Digitalis is native to Europe, Western Asia, and northwestern Africa. The flowers are tubular in shape, produced on a tall spike, and vary in colour with species, from purple to pink, white, and yellow. The name derives from the Latin word for "finger".[5] The genus was traditionally placed in the figwort family,Scrophulariaceae, butphylogenetic research led taxonomists to move it to theVeronicaceae in 2001.[6] More recent phylogenetic work has placed it in the much enlarged familyPlantaginaceae.
The best-known species is the common foxglove,Digitalis purpurea. This biennial 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 includeD. ferruginea,D. grandiflora,D. lutea, andD. parviflora.[7]
The termdigitalis is also used for drug preparations that containcardiac glycosides, particularly one calleddigoxin, extracted from various plants of this genus. Foxglove has medicinal uses but is also very toxic to humans and other animals, and consumption can even lead to death.[8]
Thegeneric epithetDigitalis is from the Latindigitus (finger).[9]Leonhart Fuchs first invented the name for this plant in his 1542 bookDe historia stirpium commentarii insignes (Notable comments on the history of plants), based upon the Germanvernacular nameFingerhut,[10][11] which translates literally as 'finger hat', but actually means 'thimble'.
The name is recorded inOld English as 'foxes glofe/glofa' or 'fox's glove'.[12] 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.[11]
Henry Fox Talbot (1847) proposed 'folks' glove', where 'folk' means fairy. Similarly, R. C. A. Prior (1863) suggested an etymology of 'foxes-glew', meaning 'fairy music'. However, neither of these suggestions account for the Old English formfoxes glofa.[12]
TheFlora Europaea originally recognised a number of species now seen as synonyms ofDigitalis purpurea, or others:D. dubia,D. leucophaea,D. micrantha andD. trojana.[14] As of 2017,Plants of the World Online recognises the following 27 species (and a number of hybrids):[1]
Digitalis ×sibirica(Lindley) Werner had been considered a valid species since it was first described by the English botanist and gardenerJohn Lindley in 1821,[15] but it was considered a hybrid ofD. grandiflora andD. laevigata by the German botanistKlaus Werner [de] in 1960.[16]
The first fullmonograph regarding this genus was written byLindley in 1821. He included two sections, a sectionIsoplexis including two species, and the main sectionDigitalis with three subsections, including 2Y species, a number of which are now seen assynonyms or hybrids.[15]
In the last full monograph of the genus in 1965, Werner classified the 19 recognised species in fivesections (four species fromMacaronesia were separated in the genusIsoplexis at the time):[17][18][19]
In their 2000 book aboutDigitalis, Luckner and Wichtl continued to uphold Werner's classification of the 19 species,[19][18][20] but molecular studies into thephylogeny of the genus published in 2004 found that although four of Werner's sections were supported by the genetics, the sectionTubiflorae waspolyphyletic, and that the speciesD. lutea andD. viridiflora should be placed in the sectionGrandiflorae.[21] This study, as well as a number of other studies published around that time, reunited the genusIsoplexis withDigitalis, increasing the number of species to 23.[18][21]
Peter Hadland Davis, an expert on the flora ofTurkey, had used a differentcircumscription than Werner in his works, and recognised eight species in the country. A 2016 molecular phylogenetic study into the relationships of the Turkish species in the sectionGlobiflorae aimed to reconcile this discrepancy, finding that the classification as proposed by Davis was largely correct:Globiflorae contained as distinct speciesD. cariensis,D. ferruginea,D. lamarckii,D. lanata andD. nervosa, andD. trojana was subsumed at the infraspecific rank asD. lanata subsp.trojana. This study listed 23 species:D. transiens,D. cedretorum,D. ikarica andD. fuscescens were not mentioned.D. parviflora andD. subalpina were not tested in this study,[16] but the 2004 study found these two species situated within the sectionGlobiflorae.[21]
Larvae of thefoxglove pug, a moth, consume the flowers of the common foxglove for food. Other species ofLepidoptera eat the leaves, including thelesser yellow underwing.[22] The shape of the foxglove's flowers makes it especially attractive to long-tongued bees, such as thecommon carder bee. The bright flowers attract the bee, which lands on the lower lip of the bloom before climbing up the tube. This means that the bee is likely to drop any pollen it may have collected from other foxgloves, thereby facilitating propagation.[23]
Nicholas Culpeper included Foxglove in his 1652 herbal medicine guide,The English Physician. He cited its use for healing wounds (both fresh and old), as a purgative, for "the King's Evil" (mycobacterial cervical lymphadenitis), for "the falling sickness" (epilepsy), and for "a scabby head".[24] There is no empirical evidence for these claims, and it is not used for these conditions in modern medicine, only for slowing excessive heart rate in certain circumstances and/or strengthening heart muscle contraction in heart failure.[25]
Digitalis is an example of a drug derived from a plant that was formerly used byherbalists; herbalists have largely abandoned its use because of its narrowtherapeutic 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 ofepilepsy and other seizure disorders, which are now considered to be inappropriate treatments.
A group of medicines extracted from foxglove plants are calleddigitalin. The use ofD. purpurea extract containingcardiac glycosides for the treatment of heart conditions was first described in the English-speaking medical literature byWilliam Withering, in 1785,[26][27][28] which is considered the beginning of modern therapeutics. In contemporary medicine, digitalis (usuallydigoxin) is obtained fromD. lanata.[29][30] It is used to increase cardiac contractility (it is a positiveinotrope) and as anantiarrhythmic 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 withcongestive 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.[31] 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 patient 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.[32]
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 asdigitoxin ordigoxin, or by brand names such as Crystodigin and Lanoxin, respectively. The two drugs differ in that digoxin has an additionalhydroxyl 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 alactone and a triple-repeating sugar called aglycoside.
Digitalis works by inhibitingsodium-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.[34] Under normal physiological conditions, the cytoplasmic calcium used in cardiac contractions originates from thesarcoplasmic reticulum, an intracellular organelle that stores 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 favour 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 theparasympathetic nervous system, and can be used to slow the ventricular rate duringatrial fibrillation (unless there'san accessory pathway, when it can paradoxically increase the heart rate).[35] The dependence on the vagal effect means digitalis is not effective when a patient has a highsympathetic nervous system drive, which is the case with acutely ill persons, and also during exercise.[36][37]
Digoxigenin (DIG) is a steroid found in the flowers and leaves ofDigitalis species, and is extracted fromD. lanata. Digoxigenin can be used as amolecular probe to detectmRNA in situ and label DNA, RNA, andoligonucleotides.[38] It can easily be attached to nucleotides such asuridine by chemical modifications. DIG molecules are often linked to nucleotides; DIG-labelled uridine can then be incorporated into RNA viain vitrotranscription. Oncehybridisation occurs, RNA with the incorporated DIG-U can be detected with anti-DIGantibodies conjugated toalkaline phosphatase. To reveal the hybridised transcripts, achromogen can be used which reacts with the alkaline phosphatase to produce a coloured precipitate.[39]
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 toxins can be absorbed via the skin[40] or ingestion.
Digitalis intoxication, known asdigitalism, results from an overdose of digitalis and can cause gastrointestinal, cardiac and neurological effects. The former include appetite loss, nausea, vomiting and diarrhoea; the cardiac symptoms include bothtachycardia, andbradycardia (either of which, if severe enough, can result insyncope—see below); and the neurological effects include fatigue, delirium, and rarelyxanthopsia (jaundiced or yellow vision).[41][42][43] Other oculotoxic effects of digitalis include generalized blurry vision, as well as the appearance of blurred outlines ('halos').[44] Other things mentioned are dilated pupils, drooling, weakness, collapse, seizures, and even death.
Digitalis poisoning can cause indirect inhibition of theatrioventricular node via a direct effect on thevagal nucleus. This results inbradycardia (decreased heart rate) or if severe enough,heart block. The direct effect ofcardiac glycosides on heart muscle cells is to increase contraction of the cells, both in force and frequency, tending to producetachycardia (increased heart rate), depending on the dose, the condition of one's heart, and the prevailing chemistry of the blood (specifically any of: low potassium, high calcium and low magnesium).[45] Electrical cardioversion (to "shock" the heart) is generally not indicated in ventricular fibrillation in digitalis toxicity, as it can make the rhythm disturbance more complicated or sustained.[46][47] Furthermore, the classic drug of choice for ventricular fibrillation in emergency setting,[48]amiodarone, can worsen the dysrhythmia caused by digitalis, therefore, the second-choice druglidocaine is more commonly used.[49] Mild toxicity is treated by stopping the medication and general supportive measures; severe toxicity is treated withanti-digoxin antibody fragments.
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.[50]
In some instances, people have confused foxglove with the relatively harmless comfrey (Symphytum) plant, which is sometimes brewed into a tea, with fatal consequences. Other fatal accidents involve children drinking the water in a vase containing digitalis plants.[51] 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.
According to 1981 speculation,Vincent van Gogh's "Yellow Period" may have been influenced by digitalis, because it had been proposed as a therapy to control epilepsy around this time, and there are two paintings by the artist where the plant is present.[52] Other studies immediately questioned this: there are a large number of other possible explanations for van Gogh's choice of palette,[53][54] there is no evidence that van Gogh was ever given the drug or that his physician prescribed it, he was tested and had noxanthopsia, and in his many letters of the time he makes it clear that he simply liked using the colour yellow,[54][55][56] but it has remained a popular theory.[57]
^Fuchs, Leonhart (1542).De historia stirpium commentarii insignes (in Latin). Basel: In officina Isingriniana. pp. 892–893.Apellauimus autem Digitalem, alludentes ad germanicam nomenclaturam...
^abKlingaman, Gerald (17 May 2002)."Plant of the Week: Foxglove".University of Arkansas System Division of Agriculture. Archived fromthe original on 22 April 2020. Retrieved17 April 2018.
^Linné, Carl von, & Salvius, Lars. (1753). Caroli Linnaei ... Species plantarum :exhibentes plantas rite cognitas, ad genera relatas, cum differentiis specificis, nominibus trivialibus, synonymis selectis, locis natalibus, secundum systema sexuale digestas... (Vol. 2, p. 621). Impensis Laurentii Salvii.https://www.biodiversitylibrary.org/page/358642
^Werner, Klaus (1965). "Taxonomie und Phylogenie der GattungenIsoplexis (Lindl.) Benth. undDigitalis L.".Feddes Repertorium (in German).70 (1–3):109–135.doi:10.1002/fedr.19650700106.
^Luckner, M.; Wichtl, Max (2000).Digitalis: Geschichte, Biologie, Chemie, Physiologie, Molekularbiologie, medizinische Anwendung. Handbuch für Ärzte, Apotheker und andere Naturwissenschaftler (in German). Stuttgart: Wissenschaftliche Verlagsgesellschaft.ISBN3-8047-1705-5.
^abcBräuchler, C.; Meimberg, H.; Heubl, G. (2004). "Molecular phylogeny of the generaDigitalis L. andIsoplexis (Lindley) Loudon (Veronicaceae) based on ITS- and trnL-F sequences".Plant Systematics and Evolution.248 (1–4):111–128.Bibcode:2004PSyEv.248..111B.doi:10.1007/s00606-004-0145-z.S2CID25480255.
^Goldthorp, W. O. (2009). "Medical Classics: An Account of the Foxglove and Some of its Medicinal Uses by William Withering, published 1785".British Medical Journal.338: b2189.doi:10.1136/bmj.b2189.S2CID72429441.
^Simpson, Beryl Brintnall; Ogorzaly, Molly Coner (2001).Economic Botany (3rd ed.). Boston: Mc Graw Hill. p. 529.ISBN9780072909388.
^Akera, Tai; Brody, Theodore M. (1985). "Sodium ion and the cardiac actions of digitalis".Trends in Pharmacological Sciences.6:296–298.doi:10.1016/0165-6147(85)90136-1.
^"GRECIAN FOXGLOVE". Minnesota Department of Agriculture. Retrieved1 July 2021.
^Lewis, Robert Alan (1998).Lewis Dictionary of Toxicology. CRC Press. p. 387.ISBN978-1-56670-223-2.Symptoms may include gastrointestinal disturbances and pain, severe headache, nausea, vomiting, diarrhea, irregular pulse, and yellow vision...
