Digitalis

Scientific Name(s): Digitalis purpurea L.; Digitalis lanata Ehrh. Family: Scrophulariaceae (figworts)

Common Name(s): Foxglove , digitalis , purple foxglove , throatwort , fairy finger , fairy cap , lady's thimble , scotch mercury , lion's mouth , witch's bells , dead man's bells , wooly foxglove 1 , 2 , 3 , 4

Clinical Overview

Uses of Digitalis

In addition to a range of other traditional uses, digitalis has long been used as a treatment for heart failure. The plant is cultivated as an ornamental.

Digitalis Dosing

Digitalis leaf provides a narrow therapeutic index, requiring close medical supervision for safe use. Classical dosage started at 1.5 g of leaf divided between 2 daily doses. Purified digoxin is typically used at daily doses of 0.125 to 0.25 mg.

Contraindications

Do not allow children to come into contact with the potentially lethal plant.

Pregnancy/Lactation

Documented adverse cardiac effects. Avoid use.

Digitalis Interactions

There are numerous interactions with digoxin and digitalis glycosides, some of which are life-threatening (eg, amiodarone, furosemide, verapamil).

Digitalis Adverse Reactions

No data available.

Toxicology

All parts of the plant are toxic. The incidence of digitalis toxicity has been estimated to range from 5% to 25%. Ingestion of extremely small amounts of the plant may be fatal to humans, especially children, and to animals. Toxicity is cumulative.

Botany

Digitalis is typically a biennial plant, but may be annual or perennial depending on the species. It is characterized by a thick, cylindrical, downy stem that reaches a height of up to 2 m. Leaves form a thick rosette during the first year of growth. The leaves, which are wooly, veined, and covered with white hairs on the underside, have a very bitter taste. Flowers grow in the first or second year, depending on the species, and are tubular and bell-shaped, growing to 8 cm in length. Although many colors of flowers have been bred from digitalis, the flowers are rarely white. The plant is native to the British Isles, western Europe, and parts of Africa, but today is found as an ornamental throughout the world. Related species that have found some use in traditional medicine include D. lutea (straw foxglove), D. grandiflora and D. ambigua (yellow foxglove), and D. ferriginea (rusty foxglove). 1

History

Digitalis was one of the many folklore herbal remedies known to the ancient Romans. 5 Although its use has been traced back to 10th century Europe, digitalis was not widely used as a diuretic for the treatment of congestive heart failure (CHF) until its scientific investigation by British physician William Withering in the late 1700s. 1 For most of the 1800s, digitalis was used to treat a wide variety of diseases and disorders. 5 In 1875, German chemist Oswald Schmiedeberg first isolated pure digitoxin from digitalis, leading others to extract and identify other glycosides from various species of digitalis. 5 In 1957, digoxin was isolated from D. lanata and is now the main glycoside marketed in tablet form. 5

In South America, preparations of the powdered leaves are used to relieve asthma, as sedatives, and as diuretic/cardiotonics. In India, an ointment containing digitalis glycosides is used to treat wounds and burns. 1

Today, digitalis glycosides are widely used in the treatment of CHF; however, because of their narrow therapeutic margin and high potential for severe side effects, the use of these products is beginning to be supplanted by newer agents, including the angiotensin-converting enzyme inhibitors and the calcium channel blocking agents. As new pharmacotherapeutic agents arise, the use of digitalis preparations will continue to decline. 6

Digitalis was admitted into the first (1820) edition of the United States Pharmacopeia and currently is recognized by all major pharmacopeias. 5

Chemistry

Ornamental strains of D. purpurea typically have low concentrations of active compounds. Leaves of wild varieties that have been used for medicinal purposes contain at least 30 different glycosides in total quantities ranging from 0.1% to 0.6%; these consist primarily of purpurea glycoside A (yielding digitoxin) and glycoside B, the precursor of gitoxin. Upon hydrolysis, digitoxin and gitoxin lose sugar molecules, producing their respective aglycones, digitoxigenin, and gitoxigenin. Seeds also contain digitalis glycosides. 1

The main glycosides of D. lanata are the lanatosides, designated A through E. Removal of acetate groups and sugars results in formation of digitoxin, gitoxin, digoxin, digitalin, and gitaloxin. 1 , 7 D. lanata is not typically used in powder form in the United States, but serves as a major source of lanatoside C and digoxin.

Digitalis Uses and Pharmacology

Digitoxin is 1,000 times more potent than the powdered leaves and is completely and rapidly absorbed from the gastrointestinal tract. 1 Digoxin is 300 times more potent than the powder prepared from D. purpurea .

All cardiac glycosides share the characteristic of improving cardiac conduction, thereby improving the strength of cardiac contractility. These drugs also possess some antiarrhythmic activity, but will induce arrhythmias at higher dose levels.

Digitalis glycosides have been used clinically for the treatment of CHF for more than 200 years.

Research reveals no animal data regarding the use of digitalis for CHF.

Numerous studies have been conducted on the use of digitalis as a treatment of CHF in sinus rhythm. The literature identifies a role for digitalis in the treatment of this condition. 8

Recent research has shown the anticancer effects of digitalis compounds, suggesting their possible use in medical oncology. 9 Further research is needed to see whether cardiac glycosides can be used as antitumor drugs. D. lanata and D. purpurea were identified as having cytotoxic properties, including cytotoxic activity, and warrant further study. 10

Another study was supportive of investigations showing that apoptosis induction is a major effect of digitalis on several types of tumor cells. 9 The report demonstrated the anticancer activity of D. purpurea . L. heywoodi on 3 human cancer cell lines. 9

The results of one study revealed marked differences in cytotoxicity between the cardiac glycosides, both in potency and selectivity, and modes of action that differ from those of commonly used anticancer drugs. 11 More studies are needed to clarify a possible role of cardiac glycosides in chemotherapy of malignant diseases. 11

Short-term animal experiments concluded that toxic doses would be needed to produce an anticancer effect in humans. 9 However, susceptibility for cardiac glycosides differs between species, indicating that the results from animal models cannot be extrapolated into humans.

Several investigators have postulated that digitalis glycosides could be used in cancer therapy, and that they may operate through novel mechanisms; however, this idea has not found wide acceptance.

For a concise review on the medicinal use, interactions, and adverse effects of commercial products, please refer to Drug Facts and Comparisons . 12

Dosage

Digitalis leaf provides a narrow therapeutic index, requiring close medical supervision for safe use. Classical dosage started at 1.5 g of leaf divided between 2 daily doses. Purified digoxin is typically used at daily doses of 0.125 to 0.25 mg. 8 , 13

Pregnancy/Lactation

Documented adverse cardiac effects. Avoid use. 14

Interactions

There are numerous interactions with digoxin and digitalis glycosides, some of which are life-threatening. Many of the life-threatening interactions occur as a result of elevated digoxin serum levels (eg, amiodarone, cyclosporine, macrolide antibiotics [eg, erythromycin], propafenone, quinidine, tetracycline, verapamil) or electrolyte disturbances (eg, loop diuretics [eg, furosemide], thiazide diuretics [eg, chlorothiazide]) and are caused by a coadministered drug. Because these interactions are considered to be drug-drug interactions, they are more appropriately discussed in standard drug interaction texts, which the interested reader should consult for more comprehensive information. 15

Adverse Reactions

Research reveals little or no information regarding adverse reactions and the use of this product.

Toxicology

All parts of the plant are toxic. Animal toxicity occurs during grazing. Children have been made ill by sucking the flowers or ingesting seeds or parts of the leaves. 1 Deaths have been reported among persons who drank tea made from digitalis mistakenly identified for comfrey, although the bitter taste often deters ingestion or its emetic properties can induce vomiting. 2 , 16

Digitalis glycosides are excreted slowly and accumulate; therefore, intoxications during therapy are common. The incidence of digitalis toxicity has been estimated to range from 5% to 23%. More stringent dosing guidelines and monitoring techniques have dramatically reduced the incidence of therapeutic overdose.

Digitalis poisoning often is associated with intentional ingestion by adolescents and adults, sometimes with suicidal intent. 16

Signs of poisoning by the plant or purified drug include contracted pupils, blurred vision, strong but slowed pulse, nausea, vomiting, dizziness, excessive urination, fatigue, muscle weakness, and tremors; in severe cases, stupor, confusion, convulsions, and death occur. 1 , 16 , 17 Cardiac signs include atrial arrhythmias and atrioventricular block. 1 The cardiac effects are the most dangerous. 16 Chronic digitalis intoxication is characterized by visual halos, yellow-green vision, and gastrointestinal upset.

In mild cases of toxicity (atrial fibrillation with a slow ventricular response or occasional ectopic beats), temporary withdrawal of the drug and electrocardiogram monitoring is sufficient. 6

Gastric lavage or emesis together with supportive measures, such as electrolyte replacements, antiarrhythmics (eg, lidocaine, phenytoin), atropine, and other agents that can antagonize the cardiovascular effects of the glycosides, have been used to manage acute poisonings. 2 , 17

Digoxin-specific Fab antibody fragments ( Digibind ) are effective in managing acute intoxications caused by digitalis and related cardioactive glycosides. 12 , 17 , 18 , 19 This therapy is revolutionary for the severely poisoned patient. Digoxin Fab fragment antibodies by infusion are an effective antidote for some plant cardiac glycosides, but not always for digitalis. 16

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