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PubMed1993

Analgesic effects of intracerebroventricular administration of calcium channel blockers in mice.

1. The antinociceptive action of calcium channel blockers administered intracerebroventricularly to mice using the acetic acid writhing test was studied. 2. The drugs produced dose-dependent inhibition of the number of writhes induced by the intraperitoneal administration of 10 ml/kg of 0.6% acetic acid. 3. The CaCBs may be ranked from most to least potent as follows: verapamil > nimodipine > diltiazem > flunarizine > nifedipine > cinnarizine. 4. Since naloxone pretreatment was not able to inhibit the antinociception produced by CaCBs an opioid mechanism of action is excluded. 5. It is suggested that CaCBs can induce analgesia through a decrease in cellular Ca2+ availability, increasing the nociceptive threshold.

Analgesics↗

PubMed1991

Calcium-channel blockers and anaesthesia.

Verapamil was the first calcium-channel blocker (CCB). It has been used since 1962 in Europe then in Japan for its antiarrhythmic and coronary vasodilator effects. The CCB have become prominent cardiovascular drugs during the last 15 years. Many experimental and clinical studies have defined their mechanism of action, the effects of new drugs in this therapeutic class, and their indications and interactions with other drugs. Due to the large number of patients treated with CCB it is important for the anaesthetist to know the general and specific problems involved during the perioperative period, the interactions with anaesthetics and the practical use of these drugs.

Anesthetics↗

PubMed1986

Effects of calcium channel blockers on neuromuscular blockade induced by aminoglycoside antibiotics.

The effects of several calcium channel blockers (nifedipine, verapamil and diltiazem) on rat phrenic-hemidiaphragm preparations were studied. The calcium channel blockers were used either alone or associated with two aminoglycoside antibiotics, neomycin and streptomycin. All drugs investigated produced a concentration-dependent decrease in indirectly elicited diaphragmatic contractions. The order of potency was: verapamil greater than neomycin congruent to nifedipine greater than diltiazem greater than streptomycin. Moreover, neomycin-induced neuromuscular blockade was significantly increased by nifedipine (1 and 10 microM), verapamil (1 and 10 microM) and diltiazem (10 microM), whereas the streptomycin-induced neuromuscular blockade was increased only by nifedipine (1 and 10 microM) and verapamil (10 microM).

Aminoglycosides↗

PubMed2001

Poisoning with calcium channel blockers--a case report and review of the literature.

The incidence of poisoning with calcium channel blockers, accidental or intentional, has increased in recent years, associated with more frequent use. We present a clinical case of bradycardia and shock of unknown cause, which came to be revealed a poisoning by 3240 mg of slow-release diltiazem, managed with temporary transvenous pacing and dopamine in high concentration. We make a review of the cardiovascular manifestations of the three classic calcium channel blockers: verapamil, diltiazem and nifedipine; namely, hypotension, rhythm and conduction disturbances. We point out the late appearance of the beginning of manifestations with the use of slow releasing formulations. The toxicity by calcium channel blockers can lead to a wide variety of manifestations in the central nervous system, gastrointestinal system, endocrine-metabolic, hematologic and respiratory systems. There is a high clinical suspicion when the following factors are present: hypotension with bradycardia, mental state disturbances, lactic acidosis, hyperglycemia, sinus pauses and refractory shock. Treatment is based on general measures of intoxication support, decreasing the drug absorption and improvement of cardiac function. The bradyarrhythmias are corrected with the use of intravenous calcium, glucagon, atropine and pacemaker. If the intoxication causes depression of cardiac contractility, the use of calcium or/and glucagon is indicated. If there is refractoriness with these measures, catecholamines should be employed. There are alternative and adjuvant drugs such as amrinone, insulin-glucose, 4-aminopyridine and calcium entry promoters. Charcoal hemoperfusion can be useful in the overdose of sustained release preparations, but hemodialysis is unworthy of therapeutical interest.

Aged↗

PubMed1984

Calcium channel blockers as antihypertensive agents.

Because of their unique action on the cardiovascular system, the calcium channel blockers have generated a great deal of excitement among pharmacologists, physiologists, and clinicians. One obvious potential application for these drugs is in antihypertensive therapy and, although experience with these agents for this indication is limited in the United States, it is considerable in Europe and Japan. These agents' ultimate role in antihypertensive therapy, however, has not been established. Since the available calcium channel blockers are structurally diverse, it is uncertain whether they will have comparable effects in hypertension. The rationale for the use of calcium channel blockers in treating hypertension and the relevant pharmacologic actions of these agents is discussed, along with a summary of some of the clinical trials, observations from our own experience with these drugs, and speculation about their future role in antihypertensive therapy.

Blood Pressure↗

PubMed1985

Inhibition of rabbit platelet phosphodiesterase activity and aggregation by calcium channel blockers.

Rabbit platelet cyclic AMP phosphodiesterase is inhibited by the three calcium channel blockers nifedipine, diltiazem, and verapamil with IC50's of 100 microM, 100 microM and 420 microM, respectively. Also, platelet aggregation induced by 4 microM ADP is inhibited by those compounds. Verapamil is the most potent aggregation inhibitor with an IC50 of 260 microM while diltiazem and nifedipine have IC50's of 630 microM and 840 microM, respectively. All three compounds display a maximum inhibition of 80-85%. Diltiazem and PGD2 potentiate the antiaggregatory activity of each other in that the inhibitions occurring in the presence of the combination of the two (at varying concentrations) exceed the calculated sums of the inhibitions produced by each alone. On the other hand, the antiaggregatory activities of verapamil or nifedipine, are additive with that of PGD2 in that no significant differences exist between the observed inhibitions produced by the combinations and the calculated summed values of the individual inhibitions. Our data suggest, therefore, that in addition to lowering intracellular calcium ions, which are required for platelet aggregation, the three calcium channel blockers inhibit the breakdown of cyclic AMP thereby promoting antiaggregation.

1-Methyl-3-isobutylxanthine↗

PubMed1988

Efficacy and mechanism of action of a calcium channel blocker after global cerebral ischemia in rats.

Dihydropyridine calcium channel blockers such as nicardipine are under evaluation for treating acute cerebral ischemia because they may increase cerebral blood flow by causing vasodilation and because they may be cytoprotective in part by limiting production of arachidonic acid metabolites. We demonstrated in a previous study that nicardipine improves postischemic neuronal function, as measured by somatosensory evoked potentials, without reducing the extent of light-microscopic CA-1 hippocampal histologic damage. To characterize further the effect of nicardipine on global ischemic injury, we administered the drug beginning 24 hours before 30 minutes of four-vessel ischemia in Wistar rats. We then measured hippocampal ATP, phosphocreatine, and glucose contents immediately and 2 hours after ischemia, and measured learning ability (working and reference errors) on an eight-arm radial maze beginning 30 days after ischemia. To gain insight into the possible mechanism of action, we measured production of arachidonic acid metabolites (eicosanoids: TXB2 and 6-keto-PGF1 alpha) and hemispheric and hippocampal cerebral blood flow by the [14C]butanol indicator fractionation technique immediately and 2 hours after ischemia. Nicardipine was associated with fewer working errors (p less than 0.02) but no difference in reference errors. The drug had no effect on energy metabolites, cerebral blood flow, or eicosanoids immediately after ischemia, but ATP, phosphocreatine, and cerebral blood flow all returned to normal levels significantly more rapidly during reperfusion in treated rats. Nicardipine improves behavioral, electrophysiologic, and mitochondrial function after ischemia without preventing cellular damage and improves postischemic reperfusion. The drug's positive effect appears to occur during reperfusion.

Adenosine Triphosphate↗

PubMed2005

Calcium channel blockers and stroke.

The most frequent indication for Calcium Channel Blockers (CCBs) is their use as antihypertensive agents for primary or secondary stroke prevention. Hypertension contributes to virtually all mechanisms of stroke, of atherothrombotic, lacunar, cardioembolic and intraparenchymal hemorrhage types. In comparison with the rather univocal mechanisms underlying coronary artery or peripheral artery disease, the variable mechanisms of stroke are the main reason explaining not only the different impact of vascular risk factors, but also the different effects of drugs given for prevention. In an acute stroke setting, lowering blood pressure is potentially harmful, especially if it is carried out using short-acting dihydropyridine derivatives. Some CCBs, such as nicardipine, are preferred in certain conditions (including acute thrombolysis). In stroke, CCBs may also play a role as neuroprotectants. Then twofold effect--against vessel wall changes and as neuroprotectants (after ischemia or degenerative insults)--make this class of drugs of interest for their possible application in the setting of dementias, particularly that of vascular dementia. Some CCBs have been tested and are of benefit when used for preventing or treating cerebral vasospasm after subarachnoid hemorrhage. CCBs must be considered effective in preventing stroke in hypertensive patients. In comparison with other antihypertensive agents, their effects are similar to or even better than those exerted by other drugs. This may be due to the fact that stroke includes different types, with differing underlying pathophysiological mechanisms. The anti-atherosclerotic properties of CCBs may be useful in preventing the atherothrombotic type of stroke at the large pre-cerebral artery level. Dihydropyridinic derivatives may play a selective role in relation to small-vessel disease of the brain, which leads to multiple stroke-associated conditions, including lacunar infarct, intra-cerebral hemorrhage and subcortical vascular dementia. Oral nimodipine is recommended in the prevention/treatment of cerebral vasospasm following subarachnoid hemorrhage (SAH). CCBs, particularly nimodipine, may be of some benefit in vascular or mixed degenerative and vascular dementia or, taking into account subtypes, more selectively in subcortical vascular dementia. In this setting, CCBs may contribute toward reducing the risk of recurrent stroke in patients who are usually at high risk of recurrence.

Aged↗

PubMed1996

Acute hypertension and calcium-channel blockers.

Acute arteriolar vasoconstriction is considered to be the common physiologic pathway for hypertensive crises. Calcium plays a critical role in this process as a required element in the generation of vascular smooth muscle contraction. Within the vascular smooth muscle cell, calcium homeostasis is maintained through a complex set of mechanisms that control cellular calcium influx and efflux as well as intracellular calcium storage. Extracellular calcium enters the intracellular free space of the vascular smooth muscle cell through four portals: a passive slow leak, voltage-gated channels, hormone-mediated receptor-operated channels, and stretch-activated channels. The myofilaments actin and myosin contract upon the increase in cytosolic calcium. Calcium-channel blockers are commonly used as vasodilators for the treatment of hypertensive crises. There are three families of commercially available calcium-channel blockers: 1,4 dihydropyridines, phenylalkylamines, and benzothiazepines. These drugs block extracellular calcium entry through the L-type voltage-gated channel. Systemic vasodilation is produced as the cytosolic calcium level is lowered and myosin-actin contraction cannot be maintained. The precise mechanism of blockade and the tissue site selectivity varies among the three drug families. The 1,4 dihydropyridines are selective for the arteriolar beds, while the phenylalkylamines and benzothiazepines are selective for the atrioventricular node. Of the calcium-channel blockers, the dihydropyridines nifedipine and nicardipine are recommended as first-line agents for hypertensive emergencies and urgencies because of their peripheral arteriolar bed selectivity and their pharmacologic and kinetic profiles.

Acute Disease↗

PubMed1985

Differing potencies and dose-response characteristics in the ability of slow-calcium-channel blockers to reduce enzyme leakage in the calcium paradox.

In studies of the calcium paradox, we have used an isolated rat heart preparation to investigate the relationship between myocardial creatine kinase leakage and the concentration of slow-calcium-channel blockers (nifedipine or verapamil) in the perfusion fluid during a cycle of calcium reduction and repletion. The results indicated that enzyme leakage could be further reduced to a degree greater than that seen under conditions of a full calcium paradox (complete calcium depletion). Detailed dose-response studies with verapamil and nifedipine at a calcium concentration of 1.0 mM during a 20-min period of calcium repletion following a 10-min period of calcium reduction (12 microM calcium) revealed complex dose-response characteristics for each drug. In the dose range studied (0-20 microM), nifedipine was able to reduce enzyme leakage maximally by 57 +/- 8% and verapamil by 37 +/- 4%. Optimal concentrations for verapamil and nifedipine were 4.0 and 2.0 microM, respectively. Both drugs exhibited bell-shaped dose-response curves without a loss of efficacy at higher concentrations. There was no resumption in contractile activity in the drug-treated groups. Simultaneous use of verapamil and nifedipine at their optimal concentrations failed to improve the reduction in enzyme leakage to a reduction greater than that observed with one drug alone.

Animals↗

PubMed1998

Absence of a deleterious effect of calcium channel blockers in patients with left ventricular dysfunction after myocardial infarction: The SAVE Study Experience. SAVE Investigators. Survival and Ventricular Enlargement.

BACKGROUND: As a result of randomized controlled trials with calcium channel blockers after myocardial infarction, concern has developed that these agents are associated with an increased risk of cardiovascular events, particularly in the presence of left ventricular dysfunction. METHODS: To test the hypothesis that calcium channel blockers increase cardiovascular events in such patients, the incidence of all-cause mortality, cardiovascular death, severe heart failure, and recurrent infarction was examined in 940 patients taking calcium channel blockers and 1180 not taking them 24 hours before randomization to placebo or captopril in the Survival and Ventricular Enlargement (SAVE) Trial. All patients had an ejection fraction < or =40%. Relative risks for calcium channel blocker users versus nonusers and the 95% confidence intervals were computed with univariate and multivariate Cox regressions. Adjustments were made for differences in baseline covariates. RESULTS: For all causes of mortality, the relative risk for calcium channel blocker users versus nonusers was 0.96, with the 95% confidence interval of 0.78 to 1.17. In the SAVE placebo and captopril groups, the relative risks for the development of severe heart failure among the calcium channel block users versus nonusers were 0.95 and 1.23, with the 95% confidence interval of 0.72 to 1.25 and 0.88 to 1.71, respectively. A similar neutral result held for patients with and without a history of hypertension. Furthermore, calcium channel blockers did not alter the benefit of the angiotensin converting enzyme inhibitor, captopril. CONCLUSIONS: This analysis of the nonrandomized clinical use of calcium channel blockers in the postmyocardial infarction population with left ventricular dysfunction did not identify either a clinical deterioration or improvement with respect to subsequent cardiovascular events.

Adult↗

PubMed1988

Dose response to hydrochlorothiazide in hypertensives receiving a calcium channel blocker.

Seven hypertensive patients receiving the dihydropyridine calcium channel blocking agent nicardipine were given placebo, 6.25, 12.5, 25 and 50 mg hydrochlorothiazide (HCTZ) in a randomized crossover design. Blood pressure (BP) decreased by about 7/3 mmHg irregardless of dose. In contrast, potassium, glucose and uric acid increased in a dose-dependent fashion. The hypokalemic and hyperglycemic responses at 50 mg were larger than usually seen with HCTZ. Low doses of HCTZ provided a modest antihypertensive effect, but 25 and 50 mg of HCTZ were no more effective in lowering BP and gave unusually large metabolic side effects when combined with a calcium channel blocker.

Blood Glucose↗

PubMed1985

Centrally-induced vasodepressor responses to diltiazem, a calcium channel blocker, in rats.

The effects of a calcium channel blocker, diltiazem, on central cardiovascular regulation were investigated by injecting it intracerebroventricularly (i.c.v.) in urethane-anaesthetized rats. The blood pressure decreased immediately after the injection returning to baseline level 20-30 min later. Both heart rate and abdominal sympathetic nerve activity decreased correspondingly. Diltiazem injected intravenously (i.v.) decreased both blood pressure and heart rate without affecting sympathetic nerve firing. Although the central pressor responses to carbachol and prostaglandin E2 were not affected by i.c.v. pretreatment with diltiazem, diltiazem attenuated the pressor responses to angiotensin II. Furthermore, electrical lesioning of the anteroventral third ventricle (AV3V) area significantly attenuated the depressor responses to diltiazem injected i.c.v. These results suggest that diltiazem injected i.c.v. affects the central nervous system to decrease sympathetic outflow, and thereby to attenuate the central vasopressor effects of angiotensin II in the brain AV3V area.

Angiotensin II↗

PubMedDate not supplied

Potentiation of doxorubicin cytotoxicity by the calcium channel blocker verapamil in Ehrlich ascites cells.

The calcium channel blocker verapamil increased the intracellular level of doxorubicin in Ehrlich ascites cells. The high cellular drug level was directly related to the enhancement of the cytotoxicity of the antitumor agent. Tumor-bearing mice pretreated with verapamil showed a 2.3-fold increase in long-term survival effect of doxorubicin together with a pronounced inhibitory effect on tumor DNA, RNA and protein content. This study suggests the possible novel use of verapamil to enhance the antitumor activity of doxorubicin, allowing its dose, and consequently the serious side effects, to be reduced.

Animals↗

PubMed1990

Calcium channel blockers and the prevention of atherosclerosis.

The presence of calcium in atherosclerotic plaques has long been recognized; however, its role in plaque formation is not yet fully elucidated. Over the past decade, investigators have studied the effects of various calcium channel blockers on atherogenesis in animals and have demonstrated that such agents may retard plaque formation. Recent studies in patients with coronary artery disease have demonstrated that the calcium channel blocker nifedipine may impede or prevent the development of atherosclerotic plaques in humans as well.

Animals↗

PubMed1994

Calcium anti-ionophoretic effect of some calcium channel blockers in rat liver mitochondria.

Beyond their classical action on calcium channels, some calcium channel blockers also exhibit a calcium anti-ionophoretic effect. We studied this effect on respiratory control and Ca2+ fluxes in a mitochondrial model to compare calcium antagonists chosen among three clinical classes: vascular, cardiac, and mixed effects. Synthetic calcium ionophore A23187 decreases respiratory control and modifies Ca2+ fluxes. We show that calcium antagonists partially restore the parameters altered by A23187. By calculating the percentage of restoration, we found that vascular drugs exhibit a strong anti-ionophoretic effect, cardiac drugs exert no significant effect, and mixed calcium antagonists exert an intermediate effect. Thus, it appears possible to link the intensity of calcium anti-ionophoretic effect with the clinical interest of a calcium antagonist.

Animals↗

PubMed1995

[Evaluation of trandolapril alone or in combination with a calcium channel blocker in hypertensive patients over 60 years of age].

The efficacy and safety of trandolapril alone and in combination with a calcium channel blocker were evaluated in 13,147 hypertensive patients over 60 years old. Two patient groups were constituted. After a 2-week wash-out period, the patients in group I received monotherapy with trandolapril 2 mg/day for 4 weeks. Trandolapril was continued for another 4 weeks in responding patient, otherwise the dosage of trandolapril was doubled or another antihypertensive was added. Group 2, composed of patients previously treated with a calcium channel blocker with insufficient efficacy, was treated according to the same treatment regimen, but the calcium channel blocker was maintained throughout the study. 13,147 patients (group 1: 11,329 patients, group 2: 1,818 patients) with a mean age of 68 +/- 7 years were followed. After 4 weeks of treatment, the blood pressure measured by mercury sphygmomanometer decreased from 176 + 11/99 +/- 8 mmHg to 164 +/- 12/87 +/- 7 mmHg (p < 0.0001). This blood pressure fall was similar in group 1 (-22 +/- 12/-12 +/- 8 mmHg) and in group 2 (-21 +/- 11/-12 +/- 8 mmHg). In the pure systolic HT subgroup treated by trandolapril monotherapy, the antihypertensive effect predominantly affected the SBP (-23 +/- 12/- 4 +/- 6 mmHg). The antihypertensive effect was correlated with the initial blood pressure. In group 1, in the case of insufficient response to trandolapril monotherapy, the addition of a calcium channel blocker was the strategy which achieved the most marked antihypertensive effect (ANOVA, p < 0.0001). This bitherapy was more effective than the trandolapril+diuretic combination (-18 +/- 11/- 11 +/- 8 mmHg and -15 +/- 10/- 9 +/- 7 mmHg, respectively (p < 0.001). A total of 1,270 adverse events were reported by 996 patients (7.6%), leading to discontinuation of treatment in 372 patients (2.8%). The most frequent adverse effects were cough (2.8%), headache (0.8%), vertigo (0.8%) and nausea (0.5%). Only one minor equivalent of angioneurotic oedema was reported. In conclusion, trandolapril is effective and well tolerated in elderly hypertensive patients. In the case of pure systolic HTA, its action is essentially exerted on SBP. The combination of trandolapril+calcium channel blocker appears to be the most effective strategy in the case of incomplete blood pressure control by trandolapril alone.

Age Factors↗

PubMed1995

The effects of calcium channel blockers, verapamil, nifedipine and diltiazem, on metabolic control in diabetic rats.

The effects of calcium channel blockers (CCB)-verapamil, nifedipine, diltiazem on metabolic control in streptozotocin-induced long-term diabetes in rats were investigated. Diabetes mellitus was induced by single intravenous injection of streptozotocin (65 mg/kg body wt.). The animals were divided into five groups: a healthy control group, a diabetic group and three diabetic groups treated with one of the calcium channel blockers (verapamil, 25 mg/kg/day, nifedipine, 20 mg/kg/day, and diltiazem, 30 mg/kg/day, respectively). Body weight, glycemia, glycated hemoglobin and total serum protein levels of these animals were measured at the beginning and at the end (after 13 weeks) of the experiment. It was observed that diabetic animals who were not treated with CCB had lost weight at the end of the experiment (P < 0.01). The blood glucose and glycated hemoglobin levels were increased in the diabetic group in comparison to the healthy control group (P < 0.001). However, the calcium channel blockers seem to have beneficial effects on body weight, glycated hemoglobin and blood glucose levels.

Animals↗