In 1964, Sir James Black, working with the Imperial Chemical Industries and at the Medical Unit of St. Georges Medical Hospital, London, synthesized a new adrenergic beta-receptor antagonist, pronethalol [1]. For this discovery and his ground-breaking work on receptor pharmacology, he received the Nobel prize for medicine and physiology in 1988. Pronethalol was the first substance that was somewhat specific and relatively free from sympathomimetic activity in the cardiovascular system. Later, propranolol with much less side effects was synthesized. Since then, many beta-blockers have been discovered. Currently in Germany, more than 10 distinct substances are available for medical use. In 2006 alone, 1600 million defined daily doses (DDD) were prescribed for 80 million in Germany!
The various beta-blockers are more or less specific for the different beta-adrenoceptors. Thus, they have variable actions in the organism. Usually, the cardiologist prefers beta₁-specific blockers. However, the convincing results of the studies with carvedilol in chronic heart failure demonstrated the same 35% reduction in mortality as did bisoprolol in CIBIS II (Cardiac Insufficiency Bisoprolol study II) [2]. Apparently, blocking of the adrenergic system per se in chronic heart failure is more important than any “cardiospecific” effect.
Clearly, which pharmacokinetic properties the physician selects are crucial. Most patients prefer a long-acting substance taken once daily. In addition, the results of the MERIT-HF (MEtoprolol CR/XL Randomized Intervention Trial in congestive heart failure) study [3] also demonstrated the superiority of metoprolol in the succinate form with long-lasting action. It was given once daily and resulted in reduction of mortality, whereas metoprolol tastrate (short duration of beta-blockade) did not improve prognosis in the MDC (Metoprolol in Dilated Cardiomyopathy) trial [4]. The indications for beta-blockers are wide, ranging from tachyarrhythmia in atrial fibrillation to heart failure or prevention of sudden cardiac death. Many patients with rare ventricular premature beats only or some kind of stage fright are relieved and happy with very small doses of a beta- blocker. In fact, when going through the files of my admittedly mostly cardiovascular patients, I find that 73% of them are either taking low or high doses of beta-blockers. Given the undisputed antiarrhythmic activity, it is no surprise to most cardiologists that beta-blockers with high beta₁ specificity and without intrinsic sympathomimetic activity in heart failure are at least as good as—or even more effective than—angiotensin-converting inhibitors. Later, the CIBIS-III-study [5] even seemed to indicate that the prevention of sudden cardiac death in congestive heart failure is one of the major beneficial actions of these drugs.
Of the many major drug developments in cardiovascular medicine during the last 50 years, the discovery of beta-blockers seems to be one of the most important. Without beta-blockers, I would not want to be a cardiologist.


REFERENCES

1. Black JW, Stephenson JS. Pharmacology of a new adrenergic beta- receptor-blocking compound (nethalide). Lancet 1962;2:311-314.
2. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet 1999;353( 9146): 9-13.
3. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet 1999;353(9169):2001-2007.
4. Waagstein F, Bristow MR, Swedberg K, et al. Beneficial effects of metoprolol in idiopathic dilated cardio m yo pathy. Metoprolol in Dilated Cardiomyopathy (MDC) Trial Study Group. Lancet 1993;342(8885):1441-1446.
5. Willenheimer R, van Veldhuisen DJ, Silke B, et al; CIBIS III Investigators. Effect on survival and hospitalization of initiating treatment for chronic heart failure with bisoprolol followed by enalapril, as compared with the opposite sequence: results of the randomized Cardiac Insufficiency Bisoprolol Study (CIBIS) III. Circulation 2005;112(16):2426-2435.