The fascinating foxglove

We were rounding on the hospital service when one of our patients, already hypotensive, went into atrial fibrillation. Which drug would be best to slow the rapid ventricular rate? A beta-blocker? A calcium-channel inhibitor?

Neither, it turned out. The most appropriate drug wound up being one with a long and illustrious history.

More than two hundred years ago in Staffordshire, England, Dr. John Ash was rounding on a patient who was better known throughout the infirmary as the principal of Brasenose College of Oxford. The patient's chief complaint was shortness of breath due to hydrops pectoris (pulmonary edema). Dr. Ash had already attempted to treat the eminent patient with the usual remedies, but his condition was worsening with each passing hour.

The doctor discussed the case with the colleague with whom he shared consulting space, Dr. William Withering. The latter had recently observed elderly women in the English countryside using a mixed concoction to treat “dropsy.” Following extensive botanical studies and investigations, Dr. Withering—who had no pharmaceutical company sponsorship—identified the active ingredient of this concoction as foxglove.

The foxglove plant was named for its flower blossoms, which look like women's fingers. In 1542, German botanist Leonard Fuchs called the plant Digitalis lanata—”digitalis” meaning “finger-like” and “lanata” meaning “wooly.”

Dr. Ash promptly treated his V.I.P. patient with the special foxglove mix his colleague recommended, and the pulmonary edema resolved. The treatment was considered a success.

For more than two centuries after this, digitalis—derived from the foxglove plant—was the pharmacologic bedrock of congestive heart failure and antiarrhythmic therapy. To this day, it is considered one of the few naturally occurring substances with a specific physiological function.

Dr. Withering published his An Account of the Foxglove and Its Medical Uses in 1785, but the Digitalis plant was described by Dioscorides and Galen in ancient Greece, and was mentioned in 1250 A.D. in Welsh physicians' writings. The plant was also used by herbalists for treating epilepsy, and in the healing of wounds.

The exact science behind foxglove's use in treating heart failure was not studied formally until the 19th century. E. Homolle and Theodore Oeuvenne won a cash prize in 1841 from the Société de Pharmacie de Paris for their isolation of digitalin, an active component of the plant. Oscar Schmiedeberg followed suit by isolating digitoxin in 1875, after which the English chemist Sydney Smith isolated digoxin from the foxglove plant in 1930. In the 1970s, the specific circulatory effects of digoxin were discovered as a better understanding of the relationship of left ventricular function in heart failure was achieved. At that time, the use of digoxin was limited by complex dosing and drug interactions.

The use of digoxin to treat heart failure increased in the 1980s, when the neuromodulatory capacities of the drug (including a reduction in plasma renin and norepinephrine levels) began to be studied. Shortly thereafter, digoxin use decreased again. The RADIANCE and PROVED trials demonstrated a reduction in the risk of developing worsening heart failure, evidenced by a lesser number of hospital stays and need for additional heart failure treatment in patients treated with digoxin. The DIG trial found similar results, but also demonstrated that digoxin didn't result in a lower rate of mortality.

A 2006 study in the Journal of Cardiac Failure found that, although the use of digoxin as a treatment for heart failure has decreased in the post-DIG trial era, toxicity from the drug treatment has not followed suit. Symptoms of digoxin toxicity include vomiting, diarrhea, coldness, numbness of lower extremities, mental status change, tonic-clonic seizures, hypotension and generalized weakness, among others. As Dr. William Withering pointed out in the late 1700s, knowledge of these overdose symptoms, in addition to the correct dosing and drug interactions associated with digoxin treatment, is important when prescribing the drug. Despite the controversy surrounding the drug's clinical efficacy and safety in treating heart failure patients, digoxin is still commonly used today in patients for whom other medical treatments are ineffective.

Whether using a concoction of foxglove, or a vial of intravenous digoxin, digitalis is a dangerous but potent drug. For our patient, too hypotensive to tolerate other rate-controlling modalities, it was just the right choice.