Salbutamol

In 1969, Allen & Hanburys (part of the Glaxo Group, now GlaxoSmithKline) launched the highly successful asthma drug salbutamol. Marketed just three years after its synthesis, salbutamol is still on the market, sold as Ventolin and Proventil.

Asthma is a chronic respiratory disease characterized by inflammation and narrowing of airways in the lungs, the bronchi. During an asthma attack, the smooth muscle surrounding the bronchi contracts and the lining of the bronchi swells; this swelling is life-threatening because the airways can become blocked. Asthma affects more than 30 million people in the U.S.--111 people per 1,000--and more than 4,000 died of the disease in 2002, according to the Centers for Disease Control & Prevention 2002 National Health Interview Survey. The Global Initiative for Asthma estimates that 300 million people worldwide currently have asthma and an additional 100 million people will be diagnosed by 2025. Although asthma can be managed, there is no cure for it.

Salbutamol is one of the β-agonist bronchodilators, the largest group among the various classes of inhaled asthma drugs. The recent evolution of β-agonists can be traced back to adrenal extracts that were used to treat asthma in the late 1800s and the synthesis of epinephrine, also known as adrenaline, at the turn of the 20th century.

Adrenaline is the body's natural bronchodilator, so the benefits of epinephrine were recognized in the 20th century for treating asthma. By the 1920s, injectable epinephrine was a preferred asthma treatment, followed by nebulized epinephrine in the 1930s.

Adrenaline is released in the body by the adrenal glands when a person is confronted with stress. Unfortunately, injected epinephrine comes with adverse side effects, such as anxiety, heart palpitations, tremors, and increased blood pressure. Epinephrine and other b-agonists are categorized as sympathomimetics, meaning they mimic the natural stimulation of the sympathetic nervous system. The unwanted side effects led researchers to search for an adrenaline analog that would retain the bronchodilating quality without the cardiovascular side effects.

In the 1940s, isoprenaline was synthesized. It was a more effective bronchodilator that did not increase blood pressure, and it eventually displaced epinephrine as the preferred asthma treatment. Isoprenaline wasn't an ideal solution, however. It still led to increased heart rate, and the effects were short-lived because it was metabolized quickly.

In the 1960s, an increase in asthma deaths in Britain coincided with the increase in sales of isoprenaline inhalers. The circumstantial evidence implicated the high-strength isoprenaline (known as isoprenaline-forte) used in the inhalers. There was also evidence that some patients had used it more frequently despite worsening asthma, although the exact cause of the deaths remains unknown.

In 1963, David Jack, then head of research at Allen & Hanburys, and his team began work on a new asthma drug. Jack and his team concluded that to control both causes of asthma (muscle contraction and bronchial swelling), they had to identify an improved bronchodilator and a better anti-inflammatory drug. The starting objective was a long-acting analog of isoprenaline that would be relatively stable as well as longer acting whether taken by mouth or inhalation (Science in Parliament 1992, 49, 4).

Because isoprenaline's brief effect was due to the enzyme catechol-O-methyltransferase, a senior medicinal chemist on the team decided to make a noncatechol analog of isoprenaline. The chemistry proved to be difficult--it was not until 1966 that the saligenin analog of isoprenaline was first tested. The tests revealed that the β-agonist was active on the bronchial muscle but did not affect the heart. The next drug in the series to be tested was salbutamol, which was found to be more active at the β₂-receptors, to act even more selectively on bronchial muscle with minimal cardiovascular side effects, and--best of all--to last about four hours.

The credit for getting salbutamol to market so quickly goes to Jack. "In the early stages, we experimented on one another," he recalled at a Wellcome Trust oral history seminar in 2000. "I was the first to take salbutamol by inhalation and by mouth under the supervision of [our medical director]. He had the drug next under my supervision. ... Within a month, we knew the effective doses of salbutamol, by inhalation and by mouth, the duration of the action, and the probable use-limiting side effects. Thus, it took only six months from the date of first synthesis to establish the probable efficiency and safety of the drug," he said. Jack also made the decision to conduct the different development studies concurrently rather than sequentially, which saved significant time.

Salbutamol was one of the earliest drugs developed by rational design. At the time there were no models of the β-receptors to guide the work; the human β-receptor was not characterized until the 1990s. So the researchers relied on an iterative process based on what they knew about the structure and properties of adrenaline and isoprenaline.

Asthma is an ancient disease--the history of its treatment goes back about 5,000 years. Salbutamol revolutionized asthma treatment and management within months of appearing on the market, leading to other bronchodilators and an improved quality of life for asthma sufferers.

Albuterol

Name: α-1-{[(1,1-Dimethylethyl)amino] methyl}-4-hydroxy-1,3-benzenedimethanol

CAS Registry: 18559-94-9

Other names: Aerolin, Asmol, Proventil, Respax, Respolin, Sabutamol, Salbulin, Ventodisks, Ventolin

Sales: $7.6 million β-agonist aerosols in 2004

Did you know that the Ebers Papyrus, a 3,500-year-old Egyptian medical document, prescribed an asthma remedy of a mixture of herbs to be heated on a brick so that the sufferer could inhale their fumes?