Propranolol and its current status in cardiovascular disorders

The invention of the beta-adrenergic receptor antagonist, propranolol, by Sir James Black in the 1960s initiated a revolution in the field of cardiology. For his work, Sir James Black was awarded Nobel Prize in Medicine in 1988. [1, 2] Until propranolol was invented, the only drugs available to treat angina were nitrates, which were effective only partially. Soon, it was discovered that propranolol is not only effective in the treatment of angina, but it also has therapeutic effects in other cardiovascular conditions such as hypertension, myocardial infarction, and arrhythmias.[1,2,3,4,5] Over the years, other applications of propranolol in several noncardiovascular conditions including migraine, essential tremors, anxiety, portal hypertension, hyperthyroidism, and pheochromocytoma have been recognized (Figure 1) [6].

Propranolol is a nonselective beta-blocker that acts at both beta-1 and beta-2 adrenergic receptors. By blocking the beta-adrenergic sites, propranolol inhibits sympathetic effects that act through these receptors. [7, 8]

Propranolol is highly lipophilic compound and due to this property it can cross blood-brain barrier which is responsible for some its spectacular neurological benefits (eg. migraine). Having said that, this property is also responsible for its side-effects including sleep disturbances etc.

This drug shows nearly 100% absorption from gastrointestinal tract but almost 75% is extracted by liver and thus only one-fourth drug reaches systemic circulation. Plasma half-life of propranolol is 3–6 h. [7, 8] A long-acting preparation of propranolol has also been developed with a half-life of 8–11 h. This sustained-release preparation provides the advantage of once-daily dose with similar efficacy and better patient compliance. [8]

Propranolol has a variable bioavailability and its dose needs to be individualized based on response. Dose ranges from 80 mg/day to 320 mg/day. [7]

Post myocardial infarction: Even today, more than half a century after they were first introduced, beta-blockers are still the most commonly used class of drugs for managing cardiovascular diseases. The Beta-Blocker Heart Attack Trial was a landmark trial in the history of propranolol. It was a multicentre, randomized, double-blind, placebo-controlled trial (N = 3837), which was designed to evaluate whether administration of propranolol postmyocardial infarction led to reduction in mortality. Results were encouraging with statistically significant reductions in total mortality (9.8% vs. 7.2%, P < 0.005), cardiovascular mortality (8.9% vs. 6.6%, P < 0.01), mortality due to arteriosclerotic heart disease (8.5% vs. 6.2%, P < 0.01), and sudden death (4.6% vs. 3.3%, P < 0.05). The drug also had an acceptable safety profile. The results also showed that propranolol has an antiarrhythmic effect which may, at least in part, be responsible for the observed reduction in sudden cardiac death. The positive results of this study led to widespread use of propranolol for reduction in morbidity and mortality associated with myocardial infarction. [5, 9]

Tachyarrhythmias: Barton et al. assessed the efficacy and safety of high-dose propranolol for the management of supraventricular tachyarrhythmias (SVTs) in infants (N = 287). SVTs were successfully managed in 67.3% of the study population through entire inpatient stay, and 87.7% of those discharged on propranolol were recurrence-free at follow-up. [10] Several other studies also support the efficacy of propranolol in treating SVT in infants.[11,12] Furthermore, propranolol has also shown promising results in heart failure caused by pediatric hypertrophic cardiomyopathy and is considered as treatment of choice in this condition.[13]

Antiplatelet effects: Besides the effects on hypertension and heart rate, Bonten et al. in a meta-analysis found that betablockers also decreased platelet aggregation significantly which can partly explain their effects in coronary artery disease patients. What is more interesting is that this effect was more pronounced with lipophilic beta antagonists like propranolol. [14]

Hypertension: Propranolol has been extensively used for the management of essential hypertension. Although the exact mechanism of its antihypertensive effect is not known, propranolol is known to work through several mechanisms including peripheral vasodilation, central sympathetic blockage, cardiac output reduction, and renin–angiotensin–aldosterone–sympathetic axis inhibition. [7] Further, the anxiolytic effect of propranolol is also well known. [15] Based on all these factors, presently, propranolol is being considered for the treatment of resistant arterial hypertension.

Propranolol is generally well tolerated. Common adverse events include gastrointestinal disturbances, bradycardia, hypotension, bronchospasm, exertional dyspnea, hypoglycemia, dizziness, fatigue, and insomnia. These are usually mild and can be managed conservatively without requiring discontinuation of medication. Further, propranolol has demonstrated safety for use in pediatric patients. [16]

Cardioselective betablockers like metoprolol and carvidilol, have a better safety profile in cardiac patients owing to their selective effect on beta-1 receptors that are concentrated in the myocardium. But propranolol still holds its place in the management of cardiac patients for multiple reasons.

Firstly, when it comes to cost, propranolol is much cheaper than the cardioselective betablockers. It has been found to be as beneficial as the third-generation beta-blocker, carvedilol, on left ventricular volume and function after primary coronary stenting in acute myocardial infarction. [10] This becomes relevant in the setting of a developing country like India where health care expenditure is still not lagging behind developed countries.

Secondly, cardiac patients often have multiple comorbidities and propranolol may be indicated for more than one indication in such patients. Among patients with cardiovascular disease, anxiety and formal anxiety disorders are common and associated with poor cardiovascular health, including the development and progression of coronary artery disease and heart failure. Following an ACS, 20-30% of patients experience elevated levels of anxiety [17]. While post-ACS anxiety may be transient for some patients, in half of cases anxiety persists for up to 1 year post-event. Anxiety has been associated with the incidence, and in some cases progression, of cardiovascular disease. In patients without existing cardiac disease, anxiety has been linked to the subsequent development of CAD. (Figure 2)

In such setting, a non-selective betablocker obviously offers more benefit than the cardioselective blockers by blocking the anxiety driven sympathetic drive. Cardioselective betablockers do not cross the blood-brain barrier and thus their anti-anxiety effects are not as prominent as propranolol.

Another instance can be the setting of a cardiac patient suffering from essential tremors of migraine in which a lipophilic compound will be an ideal option for handling the neurological ailment of the patient and at the same time addressing the cardiac issues.

The role of propranolol by virtue of its beta-1 and beta-2 blocking effects also makes it a suitable option for cardiac patients suffering from coexistent hyperthyroidism or pheochromocytoma.

Propranolol has a wide spectrum of utility in cardiac patients and thus its non-selective beta-blocking properties should not be solely seen in the light of adverse effect profile. By virtue of lipophilicity and additional beta-2 blocking actions, it has beneficial effects on multiple organ systems and thus its role in cardiology has been redefined in the current era. Due to improved mortality rates, cardiac patients with multiple comorbidities are commonly attended by physicians and cardiologists. In such settings a non-selective betablocker may be the drug of choice when a cardiac patient has antecedent anxiety, tremors, migraine, etc.

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