Cardiac Glycosides

CARDIAC GLYCOSIDES

Historical Background

In “An Account of the Foxglove” William Withering re-lated his experiences while in private practice more than 200 years ago. He traveled between two towns where he took care of the wealthy patients on a fee-for-service basis in one town and the poor people for free in the other. He encountered during one of his com-mutes a practitioner of the healing arts who was re-ferred to as a witch. She provided care for people with obvious signs and symptoms of fluid overload who were diagnosed with dropsy (later called CHF). She gave these patients a group of herbs that contained digitalis, and it was Withering who identified Digitalis purpura as the active plant in this mixture. Unfortunately, he lacked any insight into potential mechanisms of action. Although Withering thought that digitalis worked by in-ducing emesis, he was actually describing digitalis toxic-ity and not the mechanism of action at all.

Digitalization

Digitalis remains notorious today for its very narrow dosage window for therapeutic efficacy without toxicity. A unique process, digitalization, for dosing digitalis (digoxin [Lanoxin]; digitoxin [Crystodigin]) has been widely accepted over the years as a means of minimiz-ing toxicity. This process is to start patients on several repeated doses of digitalis over 24 to 36 hours before es-tablishing a lower daily maintenance dose. Digitalis has become the mainstay of therapy for CHF despite its toxicity, the lack of understanding of its mode of action, and the lack of any definitive evidence describing its safety and efficacy.

Toxicity

Digitalis toxicity includes nausea, vomiting, anorexia, fatigue, and a characteristic visual disturbance (green-yellow halos around bright objects). Cardiac toxicities have included tachyarrhythmias and bradyarrhythmias, including supraventricular and ventricular tachycardia and atrioventricular (A-V) block. The most classic (but not most frequent) manifestations of digitalis toxicity include atrial tachycardia with A-V block. Treatment for digitalis toxicity ranges from mild cases that respond to simply stopping the drug to the use of antidigitalis antibodies in life-threatening situations. The availability of a radioimmunoassay for digitalis levels and antidigi-talis antibodies, useful in reversing digitalis’s actions, have minimized the frequency of fatal toxicity.

Clinical Use

Randomized clinical trials have been conducted to ex-plore the safety and efficacy of digitalis in the manage-ment of CHF. The first major trial showed an improve-ment in quality of life but no mortality benefit. A second major clinical trial revealed that treatment with digitalis diminished the combined end points of death and hos-pitalizations but did not specifically improve overall survival. Thus, no studies have demonstrated that digi-talis therapy improves survival in CHF patients. However, digitalis does decrease morbidity by dimin-ishing the number of admissions to the hospital for symptoms such as dyspnea (shortness of breath) and fa-tigue. Current guidelines for the treatment of CHF in-dicate that physicians must at least consider including digitalis in the regimen. The consensus now is to pre-scribe a dose that achieves a digitalis blood level of 0.8 to 1.2 ng/dL. This lower dose reduces the incidence of side effects while optimizing the benefit.

Mechanism of Action

Digitalis has the unique characteristic of increasing con-tractility (positive inotropy) while decreasing heart rate (negative chronotropy). This pharmacological profile results from indirect as well as direct effects of digitalis glycosides on the heart. Digitalis is a fat-soluble steroid that crosses the blood-brain barrier and enhances vagal tone. The slowing and/or conversion of a patient with supraventricular arrhythmia (e.g., atrial fibrillation, supraventricular tachycardia) with digitalis results from enhancement of vagal tone. This increased vagal activity increases acetylcholine release, which in turn is coupled to the opening of a K⁺ channel. Opening of this K⁺ channel results in closing of the L-type sarcolemmal Ca⁺⁺ channel. Ca⁺⁺ channel inhibition slows the heart rate and/or converts the rhythm to a sinus mechanism.

Digitalis works directly on the heart through an ac-tion on the sodium–potassium (NA⁺ –K⁺ ) ATPase. Since all living cells have a resting membrane potential, there is an electrochemical gradient across the cell membrane that is not at a steady state electrically. There is an im-balance in that all cells are intracellularly negative com-pared to the outside of the cell. The maintenance of this gradient requires metabolic energy to maintain this dif-ference in ions. This electrochemical gradient is lost af-ter death. The activity of the NA⁺ –K⁺ ATPase results in serum sodium levels of roughly 140 to 145 mmol and serum potassium around 5 mmol. Inside cells the NA⁺ concentration is low and the K⁺ concentration is high. The reason for this difference between the intracellular and extracellular sodium and potassium is the action of the NA⁺ –K⁺ ATPase enzyme. Digitalis binds to this en-zyme and inhibits its activity. This results in an elevation in intracellular NA⁺ that leads to an increase in extru-sion of NA⁺ through the NA⁺ –Ca⁺⁺ exchanger, which functions to maintain a relatively constant level of both NA⁺ and Ca⁺⁺ in the cell. The NA⁺ –Ca⁺⁺ exchanger nor-mally extrudes Ca⁺⁺ in exchange for NA⁺ . However, in the presence of increased intracellular NA⁺ , it will ex-trude NA⁺ by exchanging it for extracellular Ca⁺⁺ . This reversal in the activity of the NA⁺ –Ca⁺⁺ exchanger re-sults in an increase in intracellular ionized free Ca⁺⁺ that enhances myocardial contractility.

The current hypothesis regarding the cellular basis for the positive inotropic effect of digitalis helps to ex-plain some of the wide individual variability in the dosage required to develop digitalis toxicity. Dif-ferences in pH, ischemia, NA⁺ , K⁺ , and Ca⁺⁺ can each alter the likelihood of developing toxicity within the same patient and between individuals.