Calcium entry blockers can decrease myocardial ischemia and coronary spasm in association with percutaneous transluminal coronary artery angioplasty (PTCA). Restenosis after PTCA has not been shown to be statistically decreased by nifedipine or diltiazem in patients who clinically did not have coronary spasm. Patients who have evidence of coronary spasm before or at PTCA have a higher incidence of restenosis after PTCA, but this is decreased by treatment with calcium entry blockers. Most patients at Emory receive a calcium entry blocker before and after PTCA while in the hospital. After discharge, long-term therapy is given to select patients, especially those with any evidence of coronary vasospasm or patients with incompletely revascularized, multivessel disease. All patients receive aspirin before and long-term after PTCA. Some physicians give calcium entry blockers to all patients after PTCA. There is a need for larger, controlled clinical trials to evaluate the current use of calcium entry blockers before, during, and after PTCA as well as other therapeutic agents to prevent acute and chronic restenosis.

Accumulating data indicate that silent ischemia is a common accompaniment of coronary artery disease. In the population at large, studies estimate that 2-4% of middle-aged men have asymptomatic coronary artery disease and silent ischemia on treadmill testing. In patients with known coronary artery disease, positive treadmill tests are unaccompanied by pain about 34% of the time. In patients with stable angina pectoris, silent ischemia comprises about 70% of total ischemic events. This frequency approaches 80% in patients with unstable angina. About 20-30% of all myocardial infarctions are silent. Of patients who survive myocardial infarction, about 5% have silent ischemia on early treadmill testing, which signals an adverse prognosis. Overall, the presence of ischemia increases the risk for any subset of patients with coronary disease. Furthermore, the risk is the same whether the ischemia is silent or symptomatic. In summary, silent ischemia is common in patients with coronary disease and adversely affects prognosis, especially in high-risk patients.

Although the vasodilator and anti-ischemic actions of calcium channel blocking drugs might be expected to produce hemodynamic benefits in chronic heart failure, none of these agents has been shown to exert favorable clinical effects in these patients. Furthermore, when left ventricular function is markedly impaired, short- and long-term therapy with calcium channel blockers can increase cardiovascular morbidity and mortality. Previous investigators have attributed these unfavorable results to the established negative inotropic effects of calcium channel blockers on the failing heart. Yet, this cardiodepressant action seems to account for only the deleterious responses seen during short-term therapy with these drugs, whereas the detrimental effects of long-term treatment can be more readily explained by the capacity of calcium channel blockers to activate endogenous neurohormonal systems, especially the renin-angiotensin system. According to this hypothesis, a number of cardioactive drugs (including calcium channel blockers, beta-blockers, and converting enzyme inhibitors) can depress myocardial contractility, but only calcium channel blockers, which activate neurohormonal systems, adversely affect patients with left ventricular dysfunction, whereas beta-blockers and converting enzyme inhibitors, which interfere with neurohormonal activity, can favorably modify the long-term outcome of these high-risk patients. If confirmed by future studies, these observations suggest that the effect of antianginal drugs on neurohormonal systems, as well as on cardiac contractility, should be an important consideration in the selection of a therapeutic agent in patients with coronary artery disease and chronic heart failure.

There is increasing evidence that the clinically available calcium entry blockers (i.e., diltiazem, nifedipine, and verapamil) improve noninvasively determined indexes of diastolic filling in patients with chronic coronary artery disease, hypertensive heart disease, and hypertrophic cardiomyopathy. These favorable alterations in diastolic function are often associated with clinical improvement. Current information suggests that salutary indirect actions of these agents on ventricular loading, sympathetic reflexes, and myocardial supply-demand relations, rather than direct effects on transsarcolemmal myocyte calcium influx, underlie these beneficial effects.

Once initiated, chronic renal disease inexorably progresses to end stage. Recent studies of various experimental renal disorders have shown that normalization of glomerular capillary flow and pressure, either by restricting protein intake or by administering converting enzyme inhibitors, slows this progression. Because the hemodynamic actions of Ca2+ channel blockers modify the angiotensin II-induced renal changes, these drugs have the potential for altering the course of renal disorders. These agents also protect the kidney from ischemic injury and nephrocalcinosis and reduce platelet aggregation, which can further contribute to the preservation of renal function. The published studies regarding the role of Ca2+ channel blockers in chronic renal disease, however, do not allow drawing firm conclusions. The effect of these agents might depend on the nature of renal disease and the drug and dose used. Controlled trials are needed before these drugs can be recommended for preservation of renal function.

In clinical arrhythmias, the main therapeutic role of calcium channel entry blockers is related to their effect on the sinus and atrioventricular (AV) node. Consequently, in cardiac arrhythmias where the AV node is part of the reentry circuit, a beneficial effect of diltiazem and verapamil can be demonstrated. These include AV nodal reentry and orthodromic tachycardia in patients with Wolff-Parkinson-White syndrome. In addition, the ventricular response by the AV node during atrial tachycardias can also be controlled with these agents. A specific type of ventricular tachycardia seen in the absence of structural heart disease has also been reported to respond to intravenous and oral verapamil. Calcium channel blockers have no proven depressant effect on accessory pathway conduction. Similarly, the value of these agents in the treatment of ventricular tachycardia in association with chronic coronary artery disease and idiopathic dilated cardiomyopathy is rather limited. The use of calcium entry blockers in patients with wide QRS tachycardia, therefore, is to be discouraged unless it can be proved that supraventricular tachycardia with aberrant conduction is the underlying basis.

Cardiac arrhythmias are generated as the result of disorders of automaticity or impulse conduction. Regardless of the mechanism, however, calcium is likely to be involved. The rate of Ca2+ flux across the membrane of automatic cells alters their firing rate. Myocardial cells that do not ordinarily initiate action potentials can do so when they are partially depolarized. Low extracellular Ca2+ concentrations or Ca2+ channel-blocking drugs can reduce or abolish such ectopic firing. Early afterdepolarizations are also induced in cardiac cells by partial depolarization, whereas delayed afterdepolarizations are induced by Ca2+ overloading. Early afterdepolarizations and delayed afterdepolarizations can both be suppressed by low external Ca2+ concentrations or by Ca2+ channel blockers. With respect to arrhythmias ascribable to disorders of conduction, Ca2+ channel blockers can aggravate conduction disturbances in the sinoatrial node or atrioventricular junction. Furthermore, these drugs can abolish those reentrant arrhythmias in which a cardiac impulse rotates around a loop in which nodal tissue is an integral element. Ca2+ channel blockers can also reduce the susceptibility for ventricular fibrillation to supervene in ischemic hearts, especially when the sympathetic nervous system is overactive.

Despite decreasing cardiac mortality rates in the elderly since 1968, rates of health care service use by persons over age 65 years have progressively increased. The growing availability of potent and effective cardiovascular drugs, together with the high prevalence of untoward side effects in the elderly, make it important that we consider the influence of age on cardiovascular response to the calcium entry blockers. The age-related structural, functional, pharmacokinetic, and pharmacodynamic changes that occur in elderly patients suggest that careful monitoring, adjustment, and frequent reassessment of the medical regimen should be performed to minimize untoward effects. Nifedipine, diltiazem, and verapamil are all well absorbed orally, are extensively protein bound, and are metabolized by the liver. The age-associated attenuation in rates of hepatic metabolism and hepatic blood flow contribute to the decreased clearance and prolonged elimination half-lives of these drugs in the elderly. Advanced age can be associated with increased susceptibility to sinoatrial depression, fatigue, constipation, hypotension, and peripheral edema after calcium entry blockade, even at modest doses. It would be prudent, therefore, to administer these agents at lower doses and at less frequent intervals.

The mosaic of essential hypertension seems to be gaining new tiles at an accelerating rate. Of the many pathophysiological factors and markers for the factors that can be considered as possible elements of a profiling algorithm, there are relatively few with solid data to support their use. Use of plasma renin activity for prospective profiling does not appear to be valid for individual patients. It remains useful for diagnosis of renal artery stenosis and primary aldosteronism. The black race does have some well-documented pathophysiological differences from the white race regarding hypertension, and there are some useful data bits for selecting specific therapy. The elderly, obese patients, and young patients with hyperdynamic circulation appear to have enough group characteristics to enable selection of drugs more targeted to their needs. Anxious patients who often display symptoms that mimic pheochromocytoma symptoms comprise a unique group. One of the largest groups is patients with hypertension plus one or more concomitant diseases. Finally, drug selection decisions must also consider the effect of drugs on serum lipoproteins, left ventricular hypertrophy and vascular compliance, sexual function and other quality of life issues, and cost.

Treatment of patients with mild to moderate essential hypertension is now commonly undertaken. Clinical trials have shown a marked decrease in strokes in treated hypertensive patients. But despite reports of decreases in coronary deaths in some trials, the overall incidence of coronary events has been largely unaffected. This disappointing outcome has raised interesting issues. The patients in comparative placebo groups often do better than expected in formal trials; apart from the benefits of lifestyle changes, many of these patients appear to normalize their blood pressures during the trial. This latter effect can be due to erroneous diagnoses of hypertension at the start of the study, and this partially dilutes the likelihood of differences in outcome between the placebo- and actively treated patients. Optimal control of blood pressure is difficult to define, and controversies exist concerning whether pressures have been decreased insufficiently or excessively in clinical trials; it has been argued, too, that systolic as well as diastolic hypertension should be the target of treatment. Inadvertent treatment-induced metabolic abnormalities, especially in blood lipids, glucose, and electrolytes can weaken the antihypertensive benefits. Failure to deal with concurrent risk factors including smoking and left ventricular hypertrophy also could explain the absence of a decrease in coronary events. Newer classes of antihypertensive agents offer the potential to address these concerns and improve the cardiovascular prognosis of treated hypertensive patients.

Calcium antagonists block the entry of calcium into vascular smooth muscle cells, producing pharmacological vasodilation. Thus, it is not surprising that these drugs are effective in treating unstable angina that is often characterized by increased vasomotion and dynamic obstruction at the site of atheromatous plaques. Nifedipine, diltiazem, and verapamil are all highly and equally effective in reducing painful and painless ischemic episodes in Prinzmetal's variant angina. In patients with unstable angina who have known or suspected significant underlying coronary artery disease, a multipharmacological approach to therapy is warranted. Nifedipine used with beta-blocker drugs is more effective than nifedipine as monotherapy. Diltiazem and verapamil have been shown to be effective when given without beta-blockers in unstable angina patients. In many patients, thrombus formation rather than vasospasm is the major pathophysiological event resulting in progression of the syndrome to infarction or sudden death. In these patients, antiplatelet, antithrombotic, or antiplatelet and antithrombotic therapy is of utmost importance to maintain adequate coronary flow. Nonresponders to medical therapy with unstable angina have a high prevalence of eccentric and multiple coronary stenoses with a high incidence of thrombi. The best responders to calcium antagonist therapy are patients with concentric coronary stenoses. In summary, calcium antagonists are highly effective in reducing ischemic episodes in patients with Prinzmetal's angina and effective for therapy for unstable angina when used in conjunction with other forms of medical treatment aimed at the processes of platelet activation and thrombus formation.

Asymptomatic myocardial ischemia likely results from an imbalance between myocardial oxygen supply and demand. Although changes in coronary vasomotor tone probably are important in the genesis of asymptomatic ischemia, heart rate increases also play a critical role. Consequently, all three classes of antianginal agents, nitrates, beta-blockers, and calcium entry blockers, have been shown efficacious as monotherapy for silent ischemia. Comparative studies have demonstrated that agents or combination therapies that control heart rate increases during normal activities are superior to regimens that increase average heart rate. Consideration of the side-effect profile of any therapy for asymptomatic patients also is important. The ideal therapy would be with one drug that reduced coronary vasomotor tone and myocardial oxygen demand during normal activities and had no adverse effects. Currently, the calcium entry blockers, diltiazem and verapamil, most closely approximate this ideal. It has yet to be proven, however, that the treatment of asymptomatic myocardial ischemia improves the prognosis of patients with coronary artery disease, and the risk-benefit ratio of pharmacological therapy is not established.

The calcium channel blockers are useful in treating many cardiovascular disorders. Due to their anti-ischemic and spasmolytic properties, the cardioprotective effects of these agents have been studied in the setting of acute myocardial infarction. This paper will review this application with respect to limitation of infarct size, reduction of mortality, and incident morbidity rates. Of the agents currently available for clinical use, nifedipine has been studied most extensively. This agent shows no beneficial effects and its use can, in fact, be harmful in this setting. Of the few trials that have been conducted with verapamil, none have shown a preventive effect on death, reinfarction, or postinfarction angina. Both verapamil and diltiazem might limit infarct size although further confirmation is required. At the present time, diltiazem is the only agent shown to have short- and long-term benefits on clinical outcome in patients with acute myocardial infarction. The success of prophylactic diltiazem is, however, critically dependent on proper patient selection. In particular, those patients with non-Q wave infarction, normal left ventricular function, or both can be expected to derive the greatest benefit in terms of reduced mortality and incident morbidity.

The calcium entry-blocking drugs produce effects on the coronary vasculature that might be expected to exert anti-ischemia activity. Although these agents cause little vasodilation of the epicardial coronary arteries during basal conditions, they block vasoconstriction that can increase stenosis severity during isometric exercise and interrupt coronary artery spasm in patients with variant angina. Administration of the calcium blockers causes transient vasodilation of the coronary resistance vessels, followed by decreased responsiveness to a brief ischemic stimulus. This results in decreased coronary reactive hyperemia after transient coronary occlusion. By preventing excessive ischemic vasodilation of the resistance vessels, these agents can enhance perfusion of the subendocardium distal to a flow-limiting coronary stenosis. The calcium entry blockers have relatively little effect on the immature coronary collateral vessels that exist at the time of acute coronary occlusion. Diltiazem, however, has been demonstrated to increase collateral blood flow in animals in which chronic coronary occlusion has resulted in growth of moderately well-developed collateral vessels.

Calcium antagonists are potent arterial vasodilators that do not lead to relevant chronic sympathetic reflex activation and sodium and volume retention. This favorable hemodynamic profile renders them suitable for monotherapy of hypertension in which they can reduce the calcium influx-dependent functional component of elevated vascular resistance that may be enhanced by altered vascular muscle cation handling and increased intracellular free calcium concentrations. Clinical studies have proved their efficacy, safety, and good tolerability alone or in combination with other drugs in uncomplicated hypertension in which they are particularly effective in older, low renin, and possibly, black patients. These properties and their efficacy in the treatment of severe and accelerated hypertension or hypertensive emergencies make them a valuable addition to already available drug therapy.

The calcium ion is recognized as having a ubiquitous role in a wide range of physiological responses. The calcium entry blockers have assumed a greater role than first thought possible in the management of cardiovascular disorders. As a group, they have multiple effects and can be tailored to meet specific needs. The drugs are well tolerated, thus making them useful for chronic administration. The efficacy of the calcium entry blockers can be enhanced when combined with other therapies such as beta-adrenoceptor antagonists and inhibitors of angiotensin converting enzyme as applied to patients with hypertension, angina pectoris, or both. The range of indications and potential uses of the calcium entry blockers demands an understanding of the role of the slow inward current in cardiac and vascular smooth muscle. This review focuses on the pharmacological actions of the calcium entry blockers and relates these events to their clinical applications in an effort to achieve an understanding of their multiple therapeutic uses.

Left ventricular hypertrophy (LVH) is a structural adaptation of the heart and is a response to increased hemodynamic and metabolic demands, which are most commonly caused by systemic hypertension. LVH induced by hypertension is associated with reduced myocardial compliance, structural alterations, and changes in coronary perfusion. Calcium entry blockers have caused LVH regression both in experimental studies and in clinical trials. Although their efficacy as antihypertensive agents is primarily due to their vasodilating properties, the mechanisms by which calcium entry blockers accomplish LVH regression are complex and include various hemodynamic and neurohumoral factors. Calcium entry blockade has decreased LVH with no apparent deterioration of left ventricular function. Because LVH is a major risk factor for sudden cardiac death and other cardiac morbidities, it is possible that the regression of LVH can improve the prognosis in hypertensive patients.

Left ventricular hypertrophy (LVH) is a common sequela of long-standing essential hypertension. LVH cannot be considered, however, an adaptive process only serving to normalize wall stress but can be considered one that significantly increases the risk of sudden death, myocardial ischemia, congestive heart failure, and other cardiovascular diseases. Patients with LVH exhibit impaired ventricular filling, ventricular arrhythmias, and myocardial ischemia even in the absence of coronary artery disease. LVH can be prevented or reversed by a variety of antihypertensive agents including calcium channel blockers and angiotensin converting enzyme inhibitors. Calcium channel blockers, more than angiotensin converting enzyme (ACE) inhibitors, suppress ectopic impulse generation, improve ventricular compliance, and alleviate myocardial ischemia while preserving or improving the contractile state. In contrast, ACE inhibitors can be particularly useful in patients with LVH and diminished ventricular contractility and in preventing chamber dilatation after myocardial infarct. These favorable cardiovascular effects of both calcium channel blockers and ACE inhibitors are a reason for optimism that carefully tailored therapy will ultimately diminish the well-documented risk of cardiovascular morbidity and mortality associated with LVH.