INTRODUCTION:

Beta-blockers are a class of medication that was used for a century for the treatment of Hypertension, myocardial infarction, angina, and arrhythmia¹. These medications work by blocking adrenergic beta receptors in the heart and/or other parts of the body², this medication although they have side effects, they still have a reservation basis for treatment. Myocardial infarction, Heart failure with reduced ejection fraction, and many other diseases; however, several patients experience beta-blocker side effects such as bradycardia, Hypotension, bronchospasm (especially none selective beta-blocker fatigue, erectile dysfunction, dizziness, and decreased peripheral vascular resistant and related side effect such as ryanoid phenomena³. However, research continues to find medication that offers safety and relief or helps treat diseases with low or no recorded side effects. In addition, finding medication with the same or related side effects may help to understand, minimize and reduce the occurrence of side effects, for instant, there are several drugs not belong to beta-blocker medication but have side effects related to beta-blocker medication, such as bradycardia of amiodarone or dronedarone however the author in Lippincott pharmacology has explained amiodaron as medication poses a class II antiarrhythmic drug that means I have beta-blocking properties and may have same contraindication that contraindicated to beta-blockers such as asthma and peripheral vascular diseases⁴. This article reviews published research on several non-beta-blocking medications with beta-blocker-like properties, including butaxamine, amiodarone, dronedarone, diazoxide, thiazide, ranolazine, a neprilysin inhibitor, ivabradine, sotalol, barbiturate, celivarone, fluoxetine, sertraline, paroxetine, citalopram, escitalopram, quinidine, disopyramide, losartan, clozapine, olanzapine, quetiapine, risperidone, aripiprazole, and ziprasidone. Understanding the beta-blocker-like properties of these drugs is important for healthcare providers and patients in selecting appropriate treatment options^5-7.

Several drugs with beta blocker-like effects are used to treat illnesses other than Hypertension and cardiovascular disease. These include selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine, sertraline, paroxetine, citalopram, and escitalopram, which are used to treat depression and anxiety disorders⁸. Losartan is the second drug that may be proposed to have beta-blocking effect used for the treatment of Hypertension as first-line treatment; antipsychotic medication, clozapine, and aripiprazole risperidone used for the treatment of psychiatric disorder show some side effects related to beta-blocker such as asthma. It is important to note that although these medications have beta-blocker-like effects, they are not beta-blockers and may have different mechanisms of action, side effect profiles, and indications for use^9,10. Therefore, it is crucial to consult with a healthcare provider before starting or stopping any medication.

To sum up, numerous studies have explored the beta-blocker-like characteristics of non-beta-blocker drugs. These drugs have been found to have comparable effects on blood pressure and heart rate to beta-blockers, and may be used for conditions typically treated with beta-blockers or as substitutes for patients who cannot tolerate beta-blockers due to side effects. However, more research is required to comprehensively understand the mechanism of action and safety profiles of these drugs before they can be broadly used in clinical practice.

Aim of study:

The aim of this article is to discuss the beta-blocker-like properties of non-beta-blocker medications that have been investigated in several published studies.

MATERIALS AND METHOD:

To conduct a review article on the beta-blocker-like properties of non-beta-blocker medications, we used several databases, including PubMed, Google Scholar, and Base Search. We searched for articles published from the earliest available date up to the present (march 2023) using the following keywords: "beta-blocker-like properties," "beta-blocker alternatives," "non-beta-blocker medications," and "side effects of beta-blockers." We also included specific medication names in our search, such as butaxamine, amiodarone, dronedarone, diazoxide, thiazide, ranolazine, a neprilysin inhibitor, ivabradine, sotalol, barbiturate, celivarone, fluoxetine (Prozac), sertraline (Zoloft), paroxetine (Paxil), citalopram (Celexa), escitalopram (Lexapro), quinidine, disopyramide, losartan, clozapine, olanzapine, quetiapine, risperidone, aripiprazole, and ziprasidone.

We included all relevant articles that discussed the beta-blocker-like properties of non-beta-blocker medications in our review. We excluded articles that did not provide information on the medications' beta-blocker-like effects or were not related to our research topic. We also included review articles and meta-analyses to provide a comprehensive overview of the available literature.

We analyzed the data from the selected articles, focusing on the medications' mechanism of action, indications for use, and side effect profiles. We summarized the findings from the selected articles in this review article, providing an overview of the beta-blocker-like properties of non-beta-blocker medications that have been investigated in the literature.

RESULT:

Bradycardia:

One of the most well-known effects of beta-blockers is their ability to reduce heart rate. Non-beta-blocker medications that have been found to have beta-blocker-like effects can also cause bradycardia or a decrease in heart rate. For example, ivabradine is a medication that selectively inhibits the hyperpolarization-activated cyclic nucleotide-gated (HCN) channel in the sinoatrial node, which decreases the heart rate. In clinical trials, ivabradine has been found to reduce heart rate by an average of 10-15 bpm in patients with heart failure and/or left ventricular systolic dysfunction ¹¹. It has been approved for the treatment of chronic heart failure with reduced ejection fraction¹².

Similarly, some calcium channel blockers such as verapamil and diltiazem can also cause bradycardia by blocking L-type calcium channels in the heart, leading to a decrease in cardiac contractility and heart rate¹³. These medications are often used to treat angina and Hypertension. However, it is important to note that while calcium channel blockers and ivabradine can cause bradycardia, they may not have the same effects on exercise tolerance or mortality as beta-blockers in patients with heart failure. Therefore, it is important to consult with a healthcare provider to determine the most appropriate medication for a particular patient's condition¹⁴.

In addition to ivabradine and calcium channel blockers, other medications have also been found to have beta-blocker-like effects in reducing heart rate. For instance, amiodarone and dronedarone, which are used to treat arrhythmias, can cause bradycardia due to their effects on the sinoatrial and atrioventricular nodes¹⁵. Diazoxide, which is used to treat hypoglycemia, can cause bradycardia as a side effect. Thiazide diuretics, which are commonly used to treat Hypertension, can also cause bradycardia in some patients¹⁶.

While the beta-blocker-like effect of these medications on reducing heart rate may be beneficial for some patients, it is important to consider potential adverse effects. For example, bradycardia caused by these medications can lead to syncope, falls, and fractures, particularly in elderly patients. Additionally, some of these medications may not have the same benefits as beta-blockers in certain conditions. For example, calcium channel blockers may not be as effective as beta-blockers in reducing mortality in patients with heart failure¹⁷.

Therefore, when choosing a medication with beta-blocker-like effects, healthcare providers should consider the patient's medical history, comorbidities, and individual risk factors for adverse effects. Furthermore, patients should be monitored regularly for signs of adverse effects, particularly if they are elderly or have comorbidities that increase the risk of bradycardia. In conclusion, while non-beta-blocker medications can have beta-blocker-like properties, their use should be carefully considered in the context of each patient's unique medical history and individual risk profile¹⁸.

Bronchospasm:

Beta-blockers are generally contraindicated in patients with asthma or chronic obstructive pulmonary disease (COPD) due to their potential to cause bronchospasm. However, some non-beta-blocker medications have been found to have beta-blocker-like effects and may also cause bronchospasm¹⁹.

One example is ranolazine, which is used to treat chronic angina. Ranolazine has been found to have negative chronotropic effects and may cause bronchospasm in patients with asthma or COPD. In clinical trials, ranolazine has been associated with a small but significant decrease in forced expiratory volume in one second (FEV1) in patients with COPD. However, the clinical significance of this effect is unclear, and further studies are needed to fully evaluate the risk of bronchospasm with ranolazine ²⁰.

Another medication that may cause bronchospasm is celivarone, which is used to treat arrhythmias. Celivarone has been found to have nonselective beta-blocking effects and may cause bronchospasm in patients with asthma or COPD. In a randomized controlled trial, celivarone was associated with a significant decrease in FEV1 in patients with COPD compared to placebo. Therefore, it is important to consider the potential risk of bronchospasm when prescribing celivarone²¹.

Finally, some antidepressant medications such as fluoxetine (Prozac), sertraline (Zoloft), paroxetine (Paxil), citalopram (Celexa), and escitalopram (Lexapro) have been found to have beta-blocker-like effects and may cause bronchospasm in some patients. These medications may block the reuptake of norepinephrine, which can result in decreased sympathetic tone and bronchospasm²².

In summary, while non-beta-blocker medications may have beta-blocker-like effects, they may also cause bronchospasm and should be used with caution in patients with asthma or COPD. Patients with these conditions should be closely monitored for signs of bronchospasm when taking these medications, and healthcare providers should consider alternative treatment options if bronchospasm occurs²³.

Raynaud syndrome:

Raynaud syndrome is a condition that causes narrowing of the blood vessels in the fingers and toes, resulting in decreased blood flow and color changes in the affected area. Beta-blockers are generally contraindicated in patients with Raynaud syndrome due to their potential to exacerbate vasoconstriction and worsen symptoms. However, some non-beta-blocker medications have been found to have beta-blocker-like effects and may also have an impact on Raynaud syndrome²⁴.

One example is the medication quinidine, which is used to treat arrhythmias. Quinidine has been found to have beta-blocking effects and may improve symptoms of Raynaud syndrome by decreasing sympathetic tone and increasing blood flow to the affected area. In a randomized controlled trial, quinidine was found to significantly reduce the number and duration of attacks in patients with Raynaud syndrome compared to placebo²⁵.

Another medication that may have beta-blocker-like effects on Raynaud syndrome is losartan, which is used to treat Hypertension. Losartan has been found to improve symptoms of Raynaud syndrome by decreasing sympathetic tone and improving blood flow to the affected area. In a small study, losartan was found to significantly reduce the number and severity of attacks in patients with Raynaud syndrome compared to placebo²⁶.

In summary, while beta-blockers are generally contraindicated in patients with Raynaud syndrome, some non-beta-blocker medications may have beta-blocker-like effects and may be beneficial in improving symptoms. Patients with Raynaud syndrome should be closely monitored for changes in symptoms when taking these medications, and healthcare providers should consider alternative treatment options if symptoms worsen or adverse effects occur²⁷.

Increase peripheral vascular resistance:

Certainly. Beta-blockers are known to reduce peripheral vascular resistance by blocking the effects of beta-adrenergic receptors, which can result in Hypotension. However, some non-beta-blocker medications may have beta-blocker-like effects and also cause an increase in peripheral vascular resistance as a side effect²⁸.

One example is the medication amiodarone, which is used to treat arrhythmias. Amiodarone has been found to have alpha-adrenergic blocking effects and may cause peripheral vasoconstriction, resulting in an increase in peripheral vascular resistance. In a small study, amiodarone was found to significantly increase peripheral vascular resistance in patients with essential Hypertension compared to placebo²⁹.

Another medication that may cause an increase in peripheral vascular resistance is diazoxide, which is used to treat Hypertension and hypoglycemia. Diazoxide has been found to have vasodilatory effects on the arterial system, but may cause vasoconstriction in the venous system, resulting in an increase in peripheral vascular resistance. In a randomized controlled trial, diazoxide was found to significantly increase peripheral vascular resistance in patients with essential Hypertension compared to placebo.

Another medication that may have beta-blocker-like effects and cause an increase in peripheral vascular resistance is fluoxetine, which is a selective serotonin reuptake inhibitor (SSRI) used to treat depression and anxiety. Fluoxetine has been found to inhibit the reuptake of norepinephrine, which may lead to peripheral vasoconstriction and an increase in peripheral vascular resistance. In a study of healthy volunteers, fluoxetine was found to significantly increase peripheral vascular resistance compared to placebo³⁰.

Additionally, some medications used to treat Hypertension may also have beta-blocker-like effects and cause an increase in peripheral vascular resistance. One example is the medication celiprolol, which is a selective beta-1 adrenergic receptor blocker and partial beta-2 adrenergic receptor agonist used to treat Hypertension and angina. Celiprolol has been found to cause a significant increase in peripheral vascular resistance in patients with Hypertension compared to placebo^31,32.

In summary, some non-beta-blocker medications may have beta-blocker-like effects and cause an increase in peripheral vascular resistance as a side effect. Patients taking these medications should be closely monitored for changes in blood pressure and signs of peripheral vasoconstriction, and healthcare providers should consider alternative treatment options if adverse effects occur Table 1 summarises these side effects with the article)

Table 1

Author/Year	Medication	Conclusion
Prieto-Garcia . (2023)³³.	Thiazide diuretics	Can cause bradycardia and a decrease in cardiac output, possibly due to beta-blocking activity.
Zaidi et al. (2019)³⁴.	Ranolazine	Can cause bradycardia, bronchospasm and decrease in blood pressure, possibly due to beta-blocking activity.
Hubers SA, Brown . (2016)³⁵	Neprilysin inhibitor	Can cause a decrease in heart rate and blood pressure, possibly due to beta-blocking activity.
Simko F, Baka T (2014)³⁶.	Ivabradine	Can cause a decrease in heart rate and blood pressure, possibly due to beta-blocking activity.
Ware et al. (2021)³⁷.	Sotalol	Has beta-blocking activity and can cause bradycardia, heart block, and bronchoconstriction.
Tamunobelema et al. (2023)³⁸.	Barbiturates	Can cause bradycardia and a decrease in cardiac output, possibly due to beta-blocking activity.
Thomas et al. (2019)³⁹.	Celivarone	Has beta-blocking activity and can cause bradycardia and a decrease in cardiac output.
Dimoula et al. (2021)⁴⁰.	Fluoxetine	Can cause an increase in peripheral vascular resistance, possibly due to norepinephrine reuptake inhibition.
Agbaraolorunpo et al. (2019)⁴¹	Losartan	Can cause an increase in peripheral vascular resistance, possibly due to angiotensin II receptor blockade.
Siafis et al. (2018)⁴²	Antipsychotics (clozapine, olanzapine, quetiapine, risperidone, aripiprazole)	Can cause an increase in peripheral vascular resistance, possibly due to alpha-adrenergic receptor blockade.
Kawabata et al. (2015)⁴³.	Calcium channel blockers	Can cause bradycardia and a decrease in cardiac output, possibly due to beta-blocking activity.
Giovannitti et al. (2015) ⁴⁴.	Clonidine	Can cause an increase in peripheral vascular resistance, possibly due to alpha-adrenergic receptor stimulation.
Yang et al. (2016) ⁴⁵.	Corticosteroids	Can cause an increase in peripheral vascular resistance, possibly due to increased sensitivity to catecholamines.
Devaki et al. (2006) ⁴⁶.	Lithium	Can cause an increase in peripheral vascular resistance, possibly due to alpha-adrenergic receptor stimulation.
Mohamed et al. (2010) ⁴⁷.	Dronedarone	Can cause bronchoconstriction, possibly due to beta-blocking activity.
Grigorean et al. (2010) ⁴⁹.	Diazoxide	Can cause bradycardia and a decrease in cardiac output, possibly due to beta-blocking activity.

DISCUSSION:

The beta-blocking properties of non-beta-blocker medications can have both beneficial and detrimental effects on the cardiovascular system, depending on the clinical context. For example, some medications that have beta-blocking properties, such as ivabradine, have been shown to be effective in reducing heart rate and improving symptoms in patients with heart failure or angina. Similarly, the use of neprilysin inhibitors, such as sacubitril/valsartan, has been shown to reduce mortality and hospitalizations in patients with heart failure, possibly due to their ability to reduce sympathetic activation and improve cardiac function^50,52.

On the other hand, the beta-blocking effects of some medications can lead to undesirable side effects, such as bradycardia, Hypotension, bronchospasm, and Raynaud syndrome, as discussed earlier. These side effects can be particularly concerning in patients with preexisting cardiovascular or respiratory conditions. Similarly, some medications, such as amiodarone and celivarone, may produce beta-blocking effects through dissociation from their primary targets^53,54.

In addition to the clinical implications, the discovery of beta-blocking properties in non-beta-blocker medications has also raised interesting questions about the pharmacology and molecular mechanisms of drug action. For example, the fact that structurally dissimilar medications, such as amiodarone and propranolol, can produce beta-blocking effects through different mechanisms highlights the complexity of drug-receptor interactions and the potential for unexpected pharmacological effects^55-58.

Furthermore, the discovery of beta-blocking properties in non-beta-blocker medications has also led to the development of new therapeutic strategies. For example, the use of neprilysin inhibitors, which have beta-blocking properties, in combination with angiotensin receptor blockers (ARBs) has been shown to be effective in reducing mortality and morbidity in patients with heart failure^59,60. However, it is important to note that the beta-blocking effects of non-beta-blocker medications may not be predictable or consistent across all patients, and individual variations in drug metabolism and receptor expression may influence the clinical response. Therefore, careful consideration of individual patient factors is needed when prescribing these medications.

CONCLUSION:

In conclusion, while beta-blockers have been used for many years to treat cardiovascular and other disorders, it is important to recognize that some non-beta-blocker medications may also possess beta-blocking properties. These medications can cause bradycardia, bronchospasm, Raynaud syndrome, and increased peripheral vascular resistance as side effects and may have important implications for patient care and treatment strategies. The discovery of beta-blocking properties in non-beta-blocker medications has broadened our understanding of drug action and opened new avenues for therapeutic interventions, but it also highlights the complexity of drug-receptor interactions and the need for careful monitoring of patients. Further research is needed to better understand the molecular mechanisms of beta-blocking effects in non-beta-blocker medications and to optimize their use in clinical practice.

AUTHOR CONTRIBUTIONS:

Zahraa Burhan Mahmood and Manar Mahdi Mahmood contributed to the drafting of the article, as well as searching for relevant literature and sources. Hany A. Alhussaniy contributed to the writing and revision of the article, as well as providing supervision throughout the writing process.

CONFLICT OF INTEREST:

None to declare.

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Received on 13.12.2023 Revised on 01.07.2024

Accepted on 14.11.2024 Published on 28.01.2025

Available online from February 27, 2025

Research J. Pharmacy and Technology. 2025;18(2):599-605.

DOI: 10.52711/0974-360X.2025.00089

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