Category:Beta Blockers

The beta blockers, more formally the beta-adrenergic receptor antagonists, are a class of medicines that blunt the effect of adrenaline and related stress hormones on the heart and other organs. They are among the most widely used medicines in cardiovascular medicine, and their discovery is the classic example of a medicine designed deliberately from a theory rather than found by chance.

The story begins not with a drug but with an idea. In 1948 the American pharmacologist Raymond Ahlquist proposed that the effects of adrenaline and noradrenaline were mediated by two distinct kinds of receptor, which he called alpha and beta, the beta receptors being responsible for, among other things, the quickening and strengthening of the heartbeat.^[1] At the time the idea was treated with some caution, because there were no agents that could selectively block one type of receptor and so demonstrate that the distinction was real.

That changed through the work of the Scottish pharmacologist James Black. In 1958 Black joined the pharmaceutical division of Imperial Chemical Industries (ICI) in England, where he set out to apply Ahlquist's theory to a practical problem: angina, the chest pain that arises when the heart's demand for oxygen outstrips its supply. Black reasoned that a medicine which blocked the beta receptors of the heart would reduce how hard the heart worked, and so reduce its oxygen demand, treating angina not by widening the arteries, as existing medicines did, but by easing the load on the heart itself.^[2]

The approach worked. An early compound, pronethalol, proved the principle but was set aside; its successor, propranolol, was launched in 1965 and became the first widely successful beta blocker.^[1] The significance was twofold. Propranolol transformed the treatment of angina and was soon found useful in disorders of heart rhythm and in high blood pressure, but beyond the drug itself, Black had demonstrated a method: beginning from a theory of how the body works and deliberately designing a molecule to act on it. This approach, now called rational drug design, became a model for the pharmaceutical industry, and in 1988 Black was awarded the Nobel Prize in Physiology or Medicine.^[2]

Black's first beta blockers, propranolol among them, blocked beta receptors throughout the body, both the beta-1 receptors concentrated in the heart and the beta-2 receptors found in the airways and elsewhere. Blocking beta-2 receptors could be a disadvantage, particularly in people with asthma. Later "cardioselective" beta blockers, among them atenolol, metoprolol, and bisoprolol, were developed to act more strongly on the heart's beta-1 receptors and less on the rest, although this selectivity is relative and diminishes at higher doses.^[3] A further group, sometimes called third-generation agents and including carvedilol, labetalol, and nebivolol, combine beta blockade with an additional widening of the blood vessels.

Beta blockers are used across a wide range of conditions. In the heart they are used for angina, for several disorders of heart rhythm, after a heart attack, and, in particular agents shown in large trials to prolong life, for chronic heart failure. They are used for high blood pressure, though in many current guidelines they are no longer a first-choice treatment for it. Beyond the cardiovascular system, beta blockers are used to prevent migraine, to control the physical symptoms of an overactive thyroid, to reduce essential tremor, and, because they blunt the bodily signs of adrenaline such as a racing heart and trembling, to ease performance anxiety, a use for which they are well known among musicians and other performers though not formally approved for it.^[4]

Beta blockers are understood to act by binding to beta-adrenergic receptors and preventing adrenaline and noradrenaline from activating them, that is, they occupy the receptor without switching it on. Blocking the beta-1 receptors of the heart slows the heart rate and reduces the force of each contraction, lowering the heart's workload and its demand for oxygen; this is understood to underlie their effect in angina and in disorders of heart rhythm. Their effect in high blood pressure and, especially, the survival benefit they provide in heart failure are understood to involve more than this, including effects on hormones that regulate blood pressure and on the longer-term remodelling of the heart muscle, and the full account is more complex. That beta blockers block these receptors is well established; the relationship between that blockade and each of their clinical effects is established to varying degrees and in some areas remains a subject of research.

The beta blockers are often grouped by generation. The first-generation, non-selective agents include propranolol, nadolol, timolol, and sotalol. The cardioselective (beta-1-selective) agents include atenolol, metoprolol, bisoprolol, and esmolol. The vasodilating agents include carvedilol, labetalol, and nebivolol. The list is not exhaustive, and the agents differ in other properties, such as how long they act and whether they enter the brain, that influence which is chosen.

The effects of beta blockers follow from what they do: by slowing the heart and lowering blood pressure they can cause tiredness, dizziness, cold hands and feet, and a slow heart rate. Because they blunt the body's adrenaline response, the non-selective agents can narrow the airways and are used with caution in people with asthma, and they can mask some of the warning signs of low blood sugar, which matters for people with diabetes. An important and well-established hazard is that beta blockers should not be stopped abruptly after regular use: sudden withdrawal can cause a rebound worsening of heart rate, blood pressure, and chest pain, and so the dose is reduced gradually under medical guidance. As with all medicines, figures for these risks vary between studies and individual response varies considerably between people.