Selective Beta-1 Blockers

Mechanism of Action

Beta-1 receptors are primarily found in cardiac nodal tissue, cardiac myocytes, other heart conduction pathway tissues, and kidneys. Beta-1 blockers exert their effect by binding to the beta-1 receptor sites selectively and inhibiting the action of epinephrine and norepinephrine on these sites. Beta-1 receptors are G-protein-coupled receptors (specifically Gs alpha subunit) whose action is exerted through the cyclic AMP (cAMP) and cAMP-dependent protein kinase action with resultant calcium ion concentration increases.[5][6] Increased intracellular calcium increase inotropy in the heart through calcium-induced exchange facilitated by the sarcoplasmic reticulum. Myosin light chains phosphorylated by PKA lead to contractility in muscle cells.[3]

Normally, activation of the beta-1 receptor in the heart increases sinoatrial (SA) nodal, atrioventricular (AV) nodal, and ventricular muscular firing, which leads to increased heart rate and contractility. Stroke volume and cardiac output will also increase as a result. In the kidney, renin is released when smooth muscle cells in the juxtaglomerular apparatus are activated. Blood volume is eventually increased because of the downstream production of angiotensin II and aldosterone production triggered by renin.[3]

Ordinarily, this adrenergic response results in increased inotropy, chronotropy, and dromotropy. The blockade of this pathway with beta-1 blockers results in decreased contractility (inotropy), decreased heart rate (chronotropy), increased relaxation (lusitropy), and decreased cardiac conduction times (dromotropy). 

Administration

Cardio-selective beta-blockers can be administered either intravenously or by mouth, depending on the desired medication. The acuteness and severity of the disease symptoms affect this decision. Intravenous administration allows for the immediate onset of action and complete bioavailability, while oral administration with most beta-1 blockers allows for maximal absorption between 1 to 4 hours post-ingestion. Extended-release formulations are also available for oral use, allowing for less frequent dosing. Esmolol is a beta-1 blocker strictly administered intravenously due to its short half-life of approximately 9 minutes.

Doses of cardioselective beta-blockers may require adjustments in patients with renal disease. For example, atenolol is a hydrophilic agent primarily excreted by the kidneys. The dose needs to be reduced by one-half to three-quarters in patients with diminished renal clearance. Lipophilic beta-blockers like metoprolol do not need to be adjusted. Conversely, metoprolol is extensively metabolized by the liver. Hepatic impairment may impact the pharmacokinetics of metoprolol. There is a prolongation of the elimination half-life of metoprolol in patients with hepatic failure.[7]

Adverse Effects

Common adverse effects of cardio-selective beta-blockers include bradycardia, decreased exercise capacity, hypotension, atrioventricular nodal block, and heart failure. Other common adverse effects include nausea, vomiting, abdominal discomfort, dizziness, weakness, headache, fatigue, and dry mouth and eyes. Less common adverse effects are sexual dysfunction, memory loss, and confusion. An additional risk of beta-1 blockers is the masking of hypoglycemia-induced tachycardia in the diabetic patient, which is a warning sign of the patient's blood glucose levels being too low. Hypoglycemia, or low blood glucose, most commonly occurs in diabetic patients due to insulin or other drugs. The onset of hypoglycemic symptoms can occur at different blood glucose levels but most commonly occurs when blood glucose falls below 70 mg/dL.[8] 

The catecholamine-triggered neurogenic hypoglycemic symptoms masked by this class of medications include tremors and palpitations. Hunger, tremor, irritability, and confusion can be hidden as well. Sweating, however, remains unmasked and might be the only consistent sign of hypoglycemia in individuals treated with β-blockers.[9] Since continuous hypoglycemia causes acute brain damage, changes in a patient's mental status should trigger fingerstick blood glucose monitoring and treatment. Treatment in responsive patients consists of fast-acting sugar like glucose tablets, candy, or juice. Intravenous dextrose or intramuscular glucagon is indicated for unresponsive patients.[8]

Some medications that may result in adverse effects when paired with beta-1 blockers include nitrates, phosphodiesterase inhibitors, ACE inhibitors, calcium channel blockers, and other blood pressure-lowering or anti-arrhythmic medications. Adverse effects also occur in overdose. In excessive doses, cardio-selective beta-blockers lose their selective binding and begin to interact with beta-2 and beta-3 adrenergic receptors.[2]

Contraindications

According to the American College of Cardiology, beta-1 blockers should not be prescribed to patients with a recent or current history of fluid retention without concurrent diuretic use. Beta-1 blockers are contraindicated in patients with complete heart block and should be used with great caution in patients with second-degree heart block. Beta-1 blockers generally are contraindicated in patients with moderate to severe asthma and patients with chronic obstructive pulmonary disease.[10] 

Controversy exists over the safety of beta-1 blocker use in persons with mild to moderate asthma. Studies examining the efficacy of beta-1 blocker use in patients with concurrent mild to moderate asthma showed little to no adverse outcomes compared to those who did not have underlying asthma, but they generally are not used due to the potential risks.[11]

Monitoring

Beta-1 blockers are monitored via the patient's vital signs. Heart rate and blood pressure checks, along with regular physical examination, are sufficient for basic patient monitoring. Regular blood level monitoring of beta-1-blocker levels is not indicated in most circumstances. If there are reasons to be concerned about reaching therapeutic levels or toxicity, then blood levels of specific beta-1 blockers can be ordered and reviewed. In cases that prove to be refractory to treatment for an overdose, more intensive measures can be taken, including continuous monitoring of heart rate, cardiac electrical activity, and blood pressure.

Toxicity

Beta-1 blockade toxicity typically presents with the triad of bradycardia, hypotension, and altered mental status. These signs are sometimes accompanied by a state of hypoglycemia and hyperkalemia, though not always. Clinicians and other caregivers must remember that in an overdose, beta-1 blockers can lose their selectivity; this means bronchopulmonary symptoms may be present. Additionally, neurologic functioning can be impaired, resulting in altered mental status in toxicity with highly lipophilic beta-1 blockers like propranolol, acebutolol, and oxprenolol. Suspected cardio-selective beta-1-blocker toxicity needs to be verified with a meticulous history, and physical examination focused on identifying specific medications ingested and any co-ingestions that could affect patient treatment.[12]

Immediate monitoring of blood pressure with a blood pressure cuff and cardiac electrical activity with an EKG is necessary. Acquiring blood glucose levels, a basic metabolic panel, and acetaminophen and salicylate levels help identify sequelae of beta-1-blocker overdose and toxicity, as well as identifying any medications that may have been co-ingested. In severely hypotensive patients, one should consider obtaining a lactate level due to the possibility of mesenteric ischemia. Patients being treated within 1 to 2 hours of ingestion may benefit from activated charcoal, or gastric lavage may be necessary for patients who present immediately after large ingestions or with severe adverse symptoms.

Intravenous fluid administration for treatment of hypotension and intravenous glucagon to antagonize beta-1-blocker effects are the initial reversal agents of choice for beta-1-blocker toxicity. Following the administration of glucagon and crystalloid fluids, the patient may require calcium and sodium bicarbonate which is indicated for QRS widening and magnesium sulfate for QTc prolongation.[12] It is important to be aware of the potential for initial treatment failure and take steps to prepare for invasive measures. More invasive measures include the use of hyperinsulinemia-euglycemia therapy, lipid emulsion therapy, vasopressors, intubation (some lipophilic beta-blockers cause CNS depression which requires immediate stabilization of airways), or intra-aortic balloon pump if hemodynamic instability is present.[13]

Glucagon reverses the actions of beta-blockade. Its actions increase contractility, heart rate, and conduction through the atrioventricular node. It works by binding the G-protein coupled receptor (Gαs-coupled proteins). This increases cAMP levels through adenylate cyclase, which in turn stimulates activation of protein kinase A (PKA).[14] Atropine is used to counteract vagally mediated bradycardia. The mechanism of action for vagally mediated bradycardia is different than the catecholamine blockade resulting in bradycardia for the patient with selective beta-blocker overdose.[12] Beta-blocker-induced bronchospasm may be treated with oxygen and bronchodilators like albuterol.  

Propranolol overdoses are especially life-threatening. Sotalol overdoses require prolonged monitoring due to the possibility of QT interval prolongation and the potential for torsades de pointes. Patients suspected of overdosing with either of these cardio-selective beta-blockers should be treated more aggressively. Patient monitoring is recommended for at least 6 hours in asymptomatic, unintentional beta-1-blocker overdose cases. In cases of overdose with propranolol, monitoring is advised for at least 12 hours. In circumstances of sotalol overdose, monitoring for 24 hours is preferable due to the potential late-onset cardiac effects.[15] Some cardio-selective beta-blockers have intrinsic agonist activity and are used in patients with an increased risk of overdose.  

Enhancing Healthcare Team Outcomes

While beta-1 blockers provide numerous benefits to patients, there is always a potential for toxicity or adverse events. The interprofessional team of clinicians, pharmacists, and nurses caring for a patient on these drugs should be aware of and report any signs or symptoms of toxicity, documenting this in the patient's chart and records, and sharing this information with all interprofessional team members so that everyone is operating from the same patient data set. An interprofessional team approach to monitoring for side effects will enhance patient outcomes. [Level 5]