Amlodipine

Synthetic Routes and Reaction Conditions: Amlodipine can be synthesized through a multi-step process involving the Hantzsch dihydropyridine synthesis. The key steps include the condensation of an aldehyde, a β-keto ester, and an amine. The reaction conditions typically involve heating the reactants in the presence of a suitable solvent .

Industrial Production Methods: Industrial production of this compound often involves wet granulation and tableting. The process includes mixing this compound besylate with excipients such as microcrystalline cellulose and crospovidone, followed by granulation, drying, and tableting .

Hydrolysis of Ester Groups

Amlodipine contains two ester moieties susceptible to hydrolysis under acidic, alkaline, or neutral conditions:

• Acidic hydrolysis : In 0.1N HCl at 80°C, the ester groups degrade into carboxylic acid derivatives. This reaction follows first-order kinetics with a degradation rate constant ($k$) of $1.58\times 10^{-3}\,\text{hr}^{-1}$ and a half-life ($t_{1/2}$) of 438 hours .

• Alkaline hydrolysis : Exposure to 0.1N NaOH at room temperature for 4 hours causes minimal degradation (~5%), but heating to 80°C in 0.05M NaHCO₃ increases degradation to 25.9% .

Table 1: Hydrolysis kinetics of this compound besylate

Oxidative Degradation

This compound undergoes oxidation via hydrogen peroxide (H₂O₂) or electrochemical means:

• 3% H₂O₂ at 80°C : Degrades 80.1% of the drug within 6 hours, forming a primary oxidative product (retention time: 14.335 min) identified as dehydro this compound ($C_{20}H_{23}N_2O_5Cl$) .

• Electrochemical oxidation : Cyclic voltammetry reveals a degradation rate of 66.5% after 9 hours, with oxidation potential shifted by 200 mV .

Photodegradation

UV light exposure induces structural changes:

• 254 nm UV light : Degrades 14.1% of this compound after 2 hours, forming three photoproducts .

• ICH photostability guidelines (14 days) : Results in 32.2% degradation with two major photoproducts .

Table 2: Photostability profile

Thermal Decomposition

Thermal stress at elevated temperatures accelerates degradation:

• 80°C in methanol : Half-life of 29.7 hours with an activation energy ($E_a$) of 12.1 kcal/mol .

• 100°C in PEG600 : Degradation follows pseudo-first-order kinetics ($k=0.05693\,\text{hr}^{-1}$) .

Metabolic Reactions

Hepatic metabolism via CYP3A4 dominates:

• Oxidation : The amine group is oxidized to pyridine derivatives.

• Ester hydrolysis : Side-chain esters are hydrolyzed to inactive carboxylic acids .

• Excretion : 60% of metabolites (e.g., inactive pyridine analogs) are renally excreted .

Table 3: Metabolic pathways

Stability in Formulations

• Aqueous suspensions : Stable for 90 days at 5°C but degrade by 14% at 25°C within 7 days .

• Solid-state stability : Unaffected by humidity but sensitive to prolonged light exposure .

Key Findings from Forced Degradation Studies

• Vulnerability : Susceptible to oxidation > photolysis > hydrolysis .

• Degradants : Include dehydro this compound, pyridine dicarboxylates, and chlorophenyl derivatives .

• pH dependence : Degradation is minimized at neutral pH (optimal stability at pH 6–7) .

For clinical formulations, this compound besylate’s stability is maximized in anhydrous, light-protected environments with pH-controlled excipients .

Amlodipine is a medication primarily used to treat hypertension and angina, demonstrating efficacy and safety in numerous randomized controlled trials . Research indicates that this compound functions as a first-rate anti-hypertensive agent, effectively controlling blood pressure and safely improving patient outcomes .

Indications and Applications

This compound is used in the treatment of several conditions :

• Hypertension
• Coronary artery disease
• Chronic stable angina
• Vasospastic angina (Prinzmetal’s or Variant angina)
• Angiographically documented coronary artery disease in patients without heart failure or an ejection fraction < 40%

This compound can be prescribed as a standalone medication or in conjunction with other antihypertensive and antianginal agents .

Clinical Trials and Studies

This compound has demonstrated benefits in several clinical trials:

• A study showed that normotensive patients treated with this compound had a decline in cardiovascular events, regression of atherosclerotic changes, fewer hospitalizations, and a significant decrease in non-fatal myocardial infarction by 26% and stroke or transient ischemic attack by 50% .
• The ACCOMPLISH trial indicated that this compound was superior to HCTZ for preventing end-stage renal disease . Patients older than 65 who progressed to dialysis had a 70% relative risk reduction in the this compound group versus the HCTZ group (p=0.053) . The this compound group also had a 48% relative risk reduction for chronic kidney disease (CKD) progression compared with the HCTZ group .
• The Prospective Randomised this compound Survival Evaluation (PRAISE) 1 trial revealed that patients with severe chronic heart failure and non-ischemic cardiomyopathy who were taking this compound had a lower risk of death than those who were taking a placebo .

Effects on Heart Failure

While this compound has been proven safe and effective in treating hypertension and angina, evidence of its effectiveness in patients with heart failure (HF) and non-ischemic cardiomyopathy is still inconclusive . this compound has demonstrated a positive effect on ventricular remodeling, a common feature of HF . It has been shown to reduce left ventricular mass and volume and improve left diastolic function, potentially leading to clinical improvements in HF patient outcomes . this compound has also been reported to have antioxidant properties, which may protect against oxidative stress and inflammation, both of which play a role in the development and progression of HF . Additionally, this compound has a vasodilatory effect, which could potentially improve myocardial perfusion and oxygen supply, leading to improved clinical outcomes .

Safety and Efficacy

Role in Renoprotection

In the ACCOMPLISH trial, hydrochlorothiazide (HCTZ) was inferior to this compound for the prevention of end-stage renal disease . Furthermore, in patients who were >65 years old at baseline, there was a 70% relative risk reduction in patients progressing to dialysis in the this compound group versus the HCTZ group (p=0.053, for the difference) . In the intention-to-treat population, the this compound group had a 48% relative risk reduction for chronic kidney disease (CKD) progression, defined as doubling of serum creatinine, estimated glomerular filtration rate (eGFR) <15 mL/min, or dialysis compared with the HCTZ group . Furthermore, patients with CKD, defined as an eGFR of 45.1 mL/min at baseline, showed a significantly greater decline in renal function with HCTZ versus this compound (−2.3 vs −1.6 mL/min; p=0.001) .

Predictive Performance

Amlodipine exerts its effects by inhibiting the influx of calcium ions into vascular smooth muscle and cardiac muscle cells. This inhibition leads to the relaxation of blood vessels, resulting in decreased peripheral vascular resistance and lower blood pressure. The molecular targets of this compound include L-type calcium channels, which play a critical role in the contraction of vascular smooth muscle .

Nifedipine

• Structural Differences : Nifedipine features a nitro group at the 3-position of the DHP ring, compared to Amlodipine’s bulky amine substituent .
• Pharmacokinetics : Shorter half-life (~2–5 hours), necessitating multiple daily doses. Rapid vasodilation can cause reflex tachycardia, a drawback mitigated by this compound’s gradual action .
• Clinical Use : Primarily for hypertension and angina, but less favored due to adverse effects like flushing and hypotension .

Table 1: Key Differences Between this compound and Nifedipine

Felodipine and Nicardipine

• Felodipine : Similar selectivity for vascular calcium channels but shorter half-life (~11 hours). Requires twice-daily dosing in some cases .
• Nicardipine: Used intravenously for hypertensive emergencies. Oral formulations have faster onset (1–2 hours) than this compound but shorter duration .

Table 2: Pharmacokinetic Comparison of DHP CCBs

This compound Salt Forms

Different salts (e.g., besylate, adipate, mesylate) exhibit bioequivalence in pharmacokinetics and pharmacodynamics:

• This compound Besylate vs. Adipate : Ratios of AUClast and Cmax for 5 mg and 10 mg doses were 0.93–1.01 and 0.89–1.09, respectively, confirming equivalence .
• Besylate vs.

Table 3: Bioequivalence of this compound Salts

Structural Analogs and Novel Derivatives

• Nitrendipine M (dehydro): A dehydrogenated derivative with unique pharmacokinetics.

Combination Therapies

• This compound/Valsartan/HCTZ: Bioequivalence studies (5/160/12.5 mg to 10/320/25 mg) showed AUC and Cmax ratios within 0.8–1.25, supporting interchangeability with monotherapies .
• This compound/Olmesartan : Fixed-dose combinations reduce systolic BP by 30.1 mmHg (53% greater than this compound alone) with fewer side effects (e.g., peripheral edema) .

Amlodipine is a widely used calcium channel blocker (CCB) primarily prescribed for hypertension and angina. Its biological activity extends beyond its antihypertensive effects, with emerging evidence suggesting antimicrobial properties and antioxidant activities. This article discusses the multifaceted biological activities of this compound, supported by recent research findings, case studies, and data tables.

This compound functions by blocking L-type calcium channels, which inhibits calcium ion influx into vascular smooth muscle and cardiac muscle cells. This action leads to vasodilation, reducing peripheral vascular resistance and lowering blood pressure. The drug exhibits a stronger effect on vascular smooth muscle compared to cardiac muscle, contributing to its efficacy in managing hypertension without significantly increasing heart rate .

Antimicrobial Activity

Recent studies have highlighted this compound's potential as an antimicrobial agent. A study evaluated its in vitro activity against Staphylococcus aureus, including methicillin-resistant strains (MRSA). The findings indicated that this compound exhibited antimicrobial activity with minimum inhibitory concentrations (MICs) ranging from 64 to 128 μg/ml. Notably, it demonstrated synergistic effects when combined with oxacillin in approximately 58% of the strains tested .

Table 1: Antimicrobial Activity of this compound Against Staphylococcus aureus

Antioxidant Properties

This compound also exhibits significant antioxidant properties. Research involving Sprague-Dawley rats indicated that this compound administration reduced oxidative stress markers and improved endothelial function. Specifically, it decreased plasma levels of isoprostanes and thromboxane A2 while increasing levels of prostacyclin and nitric oxide, which are crucial for vascular health . This antioxidant activity may contribute to its protective effects against cardiovascular diseases.

Clinical Studies and Findings

Several landmark trials have established the efficacy of this compound in various clinical settings:

• PRAISE-2 Trial : This study assessed the impact of this compound on survival in patients with heart failure. It demonstrated that this compound not only improved hemodynamic parameters but also enhanced quality of life without causing significant adverse effects .
• Hypertension Management : this compound has been shown to maintain blood pressure control for over 24 hours after a single dose, which is beneficial for patient adherence to treatment regimens .
• Comparative Studies : A study comparing this compound with other antihypertensive agents found that it increased nitric oxide production in failing hearts, suggesting additional vasoprotective benefits .

Table 2: Summary of Clinical Findings on this compound

Basic Research Questions

Q. What are the standard analytical methods for quantifying amlodipine in pharmacokinetic studies, and how are they validated?

• Methodological Answer : Reverse-phase high-performance liquid chromatography (RP-HPLC) and liquid chromatography-tandem mass spectrometry (LC-MS/MS) are widely used. Key validation parameters include specificity, linearity (e.g., 5–100 ng/mL for plasma), precision (RSD <15%), and accuracy (85–115% recovery). For example, Bhatt (2007) optimized LC-MS/MS with a C18 column, methanol:ammonium acetate mobile phase (70:30 v/v), and electrospray ionization . Alsarra (2009) validated RP-HPLC using a UV detector (λ=237 nm) and a mobile phase of acetonitrile:phosphate buffer (pH 3.0) .

Q. How can researchers address variability in reported pharmacokinetic parameters (e.g., half-life, bioavailability) of this compound across studies?

• Methodological Answer : Variability often arises from differences in study design (e.g., single vs. multiple dosing), participant demographics (e.g., renal/hepatic impairment), or analytical methods. To reconcile discrepancies, systematically compare methodologies: assess extraction techniques (protein precipitation vs. liquid-liquid extraction), calibration ranges, and statistical models (non-compartmental vs. compartmental analysis) .

Q. What experimental controls are essential when studying this compound’s interaction with co-administered drugs (e.g., perindopril) in dissolution studies?

• Methodological Answer : Include positive controls (this compound alone), negative controls (placebo formulations), and stability tests under varying pH (1.2–6.8) and temperature (37°C). For combination therapies, use a central composite design to optimize dissolution media and agitation rates, as demonstrated by Yeole (2011) for this compound-telmisartan combinations .

Advanced Research Questions

Q. How can Quality-by-Design (QbD) principles improve the robustness of this compound quantification methods?

• Methodological Answer : Apply Design of Experiments (DoE) to identify critical method parameters (e.g., mobile phase pH, column temperature). For example, Feng (2002) used response surface methodology (RSM) to optimize peak resolution (Rs >2.0) and asymmetry factor (0.9–1.1) by varying acetonitrile concentration (65–75%) and flow rate (0.8–1.2 mL/min) . Define the design space using ICH Q14 guidelines to ensure method adaptability across labs .

Q. What strategies resolve contradictions in this compound’s reported oxidative degradation pathways under stress conditions?

• Methodological Answer : Use forced degradation studies with orthogonal analytical techniques. For instance, combine HPLC-UV for primary quantification and LC-MS/MS to identify degradation products (e.g., pyridine derivatives under acidic hydrolysis). Alsarra (2009) demonstrated this approach by correlating degradation kinetics with Arrhenius plots to predict shelf-life .

Q. How should researchers design experiments to evaluate this compound’s synergistic effects with ACE inhibitors (e.g., perindopril) in hypertensive models?

• Methodological Answer : Employ factorial designs to test dose-response relationships and interaction terms. Key variables include blood pressure measurements (tail-cuff vs. telemetry), dosing intervals, and biomarkers (e.g., angiotensin II levels). A 2×2 factorial design can isolate synergistic effects, as seen in studies combining this compound and perindopril .

Q. What statistical approaches are recommended for analyzing this compound’s dose-dependent vasodilation in ex vivo vascular tissue studies?

• Methodological Answer : Use nonlinear regression (e.g., sigmoidal Emax models) to calculate EC50 values. Account for tissue variability via mixed-effects models, incorporating random effects for donor demographics. Alsarra (2009) applied this to human aortic rings, reporting EC50=1.2 nM ± 0.3 .

Q. Methodological Frameworks

• For Contradiction Analysis : Apply the FINER criteria (Feasible, Interesting, Novel, Ethical, Relevant) to prioritize hypotheses .
• For Experimental Design : Use PICO (Population: hypertensive patients; Intervention: this compound; Comparison: placebo; Outcome: BP reduction) to structure clinical queries .
• For Reproducibility : Follow STARD guidelines for diagnostic accuracy studies or CONSORT for clinical trials, ensuring raw data (e.g., chromatograms) are archived .