Digoxin

The cardiac drug digoxin, in use for more than 200 years, stemmed from an herbal remedy rather than from laboratory chemistry. English physician William Withering is credited with discovering in 1775 that the foxglove plant could help those suffering from abnormal fluid buildup, or dropsy, as it was called in those days.

In a 1785 report, Withering writes that he was asked in 1775 to evaluate a home remedy for dropsy compounded by “an old woman in Shropshire.” With her herbal concoction, she “had sometimes made cures after the more regular practitioners had failed,” according to his report.

Withering, who was also a botanist, quickly figured out that of the 20 or so herbs in the woman's remedy, foxglove was the key ingredient. In his report, he noted that foxglove was particularly helpful for his patients who developed dropsy after suffering from scarlet fever or bad sore throats. Scarlet fever and strep throat, both caused by a Streptococcus bacterium, can damage the heart valves. Improperly functioning valves can lead to congestive heart failure--a condition in which fluid builds up in the body's tissues because of the heart's weak pumping action.

Withering used dried foxglove leaves in his dropsy remedy. The leaves contain a number of glycosides--chemicals that are composed of a sugar and a cardenolide (which has a five-membered lactone ring)--that are called by the umbrella term digitalis. The flowers, seeds, and sap also contain digitalis, but less than the leaves have.

In 1930, researcher Sydney Smith of Burroughs Wellcome isolated the glycosides of the woolly foxglove, Digitalis lanata. One is digoxin. Burroughs Wellcome successor GlaxoSmithKline sells digoxin as a drug under the name Lanoxin.

For decades, digoxin has been prescribed for patients with congestive heart failure and atrial arrhythmias, a type of heart rhythm problem. Digoxin's glycosidic bonds are broken down in the body, forming digitoxin and sugars. The digitoxin slows the heart rate and increases the force and velocity of the heart's contraction. This chemical increases the amount of calcium in the heart cells, which strengthens the heartbeat.

Digoxin pills figured prominently in my childhood in the 1960s and '70s. Every morning before school, my father would wake me up and, just before he left for work, ensure I was truly out of bed and moving. After I got dressed, my job was to go to the kitchen, fish a single white digoxin pill out of a prescription bottle, and place it in a tiny plastic medicine cup. I then filled a mug with hot coffee and added a dollop of milk. I carefully carried the coffee and pill up a flight of stairs to my mother's bedside. Most mornings, she was still in bed, drowsing.

Mom, who experienced at least two bouts of rheumatic fever between the ages of nine and 18 in the days before antibiotics, had a damaged mitral valve, atrial arrhythmia, and heart failure. She would tell me the combination of the coffee's caffeine and her "heart pill" gave her the push she needed to get out of bed, walk down the stairs, and go about her day tending the home.

Researchers from Yale University, however, recently questioned whether digoxin helps women. A 2002 study concluded that the drug seems to reduce the need of patients of both genders for hospitalization due to worsening heart failure, but doesn't decrease mortality. Gender-specific analysis of the data suggested that digoxin actually may increase the death rate of women with heart failure. Controversy remains on whether this effect in women is real or a statistical fluke, since the Yale study was not designed to examine gender differences.

Some experts believe that digoxin is an effective therapy for women if the dose does not boost their blood levels of this compound beyond the drug's narrow window of therapeutic effects. An overdose of digoxin may cause convulsions and heart attack in either sex.

In her later years, as her heart failure worsened, Mom's cardiologist switched her to a beta blocker and a diuretic, a strategy viewed by some doctors as a modern, more effective treatment than digoxin. Physicians nowadays also prescribe angiotension-converting-enzyme (ACE) inhibitors for heart failure.

Modern manufacture of digoxin for use in pharmaceticals is an updated version of Withering's herbal remedy. Unlike many pharmaceutical compounds, which are synthesized in factories via chemical processes, digoxin still comes from the foxglove plant.

According to GlaxoSmithKline, farmers in the Netherlands grow fields of woolly foxglove, which is a member of the snapdragon family. Bales of dried foxglove leaves are shipped to the U.S. Here, processing facilities macerate the leaves and extract digitalis using an aqueous-alcohol solvent. Further treatment and processing yields powdered digoxin, which is compounded into tablets, injectable solutions, elixirs, and capsules. It takes about 1,000 kg of dried foxglove leaves to make 1 kg of pure digoxin, the company adds.

Engravings of the foxglove flower adorn Withering's gravestone.

Digoxin

Name
◾ (3β,5β,12β)-3-[(O-2,6-Dideoxy-β-D- ribo-hexopyranosyl-(1→4)-O-2,6-dideoxy-β-D- ribo-hexopyranosyl-(1→4)-2,6-dideoxy--D- ribo-hexopyranosyl)oxy]-12,14-dihydroxycard -20(22)-enolide

CAS Registry
◾ 20830-75-5

Other Names
◾ Lanoxin
◾ 3-chloro-10-(3-dimethhylaminopropyl) phenothiazine
◾ Digitek

Introduced
1930, Burroughs Wellcome

Sales
$137 million in 2001, for Lanoxin

This article was corrected on July 31, 2017, to reflect that Withering did not name the woman in his report.