepine, and apalutamide can decrease this compound plasma concentrations, potentially reducing its effectiveness. droracle.aidrugs.comverywellhealth.commedscape.com Studies with other calcium channel blockers primarily metabolized by CYP3A4 have shown significant reductions in plasma levels when co-administered with potent inducers. drugs.com For example, nimodipine AUC was lowered by about 7-fold in patients receiving concurrent treatment with potent CYP3A4-inducing antiepileptic agents. drugs.com

Other CYP3A4 Substrates: this compound itself can also inhibit CYP3A4, which may affect the metabolism of other co-administered drugs that are substrates of this enzyme. mdpi.com This could lead to increased exposure and potential toxicity of those medications.