The history of the drug Nebivolol

Nebivolol is often called a “not quite ordinary” beta-blocker. It combines a very high selectivity for the beta-1 receptors of the heart with the ability to dilate blood vessels through nitric oxide. To understand why this combination proved important, it is worth tracing the history of the whole class — from the first experiments of a Scottish pharmacologist to the third-generation drugs. Our editors tell how nebivolol appeared and how ideas about its mechanism changed.

The birth of beta-blockers

The history of beta-blockers begins with a theory. In 1948 the American pharmacologist Raymond Ahlquist proposed dividing adrenergic receptors into two types — alpha and beta — based on how different catecholamines affect tissues. At first this idea did not arouse particular enthusiasm, but it was precisely this that opened the way to selective pharmacology.

In the early 1960s the Scottish pharmacologist James Black, working at the company ICI, set himself an unusual task: not to increase the supply of oxygen to the heart, as was then done for angina, but to reduce its need for oxygen. To do this it was necessary to block the action of adrenaline on the heart.

The first clinically suitable drug was pronethalol, but carcinogenicity was found in it in animals. It was soon replaced by propranolol, which in the 1960s became a real revolution in the treatment of angina, arrhythmias and later arterial hypertension. In 1988 James Black received the Nobel Prize in Physiology or Medicine, in particular for this work.

Propranolol blocked both the beta-1 receptors of the heart and the beta-2 receptors of the bronchi and blood vessels. Hence the side effects: bronchospasm in people with asthma, cold extremities, worsening of peripheral blood flow, an effect on glucose metabolism. The search for a way to avoid these problems determined the further development of the class.

Three generations of the class

In 1967 Lands and colleagues proposed dividing beta-receptors into the subtypes beta-1 and beta-2. This gave pharmacologists a target for creating “cardioselective” drugs that act predominantly on the heart. Thus the second-generation drugs appeared — atenolol, metoprolol, later bisoprolol.

Cardioselective drugs significantly improved tolerability but retained a number of problems. They reduce heart rate and cardiac output but do not dilate blood vessels, so peripheral resistance may remain elevated. In addition, in some patients they worsened insulin sensitivity and the lipid profile.

The third generation combined beta-blockade with vasodilation. Some drugs achieve it through additional blockade of alpha-1 receptors (carvedilol, labetalol), others through an effect on the nitric oxide system. Nebivolol became the best-known representative of the second approach.

Let us note that the division into generations is of a historical rather than strictly pharmacological character. Each drug has its own profile, and guidelines evaluate them by the results of clinical studies, not by “generation.”

The development of nebivolol at Janssen

Nebivolol was synthesized at the Belgian company Janssen Pharmaceutica, founded by Paul Janssen. In 1988 Van de Water and colleagues published in the Journal of Cardiovascular Pharmacology the pharmacological and hemodynamic profile of the new compound, describing it as a “chemically new, potent and selective” blockade of beta-1 receptors.

The nebivolol molecule is unusual: it has four chiral centers, and the drug is a racemic mixture of two enantiomers — d-nebivolol and l-nebivolol. It turned out that the beta-1-blocking action is provided mainly by the d-isomer, whereas the l-isomer hardly blocks the receptors but participates in the vascular effects.

Already in early studies it was noticed that nebivolol reduces peripheral vascular resistance while suppressing cardiac output less than classic beta-blockers. The mechanism of this effect was at first unclear, since the drug does not block alpha-receptors, as carvedilol does.

Another feature discovered during development is the dependence of metabolism on the enzyme CYP2D6. In people with different activity of this enzyme, drug concentrations differ substantially, although clinical efficacy, as later studies showed, changes less than might have been expected.

Solving the vasodilatory effect

In 1995 Cockcroft and colleagues published in the Journal of Pharmacology and Experimental Therapeutics a study on the human forearm vessels. They showed that nebivolol dilates the vessels and that this effect is suppressed by a blocker of nitric oxide synthesis. Thus the vasodilation is linked to an L-arginine/NO-dependent mechanism.

Nitric oxide is a key signaling molecule of the endothelium that relaxes the smooth muscles of the vessels. Its deficiency is characteristic of hypertension, diabetes and atherosclerosis, so the drug’s ability to increase the bioavailability of NO was regarded as a potential advantage.

Further studies clarified the mechanism. Part of the effects is linked to an agonistic action on the beta-3 adrenergic receptors of the endothelium, which activate endothelial NO synthase. The work of Maffei and colleagues (Hypertension, 2007) showed the participation of NO mechanisms in the heart as well. In addition, antioxidant properties of the drug have been described that reduce the destruction of NO by free radicals.

The review by Munzel and Gori in the Journal of the American College of Cardiology (2009) with the telling title “Nebivolol: a somewhat different beta-blocker” summarized these data. At the same time the authors stressed that the clinical benefit of the NO effect compared with other beta-blockers requires confirmation in studies with hard endpoints.

Clinical studies and registration

In Europe nebivolol was registered for the treatment of arterial hypertension in the 1990s under the trade name “Nebilet.” Later the drug also received an indication for the treatment of stable chronic heart failure of mild and moderate degree in patients aged 70 years and older.

The basis for this indication was the SENIORS study (Flather et al., European Heart Journal, 2005), in which more than two thousand elderly patients with heart failure participated. Nebivolol reduced the frequency of a combined endpoint — death from any cause or hospitalization for cardiovascular reasons — compared with placebo.

In the US the drug was approved at the end of 2007 under the name Bystolic, only for the treatment of hypertension. The meta-analysis by Van Bortel and colleagues (2008) showed that in antihypertensive efficacy nebivolol is comparable to other classes of drugs and has good tolerability.

A separate line of research concerned metabolic effects and erectile function. In a number of works nebivolol, unlike some older beta-blockers, did not worsen insulin sensitivity and was less often associated with erectile dysfunction, which is explained by the effect on NO. However, these studies were relatively small.

• Today nebivolol is used for arterial hypertension, and in Europe also for chronic heart failure in elderly people.
• The drug is part of fixed combinations with other antihypertensive agents.
• After the expiration of patent protection, numerous generics appeared.

Editorial conclusions

Nebivolol is the result of several decades of evolution of beta-blockers: from the non-selective propranolol to cardioselective drugs and further to agents with a vasodilating action.

Its features — high selectivity for beta-1 receptors and NO-mediated dilation of blood vessels — were discovered gradually, and the mechanism was finally clarified only after the drug entered the market.

The clinical evidence base concerns primarily hypertension and heart failure in elderly people; the potential metabolic advantages remain a subject of debate.

Our materials “Nebivolol: effect on the liver and kidneys,” “Who should not take Nebivolol” and “The history of the drug Telmisartan” will help continue the topic.

References

1. Van de Water A, Janssens W, Van Neuten J, et al. Pharmacological and hemodynamic profile of nebivolol, a chemically novel, potent, and selective beta 1-adrenergic antagonist. J Cardiovasc Pharmacol. 1988;11(5):552–563.
2. Cockcroft JR, Chowienczyk PJ, Brett SE, et al. Nebivolol vasodilates human forearm vasculature: evidence for an L-arginine/NO-dependent mechanism. J Pharmacol Exp Ther. 1995;274(3):1067–1071.
3. Maffei A, Di Pardo A, Carangi R, et al. Nebivolol induces nitric oxide release in the heart through inducible nitric oxide synthase activation. Hypertension. 2007;50(4):652–656.
4. Münzel T, Gori T. Nebivolol: the somewhat-different beta-adrenergic receptor blocker. J Am Coll Cardiol. 2009;54(16):1491–1499.
5. Flather MD, Shibata MC, Coats AJ, et al. Randomized trial to determine the effect of nebivolol on mortality and cardiovascular hospital admission in elderly patients with heart failure (SENIORS). Eur Heart J. 2005;26(3):215–225.
6. Van Bortel LM, Fici F, Mascagni F. Efficacy and tolerability of nebivolol compared with other antihypertensive drugs: a meta-analysis. Am J Cardiovasc Drugs. 2008;8(1):35–44.