The most frequent adverse effects include: Decreases in heart rate, contractility, and AV node conduction. Bronchoconstriction, due to beta-2 receptor blockade, can be induced by nonselective agents and high doses of cardioselective agents. As a result, many clinicians have assumed that chronic obstructive pulmonary disease (COPD) or asthma is a contraindication to beta blocker therapy. However, beta blockers are safe and effective in patients with mild COPD/asthma who are not taking a beta-2 adrenergic agonist. Furthermore, some patients carry a diagnosis of COPD that has not been confirmed. The data supporting these observations primarily come from studies of patients with an acute coronary syndrome and are discussed elsewhere. (See "Beta blockers in acute myocardial infarction", section on COPD/asthma). Worsening of symptoms of peripheral arterial disease or Raynaud phenomenon. However, there appears to be no adverse effect on mild to moderate claudication symptoms when beta-1 selective blockers are used. (See "Medical management of claudication", section on Hypertension, and see "Clinical manifestations and diagnosis of the Raynaud phenomenon"). Fatigue may be due to the reduction in cardiac output or to direct effects on the central nervous system. Central side effects that can occur include nightmares, insomnia, and hallucinations. Although depression is often mentioned as a side effect of beta blockers, this association was not seen in randomized trials. Central side effects may be more common in the elderly. Erectile dysfunction is often a problem [16].
EFFICACY OF BETA BLOCKERS IN STABLE ANGINA — All of the beta blockers, regardless of pharmacologic properties, appear to be equally effective in the treatment of stable angina pectoris. They improve exercise capacity, reduce exercise-induced ST depression, decrease the frequency of anginal episodes, and diminish the requirement for sublingual nitroglycerin. No randomized trials have examined the effect of beta blockers on survival in patients with stable angina. (See "Improved survival in high-risk patients" below).
Nonselective agents — Propranolol was the first beta blocker introduced clinically. It is a nonselective agent that has been used extensively for stable angina.
Evidenced of long-term efficacy was provided in a study of 63 patients with severe stable angina who were treated with propranolol for five to eight years [17]. A 50 percent or greater reduction in anginal episodes occurred in 84 percent of patients (show figure 1). Those with a lesser or no response had a four-fold increase in mortality. There was no evidence of tachyphylaxis to beta blockade.
Drug dose is an important determinant of response in patients with angina. Daily doses of 160 and 320 mg of propranolol, but not 80 mg, appear to be required [18].
Cardioselective drugs — As noted above, cardioselective beta blockers (the most commonly used being atenolol and metoprolol) offer the potential advantage of not interfering with bronchodilatation or peripheral vasodilatation. The clinical applicability of this effect is uncertain since cardioselectivity may be lost at the high doses needed to treat angina [14]. Nevertheless, cardioselective drugs are used in most patients with stable angina.
Atenolol, metoprolol, and nadolol are as effective as propranolol (and more effective than placebo) and nitroglycerin in reducing anginal attacks and increasing exercise capacity [19-21]. In addition, once daily dosing of atenolol is as effective (and more convenient) as twice daily dosing [20]. Metoprolol is available in a short acting form (metoprolol tartrate) for twice daily dosing and in a long acting form (metoprolol succinate) for once daily dosing.
The efficacy of metoprolol was demonstrated in the International Multicenter Angina Exercise (IMAGE) study in which 280 patients with chronic stable angina were randomly assigned to six weeks therapy with long-acting preparations of metoprolol (200 mg daily) or nifedipine (20 mg twice daily) [22]. Metoprolol reduced the frequency of angina and increased the mean exercise time to 1-mm ST segment depression. Furthermore, the increase in exercise time was significantly greater than that seen with nifedipine (70 versus 43 seconds).
Use of an appropriate dose is important. One report compared 25, 50, 100, and 200 mg once daily dosing of atenolol with placebo in patients with angina [23]. All doses were more effective than placebo in reducing angina and the need for sublingual nitroglycerin; however, only the 100 and 200 mg doses increased exercise capacity (show figure 2).
Agents with intrinsic sympathomimetic activity — Pindolol and acebutolol are as effective in treating angina as other beta blockers but have the potential advantage of causing less depression of cardiac function. One report, for example, compared the efficacy of propranolol and pindolol in 52 patients with stable angina [24]. Both agents were equally effective in relieving angina, but pindolol caused less pronounced resting bradycardia or impairment in left ventricular function. In another study, pindolol (when compared to propranolol) was associated with a higher resting heart rate and, at low levels of exercise, a higher heart rate, cardiac output, oxygen consumption was higher in the pindolol group [15]. These differences disappeared at higher rates of exercise.
Despite some potential benefits, these drugs are rarely used in the treatment of stable angina except possibly in patients with underlying resting bradycardia. They may not decrease heart rate and blood pressure at rest and should not be given to patients with a prior myocardial infarction or heart failure in whom beta blockade improves survival.
Agents with alpha blocking activity — Carvedilol is a nonselective beta blocker that has vasodilating properties as a result of selective alpha-1 antagonism. One study of 122 patients with chronic stable angina found that carvedilol, at doses of 25 or 50 mg twice daily, was superior to placebo, significantly increasing the time to angina and to one mm ST segment depression during exercise testing [25]. There was no difference in the frequency of side effects when compared to placebo. In another randomized trial, carvedilol was at least as effective as verapamil [26].
Data are more limited with labetalol but demonstrate significant reductions in heart rate and angina frequency and an increase in exercise time [27].
Improved survival in high-risk patients — In addition to control of angina symptoms, beta blockers improve survival in certain subgroups of patients with stable coronary disease: Patients who have had a myocardial infarction. (See "Beta blockers in acute myocardial infarction"). Patients with systolic heart failure. (See "Use of beta blockers in heart failure due to systolic dysfunction").
In contrast, beta blockers have never been shown to improve survival or reduce the incidence of myocardial infarction in patients with chronic stable angina in the absence of myocardial infarction or heart failure.