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Digitalis

Scientific Name(s): Digitalis lanata Ehrh, Digitalis purpurea L.
Common Name(s): Dead man's bells, Digitalis, Fairy cap, Fairy finger, Foxglove, Lady's thimble, Lion's mouth, Purple foxglove, Scotch mercury, Throatwort, Witch's bells, Woolly foxglove

Clinical Overview

Use

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

Dosing

Digitalis leaf has a narrow therapeutic index, requiring close medical supervision for safe use. Traditional dosage starts at 1.5 g of leaf divided into 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 reactions. Avoid use.

Interactions

There are numerous interactions with digoxin and digitalis glycosides, ranging from relatively minor (eg, cimetidine, triamterene) to life-threatening (eg, amiodarone, furosemide, verapamil).

Adverse Reactions

Adverse reactions are generally related to toxicity.

Toxicology

All parts of the plant are toxic. The incidence of digitalis toxicity in therapeutic use 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 woolly, 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. Many colors of flowers have been bred from digitalis, and they are rarely white. Digitalis is native to the British Isles, western Europe, and parts of Africa, but is found today as an ornamental plant throughout the world. Related species that have found some use in traditional medicine include Digitalis lutea (straw foxglove), Digitalis grandiflora and Digitalis ambigua (yellow foxglove), and Digitalis ferriginea (rusty foxglove).Morton 1997, USDA 2010, Warren 2005

History

Digitalis was one of the many herbal remedies used by the ancient Romans. Although its use for the treatment of heart failure has been traced back to 10th century Europe, digitalis was not widely used for this indication until its scientific investigation by British physician William Withering in the late 1700s. For most of the 1800s, digitalis was used to treat a wide variety of diseases and disorders. 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. In 1957, digoxin was isolated from D. lanata and is now a major cardiac glycoside marketed in tablet form. Digitalis was admitted into the first edition of the Pharmacopeia of the United States (1820) and is currently recognized by all major pharmacopeias. 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.Belcastro 2002, Feussner 2010, Morton 1997

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 moieties, producing their respective aglycones, digitoxigenin and gitoxigenin. Biosynthetic pathways in the production of cardenolides are reliant on the enzymes of malonyltransferase and progesterone 5 beta-reductase.

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. D. lanata is not typically used in powder form in the United States, but serves as a major source of lanatoside C and digoxin (300 times more potent than the powder prepared from D. purpurea). Isolated digitoxin is 1,000 times more potent than whole powdered leaves and is completely and rapidly absorbed from the GI tract.

The seeds also contain digitalis glycosides, while steroidal saponins, flavones, the flavonoid chrysoeriol, anthraquinones, and organic acids have been identified in the leaves. High performance liquid chromatography and mass spectroscopy have been used to identify and quantify glycoside composition.Choi 2005, Gavidia 2007, Kite 2007, Kuate 2008, Morton 1977, Trease 1989, Usai 2007, Warren 2005

Uses and Pharmacology

Cardiovascular effects

Cardiac glycosides possess positive inotropic effects due to inhibition of sodium-potassium adenosine triphosphatase, which allows calcium to accumulate in myocytes leading to enhanced cardiac contractility. These drugs also possess some antiarrhythmic activity, but will induce arrhythmias at higher dose levels.Hauptman 1999, Keenan 2005, Kuate 2008

Animal data

Studies in animals center largely on evaluations of individual chemical compounds on isolated cardiac and other tissues.Hauptman 1999, Keenan 2005, Navarro 2000

Clinical data

Digitalis glycosides have been used clinically for the treatment of heart failure for more than 200 years and remain the source of commercial digoxin preparations; however, a defined place in therapy remains under debate. Reviews of the large, multicenter Digitalis Investigation Group trial and other clinical trials have found no clear effect of digitalis on mortality in heart failure. Some effect has been demonstrated for secondary outcomes of decreased hospitalizations and clinical (symptomatic) deterioration.Feussner 2010, Hood 2004 For further information, consult standard pharmacology references.

Other effects

Cancer

In vitro experiments and screening studies have shown cytotoxic properties of glycosides and flavonoids from D. purpurea and D. lantana. Activity against human cancer cell lines, including solid tumor lines, has been demonstrated. Mechanisms include direct cytotoxicity resulting in apoptosis, inhibition of aflatoxin-induced cytotoxicity, inhibition of induction of nitric oxide synthase, and increases in glutathione S-tranferase.Choi 2005, Johansson 2001, Lee 2006, Lindholm 2002, López-Lázaro 2003

Diabetes

A study in hyperglycemic and dyslipidemic rats demonstrated enhanced glucose tolerance 2 hours after the rats were given a single dose of the saponin digitonin. Positive effects on the lipid profile were also observed.Ebaid 2006

Dosing

Digitalis leaf has a narrow therapeutic index, requiring close medical supervision for safe use. Traditional dosage starts at 1.5 g of leaf divided into 2 daily doses. Purified digoxin is typically used at daily doses of 0.125 to 0.25 mg.Ebaid 2006, Hood 2004

Pregnancy / Lactation

Documented adverse cardiac reactions. Avoid use.22

Interactions

There are numerous interactions with digoxin and digitalis glycosides, ranging from relatively minor (eg, cimetidine, triamterene) to life threatening. Many of the life threatening interactions occur as a result of elevated digoxin serum levels (eg, amiodarone, cyclosporine, macrolide and tetracycline antibiotics, propafenone, quinidine, verapamil) or electrolyte disturbances (eg, diuretics).Tatro 2004 For more comprehensive information on digitalis drug interactions, refer to standard drug interaction texts.

Adverse Reactions

Adverse reactions are generally related to toxicity.

Toxicology

All parts of the plant are toxic. Animal toxicity occurs during grazing. Children have become ill by sucking the flowers or ingesting seeds or parts of the leaves. Deaths have been reported among people who drank tea made from digitalis mistakenly identified as comfrey, although the bitter taste often deters ingestion, and its emetic properties can induce vomiting, thereby limiting systemic absorption. Digitalis poisoning is also associated with intentional ingestion with suicidal intent.Jowett 2002, Lacassie 2000, Lin 2010

Digitalis glycosides accumulate and are excreted slowly; 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.

Signs of plant or purified drug poisoning include blurred vision, contracted pupils, dizziness, excessive urination, fatigue, muscle weakness, nausea, strong but slowed pulse, tremors, and vomiting; in severe cases, stupor, confusion, convulsions, and death can occur. Cardiac signs include atrial arrhythmias and atrioventricular block. Chronic digitalis intoxication is characterized by visual halos, yellow-green vision, and GI upset.Dick 1991, Hauptman 1999, Jowett 2002, Morton 1977

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.Trease 1989 Gastric lavage or emesis together with supportive measures, such as electrolyte replacements, antiarrhythmics (eg, lidocaine, phenytoin), and atropine, have been used to manage acute poisonings. Digoxin-specific Fab antibody fragments may be used in managing acute intoxications caused by digitalis and related cardioactive glycosides; however, their efficacy remains unproven by controlled clinical trials.Hauptman 1999, Lacassie 2000, Roberts 2006, Wickersham 2004

In an analysis of the Nurses’ Health Study, long-term use (more than 4 years) of digitalis (as digoxin) has been linked to an increased risk of invasive breast cancer, although conclusive evidence of causality is lacking.Ahern 2017, Xu 2013

References

Ahern T, Tamimi R, Rosner B, Hankinson S. Digoxin use and risk of invasive breast cancer: evidence from the Nurses' Health Study and meta-analysis. Breast Cancer Research And Treatment. 2017;144(2):427-435.
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Choi DY, Lee JY, Kim MR, Woo ER, Kim YG, Kang KW. Chrysoeriol potently inhibits the induction of nitric oxide synthase by blocking AP-1 activation. J Biomed Sci. 2005;12(6):949-959.16228289
Dec GW. Digoxin remains useful in the management of chronic heart failure. Med Clin North Am. 2003;87(2):317-337.12693728
Dick M, Curwin J, Tepper D. Digitalis intoxication recognition and management. J Clin Pharmacol. 1991;31(5):444-447.2050830
Digitalis purpurea L. USDA, NRCS. 2010. The PLANTS Database (http://plants.usda.gov, March 2010). National Plant Data Center, Baton Rouge, LA 70874-4490 USA.
Ebaid GM, Faine LA, Diniz YS, et al. Effects of digitonin on hyperglycaemia and dyslipidemia induced by high-sucrose intake. Food Chem Toxicol. 2006;44(2):293-299.16112785
Feussner JR, Feussner DJ. Reassessing the efficacy of digitalis: from routine treatment to evidence-based medicine. Am J Med Sci. 2010;339(5):482-484.20228671
Gavidia I, Tarrío R, Rodríguez-Trelles F, Pérez-Bermúdez P, Seitz HU. Plant progesterone 5beta-reductase is not homologous to the animal enzyme. Molecular evolutionary characterization of P5betaR from Digitalis purpurea. Phytochemistry. 2007;68(6):853-864.17184799
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Hood, Jr. WB, Dans AL, Guyatt GH, Jaeschke R, McMurray JJ. Digitalis for treatment of congestive heart failure in patients in sinus rhythm. Cochrane Database Syst Rev. 2004;(2):CD002901.15106182
Johansson S, Lindholm P, Gullbo J, Larsson R, Bohlin L, Cleason P. Cytotoxicity of digitoxin and related cardiac glycosides in human tumor cells. Anticancer Drugs. 2001;12(5):475-483.11395576
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Keenan SM, DeLisle RK, Welsh WJ, Paula S, Ball WJ Jr. Elucidation of the Na+, K+-ATPase digitalis binding site. J Mol Graph Model. 2005;23(6):465-475.15886034
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Kuate SP, Pádua RM, Eisenbeiss WF, Kreis W. Purification and characterization of malonyl-coenzyme A: 21-hydroxypregnane 21-O-malonyltransferase (Dp21MaT) from leaves of Digitalis purpurea L. Phytochemistry. 2008;69(3):619-626.17945319
Lacassie E, Marquet P, Martin-Dupont S, Gaulier JM, Lachâtre G. A non-fatal case of intoxication with foxglove, documented by means of liquid chromatography-electrospray-mass spectrometry. J Forensic Sci. 2000;45(5):1154-1158.11005196
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Navarro E, Alonso PJ, Alonso SJ, et al. Cardiovascular activity of a methanolic extract of Digitalis purpurea spp. heywoodii. J Ethnopharmacol. 2000;71(3):437-442.10940580
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Usai M, Atzei AD, Marchetti M. Cardenolides content in wild Sardinian Digitalis purpurea L. populations. Nat Prod Res. 2007;21(9):798-804.17654283
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