Propranolol and the beta blockers

Angina comes when narrowed coronary arteries cannot deliver the oxygen that working heart muscle needs. Until the 1960s the only drugs for it were nitrates, which helped only partly. In 1948 Ahlquist had proposed that adrenaline acts through two groups of receptors, alpha and beta. James Black, a British pharmacologist whose father had died suddenly of a heart attack while Black was at medical school, reasoned that blocking the beta receptors would lower the heart's workload and so its demand for oxygen.

Black joined ICI Pharmaceuticals in 1958 and began the work that year. Another group had made a beta-blocking compound, dichloroisoprenaline, in 1958; it slowed the heart but was fit only for animal studies. Taking the related molecule isoprenaline as a template, Black's group, with medicinal chemistry by John Stephenson, produced pronethalol in 1962 and propranolol in 1964. Pronethalol was later withdrawn because it could cause cancer. Propranolol, safer and more potent, was sold as Inderal.

Clinical trials bore out Black's reasoning in angina, and doctors soon noticed that pronethalol and propranolol lowered blood pressure. In 1964 B. N. Prichard and P. M. Gillam reported propranolol for hypertension, and beta blockers became a first-line treatment for it and were used for arrhythmias. In 1978 Prichard warned that heart failure and asthma were the two harmful effects to avoid by careful choice of patients.

The Beta-Blocker Heart Attack Trial, published in 1982, randomized 3,837 patients after myocardial infarction to propranolol or placebo. Total mortality was 7.2 percent on propranolol and 9.8 percent on placebo. Propranolol later found uses in migraine, essential tremor, anxiety, portal hypertension and thyrotoxicosis.

In 1972 Black characterized the histamine H2 receptor and went on to develop cimetidine for peptic ulcer. He shared the 1988 Nobel Prize in Physiology or Medicine with Gertrude Elion and George Hitchings for their discoveries of important principles for drug treatment.