Treatment Decisions in Cardiovascular Disease: Focus on Beta Blockers in Seniors

Coronary heart disease (CHD) remains the leading killer of both men and women in the United States.¹ The spectrum of CHD encompasses asymptomatic subclinical disease, chronic stable angina, unstable angina, and acute myocardial infarction (MI).¹ CHD prevalence increases with age.¹ After age 40, lifetime risk for symptomatic CHD is 49% in men and 32% in women.² In developed countries, the burden of heart disease is substantial and greatest among older patients, despite a decline in overall cardiovascular (CV) mortality in recent decades.3,4 The mean age of experiencing a first MI is 64.5 years in men and 70.⁴ years in women.² More than 80% of deaths attributed to CHD occur in seniors (ie, persons aged ≥65 years).¹ In addition, 37% of recognized acute MIs occur in persons >75 years of age.¹ Of interest, in the context of the aging population, the increasing prevalence of CHD and heart failure (HF) with age is attributed, to a large extent, to better survival of patients with acute cardiac events.²

With respect to CHD, beta blockers (BBs) have been demonstrated to be beneficial in reducing CV events andmortality in patients post-MI.¹ Even more remarkable are the long-term benefits of BBs in patients with chronic HF and depressed left ventricular function.1 BBs decrease myocardial oxygen demand in addition to improving coronary blood flow.¹ In addition, these agents are essential in the care of seniors with chronic angina.¹ Although BBs have been used in several large outcome trials in patients with hypertension, most of these trials have involved the use of a thiazide diuretic as the primary agent and a BB as an add-on agent for additional blood pressure (BP) lowering.⁵ Based on current evidence, BBs are considered firstline agents only to treat specific compelling indications (eg, post-MI, CHD) and to be additional therapy for other compelling indications (eg, HF, diabetes).⁵ Readers who wish learnmore about the use of BBs for hypertension are encouraged to review the online version of the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure.⁶ 

Associated with survival of acute cardiac events and the burden of CHD are concerns regarding medication selection, appropriate dosing, monitoring for side effects, and essential ongoing monitoring for continued effectiveness and safety as patients age. This column focuses on BBs, also called betaadrenergic antagonists, and select nuances associated with BB therapy, particularly in the senior patient population.

Although an adrenergic-receptor blocker does bind to a receptor, it does not trigger receptor-mediated intracellular responses.⁷ This agent acts by reversibly or irreversibly attaching to the receptor, thereby preventing activation of the receptor by endogenous catecholamines such as epinephrine and norepinephrine.⁷ An adrenergic-receptor blocker is classified according to its relative affinity for alpha or beta receptors in the nervous system.⁷ The terms alpha-adrenergic blocker and beta-adrenergic blocker are often shortened to alpha blocker and beta blocker, respectively.

Selection of a BB is based on its action, therapeutic uses (Table), and adverse effects. Key differences among BB categories can help NPs prescribe these agents appropriately and monitor for their safe and effective use.

Nonselective Beta Blockers—Agents in this category (eg, propranolol, nadolol, timolol) act at both beta1 and beta2 receptors. Propranolol, the prototype BB, is associated with central nervous system adverse effects such as cognitive dysfunction, confusion, emotional lability, depression, and dizziness.⁸ Nadolol has a long duration of action, and timolol, available as a systemic agent and used to treat CV disease, is also used topically to treat open-angle glaucoma.

Selective Beta1 Blockers—These agents (eg, atenolol, metoprolol), also known as cardioselective BBs, were developed to remove the beta2 effect of bronchoconstriction, which is undesirable in patients with asthma.⁷ Of note, these agents block beta1 receptors at low doses; at higher doses, they eventually lose that cardioselectivity and block beta2 receptors as well.⁸ Nebivolol, unlike other BBs, produces a nitric oxide-dependent vasodilation resulting in a reduction of systemic vascular resistance.⁸ In addition, BB-associated coldness of the extremities is less common with cardioselective BBs, which may be useful in diabetic hypertensive patients treated with insulin or oral hypoglycemic agents.⁷

Beta Blockers with Partial Agonist Activity—In addition to blocking both beta1 and beta2 receptors, these agents (eg, acebutolol, pindolol) can weakly stimulate beta1 and beta2 receptors. This stimulatory or agonist activity is referred to as intrinsic sympathomimetic activity (ISA). Because of these opposing activities, BBs in this category, compared with other BBs without ISA, have a lesser effect on cardiac rate and cardiac output.7

Mixed Alpha/Beta Blockers—Blockers of alpha1, beta1, and beta2 receptors (eg, (labetalol, carvedilol) produce vasodilation via a mechanism differing from that of nebivolol. These agents are useful in patients in whom increased peripheral vascular resistance is undesirable (eg, seniors).⁷ Labetalol may be used as an alternative to methyldopa in pregnancy (pregnancy category C; adverse effects include fetal bradycardia, hypoglycemia, and possible fetal growth restriction).^7,9 Carvedilol is helpful in HF because of its antioxidant effects and ability to decrease vascular wall thickening.^7,10 Mixed alpha/beta blockers do not alter serum lipid or blood glucose levels.^7,8

Bronchoconstriction—Propranolol can cause an immediate contraction of the smooth muscle of the bronchiole, which can be so severe—that is, it can prevent air from entering the lungs—that death has been reported secondary to asphyxiation in patients with asthma who have received this agent inadvertently.⁷ In this regard, propranolol is contraindicated in patients with asthma or COPD.^8,11 Although cardioselective BBs have relatively little effect on pulmonary function, these agents must be carefully monitored to avoid compromising respiratory activity, especially in light of their loss of selectivity at higher doses.

Dysrhythmia—Cardiac dysrhythmias may be precipitated if BBs are abruptly discontinued (long-term treatment leads to up-regulation of the beta receptor). A US Boxed Warning indicates that BB therapy should not be withdrawn abruptly, particularly in patients with coronary artery disease but, rather, should be gradually tapered—for example, over 1 week—to avoid acute tachycardia, hypertension, and/or ischemia.^7,8

Sexual Impairment—Although BBs do not affect normal ejaculation, impaired sexual activity (eg, impotence) has been reported by men who use BBs. The mechanism underlying this adverse effect is still not clear.⁷

Metabolic Disturbances—Glycogenolysis and decreased glucagon secretion occur secondary to beta blockade; as a result, some patients may experience hypoglycemia (fasting).^7,8 Hyperglycemia and hyperlipidemia have been reported.^7,8 Patients with diabetes who are receiving insulin or oral hypoglycemic agents and patients with asthma who use insulin may be treated preferentially with cardioselective BBs.⁷

Orthostatic hypotension (OH), also known as postural hypotension, is a sudden and excessive drop in BP—defined as a systolic BP decrease of >20 mm Hg or a diastolic BP decrease of >10 mm Hg—when a person changes from a supine position to a standing position.¹² OH may be associated with dizziness, light-headedness, faintness, confusion, and/or blurred vision within seconds of standing.⁹ Although BBs lower BP, they do not induce OH, which occurs with alpha blockade.⁷

Mixed alpha/beta blockers, which are venous dilating, do increase the risk for OH and dizziness, especially in seniors, particularly upon initiation of therapy.^5,7 In patients receiving mixed alpha/beta blockers who need an additional BP-lowering agent, antihypertensives such as diuretics, angiotensin-converting enzyme inhibitors (eg, lisinopril, enalapril), and angiotensin receptor blockers (eg, losartan, valsartan) are initiated at low doses. In addition to seniors, who are more sensitive to volume depletion and sympathetic inhibition, an increase in OH risk may occur in patients with diabetes and in those with severe volume depletion.⁵ OH associated dizziness and fainting may lead to an increased risk for falls in seniors.

With regard to drug–disease interactions, BBs may precipitate or exacerbate depression in persons with current or past depression.^9,13 NPs must pay particular attention to seniors and to patients with comorbidities placing them at risk for depression, such as those with persistent pain. Furthermore, BBs must be administered and titrated with caution in seniors in conjunction with a review of their current medication regimen for potential drug–drug interactions. For more information, readers are referred to the Drug Interactions Checker onDrugs.com (http://www.drugs.com/drug_interactions.html). Data sources on this website include Micromedex.

Although many older adults have asymptomatic, subclinical CHD, more than 80% of deaths attributed to CHD occur in seniors. BBs are used in the treatment of the full spectrum of CHD, and understanding the nuances of these agents as they relate to treating seniors is essential for quality care of this vulnerable population.