Beta Blockers Invented by Sir

Beta Blockers

Invented by Sir James W. Black. beta blockers are a class of pharmaceuticals that improve the heart's ability to relax. They are primarily used for the management of hypertension, cardiac protection following myocardial infarction, angina pectoris, and cardiac arrhythmias ("Heart failure," 2005) in addition, beta blockers are sometimes prescribed for hyperthyroidism, glaucoma and migraine headaches (Brygg, 2009). Beta blockers are also known as: beta-adrenergic antagonists, beta-adrenergic blocking agents, and beta antagonists.

According to Menghini (2008), beta blockers reduce cardiac inotropism and chronotropism, both while the patient is at rest and under stress. This results in a reduced cardiac rate and a reduction in pressure rate and a readjustment of the peripheral resistances. Menghini continues to note that a hypotensive effect is also realized through the reduction of renin incretion, as a result of a reduction in the release of catecholamine of the synaptic terminals. A resetting of the carotid and aortic baroceptors, and also through a mechanism of central modulation type of the sympathetic vasomotor tone. In layman's terms, beta blockers work by decreasing the manufacture of harmful substances that are produced by the body, in response to heart failure. In addition, they slow the patient's heart rate. Used over a period of time, beta blockers can improve the heart's ability to pump blood (Brygg, 2009). For these reasons, they are a critical treatment for patients with heart failure. Prescribed for patients with systolic heart failure, beta blockers are proven to improve survival rates, even for patients with severe systems ("Heart failure," 2005).

There are a variety of different types of beta blockers that have been developed. These include: Sectral (acebutolol); Zebeta (bisoprolol); Brevibloc (esmolol); Inderal (propranolol); Tenormin (atenolol); Normodyne or Trandate (labetalol); Coreg (carvedilol); and Lopressor or Toprol-XL (metoprolol) (Bryg, 2009). However, only three have received U.S. Food and Drug Administration approval for treatment in heart failure. These approved varieties include: Zebeta (bisoprolol), Coreg (carvedilol), and Toprol-XL (metopolol succinate) ("Heart failure," 2005). There are aspects patients need to be aware of when taking beta blockers.

Beta blockers can be taken at meals, bedtime or in the morning. However, consumption of food with the medication delays the absorption of beta blockers, but may also reduce side effects. The size of the dose and frequency are determined by the patient's condition. Beta blockers are not recommended for those suffering from hypotension or bradycardia. Those with severe lung congestion must have this congestion addressed prior to starting beta blocker therapy ("Heart failure," 2005). There are several side effect to treatment with beta blocker medication.

The types of side effects associated with beta blockers vary significantly. Patients may experience: Dizziness or lightheadedness, which often occurs when rising from bed or standing from a chair; tiredness; cold hands or feet; headaches; nightmares; heartburn; diarrhea; constipation; difficulty sleeping; weight gain; shortness of breath; skin rash; irregular heartbeat; swelling of feet or lower legs; chest pain; and severe vomiting ("Heart failure," 2005). The history of this revolutionary medication is of particular interest.

Beta Blocker History:

The development of today's beta blockers began centuries ago. Today's beta blocker's ancestor, digitalis, was originally used in the 1200s. According to Archard (2005), this positive inotropic agent was found to relieve symptoms of heart failure. It was most often administered in the form of a herbal remedy that contained purple foxglove, until the active ingredient was identified by William Withering and published his findings in 1785. The active glycosides found in foxglove leaves was isolated in 1930, which led to the synthetic agent digoxin as a treatment for chronic heart failure. While not improving overall life expectancy, digoxin has been shown to reduce hospitalization for patients with atrial fibrillation and is still used today.

Significant increases in angina and heart attacks, in the 1940s and 1950s, prompted increased research in to the treatment of these conditions. It was understood that these conditions were caused by a decrease in blood flow to the heart and that incidents of stress could trigger the attacks (Archard, 2005). In 1948, Raymond Ahlquist distinguished between alpha and beta adrenoceptors, which would forever change pharmaceutical innovation (Quirke, 2006). Menghini (2008) notes that the specific history of beta blockers continued in 1958, when Powell and Slater described the particular anti-adrenergic properties of a new compound named dichloroisoproterenol (DCI), as it led to the rapid acceptance of the concept of a dual receptor mechanism. Six months following Ahlquist's published research, Moran and Perkins were published in the same journal arguing "that DCI's activity belonged to Ahlquist's 'beta-adrenergic' type, and coined the term 'beta-adrenergic blocking drug', later shortened to 'beta-blocker'" (Quirke, 2006).

Quirke (2006) cites Rein Vos's book, Drugs Looking for Diseases, as arguing that Moran and Perkins' realization that DCI was an innovative new class of bio-active compound (and, in fact, the first beta blocker) was a result of "a complex process of disciplinary transformation which affected both pharmacologists and clinical scientists." However, others have argues that there was a large component of chance in this development.

Citing Desmond Fitzgerald, Quirke (2006) notes that Moran had been studying the cardiovascular effects of a variety of catecholamines. These are substances that primarily act as neurotransmitters on the central and sympathetic nervous system. It was chance that had Moran studying catecholamines when he heard about Powell and Slater's research (Fitzgerald, 2000). Chance was also involved when Sir James Black developed pronethalol, and later propranolol.

Black had just joined the cardiovascular research team at Imperial Chemical Industries, Ltd. (ICI) when he first read Moran's research. It was then that he realized the possibilities of synthesizing an analog to DCI (Kennedy, 1986). Quirke (2006) surmises that Black had hoped that this analog, unlike DCI, would be clinically useful, as it showed a degree of stimulant activity and happened to be a partial agonist.

W.S. Waring, in 1956, had released a report regarding the problem of atherosclerosis. According to Quirke (2006), Waring approached the problem in terms of an indirect attack on cholesterol sythesis. Black's approach framed the problem centering on coronary artery disease's underlying mechanism. Black's ICI report dated in 1959, as cited by Quirke, states:

One possibility, scarcely tested, is that altered fat metabolism with associated changes in blood coagulability interact, permissively, with sympathetic neurohumoural stress responses to produce fatal damage.

This was part of the breakthrough that led to the beta blockers that revolutionized the pharmaceutical industry today.

By 1962, Black, while still working for ICI, synthesized Propranolol (Inderal), which would later win him the Nobel Prize for Medicine in 1989. This was a replacement for Black's first beta blocker treatment -- pronethalol (Alderlin) -- that was removed from the market because it was found to cause thymic tumors in mice (Quirke, 2006). The first clinical studies were conducted in 1964, for the use of Propranolol in the treatment of arterial rhythm, angina, and hypertension disorders, propelling the treatment from the experimental phase towards implementation in the healthcare industry (Menghini, 2008). In 1966, it becomes the first beta blocker to be marketed in the United States (Altman, 1982).

In 1967, Menghini (2008) cites Lands as identifying a variety of models of sensitivity to a variety of sympathomimetic amines and postulated that there were two types of beta-receptors. These are beta 1 receptors, which are primarily cardiac, and beta 2 receptors which can be found primarily in the bronchial and vascular level. This has resulted in three primary types of beta blockers being developed -- cardioselective beta blockers, non-selective beta blockers and those with alpha and beta blocker properties.

Metabolism

Beta I Selective

Non-Selective

Alpha+Beta Blockers

Hepatic

Metoprolol

Betaxolol*

Propranolol

Oxprenolol*

Labetalol

Carvedilol

Intermediate

Acebutolol *

Pindolol*

Sotalol

Timolol

Bisoprolol

Renal

Atenolol

Mepindolol*

Nadolol

*ISA: Intrinsic Sympathomimetic Activity

(Menghini, 2008)

Since the 1960s, the development of more efficient beta blockers has been a primary pursuit.

Conclusion:

Not so very long ago, the favored congestive heart failure treatment was digitalis and diuretics. Today, there are several choices of far more efficient and effective pharmaceuticals available to patients. Whether cardioselective beta blockers, non-selective beta blockers or alpha and beta blocker properties are needed, cardiac patients now not only have reduced hospitalization, but also longer life expectancies thanks to Black's development of propranolol only a half a century ago.

Beta Blocker Timeline

1200s

Digitalis administered in the form of a herbal remedy containing purple foxglove used to relieve symptoms of heart failure.

William Withering identifies active ingredient in digitalis and publishes his findings.

1930

The active glycosides found in foxglove leaves are isolated, leading to the synthetic agent digoxin as a treatment for chronic heart failure.

1940s -- 1950s - Significant increases in angina and heart attacks lead to increased research into the treatment of these conditions.