Classes Of Calcium Channel Blockers Research Articles

Relationship between calcium channel blocker class and mortality in dialysis.

The comparative effectiveness of dihydropyridine (DHP) and non-DHP calcium channel blockers (CCBs) in maintenance dialysis patients has not been well-studied. A retrospective cohort of hypertensive patients initiating dialysis was created. New CCB initiators, defined as individual who had no evidence of CCB use in the first 90 days of dialysis but who were initiated by day 180, were followed from their first day of medication exposure until event or censoring; events consisted of all-cause mortality (ACM) and a combined endpoint of cardiovascular morbidity or mortality (CVMM). Cox proportional hazards models were used to determine adjusted hazard ratios (AHRs) comparing the effect of DHPs vs. non-DHPs. There were 2900 and 2704 new initiators of CCBs in the ACM and CVMM models, respectively. Adjusted for other factors, use of DHPs, compared to non-DHPs, was associated with an AHR of 0.77 (99% confidence intervals, 0.64 - 0.93, P = 0.0004) for ACM and 0.86 (0.72 - 1.02, P = 0.024) for CVMM. Results were similar when individuals who initiated therapy at any point after the cohort inception were included, with AHRs of 0.60 (0.53 - 0.69, P < 0.0001) and 0.77 (0.67 - 0.89, P < 0.0001) for ACM and CVMM, respectively. Further, elimination of individuals with chronic atrial fibrillation resulted in AHRs of 0.71 and 0.70 for ACM and CVVM, respectively. DHPs, as compared to non-DHPs, were associated with reduced hazard of death or cardiovascular morbidity and mortality; potential mechanisms of action require further study.

Reduced Risk of Parkinson's Disease in Users of Calcium Channel Blockers: A Meta-Analysis.

Aim. To pool the data currently available to determine the association between calcium channel blockers (CCBs) and risk of Parkinson's disease (PD). Methods. Literature search in PubMed, EBSCO, and Cochrane library was undertaken through March 2014, looking for observational studies evaluating the association between CCBs use and PD. Pooled relative risk (RR) estimates and 95% confidence intervals (CIs) were calculated using random-effects model. Subgroup analyses, sensitivity Analysis, and cumulative meta-analysis were also performed. Results. Six studies were included in our meta-analysis according to the selection criteria, including three cohort studies and three case-control studies involving 27,67,990 subjects including 11,941 PD cases. We found CCBs use was associated with significant decreased risk of PD, compared with not using CCBs (random effects model pooled RR, 0.81 (95% CI, 0.69–0.95)); a significant heterogeneity was found between studies (P = 0.031; I 2 54.6%). Both the classes of CCB, that is, dihydropyridine calcium channel blockers (DiCCB) (0.80 (95% CI, 0.65–0.98) P = 0.032) and non-DiCCB (0.70 (95% CI, 0.53–0.92) P = 0.013), were found to be reducing the risk of PD. Conclusion. In our analysis, we found that CCBs use was associated with a Significantly decreased risk of PD compared with non-CCB use.

Calcium channel blockers and outcomes in older patients with heart failure and preserved ejection fraction.

Little is known about associations of calcium channel blockers (CCBs) with outcomes in patients with heart failure and preserved ejection fraction (EF). Of the 10 570 hospitalized patients with heart failure and preserved EF, ≥65 years, EF ≥40%, in the Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE-HF; 2003-2004), linked to Medicare data (through December 31, 2008), 7514 had no prior history of CCB use. Of these, 815 (11%) patients received new discharge prescriptions for CCBs. Propensity scores for CCB initiation, calculated for each of the 7514 patients, were used to assemble a matched cohort of 1620 (810 pairs) patients (mean age, 80 years; mean EF, 56%; 65% women; 10% black) receiving and not receiving CCBs, balanced on 114 baseline characteristics. The primary composite end point of all-cause mortality or heart failure hospitalization occurred in 82% and 81% of patients receiving and not receiving CCBs (hazard ratio for CCBs, 1.03; 95% confidence interval, 0.92-1.14). Hazard ratios (95% confidence intervals) for all-cause mortality, heart failure hospitalization, and all-cause hospitalization were 1.05 (0.94-1.18), 1.05 (0.91-1.21), and 1.03 (0.93-1.14), respectively. Similar associations were observed when we categorized patients into those receiving amlodipine and nonamlodipine CCBs. Among 7514 prematch patients, multivariable-adjusted and propensity-adjusted hazard ratios (95% confidence interval) for primary composite end point were 1.03 (0.95-1.12) and 1.02 (0.94-1.11), respectively. In hospitalized older patients with heart failure, new discharge prescriptions for CCBs had no associations with composite or individual end points of mortality or heart failure hospitalization, regardless of the class of CCBs.

Pharmacophore Modelling, Quantitative Structure Activity Relationship (QSAR) and Docking Studies of Pyrimidine Analogs as Potential Calcium Channel Blockers

The present communication deals with the Pharmacophore modeling, 3D QSAR and docking analysis on series of Pyrimidine derivatives as potential calcium channel blockers. The computational studies showed hydrogen bond donor, hydrogen bond acceptor, and hydrophobic group are important features for calcium channel blocking activity. These studies showed that Pyrimidine scaffold can be utilized for designing of novel calcium channels blockers for CVS disorders. Calcium ions plays a vital role in the cardiovascular sys- tem, they impart their action by acting on the calcium channels. The entry of calcium inside the cell can increase the vascular tone as well as heart rate and ultimately the blood pressure. The currently approved calcium channel blockers binds with L-type calcium channels located on the vascular smooth muscle, cardiac myocytes, and car- diac nodal tissue. These channels are responsible for reg- ulating the influx of calcium into muscle cells, 1�3 which in turn stimulates smooth muscle contraction and cardiac contraction. Therefore, by blocking calcium entry into the cell, will cause vascular smooth muscle relaxation (vasodi- lation), decreased myocardial force generation decreased heart rate (negative chronotropy), and decreased conduc- tion velocity within the heart (negative dromotropy) at the AV node. The 1,4-dihydropyridine (DHP) class of calcium channel blockers are widely utilized in the treatment of cardiovascular diseases such as hypertension, angina pec- toris and other spastic smooth muscle disorders. 4�6 The SAR of calcium channel blockers signifies the presence of ester linkage and electron withdrawing group like nitro and carbonyl groups. The Pyrimidine nucleus has been showing the various pharmacological activities like calcium channel blockers, anti cancer, antimicrobial, antiviral. In this com- munication an attempt is made to design and develop novel calcium channel blockers based on the Pyrimidine scaf- fold and identification of structure requirement of these molecules in the form of 3D descriptors and Pharmacoph- oric features for optimization of these ligands.

Toxicity Effects of Amlodipine on the Body Weight and Sperm Count in Adult Wistar Rats

Amlodipine is one of the calcium channel blocker class of antihypertensive used in the treatment of hypertension. Amlodipine is widely used in Nigeria today as an antihypertensive although the side effect on health has been reported, based on researches done. This study was carried out to appraise the toxicity effects of Amlodipine on the body weight and sperm count in Adult Wistar rats. The rats were divided into 3 groups: group 1 was given normal saline while group 2 and 3 were administered with 0.052mg/g/BW and 0.104mg/g/BW of amlodipine respectively. Our preliminary observations showed that Amlodipine did not have any effect on the body weight but lead to a decrease in sperm count. These effects were totally different from the rats used in the control group and by these preliminary observations, toxic dose of Amlodipine has been shown to lead to infertility in rats.

Synthesis, characterization, and pharmacological evaluation of benzothiopyran derivatives as a novel class of calcium channel blockers

The current research aimed to investigate the importance of the heterocyclic ring system in the structure of the cardiovascular drug Diltiazem for its calcium channel blocking activity. The manuscript describes the design, synthesis, and biological testing of Benzothiopyran derivatives (7a–7f). The new compounds maintain some Diltiazem pharmacophores. Benzothiopyran has two pharmacophore: the aromatic benzene ring fused with the heterocyclic thiopyrans ring, and the stereo-chemical centers (alkyl ether). In vitro evaluation of Benzothiopyran derivatives (7a–7f) for calcium channel blocking effects revealed moderate activities. Compounds of the current series showed optimum activity when the alkyl ether chain was substituted on the 3-chloro-3,4-dihydro-2H-1-benzothiopyran-4-ol derivatives (7a–7f).

Toxicity Effects of Amlodipine on the Testis Histology in Adult Wistar Rats

Amlodipine is one of the calcium channel blocker class of antihypertensives used in the treatment of hypertension. This study was carried out to appraise the toxicity effects of Amlodipine on the testis histology in Adult Wistar rats based on the fact that amilodipine is usually consumed by the elderly who have a slow metabolic rate hence leading to accumulation of the drug in their system causing toxicity. The rats were divided into 3 groups: one group one was given normal saline while group 2 and 3 were administered with 0.052mg/g/BW and 0.104mg/g/BW of amlodipine respectively for 5 weeks. Our preliminary observations showed that administration of Amlodipine lead to an abnormal morphology of the testis in that, it had a deleterious effect on the seminiferous tubules in a dose related fashion.By these preliminary observations, alteration in the testis histology may have implication for infertility in man.

Antihypertensive drug-induced angioedema causing upper airway obstruction in children

Objective Angioedema is a well-described complication arising from the use of antihypertensive agents in the adult population. However, its occurrence and potential for upper airway compromise in pediatrics has only been sporadically reported in the literature. Our objective is to report and review the occurrence of antihypertensive-induced angioedema in the pediatric population and the potential for airway compromise. Methods Charts of 42 patients admitted to Cincinnati Children's Hospital Medical Center with the discharge diagnosis of angioedema (ICD-9 code 995.1) from January 2000 to January 2010 were reviewed. Of the 42 charts, 3 cases had angioedema induced by antihypertensive drugs and all 3 resulted in upper airway obstruction. Summary and findings of the data collected from the medical chart review included demographics, chief complaint(s), past medical history, hospital course, antihypertensive drugs used, diagnostic test(s), medical treatment, and time from onset of symptoms to resolution. In addition, a PubMed literature search using the terms angioedema and antihypertensive drugs was performed to review its occurrence in pediatrics. The previous literature case reports were compared to our cases to further characterize and emphasize the clinical features of this occurrence in children and adolescents. Results Despite the well-known occurrence of antihypertensive drug-induced angioedema causing airway obstruction in adults, only 4 case reports have been previously published in children. At our institution, we describe 3 children who developed acute angioedema with upper airway obstruction after the chronic use of antihypertensive medications [2 drugs in the ACE inhibitor class (enalapril and lisinopril), and 1 drug in the calcium channel blocker class (CCB; amlodipine)]. In all 3 cases, the symptoms resolved within 1 week after the antihypertensive agent was discontinued. Conclusion Upper airway obstruction can occur at any age when taking antihypertensive drugs. Particular caution should be applied to ACE inhibitors and CCBs in this regard. With the increasing use of antihypertensive agents in the pediatric population, clinicians should be alert to the possibility of angioedema with upper airway obstruction as a potential lethal adverse effect.

The role of calcium channel blockers and resveratrol in the prevention of paraquat-induced parkinsonism in Drosophila melanogaster: a locomotor analysis

Studies have suggested that neuronal loss in Parkinson's disease (PD) could be related to the pacemaker activity of the substantia nigra pars compacta generated by L-type Ca(v) 1.3 calcium channels, which progressively substitute voltage-dependent sodium channels in this region during aging. Besides this mechanism, which leads to increases in intracellular calcium, other factors are also known to play a role in dopaminergic cell death due to overproduction of reactive oxygen species. Thus, dihydropyridines, a class of calcium channel blockers, and resveratrol, a polyphenol that presents antioxidant properties, may represent therapeutic alternatives for the prevention of PD. In the present study, we tested the effects of the dihydropyridines, isradipine, nifedipine, and nimodipine and of resveratrol upon locomotor behavior in Drosophila melanogaster. As previously described, paraquat induced parkinsonian-like motor deficits. Moreover, none of the drugs tested were able to prevent the motor deficits produced by paraquat. Additionally, isradipine, nifedipine, resveratrol, and ethanol (vehicle), when used in isolation, induced motor deficits in flies. This study is the first demonstration that dyhidropyridines and resveratrol are unable to reverse the locomotor impairments induced by paraquat in Drosophila melanogaster.

Cytotoxic effect of some 1, 4-dihydropyridine derivatives containing nitroimidazole moiety.

The 1,4-dihydropyridine (DHP) derivatives are a known class of calcium channel blockers. Some derivatives of DHP showed significant cytotoxicity. It was shown that this effect may not be the result of interaction with Ca(2+) channels. In this study, we performed an investigation about the intrinsic cytotoxicity of some derivatives of DHP containing nitroimidazole moiety on their C4 position on four different cancer cell lines (Raji, K562, Fen and HeLa). The result showed that these compounds had moderate-good cytotoxic activity. In addition, QSAR model shows the importance of N atom in cytotoxicity; Ca(2+) channels.

Effect of the two new calcium channel blockers mebudipine and dibudipine in comparison to amlodipine on vascular flow of isolated kidney of diabetic rat

Calcium channel blockers are clinically useful vasodilators, used widely in the treatment of hypertension. These agents are reported to preserve or improve renal function in patients with essential hypertensive renal disease or diabetic renal disease. Among the classes of calcium channel blockers, dihydropyridine derivatives are widely used because of their potent vasodilating activity and weak cardiodepressant action. Mebudipine and dibudipine are two new 1,4-dihydropyridine calcium channel blockers that recently have been synthesized. In previous research mebudipine and dibudipine showed considerable relaxant effects on vascular and ileal smooth muscle cells. In this study we investigated the effects of these new drugs on vascular flow of isolated kidney of diabetic rat and compare their potencies to amlodipine. It is concluded that mebudipine and dibudipine (1-10 μM) are at least as potent as amlodipine in inhibiting PE-induced perfusion pressure in isolated kidney of diabetic rats. These new dihydropyridines improve kidney perfusion of diabetic rat in the setting of PE infusion. Similarly, amlodipine.

A Genome-Wide Association Study of Hypertension and Blood Pressure in African Americans

The evidence for the existence of genetic susceptibility variants for the common form of hypertension (“essential hypertension”) remains weak and inconsistent. We sought genetic variants underlying blood pressure (BP) by conducting a genome-wide association study (GWAS) among African Americans, a population group in the United States that is disproportionately affected by hypertension and associated complications, including stroke and kidney diseases. Using a dense panel of over 800,000 SNPs in a discovery sample of 1,017 African Americans from the Washington, D.C., metropolitan region, we identified multiple SNPs reaching genome-wide significance for systolic BP in or near the genes: PMS1, SLC24A4, YWHA7, IPO7, and CACANA1H. Two of these genes, SLC24A4 (a sodium/potassium/calcium exchanger) and CACNA1H (a voltage-dependent calcium channel), are potential candidate genes for BP regulation and the latter is a drug target for a class of calcium channel blockers. No variant reached genome wide significance for association with diastolic BP (top scoring SNP rs1867226, p = 5.8×10−7) or with hypertension as a binary trait (top scoring SNP rs9791170, p = 5.1×10−7). We replicated some of the significant SNPs in a sample of West Africans. Pathway analysis revealed that genes harboring top-scoring variants cluster in pathways and networks of biologic relevance to hypertension and BP regulation. This is the first GWAS for hypertension and BP in an African American population. The findings suggests that, in addition to or in lieu of relying solely on replicated variants of moderate-to-large effect reaching genome-wide significance, pathway and network approaches may be useful in identifying and prioritizing candidate genes/loci for further experiments.

Differential Effects of Calcium-Channel Blockers on Vascular Endothelial Function in Patients With Coronary Spastic Angina

The effects of the 3 classes of L-type calcium-channel blockers (CCBs) on vascular endothelial function have not been clarified in patients with coronary vasospasm. Twenty-five normotensive patients (age 64.0+/-1.4 years) with coronary vasospasm were randomly treated for 3 months with benidipine, diltiazem, and verapamil, which belong to the dihydropyridine, benzothiazepine, and phenylalkylamine classes of CCBs, respectively. Endothelium-dependent flow-mediated dilatation (FMD), endothelium-independent nitroglycerin-induced dilatation in the brachial arteries, and plasma cyclic guanosine 3',5'-monophosphate (cGMP), a nitric-oxide-related product, were assessed before and after treatment. At baseline, the patients with vasospasm had significantly lower FMD as compared with normal subjects (n=8). Blood pressure did not differ among the 3 groups before and after treatment. Benidipine significantly increased FMD (from 4.7+/-0.6 to 7.4+/-1.1%, P<0.05) and plasma cGMP levels. In contrast, neither diltiazem nor verapamil affected FMD and cGMP levels. None of the treatments affected nitroglycerin-induced dilatation. Benidipine, but not diltiazem or verapamil, improves endothelial dysfunction beyond blood pressure lowering effects in patients with coronary vasospasm. Upregulation of the nitric oxide - cGMP system by benidipine may partly contribute to the improvement. The dihydropyridine class may be more beneficial for vascular endothelial function than the non-dihydropyridine classes of CCBs.

QSAR Studies on some Calcium Channel Blockers

Quantitative structure-activity relationship studies have been made on some calcium channel blockers (CCBs) that include the most widely studied class of 1,4-dihydropyridines and two new classes of CCBs, namely benzazepinone analogs and quinolizidinyl derivatives. In the case of 1,4-dihydropyridines some simple correlations have been found as compared to those reported in several earlier studies and in the other two classes it could be shown that the electronic parameters and the bulk of the molecules may be important for the activity of the compounds.

Mechanistic aspects of benzothiazepines: A class of antiarrhythmic drugs

The authors have presented ab initio Hartree Fock calculations coupled with intermolecular interaction calculations to study mechanistic aspects of benzothiazepine class of calcium channel blockers. A channel model has been taken containing pore region glutamates and all three classes' sensing residues. Benzothiazepine drugs have been docked in and ternary complex (that is, drug ...Ca(2+)... channel model) stability has been studied and related to mechanistic aspects of these drugs.

Cilnidipine in management of patients with uncontrolled hypertension and white-coat effect

Introduction: Hypertension is a major public health problem worldwide. It is an established risk factor in the prognosis of cardiovascular diseases and organ damage [1]. Cilnidipine is a long-acting antihypertensive agent that lowers blood pressure by inhibiting L-type calcium channels directly associated with vascular tone, and N-type calcium channels related to sympathetic nervous activity [2]. Because it acts specifically on N-type calcium channels, cilnidipine is expected to achieve better reduction in morning blood pressure than other classes of calcium channel blockers, and to attenuate the white-coat effect caused by sympathetic nerve hyperactivity. Incomplete drug-regimen compliance (DRC) and white-coat hypertension are two of several possible causes of uncontrolled hypertension. Therefore, in this study, cilnidipine was evaluated in reducing morning blood pressure at home and in ameliorating the white-coat effect.

Effects of Antihypertensives on Glucose Metabolism

Treatment with different antihypertensive drug classes has varied effects on glucose metabolism. Thiazide diuretic use in hypertensives has been associated with the development of glucose intolerance and diabetes. Some findings suggest that the probability of worsening glucose metabolism and the development of new diabetes after thiazide initiation is associated with increasing body mass index. Nonselective or beta(1) selective beta-blockers may also lead to decreased insulin sensitivity in hypertensive patients. Newer beta-blockers that cause vasodilatation and beta-blockers that have intrinsic sympathomimetic activity may not have these deleterious effects on insulin sensitivity and glucose metabolism. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers may exert beneficial effects on glycemic control through a variety of mechanisms related to the inhibition of angiotensin II. These agents may be particularly useful in patients with microalbuminuria to slow the progression of renal disease. While there may be some small differences among different classes of calcium channel blockers, there is little net effect of these agents on glucose metabolism. The prevalence of obesity, hypertension, and type 2 diabetes mellitus is increasing in the US. In this setting, it is important to individualize antihypertensive therapy and to monitor its metabolic consequences so that potential adverse effects that would negate some of the benefits of blood-pressure lowering are minimized.

Calcium channel antagonist (nifedipine) attenuates Plasmodium berghei‐specific T cell immune responses in Balb/C mice

Nifedipine and verapamil (Martin et al. Science 1987;235:899-901) are a class of calcium channel blockers involved in the reversal of chloroquine (CQ) drug resistance in CQ-sensitive Plasmodium spp. Nifedipine alters calcium-dependent functions of macrophages and neutrophils during Plasmodium berghei malaria. However, knowledge of nifedipine-induced immunomodulation of T cell functions during P. berghei malaria is still limited. We investigated the effect of nifedipine on the immune status of splenic T cells during P. berghei malaria. The intracellular calcium levels were determined in the FURA-2A/M loaded T cells by spectrofluorometry. Splenic T cell proliferation, phosphatidylserine (PS) externalization, Fas expression and Bcl2/Bax expression were determined by flow cytometry. We report a significant increase in mean percent parasitemia in nifedipine-treated and P. berghei-infected mice. Although nifedipine treatment alone did not affect the resting state free calcium levels in splenic T cells, the rise in intracellular calcium levels of T cells following P. berghei infection was significantly less in nifedipine-treated mice compared to untreated groups at various parasitemia levels. Antigen-specific splenic T cell proliferation and apoptosis was ablated in nifedipine-treated and untreated groups at various parasitemia levels. The study unequivocally reflects the suppression of P. berghei-specific T cell immune responses by nifedipine.

Comparison of the direct negative dromotropic effect of a new calcium channel blocker, cilnidipine, with that of nicardipine

We encountered a 91-year-old woman with atrial fibrillation complicating bradycardia while she was receiving therapy with an L/N-type calcium channel blocker, cilnidipine, for hypertension, which is an unusual observation for the dihydropyridine class of calcium channel blockers. Therefore, we compared the dromotropic effect of cilnidipine with that of an L-type calcium channel blocker, nicardipine, which has a similar hypotensive activity. The canine isolated, blood-perfused atrioventricular node preparation was used. Cilnidipine as well as nicardipine slowed atrioventricular nodal conduction in a dose-related manner. However, the dromotropic action of cilnidipine was about five times less potent than that of nicardipine. These experimental results may suggest that we experienced an atypical clinical event of cilnidipine in a very old woman; otherwise one can speculate that the N-type calcium channel inhibitory component of cilnidipine might have played a role in exerting the negative dromotropic effect in this patient.

Design, synthesis, and biological testing of thiosalicylamides as a novel class of calcium channel blockers

The current research aimed to investigate the importance of the heterocyclic ring system in the structure of the cardiovascular drug diltiazem for its calcium channel blocking activity. The manuscript describes the design, synthesis, and biological testing of a total of 10 S-( p-methoxybenzyl), N-substituted thiosalicylamides as a series of non-cyclic compounds derived from diltiazem’s structure. The new compounds maintained all diltiazem pharmacophores except the thiazepine ring system. In vitro evaluation of the new series for calcium channel blocking effects revealed moderate activities with IC 50 values in the range of 4.8–56.0 μM. The data suggest that the ring system is not essential for activity; however, its absence leads to a considerable drop of activity relative to that of diltiazem (IC 50 = 0.3 μM). Compounds of the current series showed optimum activity when the aliphatic alkyl chain on the salicylamide nitrogen is part of a piperidine or piperazine ring system substituted at the terminal nitrogen with a benzyl group.