Digitoxin


Digitoxin is a cardiac glycoside used for the treatment of heart failure and certain kinds of heart arrhythmia. It is a phytosteroid and is similar in structure and effects to digoxin, though the effects are longer-lasting. Unlike digoxin, which is eliminated from the body via the kidneys, it is eliminated via the liver, and so can be used in patients with poor or erratic kidney function. While several controlled trials have shown digoxin to be effective in a proportion of patients treated for heart failure, the evidence base for digitoxin is not as strong, although it is presumed to be similarly effective.

Medical uses

Digitoxin is used for the treatment of heart failure, especially in people with impaired kidney function. It is also used to treat certain kinds of heart arrhythmia, such as atrial fibrillation.

Contraindications

Contraindications include

Adverse effects and toxicity

Digitoxin exhibits similar toxic effects to digoxin, namely: anorexia, nausea, vomiting, diarrhea, confusion, visual disturbances, and cardiac arrhythmias. Antidigoxin antibody fragments, the specific treatment for digoxin poisoning, are also effective in serious digitoxin toxicity.

Interactions

Drugs that can increase digitoxin toxicity include:
Drugs that can decrease the effectivity of digitoxin include:

Pharmacology

Mechanism of action

Digitoxin inhibits the sodium-potassium ATPase in heart muscle cells, resulting in increased force of contractions, reduced speed of electric conduction, increased excitability, and reduced frequency of heartbeat.

Pharmacokinetics

The drug is almost completely absorbed from the gut. When in the bloodstream, 90 to 97% are bound to plasma proteins. Digitoxin undergoes enterohepatic circulation. It is metabolized in part by CYP3A4; metabolites include digitoxigenin, digoxin, and conjugate esters. In healthy people, 60% are eliminated via the kidneys and 40% via the faeces. In people with impaired kidney function, elimination via the faeces is increased. The biological half-life is 7 to 8 days except when kidney and liver functions are impaired, in which case it is usually longer.

History

The first description of the use of foxglove dates back to 1775. For quite some time, the active compound was not isolated. Oswald Schmiedeberg was able to obtain a pure sample in 1875. The modern therapeutic use of this molecule was made possible by the works of the pharmacist and the French chemist Claude-Adolphe Nativelle. The first structural analysis was done by Adolf Otto Reinhold Windaus in 1925, but the full structure with an exact determination of the sugar groups was not accomplished until 1962.

Use as a weapon

Digitoxin has been used for at least 7,000 years as an arrow poison. Marie Alexandrine Becker, a Belgian serial killer, was sentenced to death for poisoning eleven people with digitoxin.

In fiction

Digitoxin is used as a poison or murder weapon in:
In The Decemberists's song, "The Rake's Song" on The Hazards of Love album, the narrator murders his daughter by feeding her foxglove.
In Metal Gear Solid V: The Phantom Pain, Venom Snake uses digitalis to obtain digoxin for tranquilizer rounds to incapacitate enemies.

Research

Digitoxin and related cardenolides display anticancer activity against a range of human cancer cell lines in vitro but the clinical use of digitoxin to treat cancer has been restricted by its narrow therapeutic index. Digitoxin glycorandomization led to the discovery of novel digitoxigenin neoglycosides which displayed improved anticancer potency and reduced inotropic activity.