Efficacy Of Calcium Channel Blockers Research Articles

Calcium channel blockers in the spectrum of antihypertensive agents

Calcium channel blockers (CCBs) are widely used in the treatment of hypertension. Through blood pressure reduction, and possibly other mechanisms such as antioxidative effects, they may play a role in diminishing the risk for a variety of cardiovascular outcomes. The combination of CCBs with other newer antihypertensive agents such, as ACE inhibitors and angiotensin receptor blockers, may provide complementary effects on risk reduction in cardiovascular adverse events and renal disease. Although the efficacy of CCBs as antihypertensive agents has been adequately demonstrated, there have been concerns regarding the use of short acting dihydropyridines after acute myocardial infarction. There have also been questions about the role of CCBs with regards to other antihypertensive agents in renal disease. For example, differential effects of dihydropyridine and non-dihydropyridine CCBs may affect progression of renal disease and risk for diabetes. Certain precautions involving drug interactions are needed because of the effects of CCBs on the CYP450 enzyme systems.

CACNA1C Polymorphisms are Associated with the Efficacy of Calcium Channel Blockers in the Treatment of Hypertension

Retrospective pharmacogenetic analysis was performed on 120 Caucasian subjects. Subjects were obtained in collaboration with the Estonian Genome Project and Egeen Inc. (CA, USA), who provided blinded medical record and genetic data to the researchers, respectively. Subjects selected from the Estonian Genome Project had a diagnosis of hypertension confirmed by at least two blood pressure measurements and multiple follow-up measurements for assessing calcium channel blocker antihypertensive treatment outcome. Treatment outcome was scored positive if at least three follow-up blood pressure measurements were nonhypertensive and no more than one follow-up measurement was hypertensive (>140/90). The genotypes of 62 single nucleotide polymorphisms (SNPs) in the calcium channel, voltage-dependent, L type, alpha 1C subunit (CACNA1C) gene were obtained for each subject from a blood sample. Univariate analyses with multiple test correction were conducted using family-wise error rate and false discovery rate methods. Three SNPs in CANCA1C had significant associations with antihypertensive outcome, combining to yield a positive treatment outcome of less than 15 to 80%.

Calcium channel blockers for primary Raynaud's phenomenon: a meta-analysis

To determine the efficacy of calcium channel blockers (CCBs) for primary Raynaud's phenomenon (RP). Primary outcomes were frequency and severity of RP attacks. A meta-analysis was conducted using primary data sources: Medline, Current Contents and the Cochrane Controlled Trials Register. Inclusion criteria were randomized controlled trials (RCTs) of >2 days' duration with <35% dropouts. Eighteen of 31 trials were eligible for inclusion [13 nifedipine vs placebo; five other CCBs vs placebo (n = 361)]. The main reasons for trial exclusion were: subset data (primary RP) not provided (n = 10); data published more than once (n = 1); lack of control group (n = 1); and lack of randomization (n = 1). Data were abstracted independently and a weighted mean difference (WMD) was calculated for the outcomes. The WMD (95% confidence interval) of all CCBs vs placebo for reduction in the frequency of attacks (n = 17) over 1 week was -5.00 (-9.02, -0.99) (P = 0.01) or -2.80 (-3.90, -1.70) when heterogeneity was considered, and -6.05 (-11.19,-0.19) (P = 0.04) for nifedipine alone (n = 10). The WMD of all CCBs vs placebo (n = 8) for reduction in severity of attacks (assessed with a 10-cm visual analogue scale) was -1.39 (-2.20, -0.58) (P = 0.0007) and -1.81 (-3.08, -0.54) (P = 0.005) for nifedipine alone (n = 5). Several small RCTs of CCBs for primary RP have been conducted and have yielded clinical improvement in the frequency and severity of ischaemic attacks. Most trials were crossover trials in which order effect was not studied; this may have introduced bias. The effect size may have been small because of low dosing in studies. The efficacy of CCBs for reducing severity and frequency of ischaemic attacks in primary RP is small (average of 2.8 to 5.0 fewer attacks per week and a 33% reduction in severity).

Blood pressure lowering efficacy of calcium channel blockers for primary hypertension

Blood pressure lowering efficacy of calcium channel blockers for primary hypertension

Calcium channel blockers as tocolytics

This article reviews the clinical and basic science investigations regarding the safety and efficacy of calcium channel blockers as tocolytic agents. The authors reviewed the English language literature on the pharmacology and clinical applications of calcium antagonists in obstetrics. A MEDLINE (1966-2000) search was performed with the terms "calcium channel blockers," "randomized controlled trial," "preterm labor," "calcium antagonist," "tocolysis," and "nifedipine." References from these data sources were then used to find additional studies. Animal data and clinical trials in humans were included. The safety of these agents was researched in published data from the nonobstetric as well as obstetric literature. The calcium channel blockers most commonly used as tocolytics are nifedipine and nicardipine. These agents act to inhibit calcium influx across cell membranes, thereby decreasing tone in the smooth muscle of the vasculature. They act as profound vasodilatory agents and have minimal effect on the cardiac conduction system. Numerous randomized clinical trials have shown them to be as effective as beta-mimetics and magnesium in achieving tocolysis. When used for tocolysis, calcium antagonists have fewer maternal side effects than other tocolytics and have no adverse effect on fetal outcome.

Current status of safety and efficacy of calcium channel blockers in cardiovascular diseases: A critical analysis based on 100 studies

Recently, serious concerns have been expressed about the long-term safety of the calcium channel blockers (CCBs) as a group. Safety and efficacy are, however, ultimately linked to each other; therefore both must be evaluated especially in the therapy of angina and hypertension, the main clinical indications for CCBs. The structural, functional, and pharmacokinetic heterogeneity of CCBs means that the efficacy and dangers of one subclass, such as the short-acting dihydropyridines (DHPs), in one situation, such as unstable angina, do not necessarily apply in other clinical situations. One hundred studies are reviewed according to their methods of data collection: case series, case control, cohort, randomized controlled trials (RCTs), and meta-analyses. Large, well-designed RCTs and the meta-analyses based on these trials remain the gold standard. Observational studies, though potentially less reliable sources of information because of selection bias, may nevertheless produce hypotheses that must then be tested in RCTs. Regarding safety, both observational studies and RCTs suggest that adverse effects of CCBs may be linked to short-acting agents, specifically short-acting nifedipine. Two good studies favor the safety of verapamil, even in short-acting form. Incomplete but increasing overall evidence favors the safety of longer-acting DHPs. Heart failure remains a class contraindication to the use of all CCBs, with some exceptions. Regarding efficacy, there are positive results of RCTs with CCBs in 2 specific clinical situations, namely, verapamil in postinfarct protection in the absence of pre-existing heart failure, and 2 outcome studies on hypertension with longer acting DHPs. These results cannot automatically be applied to other clinical situations and to other CCBs. For example, there is no evidence for the safety or efficacy of DHPs used without β blockers in postinfarct patients. In diabetic hypertensives, 2 relatively large RCTs show that the blood pressure can be reduced by DHP-based therapy in diabetics, with a reduction in hard end points. To achieve current blood pressure goals, combination therapy is almost always necessary, and in diabetics there is strong evidence that 1 essential component should be an angiotensin converting enzyme inhibitor. The future aim with CCBs must be to obtain a large database gathered from RCTs, which will give the same certainty about efficacy and safety that already holds for use of the diuretics in hypertension, β-blockers in postmyocardial infarction patients, and the angiotensin converting enzyme inhibitors in heart failure. Copyright © 2000 by W.B. Saunders CompanyProgress in Cardiovascular Diseases, Vol. 43, No. 2 (September/October), 2000: pp 171-196

Calcium channel blocker enhances lung preservation

Background The standard program for lung transplantation employs PGE 1 pretreatment for donor lungs, but its efficacy remains controversial. Calcium channel blocker has been reported more effective for reducing potassium-induced vasoconstriction. We investigate the efficacy of calcium channel blocker in the initial lung flush using rat lung transplant model. Methods The excised rat lungs ( n = 30) were flushed with either University of Wisconsin solution (UWS) with a prior injection of 50 μg/kg PGE 1 into the pulmonary artery (UWS + PGE 1; n = 7), UWS only (UWS; n = 7), or UWS containing 10 −6 M nifedipine (UWS + Nif; n = 8). After storage (4° C) for 24 hours, all lungs were reperfused for 2 hours using an isolated, pulsatile blood perfused lung model. Control lungs ( n = 8) were reperfused immediately after harvest. Blood gas analysis and shunt fraction, lung airway resistance, dynamic lung compliance, and pulmonary vascular resistance were assessed. Results The pO 2 at 30 minutes after reperfusion in the control, UWS, UWS + PGE 1, and UWS + Nif group were 88.0 ± 3.2, 49.6 ± 2.2, 52.0 ± 2.4, 85.1 ± 2.1 (mmHg), respectively. Until 30 minutes after reperfusion, the pO 2 in UWS and UWS + PGE 1 group were significantly lower than those in UWS + Nif group ( p < .001). Shunt fraction, lung airway resistance, and dynamic lung compliance also demonstrated the superiority of UWS + Nif group. Conclusions The early graft function after storage was significantly enhanced in lungs flushed with UWS containing nifedipine. Calcium channel blocker is more effective than PGE 1 in reducing the potassium-induced vasoconstriction. Optimal composition of the flush may require both calcium channel blocker for pulmonary vasodilation and PGE 1 for pulmonary protection by non-vasodilatory mechanisms.

Verapamil for severe hyperkinetic movement disorders

The use of verapamil in three cases of severe hyperkinetic movement disorders resulted in dramatic improvement in patients who had been refractory to many other treatments over a prolonged period. A videotape illustration of one of the patients is provided. The mechanism of action and evidence of efficacy of calcium-channel blockers for abnormal movements are discussed.

Calcium Channel Blockers in Heart Failure

A considerable effort has been made in the last 15 years to evaluate the safety and efficacy of calcium channel blockers (CCBs) in the treatment of patients with chronic congestive heart failure (CHF). Available studies have provided strong evidence for a potential detrimental effect of the first-generation calcium antagonists in patients with CHF, indicating the need for great caution when these drugs are used in patients with significant depression of left ventricular systolic function. A number of second-generation CCB have demonstrated a strong vasodilatory effect and favorable hemodynamic action but failed to show a similar improvement in exercise capacity, morbidity and mortality. Moreover, drugs such as nicardipine and nisoldipine have resulted in a detrimental effect in some patients and, therefore, cannot be considered safe when used in patients with moderate-to-severe heart failure. Available information from the V-HeFT III study demonstrate a lack of an unfavorable effect of felodipine on exercise tolerance in patients with chronic heart failure. Although mortality rate was similar in both the felodipine and the placebo group, because of the relatively small number of patients in this study, no clear conclusion can be drawn regarding the effect of felodipine on mortality in patients with CHF. An encouraging signal regarding a potential role of CCB in the treatment of chronic heart failure has been provided by the recently completed PRAISE study. This prospective large-scale study demonstrated the safety of amlodipine, a long-acting dihydropyridine derivative, when used in patients with heart failure due to coronary artery disease. Furthermore, this study demonstrated a substantial reduction in mortality in patients with CHF due to nonischemic cardiomyopathy and provided a strong indication for a potential therapeutic benefit of amlodipine when added to standard CHF therapy in this patient population. No clear explanation is available at the present time regarding the reason for the deleterious effect demonstrated with some of the dihydropyridines and the contrasting benefit seen with amlodipine. Finally, more information regarding the safety and efficacy of dihydropyridines should become available in the next year. The PRAISE II study is ongoing and will provide further information regarding the therapeutic role of amlodipine in patients with nonischemic dilated cardiomyopathy. The MACH-1 study is evaluating the effect of mibefradil, a predominant T-type channel blocker with an ideal activity profile, on morbidity and mortality in patients with chronic CHF.

Adverse Outcomes of Underuse of β-Blockers in Elderly Patients-Reply

In Reply. —Dr Gambassi and colleagues and Dr Holt suggest that the nondihydropyridine calcium channel blockers (eg, verapamil and diltiazem) may be safer or more effective than dihydropyridine calcium channel blockers. However, our study was designed to measure outcomes of β-blocker underuse, not to assess the comparative efficacy of calcium channel blockers. A comparative study would require a different sample (not only patients eligible for β-blockers). Instead, we studied the effects of the substitution of any calcium channel blocker for a trial of β-blockers in patients eligible for β-blockers, a practice at odds with national evidence-based guidelines.1 Gambassi et al also question whether 2 effective drug classes, aspirin and lipid-lowering agents, might be correlated with β-blocker use. Because aspirin is an over-thecounter drug, administrative claims databases do not contain reliable data on its use in community settings. However, a previous report from the United Kingdom indicates much greater use of aspirin

How do calcium channel blockers prevent cardiovascular events. Are they all alike?

The calcium channel blockers (calcium antagonists) have vasodilatory and cardiodepressant effects. These pharmacological properties explain, to a large extent, the antihypertensive, antianginal, and antiarrhythmic effects of these agents. Pharmacological differences between members of this class, e.g. differences in vascular selectivity, are well documented and can be exploited clinically. The efficacy of calcium channel blockers in the prevention of cardiovascular events may depend on factors other than their vasodilatory and cardiodepressive effects. Much interest, for example, has been shown in their possible antiatherosclerotic effects. It is, however, at present not possible to ascertain how important these and other ancillary effects (such as plaque stabilisation) are for the putative cardioprotective effects of calcium channel blockers. There are, moreover, few in vitro or in vivo (animal or clinical) studies allowing valid comparison of the different calcium channel blockers with regard to these ancillary properties.

The Effects of Nonsteroidal Anti-inflammatory Drugs on Blood Pressures of Patients With Hypertension Controlled by Verapamil

Nonsteroidal anti-inflammatory drugs may attenuate the antihypertensive effects of diuretics, beta-blockers, angiotensin-converting enzyme inhibitors, central alpha-agonists, and other vasodilators. Their effects on the antihypertensive efficacy of calcium channel blockers are inadequately studied in small numbers of patients but appear to be minimal. A three-phase, randomized, double-blind, placebo-controlled multicenter study included 162 patients aged 18 to 75 years with essential hypertension. After diastolic blood pressure was controlled to 90 mm Hg or less with once-daily verapamil hydrochloride, patients received ibuprofen, naproxen, or placebo matching capsules for 3 weeks, and blood pressure, heart rate, weight, and adverse effects were evaluated. A general linear model with 95% confidence intervals was used to compare each nonsteroidal anti-inflammatory drug treatment group with the placebo group. No significant differences in sitting, standing, or supine blood pressure were noted with naproxen or ibuprofen compared with placebo. The percentages of patients in each treatment group with increases of 10 mm Hg or more in either systolic or diastolic blood pressure were similar. Statistically significant increases in weight were seen with both nonsteroidal anti-inflammatory drug therapies. Changes in pulse rate were not significant. The incidence of adverse effects was similar across all three treatment groups. The addition of naproxen or ibuprofen to the treatment of hypertensive patients in whom blood pressure is controlled by once-daily verapamil does not cause an increase in blood pressure. Verapamil may therefore offer considerable advantages in maintaining control of blood pressure in patients who regularly receive nonsteroidal anti-inflammatory drug therapy.

Evidence for or Against the Efficacy of Calcium Channel Blockers for Management of Hypertrophic Cardiomyopathy in Cats

The positive lusitropic and direct coronary vasodilating properties of the calcium channel blocking agents are beneficial therapeutic effects not provided by the beta-adrenergic blocking agents for the management of feline HCM. Data from cats studied at the University of Tennessee suggest that diltiazem more consistently alleviates clinical signs and more effectively prolongs survival in cats with HCM than either propranolol or verapamil. Orally administered diltiazem appears to have sustained beneficial effects on left ventricular filling and cardiac performance based on its ability to reduce resting heart rate, decrease blood lactate concentration, increase venous oxygen tension, improve echocardiographic parameters, and resolve radiographic abnormalities. Long-term diltiazem administration may also reverse myocardial hypertrophy in some patients. There appear to be few if any side effects of this drug. Diltiazem, therefore, provides a safe and effective approach for the management of feline HCM.

Role of Calcium-Channel Bockers in Preventing Acute and Chronic Renal Injury

Calcium-channel blockers (CCBs) have been shown to afford protection against acute (ARF) and chronic renal failure (CRF). The effects of CCBs against acute renal injury occur at both the vascular and tubular epithelial level. At the vascular level, experimental ARF-associated loss of renal autoregulation and hypersensitivity to renal nerve stimulation has been shown to be reversed by CCBs. These beneficial vascular effects of CCBs occur on the background of the finding that renal ischemic injury is associated with an increase in cellular Ca2+ concentration. A rise in tubular epithelial Ca2+ concentration also occurs very early after a renal ischemic insult. This effect of ischemia is associated with evidence of membrane depolarization, opening of slow calcium channels, increased cellular Ca2+ uptake, and reversal by CCBs. There is evidence that the increased cellular Ca2+ uptake activates phospholipases, which prolong and increase membrane damage. Experimental CRF is also associated with increased renal cellular Ca2+ concentration, an effect that can be attenuated by CCBs. The CCBs probably slow progression of CRF by both cytoprotective and antihypertensive effects. These findings of vascular and tubular effects of CCBs in experimental ARF and CRF have led to their clinical use to prevent initial dysfunction of cadaveric kidney transplants, cyclosporine nephrotoxicity, radiocontrast-induced ARF, and progression of CRF. Randomized clinical studies are necessary to further examine the efficacy of CCBs in ARF and CRF.

Treatment with conotoxin, an ‘N-type’ calcium channel blocker, in neuronal hypoxic-ischemic injury

Therapeutic efficacy of calcium channel blockers in stroke remains controversial, but previously used agents bind almost exclusively to L-type calcium channels. The newly-discovered N-type calcium channel is specific to neurons, and therapy involving blockade of this site has not been previously attempted. We assessed the neuroprotective effect of omega-conotoxin GVIA (CgTx), a blocker of N-type calcium channels, using both in vitro hypoxic injury to rat cortical neurons and an in vivo model of reversible spinal cord ischemia in the rabbit. In cell cultures, CgTx inhibited hypoxia-induced 45Ca accumulation and neuronal injury minimally, compared to the NMDA antagonist ketamine. In vivo, the duration of spinal cord ischemia which produced permanent paraplegia in 50% of control animals (ET 50) was 24.0 ± 2.6min. Animals treated 2 h prior to ischemia with 0.5 nmol CgTx in the subarachnoid space had an ET 50 of 26.9 ± 1.8min(P = 0.36). Animals treated 24 h prior to ischemia (all had persistent systemic tremor) had a ET 50 of 28.9 ± 1.8min(P = 0.13). We conclude that pharmacologic modulation of the N-type calcium channel does not provide a significant protective effect against neuronal hypoxic-ischemic injury.

Effects of Calcium Channel Blockers on the Coronary Circulation

Calcium channel blockers are among the most effective antiischemic therapies currently available. These agents afford a reduction in vascular smooth muscle tone by interrupting the excitation-contraction coupling process dependent on calcium transport. The efficacy of calcium channel blockers in patients with myocardial ischemia is probably due in large part to their effects on coronary circulation. In experimental models of coronary occlusion, these agents have been demonstrated to increase coronary vasodilation and coronary blood flow. Recruitment of coronary vasodilator reserve by nifedipine has been demonstrated indirectly via enhancement of left ventricular function in a canine model. Additionally, calcium channel blockers have been shown to modify the reactive hyperemic response usually seen after coronary artery occlusion. These changes in coronary resistance vessels, which normally regulate myocardial blood flow in response to metabolic requirements, have important clinical implications. Larger collateral vessels are also affected by calcium channel blockers, although the results observed in experimental models are not as clear cut. Although techniques for measuring coronary blood flow in humans are more limited, considerable data have accumulated on the effects of calcium channel blockers in humans. Assessments of coronary vasodilation using quantitative angiography have produced variable results. However, improved myocardial perfusion, as measured by thallium-201 scintigraphy after administration of nifedipine, and beneficial effects on coronary blood flow and coronary vascular resistance as assessed using the precordial xenon-133 washout technique before and after sublingual administration of nifedipine have been observed. Overall, such studies have not only shown the clinical usefulness of calcium channel blockers, but have broadened our understanding about the complex interplay of their mechanisms of action.

Effects of Calcium Channel Blockers on the Coronary Circulation

Calcium channel blockers are among the most effective antiischemic therapies currently available. These agents afford a reduction in vascular smooth muscle tone by interrupting the excitation-contraction coupling process dependent on calcium transport. The efficacy of calcium channel blockers in patients with myocardial ischemia is probably due in large part to their effects on coronary circulation. In experimental models of coronary occlusion, these agents have been demonstrated to increase coronary vasodilation and coronary blood flow. Recruitment of coronary vasodilator reserve by nifedipine has been demonstrated indirectly via enhancement of left ventricular function in a canine model. Additionally, calcium channel blockers have been shown to modify the reactive hyperemic response usually seen after coronary artery occlusion. These changes in coronary resistance vessels, which normally regulate myocardial blood flow in response to metabolic requirements, have important clinical implications. Larger collateral vessels are also affected by calcium channel blockers, although the results observed in experimental models are not as clear cut. Although techniques for measuring coronary blood flow in humans are more limited, considerable data have accumulated on the effects of calcium channel blockers in humans. Assessments of coronary vasodilation using quantitative angiography have produced variable results. However, improved myocardial perfusion, as measured by thallium-201 scintigraphy after administration of nifedipine, and beneficial effects on coronary blood flow and coronary vascular resistance as assessed using the pre-cordial xenon-133 washout technique before and after sublingual administration of nifedipine have been observed. Overall, such studies have not only shown the clinical usefulness of calcium channel blockers, but have broadened our understanding about the complex interplay of their mechanisms of - action. Am J Hypertens 1990;3:299S-304S

Characterization of the spontaneous motor activity of the isolated human pregnant myometrium

The motor activity of myometrial strips from pregnant human uterus was characterized in vitro by the use of inhibitory compounds acting on the smooth muscle contractility at different levels. Spontaneous contractions were not inhibited by tetrodotoxin or a series of membrane receptor antagonists, like anticholinergics, antihistaminics, α-adrenergic blocking agents, antiserotoninergics and opioid receptor antagonists, thus excluding neuronal involvements or a local release of endogenous mediators active on the respective membrane receptors. The ineffectiveness of indomethacin (10 −5 m) minimizes a role for excitatory prostaglandins. Isoprenaline and selective β 2-adrenergic stimulants, like salbutamol and hexoprenaline (up to 10 −5 m), failed to affect the amplitude of spontaneous contractions. Conversely the adenylate cyclase activator, forskohn, had a concentration-dependent inhibitory effect. Ca 2+-free medium, trifluoperazine and all the calcium channel blockers examined produced a concentration-dependent inhibition of the spontaneous contractions in the following order of sensitivity: nifedipine ≫ verapamil ≫ diltiazem > trifluoperazine.The inhibitory effect of nifedipine was not overcome by excess calcium concentration in the bathing medium, but was completely restored by addition of the calcium agonist Bay K 864410 −7 m. From these data it can be concluded that the spontaneous activity of pregnant human myometrium in vitro is independent of neural or humoral mechanisms. The inhibitory effect of Ca 2+-free medium and the efficacy of calcium channel blockers support the view that calcium influx is an important step in initiating the contractile activity of uterine smooth muscle.

Effects of calcium channel blockers on neurologic outcome after focal ischemia in rabbits.

To determine the efficacy of calcium channel blockers in preserving neurologic function after central nervous system ischemia, we studied three such agents in two animal models. We treated rabbits after inducing ischemia in the brain with intra-arterial microspheres and in the spinal cord using a removable aortic occluding device. We found no benefit, in terms of neurologic functional outcome, from lidoflazine, nimodipine, or nicardipine. All three agents elevated regional blood flow in the spinal cord. We conclude that calcium antagonists are not likely to prove beneficial if used alone in the treatment of focal central nervous system ischemia.