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PubMedDate not supplied

Incidence of pedal edema formation with dihydropyridine calcium channel blockers: issues and practical significance.

Dihydropyridine calcium channel blockers comprise a class of powerful, well-tolerated, and safe antihypertensive agents that are widely used either alone or as a key component of combination therapy for hypertension. Peripheral edema, particularly of the lower limbs, is one of the most common adverse effects of dihydropyridine calcium channel blockers and may result in the need for dose reduction or drug withdrawal, both of which can adversely affect antihypertensive efficacy. Optimal use of these important drugs will involve careful dosing and sensitivity to strategies to diminish the likelihood of edema. Diuretics, either loop or thiazide, are usually not effective in alleviating pedal edema. Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers in combination with a dihydropyridine calcium channel blocker may be helpful in this regard. Some calcium channel blockers may be less likely to cause pedal edema compared with others. This paper will review existing explanations of why there may be differences. A favorable tolerability profile is of particular importance for an antihypertensive medication, since hypertension is a chronic disorder necessitating long-term treatment and patient compliance.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1991

Structurally novel antihypertensive compound, McN-5691, is a calcium channel blocker in vascular smooth muscle.

These studies were conducted to gain greater understanding of the mechanism of action of the chemically novel antihypertensive agent, McN-5691. McN-5691 (1 and 10 microM) prevented 60 mM KCl-induced contraction and calcium uptake and caused concentration-dependent relaxation (EC50 = 190 microM) of 30 mM KCl-contracted aortic rings. At or below 10 microM, McN-5691 had no effects on basal tone or calcium uptake (45Ca) in isolated rings of rabbit thoracic aorta. McN-5691 caused complete high affinity inhibition (Kd = 39.5 nM) of specific diltiazem binding to the benzothiazepine receptor on the voltage-sensitive calcium channel in skeletal muscle microsomal membranes. In contrast to diltiazem, McN-5691 inhibited specific dihydropyridine receptor binding, but the effect was biphasic with high (Kd = 4.7 nM) and low (Kd = 919.8 nM) affinity components. These findings suggest that McN-5691 is a voltage-sensitive calcium channel blocker. Unlike other calcium channel blockers, McN-5691 inhibited norepinephrine (NE)-induced contraction (10 microM) and calcium uptake (1 and 10 microM) and caused concentration-dependent relaxation (EC50 = 159 microM) of 1 microM NE-contracted rings of rabbit thoracic aorta. The vascular relaxant effects of McN-5691 were not related to increased calcium (45Ca) efflux from vascular smooth muscle cells. The effects of McN-5691 on NE-induced contraction were unrelated to intracellular mechanisms because McN-5691 did not affect NE-induced contraction in the absence of extracellular calcium. McN-5691 had weak activity in rat cerebral cortical membrane alpha-1 or alpha-2 adrenergic receptor binding assays. McN-5691-induced vasodilation of phenylephrine-contracted rat aortic strips was not reversible by high potassium, indicating that McN-5691 does not induce relaxation of blood vessels through potassium channel activation. In summary, these studies suggest that the primary vasodilator mechanism of McN-5691 is calcium channel blockade through competitive binding at the diltiazem site on the voltage sensitive calcium channel. McN-5691 may possess an additional vasodilator mechanism of action distinct from alpha adrenergic receptor blockade but involving a cell membrane-related event apparently leading to attenuation of receptor-operated calcium channel activity.

Animals↗
PubMed1993

Use of amrinone and glucagon in a case of calcium channel blocker overdose.

Hypotension resulting from calcium channel blocker ingestion often is refractory to standard therapeutic modalities. Amrinone and glucagon have been used separately and in combination with other agents in the treatment of calcium channel blocker overdose. We report the successful use of both amrinone and glucagon in the treatment of a 30-year-old woman who ingested 3.6 g of verapamil and presented with refractory hypotension. The use of the two agents together may provide improved inotropic support with minimal increases in myocardial oxygen consumption. In this case, the combination of amrinone and glucagon was safe and effective in the management of the hemodynamic instability associated with calcium channel blocker overdose.

Adult↗
PubMed1985

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

Combination therapy using calcium-channel blockers and beta 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 beta 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 beta 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 beta 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 beta blockers appears to have the greatest therapeutic efficacy but also the highest frequency of harmful adverse cardiac effects, whereas nifedipine plus beta 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 beta blocker, the presence of antecedent left ventricular dysfunction or conduction system disease and the possibility of drug interactions. Concomitant calcium-channel blocker and beta-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.

Adrenergic beta-Antagonists↗
PubMed1989

Nicardipine, a new calcium channel blocker: role for vascular selectivity.

Calcium channel blockers are important drugs for the treatment of chronic stable angina. However, negative inotropic and dromotropic effects may limit their usefulness in patients with atrioventricular conduction abnormalities or left ventricular dysfunction. A new generation of calcium channel blockers will soon be available that have a more vascular selective action than currently available agents. Of the new agents, nicardipine has been most extensively studied. In experimental studies, nicardipine is more specific for vascular smooth muscle than for cardiac smooth muscle and for coronary than peripheral vasculature. In controlled trials, nicardipine exhibited efficacy and safety that was comparable to older calcium blockers or beta blockers. However, nicardipine was associated with minimal negative inotropic or dromotropic effects even in patients with existing left ventricular dysfunction. Thus, nicardipine may have an advantage over existing calcium channel blockers, especially in patients with underlying cardiac disease.

Angina Pectoris↗
PubMed1991

Effects of calcium-channel blockers on cytosolic free calcium and amylase secretion in rat pancreatic acini.

We investigated the effects of verapamil and diltiazem on cytosolic free calcium and amylase secretion in rat pancreatic acini. Verapamil and diltiazem reduced a rise in cytosolic free calcium and amylase release stimulated by the maximal concentration (10(-5) M) of carbachol in a dose-dependent manner. High concentrations (500 microM) of verapamil and diltiazem inhibited both the initial and the sustained amylase secretion stimulated by 10(-5) M carbachol. However, at low concentration (1 microM), they showed no effect on amylase secretion by 10(-5) M carbachol. These calcium-channel blockers did not affect calcium mobilization and amylase secretion stimulated by either caerulein or neuromedin C. Binding of 3H-N-methylscopolamine to pancreatic acini was inhibited by verapamil and diltiazem in a dose-dependent manner. These findings suggested that verapamil and diltiazem reduced carbachol-induced amylase secretion probably not due to their calcium-channel blocking activities but due to their non-competitive effects on the level of muscarinic receptors.

Amylases↗
PubMed2003

[Advance in calcium channel blockers relaxing corpus cavernosum smooth muscle].

Calcium channels exist extensively in the membrane of cardiac, skeletal, smooth muscle cell and neuron. Calcium channel blockers (CCB) were widely used for the treatment of cardiovascular diseases because they could relax vascular smooth muscle. Experimental researches on calcium channel blockers relaxing corpus cavernosum smooth muscle have been reported recently. Whether the blockers can be used for the clinical diagnosis and treatment of erectile dysfunction still need to be further investigated.

Animals↗
PubMed1986

Calcium-channel blockers and advanced cardiac life support.

Calcium channel-blocking drugs have potent antiarrhythmic and antianginal effects and in addition may reduce the extent of cellular injury after anoxia/ischemia. Verapamil is the treatment of choice (90% effective) for uncomplicated episodes of paroxysmal supraventricular tachycardia. All three calcium-channel blockers available, diltiazem, nifedipine, and verapamil, can reduce the frequency of angina occurring both at rest and with exertion. Calcium may mediate several cytotoxic events during the reperfusion period after prolonged ischemia that lead to irreversible cell injury. There is experimental evidence that calcium-channel blockers may reduce the cellular influx of calcium after ischemia and reperfusion, and thereby attenuate cerebral and myocardial injury, although most studies have failed to show benefit of treatment unless the drug is administered before the onset of ischemia. Most trials using calcium-channel blockers in the setting of acute myocardial infarction have failed to show a benefit of treatment. The safety and efficacy of calcium-channel blockers have yet to be shown in controlled studies of human resuscitation, although the potential for such treatment, if it is effective in attenuating myocardial cerebral cellular injury, could be enormous.

Brain Ischemia↗
PubMed1997

Calcium channel blockers: an evidence-based review.

Calcium channel blockers are widely used in the treatment of cardiovascular disease, but their proper therapeutic role is controversial. Nevertheless, drugs from this class have been evaluated in many controlled clinical trials of adequate size and duration in different patient populations. Although many important questions remain unanswered, these trials have clarified when and how these drugs should be used. In general, the benefits of calcium channel blockers in controlling angina and hypertension are much more clearly documented than are their long term effects on harder end-points such as mortality. Such long term data are sorely needed, particularly for hypertension. An increased risk with dihydropyridine calcium channel blockers has been clearly seen across several studies of patients with coronary disease. In coronary patients with heart failure, the deleterious effects of nifedipine, diltiazem and verapamil outweigh any possible benefit. Long acting formulations and newer calcium channel blockers may not share all of the adverse effects of the older drugs of this class; however, their long term safety has not yet been documented. An understanding of the limitations of calcium channel blockers, based upon clinical trial evidence, often leads the practitioner to choose a drug from another class, where efficacy has been clearly proven.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1990

Protease activity in brain, nerve, and muscle of hens given neuropathy-inducing organophosphates and a calcium channel blocker.

Activity of calcium-activated neutral protease (CANP or calpain), an enzyme responsible for degradation of axonal and muscle cytoskeletal elements, was determined in brain, sciatic nerve, and gastrocnemius muscle of hens given tri-ortho-tolyl phosphate (TOTP, 360 mg/kg po) or active congener phenyl saligenin phosphate (PSP, 2.5 mg/kg im) with and without a calcium channel blocker which ameliorated clinical signs of organophosphate-induced delayed neuropathy (nifedipine 1 mg/kg/day x 5). Calcium channel blocker administration was initiated 1 day prior to administration of organophosphate (OP). OP administration caused an increase in CANP activity in brain within 4 days and in sciatic nerve and gastrocnemius muscle within 2 days of administration. This increase did not occur if nifedipine was administered to PSP-treated hens. Total sciatic nerve calcium concentrations were also increased by PSP, but not until OP-treated hens were no longer being administered calcium blockers. This indicates that calcium channel blockers may contribute to amelioration of organophosphate-induced delayed neuropathy by attenuation of calcium-mediated disruption of axonal and muscle cytoskeletal homeostasis.

Animals↗
PubMed1989

[Electrophysiologic effects of calcium channel blockers on supraventricular tachycardia in children].

Calcium channel blockers (diltiazem or verapamil) were administered in 17 pediatric patients with supraventricular tachycardia to evaluate their drug effects on electrophysiologic properties and the tachycardia zone. Using electrophysiologic technique, 10 patients were diagnosed as having orthodromic reciprocating tachycardia (ORT), including three patients with concealed atrioventricular bypass tracts. Four patients were diagnosed as having atrioventricular nodal re-entrant tachycardia (AVNRT) of the slow-fast type and three patients were diagnosed as having intra-atrial re-entrant tachycardia (IART). Diltiazem was given to 10 patients; verapamil, to eight patients at doses of 0.15-0.2 mg/kg intravenously. Electrophysiologic properties and the tachycardia zone were then evaluated before and after the administration of calcium channel blockers. Diltiazem and verapamil produced no significant changes in the sinus node and atrial functions including basic sinus cycle length, sinoatrial conduction time, maximum sinus node recovery time and the effective atrial refractory period. Although sinus cycle length was shortened after verapamil in half the cases, it was due to increased sympathetic tone secondary to hypotension rather than to direct action of verapamil. Calcium channel blockers, however, prolonged the PR interval and significantly increased the effective refractory period of the atrioventricular node. Properties of the atrioventricular bypass tracts were not affected by calcium channel blockers. Diltiazem and verapamil were markedly effective in ORT and AVNRT. Their re-entrant circuits, including the atrioventricular node and the tachycardia zones, were shortened or resolved. However, IART showed no significant change in the tachycardia zone after the administration of calcium channel blockers, because the re-entrant circuit was not present within the atrioventricular node.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1995

Mechanisms of the potent and long-lasting antihypertensive action of the new calcium channel blocker pranidipine. Evidence for strong affinity to the calcium channels or membranes.

To elucidate the mechanisms of the potent and long-lasting antihypertensive action of pranidipine (CAS 99522-79-9, OPC-13340), a wash-out experiment in isolated rat aorta preparations and a displacement binding experiment of (+)[3H]PN200-110 (isradipine) with pranidipine and other dihydropyridines to porcine skeletal T-tubules was conducted. It was revealed that the inhibition of KCl-induced contraction by pranidipine remained complete even after washing out the drug 9 times. Also, pranidipine had the lowest Ki value for (+)[3H]PN200-110 binding in skeletal T-tubules. The lipophilicity of pranidipine measured by octanol-buffer partition coefficient was the highest among the tested compounds, and the order of lipophilicity coincided with the order of potency in the displacement binding experiments. These results suggest that pranidipine has a very high affinity to Ca channels or to T-tubule membranes, and strongly support the "membrane-bilayer pathway hypothesis" which assumes the partitioning of the drug into the lipid bilayer before drug binding to Ca channels as an explanation of the potent and long-lasting action of pranidipine compared with other dihydropyridines.

Animals↗
PubMedDate not supplied

[Calcium and calcium-channel blockers in the healing of an experimental myocardial infarct].

It has been shown in experiments on 36 dogs with experimental myocardial infarction (MI) that the effect of calcium and blockers of calcium channels largely depends on the initial condition of reactivity and is realized via changes in lipid peroxidation (LPO). In MI, calcium enhances necrotic processes whereby aggravating disorders in its healing in case of high reactivity and returns them to normal, thus contributing to optimization of its healing in animals with low reactivity. Calcium channels blockers attenuate necrotic processes associated with MI and lead to its better healing in the presence of high reactivity and aggravate disorders in its healing in animals with low reactivity. Consideration of the body reactivity, the differentiated use of calcium drugs and calcium channels blockers should be regarded as an effective approach to optimization of the healing of complicated forms of MI.

Aminopyrine↗
PubMed1983

Calcium channel blockers: potential antimetastatic agents.

The calcium channel blocker nifedipine (Bay A 1040) was examined for its effects on tumor cell-platelet interactions. In vitro, nifedipine inhibited tumor cell-induced platelet aggregation and platelet enhanced tumor cell adhesion to confluent endothelial cell monolayers and in vivo nifedipine inhibited pulmonary tumor colony formation ("experimental metastasis") by intravenously injected tumor cells. This evidence suggests that calcium channel blockers may be a new class of antimetastatic agents.

Animals↗
PubMed1992

Which calcium channel blocker for ischaemic heart disease?

Calcium channel blockers have been available since the early 1960s. Extensive research has been undertaken to evaluate their usefulness in the treatment of patients with ischaemic heart disease. We have reviewed the pharmacology of these drugs and the major clinical trials. In particular, we have examined the effect of calcium channel blockers on the progression of atheroma, and their role in the following clinical settings: following myocardial infarction, following non-Q-wave myocardial infarction, and in unstable angina.

Angina, Unstable↗
PubMed2004

Effects of N-, P/Q- and L-type calcium channel blockers on nociceptive neurones of the trigeminal nucleus with input from the dura.

In anaesthetized rats, extracellular recordings were made from neurones of the spinal trigeminal nucleus, involved in the processing of nociceptive input from the dura. Blockers of voltage-gated calcium channels (VGCCs) were administered topically to the exposed brainstem. Blockade of N-type (CaV2.2) channels reduced spontaneous activity and responses of the neurones to cold and chemical stimuli applied to the dura, suggesting that N-type channels regulate excitatory synaptic activation. Blockade of L-type (CaV1) channels enhanced spontaneous discharges of the neurones. Blockade of P/Q-type (CaV2.1) channels slightly decreased responses to chemical and cold stimuli but markedly increased spontaneous activity, an effect which was absent during concomitant application of GABA to the brainstem. The data suggest that P/Q-type VGCCs regulate a tonic synaptic inhibitory control of the brainstem neurones. The risk of migraine by genetic modifications of P/Q-type channels may thus be sought in disturbed inhibition in the network that processes nociceptive dura input.

Action Potentials↗