Which mechanism of a beta blocker is responsible for the decrease in the heart rate?

Staying Calm, Cool, and Collected on the Battlefield of Sport

Beta blockers were designed primarily to improve heart function under conditions of an impaired cardiovascular system, but they also have a powerful calming effect and stabilize motor performance, which is beneficial in sports requiring precision such as golf, bowling, darts, billiards, shooting, and archery.9 In 1985, the International Olympic Committee put beta blockers on its Prohibited List. Initially, they were still permitted for medical treatment, but they were completely banned starting with 1988. They are prohibited from use only in competition for most sports, but for shooting and archery they are prohibited outside of competition as well. Details can be found on the WADA List.9

As with other PEDs, some athletes have defied the ban and suffered the consequences. Doug Barron, an American journeyman professional golfer, was the first to be banned under the PGA Tour’s antidoping policy after testing positive for beta blockers and testosterone. Bill Werbeniuk, a Canadian professional snooker and pool player, was banned for using propranolol. Perhaps, the most famous case was North Korean sport shooter Kim Jong-su, who tested positive for propranolol 3 days after winning the silver and bronze in pistol shooting at the 2008 Beijing Olympics (see the close-up at the end of this chapter).10

Beta Blockers

Because beta blockers are frequently used to treat patients with cardiovascular disease, it is important for sleep physicians to know that they can cause nightmares and/or sleep disturbance. Beta blockers can reduce nocturnal melatonin secretion. However, the mechanism by which beta blockers disturb sleep is not known. Beta blockers that have high lipid solubility (easily penetrate blood brain barrier—e.g., propanolol) and affect norepinephrine are considered more likely to be associated with nightmares. However, nightmares have also been noted with beta blockers with less lipid solubility. Beta blockers with high lipid solubility include metoprolol, propanolol, and timolol. Atenolol is an example of a beta blocker with lower lipid solubility.

Class II: β-Blockers

Class II

β-Blockers are critical to the management of many cardiac conditions, including arrhythmias. Unlike most antidysrhythmic medications, β-blockers have been shown to reduce mortality in a variety of situations, including heart failure, acute myocardial infarction, and coronary artery disease.46–49 They also decrease the rate of shocks for patients with implantable cardioverter-defibrillators and prevent degeneration of ventricular tachycardia to ventricular fibrillation.

β-Blockers may bind to β1 receptors, β2 receptors, or both. Some β-blockers also block α1 receptors. β1 Receptors are found in the cardiovascular system. β2 Receptors are noncardiac and lead to β-blocker side effects, such as pulmonary bronchospasm. α1 Receptor antagonism causes additional arteriolar vasodilation; drugs with α1 receptor blockade tend to be used more commonly for hypertension or heart failure than arrhythmias (Table 39.6).

While all β-blockers have class effects, there are slight differences in the various drugs. For example, pindolol has less of a bradycardic effect than many of the other β-blockers due to its intrinsic sympathomimetic action. As many of the beneficial cardiovascular effects seem to be observed with the β-blockers that cause the most bradycardic effects, pindolol is rarely used by cardiologists. There are also differences in the indications for the various drugs based upon clinical trial data. Carvedilol, bisoprolol, and the long-acting form of metoprolol, all oral medications, are indicated for long-term treatment of patients with heart failure in the setting of LV dysfunction.

The myriad benefits of β-blocker therapy are, for the most part, a result of blocking the effects of adrenergic stimulation.50 Adrenergic stimulation can cause a variety of negative electrophysiologic findings, including increased automaticity, triggered activity, reentrant excitation, and delayed afterdepolarizations.

Hypertension

β Blockers have long been regarded as first-line agents in the treatment of hypertension (see Chapter 23). Numerous studies have shown these agents to be safe and effective at decreasing the blood pressure equivalently to other first-line antihypertensive agents. The β blockers can be used as monotherapy to control hypertension or used in combination with other drugs, such as diuretics, to produce a more vigorous antihypertensive response. Many of the side effects associated with the use of other antihypertensives, such as Na+ and water retention or the development of tolerance, do not occur with β blockers. The effects of β blockers on blood triglycerides and glucose metabolism described previously do not preclude their use in patients with hyperlipidemia or diabetes. The only systemic β blockers not approved for use in hypertension are esmolol and sotalol. However, the first-line status of the β blockers has been questioned by several recent meta-analyses. These analyses show that there is an increased risk of stroke in patients, especially the elderly taking β blockers. Indeed, the most recent recommendations on the treatment of hypertension, JNC8, have removed β blockers from the list of the drugs of choice to treat hypertension.

Beta-blockers

Beta-blockers are very commonly prescribed as a treatment for hypertension and can decrease mortality in patients with congestive heart failure. These medications block the β1 and β2 receptors with different selectivities, antagonize the α1 receptor, and have some vasodilating properties. Beta-blockers can have adverse effects on the central nervous system, such as insomnia, fatigue, and nightmares. A review of the literature concluded that the incidence of central nervous system side effects such as nightmares, sleep disturbances, and hallucinations is low, but more commonly observed with the lipophilic beta-blockers such as propanolol or pindolol compared to the hydrophilic beta-blockers such as atenolol, due to their pharmacokinetic properties. Pharmacological studies have shown that lipophilic beta-blockers are more prone to readily cross the blood–brain barrier than their hydrophilic counterparts, explaining a higher incidence of central nervous system adverse effects. However, pharmacological binding studies showed that the main determinant linked to the occurrence of sleep disorders was in fact the affinity of the beta-blocker for the central or peripheral β2 or serotoninergic receptor. Beta-blockers also have the potential to decrease the melatonin level, which could promote insomnia; carvedilol is the only beta-blocker that does not impair melatonin secretion. A large population study in about 1300 women from Northern Europe was conducted to examine the effects of antihypertensive medications on sleep, including beta-blockers. Nightmares were reported in 13% of these women treated with beta-blockers but this was not significantly different from women not on antihypertensive therapy.

Key Points on Beta Blockers2,3

Beta blockers are recommended for all HFrEF patients (symptomatic and asymptomatic) who are on standard therapy with ACE inhibitors and optimal doses of diuretics to reduce risk of death and HF hospitalization.

Beta blockers and ACE inhibitors should be started together.

Beta blockers should be started in patients who are clinically stable and their fluid overload is controlled (euvolemic and compensated state).

It is recommended to start beta blockers at low doses and uptitrate slowly to the maximum tolerated dose.

There should be at least 2-week intervals between each dose adjustment, and patients should be reevaluated at each titration for worsening HF symptoms (increasing edema and dyspnea, fatigue, weight gain).

Uptitration of beta blockers may be slower in some patients.

The first step in the setting of increasing congestive signs and symptoms is increasing the diuretic dose. If the increased diuretic dose does not work, the beta-blocker dose should be halved.

If a patient taking a beta blocker develops severe fatigue, the beta-blocker dose should be halved, and the patient should be reevaluated 1 to 2 weeks later.

In the setting of severe decompensation, the beta-blocker dose should be halved, or the treatment should be stopped.

Asymptomatic hypotension does not require beta-blocker dose adjustment. To control hypotensive symptoms, as a first step, other vasodilators such as nitrates or CCBs should be held. The patient should be assessed regarding volume status, and downtitration of diuretics may be considered if the patient is euvolemic.

The reduction of ACE inhibitor dose may allow continuing beta blockers in patients with orthostatic hypotension. Low doses of both drug are preferred to one of them.

In the setting of bradycardia (heart rate <50 beats/min) and worsening symptoms, the beta-blocker dose should be halved. In severely symptomatic patients with bradycardia, beta blockers should be stopped.

In patients taking beta blockers who have bradycardia, it is better to reduce or hold the other rate-lowering drugs such as digoxin and amiodarone.

Contraindications to beta blockers:

High-degree atrioventricular (AV) blocks (second- and third-degree AV block) in the absence of a pacemaker

Asthma: In patients with asthma, beta1 selective blockers may be used with careful and closed monitoring.

Critical limb ischemia

Known allergy to the drug

Beta-Blockers

Beta-blocker therapy is a cornerstone of HFrEF management. The first trial to demonstrate a mortality benefit with beta-blocker therapy was the U.S. Carvedilol Heart Failure Study Group trial.74 Subsequent trials such as the Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF), the Cardiac Insufficiency Bisoprolol Study I (CIBIS-I), the Carvedilol Post-Infarct Survival Controlled Evaluation (CAPRICORN), and the Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) study all demonstrated reductions in mortality and cardiovascular morbidity.75-78 A recent network meta-analysis of 21 trials comparing beta-blockers with other beta-blockers or other treatments in patients with HFrEF confirmed that beta-blocker therapy reduced mortality by 31% (OR 0.69, 95% CI 0.56 to 0.80).79 Through indirect comparisons between different beta-blocker types, there was insufficient evidence to demonstrate a difference between types of beta-blocker. In the 2013 ACCF/AHA guidelines, carvedilol, metoprolol succinate and bisoprolol are the only recommended therapies for a patient with LV systolic dysfunction given their proven efficacy in randomized clinical trials.2

Pharmacokinetics

Beta blockers are generally well absorbed following oral administration (Wood, 1984) and their biological half-lives are considerably longer than their plasma half-lives (Weber, 2005). The wide pharmacokinetic variability between beta blockers stems from differences in lipophilicity (Weber, 2005). Lipophilic agents such as propranolol, metroprolol, and labetalol are more readily absorbed from the GI tract and exhibit a greater degree of plasma protein binding. Lipophilic beta blockers are highly hepatically metabolized and have short plasma half-lives; whereas hydrophilic beta blockers, such as atenolol and nadalol, undergo direct renal elimination and have longer plasma half-lives (Weber, 2005).

β-Blockers

β-Blockers can be divided into four subclasses based on their pharmacologic effects (Table 29-6).58 Cardioselective β-blockers—such as atenolol, bisoprolol, metoprolol, and nebivolol—selectively block β1-receptors when used in approved doses. Nonselective β-blockers also block β2-receptors in the lung and sometimes result in bronchoconstriction. β-Blockers with intrinsic sympathomimetic activity block β1- and sometimes β2-receptors but also keep them partially activated; these agents have little to no role in clinical practice and are contraindicated in patients with CAD. The mixed α-/β-blockers, carvedilol and labetalol, block peripheral α1-receptors and both β1- and β2-receptors. These agents share the pharmacologic properties of nonselective β-blockers but have a lower degree of α-blockade than pure α-blockers, and their α-blocking effects become attenuated with chronic use.

Use of β-blockers for hypertension has declined over the past several years owing to their limited efficacy in preventing CV outcomes in randomized trials and their adverse-effect profiles. Escalating doses of β-blockers can induce salt and water retention, making diuretics a needed adjunctive form of therapy. Abrupt discontinuation of a β-blocker, particularly when administered in high doses, may be followed by adrenergically mediated rebound hypertension55; therefore a stepwise reduction in dose is needed when discontinuing therapy. β-Blockers administered with either verapamil or diltiazem can cause sharp reductions in heart rate and risk of heart block, and this combination should be used with caution. Erectile dysfunction, hyperglycemia, and dyslipidemia have been reported with β-blockers, but these can be minimized by use of low to moderate doses.80,81 The metabolic side effects, hyperglycemia and dyslipidemia, are less frequent with low doses of traditional β-blockers, vasodilating β-blockers (nebivolol), and mixed α-/β-blockers (e.g., carvedilol) than with high doses of traditional β-blockers.32

For patients with uncomplicated hypertension, β-blockers are considered a first-line option in the JNC-7 guidelines8 but are considered add-on therapy in newer guidelines and scientific statements.10,18 β-Blockers have a compelling indication for treatment of CAD, especially post MI, and also come with a high coronary disease risk and a higher risk of LV dysfunction.8 They also have a compelling indication as add-on therapy in diabetes.8 These drugs may be helpful for patients with high adrenergic drive, essential tremor, tachycardia, or arrhythmias but should not supplant appropriate first-line agents—ACE inhibitors, ARBs, CCBs, and diuretics—that have been proven to be more effective in reducing risk of CV events in patients with uncomplicated hypertension.4,10 β-Blockers are useful as add-on therapy in hypertensive patients with tachycardic responses to other antihypertensive drug classes, such as dihydropyridine CCBs or arterial vasodilators.