Safety of calcium-channel blockers.
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Calcium Channel Blockers↗
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Review of calcium-channel blockers.
Calcium-channel blocking drugs were introduced to the United States in 1982. The three approved calcium-channel blockers--nifedipine, verapamil and diltiazem--have offered new treatments for angina. This article presents an overview of these drugs with emphasis on their mechanisms of action, clinical use and guidelines for the nurse practitioner in assessing the need for calcium-channel blockers in the management of angina.
Angina Pectoris↗
Calcium channel blockers for acute traumatic brain injury.
BACKGROUND: Acute traumatic brain injury is a major cause of death and disability. Calcium channel blockers have been used in an attempt to prevent cerebral vasospasm after injury, maintain blood flow to the brain and so prevent further damage. OBJECTIVES: To estimate the effects of calcium channel blockers in patients with acute traumatic brain injury and in a subgroup of brain injury patients with traumatic subarachnoid haemorrhage. SEARCH STRATEGY: Hand searching and electronic searching for randomized controlled trials available by October 1997. SELECTION CRITERIA: Randomized controlled trials in patients with all levels of severity of clinically diagnosed acute traumatic brain injury. DATA COLLECTION AND ANALYSIS: Two reviewers (JL and CG) independently assessed the identified studies for eligibility and extracted data from each study. Summary odds ratios were calculated using the Mantel-Haenszel method. MAIN RESULTS: Four RCTs were identified as eligible for inclusion in the systematic review. The effect of calcium channel blockers on the risk of death was reported in all RCTs. The pooled odds ratio for the four studies was 0.91 (95% confidence interval 0. 70 to 1.17). For the three RCTs that reported death and severe disability the pooled odds ratio was 0.85 (95% CI 0.68 to 1.07). In the two RCTs which reported the risk of death in a sub group of traumatic subarachnoid haemorrhage patients, the pooled odds ratio was 0.59 (95% CI 0.37 to 0.94). Three RCTs reported death and severe disability as an outcome in this subgroup, and the pooled odds ratio was 0.67 (95% CI 0.46 to 0.98). REVIEWER'S CONCLUSIONS: This systematic review of randomized controlled trials of calcium channel blockers in acute traumatic head injury patients shows that considerable uncertainty remains over their effects. The effect of nimodipine in a subgroup of brain injury patients with subarachnoid haemorrhage shows a beneficial effect, though the increase in adverse reactions suffered by the intervention group may mean that the drug is harmful for some patients.
Brain Injuries↗
Phospholipid-induced human platelet activation: effects of calcium channel blockers and calcium chelators.
Human platelet activation (aggregation, [14C]-5HT release and TxB2 production) induced by the phospholipids, PAF and lysophosphatidic acid (LPA) was inhibited by EGTA, TMB-8 (an intracellular calcium antagonist) and by phenylalkylamine (Class II) but not 1,4-dihydropyridine (Class I) calcium channel blockers. Primary aggregation induced by PAF was selectively inhibited by phenylalkylamine (verapamil, methoxyverapamil) calcium channel blockers. Phospholipid-induced human platelet activation depends predominantly on the influx of extracellular calcium, possibly via specific receptor-operated calcium channels.
Biological Transport↗
Calcium-calmodulin binding in ischemic rat neurons after calcium channel blocker therapy.
Calcium channel blockers such as nicardipine improve outcome after global cerebral ischemia and may attenuate ischemic neuronal injury by preventing calcium influx and binding to calmodulin. We followed the temporal and regional sequence of neuronal calcium-calmodulin binding in normal rats (n = 6), untreated ischemic rats (n = 15), and ischemic rats treated with 0.05 mg/kg/hr s.c. nicardipine (n = 13). After 30 minutes of four-vessel occlusion, 40-microns brain sections were incubated in an anti-calmodulin antibody specific for calmodulin not bound to calcium and brain protein. Light-microscopic sections were examined immediately after ischemia and after 2 and 24 hours of reperfusion. Extensive staining of unbound calmodulin was seen in all hippocampal regions and in the cortex in normal rats. In untreated ischemic control rats, staining was lost, indicating calcium-calmodulin binding immediately after ischemia in all regions. However, after 24 hours, staining returned to normal in the cortex and dentate, and minimal staining returned in CA1 and CA3. Nicardipine-treated animals had significantly less calcium-calmodulin binding in CA1 and in the dentate after 2 hours of reperfusion. This study demonstrates that in clinically relevant doses nicardipine has a limited effect on calcium-calmodulin binding in selectively vulnerable regions after severe ischemia.
Animals↗
Microcirculatory actions and uses of naturally-occurring (magnesium) and novel synthetic calcium channel blockers.
Synthetic calcium channel blockers (Ca2+ entry blockers or antagonists) have been reported to induce relaxation of smooth muscle which is not thought to be mediated by any specific action(s) on receptor sites. In addition, it has been suggested that Ca2+ channel blockers increases blood flow in a number of organ regions, including mesenteric, femoral, renal, cerebral and coronary vasculatures, via a direct action on vascular tone by inhibiting Ca2+ influx across the vascular smooth muscle membranes. Such information has prompted clinical studies with the use of Ca2+ channel blockers in the treatment of a wide variety of cardiovascular disorders. The questions, to be answered, however, are whether any of the newly-designed channel blockers can actively produce vasodilatation of arterioles and venules in regional microvasculatures, and these synthetic agents are safe and therapeutically effective. In addition, can one design site-specific (e.g., cerebral vs. coronary vasodilator) Ca2+ channel blockers. But, since the body has a natural Ca2+ antagonist, viz., magnesium ions (Mg2+), one must ask whether such divalent cations act as peripheral vasodilators and are effective as therapeutic agents. The studies reviewed herein: compare the effects of several different Ca2+ channel blockers on resistance and capacitance vessels in different regional microvasculatures (i.e., mesenteric, skeletal muscle, pial) within a single species, namely the rat, by high-resolution TV microscopy, and demonstrate the rationale, effects and mechanisms of action of Mg2+ on regional blood vessels. These data show some of the new, novel synthetic Ca2+ channel blockers (i.e., nisoldipine, nitrendipine, nimodipine) can: exert effects on both arterioles and venules in certain vasculatures; be designed to exert a wide range of potencies; and be designed to act selectively at regional microvasculatures. In addition, the data presented are consistent with the hypothesis that Mg2+ exerts a regulatory role in vascular tone, vascular reactivity and vascular resistance. Certain vascular diseases associated with a Mg2+-deficiency appear to be amenable to treatment with Mg2+.
Anesthesia↗
Calcium channel blockers.
The calcium channel blockers initially were approved for the treatment of classical and variant angina pectoris. Recent studies indicate that these agents also are useful in such diverse conditions as pulmonary and systemic hypertension, hypertrophic cardiomyopathy, arrhythmias, asthma, Raynaud's syndrome, esophageal spasm, myometrial hyperactivity, cerebral arterial spasm, and migraine.
Calcium Channel Blockers↗
Calcium channel blockers.
Calcium (Ca(++)) plays an essential role in many cardiovascular physiologic processes. Electrophysiologic properties of the sinus and atrioventricular nodes greatly depend on Ca(++) ion influx. Also, Ca(++) is the main link for excitation-contraction coupling of the myocardium. Ca(++) channel blockers are a group of heterogeneous compounds that block the ionic influx of Ca(++) into the myocardial and vascular smooth muscle cells. Because Ca(++) plays a central role, it is not surprising that Ca(++) channel blockers can produce profound alterations in cardiovascular functions. Recently several studies have shown these agents to be useful in the treatment of supraventricular tachyarrhythmia, variant angina, chronic stable angina and hypertrophic cardiomyopathy. In the future they may be found useful in preserving myocardium during cardiopulmonary bypass, in limiting infarct size and in the treatment of hypertension and congestive heart failure.
Angina Pectoris↗
Brain extraction of a calcium channel blocker.
Dihydropyridine calcium channel blockers may be effective treatment for acute cerebral ischemia, but the uptake of these drugs into the brain is unknown. A 0.2-ml bolus of [14C]nicardipine hydrochloride and [3H]water was injected into the common carotid arteries of 7 normal and 7 ischemic rats. The corrected first-pass extraction of nicardipine, compared to water, was calculated to be 30.7% into the hemispheres and 42.3% into the hippocampi. The uptake was greater into the ischemic hemispheres (p less than 0.001). These data suggest that dihydropyridines are available to binding sites and calcium channels in neurons.
Animals↗
Membrane activity, antioxidant, antiaggregatory and antihemolytic properties of four calcium channel blockers.
Four calcium channel blockers: nifedipine, fendiline, verapamil and diltiazem have been found to possess different affinity to cytomembranes of platelets and erythrocytes. Nifedipine bound to proteins of the external site of cytomembranes. Verapamil and fendiline possessed affinity to lipids of the cytoplasmic site of the cytomembranes. Diltiazem bound practically neither to erythrocyte nor to platelet membranes. All tested compounds were antioxidants, the strongest being fendiline. Antiaggregatory and antihemolytic properties of tested compounds were roughly correlated with their membrane activity.
Animals↗
Monotherapy of hypertension with darodipine: a new calcium-channel blocker.
Calcium-channel blockers are increasingly used as single agents for the treatment of essential hypertension. Following three weeks of single-blind placebo therapy, 43 patients with essential hypertension were randomized into four groups. Group 1 (10 patients) received placebo twice a day, Group 2 (13 patients) received darodipine (PY 108-068) 50 mg twice a day, Group 3 (9 patients) received darodipine 100 mg twice a day, and Group 4 (11 patients) received darodipine 150 mg twice a day. Patients were seen in the clinic weekly for 4 weeks. Clinical and laboratory evaluations were done on each patient. Darodipine caused a sustained decrease in the supine and standing systolic and diastolic blood pressure (p less than .001) and there were no significant pressure differences between the three drug dosages. The effects of the drug on heart rate were not consistent. Placebo had no effect on either blood pressure or heart rate. Side effects were few, mild, and consisted of headaches and peripheral edema, and did not necessitate discontinuation of the drug. No metabolic abnormalities were seen with either low or high doses of the drug. We conclude that: (1) darodipine is effective, safe, and well tolerated; (2) its antihypertensive effectiveness is similar at high and low doses, although the higher doses seemed to have a slightly greater effect on the diastolic arterial pressure; (3) the low dose may be preferable since side effects were dose related.
Calcium Channel Blockers↗
Lercanidipine: a novel dihydropyridine calcium-channel blocker.
Calcium-channel blockers (CCBs) have been used for the treatment of hypertension for more than 20 years, and recent clinical trials support the efficacy and safety of long-acting dihydropyridine (DHP) CCBs for a wide spectrum of hypertensive patients, including diabetic hypertensive patients. DHP CCBs are effective agents overall and are particularly effective when used in combination with other agents. Lercanidipine is a novel DHP CCB effective for the treatment of mild-to-moderate hypertension. Compared with other DHP CCBs, lercanidipine has a molecular design that imparts greater solubility within the arterial cellular membrane bilayer, membrane-controlled kinetics, and a high cholesterol tolerance factor. These favorable membrane-controlled kinetics impart a gradual onset of vasodilation and a long duration of action. Further, the unique pharmacokinetic and pharmacodynamic properties of lercanidipine appear to contribute to its efficacy and favorable safety profile. In clinical trials in the treatment of mild-to-moderate hypertension, lercanidipine was administered at a starting dose of 10 mg once daily, and increased to 20 mg once daily for nonresponders. Studies have shown that lercanidipine has a 24-hour antihypertensive effect and causes no significant increase in heart rate. Lercanidipine has been shown to be effective in a wide range of hypertensive patients, including mild-to-moderate hypertension, severe hypertension, the elderly, and those with isolated systolic hypertension. It is associated with a low rate of adverse events. Because of its efficacy and favorable safety profile, lercanidipine has the potential to improve blood pressure control in a wide range of patients, including those who have not responded to, or who have been unable to tolerate, other antihypertensive agents.
Animals↗
Pharmacologic management of ischemic heart disease with beta-blockers and calcium channel blockers.
In myocardial ischemia beta-blockers reduce myocardial oxygen demand, improve flow toward ischemic regions, and have mild antiplatelet and antiarrhythmic effects. These agents are effective in chronic stable angina and unstable angina. In chronic myocardial ischemia, the beta-blockers timolol, metoprolol, atenolol, and propranolol have cardioprotective effects, reducing overall mortality and the incidence of recurrent myocardial infarction. Calcium channel blockers, which reduce myocardial oxygen demand and improve oxygen supply, are effective in the treatment of chronic stable angina, vasospastic angina, and unstable angina. Although calcium channel blockers generally have no effect or adverse effects when used as primary therapy for acute myocardial infarction, diltiazem (when used concomitantly with nitrates or beta-blockers) has been shown to reduce the incidence of reinfarction in patients after non-Q wave myocardial infarction.
Adrenergic beta-Antagonists↗
Effects of calcium channel blockers on calcium uptake in rat aortic valve allografts.
BACKGROUND: The life span of human aortic valve allografts is finite, and many fail because of cusp rupture or calcification. Subcellular changes occurring in aortic valves in response to transplantation include the uptake of calcium. This study uses a heterotropic rat aortic valve transplant model to determine whether the calcium channel blockers diltiazem and verapamil might attenuate leaflet calcification. METHODS AND RESULTS: The 60 rats studied were divided into the following groups: 1) control: valves from normal, unoperated F1 generation of Lewis and Brown Norway cross (LBNF1) rats; 2) control: valves from syngeneic transplant combinations (Lewis/Lewis); 3) control: valves from allogeneic transplant combinations (LBNF1/Lewis, donor/recipient); 4) experimental: valves from allogeneic strain combinations treated with 30 mg/kg per day diltiazem; 5) experimental: valves from allogeneic strain combinations treated with 30 mg/kg per day verapamil. Drugs or saline (controls) were administered with osmotic pumps placed subcutaneously 2 days before transplantation. Animals were killed 3 weeks later, and the valves were harvested and prepared for calcium analysis. Energy-dispersive x-ray microanalysis was used to measure the calcium in a section of one leaflet from each valve studied. Paired t tests showed that allograft valves treated with diltiazem or verapamil contained significantly less calcium than allograft controls treated with saline (p < 0.001). When all five groups were subjected to one-way ANOVA, the valves in the allograft control group contained significantly more calcium than all other groups. All other groups were not different from each other. CONCLUSIONS: The calcium channel blockers verapamil and diltiazem were effective in preventing early calcification that occurs in aortic valves after transplantation. Thus, these agents might play a role in prolonging the life of human aortic valve allografts.
Analysis of Variance↗
Does QTc interval predict the response to beta-blockers and calcium channel blockers in hypertensives?
The QT interval corrected for heart rate (QTc) is believed to reflect sympathovagal balance. It has also been established that beta-blockers and dihydropyridine-type calcium channel blockers (DHPCCB) influence the autonomic nervous system. This study tested the hypothesis that QTc interval length is a predictor of the blood pressure reduction induced by beta1-selective beta-blockers or DHPCCB. The predictive values of pretreatment heart rate and of the heart rate change with therapy were also evaluated. The authors conducted an historical reanalysis of 5 clinical trials that looked at the antihypertensive effects of beta-blockers (nebivolol) or DHPCCB (amlodipine, felodipine, isradipine, nifedipine). Correlation and quintile analyses were performed to measure the association between QTc interval, heart rate, or heart rate change and therapeutic blood pressure response. Separate analyses were undertaken for beta-blockers and DHPCCB. Seventy-three and 98 hypertensive subjects respectively were included in the beta-blocker and DHPCCB analyses. QTc interval, pretreatment heart rate, and heart rate change with therapy were not associated with therapeutic blood pressure response. In this study, QTc interval length, pretreatment heart rate, and heart rate change with therapy were not good predictors of the blood pressure response to beta1-selective beta-blockers or DHPCCB in hypertensive subjects.
Adrenergic beta-Antagonists↗
Cellular actions and pharmacology of calcium-channel blockers.
The calcium-channel blockers represent a diverse group of chemical structures that block calcium-selective channels in the plasma membrane of a variety of excitable cells. As the calcium fluxes carried by these channels allow ionic calcium (Ca2+) to gain access to the cell interior, where Ca2+ serves as an activator--messenger, calcium-channel blockers generally act to inhibit cell function. By reducing the depolarizing currents caused by the entry of positively charged Ca2+ into the negatively charged interior of resting cells, the calcium-channel blockers also inhibit excitatory processes that depend on calcium entry across the plasma membrane. These principles account for most of the effects of calcium-channel blockers on the cardiovascular system. In vivo, the calcium-channel blockers inhibit contractile function in the heart and vascular smooth muscle and, because the initial depolarizing currents in the sinoatrial and atrioventricular nodes are carried by calcium channels, slow the heart rate and prolong atrioventricular conduction. However, in vivo in human studies, there are differences among the calcium-channel blockers. The vasodilatory effects of the calcium channel blockers, which can reduce systemic blood pressure, offer a primary basis for their potential use in the treatment of hypertension. The tissue specificity exhibited by some of the calcium-channel blockers may enhance their therapeutic value in selected hypertensive patients. Of the three calcium-channel blockers now available for use in the United States (diltiazem, nifedipine, and verapamil), diltiazem and verapamil are approximately equipotent in inhibiting calcium-channel function in cardiac and vascular smooth muscle, whereas nifedipine is more potent in vascular smooth muscle.(ABSTRACT TRUNCATED AT 250 WORDS)
Actins↗
Pharmacology and mechanisms of action of calcium-channel blockers.
The calcium-channel blockers represent a group of organic chemical structures that share the ability to inhibit Ca2+ entry into excitable cells. In coronary and peripheral arterial smooth muscle and the heart, inhibition of Ca2+ entry blunts the ability of Ca2+ to serve as an intracellular messenger. Thus, calcium-channel blockers are smooth-muscle dilators and have a negative inotropic effect on the working myocardial cells of the atria and ventricles. Calcium-channel blockers also have effects on impulse formation and conduction in some regions of the heart. A fast, Na+-dependent ionic current is responsible for the upstroke of the action potential in the working cells of the atria and ventricles and in the rapidly conducting cells of the His-Purkinje system, so that the calcium-channel blockers do not inhibit conduction in these cells. In the sinoatrial and atrioventricular nodes, where depolarization is due primarily to a Ca2+-dependent slow inward current, the calcium-channel blockers slow the sinus pacemaker and inhibit atrioventricular conduction. The actions of different calcium-channel blockers are not always similar; for example, nifedipine is much more potent as an inhibitor of calcium channels in smooth muscle than in the heart, whereas verapamil and diltiazem are approximately equipotent in heart and vascular smooth muscle. It is likely that the calcium-channel blockers reach their specific binding sites in membranes by first dissolving in the phospholipid bilayer, after which they may interact with hydrophobic regions of proteins that make up, or regulate, these channels. Further knowledge of these molecular properties should facilitate the development of new calcium-channel blockers with improved specificity.
Action Potentials↗
Action and binding of calcium channel blockers on the putative calcium channel of synaptosomal plasma membrane from the electric organ of Narke japonica.
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Acetylcholine↗