Pharmacy's Past: The Discovery of Digoxin

Digoxin (Lanoxin) is an old drug with a fascinating history. Digitalis is a genus of 20 species of flowers that grow wild in large parts of the eastern hemisphere and are widely planted by gardeners in the United States.¹

Several species have been used medically for centuries and are still the source for digoxin, which to this day is used to treat cardiac arrhythmia. William Withering, author of An Account of the Foxglove (published in 1785), popularized the medical use of digitalis.¹

Digitalis means finger-like and refers to the flowers on the foxglove (Digitalis purpurea). The plant has wide leaves, serrated edges, tall spikes, and long, bell-shaped purple flowers.¹

Withering had the idea of gathering the leaves when the blossoms came out. The leaves were dried, either in the sun or on a pan over a fire, becoming a green powder that was used directly or made into an infusion.¹

Today, the leaves are extracted to yield digoxin, which is a cardiac glycoside. Digoxin inhibits the Na+/K+ ATPase pump in cardiac muscle cells and leads to excess intracellular Na+, indirectly causing an increase in calcium ions in the sarcoplasmic reticulum. These increased calcium levels lead to a more forceful contraction of cardiac muscle and allow the heart to work more efficiently.¹

Although used as a heart drug today, Withering used digitalis for many ailments, including edema, epilepsy, hydrothorax (fluid in the pleural cavities), ovarian cysts, and tuberculosis. Withering occasionally used digitalis as a treatment of last resort, "...whilst I was less expert in the management of the digitalis, I seldom prescribed it, but when the failure of every other method compelled me to do it...if the properties of that plant had not been discovered, by far the greatest part of these patients would have died."¹

Digitalis can be extremely toxic in large and repeated doses and may cause vomiting, disturbed vision, objects to appear green or yellow, slow pulse, cold sweats, unconsciousness, or death.¹

Digoxin toxicity can occur during long-term therapy, as well, not just after an overdose. In fact, chronic toxicity is more common than acute intoxication. Toxicity can occur even when the serum digoxin concentration is within the normal therapeutic range. Digoxin toxicity may cause anorexia, nausea, vomiting, neurological symptoms, and can also trigger fatal arrhythmias.²

The visual disturbances include a tipping of the color scale toward yellow (xanthopsia) and halos around bright light. These effects can be seen in some of Vincent Van Gogh’s later work, his "yellow period." Halos around the stars and moon can be seen in his painting "The Starry Night" and other works. Theories suggest these effects are due to his use of foxglove for treatment of epilepsy. However, similar effects may be caused by alkaloids in Artemisia absinthium, used to brew absinthe, which was one of Van Gogh’s preferred drinks.¹

Charles Edmund Cullen, a nurse who may be the most prolific serial killer in American history, used digoxin as his poison of choice. He was arrested in 2003 after a 16-year murder spree. He reports killing at least 40 patients, but evidence suggests that he may actually be responsible for hundreds of deaths.¹  

References

• American Association for the Advancement of Science: https://www.aaas.org/digitalis-flower-drug-poison Digitalis: The flower, the drug, the poison Accessed March 31, 2019
• US National Library of Medicine National Institutes of Health https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4816869/: Management of digoxin toxicity Accessed March 31, 2019