Role Of Calcium Channel Blockers Research Articles

Therapeutic Strategies in the Prevention of Acute Renal Failure

The mechanisms involved and the potentially useful therapeutic strategies in the prevention of acute renal failure (ARF) are briefly reviewed. Factors mentioned are the role of calcium channel blockers, the antioxidant agents, heme oxygenase induction, and ferritin synthesis; and of substances with hemodynamic actions in ARF, such as endothelin, atrial natriuretic peptide, urodilatin, PAF antagonist, prostaglandins, diuretics, and dopamine. The loss of tubular epithelium polarity, the mechanisms involved in this process, and the usefulness of arginine-glycine-aspartic acid peptide and anti-ICAM antibodies in the prevention of tubular obstruction are also reviewed.

A personal view of the controversy regarding the use of calcium channel blockers in hypertension

Aim The purpose of this review is to add perspective to the current controversy surrounding the role of calcium channel blockers in the treatment of hypertension. Calcium blocker safety Well-conducted retrospective studies have raised concern about various aspects of the long-term safety of calcium blockers. These include: (1) a case cohort study by Psaty et al. in hypertensive patients indicating that calcium blockers were associated with an increased risk of myocardial infarction (> 50% increase) compared to diuretics or β-blockers; (2) a meta-analysis by Furberg et al. of 16 studies suggesting that nifedipine increases mortality in acute coronary syndromes; (3) a trial in which isradipine was associated with more cardiovascular events in hypertensive patients than in those taking hydrochlorothiazide; (4) a report by Pahor and colleagues of an increased risk of gastrointestinal bleeding in elderly patients taking isradipine; and (5) a further report by Pahor et al. that the incidence of most common cancers appeared to be higher in patients taking calcium blockers than other cardiac medications (relative risk = 1.72; 95% confidence interval 1.2–2.34, P = 0.0005). The majority of these observations were made with short-acting calcium blockers, which are not indicated for the treatment of hypertension. In contrast, other well-controlled clinical trials are consistent with long-term calcium blocker safety. Some reports support a difference in the safety of calcium blockers that increase heart rate and those that decrease heart rate. There is also an indication that longer acting formulations of dihydropyridines and verapamil and diltiazem may have a better long-term safety profile in hypertension than the short-acting calcium blockers (which were the primary focus of many of the adverse reports). Secondary prevention trials of diltiazem [Multicenter Diltiazem Postinfarction Trial (MDPIT), Diltiazem Reinfarction Study (DRS)] and secondary prevention trials of verapamil (Danish Study on Verapamil in Myocardial Infarction; DAVIT I, II) are generally supportive of long-term calcium blocker safety except in patients with heart failure. A retrospective study of > 11000 patients with coronary artery disease did not support an association between the use of calcium blockers and increased mortality. A case–control trial of general practice experience in the United Kingdom found no increased risk of myocardial infarction using calcium blockers compared to β-blockers for the treatment of hypertension. Conclusion I support the current recommendations of the Joint National Committee on Detection, Evaluation and Treatment of High Blood Pressure that thiazides and β-blockers be considered first as initial therapy. The studies questioning the safety of calcium blockers are certainly concerning but not sufficient to justify condemning their use in hypertension. Calcium blockers remain a reasonable alternative therapy in hypertension.

Evolving role of calcium channel blockers in heart failure.

Calcium channel blockers are theoretically effective in the treatment of chronic systolic heart failure because of their actions as arteriolar dilators, antiischemic agents, and relaxants of diastolic left ventricular function, and because they may prevent progression of myocardial dysfunction. The first-generation calcium channel blockers nifedipine, verapamil, and diltiazem cause hemodynamic and clinical deterioration and may increase the frequency of cardiac events in postmyocardial infarction patients with heart failure. These drugs depress left ventricular contractility in the short term, and can activate neurohormonal systems due to their hypotensive effects. The second-generation calcium channel blocker felodipine does not activate the sympathetic nervous and renin-angiotensin systems, but has no effect on exercise capacity or mortality. Amlodipine increases exercise time and reduces symptoms and plasma norepinephrine concentration in heart failure. It also reduces morbidity and mortality in New York Heart Association class i.v. patients with nonischemic dilated cardiomyopathy, and appears to be effective as primary therapy for patients with dilated cardiomyopathy.

The role of calcium channel blockers in the treatment of women with preeclampsia

Preeclampsia was originally known as a process whereby an unknown “toxin” was responsible for a variety of responses. While this toxin has yet to be determined, many theories have prevailed as to the appropriate therapy for this condition.Recently, antihypertensive therapy has become increasingly regarded as an important component of the medical management of women with preeclampsia. Initially, the ideal therapy for peripartum acute hypertensive emergencies was felt to be a smooth muscle relaxant and the most commonly prescribed agent was hydralazine. This drug was felt to be beneficial because of its action on vascular smooth muscle, decreasing vasospasm. Outside of the United States diazoxide was also used for this purpose, although this drug has been replaced because of the high incidence of fetal distress. Another agent that was frequently used was α-methyldopa which was initially considered to be the treatment of choice in the treatment of patieats with moderate and severe preeclampsia. Recently, α-methyldopa has been reserved for the outpatient management of gestational hypertension, especially in women with mild preeclampsia or chronic hypertension.

Role of calcium channel blockers in reducing acute ischaemia and preventing restenosis in PTCA.

Calcium channel blockers (calcium antagonists) are widely used before, during and after percutaneous transluminal coronary angioplasty (PTCA). When administered during PTCA, calcium channel blockers may be beneficial in decreasing regional ischaemia in patients with proven or suspected variant angina, as a result of their cardioprotective effects, their ability to enhance collateral flow, and their antispastic effects at the epicardial level. More recently, the agents have also proven to be effective in patients who have developed "no-reflow' phenomenon during PTCA. Preliminary findings suggest that calcium channel blockers may also have potential benefits when administered after angioplasty. The combined results of 5 studies, evaluating a total of 919 patients, showed a trend towards angiographic reduction in restenosis. These observations are of interest but may be due to reporting bias. In conclusion, calcium channel blockers are effective in reducing ischaemia induced by PTCA. These agents may, thus, be appropriate in high risk patients. Further large studies examining the effects of calcium channel blockers on restenosis are required to confirm the observations available to date.

The Role of Calcium Channel Blockers in the Treatment of Psychiatric Disorders

Summary Calcium channel blockers (CCBs) inhibit the influx of calcium ions into excitable cells through long-acting (L-) channels. Four classes of CCBs have been synthesised, all with greater activity in hyperactive than in normal cells in diverse systems. Although more generally used for the treatment of cardiovascular disorders, CCBs have been shown to be effective in a number of psychiatric disorders. Verapamil, the most widely studied of the CCBs, has been found to be superior to placebo and equivalent to lithium in the treatment of mania. However, most trials have been small and no multi centre studies have been performed. CCBs may prevent antidepressant-induced mania and reduce the frequency of rapid cycling in bipolar disorder, and they may have applications in panic disorder. The antidepressant properties of CCBs remain to be clearly demonstrated. CCBs generally are well tolerated, but still experimental, alternatives to lithium and anticonvulsants in the treatment of bipolar mood disorders.

Verapamil reverses abnormal [Ca2+]i and carbohydrate metabolism of PMNL of dialysis patients

The basal levels of cytosolic calcium ([Ca2+]i) of polymorphonuclear leukocytes (PMNL) are elevated in hemodialysis (HD) patients, and this abnormality has been implicated in the dysfunction of the PMNL of these patients. The elevated [Ca2+]i appears to be due to PTH-induced entry of calcium into PMNL, an action that may be prevented by calcium channel blockers. We examined [Ca2+]i and carbohydrate metabolism of PMNL of normal subjects and of HD patients before, after eight to nine weeks of verapamil therapy (120 mg/day), and after eight to ten weeks of discontinuation of verapamil treatment. In HD patients, the basal levels of [Ca2+]i of PMNL are elevated and their glucose uptake, the activity of total and active forms of glycogen synthetase, and glycogen content are reduced compared to values in normal subjects (P < 0.01). These derangements were normalized after verapamil therapy and re-emerged after discontinuation of treatment with verapamil despite no change in blood levels of PTH. The results indicate that the elevation in [Ca2+]i of PMNL and the consequent derangements in carbohydrate metabolism of these cells are treatable with a calcium channel blocker. The data assign a valuable role for calcium channel blockers for the amelioration of some aspects of cell dysfunction of uremia.

Calcium channel blockers and coronary atherosclerosis: From the rabbit to the real world

Many calcium channel blockers have been shown to retard the development of atherosclerosis in cholesterol-fed rabbits. The mechanisms that may contribute to this effect include stimulation of cholesteryl ester hydrolase activity in smooth muscle cells, amelioration of hypercholesterolemic-induced endothelial dysfunction, or inhibition of smooth muscle cell proliferation and migration. The effect of calcium channel blockers on the evolution of coronary atherosclerosis in humans has been assessed in three clinical trials. In the Montreal Heart Institute trial, nicardipine did not influence the overall rate of progression and regression; however, patients treated with nicardipine experienced significantly less progression of minimal lesions, defined as stenoses of less than or equal to 20% severity. In the International Nifedipine Trial on Antiatherosclerotic Therapy (INTACT), nifedipine had no effect on overall progression and regression but, by one method of analysis, reduced the rate of appearance of new coronary lesions. In a preliminary report, diltiazem prevented the development of coronary atherosclerosis in heart transplant recipients. These studies indicate that calcium channel blockers retard the development of early atherosclerosis not only in animal models but also in human coronary arteries. Other studies recently completed or now under way will help to clarify the clinical role of calcium channel blockers in antiatherosclerotic therapy.

Calcium channel blockers and dysmenorrhea

Dysmenorrhea is a significant problem in adolescents. Routine medical management has included analgesics and prostaglandin inhibitors. We describe the use of a calcium channel blocker, nicardipine, in the management of an adolescent who was refractory in routine treatment for severe dysmenorrhea. The patient had excellent resolution of menstrual cramping without serious side effects. The role of calcium channel blockers in the management of refractory dysmenorrhea should be further studied to examine a future role.

Calcium antagonists and stunned myocardium: Importance for clinicians?

Experimental evidence indicates that calcium antagonists enhance the recovery of contractile function in canine myocardium stunned by a brief, 15-minute episode of transient coronary artery occlusion. In fact, both nifedipine and verapamil have been shown to improve systolic contraction, even when treatment was delayed, that is, when the agents were administered 30 minutes after reperfusion. The beneficial effects of delayed treatment were not a consequence of myocardial high-energy phosphate preservation. Furthermore, as low-dose intracoronary nifedipine enhanced the recovery of function in the absence of systemic hemodynamic or coronary vasodilatory effects, the improved function associated with delayed administration of calcium antagonists could not be attributed solely to afterload reduction or increased coronary blood flow. These data suggest that calcium-channel blockers exert a direct effect on the previously ischemic tissue, perhaps by subtle modulation of calcium transport or flux within the stunned myocytes. Although the precise mechanism of action of these agents remain unresolved, these intriguing experimental results raise the possibility that calcium antagonists may provide a clinically useful means of attenuating postischemic dysfunction of viable myocardium salvaged by thrombolysis, angioplasty, or cardiopulmonary bypass. The potential role of calcium-channel blockers in these clinical instances of stunned myocardium awaits further evaluation.

Role of calcium channel blockers in protection against experimental renal injury

The available evidence indicates that the first generation calcium channel blocker verapamil has a protective effect against both acute and chronic renal failure. At the cell membrane, verapamil helps minimize the effects of excess calcium influx after ischemic injury, evidenced by reduced uptake of 45Ca, thus lessening tubular injury from both calcium-activated phospholipases and mitochondrial calcium overload. In experimental chronic renal failure, the long-term administration of verapamil protects against renal dysfunction and damage, independent of any effect on systemic mean arterial pressure. Protective effects of verapamil are delineated in several models, supporting the presented hypothesis of the pathogenesis of renal failure.

The Role of Calcium Channel Blockers in the Treatment of Essential Hypertension

Calcium channel blockers, originally developed for the treatment of angina and supraventricular arrhythmias, have been shown to lower elevated blood pressure effectively in hypertensive patients. Verapamil, nifedipine, and diltiazem represent prototype compounds for unique chemical classes with differing pharmacologic properties. These drugs lower elevated blood pressure with efficacy comparable with other commonly used antihypertensives. Combination therapy with other agents usually results in an additive response. Side effects are usually mild and reversible and usually are an extension of the drug's pharmacologic effects. Moreover, adverse metabolic effects on lipid, glucose, or potassium levels are not common. Because of the excellent antihypertensive effects of calcium channel blockers and their potential importance in a variety of other disease states, these agents should be routinely considered for use as a first-line antihypertensive agent in appropriately selected patients with hypertension of any severity as part of a comprehensive plan to minimize cardiovascular risk.

The role of calcium channel blockers in the treatment of essential hypertension

The role of calcium channel blockers in the treatment of essential hypertension

Hypertrophic cardiomyopathy: prognosis with medical or surgical therapy.

Over the past 30 years, knowledge of the natural history and effects of therapy in patients with hypertrophic cardiomyopathy has expanded greatly, but progress has been hampered by its variable patterns of expression. Many but not all patients show symptomatic improvement with medical treatment. Chronic beta blockage does not appear to affect long-term survival, whereas results with calcium channel blockade by verapamil have been encouraging; however, they await confirmation, and verapamil may be hazardous in some patients with severe left ventricular (LV) outflow tract obstruction and elevated LV end-diastolic pressure. Reported beneficial effects of amiodarone on survival also require further study. Surgical therapy has become the treatment of choice for medically refractory patients with proven outflow tract obstruction. In several centers, the operative risk is low, and long-term follow-up demonstrates prolonged symptomatic relief. It is hoped that work currently underway will provide more definitive information on the long-term effects of the role of calcium channel blockers, antiarrhythmic medications, and the long-term effects of surgical therapy on survival of patients with this disorder.

Calcium antagonists in heart failure.

Calcium channel blocking drugs improve systolic function, due to a decrease in left ventricular afterload, and may thus be particularly suitable for therapy of patients with concomitant congestive heart failure and myocardial ischaemia. Since ischaemic heart disease is a major cause of congestive heart failure and further ischaemia may contribute to further left ventricular dysfunction, studies were performed to establish the therapeutic role of calcium channel blockers. Concern has been raised that at high doses, calcium channel blockers have a negative inotropic effect and may lead to deterioration of myocardial systolic function. Clinical studies assessing the role of verapamil and diltiazem in congestive heart failure are scarce, because these drugs may result in a further decrease in cardiac output, especially in the presence of pre-existing left ventricular dysfunction. In vitro observations show that nifedipine is more potent on vascular smooth muscle than on myocardium. It has been suggested that in man, nifedipine does not usually reach concentrations high enough to depress myocardium and the vasodilating left ventricular unloading effect becomes dominant. Analysis of the available clinical data is difficult, but published data concerning the oral or sublingual administration of nifedipine in congestive heart failure suggest that the major haemodynamic effect is a decrease in systemic vascular resistance by 33%, resulting in an increase in cardiac output of 24%. Heart rate was generally unchanged. Right atrial pressures showed minimal change, whereas pulmonary capillary wedge pressure decreased by 16%. The response is more favourable if the congestive heart failure is more severe. A new dihydropyridine, nisoldipine, was evaluated during chronic administration over 8 weeks in patients with severe congestive heart failure.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of verapamil, oiltiazem and nifedipine on some parameters of hemostasis in the rat

Together with a mechanism such as activation of the coagulation system, vascular smooth muscle contraction and the activation of blood platelets are important processes in the hemostasis. Various calcium channel blockers besides those found to be vasodilators (1) have been shown to influence the functioning of blood platelets (2). They inhibit the aggregation induced by ADP, adrenaline, arachidonic acid or collagen (3). From these data it has been suggested that significant differences exist in the ability of calcium channel blockers to inhibit aggregatory responses (4). In order to elucidate further the possible role of calcium channel blockers in hemostasis we analyzed the effect of verapamil, diltiazem and nifedipine on the bleeding time, the amount of initial blood loss, platelet aggregation and some coagulation parameters in rats.

The role of calcium channel blockers in reactive airway disease.

The role of calcium channel blockers in reactive airway disease.

Role of calcium channel blockers in experimental exercise-induced ischemia.

Calcium channel blockers, which induce vasodilation by relaxing vascular smooth muscle cells, have proven effective in the treatment of angina pectoris. To study mechanisms of calcium blockade in ischemic heart disease, conscious chronically instrumented dogs with a single coronary artery ameroid constrictor were studied during steady-state treadmill runs which induced regional myocardial ischemia. During exercise-induced ischemia, regional systolic wall thickening and subendocardial blood flow were both significantly reduced in the ischemic zone. Calcium channel blockade with verapamil, diltiazem, or nifedipine enhanced regional systolic wall thickening. Regional subendocardial blood flow in the ischemic region, measured during diltiazem and nifedipine experiments, improved during exercise. Reduced coronary artery resistance in the native vessels and/or recruitment of collaterals appears to largely explain the increased total myocardial blood supply in the jeopardized area and the increased function. However, after diltiazem, reduced exercise heart rates as well as reduced left ventricular end-diastolic pressure also contributed to the improvement in the oxygen-supply imbalance in the ischemic myocardium. These data provide a basis for understanding the efficacy of calcium channel blocker treatment in patients with coronary artery disease.

Calcium channel blockers and treatment of hypertension.

Over the past years, research efforts have been focused on the pathophysiologic role of calcium ions, and the implication for the potential role of calcium channel blockers in the management of essential hypertension. Numerous studies have shown that nifedipine and verapamil are effective antihypertensive agents, initial experience with diltiazem is also encouraging. The magnitude of blood pressure reduction with these drugs is related to the pre-treatment blood pressure. In refractory hypertension, combination with other antihypertensive agents provide additive effect. In the elderly population and in patients with ischemic heart disease, supraventricular arrhythmia, bronchospastic disease, peripheral vascular disease or diabetes mellitus, the calcium channel blockers offer potential advantages over other antihypertensive agents. Experimental studies also suggest that these drugs may reverse ventricular hypertrophy. When long-term safety with these drugs is documented from well-controlled clinical trials, the calcium channel blockers may be our first line of therapy for the management of hypertension.

The role of calcium channel blockers in the treatment of hypertension

The role of calcium channel blockers in the treatment of hypertension