Fifty years of beta-blockers: a revolution in CV pharmacotherapy

The development and subsequent clinical application of various beta-adrenergic receptor blocking drugs during the past 50 years has provided one of the major advances in human pharmacotherapy. Beginning in 1958 with the introduction of dichloroisoproterenol, no other class of synthetic drugs, over time, has ever demonstrated such widespread utility in the treatment of both cardiovascular and non-cardiovascular diseases.

Beta-adrenergic blockers function as competitive pharmacologic inhibitors of catecholamine actions that influence a wide number of physiologic and metabolic activities in human beings. It has been shown that the effects of catecholamines ultimately depend on their chemical interactions with specific adrenergic receptors, membrane-bound macromolecular glycoprotein structures located on cell membranes, conceptual entities that were not well defined until the 1980s. More than 100 years ago, early investigators conceived that catecholamines were binding selectively to receptor-like structures in causing their pharmacologic actions. In 1948, Ahlquist conducted a series of classic pharmacologic studies and concluded from his findings that there were two distinct organ responses to catecholamine drugs that he labeled alpha- and beta-adrenergic receptor mediated.

Fifty-year history

In 1958 the compound dichloroisoproterenol, synthesized by Eli Lilly Laboratories, was found to inhibit the activities of epinephrine, and was thus considered the first beta-adrenergic blocker. However, its potential clinical application was not initially appreciated. In the early 1960s, Black (who subsequently was awarded the Nobel Prize in Medicine and Physiology for his work on beta-blockers) and his associates at Imperial Chemical Industries in Great Britain were working on a series of beta-adrenergic blocking compounds, pronethalol and propranolol, that they hypothesized would lower myocardial oxygen consumption by interfering with the effects of catecholamines, and therefore could be useful for the treatment of angina pectoris, hypertension and arrhythmia. Although pronethanol was effective in patients with angina pectoris, it was propranolol that became the prototype beta-blocker with proven efficacy in both intravenous and oral forms for the treatment of cardiovascular disease. In 1964 propranolol became the first major advance in the treatment of angina pectoris since the introduction of nitroglycerin for that indication almost 100 years earlier. In addition, propranolol quickly became an accepted treatment for arrhythmia, hypertension and hypertrophic cardiomyopathy.

The potential adverse reactions related to the anti-catecholamine effects of propranolol on heart rate, myocardial contractility and bronchial tone led to ongoing refinements in the pharmacologic structure of beta-blockers and subsequent advances in drug delivery. This evolution in drug development led to the introduction of drugs having relative selectivity for cardiac beta1-receptors (metoprolol, atenolol), partial adrenergic agonist activity (pindolol), concomitant alpha-adrenergic blocking activity (labetalol, carvedilol), and additional direct vasodilator activity (nebivolol). In addition, long-acting and ultra-short formulations of beta-blockers were developed.

William H. Frishman, MD
William H. Frishman

Years after propranolol was first introduced, studies showed the class of drugs were also useful for treating patients with mitral valve prolapse, pheochromocytoma (labetalol), the hereditary QT prolongation syndrome, hypertensive emergencies and urgencies (labetalol), and for the treatment and prevention of acute aortic dissection (see table). Moreover, both intravenous and oral forms were able to reduce mortality in survivors of MI, the first class of drugs ever shown to do so.

Remarkably, in the 1990s some beta-blockers were also shown to reduce morbidity and mortality in symptomatic patients with congestive HF, a clinical diagnosis for which these drugs had previously been thought to be contraindicated. This revelation has led to a complete rethinking of the pathophysiology of HF, thought now to be aggravated by the adverse effects of increased neurohormonal stimulation of the heart.

Non-CVD use of beta-blockers

Beta-blockers now have applications that extend beyond cardiovascular uses; the prevention of migraine headache, the treatment of benign essential tremor, for patients with pheochromocytoma and thyrotoxicosis, and in topical ophthalmic formulations for reducing intraocular pressure in patients with open angle glaucoma. The drugs have also been used to reduce portal hypertension in patients with liver cirrhosis and to aid in the management of delirium tremens and stage fright.

After decades of clinical use, the beta-blocking drugs have demonstrated a remarkable record of clinical safety in patients of all ages, and an ability to be used in combination successfully with other drug classes for the treatment of CVD. Their continued use in patients with ischemic heart disease undergoing CV and non-CV surgery has also been shown to reduce both intra-operative and peri-operative mortality and morbidity.

Almost in parallel with the clinical introduction of beta-adrenergic blockers came an explosion of research studies that contributed, on a molecular level, to the scientific understanding of receptor structure, function, and regulation. Beta-adrenergic receptor agonists and blockers have served as the biologic probes to help address fundamental molecular pharmacology questions.

Based on the concept of a functional adrenergic receptor that could mediate the effects of catecholamines, the introduction of the first beta-blocker caused a revolution in human pharmacotherapy that has continued to impact favorably on the health of millions of patients worldwide with a wide variety of CV and non-CVDs. Their introduction also opened the door to fundamental discoveries of basic receptor structure and function, which have influenced the development of other drug classes for various medical conditions. Finally, the 50-year beta-blocker experience, with the ability to modulate excessive catecholamine activity, has reaffirmed the observations and descriptions of the “Ancients” who believed that imbalances in naturally-occurring body humours could cause disease, while the reestablishment of a humoural balance would contribute to health.

For more information:

  • Ahlquist RP. A study of the adrenotropic receptors. Am J Physiol. 1948;153:586-600.
  • Black JW, Crowther AF, Shanks RG, Smith LH, Dornhorst AC. A new adrenergic beta receptor antagonist. Lancet. 1964;1:1080-1081.
  • Frishman WH. Beta-Adrenoceptor antagonists. New drugs and new indications. N Engl J Med 1981; 305: 505-506.
  • Frishman WH. Fifty years of beta-adrenergic blockade: a golden era in clinical medicine and molecular pharmacology (commentary). Am J Med. 2008;121:933-934.
  • Frishman WH. Alpha and beta-adrenergic blocking drugs. In: Frishman WH, Sonnenblick EH, Sica DA eds. Cardiovascular Pharmacotherapeutics. 2nd ed. New York: McGraw Hill; 2003:67-97.