Amlodipine besylate
Overview
Description
Amlodipine besylate is a calcium channel blocker used primarily to treat high blood pressure and angina. It is a long-acting dihydropyridine-type calcium channel antagonist that works by relaxing the blood vessels, allowing blood to flow more easily. This compound is widely prescribed due to its efficacy and relatively mild side effect profile .
Scientific Research Applications
Amlodipine besylate has a wide range of scientific research applications:
Biology: Studied for its effects on cellular calcium channels and its role in cellular signaling pathways.
Medicine: Extensively researched for its therapeutic effects in treating hypertension and angina.
Industry: Used in the formulation of various pharmaceutical products due to its stability and efficacy.
Mechanism of Action
Target of Action
Amlodipine besylate, a popular antihypertensive drug, primarily targets the L-type calcium channels in muscle cells and N-type calcium channels in the central nervous system . These channels are involved in nociceptive signaling and pain perception .
Mode of Action
This compound is a dihydropyridine calcium antagonist that inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle . It binds to both dihydropyridine and non-dihydropyridine binding sites . This inhibition of calcium ion influx leads to a reduction in peripheral vascular resistance, causing a decrease in blood pressure .
Biochemical Pathways
This compound acts by inhibiting the influx of Ca2+ ions into cells without significantly affecting inward Na+ or outward K+ currents .
Pharmacokinetics
This compound has a bioavailability of 64-90% . It is metabolized in the liver, and its metabolites are excreted in urine . The onset of action is highest 6-12 hours after an oral dose, and it has an elimination half-life of 30-50 hours . The duration of action is at least 24 hours .
Result of Action
This compound reduces the total peripheral resistance (afterload) against which the cardiac muscle functions . This leads to a reduction in blood pressure and relief of symptoms of angina . This compound also has antioxidant properties and enhances the production of nitric oxide (NO), an important vasodilator that decreases blood pressure .
Action Environment
The action of this compound can be influenced by various environmental factors. For instance, when used by people with liver problems, and in elderly individuals, doses should be reduced . Drinking alcohol can further lower your blood pressure and may increase certain side effects of amlodipine .
Safety and Hazards
Future Directions
Amlodipine besylate is used to treat high blood pressure and prevent chest pain. It is recommended to take this medicine only as directed by a doctor. Drinking alcohol can further lower blood pressure and may increase certain side effects of amlodipine . If you are being treated for high blood pressure, keep using amlodipine even if you feel well .
Biochemical Analysis
Biochemical Properties
Amlodipine besylate interacts with calcium channels in the small arterioles, leading to arterial dilation . It has antioxidant properties and an ability to enhance the production of nitric oxide (NO), an important vasodilator that decreases blood pressure .
Cellular Effects
This compound has a dilating effect on peripheral arterioles, reducing the total peripheral resistance (afterload) against which the cardiac muscle functions . This reduced work of the heart decreases both myocardial energy use and oxygen requirements .
Molecular Mechanism
This compound is a dihydropyridine calcium antagonist that inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle . This inhibition of calcium influx leads to arterial dilation, reducing blood pressure .
Temporal Effects in Laboratory Settings
This compound has been shown to have good efficacy and safety, with strong evidence from large randomized controlled trials for cardiovascular event reduction . The effects of this compound are long-lasting, with the option for single daily dosing .
Dosage Effects in Animal Models
In animal models, this compound has been shown to have various side effects. In cats, these may include vomiting, diarrhea, lack of appetite, or sleepiness. In dogs, side effects may include gingival (gum) overgrowth .
Metabolic Pathways
This compound is metabolized in the liver, primarily via dehydrogenation of its dihydropyridine moiety to a pyridine derivative . This metabolism is thought to be mediated by CYP3A4/5 .
Transport and Distribution
This compound is well absorbed after oral administration and is highly protein-bound (93%) . It is distributed widely in the body due to its lipophilic nature .
Subcellular Localization
This compound readily penetrates the plasma membrane and accumulates in the intracellular vesicles . Its visible emission and photostability allow for confocal time-lapse imaging and the monitoring of drug uptake .
Preparation Methods
Synthetic Routes and Reaction Conditions
The synthesis of amlodipine besylate involves several steps. The key intermediate, amlodipine, is synthesized through a multi-step process starting from 2-chlorobenzaldehyde. The final step involves the reaction of amlodipine with benzenesulfonic acid to form this compound .
Step 1: Condensation of 2-chlorobenzaldehyde with ethyl acetoacetate in the presence of ammonia to form 2-chlorobenzylidene ethyl acetoacetate.
Step 2: Cyclization of the intermediate with methylamine to form 2-chlorophenyl-1,4-dihydropyridine.
Step 3: Alkylation of the dihydropyridine with 2-(2-aminoethoxy)ethanol to form amlodipine.
Step 4: Reaction of amlodipine with benzenesulfonic acid to form this compound
Industrial Production Methods
Industrial production of this compound follows similar synthetic routes but is optimized for large-scale production. The process involves the use of high-efficiency mixing granulators and dry granulation techniques to ensure high yield and purity .
Chemical Reactions Analysis
Amlodipine besylate undergoes various chemical reactions, including:
Reduction: Reduction reactions are less common but can be performed under specific conditions.
Substitution: This compound can undergo substitution reactions, particularly at the aromatic ring.
Common reagents used in these reactions include hydrogen peroxide for oxidation and sodium borohydride for reduction. The major products formed depend on the specific reaction conditions but often include various derivatives of amlodipine .
Comparison with Similar Compounds
Amlodipine besylate is often compared with other calcium channel blockers such as nifedipine, felodipine, and verapamil.
Nifedipine: Similar in its mechanism of action but has a shorter half-life and requires more frequent dosing
Felodipine: Also a dihydropyridine calcium channel blocker but differs in its pharmacokinetic profile and side effect profile
Verapamil: A non-dihydropyridine calcium channel blocker that affects both vascular smooth muscle and cardiac muscle, leading to a broader range of therapeutic effects but also more potential side effects
This compound is unique due to its long half-life, allowing for once-daily dosing, and its relatively mild side effect profile .
Properties
IUPAC Name |
benzenesulfonic acid;3-O-ethyl 5-O-methyl 2-(2-aminoethoxymethyl)-4-(2-chlorophenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate |
Source
|
|---|---|---|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI |
InChI=1S/C20H25ClN2O5.C6H6O3S/c1-4-28-20(25)18-15(11-27-10-9-22)23-12(2)16(19(24)26-3)17(18)13-7-5-6-8-14(13)21;7-10(8,9)6-4-2-1-3-5-6/h5-8,17,23H,4,9-11,22H2,1-3H3;1-5H,(H,7,8,9) |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI Key |
ZPBWCRDSRKPIDG-UHFFFAOYSA-N |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Canonical SMILES |
CCOC(=O)C1=C(NC(=C(C1C2=CC=CC=C2Cl)C(=O)OC)C)COCCN.C1=CC=C(C=C1)S(=O)(=O)O |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Molecular Formula |
C26H31ClN2O8S |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
DSSTOX Substance ID |
DTXSID2043909 |
Source
|
| Record name | Amlodipine besylate | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID2043909 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
Molecular Weight |
567.1 g/mol |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
CAS No. |
111470-99-6 |
Source
|
| Record name | Amlodipine besylate | |
| Source | CAS Common Chemistry | |
| URL | https://commonchemistry.cas.org/detail?cas_rn=111470-99-6 | |
| Description | CAS Common Chemistry is an open community resource for accessing chemical information. Nearly 500,000 chemical substances from CAS REGISTRY cover areas of community interest, including common and frequently regulated chemicals, and those relevant to high school and undergraduate chemistry classes. This chemical information, curated by our expert scientists, is provided in alignment with our mission as a division of the American Chemical Society. | |
| Explanation | The data from CAS Common Chemistry is provided under a CC-BY-NC 4.0 license, unless otherwise stated. | |
| Record name | Amlodipine besylate [USAN:USP] | |
| Source | ChemIDplus | |
| URL | https://pubchem.ncbi.nlm.nih.gov/substance/?source=chemidplus&sourceid=0111470996 | |
| Description | ChemIDplus is a free, web search system that provides access to the structure and nomenclature authority files used for the identification of chemical substances cited in National Library of Medicine (NLM) databases, including the TOXNET system. | |
| Record name | AMLODIPINE BESYLATE | |
| Source | DTP/NCI | |
| URL | https://dtp.cancer.gov/dtpstandard/servlet/dwindex?searchtype=NSC&outputformat=html&searchlist=758922 | |
| Description | The NCI Development Therapeutics Program (DTP) provides services and resources to the academic and private-sector research communities worldwide to facilitate the discovery and development of new cancer therapeutic agents. | |
| Explanation | Unless otherwise indicated, all text within NCI products is free of copyright and may be reused without our permission. Credit the National Cancer Institute as the source. | |
| Record name | Amlodipine besylate | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID2043909 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
| Record name | Amlodipine besylate | |
| Source | European Chemicals Agency (ECHA) | |
| URL | https://echa.europa.eu/information-on-chemicals | |
| Description | The European Chemicals Agency (ECHA) is an agency of the European Union which is the driving force among regulatory authorities in implementing the EU's groundbreaking chemicals legislation for the benefit of human health and the environment as well as for innovation and competitiveness. | |
| Explanation | Use of the information, documents and data from the ECHA website is subject to the terms and conditions of this Legal Notice, and subject to other binding limitations provided for under applicable law, the information, documents and data made available on the ECHA website may be reproduced, distributed and/or used, totally or in part, for non-commercial purposes provided that ECHA is acknowledged as the source: "Source: European Chemicals Agency, http://echa.europa.eu/". Such acknowledgement must be included in each copy of the material. ECHA permits and encourages organisations and individuals to create links to the ECHA website under the following cumulative conditions: Links can only be made to webpages that provide a link to the Legal Notice page. | |
| Record name | AMLODIPINE BESYLATE | |
| Source | FDA Global Substance Registration System (GSRS) | |
| URL | https://gsrs.ncats.nih.gov/ginas/app/beta/substances/864V2Q084H | |
| Description | The FDA Global Substance Registration System (GSRS) enables the efficient and accurate exchange of information on what substances are in regulated products. Instead of relying on names, which vary across regulatory domains, countries, and regions, the GSRS knowledge base makes it possible for substances to be defined by standardized, scientific descriptions. | |
| Explanation | Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required. | |
Synthesis routes and methods I
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Synthesis routes and methods II
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Retrosynthesis Analysis
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Strategy Settings
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Feasible Synthetic Routes
A: Amlodipine besylate acts as a potent calcium channel blocker, specifically targeting L-type calcium channels. [, , ] This inhibition reduces the influx of calcium ions into vascular smooth muscle cells and cardiac muscle cells. [, ] By limiting calcium availability, this compound promotes vasodilation, reducing peripheral vascular resistance and ultimately lowering blood pressure. [, , , , , ] It also demonstrates efficacy in managing angina pectoris by preventing coronary artery spasm. [, , ]
A: The primary downstream effect of this compound's inhibition of calcium channels is vasodilation, leading to reduced peripheral vascular resistance and decreased blood pressure. [, , , , , ] This effect is particularly beneficial in treating hypertension. Additionally, by inhibiting calcium influx into cardiac muscle cells, this compound can help manage angina pectoris by preventing coronary artery spasm. [, , ]
A: this compound has the molecular formula C20H25ClN2O5·C6H6O3S, representing the besylate salt form of amlodipine. Its molecular weight is 567.1 g/mol. [, , , ]
A: Research indicates that this compound exhibits a maximum absorbance wavelength (λmax) around 237 nm in methanol, making UV spectrophotometry a suitable analytical technique. [, , , , ] Furthermore, FTIR and 1H-NMR spectroscopy provide valuable insights into the structural features of this compound and its inclusion complexes with cyclodextrins. []
A: this compound exhibits limited water solubility, which presents challenges for its bioavailability. [, ] To address this, researchers have explored various approaches, such as solid dispersion techniques utilizing polymers like polyethylene glycol (PEG) 4000 and PEG 6000. [] These techniques aim to enhance the drug's dissolution rate and improve its bioavailability, ultimately enhancing its therapeutic efficacy.
A: While generally stable in solid formulations, studies indicate potential incompatibility of this compound with certain excipients. For example, the presence of lactose, magnesium stearate, and water in formulations can trigger instability, leading to the formation of a glycosyl degradation product through the Maillard reaction. [] This highlights the importance of careful excipient selection during formulation development to ensure drug stability and product quality.
A: Research has investigated the stability of compounded this compound suspensions in specific pharmaceutical bases. One study demonstrated that this compound remains physically and chemically stable in PCCA Base, SuspendIt, for 90 days under refrigeration (5°C) and 7 days at room temperature (25°C). [] This finding suggests that compounded suspensions can be a viable option for patients requiring alternative dosage forms, provided they adhere to the established beyond-use dates.
A: Researchers utilize a range of analytical methods for the quantification of this compound in various matrices. High-performance liquid chromatography (HPLC) coupled with various detectors like UV-Vis, diode array detectors (DAD), and mass spectrometry (MS) is widely employed for simultaneous estimation of this compound in combination with other drugs. [, , , , , , , , , ] Additionally, UV spectrophotometry, particularly when coupled with techniques like absorption factor method and first-order derivative spectrophotometry, offers a simple and cost-effective approach for analyzing this compound in pharmaceutical formulations. [, , ] Furthermore, High-Performance Thin Layer Chromatography (HPTLC) with densitometric detection proves valuable for simultaneous estimation in combined dosage forms. [, , ]
A: Analytical methods for this compound undergo rigorous validation procedures following ICH guidelines to ensure accuracy, precision, specificity, and sensitivity. [, , , , , , , , , , , ] Researchers meticulously evaluate method performance parameters such as linearity, accuracy, precision, robustness, limit of detection (LOD), and limit of quantification (LOQ) to demonstrate the suitability of the chosen technique for its intended application.
A: Researchers have investigated the combined use of this compound with other drugs to address specific clinical challenges. For example, studies have explored the efficacy of combining this compound with valsartan in elderly patients with hypertension, demonstrating promising results in blood pressure control. [] Similarly, combining this compound with Ambovir has shown potential in managing renal hypertension, effectively reducing urinary protein, serum creatinine, and blood uric acid levels. []
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