Digitoxin

This feature is part of a year-long series of excerpts and special commentaries celebrating AFP's 50th year of publication. Excerpts from the two 1950 volumes of GP, AFP's predecessor, appear along with highlights of 50 years of family medicine.

This feature, titled "The Current Digitoxin Controversy," by Charles H. Scheifley, M.D., is reproduced from the July 1950 issue of GP, with commentary by Jeffrey T. Kirchner, D.O., associate editor of AFP.

The development of purified cardiac glycosides, the active principles of digitalis, has been a distinct step forward in the treatment of diseases of the heart. It has, however, resulted in considerable confusion as to which preparation of digitalis should be considered the one of choice. This situation is understandable when it is pointed out that men who are prominent in the field of cardiology and outstanding for their work on digitalis have shown a marked variance of opinion regarding the product which they believe to be most suitable for routine use. One group champions digitoxin; another group condemns digitoxin and champions digoxin, and finally, a third group likewise rejects digitoxin but considers whole-leaf preparations the most satisfactory form of digitalis.

Statements such as these may make the practicing physician doubtful about the digitalis preparation which he uses, especially since the varying opinions have been made by men who are leaders in their field....

Digoxin is one of the cardiac glycosides derived from Digitalis lanata, and does not have a chemical counterpart in the purpurea species. It is obtained by the hydrolysis of lanatoside C or Cedilanid. It closely resembles Cedilanid in its pharmacologic features. The accompanying figure is a simplified representation of the derivation of the cardiac glycosides from the two-plant species of the genus Digitalis....

Stewart and Newman, and DeGraff, Batterman, and Rose have expressed their disapproval of digitoxin for routine use in the treatment of heart disease. They have pointed out the disadvantages of digitoxin but at the same time have shown considerable concern regarding statements about this drug. It is my impression that at least a part of the disrepute which may have overtaken digitoxin is due as much to the criticism which has been directed at Gold's recommendations for use of the drug as to any inherent defect in the drug itself. Gold frequently stated that the "average digitalizing dose" of digitoxin is 1.2 mg and the "average maintenance dose" is 0.2 mg. It should be said that he mentioned and sometimes emphasized the fact that there are large variations in the individual's susceptibility to digitoxin just as there are to any other form of digitalis....

Variables such as size of the patient, advanced age, degree of cardiac hypertrophy, nature of the underlying disease process, and general debility of the patient must be taken into consideration when digitoxin is used, just as when any other form of digitalis is used. Because of these variations, it is inevitable that in some cases rather marked toxicity will develop if any single dose of digitalization is always used....

Batterman and DeGraff believed that digoxin is the most nearly ideal digitalis preparation. Prolonged toxicity does not accompany its use; toxic symptoms disappear in one to two days or less. Digoxin shows a rapid onset of action and is rapidly excreted. Schwab and Freedberg and Zoll pointed out that the rapidity of excretion makes maintenance of digitalization difficult, and they regarded the rapid dissipation of the drug within the body as a serious disadvantage. To further illustrate this, Rose, Batterman, and DeGraff indicated that, for the purpose of maintenance, the daily dose should not be divided but should be given as a single dose, otherwise rapid excretion of the drug resulted in inadequate maintenance...

It follows that no single preparation of digitalis can be considered the "drug of choice." On the other hand, the whole-leaf preparations, digitoxin, or digoxin may each be considered as a satisfactory product for the initiation and maintenance of digitalization. Each has its advantages and disadvantages.

If William Withering, with his crude infusions of foxglove, was able to obtain satisfactory results, the modern physician with the excellent preparations of digitalis available to him is indeed in a position to be of outstanding service to the patient with heart disease.

Whither Digitalis in the New Millenium?

Dr. Scheifley's piece called "The Current Digitalis Controversy," in which he discusses the appropriate formulations of digitalis that clinicians should be using, made me reflect on my own first exposure to this drug almost 20 years ago. Undoubtedly, the first time I heard about cardiac glycosides was in 1982, when I was a second-year medical student in a pharmacology course. As with much of the didactic lecture material I was exposed to during the first two years of medical school, soon after the examination was over, the memorized facts about digitalis pharmacology went out of sight and out of mind. These cerebral deletions were necessary to make room in my brain for information that would be on the next examination.

Digoxin "resurfaced" during my third-year internal medicine clerkship, when I was taught by much wiser interns and residents how to "digitalize" a patient admitted with rapid atrial fibrillation and how to treat patients with congestive heart failure by giving them "dig and lasix." During my internship and family practice residency in the mid to late 1980s, digoxin was still in common use. However, I recall diagnosing and treating "dig" toxicity as often as I used the drug for therapeutic purposes.

It is rather remarkable that digitalis has survived 200 years of medical use. Its longevity has persisted through several changes in formulation, as discussed by Dr. Scheifley. It has not disappeared from the medicinal armamentarium despite significant changes in the way physicians are educated and cardiac patients are treated in today's high-tech intensive care units. That being said, digitalis is the drug that the eminent cardiologist Dr. Milton Packer described in the New England Journal of Medicine(1) as being "at the center of the oldest controversy in the history of medicine."

A generation of new physicians and pharmaceutical advances notwithstanding, digitalis continues to provide clinical benefit to those who take it. Its role in the management of atrial fibrillation has definitely diminished as other, more effective agents are commonly used in the treatment of this dysrhythmia. Where the drug has held its ground even to the end of the past decade and into the new millenium is in the treatment of congestive heart failure. The Digitalis Investigators Group study(2) established for the first time sound evidence that digoxin provides symptomatic relief, a decreased rate of hospitalization and a better quality of life. Unfortunately, the outcome that matters most to patient and physician--mortality--was not an observed outcome of this landmark trial.

Current guidelines for treating congestive heart failure now recommend the use of angiotensin-converting enzyme (ACE) inhibitors, beta blockers and spironolactone, all of which appear to affect mortality rates. On the other hand, digitalis remains the only true inotropic agent that has not been shown to actually increase mortality. It is likely that digoxin will be a drug that my generation or the new generation of physicians puts to rest. To again quote Dr. Packer, "... as the list of therapeutic agents (for congestive heart failure) that prolong life increases, the use of digitalis will inevitably wane." However, considering that this is a drug that undoubtedly makes people feel better, costs about 30 cents a dose and can be taken once a day, I personally feel that reports of its demise are premature. For now I will encourage my father to keep taking his small white pill along with the ACE inhibitor and daily aspirin prescribed by his doctor.

REFERENCES

(1.) Packer M. End of the oldest controversy in medicine--are we ready to conclude the debate on digitalis? N Engl J Med 1997;336:575-6.

(2.) The Digitalis Investigation Group. The effect of digoxin on mortality and morbidity in patients with heart failure. N Engl J Med 1997;336:525-34.

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