Calcium channel blockers in geriatric hypertension

Though the calcium channel blockers have been used to treat angina pectoris for almost a decade, the long-acting forms of these agents that have become available in the last few years have made them practical for use as antihypertensive agents as well. They are becoming increasingly popular in this role, especially to treat elderly hypertensive patients. Because they are vasodilators with a mild diuretic action, they are logical treatment choices for the majority of hypertensive patients who have increased peripheral vascular resistance. They offer the advantage of a dual benefit for hypertensive patients with angina, and they have no effect on carbohydrate or lipid metabolism. Disadvantages include cost and a side effect profile that includes headaches, palpitations, ankle edema, and constipation.     

Calcium channel blockers in treatment of hypertension

Calcium channel blockers (CCBs) are among the most often prescribed drugs for the treatment of hypertension, but there is still uncertainty regarding the risks and benefits of their use as first-line drugs in the treatment of hypertension. Compared with placebo, dihydropyridine CCBs (long-acting nifedipine and nitrendipine) reduce the risk for cardiovascular endpoints, and in a pooled analysis of available studies on treatment of hypertension, significantly decrease the risk for strokes and cardiovascular and total mortality. This also holds true for patients with diabetes who have a clearly reduced risk when treated with CCBs as compared with placebo. However, compared with other active treatments in mixed study populations, CCBs are associated with a small risk increase for myocardial infarction and heart failure, but for cardiovascular mortality, there is only a very small and nonsignificant trend to a risk increase, and total mortality is similar. Among patients with diabetes, compared with angiotensin-converting enzyme inhibitors in particular, available data suggest that CCB use is associated with a moderate increase in cardiac endpoints. Therefore, among patients with diabetes and those with heart failure, angiotensin-converting enzyme inhibitors are preferable as first-line drugs; among the large fraction of patients without these conditions, there is no convincing evidence that long-acting dihydropyridine or nondihydropyridine CCBs are inferior to other blood pressure-lowering drugs. In these patients, the choice of blood pressure-lowering medication can be based on the expected tolerability, costs, and personal preferences.     

Calcium entry blockers and their effects on glucose metabolism

Calcium entry blockers have been used for cardiovascular disturbances such as angina pectoris and hypertension. Calcium is, however, involved in the release of several hormones. The process of insulin secretion by the pancreatic beta-cells is dependent on calcium. Thus, calcium-entry blockers may interfere with insulin secretion. This effect has been confirmed in vitro in isolated islets as well as in animal studies. A few case reports describe the deterioration of glycaemic control or development of frank diabetes mellitus during treatment with nifedipine or diltiazem. In general, however, there are no important negative effects of calcium-entry blockers on glucose tolerance, either in non-diabetic persons with hypertension, or in patients with diabetes mellitus. Hence, these drugs appear to be a good choice for use in diabetic patients with cardiovascular diseases.     

Calcium-channel blockers for combined angina pectoris and systemic hypertension

Calcium-channel blockers have been successfully used in the treatment of angina of effort and systemic hypertension. Many patients present with concomitant angina pectoris and hypertension. Controlled clinical trials demonstrate that the calcium-channel blockers are safe and effective as monotherapy in the treatment of these patients, and that their use compares favorably with that of propranolol. The effectiveness of these agents in hypertension appears to be primarily due to their ability to induce systemic vasodilation. Calcium-channel blockers have several therapeutic effects in angina pectoris. Beneficial actions on the major determinants of oxygen consumption, i.e. heart rate, blood pressure and contractility, are generally seen. The potent coronary vasodilating actions of these agents allow for increased coronary blood flow. Improvements in ventricular compliance, regression of left ventricular hypertrophy and cardioprotection appear to be additional effects of the calcium-channel blockers; their contribution to the drugs' overall therapeutic efficacy is presently being evaluated. Calcium-channel blockers are a welcome addition to drug regimens available for the management of patients with coexisting angina pectoris and hypertension.     

Calcium entry blockers: antihypertensive and natriuretic effects in experimental animals

Hypotensive and natriuretic effects of calcium entry blockers were studied in spontaneously hypertensive rats (SHRs) and normotensive Wistar Kyoto rats (WKYs). In SHRs, the hypotensive action of diltiazem was enhanced, while that of hydralazine was not different from its action in WKYs. Diltiazem, unlike hydralazine and nifedipine, did not cause reflex tachycardia in rats. Diltiazem and nifedipine caused an increase in urine volume and sodium excretion. The natriuretic potency of diltiazem was the same in both SHRs and WKYs and was not affected by pretreatment with indomethacin. Diltiazem increased plasma renin activity but had no influence on plasma aldosterone concentration. Hydralazine increased both plasma renin activity and plasma aldosterone concentration and decreased sodium excretion. In anesthetized dogs, diltiazem increased sodium excretion, glomerular filtration rate and renal blood flow. Diltiazem may have a direct effect on tubular sodium reabsorption. This assumption was supported by a study with short-circuit current of the isolated bullfrog bladder. It is likely that diltiazem's effect of increasing urine volume and sodium excretion is due mainly to changes in renal hemodynamics and partly to direct action on renal tubules. Diltiazem opposed angiotensin II-induced responses, such as renal vasoconstriction and reduction of glomerular filtration rate. Under this condition, a marked natriuretic effect was observed with both intravenous and intraarterial administration of diltiazem. The ability to increase urinary excretion of sodium is a desirable characteristic for an antihypertensive agent. Calcium entry blockers have this ability and are therefore able to act without causing sodium and water retention.     

Calcium antagonists for the treatment of systemic hypertension.

As shown by large-scale clinical trials, the antihypertensive effectiveness of diuretics has been associated with a dramatic decrease in the incidence of stroke. This decrease, however, has not been accompanied by a similar reduction in atherosclerotic complications of hypertension, perhaps because other risk factors are important contributors to cardiovascular disease. In particular, a pathophysiologic relationship appears to exist between high blood pressure, left ventricular hypertrophy, diabetes and dyslipidemia. Thus, metabolically neutral antihypertensive agents such as calcium antagonists, which have no adverse effects on serum lipids and insulin sensitivity and can reduce left ventricular mass, are particularly suitable for the treatment of hypertension and attendant cardiovascular complications.     

Combination of verapamil and beta blockers in systemic hypertension

The efficacy and safety of verapamil and propranolol were examined in 14 hypertensive patients (mean age 51.2, range 30 to 65) in a double-blind, randomized, crossover study of verapamil, 360 mg, propranolol, 240 mg, these 2 formulations in combination and placebo, each given for 4 weeks. Supine blood pressure, heart rate, atrioventricular conduction (PR interval) and left ventricular function were measured. All treatments reduced diastolic blood pressure (mean +/- standard deviation) (p less than 0.001): placebo to 106.6 +/- 8.1 mm Hg; propranolol to 93.8 +/- 7.7; verapamil to 89.8 +/- 7.8; the combination to 84.1 +/- 6.1, but the effect of the combination was significantly greater than that of either drug alone (p less than 0.05). Heart rate at rest (placebo, 80.2 +/- 12.2 beats/min) was reduced by propranolol (63.3 +/- 9.4, p less than 0.001), but not by verapamil (79.0 +/- 8.9). However, the addition of verapamil to propranolol led to a further reduction in heart rate (56.9 +/- 8.4, p less than 0.005). PR interval was prolonged significantly by the combination (185.5 +/- 35.3 ms) when compared with placebo (154.0 +/- 22.7); propranolol (159.1 +/- 21.2) and verapamil (165.5 +/- 32.4) (p less than 0.005 for each). The active drugs increased end-diastolic dimension and end-systolic dimension. For each variable, the effect of the combination was statistically significant (p less than 0.01). Fractional shortening was not altered significantly by any of the treatments. Thus verapamil plus propranolol is a very effective antihypertensive combination but heart rate, atrioventricular conduction and left ventricular function may be affected adversely, necessitating careful monitoring of therapy.     

Calcium-entry blockers, vascular smooth muscle and systemic hypertension

Abnormal narrowing of the arterioles, caused by contraction of arteriolar smooth muscle, contributes to the genesis and the maintenance of the increased peripheral resistance observed in hypertension. Activation of the contractile process in vascular smooth muscle requires an increase in cytoplasmic calcium. In most blood vessels, the activator ion enters the cell through specific membrane channels, which can be inhibited by a chemically heterogeneous group of drugs, the calcium-entry blockers. The antihypertensive effect of these agents is probably explained by their inhibitory effect on (1) alpha-adrenergic activation (the pharmacologic subtype of postjunctional alpha-adrenoceptor does not necessarily determine the importance of calcium entry); (2) activation by nonadrenergic neurohumoral mediators (for example, serotonin); (3) acceleration of calcium entry by metabolites of arachidonic acid formed by lipoxygenase; and (4) inherent myogenic tone.     

Impact of calcium entry blockers on glomerular injury in experimental hypertension

Summary A major problem for patients with kidney disease and their physicians is that most chronic renal diseases progress to global glomerular sclerosis and end-stage renal failure. Studies in experimental models of hypertension and renal insufficiency have advanced our understanding of the pathogenesis of progressive kidney damage. In a number of settings, sclerosis has been related to the presence of intrarenal hypertension, a consequence of the hemodynamic adaptation to a reduction in the number of functioning nephrons. A growing body of evidence also supports the hypothesis that kidney and glomerular hypetrophy constitute an independent risk factor for glomerular sclerosis. Recent studies suggest that calcium antagonists can reduce glomerular injury in experimental hypertension. Renal protection may be related to the ability of these agents to inhibit compensatory renal growth.     

Effect of beta blockers on vascular resistance in systemic hypertension

Over 20 years ago, it was established that beta blockers could reduce high blood pressure. Currently, several beta blockers with different ancillary properties are available. They all have the property of blocking beta 1 receptors but differ from each other in a number of other respects: they may or may not block beta 2 receptors in low doses (beta 1 = receptor selectivity); they may or may not possess varying degrees of partial agonist activity, also known as intrinsic sympathomimetic activity (ISA); they vary in the extent to which they are soluble in fat (lipophilicity). A review of relevant published findings indicates that the effects of beta blockers on cardiac output are not essential for their antihypertensive effect, nor is penetration of these drugs into the brain and cerebrospinal fluid. Reduction in blood pressure during long-term beta blocker therapy is always associated with reduction of total peripheral resistance. Beta blockers with sufficient ISA to prevent cardio-depression, by exerting less negative inotropic and chronotropic effects on the heart, do not cause initial reflex vasoconstriction in response to cardiac beta blockade. Unlike beta blockers devoid of ISA, these agents ultimately reduce blood pressure by lowering the increased vascular resistance in hypertension to below pretreatment values. Recent beta blocker research has revealed a number of ways to manipulate the characteristically elevated vascular resistance in hypertension. Examples of these efforts are the combination of ISA, alpha 1 or alpha 2 receptor blockade and direct vasodilating properties in the enantiomers of a single beta blocker molecule. The practical significance of these developments remains to be established.     

Calcium influx and vascular reactivity in systemic hypertension

Numerous studies have focused on functional vascular changes that characterize the hypertensive state. Recent evidence that suggests that increased vascular reactivity in hypertension is due to changes in the delivery of activator Ca++ through channels in the cell membrane will be reviewed. The primary evidence supporting this hypothesis comes from studies that characterize the effects of Ca++-free solution and calcium channel blockers on contractile properties of isolated vascular smooth muscle. In the present study, experiments were performed to investigate the role of Ca++ influx in vascular contractions produced by interventions that cause membrane depolarization. Isometric tension development in helical strips of carotid arteries from stroke-prone spontaneously hypertensive rats in response to elevated K+ and tetraethylammonium chloride was greater than that in carotid arteries from Wistar-Kyoto normotensive rats. The rate of tension development to K+-free solution in carotid arteries from stroke-prone spontaneously hypertensive rats was faster than in Wistar-Kyoto normotensive rat arteries. Contractile responses to all 3 depolarizing interventions were reduced in arterial strips incubated in Ca++-free solution containing the chelator ethylene glycol bis-(beta-aminoethyl ether) N,N,N',N'-tetraacetic acid and in arterial strips treated with the Ca++ channel blocker verapamil. These results are consistent with the hypothesis that constrictor stimuli that produce membrane depolarization cause an opening of Ca++ channels in the plasma membrane that are sensitive to the organic channel blockers. Further, a change in Ca++ permeability or membrane depolarizing mechanisms contributes to increased contractile responsiveness in carotid arteries of stroke-prone spontaneously hypertensive rats.     

Calcium channel blockers

J Clin Hypertens (Greenwich). 2011;13:687–689. ©2011 Wiley Periodicals, Inc.Key Points and Practical Recommendations

• • Calcium channel blockers, which dilate arteries by reducing calcium flux into cells, effectively lower blood pressure, especially in combination with other drugs, and some formulations of agents of this class are approved for treating angina or cardiac dysrhythmias.
• • Calcium channel blockers reduce blood pressure across all patient groups, regardless of sex, race/ethnicity, age, and dietary sodium intake.
• • Nondihydropyridine calcium channel blockers are more negatively chronotropic and inotropic than the dihydropyridine subclass, which is important for patients with cardiac dysrhythmias or who need β‐blockers.
• • Extensive experience in comparative randomized trials indicates that an initial calcium antagonist can prevent all major types of cardiovascular disease, except heart failure (for which a diuretic is superior). Initial dihydropyridine calcium channel blockers have not reduced the rate of progression of renal disease as well as inhibitors of the renin‐angiotensin system, although members of the nondihydropyridine subclass can reduce albuminuria.
• • High doses of dihydropyridine calcium channel blockers often cause edema, headache, flushing and tachycardia; high doses of verapamil can cause constipation. Diltiazem and verapamil have important drug interaction with digoxin and cyclosporine, among others.