Calcium antagonists

doi:10.1016/j.pcad.2004.04.006

Progress in Cardiovascular Diseases

Volume 47, Issue 1, July–August 2004, Pages 34-57

https://doi.org/10.1016/j.pcad.2004.04.006 Get rights and content

Abstract

Calcium antagonists were introduced for the treatment of hypertension in the 1980s. Their use was subsequently expanded to additional disorders, such as angina pectoris, paroxysmal supraventricular tachycardias, hypertrophic cardiomyopathy, Raynaud phenomenon, pulmonary hypertension, diffuse esophageal spasms, and migraine. Calcium antagonists as a group are heterogeneous and include 3 main classes—phenylalkylamines, benzothiazepines, and dihydropyridines—that differ in their molecular structure, sites and modes of action, and effects on various other cardiovascular functions. Calcium antagonists lower blood pressure mainly through vasodilation and reduction of peripheral resistance. They maintain blood flow to vital organs, and are safe in patients with renal impairment. Unlike diuretics and β-blockers, calcium antagonists do not impair glucose metabolism or lipid profile and may even attenuate the development of arteriosclerotic lesions. In long-term follow-up, patients treated with calcium antagonists had development of less overt diabetes mellitus than those who were treated with diuretics and β-blockers. Moreover, calcium antagonists are able to reduce left ventricular mass and are effective in improving anginal pain. Recent prospective randomized studies attested to the beneficial effects of calcium antagonists in hypertensive patients. In comparison with placebo, calcium antagonist—based therapy reduced major cardiovascular events and cardiovascular death significantly in elderly hypertensive patients and in diabetic patients. In several comparative studies in hypertensive patients, treatment with calcium antagonists was equally effective as treatment with diuretics, β-blockers, or angiotensin-converting enzyme inhibitors. From these studies, it seems that a calcium antagonist—based regimen is superior to other regimens in preventing stroke, equivalent in preventing ischemic heart disease, and inferior in preventing congestive heart failure. Calcium antagonists are also safe and effective as first-line or add-on therapy in diabetic hypertensive patients. Heart rate—lowering calcium antagonists (verapamil, diltiazem) may have an edge over the dihydropyridines in post—myocardial infarction patients and in diabetic nephropathy. Thus, calcium antagonists may be safely used in the management of hypertension and angina pectoris.

Section snippets

Effects on arterial pressure

Calcium antagonists lower cytosolic free calcium concentration mainly through a reduction of transmembranous calcium influx and are potent arteriolar vasodilators.10 They also reduce angiotensin II—mediated vasoconstriction and decrease angiotensin II stimulatory effect on adrenal biosynthesis and secretion of aldosterone.11 In addition, there is evidence that some of the dihydropyridines (nifedipine and nicardipine) may interfere with α-adrenoceptor—mediated vasoconstriction.12 Unlike other

Lipids

Dyslipidemia and hypertension—2 disorders that frequently coexist in the same patient—are both risk factors for cardiovascular morbidity and mortality.

Unlike diuretics and β-blockers that adversely affect lipid profile, calcium antagonists have little effect on blood lipids.36 Pasanisi et al37 showed that calcium antagonists enhance triglyceride removal, possibly by stimulating the secretion of lipoprotein lipase. Alternatively, calcium antagonists could remove triglycerides by vasodilation and

Antiatheromatous effects of calcium antagonists

Hypertension is a risk factor for the development of atherosclerosis and its complications. Several calcium-dependent processes, such as platelet aggregation, monocyte adhesion, release of growth factors, cell proliferation and migration, protein and collagen secretion and synthesis, and endothelial necrosis, are involved in the formation of the atherosclerotic lesion. Because calcium plays a key role in the genesis of atherosclerosis, it is possible that interference with the calcium

Effects on left ventricular mass and myocardial fibrosis

Left ventricular hypertrophy (LVH) has been identified as one of the strongest pressure-independent risk factors for sudden death, acute myocardial infarction, congestive heart failure, and other cardiovascular morbidity and mortality.79, 80, 81, 82, 83, 84, 85, 86, 87, 88 Although it is unclear whether a reduction in LVH confers benefit over and above the benefit of lowering blood pressure per se, the effects of various antihypertensive agents on LVH have come under scrutiny.

Not all

Renal effects

Renal function deteriorates with age. This age-related loss of renal function is accelerated when blood pressure is elevated.243 In experimental models of chronic renal disease, calcium antagonists slowed the progression of renal damage.244 Studies using the isolated perfused hydronephrotic rat kidney model demonstrated that calcium antagonists preferentially vasodilate the preglomerular vessels, thereby augmenting glomerular filtration rate. The clinical implication of these observations has

Effects of calcium antagonists on cardiovascular outcomes

Recent prospective randomized studies attested to the beneficial effects of calcium antagonists in hypertensive patients3, 4, 5, 6, 7, 8, 9, 65, 74, 261, 262, 263, 264 (Table 3). In prospective, randomized, double-blind, placebo-controlled trials, calcium antagonist—based therapy reduced major cardiovascular events and cardiovascular death significantly in elderly hypertensive patients.3, 261, 262 Active treatment with calcium antagonist reduced the total rate of stroke by 38% to 42% and the

Drug interaction

The potential for drug interactions with calcium antagonists should be taken into consideration. Because calcium antagonists are most likely prescribed for patients with cardiovascular diseases, interactions with other cardiovascular agents are particularly important. Verapamil and nitrendipine may increase digoxin levels by 40% to 90%, α-blockers may cause excessive hypotension when coadministered with calcium antagonists, and, similarly, guanidine may cause excessive hypotension when

Side effects

The main side effects of the nondihydropyridine calcium antagonists include constipation, bradycardia, and even AV block and worsening of congestive heart failure. For the dihydropyridines the main side effects include flushing, headache, leg edema, gingival hypertrophy, and tachycardia—all of which are not life-threatening.27

To date, pedal edema remains the most frequent troublesome adverse effect of the dihydropyridines. However, this side effect is less common with agents of the third

Conclusions

By definition, all antihypertensive drugs, including calcium antagonists, lower arterial pressure. However, apart from lowering arterial pressure, calcium antagonists have a variety of beneficial effects in patients with hypertensive heart disease; they reduce LVM and improve its sequelae, such as ventricular dysrhythmias, impaired filling and contractility, and myocardial ischemia. Certain calcium antagonists have been shown to reduce the reinfarction rate and to have the potential for

Dr reiffel’s clinical pearls

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Verapamil, diltiazem, and the dihydropyridines are each negatively inotropic in vitro, but in vivo their inotropic effects reflect a balance between their direct effects and the effects of reflex sympathetic actions subsequent to their vasodilating actions. All are both peripheral and coronary vasodilators; all can be used for hypertension (calcium channel blockers are more effective for this in older patients, as are ACE inhibitors), for reduction of angina pectoris, for Raynaud syndrome

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DHPs are known to act at the interface between domains III and IV of the pore domain [14,15], while PAAs and BZTs act at an overlapping site on the intracellular side of the selectivity filter [16]. Among these, the PAA verapamil is widely used in the treatment of cardiac arrhythmias [17], while DHPs such as amlodipine and nimodipine are a first-line therapy for hypertension [18]. In addition, all currently approved CCBs are state-dependent blockers and exhibit use-dependence [19,20], where sustained or repeated depolarization leads to increased drug block.
Mutations in the Ca_V1.2 L-type calcium channel can cause a profound form of long-QT syndrome known as long-QT type 8 (LQT8), which results in cardiac arrhythmias that are often fatal in early childhood. A growing number of such pathogenic mutations in Ca_V1.2 have been identified, increasing the need for targeted therapies. As many of these mutations reduce channel inactivation; resulting in excess Ca²⁺ entry during the action potential, calcium channel blockers (CCBs) would seem to represent a promising treatment option. Yet CCBs have been unsuccessful in the treatment of LQT8. Here, we demonstrate that this lack of efficacy likely stems from the impact of the mutations on Ca_V1.2 channel inactivation. As CCBs are known to preferentially bind to the inactivated state of the channel, mutation-dependent deficits in inactivation result in a decrease in use-dependent block of the mutant channel. Further, application of the CCB verapamil to induced pluripotent stem cell (iPSC) derived cardiomyocytes from an LQT8 patient demonstrates that this loss of use-dependent block translates to a lack of efficacy in correcting the LQT phenotype. As a growing number of channelopathic mutations demonstrate effects on channel inactivation, reliance on state-dependent blockers may leave a growing population of patients without a viable treatment option. This biophysical understanding of the interplay between inactivation deficits and state-dependent block may provide a new avenue to guide the development of improved therapies.
Participation of membrane calcium channels in erythropoietin-induced endothelial cell migration
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Inhibition of these voltage-dependent channels in vascular smooth muscle cells as well as in cardiomyocytes not only results in coronary and peripheral artery vasodilation, but also in decreased cardiac contractility. Stemming from this, the clinical use of calcium antagonists has been demonstrated to successfully prevent stroke, ischemic heart disease and mortality in hypertensive patients (Grossman and Messerli, 2004). According to their chemical structure, calcium antagonists may be classified as phenilalkylamine, benzothiazepine and dihydropyridine drugs.
Calcium (Ca²⁺) plays an important role in angiogenesis, as it activates the cell migration machinery. Different proangiogenic factors have been demonstrated to induce transient Ca²⁺ increases in endothelial cells. This has raised interest in the contribution of Ca²⁺ channels to cell migration, and in a possible use of channel-blocking compounds in angiogenesis-related pathologies. We have investigated the ability of erythropoietin (Epo), a cytokine recently involved in angiogenesis, to induce Ca²⁺ influx through different types of membrane channels in EA.hy926 endothelial cells. The voltage-dependent Ca²⁺ channel antagonists amlodipine and diltiazem inhibited an Epo-triggered transient rise in intracellular Ca²⁺, similarly to a specific inhibitor (Pyr3) and a blocking antibody against the transient potential calcium channel 3 (TRPC3). Unlike diltiazem, amlodipine and the TRPC3 inhibitors prevented the stimulating action of Epo in cell migration and in vitro angiogenesis assays. Amlodipine was also able to inhibit an increase in endothelial cell migration induced by Epo in an inflammatory environment generated with TNF-α. These results support the participation of Ca²⁺ entry through voltage-dependent and transient potential channels in Epo-driven endothelial cell migration, highlighting the antiangiogenic activity of amlodipine.
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Calcium channel blockers are prescribed to reduce heart rate and force of contraction. They also cause vasodilatation, leading to reduction in blood pressure (Grossman and Messerli, 2004; Lüllmann et al., 2002). The metabolism of diltiazem in mammals is well documented (Homsy et al., 1995; Molden et al., 2002a).
Diltiazem is a pharmaceutical belonging to a group of calcium channel blockers (CCB) that is widely used in the treatment of angina pectoris and hypertension. The objective of the present study was to assess the effect of diltiazem on rainbow trout (Oncorhynchus mykiss). Juvenile trout were exposed for 21 and 42 days to three nominal concentrations of diltiazem: 0.03 μg L⁻¹ (environmentally relevant concentration), 3 μg L⁻¹, and 30 μg L⁻¹ (sub-lethal concentrations). The number of mature neutrophilic granulocytes was significantly increased by 450 and 400% in fish exposed to 3 μg L⁻¹ and 30 μg L⁻¹ diltiazem compared to the control, respectively. Antioxidant enzyme activity was affected in liver and gills of fish exposed to all tested concentrations of diltiazem but the changes were mostly transient and not concentration dependent. Creatine kinase activity was markedly increased (ranging from 520 to 845%) at all tested diltiazem concentrations at the end of the exposure indicating muscle and/or kidney damage. The highest concentration was associated with histological changes in heart, liver, and kidney. These alterations can be attributed to the effects of diltiazem on the cardiovascular system, similar to those observed in the human body, as well as to its metabolism. At the environmentally relevant concentration, diltiazem was found to induce some alterations in the blood, gills, and liver of fish, indicating its potential for adverse effects on non-target organisms in the aquatic environment.
Bioconcentration, metabolism and half-life time of the human therapeutic drug diltiazem in rainbow trout Oncorhynchus mykiss
2016, Chemosphere
Diltiazem is a human therapeutic drug and a member of the group of calcium channel blockers having widespread use in the treatment of angina pectoris and hypertension. The objective of the present study was to assess the bioconcentration, metabolism, and half-life time of diltiazem in rainbow trout Oncorhynchus mykiss. Juvenile trout were exposed for 21 and 42 days to three nominal concentrations of diltiazem: 0.03 µg L⁻¹ (environmentally relevant concentration), 3 µg L⁻¹, and 30 µg L⁻¹ (sub-lethal concentrations). The bioconcentration factor (BCF) of diltiazem was relatively low (0.5–194) in analysed tissues, following the order kidney > liver > muscle > blood plasma. The half-life of diltiazem in liver, kidney, and muscle was 1.5 h, 6.2 h, and 49 h, respectively. The rate of metabolism for diltiazem in liver, kidney, muscle, and blood plasma was estimated to be 85 ± 9%, 64 ± 14%, 46 ± 6%, and 41 ± 8%, respectively. Eight diltiazem metabolites were detected. The presence of desmethyl diltiazem (M1), desacetyl diltiazem (M2), and desacetyl desmethyl diltiazem (M3) suggests that rainbow trout metabolize diltiazem mainly via desmethylation and desacetylation, similar to mammals. In addition, diltiazem undergoes hydroxylation in fish. At environmentally relevant concentrations, diltiazem and its metabolites were identified in liver and kidney, indicating the potential for uptake and metabolism in non-target organisms in the aquatic environment.

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Calcium antagonists

Abstract

Section snippets

Effects on arterial pressure

Lipids

Antiatheromatous effects of calcium antagonists

Effects on left ventricular mass and myocardial fibrosis

Renal effects

Effects of calcium antagonists on cardiovascular outcomes

Drug interaction

Side effects

Conclusions

Dr reiffel’s clinical pearls

Am J Hypertens

Am J Hypertens

Lancet

Lancet

Lancet

Lancet

Am J Kidney Dis

Am J Cardiol

Am J Cardiol

Am J Obstet Gynecol

Am J Med

Am J Hypertens

Am J Cardiol

Biochem Pharmacol

J Am Coll Cardiol

Atherosclerosis

Lancet

J Am Coll Cardiol

Am J Cardiol

Am J Cardiol

Am J Cardiol

Am J Cardiol

Am J Med

Am J Med

Am J Cardiol

Am J Cardiol

Am J Cardiol

Principal results of the Controlled Onset Verapamil Investigation of Cardiovascular End Points (CONVINCE) trial

JAMA

JAMA

A calcium antagonist vs a non-calcium antagonist hypertension treatment strategy for patients with coronary artery disease. The International Verapamil-Trandolapril Study (INVEST): A randomized controlled trial

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Enhanced vasodilatation in essential hypertension by calcium channel blockade with verapamil

Hypertension

The effect of the calcium antagonist nifedipine on pressor and aldosterone responses to angiotensin II in normal man

Eur J Clin Pharmacol

Calcium entry blockade and alpha-adrenergic vascular reactivity in human beingsDifferences between nicardipine and verapamil

Clin Pharmacol Ther

Immediate and short-term hemodynamic effects of diltiazem in patients with hypertension

Circulation

Systemic and regional hemodynamic and humoral effects of nitrendipine in essential hypertension

Circulation

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Cardiovasc Drugs Ther

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