Combination Of Calcium Channel Blocker Research Articles

End organ protection by calcium-channel blockers.

In recent years, much attention has been given to end organ protection by antihypertensive, anti-heart failure, and anti-ischemic medications. This review describes the available information on end organ protection by calcium-channel blockers (CCBs). In normotensive patients and patients with hypertension treated with long-acting dihydropyridines, medial thickness was thinner than in patients treated with atenolol or in untreated hypertensive patients. Long-term treatment was associated with significant reduction in left ventricular mass. Calcium-channel blockers also improved endothelial-dependent relaxation and reversed the vasoconstrictive response to nitric oxide inhibitors. In diabetic patients, CCBs were effective in preserving kidney function and microalbuminurea. The combination of angiotensin-converting enzyme (ACE) inhibitors and CCBs was more effective than ACE inhibitors alone in preserving kidney function. In animal experiments, CCBs prevented development of coronary atheroschlerosis; however, in humans only limited data are available on their antiatherogenic effect. Some studies suggest that CCBs exert antiplatelets properties and may therefore be beneficial in patients with coronary artery disease.

The case for combining angiotensin-converting enzyme inhibitors and calcium-channel blockers.

Tight blood pressure control among diabetic and nondiabetic patients with hypertension is perhaps the single most effective intervention used to delay progression to end-stage renal disease (ESRD). The renoprotective actions of angiotensin-converting enzyme (ACE) inhibitors in patients with diabetic and hypertensive nephropathy is well established. Drugs of this class fairly uniformly reduce glomerulosclerosis, delay the deterioration in renal function, and improve proteinuria, a predictive surrogate marker for renal injury. Calcium- channel blockers (CCBs) in the phenylalkylamine (verapamil) and benzothiazepine (diltiazem) classes also improve proteinuria and delay the progression of renal disease in diabetic and nondiabetic hypertensive nephropathy beyond that attributable to blood pressure control. The short-acting dihydropyridine CCBs worsen proteinuria and accelerate renal injury in both animal models and humans with hypertension or diabetes. A very limited number of studies in animals or humans with hypertension or diabetes have demonstrated at least an additive renoprotective effect when the combination of ACE inhibitors and nondihydropyridine CCBs has been compared with each agent administered as monotherapy. Because patients with impaired renal function and either hypertension or diabetes appear to benefit from aggressive blood pressure reduction, many of these patients will require two or more drugs to achieve the currently recommended blood pressure goals. Combinations of ACE inhibitor and CCB are attractive because they may provide better blood pressure control, appear to be better tolerated with fewer side effects than either drug alone, and may exert a greater renoprotective effect in patients at risk for renal failure than either an ACE inhibitor or a CCB.

Combination of calcium channel blockers and β‐adrenoceptor blockers for patients with exercise‐induced angina pectoris: a double‐blind parallel‐group comparison of different classes of calcium channel blockers

The combination of calcium channel blockers and beta-adrenoceptor blockers is more effective for the treatment of exercise-induced angina pectoris than beta-adrenoceptor blocker monotherapy. As ischaemia in exercise-induced angina is preceded by increase in heart rate, calcium channel blockers with negative chronotropic properties may perform better for this purpose than nonchronotropic compounds. A 335 patient double-blind parallel-group study comparing 14 day treatment with amlodipine 5 and 10 mg, with diltiazem 200 and 300 mg, and mibefradil 50 and 100 mg added to baseline beta-adrenoceptor blocker treatment was performed. Exercise testing (ETT) was performed by bicycle ergometry. Although none of the calcium channel blockers improved duration of exercise or amount of workload, all significantly delayed onset of 1 mm ST-segment depression on ETT (P<0.001 for any treatment vs baseline). In addition, mibefradil, both low and high dose treatment, produced the longest delays (low dose: different from diltiazem and amlodipine by 24.1 and 29.8 s, respectively, P<0. 003 and <0.001; high dose: different from diltiazem and amlodipine by 33.7 and 37.0 s, respectively, P<0.001 and <0.001). These effects were linearly correlated with the reduction in rate pressure product (RPP). Serious symptoms of dizziness occurred significantly more frequently on mibefradil (P<0.05), and 19 patients on mibefradil withdrew from trial. Calcium channel blockers with negative chronotropic properties provide greater delay of ischaemia in patients with exercise-induced angina, but the concomitant risk of intolerable dizziness attenuates this benefit.

Role of Glutamate Receptors and Voltage-Dependent Calcium Channels in Glutamate Toxicity in Energy-Compromised Cortical Neurons

We have examined the effect of glutamate receptor antagonists and voltage-dependent calcium channel blockers on the neuronal injury induced by the combination of a low concentration of N-methyl-D-aspartate (NMDA) or kainate and energy compromise resulting from the use of glucose-free incubation buffer. Toxicity induced by NMDA or kainate was enhanced in the glucose-free buffer. NMDA- or non-NMDA-receptor antagonists added to the glucose-free buffer at the same time inhibited the neuronal cell death induced by each agonist. An NMDA-receptor antagonist, MK-801, but not non-NMDA-receptor antagonists, inhibited the toxicity when added to the culture medium after exposure of the cells to the agonists. P/Q-type calcium channel blockers, ω-agatoxin IVA and ω-agatoxin TK, and an N-type calcium channel blocker, ω-conotoxin GVIA, significantly attenuated the neuronal injury, although an L-type calcium channel blocker, nifedipine, showed little neuroprotective effect. A combination of calcium channel blockers of the three subtypes showed the most prominent neuroprotective effect. These observations suggest that the overactivation of NMDA and non-NMDA receptors and consequent activation of the voltage-dependent calcium channels lead to neuronal cell death in energy-compromised cortical neurons.

Does combined therapy of Ca-channel blocker and angiotensin converting enzyme inhibitor exceed monotherapy in renal protection against hypertensive injury in rats?

Either calcium channel blocker (CCB) or angiotensin converting enzyme inhibitor (ACEi) is used as an antihypertensive agent, and we are recommended to use them in combination to refractory hypertension with evidence dependent on clinical observations. We examined the renal protective effect of the combined therapy with calcium channel blocker (amlodipine) and angiotensin converting enzyme inhibitor (enalapril) against hypertensive renal injury in 5/6 nephrectomized spontaneously hypertensive rats (SHRs) with salt loading, comparing with monotherapy of each drug. Forty males SHRs with 5/6 nephrectomy and salt loading were divided to five groups: group 1 as control (n = 8), group 2 received 0.2 mg/kg/day of amlodipine (n = 8), group 3 received 0.2 mg/kg/day of enalapril (n = 8), group 4 (n = 8) and group 5 (n = 8) that were treated with 0.1 mg/kg/day and 0.2 mg/kg/day of each drug in combination respectively. Either amlodipine or enalapril had remarkable effects on reducing the increases in blood pressure and urinary protein excretion. In histopathological examination, it also suppressed renal injury significantly. Additional significant effect of combined therapy was not observed in blood pressure and urinary protein. There were not remarkable, additional effects of the combination of CCB and ACEi on protecting the remnant kidney in 5/6 nephrectomized SHRs fed a high-salt diet, possibly because sodium retention was not alleviated by the combination.

Skin Depigmentation Related to Transdermal Clonidine Therapy

A 66-year-old African-American woman with essential hypertension began using the clonidine hydrochloride transdermal patch (Catapres-TTS2 [transdermal therapeutic system: clonidine hydrochloride, 0.2 mg/d for 1 week]) in May 1989. Previously, she had used other antihypertensive medications, including various combinations of calcium channel blockers, β-blockers, diuretics, and angiotensin-converting enzyme inhibitors, with poor control of blood pressure. Presently, her blood pressure is better controlled, in the range of 140/90 mm Hg, with a clonidine transdermal patch (Catapres-TTS2), chlorthalidone (100 mg/d), betaxolol hydrochloride (Kerlone, 10 mg/d), and potassium chloride (Micro-K, 10 mmol/L twice a day). Asymptomatic skin depigmentation was first noted about 1 year after therapy was initiated. The Figure shows the area of depigmentation in the left upper chest area. A similar area of depigmentation is in the right upper chest area. These sites have not been used for application of the transdermal patch for about 4 years. Despite that, repigmentation of the

Calcium-channel blockade (nitrendipine) in combination with ACE inhibition (captopril) in the treatment of mild to moderate hypertension

The antihypertensive efficacy of a combination of calcium-channel blockers and angiotensin-converting-enzyme (ACE) inhibitors in severe primary hypertension is well known, but a synergistic action of this drug combination in mild to moderate primary hypertension is still not established. Therefore, the aim of the present study was to evaluate the efficacy and tolerability of monotherapy with nitrendipine (20 mg) or captopril (100 mg), and of their combination (nitrendipine 10 mg plus captopril 50 mg), in patients suffering from mild to moderate primary hypertension, according to a single-blind, randomized, placebo-controlled design. After the first 4-week monotherapy period, both nitrendipine and captopril induced a significant decrease in systolic and diastolic blood pressure (BP) (p less than 0.001). Furthermore, nitrendipine caused a significant increase in heart rate (HR), while no change in HR was observed in patients treated with captopril. Several side effects were observed, both in the nitrendipine-treated patients (facial flushing, headache, malleolar edema) and in the captopril-treated patients (initial hypotension, dizziness, gastrointestinal disorders). However, these side effects were mild and were well tolerated. In the second combined 4-week therapy period, systolic and diastolic BP of patients treated with 10 mg nitrendipine combined with 50 mg captopril continued to decrease to a degree significantly lower (p less than 0.001) than that observed at the end of the monotherapy period. Simultaneously, no change in HR values occurred when compared to basal values. Furthermore, the incidence and intensity of some side effects observed during the combined therapy period were lower than those of the monotherapy period.(ABSTRACT TRUNCATED AT 250 WORDS)

Combination of calcium channel blocker and thrombolytic therapy in acute myocardial infarction

To evaluate the protective effect of nifedipine on ischemic myocardium, in addition to thrombolytic therapy, a total of 149 patients with acute myocardial infarction were included in a double-blind controlled study in which they received 20 mg sublingual nifedipine (74 patients in group 1) or placebo (75 patients in group 2) in the emergency ward, either intracoronary nifedipine, 0.2 mg before and 0.2 mg after reperfusion of the infarct-related vessel and 20 mg three times/day during the hospital stay, or placebo. Combined intravenous and intracoronary thrombolytic therapy was initiated by means of mechanical recanalization in nonreperfused vessels. There were no differences between group 1 and 2 with regard to age, sex, body weight, or location of infarct. Evolution of CK-MB release and cumulative CK-MB was higher in group 1 than in group 2. Changes with regard to regional and global left ventricular function and coronary anatomy were not significantly different (NS) between the two groups. Reocclusion occurred in 15 of 74 (20%) and 10 of 75 (13%) patients in groups 1 and 2, respectively. During the reperfusion period, second- and third-degree atrioventricular block occurred in 5.4% and 6.7% (NS), ventricular couplets in 17.6% and 24% (NS), ventricular tachycardia in 2.7% and 9.3%, and ventricular fibrillation in 2.7% and 8% of the patients, respectively. Mortality rates were 13% and 8%. The study demonstrates that even very early administration of nifedipine combined with intracoronary administration does not enhance the salvage of ischemic myocardium achieved by reperfusion.

Combination therapy with calcium-channel blockers and beta blockers for chronic stable angina pectoris

Combination therapy using calcium-channel blockers and β blockers in patients with refractory chronic stable angina has gained much popularity, but remains highly controversial because of the potential for serious additive deleterious hemodynamic or electrophysiologic reactions. In studies involving patients with preserved left ventricular function receiving chronic oral β blockers, short-term administration of intravenous verapamil has been shown to cause a further lowering in heart rate and blood pressure while prolonging atrioventricular node conduction; additive cardiodepressant effects were noted, including a tendency toward increased left and right heart filling pressures. Nifedipine, on the other hand, when added acutely to β blockers, causes an increase in heart rate, a decrease in blood pressure and either no change or a slight improvement in most cardiac performance variables. Controlled, double-blind clinical trials have demonstrated that combinations of calcium-channel blockers and β blockers result in augmented symptom benefit compared with either drug class alone. The predominant mechanism responsible for such improvement is increased lowering of myocardial oxygen demand by virtue of additive diminution in heart rate, blood pressure and, consequently, pressure-rate product both at rest and during exercise. Verapamil (and possibly diltiazem) plus β blockers appears to have the greatest therapeutic efficacy but also the highest frequency of harmful adverse cardiac effects, whereas nifedipine plus β blockers is generally safer but also less efficacious. Factors that should be carefully considered by clinicians contemplating combination therapy are the choice of calcium-channel blocker, the dose of calcium-channel blocker and β blocker, the presence of antecedent left ventricular dysfunction or conduction system disease and the possibility of drug interactions. Concomitant calcium-channel blocker and β-blocker therapy is an important contribution to the pharmacologic management of resistant patients who remain symptomatic during single drug treatment. However, the possibility of additive adverse cardiac effects mandates careful patient selection and close clinical monitoring.