Vérapamil
Vue d'ensemble
Description
Le vérapamil est un bloquant des canaux calciques de type phénylalkylamine principalement utilisé dans le traitement des affections cardiovasculaires telles que l'hypertension artérielle, l'angine de poitrine et certains types d'arythmies . C'était le premier antagoniste des canaux calciques introduit en thérapie au début des années 1960 . Le this compound est disponible dans diverses formulations, notamment orale et intraveineuse, et est largement reconnu pour son efficacité dans le contrôle de la fréquence cardiaque et l'amélioration du flux sanguin .
Mécanisme D'action
Target of Action
Verapamil is a non-dihydropyridine calcium channel blocker . Its primary targets are the L-type calcium channels located in the vascular smooth muscle, cardiac myocytes, and cardiac nodal tissue (AV and SA nodes) . These channels play a crucial role in regulating the influx of calcium ions, which is essential for muscle contraction and electrical conduction within the heart .
Mode of Action
Verapamil inhibits the influx of calcium ions through these L-type calcium channels . By blocking these channels, verapamil reduces the intracellular concentration of calcium ions, leading to relaxation of vascular smooth muscle and a decrease in electrical conduction within the heart . This results in dilation of the arteries, reduced force of heart contraction, and slowing of the heart rate .
Biochemical Pathways
Verapamil’s action on calcium channels affects several biochemical pathways. It has been shown to inhibit the thioredoxin-interacting protein (TXNIP)/nod-like receptor protein 3 (NLRP3) inflammasome pathway, which plays a critical role in the pathogenesis of non-alcoholic fatty liver disease . By inhibiting this pathway, verapamil can ameliorate hepatic inflammation .
Pharmacokinetics
Verapamil is well absorbed following oral administration, but only about 20–35% of an oral dose reaches systemic circulation as unchanged drug due to first-pass metabolism . The drug is extensively metabolized in the liver, and its elimination half-life ranges from 2.8 to 7.4 hours . Verapamil’s pharmacokinetics can be influenced by factors such as age, liver function, and the presence of certain genetic polymorphisms .
Result of Action
The blockade of calcium channels by verapamil leads to several cellular and molecular effects. It can boost β-cell proliferation, enhance glucose-stimulated insulin secretion, and fortify cellular resilience . Verapamil also reduces the expression of TXNIP, a molecule involved in β-cell apoptosis and glucotoxicity-induced β-cell death . This can lead to cytoprotective and proliferative effects on pancreatic β-cells .
Action Environment
The efficacy of verapamil can be influenced by various environmental factors. For instance, the onset, grade, and brain distribution of Alzheimer’s disease pathological hallmarks, the time-sequential appearances of Alzheimer’s disease-related cognitive and behavioral dysfunction, and the chronobiologic and gender impact on calcium homeostasis and Alzheimer’s disease pathogenesis may condition the efficacy of verapamil . Furthermore, the presence of other drugs, patient’s diet, and individual genetic factors can also influence the drug’s action, efficacy, and stability .
Applications De Recherche Scientifique
Verapamil has a wide range of scientific research applications:
Chemistry: Used as a model compound in studies of calcium channel blockers and their interactions with other molecules.
Medicine: Extensively studied for its therapeutic effects in treating cardiovascular diseases, migraines, and cluster headaches
Industry: Utilized in the development of sustained-release formulations and other drug delivery systems.
Analyse Biochimique
Biochemical Properties
Verapamil interacts with various enzymes and proteins, primarily through its role as a calcium channel blocker. It is known to interact with cytochrome P450 enzymes, which are involved in its metabolism . Verapamil is also a potent inhibitor of P-glycoprotein function , which plays a crucial role in drug transport and distribution.
Cellular Effects
Verapamil has been shown to have significant effects on various types of cells and cellular processes. It influences cell function by blocking calcium channels, which can impact cell signaling pathways, gene expression, and cellular metabolism . For instance, verapamil has been found to regulate the thioredoxin system and promote an anti-oxidative, anti-apoptotic, and immunomodulatory gene expression profile in human islets .
Molecular Mechanism
Verapamil exerts its effects at the molecular level primarily through its role as a calcium channel blocker. It binds to L-type calcium channels, inhibiting the influx of calcium ions into cells . This can lead to a decrease in intracellular calcium levels, which can affect various cellular processes, including muscle contraction, cell signaling, and neurotransmitter release.
Temporal Effects in Laboratory Settings
In laboratory settings, the effects of verapamil can change over time. For example, a study showed that long-term low-dose verapamil effectively prevents the development of cognitive impairment induced by a certain compound in aged animals . This suggests that verapamil may have long-term effects on cellular function in both in vitro and in vivo studies.
Dosage Effects in Animal Models
The effects of verapamil can vary with different dosages in animal models. For instance, a study showed that verapamil at a dose of 1mg/kg/d prevented the development of cognitive impairment in an aged mouse model of sporadic Alzheimer’s disease .
Metabolic Pathways
Verapamil is involved in various metabolic pathways. It is subject to extensive oxidative metabolism mediated by cytochrome P450 enzymes, with less than 5% of an oral dose being excreted unchanged in urine . Verapamil is also known to be a potent inhibitor of P-glycoprotein function, which can affect the transport and distribution of various other drugs .
Transport and Distribution
Verapamil is widely distributed throughout body tissues . It is transported and distributed within cells and tissues primarily through its interaction with P-glycoprotein, a transporter protein that plays a crucial role in drug transport and distribution .
Subcellular Localization
A study investigating the transport of fluorescence-labeled verapamil at the blood-retinal barrier suggested that verapamil may be partially sequestered in lysosomes within retinal pigment epithelial cells .
Méthodes De Préparation
Voies de synthèse et conditions réactionnelles
Le vérapamil est synthétisé par un processus en plusieurs étapes qui implique la réaction de la 3,4-diméthoxyphénéthylamine avec le chlorure d'isovaléryle pour former un intermédiaire, qui est ensuite mis à réagir avec le 3,4-diméthoxybenzylcyanure dans des conditions spécifiques . Le produit final est purifié pour atteindre un degré de pureté élevé, souvent supérieur à 99 % .
Méthodes de production industrielle
La production industrielle de this compound implique généralement une synthèse à grande échelle utilisant des voies réactionnelles similaires à celles utilisées en laboratoire, mais optimisées pour l'efficacité et la rentabilité. Des techniques telles que les résines échangeuses d'ions et les méthodes de préparation des liposomes sont utilisées pour améliorer la biodisponibilité et la libération contrôlée du médicament .
Analyse Des Réactions Chimiques
Types de réactions
Le vérapamil subit diverses réactions chimiques, notamment l'oxydation, la réduction et la substitution. Ces réactions sont essentielles pour son métabolisme et sa pharmacocinétique .
Réactifs et conditions courants
Les réactifs courants utilisés dans les réactions impliquant le this compound comprennent des agents oxydants comme l'ozone et les radicaux hydroxyles . Les conditions de ces réactions sont soigneusement contrôlées pour garantir les résultats souhaités, tels que la formation de métabolites spécifiques.
Principaux produits formés
Les principaux produits formés à partir des réactions du this compound comprennent ses métabolites, qui sont principalement excrétés par les reins . Ces métabolites sont essentiels pour comprendre les effets pharmacologiques du médicament et ses effets secondaires potentiels.
Applications de la recherche scientifique
Le this compound a un large éventail d'applications de recherche scientifique :
Médecine : Étudié de manière approfondie pour ses effets thérapeutiques dans le traitement des maladies cardiovasculaires, des migraines et des céphalées en grappes
Mécanisme d'action
Le this compound exerce ses effets en inhibant l'afflux d'ions calcium à travers les canaux lents dans les membranes cellulaires des muscles lisses artériels et des cellules myocardiques . Cette inhibition entraîne la relaxation des vaisseaux sanguins, la réduction de la fréquence cardiaque et la diminution de la demande en oxygène du myocarde . Les cibles moléculaires du this compound comprennent les canaux calciques de type L, qui jouent un rôle essentiel dans la fonction cardiovasculaire .
Comparaison Avec Des Composés Similaires
Composés similaires
Le vérapamil appartient à la classe des bloquants des canaux calciques non dihydropyridiniques, qui comprend d'autres composés comme le diltiazem et la flunarizine . Ces composés partagent des mécanismes d'action similaires, mais diffèrent par leurs structures chimiques et leurs profils pharmacocinétiques.
Unicité
Le this compound est unique en sa capacité à agir à la fois comme un antiarythmique et un antihypertenseur, ce qui le rend polyvalent dans le traitement de diverses affections cardiovasculaires . Sa structure chimique distincte permet des interactions spécifiques avec les canaux calciques, offrant une plage thérapeutique plus large par rapport aux autres bloquants des canaux calciques .
Propriétés
IUPAC Name |
2-(3,4-dimethoxyphenyl)-5-[2-(3,4-dimethoxyphenyl)ethyl-methylamino]-2-propan-2-ylpentanenitrile |
Source
|
|---|---|---|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI |
InChI=1S/C27H38N2O4/c1-20(2)27(19-28,22-10-12-24(31-5)26(18-22)33-7)14-8-15-29(3)16-13-21-9-11-23(30-4)25(17-21)32-6/h9-12,17-18,20H,8,13-16H2,1-7H3 |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI Key |
SGTNSNPWRIOYBX-UHFFFAOYSA-N |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Canonical SMILES |
CC(C)C(CCCN(C)CCC1=CC(=C(C=C1)OC)OC)(C#N)C2=CC(=C(C=C2)OC)OC |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Molecular Formula |
C27H38N2O4 |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
DSSTOX Substance ID |
DTXSID9041152 |
Source
|
| Record name | (+/-)-Verapamil | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID9041152 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
Molecular Weight |
454.6 g/mol |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Physical Description |
Solid |
Source
|
| Record name | Verapamil | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0001850 | |
| Description | The Human Metabolome Database (HMDB) is a freely available electronic database containing detailed information about small molecule metabolites found in the human body. | |
| Explanation | HMDB is offered to the public as a freely available resource. Use and re-distribution of the data, in whole or in part, for commercial purposes requires explicit permission of the authors and explicit acknowledgment of the source material (HMDB) and the original publication (see the HMDB citing page). We ask that users who download significant portions of the database cite the HMDB paper in any resulting publications. | |
Boiling Point |
BP: 245 °C at 0.01 mm Hg, 243-246 °C at 1.00E-02 mm Hg |
Source
|
| Record name | Verapamil | |
| Source | Hazardous Substances Data Bank (HSDB) | |
| URL | https://pubchem.ncbi.nlm.nih.gov/source/hsdb/3928 | |
| Description | The Hazardous Substances Data Bank (HSDB) is a toxicology database that focuses on the toxicology of potentially hazardous chemicals. It provides information on human exposure, industrial hygiene, emergency handling procedures, environmental fate, regulatory requirements, nanomaterials, and related areas. The information in HSDB has been assessed by a Scientific Review Panel. | |
| Record name | Verapamil | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0001850 | |
| Description | The Human Metabolome Database (HMDB) is a freely available electronic database containing detailed information about small molecule metabolites found in the human body. | |
| Explanation | HMDB is offered to the public as a freely available resource. Use and re-distribution of the data, in whole or in part, for commercial purposes requires explicit permission of the authors and explicit acknowledgment of the source material (HMDB) and the original publication (see the HMDB citing page). We ask that users who download significant portions of the database cite the HMDB paper in any resulting publications. | |
Solubility |
Solubility (mg/mL): water 83, ethanol (200 proof) 26, propylene glycol 93, ethanol (190 proof) >100, methanol >100, 2-propanol 4.6, ethyl acetate 1.0, DMF >100, methylene chloride >100, hexane 0.001; Freely soluble in chloroform, practically insoluble in ether /Verapamil hydrochloride/, Practically insoluble in water, Sparingly soluble in hexane; soluble in benzene, ether; freely soluble in the lower alcohols, acetone, ethyl acetate, chloroform, 4.47 mg/L |
Source
|
| Record name | Verapamil | |
| Source | Hazardous Substances Data Bank (HSDB) | |
| URL | https://pubchem.ncbi.nlm.nih.gov/source/hsdb/3928 | |
| Description | The Hazardous Substances Data Bank (HSDB) is a toxicology database that focuses on the toxicology of potentially hazardous chemicals. It provides information on human exposure, industrial hygiene, emergency handling procedures, environmental fate, regulatory requirements, nanomaterials, and related areas. The information in HSDB has been assessed by a Scientific Review Panel. | |
| Record name | Verapamil | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0001850 | |
| Description | The Human Metabolome Database (HMDB) is a freely available electronic database containing detailed information about small molecule metabolites found in the human body. | |
| Explanation | HMDB is offered to the public as a freely available resource. Use and re-distribution of the data, in whole or in part, for commercial purposes requires explicit permission of the authors and explicit acknowledgment of the source material (HMDB) and the original publication (see the HMDB citing page). We ask that users who download significant portions of the database cite the HMDB paper in any resulting publications. | |
Mechanism of Action |
Verapamil inhibits L-type calcium channels by binding to a specific area of their alpha-1 subunit,Cav1.2, which is highly expressed on L-type calcium channels in vascular smooth muscle and myocardial tissue where these channels are responsible for the control of peripheral vascular resistance and heart contractility. Calcium influx through these channels allows for the propagation of action potentials necessary for the contraction of muscle tissue and the heart's electrical pacemaker activity. Verapamil binds to these channels in a voltage- and frequency-dependent manner, meaning affinity is increased 1) as vascular smooth muscle membrane potential is reduced, and 2) with excessive depolarizing stimulus. Verapamil's mechanism of action in the treatment of angina and hypertension is likely due to the mechanism described above. Inhibition of calcium influx prevents the contraction of vascular smooth muscle, causing relaxation/dilation of blood vessels throughout the peripheral circulation - this lowers systemic vascular resistance (i.e. afterload) and thus blood pressure. This reduction in vascular resistance also reduces the force against which the heart must push, decreasing myocardial energy consumption and oxygen requirements and thus alleviating angina. Electrical activity through the AV node is responsible for determining heart rate, and this activity is dependent upon calcium influx through L-type calcium channels. By inhibiting these channels and decreasing the influx of calcium, verapamil prolongs the refractory period of the AV node and slows conduction, thereby slowing and controlling the heart rate in patients with arrhythmia. Verapamil's mechanism of action in the treatment of cluster headaches is unclear, but is thought to result from an effect on other calcium channels (e.g. N-, P-, Q-, or T-type). Verapamil is known to interact with other targets, including other calcium channels, potassium channels, and adrenergic receptors., Calcium antagonists inhibit excitation-contraction coupling in myocardial and smooth muscle by blocking the transmembrane carrier of calcium. This results in decreased myocardial contractility and in vasodilatation. ... /Salt not specified/, Verapamil has been shown to be neuroprotective in several acute neurotoxicity models due to blockade of calcium entry into neurons. However, the potential use of verapamil to treat chronic neurodegenerative diseases has not been reported. Using rat primary mesencephalic neuron/glia cultures, we report that verapamil significantly inhibited LPS-induced dopaminergic neurotoxicity in both pre- and post-treatment experiments. Reconstituted culture studies revealed that the presence of microglia was essential in verapamil-elicited neuroprotection. Mechanistic studies showed that decreased production of inflammatory mediators from LPS-stimulated microglia underlay neuroprotective property of verapamil. Further studies demonstrated that microglial NADPH oxidase (PHOX), the key superoxide-producing enzyme, but not calcium channel in neurons, is the site of action for the neuroprotective effect of verapamil. This conclusion was supported by the following two observations: 1) Verapamil failed to show protective effect on LPS-induced dopaminergic neurotoxicity in PHOX-deficient (deficient in the catalytic subunit of gp91(phox)) neuron/glia cultures; 2) Ligand binding studies showed that the binding of (3)H-verapamil onto gp91(phox) transfected COS7 cell membranes was higher than the non-transfected control. The calcium channel-independent neuroprotective property of verapamil was further supported by the finding that R(+)-verapamil, a less active form in blocking calcium channel, showed the same potency in neuroprotection, inhibition of pro-inflammatory factors production and binding capacity to gp91(phox) membranes as R(-)-verapamil, the active isomer of calcium channel blocker. In conclusion, our results demonstrate a new indication of verapamil-mediated neuroprotection through a calcium channel-independent pathway and provide a valuable avenue for the development of therapy for inflammation-related neurodegenerative diseases. |
Source
|
| Record name | Verapamil | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB00661 | |
| Description | The DrugBank database is a unique bioinformatics and cheminformatics resource that combines detailed drug (i.e. chemical, pharmacological and pharmaceutical) data with comprehensive drug target (i.e. sequence, structure, and pathway) information. | |
| Explanation | Creative Common's Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/legalcode) | |
| Record name | Verapamil | |
| Source | Hazardous Substances Data Bank (HSDB) | |
| URL | https://pubchem.ncbi.nlm.nih.gov/source/hsdb/3928 | |
| Description | The Hazardous Substances Data Bank (HSDB) is a toxicology database that focuses on the toxicology of potentially hazardous chemicals. It provides information on human exposure, industrial hygiene, emergency handling procedures, environmental fate, regulatory requirements, nanomaterials, and related areas. The information in HSDB has been assessed by a Scientific Review Panel. | |
Color/Form |
Viscous, pale yellow oil | |
CAS No. |
52-53-9 |
Source
|
| Record name | Verapamil | |
| Source | CAS Common Chemistry | |
| URL | https://commonchemistry.cas.org/detail?cas_rn=52-53-9 | |
| 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 | Verapamil [USAN:INN:BAN] | |
| Source | ChemIDplus | |
| URL | https://pubchem.ncbi.nlm.nih.gov/substance/?source=chemidplus&sourceid=0000052539 | |
| 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 | Verapamil | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB00661 | |
| Description | The DrugBank database is a unique bioinformatics and cheminformatics resource that combines detailed drug (i.e. chemical, pharmacological and pharmaceutical) data with comprehensive drug target (i.e. sequence, structure, and pathway) information. | |
| Explanation | Creative Common's Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/legalcode) | |
| Record name | (+/-)-Verapamil | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID9041152 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
| Record name | Verapamil | |
| Source | European Chemicals Agency (ECHA) | |
| URL | https://echa.europa.eu/substance-information/-/substanceinfo/100.000.133 | |
| 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 | VERAPAMIL | |
| Source | FDA Global Substance Registration System (GSRS) | |
| URL | https://gsrs.ncats.nih.gov/ginas/app/beta/substances/CJ0O37KU29 | |
| 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. | |
| Record name | Verapamil | |
| Source | Hazardous Substances Data Bank (HSDB) | |
| URL | https://pubchem.ncbi.nlm.nih.gov/source/hsdb/3928 | |
| Description | The Hazardous Substances Data Bank (HSDB) is a toxicology database that focuses on the toxicology of potentially hazardous chemicals. It provides information on human exposure, industrial hygiene, emergency handling procedures, environmental fate, regulatory requirements, nanomaterials, and related areas. The information in HSDB has been assessed by a Scientific Review Panel. | |
| Record name | Verapamil | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0001850 | |
| Description | The Human Metabolome Database (HMDB) is a freely available electronic database containing detailed information about small molecule metabolites found in the human body. | |
| Explanation | HMDB is offered to the public as a freely available resource. Use and re-distribution of the data, in whole or in part, for commercial purposes requires explicit permission of the authors and explicit acknowledgment of the source material (HMDB) and the original publication (see the HMDB citing page). We ask that users who download significant portions of the database cite the HMDB paper in any resulting publications. | |
Melting Point |
< 25 °C |
Source
|
| Record name | Verapamil | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0001850 | |
| Description | The Human Metabolome Database (HMDB) is a freely available electronic database containing detailed information about small molecule metabolites found in the human body. | |
| Explanation | HMDB is offered to the public as a freely available resource. Use and re-distribution of the data, in whole or in part, for commercial purposes requires explicit permission of the authors and explicit acknowledgment of the source material (HMDB) and the original publication (see the HMDB citing page). We ask that users who download significant portions of the database cite the HMDB paper in any resulting publications. | |
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Retrosynthesis Analysis
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| Template Set | Pistachio/Bkms_metabolic/Pistachio_ringbreaker/Reaxys/Reaxys_biocatalysis |
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Feasible Synthetic Routes
Q1: What is Verapamil's primary molecular target?
A1: Verapamil primarily targets L-type voltage-gated calcium channels (Cav1.2) [, , , ]. These channels play a crucial role in calcium influx, influencing various physiological processes, particularly in cardiac and smooth muscle cells.
Q2: How does Verapamil interact with L-type calcium channels?
A2: Verapamil exhibits a higher affinity for the inactivated state of L-type calcium channels []. Binding to these channels, Verapamil inhibits calcium influx, leading to a decrease in intracellular calcium concentration.
Q3: What are the downstream effects of Verapamil's interaction with its target?
A3: By inhibiting calcium influx through L-type channels, Verapamil exerts several downstream effects, including:
- Cardiac: Decreased heart rate, reduced myocardial contractility, and prolonged atrioventricular (AV) nodal conduction time [, , , ].
- Vascular: Relaxation of vascular smooth muscle, leading to vasodilation and reduced blood pressure [, , ].
Q4: What is the molecular formula and weight of Verapamil?
A4: Verapamil's molecular formula is C27H38N2O4, and its molecular weight is 454.6 g/mol.
Q5: What is the bioavailability of orally administered Verapamil?
A5: Oral Verapamil has a low and variable bioavailability, averaging around 22% due to significant first-pass metabolism [].
Q6: How does Verapamil's metabolism impact its pharmacokinetic profile?
A6: Verapamil undergoes extensive hepatic metabolism, primarily by cytochrome P450 enzymes, particularly CYP3A4 [, ]. This leads to the formation of several metabolites, including norVerapamil, which also possesses pharmacological activity [, ].
Q7: Does Verapamil interact with other drugs?
A7: Yes, Verapamil can interact with various drugs due to its effects on drug-metabolizing enzymes and P-glycoprotein. For example, it can increase digoxin concentrations [], potentially leading to toxicity.
Q8: What are the main clinical applications of Verapamil?
A8: Verapamil is clinically used for treating various cardiovascular conditions, including:
- Supraventricular tachycardia (SVT): Intravenous Verapamil effectively terminates AV nodal reentrant tachycardia [].
- Hypertension: Verapamil lowers blood pressure [, ] and was found to be as effective as hydrochlorothiazide in achieving target blood pressure but with fewer patients requiring combination therapy [].
- Angina pectoris: Verapamil improves exercise capacity and reduces angina symptoms [, , ].
- Hypertrophic cardiomyopathy: Verapamil improves hemodynamic parameters and exercise capacity in patients with this condition [, ].
Q9: Are there differences in Verapamil's efficacy in different patient populations?
A9: Research suggests potential differences in Verapamil's effectiveness among different patient groups:
- Age: In elderly patients with ischemic heart disease, Verapamil was less effective than Diltiazem in increasing exercise duration, although it improved ischemic thresholds [].
- Training Status: Studies on sweating responses showed that L-type calcium channel blockade with Verapamil had a more pronounced effect on cholinergic sweating in trained individuals compared to untrained individuals [].
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