There has been much debate about whether we as a society are too willing to take medications that are unnecessary, and at worst, harmful. The excessive use of medications, known as “polypharmacy,” is a problem particularly among the elderly who tend to have multiple comorbidities and have been therefore prescribed multiple medications.
In reality, the risk of “taking a pill for everything” is a growing concern among all segments of society. In many parts of the world, health care has become more accessible, and the idea of being on any type of medication has become more palatable.
I witnessed this firsthand in medical school, where students seek to take “medications” that can increase concentration and performance. One of these medication types is beta-blockers, which can regulate heart rhythms (often dysregulated in anxiety) and has supposed calming properties.
Protective and Powerful
Beta-blockers are a class of medications that, without exaggeration, form part of the foundation of modern medicine today. They are a competitive antagonist of adrenergic receptors and protective of the cardiovascular system. Their use is warranted in a number of established conditions: hypertension, myocardial infarction, angina, congestive heart failure, and atrial fibrillation.
Scientists are discovering new indications for beta-blockers, such as cancer and migraine headaches. In cancer, they theorize that beta-blockers may alter the tumor microenvironment and protect against disease deterioration. For migraines, researchers posit that beta-blockers normalize contingent negative variation, which correlates positively with treatment response.
If researchers do indeed find more and more indications for the use of beta-blockers, they may be among the most ubiquitous, and powerful, medications on the planet. In Pharmacological Research, Fumagalli et al wrote, “After more than 50 years from their discovery, new evidence is emerging, suggesting their protective effect extends beyond the cardiovascular system.”
Applications in PAH
It is perhaps understandable then that beta-blockers have also been used in the management of pulmonary arterial hypertension (PAH). Given our increasing tendency to prescribe beta-blockers for any heart-related condition, their usage in PAH should not come as a surprise.
In PAH, a progressive reduction in cardiac output due to the uncoupling of the right ventricular to pulmonary circulation often results in heart failure. This is counteracted by the activation of the sympathetic nervous system, which can manifest as left ventricular dysfunction.
In Vascular Pathology, Badagliacca and colleagues wrote, “The [right ventricle] adapts to increased afterload in PAH by an increased contractility to preserve its coupling to the pulmonary circulation, and relies on increased dimensions (ie, Starling’s heterometric adaptation) when this basic homeometric adaptation gets exhausted, representing the pathophysiologic assumption for molecular pathways.”
Read more about PAH etiology
Scientists have proposed a clear physiological basis for the prescription of beta-blockers in PAH. Alveolar-capillary membrane diffusion measured by carbon monoxide reduces in correlation with increased PAH severity. The alveolar-capillary membrane is said to be an important target of the sympathetic system, given that it includes around 90% of alveolar beta-receptors. Prolonged sympathetic stimulation increases membrane diffusion; its blockage with beta-blockers reduces lung diffusion, thus providing relief in left ventricular heart failure.
In addition, beta-blockers have been extensively tested in animal models. Let’s go through a few:
- Bisoprolol was able to increase right ventricular contractility and filling in monocrotaline-induced pulmonary hypertension models.
- Carvedilol was able to reduce right ventricular hypertrophy and dilation in a hypoxic pulmonary hypertension rat model.
- Scientists observed the reversal of pathological right ventricular remodeling in a pulmonary hypertension rat model treated with carvedilol.
- Metoprolol was able to delay right ventricular failure and improve right ventricular function in pulmonary hypertension rat models.
Effects in Advanced PAH
So the evidence for the use of beta-blockers in PAH is airtight, right? Not quite. While there is general consensus that beta-blockers improve outcomes in the early stages of PAH, there is some debate about their effect during advanced stages of the disease.
Badagliacca theorized that beta-blockers could initiate a vicious cycle in advanced stages of PAH. It would go like this:
Beta-blockers downregulate B1-adrenergic receptors. This decreases ionotropic, chronotropic, and lusitropic responsiveness of the right ventricle. This then decreases cardiac output and increases venous congestion, which leads to reduced renal perfusion and the increased release of renin. This then activates the renin-angiotensin-aldosterone-system and the sympathetic nervous system, which leads to chronic neurohormonal upregulation. This then downregulates B1-adrenergic receptors, and the cycle continues.
Read more about PAH patient education
In other words, beta-blockers may counteract the compensatory adrenergic-mediated effects of low cardiac output in advanced stages of PAH.
This theory puts a big question mark on whether beta-blockers help or hurt during advanced stages of PAH. This line of questioning is good, because it allows physicians to reflect on the consequences of each drug prescribed. As physicians, we are at risk of prescribing medications almost nonchalantly, and we later wonder why patients have such a hard time keeping track of all the medications they need to take.
Perhaps a re-evaluation of the medications we prescribe is just what the doctor ordered. We want to make sure that the medications prescribed are meaningful and evidence-based for the patient’s condition. Otherwise, a little bit of caution may go a long way.
Badagliacca R, Mercurio V, Romeo E, et al. Beta-blockers in pulmonary arterial hypertension: time for a second thought? Vascul Pharmacol. 2022;144:106974. doi:10.1016/j.vph.2022.106974
Fumagalli C, Maurizi N, Marchionni N, Fornasari D. β-blockers: Their new life from hypertension to cancer and migraine. Pharmacol Res. 2020;151:104587. doi:10.1016/j.phrs.2019.104587