Potential causes for the development of acute myocardial ischemia include extracardiac factors, rapid progression of atherosclerosis, dynamic coronary artery thrombosis, platelet activation in diseased vessels, abnormal constriction of a coronary artery, and abnormal arachidonic acid metabolism. It is entirely possible that all or many of these potential causes may be occurring in the individual patient.

Ambulatory electrocardiographic (ECG) monitoring of ischemia in patients with coronary artery disease (CAD) provides a new technique for the assessment of ischemic activity and the evaluation of therapies outside of the hospital. Numerous studies have demonstrated that the majority of patients with CAD have episodes of symptomatic and asymptomatic ST segment depression during routine daily activities. Rubidium-82 positron-emission tomographic studies have provided evidence for decreased myocardial perfusion during these episodes of ST segment depression. The prognostic importance of asymptomatic ischemia has been shown in patients with unstable angina to be a marker for early unfavorable cardiac events. Preliminary results suggest a poorer outcome for those patients with chronic stable angina who show episodes of ischemia as well. Ambulatory monitoring studies suggest that total ischemic activity may be underestimated by conventional testing. Whether all ischemic activity detected by ambulatory monitoring requires treatment awaits further study.

Because vasodilator therapy has become an established approach to the treatment of patients with severe chronic heart failure, there has been increasing interest in the use of the calcium channel-blocking drugs in the management of this disorder. This approach has particular appeal because approximately 60% of patients with heart failure have severe left ventricular dysfunction associated with coronary artery disease, and left ventricular systolic and diastolic performance in these patients may improve after interventions directed at improving myocardial blood flow. Unfortunately, all available calcium channel-blocking drugs possess potent negative inotropic effects; these are normally offset in patients without heart failure by activation of the sympathetic nervous system. Patients with severe left ventricular dysfunction, however, are exquisitely dependent on the transmembrane transport of calcium for maintenance of contractile function and show marked attenuation of adrenergic reflexes, which can no longer serve a homeostatic support function; hence, such patients are likely to experience notable cardiodepressant effects after calcium-channel blockade. In clinical trials, although some patients with severe chronic heart failure have been reported to benefit from short-term calcium-channel blockade, the hemodynamic benefits seen are modest compared with those from conventional vasodilator drugs, and little long-term improvement has been observed in randomized, double-blind trials. In addition, 10% to 40% of patients who receive short- and long-term therapy with verapamil, nifedipine, and diltiazem show evidence of serious hemodynamic or clinical deterioration.(ABSTRACT TRUNCATED AT 250 WORDS)

The hemodynamic properties of the calcium entry-blocking agents result principally from the inhibition of transcellular calcium flux in the myocardium and in vascular smooth muscle. The composite effect(s) of these compounds on cardiovascular function derive from a complex interplay between their direct (myocardial depression) and indirect (afterload reduction by peripheral arterial vasodilation, reflex sympathetic stimulation) actions. While qualitatively similar, the currently available agents (diltiazem, nifedipine, verapamil) differ considerably in relative negative inotropic, vasodilator, and reflex properties. The hemodynamic actions of a particular calcium blocker also critically depend on the baseline cardiocirculatory status. Current information regarding these issues from basic and clinical investigations is reviewed.

The interpretation of a change in coronary flow that accompanies administration of a calcium-entry blocker or other pharmacologic agent remains complicated by the variety of factors potentially altered by the agent that can themselves affect flow. These factors are reviewed in the context of steady-state coronary pressure-flow relationships, emphasizing the complexities induced by coronary artery disease. Limitations of currently available approaches for the measurement of coronary reserve, examination of flow heterogeneity, and the calculation of coronary vascular resistance are also addressed. Calcium entry-blocking agents have a number of hemodynamic effects that are likely to augment coronary flow favorably. However, parodoxical and potentially deleterious effects on local flow also seem possible in selected situations.

This review focuses on the potential use of the calcium antagonists diltiazem, nifedipine, and verapamil in the treatment of hypertensive emergencies. Prompt reduction of blood pressure can be achieved after either intravenous administration of diltiazem or verapamil or sublingual/oral administration of nifedipine. Effects on cardiac hemodynamics with these drugs are variable. Effects on the kidney are predictable; administration is associated with prompt diuresis and natriuresis. Effects on the cerebral circulation are more complex; although cerebral vasodilation may occur, the potential exists for uneven cerebral perfusion and an increase in intracranial pressure. Precipitous decreases in mean arterial pressure may decrease cerebral blood flow below the lower limit of autoregulation, inducing cerebral ischemia. Because of the complex interaction of these drugs on the heart, kidney, and brain, short-term therapy should be instituted only in the hospital setting, with appropriate supervision and hemodynamic monitoring.

This review compares the calcium antagonists with diuretics in the management of mild-to-moderate essential hypertension. The antihypertensive efficacy of calcium antagonists appears comparable to that of oral diuretics such as hydrochlorothiazide when used as monotherapy. Peripheral vascular dilation appears to be the principal mechanism of the long-term blood pressure-lowering effects of both calcium antagonists and diuretics. Peripheral vasoconstrictor responses to cardioreflex-mediated sympathetic nervous system activation is attenuated by calcium antagonists but not by diuretics. Long-term calcium antagonist therapy is generally not associated with reflex activation of the sympathetic nervous system or of the renin-angiotensin-aldosterone axis, whereas diuretic therapy results in considerable activation of the renin-angiotensin-aldosterone system. Calcium antagonists appear to have a greater beneficial effect than diuretics with respect to maintenance of renal blood flow and glomerular filtration rate. Calcium antagonists, because of their effects on coronary blood flow and heart rate-blood pressure product, offer advantages over diuretics in the treatment of hypertensive patients with concomitant ischemic heart disease. Metabolic abnormalities associated with diuretic antihypertensive therapy, such as hypokalemia, hypercalcemia, hyperuricemia, lipid changes, and hyperglycemia, are generally not observed with calcium antagonists. Many of these deleterious metabolic changes observed with diuretic therapy may be minimized by the use of smaller doses of these agents than have generally been employed in the past. Diuretics are less expensive and require less frequent dosing than calcium antagonists. Thus, they continue to be preferable first-line antihypertensive agents in many patients with mild-to-moderate hypertension.

The rationale for evaluating the efficacy and safety of calcium entry-blocking drugs to prevent secondary complications in patients after myocardial infarction is presented. The data currently available from postinfarction trials involving verapamil, nifedipine, and diltiazem are critically reviewed, and a comparison of the findings from three major trials of calcium entry-blocking drugs is provided.

Sustained-release diltiazem (D-SR) and sustained-release verapamil (V-SR) when given twice a day have been successfully used to treat both essential hypertension and angina pectoris. Review of available studies indicates that 120 to 180 mg D-SR twice a day and 240 mg V-SR once or twice a day can lower diastolic pressure in 40% to 80% of patients with essential hypertension and that the drugs may be especially useful in patients with low-renin hypertension such as elderly and black populations. D-SR and V-SR prolong treadmill capacity and reduce frequency of angina in patients with stable effort angina. Improvement is mediated primarily by a reduction in resting and submaximal exercise heart rate. Biopharmaceutics of D-SR and V-SR feature a prolonged apparent plasma half-life and reduced peak-to-trough plasma concentration ratios during steady-state dosing.

Cardiovascular disease is the major cause of death in American adults. The chief form of cardiovascular disease is coronary heart disease (CHD). Prevention of CHD depends on the identification of risk factors in asymptomatic individuals. The American Heart Association recommends that all adults be examined periodically for the presence of silent cardiovascular disease and coronary risk factors. The major risk factors for CHD are smoking, high blood pressure, and high blood cholesterol. Additional factors associated with CHD are high blood triglycerides, reduced levels of high-density lipoproteins, diabetes mellitus, obesity, sedentary lifestyle, and certain behavioral characteristics. Available data suggest that the predominance of CHD among Americans can be attributed to these risk factors, and increasing evidence indicates that appropriate modification of these factors will markedly reduce coronary risk. The purpose of this report is to identify the risk factors, indicate their relation to coronary disease, and recommend an approach to their detection in adults during periodic health examinations.

This article reviews controlled trials of medical therapy for coronary artery spasm. The calcium antagonists, either alone or in combination with long-acting nitrates, are effective therapy for patients with coronary artery spasm. These drugs definitely decrease angina and the frequency of ischemic ST shifts recorded during continuous electrocardiographic monitoring. Therapy is still relatively nonspecific, however, since the mechanism(s) that lead to spasm remain unknown. Interestingly, the initial response to therapy is similar regardless of the presence or absence of severe coronary artery disease accompanying spasm. Drugs that block adrenergic or serotonin receptors or that alter platelet aggregability or prostaglandin production have been ineffective in relieving angina or decreasing the frequency of ischemic ST shifts. Patients with resting angina syndromes are a heterogeneous group; many do not have coronary spasm since other mechanisms also precipitate ischemic episodes at rest. Prevention of angina or ischemic ST shifts may not necessarily prevent acute myocardial infarction and sudden cardiac death. Both initial and long-term therapies should be individualized according to a detailed clinical and angiographic assessments of each patient.

Whether or not the kidney is involved in the genesis of hypertension in an individual patient, it becomes a major determinant of the response to antihypertensive therapy once a treatment strategy is adopted. The major mechanisms through which the kidney influences blood pressure are renin release and sodium retention, either together or separately, but additional mechanisms may also contribute. When sodium intake is restricted or a diuretic is used, the reactive increase in plasma renin activity makes a substantial contribution to limiting the decrease in blood pressure. When vasodilators or agents that block the sympathetic nervous system are used, sodium retention plays an important role. Among newer agents, the effectiveness of calcium-channel blockers, converting-enzyme inhibitors, and perhaps dopamine analogs reflects, for reasons that differ from one class of agent to another, a special action on the kidney that limits the reactive renal response to the reduction in blood pressure. Treatment strategies that address the problem of the renal response are more likely to be effective than approaches that avoid or ignore it.

The increasing use of the calcium-entry blockers has led to an enhanced potential for drug interactions with a variety of different drugs. Interactions with cardiovascular agents are of great concern because of the consequences of synergistic negative dromotropism or inotropism. We therefore assessed the concomitant use of calcium-entry blockers and cardiac glycosides, beta-blockers, antiarrhythmic agents, and other chemical types of calcium-entry blockers from a standpoint of clinical relevance. We also evaluated reported drug interactions with H2-receptor antagonists, anticonvulsants, lithium carbonate, general anesthetics, cytostatic drugs, rifampin, and sulfinpyrazone with regard to clinical implications, along with the modification of calcium-entry blocker dose for concurrent social drug use, such as cigarette smoking and ethanol intake. Although a myriad of potential drug interactions exists for these agents, combination therapy is still a reasonable alternative if doses are adjusted appropriately.

The use of calcium-channel blockers to treat essential hypertension is increasing, and in the United States several new drug applications for this indication are under consideration by the Food and Drug Administration. Although the ability of the calcium-channel blockers to lower blood pressure has been established, their efficacy and safety in relation to current therapy require further clarification. This article reviews studies in which calcium-channel blockers and beta-blockers have been compared, including seven with verapamil, four with nifedipine and nitrendipine and two with diltiazem. These studies indicate that the two classes of agents produce similar antihypertensive effects and are associated with a comparable incidence of adverse reactions. In addition, the preliminary findings of a multicenter trial in which 50 subjects with mild or moderate hypertension were treated with diltiazem (60 to 180 mg bid) or propranolol (80 to 240 mg bid) for 4 to 6 months are presented. Both medications significantly lowered blood pressure (from 148 +/- 17/101 +/- 5 to 133 +/- 25/88 +/- 9 mm Hg on diltiazem and from 154 +/- 22/104 +/- 6 to 146 +/- 23/91 +/- 11 mm Hg on propranolol). Fifty-nine percent of the patients on diltiazem and 40% of those on propranolol achieved the treatment goal of a supine diastolic blood pressure under 90 mm Hg together with minimum 10 mm Hg reduction. In a similar study, exercise blood pressure and exercise capacity were also examined, with the most important finding being a reduction in maximal oxygen consumption and exercise duration on propranolol without a significant change on diltiazem.(ABSTRACT TRUNCATED AT 250 WORDS)

Despite the proven effectiveness of calcium-channel and beta-blockers as monotherapy in patients with chronic stable angina pectoris, some patients remain symptomatic. Such patients have been shown to benefit from the application of combined treatment with beta-blockers and nitrates or, more recently, beta-blockers plus calcium-channel blockers. There have been few studies evaluating the long-term effectiveness of the combination of calcium blockers and nitrates, but available evidence suggests that symptoms of excessive vasodilation such as orthostatic hypotension may limit the usefulness of this approach. Recently, the additional benefit of adding a calcium blocker to therapy of patients with chronic stable angina who remain symptomatic on beta-blockers and nitrates has been demonstrated. Side effects related to vasodilation were the major limiting feature of this triple therapy. Thus, a triple therapy regimen may be of value in selected patients who do not respond to the combination of beta-blockers and nitrates or beta-blockers plus calcium blockers. However, caution must be exercised in patients with reduced left ventricular function and conduction system disease, since such patients have been excluded from the reported studies.

Recent clinical observations have extended our classification of unstable angina to include new groups of patients now recognized at high risk of subsequent infarction. Patients with non-Q wave myocardial infarction and those with early postinfarction ischemia share a prognosis similar to that of patients with crescendo angina or with acute coronary insufficiency. Unstable angina after coronary angioplasty and after coronary artery surgery also form particular subsets of patients. Pathologic, coronary angiographic, and coronary angioscopic studies have extended the role of the obstructive atherosclerotic plaque to include a dynamic component to explain the unstable state. Recognized dynamic components are rapid progression of the disease, active vasomotion, plaque fissuring, and thrombus formation. Activation of platelets and blood coagulation factors may play a major role in triggering the syndrome. Our therapeutic approach has also become more specific for the correction of the cause of the disease. Our understanding of unstable angina now appears to be at a turning point, and a pathophysiologic basis for its clinical classification and for its management may soon be available.

In recent years therapy with the calcium entry-blocking drugs nifedipine, verapamil, and diltiazem has made a major impact on the treatment of cardiovascular disease. Although all three of these drugs are approved for the treatment of angina pectoris, some are effective in treating supraventricular tachyarrhythmias and all appear to be effective in the treatment of mild-to-moderate hypertension. Reports of their therapeutic potential, however, are not confined to the cardiovascular system, which reflects the ubiquity of calcium ions as stimulus-effect couplers in a wide variety of organ systems. Although chemically heterogeneous, all three drugs produce similar negative inotropic effects in the myocardium and similar relaxant effects in vascular smooth muscle. From a review of the excitation-contraction coupling process in cardiac and smooth muscle it is apparent that "calcium blockade" could occur at any one of several loci. Our present understanding is that the effect of nifedipine, verapamil, and diltiazem is confined to an inhibitory one on channel-mediated membrane calcium influx. There is, in fact, a close parallel between their ability to decrease slow-channel calcium influx in the myocardium and the negative inotropic action of the drugs. Similarly, in vascular smooth muscle their ability to inhibit voltage- or receptor-mediated calcium influx parallels their vasorelaxant properties. With the use of radiolabeled ligands, particularly of the dihydropyridines (nifedipine, nitrendipine, nicardipine, nisoldipine) it has been shown that the drugs show high-affinity stereospecific binding to vascular smooth muscle channels in the same concentration range as their relaxant properties. In contrast, it was originally thought that myocardial binding was of a lower affinity and correlated poorly with the negative inotropic effect. More recent data, however, have cast some doubt on the validity of these observations. Attempts to define specific drug receptors are incomplete at this time. It appears that the dihydropyridine receptor is a 30-60 K D peptide subunit of the calcium channel. Distinct receptors for verapamil and diltiazem are poorly defined, but appear to be allosterically related to the dihydropyridine receptor. By their interactions with the calcium channel, the calcium entry-blocking drugs modulate excitation-contraction coupling, which produces their negative inotropic and vasorelaxant effects. They also interact with other slow channel-dependent functions in the specialized conducting tissues of the heart to slow the spontaneous sinus rate and decrease atrioventricular conduction.(ABSTRACT TRUNCATED AT 400 WORDS)

Patients with chronic heart failure have a high incidence of both complex ventricular arrhythmias and sudden death. Therefore administration of antiarrhythmic agents to these patients to prevent lethal ventricular arrhythmias is theoretically appealing. However, at present there are no prospective randomized studies supporting this approach, whereas retrospective studies have yielded conflicting results. Moreover, the use of antiarrhythmic agents in patients with heart failure has two potentially serious side effects: worsening of ventricular pump function and exacerbation of ventricular arrhythmias. Such information suggests that the use of antiarrhythmic agents to treat patients with heart failure who do not have symptomatic ventricular arrhythmias is currently not indicated.