Digitalis

Digitalis (/ˌdɪdʒɪˈteɪlɪs/[1] or /ˌdɪdʒɪˈtælɪs/[2]) is a genus of about 20 species of herbaceous perennials, shrubs, and biennials commonly called foxgloves.

"Foxglove" redirects here. For other uses, see Foxglove (disambiguation).

For the drug used to treat heart conditions, see Digoxin.

For the foxglove-tree, which has similar-looking blooms, see Paulownia tomentosa.

Foxglove
Digitalis purpurea (Common foxglove)
Scientific classification
Kingdom:	Plantae
Clade:	Tracheophytes
Clade:	Angiosperms
Clade:	Eudicots
Clade:	Asterids
Order:	Lamiales
Family:	Plantaginaceae
Tribe:	Digitalideae
Genus:	Digitalis L.
Species
Over 20 species, including: Digitalis canariensis Digitalis cariensis Digitalis ciliata Digitalis davisiana Digitalis dubia Digitalis ferruginea Digitalis grandiflora Digitalis isabelliana Digitalis laevigata Digitalis lanata Digitalis leucophaea Digitalis lutea Digitalis mariana Digitalis micrantha Digitalis obscura Digitalis parviflora Digitalis purpurea Digitalis sceptrum Digitalis thapsi Digitalis trojana Digitalis viridiflora

Digitalis lutea

Pink common foxglove with bee

This genus was traditionally placed in the figwort family Scrophulariaceae, but recent phylogenetic research has placed it in the much enlarged family Plantaginaceae.[3] This genus is native to western and southwestern Europe,[4] western and central Asia and northwestern Africa. The flowers are produced on a tall spike, are tubular, and vary in colour with species, from purple to pink, white, and yellow. The scientific name means "finger-like" and refers to the ease with which a flower can be fitted over a human fingertip.

The best-known species is the common foxglove, Digitalis purpurea. This biennial plant is often grown as an ornamental plant due to its vivid flowers which range in colour from various purple tints through pink, and purely white. The flowers can also possess various marks and spottings. Other garden-worthy species include D. ferruginea, D. grandiflora, D. lutea and D. parviflora.[5]

The term digitalis is also used for drug preparations that contain cardiac glycosides, particularly one called digoxin, extracted from various plants of this genus. Foxglove has medicinal uses but can also be toxic to humans and other animals.

Etymology

Hendrik Goltzius, A Foxglove in Bloom, 1592, National Gallery of Art, NGA 94900

The name "foxglove" was first recorded in the year 1542 by Leonhard Fuchs, whose family name, Fuchs, is the German word for "fox" (the plant genus Fuchsia is also named for him). The genus digitalis is from the Latin digitus (finger), perhaps referencing the shape of the flowers, which accommodate a finger when fully formed.[6]

Thus the name is recorded in Old English as foxes glofe/glofa or fox's glove.[7] Over time, folk myths obscured the literal origins of the name, insinuating that foxes wore the flowers on their paws to silence their movements as they stealthily hunted their prey. The woody hillsides where the foxes made their dens were often covered with the toxic flowers. Some of the more menacing names, such as "witch's glove," reference the toxicity of the plant.[8]

Henry Fox Talbot (1847) proposed folks' glove, where folk means fairy.[7] Similarly, R. C. A. Prior (1863) suggested an etymology of foxes-glew, meaning 'fairy music'.[7] However, neither of these suggestions accounts for the Old English form foxes glofa.[9]

Habitat

A patch of Digitalis purpurea and Digitalis lutea in Seattle, WA.

Digitalis species thrive in acidic soils, in partial sunlight to deep shade, in a range of habitats, including open woods, woodland clearings, moorland and heath margins, sea-cliffs, rocky mountain slopes and hedge banks.[4][10] It is commonly found on sites where the ground has been disturbed, such as recently cleared woodland, or where the vegetation has been burnt.[11]

Larvae of the foxglove pug, a moth, consume the flowers of the common foxglove for food. Other species of Lepidoptera eat the leaves, including the lesser yellow underwing.

Medicinal uses

Cardiac

A group of medicines extracted from foxglove plants are called digitalin. The use of D. purpurea extract containing cardiac glycosides for the treatment of heart conditions was first described in the English-speaking medical literature by William Withering, in 1785,[12][13][14] which is considered the beginning of modern therapeutics.[15][16] It is used to increase cardiac contractility (it is a positive inotrope) and as an antiarrhythmic agent to control the heart rate, particularly in the irregular (and often fast) atrial fibrillation. Digitalis is hence often prescribed for patients in atrial fibrillation, especially if they have been diagnosed with congestive heart failure. Digoxin was approved for heart failure in 1998 under current regulations by the Food and Drug Administration on the basis of prospective, randomized study and clinical trials. It was also approved for the control of ventricular response rate for patients with atrial fibrillation. American College of Cardiology/American Heart Association guidelines recommend digoxin for symptomatic chronic heart failure for patients with reduced systolic function, preservation of systolic function, and/or rate control for atrial fibrillation with a rapid ventricular response. Heart Failure Society of America guidelines for heart failure provide similar recommendations. Despite its relatively recent approval by the Food and Drug Administration and the guideline recommendations, the therapeutic use of digoxin is declining in patients with heart failure—likely the result of several factors. The main factor is the more recent introduction of several drugs shown in randomised controlled studies to improve outcomes in heart failure.[17] Safety concerns regarding a proposed link between digoxin therapy and increased mortality seen in observational studies may have contributed to the decline in therapeutic use of digoxin, however a systematic review of 75 studies including four million (?) years of patient follow-up showed that in properly designed randomised controlled studies, mortality was no higher in patients given digoxin than in those given placebo.[18]

Variations

Digitalis purpurea -- light purple

A group of pharmacologically active compounds are extracted mostly from the leaves of the second year's growth, and in pure form are referred to by common chemical names, such as digitoxin or digoxin, or by brand names such as Crystodigin and Lanoxin, respectively. The two drugs differ in that digoxin has an additional hydroxyl group at the C-3 position on the B-ring (adjacent to the pentane). This results in digoxin having a half-life of about one day (and increasing with impaired kidney function), whereas digitoxin's is about 7 days and not affected by kidney function. Both molecules include a lactone and a triple-repeating sugar called a glycoside.

Mechanism of action

Digitalis works by inhibiting sodium-potassium ATPase. This results in an increased intracellular concentration of sodium ions and thus a decreased concentration gradient across the cell membrane. This increase in intracellular sodium causes the Na/Ca exchanger to reverse potential, i.e., transition from pumping sodium into the cell in exchange for pumping calcium out of the cell, to pumping sodium out of the cell in exchange for pumping calcium into the cell. This leads to an increase in cytoplasmic calcium concentration, which improves cardiac contractility. Under normal physiological conditions, the cytoplasmic calcium used in cardiac contractions originates from the sarcoplasmic reticulum, an intracellular organelle that specializes in the storage of calcium. Human newborns, some animals, and patients with chronic heart failure lack well developed and fully functioning sarcoplasmic reticula and must rely on the Na/Ca exchanger to provide all or a majority of the cytoplasmic calcium required for cardiac contraction. For this to occur, cytoplasmic sodium must exceed its typical concentration to favor a reversal in potential, which naturally occurs in human newborns and some animals primarily through an elevated heart rate; in patients with chronic heart failure it occurs through the administration of digitalis. As a result of increased contractility, stroke volume is increased. Ultimately, digitalis increases cardiac output (Cardiac Output=Stroke Volume x Heart Rate). This is the mechanism that makes this drug a popular treatment for congestive heart failure, which is characterized by low cardiac output. Digitalis also has a vagal effect on the parasympathetic nervous system, and as such is used in re-entrant cardiac arrhythmias and to slow the ventricular rate during atrial fibrillation. The dependence on the vagal effect means digitalis is not effective when a patient has a high sympathetic nervous system drive, which is the case with acutely ill persons, and also during exercise.

Toxicity

Digitalis purpurea drawings by Franz Köhler

Digitalis toxicity (also known as digitalis intoxication and digitalism) results from an overdose of digitalis and causes nausea, vomiting and diarrhea, as well as sometimes resulting in xanthopsia (jaundiced or yellow vision) and the appearance of blurred outlines (halos), drooling, abnormal heart rate, cardiac arrhythmias, weakness, collapse, dilated pupils, tremors, seizures, and even death. Bradycardia also occurs. Because a frequent side effect of digitalis is reduction of appetite, some individuals have used the drug as a weight-loss aid.

Digitalis is an example of a drug derived from a plant that was formerly used by folklorists and herbalists; herbalists have largely abandoned its use because of its narrow therapeutic index and the difficulty of determining the amount of active drug in herbal preparations. Once the usefulness of digitalis in regulating the human pulse was understood, it was employed for a variety of purposes, including the treatment of epilepsy and other seizure disorders, which are now considered to be inappropriate treatments.

Depending on the species, the digitalis plant may contain several deadly physiological and chemically related cardiac and steroidal glycosides. Thus, the digitalis plants have earned several, more sinister, names: dead man's bells and witch's gloves.

The entire plant is toxic (including the roots and seeds). Mortality is rare, but case reports do exist. Most plant exposures occur in children younger than six years and are usually unintentional and without associated significant toxicity. More serious toxicity occurs with intentional ingestion by adolescents and adults.[19] Early symptoms of ingestion include nausea, vomiting, diarrhea, abdominal pain, wild hallucinations, delirium, and severe headache. Depending on the severity of the toxicosis, the victim may later suffer irregular and slow pulse, tremors, various cerebral disturbances, especially of a visual nature (unusual colour visions (see xanthopsia) with objects appearing yellowish to green, and blue halos around lights), convulsions, and deadly disturbances of the heart. For a case description, see the paper by Lacassie.[20] Vincent van Gogh's "Yellow Period" may have been influenced by digitalis therapy which, at the time, was thought to control seizures. As noted above, other oculotoxic effects of digitalis include generalized blurry vision, as well as seeing a "halo" around each point of light.[21]

In some instances, people have confused digitalis with the relatively harmless comfrey (Symphytum) plant, which is often brewed into a tea, with fatal consequences. Other fatal accidents involve children drinking the water in a vase containing digitalis plants.[22] Drying does not reduce the toxicity of the plant. The plant is toxic to animals, including all classes of livestock and poultry, as well as felines and canines.

Digitalis poisoning can cause heart block and either bradycardia (decreased heart rate) or tachycardia (increased heart rate), depending on the dose and the condition of one's heart. Notably, the electric cardioversion (to "shock" the heart) is generally not indicated in ventricular fibrillation in digitalis toxicity, as it can increase the dysrhythmia.[23][24] Furthermore, the classic drug of choice for ventricular fibrillation in emergency setting,[25] amiodarone, can worsen the dysrhythmia caused by digitalis, therefore, the second-choice drug lidocaine is more commonly used.[26]

Digoxigenin

Digoxigenin (DIG) is a steroid found exclusively in the flowers and leaves of the plants D. purpurea and D. lanata. It is used as a molecular probe to detect DNA or RNA. It can easily be attached to nucleotides by chemical modifications. DIG molecules are often linked to uridine nucleotides; DIG-labelled uridine (DIG-U) can then be incorporated into RNA probes via in vitro transcription. Once hybridisation occurs in situ, RNA probes with the incorporated DIG-U can be detected with anti-DIG antibodies that are conjugated to alkaline phosphatase. To reveal the hybridised transcripts, alkaline phosphatase can be reacted with a chromogen to produce a coloured precipitate.

References

1. OED: "Digitalis"
2. Digitalis at Dictionary.com]
3. Olmstead, R. G.; dePamphilis, C. W.; Wolfe, A. D.; Young, N. D.; Elisons, W. J. & Reeves P. A. (2001). "Disintegration of the Scrophulariaceae". American Journal of Botany. American Journal of Botany, Vol. 88, No. 2. 88 (2): 348–361. doi:10.2307/2657024. JSTOR 2657024. PMID 11222255.
4. Anon. "Foxglove (Digitalis purpurea)". Arkive: images of life on Earth. Wildscreen. Archived from the original on 13 June 2010. Retrieved 6 May 2010.
5. Brickell, Christopher, ed. (2008). The Royal Horticultural Society A-Z Encyclopedia of Garden Plants. United Kingdom: Dorling Kindersley. p. 377. ISBN 9781405332965.
6. Hollman, A (September 1985). "Plants and cardiac glycosides". Br. Heart J. 54 (3): 258–261. doi:10.1136/hrt.54.3.258. PMC 481893. PMID 4041297.
7. Liberman, Anatoly (10 November 2010). "Etymologists at War with a Flower: Foxglove | OUPblog". Archived from the original on 8 May 2013. Retrieved 10 August 2015.
8. "Foxglove". Foxglove. Retrieved 17 April 2018.
9. Liberman, Anatoly (10 November 2010). "Etymologists at War with a Flower: Foxglove | OUPblog". Archived from the original on 8 May 2013. Retrieved 10 August 2015.
   • Liberman writes: "In sum, foxglove means foxglove, and this disturbing fact has to be accepted."
10. Anon. "Foxglove: Digitalis purpurea (Scrophulariaceae)". Wildflowers in Bloom. Wildseed farms. Retrieved 7 May 2010.
11. Klein, Carol (18 May 2002). "How to grow: Foxgloves". The Telegraph. London, UK: Telegraph Media Group Limited. Retrieved 6 May 2010.
12. William Withering, An Account of the Foxglove and some of its Medical Uses (Birmingham, England: M. Swinney, 1785).
13. Goldthorp WO (2009). "Medical Classics: An Account of the Foxglove and Some of its Medicinal Uses by William Withering, published 1785". Br Med J. 338: b2189. doi:10.1136/bmj.b2189.
14. Simpson, Beryl Brintnall; Ogorzaly, Molly Coner (2001). Economic Botany (3rd ed.). Boston: Mc Graw Hill. p. 529. ISBN 9780072909388.
15. In contemporary medicine, a purer form of digitalis (usually digoxin) is obtained from D. lanata.
16. Digoxin comes from Digitalis lanata. Hollman A. BMJ 1996;312:912. online version accessed 18 October 2006
17. Anon. "Medications Used to Treat Heart Failure". www.heart.org. American Heart Association. Retrieved 13 August 2020.
18. Ziff, Oliver J.; Lane, Deirdre A.; Samra, Monica; Griffith, Michael; Kirchhof, Paulus; Lip, Gregory Y. H.; Steeds, Richard P.; Townend, Jonathan; Kotecha, Dipak (30 August 2015). "Safety and efficacy of digoxin: systematic review and meta-analysis of observational and controlled trial data". BMJ. doi:10.1136/bmj.h4451. Retrieved 13 August 2020.
19. "Cardiac Glycoside Plant Poisoning: Medscape reference". Retrieved 3 July 2012.
20. A non-fatal case of intoxication with foxglove, documented by means of liquid chromatography-electrospray-mass spectrometry. Lacassie E et al., J Forensic Sci. 2000 Sep;45(5):1154–8. Abstract accessed online 19 September 2006.
21. Goldfrank LW (2006). Goldfrank's Toxicologic Emergencies (8th ed.). New York: McGraw-Hill.
22. Anon. "Notes on poisoning:Digitalis purpura". Canadian poisonous plants information system. Canadian Biodiversity Information Facility. Archived from the original on 13 October 2011. Retrieved 9 March 2013.
23. Abou-Donia, Mohamed (2015). Mammalian Toxicology. John Wiley & Sons. p. 631. ISBN 9781118683316.
24. Robert Alan Lewis, Lewis' Dictionary of Toxicology, 1998, page 387, 1566702232. "See also digitalis. digitalis poisoning. digitalism; acute or cumulative chronic poisoning by digitalis. Symptoms may include gastrointestinal disturbances and pain, severe headache, nausea, vomiting, diarrhea, irregular pulse, and yellow vision ..."
25. "European Resuscitation Council".
26. Lee Lopez, Orchid (2011). Back to Basics: Critical Care Transport Certification Review. Xlibris Corporation. p. 290. ISBN 9781456862749.

External links

• Flora Europaea: Digitalis species list
• Molecule of the Month - Digitalis
• eMedicine link
•  "Foxglove" . Collier's New Encyclopedia. 1921.