In patients with relatively low blood pressure, dihydropyridines can cause further deleterious lowering of pressure. Verapamil and diltiazem appear to produce less hypotension and may be better tolerated in these circumstances. In patients with a history of atrial tachycardia, flutter, and fibrillation, verapamil and diltiazem provide a distinct advantage because of their antiarrhythmic effects. In the patient receiving digitalis, verapamil should be used with caution, because it may increase digoxin blood levels through a pharmacokinetic interaction. Although increases in digoxin blood level have also been demonstrated with diltiazem and nifedipine, such interactions are less consistent than with verapamil.
In patients with unstable angina, immediate-release short-acting calcium channel blockers can increase the risk of adverse cardiac events and therefore are contraindicated (see Toxicity, above). However, in patients with non–Q-wave myocardial infarction, diltiazem can decrease the frequency of postinfarction angina and may be used.
Although they are not vasodilators (with the exception of carvedilol and nebivolol), β-blocking drugs (see Chapter 10) are extremely useful in the management of effort angina and are considered first-line drugs in chronic effort angina. The beneficial effects of β-blocking agents are related to their hemodynamic effects— decreased heart rate, blood pressure, and contractility—which decrease myocardial oxygen requirements at rest and during exercise. Lower heart rate is also associated with an increase in diastolic perfusion time that may increase coronary perfusion. However, reduction of heart rate and blood pressure, and consequently decreased myocardial oxygen consumption, appear to be the most important mechanisms for relief of angina and improved exercise tolerance. Beta blockers may also be valuable in treating silent or ambulatory ischemia. Because this condition causes no pain, it is usually detected by the appearance of typical electrocardiographic signs of ischemia. The total amount of “ischemic time” per day is reduced by long-term therapy with a β blocker. Beta-blocking agents decrease mortality of patients with heart failure or recent myocardial infarction and improve survival and prevent stroke in patients with hypertension. Randomized trials in patients with stable angina have shown better outcome and symptomatic improvement with β blockers compared with calcium channel blockers.
Undesirable effects of β-blocking agents in angina include an increase in end-diastolic volume and an increase in ejection time, both of which tend to increase myocardial oxygen requirement. These deleterious effects of β-blocking agents can be balanced by the concomitant use of nitrates as described below.
Contraindications to the use of β blockers are asthma and other bronchospastic conditions, severe bradycardia, atrioventricular blockade, bradycardia-tachycardia syndrome, and severe unstable left ventricular failure. Potential complications include fatigue, impaired exercise tolerance, insomnia, unpleasant dreams, worsening of claudication, and erectile dysfunction.
Because of the high prevalence of angina, new drugs are actively sought for its treatment. Some of the drugs or drug groups currently under investigation are listed in Table 12–6.
Ranolazine appears to act by reducing a late sodium current (INa) that facilitates calcium entry via the sodium-calcium exchanger (see Chapter 13). The reduction in intracellular calcium concentration that results from ranolazine reduces diastolic tension, cardiac contractility, and work. Ranolazine is approved for use in angina in the USA. Several studies demonstrate its effectiveness in stable angina, but it does not reduce the incidence of death in acute coronary syndromes. Ranolazine prolongs the QT interval in patients with coronary artery disease (but shortens it in patients with long QT syndrome, LQT3). It has not been associated with torsades de pointes arrhythmia and may inhibit the metabolism of digoxin and simvastatin.